The pharmacokinetics of propranolol vary according to the route and duration of administration. After i.v. administration, the decline in drug concentrations is biphasic and the drug is cleared very efficiently by the liver, so that its elimination is dependent largely on liver blood flow. Although the drug is some 90-95% bound to plasma, hepatic removal is so avid that both bound and free forms are extracted. Consequently, hepatic elimination is unaffected by drug binding in blood, In contrast, the distribution of drug into the tissues is reduced by plasma binding, so that drug half-life (T 1/2), which varies from 11/2-3 hours among individuals is more prolonged in people with relatively low plasma binding. Recent evidence shows that at all times after i.v. administration the beta-blocking effects of propranolol are related to its plasma concentrations according to the receptor theory. In addition individual differences in the response due to a given total concentration are largely due to variations in plasma binding, the drug's effects being a function of free (unbound) drug in plasma water. After the administration of single oral doses, hepatic extraction remains high and much of the dose is eliminated from hepatic portal blood during transfer from the gut, so that little drug reaches the systemic circulation. In addition, significant amounts of an active metabolite, 4-OH propranolol, are produced so that 2 hours after dosing, propranolol appears more potent that its plasma levels would suggest. With continued administration, the avid removal process becomes saturated, extraction ratio falls and propranolol accumulates some 2-fold. Drug T 1/2 is prolonged to 3-6 hours under these conditions, the ratio of propranolol to its active metabolite increases so that most of its effects can be attributed to the parent drug. Perhaps the most important kinetic fact to emerge is the 20-fold variation in plasma levels found after chronic administration of the same oral dose to different patients. This accounts for most of the individual variation in dosage requirements. Concerning propranolol withdrawal, there is no evidence that the effects of the drug last longer than appropriate for its T 1/2, so that larger doses last longer. Nonetheless, 24-48 hours is more that sufficient for the effects of the drug to dissipate. In view of the rebound angina, arrhythmias and infarction that may occur, abrupt withdrawal should be avoided if possible.