Circulatory failure, or the inability of the heart to provide sufficient cardiac output to sat­isfy tissue metabolic requirements, is the most important and most common cause of altered pharmacokinetics during cardiac emergencies. Circulatory failure may result from decreased myocardial contractility, arrhythmias that allow insufficient time for diastolic filling or impair atrioventricular synchrony, circulatory stresses such as increased afterload or hypovolaemia, valvular dysfunction, tamponade, or a variety of less common insults.

Regardless of the aetiology, circulatory fail­ure elicits characteristic compensatory haemodynamic adjustments, mediated in large part by activation of the sympathetic nervous system [Peniel & Benowitz 1984; Benowitz & Meister 1978]. Enhanced sympathetic tone in­creases cardiac contractility and peripheral vas­cular resistance, both of which serve to main­tain arterial blood pressure. The increase in peripheral vascular resistance, however, is not uniform among different vascular beds.

Organs with high metabolic requirements such as the heart and brain exhibit autoregulation; despite sympathetic stimulation, the vessels in these or­gans remain relatively vasodilated as a result of the local effects of hypoxia, lactic acid or other products of anaerobic metabolism that accu­mulate when organ perfusion is reduced. Blood flow to the heart and brain tends to be pre­served, while vasoconstriction decreases blood flow in other organs such as the skin, muscles, and splanchnic organs.

Pathophysiology of Cardiopulmonary Resuscitation (CPR)

Cardiac output during cardiopulmonary resuscitation (CPR) is severely compromised; in humans the mean arterial pressure is less than 50% of normal (Chandra et al. 1981; McDonald 1981), and cardiac output in dogs is less than 30% of normal (Vorhees et al. 1980). Haemodynamic measurements are difficult to obtain in patients during CPR, but animal data suggest that changes in blood flow distribution are qualitatively similar to those observed with circulatory failure and spontaneous circulation.

Blood flow during CPR in anaesthetised, electrically fibrillated dogs is reduced to all organs, but is least reduced to the brain and next least to the heart (Vorhees et al. 1980). For the purpose of pharmacokinetic considerations, CPR and circulatory failure with spontaneous circulation can be considered to be similar, in that total cardiac output is reduced and the pattern of blood redistribution during promptly initiated CPR resembles that seen in circulatory failure.

The mechanism by which anaesthetic drugs produce unconsciousness is still unknown. Meyer in 1899 and Overton in 1901 noted that within any group of drugs, anaesthetic potency correlates well with lipid solubility, and most modern theories agree that the site of action is probably the lipid bilayer of nerve cell mem­branes, or possibly a protein receptor in this sit­uation, but further knowledge is limited.

Inhalational Agents

Anaesthetic practice is unique in that a high proportion of the drugs are administered by the inhalational route. Such agents must either be gaseous, or the vapour of volatile liquids (Vari­ous Authors 1984).
Of the original three inhalational agents – ni­trous oxide, ether and chloroform – the first two are still used widely.

The greatest disadvantage of many of the volatile liquids and gases has been their flammable nature; the main reason for the decline of cyclopropane, which enjoyed wide popularity until the advent of halothane in 1956. Halothane, which has been firmly es­tablished as the basis of many general anaes­thetic techniques over the past 25 years, is not without its drawbacks, and investigation of new compounds continues. None of these is better overall than halothane, but in recent years ha­lothane has been slowly yielding popularity to enflurane and more recently to isoflurane.

Disposition and Pharmacological Properties

The uptake and distribution of inhalational anaesthetics is complex (Eger 1974). One must distinguish between an effective gas tension (partial pressure) and the total amount of drug dissolved in blood; it is the tension which de­termines the depth of anaesthesia. When a con­stant concentration of the anaesthetic is in­haled, the concentration in the alveoli rises gradually toward the inhaled level.

How quickly it rises will depend on the ventilation of the al­veoli (which may be reduced if the drug is ir­ritant or depresses respiration) and on the rate at which the drug is taken up into the blood from the alveoli. If the solubility (blood/gas sol­ubility coefficient) of the drug is high, then it will take longer for equilibrium to be attained, because (a) more of the drug needs to be dissolved in the blood for a given tension to be reached, and (b) the more rapid removal of the drug from the alveoli reduces the concentration here, and therefore reduces the gradient driving it from alveolus to capillary blood. A less sol­uble drug will likewise reach equilibrium more rapidly.

The rate of removal of drug into the blood will also depend on the cardiac output, which may be influenced by the drug itself; and finally the rate at which the tension of the drug in the blood rises toward that in alveoli will also depend on the rate at which it is distributed to other tissues, not only the target organ (brain), but also muscle, fat depots, etc. Such differences between infants and adults helps to explain the more rapid alveolar uptake of inhalational anaesthetics in the neonate. (Cook 1976; Eger et al. 1971).

The ability of the drug in the blood to pro­duce anaesthesia will depend on its anaesthetic potency. The minimal alveolar concentration (MAC) of the drug which will cause anaesthesia in 50% of patients is a measure often used to compare the potencies of different inhalational agents.