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Drugs and the body Pharmacokinetics describes how drugs are absorbed, distributed and excreted by the body and pharmacodynamics how they act within it. What follows is a simple introduction to some of the (italicised) terms and concepts most frequently encountered. Drugs taken by mouth are only effective if absorbed, unless, like Gaviscon ® or nystatin, they act on, or in, the gut. Many antibiotics are destroyed when given by mouth, although a small alteration in structure may change a drug like benzylpenicillin (penicillin G), which is destroyed by acid, into a drug like penicillin V, which is not. Food may reduce intestinal absorption; milk, for example, reduces the absorption of tetracycline. Delayed gastric emptying, poor peristalsis or ileus will delay arrival in the upper small intestine, where most absorption occurs. Some drugs (like aciclovir) are never completely absorbed. Others, though well absorbed, also show reduced bioavailability because they are metabolised by the liver, before reaching the rest of the body. These are said to show extensive first-pass metabolism. Morphine by mouth shows about 30% bioavailability for this reason. If a drug is well absorbed, this delay can be circumvented by rectal (diazepam), buccal or nasal (midazolam) administration. Intramuscular administration is usually effective, but drug release from the intramuscular ‘depot’ may be slow (naloxone), or deliberately made slow (insulin), and may make IM treatment unpredictable (phenytoin). Intravenous administration is usually the most reliable strategy, but drugs (like vancomycin) may need to be given slowly because even transiently high levels cause problems (such as histamine release). Consistent side effects like this (and the toxic effects of overtreatment) are easier to anticipate than less predictable adverse reactions. For some drugs, tissue levels exceed plasma levels; such drugs are said to have a volume of distribution (V D ) in l/kg that exceeds one. Most drugs are structurally altered by oxidation, reduction or hydrolysis in the liver, and most of the resultant products are pharmacologically inactive. However, some drugs only become active after modification. One such prodrug, chloral hydrate, is inert until transformed into trichloroethanol. Other drugs are ‘neutralised’ (and made more water soluble) by conjugation. However, N-demethylation of diazepam produces desmethyl- diazepam, which remains active in the body for longer than diazepam itself. Babies are slow to deal with many drugs because enzyme levels controlling conjugation (such as acetylation, glucuronidation, methylation and sulphation) are low after birth. Drug interactions can speed up (phenobarbitone) or slow down (cimetidine) the metabolism of other drugs by the liver. Many drugs are eliminated by the kidneys. For some unmetabolised drugs, like gentamicin, glomerular filtration is the only means of elimination. The speed of elimination only changes slowly, therefore, in the weeks after birth. Other drugs, like the penicillins, are excreted with increasing rapidity after delivery as renal tubular secretion becomes more active. The dose required depends on the drug’s distribution within the body, and dose frequency on its speed of elimination. This is usually proportional to the amount present, unless saturation occurs (as with phenytoin). It can be described by the time it takes for the blood level to halve (elimination half life or t 1/2 ), a relationship (Fig. 1a) that is linear when plotted on a log scale (Fig. 1b). The aim is to achieve and sustain levels in the safe therapeutic range. Response to a drug may improve as levels increase (Fig. 1c), but toxic effects may also appear, and the ratio of the toxic to the therapeutic level (therapeutic index) may be quite small. A drug has to be given for a time equal to 4 half lives before levels stabilise (Fig. 1d), unless a loading dose is given (Fig. 1e). 9 0 1 2 Days 3 4 5 (a) 20 10 Levels after a single IV dose Plasma theophylline (mg/L) 0 0 1 2 Days 3 4 5 (d) 20 10 Twice daily treatment 0 0 1 2 Days 3 4 5 (b) 20 10 5 2 1 Log plot Half life 24 hours 0 0% 25% 50% Proportion of babies free of apnoea 75% 100% (c) 40 30 20 10 SVT Fits Tachycardia Toxic range 0 See caption 0 1 2 Days 3 4 5 (e) 20 10 Loading dose and twice daily treatment Loading dose 0 Fig. 1 Baby with a theophylline half life of 24 hours. The therapeutic range (8 –15 mg/l) is shaded. SVT, supraventricular tachycardia. Neonatal Formulary 6: Drug Use in Pregnancy and the First Year of Life, Edited by Edmund Hey C 2011 by Blackwell Publishing Ltd. Published 2011 by Blackwell Publishing Ltd.
