sign in sign up
<<
Home , Adrenergic antagonist, Alpha blocker, Phentolamine

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 : an alpha-1, alpha-2 antagonist for the treatment of

I Goldstein1

1Department of Urology, Boston University School of Medicine, Boston, MA, USA

Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic 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, -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 (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 . 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; ; oral agents; erectile dysfunction

Role of adrenergic is the physiologic autonomic neuro- transmitter and binds both to alpha-1 and alpha-2 adrenergic receptors (Figure 1). is Detumescence of the erect penis is initiated by another alpha-1 and alpha-2 receptor . Meth- 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 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 rate and systolic controversial. Intracavernosal administration of 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 , 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 . 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 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 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 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 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 ) and speci®c alpha-2

20 receptor ligands ( 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 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 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 changes in the receptor, there is no activation of the Gq=11 protein.

International Journal of Impotence Research Oral Phentolamine I Goldstein 78 rauwolscine. The relatively high af®nity of phento- enhancer ef®ciency in relaxing trabec- lamine mesylate for alpha-1 and -2 adrenergic ular smooth muscle. This additional pathway was receptors suggests that 30±40 min following oral found to result in increased intracellular cyclic ingestion of 40 mg of phentolamine (Vasomax), the nucleotide levels, augmenting reduced intracellu- mean plasma phentolamine concentrations (40± lar calcium release and corporal smooth muscle 50 nM) are suf®cient to occupy the alpha adrenergic relaxation.4 receptors in corpus cavernosum erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity 4 In corpus cavernosum erectile tissue, phentol- Clinical Trials amine mesylate shifted the dose response of phenyl- ephrine (selective alpha-1 mediated) and UK14,304 (selective alpha-2 mediated) contraction in a The ef®cacy and safety of oral phentolamine (40 mg concentration-dependent manner. Phentolamine or 80 mg) was examined for the treatment of mild to mesylate also induced concentration dependent moderate erectile dysfunction.5,6 The patient inclu- relaxation in erectile tissue pre-contracted with the sion criteria included a 6 month history of: (1) a selective alpha-1 receptor agonists consistent change in the quality of erection that and oxymetazoline, the selective alpha-2 receptor adversely affected patient satisfaction with sexual agonist UK14,304 and the non-selective agonist intercourse; (2) reduced but not absent incidence of norepinephrine. These data indicate that phentola- awakening with a full erection; (3) dif®culty achiev- mine alpha-adrenergic binding activity mediates the ing an erection prior to intercourse; (4) dif®culty physiologic inhibition of adrenergic induced corpus maintaining an erection during intercourse; and (5) cavernosum contractile tone and the resulting neutral to extreme dissatisfaction with the current relaxation response.4 level of sexual function. At visit 1 (screening) Contractile responses by 80 mM KCl and endo- patients were instructed to attempt intercourse four thelin are mediated by nonadrenergic mechanisms. times over four weeks and record results on `Sexual Those mediated by KCl are thought to occur by Encounter Pro®le' cards. A Sexual Encounter Pro®le electromechanical coupling via depolarization of score of 8±16 meant inclusion into the study. Less the corpus cavernosum smooth muscle primarily by than 8 or more than 16 meant exclusion from the activation of L-type calcium channels and calcium study. At visit 2 (baseline), the International Index in¯ux. Those mediated by endothelin are thought to of Erectile Function was administered. A total of 459 occur via receptor mediated intracellular calcium patients were randomized into placebo, phentola- release. Phentolamine mesylate, however, induced mine 40 mg or 80 mg. Patients were again instructed relaxation of corpus cavernosum strips pre-con- to attempt intercourse four times over four weeks tracted with 80 mM KCl or endothelin. Such data and record results on `Sexual Encounter Pro®le' suggest that phentolamine mediates corpus caver- cards. A total of 424 patients completed the study. nosum tissue contractility by both adrenergic and At visit 3 (end of treatment), the International Index non-adrenergic pathways. This relaxation response of Erectile Function was again administered. A total was attenuated by the competitive nitric oxide of 139, 139 and 146 patients completed placebo, synthase inhibitor L-nitroarginine and by the me- 40 mg and 80 mg oral phentolamine, respectively. chanical disruption of the endothelium. One likely The mean age was 57.7, 58.9 and 58.4 y, respec- possibility to explain phentolamine mesylate-in- tively. The mean height was 69.9, 70.5 and 70.0 duced relaxation of KCl contracted tissue was an inches, respectively. The mean weight was 198.3, additional non-adrenergic, endothelial-based, nitric- 199.6 and 196.4 pounds, respectively. oxide mechanism.4 The primary ef®cacy criteria were the results of Indirect antagonism is a recognized complemen- the erection domain of the International Index of tary pharmacologic mechanism of action of many Erectile Function scores (Questions 1±5 and 15) natural and synthetic agonists and antagonists. from screening to the end of treatment and from Phentolamine mesylate is an adrenergic antagonist baseline to the end of treatment. The mean change in to the contractile substance norepinephrine. Phen- the erectile function domain of the International tolamine was found to also possess the agonist Index of Erectile Function scores (Questions 1±5 function of tissue relaxation via endothelial nitric and 15) from screening to the end of treatment was: oxide pathways. In erectile tissue, phentolamine 7 0.98, 2.15 (P < 0.0001) and 3.63 (P < 0.0001) for thus was found to elicit activity via a dual mechan- placebo, 40 mg and 80 mg, respectively. The mean ism of action. One pathway was by direct antagon- change in the erectile function domain of the ism of alpha-1 and -2 receptors agonists, at the International Index of Erectile Function scores receptor level, resulting in reduced intracellular (Questions 1±5 and 15) from baseline to the end of calcium release and inhibition of contractility. The treatment was: 72.3, 5.65 and 6.66 for placebo, other mechanism was probably by an indirect, 40 mg and 80 mg, respectively. Improvement in functional antagonism, in which phentolamine erectile function domain scores for placebo, 40 mg

International Journal of Impotence Research Oral Phentolamine I Goldstein 79 and 80 mg were noted in 28%, 53% and 63% of Other secondary ef®cacy criteria were the results patients, respectively. of questions 3 and 4 of the erectile function domain Additional primary ef®cacy criteria included the concerning frequency of penetration and frequency ability to achieve vaginal penetration and the ability of maintaining an erection. Concerning frequency of to maintain erection after penetration and achieve penetration, the mean change from baseline (visit 2) ejaculation in at least 75% of attempts. A total of to end of treatment (visit 3) was: 7 0.25, 0.3 38%, 51% (P ˆ 0.012) and 53% (P ˆ 0.005) of (P ˆ 0.0012), 0.6 P < 0.0001) for placebo, 40 mg and patients on placebo, 40 mg and 80 mg, respectively, 80 mg, respectively. Concerning frequency of pene- reported the ability to achieve vaginal penetration. tration, the mean change from baseline (visit 2) The secondary ef®cacy criteria were the results of to end of treatment (visit 3) was: 7 0.25, 0.3 other domain scores of the International Index of (P ˆ 0.0012), 0.6 (P < 0.0001) for placebo, 40 mg Erectile Function scores concerning orgasmic func- and 80 mg, respectively. Concerning frequency of tion, sexual desire, intercourse satisfaction, and maintaining erection, the mean change from base- overall satisfaction. Concerning orgasmic function, line (visit 2) to end of treatment (visit 3) was: 7 0.1, the mean change from baseline (visit 2) to end of 0.5 (P ˆ 0.0002), 0.8 (P < 0.0001) for placebo, 40 mg treatment (visit 3) was: 7 0.04, 0.78 (P ˆ 0.0318), and 80 mg, respectively. 1.05 (P < 0.0026) for placebo, 40 mg and 80 mg, Other secondary ef®cacy criteria were the results respectively. Concerning sexual desire, the mean of overall satisfaction with treatment. The propor- change from baseline (visit 2) to end of treatment tion of patients satis®ed or very satis®ed with the (visit 3) was: 0.05, 0.32 (NS), 0.18 (NS) for placebo, study medication was 10%, 33% and 40% for 40 mg and 80 mg, respectively. Concerning inter- placebo, 40 mg and 80 mg, respectively. Additional course satisfaction, the mean change from baseline secondary ef®cacy criteria were the results of shifts (visit 2) to end of treatment (visit 3) was: 0.23, 0.8 in clinical dysfunction for the erectile function (P ˆ 0.0005), 1.1 (P < 0.0001) for placebo, 40 mg and domain score on IIEF at baseline (visit 2) and 80 mg, respectively. Concerning overall satisfaction, following end of treatment (visit 3). At baseline, 0± the mean change from baseline (visit 2) to end of 6 points was considered severe dysfunction, 7±12 treatment (visit 3) was: 7 0.2, 1.3 (P ˆ 0.0003), 1.35 was considered moderate-severe dysfunction, 13±18 (P < 0.0002) for placebo, 40 mg and 80 mg, respec- was considered moderate dysfunction, 19±24 was tively. considered mild dysfunction, and 25±30 was con-

Map of Pharmacological First-line Therapies

Satisfaction city

Potency place

Town of desire Combination st.

Function freeway

PDE type 5 inhibitor parkway

Choice terrace α blocker boulevard Dysfunction detour

Central activator avenue

Topical turnpike

© L. Messenger

Figure 5 Cartoon depiction of potential future options for pharmacologic management of men with erectile dysfunction.

International Journal of Impotence Research Oral Phentolamine I Goldstein 80 sidered normal function. At the end of treatment, disturbances associated with sildena®l.7 At 40 mg, the percent of patients categorically improved was 7.7% experienced rhinitis and fewer than 3.1% 15%, 40% (P ˆ 0.001) and 53% (P ˆ 0.001) for experienced any other side effect of treatment. placebo, 40 mg and 80 mg, respectively. In the step-care management of men with erectile Concerning side effects, the proportion of patients dysfunction, there will likely be several choices of reporting treatment-related adverse events during pharmacological ®rst-line therapy for the manage- the study period was as follows. A total of 3.8%, ment of erectile dysfunction (Figure 5). The mech- 7.7% and 20.9% reported rhinitis for placebo, 40 mg anism of erectogenic will vary. One class, and 80 mg, respectively. A total of 1.7%, 3.1% and already FDA-approved for the safe and effective 4.5% reported headache for placebo, 40 mg and treatment of erectile dysfunction, acts by inhibition 80 mg, respectively. A total of 0.2%, 2.0% and 7.0% of the phosphodiesterase type 5 . Phentola- reported dizziness for placebo, 40 mg and 80 mg, mine is an example of a that facilitates respectively. A total of 0.6%, 1.5% and 7.0% erections by alpha-1 and alpha-2 adrenergic block- reported for placebo, 40 mg and 80 mg, ade.1 Another class of agents activates central respectively. A total of 0%, 0.7% and 3.5% reported mechanisms involved in penile erection.8 Another for placebo, 40 mg and 80 mg, respectively. A class will utilize E1 administered via total of 0%, 0.2% and 2.0% reported topical administration.9 It is likely that phentol- for placebo, 40 mg and 80 mg, respectively. A total of amine mesylate will achieve widespread use as an 0.2%, 0% and 2.0% reported for oral alpha-1 and alpha-2 blocking agent for the placebo, 40 mg and 80 mg, respectively. treatment of erectile dysfunction. In conclusion, oral administration of phentola- mine in doses of 40 mg and 80 mg has been shown to be effective in enhancing erectile function in men with mild to moderate erectile dysfunction. Phento- lamine has been found to signi®cantly improve the References various domains of the International Index of Erectile Function compared to placebo in terms of 1 Lue TF, Tanagho EA. Physiology of erection and pharmaco- erectile function, orgasmic function, intercourse logic management of impotence. J Urol 1987; 137: 829±836. satisfaction and overall satisfaction. Three to four 2 Brindley GS Cavernosal alpha-blockade: A new technique for times as many patients receiving phentolamine investigating and treating erectile impotence. Br J Psychiatry reported being satis®ed or very satis®ed with study 1983; 143: 332±337. 3 Muller J. JAMA 1996; 275: 1405±1409. medication compared with those receiving placebo. 4 Traish A, Gupta S, Gallant C, Huang YH, Goldstein, I. Partner satisfaction correlated with patient satisfac- Phentolamine mesylate relaxes penile corpus cavernosum tion which was statistically signi®cant. At doses of tissue by adrenergic and non-adrenergic mechanisms. Int J 40 mg and 80 mg respectively, 55% and 59% of men Imp Res 1998; 10: 215±223. were able to achieve vaginal penetration with 51% 5 Goldstein I, the Vasomax Study Group: Update of Safety and Ef®cacy of Oral Phentolamine (Vasomax) in Patients with and 53% achieving penetration on 75% of attempts. Erectile dysfnction. Int J Imp Res 1999; 11 (Supple 1): S71. The correction of erectile dysfunction or improve- 6 Wyllie M G, Andersson K-E. Oraly Active Agents: The ment to a less severe category of dysfunction was Potential of Alpha-adrenergic Antagonists. In: Carson C, Kirby experienced by 53% of men with the 80 mg dose and R, Goldstein, I. eds, Textbook of Erectile Dysfunction. ISIS 40% with the 40 mg dose of phentolamine. All Medical Media: Oxford 1999; pp. 317±322. 7 Goldstein I, Lue T, Padma-Nathan H, Rosen R, Steers W and trends of response were the same regardless of any Wicker P. Oral sildena®l in the treatment of erectile dysfunc- concomitant medication. tion. New Engl J Med 1998; 338: 1397±1404. Phentolamine is a safe and well-tolerated with an 8 Lal S, et al. -induced penile tumescence in adverse event pro®le consistent with its vaso- impotent patients- preliminary ®ndings. Prog Neuropsycho- relaxant properties. There were no severe adverse pharmacol Biol Psychiatr. 1987; 11: 235±242. 9 Goldstein I, Payton T, Schechter, P.J. Double-blind, Placebo- events including no major systemic cardiovascular controlled Study of Topiglan, a Topical Gel Formulation of 1% hemodynamic changes over the therapeutic dose Alprostadil for the In-of®ce Treatment of Erectile Dysfunction. range. There is no evidence of dyspepsia and visual Int J Imp Res 1999; 11 (Supple 1): S71.

International Journal of Impotence Research