Pharmacokinetic and Pharmacodynamic Considerations in Drug Therapy of Cardiac Emergencies

In the drug therapy of cardiac emergencies, it is necessary to rapidly achieve therapeutic drug concentrations and adjust drug dose as the patient’s clinical status changes. Cardiac dysfunction is often present and may alter drug pharmacokinetics. Circulatory failure causes sympathetically mediated vasoconstriction in most tissues, with relative sparing of the brain and heart due to autoregulation. Blood flow to vasoconstricted tissues is reduced, and the available cardiac output is redistributed so that the heart and brain receive a greater fraction. Drug distribution to tissues is therefore slowed, and the initial concentration of drug in blood is higher when circulatory failure is present than when it is absent. This higher blood concentration is reflected by higher concentrations of drug in the brain and heart, which are relatively well perfused. Initial doses of many drugs need to be reduced in patients with circulatory failure to prevent cardiac or central nervous system toxicity. Cardiac output is markedly diminished during cardiopulmonary resuscitation (CPR), but blood flow distribution is qualitatively similar to that of circulatory failure with spontaneous circulation. Pneumatic trousers increase lower extremity vascular resistance and may produce a similar redistribution of blood flow. Drug distribution during the use of CPR or pneumatic trousers should be similar to that of circulatory failure with spontaneous circulation, but few data are available to guide drug dosing during the use of these interventions. Animal data suggest that the central volume of distribution of some drugs during CPR may be as small as one-tenth of normal. Drug metabolism in circulatory failure may be impaired by reduced hepatic blood flow resulting in decreased clearance of highly extracted drugs, or by hepatocellular dysfunction resulting in decreased clearance of poorly extracted drugs. Drug excretion may be impaired by reduced renal blood flow resulting in decreased filtration or secretion and increased reabsorption. The maintenance dose of many drugs must therefore be reduced in the presence of circulatory failure. Intravenous drug administration is preferred in patients with circulatory failure. The central intravenous route is often convenient but must be used cautiously when administering potentially cardiotoxic drugs. Intratracheal administration appears to be a promising alternative for some drugs, such as adrenaline (epinephrine). Intracardiac injections are hazardous and offer no demonstrated advantage over other routes. Interpretation of drug concentrations in blood during cardiac emergencies must take account of the degree of protein binding of drug. Increases in the acute phase reactant α₁-acid glycoprotein may decrease the unbound concentration of highly extracted drugs or increase the total concentration of poorly extracted drugs. Heparin can displace drugs from albumin by increasing free fatty acid concentrations, but this appears to be an in vitro artefact. The site of drug sampling may also be important: arterial concentrations of drug may greatly exceed venous concentrations during the distribution phase due to tissue uptake of drug. Most antiarrhylhmic drugs have half-lives of at least several hours and require many hours to reach a steady-state blood concentration when administered as a constant rate intravenous infusion. Therapeutic blood concentrations of such drugs can be achieved more rapidlv by administering a loading dose consisting of I or more intravenous bolus doses or rapid infusions. Catecholamines have half-lives of several minutes, so a loading dose is not required. The application of pharmacokinetic and pharmacodynamic considerations to drug dosing in cardiac emergencies is illustrated by considering the use of several anti-arrhythmic agents [lignocaine (lidocaine), procainamide, verapamil, propranolol, bretylium], inotropic and vasopressor agents [noradrenaline (norepinephrine), adrenaline, dopamine, dobutamine, isoprenaline (isoproterenol)], and atropine.