To make rational therapeutic decisions, it is necessary to understand the fundamental concepts linking drug doses to concentrations to clinical responses. The concentration-response relationships for drugs may be graded or quantal. A graded concentration-response curve can be constructed for responses measured on a continuous scale, eg, heart rate. Graded concentration-response curves relate the intensity of response to the size of the dose and, hence, are useful to characterize the actions of drugs. A quantal concentration-response curve can be constructed for drugs that elicit an all-or-none response, eg, presence or absence of convulsions. For most drugs, the doses required to produce a specified quantal effect in a population are log normally distributed, so that the frequency distribution of responses plotted against log dose is a gaussian normal distribution curve. The percentage of the population requiring a particular dose to exhibit the effect can be determined from this curve. When these data are plotted as a cumulative frequency distribution, a sigmoidal dose-response curve is generated. Show
Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drug’s maximal effect as depicted by a graded dose-response curve. EC50 equals KD when there is a linear relationship between occupancy and response. Often, signal amplification occurs between receptor occupancy and response, which results in the EC50 for response being much less (ie, positioned to the left on the x-axis of the log dose-response curve) than KD for receptor occupancy. Potency depends on both the affinity of a drug for its receptor and the efficiency with which drug-receptor interaction is coupled to response. The dose of drug required to produce an effect is inversely related to potency. In general, low potency is important only if it results in a need to administer the drug in large doses that are impractical. Quantal dose-response curves provide information on the potency of drugs that is different from the information derived from graded dose-response curves. In a quantal dose-response relationship, the ED50 is the dose at which 50% of individuals exhibit the specified quantal effect.
The median inhibitory concentration, or IC50, is the concentration of an antagonist that reduces a specified response to 50% of the maximal possible effect.
Efficacy (also referred to as intrinsic activity) of a drug is the ability of the drug to elicit a response when it binds to the receptor. As discussed above, conformational changes in receptors as a result of drug occupancy initiate biochemical and physiologic events that characterize the drug’s response. In some tissues, agonists demonstrating high efficacy can result in a maximal effect, even when only a small fraction of the receptors is occupied (the concept of spare receptors is discussed above).
Selectivity refers to a drug’s ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors. For example, cyclooxygenase-2 (COX-2) preferential NSAIDs demonstrate partial specificity for COX-2, the inducible enzyme formed at sites of inflammation. By comparison, COX-2 selective NSAIDs are without significant effect on COX-1, the constitutive enzyme that performs a range of physiologic functions. For certain drugs, selectivity is species dependent. For example, S(+)-carprofen is COX-2 selective in dogs and cats, nonselective of COX-1 and COX-2 in horses, and COX-2 preferential in calves.
Specificity of drug action relates to the number of different mechanisms involved. Examples of specific drugs include atropine (a muscarinic receptor antagonist), salbutamol (a β2-adrenoceptor agonist), and cimetidine (an H2-receptor antagonist). By contrast, nonspecific drugs result in drug effects through several mechanisms of action. For example, phenothiazine causes blockade of D2-dopamine receptors, α-adrenergic receptors, and muscarinic receptors.
The affinity of a drug for a receptor describes how avidly the drug binds to the receptor (ie, the KD). The chemical forces in drug-receptor interactions include electrostatic forces, van der Waal forces, and the forces associated with hydrogen bonds and hydrophobic bonds. Variation in the strength of these forces, and therefore the thermal energy in the system, determines the degree of association and dissociation of the drug and the receptor. Covalent binding of drug to receptor (exemplified by fluoroquinolones acting on bacteria) leads to formation of an irreversible link.
The therapeutic index of a drug is the ratio of the dose that results in an undesired effect to the dose that results in a desired effect. The therapeutic index of a drug is usually defined as the ratio of LD50 to ED50 (median lethal and median effective doses, respectively, in 50% of individuals), which indicates how selective the drug is in eliciting its desired effect. Values of LD50 and ED50 for this purpose are derived from quantal dose-response curves generated in animal studies.
The information obtained from dose- and concentration-response curves is critically important when choosing between drugs and when determining the dose to administer. A drug is chosen largely on the basis of its clinical effectiveness for a particular therapeutic indication. In this context, the drug concentration at the receptor (determined by the pharmacokinetic properties of the drug) and the efficacy of the drug-receptor complex are the primary determinants of a drug’s clinical effectiveness. The administered dose of a drug, by comparison, depends to a greater extent on potency than on maximal efficacy.
The maximal efficacy of the drug-receptor complex to result in a graded effect is Emax or Imax on a graded dose-response curve. Emax or Imax is derived from a quantitative dose-response relationship for a single animal and varies among individuals. The extrapolation of this value of Emax to a clinical case is only an estimate, but it facilitates a comparison of the maximal efficacy of drugs that result in a specified effect by identical receptors. A drug’s potency (ie, EC50, ED50, or IC50) obtained from either graded or quantal dose-response curves is used to determine the dose that should be administered. The slope of the graded dose-response curve (n in the Hill equation, above) provides information concerning the dose range over which a drug elicits its effect. Other information concerning the selectivity of drug action and the therapeutic index is also obtained from the graded dose-response curve. When quantal effects are being considered, information concerning pharmacologic potency, selectivity of drug action, the margin of safety, and the potential variability of responsiveness among individuals is obtained from quantal dose-response curves. This article may need to be rewritten to comply with Wikipedia's quality standards.(February 2019) This article's tone or style may not reflect the encyclopedic tone used on Wikipedia.(February 2019) The term selectivity describes a drug’s ability to target a single receptor, rendering a predictable physiological response. For example, the binding of acetylcholine to muscarinic tracheal smooth-muscle receptors (M3) results in smooth muscle contractions.
When free-receptors become occupied by agonists - drugs that bind and activate receptors - and antagonists - drugs that inhibit/block activation -, the opportunity for drugs to target their intended receptor decreases as most receptors are already occupied. Therefore, when the amount of free-receptors decreases, the drugs begin binding to other secondary receptors, causing side-effects.
Additive drug-drug interactions occur when numerous substances are added to the body. These can be synergistic (resulting in a larger effect), or antagonistic (resulting in a lesser effect). For example, consuming both ambien and alcohol (both depressants) influxes the GABAA receptors, resulting in the over-stimulation of sleep-inducing chemicals, resulting in unconsciousness. The risk of a drug-drug interaction increases with the number of drugs used.[1] Over a third (36%) of the elderly in the U.S. regularly use five or more medications or supplements, and 15% are at risk of a significant drug-drug interaction.[2] Drug interactions can be additive (the result is what you expect when you add together the effect of each drug taken independently), synergistic (combining the drugs leads to a larger effect than expected), or antagonistic (combining the drugs leads to a smaller effect than expected).[3] On some occasions it is difficult to distinguish between synergistic or additive interactions, since the individual effects of each drug may vary from patient to patient.[4] A synergistic interaction may be beneficial for patients, but may also increase the risk of overdose. Drug interaction predictors enable risk assessment of multiple drugs simultaneously with visualizations risk per therapeutic classes, to indicate a spectrum from no risk to high risk.[5] Both synergy and antagonism can occur during different phases of the interaction between a drug and an organism. The different responses of a drug receptor have resulted in a number of classifications, such as "partial agonist", "competitive agonist", etc. These concepts have fundamental applications in the pharmacodynamics of these interactions. The proliferation of existing classifications at this level and lack of knowledge around drug mechanisms means that it is difficult to offer a clear classification for these concepts. It is possible that authors would misapply any given classification.[6] Direct interactions between drugs are also possible and may occur when two drugs are mixed prior to intravenous injection. For example, mixing Thiopentone and Suxamethonium can lead to the precipitation of thiopentone.[7] The change in an organism's response upon administration of a drug is an important factor in pharmacodynamic interactions. These changes are extraordinarily difficult to classify given the wide variety of modes of action that exist, and the fact that many drugs can cause their effect through a number of different mechanisms. This wide diversity also means that in all but the most obvious cases, it is important to investigate and understand these mechanisms. The well-founded suspicion exists that there are more unknown interactions than known ones.
Pharmacodynamic interactions can occur on:
Modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolism, or excretion of one or both of the drugs compared with the expected behavior of each drug when taken individually. These changes are basically modifications in the concentration of the drugs. In this respect, two drugs can be homergic if they have the same effect on the organism and heterergic if their effects are different. Absorption interactionsChanges in motilitySome drugs, such as prokinetic agents, increase the speed with which a substance passes through the intestines. If a drug is present in the digestive tract's absorption zone for less time its blood concentration will decrease. The opposite will occur with drugs that decrease intestinal motility.
Certain drugs require an acid stomach pH for absorption. Others require the basic pH of the intestines. Any modification in the pH could change this absorption. In the case of the antacids, an increase in pH can inhibit the absorption of other drugs such as zalcitabine (absorption can be decreased by 25%), tipranavir (25%) and amprenavir (up to 35%). However, this occurs less often than an increase in pH causes an increase in absorption. Such as occurs when cimetidine is taken with didanosine. In this case, a gap of two to four hours between taking the two drugs is usually sufficient to avoid the interaction.[11]
Transport and distribution interactionsThe main interaction mechanism is competition for plasma protein transport. In these cases the drug that arrives first binds with the plasma protein, leaving the other drug dissolved in the plasma, which modifies its concentration. The organism has mechanisms to counteract these situations (by, for example, increasing plasma clearance), which means that they are not usually clinically relevant. However, these situations should be taken into account if other associated problems are present such as when the method of excretion is affected.[14] Metabolism interactionsDiagram of cytochrome P450 isoenzyme 2C9 with the haem group in the centre of the enzyme. Many drug interactions are due to alterations in drug metabolism.[15] Further, human drug-metabolizing enzymes are typically activated through the engagement of nuclear receptors.[15] One notable system involved in metabolic drug interactions is the enzyme system comprising the cytochrome P450 oxidases. CYP450Cytochrome P450 is a very large family of haemoproteins (hemoproteins) that are characterized by their enzymatic activity and their role in the metabolism of a large number of drugs.[16] Of the various families that are present in human beings the most interesting in this respect are the 1, 2 and 3, and the most important enzymes are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.[17] The majority of the enzymes are also involved in the metabolism of endogenous substances, such as steroids or sex hormones, which is also important should there be interference with these substances. As a result of these interactions, the function of the enzymes can either be stimulated (enzyme induction) or inhibited (enzyme inhibition). Enzymatic inhibitionIf drug A is metabolized by a cytochrome P450 enzyme and drug B inhibits or decreases the enzyme's activity, then drug A will remain with high levels in the plasma for longer as its inactivation is slower. As a result, enzymatic inhibition will cause an increase in the drug's effect. This can cause a wide range of adverse reactions. It is possible that this can occasionally lead to a paradoxical situation, where the enzymatic inhibition causes a decrease in the drug's effect: if the metabolism of drug A gives rise to product A2, which actually produces the effect of the drug. If the metabolism of drug A is inhibited by drug B the concentration of A2 that is present in the blood will decrease, as will the final effect of the drug. Enzymatic inductionIf drug A is metabolized by a cytochrome P450 enzyme and drug B induces or increases the enzyme's activity, then blood plasma concentrations of drug A will quickly fall as its inactivation will take place more rapidly. As a result, enzymatic induction will cause a decrease in the drug's effect. As in the previous case, it is possible to find paradoxical situations where an active metabolite causes the drug's effect. In this case, the increase in active metabolite A2 (following the previous example) produces an increase in the drug's effect. It can often occur that a patient is taking two drugs that are enzymatic inductors, one inductor, and the other inhibitor or both inhibitors, which greatly complicates the control of an individual's medication and the avoidance of possible adverse reactions. An example of this is shown in the following table for the CYP1A2 enzyme, which is the most common enzyme found in the human liver. The table shows the substrates (drugs metabolized by this enzyme) and the inductors and inhibitors of its activity:[17]
Enzyme CYP3A4 is the most commonly used substrate in a great number of drugs. Over 100 drugs depend on its metabolism for their activity and many others act on the enzyme as inductors or inhibitors. Some foods also act as inductors or inhibitors of enzymatic activity. The following table shows the most common:
Grapefruit juice can act as an enzyme inhibitor. Any study of pharmacological interactions between particular medicines should also discuss the likely interactions of some medicinal plants. The effects caused by medicinal plants should be considered in the same way as those of medicines as their interaction with the organism gives rise to a pharmacological response. Other drugs can modify this response and also the plants can give rise to changes in the effects of other active ingredients. There is little data available regarding interactions involving medicinal plants for the following reasons: St John's wort can act as an enzyme inductor.
They are usually included in the category of foods as they are usually taken as tea or food supplement. However, medicinal plants are increasingly being taken in a manner more often associated with conventional medicines: pills, tablets, capsules, etc. Excretion interactionsRenal excretionHuman kidney nephron. Only the free fraction of a drug that is dissolved in the blood plasma can be removed through the kidney. Therefore, drugs that are tightly bound to proteins are not available for renal excretion, as long as they are not metabolized when they may be eliminated as metabolites.[22]Creatinine clearance is used as a measure of kidney functioning but it is only useful in cases where the drug is excreted in an unaltered form in the urine. The excretion of drugs from the kidney's nephrons has the same properties as that of any other organic solute: passive filtration, reabsorption, and active secretion. In the latter phase, the secretion of drugs is an active process that is subject to conditions relating to the saturability of the transported molecule and competition between substrates. Therefore, these are key sites where interactions between drugs could occur. Filtration depends on a number of factors including the pH of the urine, it having been shown that the drugs that act as weak bases are increasingly excreted as the pH of the urine becomes more acidic, and the inverse is true for weak acids. This mechanism is of great use when treating intoxications (by making the urine more acidic or more alkali) and it is also used by some drugs and herbal products to produce their interactive effect.
Bile excretionBile excretion is different from kidney excretion as it always involves energy expenditure in active transport across the epithelium of the bile duct against a concentration gradient. This transport system can also be saturated if the plasma concentrations of the drug are high. Bile excretion of drugs mainly takes place where their molecular weight is greater than 300 and they contain both polar and lipophilic groups. The glucuronidation of the drug in the kidney also facilitates bile excretion. Substances with similar physicochemical properties can block the receptor, which is important in assessing interactions. A drug excreted in the bile duct can occasionally be reabsorbed by the intestines (in the enterohepatic circuit), which can also lead to interactions with other drugs. Herb-drug interactions are drug interactions that occur between herbal medicines and conventional drugs.[24] These types of interactions may be more common than drug-drug interactions because herbal medicines often contain multiple pharmacologically active ingredients, while conventional drugs typically contain only one.[24] Some such interactions are clinically significant,[25] although most herbal remedies are not associated with drug interactions causing serious consequences.[26] Most herb-drug interactions are moderate in severity.[27] The most commonly implicated conventional drugs in herb-drug interactions are warfarin, insulin, aspirin, digoxin, and ticlopidine, due to their narrow therapeutic indices.[27][28] The most commonly implicated herbs involved in such interactions are those containing St. John’s Wort, magnesium, calcium, iron, or ginkgo.[27] ExamplesExamples of herb-drug interactions include, but are not limited to:
MechanismsThe mechanisms underlying most herb-drug interactions are not fully understood.[31] Interactions between herbal medicines and anticancer drugs typically involve enzymes that metabolize cytochrome P450.[29] For example, St. John's Wort has been shown to induce CYP3A4 and P-glycoprotein in vitro and in vivo.[29] It is possible to take advantage of positive drug interactions. However, the negative interactions are usually of more interest because of their pathological significance, and also because they are often unexpected, and may even go undiagnosed. By studying the conditions that favor the appearance of interactions, it should be possible to prevent them or at least diagnose them in time. The factors or conditions that predispose the appearance of interactions include:[6]
Among US adults older than 56, 4% are taking medication and or supplements that put them at risk of a major drug interaction.[35] Potential drug-drug interactions have increased over time[36] and are more common in the low educated elderly even after controlling for age, sex, place of residence, and comorbidity.[37]
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