Clinical Pharmacokinetics and Endocrine Disorders Therapeutic Implications

Abstract

Endocrine disorders are common and produce widespread changes in cellular and organ function. Alterations in the sensitivity of patients with thyroid disorders to digoxin, anticoagulants and sedatives have been recognised for many years. Many of the recently documented kinetic alterations in endocrine patients are explicable on the basis of disease-induced changes in hepatic drug metabolism, protein binding and renal function. In hyperthyroidism the rate of absorption of paracetamol, propranolol and oxazepam is increased due to increased gastrointestinal motility. The volume of distribution of propranolol and digoxin is increased and there is decreased binding of both basic and acidic drugs as a consequence of alterations in α₁-acid glycoprotein and albumin concentration. The rate of glucuronidation of paracetamol and oxazepam is increased in hyperthyroidism. While oxidative metabolism of antipyrine, propranolol, metoprolol and theophylline is enhanced, the clearance of a number of other agents, including diazepam, warfarin, antithyroid drugs and phenytoin, is unaltered. The systemic clearance of propranolol is enhanced as a consequence of a 50% increase in liver blood flow. The rate of elimination of a number of endogenous substances, including Cortisol, thyroid hormones and insulin, also appear to be enhanced. Hyperthyroidism has a variable effect on renal function, with a possible increase in digoxin elimination, but no effect on the clearance of renally excreted β-blockers, atenolol, sotalol and nadolol. These kinetic changes suggest that individualisation and higher than normal dosage of propranolol is necessary to control hyperthyroidism, and in thyrotoxic atrial fibrillation higher doses of digoxin or additional therapy with β-blockers, or verapamil, may be indicated. The increased sensitivity of thyrotoxic patients to warfarin suggests care with dosage and frequent monitoring of response are warranted. Less information is available concerning hypothyroidism, but there is a general trend for decreased absorption of paracetamol and propranolol. In addition, the volume of distribution of digoxin is reduced, as is renal clearance. Limited studies suggest no alteration in the glucuronidation of oxazepam, but antipyrine clearance appears to be reduced. Steady-state propranolol concentrations are elevated in hypothyroidism and there appears to be a decreased metabolism of thyroid hormones and Cortisol. Preliminary information suggests the binding of propranolol is increased. Thus, in the treatment of hypothyroid patients, a lower dosage of propranolol may be required. These patients also appear to be extremely sensitive to digoxin, partly because of decreased renal elimination and distribution; thus a smaller maintenance and loading dose is required. Increased sensitivity to oxazepam has been recorded, which cannot be explained on the basis of kinetic alterations. Obesity may produce profound alterations in kinetics, particularly distribution. A small increase in the volume of distribution of Cimetidine, prednisolone and digoxin, and a moderate increase in that of aminoglycosides, paracetamol, theophylline, Ibuprofen, lorazepam, alprazolam and oxazepam has been noted. The greatest increase has been found with highly soluble drugs such as thiopentone, verapamil, lignocaine (lidocaine), diazepam and midazolam. Whereas drug absorption does not appear to be altered in obesity, the hepatic metabolism of drugs that are conjugated increases as a function of bodyweight. Therefore the clearance of oxazepam, lorazepam and paracetamol is enhanced. Variable results have been found with regard to oxidation, with no alteration in antipyrine, theophylline or caffeine clearance, but increased metabolism of prednisolone, diazepam and Ibuprofen. The systemic elimination of high clearance drugs such as verapamil and lignocaine does not appear to be altered. The marked increases in procainamide and Cimetidine renal clearance suggest an alteration in renal tubule transport mechanisms. Digoxin clearance is unaltered. While there are increased concentrations of α₁-acid glycoprotein and binding of propranolol, generally drugs bound to albumin show no alteration. Because of the large changes in drug distribution, alteration in dosages may be necessary. For highly lipid-soluble drugs such as theophylline and lignocaine, loading dose should be based on actual bodyweight because of increased volume of distribution. For digoxin, on the other hand, with the normal volume of distribution, dosage should be based on ideal rather than actual bodyweight. While prednisolone clearance is increased, there is an accompanying enhanced sensitivity to adrenosuppression, thus negating the necessity to adjust dosage and emphasising the need for complementary kinetic and dynamic studies. Similarly, although there is an increased volume of distribution of thiopentone, patients appear unusually sensitive. Due to enhanced conjugation, doses of lorazepam, oxazepam and paracetamol should be increased in proportion to total bodyweight. Less information is available concerning the influence of diabetes on drug kinetics. The intramuscular absorption of some antibiotics may be erratic, and in patients with serious infections the intravenous route should be used. The conjugation of phenacetin is impaired in uncontrolled diabetes, but restored with insulin therapy. The oxidation of antipyrine may be altered. There is some evidence to suggest enhanced renal elimination of penicillin, probably secondary to increased glomerular filtration rate. The binding of diazepam, warfarin, lignocaine and phenytoin is decreased, probably due to glycosylation and alterations in plasma proteins. There have been no concomitant kinetic and dynamic studies in diabetic patients, and therefore therapeutic implications of these changes are speculative. Little information is available concerning drug kinetics in less common endocrine disorders. A number of endocrine agents (oral contraceptive steroids, hydrocortisone and growth hormone) may also influence drug kinetics. As well as additional pharmacokinetic information there is a major need for complementary dynamic studies to increase the therapeutic relevance of pharmacokinetic data.