PDE5 inhibitors: Uses, common brands, and safety infor

In 1989, two British scientists at the pharmaceutical company Pfizer were investigating a potential high blood pressure and angina drug called UK-92480, a phosphodiesterase type 5 inhibitor (PDE5 inhibitor). Early clinical trials studying the drug for angina, a condition in which the blood vessels that supply the heart with blood narrow causing chest pain and breathlessness, were largely disappointing. Pfizer was on the verge of abandoning the drug until reports were received that many male trial participants were experiencing an unusual side effect – a significant increase in the number of erections.

Based on the way the drug worked, by increasing blood flow through the arteries, this side effect was not unexpected. Studies for its use in impotent men soon followed and the effect of the drug was dramatic. The U.S. Food and Drug Administration (FDA) approved the newly branded drug Viagra (generic name sildenafil) in 1998 as the first oral treatment of erectile dysfunction (ED).  Based on the pharmacology of PDE5 inhibitors, later studies found effectiveness as treatment options for pulmonary hypertension and enlarged prostate in men.

The following table lists the PDE5 inhibitor medications approved for use by the FDA, followed by information on how they work, what conditions they treat, safety, and cost.

What are PDE5 inhibitors?

PDE5 inhibitors are drugs that improve vascular blood flow to certain tissues in the body, including the tissue of the penis. Although they were originally designed to treat cardiovascular conditions such as high blood pressure and angina, today they are the standard of care to treat erectile dysfunction (ED) in men. 

How do PDE5 inhibitors work?

To attain or maintain normal erectile function, nitric oxide (NO) is released from endothelial cells within the penis following sexual stimulation. The NO concentration is significantly increased which contributes to the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP). Downstream, cGMP decreases intracellular calcium ions in the corpus cavernosum smooth muscles, leading to smooth-muscle relaxation causing vasodilation and reduced drainage of arterial blood thereby sustaining the erection. cGMP is metabolized by the enzyme phosphodiesterase type 5 (PDE-5) so that it cannot maintain its erectile effects. 

ED is a type of sexual dysfunction defined as the inability to attain or maintain a penile erection sufficient for sexual intercourse. PDE5 inhibitors work by inhibiting the PDE-5 enzyme. By inhibiting this enzyme, PDE5 inhibitors decrease cGMP metabolism and ultimately lead to successful attainment and maintenance of an erection. PDE5 inhibitors also act to relax blood vessel smooth muscle cells in other parts of the body such as the bladder and prostate to reduce symptoms of benign prostatic hyperplasia (BPH) and in the lungs to treat pulmonary arterial hypertension (PAH).

What are PDE5 inhibitors used for?

PED5 inhibitors are recommended as first-line treatment for ED. Other disease states specific PDE5 inhibitors are approved to treat include:

• Cialis (tadalafil) is approved to treat lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with or without accompanying ED.

• Adcirca (tadalafil) and Revatio (sildenafil) are approved to treat pulmonary arterial hypertension (PAH).

Who can take PDE5 inhibitors?

Men

PDE5 inhibitors, with proven safety profiles and relatively low incidence of adverse events, are the mainstays of ED treatment for men. Although ED is often associated with aging, clinical trials demonstrated effectiveness in men from their 20s to elderly patients in their 80s.  For the treatment of BPH in men, Cialis (tadalafil) was found to be safe and effective in clinical trial participants ages 44 to 93. Clinical studies for the use of PDE5 inhibitors in PAH patients included subjects from 14 to 90 years old.

Women 

PDE5 inhibitors have not been shown to be effective and are not approved for use in women to improve sexual response. Women were included in the PAH clinical studies for Adcirca (tadalafil) and Revatio (sildenafil) and both drugs are approved for female patients 18 years and older. 

There have been no adequate and well-controlled studies on the use of PDE5 inhibitors in pregnant or nursing women. Adcirca (tadalafil) for PAH should only be used if the potential benefit justifies the potential risk. 

Children and Adolescents

PDE5 inhibitors are not approved for use in children and adolescents under 18 years of age. Revatio (sildenafil) was clinically studied in children for PAH however its use is not recommended.

Seniors

In clinical studies, no overall differences in efficacy or safety were observed between older (greater than 65 years of age) and younger (65 years of age or younger) patients treated with PDE5 inhibitors. Even though no dose adjustment is required based on age alone, the lowest recommended starting dose is advised based on a greater sensitivity to medications in some older individuals.

Are PDE5 inhibitors safe?

The overall safety profile of PDE5 inhibitors is good when taken as prescribed, however, there are potential adverse effects and certain situations in which a person should not receive a PDE5 inhibitor because it may be harmful. 

Contraindications

You should not take any PDE5 inhibitor:

• If you are allergic to any of the active or inactive ingredients

• If you take medicines called “nitrates” or nitroglycerin (often used to control chest pain) or recreational drugs called “poppers,” such as amyl nitrate or butyl nitrate because the combination can cause a sudden and unsafe drop in blood pressure

Recalls

• AvKare issues voluntary nationwide recall of sildenafil 100mg tablets and trazodone 100mg tablets due to product mix-up, December 2020

Restrictions

You should ask your healthcare provider if it is safe for you to have sexual activity.  You should not take PDE5 inhibitors or they should be used cautiously if you have any of the following risk factors:

• Heart disease or cardiovascular diseases such as angina, heart failure, irregular heartbeats, or have had a heart attack (myocardial infarction)

• Low blood pressure (hypotension) 

• High blood pressure that is not controlled

• Had a stroke

• Liver problems

• Kidney problems or require dialysis

• Have retinitis pigmentosa, a rare genetic eye disease

• Ever had severe vision loss, including a condition called non-arteritic anterior ischemic optic neuropathy (NAION)

• Stomach ulcers

• A bleeding problem

• A deformed penis shape or Peyronie’s disease

• Ever had an erection that lasted more than 4 hours

• Blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia

• Have hearing problems

Drug-drug interactions

PDE5 inhibitors and other medicines may affect each other. Always check with your healthcare provider before starting or stopping any medicines. Before starting a PDE5 inhibitor tell your healthcare provider if you take any of the following:

• Medicines called “nitrates” or recreational drugs called “poppers”

• Alpha blockers such as  Hytrin (terazosin), Flomax (tamsulosin), Cardura (doxazosin), Minipress (prazosin), Uroxatral (alfuzosin), Jalyn (dutasteride and tamsulosin) or Rapaflo (silodosin)

• Medicines to treat hypertension (high blood pressure)

• HIV protease inhibitors such as Norvir or Kaletra (ritonavir)

• Some oral antifungals such as Nizoral (ketoconazole) or Sporanox (itraconazole)

• Some antibiotics such as Biaxin (clarithromycin), Ketek (telithromycin), or erythromycin (several brand names are available)

• Other medicines or treatments for ED

This is not a complete list of drugs that may interact with PDE5 inhibitors. Talk to your healthcare professional before starting a PDE5 inhibitor about any other prescription or over-the-counter medicines you may take.

Are PDE5 inhibitors controlled substances?

No, PDE5 inhibitors are not controlled substances.

Common PDE5 inhibitor side effects

The following are potential common side effects when taking PDE5 inhibitors. This is not an exhaustive list and you should always talk to your healthcare professional and seek medical advice about what adverse reactions to expect and how to address them.

• Headache

• Indigestion

• Upset stomach

• Dizziness

• Back pain

• Muscle aches

• Getting red or hot in the face (flushing)

• Nasal congestion

• Runny nose

Uncommon, but significant, side effects that require immediate medical attention include:

• Priapism (an erection that lasts more than 4 hours)

• A sudden decrease or loss of vision in one or both eyes or color vision changes

• Sudden loss or decrease in hearing, sometimes with ringing in the ears and dizziness

How much do PDE5 inhibitors cost?

PDE5 inhibitors have a wide price range depending on the specific drug, quantity, dosage, and dosing regimen. Medicare and some insurance plans do not cover ED medicines but usually cover PDE5 inhibitors for PAH and BPH. Since most PDE5 inhibitors are available in generic formulations, they are much less expensive than their brand-name counterpart. A SingleCare discount card could reduce prescription costs up to 80% at participating pharmacies.