Intracavernous pharmacotherapy medications


Papaverine is the time-tested medication

Papaverine was the first clinically effective medication for impotence tried as an intracavernous injection. As a good smooth muscle relaxant, papaverine has shown to induce relaxation of penile blood vessels.

The intracavernous injection of papaverine resulted both in penile tumescence and rigidity.

Papaverine caused marked vasodilation of the penile arteries and decreased venous outflow. An intracavernous injection of papaverine in normal volunteers and patients with psychogenic impotence produced rigid erections in most cases. Its success rates were reported to range between 93% and 97%.

Papaverine may cause excessively long erections in approximately 11% of men, and even priapism in approximately 2% of men, when papaverine was intentionally or accidentally overdosed.

Papaverine hydrochloride is marketed in many countries under a variety of trade names, mostly in 2 ml ampoules containing 20 mg papaverine per 1 ml.

Papaverine was known since 19th century, long before PGE1 and Sildenafil were synthesized. Papaverine is used so far and this single fact speaks more than butts and tons of declamation.

Papaverine (C21H21NO4) crystallises from alcohol in white needles or scales. It possesses scarcely any alkaline reaction, but its salts have an acid reaction; it has but little effect on a ray of polarised light. It is almost insoluble in water; it is easily soluble in acetone, amyl alcohol, alcohol, and chloroform. One part of the alkaloid is dissolved in 36·6 of benzene, and in 76 parts of amyl alcohol. Petroleum ether dissolves it by the aid of heat, but the alkaloid separates in crystals on cooling. Chloroform extracts it from either acid or alkaline solutions. Papaverine gives no crystalline sublimate. The melting-point of pure samples in a tube is 147°, with scarcely any colour; it solidifies again to crystals on cooling; in the subliming cell it melts at 130°, and decomposes about 149°; the vapours are alkaline; the residue is amorphous, light brown, and is not characteristic. Concentrated sulphuric acid colours it a deep violet-blue, and dissolves it to a violet, slowly fading. This solution, by permanganate of potash, is first green and then grey. Fröhde’s reagent gives a beautiful violet colour, which becomes blue, and vanishes after twenty-four hours. Diluted solutions of salts of papaverine are not precipitated by phosphomolybdic acid. It is precipitated by ammonia, by the caustic and carbonated alkalies, by potassic-cadmic iodide, iodine in hydriodic acid, and by alkaloidal reagents generally—save by the important exception mentioned above. A solution in amyl alcohol is also precipitated by bromine; the precipitate is crystalline. An alcoholic solution of platinic chloride also separates papaverine platin chloride in crystals. An alcoholic solution of iodine, added to an alcoholic solution of papaverine, separates in a little time crystals of the composition C21H21NO4I3. From the mother-liquor, by concentration, can be obtained needles of another iodine combination, C21H21NO4I5; the latter heated above 100° parts with free iodine. These compounds with iodine are decomposed by ammonia and potash, papaverine separating. The decomposition may be watched under the microscope. Nitric acid precipitates from a solution of the sulphate a white nitrate soluble in excess; the precipitate does not appear at once, but forms in the course of an hour; it is at first amorphous, but subsequently crystalline; this, with its physical properties, is a great assistance to identification.

Ztschr. d. Wien. Aerzte, pp. 13, 115, 1868.

Arch. Anat. Phys., p. 70, 1869.


Papaverine hydrochloride for injection.

Papaverine hydrochloride is the hydrochloride of an alkaloid prepared synthetically. It belongs to the benzylisoquinoline group of alkaloids. It does not contain a phenanthrene group as do morphine and codeine.

Papaverine hydrochloride occurs as white crystals or white crystalline powder. One gram dissolves in about 30 mL of water and in 120 mL of alcohol. It is soluble in chloroform and practically insoluble in ether.

Papaverine hydrochloride Injection, is a clear, colorless to pale-yellow solution. Papaverine hydrochloride, for parenteral administration, is a smooth-muscle relaxant that is available in vials containing 30 mg/mL. Each vial also contains edetate disodium 0.005 %. The 10 mL vials also contain chlorobutanol 0.5 % as a preservative. pH may be adjusted with sodium citrate and/or citric acid.

Pharmacological effects

The most characteristic effect of papaverine is relaxation of the tonus of all smooth muscle, especially when it has been spasmodically contracted. Papaverine hydrochloride apparently acts directly on the muscle itself. This relaxation is noted in the vascular system and bronchial musculature and in the gastrointestinal, biliary and urinary tracts.

The main actions of papaverine are exerted on cardiac and smooth muscle. Papaverine relaxes various smooth muscles, especially those of larger arteries; this relaxation may be prominent if spasm exists. The antispasmodic effect is a direct one and unrelated to muscle innervation, and the muscle still responds to drug and other stimuli causing contraction. Papaverine has minimal actions on the central nervous system, although very large doses tend to produce some sedation and sleepiness in some patients. In certain circumstances, mild respiratory stimulation can be observed, but this is therapeutically inconsequential. Papaverine stimulates respiration by acting on carotid and aortic body chemoreceptors.

Papaverine relaxes the smooth musculature of the large blood vessels, including the coronary, cerebral, peripheral, and pulmonary arteries. This action is particularly evident when such vessels are in spasm, induced reflexly or by drugs, and it provides the basis for clinical use of Papaverine in peripheral or pulmonary arterial embolism.

Administration and dosage

Papaverine hydrochloride may be administered intravenously or intramuscularly. The intravenous route is recommended when an immediate effect is desired.

Parenteral administration of papaverine hydrochloride in doses of 1 to 4 mL is repeated every 3 hours as indicated.

Store at 20° to 25° C (68° to 77° F).

Alpha-adrenoceptor blockers


Phentolamine

Phentolamine is a competitive, non-selective α1-and α2-adrenoceptor blocker that acts on α-adrenoceptors. The intracavernous injection of phentolamine only resulted in penile tumescence but not rigidity.

Moxisylyte

Moxisylyte is an α-adrenoceptor blocker. Moxisylyte was developed for self-injection therapy iand marketed in several European countries. Although its success rates were reported to range between 41% and 59%, regarding the induction of rigid erections sufficient for successful vaginal penetration.

Drug combinations for self-injection therapy

Combination of papaverine and phentolamine

Self-injection therapy with PGE1 (Alprostadil, Caverject, etc.) are always painful to a certain degree.

Self-injections with papaverine are painless.

Therefore, indication for using the mixture of papaverine/phentolamine and papaverine, as monotherapy, are also patients in whom PGE1-induced erections were felt painful.

The combination of papaverine/phentolamine has become popular since 1985. The mixture of papaverine/phentolamine is commercially available and approved in several countries worldwide, especially in Europe.

Vasoactive intestinal polypeptide

Vasoactive intestinal polypeptide was considered to be one of the strong candidates for penile erection in the 1980s. The reasons for that is the fact that it is one of the naturally occurring neurotransmitters present in considerable amounts in the male genital tract.

Vasoactive intestinal polypeptide is said to mediate facilitating effects on blood flow, secretion and muscle tone, suggesting that this peptide neurotransmitter may play a significant role in the neural control of male erectile function.

Another finding from this study was that intracavernous injection of Vasoactive intestinal polypeptide in man produced tumescence and not erection.

Therefore, the finding that Vasoactive intestinal polypeptide was not able to induce penile rigidity adequate for sexual intercourse, when injected intracavernosally in normal young volunteers and impotent men, made a potential role as a primary neurotransmitter for erection.

This is in line with the results obtained in healthy male volunteers in whom no significant changes were detected in systemic and cavernous plasma levels of Vasoactive intestinal polypeptide after the flaccid penis became rigid.

Drug combinations for self-injection therapy

PGE1 mono therapy, several potentially useful combinations have been used for self-injection therapy. The vasoactive agents used in combination therapy, were phentolamine, papaverine, PGE1, and Vasoactive intestinal polypeptide.

Combination of papaverine/phentolamine/PGE1

The use of the triple drug combination of papaverine/phentolamine/PGE1 was reported for the first time in 1990.

The patients or the pharmacists have to reconstitute this combination themselves, which is relatively complicated for many patients.

Combination of Vasoactive intestinal polypeptide and Phentolamine

The use of the combination of Vasoactive intestinal polypeptide and phentolamine in a larger series of patients with ED was published for the first time in 1992.

The mixture of Vasoactive intestinal polypeptide/phentolamine was introduced and approved in some countries. It was not marketed worldwide.

The Vasoactive intestinal polypeptide/phentolamine combination is not officially available in some countries.