TriMix Injection

Overview

TriMix is an intracavernous injectable drug used as an alternative to oral PDE5 inhibitor tablets such as Viagra, Cialis, and Levitra. It is composed of Papaverine, Phentolamine, and Prostaglandin E1, which work together in different ways to treat erectile dysfunction.¹ The American Urologic Association calls TriMix the most powerful non-surgical treatment of erectile dysfunction (ED). It is reported to have a 90% success rate as compared to a 60% success rate for men using oral PDE5 inhibitor medications. As such, TriMix is the treatment of choice for patients not responsive to oral PDE5 inhibitors.²

Papaverine

Papaverine is a vasodilator that causes blood vessels to expand. It was one of the first effective therapies for erectile dysfunction administered by penile injection.³ Papaverine works by increasing cyclic adenosine monophosphate (cAMP), which causes a relaxation of penile smooth muscle and an increase in blood flow to the area.⁴ Papaverine also works by inhibiting the phosphodiesterase enzyme.⁵ The multiple actions by which this drug works may be concentration dependent. Experimental data shows papaverine acts to relax the penile arteries, the cavernosal sinusoids, and the penile veins.⁶ 

Papaverine has been studied clinically in men suffering from erectile dysfunction. The drug has been administered as an intracavernosal injection containing between 30 mg and 60 mg. Several studies report positive findings such as its ability to obtain up to an 80% success rate in erection achievement within 20-30 minutes and to improve sexual potency. In summary, papaverine is an overall effective treatment of erectile dysfunction.^{7, 8, 9, 10}

Phentolamine

Norepinephrine maintains smooth muscle tone of the penile tissues in a contracted state. One way an erection can be achieved is by blocking the alpha-adrenoreceptors in the local area to allow the tissues to relax. Phentolamine is an alpha-adrenoceptor antagonist and competes with norepinephrine at the alpha-adrenoreceptor. It induces an erection by relaxing and dilating the blood vessels of the penis and by increasing cardiac output.^{11, 12}

Since phentolamine is cleared by the liver, its effectiveness in the treatment of erectile dysfunction is best administered by injection. Phentolamine is short-acting, reaching a maximum serum concentration within 20 to 30 minutes and acts for a duration between 2.5 to 4 hours.^{13, 14}

Phentolamine is usually added with papaverine to increase erectile response.^{15, 16} Papaverine 30 mg and phentolamine 1 mg when combined in an intracavernosal injection has been studied clinically and has been found to produce an erection in 90% of the subjects within 20-30 minutes of administration.⁸ Side effects of phentolamine are rare however orthostatic hypotension, tachycardia, arrhythmias and myocardial infarction have occurred after penile injection.

Prostaglandin E1

Alprostadil is the naturally occurring prostaglandin E1 (PGE1). As a hormone-like substance, PGE1 exerts a variety of pharmacologic actions including its ability to promote systemic vasodilation, prevent platelet aggregation, and stimulate intestinal activity. It induces an erection by allowing for more blood into the penis and less blood out. It works by relaxing blood vessels, dilating cavernosal arteries, increasing arterial inflow velocity, and increasing venous outflow resistance.

When injected into penile tissue prostaglandin E1 is readily metabolized into other erectile promoting molecules. These molecules potentiate the efficacy of prostaglandin E1. It is believed prostaglandin E1 primarily acts directly by increasing cAMP to promote muscular relaxation.¹⁷ Prostaglandin E1 has also been shown to decrease the concentrations of noradrenalin.¹⁸

Prostaglandin E1 appears to be short-acting and is rapidly metabolized throughout the body upon systemic administration.¹⁹ As such, when given locally as a intracavernosal injection, the drug mainly acts on penile tissues and explains the rare propensity for circulatory side effects.

Prostaglandin E1 is administered intracavernosally and is prescribed as a second-line treatment for erectile dysfunction, after oral PDE5 inhibitors have been ineffective.²⁰ Studies demonstrate that 40 to 70% of erectile dysfunction patients respond to treatment with prostaglandin E1. The cause for the failure response rate to prostaglandin E1 is unknown.²¹ Medications to activate alternative relaxant pathways in addition to prostaglandin E1 may be necessary in patients who fail to respond to prostaglandin E1 alone.