Risk of persistent visual side effects in Viagra users

Sildenafil is commonly used to treat erectile dysfunction and is generally regarded as safe with limited side effects.

However, a recent study in Frontiers in Neurology has highlighted the risk of persistent visual side-effects, such as light sensitivity and color vision impairment, in men who have taken the highest recommended dose of Viagra.

While these effects appear to be rare, the research suggests that first-time Viagra users should start with a lower dose before increasing it, if necessary.

Erectile dysfunction can have significant psychological consequences for men who are affected by it, and it can make fulfilling sexual relationships more difficult to achieve. Sildenafil, more commonly known by its tradename Viagra, became available in 1998 as a treatment for erectile dysfunction.

It soon became the fastest selling drug in history, demonstrating the phenomenal demand for treatments that enhance sexual performance.

Originally developed as a treatment for high blood pressure, the drug dilates blood vessels and relaxes smooth muscle in the penis, making it easier to achieve and maintain an erection.

The effects of the drug normally last 3-5 hours and although side-effects such as headache and blurred vision occasionally occur, they usually disappear relatively quickly.

However, Dr. Cüneyt Karaarslan of the Dünyagöz Adana hospital in Turkey, noticed a pattern in 17 male patients who attended the hospital.

In the new study, Karaarslan reports that the patients suffered numerous visual disturbances, including abnormally dilated pupils, blurred vision, light sensitivity, and color vision disturbances, which included intensely blue colored vision with red/green color blindness.

All 17 patients had taken sildenafil for the first time, and all took the highest recommended dose of 100 mg.

None of the men had been prescribed the medication.

The visual side-effects began once the drug took effect, and were still present when the men arrived at the clinic 24-48 hours later.

The doctors in the clinic conducted various eye tests and monitored the patients over time to see how their symptoms developed. Fortunately, in all 17 patients the symptoms had cleared up by 21 days later, but this was doubtless a difficult experience for the men involved.

“Many men use non-prescription performance enhancing drugs to help with sexual anxiety and erectile dysfunction,” said Karaarslan.

“For the vast majority of men, any side-effects will be temporary and mild. However, I wanted to highlight that persistent eye and vision problems may be encountered for a small number of users.”

So, why were these men susceptible to such long-lived side-effects?

It may be possible that a small subsection of the population does not break sildenafil down and eliminate it from the body efficiently, leading to very high concentrations in the blood compared with most users.

The effects of the drug normally last 3-5 hours and although side-effects such as headache and blurred vision occasionally occur, they usually disappear relatively quickly.

These men also took the highest recommended dose of sildenafil on their first time taking the drug.

Starting with a lower dose may have meant less severe side-effects.

In addition, taking the drug under medical supervision would likely have meant that the men would not have used such a high dose on their first time.

So, if you are struggling with erectile dysfunction, should you be worried about trying Viagra? In short, no. Such persistent side-effects appear to be very rare.

However, it is always best practice to consult your physician first, it may be best not to start at the highest dose, and in case you are particularly sensitive, consider first using the drug under medical supervision.

“Although these drugs, when used under the control of physicians and at the recommended doses, provide very important sexual and mental support, uncontrolled and inappropriate doses should not be used or repeated,” said Karaarslan.

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The discovery of phosphodiesterase 5 inhibitors (PDE5 inhibitors) for causing the erection of the penis was accidental, noticed as a side effect while being administered to investigate their ability to treat hypertension and angina. The problem of erectile dysfunction has become extremely prevalent, with recent figures estimating that about 320 million will encounter the disorder by 2025. [1] There are several available PDE5 inhibitors: sildenafil, vardenafil, tadalafil, and avanafil, which are FDA approved, lodenafil, udenafil & microdenafil are the other non-FDA commercially available drugs. 

1. Erectile Dysfunction– They are recommended as the first-line treatment for ED due to psychogenic, vascular, and neuropathic causes when combined with etiology specific therapy.
2. Idiopathic Pulmonary Hypertension– The presence of abundant PDE-5 receptors in the pulmonary vasculature makes PDE5 inhibitors an important modality to manage pulmonary hypertension. These drugs are preferred in patients with NYHA class 2 or 3 with negative acute vasodilator response and are not indicated in patients with NYHA class 4, where prostacyclin agonists like epoprostenol and iloprost are more appropriate.
3. Premature Ejaculation (PE) associated with erectile dysfunction-. PDE5 inhibitors are effective in the management of premature ejaculation associated with erectile dysfunction but not in patients with PE alone. PDE5 receptors get expressed throughout the contractile tissue of the male reproductive tract and the accessory glands, and their inhibition increases the ejaculatory latency. 
4. High altitude illness-Treatment with sildenafil has shown to reduce the incidence of pulmonary hypertension in people with altitude-induced high pulmonary systolic arterial pressure, but no improvement in arterial oxygen saturation, heart rate, and acute mountain sickness.[2]
5. Penile rehabilitation after Radical Prostatectomy– Early use of sildenafil after radical prostatectomy has been found beneficial for the treatment of ED post RP due to neuro-regenerative effects on the cavernous nerve, which usually gets damaged in the procedure.
6. Antianginal – Brought into the market as an antianginal initially, these drugs through strong evidence obtained from certain studies have shown to reduce mortality due to major cardiovascular events in people with diabetes through their effects on endothelial function.[3] Although they play a role in the prevention of coronary events, they are currently in use for this purpose.
7. Lower Urinary Tract Symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with the simultaneous presence of erectile dysfunction; these drugs reduce the symptoms of hesitancy, urgency, frequency due to an obstructive cause in patients with the simultaneous presence of ED. These drugs have not shown any advantage in combating the symptoms of LUTS alone, and when used in combination with alpha-blockers, had similar or inferior outcomes compared to alpha-blockers alone.[4]

Following are the indications where emerging evidence has revealed the advantages of using PDE5 inhibitors, but more research, particularly on human subjects needs to be undertaken to understand their efficacy-

1. Heart Failure – PDE5 inhibitors have reduced cardiac hypertrophy in mouse and canine models. Due to the presence of PDE5 receptors in myocardial tissue, their manipulation can subsequently be beneficial for modifying the progression of numerous heart diseases.[5] PDE5 receptors also express in normal myocardium, and their expression increases significantly in dilated cardiomyopathy, right ventricular hypertrophy, and pulmonary hypertension. Taking a setback in the management of heart failure, the largest trial (RELAX), conducted to study the benefits of PDE5 inhibitors in patients with heart failure with preserved ejection fraction, found no improvement in functional outcome and clinical status of the patients.[6]
2. Stroke – Recent studies conducted in animals have observed a decrease in the infarct size and increased protection against ischemic reperfusion injury through markedly increasing cGMP levels and angiogenesis if PDE5 inhibitors are administered 24 hours after stroke.[7] Administration of PDE5 inhibitors has been shown to improve neural growth and improve short term memory, therefore potentially reversing the effects of decreased cGMP levels observed in aging. A study aimed at measuring cerebral blood flow found no change in the blood velocity with the use of PDE5 inhibitors but increased blood velocity in patients with erectile dysfunction, pulmonary hypertension, and other diseases with an impaired endothelial dilatory response.[8]
3. Peripheral neuropathy– A report was published, suggesting that daily use of PDE5 inhibitors, through the improvement of blood flow through vasa vasorum, helped to alleviate the symptoms of peripheral neuropathy.
4. Improving fertility– Oral administration of PDE5Is has shown to increase the motility of sperms in infertile men with oligospermia but, surprisingly, did not affect normal patients.[9]
5. Peripheral Arterial Disease (PAD)– Chronic administration of PDE5 inhibitors has shown to improve walking distance in patients with peripheral arterial disease (PAD), likely through the manipulation of the NO pathway. It has also demonstrated a reduction in the incidence of digital ulcers in patients with systemic sclerosis.
6. Diabetic Nephropathy– PDE5 inhibitor’s role in diabetic nephropathy has been the target of a few studies through improving insulin sensitivity and reducing the severity of albuminuria observed in nephropathy.[3]

Mechanism of Action

To understand the mechanism of action of PDE5 inhibitors, one must first understand the normal physiology of penile erection, an area of medicine where most of the PDE5 inhibitors are currently in use.

After sexual stimulation, nerve impulses release neurotransmitters in the corpora cavernosa, causing the production of nitric oxide by endothelial cells, which diffuses into the adjacent smooth muscle cells and stimulates the formation of cGMP, leading to vasodilation and increased penile blood flow.

Mechanism of working of PDE-5 Inhibitors on cGMP

These drugs inhibit the enzyme phosphodiesterase-5 (PDE-5), present in the smooth muscle cells of the vessels.

By inhibiting this enzyme, these drugs prevent the degradation of cGMP by PDE-5. cGMP through activation of protein kinase G causes relaxation of the vascular smooth muscle.

Prevention of degradation of cGMP by PDE-5 leads to the accumulation of cGMP in the vascular smooth muscle, thereby leading to dilatation of the blood vessels through phosphorylation of different downstream effector molecules.

Dilatation of the penile arteries leads to a more prolonged erection.

PDE5Is improve endothelial function and reduce apoptosis of vascular smooth muscle cells in corpus cavernosum.

A similar mechanism of action has also been elucidated to result in vasodilation of the pulmonary arteries relieving the symptoms of pulmonary hypertension. They also inhibit the remodeling of the pulmonary vasculature.

When given in subjects suffering from heart failure, they have been known to inhibit the remodeling of the myocardium.

All the PDE5 inhibitors mentioned above have the same mechanism of action but differ in their PDE isozyme selectivity with PDE6 (sildenafil), and PDE11 (tadalafil) are usually affected by the cross-reactivity, leading to the presentation of specific side effects associated with PDE5 inhibitor use.

Administration

Following oral doses are usually recommended for Erectile dysfunction-

• Sildenafil: 25 to 100 mg PO 1 hour before intercourse
• Tadalafil: 5 to 20 mg PO 1 hour before intercourse
• Vardenafil: 10 to 20 mg PO 1 hour before intercourse
• Some clinicians and researchers recommend chronic daily use of low dose PDE5 inhibitors. They have increased penile blood flow and improved endothelial function, in addition to a reduction of apoptosis of vascular smooth muscle cells in the corpus cavernosum. 

The oral doses of PDE5 inhibitors recommended for the treatment of pulmonary arterial hypertension (PAH):

• Sildenafil 20 mg three times daily
• Tadalafil 40 mg once daily

For patients with lower urinary tract symptoms of benign prostatic hyperplasia (BPH) with concomitant ED – tadalafil 5 mg is preferred.

Characteristics of different types of PDE5Is has been illustrated in Table 1

Adverse Effects

None of the PDE5 inhibitors are genuinely selective for the receptor PDE5, and most of the harmful effects occur due to cross-reactivity with other PDE isoenzymes. These effects are usually dose-dependent. Some of the common adverse effects encountered with the administration of PDE5Is are:

• Mild headache 
• Flushing – experienced more with sildenafil
• Dyspepsia
• Altered color vision presenting as a slight and transient blue tinge to the vision – the presence of a high concentration of PDE6 enzyme in rods and cones of retina makes these cells a susceptible target for PDE5 inhibitors, especially with sildenafil which has a high affinity for inhibiting PDE6 in addition to PDE5. This effect has been found to be not accompanied by any structural and functional changes of the retina.
• Back pain and myalgias – due to a high concentration of PDE11 enzyme in skeletal muscle, which shows significant cross-reactivity with the use of tadalafil.
• Hypotension and dizziness 
• Rhinitis 

Nevertheless, the adverse outcomes encountered with the use of PDE5 inhibitors rarely lead to their discontinuation. 

PDE5Is use has also correlated with specific less known, rarely encountered side effects, and the low frequency of the occurrence of these adverse effects does not necessitate the withdrawal of the drugs from the market-

• NAION (Non-arteritic anterior ischemic optic neuropathy) and painless decrease in vision in one eye, which is usually irreversible. Its pathophysiology is unknown, but it shows an increased incidence in patients with hypertension, diabetes, hyperlipidemia, and cardiovascular disease.
• Hearing loss – Sensorineural hearing loss due to unclear pathophysiology has been observed in a few case studies, which prompted the FDA to issue a warning about the risk of hearing loss from the use of PDE5I. 
• Priapism occurs infrequently, but the risk increases if concomitantly used with other ED meds. Some recent studies have documented using PDE5 inhibitors daily to prevent the development of this rare occurrence of priapism.
• Melanoma – Emerging studies have focused interest on the risk of melanoma with chronic administration of PDE5Is. [10] There is a hypothesis that low levels of PDE5I through mitogen-activated protein kinase can increase the risk, especially in patients with BRAF gene mutation.
• Prostate cancer
• Researchers have noted an incidence of prostate cancer recurrence after radical prostatectomy in some recent studies, but the data is not substantial enough to require their discontinuation in these patients.

Contraindications

Absolute contraindication-

• In patients taking nitrates or nitroglycerin, concomitant use of PDE5 inhibitors leads to excessive preload reduction. This phenomenon is common in patients using long-acting nitrates like isosorbide mononitrate, isosorbide dinitrate, and transdermal nitroglycerin patches as a means of prophylaxis for chronic angina who concomitantly initiate PDE5 inhibitors. American College of Cardiology recommends that patients taking PDE5Is should wait for at least 1 to 2 days after the last PDE5I dose before administering nitrates.[1]
• Vardenafil is known to cause minor QT prolongation and therefore contraindicated in patients taking type 1A, type 3 antiarrhythmics, and patients with congenital prolonged QT syndrome.

Caution is necessary for patients with the following relative contraindications)

• History of MI, stroke or life-threatening arrhythmia in the past six months
• Resting hypotension or hypertension
• History of heart failure or unstable angina 
• Concomitant administration of alpha-blockers

Monitoring

As mentioned above, certain drugs like nitrates are absolutely contraindicated in patients taking PDE5 inhibitors, and therefore ED patients should be advised about not administering the two drugs concomitantly. Co-administration of PDE5 inhibitors and nitrates is contraindicated, but if the need arises, thorough hemodynamic monitoring is necessary. 

Some medications like alpha-blockers are needed to relieve concomitant symptoms of BPH in patients with ED and, therefore, require caution with frequent monitoring of blood pressure levels and prompt arrangement of an appointment with a physician if hypotensive symptoms present which may necessitate discontinuation of PDE5 inhibitor.

PDE5 inhibitors should be only administered in stable patients taking alpha-blockers. Proper titration and increase dosing in stepwise fashion if co-administered with alpha-blockers.

Patients should consult a physician if they encounter a sustained erection persisting for more than 4 hours as prolonged blood engorgement of blood in the penis can compromise the arterial supply and lead to penile necrosis.

If patients experience an inadequate response to treatment with a PDE5 inhibitor, consider direct injections of PGE1, papaverine, phentolamine, or a combination with improvement in patients with intact vasculature. If still no response, get duplex Doppler ultrasonography, penile cavernosography, and pudendal arteriography to recognize the cause of refractory ED.

All the PDE5 inhibitors undergo extensive tubular reabsorption in the kidney and get extensively excreted as metabolites in the stool. Nonetheless, in patients with severe renal insufficiency (CrCl less than 30 ml/min), where the presence of concomitant ED is fairly common with some studies reporting prevalence rates as high as 80% in patients undergoing dialysis,[11] it is advised to initiate PDE5 inhibitor therapy at the lowest dose possible with gradual up-titration.[12]

PDE5 inhibitors undergo rapid metabolism in the liver, most notably through the CYP3A pathway. Similar to the recommendations for the usage of PDE5 inhibitors in renal dysfunction, impairment of hepatic function also warrants starting lower doses and gradual up-titration while monitoring for adverse effects. Regularly scheduled follow-ups and frequent monitoring for side effects should take place.

Toxicity

No evidence has emerged concerning the development of any form of dependence or tolerance with the chronic use of PDE5 inhibitors. Some recent reports have found them being misused concomitantly with alcohol and illicit drugs. A few case reports of seizures and myocardial infarction with the administration of PDE5 inhibitors have come forward, likely due to cerebral vasodilatory and cytochrome P450 inhibition of the illicit drugs that are sometimes taken concurrently with the meds.[13][14]

A case study conducted on a middle-aged man who consumed 24 tablets of 100 mg sildenafil and presented with transient visual complications except for a visual field defect and annular scotoma that persisted chronically.[15]

Enhancing Healthcare Team Outcomes

Managing the underlying cause

Erectile dysfunction can be due to multiple reasons – psychogenic, neurogenic, vascular, or hormonal. Therapy with symptomatic management with PDE5 inhibitors should be accompanied by simultaneous removal of the etiology causing ED. Hence it is crucial to obtain a relevant history and performing appropriate physical examination. 

Patients with psychogenic causes of ED usually have typical early morning and nocturnal erections but are unable to achieve or maintain an erection during a sexual encounter with a specific partner. These patients will benefit from counseling and a referral to a psychiatric if unremitting symptoms are present. 

It is essential to identify atherosclerotic risk factors like smoking, hypertension, diabetes mellitus, and hyperlipidemia in patients presenting with a vascular cause of ED.

These patients, in addition to the absence of nocturnal and early morning erections, may present with symptoms of atherosclerosis of major blood vessels, particularly angina, claudication, or a history of a significant cardiovascular event.

Therefore, it is recommended to monitor blood pressure, blood glucose, HbA1C, and lipid levels, and initiate treatment for the underlying cause. Patients should be counseled on the importance of smoking cessation, maintaining appropriate dietary and lifestyle habits.

ED patients with a concomitant history of long-standing diabetes should be monitored for their diabetic status and through frequent neurological examinations to check for autonomic neuropathy.

Patients with hormonal causes of ED present with reduced libido, suggesting hypogonadism as the cause of ED, which is manageable accordingly.

Treating the underlying cause of ED can have a tremendous impact on the resolution of symptoms without the need to administer PDE5 inhibitors. Concomitant administration of statins, anti-oxidants, and testosterone supplements may aid in alleviating the condition.

Careful attention should be given to ED patients with comorbidities like hypertension, diabetes, and hyperlipidemia because it has been observed that strict control of blood pressure, glucose, and lipid profile accentuates the sensitivity of ED to PDE5 inhibitors.

As the above exemplifies, to cover all aspects of ED and use PDE5  inhibitors requires an interprofessional team approach. All the clinicians listed above are candidates for starting therapy in the patient, but they need to work across disciplines with each other to ensure safe treatment and minimal adverse effects.

Along this line, the pharmacist should also have significant involvement, checking for drug-drug interactions, verifying dosing based on the issue (ED vs. pulmonary HTN), and counseling the patients on proper dosing and administration.

Nursing can also help assess treatment effectiveness and patient compliance. Both pharmacists and nurses need to be able to contact the prescriber with any concerns they may encounter.

As clinicians, specialists, nurses, and pharmacists all take an active, collaborative role, PDE5 inhibitor therapy can be most effective for the patient with minimal adverse effects. [Level V]

Expansion of utilities for PDE5 inhibitors

Heart diseases

New emerging benefits of PDE5 inhibitors, namely their advantages in the management of Heart failure, prevention of myocardial remodeling post-infarction. The advantages of using PDE5 inhibitors in these diseases need to be studied extensively for inclusion in the treatment plans for these conditions.

Oncology

Due to the increased expression of PDE5 receptors on tumor cells, including colon, breast, lung, bladder, and prostate, these drugs have shown a positive response through increasing apoptosis of cancerous cells and blocking one or more Multidrug-resistant transporters such as P-glycoproteins.

Diabetes Mellitus

One study through the chronic administration of PDE5 inhibitors, particularly tadalafil, has given a promising result of reducing pro-inflammatory cytokine levels in patients with type 2 diabetes.[3]

Angina

For patients with co-existent angina, a new drug is available in the market known as ranolazine, which is indicated for prophylactic treatment in chronic angina in patients refractory to first-line antianginal drugs like nitrate and beta-blockers with an added advantage of being safely co-administered with PDE5 inhibitors.

Improving drug administration

The most vital modality to enhance efficacy and compliance of PDE5 inhibitors involves providing instructions to the patients regarding appropriate administration and the associated adverse effects that are possible while taking PDE5 inhibitors. Since about 30 to 35% of patients do not respond to on-demand administration of PDE5 inhibitors, chronic daily administration of these medications can be considered a reasonable alternative to induce normal sexual functioning with the added advantage of not exhibiting tachyphylaxis.

A new type of orodispensable sildenafil formulation is in the market, which disintegrates within seconds of ingestion and hence absorbed quickly in the mouth.

This formulation offers an added advantage in patients with dysphagia and improves adherence due to rapid effect.[16]

As an epilogue, the role of PDE5 inhibitors, especially sildenafil and tadalafil, has been well established clinically in erectile dysfunction and pulmonary hypertension.

Nevertheless, these drugs offer tremendous potential in other areas of medicine like heart failure, peripheral neuropathy, and peripheral arterial disease, which requires extensive research before they can enter the market for the treatment of these disorders.

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Source:
Frontiers