CLINICAL PHARMACOLOGY 2003 (PART 9C)

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The following mechanisms are involved. Glomerular filtration. The rate at which a drug enters the glomerular filtrate depends on the concentration of free drug in plasma water and on its molecular weight. Substances that have a molecular weight in excess of 50 000 are excluded from the glomerular filtrate while those of molecular weight less than 10 000 (which includes almost all drugs)21 pass easily through the pores of the glomerular membrane. Renal tubular excretion. Cells of the proximal renal tubule actively transfer strongly charged molecules from the plasma to the tubular fluid. There are two such systems, one...

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E LIM I N A T I O N 7 RENAL ELIMINATION absorbed from the gut, e.g. neomycin. Drug in the blood may also diffuse passively into the gut The following mechanisms are involved. lumen, depending on its pKa and the pH difference between blood and gut contents. The effectiveness Glomerular filtration. The rate at which a drug of activated charcoal by mouth for drug overdose enters the glomerular filtrate depends on the con- depends partly on its adsorption of such diffused centration of free drug in plasma water and on its drug, which is then eliminated in the faeces (see molecular weight. Substances that have a molecular p. 155). weight in excess of 50 000 are excluded from the glomerular filtrate while those of molecular weight Biliary excretion. In the liver there is one active less than 10 000 (which includes almost all drugs)21 transport system for acids and one for bases, similar pass easily through the pores of the glomerular to those in the proximal renal tubule and, in addition, membrane. there is a system that transports un-ionised molecules, e.g. digoxin, into the bile. Small molecules tend to Renal tubular excretion. Cells of the proximal renal be reabsorbed by the bile canaliculi and in general tubule actively transfer strongly charged molecules only compounds that have a molecular weight from the plasma to the tubular fluid. There are two greater than 300 are excreted in bile. (See also, such systems, one for acids, e.g. penicillin, probenecid, enterohepatic circulation, p. 105) frusemide, and another for bases, e.g. amiloride, amphetamine. PULMONARY ELIMINATION Renal tubular reabsorption. The glomerular filtrate contains drug at the same concentration as it is free The lungs are the main route of elimination (and of in the plasma, but the fluid is concentrated uptake) of volatile anaesthetics. Apart from this, progressively as it flows down the nephron so that they play only a trivial role in drug elimination. The a gradient develops, drug in the tubular fluid route however, acquires notable medicolegal sig- becoming more concentrated than in the blood nificance when ethanol concentration is measured in perfusing the nephron. Since the tubular epithelium the air expired by vehicle drivers involved in road has the properties of a lipid membrane, the extent traffic accidents (via the breathalyser). to which a drug diffuses back into the blood will depend on its lipid solubility, i.e. on its pKa in the case of an electrolyte, and on the pH of tubular CLEARANCE fluid. If the fluid becomes more alkaline, an acidic Elimination of a drug from the plasma is quantified drug ionises, becomes less lipid-soluble and its in terms of its clearance. The term has the same reabsorption diminishes, but a basic drug becomes meaning as the familiar renal creatinine clearance, un-ionised (and therefore more lipid-soluble) and which is a measure of removal of endogenous its reabsorption increases. Manipulation of urine creatinine from the plasma. Clearance values can pH is given useful expression when sodium provide useful information about the biological fate bicarbonate is given to alkalinise the urine to treat of a drug. There are pharmacokinetic methods for overdose with aspirin. calculating total body and renal clearance, and the difference between these is commonly taken to FAECAL ELIMINATION represent hepatic clearance. Renal clearance of a drug that is eliminated only by filtration by the When a drug intended for systemic effect is taken kidney obviously cannot exceed the glomerular by mouth, a proportion may remain in the bowel filtration rate (adult male 124 ml/min, female 109 and be excreted in the faeces. Sometimes the ml/min). If a drug is found to have a renal clearance objective of therapy is that drug should not be in excess of this, then it must in addition be actively secreted by the kidney tubules, e.g. benzylpenicillin 21 Most drugs have a molecular weight less than 1000. (renal clearance 480 ml/min). 115
7 GENERAL PHARMACOLOGY BREAST MILK moderate amounts of sulpiride enter milk. Lithium is probably best avoided. Most drugs that are present in a mother's plasma Anxiolytics and sedatives. Benzodiazepines are appear to some extent in her milk though the safe if use is brief but prolonged use may cause amounts are so small that loss of drug in milk is of somnolence or poor suckling. no significance as a mechanism of elimination.22 Beta-adrenoceptor blockers. Neonatal hypoglycaemia Even small amounts, however, may sometimes be may occur. Satalol and atenolol are present in the of significance for the suckling child whose drug highest amounts. metabolic and eliminating mechanisms are immature. Hormones. Oestrogens, progestogens and andro- Whilst most drugs taken by the mother pose no gens suppress lactation in high dose. Oestrogen/ hazard to the child, there are exceptions, as follows: progestogen oral contraceptives are present in amounts too small to be harmful but may suppress DRUGS AND BREAST FEEDING23 lactation if it is not well established. Miscellaneous. Bromocriptine suppresses lactation. Alimentary tract. Sulphasalazine may cause Caffeine may cause infant irritability in high doses. adverse effects and mesalazine appears preferable. Antiasthma. Theophylline and diprophylline are eliminated slowly by the neonate: observe the infant for irritability or disturbed sleep. Anticancer. Regard as unsafe because of inherent Drug dosage toxicity. Antidepressants. Avoid doxepin, a metabolite of Drug dosage can be of five main kinds: which may cause respiratory depression. • Fixed dose. The effect that is desired can be Antiarrhythmics (cardiac). Amiodarone is present obtained at well below the toxic dose (many in high and disopyramide in moderate amounts but mydriatics, diuretics, analgesics, oral effects in the infant have not been reported. contraceptives, antimicrobials) and enough drug Antiepilepsy. General note of caution: observe the can be given to render individual variation infant for sedation and poor suckling. Primidone, clinically insignificant. ethosuximide and phenobarbital are present in milk • Variable dose—with crude adjustments. Here fine in high amounts; phenytoin and sodium valproate adjustments make comparatively insignificant less so. differences and the therapeutic end-point may be Anti-inflammatory. Regard aspirin (salicylates) as hard to measure (depression, anxiety), may unsafe (possible association with Reye's syndrome). change only slowly (thyrotoxicosis), or may very Antimicrobials. Metronidazole is present in milk because of pathophysiological factors in moderate amounts; avoid prolonged exposure. (analgesics, adrenal steroids for suppressing Nalidixic acid and nitrofurantoin should be avoided disease). where glucose-6-phosphate dehydrogenase deficiency • Variable dose—with fine adjustments. Here a vital is prevalent. Avoid clindamycin, dapsone, lincomycin, function (blood pressure, blood sugar), that often sulphonamides. Regard chloramphenicol as unsafe. changes rapidly in response to dose changes and Antipsychotics. Phenothiazines, butyrophenones can easily be measured repeatedly, provides the and thioxanthenes are best avoided unless the end-point. Adjustment of dose must be accurate. indications are compelling: amounts in milk are Adrenocortical replacement therapy falls into small but animal studies suggest adverse effects on this group, whereas adrenocortical the developing nervous system. In particular, pharmacotherapy falls into the group above. • Maximum tolerated dose is used when the ideal 22 therapeutic effect cannot be achieved because of But after mercury poisoning breast milk is a major route of elimination. the occurrence of unwanted effects (anticancer 23 Bennett P N (ed) 1996 Drugs and human lactation. Elsevier, drugs; some antimicrobials). The usual way of Amsterdam. finding this is to increase the dose until 116
DOSING SCHEDULES 7 unwanted effects begin to appear and then to much on the t1// itself, as is illustrated by the reduce it slightly, or to monitor the plasma following cases: concentration. 1. Half-life 6-12 h. In this instance, replacing half Minimum tolerated dose. This concept is not so the initial dose at intervals equal to the t1// can common as the one above, but it applies to long- indeed be a satisfactory solution because dosing term adrenocortical steroid therapy against every 6-12 h is acceptable. inflammatory or immunological conditions, e.g. 2. Half-life greater than 24 h. With once-daily dosing in asthma and some cases of rheumatoid (which is desirable for compliance) giving half arthritis, when the dose that provides the priming dose every day means that more symptomatic relief may be so high that serious drug is entering the body than is leaving it each adverse effects are inevitable if it is continued day, and the drug will accumulate indefinitely. indefinitely. The patient must be persuaded to The solution is to replace only that amount of accept incomplete relief on the grounds of safety. drug that leaves the body in 24 h. This quantity This can be difficult to achieve. can be calculated once the inital dose and dose interval have been decided and the tl/2 is known. Dosing schedules 3. Half-life less than 3 h. Dosing at intervals equal to the i\ would be so frequent as to be unacceptable, and the answer is to use Whatever their type, dosing schedules are simply continuous intravenous infusion if the il/2 is very schemes aimed at achieving a desired effect whilst short, e.g. dopamine il/2, 2 min; steady-state avoiding toxicity. In the discussion that follows it is plasma concentration will be reached in assumed that drug effect relates closely to plasma 5 x t1/, = 10 min) or, if the i\ is longer, e.g. concentration, which in turn relates closely to the lignocaine (iY2,90 min) to use a priming dose as amount of drug in the body. The objectives of a an intravenous bolus followed by a constant dosing regimen where continuing effect is required intravenous infusion. Intermittent are: adminstration of a drug with short t/^ is nevertheless reasonable provided large To specify an initial dose that attains the desired fluctuations in plasma concentration are effect rapidly without causing toxicity. Often the acceptable, i.e. that the drug has a large dose that is capable of initiating drug effect is the therapeutic index. Benzylpenicillin has a il/2 of same as that which maintains it. On repeated 30 min but is effective in a 6-hourly regimen dosing however, it takes 5 x t1/, periods to reach because the drug is so nontoxic that it is possible steady-state concentration in the plasma and this safetly to give a dose that acheives a plasma lapse of time may be undesirable. The effect may be concentration many times in excess of the achieved earlier by giving an inital dose that is minimum inhibitory concentration for sensitive larger than the maintenance dose; the initial dose is organisms. then called the priming or loading dose, i.e. the priming dose is that dose which will acheive a therapeutic effect in an individual whose body does DOSE CALCULATION BY BODY not already contain the drug. WEIGHT AND SURFACE AREA To specify a maintenance dose: amount and There are many circumstances in which a fixed frequency. Intuitively, the maintenance dose might drug dose is likely to be ineffective or toxic in a be half the initial/priming dose at intervals equal to significant number of individuals, e.g. cytotoxic its plasma il/2, for this is the time by which the chemotherapy, aminoglycoside antibiotics. It is plasma concentration that achieves the desired effect usual then to calculate the dose according to body declines by half. Whether or not this approach is weight. Adjustment according to body surface area is satisfactory or practicable, however, depends very also used and may be more appropriate, for this 117
7 GENERAL PHARMACOLOGY correlates better with many physiological phenomena, Sustained-release (oral) preparations can reduce e.g. metabolic rate. The relationship between body the frequency of medication to once a day, and surface area and weight is curvilinear but a compliance is made easier for the patient. Most reasonable approximation is that a 70 kg human has long-term medication for the elderly can now be a body surface area of 1.8 m2. A combination of given as a single morning dose. In addition sustained- body weight and height gives a more precise value release preparations may avoid local bowel toxicity for surface area (which can be obtained from due to high local concentrations, e.g. ulceration of the standard nomograms) and there are several more small intestine with potassium chloride tablets, sophisticated methods.24 and may also avoid the toxic peak plasma con- The issue takes on special significance in the case centrations that can occur when dissolution of the of children if only the adult drug dose is known; formulation, and so absorption of the drug, are rapid. adjustment is then commonly made on the basis of Some sustained-release formulations also contain an body weight, or body surface area, among other immediate-release component to provide rapid, as factors (see p. 126). well as sustained, effect. PROLONGATION OF DRUG ACTION Depot (injectable) preparations are more reliable because the environment in which they are deposited • A larger dose is the most obvious way to prolong is more constant than can ever be the case in the a drug action. As this is not always feasible, alimentary tract and medication can be given at other mechanisms are used. longer intervals, even weeks. In general such pre- • Vasoconstriction will reduce local blood flow so parations are pharmaceutical variants, e.g. micro- that distribution of drug away from an injection crystals, or the original drug in oil, wax, gelatin or site is retarded, e.g. local anaesthetic action is synthetic media. They include phenothiazine neuro- prolonged by combination with adrenaline leptics, the various insulins and penicillins, pre- (epinephrine). parations of vasopressin, and medroxyprogesterone • Slowing of metabolism may usefully extend (i.m., s.c.). Tablets of hormones are sometimes drug action, as when a dopa decarboxylase implanted subcutaneously. The advantages of infre- inhibitor, e.g. carbidopa, is combined with quent administration and better patient compliance levodopa (as co-careldopa) for parkinsonism. in a variety of situations are obvious. • Delayed excretion is seldom practicable, the only important example being the use of probenecid to block renal tubular excretion of penicillin, e.g. REDUCTION OF ABSORPTION TIME when the latter is used in single dose to treat This can be achieved by making a soluble salt of the gonorrhoea. drug which is rapidly absorbed from the site of • Molecular structure may be altered to prolong administration. In the case of s.c. or i.m. injections the effect, e.g. the various benzodiazepines. same objective may be obtained with hyaluronidase, • Pharmaceutical formulation. Manipulating the an enzyme which deploymerises hyaluronic acid, a formulation in which a drug is presented by constituent of connective tissue that prevents the modified-release25 systems can achieve the spread of foreign substances, e.g. bacteria, drugs. objective of an even as well as a prolonged effect. Hyaluronidase combined with an i.m. injection e.g. a 24 local anaesthetic, or a subcutaneous infusion, leads to For example: Livingston EH, Lee S 2001 Body surface area prediction in normal-weight and obese patients. American increased permeation with more rapid absorption. Journal of Physiology Endocrinology and Metabolism 281: Hyaluronidase can also be used to promote resorp- 586-591 tion of tissue accumulation of blood and fluid. 25 The term modified covers several drug delivery systems. Delayed-release: available other than immediately after administration (mesalazine in the colon); sustained-release: slow FIXED-DOSE DRUG COMBINATIONS release as governed by the delivery system (iron, potassium); controlled-release: at a constant rate to maintain unvarying This section refers to combinations of drugs in a plasma concentration (nitrate, hormone replacement therapy). single pharmaceutical formulation. It does not refer 118
DOSING SCHEDULES 7 to concomitant drug therapy, e.g. in infections, consider that the patient needs all the drugs in the hypertension and in cancer, when several drugs are formulation and that the doses are appropriate and given separately. will not need to be adjusted separately. Rational Fixed-dose drug combinations are appropriate combinations can provide advantage, just as for: inappropriate combinations may be dangerous. Thus a combination of iron with folic acid and • Convenience, with improved patient compliance. cyanocobalamin would be hazardous if it delays This is particularly appropriate when two drugs the diagnosis of pernicious anaemia. But the fact are used at constant dose, long term, for an that iron plus a little folic acid is properly used in asymptomatic condition, e.g. a thiazide plus a B- pregnancy for routine anaemia prophylaxis simply adrenoceptor blocker in mild or moderate confirms that combinations can be rationally devised hypertension. The fewer tablets the patients have to meet particular needs. to take, the more reliably will they use them, especially the elderly—who as a group receive more drugs because they have multiple pathology. • Enhanced effect. Single-drug treatment of tuberculosis leads to the emergence of resistant Chronic pharmacology mycobacteria; this effect is prevented or delayed With many drugs there are differences in pharmaco- by using two or more drugs simultaneously. dynamics and pharmacokinetics according to Combining isoniazid with rifampicin (Rifinah, whether their use is in a single dose or over a brief Rimactazid) ensures that single drug treament period (acute pharmacology) or long term (chronic cannot occur; treatment has to be two drugs or pharmacology). The proportion of the population no drug at all. Oral contraception (with an taking drugs continuously for large portions of oestrogen and progestogen combination) is used their lives increases as tolerable suppressive and for the same reason. prophylactic remedies for chronic or recurrent • Minimisation of unwanted effects. Combining conditions are developed; e.g. for arterial hyper- levodopa with benserazide (Madopar) or with tension, diabetes mellitus, mental diseases, epilepsies, carbidopa (Sinemet) slows its metabolism gout, collagen diseases, thrombosis, allergies and outside the central nervous system so that various infections. In some cases long-term treatment smaller amounts of levodopa can be used; this introduces significant hazard into patients' lives reduces adverse effects. and the cure can be worse than the disease if Fixed-dose drug combinations are inappropriate: it is not skilfully managed. In general the dangers • When the dose of one or more of the component of a drug are not markedly increased if therapy drugs may need to be adjusted independently. A lasts years rather than months; exceptions include drug with a wide dose-range that must be renal damage due to analgesic mixtures, and adjusted to suit the patient's response is carcinogenicity. unsuitable for combination with a drug that has a narrow dose range. INTERFERENCE WITH SELF- • If the time course of drug action demands REGULATING SYSTEMS different intervals between administration of the components. When self-regulating physiological systems (gen- • If irregularity of administration, e.g. in response erally controlled by negative feedback systems, to a symptom such as pain or cough, is desirable e.g. endocrine, cardiovascular) are subject to inter- for some ingredients but not for others. ference, their control mechanisms respond to minimise the effects of the interference and to restore the previous steady state or rhythm: this is CONCLUSIONS homeostasis. The previous state may be a normal Therapeutic aims should be clear. Combinations should function, e.g. ovulation (a rare example of a positive not be prescribed unless there is good reason to feedback mechanism), or an abnormal function, e.g. 119
7 GENERAL PHARMACOLOGY high blood pressure. If the body successfully restores receptors (up-regulation). At least some of this may the previous steady state or rhythm then the subject be achieved by receptors moving inside the cell and has become tolerant to the drug, i.e. a higher dose is out again (internalisation and externalisation). needed to produce the desired previous effect. In the case of hormonal contraceptives, persistence Down-regulation and the accompanying receptor of suppression of ovulation occurs and is desired, changes may explain the tolerant or refractory state but persistence of other effects, e.g. on blood seen in severe asthmatics who no longer respond to coagulation and metabolism, is not desired. (3-adrenoceptor agonists. In the case of arterial hypertension, tolerance to a single drug commonly occurs, e.g. reduction of Up-regulation. The occasional exacerbation of peripheral resistance by a vasodilator is compensated ischaemic cardiac disease on sudden withdrawal of by an increase in blood volume that restores the a (3-adrenoceptor blocker may be explained by up- blood pressure; this is why a diuretic is commonly regulation during its administration, so that on used together with a vasodilator in therapy. withdrawal, an above-normal number of receptors suddenly becomes accessible to the normal chemo- Feedback systems. The endocrine system serves transmitter, i.e. noradrenaline (norepinephrine). fluctuating body needs. Glands are therefore capable Up-regulation with rebound sympathomimetic either of increasing or decreasing their output effects may be innocuous to a moderately healthy by means of negative (usually) feedback systems. cardiovascular system, but the increased oxygen An administered hormone or hormone analogue demand of these effects can have serious con- activates the receptors of the feedback system so that sequences where ischaemic disease is present and high doses cause suppression of natural production increased oxygen need cannot be met (angina pectoris, of the hormone. On withdrawal of the administered arrhythmia, myocardial infarction). Unmasking of a hormone restoration of the normal control mech- disease process that has worsened during prolonged anism takes time; e.g. the hypothalamic/pituitary/ suppressive use of the drug, i.e. resurgence, may also adrenal cortex system can take months to recover full contribute to such exacerbations. sensitivity, and sudden withdrawal of adminstered corticosteroid can result in an acute deficiency state The rebound phenomenon is plainly a potential that may be life-endangering. hazard and the use of a (3-adrenoceptor blocker in the presence of ischaemic heart disease would be Regulation of receptors. The number (density) of safer if rebound could be eliminated. (3-adrenoceptor receptors on cells (for hormones, autacoids or local blockers that are not pure antagonists but have hormones, and drugs), the number occupied (receptor some agonist (sympathomimetic ischaemic) activity, occupancy) and the capacity of the receptor to i.e. partial agonists, may prevent the generation of respond (affinity, efficacy) can change in reponse to additional adrenoceptors (up-regulation). Indeed the concentration of the specific binding molecule there is evidence that rebound is less or is absent or ligand,26 whether this be agonist or antagonist with pindolol, a partial agonist (3-adrenoceptor (blocker). The effects always tend to restore cell blocker. function to its normal or usual state. Prolonged high Sometimes a distinction is made between rebound concentrations of agonist (whether administered as a (recurrence at intensified degree of the symptoms drug or over-produced in the body by a tumour) for which the drug was given) and withdrawal cause a reduction in the number of receptors syndrome (appearance of new additional symptoms). available for activation (down-regulation); changes in The distinction is quantitative and does not imply receptor occupancy and affinity and the prolonged different mechanisms. occupation of receptors by inert molecules Rebound and withdrawal phenomena occur (antagonists) leads to an increase in the number of erratically. In general, they are more likely with drugs having a short half-life (abrupt drop in plasma concentration) and pure agonist or antagonist 26 24 Latin: ligare, to bind. action. They are less likely to occur with drugs 120
DOSING SCHEDULES 7 having a long half-life and (probably) with those Specific cell injury or cell functional disorder having a mixed agonist/antagonist (partial agonist) occur with individual drugs or drug classes, e.g. action on receptors. tardive dyskinesia (dopamine receptor blockers), retinal damage (chloroquine, phenothiazines), retro- peritoneal fibrosis (methysergide), NSAIDs (nephro- ABRUPTWITHDRAWAL pathy). Cancer may occur, e.g. with oestrogens Clinically important consequences are known, and (endometrium) and with immunosuppressive might occur for a variety of reasons, e.g. a patient (anticancer) drugs. interrupting drug therapy to undergo surgery. The following are examples: Drug holidays. This term means the deliberate interruption of long-term therapy with the objective • Cardiovascular system: b-adrenoceptor blockers, of restoring sensitivity (which has been lost) or to antihypertensives (especially clonidine). reduce the risk of toxicity. Plainly the need for • Nervous system: all depressants (hypnotics, holidays is a substantial disadvantage for any drug. sedatives, alcohol, opioids), antiepileptics, The principal example is methysergide for refractory antiparkinsonian agents, tricyclic migraine (see Index). Patients sometimes initiate antidepressants. their own drug holidays (see Patient compliance). • Endocrine system: adrenal steroids. • Immune inflammation: adrenal steroids. Dangers of intercurrent illness. These are par- ticularly notable with anticoagulants, adrenal ster- Resurgence of chronic disease which has progressed oids and immunosuppressives. in severity although its consequences have been wholly or partly suppressed, i.e. a catching-up Dangers of interactions with other drugs or food: phenomenon, is an obvious possible consequence see index, food, interactions, individual drugs. of withdrawal of effective therapy, e.g. levodopa in Parkinson's disease; in corticosteroid withdrawal in autoimmune disease there may be both resurgence CONCLUSIONS and rebound. Drugs not only induce their known listed primary actions, Drug discontinuation syndromes, i.e. rebound, but they: withdrawal and resurgence (defined above) are • Evoke compensatory responses in the complex inter- phenomena that are to be expected. In many cases related physiological systems they perturb, and these systems need time to recover on withdrawal of the the exact mechanisms remain obscure but clinicians drug (gradual withdrawal can give this time; it is have no reason to be surprised when they occur, sometimes mandatory and never harmful) and in the case of rebound they may particularly • Induce metabolic changes that may be trivial in the wish to use gradual withdrawal wherever drugs short term, but serious if they persist for a long have been used to modify complex self-adjusting time systems, and to suppress (without cure) chronic • May produce localised effects in specially susceptible diseases. tissues and induce serious cell damage or malfunction • Increase susceptibility to intercurrent illness and to interaction with other drugs that may be taken for OTHERASPECTS OF CHRONIC DRUG new indications. USE Metabolic changes over a long period may induce That such consequences will occur with prolonged disease, e.g. thiazide diuretics (diabetes mellitus), drug use is to be expected. With a knowledge of adrenocortical hormones (osteoporosis), phenytoin physiology, pathology and pharmacology, combined (osteomalacia). Drugs may also enhance their own with an awareness that the unexpected is to be metabolism, and that of other drugs (enzyme expected (There are more things in heaven and induction). earth, Horatio, than are dreamt of in your 121
7 GENERAL PHARMACOLOGY philosophy'27) those patients requiring long-term type of curve that describes the distribution of therapy may be managed safely, or at least with height, weight or metabolic rate in a population. The minimum risk of harm, and enabled to live happy curve is the result of a multitude of factors, some lives. genetic (multiple genes) and some environmental, that contribute collectively to the response of the individual to the drug; they include race, sex, diet, weight, environmental and body temperature, Individual or biological circadian rhythm, absorption, distribution, meta- variation bolism, excretion and receptor density, but no single factor has a predominant effect. Less commonly, variation is discontinuous when differences in response reveal a discrete proportion, Prescribing for special risk large or small, who respond differently from the groups rest, e.g. poor drug oxidisers or fast and slow acetylators of isoniazid. Discontinuous variation That individuals respond differently to drugs, both most commonly occurs when response to a drug is from time to time and from other individuals, is a controlled by a single gene. The term genetic matter of everyday experience. Doctors need to polymorphism refers to the existence in a popula- accommodate for individual variation, for it may tion of two or more discontinuous forms of a explain both adverse response to a drug and failure species which are subject to simple inheritance. By of therapy. Sometimes there are obvious physical convention the frequency of each species is 1% characteristics such as age, race (genetics) or disease or more. that warn the prescriber to adjust drug dose, but there are no external features that signify, e.g., Pharmacogenetics is concerned with drug responses pseudocholinesterase deficiency, which causes pro- that are governed by heredity (see also pharma- longed paralysis after suxamethonium. An under- cogenomics p. 42). Inherited factors causing different standing of the reasons for individual variation in responses to drugs are commonly biochemical because single genes govern the production of enzymes. response to drugs is relevant to all who prescribe. Pharmacogenetic polymorphism is often expressed in the Both pharmacodynamic and pharmacokinetic effects form of different drug metabolising capacities, i.e. genetic are involved and the issues fall in two general differences in a single enzymes. Inherited abnormal categories: inherited influences and environmental responses to drugs mediated by single genes are called and host influences. idiosyncrasy and cause increased, decreased and bizarre responses to drugs. Inherited influences: SOME HERITABLE CONDITIONS Pharmacogenetics CAUSING INCREASED ORTOXIC RESPONSES Consider how individuals in a population might be expected to respond to a fixed dose of a drug; some Defective oxidation. Variation in response to some would show less than the usual response, most drugs can be attributed to genetic polymorphisms would show the usual response and some would involving oxidation of their carbon centres (see show more than the usual response. This type of Metabolism p. 112). The condition was recognised variation is described as continuous and in a graph by abnormal metabolism and response to a standard the result would appear as a normal or Gaussian dose of debrisoquine.28 Individuals may be classed (bell-shaped) distribution curve, similar to the as extensive or poor oxidisers and the latter are at special risk of adverse effects from drugs whose 27 W Shakespeare (1564-1616) Hamlet: IV. 166. inactivation is strongly dependent on the defective 122
I N H E R I T E D I N F L U E N C E S : P H A R M A C O G E N ET I CS 7 isoenzyme. People who have inherited the 'poor' and pyridoxine is added to the antituberculosis oxidiser form of CYP 2D6 may show exaggerated or regimen where there is special risk, e.g. in diabetes, toxic responses to standard doses of a range of drugs alcoholism, renal failure. Acute hepatocellular that include bufuralol, metoprolol, timolol (increased necrosis with isoniazid is more common in rapid -blockade), haloperidol (excessive sedation), fle- acetylators, perhaps because they more readily cainide and nortriptyline. The frequency of poor form an hepatotoxic metabolite. Sulphasalazine oxidisers ranges from 1% in Asians to 6% in whites (salicylazosulphapyridine) (used for rheumatoid (there are over 5 million slow oxidisers in the UK). arthritis) causes adverse effects more frequently in Additionally, a group of ultra-rapid metabolisers is slow acetylators, probably because of the sulpha- now recognised; they may fail to respond to standard pyridine component which is inactivated by drug doses. A similar but distinct condition is acetylation. Dapsone appears to cause more red-cell characterised by deficiency in metabolism of the haemolysis in slow acetylators; rapid acetylators antiepileptic drug mephenytoin (CYP 2C19) and may need higher doses to control dermatitis herpeti- affects 8-23% of Asians and 3-6% of whites. Substrate formis and leprosy. Hydralazine and procaina- drugs include diazepam, citalopram, omeprazole and mide may cause antinuclear antibodies to develop proguanil. A polymorphism of CYP 2C9 affects up to in the plasma of slow acetylators, and some 30% of people and results in slow metabolism (and proceed to systemic lupus erythematosus. risk of toxicity) of warfarin, tolbutamide and losartan. Glucose-6-phosphate dehydrogenase (G6PD) Acetylation is an important route of metabolism deficiency. G6PD activity is important to the for many drugs that possess an amide (-NH2) integrity of the red blood cell through a chain of group. Population studies have shown that most reactions: individuals are either rapid or slow acetylators • It is an important source of reduced but the proportion of each varies greatly between nicotinamide-adenine dinucleotide phosphate races. Some 90% of Japanese are rapid acetylators (NADPH) which maintains erythrocyte whereas in Western populations the proportion is glultathione in its reduced form. 50% or less. Global trends are also recognised. • Reduced glutathione is necessary to keep Along the Pacific Asian littoral, the frequency of haemoglobin in the reduced (ferrous) rather than fast acetylators is highest near the Arctic (Inuit 95%) in its ferric state (methaemoglobin) which is and falls towards the Equator. useless for oxygen carriage. Acetylator status is relevant to therapy with • Build-up of methaemoglobin in erythrocytes certain drugs. Isoniazid may cause peripheral impairs the function of sulphydryl groups, neuropathy in slow acetylators on standard doses especially those associated with the stability of the cell membrane. 28 The poor oxidiser state was first revealed in the laboratory of Individuals who are G6PD deficient may suffer R L Smith, Professor of Biochemical Pharmacology, St Mary's Hospital Medical School, London, who was investigating the from acute haemolysis if they are exposed to cert- variable dose requirements of patients receiving the two ain oxidant substances, including drugs. Charac- antihypertensive drugs debrisoquine and bethanidine. He teristically there is an acute haemolytic episode writes: 'I took 40 mg of debrisoquine sulphate; within two 2-3 days after starting the drug. The haemolysis is hours my blood pressure crashed to 70/50 mmHg and I was self-limiting, only older cells with least enzyme unable to stand for four hours due to incapacitating postural hypotension ... it was two days until the blood pressure being affected. The condition is common in African, returned to normal. Analysis of my urine revealed that Mediterranean, Middle East and South East Asian nearly all the dose was excreted as unchanged drug, whereas races and in their descendants and, throughout other subjects who showed little if any cardiovascular the world, affects some 100 million people. As response to the same dose of debrisoquine, coverted it to the deficiency may result from inheritance of any one of 4-hydroxy metabolite. However, the drama of the clinical response to a single dose of debrisoquine catalysed a search numerous variants of G6PD, affected individuals for its explanation and culminated in the uncovering of the exhibit differing susceptibility to haemolysis, i.e. a first example of a genetic polymorphism of drug oxidation'. substance which affects one G6PD deficient subject 123
7 GENERAL PHARMACOLOGY adversely may be harmless in another. It is usually Alcohol (p. 184). dose related. The following guidelines apply:29 Drugs that carry a definite risk of haemolysis in most G6PD deficient subjects include: dapsone (and SOME HERITABLE CONDITIONS other sulphones), methylene blue, niridazole, nitro- CAUSING DECREASED DRUG furantoin, pamaquin, primaquine, quinolone anti- RESPONSES microbials, some sulphonamides. Drugs that carry a possible risk of haemolysis in Resistance to coumarin anticoagulants. Subjects some G6PD deficient subjects inclulde: aspirin (when of this rare inherited abnormality possess a variant dose exceeds 1 g/d), menadione, probenecid, quini- of the enzyme that coverts vitamin K to its reduced dine; chloroquine and quinine (both are acceptable and active form, which enzyme the coumarins in acute malaria). normally inhibit; patients require 20 times or more Affected individuals are also found to be of the usual dose to obtain an adequate clinical susceptible to exposure to nitrates, anilines and response. A similar condition also occurs in rats and naphthalenes (found in moth balls). Some indi- has practical importance as warfarin, a coumarin, is viduals, particularly children, experience haemoly- used as a rat poison (rats with the gene are dubbed sis after eating the broad bean, Viciafaba, and hence 'super-rats' by the mass media). the term 'favism'.30 Resistance to heparin. Patients with antithrombin Pseudocholinesterase deficiency. The neuromus- deficiency require large doses of heparin therapy cular blocking action of suxamethonium is termin- for anticoagulant effect. (The action of heparin is ated by plasma pseudocholinesterase. 'True' cholin- dependent on the presence of antithrombin in the esterase (acetylcholinesterase) hydrolyses acetyl- plasma.) choline released by nerve endings, whereas various tissues and plasma contain other nonspecific, Resistance to suxamethonium. This rare condition hence 'pseudo', esterases. Affected individuals form is characterised by increased pseudocholinesterase so little plasma pseudocholinesterase that metabol- activity and failure of normal doses of suxameth- ism of suxamethonium is seriously reduced. The onium to cause muscular relaxation (cf Cholin- deficiency characteristically comes to light when a esterase deficiency, above). patient fails to breathe spontaneously after a surgical operation, and assisted ventilation may Resistance to vitamin D. Individuals develop rickets have to be undertaken for hours. Relatives of an which responds only to huge doses of vitamin D, affected individual—for this as for other inherited i.e. x 1000 the standard dose. abnormalities carrying avoidable risk—should be sought out, checked to assess their own risk, and told of the result. The prevalence of pseudo- Bacterial resistance to drugs is genetically deter- cholinesterase deficiency in the UK population is mined and is of great clinical importance. about 1 in 2500. CONCLUSION Malignant hyperthermia (p. 427). As the components of the human genome, and their Porphyria (p. 139). function, are progressively identified, it is certain that many clinically important single gene dif- Thiopurine methyltransferase (p. 292). ferences in response to drugs will be discovered. Once a genetic difference, e.g. a metabolic reaction, 29 is understood, it will be possible to predict what Data based on British National Formulary, 2002. 30 A danger that was recognised by Pythagoras (Greek will happen when drugs of particular molecular philosopher, 580-c500 BC). Nebert D W 1999 Clinical structures are administered. But whether patients Genetics 56: 345-347. should be screened routinely for such differences in 124
E N V IR O N M E N T A L A N D H O S T I N F L U E N C E S 7 drug response is a matter of clinical importance as • Drugs or other substances that come in contact well as economics and logistics. with the skin are readily absorbed as the skin is well hydrated and the stratum corneum is thin; overdose toxicity may result, e.g. with hexachlorophane used in dusting powders and Environmental and host emulsions to prevent infection. influences An understandable reluctance to test drugs extensively in children means that reliable infor- A multitude of factors related both to individuals mation is often lacking. Many drugs do not have a and their environment contribute to differences in licence to be used for children, and their prescription drug response. In general, their precise role is less must be 'off licence', a practice that is recognised as well documented than is the case with genetic necessary, if not actually promoted, by the UK drug factors but their range and complexity are regulatory authorities. illustrated by the following list of likely candidates: age, sex, pregnancy, lactation, exercise, sunlight, Distribution of drugs is influenced by the fact that disease, infection, occupational exposures, drugs, total body water in the neonate amounts to 80% as circadian and seasonal variations, diet, stress, fever, compared to 65% in older children. Consequently: malnutrition, alcohol intake, tobacco or cannabis • Weight-related priming doses of amino- smoking and the functioning of the cardiovascular, glycosides, aminophylline, digoxin and gastrointestinal, hepatic, immunological and renal frusemide need to be larger for neonates than for systems.31 Some of the more relevant influences are older children. discussed here. • Less extensive binding of drugs to plasma proteins is generally without clinical importance AGE but there is a significant risk of elevation of plasma bilirubin (in the neonate) following its The neonate, infant and child32 displacement from protein binding sites by vitamin K, x-ray contrast media or Young human beings differ greatly from adults, not indomethacin. merely in size but also in the proportions and constituents of their bodies and the functioning of Metabolism. Although the enzyme systems that their physiological systems. These differences are inactivate drugs are present at birth, they are reflected in the way the body handles and responds functionally immature, expecially in the preterm to drugs and are relevant to prescribing. baby, and especially for oxidation and for conjugation • Rectal absorption is efficient with an appropriate with glucuronic acid. Inability to conjugate and formulation and has been used for diazepam thus inactivate chloramphenicol causes the fatal and theophyllines; this route may be preferred 'grey' syndrome in neonates. After the first weeks with an uncooperative infant. of life the drug metabolic capacity increases rapidly • The intramuscular or subcutaneous routes tend and young children may require a higher weight- to give unpredictable plasma concentrations, e.g. related dose than adults because of their more rapid of digoxin or gentamicin, because of the relatively metabolic rates. low proportion of skeletal muscle and fat. Intravenous administration is preferred in the Elimination. Glomerular filtration, tubular secretion seriously ill newborn. and reabsorption are low in the neonate (even lower in preterm babies) only reaching adult values 31 in relation to body surface area at 2-5 months. Vessell E S 1982 Clinical Pharmacology and Therapeutics 31:1. Therefore drugs that are eliminated by the kidney 32 A neonate is under 1 month and an infant is 1-12 months (e.g. aminoglycosides, penicillins, diuretics) must of age. be given in reduced dose; after about 6 months, 125
7 GENERAL PHARMACOLOGY body weight- or surface area-related daily doses are reduced. Hence standard doses of drugs, the same for all ages. especially the priming doses of those that are water-soluble, may exceed the requirement. Dosage in the young. No single rule or formula • Plasma albumin concentration tends to be well suffices for all cases. The dose may be established maintained in the healthy elderly but may be by scaling for body weight but this approach may reduced by chronic disease, giving scope for a overdose an obese child, for whom the ideal weight greater proportion of unbound (free) drug; this should calculated from age and height. Doses based may be important when priming doses are on body surface area are generally more accurate, given. and preferably should take into account both body weight and height.33 The fact that the surface area of Metabolism is reduced because liver mass and a 70 kg adult human is 1.8m2 (see p. 118) may then liver blood flow are decreased. Consequently: be used for adjustment, as follows: • Metabolic inactivation of drugs is slower. • Drugs that are normally extensively eliminated Approximate dose = surface area of child (m2)/ in first-pass through the liver appear in higher 1.8 x adult dose concentration in the systemic circulation and Information is increased by making pharmaco- persist in it for longer. There is thus particular kinetic and pharmacodynamic measurements when cause initially to use lower doses of most opportunities present. General guidance is avail- neuroleptics, tricyclic antidepressants and able from formularies, e.g. the British National cardiac antiarrhythmic agents. Formulary, and specialist publications.34 • Capacity for hepatic enzyme induction appears to be lessened. The elderly Elimination. Renal blood flow, glomerular filtration The incidence of adverse drug reactions rises with and tubular secretion decrease with age above 55 age in the adult, especially after 65 years because of: years, a decline that is not signalled by raised serum creatinine concentration because production of this • The increasing number of drugs that they need metabolite is diminished by the age-associated to take because they tend to have multiple diminution of muscle mass. Indeed, in the elderly, diseases serum creatinine may be within the concentration • Poor compliance with dosing regimens range for normal young adults even when the • Bodily changes of aging that require creatinine clearance is 50 ml/min (compared to modification of dosage regimens. 127 ml/min in adult male). Particular risk of adverse effects arises with drugs that are eliminated Absorption of drugs may be slightly slower mainly by the kidney and that have a small because gastrointestinal blood flow and motility are therapeutic ratio, e.g. aminoglycosides, chlorpro- reduced but the effect is rarely important. pamide, digoxin, lithium. Distribution is influenced by the following changes: Pharmacodynamic response may alter with age, to • There is a significant decrease in lean body mass produce either a greater or lesser effect than is so that standard adult doses provide a greater anticipated in younger adults, for example: amount of drug per kg. • Drugs that act on the central nervous system • Total body water is less and in general the appear to produce an exaggerated response in distribution volume of water-soluble drugs is relation to that expected from the plasma 33 concentration, and sedatives and hypnotics may For example: Insley J 1996 A Paediatric Vade-Mecum, 13th have a pronounced hangover effect. These drugs Edition, London, Arnold. 34 Royal College of Paediatrics and Child Health, Neonatal are also more likely to depress respiration and Paediatric Pharmacists Group. Pocket Medicines for because vital capacity and maximum breathing Children. 2001, London. capacity are lessened in the elderly. 126
ENVI RON MENTAL AND HOST INFLUENCES 7 • Response to (3-adrenoceptor agonists and efficacy. Few fixed combinations meet this antagonists appears to be blunted in old age standard. partly, it is believed, through reduction in the 8. When adding a new drug to the therapeutic number of receptors. regimen, see whether another can be withdrawn. • Baroreceptor sensitivity is reduced leading to the 9. Attempt to check whether the patient's potential for orthostatic hypotension with drugs compliance is adequate, e.g. by counting that reduce blood pressure. remaining tablets. Has the patient (or relatives) been properly instructed? These pharmacokinetic and pharmacodynamic diff- 10. Remember that stopping a drug is as erences, together with broader issues particular to important as starting it. the elderly find expression in the choice and use of drugs for this age group, as follows: The old (80+ years) are particulary intolerant of neuroleptics (given for confusion) and of diuretics (given for ankle swelling that is postural and not Rules of prescribing for the elderly35 due to heart failure) which cause adverse electrolyte 1. Think about the necessity for drugs. Is the changes. Both classes of drug may result in admission diagnosis correct and complete? Is the drug to hospital of semicomatose 'senior citizens' who really necessary? Is there a better alternative? deserve better treatment from their juniors. 2. Do not prescribe drugs that are not useful. Think carefully before giving an old person a drug that may have major side-effects, and PREGNANCY consider alternatives. As the pregnancy evolves, profound changes occur 3. Think about the dose. Is it appropriate to in physiology, including fluid and tissue composition. possible alterations in the patient's physiological state? Is it appropriate to the Absorption. Gastrointestinal motility is decreased patient's renal and hepatic function at the but there appears to be no major defect in drug time? absorption except that reduced gastric emptying 4. Think about drug formulation. Is a tablet the delays the appearance in the plasma of orally admin- most appropriate form of drug or would an istered drugs, especially during labour. Absorp- injection, a suppository or a syrup be better? Is tion from an intramuscular site is likely to be the drug suitably packaged for the elderly efficient because tissue perfusion is increased due patient, bearing in mind any disabilities? to vasodilatation. 5. Assume any new symptoms may be due to drug side-effects, or more rarely, to drug Distribution. Total body water increases by up to 8 withdrawal. Rarely (if ever) treat a side-effect litres creating a larger space within which water- of one drug with another. soluble drugs may distribute. As a result of 6. Take a careful drug history. Bear in mind haemodilution, plasma albumin (normal 33-55 g/1) the possibility of interaction with substances declines by some 10 g/1. Thus there is scope for the patient may be taking without your increased free concentration of drugs that bind to knowledge, such as herbal or other albumin. Unbound drug, however, is free to nonprescribed remedies, old drugs taken from distribute and to be metabolised and excreted; e.g. the medicine cabinet or drugs obtained from the free (and pharmacologically active) concentration friends. of phenytoin is unaltered, although the total plasma 7. Use fixed combinations of drugs only when concentration is reduced. they are logical and well studied and they Therapeutic drug monitoring interpreted by either aid compliance or improve tolerance or concentrations appropriate for nonpregnant women thus may mislead. A useful general guide during 35 By permission from Caird FI (ed) 1985 Drugs for the pregnancy is to maintain concentrations at the lower elderly. WHO (Europe) Copenhagen. end of the recommended range. Body fat increases 127
7 GENERAL PHARMACOLOGY by about 4 kg and provides a reservoir for lipid- adverse responses especially with initial doses of soluble drugs. those that are highly protein bound, e.g. phenytoin. Hepatic metabolism increases, though not blood Metabolism. Acute inflammatory disease of the flow to the liver. Consequently, there is increased liver (viral, alcoholic) and cirrhosis affect both the clearance of drugs such as phenytoin and theo- functioning of the hepatocytes and blood flow phylline, whose elimination rate depends on liver through the liver. Reduced extraction from the enzyme activity. Drugs that are so rapidly meta- plasma of drugs that are normally highly cleared in bolised that their elimination rate depends on their first pass through the liver results in increased delivery to the liver, i.e. on hepatic blood flow, have systemic availability of drugs such as metoprolol, unaltered clearance, e.g. pethidine. labetalol and chlormethiazole. Many other drugs exhibit prolonged il/2 and reduced clearance in Elimination. Renal plasma flow almost doubles patients with chronic liver disease, e.g. diazepam, and there is more rapid loss of drugs that are tolbutamide, rifampicin (see Drugs and the liver, excreted by the kidney, e.g. amoxycillin, the dose of p. 652). Thyroid disease has the expected effects, i.e. which should be doubled for systemic infections drug metabolism is accelerated in hyperthyroidism (but not for urinary tract infections as penicillins are and diminished in hypothyroidism. highly concentrated in the urine). Elimination. Disease of the kidney (p. 541) has profound effects on the pharmacokinetics and thence Placenta: see page 98. the actions of drugs that are eliminated by that organ. DISEASE Pharmacodynamic changes • Asthmatic attacks can be precipitated by Pharmacokinetic changes 3-adrenoceptor blockers. • Malfunctioning of the respiratory centre (raised Absorption intracranial pressure, severe pulmonary • Surgery that involves resection and insufficiency) causes patients to be intolerant of reconstruction of the gut may lead to opioids, and indeed any sedative may malabsorption of iron, folic acid and fat-soluble precipitate respiratory failure. vitamins after partial gastrectomy, and of • Myocardial infarction predisposes to cardiac vitamin B12 after ileal resection. arrhythmia with digitalis glycosides or • Delayed gastric emptying and intestinal stasis sympathomimetics. during an attack of migraine interfere with • My asthenia gravis is made worse by quinine and absorption of drugs. quinidine and myasthenics are intolerant of • Severe low output cardiac failure or shock (with competitive neuromuscular blocking agents and peripheral vasoconstriction) delays absorption aminoglycoside antibiotics. from subcutaneous or intramuscular sites; reduced hepatic blood flow prolongs the presence in the plasma of drugs that are so FOOD rapidly extracted by the liver that removal • The presence of food in the stomach, especially if it depends on their rate of presentation to it, e.g. is fatty, delays gastric emptying and the absorption lignocaine. of certain drugs; the plasma concentration of ampicillin and rifampicin may be much reduced if Distribution. Hypoalbuminaemia from any cause, they are taken on a full stomach. More specifically, e.g. burns, malnutrition, sepsis, allows a higher calcium, e.g. in milk, interferes with absorption of proportion of free (unbound) drug in plasma. tetracyclines and iron (by chelation). Although free drug is available for metabolism and • Substituting protein for fat or carbohydrate in excretion, there remains a risk of enhanced or the diet is associated with an increase in drug 128
DRUG I N T E R A C T I O N S 7 oxidation rates. Some specific dietary factors one time, the number of possible combinations induce drug metabolising enzymes, e.g. alcohol, would be more than 64 million. There can be no charcoal grilled (broiled) beef, cabbage and doubt that the number of drug interactions that Brussels sprouts. might occur in this imagined situation would be too large to commit to memory or to paper. But the Protein malnutrition causes changes that are observation that one drug can be shown measurably likely to influence pharmacokinetics, e.g. loss of body to alter the disposition or effect of another drug does weight, reduced hepatic metabolising capacity, hypo- not mean that the interaction is necessarily of clinical proteinaemia. importance. In this section we highlight the circum- Citrus flavinoids in grapefruit (but not orange) stances in which clinically important interactions juice decrease hepatic metabolism and may lead to can occur; we describe their pharmacological basis risk of toxicity from amiodarone, terfenadine (cardiac and provide a schematic framework to identify arrhythmia), benzodiazepines (increased sedation), potential drug interactions during clinical practice. ciclosporin, felodipine (reduced blood pressure). Clinically important adverse drug interactions Alterations in drug action caused by diet are become likely with the following: termed drug-food interactions • Drugs that have a steep dose-response curve and a small therapeutic index (p. 94) so that Drug interactions relatively small quantitative changes at the target site, e.g. receptor or enzyme, will lead to When a drug is administered, a response occurs; if a substantial changes in effect, as with digoxin or second drug is given and the response to the first lithium drug is altered, a drug interaction is said to have • Drugs that are known enzyme inducers or occurred.36 A drug interaction may be desired or inhibitors (pp. 113,114) undesired, i.e. beneficial or harmful. It is deliberately • Drugs that are exhibit saturable metabolism (zero- sought in multidrug treatment of tuberculosis and order kinetics), when small interference with when naloxone is given to treat morphine overdose. kinetics may lead to large alteration of plasma It is an embarrassment when a woman taking a concentration, e.g. phenytoin, theophylline combined oestrogen/progestogen oral contraceptive • Drugs that are used long-term, where precise for a desired interaction is prescribed a drug that is plasma concentrations are required, e.g. oral a metabolic enzyme inducer, with the result that she contraceptives, antiepilepsy drugs, cardiac becomes pregnant. Although dramatic unintended antiarrhythmia drugs, lithium interactions attract most attention and are the • When drugs that may interact are used to treat principal subject of this section they should not the same disease, for this increases their chance distract attention from the many therapeutically of being given concurrently, e.g. theophylline useful interactions that are the basis of rational and salbutamol given for asthma may cause polypharmacy. These useful interactions are referred cardiac arrhythmia to throughout the book whenever it is relevant to • In severely ill patients, for they may be receiving do so. several drugs; signs of iatrogenic disease may be difficult to distinguish from those of existing CLINICAL IMPORTANCE OF DRUG disease and the patients' condition may be such INTERACTIONS that they cannot tolerate further adversity • In patients with significantly impaired liver or If doctors were to limit their prescribing to the kidney function, for these are the principal model list of Essential Drugs (WHO) (p. 28) and organs that terminate drug action were to prescribe four drugs for any patient at any • In the elderly, for they tend to have multiple 36 The term drug-drug interaction is also used, to make the pathology, may receive several drugs distinction from drug-food interactions, and interaction with concurrently, and are specially susceptible to endogenous transmitters and hormones. adverse drug effects (p. 126). 129
7 GENERAL PHARMACOLOGY PHARMACOLOGICAL BASIS OF DRUG i.e. 2 + 2 = 5. Sometimes the two drugs both INTERACTIONS have the action concerned (trimethoprim plus sulphonamide) and sometimes one drug lacks Some knowledge of the pharmacological basis of the action concerned (benserazide plus how one drug may change the action of another is levodopa), i.e. 0 + 2 = 5. useful in obtaining those interactions that are wanted, as well as in recognising and preventing those that are not. IDENTIFYING POTENTIAL DRUG Drug interactions are of two principal kinds: INTERACTIONS 1. Pharmacodynamic interaction: both drugs act on Drugs can interact at any stage from when they are the target site of clinical effect, exerting mixed with other drugs in a pharmaceutical for- synergism (below) or antagonism. The drugs mulation or by a clinician, e.g. in an i.v. infusion or may act on the same or different receptors or syringe, to their final excretion either unchanged or processes, mediating similar biological as metabolites. When a drug is added to an existing consequences. Examples include: alcohol + regimen, a doctor can evaluate the possibility of an benzodiazepine (to produce sedation), interaction by logically thinking through the usual morphine + naloxone (to reverse opioid sequence of processes to which a drug is subject overdose), rifampicin + isoniazid (effective and which are outlined earlier in this chapter, i.e. antituberculosis combination). interactions may occur: 2. Pharmacokinetic interaction: the drugs interact remotely from the target site to alter plasma • outside the body (and other tissue) concentrations so that the • at the site of absorption amount of the drug at the target site of clinical • during distribution effect is altered, e.g. enzyme induction by • on receptors or body systems rifampicin will reduce the plasma concentration (pharmacodynamic interactions) of warfarin; enzyme inhibition by ciprofloxacin • during metabolism will elevate the concentration of theophylline. • during excretion. Interaction may result in antagonism or synergism. INTERACTIONS OUTSIDETHE BODY Antagonism occurs when the action of one drug Intravenous fluids offer special scope for interactions opposes the action of another. The two drugs (incompatibilities) when drugs are added to the simply have opposite pharmacodynamic effects, reservoir or syringe, for a number of reasons. Drugs e.g. histamine and adrenaline on the bronchi exhibit commonly are weak organic acids or bases. They physiological or functional antagonism; or they are often insoluble and to make them soluble it is compete reversibly for the same drug receptor, e.g. necessary to prepare salts. Plainly, the mixing of flumazenil and benzodiazepines exhibit competitive solutions of salts can result in instability which may antagonism. or may not be evident from visible change in the solution, i.e. precipitation. Furthermore, the solutions Synergism37 is of two sorts: have little buffering capacity and pH readily 1. Summation or addition occurs when the effects changes with added drugs. Dilution of a drug in the of two drugs having the same action are reservoir fluid may also lead to loss of stability. additive, i.e. 2 + 2 = 4 (a fi-adrenoceptor blocker A serious loss of potency can result from plus a thiazide diuretic have an additive incompatibility between an infusion fluid and a antihypertensive effect). drug that is added to it. Issues of compatibility 2. Potentiation (to make more powerful) occurs are complex but specific sources of information when one drug increases the action of another, are available in manufacturers' package inserts, formularies or from the hospital pharmacy (where 37 Greek: syn,together; ergos, work. syn, together; ergos, work. the addition ought to be made). The general rule 130
DRUG INTERACTIONS 7 must be to consult these sources before ever adding anaesthetics to delay absorption and usefully a drug to an infusion fluid or mixing in a syringe. prolong local anaesthesia. Mixing drugs formulated for injection in a syringe may cause interaction, e.g. protamine zinc insulin INTERACTIONS DURING contains excess of protamine which binds with DISTRIBUTION added soluble insulin and reduces the immediate effect of the dose. Displacement from plasma protein binding sites may contribute to adverse reaction. A drug that is extensively protein bound can be displaced from its INTERACTIONS AT SITE OF binding site by a competing drug, so raising the free ABSORPTION (and pharmacologically active) concentration of In the complex environment of the gut there are the first drug. Unbound drug, however, is available opportunities for drugs to interfere with each for distribution away from the plasma and for other both directly and indirectly via alteration of metabolism and excretion. Commonly, the result is gut physiology. Usually the result is to impair that the free concentration of the displaced drug absorption. quickly returns close to its original value and any extra effect is transient. Direct chemical interaction in the gut is a For a displacement interaction to become significant cause of reduced absorption. Antacids clinically important, a second mechanism usually that contain aluminium and magnesium form operates: sodium valproate can cause phenytoin insoluble complexes with tetracyclines, iron and toxicity because it both displaces phenytoin from its prednisolone. Milk contains sufficient calcium to binding site on plasma albumin and inhibits its warrant its avoidance as a major article of diet when metabolism. Similarly aspirin and probenecid (and tetracyclines are taken. Colestyramine interferes with possibly other nonsteroidal anti-inflammatory drugs) absorption of levothyroxine, digoxin and some acidic displace the folic acid antagonist methotrexate drugs, e.g. warfarin. Sucralfate reduces the absorption from its protein-binding site and reduce its rate of of phenytoin. Interactions of this type depend on active secretion by the renal tubules; the result is both drugs being in the stomach at the same time, serious methotrexate toxicity. and can be prevented if the doses are separated by Bilirubin is displaced from its binding protein at least 2 hours. by sulphonamides, vitamin K, X-ray contrast media or indomethacin; in the neonate this may Gut motility may be altered by drugs. Slowing of cause a significant risk of kernicterus, for its gastric emptying, e.g. opioid analgesics, tricyclic capacity to metabolise bilirubin is immature. antidepressants (antimuscarinic effect), may delay Direct interaction between drugs may also take and reduce the absorption of other drugs. Purgatives place in the plasma, e.g. protamine with heparin; reduce the time spent in the small intestine and give desferrioxamine with iron; dimercaprol with arsenic less opportunity for the absorption of poorly soluble (all useful). substances such as adrenal steroids and digoxin. Displacement from tissue binding may cause Alterations in gut flora by antimicrobials may unwanted effects. When quinidine is given to patients potentiate oral anticoagulant by reducing bacterial who are receiving digoxin, the plasma concentration synthesis of vitamin K (usually only after anti- of free digoxin may double because quinidine microbials are given orally in high dose, e.g. to treat displaces digoxin from binding sites in tissue (as Helicobacter pylori). well as plasma proteins). As with interaction due to Interactions other than in the gut are exemplified displacement from plasma proteins, however, an by the use of hyaluronidase to promote dissipation additional mechanism contributes to the overall of a s.c. injection, and by the addition of vaso- effect, for quinidine also impairs renal excretion of constrictors, e.g. adrenaline, felypressin, to local digoxin. 131
7 GENERAL PHARMACOLOGY INTERACTIONS DIRECTLY ON cause dangerous bradycardia since both drugs RECEPTORS OR ON BODY SYSTEMS delay atrioventricular conduction. Theophylline potentiates b-adrenergic effects, e.g. This category of pharmacodynamic interactions of salbutamol, and cardiac arrhythmia may result comprises specific interactions between drugs on during treatment of asthma. the same receptor, and includes less precise inter- Lithium toxicity may result if a thiazide diuretic actions involving the same body organ or system; is co-administered; when there is sodium whatever the precise location, the result is altered depletion, resorption of lithium by the proximal drug action. renal tubule is increased and plasma concentrations rise. Action on receptors provides numerous examples. Central nervous system depressant drugs including Beneficial interactions are sought in overdose, as benzodiazepines, several H1-receptor with the use of naloxone for morphine overdose antihistamines, alcohol, phenothiazines, (opioid receptor), of atropine for anticholin- antiepilepsy drugs interact to augment their esterase, i.e. insecticide poisoning (acetylcholine sedative effects. receptor), of isoproterelol (isoprenaline) for overdose Loop diuretics and aminoglycoside antibiotics are with a b-adrenoceptor blocker (b-adrenoceptor), of both ototoxic in high dose; the chance of an adverse phentolamine for the monoamine oxidase inhibitor- event is greater if they are administered together. sympathomimetic interaction ( -adrenoceptor). Unwanted interactions include the loss of the antihypertensive effect of b-blockers when common INTERACTIONS DURING cold remedies containing ephedrine, phenylprop- METABOLISM anolamine or phenylephrine are taken, usually unknown to the doctor; their -adrenoceptor agonist Enzyme induction by drugs and other substances action is unrestrained in the b-blocked patient. (see p. 113) accelerates metabolism and is a cause of therapeutic failure. The following are examples: Actions on body systems provide scope for a variety Oral contraceptive steroids are metabolised more of interactions. The following list shows something rapidly when an enzyme inducer, e.g. phenytoin, is of the range of possibilities; others may be found added, and unplanned pregnancy has occured under accounts of individual drugs: (doctors have been successfully sued for ft-adrenoceptor blockers lose some antihypertensive negligence). In this circumstance an oral efficacy when nonsteroidal anti-inflammatory drugs contraceptive of high oestrogen content may be (NSAIDs), especially indomethacin, are co- substituted (or an alternative contraceptive administered; the effect involves inhibition of method); if breakthrough bleeding occurs, the production of vasodilator prostaglandins by the oestrogen content is not high enough. The kidney leading to sodium retention. metabolism of progestogens is also increased by Diuretics, especially of the loop variety, lose enzyme induction. efficacy if administered with NSAIDs; the Anticoagulant control with warfarin is mechanism may involve inhibition of dependent on a steady state of elimination by prostaglandin synthesis, as above. metabolism. Enzyme induction leads to Potassium supplements, given with potassium- accelerated metabolism of warfarin, loss of retaining diuretics, e.g. amiloride, spironolactone, anticoagulant control and danger of thrombosis. or with ACE-inhibitors may cause dangerous Conversely, if a patient's anticoagulant control is hyperkalaemia. stable on warfarin plus an inducing agent, there is Digoxin is more effective, but also more toxic in a danger of haemorrhage if the inducing agent is the presence of hypokalaemia, which may be discontinued because warfarin will be eliminated caused by thiazide or loop diuretics. at a slower rate. Vempamil given i.v. with a b-blocker, e.g. Chronic alcohol ingestion causing enzyme atenolol, for supraventricular tachycardia may induction is a likely explanation of the tolerance 132
DRUG I N T E R A C T I O N S 7 shown by alcoholics to hydrocarbon anaesthetics INTERACTIONS DURING EXCRETION and to tolbutamide. Clinically important interactions, both beneficial Cidosporin is extensively metabolised; its and potentially harmful, occur in the kidney. concentration in blood may be reduced due to enzyme induction by rifampicin, with danger of Interference with passive diffusion (see p. 96). inadequate immunosuppression hazarding an Reabsorption of a drug by the renal tubule can be organ or marrow transplant. reduced, and its excretion increased, by altering urine pH (see Drug overdose, p. 155). Enzyme inhibition by drugs (see p. 114) potentiates other drugs that are inactivated by metabolism, Interference with active transport. Organic acids causing adverse reactions. Examples appear below, are passed from the blood into the urine by active and it will be noted that inhibitors of isoenzymes of transport across the renal tubular epithelium. microsomal cytochrome P450 figure prominently. Penicillin is mostly excreted in this way. Probenecid, The drugs with which they interact are also given an organic acid that competes successfully with but the list is not complete, and there should be a penicillin for this transport system, may be used to general awareness of the possibility of metabolic prolong the action of penicillin when repeated inhibition when the following drugs are used. administration is impracticable, e.g. in sexually Cimetidine is an inhibitor of several cytochrome transmitted diseases, where compliance is notoriously P450 isoenzymes and so potentiates a large number poor. Interference with renal excretion of methotrexate of drugs ordinarily metabolised by that system, by aspirin, of zidovudine by probenecid and of notably, theophylline, warfarin, phenytoin and digoxin by quinidine, contribute to the potentially propranolol. Depending on the interacting drug, harmful interactions with these combinations. up to 50% inhibition of metabolism may occur when cimetidine 2000 mg/d is taken. Erythromycin inhibits a cytochrome P450 isoenzyme and impairs the metabolism of GUIDETO FURTHER READING theophylline, warfarin, carbamazepine and methylprednisolone. The mean reduction in drug Chamberlain G 1991 The changing body in pregnancy. clearance is 20-25%. British Medical Journal 302: 719-722 Quinolone antimicrobials inhibit specific Ito S 2000 Drug therapy for breast-feeding women. isoenzymes of P450 responsible for the metabolism New England Journal of Medicine 343:118-126 of methylxanthines; thus the clearance of Koren G, Pastuszak A, Ito S 1998 Drugs in pregnancy. theophylline is reduced by ciprofloxacin. New England Journal of Medicine 338:1128-1137 Monoamine oxidase inhibitors (MAOI) are not Pirmohamed M 2001 Pharmacogenetics and completely selective for MAO and impair the pharmacogenomics. British Journal of Clinical metabolism of tricyclic antidepressants, of some Pharmacology 54: 345-357 sympathomimetics, e.g. phenylpropanolamine, Report 1997 Medication for older people. Royal amfetamine, of opioid analgesics, especially College of Physicians, London pethidine, and of mercaptopurine. Rolf S, Harper N J N 1995 Ability of hospital doctors Sodium valproate appears to be a nonspecific to calculate drug doses. British Medical Journal inhibitor and impairs the metabolism of phenytoin, 310: 1173 phenobarbitone and primidone. Roses A D Pharmacogenetics and future drug Serotonin specific reuptake inhibitors (see p. 350) development and delivery. Lancet 355:1358-1361 Allopurinol specifically inhibits xanthine oxidase Strauss S E 2001 Geriatric medicine. British Medical and thus prevents metabolism of azathioprine to Journal 322: 86-88 mercaptopurine (with potentially dangerous Tucker G T 2000 Chiral switches. Lancet 355: toxicity). 1085-1087 133