CLINICAL PHARMACOKINETICS OF VASODILATORS - PART 1

Understanding the mechanism of action and the pharmacokinetic properti es of vasodilatory drugs facilitates optimal use in clinical practice. It should be kept in mind that a drug belongs to a class but is a dis tinct entity, sometimes derived from a prototype to achieve a specific effect. The most common pharmacokinetic drug improvement is the devel opment of a drug with a half-life sufficiently long to allow an adequa te once-daily dosage, Developing a controlled release preparation can increase the apparent half-life of a drug. Altering the molecular stru cture may also increase the half-life of a prototype drug. Another des irable improvement is increasing the specificity of a drug, which may result in fewer adverse effects, or more efficacy at the target site. This is especially important for vasodilatory drugs which may be admin istered over decades for the treatment of hypertension, which usually does not interfere with subjective well-being. Compliance is greatly i ncreased with once-daily dosing. Vasodilatory agents cause relaxation by either a decrease in cytoplasmic calcium, an increase in nitric oxi de (NO) or by inhibiting myosin light chain kinase. They are divided i nto 9 classes: calcium antagonists, potassium channel openers, ACE inh ibitors, aneiotensin-II receptor antagonists, alpha-adrenergic and imi dazole receptor antagonists, beta(1)-adrenergic agonists, phosphodiest erase inhibitors, eicosanoids and NO donors. Despite chemical differen ces, the pharmacokinetic properties of calcium antagonists are similar . Absorption from the gastrointestinal tract is high, with all substan ces undergoing considerable first-pass metabolism by the liver, result ing in low bioavailability and pronounced individual variation in phar macokinetics. Renal impairment has little effect on pharmacokinetics s ince renal elimination of these agents is minimal. Except for the newe r drugs of the dihydropyridine type, amlodipine, felodipine, isradipin e, nilvadipine, nisoldipine and nitrendipine, the half-life of calcium antagonists is short. Maintaining an effective drug concentration for the remainder of these agents requires multiple daily dosing, in some cases even with controlled release formulations. However, a coat-core preparation of nifedipine has been developed to allow once-daily admi nistration. Adverse effects are directly correlated to the potency of the individual calcium antagonist. Treatment with the potassium channe l opener minoxidil is reserved for patients with moderately severe to severe hypertension which is refractory to other treatment. Diazoxide and hydralazine are chiefly used to treat severe hypertensive emergenc ies, primary pulmonary and malignant hypertension and in severe pre-ec lampsia. ACE inhibitors prevent conversion of angiotensin-I to angiote nsin-II and are most effective when renin production is increased. Sin ce ACE is identical to kininase-II, which inactivates the potent endog enous vasodilator bradykinin, ACE inhibition causes a reduction in bra dykinin degradation. ACE inhibitors exert cardioprotective and cardior eparative effects by preventing and reversing cardiac fibrosis and ven tricular hypertrophy in animal models. The predominant elimination pat hway of most ACE inhibitors is via renal excretion. Therefore, renal i mpairment is associated with reduced elimination and a dosage reductio n of 25 to 50% is recommended in patients with moderate to severe rena l impairment. Separating angiotensin-II inhibition from bradykinin pot entiation has been the goal in developing angiotensin-II receptor anta gonists. The incidence of adverse effects of such an agent, losartan, is comparable to that encountered with placebo treatment, and the trou blesome cough associated with ACE inhibitors is absent.