Tri-Mix Injection

Tri-Mix is administered as a penile self-injection, typically considered to be the most powerful class of anti-erectile dysfunction agents.^[1] While the components of Tri-Mix (Papaverine, Phentolamine, Prostaglandin E1) are, on their own, indicated for a vast number of different conditions, the practice of bringing them together in concert to treat erectile dysfunction has become commonplace in sexual medicine and is now considered to be the go-to treatment if conventional PDE5 inhibitors are contraindicated or nonresponsive.^[2][1] and is now considered the go-to treatment if a patient is not responsive to conventional PDE5 inhibitors such as Viagra or Cialis.^[1] Tri-Mix is indicated in the treatment of erectile dysfunction in males. Tri-Mix contains three drugs from complimentary classes designed to act synergistically, mixed into a sterile injection. They are:

Papaverine HCl

A drug that causes blood vessels to expand (vasodilator); it produces an erection by allowing for increased blood flow to the penis. Papaverine interacts with adenylate cyclase resulting in increased cyclic adenosine monophosphate (cAMP) production, ultimately resulting in increased erectile capacity by relaxation of penile smooth muscle.^[3] This drug was one of the first effective therapies for erectile dysfunction administered by penile injection.^[4] Papaverine works by inhibiting phosphodiesterase nonspecifically, there are also multiple other mechanisms by which this drug acts to improve erectile capacity.^[5] The current body of medical literature has not established the predominant mechanism by which papaverine works. The multi-mechanistic manner by which this drug acts may be concentration dependent. Experimental data, performed in-vitro, displays papaverine acting to relax the penile arteries, the cavernosal sinusoids, and the penile veins.^[6] Experiments carried out in dogs display papaverine’s ability to decrease the resistance to arterial inflow while also increasing the resistance to venous outflow.^[7] Papaverine’s ability to decrease resistance to venous outflow has been replicated in clinical studies.8 A veno-occlusive mechanism may be responsible for the aforementioned findings.

Biweekly intracavernous administration of papaverine for erectile dysfunction.^[9]

Participants: 50 patients age 40 to 70 years old
Administration: intracavernosal injection at base of the penis
Dosage: 60 mg papaverine in 5 ml saline every 2 weeks
Results: Erection of 80% or more of normal was achieved by all but one patient, improves sexual potency

Medical treatment of impotence with papaverine and phentolamine intracavernosal injection.^[10]

Participants: 20 patients age 32 to 72 years old
Administration: intracavernosal injection
Dosage: 30 mg papaverine and phentolamine 1 mg
Results: Response with erection in 20- 30 minutes, phentolamine and papaverine produced an erection sufficient for intercourse in 18 of the 20 subjects

Treatment of impotence by intrapenile injections of papaverine and phenoxybenzamine: a double blind, controlled trial.^[11]

Participants: 39 patients age 27 to 67 years old
Administration: intracavernosal injection
Dosage: 60 mg Papaverine in 10 ml saline
Results: 35% full restoration of erectile capacity 65% partial restoration of erectile capacity

Evaluating erectile dysfunction: oral sildenafil versus intracavernosal injection of papaverine.^[12]

Participants: 39 patients age 21 to 65 years old
Administration: intracavernosal injection
Dosage: 30 mg papaverine
Results: Papaverine improved length and circumference papaverine is effective as injection therapy for erectile dysfunction

Phentolamine Mesylate

When injected into the penis, it induces an erection by relaxing and dilating the blood vessels of the penis, as well as by elevating cardiac output.

Phentolamine is classified as an Alpha-Adrenoceptor Antagonists. Noradrenaline effects the smooth muscle tone of the penile tissues by keeping the corpora cavernosa in a contracted state. By blocking the functional noradrenaline receptors, the Alpha-Adrenoceptor, erectile response can be achieved. Phentolamine competes with endogenous norepinephrine for the Alpha1-Adrenoceptor and Alpha2-Adrenoceptor. Phentolamine has similar binding capacities to both receptors. The current literature suggests that this is the main mechanism by which phentolamine exerts its physiological effects. Phentolamine also blocks 5-HT receptors, inducing the release of histamine from mast cells. Some studies also show that NOS activation could possibly be involved in another mechanism, inducing increased vasodilation.^[13][14]

The Alpha-Adrenoceptor Antagonist of phentolamine is considered to be complex. The non-selective receptor blocking action interacts with adrenergic nerves in a complex fashion. Phentolamine action on adrenergic nerves has not been fully established. It is thought that there might be counteracting regulation on pre-and post-junctional nerves. It is not known how the counteracting regulation might affect the efficacy of phentolamine for the treatment of erectile dysfunction.

In animal studies, penile arterial inflow resistance was decreased. This proves in vivo that the physiological response to phentolamine acts in a manner to achieve erectile response.7 However, phentolamine has not displayed a significant effect on the venous outflow from penile tissues in humans.^[15] The current body of literature has not established pharmacokinetics for phentolamine.

First pass metabolism effectively reduces the efficacy in the treatment of erectile dysfunction. Therefore, this drug has to be administered by injection. The half-life of phentolamine is 30 minutes, with an effect duration of 2.5 to 4 hours.^[16] After penile injection the concentration of phentolamine in serum reaches a maximum within 20 to 30 minutes. After this amount of time has passed the drug rapidly is metabolized.^[17]

Side effects of phentolamine are rare. However, it has been reported that orthostatic hypotension, tachycardia, arrhythmias and myocardial infarction, have occurred after penile injection. The mechanism to which this set of side effects occur has not been rationally deduced through scientific study. Phentolamine is usually added in combination with papaverine or vasoactive intestinal peptide to increase erectile response.^[18][19]

Medical treatment of impotence with papaverine and phentolamine intracavernosal injection.^[10]

Participants: 20 patients age 32 to 72 years old
Administration: intracavernosal injection
Dosage: 30 mg papaverine and phentolamine 1 mg
Results: Response with erection in 20- 30 minutes, phentolamine and papaverine produced an erection sufficient for intercourse in 18 of the 20 subjects

Prostaglandin E1

A potent hormone-like substance that induces erection by relaxing the penis’s blood vessels and dilating cavernosal arteries-dilation of the cavernosal arteries is accompanied by increased arterial inflow velocity and increased venous outflow resistance allowing for more blood into the penis and less blood out.

Prostaglandin E1 is administered intracavernosally. This drug is prescribed as a second-line treatment, after oral PDE5 inhibitors have been ineffective for treatment of erectile dysfunction.^[20] Several aspects of its effects and clinical use have been reviewed previously.^[21][22] Currently the body of medical literature demonstrates that 40 to 70% of erectile dysfunction patients respond to treatment with prostaglandin E1. The failure to respond to prostaglandin E1 has not been established. The demonstration that prostaglandin E1 with S-nitrosoglutathione in combination is more effective than prostaglandin E1 alone may shed light on the lack of efficacy in some patients.^[23]

Medications to activate alternative relaxant pathways in addition to by prostaglandin E1 may be necessary in patients who fail to respond to prostaglandin E1. Relaxation of smooth muscle is a critical component of erectile capacity. Additional agents to work in combination with prostaglandin E1 might have significant therapeutic benefits. Prostaglandin E1 with S-nitrosoglutathione or other erectile dysfunction medications, might have advantages in the treatment of male erectile dysfunction. Empower Pharmacy strives to compound medications that take advantage of multi-compound synergy. When injected into penile tissue prostaglandin E1 is readily metabolized into other erectile promoting molecules. These molecules potentiate the efficacy of prostaglandin E1. Prostaglandin E1 has been demonstrated to alter the concentrations of noradrenalin, adding a secondary mechanism of action.^[24] However, it is still believed prostaglandin E1 primarily acts directly by increasing cAMP synthesis via EP receptor interaction, increasing muscular relaxation.^[25]

Prostaglandin E1 has ubiquitous actions in controlling processes in many tissues. Known effects of prostaglandin E1 include systemic vasodilation, prevention of platelet aggregation, and ask to stimulate intestinal activity. Thus, prostaglandin E1 has very rarely been administered in a fashion to elicit a systemic response. Pharmacokinetics data is currently lacking on prostaglandin E1, the current data suggest short action duration and high rate of metabolic breakdown. After the first pass through the lungs 70% is metabolized.26 Because prostaglandin E1 is readily metabolized throughout the body, penile injection effects mainly penile tissues. Furthermore, this further explains the rare circulatory side effects.

For more information on Tri-mix, see our post that goes into detail about Tri-mix information.

Do not take this medicine with any of the following medications: hypersensitivity or allergy to any component of this formulation; conditions predisposing you to priapism (painful erection lasting 4 hours or more): sickle cell anemia, multiple myeloma or leukemia; anatomical deformation of the penis or penile implants; direction by your physician that sexual activity is inadvisable or contraindicated. Tell your doctor if you have a condition or are taking a medicine that interferes with blood clotting.

Mild to moderate pain during injection; painful sensation with erection; small amount of bleeding at the injection site. Call your healthcare provider if you notice any redness, lumps, swelling, tenderness or curvature of the erect penis. If you experience an erection lasting more than 2 hours, you may take 2 – 4 pseudoephedrine 30 mg by mouth once and apply an ice pack.^[6] If your erection does not go away within the next hour, seek professional help immediately. Erections that last more than 6 hours can cause serious damage to the penile tissue.

Store dry powder at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Once reconstituted keep this medicine in a refrigerator between 36°F to 46°F (2°C to 8°C). Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1. Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: The management of erectile dysfunction: an AUA update. *J Urol* 2005;174:230-9. Available at https://pubmed.ncbi.nlm.nih.gov/15947645/
2. Leungwattanakij S, Flynn V, Hellstrom WJG. Intracavernosal injection and intraurethral therapy for erectile dysfunction. *Urol Clin North Am* 2001;28:343-354. Available at https://pubmed.ncbi.nlm.nih.gov/11402586/
3. Andersson K E. Pharmacology of penile erection. *Pharmacol Rev* 2001;53(3):417-50. Available at https://pubmed.ncbi.nlm.nih.gov/11546836/
4. Virag R, et al. Vasoactive intestinal polypeptide release during penile erection in man. *Lancet* 1982;2(8308):1166. Available at https://pubmed.ncbi.nlm.nih.gov/6128487/
5. Andersson K E. Pharmacology of erection: agents which initiate and terminate erection. *Sex Disabil* 1994;12:53-79. Available at https://doi.org/10.1007/BF02547898
6. Kirkeby H J, et al. [Infusion cavernosography and erectile dysfunction]. *Ugeskr Laeger* 1990;152(24):1724-6. Available at https://pubmed.ncbi.nlm.nih.gov/2360289/
7. Juenemann K P, et al. Hemodynamics of papaverine- and phentolamine-induced penile erection. *J Urol* 1986;136(1):158-61. Available at https://pubmed.ncbi.nlm.nih.gov/3712604/
8. Delcour C, et al. The effect of papaverine on arterial and venous hemodynamics of erection. *J Urol* 1987;138(1):187-9. Available at https://pubmed.ncbi.nlm.nih.gov/3599210/
9. Mooradian A D, et al. Biweekly intracavernous administration of papaverine for erectile dysfunction. *West J Med* 1989;151(5):515-7. Available at https://pubmed.ncbi.nlm.nih.gov/2603417/
10. Dinsmore W W. Medical treatment of impotence with papaverine and phentolamine intracavernosal injection. *Ulster Med J* 1990;59(2):174-6. Available at https://pubmed.ncbi.nlm.nih.gov/2278115/
11. Keogh E J, et al. Treatment of impotence by intrapenile injections of papaverine and phenoxybenzamine: a double-blind, controlled trial. *Aust N Z J Med* 1989;19(2):108-12. Available at https://pubmed.ncbi.nlm.nih.gov/2669713/
12. Viswaroop B, Antonisamy B, Gopalakrishnan G. Evaluating erectile dysfunction: oral sildenafil versus intracavernosal injection of papaverine. *Natl Med J India* 2005;18(6):299-301. Available at https://pubmed.ncbi.nlm.nih.gov/16483029/
13. Traish A M, et al. Expression of functional alpha2-adrenergic receptor subtypes in human corpus cavernosum and in cultured trabecular smooth muscle cells. *Recept Signal Transduct* 1997;7(1):55-67. Available at https://pubmed.ncbi.nlm.nih.gov/9285531/
14. Traish A, et al. Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. *Int J Impot Res* 1998;10(4):215-23. Available at https://pubmed.ncbi.nlm.nih.gov/9884917/
15. Wespes E, Rondeux C, Schulman C C. Effect of phentolamine on venous return in human erection. *Br J Urol* 1989;63(1):95-7. Available at https://pubmed.ncbi.nlm.nih.gov/2920269/
16. P R I, G B, B L. Human pharmacology of orally administered phentolamine. In: *Phentolamine in Heart Failure and Other Cardiac Disorders.* Proceedings of an International Workshop; London, 1975. Available at https://link.springer.com/chapter/10.1007/978-3-642-74209-5_4
17. O H, U W, K U. Systemic pharmacokinetics of papaverine and phentolamine: comparison of intravenous and intracavernous application. *Int J Impot Res* 1990;2(Suppl 2):247-248. Available at https://ouci.dntb.gov.ua/en/works/9GBmdvxl/#17
18. Eardley I, et al. Pharmacotherapy for erectile dysfunction. *J Sex Med* 2010;7(1 Pt 2):524-40. Available at https://pubmed.ncbi.nlm.nih.gov/20092451/
19. Dinsmore W W, Wyllie M G. Vasoactive intestinal polypeptide/phentolamine for intracavernosal injection in erectile dysfunction. *BJU Int* 2008;102(8):933-7. Available at https://pubmed.ncbi.nlm.nih.gov/18485029/
20. Albersen M, et al. Evaluation and treatment of erectile dysfunction. *Med Clin North Am* 2011;95(1):201-12. Available at https://pubmed.ncbi.nlm.nih.gov/21095423/
21. Linet O I, Ogrinc F G. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. *N Engl J Med* 1996;334(14):873-7. Available at https://pubmed.ncbi.nlm.nih.gov/8596569/
22. Porst H. The rationale for prostaglandin E1 in erectile failure: a survey of worldwide experience. *J Urol* 1996;155(3):802-15. Available at https://pubmed.ncbi.nlm.nih.gov/8583582/
23. Angulo J, et al. Rationale for the combination of PGE₁ and S-nitroso-glutathione to induce relaxation of human penile smooth muscle. *J Pharmacol Exp Ther* 2000;295(2):586-93. Available at https://pubmed.ncbi.nlm.nih.gov/11046092/
24. Molderings G J, et al. Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein by presynaptic histamine H₃ receptors. *Naunyn Schmiedebergs Arch Pharmacol* 1992;346(1):46-50. Available at https://pubmed.ncbi.nlm.nih.gov/1328894/
25. Palmer L S, et al. Characterization of cyclic AMP accumulation in cultured human corpus cavernosum smooth muscle cells. *J Urol* 1994;152(4):1308-14. Available at https://pubmed.ncbi.nlm.nih.gov/8072124/
26. Golub M, et al. Metabolism of prostaglandins A₁ and E₁ in man. *J Clin Invest* 1975;56(6):1404-10. Available at https://pubmed.ncbi.nlm.nih.gov/1202078/