Jan 25, 2020 in Medicine
PDE5 Inhibitors and Treatment of Erectile Dysfunction

Abstract

Erectile dysfunction is described as the persistent inability to achieve or even maintain an erection that is sufficient to sustain sexual intercourse. The problem is common, affecting one out of five men globally. Apart from the inability to perform sexually, erectile dysfunction patients face a number of challenges, including low self-confidence, poor self-image, as well as depression. Thus, a viable remedy is necessary for such men to lead a normal and natural sex life. Although erectile dysfunction affects men of all age groups, its prevalence increases with age. Phosphodiesterase type 5 inhibitors are recommended as a first-line treatment for this complication. Principally, phosphodiesterase type 5 inhibitors work through competitive inhibition, thereby preventing the degradation of cyclic guanosine monophosphate. Vardenafil, sildenafil, and tadalafil are the phosphodiesterase type 5 inhibitors that are currently used for erectile dysfunction treatment. This paper explores the pharmacological use of phosphodiesterase type 5 inhibitors in erectile dysfunction patients. In addition, it discusses the nursing implications of this class of drugs with reference to side effects and contraindications.

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PDE5 Inhibitors and Treatment of Erectile Dysfunction

Erectile dysfunction (ED) can be defined as a condition in which a man is unable to maintain or even achieve an erection that is rigid enough for satisfactory sexual performance over a long duration. Currently, epidemiological evidence shows that 8% of men in their 40s report moderate or complete erectile dysfunction. Prevalence does increase with age as 40% of men aged between 40 and 60 years report ED. Erectile dysfunction impacts negatively on the quality of life of patients, as well as their partners. Its negative effects may include poor self-confidence, low self-esteem, and depression among patients. The problem is widespread, affecting 1 out of 5 men worldwide. However, the advent of phosphodiesterase type 5 (PDE5) inhibitors has revolutionized erectile dysfunction treatment. The drugs have availed effective and minimally invasive therapies to restore sexual function in affected men. This paper discusses the pharmacological use of phosphodiesterase type 5 inhibitors in the management of erectile dysfunction and the nursing implications of PDE5 inhibitors.

Erectile dysfunction (ED) can be defined as a condition in which a man is unable to maintain or even achieve an erection that is rigid enough for satisfactory sexual performance over a long duration. Currently, epidemiological evidence shows that 8% of men in their 40s report moderate or complete erectile dysfunction. Prevalence does increase with age as 40% of men aged between 40 and 60 years report ED. Erectile dysfunction impacts negatively on the quality of life of patients, as well as their partners. Its negative effects may include poor self-confidence, low self-esteem, and depression among patients. The problem is widespread, affecting 1 out of 5 men worldwide. However, the advent of phosphodiesterase type 5 (PDE5) inhibitors has revolutionized erectile dysfunction treatment. The drugs have availed effective and minimally invasive therapies to restore sexual function in affected men. This paper discusses the pharmacological use of phosphodiesterase type 5 inhibitors in the management of erectile dysfunction and the nursing implications of PDE5 inhibitors.

In fact, there are eleven types of PDE enzymes, which are distributed all over the body. PDE enzymes are generally responsible for the breakdown of cyclic guanosine monophosphate at the cellular level. PDE5 enzymes are specifically found in the skeletal muscle cerebella and pancreatic tissue, vascular and visceral smooth muscle, and, most importantly, the smooth muscle of the corpus cavernosum. Nitrogen oxide (NO) is often produced from the synapses of neurons of the corpus cavernosum, following sexual arousal. The released NO activates guanylyl cyclase enzyme, which in turn catalyzes the conversion from guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). It should be noted that cGMP is broken by the phosphodiesterase type 5 enzyme to 5-GMP at the cellular level. The accumulation of cGMP lowers intracellular calcium via a molecular cascade, causing relaxation of the vascular smooth muscle of the corpus cavernosum. This results in an increased blood flow, thereby facilitating the initiation as well as maintenance of penile erection. Unlike intracavernosal injections, the pharmacological action of PDE inhibitors is evidenced when an individual is sexually stimulated.

All the PDE5 inhibitors that are available for prescription are efficacious in addition to the fact that they are safe and effective in most men. However, the selectivity and tissue localization of phosphodiesterase type 5 inhibitors determine the safety and side effects of each drug. Perhaps, the drugs are not suitable to be used by patients with certain health conditions. They may include uncontrolled high blood pressure, severe cardiac failure, significantly low blood pressure, and history of myocardial infarction or stroke. Other conditions contain end-stage kidney disease requiring dialysis, unstable angina, and severe liver impairment.

Our Process

PDE5 inhibitors exhibit different pharmacokinetic profiles, possible side effects, and interactions with drugs and food. These differences explain why PDE5 inhibitor drugs have unique clinical effects. Despite the differences, these drugs demonstrate the same mechanism of action, the inhibition of PDE. Given that these drugs are competitive inhibitors of PDE5, their structures are derived from cyclic guanosine monophosphate. Vardenafil and sildenafil have very similar structures, whereas tadalafil has a chemical structure that is quite different from the other two. Despite the different chemical structures, all the three drugs retain the elements required for PDE5 inhibition.

PDE5 inhibitors also exhibit different selectivities for PDE5 isozymes; they are potent and elective inhibitors of PDE5. Eleven separate isozymes have so far been identified and characterized depending on a number of factors, such as amino acid sequence, inhibitor sensitivity, and substrate specificity. Sildenafil has an IC50 of 0.96nm, while those of tadalafil and vardenafil are 0.94nm and 0.16nm respectively. The inhibitors have a range of specificities for other phosphodiesterase type 5 isozymes. The unique structure of tadalafil is further reflected in its selectivity for PDE isozymes and pharmacokinetic properties. For instance, tadalafil is more selective for PDE11 than vardenafil and sildenafil.

The absorption rate of all the three inhibitors in the gastrointestinal tract is rapid. However, they have distinct pharmacokinetic profiles. The latter impacts the clinical use of PDE5 inhibitors with regards to the initiation of optimal pharmacological effect, as well as the duration of pharmacological action. Peak plasma of sildenafil is attained in less than 1 hour. The pharmacokinetics of vardenafil is quite similar to that of sildenafil as it is absorbed in the average time to peak plasma concentration of about 1 hour. Peak plasma of tadalafil takes a relatively longer time to be reached that is approximately 2 hours.

Food, especially fatty food, is known to delay the absorption of vardenafil and sildenafil. On the contrary, food does not alter the rate and extent of absorption of tadalafil. Therefore, vardenafil can safely be taken with no regard to food. When sildenafil is taken with food as opposed to the fasted state, the absorption rate of the inhibitor is decreased by approximately 30%, while the mean time to maximum concentration is hindered by almost 1 hour. Similarly, the absorption of vardenafil is delayed by high-fat meal for nearly 1 hour, and maximum concentration is reduced by about 20% when compared with the fasted state. Notably, alcohol does not affect the pharmacokinetics of the three PDE5 inhibitors. In spite of that, men may wish to avoid alcohol as its consumption has been associated with erectile dysfunction.

Half-life is another pharmacokinetic variable of PDE5 inhibitors. The variable indicates the duration for which any particular drug will remain pharmacologically active after its ingestion. Both vardenafil and sildenafil have a terminal half-life of about 4 hours, while that of tadalafil is about 17.5 hours. All the three inhibitors are eliminated from the body by hepatic metabolism. Sildenafil is mainly metabolized into an N-desmethyl metabolite by cytochrome P450. The metabolite also exhibits some PDE5 activity and is thought to account for about a fifth of the drug’s activity. Similarly, vardenafil is broken down into an active metabolite that is thought to account for 7% of its pharmacological activity. Unlike the previous two, tadalafil lacks an active metabolite, and its activity is done solely through the parent drug.

All the three inhibitors are largely excreted as metabolites in feces and slightly in urine. Since PDE5 inhibitors are principally metabolized via cytochrome P450 isoform 3A4 by hepatic enzymes, inhibitors of this enzyme may reduce the clearance of PDE5 inhibitors. Hepatic enzyme inhibitors include indinavir, cimetidine, ritonavir, ketoconazole, saquinavir, and itraconazole. In addition to slowing down the liver metabolism of PDE5 inhibitors, these enzymes may also increase plasma levels and thereby affect the net effect of the drugs. Likewise, grapefruit juice may also slow down the liver metabolism of PDE5 inhibitors.

All the three inhibitors are largely excreted as metabolites in feces and slightly in urine. Since PDE5 inhibitors are principally metabolized via cytochrome P450 isoform 3A4 by hepatic enzymes, inhibitors of this enzyme may reduce the clearance of PDE5 inhibitors. Hepatic enzyme inhibitors include indinavir, cimetidine, ritonavir, ketoconazole, saquinavir, and itraconazole. In addition to slowing down the liver metabolism of PDE5 inhibitors, these enzymes may also increase plasma levels and thereby affect the net effect of the drugs. Likewise, grapefruit juice may also slow down the liver metabolism of PDE5 inhibitors.

All the three inhibitors lack the capacity to act immediately; rather, studies have shown that they have an onset of action between 30 minutes to 1 hour. Meanwhile, the rate of the onset of each inhibitor varies from one individual to another. For sildenafil, prescribing information recommends taking the dose 60 minutes before sexual activity. Similarly, dosing for vardenafil should be done 25 to 60 minutes before sexual activity. Prescribing information on tadalafil indicates that the dose should be taken 30 minutes prior to sexual activity. However, a study has shown that the onset of drug action is much shorter, 16 minutes following the dose.

Notably, the three PDE5 inhibitors exhibit marked differences with regard to the duration of effect. Sildenafil and vardenafil both have a similar duration of the effect of approximately 4-5 hours as per prescribing information. On the other hand, tadalafil’s duration of effect is 36 hours, consistent with its half-life of 17.5 hours. This long duration of responsiveness gives patients with erectile dysfunction to choose, without much pressure, when to participate in sexual intercourse.

Generally, the adverse event profiles of phosphodiesterase type 5 inhibitors are similar. There are several class-specific effects, including headache, dyspepsia, nasal congestion, myalgia, and flushing. Rare but adverse effects of PDE5 inhibitors comprise syncope, dizziness, and nonarteritic anterior optic neuropathy. They normally reflect the vasodilatory impact on capillary smooth muscles in parts of the body apart from the penis. Since PDE5 inhibitors are mild dilators, the drugs are associated with slight reductions in blood pressure in healthy individuals, though reduction is usually clinically insignificant. Vardenafil reduces blood pressure by about 7/8 mm Hg (decrease in systolic/decrease in diastolic blood pressure). In turn, sildenafil reduces blood pressure by approximately 8/6 mm Hg, while tadalafil lowers blood pressure by 0.2/4.6 mm Hg in the standing position and 1.6/0.8 mm Hg in the supine position. Increase in heart rate tends to be minimal, often less than 5 beats/minute, due to PDE5 inhibitors.

Concurrent administration of PDE5 inhibitors with nitrates or potassium channel activator nicorandil can result in hypertension and is consequently contraindicated. Organic nitrates, including long-acting and short-acting nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, and amyl nitrate, increase the production of cGMP among others. On the contrary, PDE5 inhibitors decrease the breakdown of cGMP. Consequently, there is a synergistic drop in blood pressure when organic nitrates are given with PDE5 inhibitors; this causes symptomatic hypotension in some patients.

Studies have also indicated that phosphodiesterase type 5 inhibitors are effective in specific patient populations. Such populations include people suffering from erectile dysfunction and stable cardiovascular diseases, clinical depression and diabetes. It is noteworthy that sildenafil should be taken with caution in patients taking α-blockers. The utmost caution must be exercised owing to the fact that simultaneous co-administration of the two drugs may lead to symptomatic hypertension in some men. More than 25 mg of sildenafil should not be taken within 4 hours of α-blocker dosing. Like sildenafil, vardenafil is also considered to be effective in most hypertensive and cardiac patients.

Unless a patient is stabilized on his α-blocker therapy, the concomitant use of α-blocking drugs, such as doxazosin and vardenafil, will not be recommended. In such patients, the maximum dose of vardenafil must not surpass 5 mg. Additionally, vardenafil dosing should not be done within 6 hours of α-blocker dose, except tamsulosin for this precaution that does not hold much weight. Tadalafil has demonstrated comparable efficacy in erectile dysfunction patients with or without cardiovascular risk factors, as well as patients who had suffered from hypertension. Prazosin, doxazosin, alfuzosin, and terazosin are examples of alpha-adrenoreceptor antagonists that cause low blood pressure when taken with PDE5 inhibitors. Alpha-adrenoreceptor antagonists are normally used to provide relief for symptoms of the lower urinary tract (LUTS) and as antihypertensive agents.

PDE5 inhibitors are also active in ED patients suffering from diabetes. Such patients experience erectile improvements following the administration of sildenafil as well as vardenafil. In patients with erectile dysfunction resulting from bilateral nerve-sparing radical prostatectomy, tadalafil improves the proportion of successful penetration and intercourse attempts. In addition, the drug increases the mean Internal Index of Erection Function (IIEF) in such patients. Remarkably, early therapy of PDE5 inhibitors following prostatectomy in ED patients may improve outcomes. This introduces the possibility of employing phosphodiesterase type 5 inhibitors as a prophylactic measure to preserve erectile function as well as penile smooth muscle after radical prostatectomy.

The difference in selectivity of the three PDE5 inhibitors may account for other differences in the side effects of the drugs. The US Food and Drug Administration decided to update labels on the three drugs after rare postmarketing reports of non-arteritic anterior ischemic optic neuropathy (NAION). It was found that NAION led to the abrupt loss of vision in men taking PDE5 inhibitors. The current labels advise doctors to discontinue the use of phosphodiesterase type 5 inhibitors in case of sudden vision loss by patients in one or both eyes. In addition, it is recommended that doctors should discuss the increased risk of NAION in men who have previously experienced it. However, it is presently possible to establish whether the sudden loss is related to PDE5 inhibitors or other factors. Other vision problems associated with PDE5 dosing, particularly sildenafil, include increased sensitivity to light, blood vision, as well as temporary difficulty in distinguishing green and blue colors. The reason is that sildenafil is less selective and inhibits PDE6 in the retina.

Remarkably, some patients will inevitably fail to register a positive response to their first choice of treatment. Nevertheless, the patient’s inability to respond to a particular PDE5 inhibitor does not necessarily mean that he/she will not respond to other drugs of the same class. Patients should only be considered for a failed response after at least eight occasions on the maximum dose of medication. However, starting with the lowest dose of phosphodiesterase type 5 inhibitors is recommended. Essentially, patients who totally fail to respond to one particular PDE5 inhibitor may respond to another.

Furthermore, some patients who have failed to respond at the initial instances can actually derive benefits from regular dosing schedule. It is also necessary to remember that a section of patients may not respond to erectile dysfunction therapy for other reasons, such anxiety and associated androgen deficiency among others. Androgen replacement therapy can be instituted to overcome the challenges associated with androgen deficiency. Naturally, individuals initiating treatment with a PDE5 inhibitor will experience some level of anxiety concerning whether this PDE5 inhibitor indeed induce an erection. In turn, anxiety may reduce or inhibit sexual arousal. Since sexual arousal is a necessary condition for the pharmacological action of PDE5 inhibitors, its reduction may prevent the realization of the desired action.

Our Benefits

Conclusion

Restoration of a normal and natural sex life is the main goal of PDE5 inhibitors’ therapy for patients with erectile dysfunction. Therefore, the need as well as preferences of patients should be accorded some weight when healthcare providers consider the available options of treatment. Furthermore, with numerous similarities in tolerability and effectiveness of the three drugs, patient preference will increasingly influence treatment decisions. Apart from restoring a normal sex life, successful PDE5 inhibitors’ therapy boosts patients’ self-confidence and self- esteem and improves relationships with their partners. Considering the drugs’ side effects as well as contraindications is crucial in ensuring the safety of patients with erectile dysfunction.

Summary

Erectile dysfunction (ED) can be regarded as a condition when a person cannot maintain or even attain enough erection for successful intercourse for a long period . Despite the various means of ED treatment, phosphodiesterase type 5 (PDE5) inhibitors are the recommended first-line treatment for the complication. There are three types of PDE5 inhibitors available for prescription, including vardenafil, sildenafil, and tadalafil. All of them are efficacious and demonstrate the same mechanism of action. They limit the breakdown of cyclic guanosine monophosphate (cGMP) by PDE enzymes through competitive inhibition. Despite the similarities, PDE5 inhibitors exhibit differences in a number of factors, such as pharmacokinetic profile, possible side effects, as well as interactions with drugs and food. An absorption rate of sildenafil and vardenafil in the gastrointestinal tract is considerably delayed by fatty foods. However, the absorption of tadalafil is not affected by food. PDE5 inhibitors are eliminated from the body through hepatic metabolism. Though, the duration of effect varies from one drug to another, depending on the half-life. Notably, PDE5 inhibitors have side effects in patients, including headache, flushing, and nasal congestion among others.

Although PDE5 inhibitors are effective in almost all populations, there are contraindications associated with the drugs. A lot of caution is necessary when administering PDE5 drugs to patients on alpha blockers. Remarkably, concurrent administration of organic nitrates with PDE5 inhibitors is contraindicated. Moreover, administering the two classes of drugs concurrently causes a synergistic drop in blood pressure, which often results in symptomatic hypotension in some patients. In a few instances, erectile dysfunction patients show no response following administration of their first choice drug. Conversely, such patients may respond to other drugs of the same class or regular dosing schedule. Individuals who fail to respond as a result of associated androgen deficiency may put on androgen replacement therapy before PDE5 inhibitors’ administration.

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