As the pregnancy evolves, profound changes occur in physiology, including fluid and tissue composition.
Absorption. Gastrointestinal motility is decreased but there appears to be no major defect in drug absorption except that reduced gastric emptying delays the appearance in the plasma of orally administered drugs, especially during labour. Absorption from an intramuscular site is likely to be efficient because tissue perfusion is increased due to vasodilatation.
Distribution. Total body water increases by up to 8 litres creating a larger space within which water-soluble drugs may distribute. As a result of haemodilution, plasma albumin (normal 33-55 g/1) declines by some 10 g/1. Thus there is scope for increased free concentration of drugs that bind to albumin. Unbound drug, however, is free to distribute and to be metabolised and excreted; e.g. the free (and pharmacologically active) concentration of phenytoin is unaltered, although the total plasma concentration is reduced.
Therapeutic drug monitoring interpreted by concentrations appropriate for nonpregnant women thus may mislead. A useful general guide during pregnancy is to maintain concentrations at the lower end of the recommended range. Body fat increases by about 4 kg and provides a reservoir for lipid-soluble drugs.
Hepatic metabolism increases, though not blood flow to the liver. Consequently, there is increased clearance of drugs such as phenytoin and theophylline, whose elimination rate depends on liver enzyme activity. Drugs that are so rapidly metabolised that their elimination rate depends on their delivery to the liver, i.e. on hepatic blood flow, have unaltered clearance, e.g. pethidine.
Elimination. Renal plasma flow almost doubles and there is more rapid loss of drugs that are excreted by the kidney, e.g. amoxycillin, the dose of which should be doubled for systemic infections (but not for urinary tract infections as penicillins are highly concentrated in the urine).
Placenta: see page 98. DISEASE
• Surgery that involves resection and reconstruction of the gut may lead to malabsorption of iron, folic acid and fat-soluble vitamins after partial gastrectomy, and of vitamin B12 after ileal resection.
• Delayed gastric emptying and intestinal stasis during an attack of migraine interfere with absorption of drugs.
• Severe low output cardiac failure or shock (with peripheral vasoconstriction) delays absorption from subcutaneous or intramuscular sites; reduced hepatic blood flow prolongs the presence in the plasma of drugs that are so rapidly extracted by the liver that removal depends on their rate of presentation to it, e.g. lignocaine.
Distribution. Hypoalbuminaemia from any cause, e.g. burns, malnutrition, sepsis, allows a higher proportion of free (unbound) drug in plasma. Although free drug is available for metabolism and excretion, there remains a risk of enhanced or adverse responses especially with initial doses of those that are highly protein bound, e.g. phenytoin.
Metabolism. Acute inflammatory disease of the liver (viral, alcoholic) and cirrhosis affect both the functioning of the hepatocytes and blood flow through the liver. Reduced extraction from the plasma of drugs that are normally highly cleared in first pass through the liver results in increased systemic availability of drugs such as metoprolol, labetalol and chlormethiazole. Many other drugs exhibit prolonged t1/, and reduced clearance in patients with chronic liver disease, e.g. diazepam, tolbutamide, rifampicin (see Drugs and the liver, p. 652). Thyroid disease has the expected effects, i.e. drug metabolism is accelerated in hyperthyroidism and diminished in hypothyroidism.
Elimination. Disease of the kidney (p. 541) has profound effects on the pharmacokinetics and thence the actions of drugs that are eliminated by that organ.
• Asthmatic attacks can be precipitated by p-adrenoceptor blockers.
• Malfunctioning of the respiratory centre (raised intracranial pressure, severe pulmonary insufficiency) causes patients to be intolerant of opioids, and indeed any sedative may precipitate respiratory failure.
• Myocardial infarction predisposes to cardiac arrhythmia with digitalis glycosides or sympathomimetics.
• Myasthenia gravis is made worse by quinine and quinidine and myasthenics are intolerant of competitive neuromuscular blocking agents and aminoglycoside antibiotics.
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