PDE5 inhibitors

Sildenafil (Viagra) was the first PDE5 inhibitor, followed by vardenafil (Levitra) and tadalafil (Cialis). Avanafil (Standra) is currently being approved by the FDA. The three agents taken together as a class have been studied in men of different ages and races, with diabetes, hypertension, cigarette smoking, high cholesterol, obesity, spinal cord injury, multiple sclerosis and more. The safety and efficacy of these products for erectile dysfunction are well documented.

When a man with erectile dysfunction is given a PDE5 inhibitor, not only is sexual function improved, but that of his untreated woman partner is improved as well if she was initially without sexual dysfunction. When the man with ED is given a placebo (sugar pill), the sexual function of the untreated woman partner worsens, assuming she was without sexual dysfunction before. Sexual dysfunctions and sexual treatments can affect both members of the couple even though only one member is treated.

The PDE5 inhibitors are the recommended first-line treatment for ED. However, their use is not recommended in men who have recent history of stroke or myocardial infarction (within the last 6-8 weeks), or who have significantly low blood pressure, uncontrolled high blood pressure, unstable angina, severe cardiac failure, severe liver impairment or end-stage kidney disease requiring dialysis. Prescribers should consult the prescribing information of the individual PDE5 inhibitors.

Although the PDE5 inhibitors show the same mechanism of action, these drugs have some pharmacological differences that translate into differing clinical effects.

Following sexual stimulation, penile erection occurs through the release of nitric oxide (NO), which causes dilation of the blood vessels of the corpus cavernosum via an accumulation of cyclic guanosine monophosphate (cGMP). PDE5, an enzyme that breaks down cGMP, can be inhibited and thereby the vasodilatory effect of NO is enhanced . All three PDE5 inhibitors share this common mechanism of action and are only pharmacologically active when cGMP synthesis is activated. The action of the PDE5 inhibitors therefore requires sexual arousal.

Schematic diagram illustrating the mechanism of action of the phosphodiesterase type 5 (PDE5) inhibitors. Following sexual arousal, nitric oxide is released from the synapses of neurones in the corpus cavernosum of the penis. This results in accumulation of cyclic guanosine monophosphate (cGMP), produced from Guanosine triphosphate (GTP), which causes smooth muscle relaxation leading to an erection. By preventing cGMP breakdown, PDE5 inhibitors enhance erectile function

How do PDE5 Inhibitors work

As competitive inhibitors of PDE5, this class of drugs has structures derived from cGMP. Sildenafil and vardenafil have very similar molecular structures. In contrast, tadalafil has a different chemical structure from avanafil, sildenafil and vardenafil, while still retaining the elements required for inhibition of PDE5. These structural differences are reflected in the pharmacokinetic properties of tadalafil and its selectivity for PDE isozymes.

Food (in particular fatty food) is known to delay the absorption of sildenafil and vardenafil, but it has no effect on the rate and extent of absorption of tadalafil. When taken with food the rate and extent of sildenafil absorption is reduced with the maximal plasma concentration of sildenafil decreased by almost 30% and the mean time to the maximum concentration delayed by approximately 1 h, compared with administration in the fasted state. As with sildenafil, a high-fat meal delays the absorption of vardenafil by up to 1 h and decreases the maximal concentration of vardenafil by approximately 20% compared with the fasted state. Food has no effect on the rate and extent of absorption of tadalafil, so this agent can be taken without regard to food. The pharmacokinetics of the three currently available PDE5 inhibitors are not affected by alcohol, although men may wish to refrain from alcohol, as alcohol consumption has been shown to be associated with ED.

Sildenafil and vardenafil both have a terminal half-life of approximately 4 h, and tadalafil has a half-life of 17.5 h. Avanafil / Stendra has the shortest half-life. All three currently available PDE5 inhibitors are eliminated by hepatic metabolism. Sildenafil is predominantly metabolised by cytochrome P450 into an N-desmethyl metabolite that also has some PDE5 activity. This metabolite is thought to account for approximately a fifth of the drug’s activity. Vardenafil also has an active metabolite that accounts for approximately 7% of total pharmacological activity. The activity of tadalafil is solely through the parent drug, as it does not have any active metabolites. All the PDE5 inhibitors are excreted as metabolites predominantly in the faeces and to a lesser extent in the urine.

How fast to the drugs work?

None of the three PDE5 inhibitors act immediately. Stendra seems to work quickest. Most studies have illustrated that the drugs have an onset of action between 30 and 60 min, but the rate of onset of each drug varies between individuals. Stendra starts in as little as 15 minutes. The prescribing information for sildenafil recommends dosing 60 min before sexual activity, although achievement of an erection that led to successful intercourse was reported in 35% (vs. 22% for placebo) of patients within 14 min and in 51% (vs. 30% for placebo) of patients within 20 min of sildenafil dosing (both statistically significant compared with placebo) in one study. Vardenafil also has a similar duration of onset, with a recommendation in the prescribing information that patients should take vardenafil 25-60 min before sexual activity.However, one study reported onset of action with vardenafil 10 mg at 10 min that was statistically significant compared with placebo (21% vs. 14% of intercourse attempts were successful). Of note, 72% of the population were previous responders to PDE5 inhibitors.The prescribing information for tadalafil states that patients should wait 30 min before engaging in sexual activity, although a study has shown onset of action for tadalafil as early as 16 min.In this study, 16% of intercourse attempts with tadalafil were successful within 16 min, vs. 8% with placebo. However, onset times of the three products cannot be compared directly because separate clinical trials with different designs were used to determine the onset of erectogenic effects.

The PDE5 inhibitors show marked differences in their duration of effect. According to the prescribing information, the duration of effect with sildenafil and vardenafil is approximately 4-5 h. However, consistent with its half-life of 17.5 h, tadalafil’s duration of effect is up to 36 h. This broad window of responsiveness allows patients with ED more freedom to choose when they participate in sexual intercourse.

PDE5 Inhibitors Side Effects

The most commonly reported side effects of the erectile dysfunction drugs are headaches, flushing of the face, upset stomach and nasal congestion. Other, less common, side effects include sensitivity to light, blurred vision, urinary tract infection, diarrhea and dizziness. Sildenafil might also share common side effects of some prescription medications, including antihistamines, antidepressants, antihypertensives, antipsychotics, beta blockers, diuretics, tranquilizers, appetite suppressants, cimetidine (Tagamet) and finasteride (Propecia).

The adverse event profiles of the PDE5 inhibitors are generally similar . Class-specific side effects include headache, flushing, nasal congestion, dyspepsia and myalgia, which are a reflection of vasodilatory effects on the capillary smooth muscle in other parts of the body. Another consequence of the vasodilatory effects of PDE5 inhibitors is that their concurrent administration with nitrates or the potassium channel activator nicorandil is contraindicated, as hypotension can result. As described earlier, differences in PDE selectivity may explain other differences in the side effect profiles of the PDE5 inhibitors. Rare postmarketing reports of non-arteritic anterior ischaemic optic neuropathy (NAION) causing sudden loss of vision in patients taking PDE5 inhibitors led the US Food and Drug Administration to update the labels of all three products. The labels now advise doctors to stop PDE5 inhibitors therapy in the sudden event of loss of vision in one or both eyes and to discuss the increased risk of NAION in patients who have already experienced NAION. At present, however, it is not possible to determine whether these events were related to PDE5 inhibitors or to other factors.


PDE5 inhibitors are a good choice for men at any age who are in good health and who do not have conditions that preclude taking them.

However, PDE5 inhibitors are not suitable for everyone. Men who take nitrate drugs for angina, or certain types of alpha-blockers for high blood pressure and benign prostatic hyperplasia, should not take PDE5 inhibitors. The PDE5 inhibitors are less effective in men with diabetes and in men who have been treated for prostate cancer.

Men with the following conditions should not take PDE5 inhibitors without the recommendation of their doctors and even then should use them with caution:

  • Severe heart disease, such as unstable angina, a recent heart attack, or arrhythmias. Men with heart disease may benefit from an exercise test to determine whether resuming sexual activity increases their risk of a heart attack.
  • Recent history of stroke
  • Hypotension (very low blood pressure)
  • Uncontrolled hypertension (high blood pressure)
  • Uncontrolled diabetes
  • Severe heart failure
  • Retinitis pigmentosa. (With this genetic disease, people do not produce phosphodiesterase-5 and do not respond to PDE5 inhibitors.)

Natural phosphodiesterase inhibitors

Plant extracts traditionally used for male impotence (Tribulus terrestris extract, Epimedium brevicornum, Ferula hermonis, Cinnamomum cassia), and the individual compounds cinnamaldehyde, ferutinin, and icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Only E. brevicornum extract and its active principle icariin were active. To improve its inhibitory activity, icariin was subjected to various structural modifications. Thus, 3,7-bis(2-hydroxyethyl)icaritin, where both sugars in 1 were replaced with hydroxyethyl residues, potently inhibited PDE5A1 with an IC50 very close to that of sildenafil. Thus, 3,7-bis(2-hydroxyethyl)icaritin was 80 times more potent than icariin, and its selectivity versus phosphodiesterase-6 (PDE6) and cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) was much higher in comparison with sildenafil. The improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make 3,7-bis(2-hydroxyethyl)icaritin a promising candidate for further development.


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