General Pharmacology

Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. Drug can be defined as a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.

Sources of Drug
Drugs may be synthetic chemicals, chemicals obtained from plants or animals, or products of genetic engineering. A medicine is a chemical preparation, which usually but not necessarily contains one or more drugs, administered with the intention of producing a therapeutic effect. Medicines usually contain other substances (excipients, stabilisers, solvents, etc.) besides the active drug, to make them more convenient to use. To count as a drug, the substance must be administered as such, rather than released by physiological mechanisms. Many substances, such as insulin or thyroxine, are endogenous hormones but are also drugs when they are administered intentionally. Many drugs are not used in medicines but are nevertheless useful research tools.

 The substances used in pharmacology may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined as the science of substances used to prevent, diagnose, and treat disease.

 Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems. Materia medicathe science of drug preparation and the medical use of drugs began to develop as the precursor to pharmacology.

 Biotechnology. Originally, this was the production of drugs or other useful products by biological means (e.g. antibiotic production from microorganisms or production of monoclonal antibodies). Currently in the biomedical sphere, biotechnology refers mainly to the use of recombinant DNA technology for a wide variety of purposes, including the manufacture of therapeutic proteins, diagnostics, genotyping, production of transgenic animals, etc. The many non-medical applications include agriculture, forensics, environmental sciences, etc.

 Pharmacogenetics. This is the study of genetic influences on responses to drugs. Originally, pharmacogenetics focused on familial idiosyncratic drug reactions, where affected individuals show an abnormal-usually adverse-response to a class of drug. It now covers broader variations in drug response, where the genetic basis is more complex.

 Pharmacogenomics. This recent term overlaps with pharmacogenetics, describing the use of genetic information to guide the choice of drug therapy on an individual basis. The underlying principle is that differences between individuals in their response to therapeutic drugs can be predicted from their genetic make-up.

 Pharmacoepidemiology. This is the study of drug effects at the population level. It is concerned with the variability of drug effects between individuals in a population, and between populations. It is an increasingly important topic in the eyes of the regulatory authorities who decide whether or not new drugs can be licensed for therapeutic use. Variability between individuals or populations has an adverse effect on the utility of a drug, even though its mean effect level may be satisfactory. Pharmacoepidemiological studies also take into account patient compliance and other factors that apply when the drug is used under real-life conditions.

 Pharmacoeconomics. This branch of health economics aims to quantify in economic terms the cost and benefit of drugs used therapeutically. It arose from the concern of many governments to provide for healthcare from tax revenues, raising questions of what therapeutic procedures represent the best value for money. This, of course, raises fierce controversy, because it ultimately comes down to putting monetary value on health and longevity. As with pharmacoepidemiology, regulatory authorities are increasingly requiring economic analysis, as well as evidence of individual benefit, when making decisions on licensing.

General Principles of Pharmacology

The Nature of Drugs Drug may be defined as any substance that brings about a change in biologic function through its chemical actions. The drug molecule interacts as an agonist (activator) or antagonist (inhibitor) with a specific molecule in the biologic system that plays a regulatory role. This molecule is called a receptor

 Drugs known as chemical antagonists may interact directly with other drugs, whereas a few drugs (osmotic agents) interact almost exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones ) or may be chemicals not synthesized in the body. Poisons are drugs that have almost exclusively harmful effects. Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants or animals, in contrast to inorganic poisons such as lead and arsenic.

 To interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a location distant from its intended site of action, eg, a pill given orally to relieve a headache

The Physical Nature of Drugs Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide). These factors often determine the best route of administration. The various classes of organic compounds carbohydrates, proteins, lipids, and their constituentsare all represented in pharmacology.

 A number of useful or dangerous drugs are inorganic elements, e.g, lithium, iron, and heavy metals. Many organic drugs are weak acids or bases. This fact has important implications for the way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of such drugs

Drug Size The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase [tPA], a protein of MW 59,050). However, most drugs have molecular weights between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. To have a good "fit" to only one type of receptor, a drug molecule must be sufficiently unique in shape, charge, and other properties, to prevent its binding to other receptors.

 The upper limit in molecular weight is determined primarily by the requirement that drugs must be able to move within the body (eg, from the site of administration to the site of action). Drugs much larger than MW 1000 do not diffuse readily between compartments of the body

 Therefore, very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect. In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into the vascular compartment by intravenous or intraarterial infusion.

Drug Reactivity and Drug-Receptor Bonds Drugs interact with receptors by means of chemical forces or bonds. These are of three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. Thus, the covalent bond formed between the acetyl group of aspirin and cyclooxygenase, its enzyme target in platelets, is not readily broken. The platelet aggregationblocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes) and is reversed only by the synthesis of new enzyme in new platelets, a process that takes several days

 Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds.

 Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets."

 In order to design a highly selective shortacting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds.

 Drug Shape The drug's shape should be complementary to that of the receptor site in the same way that a key is complementary to a lock. The phenomenon of chirality (stereoisomerism) is also very important and more than half of all useful drugs are chiral molecules; that is, they can exist as enantiomeric pairs. Drugs with two asymmetric centres have four diastereomers, eg, ephedrine, a sympathomimetic drug. In most cases, one of these enantiomers is much more potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. If one imagines the receptor site to be like a glove into which the drug molecule must fit to bring about its effect, it is clear why a "leftoriented" drug is more effective in binding to a left-hand receptor than its "right-oriented" enantiomer.

 Rational Drug Design Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug on the basis of information about its biologic receptor. Until recently, no receptor was known in sufficient detail to permit such drug design. However, the characterization of many receptors during the past three decades has changed this picture. A few drugs now in use were developed through molecular design based on a knowledge of the three-dimensional structure of the receptor site. Computer programs are now available that can optimize drug structures to fit known receptors. As more becomes known about receptor structure, rational drug design will become more common.

Drug-Body Interactions
The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamic processes. These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. The actions of the body on the drug are called pharmacokinetic processes. Pharmacokinetic processes govern the Absorption, Distribution, Metabolism and Elimination of drugs and are of great practical importance in the choice and administration of a particular drug for a particular patient, eg, a patient with impaired renal function.

The protein targets for drug action on mammalian cells are receptors ion channels enzymes carrier molecules (transporters).

 Receptors are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body, the chemical messengers being the various hormones, transmitters and other mediators. Many therapeutically useful drugs act, either as agonists or antagonists, on receptors for known endogenous mediators.

Ion Channels
Some ion channels (known as ligand-gated ion channels or ionotropic receptors) incorporate a receptor and open only when the receptor is occupied by an agonist; others are gated by different mechanisms. In general, drugs can affect ion channel function by interacting either with the receptor site of ligand-gated channels, or with other parts of the channel molecule. For example, vasodilator drugs of the dihydropyridine type, inhibit the opening of Ltype calcium channels

Enzymes and Carrier molecules

Many drugs are targeted on enzymes, for example captopril acts on angiotensin-converting enzyme (ACE) and inhibits it. The transport of ions and small organic molecules across cell membranes generally requires a carrier protein, because the permeating molecules are often too polar (i.e. insufficiently lipidsoluble) to penetrate lipid membranes on their own. There are many examples of such carriers, including those responsible for the transport of glucose and amino acids into cells, the transport of ions and many organic molecules by the renal tubule, the transport of Na+ and Ca2+ out of cells, and the uptake of neurotransmitter precursors (such as choline) or of neurotransmitters themselves (such as noradrenaline, 5-hydroxytryptamine [5-HT],

Pharmacodynamic Principles
Most drugs must bind to a receptor to bring about an effect. However, at the cellular level, drug binding is only the first in what is often a complex sequence of steps: Drug (D) + receptor-effector (R)drug-receptor-effector complex effect D + Rdrug-receptor complexeffector moleculeeffect D + RD-R complexactivation of coupling molecule effector moleculeeffect Inhibition of metabolism of endogenous activatorincreased activatorincreased effect Final change in function is accomplished by an effector mechanism. The effector may be part of the receptor molecule or may be a separate molecule. A very large number of receptors communicate with their effectors through coupling molecules

Coupling
When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacologic response. The transduction process that links drug occupancy of receptors and pharmacologic response is often termed coupling. The relative efficiency of occupancy-response coupling is partially determined by the initial conformational change in the receptor

 Affinity is the ability of the drug to bind to the receptor Intrinsic efficacy is the ability of the drug to produce a response The effect occurring in the absence of agonist is termed as constitutive activity

AGONISTS
Agonists are the molecules that upon binding causes a change in the activity of those targets by producing a conformational change Full Agonists have affinity and full intrinsic efficacy i.e. they can activate their targets to maximal extent possible. For example acetylcholine binds to nicotinic receptors and induces a conformational change in the receptorassociated ion channel from non conducting to fully conducting state

 Partial Agonist produce a submaximal response upon binding to their targets i.e. such drugs are said to have low intrinsic efficacy. Thus pindolol a beta adrenoceptor partial agonist may either act as agonist (if no full agonist is present or as an antagonist ( if full agonist such as epinephrine is present)

 Inverse agonists reduce any constitutive activity, thus resulting in in effects that are opposite to the effects produced by conventional agonists at that receptor. They can cause constitutively active targets to become inactive. One of the examples of such a system is the gamma-aminobutyric acid (GABAA) receptor-effector (a chloride channel) in the nervous system. This receptor is activated by the endogenous transmitter GABA and causes inhibition of postsynaptic cells. Conventional exogenous agonists such as benzodiazepines also facilitate the receptor-effector system and cause GABAlike inhibition with sedation as the therapeutic result.

 A model of drug-receptor interaction. The receptor is able to assume two conformations. In the Ri conformation, it is inactive and produces no effect, even when combined with a drug molecule. In the Ra conformation, the receptor can activate downstream mechanisms that produce a small observable effect, even in the absence of drug (constitutive activity). In the absence of drugs, the two isoforms are in equilibrium, and the Ri form is favored. Conventional full agonist drugs have a much higher affinity for the Ra conformation, and mass action thus favors the formation of the RaD complex with a much larger observed effect. Partial agonists have an intermediate affinity for both Ri and Ra forms. Conventional antagonists, according to this hypothesis, have equal affinity for both receptor forms and maintain the same level of constitutive activity. Inverse agonists, on the other hand, have a much higher affinity for the Ri form, reduce constitutive activity and may produce a contrasting physiologic result.

 Antagonists inhibit the ability of their targets to be activated (or inactivated) by physiological or pharmacological antagonists Receptor antagonists bind to receptors but do not activate them. The primary action of antagonists is to prevent agonists (other drugs or endogenous regulatory molecules) from activating receptors.

 Antagonists are divided into Competitive antagonism 1. Reversible (competitive) antagonist 2. Irreversible antagonist Non competitive Antagonism

Competitive antagonism
In the presence of a fixed concentration of agonist, increasing concentrations of a reversible competitive antagonist progressively inhibit the agonist response; high antagonist concentrations prevent response completely. Conversely, sufficiently high concentrations of agonist can surmount the effect of a given concentration of the antagonist; that is, the Emax for the agonist remains the same for any fixed concentration of antagonist.

 The concentration of an agonist required to produce a given effect in the presence of a fixed concentration of competitive antagonist is greater than the agonist concentration required to produce the same effect in the absence of the antagonist.

 The degree of inhibition produced by a competitive antagonist depends on the concentration of antagonist. The competitive -adrenoceptor antagonist propranolol provides a useful example. Patients receiving a fixed dose of this drug exhibit a wide range of plasma concentrations, owing to differences among individuals in clearance of propranolol. As a result, inhibitory effects on physiologic responses to norepinephrine and epinephrine (endogenous adrenergic receptor agonists) may vary widely, and the dose of propranolol must be adjusted accordingly.

 Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to receptors. Here also propranolol provides a useful example: When this drug is administered at moderate doses sufficient to block the effect of basal levels of the neurotransmitter norepinephrine, resting heart rate is decreased. However, increase in the release of norepinephrine and epinephrine that occurs with exercise, postural changes, or emotional stress may suffice to overcome this competitive antagonism. Accordingly, the same dose of propranolol may have little effect under these conditions, thereby altering therapeutic response.

 Some receptor antagonists bind to the receptor in an irreversible or nearly irreversible fashion, either by forming a covalent bond with the receptor or by binding so tightly that, for practical purposes, the receptor is unavailable for binding of agonist. After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit a response comparable to the previous maximal response

 Therapeutically, irreversible antagonists present distinct advantages and disadvantages. Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses. Consequently, the duration of action of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent on the rate of turnover of receptor molecules.

 Phenoxybenzamine, an irreversible -adrenoceptor antagonist, is used to control the hypertension caused by catecholamines released from pheochromocytoma, a tumor of the adrenal medulla. If administration of phenoxybenzamine lowers blood pressure, blockade will be maintained even when the tumor episodically releases very large amounts of catecholamine. In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage. If overdose occurs, however, a real problem may arise. If the -adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized "physiologically," ie, by using a pressor agent that does not act via receptors.

 Antagonists can function noncompetitively in a different way; that is, by binding to a site on the receptor protein separate from the agonist binding site and thereby preventing receptor activation without blocking agonist binding. Although these drugs act noncompetitively, their actions are reversible if they do not bind covalently. Some drugs, often called allosteric modulators, bind to a separate site on the receptor protein and alter receptor function without inactivating the receptor. For example, benzodiazepines bind noncompetitively to ion channels activated by the neurotransmitter -aminobutyric acid (GABA), enhancing the net activating effect of GABA on channel conductance.

Non competitive antagonism

Non-competitive antagonism describes the situation where the antagonist blocks at some point the chain of events that leads to the production of a response by the agonist. For example, drugs such as verapamil and nifedipine prevent the influx of Ca2+ through the cell membrane and thus block nonspecifically the contraction of smooth muscle produced by other drugs.

Chemical Antagonism Chemical antagonism refers to the uncommon situation where the two substances combine in solution; as a result, the effect of the active drug is lost. Examples include the use of chelating agents (e.g. dimercaprol) that bind to heavy metals and thus reduce their toxicity, and the use of neutralising antibodies against protein mediators, such as cytokines and growth factors, a strategy recently applied for therapeutic use

 Protamine, a protein that is positively charged at physiologic pH, can be used clinically to counteract the effects of heparin, an anticoagulant that is negatively charged. In this case, one drug acts as a chemical antagonist of the other simply by ionic binding that makes the other drug unavailable for interactions with proteins involved in blood clotting.

Physiologic antagonism Physiological antagonism is a term used loosely to describe the interaction of two drugs whose opposing actions in the body tend to cancel each other. This type of antagonism occurs between endogenous regulatory pathways mediated by different receptors. For example, several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin.

Pharmacokinetic antagonism This antagonism describes the situation in which the 'antagonist' effectively reduces the concentration of the active drug at its site of action. This can happen in various ways. The rate of metabolic degradation of the active drug may be increased (e.g. the reduction of the anticoagulant effect of warfarin when an agent that accelerates its hepatic metabolism, such as phenobarbital

 The rate of absorption of the active drug from the gastrointestinal tract may be reduced, or the rate of renal excretion may be increased.

Desensitization and Tachyphylaxis

The effect of a drug gradually diminishes when it is given continuously or repeatedly. Desensitisation andtachyphylaxis are synonymous terms used to describe this phenomenon, which often develops in the course of a few minutes. The term tolerance is conventionally used to describe a more gradual decrease in responsiveness to a drug, taking days or weeks to develop, but the distinction is not a sharp one.

 The term refractoriness is also sometimes used, mainly in relation to a loss of therapeutic efficacy. Drug resistance is a term used to describe the loss of effectiveness of antimicrobial or antitumour drugs.

Many different mechanisms can give rise to this type of phenomenon. change in receptors loss of receptors exhaustion of mediators increased metabolic degradation of the drug physiological adaptation active extrusion of drug from cells (mainly relevant in cancer chemotherapy

Change in receptors
Among receptors directly coupled to ion channels, desensitisation is often rapid and pronounced. At the neuromuscular junction, the desensitised state is caused by a conformational change in the receptor, resulting in tight binding of the agonist molecule without the opening of the ionic channel. Phosphorylation of intracellular regions of the receptor protein is a second, slower mechanism by which ion channels become desensitised

Loss of receptors
Prolonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell surface, as a result of internalisation of the receptors. This is shown for -adrenoceptors in and is a slower process than the uncoupling described above. In studies on cell cultures, the number of - adrenoceptors can fall to about 10% of normal in 8 hours in the presence of a low concentration of isoprenaline, and recovery takes several days.

 Similar changes have been described for other types of receptor, including those for various peptides. The internalised receptors are taken into the cell by endocytosis of patches of the membrane, a process that also depends on receptor phosphorylation. This type of adaptation is common for hormone receptors and has obvious relevance to the effects produced when drugs are given for extended periods. It is generally an unwanted complication when drugs are used clinically

Exhaustion of mediators
In some cases, desensitisation is associated with depletion of an essential intermediate substance. Drugs such as amphetamine, which acts by releasing amines from nerve terminals, show marked tachyphylaxis because the amine stores become depleted.

Altered drug metabolism

Tolerance to some drugs, for example barbiturates and ethanol , occurs partly because repeated administration of the same dose produces a progressively lower plasma concentration, because of increased metabolic degradation. On the other hand, the pronounced tolerance to nitrovasodilators, results mainly from decreased metabolism, which reduces the release of the active mediator, nitric oxide.

Physiological adaptation
Decrease of a drug's effect may occur because it is nullified by a homeostatic response. For example, the blood pressure-lowering effect of thiazide diuretics is limited because of a gradual activation of the renin-angiotensin system. Such homeostatic mechanisms are very common, and if they occur slowly the result will be a gradually developing tolerance.

Some important definitions

Homergic Drugs that elicit the same quality of effect and are mutually interactive are called homergic, regardless of whether there is anything in common between the separate response systems. Two drugs are said to be homergic when they produce the same response Heterergic Drugs not sharing the same pharmacodynamic activity, but capable of altering one anothers effects. Two drugs are said to be heterergic, if the drugs donot cause the effect of same quality

Synergism When two drugs combine and the combined effect is greater than the sum of the effect of separate drugs , the phenomenon occurs is synergism. For e.g. Septran contains 2 components sulfamethoxazole and trimethoprim, when given individually they have bacteriostatic effect but when combined together they have bactericidal effects

 Another example is of the cell wall synthesis inhibitor and aminoglycoside. The cell wall synthesis inhibitor (for e.g vancomycin) disrupts cell wall of bacteria, thus enabling aminoglycosides to reach within the cell and effectively kill bacteria

Additive effect of drugs In some cases the drugs don't interact and the effect of the combination is simply the sum of the effects of each drug used individually for example barbiturates and alcohol.

Potentiation Sometimes it is used as synonym of synergism but to precisely differentiate it from synergism, it is applied to that special case of synergism where one of the two drugs possess no efficacy in relation to other drug used. One drug only enhances the effect of the other drug. For example adrenaline is added with the local anaesthetic (LA) to prolong the effect of LA. Adrenaline acts as vasoconstrictor and prolongs the action of LA whereas, it self doesn't possess any local anaesthetic effect

Relation between Drug Dose & Clinical Response

Receptors act as molecules and can quantitatively account for the relation between dose or concentration of a drug and pharmacologic responses, at least in an idealized system. When faced with a patient who needs treatment, the prescriber must make a choice among a variety of possible drugs and devise a dosage regimen that is likely to produce maximal benefit and minimal toxicity.

 To make rational therapeutic decisions, the prescriber must understand how drug-receptor interactions underlie the relations between dose and response in patients, the nature and causes of variation in pharmacologic responsiveness, and the clinical implications of selectivity of drug action. Two major types of dose-response relationships are described Graded dose-response relationship describes the effect of various doses of drug on an individual Quantal dose-response relationship show the effect of various doses of a drug on population of individuals.

Graded Dose-Response Relations

To choose among drugs and to determine appropriate doses of a drug, the prescriber must know the relative pharmacologic potency and maximal efficacy of the drugs in relation to the desired therapeutic effect. These two terms can be explained by the figure which depicts graded dose-response curves that relate the dose of four different drugs to the magnitude of a particular therapeutic effect.

Potency Drugs A and B are said to be more potent than drugs C and D because of the relative positions of their doseresponse curves along the dose axis. Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug's maximal effect. Thus, the pharmacologic potency of drug A is less than that of drug B, a partial agonist because the EC50 of A is greater than the EC50 of B. Potency of a drug depends in part on the affinity (Kd) of receptors for binding the drug and in part on the efficiency with which drug-receptor interaction is coupled to response.

 Some doses of drug A can produce larger effects than any dose of drug B, despite the fact that we describe drug B as pharmacologically more potent. The reason for this is that drug A has a larger maximal efficacy

Maximal Efficacy This parameter reflects the limit of the dose-response relation on the response axis. Drugs A, C, and D in Figure have equal maximal efficacy, whereas all have greater maximal efficacy than drug B. The maximal efficacy (sometimes referred to simply as efficacy) of a drug is obviously crucial for making clinical decisions when a large response is needed. It may be determined by the drug's mode of interactions with receptors (as with partial agonists) or by characteristics of the receptor-effector system involved.

 In an idealized in vitro system, efficacy denotes the relative maximal efficacy of agonists and partial agonists that act via the same receptor. In therapeutics, efficacy denotes the extent or degree of an effect that can be achieved in the intact patient. Thus, therapeutic efficacy may be affected by the characteristics of a particular drug-receptor interaction, but it also depends on a host of other factors

Spare receptors
The maximal effect of drug when achieved at a lower dose of agonist than that required for receptor saturation, that is, the EC50 is less than the Kd . This type of discrepancy between the drug receptor binding curve and the doseresponse curve signies the presence of spare receptors . At least two molecular mechanisms are thought to be responsible for the spare receptor phenomenon. First, the receptor could remain activated after the agonist departs, allowing one agonist molecule to activate several receptors.

 Second, the cell signaling pathways could allow for signicant amplication of a relatively small signal, and activation of only a few receptors could be sufcient to produce a maximal response.

Quantal Dose-Effect Curves

Graded dose-response curves of the sort described above have certain limitations in their application to clinical decision making. For example, such curves may be impossible to construct if the pharmacologic response is an either-or (quantal) event, such as prevention of convulsions, arrhythmia, or death.

 The specified quantal effect may be chosen on the basis of clinical relevance (eg, relief of headache) or for preservation of safety of experimental subjects (eg, using low doses of a cardiac stimulant and specifying an increase in heart rate of 20 bpm as the quantal effect), or it may be an inherently quantal event (eg, death of an experimental animal).

 The quantal dose-effect curve is often characterized by stating the median effective dose (ED50), which is the dose at which 50% of individuals exhibit the specified quantal effect. Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50). If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined.

 Such values provide a convenient way of comparing the potencies of drugs in experimental and clinical settings: Thus, if the ED50s of two drugs for producing a specified quantal effect are 5 and 500 mg, respectively, then the first drug can be said to be 100 times more potent than the second for that particular effect.

Therapeutic index
Quantal dose-effect curves may also be used to generate information regarding the margin of safety to be expected from a particular drug used to produce a specified effect. One measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect, is the therapeutic index.

 In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50 for some therapeutically relevant effect. The precision possible in animal experiments may make it useful to use such a therapeutic index to estimate the potential benefit of a drug in humans. Of course, the therapeutic index of a drug in humans is almost never known with real precision; instead, drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses.

 The therapeutic window, is the range of steady-state concentrations of drug that provides therapeutic efficacy with minimal toxicity. In clinical studies, the dose, or preferably the concentration, of a drug required to produce toxic effects can be compared with the concentration required for therapeutic effects in the population to evaluate the clinical therapeutic index.

Variation in drug responsiveness

Hypersensitivity
Hypersensitivity can be classified as antibodymediated or cell-mediated. Three types of hypersensitivity are antibody-mediated (types I III), while the fourth is cell-mediated (type IV). Hypersensitivity occurs in two phases: the sensitization phase and the effector phase. Sensitization occurs upon initial encounter with an antigen; the effector phase involves immunologic memory and results in tissue pathology upon a subsequent encounter with that antigen.

Type I Hypersensitivity
Immediate, or type I, hypersensitivity is IgEmediated, with symptoms usually occurring within minutes following the patient's encounter with antigen. Type I hypersensitivity results from cross-linking of membrane-bound IgE on blood basophils or tissue mast cells by antigen. This cross-linking causes cells to degranulate, releasing substances such as histamine, leukotrienes, and eosinophil chemotactic factor, which induce anaphylaxis, asthma, hay fever, or urticaria (hives) in affected individuals.

 A severe type I hypersensitivity reaction such as systemic anaphylaxis (eg, from insect envenomation, ingestion of certain foods, or drug hypersensitivity) requires immediate medical intervention. Anaphylactic reactions are acute, generalized reactions that occur when a previously sensitized person is re-exposed to a particular antigen. Reactions range in severity from pruritus and urticaria to bronchospasm, respiratory distress, laryngeal edema, circulatory collapse, and death.