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This Month in Investigative Urology: Intracavernosal Injection Therapy for Impotence
0022-534 7/87 /1385-1262$02.00/0 Vol. 138, November Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1987 by The Williams & Wilkins Co.
THIS MONTH IN INVESTIGATIVE UROLOGY INTRACA VERNOSAL INJECTION THERAPY FOR IMPOTENCE The intracavernosal injection of vasoactive drugs in the evaluation and treatment of erectile dysfunction is currently one of the most popular, as well as controversial, topics in urology. Although it has been just four years since Virag and Brindley first observed that papaverine and phenoxybenzamine injected intracorporally produce penile erection, the clinical use of such agents has gained widespread acceptance. The utilization of intracorporeal injection techniques has occurred so rapidly that many basic, very important, questions remain unanswered. Two articles in this issue of the Journal of Urology address the problems of potential complications of intracavernosal injection as it is currently being practiced, as well as the future use of newer pharmacologic agents in the treatment of impotence. In their paper, "Chronic Papaverine Treatment: The Effect of Repeated Injections on the Simian Erectile Response and Penile Tissue", Abozeid and associates describe significant pathologic changes which were associated with 100 intracavernosal injections of papaverine over a one year period in monkeys. They observed not only minimal to marked fibrosis at the injection site, but also hypertrophy of smooth muscle in non-injected areas of the corpora. The reasons for these pathologic changes as well as their clinical implications are not clear. Fibrosis of the corpora cavernosa has been previously described as a complication of intracavernosal injection therapy. Since significant fibrosis can occur after only one injection of papaverine, this tissue response is probably secondary to irritative properties of papaverine itself or the low pH (approximately 4.0) of this agent. Smooth muscle hypertrophy of the corpora at sites proximal to the areas of injection may well be a response to repeated, prolonged erections. The paper by Abozeid and associates underscores the fact that we do not understand the long term effects of repeated intracavernosal injections. One can argue that the only other treatment modality available to these patients is a penile prosthesis, and that if fibrosis and/or smooth muscle hypertrophy become problematic, a prosthesis can always be placed. My opinion, however, is that a significant number of patients presently being treated with intracavernosal injection techniques are impotent on a psychogenic basis. The fact that long term effects of injection therapy are not clear necessitates caution in patient selection. Fibrosis and possible adverse effects from the observed smooth muscle hypertrophy must certainly be added to the list of possible complications from this new treatment modality. The incidence of these occurrences, as well as the incidence of the previously recognized problems of priapism, infection, ecchymosis and hematoma, and cardiovascular side effects are not well documented. Continued reporting of clinical complications and basic research in this area is needed. The article by Fovaeus and associates explores the effects of calcium channel blocking agents on in vitro strips of human corpora cavernosa. This well-designed and controlled study demonstrates that these drugs inhibit both electrically and pharmacologically induced contraction of this tissue. Since smooth muscle relaxation is a requirement for the production of penile erection, such drugs should promote erectile activity. In fact, penile erection secondary to the intracavernosal injection of verapamil (a calcium channel blocker) has been previously reported. 1 Whether the oral administration of these commonly used drugs affects penile erection is not known.
Many drugs injected intracorporally have been noted to produce penile erection. These agents include not only papaverine, phentolamine and verapamil, but also vasoactive intestinal polypeptide, phenoxybenzamine, imipramine, prostaglandin E 1 and others. It appears that any drug which causes relaxation of the corporal smooth muscle and arteriolar dilation by any of a number of mechanisms (including alpha adrenergic blockade, calcium channel blockade, activation of the adenyl cyclase system, or other direct smooth muscle actions) is capable of producing penile erection. It should be kept in mind that smooth muscle contraction (promoting penile flaccidity) is most probably an alpha adrenergic mediated event. The normal physiologic mechanisms which cause erection (arteriolar relaxation and corporal smooth muscle relaxation) are less well understood. Cholinergic mechanisms, as well as non-cholinergic non-adrenergic (possibly peptidergic) neural mechanisms, are probably involved. In addition, the recently described endothelial relaxation factor may also be important. Future studies similar to that of Fovaeus and associates are necessary to elucidate not only the pharmacology, but also the physiology of corporal smooth muscle and normal penile erection. The pharmacology of penile erection, particularly as it relates to the treatment of impotence, is in its infancy. Although papaverine alone and combinations of papaverine and phentolamine are extensively utilized, very basic pharmacologic questions remain unanswered. Drug doses are largely empiric and, to my knowledge, responses to varying drug doses have not been established. The pharmacokinetics of drug combinations have not been reported. Specifically, what is the stability of phentolamine when the lyophylized drug is reconstituted and then mixed with papaverine? 2 Are other vasoactive agents currently available more efficacious and less toxic than papaverine and phentolamine? Will prostaglandin E 1 replace papaverine and phentolamine as the drug therapy of choice? Prostaglandin E 1 appears efficacious in European and Japanese trials and the fact that it is probably metabolized by penile tissue would, at least theoretically, appear to lower the incidence of such complications as priapism. What is the best drug (norepinephrine, epinephrine, phenylephrine, metaraminol, etc.) and drug dose to treat pharmacologically induced priapism? The answers to these and other questions ·will hopefully be forthcoming. The pharmacologic treatment of impotence has quickly (probably too quickly) gained widespread acceptance. In our enthusiasm for the advancement of our newfound therapy, we must be careful to ensure that we bring a scientific basis with us. The two papers relating to this topic in this journal provide valuable information, but, just as importantly, remind us of the vast gaps in our knowledge.
1262
George S. Benson, M.D. Professor of Surgery University of Texas Health Science Center at Houston Houston, Texas REFERENCES
1. Brindley, G. S.: Pilot experiments on the actions of drugs injected
into the human corpus cavernosum penis. Br. J. Pharmacol., 87: 495, 1986.
2. Lee, M. and Sharifi, R.: Information and treatment with intracavernous injections of papaverine and phentolamine. Letter to the Editor. J. Urol., 137: 1008, 1987.
THE JOURNAL OF UROLOGY
Copyright© 1987 by The Williams & Wilkins Co.
THIS MONTH IN INVESTIGATIVE UROLOGY INTRACA VERNOSAL INJECTION THERAPY FOR IMPOTENCE The intracavernosal injection of vasoactive drugs in the evaluation and treatment of erectile dysfunction is currently one of the most popular, as well as controversial, topics in urology. Although it has been just four years since Virag and Brindley first observed that papaverine and phenoxybenzamine injected intracorporally produce penile erection, the clinical use of such agents has gained widespread acceptance. The utilization of intracorporeal injection techniques has occurred so rapidly that many basic, very important, questions remain unanswered. Two articles in this issue of the Journal of Urology address the problems of potential complications of intracavernosal injection as it is currently being practiced, as well as the future use of newer pharmacologic agents in the treatment of impotence. In their paper, "Chronic Papaverine Treatment: The Effect of Repeated Injections on the Simian Erectile Response and Penile Tissue", Abozeid and associates describe significant pathologic changes which were associated with 100 intracavernosal injections of papaverine over a one year period in monkeys. They observed not only minimal to marked fibrosis at the injection site, but also hypertrophy of smooth muscle in non-injected areas of the corpora. The reasons for these pathologic changes as well as their clinical implications are not clear. Fibrosis of the corpora cavernosa has been previously described as a complication of intracavernosal injection therapy. Since significant fibrosis can occur after only one injection of papaverine, this tissue response is probably secondary to irritative properties of papaverine itself or the low pH (approximately 4.0) of this agent. Smooth muscle hypertrophy of the corpora at sites proximal to the areas of injection may well be a response to repeated, prolonged erections. The paper by Abozeid and associates underscores the fact that we do not understand the long term effects of repeated intracavernosal injections. One can argue that the only other treatment modality available to these patients is a penile prosthesis, and that if fibrosis and/or smooth muscle hypertrophy become problematic, a prosthesis can always be placed. My opinion, however, is that a significant number of patients presently being treated with intracavernosal injection techniques are impotent on a psychogenic basis. The fact that long term effects of injection therapy are not clear necessitates caution in patient selection. Fibrosis and possible adverse effects from the observed smooth muscle hypertrophy must certainly be added to the list of possible complications from this new treatment modality. The incidence of these occurrences, as well as the incidence of the previously recognized problems of priapism, infection, ecchymosis and hematoma, and cardiovascular side effects are not well documented. Continued reporting of clinical complications and basic research in this area is needed. The article by Fovaeus and associates explores the effects of calcium channel blocking agents on in vitro strips of human corpora cavernosa. This well-designed and controlled study demonstrates that these drugs inhibit both electrically and pharmacologically induced contraction of this tissue. Since smooth muscle relaxation is a requirement for the production of penile erection, such drugs should promote erectile activity. In fact, penile erection secondary to the intracavernosal injection of verapamil (a calcium channel blocker) has been previously reported. 1 Whether the oral administration of these commonly used drugs affects penile erection is not known.
Many drugs injected intracorporally have been noted to produce penile erection. These agents include not only papaverine, phentolamine and verapamil, but also vasoactive intestinal polypeptide, phenoxybenzamine, imipramine, prostaglandin E 1 and others. It appears that any drug which causes relaxation of the corporal smooth muscle and arteriolar dilation by any of a number of mechanisms (including alpha adrenergic blockade, calcium channel blockade, activation of the adenyl cyclase system, or other direct smooth muscle actions) is capable of producing penile erection. It should be kept in mind that smooth muscle contraction (promoting penile flaccidity) is most probably an alpha adrenergic mediated event. The normal physiologic mechanisms which cause erection (arteriolar relaxation and corporal smooth muscle relaxation) are less well understood. Cholinergic mechanisms, as well as non-cholinergic non-adrenergic (possibly peptidergic) neural mechanisms, are probably involved. In addition, the recently described endothelial relaxation factor may also be important. Future studies similar to that of Fovaeus and associates are necessary to elucidate not only the pharmacology, but also the physiology of corporal smooth muscle and normal penile erection. The pharmacology of penile erection, particularly as it relates to the treatment of impotence, is in its infancy. Although papaverine alone and combinations of papaverine and phentolamine are extensively utilized, very basic pharmacologic questions remain unanswered. Drug doses are largely empiric and, to my knowledge, responses to varying drug doses have not been established. The pharmacokinetics of drug combinations have not been reported. Specifically, what is the stability of phentolamine when the lyophylized drug is reconstituted and then mixed with papaverine? 2 Are other vasoactive agents currently available more efficacious and less toxic than papaverine and phentolamine? Will prostaglandin E 1 replace papaverine and phentolamine as the drug therapy of choice? Prostaglandin E 1 appears efficacious in European and Japanese trials and the fact that it is probably metabolized by penile tissue would, at least theoretically, appear to lower the incidence of such complications as priapism. What is the best drug (norepinephrine, epinephrine, phenylephrine, metaraminol, etc.) and drug dose to treat pharmacologically induced priapism? The answers to these and other questions ·will hopefully be forthcoming. The pharmacologic treatment of impotence has quickly (probably too quickly) gained widespread acceptance. In our enthusiasm for the advancement of our newfound therapy, we must be careful to ensure that we bring a scientific basis with us. The two papers relating to this topic in this journal provide valuable information, but, just as importantly, remind us of the vast gaps in our knowledge.
1262
George S. Benson, M.D. Professor of Surgery University of Texas Health Science Center at Houston Houston, Texas REFERENCES
1. Brindley, G. S.: Pilot experiments on the actions of drugs injected
into the human corpus cavernosum penis. Br. J. Pharmacol., 87: 495, 1986.
2. Lee, M. and Sharifi, R.: Information and treatment with intracavernous injections of papaverine and phentolamine. Letter to the Editor. J. Urol., 137: 1008, 1987.