Oral Agents

Oral Agents


Sildenafil was originally developed for heart disease, but was found to have a unique mechanism of action that targeted only factors in the penis, even though it is taken orally. Sildenafil is the first orally administered treatment of proven efficacy for erectile dysfunction. Taken for one hour before planned sexual intercourse, it is effective for a wide range of disorders causing erectile dysfunction.

The rationale for the use of sildenafil is based upon the role of nitric oxide-induced vasodilation (which is mediated by cyclic GMP) in initiating and maintaining an erection. Detumescence is associated with catabolism of cyclic GMP by type 5 cyclic GMP phosphodiesterase. Sildenafil acts by blocking the latter enzyme and as a result increases both the number and duration of erections in men with erectile dysfunction.

In order to understand the action of sildenafil as well as some of its side effects, it would be worthwhile to briefly recall the physiology of penile erection.

Physiology of Penile Erection

With sexual arousal through imaginative, visual, auditory, tactile, olfactory, and other erotic stimuli, nitric oxide (NO) is released by nonadrenergic, noncholinergic (NANC) neurons. Originally termed endothelial-derived relaxing factor, NO is known to be the most important physiologically occurring vasoactive molecule in the entire cardiovascular system. This also applies to corpus cavernosum function, where local smooth muscle relaxation, and in turn erection, is mediated predominantly by NO release.

Dilation of the helicine arterioles and relaxation of the sinusoids lead to engorgement of sinusoidal spaces with blood. Expansion against the tunica albuginea compresses blood-draining subtunical venules, resulting in blockade of cavernous venous outflow. This leads to complete filling of the cavernous sinusoids and subsequently to a considerable increase of the intracavernous pressure. In the phase of full rigidity, intracavernous pressure reaches values considerably higher than systemic (systolic) blood pressure.During male sexual arousal, NO is released either at parasympathetic NANC nerve terminals on the cavernous smooth muscle cell or at parasympathetic cholinergic nerve terminals on the endothelial cell lining of the sinusoids. Through membrane-bound G proteins, NO activates guanylate cyclase, which induces cleavage of guanosine triphosphate to 3',5'-cyclic guanosine monophosphate (3',5'-cGMP).The smooth muscle-relaxing effects of NO are mediated by this second messenger (cGMP). Cyclic GMP activates protein kinase G (PKG), which phosphorylates proteins at the so-called maxi-potassium channels. This results in an outflow of potassium (K+) ions into the extracellular space with subsequent hyperpolarization, with inhibition or blockade of voltage-dependent calcium (Ca++) channels and therefore a decrease in intracellular Ca++ ion concentrations.

Relaxation of Penile Smooth Muscle via cGMP Pathway Relaxation of Penile Smooth Muscle via cGMP Pathway

The intracellular decline in Ca++ ions suppresses the activity of myosin light chain (MLC) kinase and thus increases the intracellular content of dephosphorylated MLC, which enables the smooth muscle cell to relax. It is well established that NO and cGMP are the most important transmitters for onset and maintenance of erection.

A simpler biochemical cascade is seen below. Although some events in the cascade resulting in penile erection await clarification, NO, a gas with intrinsic vasodilator properties, activates guanylate cyclase and in turn stimulates the formation of cGMP. This substance then acts as a second messenger, playing a pivotal role in vasodilatation and relaxation of corporal smooth muscle, the structural changes responsible for penile erection.

Nitric Oxide - cGMP Mechanism

For detumescence to take place, the raised levels of cGMP have to be lowered. PDE5 and, to a much lesser extent, PDE2 and PDE3, are localized to the corpus cavernosum of the penis, where they catalyze the transformation of cGMP to its inactive form 5_-GMP. The breakdown of cGMP reverses the erectile process, restoring the penis to its flaccid state.

The PDEs are responsible for enzymatic degradation of the biologically active cGMP and cAMP to the biological inactive molecules GMP and AMP. By inhibiting the degradation of cGMP, PDE5 inhibitors prolong the activity of this cyclic nucleotide second messenger within the cavernous vasculature and smooth musculature, thus potentiating the erectile response.

Smooth Muscle Relaxation & Erection PDE5 inhibition and the response to sexual stimulation. cGMP, cyclic guanosine monophosphate; GTP, guanosine 5'-triphosphate; PDE5, phosphodiesterase 5

The prototype of this new class of selective PDE5 inhibitors for the treatment of ED was sildenafil.


Initial studies with sildenafil (Viagra) included men with both psychogenic and organic causes of erectile dysfunction. Pooled data from a controlled trial of 416 men found that improved erectile function was reported by 28 percent of the men treated with placebo, compared to 61, 72, and 78 percent of those treated with 25, 50, and 100 mg of sildenafil.

All do not respond to the drug as well, however. Only 56 percent of diabetic men have improved erections with sildenafil.


Sildenafil is absorbed well during fasting, and the plasma concentrations are maximal within 30 to 120 minutes (mean, 60). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about four hours. The recommended starting dose is 50 mg taken one hour before sexual activity. The maximal recommended frequency is once per day. On the basis of effectiveness and side effects, the dose may be increased to 100 mg or decreased to 25 mg.

Adverse Effects and Drug Interactions

An inhibitor of the PDE normally responsible for the breakdown of corporal cGMP, the second messenger in penile erection, oral sildenafil citrate exerts no erectogenic effect in the absence of sexual stimulation.

Cardiovascular Effects.

Men at highest risk for syncope are those who take other vasodilators such as nitrates. Concurrent use of sildenafil and nitrates in any form, regularly or intermittently, is contraindicated. If a man who has taken sildenafil has an acute ischemic syndrome, nitrates should not be prescribed within 24 hours (longer in patients with renal or hepatic dysfunction). Support for this negative interaction comes from one randomized, placebo-controlled study of patients with stable coronary artery disease who were treated with isosorbide mononitrate for five to seven days before a dose of sildenafil and a second study in which sublingual nitroglycerin was given one hour before sildenafil. Coadministration of sildenafil with either nitrate produced a significantly greater reduction in blood pressure compared to the nitrate alone.

More serious complications, such as myocardial infarction or sudden death, can occur. By November 1998, the United States Food and Drug Administration had received reports of 130 men who died within hours to days after taking sildenafil. In the majority, myocardial infarction was confirmed; another 27 deaths were attributed to cardiac arrest. In 48 men, the cause of death could not be ascertained. One death was ascribed to homicide and another to drowning. Seventy percent of the men who died had known cardiovascular disease and several were using nitrate medication concurrently with sildenafil.

*Cause Of Death ³No. Of Patients
Definite or suspected myocardial infarction 41
Cardiac arrest 27
Cardiac symptoms 6
Coronary artery disease 3
Stroke 3
Homicide or drowning 2
Unknown 48
Total 130
*Deaths were reported by the Food and Drug Administration from late March to mid-November 1998.During this period, 6 million outpatient prescriptions were dispensed,in doses ranging from 25 to 100 mg.
³The average age of the patients was 64 years(range, 29 to 87). Sixteen patients who died were using nitroglycerin or other nitrates. Fourty-four patients died less than four hours after taking sildenafil; 27 of these died during sexual intercourse or immediately there after.

Sexual activity was thought to be a likely contributor to myocardial infarction in only 0.9 percent of 858 men in one study. Thus, the absolute increase in risk caused by sexual activity is low (one chance in a million for a healthy man). According to data from the National Center for Health Statistics and the Framingham Heart Study, the rate of death from myocardial infarction or stroke for men in the age range in which erectile dysfunction is common is approximately 170 per million men per week. Therefore, it appears that sildenafil therapy is safe for most men. Nevertheless, given that most of the men who died had underlying cardiovascular disease, cardiovascular status should be carefully assessed before treatment.

In response to the concern of physicians, the American Heart Association has published a guideline for sildenafil therapy.

Recommendations For Use Of Sildenafil By Men With Cardiac Disease

  1. Sildenafil is absolutely contraindicated in men taking long-acting or short-acting nitrate drugs.
  2. If the man has stable coronary disease and does not need nitrates regularly,the risks of sildenafil should be carefully discussed with him.If the man requires nitrates because of mild-to-moderate exercise limitation due to coronary disease,sildenafil should not be given.
  3. All men taking an organic nitrate(including amyl nitrate) should be informed about the nitrate-sildenafil hypotensive interaction.
  4. Men must be warned of the danger of taking sildenafil 24 hours before or after taking a nitrate preparation.
  5. Before sildenafil is prescribed,treadmill testing may be indicated in some men with cardiac disease to assess the risk of cardiac ishemia during sexual intercouse.
  6. Initial monitoring of blood pressure after the administration of sildenafil may be indicated in men with congestive heart failure who have boderline low blood pressure and low status and men being treated with complicated, multidrug antihypertensive regimens.

* The recommendations were prepared by the American Heart Association40

Other side effects

Among more than 3700 men with 1631 patient years of exposure to sildenafil, most adverse events were mild to moderate and self-limited in duration. Among men taking 25 to 100 mg of sildenafil, 16 percent reported headache, 10 percent flushing, 7 percent dyspepsia, 4 percent nasal congestion, and 3 percent abnormal vision (described as a mild and transient color tinge or increased sensitivity to light). These rates were twice as high among men taking 100 mg of sildenafil as among men who were taking lower doses. The visual effect is probably related to inhibition of phosphodiesterase type 6 in the retina. No chronic visual impairment has been reported, and the incidence of visual side effects was similar in diabetic and nondiabetic men.


    There are no clinical data on the safety and efficacy of sildenafil in the following groups:
  • Men who have had a myocardial infarction, stroke, or life-threatening arrhythmia within the last six months
  • Men with resting hypotension (<90/50 mmHg) or hypertension (>170/110 mmHg)
  • Men with cardiac failure or coronary artery disease causing unstable angina
  • Men with retinitis pigmentosa (a minority of whom have genetic disorders of retinal phosphodiesterase)

One suggests caution when prescribing sildenafil to these groups of men. A consensus statement from the American College of Cardiology/American Heart Association published in January 1999 presented recommendations about the use of sildenafil in men with cardiovascular disease.

    The statement concluded that sildenafil was clearly contraindicated in men taking nitrates. Other men in whom it is potentially hazardous include:
  • Those with active coronary ischemia (eg, positive exercise test) who are not taking nitrates
  • Those with congestive heart failure and borderline low blood pressure or low volume status
  • Those taking a complicated, multidrug, antihypertensive drug regimen
  • Those taking drugs that can prolong the half-life of sildenafil by blocking CYP3A4; on the other hand, drugs that induce CYP3A4 such as rifampin and phenytoin can be expected to reduce the effectiveness of a dose of sildenafil

Men who are considering sildenafil therapy should be questioned regarding exercise tolerance; resumption of sexual activity after a prolonged period of inactivity is analogous to beginning a new exercise regimen. Sildenafil can be considered in men who are participating in aerobic activities that are roughly equivalent in energy expenditure to sex. If such activity cannot be documented, more formal testing of exercise tolerance (eg, exercise treadmill testing) should be considered.

Other Drugs

Tadalafil and Vardenafil

These are very selective inhibitors of PDE5 and are undergoing clinical trials. They seem to be more efficacious and work faster and longer than sildenafil citrate. The fact that they are more selective than sildenafil offers the hope that they would be safer, but this will only be revealed after the results of the clinical trials are in.

Drugs such as Compound 14 and T-1032 are similar in action and are still in the very initial stages.

Hormonal Therapy


Historically, androgens were touted as enhancing male sexual function.

Testosterone is usually ineffective in treating erectile dysfunction in patients with normal serum testosterone concentrations and may exacerbate the problem by increasing a patient's sexual drive without improving his ability to perform. It may be given orally but is usually given as an intramuscular depot injection at intervals of 3-4 weeks, by daily patches, or by implants every six months. Great care should be exercised in patients with possible carcinoma of the prostate, and levels of prostate specific antigen (PSA) should be checked initially and every six months.

It rarely would help a person with diabetes unless a significant decrease in the levels was present.


Dehydroepiandrosterone sulfate (DHEAS) is a male hormone used in the production of testosterone; levels of this hormone fall as a man ages. In one small study, those who took DHEA for 16 weeks experienced some improvement in erectile dysfunction. It should be noted, however, that the long-term effects of this potent hormone are unknown, particularly on the risks for prostate cancer.


If excessive levels of the hormone prolactin are the cause of erectile dysfunction, the drug bromocriptine is helpful in lowering these levels. All attempts have to be made to find the cause for the raised prolactin levels before blindly starting bromocryptine therapy.

For a brief list of the causes of raised prolactin, click here

Other Oral Drugs


Yohimbine is an a2-adrenergic-receptor antagonist produced in the bark of yohim trees.

Yohimbine has been used for many decades and may be taken as a 5 mg tablet three times daily or as 5-15 mg about an hour before intercourse. It is more effective in patients with psychological erectile dysfunction. Although it has been claimed to work for about half of patients, many specialists believe its effects to be largely placebo related.

The most common adverse effects observed with yohimbine included anxiety, increased urinary frequency, tachycardia, and increased arterial pressure. It is contraindicated in severe hypertension.

Yohimbine is not recommended for men with organic erectile dysfunction because its effect is marginal in such cases.

Although a rich folk lore has imbued yohimbine with mystical aphrodisiacal properties, it has limited clinical effectiveness, if any. Moreover, it is not licensed, and no long term toxicological data are available.


Aphrodisiacs are substances that are supposed to increase sexual drive, performance, or desire. Foods that some people claim have aphrodisiacal qualities include chillies, chocolate, licorice, lard, scallops, oysters, and anchovies. No evidence exists for these claims and certainly no one would ever advocate eating large amounts of such foods, which, in cases such as licorice and lard, can be dangerous. Spanish fly, or cantharides, made from dried beetles is the most widely-touted aphrodisiac and is particularly harmful. It irritates the urinary and genital tract and can cause infection, scarring, and burning of the mouth and throat; in some cases, this substance can be life threatening.

These so-called aphrodisiac's have no role to play in the management of erectile dysfuntion seen in a person with diabetes.