Clinical Pharmacokinetics of Clonidine

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Abstract
Clonidine is a centrally active antihypertensive agent effective in the treatment of mild, moderate and severe hypertension, alone or in combination with other drugs. Use of oral clonidine has often been limited by side effects which include dry mouth and drowsiness. Transdermal clonidine was therefore developed as an alternative to oral therapy. Ideally, a drug administered at a constant rate into the systemic circulation should attain steady-state concentrations with less peak-to-trough fluctuation than that associated with intermittent oral dosing. In theory, transdermal administration should thus minimise the adverse effects associated with peak plasma drug concentration, while avoiding the potential for decreased efficacy associated with trough levels. Clonidine has been incorporated into a small, pliable adhesive cutaneous delivery device designed to provide therapeutically effective doses of drug at a constant rate for at least 7 days. The transdermal therapeutic system is a laminate consisting of an external film impermeable to moisture and to the drug, a thin layer of active drug dispersed within a highly drug-permeable matrix, a membrane with a controlled intrinsic permeability regulating the rate of delivery of drug to the skin, and an adhesive coating that attaches the system to the skin surface. The permeation of drug through the skin occurs primarily by diffusion. Application of the clonidine transdermal system to both normotensive and hypertensive subjects has consistently reduced systolic and diastolic blood pressures. Maximum reduction in blood pressure occurs 2 to 3 days after initial application, and is maintained for at least 7 days or until the system is removed. The rate at which clonidine is presented to the skin surface is controlled by the microporous membrane: this rate is the same for all strengths of transdermal clonidine, the amount of clonidine released being proportional to its surface area. Thus, the daily dose is regulated by the area of skin covered. Typically, steady-state plasma concentrations are reached on the fourth day after initial transdermal system application. The lack of dose dependency in half-life and renal clearance estimates emphasise that the transdermal absorption of clonidine is linear. The plasma clonidine concentration produced by a particular transdermal dose varies considerably between individuals as a result of interindividual variation in renal clearance. For this reason, it is recommended that dosages be titrated up from the smallest system (3.5cm2) until the desired pharmacological effect has been obtained. Blood pressure returns to pretreatment values over 3 to 4 days after removal of the transdermal system. Because the decline in plasma clonidine concentrations is slower following cessation of transdermal delivery than with oral therapy, rebound hypertension which has been observed in some patients upon abrupt cessation of high doses of oral clonidine does not appear to be a problem with discontinuing transdermal clonidine therapy. Blood pressure control with the transdermal clonidine system has been demonstrated to be equal to or in some cases better than that achieved with oral clonidine. Side effects associated with oral clonidine have been reported to be substantially reduced or eliminated in many patients. Additionally, once weekly transdermal clonidine dosing offers the potential for improved patient compliance.