/droog/, n. Zoroastrianism.
the cosmic principle of disorder and falsehood. Cf. Asha.
[ < Avestan drauga]

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Any chemical agent that affects the function of living things.

Some, including antibiotics, stimulants, tranquilizers, antidepressants, analgesics, narcotics, and hormones, have generalized effects. Others, including laxatives, heart stimulants, anticoagulants, diuretics, and antihistamines, act on specific systems. Vaccines are sometimes considered drugs. Drugs may protect against attacking organisms (by killing them, stopping them from reproducing, or blocking their effects on the host), substitute for a missing or defective substance in the body, or interrupt an abnormal process. A drug must bind with receptors in or on cells and cannot work if the receptors are absent or its configuration does not fit theirs. Drugs may be given by mouth, by injection, by inhalation, rectally, or through the skin. The oldest existing catalogue of drugs is a stone tablet from ancient Babylonia (с 1700 BC); the modern drug era began when antibiotics were discovered in 1928. Synthetic versions of natural drugs led to design of drugs based on chemical structure. Drugs must be not only effective but safe; side effects can range from minor to dangerous (see drug poisoning). Many illegal drugs also have medical uses (see cocaine; heroin; drug addiction). See also drug resistance; pharmacology; pharmacy.
(as used in expressions)
nonsteroidal anti inflammatory drugs

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▪ chemical agent

      any chemical substance that affects the functioning of living things and the organisms (such as bacteria, fungi, and viruses) that infect them. pharmacology, the science of drugs, deals with all aspects of drugs in medicine (medicine, history of), including their mechanism of action, physical and chemical properties, metabolism, therapeutics, and toxicity. This article focuses on drugs used in the treatment and prevention of human diseases. For a discussion of the nonmedical use of drugs, see drug use.

      Until the mid-19th century the approach to drug therapeutics was entirely empirical. This thinking changed when the mechanism of drug action began to be analyzed in physiological terms and when some of the first chemical analyses of naturally occurring drugs were performed. The end of the 19th century signaled the growth of the pharmaceutical industry and the production of the first synthetic drugs. chemical synthesis has become the most important source of therapeutic drugs, although genetic engineering is developing as a means of synthesizing proteins.

      Drugs produce harmful as well as beneficial effects, and decisions about when and how to use them therapeutically always involve the balancing of benefits and risks. Drugs approved for human use are divided into those available only with a prescription and those that can be bought freely over the counter. The availability of drugs for medical use is regulated by law.

      Drug treatment is the most frequently used type of therapeutic intervention in medicine. Its power and versatility derive from the fact that the human body relies extensively on chemical communication systems to achieve integrated function among billions of separate cells. The body is, therefore, highly susceptible to the calculated chemical subversion of parts of this communication network that occurs when drugs are administered.

Principles of drug action

      With very few exceptions, in order for a drug to affect the function of a cell, an interaction at the molecular (molecule) level must occur between the drug and some target component of the cell. In most cases the interaction consists of a loose, reversible binding of the drug molecule, although some drugs can form strong chemical bonds with their target sites, resulting in long-lasting effects. Three types of target molecules can be distinguished: (1) receptors, (2) macromolecules that have specific cellular functions, such as enzymes, transport molecules, and nucleic acids, and (3) membrane lipids.

      Receptors (receptor) are protein molecules that recognize and respond to the body's own (endogenous) chemical messengers, such as hormones or neurotransmitters. Drug molecules may combine with receptors to initiate a series of physiological and biochemical changes. Receptor-mediated drug effects involve two distinct processes: binding, which is the formation of the drug-receptor complex, and receptor activation, which moderates the effect. The term affinity describes the tendency of a drug to bind to a receptor; efficacy (sometimes called intrinsic activity) describes the ability of the drug-receptor complex to produce a physiological response. Together, the affinity and the efficacy of a drug determine its potency.

      Differences in efficacy determine whether a drug that binds to a receptor is classified as an agonist or as an antagonist. A drug whose efficacy and affinity are sufficient for it to be able to bind to a receptor and affect cell function is an agonist. A drug with the affinity to bind to a receptor but without the efficacy to elicit a response is an antagonist. After binding to a receptor, an antagonist can block the effect of an agonist.

      The degree of binding of a drug to a receptor can be measured directly by the use of radioactively labeled drugs or inferred indirectly from measurements of the biological effects of agonists and antagonists. Such measurements have shown that the reaction (chemical reaction)

drug + receptor ⇌ drug-receptor complex
generally obeys the law of mass action in its simplest form. Thus, there is a relationship between the concentration of a drug and the amount of drug-receptor complex formed.

      The structure-activity relationship describes the connection between chemical structure and biological effect. Such a relationship explains the efficacies of various drugs and has led to the development of newer drugs with specific mechanisms of action. The contribution of the British pharmacologist Sir James Black (Black, Sir James) to this field led to the development, first, of drugs that selectively block the effects of epinephrine and norepinephrine on the heart (beta blockers (beta-blocker), or beta-adrenergic blocking agents) and, second, of drugs that block the effect of histamine on the stomach (-blocking agents), both of which are of major therapeutic importance.

      Receptors for many hormones and neurotransmitters have been isolated and biochemically characterized. All these receptors are proteins, and most are incorporated into the cell membrane (membrane) in such a way that the binding region faces the exterior of the cell. This allows the endogenous chemicals freer access to the cell. Receptors for steroid hormones (e.g., hydrocortisones and estrogens) differ in being located in the cell nucleus and therefore being accessible only to molecules that can enter the cell across the membrane.

      Once the drug has bound to the receptor, certain intermediate processes must take place before the drug effect is measurable. Various mechanisms are known to be involved in the processes between receptor activation and the cellular response (also called receptor-effector coupling). Among the most important ones are the following: (1) direct control of ion (ionization) channels in the cell membrane, (2) regulation of cellular activity by way of intracellular chemical signals, such as cyclic adenosine 3′,5′-monophosphate (cAMP), inositol phosphates, or calcium ions, and (3) regulation of gene expression.

      In type 1 mechanisms, the ion channel is part of the same protein complex as the receptor, and no biochemical intermediates are involved. Receptor activation briefly opens the transmembrane ion channel, and the resulting flow of ions across the membrane causes a change in the transmembrane potential of the cell that leads to the initiation or inhibition of electrical impulses. Such mechanisms are common for neurotransmitters (neurotransmitter) that act very rapidly. Examples include the receptors for acetylcholine and for other fast excitatory or inhibitory transmitter substances in the nervous system, such as glutamate and gamma-aminobutyric acid (GABA).

      In type 2 mechanisms, chemical reactions that take place within the cell trigger a series of responses. The receptor may control calcium influx through the outer cell membrane, thereby altering the concentration of free calcium ions within the cell, or it may control the catalytic (catalysis) activity of one or more membrane-bound enzymes. One of these enzymes is adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) within the cell to cAMP, which in turn binds to and activates intracellular enzymes that catalyze the attachment of phosphate groups to other functional proteins; these may be involved in a wide variety of intracellular processes, such as muscle contraction, cell division, and membrane permeability to ions. A second receptor-controlled enzyme is phosphodiesterase, which catalyzes the cleavage of a membrane phospholipid, phosphatidylinositol, releasing the intracellular messenger inositol triphosphate. This substance in turn releases calcium from intracellular stores, thus raising the free calcium ion concentration. Regulation of the concentration of free calcium ions is important because, like cAMP, calcium ions control many cellular functions.

      In type 3 mechanisms, which are peculiar to steroid hormones (steroid hormone) and related drugs, the steroid binds to a receptor that consists primarily of nuclear proteins. Because this interaction occurs inside the cell, agonists for this receptor must be able to cross the cell membrane. The drug-receptor complex acts on specific regions of the genetic material deoxyribonucleic acid (DNA) (DNA) in the cell nucleus, resulting in an increased rate of synthesis for some proteins and a decreased rate for others. Steroids generally act much more slowly (hours to days) than agents that act by either mechanism 1 or 2.

      Many receptor-mediated events show the phenomenon of desensitization, which means that continued or repeated administration of a drug produces a progressively smaller effect. Among the complex mechanisms involved are conversion of the receptors to a refractory (unresponsive) state in the presence of an agonist, so that activation cannot occur, or the removal of receptors from the cell membrane (down-regulation) after prolonged exposure to an agonist. Desensitization is a reversible process, although it can take hours or days for receptors to recover after down-regulation. The converse process (up-regulation) occurs in some instances when receptor antagonists are administered. These adaptive responses are undoubtedly important when drugs are given over a period of time, and they may account partly for the phenomenon of tolerance (an increase in the dose needed to produce a given effect) that occurs in the therapeutic use of some drugs.

Functional macromolecules (macromolecule)
      Many drugs work not by combining with specific receptors but by binding to other proteins, particularly enzymes (enzyme) and transport proteins. For example, physostigmine inhibits the enzyme acetylcholinesterase, which inactivates the neurotransmitter acetylcholine, thereby prolonging and enhancing its actions; allopurinol inhibits an enzyme that forms uric acid and is used therefore in treating gout. Transport proteins are important in many processes, and they may be targets for drug action. For example, some antidepressant drugs work by blocking the uptake of norepinephrine or serotonin by nerve terminals.

membrane lipids
      Some drugs produce their effects by interaction with membrane lipids (lipid). A drug of this type is the antifungal agent amphotericin B, which binds to a specific molecule (ergosterol) found in fungal cells. This binding results in the formation of pores in the membrane and leakage of intracellular components, leading to death of the cell.

Other types of drug action
      Certain drugs act without engaging in any direct interaction with the components of the cell. An example is mannitol, an inert polysaccharide that acts purely by its osmotic effect. This drug increases urine production markedly because it interferes with water reabsorption by the kidney tubule. Another example is magnesium sulfate, which works similarly in the intestine and has a cathartic effect.

Fate of drugs in the body
Dose-response relationship
      The effect produced by a drug varies with the concentration that is present at its site of action and usually approaches a maximum value beyond which a further increase in concentration is no more effective. A useful measure is the median effective dose, ED50, which is defined as the dose producing a response that is 50 percent of the maximum obtainable. ED50 values provide a useful way of comparing the potencies of drugs that produce physiologically similar effects at different concentrations. Sometimes the response is measured in terms of the proportion of individuals in a sample population that show a given all-or-nothing response (e.g., loss of reaction to a painful stimulus or appearance of convulsions) rather than as a continuously graded response; as such, the ED50 represents the dose that causes 50 percent of a sample population to respond. Similar measurements can be used as a rough estimate of drug toxicity, the result being expressed as the median lethal dose (LD50), which is defined as the dose causing mortality in 50 percent of a group of animals.

      When a drug is used therapeutically, it is important to understand the margin of safety that exists between the dose needed for the desired effect and the dose that produces unwanted and possibly dangerous side effects. This relationship, termed the therapeutic index, is defined as the ratio LD50:ED50. In general, the narrower this margin, the more likely it is that the drug will produce unwanted effects. The therapeutic index has many limitations, notably the fact that LD50 cannot be measured in humans and, when measured in animals, is a poor guide to the likelihood of unwanted effects in humans. Nevertheless, the therapeutic index emphasizes the importance of the margin of safety, as distinct from the potency, in determining the usefulness of a drug.

Variability in response
      The response to a given dose of a drug is likely to vary when it is given to different persons or to the same person on different occasions. This is a serious problem, for it can result in a normally effective dose of a drug being ineffective or toxic in other circumstances. Many factors are known to contribute to this variability; some important ones are age, genetics, absorption, disease states, drug interactions, and drug intolerance.

Adverse effects
      No drug is wholly nontoxic or completely safe. Adverse effects can range from minor reactions, such as dizziness or skin reactions, to serious and even fatal effects. Adverse reactions can be divided broadly into effects that result from an exaggeration of the basic action of the drug, which can usually be controlled by reducing the dosage, and effects that are unrelated to the basic action of the drug and occur in only a small proportion of individuals, irrespective of the dose given. Effects of the latter type are known as idiosyncratic effects and include some very severe reactions, such as sudden cardiovascular collapse or irreversible suppression of blood cell production. Some reactions of this type have an allergic basis. Toxic effects of this kind, though rare, are unpredictable and sometimes highly dangerous, and they severely limit the usefulness of many effective drugs. It has been increasingly recognized that drugs can produce other kinds of unwanted effects, such as interference with fetal development (teratogenesis (teratology)) or long-term genetic damage that may make a person susceptible to the development of cancer.

      The sporadic and delayed nature of many adverse drug reactions and the fact that they may not be predictable from animal tests pose serious practical problems. Often such effects are, and indeed can only be, discovered after a drug has been used in humans for some time.

Absorption, distribution, and elimination
      In order to produce an effect, a drug must reach its target site in adequate concentration. This involves several processes embraced by the general term pharmacokinetics. In general, these processes are: (1) administration of the drug, (2) absorption from the site of administration into the bloodstream, (3) distribution to other parts of the body, including the target site, (4) metabolic alteration of the drug, and (5) excretion of the drug or its metabolites.

      An important step in all these processes is the movement of drug molecules through cellular barriers (e.g., the intestinal wall, the walls of blood vessels, the barrier between the bloodstream and the brain, and the wall of the kidney tubule), which constitute the main restriction to the free dissemination of drug molecules throughout the body. To cross most of these barriers, the drug must be able to move through the lipid layer of the cell membrane. Drugs that are highly lipid-soluble do this readily; hence, they are rapidly absorbed from the intestine and quickly reach most tissues of the body, including the brain. They readily enter liver cells (one of the main sites of drug metabolism) and are consequently liable to be rapidly metabolized and inactivated. They can also cross the renal tubule easily and thus tend to be reabsorbed into the bloodstream rather than being excreted in the urine.

      Non-lipid-soluble drugs (e.g., many neuromuscular blocking drugs) behave differently because they cannot easily enter cells. Therefore, they are not absorbed from the intestine, and they do not enter the brain. Because they may escape metabolic degradation in the liver, they are excreted unchanged in the urine. Certain of these drugs cross cell membranes, particularly in the liver and kidney, with the help of special transport systems, which can be important factors in determining the rate at which drugs are metabolized and excreted.

      Drugs are given by two general methods: enteral and parenteral administration. Enteral administration involves the esophagus, stomach, and small and large intestines (i.e., the gastrointestinal tract). Methods of administration include oral, sublingual (dissolving the drug under the tongue), and rectal. Parenteral routes, which do not involve the gastrointestinal tract, include intravenous (injection into a vein), subcutaneous (injection under the skin), intramuscular (injection into a muscle), inhalation (infusion through the lungs), and percutaneous (absorption through intact skin).

      After oral administration of a drug, absorption into the bloodstream occurs in the stomach and intestine, which usually takes about one to six hours. The rate of absorption depends on factors such as the presence of food in the intestine, the particle size of the drug preparation, and the acidity of intestinal contents. Intravenous administration of a drug can result in effects within a few seconds, making this a useful method for emergency treatment. Subcutaneous or intramuscular injection usually produces effects within a few minutes, depending largely on the local blood flow at the site of the injection. Inhalation of volatile or gaseous agents also produces effects in a matter of minutes and is mainly used for anesthetic agents.

      The bloodstream carries drugs from the site of absorption to the target site and also to sites of metabolism or excretion, such as the liver, kidneys, and, in some cases, the lungs. Many drugs are bound to plasma proteins, and in some cases more than 90 percent of the drug present in the plasma is bound in this way. This bound fraction is inert. Protein binding reduces the overall potency of a drug and provides a reservoir to maintain the level of the active drug in blood plasma. To pass from the bloodstream to the target site, drug molecules must cross the walls of blood capillaries. This occurs rapidly in most regions of the body. The capillary walls of the brain and spinal cord, however, are relatively impermeable, and in general only drugs that are highly lipid-soluble enter the brain in any appreciable concentration.

Chemical alteration
      In order to alter or stop a drug's biological activity and prepare it to be eliminated from the body, it must undergo one of many different kinds of chemical transformations. One particularly important site for these actions is the liver. Metabolic (metabolism) reactions in the liver are catalyzed by enzymes located on a system of intracellular membranes known as the endoplasmic reticulum. In most cases the resultant metabolites are less active than the parent drug; however, there are instances where the metabolite is as active as, or even more active than, the parent. In some cases the toxic effects of drugs are produced by metabolites rather than the parent drug.

      Many different kinds of reactions are catalyzed by drug-metabolizing enzymes, including oxidation, reduction, the addition or removal of chemical groups, and the splitting of labile (chemically unstable) bonds. The product is often less lipid-soluble than the parent and is consequently excreted in the urine more rapidly. Many of the causes of variability in drug responses reflect variations in the activity of drug-metabolizing enzymes. Competition for the same drug-metabolizing enzyme is also the source of a number of drug interactions.

      The main route of drug excretion is through the kidneys (kidney); however, volatile and gaseous agents are excreted by the lungs (lung). Small quantities of drugs may pass into sweat, saliva, and breast milk, the latter being potentially important in breast-feeding mothers. Although some drugs are excreted mainly unchanged into the urine, most are metabolized first. The first stage in excretion involves passive filtration of plasma through structures in the kidneys called glomeruli, through which drug molecules pass freely. The drug thus reaches the renal tubule, where it may be actively or passively reabsorbed, or it may pass through into the urine. Many factors affect the rate of renal excretion of drugs, important ones being binding to plasma proteins (which impedes their passage through the glomerular filter) and urinary acidity (which can affect the rate of passive reabsorption of the drug by altering the state of its ionization).

Time course of drug action
 The rise and fall of the concentration of a drug in the blood plasma over time determines the course of action for most drugs. If a drug is given orally, two phases can be distinguished: the absorption phase, leading to a peak in plasma concentration, and the elimination phase, which occurs as the drug is metabolized or excreted (see the figure—>).

      For therapeutic purposes, it is often necessary to maintain the plasma concentration within certain limits over a period of time. If the plasma half-life (t1/2)—the time it takes for the plasma concentration to fall to 50 percent of its starting value—is long, doses can be given at relatively long intervals (e.g., once per day), but if the t1/2 is short (less than about 24 hours), more frequent doses will be necessary.

Types of drugs

Antimicrobial (antimicrobial agent) drugs
      Antimicrobial drugs can be used for either prophylaxis (prevention) or treatment of disease caused by bacteria, fungi, viruses, protozoa, or helminths. The term antibiotics is now popularly used to refer to drugs that combat any of these microbes, but this article retains the traditional use of antibiotics to refer only to drugs that kill or inhibit bacteria.

      The production and use of penicillin in the early 1940s became the basis for the era of modern antimicrobial chemotherapy. streptomycin was discovered in 1944, and since then many other antibiotics have been found and put into use. Chemotherapeutic agents that are used in the treatment of disease are of three types: (1) synthetic chemicals, (2) chemical substances or metabolic products made by microorganisms, and (3) chemical substances derived from plants.

      A major discovery following the introduction of antimicrobials to medicine was the finding that their basic structure could be modified chemically to improve their characteristics. The finding of a bacterium that produces the basic structural component responsible for the antibiotic activity of penicillins and cephalosporins now permits engineering of compounds with activity specific for certain microorganisms.

      An ideal antimicrobial agent is one that is cidal (kills) rather than static (inhibits growth). It should affect a specific microbe or tissue cell and not affect other microbes or normal cells. It should be one to which the infectious organism does not become resistant and one that is not allergic or toxic to the human being. An ideal agent must have pharmacological attributes favourable for its use. Therefore, if it is to affect organisms in the gastrointestinal tract, it must remain in the intestinal tract and not be absorbed or inactivated when given orally. If an oral drug is used to affect organisms in the blood or tissues, then it must be absorbed from the intestinal tract. Alternatively, it must be capable of being given parenterally (by injection). It must be able to penetrate tissues and be maintained for adequate periods of time at the site of the infection in concentrations sufficient to affect the microorganism.

      None of the antimicrobial agents presently in use meets all these criteria. In fact, a number of compounds that produce significant toxic effects in humans are used because they have a favourable chemotherapeutic index; that is, the amount required for a therapeutic effect is below the amount that causes a toxic effect. The levels of these drugs in the patient must be controlled carefully so as not to reach toxic levels. Persons with certain altered organ functions, such as occurs in liver or kidney disease, are often especially susceptible to drug toxicity. Chemotherapeutic agents, however, can be used safely if drug concentrations in the blood are measured, the dose adjusted to avoid toxic levels, and organ function or toxicity monitored closely.

      Whether an antimicrobial agent affects a microorganism depends on several factors. The drug must be delivered to a sensitive site in the cell, such as an enzyme that is involved in the synthesis of a cell wall or a protein or enzyme responsible for the synthesis of proteins, nucleic acids, or the cell membrane. Whether the antimicrobial agent enters the cell depends on the ability of the drug to penetrate the outer membrane of the cell, on the presence or absence of transport systems for the antimicrobial, or on the availability of channels in the cell surface. In some cases the microorganism prevents the entry of the antimicrobial by producing an enzyme that destroys or modifies the antimicrobial by transferring a chemical group. If the antimicrobial agent does not penetrate the organism or is destroyed or modified or if the organism does not contain a sensitive site, then the microorganism will not be affected; in such a case it is said to be resistant.

      All agents can have adverse effects ranging from relatively harmless to serious and life-threatening. Direct toxicities are expressed in a variety of ways, and many of these are associated with the gastrointestinal tract (nausea, vomiting, and diarrhea) and skin rashes. They are usually minor and do not limit the use of the agent. In more extreme cases, the toxicities can result in serious damage to organs such as the kidneys, liver, and ears and to the nervous system. Some antimicrobial agents affect normal red blood cells, which can result in anemia. Allergic or hypersensitivity reactions can range from minor effects such as skin rash and itching to more serious effects that include choking and difficulty in breathing. In some cases, a sudden and severe form of allergic reaction ( anaphylaxis) can result in death.

      The use of antimicrobial agents, in particular the broad-spectrum agents (see below Antibiotics), can result in an alteration in the number and type of microorganisms normally found on the skin and mucosal surfaces. This is due to the inhibitory activity of the antimicrobial agent on sensitive microorganisms found on these tissues. The eradication of some organisms relieves the inhibitory activity they have on each other, thereby allowing the surviving organisms to multiply. In some cases, organisms (such as yeast) that are generally resistant to antibiotics increase to numbers sufficient to invade and infect tissue.

      Some microorganisms have become resistant to drugs, requiring a continuing search for different (and often more expensive) agents. This increase in resistance to drugs has resulted from their widespread and sometimes indiscriminate use. Bacteria undergo spontaneousmutations, and exposure to an antibiotic can eradicate those bacteria sensitive to it while the resistant ones survive and multiply; by such means populations become resistant to a particular drug and sometimes to related drugs. Bacteria sensitive to antibiotics also can become resistant by acquiring resistance genes from other organisms, either by mating (conjugating) with bacteria containing resistance genes or by transduction (a process by which a bacterial virus, or bacteriophage, with resistance genes infects and incorporates these genes into a bacterium, thus conferring resistance). Resistance to antimicrobial agents also results from (1) decreased permeability of the organism to the drug, (2) deactivation or modification of the drug by an enzyme, (3) modification of the drug receptor or binding site, (4) increased synthesis of an essential metabolite whose production is blocked by the antimicrobial agent, or (5) production of an enzyme that is altered so that it is not inhibited or affected by the drug. Resistant bacteria are common in hospitals (nosocomial infections), where patients whose immunity is decreased can be infected.

       AntibioticsAntibiotics are categorized as narrow-, broad-, or extended-spectrum agents. Narrow-spectrum agents (e.g., penicillin G) affect primarily gram-positive bacteria. Broad-spectrum antibiotics, such as tetracyclines (tetracycline) and chloramphenicol, affect both gram-positive and some gram-negative bacteria. An extended-spectrum antibiotic is one that, as a result of chemical modification, affects additional types of bacteria, usually gram-negative bacteria. Some common antibiotics are listed in the table (Antibiotics).

      Antibiotics (antibiotic) are substances that can inhibit the growth of or kill a bacterium. They are produced commonly by soil microorganisms and probably represent a means by which organisms in a complex environment, such as soil, control the growth of competing microorganisms. The microorganisms that produce antibiotics useful in preventing or treating disease include the bacteria (Bacillus and Streptomyces) and the fungi (Penicillium, Cephalosporium, and Micromonospora).

      A large number of antibiotics inhibit the synthesis of the cell wall. Bacteria, unlike animal cells, have a cell wall surrounding a cytoplasmic membrane. Production of the cell wall involves the partial assembly of wall components inside the cell, transport of these structures through the cell membrane to the growing wall, assembly into the wall, and finally cross-linking of the strands of wall material. Antibiotics that inhibit the synthesis of the cell wall have a specific effect on one or another phase. The result is an alteration in the cell wall and shape of the organism and eventually the death of the bacterium.

      Other antibiotics, such as the aminoglycosides, chloramphenicol, erythromycin, and clindamycin, inhibit protein synthesis in bacteria. The basic process by which bacteria and animal cells synthesize proteins is similar, but the proteins involved are different. Those antibiotics that are selectively toxic utilize these differences to bind to or inhibit the function of the proteins of the bacterium, thereby preventing the synthesis of new proteins and new bacterial cells.

      Antibiotics such as polymyxin B and polymyxin E (colistin) bind to phospholipids (phospholipid) in the cell membrane of the bacterium and interfere with its function as a selective barrier; this allows essential macromolecules in the cell to leak out, resulting in the death of the cell. Because other cells, including human cells, have similar or identical phospholipids, these antibiotics are somewhat toxic.

      Some antibiotics, such as the sulfonamides, are competitive inhibitors of the synthesis of folic acid (folate), which is an essential preliminary step in the synthesis of nucleic acids. Sulfonamides are able to inhibit folic acid synthesis because they are similar to an intermediate compound (p-aminobenzoic acid) that is converted by an enzyme to folic acid. The similarity in structure between these compounds results in competition between p-aminobenzoic acid and the sulfonamide for the enzyme responsible for converting the intermediate to folic acid. This reaction is reversible by removing the chemical, which results in the inhibition but not the death of the microorganisms. One antibiotic, rifampin, interferes with ribonucleic acid (RNA) (RNA) synthesis in bacteria by binding to a subunit on the bacterial enzyme responsible for duplication of RNA. Since the affinity of rifampin is much stronger for the bacterial enzyme than for the human enzyme, the human cells are unaffected at therapeutic doses.

Penicillins, cephalosporins, and other β-lactam antibiotics
      The penicillins (penicillin) have a unique structure, a β-lactam ring, that is responsible for their antibacterial activity. The β-lactam ring interacts with proteins in the cell responsible for the final step in the assembly of the cell wall.

      The penicillins can be divided into two groups: the naturally occurring penicillins (penicillin G, penicillin V, and benzathine penicillin) and the semisynthetic penicillins. The semisynthetic penicillins are produced by growing the mold Penicillium under conditions whereby only the basic molecule (6-aminopenicillanic acid) is produced. By adding certain chemical groups to this molecule, several different semisynthetic penicillins are produced that vary in resistance to degradation by β-lactamase (penicillinase), an enzyme that specifically breaks the β-lactam ring, thereby inactivating the antibiotic. In addition, the antibacterial spectrum of activity and pharmacological properties of the natural penicillins can be changed and improved by these chemical modifications. The addition of a β-lactamase inhibitor, such as clavulanic acid, to a penicillin dramatically improves the effectiveness of the antibiotic. Several naturally occurring inhibitors have been isolated, and others have been chemically synthesized.

      The naturally occurring penicillins are still the drugs of choice for treating streptococcal (Streptococcus) sore throat, tonsillitis, endocarditis caused by some streptococci, syphilis, and meningococcal infections. Several bacteria, most notably Staphylococcus, have developed resistance to the naturally occurring penicillins, which has led to the production of the penicillinase-resistant penicillins (methicillin, oxacillin, nafcillin, cloxacillin, and dicloxacillin).

      To extend the usefulness of the penicillins to the treatment of infections caused by gram-negative rods, the broad-spectrum penicillins ( ampicillin, amoxicillin, carbenicillin, and ticarcillin) were developed. These penicillins are sensitive to penicillinase, but they are useful in treating urinary tract infections caused by gram-negative rods as well as in treating typhoid (typhoid fever) and enteric fevers.

      The extended-spectrum agents (mezlocillin and piperacillin) are unique in that they have greater activity against gram-negative bacteria, including Pseudomonas aeruginosa, a bacterium that often causes serious infection in people whose immune systems have been weakened. They have decreased activity, however, against penicillinase-producing Staphylococcus aureus, a common bacterial agent in food poisoning.

      The penicillins are the safest of all antibiotics. The major adverse reaction associated with their use is hypersensitivity, with reactions ranging from a rash to bronchospasm and anaphylaxis. The more serious reactions are uncommon.

      The cephalosporins (cephalosporin) have a mechanism of action identical to that of the penicillins; however, the basic chemical structure of the penicillins and cephalosporins differs in other respects, resulting in some difference in the spectrum of antibacterial activity. The original cephalosporins (cephalosporin) were produced by the fungus Cephalosporium acremonium. Modification of the basic molecule (7-aminocephalosporanic acid) has resulted in four generations of cephalosporins. The first-generation cephalosporins (cefazolin, cephalothin, and cephalexin) have a range of antibacterial activity similar to the broad-spectrum penicillins described above—for instance, they are effective against most staphylococci and streptococci as well as penicillin-resistant pneumococci. The second-generation cephalosporins (cefamandole, cefaclor, cefotetan, cefoxitin, and cefuroxime) have an extended antibacterial spectrum that includes greater activity against additional species of gram-negative rods. Thus, these drugs are active against Escherichia coli and Klebsiella and Proteus species. Cefamandole is active against many strains of Haemophilus influenzae and Enterobacter, while cefoxitin is particularly active against Bacteroides fragilis. Second-generation cephalosporins have decreased activity, however, against gram-positive bacteria. The third-generation cephalosporins (ceftriaxone, cefixime, and ceftazidime) have increased activity against the gram-negative organisms compared with the second-generation agents. Most Enterobacter species are susceptible to these drugs, as are H. influenzae and various species of Neisseria. The antibacterial spectrum of the fourth-generation compounds (cefepime) is similar to that of the third-generation drugs, but the fourth-generation drugs have more resistance to β-lactamases. Like the penicillins, the cephalosporins are relatively nontoxic. Because the structure of the cephalosporins is similar to that of penicillin, hypersensitivity reactions can occur in penicillin-hypersensitive patients.

      Imipenem is a β-lactam antibiotic that works by interfering with cell wall synthesis. It is highly resistant to hydrolysis by most β-lactamases. This drug must be given by intramuscular injection or intravenous infusion because it is not absorbed from the gastrointestinal tract. Imipenem is hydrolyzed by an enzyme present in the renal tubule; therefore, it is always administered with cilastatin, an inhibitor of this enzyme. Neurotoxicity and seizures have limited the use of imipenem.

      The aminoglycosides ( streptomycin, neomycin, paromomycin, amikacin, and tobramycin) all inhibit protein synthesis. The aminoglycosides are poorly absorbed from the gastrointestinal tract, so, with some exceptions, they are given parenterally. Neomycin is very toxic to kidney cells and is no longer used parenterally. It is only used topically. Streptomycin was the first of the aminoglycosides to be discovered and the second antibiotic used in chemotherapy. One of its more important uses was as part of the combination therapy for tuberculosis. It still has some use in combination with penicillin for treating infections of heart valves ( endocarditis) and with tetracyclines in the treatment of plague, tularemia, and brucellosis. Gentamicin and tobramycin are similar in their range of antimicrobial activity. They are effective against infections caused by Staphylococcus and gram-negative bacteria, including Pseudomonas aeruginosa.

      The major problem with the aminoglycosides is that the margin of safety between a toxic and a therapeutic dose is narrow. Nephrotoxicity (harmful to kidney cells) and ototoxicity (harmful to the innervation of the organs of hearing and balance) are frequent, and the risk of these reactions increases with age and with preexisting renal diseases or hearing loss. Once-a-day dosing allows the plasma level of the drug to fall below toxic levels and does not reduce the antibacterial effect.

Tetracyclines (tetracycline)
      Tetracyclines (tetracycline) have a common structure but differ from each other by the presence or absence of chloride, methyl, and hydroxyl groups. Although these modifications do not change their broad-spectrum antibacterial activity, they do affect pharmacological properties such as half-life and binding to proteins in serum. The tetracyclines all have the same antibacterial spectrum, although there are some differences in sensitivity of the bacteria to the various types of tetracyclines. They inhibit protein synthesis in both bacterial and human cells. Bacteria have a system that allows tetracyclines to be transported into the cell, whereas human cells do not; human cells therefore are spared the effects of tetracycline on protein synthesis.

      All tetracyclines are absorbed from the gastrointestinal tract after oral administration, and most can be given intravenously or intramuscularly. Because calcium, magnesium, aluminum, and iron form insoluble products with most tetracyclines, they cannot be given simultaneously with substances containing these minerals (e.g., milk). They are the drugs of choice in the treatment of cholera, rickettsial infections, trachoma (a chronic infection involving the eye), psittacosis (a disease transmitted by certain birds), brucellosis, and tularemia. Tetracyclines also are used in the treatment of acne. Because not all of the tetracycline administered orally is absorbed from the gastrointestinal tract, the bacterial population of the intestine can become resistant to tetracyclines, resulting in overgrowth (suprainfection) of resistant organisms. Complexes between tetracyclines and calcium can cause staining of teeth and retardation of bone growth in young children or in newborns if tetracyclines are taken after the fourth month of pregnancy. Tetracycline can also cause photosensitivity in patients exposed to sunlight.

       chloramphenicol is administered either orally or parenterally, but since it is readily absorbed from the gastrointestinal tract, parenteral administration is reserved for serious infections. It is a broad-spectrum antibiotic, but it is seldom used because of its potential toxicity and the availability of safer drugs. However, it has been important in the treatment of typhoid fever and other Salmonella infections. It is also effective in treating meningitis because the most common pathogens are sensitive to the drug. For many years chloramphenicol, in combination with ampicillin, was the treatment of choice for H. influenzae infections, including meningitis. Chloramphenicol is also useful in the treatment of pneumococcal (pneumococcus) or meningococcal meningitis in penicillin-allergic patients.

      The macrolides (e.g., erythromycin, clarithromycin, azithromycin) are usually administered orally, but they can be given parenterally. These drugs, which inhibit protein synthesis, are valuable in treating pharyngitis and pneumonia caused by Streptococcus in persons sensitive to penicillin. They are also used in treating pneumonias caused either by Mycoplasma species or by Legionella pneumophila (the organism that causes Legionnaire disease); they are also used in treating pharyngeal carriers of Corynebacterium diphtheriae, the bacillus responsible for diphtheria.

      Clindamycin is a derivative of lincomycin that has better microbial activity and rate of gastrointestinal absorption. As a result, lincomycin has limited use. Clindamycin is active against Staphylococcus, some Streptococcus, and anaerobic bacteria. Because it has been associated with pseudomembranous colitis (inflammation of the small intestine and the colon), it must be used with caution.

      The oxazolidinones are a novel class of synthetic agents that inhibit protein synthesis by microbes. Linezolid is highly active in vivo against infections caused by many common gram-positive pathogens, including Enterococcus bacteria that are resistant to vancomycin (described in the section Other antibiotics (drug)). It is available orally or intravenously. One major side effect is an increase in blood pressure.

Sulfonamides (sulfa drug)
      The sulfonamides (sulfonamide) are broad-spectrum agents and were once used widely. Their use has diminished because of the availability of antibiotics that are better and safer and because of increased instances of drug resistance. Sulfonamides are still used, but largely for treating urinary tract infections and preventing infection of burns. They are also used in the treatment of certain forms of malaria.

      The several forms (congeners) of sulfonamides differ from one another in solubility, half-life, ability to bind to plasma proteins, and potency for inhibiting certain bacteria. All affect bacterial growth by interfering with the synthesis of folic acid. Humans are usually not adversely affected by the drugs, because they do not synthesize folic acid but rather obtain it from their diet. Trimethoprim, one of these antibiotics, also affects the pathway of folic acid synthesis, but at a point different from that inhibited by the sulfonamides. When trimethoprim and sulfamethoxazole are given together, the sequential blockage of the pathway produced by the two drugs achieves markedly greater inhibition of folic acid synthesis. As a result, this combination is valuable in treating urinary tract infections and some systemic infections. The sulfonamides are relatively safe, but hypersensitivity reactions (rashes, eosinophilia, and fever) can occur.

      The sulfones (sulfone) are related to the sulfonamides and are inhibitors of folic acid synthesis. They tend to accumulate in skin and inflamed tissue and are retained in the tissue for long periods. Thus, sulfones such as dapsone are useful in treatment of leprosy.

      The fluoroquinolone antibiotics (e.g., norfloxacin, ciprofloxacin, enoxacin, trovafloxacin) are synthetic compounds based on the chemical structure of nalidixic acid, a quinolone that is used as a urinary tract antiseptic. Originally the fluoroquinolones were used in the treatment of urinary tract infections, but now they are used in the oral treatment of a number of infections that were previously treatable only with parenteral drugs. These drugs work by interfering with the action of an enzyme involved in the replication of deoxyribonucleic acid (DNA). The fluoroquinolones have activity against gram-positive bacteria and have excellent activity against some gram-negative organisms as well. Most of the gram-negative bacteria that cause urinary tract infections are very sensitive to the fluoroquinolones.

Polymyxins (polymyxin)
      The polymyxins (polymyxin) are produced by the bacterium Bacillus polymyxa. Two of these, polymyxin B and polymyxin E (colistin), are useful in treating infection. Polymyxins accumulate in the bacterial cell membrane and affect selective permeability. They also react with and affect the membranes of human cells, resulting in kidney damage and neurotoxicity. Because they are not well absorbed from the gastrointestinal tract, oral administration is occasionally used for the treatment of diarrhea. Polymyxins can be administered by intramuscular injection. They are used primarily in treating infections caused by Pseudomonas aeruginosa, but they are also used topically for the treatment of eye and ear infections. The availability of better antibiotics limits the use of polymixins.

      The nitrofurans (nitrofurantoin and nitrofurazone) are broad-spectrum agents that undergo chemical reduction, resulting in the production of superoxide and other toxic oxygen compounds. These compounds oxidize essential components of the cell and make them nonfunctional. Nitrofurantoin is given orally, and, because it accumulates in urine, it is used in the treatment of urinary tract infections. Nitrofurazone is used topically for the treatment of burns.

Other antibiotics
       isoniazid, ethambutol, pyrazinamide, and ethionamide are synthetic chemicals used in treating tuberculosis. Isoniazid, ethionamide, and pyrazinamide are similar in structure to nicotinamide adenine dinucleotide (NAD), a coenzyme essential for several physiological processes. Ethambutol prevents the synthesis of mycolic acid, a lipid found in the tubercule bacillus. All these drugs are absorbed from the gastrointestinal tract and penetrate tissues and cells. An isoniazid-induced hepatitis can occur, particularly in patients 35 years of age or older. Cycloserine, an antibiotic produced by Streptomyces orchidaceus, is also used in the treatment of tuberculosis. A structural analog of the amino acid D-alanine, it interferes with enzymes necessary for incorporation of D-alanine into the bacterial cell wall. It is rapidly absorbed from the gastrointestinal tract and penetrates most tissues quite well; high levels are found in urine. Rifampin, a semisynthetic agent, inhibits RNA synthesis. It is absorbed from the gastrointestinal tract, penetrates tissue well (including the lung), and is used in the treatment of tuberculosis. Rifampin administration is associated with several side effects, mostly gastrointestinal in nature. The drug can turn urine, feces, saliva, sweat, and tears red-orange in colour.

      Aztreonam is a synthetic antibiotic that works by inhibiting cell wall synthesis, and it is naturally resistant to β-lactamases. It has excellent activity against Pseudomonas aeruginosa and Enterobacteriaceae. Aztreonam has a low incidence of toxicity, but it must be administered parenterally. Bacitracin is produced by a special strain of Bacillus subtilis. Because of its severe toxicity to kidney cells, its use is limited to the topical treatment of skin infections caused by Streptococcus and Staphylococcus and for eye and ear infections. Vancomycin, an antibiotic produced by Streptomyces orientalis, is poorly absorbed from the gastrointestinal tract and is usually given by intravenous injection. It is an excellent antibiotic for the treatment of serious staphylococcal infections caused by strains resistant to the various penicillins.

Antifungal drugs
      The fungi (fungus) appear in two morphologies, or forms: a single cell that is round or oval ( yeast) and a filamentous form ( mold). Fungi differ from bacteria in several ways, including the chemical composition of the cell wall and cell membrane. Unlike bacteria, fungi have a nucleus surrounded by a membrane, an endoplasmic reticulum, and mitochondria. These differences between the bacteria and fungi are reflected in the action of different chemotherapeutic agents.

      Amphotericin B and nystatin are antimicrobial drugs that interact with ergosterol, a type of steroid that is found in fungal membranes; this binding results in the loss of membrane-selective permeability and of cytoplasmic components. These agents do not affect bacteria, because, with the exception of Mycoplasma species, bacteria do not have these types of steroids in the cell membrane. Human cell membranes do, however, and there is some toxicity associated with the use of these drugs. Amphotericin B is used primarily in the treatment of serious fungal diseases, such as cryptococcal meningitis, histoplasmosis, and blastomycosis. During administration an individual may experience fever, chills, hypotension, nausea, and shortness of breath. Most patients who receive amphotericin B experience some degree of toxicity to the kidney, but renal function usually improves after completion of therapy. Lipid-based formulations of amphotericin B are thought to have reduced toxicity while retaining antifungal action. Nystatin is more toxic and is not used systemically. It is not absorbed from the gastrointestinal tract and is only used orally or topically for the treatment of infections of the skin and mucous membranes caused by Candida albicans.

      A group of antifungal agents called imidazoles (imidazole) and triazoles binds to fungal membranes and blocks the synthesis of fungal lipids, especially ergosterol. The azoles have broad antifungal activity and are active against fungi that infect the skin and mucous membranes and those that cause deep tissue infections. Clotrimazole, econazole, miconazole, and tioconazole are given topically and are used for treating oral, skin, and vaginal infections. Introduction of the triazoles (fluconazole and itraconazole) provided an alternative to amphotericin B in the treatment of endemic mycoses. The triazoles are active against most of the organisms that cause systemic or deep-seated fungal infections, such as cryptococcosis, candidiasis, histoplasmosis, blastomycosis, and paracoccidiosis.

      The allylamines (terbinafine and naftifine) are synthetic antifungal agents that are effective in the topical and oral treatment of dermatophytes (fungi that infect the skin and other integumentary structures). Like the azoles, the allylamines act through inhibition of fungal ergosterol biosynthesis. Oral terbinafine is used in the oral treatment of nail infections by dermatophytes.

       griseofulvin is given orally for the treatment of several superficial fungal infections of the skin (e.g., ringworm, athlete's foot) and diseases of the hair and nails. Griseofulvin binds to keratin, thus depositing high levels in the skin. Griseofulvin affects the fungus by binding to microtubules, structures responsible for forming mitotic spindles during cell division and for processing cell wall components needed for growth.

      Flucytosine (5-FC) is unique in that it becomes active only when converted to 5-fluorouracil (5-FU) by an enzyme, cytosine deaminase, found in fungi but not present in human cells. Flucytosine inhibits RNA and DNA synthesis. When administered parenterally, 5-FC is used primarily in the treatment of systemic cryptococcal and candida infections and chronomycosis.

Antiprotozoal drugs
      The protozoans, unlike bacteria and fungi, do not have a cell wall. They have a nucleus and a cytoplasm that is surrounded by a selectively permeable cell membrane. The cytoplasm contains organelles similar to those found in other animal and plant cells (e.g., mitochondria, Golgi apparatus, and endoplasmic reticulum). Thus, most of the antibiotics effective in inhibiting bacteria are not active against protozoans.

      Metronidazole is usually given orally for the treatment of vaginal infections caused by Trichomonas vaginalis, and it is effective in treating bacterial infections caused by anaerobes. It affects these organisms by causing nicks in, or breakage of, strands of DNA or by preventing DNA replication. Metronidazole is also the drug of choice in the treatment of giardiasis, an infection of the intestine caused by a flagellated amoeba.

      Iodoquinol inhibits several enzymes of protozoans. It is given orally for treating asymptomatic amoebiasis and is given either by itself or in combination with metronidazole for intestinal and hepatic amoebiasis.

      Trypanosomes are flagellated protozoans that cause a number of diseases. Trypanosoma cruzi, the causative agent of Chagas disease (Chagas' disease), is treated with nifurtimox, a nitrofuran derivative. It is given orally and results in the production of activated forms of oxygen, which are lethal to the parasite. Other forms of trypanosomiasis (African trypanosomiasis, or sleeping sickness) are caused by T. brucei gambiense or T. brucei rhodesiense. When these parasites invade the blood or lymph, the drug of choice for either form is suramin, a nonmetallic dye that affects glucose utilization and hence energy production. Because suramin is not absorbed from the gastrointestinal tract, it is given by intravenous injection.

      Pneumocystis carinii causes pulmonary disease in immunocompromised patients. These infections are treated with trimethoprim-sulfamethoxazole, which inhibits folic acid synthesis in protozoans. An alternative agent for treatment of these diseases is pentamidine isethionate, which probably affects the parasite by binding to DNA.

       malaria is one of the more serious protozoal infections. chloroquine phosphate, given orally, is the drug of choice for the prevention and treatment of uncomplicated cases. In regions where chloroquine-resistant Plasmodium falciparum is encountered, however, mefloquine or doxycycline are used for prevention of the disease. quinine sulfate, along with pyrimethamine and sulfadoxine, is used to treat infections caused by chloroquine-resistant P. falciparum. A high level of quinine in the plasma frequently is associated with cinchonism, a mild adverse reaction associated with such symptoms as a ringing noise in the ears ( tinnitus), headache, nausea, abdominal pain, and visual disturbance. primaquine phosphate is given orally to prevent malaria after a person has left an area where P. vivax and P. ovale are endemic and to prevent relapses with the same organisms.

Anthelmintics (anthelmintic)
      Helminths (worms) can be divided into three groups: cestodes, or tapeworms (tapeworm); nematodes (nematode), or roundworms; and trematodes, or flukes (fluke). The helminths differ from other infectious organisms in that they have a complex body structure. They are multicellular and have partial or complete organ systems (e.g., muscular, nervous, digestive, and reproductive). Several of the drugs used to treat worm infections affect the nervous system of the parasite and result in muscle paralysis. Other drugs affect the uptake of glucose and thus energy stores. All are chemical agents and are generally administered orally. There are no antibiotics available for the treatment of these infestations.

      Tapeworms (tapeworm) attach to the intestinal tract by a sucker or a sucking groove on the head (scolex). Unlike the nematodes and trematodes, tapeworms do not enter the host tissues. The primary drugs used for these infections (cestodiasis) are albendazole and praziquantel. Albendazole inhibits the uptake of glucose by the helminth and therefore the production of energy. It has a spastic or paralytic effect on the worm. Praziquantel also produces tetanus-like contractions of the musculature of the worm. Unlike albendazole, praziquantel is readily absorbed from the intestinal tract. It is a broad-spectrum anthelmintic affecting both flukes and tapeworms.

      Treatment of roundworms is complicated by the fact that some live in blood, lymphatics, and other tissues (filarial worms) and thus require use of drugs that are absorbed from the intestinal tract and penetrate into tissues. Others are found primarily or solely in the intestinal tract (intestinal nematodes). diethylcarbamazine and ivermectin, used for treating filarial worm infections, are absorbed from the intestinal tract. Blood levels are reached quickly, and action against the microfilariae is rapid. A severe allergic or febrile reaction due to the death of the microfilariae can follow the use of these drugs.

      Like albendazole, mebendazole interferes with glucose uptake and consequently with the production of energy. Mebendazole accumulates in the intestine and is used for treating Ascaris, hookworm (hookworm disease), and whipworm infections. It is well tolerated, but abdominal discomfort and diarrhea can occur in patients with a strong infestation.

      Pyrantel pamoate causes spastic paralysis of helminth muscle. Most of the drug is not absorbed from the intestinal tract, resulting in high levels in the intestinal lumen. It is a drug of choice in treating pinworm and is an alternative therapy for Ascaris infection, hookworm, and trichostrongolosis.

      Praziquantel is the most effective drug in treating infections caused by intestinal, liver, and lung flukes and is the drug of choice in the treatment of schistosomiasis (infections of blood flukes). Praziquantal causes contraction and spastic paralysis of the worm and also damages the membranes of the worm, which activates host defense mechanisms.

Antiviral drugs
      Viruses (virus) are among the most common and widespread causes of infectious diseases. They cause such illnesses as AIDS, influenza, herpes simplex type I (cold sores of the mouth) and type II (genital herpes), shingles, viral hepatitis, encephalitis, infectious mononucleosis, and the common cold. Viruses remain one of the least understood and most difficult of all infectious organisms to control, but this is changing as more is learned about their structure and replication. Viruses consist of nucleic acid, either DNA or RNA, and a protein coat. Because viruses do not have the enzymes that are needed to manufacture cellular components, they are obligate parasites, which means they must enter a cell for replication to occur. The nucleic acid of the virus instructs the host cell to produce viral components, which leads to an infectious virus. In some cases, as in herpes infections, the viral nucleic acid may remain in the host cell without causing replication of the virus and damage to the host (viral latency). In other cases, the production of virus by the host cell may cause the death of the cell. A major problem in treating some viral diseases is that latent viruses can become activated.

      Many factors account for the difficulty in developing antiviral chemotherapeutic agents. The structure of each virus differs, and specific therapy is often unsuccessful because of periodic changes in the antigenic proteins of the virus. The need for a host cell to support the multiplication of the virus makes treatment difficult because the chemotherapeutic agent must be able to inhibit the virus without seriously affecting the host cells.

      The greatest success against virus infections has been by increasing immunity through vaccination (vaccine) (in the prevention of influenza, poliomyelitis, measles, mumps, and smallpox) with live attenuated (weakened) or killed viruses. Vaccination has eradicated smallpox. While vaccination has proved to be effective against the specific virus used for smallpox, influenza is caused by viruses that constantly change their antigenic protein, thereby requiring revaccination as the antigenic makeup of the virus changes. Some virus groups contain 50 or more different viruses.

      Passive immunization with serum or globulin (antibodies) from immune persons has been used to prevent viral infections. Immunoglobulins, such as those used against hepatitis and respiratory syncytial virus, are effective only for prevention, not for treatment.

      An antiviral agent must act at one of five basic steps in the viral replication cycle in order to inhibit the virus: (1) attachment and penetration of the virus into the host cell, (2) uncoating of virus (e.g., removal of the protein surface and release of the viral DNA or RNA), (3) synthesis of new viral components by the host cell as directed by the virus DNA, (4) assembly of the components into new virus, and (5) release of the virus from the host cell.

      Herpesvirus (herpes simplex) is the DNA-containing virus that causes such diseases as genital herpes, chickenpox, retinitis, and infectious mononucleosis. After the viral particle attaches to the cell membrane and uncoats, the viral DNA is transferred to the nucleus and transcribed into viral mRNA for the viral proteins. Drugs that are effective against herpesviruses interfere with DNA replication. The nucleoside analogs (acyclovir and ganciclovir) actually mimic the normal nucleoside and block the viral DNA polymerase enzyme, which is important in the formation of DNA. All the nucleoside analogs must be activated by addition of a phosphate group before they have antiviral activity. Some of the agents (acyclovir) are activated by a viral enzyme, so they are specific for the cells that contain viral particles. Other agents (idoxuridine) are activated by cellular enzymes, so these have less specificity. Non-nucleoside inhibitors of herpesvirus replication include foscarnet, which directly inhibits the viral DNA polymerase, thus blocking formation of new viral DNA.

       influenza is caused by two RNA-containing viruses, influenza A and influenza B. When the RNA is released into the cell, it is directly replicated and also is used to make protein to form new viral particles. Amantadine and rimantadine are oral drugs that can be used for the prevention and treatment of influenza A, but they have no effect against influenza B viruses. The action of amantadine is to block uncoating of the virus within the cell, thus preventing the release of viral RNA into the host cell. Zanamivir and oseltamivir are active against both influenza A and influenza B. Zanamivir is given by inhalation only, while oseltamivir can be given orally. These drugs are inhibitors of neuramidase, a glycoprotein on the surface of the influenza virus. Inhibition of neuramidase activity decreases the release of virus from infected cells, increases the formation of viral aggregates, and decreases the spread of the virus through the body. If taken within 30 hours of the onset of influenza, both drugs can shorted the duration of the illness.

      Respiratory syncytial virus (RSV) causes a potentially fatal lower respiratory disease in children. The only pharmacological therapy available for treatment of the infection is ribavirin, which can be administered orally, parenterally, or by inhalation. Ribavirin must also be activated by phosphorylation in order to be effective. An injectable humanized monoclonal antibody is available for prevention of RSV infection in high-risk infants and children. It provides passive immunity and must by given by intramuscular injection once a month during RSV season.

      The human immunodeficiency virus (HIV), the virus that causes AIDS, is a retrovirus. Like other retroviruses, HIV contains reverse transcriptase, an enzyme that converts viral RNA into DNA. This DNA is integrated into the DNA of the host cell, where it replicates. Reverse transcriptase (RT) inhibitors work by inhibiting the action of reverse transcriptase. There are two groups of RT inhibitors. Nucleoside RT inhibitors (e.g., zidovudine, didanosine, zalcitabine, lamivudine, and stavudine) must be phosphorylated to become active. These drugs mimic the normal nucleosides and block reverse transcriptase. Because the different nucleoside RT inhibitors mimic different purines and pyrimidines, use of two of the drugs in this group is more effective than one alone. The second group of RT inhibitors are the non-nucleoside inhibitors (e.g., delaviridine, efanvirenz, and nevirapine), which do not require activation and, because they act through a different mechanism, exhibit a synergistic inhibition of HIV replication when used with the nucleoside RT inhibitors.

      The biggest problem with the use of RT inhibitors is the development of resistance; because HIV replicates continuously at a very high rate, there are many chances for mutation and hence the emergence of a virus resistant to many drugs. To combat the emergence of resistant virus, a class of HIV drugs called nucleotide RT inhibitors (e.g., tenofovir) has been developed. These drugs are “preactivated”; that is, they are already phosphorylated and require less cellular processing. Otherwise, they are similar to nucleoside RT inhibitors and non-nucleoside RT inhibitors.

      Protease inhibitors (e.g., ritonavir, saquinavir, and indinavir) block the spread of HIV to uninfected cells by inhibiting the viral enzymes involved in the synthesis of new viral particles. Because they act at a different point in the life cycle of HIV, use of a protease inhibitor with an RT inhibitor suppresses replication better than either drug alone. Protease inhibitors also slow the emergence of resistant virus. The principal adverse effects of protease inhibitors are nausea and diarrhea. Long-term use can bring on a syndrome known as lipodystrophy (wasting of peripheral fat, accumulation of central fat, hyperlipidemia, and insulin resistance).

      Yet another class of HIV drugs is the fusion inhibitors (e.g., enfuvirtide). Fusion inhibitors work by blocking the HIV virus from entering human cells. Serious side effects include allergic reactions and infections at sites where the medicine is given intravenously.

      Interferons (interferon) represent a group of nonspecific antiviral proteins produced by host cells in response to viral infections as well as in response to the injection of double-stranded RNA, some protozoal and bacterial components, and other chemical substances. Interferon results in the production of a protein that prevents the synthesis of viral components from the viral nucleic acid template. The interferons are of interest because they have broad-spectrum antiviral activity and because they inhibit the growth of cancer tissue. However, the use of interferon is limited by adverse effects, a relative lack of efficacy, and the requirement for local or intravenous administration.

Central nervous system drugs
General anesthetics
      Anesthetics (anesthetic) are drugs that induce a temporary inability to perceive any sensory stimuli. They achieve this effect by acting on the brain or peripheral nervous system to suppress responses to sensory stimulation, primarily to touch, pressure, and pain. The unresponsive state induced by anesthetic drugs is known as anesthesia. General anesthetics induce anesthesia throughout the body and can be administered either by inhalation or by direct injection into the bloodstream.

      The relationship between the amount of general anesthetic administered and the depression of the brain's sensory responsiveness is arbitrarily, but usefully, divided into four stages. Stage I is the loss of consciousness, with modest muscular relaxation, and is suitable for short, minor procedures. Additional anesthetic induces stage II, in which increased excitability and involuntary activity make surgery impossible; rapid passage through stage II is generally sought by physicians. Full surgical anesthesia is achieved in stage III, which is further subdivided on the basis of the depth and rhythm of spontaneous respiration (respiration, human), pupil reflexes, and spontaneous eye movements. Stage IV anesthesia is indicated by the loss of spontaneous respiration and the imminent collapse of cardiovascular control.

      Not infrequently, general anesthetics are combined with drugs that block neuromuscular impulse transmission. These additional drugs are given to relax muscles in order to make surgical manipulations easier. Under these conditions, artificial respiration may be required to maintain proper levels of oxygen and carbon dioxide in the blood. The ideal anesthetic agent allows rapid and pleasant induction (the process that brings about anesthesia), close control of the level of anesthesia and rapid reversibility, good muscle relaxation, and few toxic or adverse effects. Some anesthetics have been rejected for therapeutic use because they form explosive mixtures with air, because of their excessive irritant action on the cells that line the major bronchioles of the lung, or because of their adverse effects on the liver or other organ systems.

      Inhalational anesthetics are administered in combination with oxygen, and most are excreted by the lungs with little or no metabolism by the body. Except for the naturally occurring gas nitrous oxide, all the currently used major inhalational anesthetics are hydrocarbons (hydrocarbon), which are compounds formed of carbon and hydrogen atoms. Each carbon has the potential to bind four hydrogen atoms. The potency of a given series of hydrocarbons depends on the nature of the bonds between the carbons and the degree to which the hydrogen atoms have been replaced with halogens (halogen element). In the ethers (ether), the carbon atoms are connected through a single oxygen, as in diethyl ether, and again halogen substitution increases potency, as is seen in enflurane and methoxyflurane. A peculiar, unpredictable, and serious adverse property of halogen anesthetics and muscle relaxants is their ability to trigger a hypermetabolic reaction in the skeletal muscles of certain susceptible individuals. This potentially fatal response, called malignant hyperthermia, produces a very rapid rise in body temperature, oxygen utilization, and carbon dioxide production.

      Rapid, safe, and well-controlled anesthesia can be obtained by the intravenous administration of depressants (depressant) of the central nervous system, such as the barbiturates (barbiturate) (e.g., thiopental), the benzodiazepines (e.g., midazolam), or other drugs such as propofol, ketamine, and etomidate. These systemic anesthetics result in a rapid onset of anesthesia after a single dose because of their high solubility in lipids and their relatively high perfusion rate in the brain. The intravenous anesthetics are frequently used for induction of anesthesia and are followed by an inhalational agent for maintenance of the anesthetic state.

Floyd E. Bloom

Local anesthetics
      Local anesthetics provide restricted anesthesia because they are administered to the peripheral sensory nerves innervating a region, usually by injection. Thus, local anesthetics are useful in minor surgical procedures, such as the extraction of teeth. The first known and generally used local anesthetic was cocaine, an alkaloid extracted from coca leaves obtained from various species of Erythroxylum. In the 1880s cocaine was first introduced to the field of ophthalmology for anesthetizing the cornea; later it was used in dental procedures.

      The feeling of pain depends upon the transmission of information from a traumatized region to higher centres in the brain. The information is passed along fine nerve (sensory) fibres from the peripheral areas of the body to the spinal cord and then to the brain. Local anesthetics cause a temporary blocking of conduction along these nerve fibres, producing a temporary loss of pain sensation.

      Local anesthetics can block conduction of nerve impulses along all types of nerve fibres, including motor nerve fibres that carry impulses from the brain to the periphery. It is a common experience with normal dosages of an anesthetic, however, that, while pain sensation may be lost, motor function is not impaired. For example, use of a local anesthetic in a dental procedure does not prevent movement of the jaw. The selective ability of local anesthetics to block conduction depends on the diameter of the nerve fibres and the length of the fibre that must be affected to block conduction. In general, thinner fibres are blocked first, and conduction can be blocked when only a short length of fibre is inactivated. Fortunately, the fibres conveying the sensation of dull aching pain are among the thinnest and the most susceptible to local anesthetics. If large amounts of local anesthetic are used, pain is the first sensation to disappear, followed by sensations of cold, warmth, touch, and deep pressure.

      Many synthetic local anesthetics are available, such as procaine (procaine hydrochloride) (Novocaine™), lidocaine, and tetracaine. It is the convention to end the names of local anesthetics with -caine, after cocaine, which was the first local anesthetic known. In general they are secondary or tertiary amines linked to aromatic groups by an ester or amide linkage. The hydrophobic nature of the molecules makes it possible for them to penetrate the fatty membrane of the nerve fibres and exert their effects from the inside. When an impulse passes along a nerve, there are transient changes in the properties of the membrane that allow small electrical currents to flow. These currents are carried by sodium ions. The influx of these sodium ions through small channels that open briefly in the surface of the nerve membrane during excitation transports the impulse. Local anesthetics block these channels from the inside, preventing the movement of the sodium ions and small electrical currents. The action of a local anesthetic is terminated as the agent is dispersed, metabolized, and excreted by the body. Its dispersal from the injection site depends, in part, on the blood flow through the region. In some cases epinephrine (epinephrine and norepinephrine) is added to the local anesthetic solution to cause local vasoconstriction and to prolong the action of the local anesthetic.

      Local anesthetics are used to induce limited areas of anesthesia. The limited area is achieved largely by the site and method of administration and partly by the physiochemical properties of the drug molecules. The drug may be injected subcutaneously around sensory nerve endings, enabling minor procedures such as repair of skin laceration. This is called infiltration anesthesia. Some local anesthetics are applied directly to mucous membranes (mucous membrane), such as those of the nose, throat, larynx, and urethra or those of the conjunctiva of the eye. This is called surface or topical anesthesia. A familiar example of topical anesthesia is the use of certain local anesthetics in throat lozenges to relieve the pain of a sore throat. Local anesthetics may be injected near a main nerve trunk in a limb to produce what is called regional nerve block anesthesia. In this situation, conduction in both motor and sensory fibres is blocked, enabling procedures to be carried out on a limb while the patient remains conscious. A special form of regional nerve block may be achieved by injecting a local anesthetic into the spinal canal, either into the space between the two membranes (the durae) that surround the cord (epidural anesthesia) or into the cerebrospinal fluid (spinal or intrathecal anesthesia). In spinal anesthesia, the specific gravity of the local anesthetic solution is appropriately adjusted and the patient is positioned in such a way that the anesthesia is confined to a particular region of the spinal cord. In both epidural and spinal anesthesias, the anesthetic blocks conduction in nerves entering and leaving the cord at the desired level.

Alan William Cuthbert

Analgesics (analgesic)
       drug analgesicsAnalgesics (analgesic) are drugs that relieve pain selectively without affecting consciousness or sensory perception. This selectivity in relieving pain is an important distinction between an analgesic and an anesthetic. Analgesics may be classified into two types: anti-inflammatory drugs, which alleviate pain by reducing local inflammatory responses; and the opioids, which act on the brain. The opioid analgesics were once called narcotic drugs because they can induce sleep. The opioid analgesics can be used for either short-term or long-term relief of severe pain. In contrast, the anti-inflammatory compounds are used for short-term pain relief and for modest pain, such as that of headache, muscle strain, bruising, or arthritis. Some common analgesics are listed in the table (drug analgesics).

Anti-inflammatory analgesics
      Several chemically unrelated series of complex organic acids have the ability to relieve mild to moderate pain through actions that reduce inflammation at its source. Acetylsalicylic acid, or aspirin, is the most widely used mild analgesic, although more potent antipyretic (fever-reducing) analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), are available. Like aspirin, many of the drugs of this class reduce fever, and those that resemble aspirin most closely share what is presumed to be its molecular mechanism of action—namely, inhibition of the synthesis of prostaglandins (prostaglandin) (natural products of inflamed leukocytes (leukocyte)) that induce the responses in local tissue that include pain and inflammation.

      Research has shown that small doses of certain prostaglandins can mimic almost all the signs and symptoms of localized inflammation. Prostaglandins are naturally occurring by-products of arachidonic acid synthesis. They are thought to be released at the site of inflammation when leukocytes are attracted to injured or inflamed areas. All cells except red blood cells can produce prostaglandins, and when injured, the cells release large amounts of these substances. All aspirin-like analgesics, including NSAIDs, inhibit prostaglandin synthesis and release.

      The NSAIDs (e.g., ibuprofen, naproxen, and fenoprofen) produce their therapeutic action by inhibition of the cyclooxygenase (COX) enzyme, which is responsible for the synthesis of prostaglandins and related compounds. There are two forms of the COX enzyme, COX-1 and COX-2. COX-1 is found in most normal tissues, while COX-2 is induced in the presence of inflammation. Because COX-2 is not normally expressed in the stomach, the use of COX-2 inhibitors (e.g., rofecoxib, celecoxib) seems to result in less gastric ulceration than occurs with other anti-inflammatory analgesics. However, COX-2 inhibitors do not reduce the ability of platelets to form clots.

      As might be expected from their common mechanisms of action, many of the anti-inflammatory analgesic drugs share similar side effects. Hypersensitivity responses to aspirin-like drugs are thought to be due to an accumulation of prostaglandins after the pathways that break down prostaglandins are blocked. These responses can be fatal when very strong anti-inflammatory compounds are given. Inhibition of prostaglandin synthesis may result in other serious side effects, such as peptic ulcers (peptic ulcer) (which may also be due in part to the irritant activity of large doses of aspirin on the lining of the stomach) and a reduced ability of platelets in the blood to aggregate and form clots. The latter effect, however, has given aspirin an added use as a prophylactic antithrombotic drug to reduce chances of cardiac or cerebral vascular thrombosis. Some of these aspirin-like analgesics also have specific toxic effects: liver damage occasionally occurs after administration of acetaminophen, and renal toxicity is sometimes seen with use of NSAIDs. Aspirin is thought to be a causative agent of Reye syndrome, a rare and serious degenerative disease of the brain and fatty tissue of the liver that accompanies certain viral infections in children and young adults.

Opioid analgesics
      The term opioid has been adopted as a general classification of all of those agents that share chemical structures, sites, and mechanisms of action with the endogenous opioid agonists. Opioid substances encompass all the natural and synthetic chemical compounds closely related to morphine, whether they act as agonists or antagonists. Although interest in these drugs has always been high because of their value in pain relief and because of problems of abuse and addiction, interest was intensified in the 1970s and '80s by discoveries about the naturally occurring morphinelike substances, the endogenous opioid neuropeptides.

       opium is the powder from the dried juice of the poppy Papaver somniferum. When taken orally, opium produces sleep and induces a state of peaceful well-being. Its use dates back at least to Babylonian civilization. In the early 19th century opium extract was found to contain more than 20 distinct complex organic bases, termed alkaloids (alkaloid), of which morphine, codeine, and papaverine are the most important. These pure alkaloids replaced crude opium extracts in therapeutics.

      In the 1950s several new morphinelike drugs were developed. Despite the increase in the number of compounds available for pain relief, however, little was understood of their sites and mechanisms of action. The first real breakthrough came from the discovery, by neuroscientists John W. Hughes and Hans W. Kosterlitz at the University of Aberdeen in Scotland, of two potent naturally occurring analgesic pentapeptides (peptides containing five linked amino acids) in extracts of pig brain. They called these compounds enkephalins, and since then at least six more have been found. Larger peptides, called endorphins (endorphin), have been isolated, and these contain sequences of amino acids that can be split off as enkephalins. There are at least three types of receptors on brain neurons that are activated by the enkephalins. Morphine and its congeners are thought to exert their effects by activating one or more of these receptors.

      Opioid drugs are useful in the treatment of general postoperative pain, severe pain, and other specific conditions. The use of opioids to relieve the pain associated with kidney stones (kidney stone) or gallstones (gallstone) presumably depends on their ability to affect opioid receptors in these tissues and to inhibit contractility. By a similar mechanism, opioids are also able to relieve the abdominal distress and fluid loss of diarrhea. Central receptors appear to account for the ability of morphine and analogs to suppress coughing, an effect that requires lower doses than those needed for analgesia. Low doses of opioids are also used for relief of the respiratory distress that accompanies acute cardiac insufficiency complicated by the buildup of fluid in the lungs.

      Several commonly used natural or synthetic derivatives of morphine are used in drug therapeutics. codeine, a naturally occurring opium alkaloid that can be made synthetically, is a useful oral analgesic, especially when used in combination with aspirin. meperidine was an early synthetic analog of morphine, marketed under the trade name Demerol™, that was originally thought to be able to provide significant short-lasting analgesia and little or no addiction because of its shortened duration of action; however, this belief proved false. methadone, a synthetic opioid analgesic, has long-lasting analgesic effects (six to eight hours) when taken orally and is used to moderate the effects of withdrawal from heroin addiction. Among the opioid antagonist drugs, naloxone and its longer-lasting orally active version, naltrexone, are used primarily to reverse morphine overdoses and to reverse the chemical stupor of a wider variety of causes, including alcohol intoxication and anesthesia. In opioid overdoses, these drugs provide recovery within minutes of injection. They can, however, also precipitate severe withdrawal reactions in a person addicted to opiates.

      The effectiveness of a given dose of an opioid drug declines with its repeated administration in the presence of intense pain. This loss in effectiveness is called tolerance. Evidence suggests that tolerance is not due to alterations in the brain's responses to drugs. Animals exhibiting tolerance to morphine after repeated injections in a familiar environment show little or no tolerance when given the same doses and tested for pain sensitivity in new environments. Thus, there is almost certainly a learned aspect of tolerance. The cellular and molecular mechanisms underlying this loss of responsiveness are not clear. Physical dependence and addiction in a person using intravenous administration closely follow the dynamics of drug tolerance; increasing doses are required to produce the psychological effects, while tolerance protects the brain against the respiratory depressant actions of the drug. In the tolerant individual, intense adverse reactions can be precipitated by administration of an opioid antagonist, thus revealing the dynamic internal equilibrium that previously appeared to neutralize the response of the brain to the opioids. The signs of the withdrawal response (e.g., anxiety, tremors, elevation of blood pressure, abdominal cramps, and hyperthemia) can be viewed as signs of an activated sympathetic nervous system and to some extent an extreme, but nonspecific, arousal response.

       psychiatric drugsBehaviour (human behaviour) and emotions are higher functional properties of the brain that depend on the network of neurons and chemical neurotransmitters that exist throughout the body; however, the means by which neurons achieve changes in behaviour and in mood remains unknown. Nevertheless, certain neurotransmitters, such as norepinephrine, dopamine, epinephrine, serotonin, and acetylcholine, appear to be closely linked to these aspects of brain function. Drugs that influence the operation of these neurotransmitter systems can profoundly influence and alter the behaviour of patients with mental disorders (mental disorder). Some common psychiatric drugs are listed in the table (psychiatric drugs).

      Psychiatric drugs, those that affect mood and behaviour, can be classified (psychopharmacology) as follows: antianxiety agents, antidepressants, antipsychotics, and antimanics. Such drugs should be reserved for severe disruptions of normal emotional well-being and should not be used to relieve the boredom, tension, or sadness that may be properly regarded as a normal part of life.

Antianxiety drugs
       anxiety is a state of pervasive apprehension that may be triggered by specific environmental or personal factors. Anxiety states are generally combined with emotions such as fear, anger, or depression. A person with anxiety may complain of physical symptoms such as palpitations, nausea, dizziness, headaches, and chest pains, as well as sleeplessness and fatigue. When such apprehension is severe and incapacitating, the person may require treatment with both medication and psychotherapy.

      After World War II Swiss pharmacologists discovered muscle-relaxant properties in a compound under investigation as an antibiotic. Modification of that compound led to the tranquilizing drug meprobamate. Another discovery showed that the benzodiazepines, which are complex ringed compounds, had even greater relaxing properties. Hundreds of analogs of the basic benzodiazepine ring were subsequently synthesized. Different formulations of the basic benzodiazepine structure in higher dosages are used as muscle relaxants, antiepileptics, and sedative-hypnotics (see below Sedative-hypnotic drugs (drug) and Antiepileptic drugs (drug)).

      The brain exhibits highly specific, high-affinity binding sites that can selectively recognize, or bind, the benzodiazepine compounds. The cellular and subcellular locations of these sites are near ion channels in the membrane that can admit chloride ions into the cell and also near sites where a neurotransmitter, gamma-aminobutyric acid (GABA), acts. Benzodiazepine agonists in general enhance the effects of GABA.

      Acute treatment with benzodiazepines generally begins with doses taken before bedtime to facilitate sleep. Tolerance may develop to the sedation. Because of the alterations in the effectiveness of inhibitory transmitter actions of GABA, which are profound in the cerebellum and cerebral cortex, the patient may also exhibit confusion and loss of motor coordination as side effects of the drug.

      Zolpidem and saleplon are antianxiety drugs that are GABA agonists, though structurally they are not benzodiazepines. The probability of developing dependence to these drugs is limited, even with repeated or prolonged use. They are used in the short-term treatment of insomnia.

      Buspirone is an antianxiety drug that is unrelated to the benzodiazepines. It does not affect the GABA receptor, nor does it have any muscle-relaxant or anticonvulsive properties. It also lacks the prominent sedative effect that is associated with other drugs used to treat anxiety. Instead, buspirone is thought to be a partial agonist at a specific receptor for serotonin, a neurotransmitter found in the brain that is associated with mood changes. It has a much lower potential for abuse and is not associated with any withdrawal phenomena.

Antidepressants (antidepressant)
       depression is characterized by a sad or hopeless mood, a loss of interest in one's usual activities, reduced energy, change of appetite, disturbed sleep patterns, and often contemplation of suicide. The disorder must be distinguished from grief felt in reaction to the death of a loved one or some other unfortunate circumstance.

      In 1957 imipramine emerged as the first therapeutically useful antidepressant. An accidental discovery led to the finding that the drug iproniazid caused some patients to become extremely euphoric and hyperactive by inhibiting monoamine oxidase, a liver and brain enzyme that normally breaks down norepinephrine (epinephrine and norepinephrine) and other neurotransmitters. Drugs that were better at blocking the activity of this enzyme were even more effective in evoking euphoria. Shortly thereafter the monoamine oxidase inhibitors (MAOIs), as they were later called, were introduced for the treatment of depression.

      Another class of antidepressants, named tricyclics for their basic three-carbon ring structure, were discovered about the same time as the MAOIs. Tricyclics inhibit the active reuptake of the neurotransmitters norepinephrine, serotonin, and dopamine in the brain. Inhibition of reuptake allows the neurotransmitters to remain in contact longer with their postsynaptic receptors. This mechanism seems to support the hypothesis that depression is caused by a chemical imbalance in the levels of neurotransmitters. The most common antidepressants used today are selective serotonin reuptake inhibitors (SSRIs), primarily because they have fewer side effects than tricyclics or MAOIs. Introduced in the late 1980s, SSRIs include fluoxetine ( Prozac), paroxetine (Paxil), and sertraline (Zoloft). SSRIs are also used in the treatment of anxiety, eating disorders, panic disorder, obsessive-compulsive disorder, and borderline personality disorder.

      Other antidepressants inhibit reuptake of serotonin and norepinephrine in variable amounts. For example, venlafaxine is a nonselective inhibitor of the uptake of serotonin, norepinephrine, and dopamine. Nefazodone inhibits serotonin and norepinephrine reuptake and is an antagonist at certain serotonin receptors and α1-receptors.

      Side effects vary among the types of antidepressants and may include sleepiness, tremors, anxiety, loss of sexual desire, and nausea. Three to four weeks are typically required to produce significant improvement in individuals who are taking antidepressant medications for the treatment of their depression. Most physicians recommend that patients continue to take antidepressants for at least six months to prevent a relapse.

       mania is a severe form of emotional disturbance in which a person is progressively and inappropriately euphoric and simultaneously hyperactive in speech and locomotor behaviour. This is often accompanied by significant insomnia, excessive talking, extreme confidence, and increased appetite. As the episode builds, the person experiences racing thoughts, extreme agitation, and incoherence, frequently replaced with delusions, hallucinations, and paranoia, and ultimately may become hostile and violent and may finally collapse. In some persons, periods of depression and mania alternate, giving rise to bipolar disorder, formerly called manic-depressive disorder. The most effective medications for bipolar disorder are the simple salts lithium chloride or lithium carbonate (lithium). Although some serious side effects can occur with large doses of lithium, the ability to monitor blood levels and keep the doses within modest ranges makes it an effective treatment for manic episodes, and it can also stabilize the mood swings of the patient with bipolar disorder. The precise mechanism of action of lithium is not known.

      If patients take an overdose, or if their normal salt and water metabolism becomes unbalanced by intervening infections that cause anorexia or fluid loss, then loss of coordination, drowsiness, weakness, slurred speech, and blurred vision, as well as more serious chaotic cardiac rhythm and brain-wave activity with seizures may occur. Because lithium is generally excreted along with sodium in the urine, rehydration and supportive therapy are all that is required for treatment. Prolonged use of lithium, however, can in fact damage the body's ability to respond properly to the hormone vasopressin, which stimulates the reabsorption of water, thus causing the emergence of diabetes insipidus, a disorder characterized by extreme thirst and excessive production of very dilute urine. Lithium can also interfere with the response of the thyroid gland to the thyroxin-stimulating hormone produced in the pituitary gland.

      A number of other compounds are now used to stabilize mood. Most of these drugs, such as valproic acid, carbamazepine, and gabapentin, are more commonly classified as antiepileptic agents.

      The severe form of mental illness known as schizophrenia is usually a chronic, often lifelong, inability to think logically and act appropriately. Effective treatments for some forms of schizophrenia have revolutionized thinking about the disease and have prompted investigations into its possible genetic origins and pathological causes.

      The first major class of drugs used successfully in the treatment of schizophrenia have a colourful origin. The history of reserpine can be traced to an Indian shrub, called Rauwolfia serpentina for its snakelike appearance, which historically was used to treat snake bites, insomnia, high blood pressure, and insanity. Reserpine, the principle alkaloid of the plant, was first isolated in the 1950s and was used in the treatment of hypertension. It was later given to persons with schizophrenia, in whom the drug was found to act as a behavioral depressant. In fact, the depression of patients given the drug for hypertension was a major side effect. The basic mechanisms of action of reserpine in producing depression are attributed to its ability to deplete the brain's stores of serotonin and norepinephrine.

      The second major class of antipsychotic drugs, the phenothiazines (phenothiazine), arose from modifications of the dye methylene blue, which was under investigation as an antagonist of histamine. Attempts to modify this series to increase their activity in the central nervous system and reduce the need for surgical anesthetics ultimately led to the first effective drug of this class, chlorpromazine. Its ability to stabilize behaviour and to improve lucidity as well as to reduce hallucinatory behaviour was recognized within a few years of its introduction. The use of chlorpromazine changed the role of the mental hospital and resulted in the large-scale, perhaps excessive, discharge of persons with schizophrenia into the outside world.

      A third class of antipsychotics, the butyrophenones, emerged when a small Belgian drug company embarked on an ill-conceived plan to develop analogs of meperidine through inexpensive chemical substitutions. Experiments gave rise to a compound that caused chlorpromazine-like sedation but had a completely different structure. This led to the compound haloperidol, a more powerful antipsychotic with relatively fewer side effects.

      A fourth class of drugs, commonly known as “atypicals” but more properly called atypical antipsychotics or serotonin-dopamine antagonists, is related to chlorpromazine and to haloperidol. These antipsychotics can improve both the so-called positive symptoms (e.g., hallucinations, delusions, and agitation) and the negative symptoms of schizophrenia, such as catatonia and flattening of the ability to experience emotion. Each agent in this group has a unique profile of receptor interactions. Virtually all antipsychotics block dopamine receptors and reduce dopaminergic transmission in the forebrain. The atypical antipsychotics also have affinity for serotonin receptors.

      The major acute side effects of chlorpromazine and haloperidol are oversedation and a malaise that makes the drugs poorly received by the patient and makes compliance with chronic self-medication difficult. Prolonged treatment of middle-aged and even young adults with antipsychotic drugs can evoke serious movement disorders that in part resemble Parkinson disease (parkinsonism), a degenerative condition of the nerves. First to appear are tremors and rigidity, followed by more complex movement disorders commonly associated with involuntary twitching movements on the arms, lips, and tongue, called tardive dyskinesia. The newer atypical antipsychotics do not produce the movement disorders that are seen with the use of the older drugs, probably due to their affinity for both serotonin and dopamine receptors. None of the antipsychotics is curative, because none eliminates the fundamental disorder of thought processes.

      Neuroleptic malignant syndrome is a rare, potentially fatal neurological side effect of antipsychotic drug use. Individuals develop a severe rigidity with catatonia, autonomic instability, and stupor, which may persist for more than one week. Neuroleptic malignant syndrome has occurred with all antipsychotics, but the disorder is more common with relatively high doses of more potent agents such as haloperidol.

Sedative-hypnotic drugs (sedative-hypnotic drug)
      Drugs that reduce tension and calm anxiety at low doses (see the section Antianxiety drugs (drug)) and that produce drowsiness and facilitate the onset of sleep at higher doses are called sedative-hypnotics (sedative-hypnotic drug). Because this state of sleep is one from which a patient can normally be aroused, its production was once attributed to “hypnotic” actions, but the sleep that is induced is actually quite natural. Still-higher doses of some sedative-hypnotics can produce deep unconsciousness sufficient to make them useful as general anesthetics.

      The dose level at which calm, sleep, or anesthesia is induced depends on the drug class and its mechanism of action. Since similar effects can be obtained with other drugs, such as analgesic opioids or benzodiazepines, the distinctive characteristic of primary sedative-hypnotics is their selective ability to induce these actions without affecting mood or sensitivity to pain.

      Alcoholic (alcohol consumption) beverages and alcoholic extracts of opium were traditionally used as sedative-hypnotics, but the first substance introduced specifically as a sedative and as a hypnotic was a liquid solution of bromide salts. In 1869 chloral hydrate became the first synthetic organic molecule to be employed specifically for its sedative-hypnotic effect, and it was followed by several others, notably paraldehyde. (Chloral hydrate was used notoriously as “knock-out” drops.) Barbiturates (barbiturate), with their more complex organic ring structure, were introduced in the early 1900s, and hundreds of barbiturate analogs were then synthesized with varying potencies and durations of action. Potent analogs of barbiturates have been used to induce surgical anesthesia and to reduce voluntary inhibition during psychiatric examinations (for which they have sometimes been dubbed “truth serums”). Use of barbiturates declined after the development in the 1950s of the benzodiazepines, many of which exhibit the ideal properties of a short-acting, intense facilitator of natural sleep with a reduced risk of adverse effects. The benzodiazepines act on the inhibitory sites at which gamma-aminobutyric acid (GABA) is the neurotransmitter.

      When sedatives are taken frequently as sleeping tablets, tolerance and a reduction in effectiveness occur. Despite popular beliefs to the contrary, alcoholic beverages in particular are only of modest benefit in inducing sleep. On frequent exposure to alcohol, the nervous system adapts to the drug, and this results in early morning awakening. Barbiturates can be selected to provide both early onset of sleep and a prolongation of sleep. Analysis of electroencephalographic (EEG) patterns during barbiturate-induced sleep, however, shows that there is more disruption of sleep. There have been reports that some benzodiazepines used as sleep inducers produce less disruption of the sleep phases, a property that makes them especially useful for persons with sleep disturbances.

      In certain persons, low doses of barbiturates and some benzodiazepines produce transiently enhanced mood or euphoria along with antianxiety effects. These behavioral effects can lead to abuse of these substances and to dependence upon them with prolonged use. High doses can depress critical centres in the brain stem for the regulation of cardiovascular and respiratory function.

Antiepileptic drugs
       epilepsy is a general term for a group of central nervous system disorders characterized by transient but repeated episodes of abnormal electroencephalographic activity (seizures) that correlate with abnormal motor behaviour (convulsions (convulsion)) and, less commonly, with sensory, autonomic, or psychological manifestations. Although some forms of epilepsy may be caused by high fevers, especially in infants, and while some forms of epilepsy in adults can be traced to previous brain injury (with resulting scars) or to brain tumours (tumour), the causes of most forms are unknown. Recent analysis of some inherited epilepsies has shown that recurrent seizures may be due to genetic alterations in ion channels. The treatment of epilepsy is directed toward reducing the frequency of seizures. An accurate diagnosis of the form of epilepsy is critical to selection of the drug most likely to be effective.

      Many antiepileptic drugs were discovered by testing their ability to prevent seizures in experimental animals after electrical stimulation of the brain or after the administration of convulsant drugs such as strychnine or pentylenetetrazol. Others, such as phenytoin, were discovered as a result of persistent testing of a series of drugs. Phenytoin is effective in the long-term treatment of many varieties of epilepsy and is thought to work through an interaction with sodium channels. The barbiturates and the benzodiazepines act as antiepileptics by enhancing the effectiveness of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

      The tricyclic antidepressant drug carbamazepine, used in the treatment of trigeminal neuralgia, was later found to have value in the treatment of epileptic disorders. The effectiveness of the drug has been attributed to a combination of effects, including the blockage of repetitive neuron firing through an interaction with sodium channels.

      Because most epileptic conditions are long-lasting and of unknown origin, their treatment is largely confined to drugs. As might be expected, side effects after prolonged use are common. Phenytoin, for example, may be directly toxic to neurons of the cerebellum. In addition, this drug can cause gingival hyperplasia (enlargement of the gums) and hirsutism (excessive facial and body hair), side effects that may lead patients to abandon it. The barbiturates and benzodiazepines are effective antiepileptics but are generally avoided because of their sedative properties.

Anti-Parkinson drugs
      Parkinson disease (parkinsonism), or paralysis agitans, is a severe progressive degenerative disease of the nerves characterized by tremor of the hands that disappears when movement is initiated. Later in the course of the disease the muscles become rigid, and the initiation and termination of movements become so difficult as to be incapacitating. In the final stages the patient is unable to maintain an erect posture, speak, write, or focus the eyes. Although the loss of pigmented neurons of the brain region called the substantia nigra had been a pathological finding in cadavers since the early 20th century, a pathophysiological explanation of the disorder was not found until 1960. These neurons use the substance dopamine as their neurotransmitter, and they project onto the basal ganglia, a centre for the coordination of movement. Patients with Parkinson disease were found to have basal ganglia greatly deficient in dopamine.

      Recognition that this chemical deficiency of a specific neurotransmitter was a central feature of the disease led to a new therapy based on the use of the amino acid L-3,4-dihydroxyphenylalanine (levodopa, or L-dopa), the precursor of dopamine. When given orally in large daily doses, some levodopa is able to escape metabolism in the bloodstream and enter the brain, where surviving dopamine neurons convert it to dopamine. To increase the delivery of this dopamine precursor to the brain, levodopa therapy is supplemented with carbidopa, an analog of levodopa that inhibits decarboxylation to dopamine in the intestine and in the general circulation but is unable to penetrate into the brain. As a result, carbidopa increases the effectiveness of levodopa. Overdosage with levodopa can cause schizophrenia-like episodes, presumably due to the excess formation of dopamine. The use of levodopa to treat Parkinson disease, moreover, is not the radical cure that it was once thought to be but only a measure that modifies the symptoms of the disease. Some patients are helped by bromocriptine, a dopamine agonist so modified as to be able to gain access to the brain. Also in an effort to increase dopamine levels, drugs such as tolcapone and entacapone have been developed that inhibit the enzymatic breakdown of the compound.

Floyd E. Bloom

Cardiovascular drugs
       cardiovascular drugsDrugs that affect the function of the heart and blood vessels (blood vessel) are among the most widely used in medicine. Although these drugs may exert their primary effect either on the blood vessels or on the heart itself, the cardiovascular system functions as an integral unit. Thus, drugs that affect blood vessels are often useful in treating conditions in which the primary disorder lies in the heart itself, or vice versa. Examples of disorders in which such drugs may be useful include hypertension (high blood pressure), angina pectoris (pain resulting from inadequate blood flow through the coronary vessels to the muscular wall of the heart), heart failure (inadequacy of the output of the heart in relation to the needs of the rest of the body), and arrhythmias (disturbances of cardiac rhythm). Some common cardiovascular drugs are listed in the table (cardiovascular drugs).

Drugs affecting the heart
      Drugs affect the function of the heart in three main ways. They can affect the force of contraction of the heart muscle (inotropic effects); they can affect the frequency of the heartbeat, or heart rate (chronotropic effects); or they can affect the regularity of the heartbeat (rhythmic effects).

      Inotropic agents are drugs that influence the force of contraction of cardiac muscle, thereby affecting cardiac output. Drugs have a positive inotropic effect if they increase the force of the heart's contraction. The most important group of inotropic agents are the cardiac glycosides, substances that occur in the leaves of the foxglove (Digitalis purpurea) and other plants. Although they have been used for many purposes throughout the centuries, the effectiveness of cardiac glycosides in heart disease was established in 1785 by English physician William Withering, who successfully used an extract of foxglove leaves to treat heart failure. The two compounds most often used therapeutically are digoxin and digitoxin.

      Cardiac glycosides, however, have disadvantageous side effects. These include a tendency to block conduction of the electrical impulse that causes contraction as it passes from the atria (atrium) to the ventricles (ventricle) of the heart ( heart block). Cardiac glycosides also have a tendency to produce an abnormal cardiac rhythm by causing electrical impulses to be generated at points in the heart other than the normal pacemaker region, the cells that rhythmically maintain the heartbeat. These irregular impulses result in ectopic heartbeats, which are out of sequence with the normal cardiac rhythm. Occasional ectopic beats are harmless, but if this process continues to a complete disorganization of the cardiac rhythm ( ventricular fibrillation), the pumping action of the heart is stopped, causing death within minutes unless resuscitation is performed. Because the margin of safety between the therapeutic and the toxic doses of glycosides is relatively narrow, they must be used carefully.

      Cardiac glycosides are believed to increase the force of cardiac muscle contraction by binding to and inhibiting the action of a membrane enzyme that extrudes sodium ions from the cell interior. These drugs also enhance the release of calcium from internal stores, resulting in a rise in intracellular calcium. This subsequently increases the force of contraction, since intracellular calcium ions are responsible for initiating the shortening of muscle cells.

      The disturbances of rhythm that may be caused by cardiac glycosides result partly from the depolarization and partly from the increase in intracellular calcium. Because these rhythm disturbances are caused by the same underlying mechanism that causes the beneficial effect, there is no likelihood of finding a cardiac glycoside with a significantly better margin of safety. Apart from their cardiac actions, these glycosides tend to cause nausea and loss of appetite. Because digoxin and digitoxin have long plasma half-lives (two and seven days, respectively), they are liable to accumulate in the body. Treatment with either of these drugs must involve careful monitoring to avoid the adverse effects that may result from their slow buildup in the body.

      The second type of inotropic agents that increase the force of cardiac muscle contraction includes dobutamine. Administered intravenously in moderate doses, dobutamine will increase contractility without affecting blood pressure or heart rate.

Heart rate
      The heart rate is controlled by the opposing actions of sympathetic and parasympathetic nerves and by the action of epinephrine (epinephrine and norepinephrine) released from the adrenal gland. Norepinephrine, released by sympathetic nerves in the heart, and epinephrine, released by the adrenal gland, increase the heart rate, while acetylcholine, released from parasympathetic nerves, decreases it. A competitive antagonist that acts to inhibit the stimulating action of norepinephrine on the heart is propanolol, which slows the heart and is often used to treat anginal attacks and disturbances of cardiac rhythm. atropine blocks acetylcholine receptors and is used during anesthesia to prevent excessive cardiac slowing.

      Many types of cardiovascular disease lead to disturbances of the cardiac rhythm, a common example being the occurrence of ventricular arrhythmias (arrhythmia) following heart attacks (heart attack). Arrhythmias are undesirable because they compromise the pumping action of the heart and because they can worsen suddenly and lead to cardiac arrest. The regularity of the heartbeat depends on the activity of the pacemaker area, located in the sinoatrial node of the heart, which generates electrical impulses at a frequency of 70 per minute. The rate is regulated by the opposing influences of the sympathetic and parasympathetic nerves and by the action of epinephrine (epinephrine and norepinephrine) released from the adrenal gland. Norepinephrine, released by the sympathetic nerves in the heart, and epinephrine, released by the adrenal gland, increase the heart rate, while acetylcholine, released from the parasympathetic nerves, decreases it. The impulse from the pacemaker spreads in an orderly sequence to the rest of the heart, resulting in a contraction of the atrial chambers, forcing the blood in these chambers into the ventricles. This is followed about 0.3 second later by contraction of the ventricles, the main pumping chambers, which forces the blood into the arteries.

      The cardiac rhythm can be disturbed in several ways: (1) The conduction pathway may be disorganized, resulting in a reentrant rhythm in which an impulse circulates continuously in a local area of the heart (often a damaged region), causing irregular reexcitation of the rest of the heart at an abnormally high rate. When this happens in the atria, it is called atrial fibrillation, and the ventricular beat continues, though sometimes with an irregular rhythm. When this irregular heart rate occurs in the ventricles, it is called ventricular fibrillation, (ventricular fibrillation) and the pumping action of the heart ceases. (2) Ectopic, or abnormally placed, pacemakers may appear in regions of the heart other than the sinoatrial node, and these can drive the heart at an abnormally high rate. (3) Various forms of heart block can occur, in which the impulse fails to continue in the heart at some point because of local damage. This results in slowing or complete cessation of the heartbeat.

      Drugs are useful in treating all these types of arrhythmia. Reentrant rhythm and ectopic pacemakers cause abnormally high heart rates ( tachycardia), and they require treatment with drugs that slow the heart and reduce the electrical excitability of the muscle cells. Reentrant rhythms can be eliminated by increasing the refractory period of the cells, which is the interval following transmission of an electrical impulse during which the cell cannot be reexcited by another impulse. Increasing the refractory period has the effect of reducing the frequency at which impulses can be transmitted.

       quinidine, procainamide, lidocaine, and phenytoin exert their antiarrhythmic effects by reducing electrical excitability. Quinidine and procainamide have the disadvantage that they reduce the force of contraction of the heart and tend to lower blood pressure. They are also liable to cause side effects such as nausea and skin rashes. lidocaine, which is also used as a local anesthetic, has a very short duration of action and must be given intravenously; its main use is in the prevention of ventricular arrhythmias following acute occlusion (blockage) of a coronary artery.

      An important factor tending to exacerbate ectopic pacemakers is the release of norepinephrine from sympathetic nerves. Norepinephrine acts on β-adrenoceptors in the heart to increase its rate, which strongly increases the tendency for ectopic pacemakers to develop. Beta-adrenoceptor-blocking drugs (e.g., propranolol), commonly known as beta-blockers (beta-blocker), are widely used to control these types of arrhythmia because they slow the actions of the heart. They also tend to reduce the force of contraction of the heart, which can be a disadvantage, and they produce various other unwanted effects.

      In the mid-1970s the calcium channel blockers, another type of antiarrhythmic drug, were introduced. Verapamil and diltiazem are important examples of this class of drugs. They reduce the influx of calcium ions through the cell membrane, which normally occurs when the cell is depolarized. This movement of calcium ions across the membrane appears to be important in the genesis of reentrant rhythms and ectopic heartbeats. Inhibiting the influx of calcium ions is effective in controlling many types of arrhythmia. Since calcium entry is essential for initiating the contraction of heart muscle cells, calcium channel blockers tend to impair muscle contractility. Since calcium entry is also important in the contraction of blood vessel smooth muscle, these drugs cause vasodilation and tend to lower arterial blood pressure.

      All the antiarrhythmic drugs discussed so far impair the conduction of the impulse for contraction from atria to ventricles and therefore can cause heart block. Antiarrhythmic drugs should be used carefully to avoid the various hazards and side effects that they may produce. Heart block causes a pathological slowing of the heart and is not usually treated with drugs, although β-adrenoceptor agonists such as isoproterenol are sometimes used in emergencies. An artificial electrical pacemaker device is usually fitted to provide effective long-term control.

Drugs affecting the blood vessels (blood vessel)
      Drugs affect blood vessels (blood vessel) by altering the state of contraction of the smooth muscle in the vessel wall, altering its diameter and thereby regulating the volume of blood flow. Such drugs are classified as vasoconstrictors when they cause the smooth muscle lining to contract and vasodilators when they cause it to relax. Drugs may act directly on the smooth muscle cells, or they may act indirectly—for example, by altering the activity of nerves of the autonomic nervous system that regulate vasoconstriction or vasodilation (see the section Autonomic nervous system drugs (drug)). Another type of indirect mechanism is the action of vasodilator substances that work by releasing a smooth muscle relaxant substance from the cells lining the interior of the vessel. Some drugs mainly affect arteries (artery), which control the resistance to blood flow in the vascular system, an important determinant of the arterial blood pressure; others mainly affect the veins (vein), which control the pressure of blood flowing back to the heart and hence the cardiac output (i.e., the volume of blood pumped out by the heart per minute).

      Apart from the actions of the autonomic nervous system, several other physiological mechanisms regulate vascular smooth muscle. Of particular pharmacological importance are the renin-angiotensin system and locally acting vasodilator substances, such as histamine, bradykinin, prostaglandins, and nitric oxide.

       renin is an enzyme that is released into the bloodstream by the kidney when the blood pressure falls. It acts on a plasma protein to produce a peptide, angiotensin I, which consists of a chain of 10 amino acids. This in turn is acted on by angiotensin converting enzyme (ACE) to produce an eight-amino-acid peptide, angiotensin II (a potent vasoconstrictor), which raises the blood pressure. ACE inhibitors, which block the formation of angiotensin II, are used in treating high blood pressure ( hypertension), which is produced by excessive constriction of the small arteries. Drugs that block the binding of angiotensin II to its receptor can also be used.

      Other drugs used in the treatment of hypertension include methyldopa and clonidine, which probably work at the level of the central nervous system; adrenoceptor-blocking drugs (e.g., propranolol, which lowers blood pressure by reducing the cardiac output, and prazosin, which blocks the vasoconstrictor action of norepinephrine); calcium channel blockers (e.g., nifedipine); and nitrates (e.g., nitroglycerin tablets). Hypotensive drugs, particularly nitroglycerine tablets and calcium channel blockers, are often used to relieve angina pectoris, a pain that occurs when the blood supply to the heart is inadequate for its needs. Angina often is the result of partial occlusion of the coronary vessels by fatty deposits (atheroma) or blood clots. Hypotensive drugs reduce arterial blood pressure and cardiac output, thereby lowering the work and oxygen consumption of the heart. They also have some effect on the coronary vessels themselves, and many direct blood toward the regions in which the flow is impaired.

      Most antihypertensive drugs have a variety of unwanted effects, such as drowsiness, dizziness on standing (due to an excessive postural fall in arterial pressure), impotence, and allergic reactions. Though often fairly minor, side effects are a serious problem because of the long-term nature of antihypertensive therapy, and better drugs are constantly being sought.

Humphrey P. Rang Janet L. Stringer

Drugs affecting blood
      When a small blood vessel is cut, a repair mechanism (hemostasis) is activated that eventually seals the cut and prevents further blood loss. What is in fact a lifesaving mechanism that protects the wounded body from hemorrhage becomes life-threatening when clots (thrombi) form within functional blood vessels ( thrombosis). Thrombosis tends to occur in blood vessels damaged by atherosclerosis or in vessels with a sluggish blood flow. In veins, portions of the thrombi (emboli) may break off and pass along the bloodstream to become lodged in the arteries of the heart. The drugs described in this section inhibit hemostasis.

      The clotting (coagulation) process essentially involves the conversion of a soluble plasma protein, fibrinogen, into strands of the insoluble protein fibrin, which forms a mesh that traps platelets. The trigger for hemostasis is an injury to the endothelium, the cells lining the blood vessels, so that the underlying layer of collagen is exposed. The series of events leading to clot formation in a cut blood vessel are (1) constriction of the blood vessel by serotonin, epinephrine (epinephrine and norepinephrine), and the thromboxane A2, which diminishes blood loss, (2) formation of a plug of platelets (the platelet phase) by adenosine diphosphate (ADP) and thromboxane A2, also released by platelets, which act in a positive feedback process that makes more platelets adhere to the collagen and to each other, and (3) the conversion of the plug into a clot of fibrin (the coagulation phase). The formation of fibrin entails the sequential interaction of more than a dozen clotting factors, which are protease enzymes (i.e., they accelerate the breakdown of proteins). Each of these clotting factors activates the next in a coagulation cascade of proteolytic reactions that break down protein molecules. The penultimate reaction is the conversion of the soluble fibrinogen to soluble fibrin under the influence of the enzyme thrombin (factor IIa). Soluble fibrin is converted to insoluble fibrin strands by activated factor XIII (fibrin-stabilizing factor), and covalent cross-linkages form between the fibrin strands to give a strong and rigid network. Several of the clotting factors (II, VII, IX, X) require the presence of vitamin K for their activation. Consequently, inhibition of vitamin K blocks the propagation of coagulation pathways.

      Under normal conditions the adhesion of platelets to vessel walls is prevented by the vascular endothelial cells, at least in part by their ability to release prostaglandins called prostacyclin or prostaglandin I2, which reduce platelet stickiness and cause dilation of the blood vessels.

Anticoagulants (anticoagulant)
      Anticoagulant drugs prevent the formation of thrombi by inhibiting the coagulation phase. They are used to prevent the formation and spread of venous and arterial thrombi; however, they are ineffective against existing thrombi. Anticoagulant therapy is used to treat deep-vein thrombosis and pulmonary (pulmonary embolism) embolism arising after immobilization or surgery; systemic or coronary arterial embolism caused by heart diseases or replacement of the prosthetic valve; and disseminated intravascular coagulation, which is a systemic activation of the coagulation system that leads to consumption of coagulation factors and hemorrhage.

       heparin, used primarily in hospitalized patients, is a mixture of negatively charged mucopolysaccharides. An endogenous substance whose physiological role is not understood, heparin blocks the coagulation cascade by promoting the interaction of a circulating inhibitor of thrombin (antithrombin III) with activated clotting factors. Because it is not well absorbed from the gastrointestinal tract, heparin is given intravenously to inhibit coagulation immediately, or it is given subcutaneously. Heparin is not bound to plasma proteins, it is not secreted into breast milk, and it does not cross the placenta. The drug's action is terminated by metabolism in the liver and excretion by the kidneys. The major side effect associated with heparin is hemorrhage; thrombocytopenia (reduced number of circulating platelets) and hypersensitivity reactions also may occur. Oral anticoagulants and heparin have additional anticoagulant effects. Heparin-induced hemorrhage may be reversed with the antagonist protamine, a positively charged protein that has a high affinity for heparin's negatively charged molecules, thus neutralizing the drug's anticoagulant effect.

      Oral anticoagulants are derivatives of coumarin or indandione. Structurally, the coumarin derivatives resemble vitamin K, an important element in the synthesis of a number of clotting factors. Interference in the metabolism of vitamin K in the liver by coumarin derivatives gives rise to clotting factors that are defective and incapable of binding calcium ions (another important element in the activation of coagulation factors at several steps in the coagulation cascade). When anticoagulants are taken orally, several hours are required for the onset of the anticoagulant effect because time is required both for their absorption from the gastrointestinal tract and for the clearance of biologically active clotting factors from the blood. Warfarin, the most commonly used oral anticoagulant, is rapidly and almost completely absorbed.

      Oral anticoagulants bind extensively to plasma proteins, have relatively long plasma half-lives, and are metabolized by the liver and excreted in the urine and feces. They may cross the placenta to cause fetal abnormalities or hemorrhages in newborns; however, their appearance in breast milk apparently has no adverse effect on nursing infants. Hemorrhage is the principal toxic effect during oral anticoagulant therapy. Vitamin K, when given intravenously to promote the synthesis of functional clotting factors, stops bleeding after several hours. Plasma that contains normal clotting factors is given to control serious bleeding. Oral anticoagulants may interact adversely with other drugs that bind to plasma proteins or are metabolized by the liver.

Drugs affecting platelets (platelet)
      Platelet aggregates and thrombi formed in coronary arteries may cut off the blood supply to a region of the heart and cause a myocardial infarction (heart attack). When administered during a heart attack, drugs affecting platelets can reduce the extent of damage to the heart muscle and the incidence of immediate reinfarction and death.

      Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit an enzyme (cyclooxygenase) involved in the production of thromboxane A2 in platelets and of prostacyclin in the endothelial cells that line the heart cavities and walls of the blood vessels. Cyclooxygenase is synthesized by endothelial cells but not by platelets. The goal of NSAID therapy is to neutralize cyclooxygenase only in platelets, which inhibits thromboxane A2 synthesis and therefore platelet aggregation, but to continue the production of cyclooxygenase and prostacyclin in endothelial cells. The occurrence of coronary embolization and the incidence of acute myocardial infarction and death also are reduced with the administration of low-dose aspirin therapy.

      Dipyridamole, a coronary artery vasodilator, decreases platelet adhesiveness to damaged endothelium. The drug prevents platelet aggregation and release by increasing the concentration of platelet cyclic adenosine monophosphate (cAMP) in two ways: by inhibiting an enzyme (phosphodiesterase) that degrades cAMP and by increasing the stimulating effect of prostacyclin on an enzyme (adenylate cyclase) that synthesizes cAMP. Dipyridamole alone does not reduce the incidence of death following myocardial infarction, but it works effectively in combination with other inhibitors of platelet function or with anticoagulants.

      Other antiplatelet drugs, including ticlopidine, abciximab, eptifibatide, and tirofiban, bind to various receptors found on the surface of platelets that must be stimulated to activate platelets, thus inhibiting platelet aggregation.

Fibrinolytic drugs
      A fibrinolytic system that exists in the body restricts thrombus propagation beyond the site of injury and is also involved in the lysis, or dissolution, of clots as wounds heal. The fibrinolytic system degrades fibrin and fibrinogen to products that act to inhibit the enzyme thrombin. The active enzyme involved in the fibrinolytic process is plasmin, which is formed from its precursor, plasminogen, under the influence of an activating factor released from endothelial cells. If formed in the circulating blood, plasmin is normally inhibited by a circulating plasmin inhibitor.

      Fibrinolytic drugs (also known as thrombolytic drugs) activate the fibrinolytic pathway and lyse clots. The fibrinolytic drugs are distinct from the coumarin derivatives and heparin. One fibrinolytic drug is streptokinase, which is produced from streptococcal (Streptococcus) bacteria. When administered systemically, streptokinase lyses acute deep-vein, pulmonary, and arterial thrombi; however, the drug is less effective in treating chronic occlusions (blockages). When administered intravenously soon after a coronary occlusion has formed, streptokinase is effective in reestablishing the flow of blood through the heart and vessels after a heart attack and in limiting the size of the area of infarct (tissue death). Streptokinase can also be administered directly into the coronary blood vessels to deliver a high dose directly to the site of the clot. Heparin, aspirin, dipyridamole, or a combination of these three drugs can be added to therapy to help prevent the recurrence of occlusive clots. An overdose of streptokinase may lead to bleeding from systemic fibrinogenolysis, which is the breakdown of the coagulation factors by plasmin.

      Urokinase, a protease enzyme that activates plasminogen directly, is obtained from tissue culture of human kidney cells. Urokinase lyses recently formed pulmonary emboli and, compared with streptokinase, it produces fibrinolysis without extensive breakdown of the coagulation factors.

      Tissue plasminogen activator (t-PA) stimulates fibrinolysis, and it has several important advantages over streptokinase and urokinase in treating coronary thrombosis. It binds readily to fibrin and, after intravenous administration, activates only the plasminogen that is bound to the clot; thus, fibrinolysis occurs in the absence of an extensive breakdown of the coagulation factors. It may be used to initiate treatment of heart attack victims en route to the hospital, eliminating the time spent in the hospital preparing the patient for intracoronary injections of streptokinase. This is extremely useful because the rapid reestablishment of coronary blood flow is critically important to minimize the amount of damage to the heart after a heart attack.

      An elevation in the level of circulating plasmin due to excessive activation of the fibrinolytic system may result in fibrinogenolysis and hemorrhage. The antifibrinolytic drug aminocaproic acid is a specific antagonist of plasmin and inhibits the effects of fibrinolytic drugs.

Jeffrey S. Fedan

lipid-lowering drugs
      The incidence of coronary artery disease, heart attacks, and strokes is correlated with the levels of lipoprotein particles in the blood. Lipoproteins are macromolecules that contain both lipids (e.g., cholesterol, triglycerides, phospholipids) and proteins. HMG-CoA reductase inhibitors (e.g., simvastatin, pravastatin, lovastatin), also called statins, inhibit the enzyme HMG-CoA, which is required for the synthesis of cholesterol. Statins are generally quite safe, but side effects may include muscle pain and fatigue.

       bile acids, which aid in the digestion of fats, are produced in the liver from cholesterol. Bile acid sequestrants (resins) bind bile acids in the small intestine, and the drug–bile acid complex is carried out of the body. To compensate, more cholesterol is converted to bile acids, which also bind to resins and are excreted, eventually resulting in a decrease in the level of cholesterol in the blood. These drugs (e.g., cholestyramine and colestipol) can affect the absorption of the fat-soluble vitamins, so a supplement may be necessary.

       niacin (nicotinic acid) is one of the oldest drugs used to treat increased plasma lipid levels. Its use is limited by side effects, particularly flushing of the skin on the face and upper trunk. Niacin in large amounts can also cause liver dysfunction and liver failure.

Anti-anemic drugs
       anemia is a disorder in which red blood cells are reduced in number or are deficient in hemoglobin, a protein that transports oxygen to the tissues of the body. Iron salts, such as ferrous sulfate, are used to treat iron-deficiency anemia (iron deficiency anemia), which occurs when the body is deficient in iron, an essential component of hemoglobin. folic acid and 12 (vitamin B12) are used to treat anemias that are due to deficiencies of these vitamins, also necessary for red blood cell formation (see folic acid deficiency anemia).

Janet L. Stringer

Digestive system (digestive system disease) drugs
       gastrointestinal system drugsDrugs may act on the digestive system (digestive system, human) either by affecting the actions of the involuntary muscle (motility) and thus altering movement or by altering the secretion of digestive juices or gastric emptying. Some common digestive system drugs are listed in the table (gastrointestinal system drugs).

Antidiarrheal drugs
       diarrhea is the frequent passage of a watery, loose stool. Its causes range from serious organic disease to mental stress. In the treatment of diarrhea, kaolin powder is the most widely used adsorbent powder. Kaolin is a naturally occurring hydrated aluminum silicate, which is prepared for medicinal use as a fine powder. It is not harmful, and it is effective in many cases if taken in doses that are large enough (e.g., an initial dose of 2 to 10 grams followed by the same amount after every bowel movement).

       morphine, codeine, and the synthetic opioids (narcotic) and their analogs have a constipating action (morphine was used for this effect long before it was used as a painkiller). The dangers of dependency and addiction clearly prevent the use of certain opioids (e.g., morphine, meperidine, and heroin) as a treatment for diarrhea. Other opioids (codeine and the synthetic analogs diphenoxylate and loperamide) produce little dependence, however, and they have been used successfully in the treatment of the condition.

Laxatives (laxative)
      There are four kinds of medication available for relief of constipation: saline purgatives, fecal softeners, contact purgatives, and bulk laxatives.

      Saline purgatives are salts containing highly charged ions that do not readily cross cell membranes and therefore remain inside the lumen, or passageway, of the bowel. By retaining water through osmotic forces, saline purgatives increase the volume of the contents of the bowel, stretching the colon and producing a normal stimulus for contraction of the muscle, which leads to defecation. Some commonly used salts are magnesium sulfate (Epsom salts), magnesium hydroxide (milk of magnesia), sodium sulfate (Glauber salt (Glauber's salt)), and potassium sodium tartrate ( Rochelle salt or Seidlitz powder).

      Fecal softeners are not absorbed from the gastrointestinal tract and act to increase the bulk of the feces. Liquid paraffin ( mineral oil) can be used either as the oil itself or as a white emulsion. Other fecal softeners have a detergent action that increases the penetration of the stool by water.

      Contact purgatives include the anthraquinone derivatives (cascara, aloe, senna, and rhubarb), phenolphthalein, and ricinoleic acid ( castor oil). Although their exact mechanism of action is unknown, these drugs irritate the lining of the bowel, which may account for their effect. After regular use, their effect tends to lessen, so that larger and more frequent doses are necessary until finally they cease to be effective. They are useful, however, when short-term purging is required (e.g., before surgery or after an illness).

      Bulk laxatives act by increasing the size of the feces, in part because of their capacity to attract water. This group includes methylcellulose and carboxymethylcellulose, the gums agar and tragacanth, psyllium ( Plantago) seed, and dietary fibre.

      Emetics produce nausea and vomiting, and their use is limited to the treatment of poisoning with certain toxins that have been swallowed. The most commonly used drug for this purpose is ipecac syrup, prepared from the dried roots of Cephaelis ipecacuanha, a plant indigenous to Brazil and Central America.

      Antiemetics are drugs that prevent vomiting. Broadly, they may be divided into two groups: drugs that are effective in combating motion sickness and drugs that are effective against nausea and vomiting due to other causes. The exact way in which these drugs work is not known, although they may act by depressing the chemoreceptor trigger zone in the hypothalamus that controls vomiting.

      Anticholinergic drugs and antihistamines are effective against motion sickness. Although many are available for use, none is entirely free from side effects (e.g., dry mouth and blurred vision with the anticholinergics, drowsiness with the antihistamines). The most effective drugs in this group are the anticholinergic drug scopolamine and the antihistamine promethazine.

      Nausea and vomiting other than that associated with motion sickness are present in many diseases—e.g., radiation sickness, postoperative vomiting, and liver disease. In these cases, the most effective antiemetics are the phenothiazines (phenothiazine) (also used in psychiatric medicine) and metoclopramide. Serotonin antagonists, such as ondansetron, have proved effective in the prevention of nausea and vomiting associated with cancer chemotherapy.

Proton pump inhibitors
      Acid peptic disorders include gastroesophageal reflux disease (GERD), peptic ulcers (peptic ulcer) of the stomach and duodenum, and ulcers (ulcer) secondary to the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Duodenal and gastric ulcers and possibly gastric cancer are caused by an infection of the upper gastrointestinal tract with the bacterium Helicobacter pylori. The treatment of peptic ulcer disease targets eradication of this bacteria with a combination of antibiotics and acid reduction.

      The most effective suppressors of gastric acid secretion are the proton pump inhibitors (e.g., omeprazole, lansoprazole, rabeprazole). These agents inhibit an enzyme in the parietal cells of the stomach that exchanges acid for potassium ions, which results in a decrease in acid secretion into the stomach. The proton pump inhibitors are used in the treatment of erosive esophagitis and peptic ulcer disease. When given in sufficient dosage, these drugs can reduce acid secretion by more than 95 percent.

H2 blockers
      Another class of drugs that blocks gastric acid secretion is the H2 blockers (see below Histamine and antihistamines (drug)). These drugs (e.g., cimetidine, ranitidine) prevent histamine-induced acid release and are used for short-term treatment of gastroesophageal reflux and, in combination with antibiotics, for peptic ulcer disease.

Antacids (antacid)
      Excess acid may be neutralized in the stomach with antacid tablets. The main constituents of antacids are aluminum and magnesium hydroxides. There are three side effects of antacid therapy, which depend on the compound used. First, many have an action on the bowel: some have a mild laxative effect, and some are constipating. Second, if the positively charged compounds are absorbed, the blood may be made alkaline. Third, antacids may affect the absorption of other drugs by binding with them in the gastrointestinal tract.

Mucosal protective agents
      The mucosal barrier is the name given to the barrier in the stomach that resists the back-diffusion of hydrogen ions. The barrier is a layer of thick mucus secreted together with an alkaline fluid. Since the mucus is a gel, it entraps the alkaline fluid so that the stomach is coated. Sucralfate, a polymer of sucrose with aluminum hydroxide, forms a protective coating on the mucosal lining, particularly in ulcerated areas. In the presence of acid, it becomes a gel that adheres to epithelial cells and ulcer craters. Sulcralfate is only minimally absorbed and can cause constipation.

      Misoprostal is a prostaglandin analog that increases release of bicarbonate and mucin (a component of mucus) and reduces acid secretion by binding to prostaglandin receptors on parietal cells. Because NSAIDs inhibit prostaglandin formation, providing a synthetic prostaglandin such as misoprostal is a rational approach to reducing NSAID-induced damage.

Margaret Ann Sumner Janet L. Stringer

Reproductive system (reproductive system, human) drugs
      Several sites in the reproductive system (reproductive system, human) either are vulnerable to chemicals or can be manipulated by drugs. Within the central nervous system, sensitive sites include the hypothalamus (and adjacent areas of the brain) and the anterior lobe of the pituitary gland. Regions outside the brain that are vulnerable include the gonads (i.e., the ovaries (ovary) in the female and the testes (testis) in the male), the uterus in the female, and the prostate gland in the male.

      The body has anatomic or physiological barriers that tend to protect the reproductive system. The so-called placental barrier and the blood-testis barrier impede certain chemicals, although both allow most fat-soluble chemicals to cross. Drugs that are more water-soluble and that possess higher molecular weights tend not to cross either the placental or the blood-testis barrier. In addition, if a drug binds to a large molecule such as a blood-borne protein, it is less likely to be transported into the testes or less likely to come in contact with the fetus. If the fetus is exposed in the uterus to certain drugs, it may develop abnormalities; those toxic substances are described as teratogenic (teratology) (literally, “monster-producing”). About 3 percent of developmental abnormalities have been proved to be drug-induced. It is wise to avoid all drugs (including nicotine) during pregnancy, unless the medicine is well-tried and essential. Drugs taken by males may be teratogenic if they damage the genetic material (chromosomes) of the spermatozoa. There appears to be little, if any, barrier to chemicals or drugs gaining entry to breast milk or semen.

Oral contraceptives
      Oral contraceptives (contraception), or birth control pills, constitute a class of synthetic steroid hormones that suppress the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior lobe of the pituitary gland in the female body. Known collectively as gonadotrophic hormones, FSH and LH stimulate the release of progesterone and estrogen from the ovaries; all these hormones are responsible for modulating the menstrual cycle (menstruation). ovulation is believed to be related to a mid-cycle release of LH, which can be effectively suppressed or blocked by the systematic administration of synthetic hormones. There are many commercial preparations of oral contraceptives, but most of them contain a combination of an estrogen (usually ethinyl estradiol) and a progestin (commonly norethindrone). In general, oral contraceptives are taken in a monthly regimen that parallels the menstrual cycle. Protection from pregnancy is often unreliable until the second or third drug cycle, and during this time certain side effects such as nausea, breast tenderness, or bleeding may be evident. More serious side effects, including blood clots and a rise in blood pressure, are possible, especially in women over 34 years of age. However, the incidence of side effects from oral contraceptives has been significantly reduced by decreasing the amounts of estrogen and progesterone in the preparations. Normal ovulation usually commences two to three months after the drug is stopped.

      Progestin-only preparations (the so-called Minipill) thicken the mucus lining the cervix and make it more acidic, thereby rendering it hostile to spermatozoa. Progestin-only preparations are somewhat less reliable than the combination preparations but produce fewer side effects. Under certain circumstances, the progestin may be administered as an intramuscular deposit that gradually releases the hormone over the course of one to three months.

Antiestrogens and antiprogestins
      Estrogen can be both a beneficial and a harmful hormone. It maintains skeletal strength by preventing the loss of bone and enhancing calcium retention. However, estrogen causes the proliferation of cells in the breast and the uterus, which can increase a woman's chance of developing cancer at these sites. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, produce estrogen action in those tissues (e.g., bone, brain, liver) where that action is beneficial and have either no effect or an antagonistic effect in tissues, such as the breast and uterus, where estrogen action may be harmful. Tamoxifen is used in the prevention and treatment of breast cancer. Raloxifene, used in the prevention and treatment of osteoporosis (the loss of bone mass) in postmenopausal women, also acts as an estrogen agonist in reducing total and low-density lipoprotein (LDL) cholesterol. Adverse effects of raloxifene include hot flashes, leg cramps, and increased risk of deep-vein thrombosis and pulmonary embolism.

      Antiestrogens are antagonists at all estrogen receptors. Clomiphene can be used as a fertility drug to stimulate ovulation in some women who are otherwise unable to become pregnant. It interferes with the inhibitory feedback of estrogens on the pituitary. This results in an increase in FSH and LH release which, in turn, stimulate ovarian function.

      Antiprogestins are used for contraception, labour induction, and treatment of endometriosis and breast cancer. Mifepristone was the first antiprogestin to be described. Under such trade names as RU-486, it is effective at inducing abortion (see below).

      An abortifacient is any drug or chemical preparation that induces abortion. For centuries, herbal abortifacients have been made from infusions or oils of plants such as pennyroyal (Mentha pulegium), angelica (Angelica species), and tansy (Tanacetum vulgare). Such preparations are no more likely to terminate a pregnancy than they are to induce potentially lethal reactions such as vomiting, hemorrhages, and convulsions in the women who take them. Truly effective abortifacients were not developed until the end of the 20th century, when the biochemical processes behind cell division and growth and the role of hormones in reproductive processes were understood. The most common agents of medical abortion today are mifepristone, a steroid, and methotrexate, an antimetabolite; both are used during the early weeks of pregnancy in conjunction with the synthetic prostaglandin misoprostol.

      Misoprostol, administered in prescribed doses either orally or as a vaginal suppository, causes the uterus to contract much as it would at the beginning of labour or during a miscarriage. Taken alone, it is rarely sufficient to expel the embryo and placenta from the uterus, but as a sequel to treatment with mifepristone or methotrexate it is very effective. mifepristone (frequently referred to by its original trade name, RU-486) acts as a competitive receptor antagonist for progesterone, preventing that hormone from stimulating the inner lining of the uterus to prepare for implantation by a fertilized ovum. When administered early in pregnancy, mifepristone causes the breakdown of the uterine lining; a follow-up dose of misoprostol induces expulsion of the embryo and other uterine contents. Methotrexate, administered by injection, blocks the rapid cell division characteristic of embryonic and placental growth. Once this growth is ended, administration of misoprostol completes the abortion.

John A. Thomas Janet L. Stringer

Androgens (androgen) and antiandrogens
       testosterone is the principal androgen in males. Secreted by cells in the testes (testis) in response to luteinizing hormone released from the pituitary gland, testosterone can directly bind to androgen receptors and is converted in some tissues to dihydrotestosterone, which also binds to androgen receptors. Activation of androgen receptors results in differentiation of the external genitalia, increased hair growth during puberty, and stimulation of the prostate gland. Testosterone also contributes to the mass and strength of skeletal muscle, which explains the abuse of androgen analogs (steroids) by some athletes. Testosterone is also converted to estrogen, which then binds to estrogen receptors and mediates closure of the epiphyses in the bone. The major condition for which testosterone is used therapeutically is male hypogonadism. Because it is metabolized completely in the liver, testosterone is usually administered transdermally.

      A number of drugs have antiandrogenic effects. Some were designed for this purpose, but others were developed for some other therapeutic goal. For example, ketoconazole, an antifungal drug, blocks the synthesis of steroids, including testosterone and cortisol. Spironolactone, a diuretic, is also a weak inhibitor of the androgen receptor and a weak inhibitor of testosterone synthesis. Androgen-receptor antagonists can be used in combination with a gonadotropin-releasing hormone (GnRH) analog in the treatment of metastatic prostate cancer.

      In some tissue, testosterone is converted to dihydrotestosterone by an enzyme called 5-alpha-reductase. An inhibitor of this enzyme, finasteride, was designed as a treatment for benign prostatic hypertrophy. When it is administered to men with moderately severe symptoms, urine flow increases and prostatic volume decreases. Impotence is an infrequent side effect of the use of finasteride, which is also approved for the topical treatment of male pattern baldness.

Anti-impotence drugs
      Erectile dysfunction, or impotence, is a disorder in which a man cannot achieve or maintain erection of the penis. A novel means of relieving this disorder is found in the category of oral drugs known as phosphodiesterase-5 (PDE-5) inhibitors. PDE-5 inhibitors (PDE-5 inhibitor) such as sildenafil (Viagra™) and vardenafil (Levitra™) work by enhancing the effects of nitric oxide, a chemical that, upon sexual arousal, is normally produced by cells in the corpus cavernosum, a column of erectile tissue that is part of the body of the penis. The nitric oxide stimulates the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP), which leads to relaxation of the smooth muscle of the corpus cavernosum. The increased flow of blood through the corpus cavernosum causes an erection. Under normal circumstances cGMP is inactivated by the enzyme PDE-5. PDE-5 inhibitors block this enzyme, thus bringing about increased and prolonged levels of cGMP. The drugs have some significant side effects, the most dangerous of which is an interaction with nitrates (e.g., nitroglycerin), another class of drugs used to relax smooth muscle. Nitrates are converted into nitric oxide, which produces a further increase in cGMP; in the presence of sildenafil and vardenafil, the nitrates can produce a significant decrease in blood pressure.

Janet L. Stringer

Endocrine system (endocrine system, human) drugs
      Control of most body functions is achieved by the nervous system and the endocrine system, which constitute the two main communication systems of the body. They function in a closely coordinated way, each being dependent on the other for its proper operation. The total behaviour of the organism is integrated by a constant traffic of both neural and hormonal (hormone) signals, which are received and responded to by appropriate tissues. The activities of the central nervous system and of the endocrine glands are themselves dependent on feedback control through neural and hormonal stimuli. This control is related to the toxicity of hormones when used therapeutically, because prolonged use of certain hormones or their analogs in this way may quell, sometimes irreversibly, the appropriate gland's output of endogenous hormone.

      The natural hormones belong to only a few chemical classes. Most are polypeptides, some are derivatives of amino acids (epinephrine, norepinephrine, dopamine, or thyroid hormones), and some are steroids (the sex hormones and the hormones of the adrenal cortex). Polypeptide and amino acid hormones bring about their effects by acting on cell membrane receptors that are specifically sensitive to their action. Steroid hormones penetrate the cell membrane and interact with receptors on specific binding proteins, which then act on the cell nucleus to modify protein synthesis. The techniques (genetics) of recombinant DNA technology have begun to provide improved methods for obtaining large amounts of scarce human hormones in pure form.

      The functions of hormones fall into three general categories: (1) morphogenesis, which is a process that uses hormones to regulate the growth, differentiation, and maturation of the organism (e.g., the development of secondary sex characteristics under the influence of ovarian or testicular hormones), (2) homeostasis, or metabolic regulation, in which hormones are used to maintain a dynamic equilibrium of the components of the body, such as fats, carbohydrates, proteins, electrolytes, and water, and (3) functional integration, whereby hormones regulate or reinforce functions of the nervous system and patterns of behaviour (e.g., the influence of sex hormones on sexual activity and maternal behaviour).

      The endocrine system comprises the anterior and posterior lobes of the pituitary gland, the adrenal glands, the pancreas, the gonads (ovaries and testes), and the thyroid and parathyroid glands. Several of the endocrine glands (thyroid, adrenal cortices, ovaries, and testes) are under the control of the hormones of the anterior lobe of the pituitary gland. The hormones that are released to control the actions of other hormones are called trophic hormones. The release of trophic hormones is under the control of neurons of the hypothalamus, and it is mainly at this level that integration of the activities of the nervous and endocrine systems takes place.

      The therapeutic use of hormones is concerned primarily with replacement therapy in deficiency states (e.g., deficiency of glucocorticoids in Addison disease). Hormones and their analogs and antagonists, however, can be used for a variety of additional purposes—e.g., topical corticosteroids to control dermatitis and oral contraceptives to control ovulation.

Pituitary hormones
      The pituitary gland (also called the hypophysis) is situated at the base of the brain. The gland itself is composed of three distinct lobes: the anterior lobe (also called the adenohypophysis), the posterior lobe (also called the neurohypophysis), and the intermediate lobe (or pars intermedia). The pituitary gland is connected by a bridge, the pituitary stalk, through which it receives its blood supply and many neurohumoral and hormonal signals from the region of the brain known as the hypothalamus. Neurotransmitters (neurotransmitter) are chemical signals produced by nerve cells, and hormones are produced by endocrine glands; both act in different ways to affect the endocrine system. Hormones emanating from the hypothalamus, called hypothalamic-releasing hormones, affect the secretion or release of hormones stored in the anterior lobe of the pituitary. For each anterior pituitary hormone there is an appropriate corresponding hypothalamic-releasing hormone. Some clinically important trophic hormones of the anterior pituitary gland are growth hormone (GH, also called somatotropin), prolactin, thyrotropin (thyroid-stimulating hormones, or TSH), and adrenocorticotropin (adrenocorticotrophic hormone, or ACTH).

      The posterior pituitary gland secretes two hormones, oxytocin and vasopressin. Vasopressin is also called antidiuretic hormone (ADH) since one of its physiological actions is exerted on the kidney, leading to a reduction in urinary output. Oxytocin and ADH are octapeptides whose secretion is modulated by secretory activities of nerve cells (neurosecretion (neurohormone)) located in specialized regions of the hypothalamus.

      As its name implies, growth hormone (GH; somatotropin) stimulates the growth of cells in the body. It acts not on a specific group of cells or organs but rather on all the cells of the body to promote their growth and proliferation. Growth hormone is a protein hormone whose molecular structure consists of a sequence of 191 amino acids. It stimulates bone growth; hence, it plays an important role in the growing child. The consequence of growth hormone deficiency in children is dwarfism, and it is treated by replacement therapy with human growth hormone produced by recombinant DNA technology. Pituitary tumours can sometimes result in oversecretion of GH, leading to gigantism or acromegaly. An excess of the hormone is treated with synthetic derivatives of GH such as octreotide, which is administered subcutaneously.

      Prolactin, along with other hormones (e.g., oxytocin), acts on cells of the breast to stimulate growth and enhance the secretion of milk ( lactation). Prolactin mediates these hormonal actions through receptors that are located within the mammary glands. Inappropriate or excessive secretion of prolactin may be suppressed by treatment with bromocriptine.

      Thyrotropin (thyroid-stimulating hormone, or TSH) is secreted by the anterior lobe of the pituitary gland upon the command of thyrotropin-releasing hormone (TRH). Through receptors located in the thyroid gland, TSH stimulates the biosynthesis of a thyroid hormone, thyroxine, and other iodine-containing precursors. If TSH causes the thyroid gland to manufacture too much thyroxine, then thyroxine can travel to the pituitary gland and act on receptors that slow down the secretion of TSH and hence TRH. This negative feedback by thyroxine contributes to the body's ability to maintain appropriate levels of the hormones. Thyrotropin is used as a diagnostic test for hypothyroidism.

      Adrenocorticotropin (ACTH), a peptide chain of 39 amino acids, is the smallest of the hormones of the anterior pituitary. Adrenocorticotropin, which is under the central control of corticotropin-releasing factor (CRF), stimulates the cortex of the adrenal gland to produce a variety of corticosteroids that affect electrolyte and water balance (mineralocorticoids) or carbohydrate, fat, and protein metabolism (glucocorticoids). The principal hormonal action of ACTH is to stimulate steroid biosynthesis, especially cortisol. It is used mainly to verify the diagnosis of adrenal insufficiency (Addison disease), but occasionally it is used in nonendocrine disorders that show some response to glucocorticoids (e.g., multiple sclerosis).

       diabetes insipidus is characterized by the excessive production of urine with a high concentration of water, which is a result of the failure of kidney tubules to reabsorb the proper amount of water. A common cause of diabetes insipidus is inadequate production of vasopressin (antidiuretic hormone) by the pituitary gland. The condition may be treated by replacement of vasopressin or by the use of its synthetic analog desmopressin.

       oxytocin occurs naturally as a hormone secreted by the posterior lobe of the pituitary gland, or it can be made synthetically. Physiologically, it promotes the secretion of breast milk and stimulates the contraction of the uterus during labour. Oxytocin may be used to induce labour (parturition), especially when gestation approaches or exceeds 40 weeks. It can also be given to control bleeding after childbirth (parturition), although one of the ergot alkaloids (e.g., methylergonovine) is more commonly used. Oxytocin can be administered intravenously, sublingually, or by nasal spray. It cannot be adminstered orally because it is destroyed in the gastrointestinal tract.

Glucocorticoids and mineralocorticoids
      The adrenal gland is a compound organ situated on top of the kidney. It consists of an outer cortex (adrenal cortex) and an inner medulla (adrenal medulla). The hormones secreted from the cortex are steroids, generally classified as glucocorticoids (e.g., cortisol) and mineralocorticoids (e.g., aldosterone, which causes sodium retention and potassium excretion by the kidney). Those substances emanating from the medulla are amines, such as epinephrine (epinephrine and norepinephrine) and norepinephrine. Epinephrine and norepinephrine are catecholamines, which are present in several cell types in the body and serve as neurotransmitters both in the brain and in the autonomic nervous system. Thus, the adrenal medulla functions with the sympathetic nervous system.

      Glucocorticoids together with mineralocorticoids are used in replacement therapy in acute or chronic adrenal insufficiency ( Addison disease). Glucocorticoids, including a range of synthetic analogs (e.g., prednisolone, triamcinolone, and dexamethasone), are also used as anti-inflammatory and immunosuppressant agents. As anti-inflammatory agents, they are used in the treatment of bronchial asthma. Glucocorticoids indirectly inhibit the activity of phospholipase A2, an enzyme that plays an essential role in the synthesis of prostaglandins and leukotrienes; its inhibition by lipocortin-1 underlies part of the anti-inflammatory effects of glucocorticoids. Glucocorticoids also reduce the synthesis of some proteins that directly mediate the inflammatory response.

Thyroid (thyroid gland) and parathyroid hormones
      Anatomically, there is close proximity between the thyroid (thyroid gland) and the parathyroid gland, yet they have very different hormonal functions and different mechanisms of stimulation. Secretion of thyroxine and triiodothyronine from the thyroid gland is stimulated by TSH, whereas secretion of parathyroid hormone from the parathyroid gland and of calcitonin from the thyroid gland are modulated by circulating levels of calcium and phosphate in the blood.

      Parathyroid hormone (PTH) is a single-chain amino acid molecule secreted by the chief cells of the parathyroid gland. The major regulator of PTH is the level of ionized calcium in the blood. Receptors for PTH are located in bones and in the kidney. The primary function of PTH is to prevent hypocalcemia (lowered blood calcium levels) by stimulating the release of calcium from bone and by increasing the reabsorption of calcium in the kidney. tetany, often characterized by muscle twitching, spasms, and sometimes convulsions, is the result of precariously low levels of blood calcium. Tetany resulting from hypocalcemia can be treated by administering calcium gluconate and vitamin D. A recombinant human PTH called teriparatide stimulates bone formation and can be used in the treatment of osteoporosis. It must be given by daily subcutaneous injection.

       calcitonin is synthesized in the thyroid. It is capable of counteracting the calcium-releasing effects of PTH, because calcitonin reduces blood calcium levels by increasing its deposition in bone and enhancing its excretion in the urine. Calcitonin, which must be administered subcutaneously or by nasal spray, inhibits osteoclastic activity (breakdown of bone) and can be used in the treatment of osteoporosis; it has some analgesic activity, so it may be of benefit in patients with fractures (fracture).

thyroxine and triiodothyronine
       thyroxine (T4) and triiodothyronine (T3) are the major iodine-containing hormones synthesized in the thyroid gland. Their synthesis is stimulated by pituitary thyroid-stimulating hormone (TSH), and iodine is required in their manufacture. The biochemical actions of the thyroid hormones are complex, although their most evident effect is stimulation of cellular metabolism. Both T4 and T3 increase the basal metabolic rate (measure of the minimum number of calories needed to sustain only the activities essential to life) and are calorigenic (energy-producing).

      Thyroid deficiency ( hypothyroidism) in newborns can lead to cretinism, which is characterized by mental retardation. In adults, hypothyroidism leads to a condition called myxedema, which is characterized by intolerance to cold, lethargy, poor appetite, and constipation. Synthetic levothyroxine, an orally active form of T4, is used to treat hypothyroid conditions in both infants and adults. T4 is metabolized to T3 throughout the body.

Antidiabetic drugs
      The pancreas has both an endocrine function (secretion of insulin and glucagon) and a digestive function. One of the important physiological actions of insulin is to control levels of blood sugar ( glucose). This carbohydrate is an important nutrient for cellular metabolism, and the cell must receive neither too little nor too much. A deficiency in the pancreatic secretion of insulin, or lack of tissue sensitivity to the hormone, leads to diabetes mellitus, a group of syndromes characterized by hyperglycemia (high blood sugar). Most patients can be classified as having either type I diabetes, formerly known as insulin-dependent diabetes, or type II diabetes, formerly known as noninsulin-dependent diabetes. Type I diabetes is characterized by a lack of production of insulin, while type II diabetes is characterized by tissue resistance to the insulin that is produced by the pancreas. The islets of Langerhans (Langerhans, islets of) in the pancreas contain a specialized type of cell called the beta, or B, cell, which secretes insulin. Once secreted by the B cell into the bloodstream, insulin can affect a number of important metabolic actions on cells located in the muscles, liver, and other sites. Normally, insulin secretion is increased following the ingestion of carbohydrates; the liver is responsible for eventually curtailing the biological actions of insulin. Insulin has a number of important metabolic actions upon both fat and protein as well.

      Insulin cannot be administered orally, because it is a polypeptide whose physiological properties are destroyed by proteolytic enzymes present in the stomach and gastrointestinal tract. Insulin must be injected parenterally so that it enters the bloodstream and eventually reaches the body's cells. Insulin can be obtained from the pancreas of domestic animals, and the hormone now can be made by recombinant DNA techniques. An overdose of insulin can produce hypoglycemia (low blood sugar), which may lead to convulsions. Several other hormones (e.g., growth hormone and glucocorticoids) can antagonize insulin's actions.

      Type II diabetes often may be treated with oral hypoglycemic drugs instead of with insulin. The sulfonylureas stimulate B cells to produce more insulin. With long-term use this effect appears to diminish, but plasma glucose levels remain low. The most common adverse effect of these drugs is hypoglycemia. Repaglinide is another orally active compound that increases insulin release from the pancreas. The thiazolidinediones (e.g., pioglitazone, rosiglitazone) decrease insulin resistance; regular monitoring of liver metabolism should be performed in individuals taking these drugs. Metformin lowers glucose levels by decreasing liver production of glucose and increasing the action of insulin in fat and muscle.

      Another set of specialized cells located in the pancreas secrete a protein hormone called glucagon. Glucagon can stimulate the breakdown of liver glycogen, leading to a release of glucose into the bloodstream. Thus, in certain instances, glucagon can counteract the actions of insulin. The physiological or pathological significance of the antagonistic relationship between insulin and glucagon is not fully understood. There is no known human disease associated with either increased or decreased levels of glucagon, unlike insulin.

John A. Thomas Janet L. Stringer

Renal system (renal system disease) drugs
      The kidney is primarily concerned with maintaining the volume and composition of body fluids. It nonselectively filters blood, under pressure, in millions of small units called glomeruli. Large molecules (such as proteins) and cells (such as red blood cells) do not normally pass through the filter into the urine. The filter differentiates only by size, so that useful substances (such as glucose) are filtered out as well as waste products (such as urea, the end-product of nitrogen metabolism). The kidney compensates for this by reabsorbing essential substances and water through the walls of fine tubules, or nephrons (nephron), which collect together to deliver their contents into the ureter and then to the bladder, from which urine can be voided. One litre of filtrate is formed in eight minutes, yet 99 percent of this volume is normally reabsorbed, unless there has been excess fluid intake. All body fluids have approximately the same strength, or tonicity; otherwise, considerable osmotic (osmosis) pressures would develop between different compartments.

       edema is a condition characterized by an accumulation of body fluid with dissolved solutes in the intercellular spaces of the connective tissue. When these solutes are absorbed through the walls of the nephrons (nephron) after filtration by the glomeruli, an obligatory movement of water, driven by osmotic forces, prevents the body from eliminating excess fluid. By preventing reabsorption of solutes across the walls of the nephrons, both excess solutes and water pass into the bladder. The major use of diuretics (diuretic) is to rid the body of fluid that builds up in edema by interfering with the mechanisms of solute transport, thus increasing the production of urine.

      A nephron can be divided into distinct regions in which the absorptive processes are different: the proximal tubule, leading directly from the glomerulus; the loop of Henle; the distal tubule, leading away from the loop; and the collecting duct. The majority of useful solutes and water are reabsorbed in the proximal tubule, while selective absorption, regulation, and fine-tuning to maintain the composition of body fluids in the correct ranges take place in the remaining regions.

       carbonic anhydrase inhibitors, such as acetazolamide and methazolamide, depress the reabsorption of sodium bicarbonate in the proximal tubule by inhibiting an enzyme, carbonic anhydrase, which is involved in the reabsorption of bicarbonate. Urine formation is increased. The urine, which is rich in sodium bicarbonate and is alkaline, also has an increased concentration of potassium ions, which can lead to a serious loss of potassium from the body (hypokalemia).

      Diuretics that act in the loop of Henle produce a rapid peak in the excretion of urine (diuresis), which then wanes as the drugs are excreted and because of the compensatory factors due to fluid loss. These diuretics clear sodium chloride (salt) from the body and interfere indirectly with the mechanisms by which water is reabsorbed from the collecting duct. Consequently, large volumes of dilute urine containing sodium, potassium, and chloride ions are formed. The loop diuretics are also called “high-ceiling diuretics” because they can produce an extra level of diuresis over and above the maximum produced by other classes of diuretic drugs. Examples of this class are furosemide, ethacrynic acid, and bumetanide. Loop diuretics are used in the treatment of pulmonary edema associated with congestive heart failure. The major side effect of these drugs is hypokalemia.

      The thiazide class of diuretics, which are widely used in the treatment of hypertension, interferes with salt reabsorption in the first part of the distal tubule. A mild diuresis results in which sodium, potassium, and chloride ions are eliminated in the urine. Examples of these drugs are chlorothiazide and hydrochlorothiazide.

      The adrenal gland releases a hormone, aldosterone, which promotes sodium absorption in the latter part of the distal tubule. Its function is to increase sodium retention in sodium-depleted states. Aldosterone levels, however, may be abnormally high in hyperaldosteronism and in hypertension. Drugs such as spironolactone act as antagonists of aldosterone and compete with it for its site of action in the distal tubule. As with most antagonists, spironolactone has no direct action of its own but simply prevents the action of the hormone, thereby correcting the excess sodium reabsorption.

      In the latter part of the distal tubule there are mechanisms that exchange one ion for another; for example, sodium is exchanged for potassium and hydrogen. Sodium is absorbed across the tubule wall while potassium and hydrogen are added to the urine. Thus, diuretics such as the thiazides, loop diuretics, and carbonic anhydrase inhibitors, which prevent sodium absorption in the early parts of the nephron, cause an unusually large sodium load to be delivered to the distal tubule, where sodium may be exchanged for other ions, especially potassium, and reabsorbed from the urine. The result is that the body loses a large amount of potassium ions, which is serious if the loss exceeds the capacity of the diet to restore it. Potassium depletion (potassium deficiency) leads to failure of neuromuscular function and to abnormalities of the heart, among other serious effects. The potassium-sparing diuretics block the exchange processes in the distal tubule and thus prevent potassium loss. Sometimes a mixture of diuretics is used in which a thiazide is taken together with a potassium-sparing diuretic to prevent excess potassium loss. In other instances, the potassium loss may be made up by taking oral potassium supplements in the form of potassium chloride.

      Osmotic diuretics (e.g., mannitol) are substances that have a low molecular weight and are filtered through the glomerulus. They limit the reabsorption of water in the tubule. Osmotic diuretics cannot be reabsorbed from the urine, and so they set up a situation of nonequilibrium across the tubule membrane. In order to maintain normal osmotic pressure, water is moved across the membrane, increasing the volume of urine.

      In some situations it is desirable to change the acidity or alkalinity of the urine, usually to promote the loss of toxic substances from the body. Urine may be made more alkaline by giving sodium bicarbonate or citrate salts. It may be made more acid by giving ammonium chloride.

Alan William Cuthbert

Dermatologic drugs
      The skin consists of layers called the epidermis and the dermis and of certain appendages such as sweat glands (sweat gland), sebaceous glands (sebaceous gland) (which secrete an oily substance), hair, and nails. There also exists a subcutaneous layer beneath the dermis. The outermost layer of the epidermis, called the stratum corneum, consists principally of dead epithelial cells that are filled with the protein keratin, which waterproofs and toughens the skin. Underlying the stratum corneum are layers comprising keratinocytes and melanocytes. The dermis, which is below the epidermis, comprises connective tissue and a number of different cell types; it maintains and nourishes the epidermis through its network of capillaries and lymphatic vessels. Sweat glands and hair follicles, which originate in the dermis and penetrate the stratum corneum of the epidermis, represent a potential route of penetration by drugs. The subcutaneous layer is the innermost layer and is composed of loose connective tissue and many fat cells. It provides some degree of insulation and is a location for food storage and the site for subcutaneous injection.

      Few drugs are absorbed rapidly through intact skin. In fact, the skin effectively retards the diffusion and evaporation even of water except through the sweat glands. There are, however, a few notable exceptions (e.g., scopolamine and nitroglycerin) and instances where a penetration enhancer (e.g., dimethyl sulfoxide) serves as a vehicle for the drug.

      Several factors affect the transport of drugs through the skin (transdermal penetration) once they are applied topically. The absorption of drugs through the skin is enhanced if the drug is highly soluble in the fats (lipids) of the subcutaneous layer. The addition of water (hydration) to the stratum corneum greatly enhances the transdermal movement of corticosteroids (corticoid) (anti-inflammatory steroids) and certain other topically applied agents. Hydration can be effected by wrapping the appropriate part of the body with plastic film, thereby facilitating dermal absorption. If the epithelial layer has been removed, or denuded, by abrasion or burns or if it has been affected by a disease (skin disease), penetration of the drug may proceed more rapidly. A drug will be distributed, or partitioned, between the solvent and the lipids of the skin according to the solubility of the solvent in water or lipids. Topical absorption of drugs is facilitated when they are dissolved in solvents that are soluble in both water and lipids.

      Topical application of drugs provides a direct, localized effect on a specific area of the skin. When drugs are applied topically to the skin, they may be dissolved in a variety of vehicles or formulations, ranging from simple solutions to greasy ointments. The particular type of dermal formulation used (e.g., powder, ointment) depends, in part, on the type of skin lesion or disease process.

      Topical medications can relieve itching, exert a constricting or astringent action on the pores, or dissolve or remove the epidermal layers. Other pharmacological effects from topically applied drugs include antibacterial, anti-inflammatory, antifungal, and antiparasitic actions. Analgesic balms (e.g., wintergreen oil or methyl salicylate) have been used topically to relieve minor muscle aches and pains.

      The skin can be affected by other means, including sunscreens, photosensitizing drugs, and pigmenting agents (psoralens). Sunscreens, which act as barriers to sunlight by blocking, scattering, or otherwise reflecting the light, include such agents as para-aminobenzoic acid. Other chemicals (e.g., coal tar) act in conjunction with sunlight on the skin to achieve a high sensitivity to sunlight (photosensitization). Drugs capable of causing photosensitization generally exert their effects following the absorption of light energy. For example, the topical or systemic administration of methoxsalen or trioxsalen prior to exposure to the ultraviolet radiation of the sun augments the production of melanin pigment in the skin. These and other psoralens have been used in the treatment of the skin disorder vitiligo in an effort to repigment the whitish patches that commonly occur on the hands and face.

      The transdermal application of drugs can also achieve a systemic rather than local effect. The administration of a drug through the skin not only minimizes the metabolism of the drug before it reaches the rest of the body but also eliminates the high and low blood levels associated with oral administration. A major limitation of transdermal drug administration is that only a small amount of drug can be given through the skin.

      Transdermal drug administration makes use of a variety of structures from which the drug is distributed. The rate of drug release is determined by the properties of the synthetic membrane of the vehicle and the difference in drug concentration across the membrane. Because the anatomic site can influence this rate, testing for the most suitable areas of placement is done for each drug. Examples of transdermal drugs are nitroglycerin, in impregnated disks applied to the upper chest or upper arm, and scopolamine (a drug used to treat motion sickness and nausea), in a polymer device applied behind the ear.

      Drugs may be applied to mucous membranes (mucous membrane), including those of the conjunctiva, mouth, nasopharynx, vagina, colon, rectum, urethra, and bladder. They may either exert a local action or be absorbed into the bloodstream to act elsewhere. Examples include nitroglycerin, which is absorbed from under the tongue (sublingually) to act on the heart and relieve anginal pain, and acetaminophen, an analgesic sometimes taken in suppositories. Nasal insufflation, or inhalation, involves the local application of a drug to the mucous membranes of the nose to achieve a systemic action. This represents an effective delivery route of antidiuretic hormone (vasopressin) and its analogs in the treatment of diabetes insipidus. Relatively unsuccessful efforts have been made to get hormones of larger molecular weight, such as insulin or growth hormone, to penetrate the mucous membranes of the nasal cavity and thereby avoid the need to inject such hormones. Although certain medications can be applied successfully to mucous membranes, the topical application of drugs to the skin represents a more widespread and important therapeutic method of administration.

Drugs affecting muscle
Drugs that affect smooth muscle
      Smooth muscle is found primarily in the internal body organs and performs many functions, including control of the diameter of blood vessels, control of the propulsive activity of the gastrointestinal tract, contraction of the urinary bladder, contraction of the uterus, control of ocular focusing and pupil diameter, and control of the diameter of the respiratory airways. Whereas striated, or skeletal, muscle is controlled from the central nervous system by way of somatic motor nerves, smooth muscle is controlled by the autonomic nervous system and by hormones. In many situations, smooth muscle undergoes spontaneous, often rhythmic contractions that are not dependent on outside nerve impulses. Smooth muscle contracts much more slowly than striated muscle and in general shows a much broader sensitivity to drugs.

      Smooth muscle contraction is initiated by depolarization (the sharp influx of positively charged ions) of the cell membrane. This causes calcium-selective ion channels in the membrane to open, allowing calcium to flow into the cell. The contractile mechanism of smooth muscle cells, like that of striated muscle, involves the sliding action of overlapping protein filaments composed of actin and myosin molecules. The free calcium ions diffuse to the myosin and activate its enzymatic activity, which begins the process of contraction. Most of the drugs that stimulate or inhibit smooth muscle contraction do so by regulating the concentration of intracellular calcium, but other intracellular messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are also involved (see the section Principles of drug action (drug)).

      Adrenoceptor agonists, muscarinic agonists, nitrates, and calcium channel blockers are considered in other sections and are not discussed here.

      Hormones (hormone) can influence smooth muscle function. Apart from histamine (see the section Drugs affecting blood (drug)), agents known to function as local hormones are prostanoids. Prostanoids (e.g., prostaglandins (prostaglandin)) and leukotrienes (a related group of lipids (lipid)) are derived by enzymatic synthesis from one of three 20-carbon fatty acids (fatty acid), the most important being arachidonic acid, a constituent of cell membranes. When a membrane enzyme, phospholipase C, is activated, arachidonic acid is released and converted by intracellular enzymes to unstable intermediates, which are further metabolized, depending on the group of enzymes involved, to prostanoids or leukotrienes. The synthesis and release of prostanoids and leukotrienes occurs when cells are damaged, even mildly. They are important in producing tissue responses to injury as well as in other physiological reactions. Derivatives of prostanoids have as their basic structure a five-carbon ring with two side chains, and they differ from each other in the substitutions on the ring structure. The derivatives are distinguished by the letters A through I. In relation to smooth muscle, the most important prostanoids are prostaglandins E1, E2, and F2 (the subscript numbers denoting the 20-carbon precursor and the number of double bonds in the molecule) and leukotrienes C4 and D4; the most important sites of action are bronchial and uterine smooth muscle. Leukotrienes are powerful bronchoconstrictors, and they are believed to be synthesized and released during asthmatic attacks. Some drugs for the treatment of asthma block the binding of leukotrienes to their receptor. For example, zileuton blocks the conversion of arachidonic acid to leukotrienes by inhibition of the enzyme 5-lipoxygenase. Prostaglandins in minute amounts produce a broad range of physiological effects in almost every system of the body. Prostaglandins E1 and E2 are dilators and prostaglandins of the F series are bronchoconstrictors. Prostaglandin E1 also dilates blood vessels, and it is sometimes administered by intravenous infusion to treat peripheral vascular disease. Most prostaglandins cause uterine contraction, and they are sometimes administered to initiate labour (parturition) (see the section Reproductive system drugs (drug)).

       ergot alkaloids are produced by a parasitic fungus that grows on cereal crops. Among the many biologically active constituents of ergot, ergotamine and ergonovine are the most important. The main effect of ergotamine is to constrict blood vessels, sometimes so severely as to cause gangrene of fingers and toes. Dihydroergotamine, a derivative, can be used in treating migraine. Ergonovine has much less effect on blood vessels but a stronger effect on the uterus. It can induce abortion, though not reliably. Its main use is to promote a strong uterine contraction immediately after labour, thus reducing the likelihood of bleeding.

Drugs that affect skeletal muscle (striated muscle)
      Skeletal muscle contracts in response to electrical impulses that are conducted along motor nerve fibres originating in the brain or spinal cord. The motor nerve fibres reach the muscle fibres at sites called motor end plates, located roughly in the middle of each muscle fibre. The motor end plate stores vesicles of the neurotransmitter acetylcholine. An impulse arriving at the motor end plate causes many acetylcholine-containing vesicles to be discharged into the narrow synaptic cleft between the end plate and the membranes of the muscle fibre. Acetylcholine binds to nicotinic receptors on the muscle fibre membrane, causing ion channels to open and allowing a local influx of positively charged ions into the muscle fibre. The muscle fibre is thus depolarized (i.e., its internal potential becomes less negative), and, if this local depolarization is large enough, the contractile machinery along the whole length of the fibre is activated. The process occurs within one to two milliseconds. The released acetylcholine is inactivated within one millisecond by the action of the enzyme acetylcholinesterase, which is located in the synaptic cleft. The process normally has a large margin of safety because the amount of acetylcholine released is more than enough to activate the muscle fibre.

      Because the contractile mechanism of skeletal muscles is relatively insensitive to drug action, the most important group of drugs that affect the neuromuscular junction act on (1) acetylcholine release, (2) acetylcholine receptors, or (3) acetylcholinesterase.

      Botulinum toxin causes neuromuscular paralysis by blocking acetylcholine release (see the section Autonomic nervous system drugs (drug)). There are a few drugs that facilitate acetylcholine release, including tetraethylammonium and 4-aminopyridine. They work by blocking potassium-selective channels in the nerve membrane, thereby prolonging the electrical impulse in the nerve terminal and increasing the amount of acetylcholine released. This can effectively restore transmission under certain conditions, but these drugs are not selective enough for their actions to be of much use therapeutically.

      Neuromuscular blocking drugs act on acetylcholine receptors and fall into two distinct groups: nondepolarizing (competitive) and depolarizing blocking agents.

      Competitive neuromuscular blocking drugs act as antagonists at acetylcholine receptors, reducing the effectiveness of acetylcholine in generating an end-plate potential. When the amplitude of the end-plate potential falls below a critical level, it fails to initiate an impulse in the muscle fibre, and transmission is blocked. The most important competitive blocking drug is tubocurarine, which is the active constituent of curare, a drug with a long history and one of the first drugs whose action was analyzed in physiological terms. Claude Bernard, a 19th-century French physiologist, showed that curare causes paralysis by blocking transmission between nerve and muscle, without affecting nerve conduction or muscle contraction directly. Curare is a product of plants (mainly Chondodendron species) that grow primarily in South America and has been used there for centuries as an arrow poison.

      Tubocurarine has been used in anesthesia to produce the necessary level of muscle relaxation. It is given intravenously, and the paralysis lasts for about 20 minutes, although some muscle weakness remains for a few hours. After it has been given, artificial ventilation is necessary because breathing is paralyzed. Tubocurarine tends to lower blood pressure by blocking transmission at sympathetic ganglia, and, because it can release histamine in tissues, it also may cause constriction of the bronchi. Synthetic drugs are available that have fewer unwanted effects—for example, gallamine and pancuronium.

      The action of competitive neuromuscular blocking drugs can be reversed by anticholinesterases (see the section Autonomic nervous system drugs (drug)), which inhibit the rapid destruction of acetylcholine at the neuromuscular junction and thus enhance its action on the muscle fibre. Normally this has little effect, but, in the presence of a competitive neuromuscular blocking agent, transmission can be restored. This provides a useful way to terminate paralysis produced by tubocurarine or similar drugs at the end of surgical procedures. Neostigmine often is used for this purpose, and an antimuscarinic drug is given simultaneously to prevent the parasympathetic effects that are enhanced when acetylcholine acts on muscarinic receptors.

       anticholinesterase drugs also are useful in treating myasthenia gravis, in which progressive neuromuscular paralysis occurs as a result of the formation of antibodies against the acetylcholine receptor protein. The number of functional receptors at the neuromuscular junction becomes reduced to the point where transmission fails. Anticholinesterase drugs are effective in this condition because they enhance the action of acetylcholine and enable transmission to occur in spite of the loss of receptors; they do not affect the underlying disease process. Neostigmine and pyridostigmine are the drugs most often used because they appear to have a greater effect on neuromuscular transmission than on other cholinergic synapses, and this produces fewer unwanted side effects. The immune mechanism responsible for the inappropriate production of antibodies against the acetylcholine receptor is not well understood, but the process can be partly controlled by treatment with steroids or immunosuppressant drugs such as azathioprine.

      Depolarizing neuromuscular blocking drugs, of which succinylcholine is the only important example, act in a more complicated way than nondepolarizing, or competitive, agents. Succinylcholine has an action on the end plate similar to that of acetylcholine. When given systemically, it causes a sustained end-plate depolarization, which first stimulates muscle fibres throughout the body, causing generalized muscle twitching. Within a few seconds, however, the maintained depolarization causes the muscle fibres to become inexcitable and therefore unable to respond to nerve stimulation. The paralysis lasts for only a few minutes because the drug is quickly inactivated by cholinesterase in the plasma. Succinylcholine often is used to produce paralysis quickly at the start of a surgical procedure (and then is supplemented later with a competitive blocking agent) or for brief procedures. It is used widely, despite a number of disadvantages. Generalized muscle aches are commonly experienced for a day or two after recovery. More seriously, a small proportion of people (about 1 in 3,000) have abnormal plasma cholinesterase and may remain paralyzed for a long time. Succinylcholine also causes the release of potassium ions from muscles and an increase in the concentration of potassium in the plasma. This happens particularly in patients with severe burns or trauma, in whom it can cause potentially dangerous cardiac disturbances. Another hazard is the development of malignant hyperthermia, a sudden rise in body temperature caused by increased tissue metabolism. This condition is very rare, but it is often fatal if not treated rapidly enough.

Humphrey P. Rang

histamine and antihistamines
       histamine is a chemical messenger involved in a number of complex biological actions. It occurs mainly in an inactive bound form in most body tissues. When released, it interacts with specific histamine receptors on the cell surface or within a target cell to elicit changes in many different bodily functions. Free histamine produces many powerful and varied biological actions. The receptors on which it acts have not been isolated or identified, but their presence is inferred by the use of synthetic drugs. Three types of pharmacological histamine receptor have been described, and they are designated as H1, H2, and H3. Histamine stimulates many smooth muscles to contract, such as those in the gastrointestinal tract, the uterus, and the bronchi. In some smooth muscle, however, it causes relaxation, notably that of fine blood vessels, whose dilation may produce a pronounced fall in blood pressure. Histamine also increases the permeability of the walls of the capillaries so that more of the constituents of plasma can escape into tissue spaces, leading to an increase in the flow of lymph and its protein content and to the formation of edema. These effects are manifested in the redness and rash associated with histamine release, as may occur after a scratch from a blunt instrument or a bee sting. Histamine appears to have a physiological role in the body's defenses against a hostile environment since it is found in the body's surfaces: in the skin, in the respiratory membrane and adjacent tissue, and in the lining of the digestive tract. Histamine may be released from tissue mast cells (mast cell) and blood basophils when the body is subjected to trauma, infection, or some drugs. Histamine assists the body in removing the products of cell damage from inflammation. The most common circumstance in which histamine is liberated is as a result of the antibodies (antibody) produced by foreign proteins. Under extreme circumstances, the effects of histamine become pathological, leading to exaggerated responses with distressing results, as may occur in some allergic conditions.

      Antihistamines (antihistamine) are a group of synthetic drugs that can inhibit various actions of histamine. They have some chemical resemblance to histamine and act as antagonists by competing with histamine for occupation of its receptor sites, thereby preventing histamine from eliciting its usual responses. They are helpful therapeutically in preventing rather than in reversing histamine actions. Antihistamines (such as diphenhydramine and chlorpheniramine) have been available since 1945, although subsequently they have been designated more precisely as H1-receptor histamine antagonists or H1-receptor blockers. The H1 antihistamines are used to suppress or alleviate the symptoms in various allergic (allergy) conditions; they do so by competing with the released histamine for occupation of its H1 receptors. They may be effective in the treatment of seasonal hay fever (seasonal rhinitis and conjunctivitis) to relieve sneezing, rhinorrhea (runny nose), and itching of eyes, nose, and throat. In general, the H1 antihistamines tend to be more successful in controlling acute than chronic conditions; thus, they are most useful at the beginning of the hay-fever season, when the allergens are present in low concentration, but in perennial vasomotor rhinitis (nonseasonal, nonallergic inflammation of the mucous membranes of the nose brought on by environmental or emotional stimuli) they are only of limited value. They are not usually effective in treating asthma, indicating that in this condition histamine is not the main agent producing the symptoms. Certain allergic skin reactions respond favourably to H1 antihistamines, which are particularly effective for treatment of acute urticarial rashes of the skin and the itch and swelling of insect bites.

      The H1 antihistamines are relatively free from serious side effects. Less-serious side effects are common, the most notable being drowsiness. Because they do not cross the blood-brain barrier, newer H1 antihistamines, however, are relatively free of this side effect. The action of some H1 antihistamines (e.g., diphenhydramine and promethazine) on the central nervous system has been put to advantage in the prevention and treatment of motion sickness. Because they also possess sedative action (especially dimenhydrinate and promethazine), they may impair a person's performance while driving and enhance the effects of alcohol and other depressant drugs that act on the central nervous system. The older antihistamines bind strongly to H1 receptors in the brain but also bind to muscarinic receptors in the brain, and this action may contribute to their beneficial effect.

      Histamine has a physiological role in regulating the secretion of acid in the stomach, where it stimulates the parietal cells to produce hydrochloric acid. This is probably protective, since the acid controls the local bacterial population. In the 1970s a new class of synthetic drugs was invented that blocked the action of histamine at its H2 receptors (see the section Digestive system drugs (drug)). These drugs were shown to be extremely effective in antagonizing the action of histamine in stimulating acid secretion and in blocking other stimulants of acid secretion, including the hormone gastrin and food. The H2-receptor antagonist drugs, such as cimetidine and ranitidine, rapidly established a place in the treatment of conditions involving the hypersecretion of gastric acid, such as peptic ulcers (peptic ulcer).

C. Robin Ganellin

Pharmacology of the autonomic system
      The nervous system (nervous system, human) comprises two main divisions: the central nervous system, which includes the brain and spinal cord; and the peripheral nervous system, which can be further divided into the somatic nervous system, whose main function is to innervate body structures (e.g., most skeletal muscles) under conscious (consciousness), voluntary control, and the autonomic nervous system, which is concerned with the involuntary processes of the glands, large internal organs, cardiac muscle, and blood vessels. The autonomic nervous system consists of the sympathetic and the parasympathetic systems, which are distinct both functionally and anatomically.

       autonomic nerv sysThe sympathetic system initiates a series of reactions, called “fight-or-flight” reactions, that prepare the body for activity. The heart rate increases, blood pressure rises, and breathing quickens. The amount of glucose in the blood rises, providing a reservoir of quick energy. The flow of blood to the skin and organs decreases, allowing more blood to flow to the heart and muscles. The parasympathetic system generally functions in an opposite way, initiating responses associated with rest and energy conservation; its activation causes breathing to slow, salivation to increase, and the body to prepare for digestion. This is, however, a considerable oversimplification. The autonomic nervous system as a whole exerts a continuous, local control over the function of many organs (such as the eye, lung, urinary bladder, and genitalia), regardless of whether the body is preparing to react or to rest. The main physiological actions produced by the autonomic nervous system are shown in the table (autonomic nerv sys).

      The autonomic nervous system exerts its control through a network of nerve fibres originating from neurons in the spinal cord and brain stem. Each of these fibres ends by forming a junction with a second neuron, often called a ganglion cell because in some cases these second neurons are grouped together in swellings called ganglia. The first neuron is therefore called preganglionic and the second postganglionic. The junction between the preganglionic and postganglionic neurons is called a synapse. As the electrical nerve impulse reaches the end of the preganglionic neuron, it causes the release of a chemical substance called a neurotransmitter. There is no direct contact between the two neurons. The neurotransmitter diffuses across the gap between the two neurons (synaptic cleft) and acts on the postganglionic neuron. Postganglionic neurons innervate the target organs and elicit responses in them once again by inducing release of a neurotransmitter.

      In 1914 British physiologist Sir Henry Dale (Dale, Sir Henry) suggested that acetylcholine was the neurotransmitter at the synapse between preganglionic and postganglionic sympathetic neurons and also at the ends of postganglionic parasympathetic nerves. He showed that acetylcholine could produce many of the same effects as direct stimulation of parasympathetic nerves. Firm evidence that acetylcholine was in fact the neurotransmitter came in 1921, when German physiologist Otto Loewi (Loewi, Otto) discovered that stimulation of the autonomic nerves to the heart of a frog caused the release of a substance, later identified to be acetylcholine, which slowed the beat of a second heart perfused with fluid from the first. Similar direct evidence of the release of a sympathetic neurotransmitter, later shown to be norepinephrine (noradrenaline), was obtained by American physiologist Walter Cannon (Cannon, Walter Bradford) in 1921.

 In the autonomic nervous system, nerve fibres (axon) are classified on the basis of the neurotransmitter released at the synapse. Nerve fibres that release the neurotransmitter acetylcholine are called cholinergic fibres; nerve fibres that release the neurotransmitter norepinephrine (epinephrine and norepinephrine) are called adrenergic fibres (adrenergic nerve fibre). Cholinergic fibres comprise the axons of the preganglionic sympathetic neurons and both the preganglionic and the postganglionic parasympathetic neurons. The axons of the postganglionic sympathetic neurons are generally autonomic adrenergic fibres. The scheme in the figure—> is complicated by the fact that these neurotransmitters have a negative feedback effect in inhibiting their own further release. They do this by combining with presynaptic receptors on the nerve terminals as well as with the postsynaptic receptors on the target organs.

      Both acetylcholine and norepinephrine act on more than one type of receptor. Dale found that two foreign substances, nicotine and muscarine, could each mimic some, but not all, of the parasympathetic effects of acetylcholine. Nicotine stimulates skeletal muscle and sympathetic ganglia cells. Muscarine, however, stimulates receptor sites located only at the junction between postganglionic parasympathetic neurons and the target organ. Muscarine slows the heart, increases the secretion of body fluids, and prepares the body for digestion. Dale therefore classified the many actions of acetylcholine into nicotinic effects and muscarinic effects.

      A similar analysis of the sympathetic effects of norepinephrine, epinephrine, and related drugs was carried out by American pharmacologist Raymond Ahlquist, who suggested that these agents acted on two principal receptors. A receptor that is activated by the neurotransmitter released by an adrenergic neuron is said to be an adrenoceptor. Ahlquist termed the two kinds of adrenoceptor alpha (α) and beta (β). This theory was confirmed when Sir James Black (Black, Sir James) developed a new type of drug that was selective for the β-adrenoceptor.

      Both α-adrenoceptors and β-adrenoceptors are divided into subclasses: α1 and α2; β1, β2, and β3. These receptor subtypes were recognized by their responses to specific agonists and antagonists. Once recognized, they provide important leads in developing new drugs with high activity of a certain kind. For example, salbutamol was discovered as a specific β2-adrenoceptor agonist. It is used to treat asthma and is a great improvement over its predecessor, isoproterenol; because the activity of isoproterenol is not specific, it acts on β1-adrenoceptors as well as β2-adrenoceptors, resulting in cardiac effects that are sometimes dangerous.

      A complex relationship exists between function and receptor type for α-adrenoceptors and β-adrenoceptors. Alpha1-adrenoceptors usually mediate smooth muscle contraction, particularly the constriction of the blood vessels (vasoconstriction) that results from a buildup of calcium ions within the cell. Alpha2-adrenoceptors are located primarily on nerve terminals, where they act to inhibit the release of the neurotransmitter. Beta1-adrenoceptors are found in the heart and increase the force and rate of the heart's action; β2-adrenoceptors are found primarily in smooth muscle and produce relaxation; and β3-adrenoreceptors are found in adipose tissue and cause the breakdown of lipids. Beta-adrenoceptors are involved in the metabolic effects of epinephrine and norepinephrine on liver, fat, and muscle cells, which convert energy stores to freely usable metabolic fuels.

      It is now known that acetylcholine and norepinephrine are not the only neurotransmitters. dopamine, a metabolic precursor of norepinephrine, is also thought to mediate vasodilator responses in some organs, especially the kidney. A wide variety of peptides, such as substance P, vasoactive intestinal polypeptide, and cholecystokinin, all of which exert powerful effects on target organs, have been detected in autonomic neurons, and it is likely that these also function as neurotransmitters. There is evidence that adenosine triphosphate (ATP), a substance of special importance as a metabolic energy source within cells, also functions as a neurotransmitter in autonomic neurons.

      Chemical transmission of nerve impulses in the autonomic nervous system involves several steps, some of which are susceptible to interference by drugs: (1) synthesis of the neurotransmitter from simple chemical compounds, (2) storage of the neurotransmitter in a releasable form (generally believed to be in vesicles within nerve terminals), (3) release of the neurotransmitter, which normally occurs when the nerve terminal is invaded by an electrical impulse in the neuron, (4) feedback action of the neurotransmitter on receptors regulating the release of the neurotransmitter, and (5) termination of action of the released neurotransmitter by enzymic breakdown or reuptake into nerve terminals.

Cholinergic drugs (cholinergic drug)
       Drugs acting on cholinergic and adrenergic receptorsCholinergic drugs (cholinergic drug) inhibit, enhance, or mimic the action of acetylcholine within the body. Drugs that act on cholinergic receptors are listed in the table (Drugs acting on cholinergic and adrenergic receptors). Acetylcholine release by nerve impulses can be blocked by botulinum toxin, a very potent chemical that is produced in food contaminated by the bacteria Clostridium botulinum and is an occasional cause of severe food poisoning ( botulism). The most serious effect is paralysis of the skeletal muscle. However, when botulinum toxin is locally injected, it can be used to treat severe muscle spasm or severe, uncontrollable sweating. Under such trade names as Botox™, it is also used for cosmetic purposes; botulinum toxin injected locally will paralyze muscles of the face, thus relaxing the skin and reducing wrinkles.

      Many drugs interact with acetylcholine receptors. Acetylcholine itself produces extremely short-lived effects because it is destroyed rapidly in the blood. One acetylcholine-like drug that is employed therapeutically is pilocarpine, a selective muscarinic-receptor agonist that is used in eyedrops to constrict the pupil and to decrease the intraocular pressure that is raised in the disease glaucoma.

      Antagonists acting on muscarinic receptors include such drugs as atropine and scopolamine. These drugs suppress all the actions of the parasympathetic system, which results in drying up of the secretions of the body (e.g., saliva, tears, sweat, bronchial secretions, and gastrointestinal secretions); relaxation of the smooth muscle in the intestine, bronchi, and urinary bladder; an increase in the heart rate; dilation of the pupils; and paralysis of ocular focusing. These drugs are widely used to dry up secretions and dilate the bronchi during anesthesia and to dilate the pupils during ophthalmological procedures. Scopolamine is also used to treat motion sickness, an effect that depends on its ability to depress the activity of the central nervous system.

      Nicotinic-receptor antagonists are divided into those that act mainly on skeletal muscle and those that act on ganglia cells. The latter group includes hexamethonium and trimethaphan. These drugs cause overall paralysis of the autonomic nervous system because they do not distinguish between sympathetic and parasympathetic ganglia and therefore are not specific in their action. They were the first effective agents to reduce high blood pressure (antihypertensive drugs), but they have many troublesome side effects associated with paralysis of the autonomic nervous system (e.g., blurred vision, constipation, impotence, inability to urinate). They have been replaced by more selective drugs (see the section Cardiovascular system drugs (drug)). The nicotinic-receptor antagonists that act at the neuromuscular junction are used during surgical procedures to produce muscle relaxation.

      Acetylcholine is inactivated by the enzyme acetylcholinesterase, which is located at cholinergic synapses and breaks down the acetylcholine molecule into choline and acetate. One group of acetylcholinesterase inhibitors (anticholinesterase drugs) is used to treat myasthenia gravis, a disorder characterized by muscle weakness. Neostigmine and pyridostigmine are drugs that can access the neuromuscular junction, but they cannot enter the ganglia of the autonomic nervous system and thus do not cross the blood-brain barrier. Therefore, these agents prolong the action of acetylcholine specifically at the neuromuscular junction.

Adrenergic drugs (adrenergic drug)
      The release of norepinephrine (noradrenaline) can be evoked or inhibited by the actions of adrenergic drugs (adrenergic drug). Drugs that evoke norepinephrine produce effects resembling those of sympathetic nerve activity and are called sympathomimetic agents. They include amphetamine and ephedrine, which act indirectly, mainly by expelling norepinephrine from its storage area in nerve terminals. They cause an increase in the heart rate (sometimes leading to arrhythmias, or irregular heartbeats) and other sympathetic effects. Ephedrine is occasionally used as a nasal decongestant. Amphetamine-like drugs also have strong effects on the brain, causing feelings of excitement and euphoria as well as reducing appetite, the latter effect leading to their use in treating obesity. Their effects on the brain have led to their recreational use and to their use as agents to enhance athletic performance. These drugs are liable to cause addiction, and overdosage may have dangerous cardiovascular and mental effects. Methylphenidate, an amphetamine-like compound sold under the trade name Ritalin™, has been shown to be useful in the treatment of attention-deficit/hyperactivity disorder (ADHD).

       Drugs acting on cholinergic and adrenergic receptorsDrugs that act as agonists or antagonists to adrenoceptors are listed in the table (Drugs acting on cholinergic and adrenergic receptors). Alpha1-adrenoceptor antagonists are important because they block the ability of norepinephrine to constrict the blood vessels (vasoconstriction). Since most blood vessels are subject to the continuous vasoconstrictor influence of sympathetic nerves, blocking these receptors causes a widespread relaxation of the blood vessels (vasodilation). These drugs are sometimes used to treat high blood pressure ( hypertension) and cardiac failure (heart failure) (see the section Cardiovascular drugs (drug)). Alpha1 antagonists can also be used in the treatment of some urinary bladder dysfunction conditions because they block the contraction of the sphincter at the bladder outlet that is mediated by α1-receptors.

      Beta-adrenoceptor antagonists are extremely useful in treating various kinds of cardiovascular diseases, particularly hypertension, dysrhythmias, and angina. The effect is usually achieved by blocking the β1-adrenoceptor; however, some drugs also block the β2-adrenoceptor. This gives rise to various unwanted side effects, such as constriction of the bronchial smooth muscle, which can be dangerous to patients with asthma, and constriction of certain blood vessels, which may cause patients to have cold hands and feet. Beta-adrenoceptor antagonists are also useful in controlling muscle tremors and anxiety that result from overactivity of the sympathetic system.

      Alpha2 agonists, such as clonidine, are used to treat hypertension. Clonidine lowers blood pressure by inhibiting the release of norepinephrine from sympathetic nerves, an effect mediated by presynaptic α2-adrenoceptors, and by acting on centres in the brain that are concerned with the control of blood pressure. It is a potent and effective drug, but it has the disadvantage that the blood pressure may rise to a dangerously high level if the drug is stopped or even if the patient misses a dose.

      Beta2 agonists relax smooth muscle in many parts of the body (see the section Drugs that affect smooth muscle (drug)) and are used mainly to treat asthma. None of the available drugs are completely selective for the β2-adrenoceptor, and they tend to produce unwanted effects on the heart, such as increased heart rate and disturbances of cardiac rhythm, through their action on cardiac β1-adrenoceptors. To reduce these side effects, the β2 agonists are usually given by inhalation.

      The action of the released norepinephrine is terminated when it is recaptured by sympathetic nerve terminals, a process that involves a selective transport mechanism in the neuronal membrane. Various drugs block this transport system and thus enhance the effects of sympathetic nerve activity; the most important examples are cocaine and certain antidepressant drugs such as imipramine. Overdosage with these drugs results in overactivity of the sympathetic system and the occurrence of cardiac arrhythmias. The effects of these drugs on brain function, which are of more clinical importance than their peripheral sympathomimetic effects, may be due to this action of inhibiting the uptake of norepinephrine into adrenergic neurons in the brain.

Humphrey P. Rang

       cancer chemotherapy uses compounds that can differentiate to some degree between normal tissue cells and cancer cells. Chemotherapy is used in the treatment of cancer; no therapeutic agents are available for prevention of the disease. The decision to use a certain antineoplastic (tumour-fighting) drug depends on many factors, including the type and location of the cancer, its severity, whether surgery or radiation therapy can or should be used, and the side effects associated with the drug.

      Mechlorethamine, a derivative of the chemical warfare agent nitrogen mustard, was first used in the 1940s in the treatment of cancer and was shown to be effective in treating lymphomas (lymphoma). Since then, many antineoplastic drugs have been developed and used with much success.

      Unlike other antimicrobial agents, where the goal is to destroy an invading microorganism, the treatment of cancer is complicated in that the chemotherapeutic agent is aimed toward human cells, albeit cells that have undergone genetic changes and are dividing at a fast and uncontrolled rate. Because cancer cells are similar to normal human cells, the anticancer agents are generally toxic to normal cells and can cause numerous side effects, some of which are life-threatening. These side effects include hair loss, sores in the mouth and on other mucous membranes, cardiac anomalies, bone marrow toxicity, and severe nausea and vomiting. The bone marrow toxicities result in anemia as well as in decreased resistance to infectious agents. Permanent infertility can also result. These adverse effects may require that the drug dosage be reduced or the antineoplastic drug regimen be changed to make the drug tolerable to the patient. While most are administered intravenously, many antineoplastic drugs can be taken orally, and some can be injected intramuscularly or intrathecally (within the spinal cord).

      Antineoplastic agents are divided into categories based on their mode of action. Since most of the drugs exert their effects in a certain part of the cell cycle (e.g., cell growth phase, cell division phase, resting phase), many treatment regimens require two or more of these agents. One drug may be used to stop the growth of the cancer cells in a certain phase, whereas another agent may work at a different phase. Using multiple agents, therefore, lessens the incidence of cellular resistance to an antineoplastic agent. The use of multiple agents also often enables the use of lower dosages of each drug, thereby reducing the side effects caused by each. In addition to using complex regimens that employ several drugs, chemotherapy is often combined with surgery to reduce the number of cancer cells and with radiation treatment to destroy more cells.

Alkylating agents
      Alkylating agents were the first anticancer drugs used, and, despite their hazards, they remain a cornerstone of anticancer therapy. Some examples of alkylating agents are nitrogen mustards (chlorambucil and cyclophosphamide); cisplatin; nitrosoureas (carmustine, lomustine, and semustine); alkylsulfonates (busulfan); ethyleneimines (thiotepa); and triazines (dacarbazine). These chemical agents are highly reactive and bind to certain chemical groups (phosphate, amino, sulfhydryl, hydroxyl, and imidazole groups) commonly found in nucleic acids and other macromolecules. These agents bring about changes in the deoxyribonucleic acid (DNA) (DNA) and ribonucleic acid (RNA) (RNA) of both cancerous and normal cells. For example, the nucleic acid may lose a basic component (purine), or it may break, or strands of DNA may cross-link. The result is that the nucleic acid will not be replicated. Either the altered DNA will be unable to carry out the functions of the cell, resulting in cell death (cytotoxicity), or the altered DNA will change the cell characteristics, resulting in an altered cell (mutagenic change). This change may result in the ability or tendency to produce cancerous cells (carcinogenicity). Normal cells may also be affected and become cancer cells. The alkylating agents can cause severe nausea and vomiting as well as decreases in the number of red and white blood cells. The decrease in the number of white blood cells results in susceptibility to infection. Alkylating agents have found use in the treatment of lymphoma, leukemia, testicular cancer, melanoma, brain cancer, and breast cancer. They are most often used in combination with other anticancer drugs.

Antimetabolites (antimetabolite)
      Antimetabolites are antineoplastic agents that are structurally similar to compounds that are found naturally in humans (vitamins, amino acids, or precursors of DNA and RNA). They incorporate into either DNA or RNA (purine and pyrimidine nucleotides) and interfere with cellular function. Some inhibit an enzyme necessary for macromolecular synthesis. Examples of these include antagonists of purines ( azathioprine, mercaptopurine, and thioguanine) and antagonists of pyrimidine (fluorouracil and floxuridine). Cytarabine, which also has antiviral properties, interferes with dihydrofolate reductase, which is necessary for the synthesis of tetrahydrofolate and subsequently for the synthesis of the folic acid needed for DNA formation.

      Because the antimetabolites act primarily upon cells undergoing synthesis of new DNA for formation of new cells, it follows that most of the toxicities associated with these drugs are seen in cells that are growing and dividing quickly. They are known to cause severe damage to the mucous membranes of the mouth and other parts of the gastrointestinal tract and also to produce skin disorders and hair loss. Anemia can occur, along with a decrease in number of the white blood cells that are necessary to prevent infections. methotrexate, used most often in the treatment of acute leukemia, breast cancer, lung cancer, and osteogenic sarcoma (osteosarcoma), has also been used in low doses for the treatment of rheumatoid arthritis.

      Antineoplastic antibiotics (antibiotic) (doxorubicin, daunorubicin, bleomycin, mitomycin, and dactinomycin) are derived from Streptomyces species. While they may have antibacterial activity, they are generally too dangerous and toxic for that use. These antibiotics affect DNA synthesis and replication by inserting into DNA or by donating electrons which result in the production of highly reactive oxygen compounds (superoxide) that cause breakage of DNA strands. These agents are associated with blood cell damage, hair loss, and other toxicities common to the antimetabolites and alkylating agents, and severe cardiac or lung toxicity also results. The effects vary in proportion to the dose and length of treatment. These antibiotics are administered exclusively by intravenous infusion for the treatment of lymphoma and leukemia, nephroblastoma (Wilm tumour), sarcoma, and cancers of the testicle, breast, thyroid, lung, and stomach.

Hormones (hormone)
      Hormones (hormone) are used primarily in the treatment of cancers of the breast (breast cancer) and sex organs. These tissues require hormones such as androgens (androgen), progestins, or estrogens (estrogen) for growth and development. By countering these hormones with an antagonizing hormone, the growth of that tissue is inhibited, as is the cancer growing in the area. For example, estrogens are required for female breast development and growth. tamoxifen competes with endogenous estrogens for receptor sites in breast tissue where the estrogens normally exert their actions. The result is a decrease in the growth of breast tissue and of breast cancer tissue. Adrenocorticosteroids are also used for treating some types of cancer. An unusual approach to cancer chemotherapy has been the use of a hybrid molecule (estramustine) that is a complex of an estrogen and a nitrogen mustard. The hormones are an example of a site-specific antineoplastic drug, but they work only on certain types of cancer.

Other agents
      Understanding of the basic biology of cancer cells has led to drugs with entirely new targets. One agent, interleukin-2, regulates the proliferation of tumour-killing lymphocytes. Interleukin-2 is used in the treatment of malignant melanoma and renal cell carcinoma. Trans-retinoic acid can promote remission in patients with acute promyelocytic leukemia by inducing normal differentiation of the cancerous cells. A related compound, 13-cis-retinoic acid, prevents the development of secondary tumours in some individuals. A particularly exciting application of cancer biology stems from the understanding of DNA translocation in chronic myelocytic leukemia. This translocation codes for a tyrosine kinase, an enzyme that phosphorylates other proteins and is essential for cell survival. Inhibition of the kinase by imatinib has been shown to be highly effective in treating patients who are resistant to standard therapies.

      Hydroxyurea inhibits the enzyme ribonucleotide reductase, an important element in DNA synthesis. It is used to reduce the high granulocyte count found in chronic myelocytic leukemia. Asparaginase breaks down the amino acid asparagine to aspartic acid and ammonia. Some cancer cells, particularly in certain forms of leukemia, require this amino acid for growth and development. Other agents, such as dacarbazine and procarbazine, act through various methods, although they can act as alkylating agents. Mitotane, a derivative of the insecticide DDT, causes necrosis of adrenal glands.

      A number of agents synthesized from plants are used in the treatment of cancer. Paclitaxel was first isolated from the bark of the western yew (Pacific yew) tree. It stops cell division by an action on the microtubules and has been tested for activity against ovarian (ovarian cancer) and breast cancers. The camptothecins are a class of antineoplastic agents that target DNA replication. The first compound in this class was isolated from the Chinese camptotheca tree. Irinotecan and topotecan are used in the treatment of colorectal (colorectal cancer), ovarian, and small-cell lung cancer. Vinblastine and vincristine (vinca alkaloids), derived from the periwinkle plant, along with etoposide, act primarily to stop spindle formation within the dividing cell during DNA replication and cell division. These drugs are important agents in the treatment of leukemias, lymphomas, and testicular cancer. Etoposide, a semisynthetic derivative of a toxin found in roots of the American mayapple, affects an enzyme and causes breakage of DNA strands.

Irvin S. Snyder Janet L. Stringer

      The dramatic progress made in the transplantation of tissue and organs has been in part due to the use of drugs that modify the immune response in recipients of these tissue and organs. The immunosuppressants are a class of drugs capable of inhibiting the immune system. The action of most cytotoxic drugs or hormonal agents is nonspecific; they may also act upon components of the immune system that are beneficial. Cytotoxic agents, with their inherent ability to kill any cell that will replicate, were originally synthesized as antineoplastic drugs (see the section Cancer chemotherapy (drug)). It was soon discovered, however, that these drugs not only inhibit tumour cell growth but are also able to suppress the cells of the immune system. Subsequently these cytotoxic agents were employed clinically to suppress the immune system to prevent organ or graft rejection in patients undergoing transplants. The major classes of immunosuppressants used in organ transplantation are calcineurin inhibitors, glucocorticoids, and antiproliferative and antimetabolic agents. Monoclonal and polyclonal antibodies are important adjunct therapies.

      Calcineurin inhibitors are the most effective immunosuppressive drugs in use. These drugs target intracellular signaling pathways induced by the activation of T lymphocytes (lymphocyte) (or T cells), a type of white blood cell that directly attacks and eliminates foreign molecules from the body. Cyclosporine and tacrolimus bind to different molecular targets, but both drugs inhibit calcineurin and, as a result, the function of T cells. Cyclosporine is used in patients who are undergoing kidney, liver, heart and other organ transplantation, and it is used for the treatment of rheumatoid arthritis and the skin disease psoriasis. Cyclosporine is usually used in combination with other agents, especially glucocorticoids. Tacrolimus is indicated for the prevention of graft rejection and as emergency therapy for transplant recipients who do not respond to cyclosporine.

      Glucocorticoids, of which the exact mechanism of immunosuppression is unknown, are commonly used in combination with other immunosuppressives both to prevent and to treat transplant rejection.

      A number of antiproliferative and antimetabolite drugs are used as immunosuppressives. Sirolimus, produced by Streptomyces hygroscopicus, inhibits the activation and proliferation of T cells. It is used in combination with a calcineurin inhibitor and glucocorticoids to prevent transplant rejection. Mycophenolate mofetil inhibits the synthesis of guanine nucleotides needed for DNA and RNA synthesis. It also is used in combination with glucocorticoids and a calcineurin inhibitor to prevent transplant rejection. Azathioprine, a relatively toxic drug, exerts its pharmacological action by inhibiting several enzymatic pathways required for the synthesis of DNA. This drug is more effective in suppressing proliferating (dividing) lymphocytes; it is less active against nondividing cells.

      Both polyclonal and monoclonal antibodies (monoclonal antibody) are used in the prevention and treatment of transplant rejection. Antithymocyte globulin is a highly effective immunosuppressant. Antibodies, including muromonab-CD3, directed at a particular protein on the surface of T cells (CD3 antigen) have also proved to be highly effective immunosuppressive agents. Daclizumab and basiliximab, which have been produced with recombinant DNA technology, bind to a receptor found only on the surface of activated T cells. Infliximab is an antibody that binds to the cytokine tumour necrosis factor alpha (TNFα), which prevents TNFα from binding to its receptor. TNFα is thought to play a role in the development of rheumatoid arthritis and Crohn disease, and infliximab, which blocks the activity of TNFα, has been shown to be beneficial in the treatment of patients with these inflammatory diseases.

John Scarne Janet L. Stringer

Additional Reading

Principles of drug action
The basis and mechanisms of drug action are examined in Ernst Mutschler et al., Drug Actions: Basic Principles and Therapeutic Aspects (1995); and Ruth R. Levine, Carol T. Walsh, and Rochelle D. Schwartz-Bloom, Pharmacology: Drug Actions and Reactions, 6th ed. (2000). Drug Facts and Comparisons is an annual publication with monthly updates that describes mechanisms of action, pharmacological properties, and recommended uses of drugs. Comprehensive sources with an emphasis on the clinical applications of drugs include Joel G. Hardman and Lee E. Limbird (eds.), Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001); Bertram G. Katzung, Basic and Clinical Pharmacology, 8th ed. (2001); Theodore M. Brody, Joseph Larner, and Kenneth P. Minneman (eds.), Human Pharmacology: Molecular to Clinical, 3rd ed. (1998); G. Carruthers et al. (eds.), Melmon and Morelli's Clinical Pharmacology, 4th ed. (2000); Harold Kalant and Walter H.E. Roschlau, Principles of Medical Pharmacology, 6th ed. (1998); and Charles R. Craig and Robert E. Stitzel (eds.), Modern Pharmacology with Clinical Applications, 6th ed. (2004).

Antimicrobial drugs
For a discussion of the many aspects of antimicrobial therapy, see Eric M. Scholar and William B. Pratt, The Antimicrobial Drugs, 2nd ed. (2000); and Paul H. Axelsen, Essentials of Antimicrobial Pharmacology (2002). Mark Abramowicz (ed.), Handbook of Antimicrobial Therapy, 16th ed. (2002), is a reference source that gives a summary of antimicrobial agents, their use for specific diseases, doses, costs, and adverse effects.

Nervous system drugs
Eric J. Nestler, Steven E. Hyman, and Robert C. Malenka, Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2001); and S.J. Enna and Joseph T. Coyle, Pharmacological Management of Neurological and Psychiatric Disorders (1998), provide an introduction to the many aspects of neuropharmacology. Margaret Wood and Alastair J.J. Wood (eds.), Drugs and Anesthesia: Pharmacology for Anesthesiologists, 2nd ed. (1990), is a comprehensive reference source. Drugs that affect mood and behaviour are the subject of Alan F. Schatzberg and Charles B. Nemeroff (eds.), The American Psychiatric Press Textbook of Psychopharmacology, 2nd ed. (1998; also published as Essentials of Clinical Pharmacology, 2001); Robert S. Feldman, Jerrold S. Meyer, and Linda F. Quenzer, Principles of Neuropsychopharmacology (1997); and Stuart Yudofsky, Robert E. Hales, and Tom Ferguson, What You Need to Know About Psychiatric Drugs (1991). Applications of antiepileptic drugs are the topic of René H. Levy et al., Antiepileptic Drugs, 5th ed. (2002).

Cardiovascular drugs
William H. Frishman and Edmund H. Sonnenblick (eds.), Cardiovascular Pharmacotherapeutics, 2nd ed. (2002); Alan R. Leff (ed.), Pulmonary and Critical Care Pharmacology and Therapeutics (1996); G.D. Johnston, Fundamentals of Cardiovascular Pharmacology (1999); and William W. Parmley and Kanu Chatterjee (eds.), Cardiovascular Pharmacology (1994), provide an overview of the therapeutic and physiological effects of cardiovascular agents. Robert W. Colman et al. (eds.), Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 4th ed. (2000), is a comprehensive treatment of drugs used in blood coagulation disorders.

Digestive system drugs
Gerald Friedman, Eugene D. Jacobson, and Richard W. McCallum (eds.), Gastrointestinal Pharmacology and Therapeutics (1997); and Mark Feldman, Lawrence S. Friedman, and Marvin H. Sleisenger (eds.), Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management, 7th ed., 2 vol. (2002), provide an analysis of the effects of drugs on the digestive system.

Reproductive and endocrine system drugs
Fran S. Greenspan and David G. Gardner (eds.), Basic and Clinical Endocrinology, 7th ed. (2003); Samuel S.C. Yen, Robert B. Jaffe, and Robert L. Barbieri (eds.), Reproductive Endocrinology, 4th ed. (1999); and Robert Hardin Williams and P. Reed Larsen, Williams Textbook of Endocrinology, 10th ed. (2003), are comprehensive texts that cover hormones used as drugs. David B. Seifer and Elizabeth A. Kennard (eds.), Menopause: Endocrinology and Management (1999), offers a discussion of hormone replacement therapy.

Renal system drugs
Donald Seldin and Gerhard Giebisch (eds.), Diuretic Agents: Clinical Physiology and Pharmacology (1997), is a comprehensive source covering the pharmacology and toxicology of this class of diuretics.

Cancer chemotherapy
Robert C. Bast, Jr., et al. (eds.), Cancer Medicine, 5th ed. (2000), is a comprehensive textbook. Gail M. Wilkes and Terri B. Ades, Patient Education Guide to Oncology Drugs, 2nd ed. (2004), provides easily understandable information on commonly used cancer medications.John Scarne

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