B. R. Graham

Vasodilating Mechanism and Response to Physiological Pressor Stimuli of Acute Doses of Carvedilol Compared with Labetalol, Propranolol and Hydralazine

SummaryThere is conflicting evidence regarding the main mechanism of the vasodilating effect with carvedilol at therapeutic doses, and to examine this, single doses of carvedilol 50mg and 100mg were compared with labetalol 400mg, propranolol 160mg, propranolol 80mg plus hydralazine 50mg and placebo in healthy subjects. Dose-response studies (required to increase heart rate or systolic blood pressure by 25 beats/min and 20mm Hg, respectively) were performed with phenylephrine, angiotensin and isoprenaline after each drug, and placebo administration and the effects of physiological pressor stimuli were compared. Phenylephrine systolic pressure dose-response curves were shifted by labetalol (dose ratio 2.4) and both carvedilol doses (dose ratios 50mg 1.9, 100mg 20.2). The slight shift to the right of the angiotensin dose-response curves with hydralazine plus propranolol (dose ratio 1.4) and carvedilol 50mg (dose ratio 1.4) was not significant. β-Blockade was greatest with propranolol 160mg, followed by carvedilol 100mg, propranolol 80mg plus hydralazine 50mg, carvedilol 50mg and was least with labetalol 400mg (isoprenaline dose ratios required to increase heart rate by 25 beats/min were 55.2, 27.2, 20.2, 14.2, 11.5, respectively). Blood pressure rise with cold pressor and isometric exercise was inhibited most by labetalol. At these acute doses carvedilol displayed some α-blockade, but the lower ratio of α-blockade to β-blockade differed from that seen with labetalol, which may account for the different haemodynamic responses at rest and during physiological pressor stimuli with the 2 drugs. There was no definite evidence of direct vasodilator effect.

THE USE OF MOXONIDINE IN THE TREATMENT OF HYPERTENSION

Background Imidazoline I1-receptor agonism represents a new mode of antihypertensive action to inhibit peripheral α-adrenergic tone by a central mechanism. Adrenaline, noradrenaline and renin levels are reduced, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that moxonidine results in an acute decrease in blood pressure due to a fall in systemic vascular resistance, whereas the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months of treatment. Pharmacokinetics Following oral administration, maximum concentration is reached at about 1 h, and bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, and biotransformation is unimportant. The half-life of moxonidine is 2.5 h, which is prolonged by renal insufficiency. However, the antihypertensive effect lasts longer than would be expected from the half-life, suggesting possible retention in the central nervous system. Drug effects Decreases of about 20–30 mmHg systolic and 10–20 mmHg diastolic blood pressure have been found in open studies with moxonidine. The dosage of 0.2–0.4 mg moxonidine daily controls hypertension in most patients. Moxonidine has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both α- and β-blocking drugs, calcium antagonists and angiotensin converting enzyme inhibitors. Blood pressure control has been observed to be similar with moxonidine and these other agents. Generally, the overall incidence of side-effects has been found to be similar, although the incidence of side-effects with clonidine is greater than that seen with moxonidine. Conclusions A meta-analysis of controlled studies with moxonidine found that moxonidine gave similar reductions in blood pressure in both men and women, in those aged below 50, 50–60 and over 60 years, and regardless of body weight. As often seen with some other drugs, higher systolic blood pressures are associated with larger reductions in systolic blood pressure and the same appears to be the case with diastolic blood pressure.

I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors. Implications for the treatment of the elderly

In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central alpha2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for alpha2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with alpha2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine. Both moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t(1/2)) of rilmenidine and moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t(1/2) values are increased in patients with reduced renal function, and in elderly individuals. Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with moxonidine or rilmenidine is similar to that with established drugs, i.e. alpha-blocking drugs, calcium antagonists, ACE inhibitors, beta-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients. The overall adverse effect profile of moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo. An overshoot of blood pressure was seen when treatment with clonidine, but not moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central α2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for α2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with α2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine.Both moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t½)of rilmenidine and moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t½ values are increased in patients with reduced renal function, and in elderly individuals.Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with moxonidine or rilmenidine is similar to that with established drugs, i.e. α-blocking drugs, calcium antagonists, ACE inhibitors, β-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients.The overall adverse effect profile of moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo.An overshoot of blood pressure was seen when treatment with Clonidine, but not moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.

Clinical pharmacology of carvedilol

SummaryAnimal work has shown that carvedilol is a nonselective β-blocking drug. It has a vasodilator action from α-receptor blockade, but there is evidence that it has further action to relax smooth muscle, possibly from calcium channel antagonism. Carvedilol is lipid soluble and 25% bioavailable, and it has a half-life of about 7 h. It lowers blood pressure at rest and reduces the tachycardia and the rise of blood pressure on exercise. It reduces the level of blood pressure reached during isometric exercise or the cold pressor test. Cardiac output at rest is maintained, and the haemodynamics in the compromised heart is improved. It has an important peripheral vasodilator action, peripheral flow being maintained to important organs, e.g. kidneys, despite the fall in blood pressure. Exercising renin and noradrenaline levels are increased, as are the latter at rest. Carvedilol is lipid neutral. Carvedilol shifts the dose-response curve to isoprenaline to the right, as well as to α-stimulants such as phenylephrine. Responses to angiotensin are little affected. The ratio of β- to α-blockade has been found to be 7.6 for 50 mg and 12.5 for 100 mg of carvedilol. There is no evidence of a decline in α-blockade after 1 week of continuous administration.

The effect of urapidil on responses to phenylephrine, angiotensin and isoprenaline in man

SummaryIntravenous urapidil, 40 mg bolus followed by an infusion of 18 mg·h−1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 μg·min−1 before to 685 μg·min−1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has α1-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.

Effects of noradrenaline infusion on platelet catecholamine levels and platelet aggregation.

Noradrenaline infusions were administered to 10 normal subjects through stepped doses and continued at 60 ng/kg per min for 2 h. Plasma noradrenaline rose from 1.7 +/- 0.3 to 7.7 +/- 0.7 pmol/ml and platelet noradrenaline rose from 2.1 +/- 0.2 to 2.6 +/- 0.2 pmol/mg protein. There was no change in plasma or platelet adrenaline. Platelet aggregation studies using ADP, adrenaline, collagen and thrombin as aggregants showed no overall change during the course of the infusion. Blood was sampled from a heated hand vein (hot box at 60 degrees C) to test the degree of arterialization. Plasma noradrenaline and blood pO2 and pCO2 showed intermediate levels at this sampling site compared with venous and true arterial values. Changes in platelet noradrenaline content can occur over 2 h when plasma levels are considerably increased by noradrenaline infusion. No change in platelet sensitivity to aggregation was observed. The heated hand vein did not provide true arterial levels of noradrenaline.