Phenoxybenzamine effects

A large number of diugs interfere with the smooth muscle contraction. These compounds lower blood pressure and are referred to as antihypertensive. In this section, only those coumpounds will be mentioned that have a direct effect on smooth muscle tone. Phenylephrine is an agonist on most smooth muscles and activates ax adrenoceptors. Carbachol is an agonist on some smooth muscles and activates contraction through muscarinic receptors. Blockers of the ax-adrenoceptors such as prazosin and urapidil are competitive inhibitors of the ax-receptor in vascular and bladder smooth muscle. Phenoxybenzamine is an ineversible blocker of ax receptors and phentol-amine blocks ax and a2 receptors. Ca2+ channel blockers such as the dihydropyiidines, phenylalkyla-mines and benzothiazepines lower smooth muscle tone by blocking the L-type calcium channel. 

Noradrenergic antagonists such as phenoxybenzamine, phentolamine, and propranolol had no effect on stimulant (amphetamine) self-administration (DeWit and Wise 1977 Risner and Jones 1976 Yokel and Wise 1976). 

FIGURE 1.23 Effect of a 10-min exposure to two concentrations of a phenoxybenzamine-like compound, dibenamine (DB), on the contractile response of a strip of rabbit aorta to adrenaline (epinephrine). (From Furchgott, R. F., Adv. Drug Res., 3, 21-55, 1966.)... 

Phentolamine and phenoxybenzamine are older O -adrenoceptor antagonists, which may be used occasionally in course of the surgical removal of phaeochromocytoma, with the aim to suppress the vasoconstrictor effects of noradrenaline/adrenaline released from the tumor as a result of surgical manipulation. 

Deficiency of adrenal medullary catecholamines appears to give no ill effects, and replacement therapy is therefore not used, but adrenal medullary tumours, phaeochromocytomas, secrete excess catecholamines often causing hypertension with dramatic episodes of headache, palpitations, pallor, sweating and anxiety. This condition is normally treated surgically, but preoperative preparation is mandatory to avoid catastrophic effects of surges of catecholamine release. A combination of alpha- and beta-adrenergic receptor blockade is normally used, with drugs such as phenoxybenzamine or doxazosin as alpha-blockers, and propranolol as a non-selective beta-blocker. 

Hemodynamic effects Decreased peripheral vascular resistance and blood pressure Venodilation is prominent Cardiac stimulation occurs because of cardiovascular reflexes and enhanced release of norepinephrine Similar to phenoxybenzamine Decreased peripheral vascular resistance and blood pressure Veins seem to be less susceptible to antagonism than arteries thus, postural hypotension is less of a problem Cardiac stimulation is less because release of norepinephrine is not enhanced... 

Phenoxybenzamine and phentolamine, in addition to blocking postsynaptic a-receptors, also block aj-receptors on nerves and therefore can enhance the release of norepinephrine. When norepinephrine exerts a postsynaptic action by means of -adrenoceptors (e.g., cardiac stimulation, renin release), blockade of presy-naptic a2-receptors by phenoxybenzamine and phentolamine may actually potentiate the responses. Prazosin blocks responses mediated by postsynaptic aj-receptors but has no effect on the presynaptic a2-receptors. Thus,... 

A dose of 1 at 30 mg/kg increased the effects of intravenous doses of epinephrine at 5 g/kg and of dl-noreplnephrine at 10 ug/kg on both blood flow and blood pressure. Intravenous phenoxybenzamine at 15 mg/kg plus tolazollne at 2 mg/kg prevented almost completely the actions of I on blood pressure and blood flow Intravenous reserpine at 2 mg/kg increased markedly the effects of I at 30 mg/kg on blood pressure and peripheral resistance, but converted the usual immediate, small, temporary increase in blood flow into an immediate, small, temporary decrease. These various responses would be expected from either a mild sympathomimetic amine or an inhibitor of the breakdown of endogenous catecholamines Indeed, I at 10 M, was found to inhibit the monoamlneoxldase of the rat s liver. If the dose of I used in these experiments were distributed into the same fraction of the body water as that estimated for the human body,the concentration in the plasma would be about 9 times that stated above as the effective concentration for inhibiting the mono amine oxIdase. It is possible that inhibition of monoamlneoxldase by I plays a part in inducing the effects of the oxime on blood vessels and blood pressure. It is possible also that I interferes with reuptake of catecholamines by nerve endings this possibility seems not to have been explored. 

Because of their peripheral vasodilator effect, these drugs are used in the treatment of hypertension. They act beneficially in shock and frostbite by increasing peripheral circulation. Some, like phenoxybenzamine, also have cholinergic effects, indicating that these antagonists cross-react with the AChR. 

It is a potent alpha-adrenergic blocking agent and only haloalkylamine used clinically. It effectively prevents the responses mediated by alpha receptors and diastolic blood pressure tends to decrease. It interferes with the reflex adjustment of blood pressure and produces postural hypotension. It increases the cardiac output and decreases the total peripheral resistance. It also antagonizes cardiac arrhythmias provoked by catecholamines. Apart from these effects, phenoxybenzamine has other actions also e.g. antagonism of acetylcholine, histamine, 5-hydroxytryptamine (serotonin). However, the vasodilatation produced by phenoxybenzamine is because of alpha blockage. Adverse reactions are miosis, dryness of mouth, inhibition of ejaculation, palpitation, nasal stuffiness and in higher doses, postural hypotension and reflex bradycardia. 

Alpha-adrenoceptor antagonists are used as antihypertensives and to reduce afterload in the treatment of heart failure. Urapidil and, to a lesser extent, ketanserin are used in the treatment of essential hypertension and acute perioperative hypertension. In contrast to other vasodilators urapidil does not increase intracranial pressure when given intravenously, making it preferable for use in neurosurgical interventions. The effects of the excessive catecholamine concentrations in patients with phaeochromocytoma can be treated by the non-selective ol- and o2-adrenoceptor antagonists phentolamine or phenoxybenzamine. 

The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of -receptor-mediated events. The most significant effect is attenuation of catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic k2 receptors in cardiac sympathetic nerves. 

Most adverse effects of phenoxybenzamine derive from its -receptor-blocking action the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the central nervous system, it may cause less specific effects, including fatigue, sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized. 

Prazosin is a piperazinyl quinazoline effective in the management of hypertension (see Chapter 11). It is highly selective for i receptors and typically 1000-fold less potent at k2 receptors. This may partially explain the relative absence of tachycardia seen with prazosin compared with that of phentolamine and phenoxybenzamine. Prazosin relaxes both arterial and venous vascular smooth muscle, as well as smooth muscle in the prostate, due to blockade of K receptors. Prazosin is extensively metabolized in humans because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The half-life is normally about 3 hours. 

Alpha-receptor-blocking drugs do not seem to be effective in the treatment of peripheral vascular occlusive disease characterized by morphologic changes that limit flow in the vessels. Occasionally, individuals with Raynaud s phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from prazosin or phenoxybenzamine, although calcium channel blockers may be preferable for most patients. 

Because neuronal uptake is necessary for the hypotensive activity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal (see Chapter 6) block its effects. These include cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine. 

A wide variety of drugs with actions at other receptors (eg, a adrenoceptors, Hi-histamine receptors) also have serotonin receptor-blocking effects. Phenoxybenzamine (see Chapter 10) has a long-lasting blocking action at 5-HT2 receptors. In addition, the ergot alkaloids... 

Another group of transmitters involved in the control of the cardiovascular system by the autonomous nervous system includes the catecholamines, adrenaline and noradrenaline. In acinar submandibular gland cells of the rat the administration of 10 4 mol/1 adrenaline elicits a reduction in dye coupling from 97 to 75.3% dye-coupled cells [Kanno et al., 1993]. This could not be mimicked with isoprenaline, but was inhibited with phenoxybenzamine. Thus, the uncoupling effect of adrenaline in this preparation is mediated by stimulation of the a-adre-noceptor, whereas a stimulation of the P-adrenoceptor has no effect. 

In other cells, i.e. in rat submandibular gland, adrenaline (100 pmol/l) has been shown to decrease the percentage of dye-coupled cells [Kanno et al., 1993], whereas isoproterenol was ineffective, so that the authors concluded that the mechanism was transmitted via action on the -adrenoceptors. This was supported since the adrenaline effect could be suppressed by coadministration of 10 pmol/1 phenoxybenzamine. 

Phenylephrine is a specific a-agonist with very little effect on p-receptors The other name for this drug, a brand name, is Neosynephrine and it can be found in nasal decongestant sprays and as a dilator in opthamology. It can also be used with the antihypertensive drug phenoxybenzamine and the smooth muscle relaxant papaverine in order to treat impotence in males. 

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