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Oral Phentolamine: an Alpha-1, Alpha-2 Adrenergic Antagonist for the Treatment of Erectile Dysfunction

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Oral Phentolamine: an Alpha-1, Alpha-2 Adrenergic Antagonist for the Treatment of Erectile Dysfunction International Journal of Impotence Research (2000) 12, Suppl 1, S75±S80 ß 2000 Macmillan Publishers Ltd All rights reserved 0955-9930/00 $15.00 www.nature.com/ijir Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction I Goldstein1 1Department of Urology, Boston University School of Medicine, Boston, MA, USA Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high af®nity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30±40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are suf®cient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1±5 and 15) from screening to the end of treatment was signi®cantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satis®ed or very satis®ed compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts. The correction of erectile dysfunction or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. All trends of response were the same regardless of any concomitant medication. There were no severe adverse events. At 40 mg, 7.7% experienced rhinitis and fewer than 3.1% experienced any other side effect of treatment. Phentolamine is safe, well tolerated and ef®cacious for the treatment of erectile dysfunction. International Journal of Impotence Research (2000) 12, Suppl 1, S75±S80 Keywords: penile erection; alpha blocker; oral agents; erectile dysfunction Role of adrenergic agonists Norepinephrine is the physiologic autonomic neuro- transmitter and binds both to alpha-1 and alpha-2 adrenergic receptors (Figure 1). Oxymetazoline is Detumescence of the erect penis is initiated by another alpha-1 and alpha-2 receptor agonist. Meth- adrenergic agonist stimulation. Adrenergic stimula- oxamine, on the other hand, binds primarily to tion results in contraction of the cavernosal arteries alpha-1 adrenergic receptors while the compound with reduced cavernosal arterial in¯ow as well as UK-14,304 binds primarily to alpha-2 adrenergic contraction of the trabecular smooth muscle leading receptors. to collapse of the lacunar spaces. The resultant loss There are several physiologic activities associated of corporal veno-occlusive function leads to detu- with norepinephrine or catecholamine release at the mescence. The role of the adrenergic neuroeffector adrenergic synapse. Sexual intercourse and orgasm system as a mediator of detumescence is non- is associated with increased heart rate and systolic controversial. Intracavernosal administration of blood pressure secondary to catecholamine release adrenergic agonists initiate detumescence and have (Figure 2).3 Psychologic-mediated release of cate- 2 become a routine treatment for prolonged erection. cholamines may occur following stressful situations There are several adrenergic agonists with vary- associated with sexual activity such as fear of ing af®nities for the alpha adrenergic receptors. failure, performance anxiety, anger, shame and embarrassment. Physiologic and=or psychologic- mediated catecholamine release may occur second- Correspondence: I Goldstein, 720 Harrison Ave, ary to pain associated with Peyronie's disease, Boston, MA 02118. prostatitis, epididymitis, or non-genital pain such Received 1 October 1999; accepted 23 November 1999 as headache. All of these above conditions, from Oral Phentolamine I Goldstein 76 Chemical Formulas of Norepinephrine treatment of erectile dysfunction are as follows. and Phentolamine Adrenergic blockade might delay detumescence of CH the penile erection. Adrenergic blockade might 3 prolong the duration of the erection initiated by sexual stimulation. Adrenergic blockade might potentiate the stimulatory effect of smooth muscle OH OH OH N relaxation by removing inhibitory responses mediated by catecholamine release by the sym- NH CH CH OH CH2 N 2 2 pathetic nervous system. Further research in the N effect of alpha adrenergic blockade on the erectile response is needed. Norepinephrine Phentolamine Figure 1 Schematic chemical formulas of norepinephrine and phentolamine. Phentolamine Ð an alpha-1 and alpha-2 adrenergic antagonist sexual intercourse to stress to pain are associated with catecholamine release and an erectolytic effect on penile erection. Phentolamine mesylate is an alpha-1 and alpha-2 adrenergic antagonist 4±6 which is currently being investigated for its safety and ef®cacy as an oral Principles of adrenergic blockade in the agent in the treatment of male erectile dysfunction. treatment of erectile dysfunction Pharmacokinetics Since activation of adrenergic agonists initiates detumescence, antagonizing the alpha adrenergic contractile response may facilitate the erectile Pharmacokinetic studies in normal volunteers have response in men with erectile dysfunction. The revealed that the mean phentolamine plasma con- principles of adrenergic blockade utilization in the centration 30 min after oral ingestion of 40 mg Catecholamine Loading During Sexual Performance 200 175 165 mmHg 150 150 mmHg 125 Blood pressure 110 mmHg 115 beats/min 100 85 beats/min 75 mmHg 75 70 mmHg Heart rate 55 beats/min Catecholamine 50 release - causes penile smoothmuscle to contract 25 0 Desire Arousal Orgasm © L. Messenger Sexual Response Cycle Figure 2 Hypothetical release of catecholamine associated with sexual performance from desire to arousal to orgasm. Coital-mediated increases in catecholamine result in an approximate doubling of the resting pulse and a 50% increase in resting systolic blood pressure. Catecholamine release during sexual activity may explain early loss of erection (failure to maintain erectile dysfunction) in some men. International Journal of Impotence Research Oral Phentolamine I Goldstein 77 phentolamine (Vasomax) tablets was 16±22 ng=ml Molecular mechanisms (42± 50 nM) and after 80 mg was 36±44 ng=ml (80± 100 nM). In 32 individuals, the area under curve The mechanism of action of phentolamine in (AUC), Cmax,Tmax and half-life values for 40 mg and 80 mg phentolamine (Vasomax) tablets were regulating corpus cavernosum smooth muscle tone 56.1 Æ 31.6 and 136 Æ 58.2 ngh=ml; 19.3 Æ 8.2 and has been postulated to be via alpha adrenergic 46.0 Æ 21.5 ng=ml; 0.69 Æ 0.25 and 0.67 Æ 0.26 h; receptor blockade (Figure 4). Detailed biochemical 2.14 Æ 1.88 and 2.76 Æ 0.99 h, respectively (Figure 3). and physiological studies of the mechanism of action of phentolamine mesylate in human corpus cavernosum tissue have recently been reported.4 60 Phentolamine mesylate was found to be an effective 50 alpha-1 and alpha-2 adrenergic receptor blocker in Days 1,7,14 (pooled) - 40 mg dose Days 1,7,14 (pooled) - 80 mg dose corpus cavernosum erectile tissue. Phentolamine 40 competitively displaced speci®c alpha-1 receptor 30 ligands (HEAT and prazosin) and speci®c alpha-2 20 receptor ligands (rauwolscine and RX 821002). The af®nity of phentolamine for alpha-1 adrenergic 10 Plasma phentolamine concentration (ng/mL) receptors was comparable to the alpha-1a selective 0 receptor antagonist 5-methylurapidil but was less 0 1 2 3 4 5 6 7 8 9 10 11 12 than that of prazosin. The af®nity of phentolamine Time (hours) for the alpha-2 adrenergic receptors was greater than Figure 3 Pharmacokinetic pro®le of phentolamine. Phentola- that of the alpha-2 receptor agonist UK-14,304 and mine represents an agent that has fast onset of therapeutic blood levels (approximately 30±40 min) and fast metabolism (half-life norepinephrine but was less than that of the alpha-2 approximately 2 h). receptor antagonists delequamine (RS 1385-197) and Phentolamine is an α-selective Receptor Antagonist Norepinephrine Phentolamine OH CH3 OH NH2 CH2 CH OH OH N CH2 N N Extracellular X Norepinephrine Cell membrane unable to bind α γ β Intracellular Gq/11 protein α α γ 1 adrenergic β receptor Gq/11 protein α 1 adrenergic receptor Extracellular Cell membrane γ β Intracellular α α γ β α adrenergic Gq/11 Gq/11 1 α receptor activated protein 1 adrenergic protein not activated © L. Messenger receptor not activated activated Figure 4 Schematic representatation of the mechanism of alpha blockade by phentolamine. The left-hand side of the ®gure reveals that the sympathetic neurotransmitter alpha-agonist norepinephrine binds to the cell membrane alpha-1 adrenergic receptor initiating receptor conformational changes and activating Gq=11 protein (a critical step to initiate increased intracellular calcium concentration and smooth muscle contraction). The right-hand side of the ®gure reveals that in the presence of phentolamine, which has high af®nity for the alpha receptor, norepinephrine can no longer bind to the oocupied alpha receptor. Since phentolamine binding to the alpha receptor does not induce conformational
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