Indoramin

Summary

Synopsis: Indoramin¹ is a postsynaptic selective α₁-adrenoceptor antagonist used in the treatment of hypertension. In contrast to some other α-blockers, animal studies suggest that its blood pressure lowering effect results from relaxation of peripheral arterioles as a consequence of blockade of postsynaptic α₁-adrenoceptors. Furthermore, unlike some other α-blockers, this lowering of blood pressure is rarely associated with reflex tachycardia or postural hypotension.

Therapeutic trials have shown indoramin to be effective in lowering blood pressure in all grades of hypertension: mild and moderate hypertension when used alone, but generally in combination with a thiazide diuretic, and in moderate to moderately severe hypertension when used in combination with a β-blocker and diuretic. In a few small comparative studies, no significant difference was found in the blood pressure lowering effects between indoramin and methyldopa, propranolol and prazosin. Side effects were similar for indoramin, propranolol and methyldopa; however in the 1 comparative study with prazosin, prazosin produced a lower incidence of sedation. Indeed, the most common side effect with indoramin therapy has been sedation of a mild to moderate and/or transient nature, reported in about 19% of cases. Other side effects which have sometimes led to a withdrawal of indoramin treatment have been dry mouth, dizziness, and in males, failure of ejaculation; however, side effects may be reduced by starting therapy with smaller doses and titrating more gradually.

Pharmacodynamic Properties: Indoramin, as a competitive postsynaptic α₁-adrenoceptor antagonist, produces vasodilation both in animals and man which leads to decreases in systolic and diastolic blood pressures. Unlike other α-adrenoceptor antagonists (e.g. phentolamine), this vasodilation does not appear to be consistently associated with reflex tachycardia. Although animal studies have demonstrated a direct effect of indoramin in slowing both the rate and force of contraction of the heart, in humans 10 to 20mg intravenously has produced no depression of myocardial function. The local anaesthetic and antidysrhythmic activity also possessed by the drug points to a myocardial membrane-stabilising ability, which would in part account for the lack of effect of indoramin on heart rate. Since indoramin is specific for α₁-receptors and therefore allows noradrenaline (norepinephrine) to act unopposed on presynaptic α₂-receptors, subsequent noradrenaline release is inhibited. Thus, noradrenaline β ₁ activation in the myocardium and tachycardia is reduced. Although other actions such as a reduction of baroreceptor activity and prolongation of repolarisation time may be contributory to this effect, the precise reasons for this relative lack of tachycardia after indoramin administration remain unclear. In addition, reduced noradrenaline β ₁ activation may reduce noradrenaline activation of postsynaptic α₂-receptors in vascular smooth muscle, and since α₂-receptors are probably also vasoconstrictor, this effect may contribute to a reduction in peripheral vascular resistance. No other significant haemodynamic changes have been seen in healthy subjects, but patients with congestive heart failure have experienced significant beneficial changes in cardiac output and right and left ventricular filling pressures.

The antihypertensive activity of indoramin in man may be associated with a rise in plasma noradrenaline concentrations and a slight increase in plasma renin activity. Apart from the expected improvement of blood flow in the limbs and digits, the most significant observation from studies of the effects of indoramin on peripheral blood flow in healthy subjects was the increase in cutaneous blood flow to the hands but not the chest, indicating the ability of indoramin to release vasoconstrictor tone by α-adrenoceptor blockade.

Short and long term treatment of hypertensive patients with indoramin has produced no significant deleterious effects on renal function.

Pharmacokinetics: Peak plasma concentrations of 15 to 45 μg/L were attained 1 to 2 hours after oral administration of single doses of indoramin 40mg in healthy subjects and patients. Long term oral therapy with indoramin 150mg, 120mg and 60mg daily led to mean plasma concentrations of 126, 51 and 23 μg/L, respectively, in patients with hypertension. Peak plasma concentrations following intravenous administration of indoramin 0.14 mg/kg in healthy subjects ranged from about 38 to 48 μg/L. The bioavailability of indoramin has been calculated to be 0.31, which together with the fact that the total metabolite concentration in plasma was approximately 10-fold that of unchanged drug, would suggest that the drug undergoes extensive first-pass metabolism.

Indoramin has a volume of distribution of 7.4 L/kg following intravenous administration of 0.14 mg/kg and 15mg in healthy volunteers. Although plasma protein binding was seen to change with plasma concentration in one study (85.6% bound at 81 μg/L and 72.2% bound at 129 mg/L) it remained fairly constant at 91.7% over a range of 54 to 205 μg/L in another study.

Recovery of indoramin and its metabolites in faeces (46.5 to 49.7%) has been slightly greater than that found in urine (31.7 to 35.4%). The majority of renally excreted material (35 to 40%) is composed of 2 urinary metabolites, with only 0.6 to <11% of unchanged drug being found in the urine. Plasma clearance values ranged from 66 to 114 L/h following intravenous and oral indoramin administration, but more than doubled in value when the drug was administered after food. The elimination half-life of indoramin is slightly longer after oral (5.5 hours) than after intravenous (4 hours) administration. In patients with hepatic cirrhosis, the volume of distribution and elimination half-life of indoramin are increased while clearance of the drug is decreased.

No significant correlation has been found between the plasma concentration of indoramin and its blood pressure lowering effect.

Therapeutic Trials: Indoramin has undergone trials as the sole agent for initial anti-hypertensive therapy although the majority of trials have involved coadministration of a thiazide diuretic. The latter has either been added to improve blood pressure control over that achieved with indoramin alone, or indoramin has been added to the treatment regimen of patients with mild to moderate essential hypertension unresponsive to diuretic alone. In nearly all studies the dosage of indoramin has been titrated for each patient within the range 50 to 200mg daily, the majority of patients being controlled on up to 150mg of indoramin monotherapy and lower doses (75 to 100mg) when it is used in conjunction with a diuretic. Non-comparative trials have suggested that indoramin in combination with a thiazide diuretic is an effective antihypertensive regimen in more than 70% of patients.

Indoramin has been shown to be consistently better than placebo in parallel group and crossover studies, although, in placebo-controlled trials, a slightly lower percentage of satisfactory blood pressure responses to indoramin alone was found in patients with mild to moderately severe essential hypertension. As third-line therapy to β-blockade and a diuretic in moderately severe hypertensive patients, indoramin was able to bring about a further decrease of 12%, 16% and 17% in mean arterial supine blood pressure, standing blood pressure and blood pressure after exercise, respectively.

Indoramin (50 to 200mg) has produced similar response rates and mean decreases in blood pressure to methyldopa (500mg to 2g daily) in studies reported so far. Trials comparing indoramin (50 to 200mg) and propranolol (80 to 240mg) suggest that these 2 drugs are almost equally effective. However, even though attainment of ‘satisfactory’ blood pressure control was greater in the indoramin patients given the lowest dose (50mg), a greater overall reduction in blood pressure occurred in the propranolol group. Results of a single-blind and of double-blind trials of indoramin (30 to 150mg) and prazosin (3 to 15mg) in hypertensive patients unresponsive to β-blockade and diuretic therapy found no significant difference between the 2 drugs with respect to blood pressure decrease and heart rate response. All of these comparative studies involved only small numbers of patients and probably could not have been expected to identify at a statistically significant level any small differences between drugs.

Studies of the use of indoramin to relieve bronchoconstriction in patients with asthma have shown that the drug provides symptomatic improvement only in patients with mild disease. Indoramin, given orally in doses of 90 to 150mg or intravenously in doses of 0.1 to 0.17 mg/kg, has been shown to significantly improve digital blood flow in patients with Raynaud’s phenomenon. Although little consistent success has been obtained in migraine and nocturnal enuresis, indoramin has shown some antianginal activity in patients with coronary artery disease.

Side Effects: The most frequent side effects associated with indoramin therapy have been sedation, dry mouth and dizziness. Cardiovascular effects such as tachycardia, or postural hypotension (common problems with other antihypertensive drugs) have been rare. Sedation (mild to moderate and/or transient in nature) has been reported in a fairly high percentage of patients (19%) but it may in part be an indication of excessive dosage. Similarly, failure of ejaculation in males has been reported and is more frequently associated with higher initial doses of the drug. Thus, the overall incidence of side effects appears to be associated with initially high indoramin doses and shows a progressive decline with time. The most common contributing reasons for withdrawal of indoramin therapy were sedation, dizziness, headache, light-headedness, lack of energy, and nausea.

Dosage and Administration: The initial oral dose for all patients with all grades of essential hypertension is 25mg twice daily. The dose can then be titrated as necessary to control blood pressure up to a maximum of 200mg daily in 2 or 3 divided doses. During dose titration, increases in the daily dose should be in 25 or 50mg increments at 2-weekly intervals. When indoramin is used in combination with other antihypertensive agents, the initial dose should be reduced, and then increased again as necessary.