Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 9B) doc

7 GENERAL PHARMACOLOGY Time to reach steady state Decline in plasma concentration If a drug is administered by constant-rate i.v infusion it is important to know when steady state has been reached, for maintaining the same dosing schedule will then ensure a constant amount of drug in the body and the patient will experience neither acute toxicity nor decline of effect The t1/2 provides the answer: with the passage of each t1/2 period of time, the plasma concentration rises by half the difference between the current concentration and the ultimate steady-state (100%) concentration Thus: Since t1/2 is the time taken for any plasma concentration to decline by one-half, starting at any steady-state (100%) plasma concentration, in x t1/2 the plasma concentration will fall to 50%, in x t1/2 to 25%, in xt1/2to 12.5%, in xt1/2to 6.25% and in x t1/2 to 3.125% of the original steady-state concentration Hence the il/2 can predict the rate and extent of decline in plasma concentration after dosing is discontinued The relation between t/£ and time to reach steady-state plasma concentration applies to all drugs that obey first-order kinetics, as much to dobutamine (t/£ min) when it is useful to know that an alteration of infusion rate will reach a plateau within 10 min, as to digoxin (il/2 36 h) when a constant (repeated) dose will give a steady-state plasma concentration only after 7.5 days Plasma t1/2 values are given in the text where they seem particularly relevant Inevitably, natural variation within the population produces a range in tl/2 values for any drug For clarity only, single average t1/2 values are given while recognising that the population range may be as much as 50% from the stated figure in either direction A few t1/2 values are listed in Table 7.1 so that they can be pondered upon in relation to dosing in clinical practice in x t1/2, the concentration will reach (100/2) 50%, in x t1/2 (50 + 50/2) 75%, in x i\ (75 + 25/2) 87.5%, in x ty2 (87.5 + 12.5/2) 93.75% in x i\ (93.75 + 6.25/2) 96.875% of the ultimate steady state When a drug is given at a constant rate (continuous or intermittent) the time to reach steady state depends only on the t'/2 and, for all practical purposes, after x t'/2 the amount of drug in the body will be constant and the plasma concentration will be at a plateau Changes in plasma concentration The same principle holds for change from any steady-state plasma concentration to a new steady state brought about by increase or decrease in the rate of drug administration, provided the kinetics remain first-order Thus when the rate of administration is altered to cause either a rise or a fall in plasma concentration, a new steady-state concentration will eventually be reached and it will take a time equal to x tl/2 to reach the new steady state Note that the actual level of any steady-state plasma concentration (as opposed to the time taken to reach it) is determined only by the difference between the rate of drug administration (input) and the rate of elimination (output) If drug elimination remains constant and administration is increased by 50%, in time a new steady-state concentration will be reached which will be 50% greater than the original 102 Biological effect t^ is the time in which the biological effect of a drug declines by one half With drugs that act competitively on receptors (a- and (3adrenoceptor agonists and antagonists) the biological effect t1/2 can be provided with reasonable accuracy TABLE 7.1 Plasma t'/2 of some drugs Drug t'/2 adenosine dobutamine benzylpenicillin amoxycillin paracetamol midazolam tolbutamide atenolol dothiepin (dosulepin) diazepam piroxicam ethosuximide 60 for CYP2C9 and > 50 for CYP2C19.20 Another isoenzyme CYP 2E1, catalyses a reaction involved in the metabolism of alcohol, paracetamol, oestradiol and ethynyloestradiol In all there may be as many as 200 separate P450 isoenzymes and this is why we not need to possess new enzymes for every existing or yet-to-be synthesised drug Each enzyme is encoded by a separate gene and variation in these genes leads to differences between individuals, and sometimes between ethnic groups, in the ability to metabolise drugs Persons characterised by polymorphisms (see p 122) inherit diminished ability to metabolise substrate drugs and if inactivation is dependent on the particular isoenzyme, toxicity may result when these drugs accumulate 19 An isoenzyme is one of a group of enzmes that catalyse the same reaction but differ in protein structure 20 Wolf C R, Smith G, Smith R L 2000 Pharmacogenetics British Medical Journal 320: 987-990 Phase I oxidation of some drugs results in the formation of epoxides which are short-lived and highly reactive metabolites Epoxides are important because they can bind irreversibly through covalent bonds to cell constituents; indeed, this is one of the principal ways in which drugs are toxic to body tissues Glutathione is a tripeptide that combines with epoxides, rendering them inactive, and its presence in the liver is part of an important defence machanism against hepatic damage by halothane and paracetamol Phase II metabolism involves union of the drug with one of several polar (water-soluble) endogenous molecules that are products of intermediary metabolism, to form a water-soluble conjugate which is readily eliminated by the kidney or, if the molecular weight exceeds 300, in the bile Morphine, paracetamol and salicylates form conjugates with glucuronic acid (derived from glucose); oral contraceptive steroids form sulphates; isoniazid, phenelzine and dapsone are acetylated Conjugation with a more polar molecule is also a mechanism by which natural substances are eliminated, e.g bilirubin as glucuronide, oestrogens as sulphates Phase II metabolism almost invariably terminates bilogical activity ENZYME INDUCTION The mechanisms that the body evolved over millions of years to metabolise foreign substances now enable it to meet the modern environmental challenges of tobacco smoke, hydrocarbon pollutants, insecticides and drugs At times of high exposure, our enzyme systems respond by increasing in amount and so in activity, i.e they are induced; when exposure falls off, enzyme production lessens For example, a first alcoholic drink taken after a period of abstinence from alcohol may have quite a significant effect on behaviour but the same drink taken at the end of two weeks' regular imbibing may pass almost unnoticed because the individual's liver enzyme activity is increased (induced) so that alcohol is metabolised more rapidly and has less effect, i.e tolerance has been acquired Inducing substances in general share some important properties: they tend to be lipid-soluble; they are 113 GENERAL PHARMACOLOGY substrates, though sometimes only minor ones, e.g DDT, for the enzymes they induce and generally have long il/r The time for onset and offset of induction depends on the rate of enzyme turnover but significant induction generally occurs within a few days and it passes off over or weeks following withdrawal of the inducer It follows that the capacity of the body to metabolise drugs can be altered by certain medicinal drugs themselves and by other substances, especially when these are used long-term; clearly this phenomenon has implications for drug therapy More than 200 substances have been shown to induce enzymes in animals but the list of proven enzyme inducers in man is much more restricted barbecued meats barbiturates Brussels sprouts carbamazepine DDT (dicophane, and other insecticides) ethanol (chronic use) glutethimide griseofulvin meprobamate phenobarbital phenytoin primidone rifampicin Saint John's Wort sulphinpyrazone tobacco smoke Enzyme induction is relevant to drug therapy for the following reasons: • Clinically important drug interactions may result, e.g in failure of oral contraceptives, loss of anticoagulant control, failure of cytotoxic chemotherapy • Disease may result Antiepilepsy drugs increase the breakdown of dietary and endogenously formed vitamin D, producing an inactive metabolite — in effect a vitamin D deficiency state, which can result in osteomalacia The accompanying hypocalcaemia can increase the tendency to fits and a convulsion may lead to fracture of the demineralised bones • Tolerance to drug therapy may result in and provide an explanation for suboptimal treatment, e.g with an antiepilepsy drug • Variability in response to drugs is increased Enzyme induction caused by heavy alcohol drinking or heavy smoking may be an 114 unrecognised cause for failure of an individual to achieve the expected response to a normal dose of a drug, e.g warfarin, theophylline • Drug toxicity may be more likely A patient who becomes enzyme-induced by taking rifampicin is more likely to develop liver toxicity after paracetamol overdose by increased production of a hepatotoxic metabolite (Such a patient will also present with a deceptively low plasma concentration of paracetamol due to accelerated metabolism, see p 287) ENZYME INHIBITION Consequences of inhibiting drug metabolism can be more profound than those of enzyme induction Effects of enzyme inhibition by drugs also tend to be more selective than those of enzyme induction Consequently, enzyme inhibition offers more scope for therapy (see Table 7.4) Enzyme inhibition by drugs is also the basis of a number of clinically important drug interactions (see p 133) Elimination Drugs are eliminated from the body after being partly or wholly converted to water-soluble metabolites or, in some cases, without being metabolised To avoid repetition the following account refers to drug whereas the processes deal with both drug and its metabolites TABLE 7.4 Some drugs that act by enzyme inhibition Drug Enzyme inhibited Treatment of acetazolamide allopurinol benserazide carbonic anhydrase xanthine oxidase DOPA decarboxylase aldehyde dehydrogenase angiotensin converting enzyme MAO A type cyclooxygenase glaucoma gout Parkinson's disease alcoholism hypertension, cardiac failure depression pain, inflammation MAO B type Parkinson's disease disulfiram enalapril moclobemide nonsteroidal anti-inflammatory drugs selegiline ... sensitivity determine the outcome THERAPEUTIC MONITORING The issues that concern the practising doctor are not primarily those of changing drug plasma concentration but relate to drug effect:... same as, tissue concentration Indeed, for many drugs, correlation between plasma concentration and clinical effect is better than that between dose and effect Yet monitoring therapy by measuring... may cause misleading results if only total drug concentration is measured Many basic drugs, e.g lidocaine, disopyramide, bind to acute phase proteins, e.g o^-acid glycoprotein, which are present