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Biomedical subjects

D G Shand

Publications and source records attributed to D G Shand.

At least 109 records · Page 6Linked to original sources
PubMed1976

Disposition of propoxyphene and propranolol in children.

The disposition of propoxyphene and propranolol was studied in children by means of two protocols which minimized the number of blood samples taken from each child. Propoxyphene and its metabolite, norpropoxyphene, were measured in two plasma samples obtained from different children at various times after a single oral dose. These data were pooled and a plasma concentration/time curve was obtained which was consistent with an average T 1/2 of 3.5 hr in this population. The bioavailability of tablets and a solution of propranolol was compared with a crossover design by obtaining plasma samples at the end of the dosage interval during chronic oral administration of various doses. No clear differences in the bioavailability of the two formulations could be detected. Both drugs showed marked interindividual differences in plasma concentrations following oral administration. These findings are consistent with the high hepatic extraction ratio and large presystemic (first pass) effect previously described in adults. The large individual variability supports the concept of monitoring plasma levels as an aid to therapy and demonstrates that the use of a weight-adjusted dose in children can be only an approximation for initial treatment.

Adolescent↗
PubMed1976

Plasma binding and the affinity of propranolol for a beta receptor in man.

The effects of plasma drug binding on the relationship between propranolol concentration and the antagonism of isoproterenol tachycardia have been investigated in 8 normal subjects and 8 hypertensive patients. During chronic intravenous infusion of propranolol giving a narrow range of total plasma concentrations (22.5 to 50 ng/ml), there was, at best, a poor correlation with effects. On the other hand, there was excellent correlation between efficacy and free drug concentration, which fitted the predictions of the receptor theory of competitive antagonism. The true affinity constant for the binding of propranolol to its receptor can be calculated in terms of free drug concentration (KAfree) and was found to vary 2-fold compared to the affinity constant in terms of total plasma concentration (KAtotal) which varied 4-fold, the greater variation being due to plasma binding differences. Compared to normal subjects, KAfree and KAtotal were smaller in hypertensive subjects, implying lesser sensitivity to the drug, and plasma propranolol binding was greater. There was no difference in KAfree between high- and low-renin essential hypertensives, but KAtotal was smaller in the high-renin group due to increased plasma binding which did not reach statistical significance. It is concluded that the effect of propranolol on heart rate is a predictable function of free drug concentration in man and that the contribution of individual variation in receptor sensitivity to differences in oral dosage requirement is minor compared to that of variations in bioavailability.

Adult↗
PubMed1976

Altered hepatic blood flow and drug disposition.

For some drugs, delivery to the liver by the hepatic circulation is an important determinant of removal by this organ. Classical pharmacokinetic analyses cannot predict the changes produced by altering any of the biological determinants of drug elimination by the liver; hepatic blood flow, metabolic enzyme activity, drug binding and route of administration. However, with the use of a physiological model of hepatic drug elimination, such predictions can be made. This model has been tested experimentally and appears to be valid. Hepatic blood flow can vary over about a 4-fold range from half normal flow to twice logical changes affecting the circulation. For drug clearance to be affected significantly by these changes in flow, the drug must be avidly removed by the liver as reflected in a high hepatic extraction ratio and intrinsic hepatic clearance. This latter term is a useful way to characterise the ability of the liver to irreversibly remove drug from the circulation in the absence of any flow limitation. The clearance of drugs with low intrinsic clearance will not be affected significantly by changes in liver blood flow.

Administration, Oral↗
PubMed1976

Propranolol disposition in chronic liver disease: a physiological approach.

The pharmacokinetics of propranolol can be quantitatively explained on a physiological basis from a knowledge of the effects of four biological determinants: (1) the activity of the drug metabolising enzymes (intrinsic clearance); (2) hepatic blood flow; (3) drug binding, and (4) the anatomical arrangement of the hepatic circulation. Distrubances of all these determinants can occur in chronic liver disease and result in predictable changes in propranolol disposition. These changes, as well as those occurring with other drugs in chronic liver may be explained by 'intact hepatocyte theory' which postulates that the major pathophysiological change occurring in compensated chronic liver disease is a reduction in relatively normally perfused and functioning cell mass with the development of intrahepatic portasystemic vascular shunts.

Administration, Oral↗
PubMed1976

Pharmacokinetics of propranolol: a review.

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.

Biological Availability↗
PubMed1975

Commentary: a physiological approach to hepatic drug clearance.

A physiological approach has been developed recognizing that hepatic blood flow, the activity of the overall elimination process (intrinsic clearance), drug binding in the blood, and the anatomical arrangement of the hepatic circulation are the major biological determinants of hepatic drug clearance. This approach permits quantitative prediction of both the unbound and total drug concentration/time relationships in the blood after intravenous and oral administration, and any changes that may occur as a result of alterations in the above biological parameters. These considerations have led to a classification of drug metabolism based on the hepatic extraction ratio. The proposed classification allows prediction and interpretation of the effects of individual variations in drug-metabolizing activity, route of administration, pharmacokinetic interactions, and disease states on hepatic drug elimination.

Administration, Oral↗
PubMed1975

Plasma concentrations and the time-course of beta blockade due to propranolol.

The effectiveness of intravenously administered propranolol in antagonizing the chronotropic effect of isoproterenol and exercise has been investigated, and has been found at all times to be a predictable function of its plasma concentrations according to the classical drug-receptor theory for competitive antagonism. The data show further that the relationship between effectiveness and time depends on the way in which antagonism is measured. If the dose ratio to isoproterenol (DR) is measured, then (DR-1) declines with time in parallel with drug concentration. On the other hand, if propranolol's effects are measured as percentage reduction in a given response, then this declines linearly with time, even though plasma concentrations decline exponentially. This fact explains why confusion has in the past arisen concerning the relationship of the duration of beta blockade and pharmacokinetic half-life.

Adrenergic beta-Antagonists↗
PubMed1975

Effects of route of administration and blood flow on hepatic drug elimination.

The effects of route of administration and blood flow on the elimination of lidocaine, diphenylhydantoin and propranolol have been investigated in the isolated perfused rat liver. After administration directly into the portal vein, drug concentrations in the reservoir were the same at a given flow rate as concentrations in the hepatic vein after drug was placed directly into the reservoir. The apparent clearance of the drug calculated from these concentrations gave an estimate of intrinsic drug clearance, which is an estimate of the activity of the drug-metabolizing enzymes. Intrinsic clearance is defined as drug clearance when flow is not rate limiting and therefore should be independent of flow. This was confirmed by showing that, at steady state, neither hepatic venous drug concentrations nor concentrations in the reservoir after portal venous administration of lidocaine were affected by altering hepatic blood flow from 10 to 20 ml/min. Propranolol was given as a single dose into the reservoir at flows of 10 and 20 ml/min. The area under the concentration-time curve (AUC) in the reservoir was decreased by increased flow, but AUC for hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged, higher peak concentrations and a more rapid half-life was seen in keeping with the clearance of drug from the reservoir. These data suggest that after oral drug administration, steady-state concentrations or AUC in systemic blood is dependent only on the activity of the enzymes involved (i.e., intrinsic clearance) and unaffected by flow, provided drug is completely absorbed and eliminated only by the liver. Furthermore, this will apply even to drugs whose systemic clearance and drug half-life after i.v. administration is profoundly affected by altered hepatic blood flow.

Administration, Oral↗
PubMed1974

Propranolol.

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Administration, Oral↗
PubMed1974

Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow.

The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.

Animals↗