CLINICAL PHARMACOLOGY
Ismelin acts at the sympathetic neuroeffector junction by inhibiting or interfering with the release and/or distribution of the chemical mediator (presumably the catecholamine norepinephrine), rather than acting at the effector cell by inhibiting the association of the transmitter with its receptors. In contrast to ganglionic blocking agents, Ismelin suppresses equally the responses mediated by alpha-and beta-adrenergic receptors but does not produce parasympathetic blockade. Since sympathetic blockade results in modest decreases in peripheral resistance and cardiac output, Ismelin lowers blood pressure in the supine position. It further reduces blood pressure by decreasing the degree of vasoconstriction that normally results from reflex sympathetic nervous activity upon assumption of the upright posture, thus reducing venous return and cardiac output more. The inhibition of sympathetic venoconstrictive mechanisms results in venous pooling of blood. Therefore, the effect of Ismelin is especially pronounced when the patient is standing. Both the systolic and diastolic pressures are reduced.
Other actions at the sympathetic nerve terminal include depletion of norepinephrine. Once it gains access to the neuron, Ismelin accumulates within the intraneuronal storage vesicles and causes depletion of norepinephrine stores within the nerve terminal. Prolonged oral administration of Ismelin produces a denervation sensitivity of the neuroeffector junction, probably resulting from the chronic reduction in norepinephrine released by the sympathetic nerve endings. Systemic responses to catecholamines released from the adrenal medulla are not prevented and may even be augmented as a result of this denervation sensitivity. A paradoxical hypertensive crisis may occur if Ismelin is given to patients with pheochromocytoma or if norepinephrine is given to a patient receiving the drug.
Due to its poor lipid solubility, Ismelin does not readily cross the blood-brain barrier. In contrast to most neural blocking agents, Ismelin does not appear to suppress plasma renin activity in many patients.
Pharmacokinetics
The pharmacokinetics of Ismelin are complex. The amount of drug in plasma and in urine is linearly related to dose, although large differences occur between individuals because of variation in absorption and metabolism. Adrenergic blockade occurs with a minimum concentration in plasma of 8 ng/ml; this concentration is achieved in different individuals with dosages of 10-50 mg/day at steady state. Ismelin is eliminated slowly because of extensive tissue binding. After chronic oral administration, the initial phase of elimination with a half-life of 1.5 days is followed by a second phase of elimination with a half-life of 4-8 days. The renal clearance of Ismelin is 56 ml/min. Ismelin is converted by the liver to three metabolites, which are excreted in the urine. The metabolites are pharmacologically less active than Ismelin.
|
