Phosphodiesterase type V inhibitors

Cardiovascular

In several reviews, in which the same data have been analysed, sildenafil has been rated as being well tolerated [ , ] and extremely safe [ ]. Concerns about its cardiovascular safety profile have stemmed primarily from sporadic reports of myocardial infarction and stroke.

• One patient without a history of previous chest pain or risk factors for cardiovascular disease, developed a well-documented myocardial infarction 30 minutes after he took sildenafil 50 mg and before any attempt at sexual intercourse [ ].

The interpretation of these sporadic cases is controversial, although some have argued that the reported cardiovascular adverse effects occur more often with sildenafil than with other pharmacological treatments of erectile dysfunction. It is at present unclear whether there is an increased risk with sildenafil. For example, in placebo-controlled trials there have been no differences in the incidences of myocardial infarction, angina, or coronary artery disorders between sildenafil and placebo [ ]. Exclusion criteria in clinical trials may have prevented the inclusion of patients who are at increased risk of adverse events. On the other hand, sexual activity itself increases cardiac workload and the risk of myocardial infarction. Patients with cardiovascular disease should be cautious in their use of sildenafil.

Prolongation of the QT _c interval has been reported but usually without serious dysrhythmias, although ventricular tachycardia has been reported after sildenafil.

• A 54-year-old man with hypertrophic cardiomyopathy, for which he took verapamil, felt unwell after a single tablet of sildenafil [ ]. Holter monitoring after repeat sildenafil showed an increase in ventricular extra beats and episodes of non-sustained ventricular tachycardia. On echocardiography, left ventricular dimensions were reduced and the subaortic gradient was markedly increased.

• Two other patients with severely depressed left ventricular function developed ventricular tachycardia [ ].

• A healthy 50-year-old man took vardenafil 10 mg and 15 minutes later developed persistent palpitation lasting 2 hours [ ]. He had atrial fibrillation and no structural heart disease. The dysrhythmia converted spontaneously to sinus rhythm 4 hours later.

The authors suggested that hypotension induced by vardenafil had led to a reflex tachycardia.

Acute events occurring within a suspected time frame after intake of phosphodiesterase V inhibitors are likely to be ascribed to these drugs even though a logical pathogenetic mechanism is not obvious.

• A 61-year-old man was a regular user of sildenafil for 2 years when he was now admitted to the hospital because of vomiting, diarrhea and abdominal pain 30 minutes after he ingested 50 mg of sildenafil and before he engaged in sexual intercourse. He later developed chest pain and echocardiography and computer tomography established the diagnosis of ascending aortic dissection.

Vasodilatory drugs would not be expected to cause dissection. The authors advance a few quite speculative arguments: the relaxant effect on the aortic wall may differ between layers favouring intimal tears, an anti-proliferative effect on the aorta renders the wall more vulnerable. However, in the acute phase of dissection strong vasodilating drugs are often use to lower blood pressure and to protect patients from progressing dissection [ ].

Sildenafil has been associated with venous thrombosis [ ] and tadalafil with thrombophlebitis [ ].

• A 57-year-old man had a deep vein thrombosis in a leg, severe thrombosis of the hemorrhoidal plexus, and venous sinus thrombosis all within a single year. He took regular sildenafil, roughly twice a week, and two of the episodes occurred within 24 hours after treatment.

• A 45-year-old man twice developed phlebitis of a superficial penile vein after taking tadalafil followed by sexual intercourse. Intercourse without tadalafil never caused the same problem.

Apart from priapism, phosphodiesterase V inhibitors have hitherto not been associated with venous thrombosis. In the second case, local anatomical factors, such as prolonged overexpansion of the corpora cavernosa, may have caused compression of the superficial veins and contributed to the inflammation. In the first case, a causative link to thrombosis was not obvious for a drug with no known adverse effect on coagulation.

Ear, nose, throat

Two men developed prolonged epistaxis a few hours after taking sildenafil 50 mg to enhance their sexual performance (before the nose bleeding started); both had well-controlled hypertension [ ]. Epistaxis is not an unusual problem in elderly people with hypertension, and venous engorgement is thought to be the main causative factor. Whether this is amplified by sildenafil (and/or by sexual activity) is an open question.

Nervous system

Headache is the one of the most common adverse effects of inhibitors of phosphodiesterase type V, being reported by 15–30% of patients. There is debate about whether migraine attacks are provoked by these drugs [ ]. A typical migraine attack occurred after ingestion of sildenafil in 10 of 12 women with a history of migraine [ ].

A tadalafil-associated case of typical migraine aura but without headache has been reported [ ].

• A 64-year-old man developed stereotypical visual phenomena (a bright ill-defined triangular shape in the visual field) for about 20 minutes. He had been on sildenafil for 4 years without having such an experience and began noticing these episodes a few months after switching to tadalafil. After discontinuation of tadalafil and later after restarting sildenafil he kept experiencing the aura but less frequently. Here too, a causal relationship with tadalafil intake remains difficult to explain. Tadalafil has a much longer half-life than sildenafil, but there was no strict temporal relationship between ingestion of a tablet and onset of the aura.

Epileptic seizures have been reported in a few patients after use of sildenafil [ ]. They have also been described with vardenafil in two patients, in the first shortly after intake of a high dose (40 mg), in the second after the second intake of a normal dose (10 mg) [ ].

Clinical trials of sildenafil have not shown increased risks of stroke or myocardial infarction. However, postmarketing drug surveillance programs have mentioned strokes associated with sildenafil, and case reports have been published.

• A 50-year-old man took sildenafil 50 mg, and 2 hours later developed a hemiparesis and altered hemibody sensation, a facial paresis, and slurred speech [ ]. The symptoms gradually disappeared 4 hours later, but recurred the next week when he took sildenafil 100 mg. On the second occasion the symptoms did not resolve, and an MRI scan showed a recent infarct in the left internal capsule and lateral thalamus. No other cause of the stroke was found by evaluation of the heart and extracranial vessels. The symptoms gradually improved over 6 months.

• A 44-year-old man developed a severe headache and vomiting after taking four tablets of sildenafil (of unknown strength) followed by sexual intercourse [ ]. A CT scan showed a left-sided temporal intracranial hemorrhage. He died of cerebral edema and pneumonia a few days later. Autopsy showed no vascular abnormality.

• A 67-year-old man took two tablets of sildenafil 25 mg 1 hour apart [ ]. He complained of headache, confusion, and nervousness after the first tablet, his symptoms increased, and he developed language difficulty after the second tablet. He did not have sexual intercourse. A few days later, an MRI scan showed a large left temporal subcortical hemorrhage. The symptoms resolved partially over a few days.

• A 62-year-old hypertensive man developed left-sided hemiballismus secondary to a small hemorrhage in the right subthalamic–thalamic region [ ]. He had recently taken sildenafil 50 mg before having sexual intercourse.

Whereas the suspected mechanism for ischemic stroke is analogous to that leading to myocardial infarction (hypoperfusion distal to a critical lesion), intracerebral bleeding [ , ] may be more difficult to explain. The authors considered the likelihood of sildenafil-induced spontaneous intracerebral hemorrhage due to the vasodilatory effects of the drug on the cerebral vasculature (as evidenced by headache, flushing, and nasal congestion).

• A third-nerve palsy occurred 36 hours after a second dose of sildenafil in a 56-year-old man.

The authors suggested that sildenafil had caused systemic hypotension sufficient to cause neurological dysfunction, but 36 hours is a long lag time for a drug with a half-life of only a few hours [ ].

Unexpected functional disturbances, which occur shortly after the use of sildenafil, are likely to be attributed to the drug.

• A 51-year-old man had transient global amnesia 30 minutes after taking sildenafil 25 mg [ ].

• A 79-year-old man had acute vertigo, vomiting, and tinnitus resembling vestibular neuronitis 2 hours after first taking 50 mg; the symptoms lasted for 24 hours [ ].

Sensory systems

Sildenafil has weak inhibitory effects on phosphodiesterase type V in the retina, leading to temporary changes in the perception of color hue and brightness. The importance of reversible changes in the electroretinogram observed in volunteers after sildenafil 100 mg, ascribed to inhibition of phosphodiesterase type 5 in the retina, is unclear [ ].

There have been reports of a temporal association between vascular events in the eye and sildenafil administration.

• A fit, healthy, 69-year-old man presented with sudden painless loss of vision in the left eye a few hours after taking sildenafil 100 mg [ ]. Fundus examination showed occlusion of a branch of the retinal artery. No cardiovascular abnormality was detected.

• A 52-year-old man developed sweating, headache, and blurred vision in his left eye 1 hour after a first dose of sildenafil 50 mg [ ]. The same symptoms recurred on the next night, after a second dose of sildenafil. Fundoscopy a few days later showed an ischemic optic neuropathy.

• A 42-year-old man presented with anterior ischemic optic neuropathy, leading to a visual field defect in that eye within 24 hours of having taken sildenafil [ ].

Non-arteritic anterior ischemic optic neuropathy (NAION) is a disorder whose pathophysiology is poorly understood. It is the most common acquired optic neuropathy after the age of 50 and has repeatedly been connected to inhibitors of phosphodiesterase type V, most often sildenafil. Case reports are being published in ever increasing numbers, but they do not clarify the problem. In a review the weak points in the possible connection between inhibitors of phosphodiesterase type V and NAION have been emphasized [ ]. The difference between the intraocular pressure and the perfusion pressure in the posterior ciliary arteries determines the circulation in the optic disc, and a reduction in this difference may contribute to ischemia.

• A 51-year-old man with poorly controlled hypertension had sudden superior hemifield loss in the left eye during sexual activity 4 hours after taking sildenafil 100 mg [ ]. He had used sildenafil repeatedly over the previous few weeks without unwanted effects. Fundoscopy and fluorescein angiography confirmed an embolic occlusion of the inferior hemiretinal artery.

The authors thought that debris from an atherosclerotic plaque at the carotid bifurcation had been dislodged as a result of increased cardiac workload during sexual activity, rather than a direct effect of sildenafil itself.

Several other cases of non-arteritic ischemic optic neuropathy have been reported in men taking sildenafil [ , ].

Serous chorioretinopathy has been attributed to sildenafil [ ].

• A 37-year-old man took regular sildenafil and developed acute visual loss and a pressure sensation in his right eye. Fundoscopy showed an area of subretinal fluid, pointing to central serous chorioretinopathy. He was encouraged to refrain from sildenafil, but continued to use it and the symptoms worsened. When he later stopped using it, the disorder completely resolved within 3 weeks. Palpebral edema has been attributed to tadalafil [ ].

• A 56-year-old patient with diabetes and no history of allergy noticed bilateral eyelid edema the morning after a first pill of tadalafil. The symptoms regressed spontaneously within 72 hours but recurred 1 week later after a second dose of the drug. The absence of any other known cause of palpebral edema, the time course, and recurrence on rechallenge were strong arguments for a causative link with tadalafil.

A possible connection between use of phosphodiesterase V inhibitors and non-arteritic anterior ischemic optic neuropathy (NAION) remains controversial and debated [ ]. Whereas new individual cases on a temporal relationship keep being published, experts stress in reviews that it is still not possible on the basis of the available literature to determine whether NAION is directly related to the use of these drugs, underlying cardiovascular risk factors, ocular anatomical defects, a combination of these variables or as yet unidentified factors [ , ]. Meanwhile, a retrospective matched case-control study on 38 cases observed a positive association between NAION and exposure to phosphodiesterase V inhibitors which however was only significant for patients with a history of myocardial infarction [ ].

Subretinal and choroidal hemorrhage was reported in a patient with an unsuspected uveal melanoma, a few hours after intake of a single dose of 20 mg tadalafil [ ].

A 63-year-old man woke up with a painful red eye with limited vision after intake of a single tablet the evening before. He was also on chronic aspirin. The vision did not improve and further evaluation led to the discovery of a malignant melanoma of the choroid with recent hemorrhage. The authors suggested that the vasodilatory effects of tadalafil may have led to congestion of the tumor and rupture of a neovascular membrane beneath the retinal pigment endothelium, causing the accumulation of blood.

A first case of sensorineural hearing loss is reported following ingestion of sildenafil [ ].

• A 44-year-old man started taking sildenafil 50/daily for erectile dysfunction and noticed on the fifth day a ringing sensation, first in one and later in both ears. A week later, while still taking sildenafil, he developed hearing difficulty which progressed to bilateral unremitting deafness over a few days.

The authors speculate that the hearing loss resulted from cochleotoxicity of sildenafil. Still, sudden sensorineural hearing loss is a poorly understood condition that has been described in conjunction with a variety of diseases, syndromes and drugs.

Nasal congestion is one of the common discomforts after intake of oral drugs for erectile dysfunction. In a small study on 16 patients suffering from impotence medicated with sildenafil. Nasal patency was examined with anterior rhinomanometry before and after intake of 50 mg of the drug. Nasal air flow values decreased significantly and all but three patients had a sensation of nasal obstruction [ ].

Liver

Acute hepatitis has been reported in a patient using sildenafil [ ].

• A 65-year-old man with diabetes and hypertension had taken 50 mg of sildenafil about once every 2 weeks for 1 year, when he suddenly felt generally unwell. He had a tender liver, and blood tests showed mild thrombocytopenia, a lymphocytosis, and markedly raised aminotransferases, which had been normal shortly before and returned to normal over a few weeks after withdrawal of sildenafil, while he continued to take his antidiabetic and antihypertensive drugs. Other causes of hepatitis were ruled out by appropriate tests.

Definite proof of liver toxicity of a drug is difficult to provide. The authors invoke an ischemic rather than an immunoallergic pathogenesis to explain the hepatotoxic effect of sildenafil in this patient. This could also have explained his subsequent occasional use of sildenafil without recurrence of liver toxicity. The concomitant use of antihypertensive drugs may have facilitated the single episode of hepatitis.

There have been further reports of acute hepatitis in two men, aged 49 and 56 years, without apparent risk factors for liver disease [ , ]. The evidence in favor of a link between acute liver disease and sildenafil is largely circumstantial but corresponds to accepted criteria for drug-induced hepatitis.

• Fatal variceal rupture occurred in a 41-year-old man with alcoholic liver cirrhosis and portal hypertension 3–4 hours after he took an unknown dose of sildenafil [ ].

The authors hypothesized that sildenafil caused vasodilatation and increased splanchnic blood flow, thereby augmenting intravariceal pressure. He also had a high blood concentration of ethanol, another vasodilator.

• A 68-year-old man with alcoholic cirrhosis and small esophageal varices (degree of severity classified as Child I) started bleeding after taking sildenafil 25 mg for the first time [ ].

Sudden overload of the portal venous system related to splanchnic vasodilatation was a possible provoking factor in this case. Gastroesophageal reflux secondary to a lower esophageal sphincter tone and causing mucosal erosion was an alternative explanation.

Skin

Rashes have been attributed to sildenafil.

• A 57-year-old man developed lichenoid lesions on the upper half of the body [ ]. Biopsy showed degeneration of keratinocytes and a dense lymphohistioid infiltrate arranged in a lichenoid pattern. He had been taken sildenafil irregularly. The eruption resolved within 3 weeks of withdrawal of sildenafil and recurred after rechallenge a few weeks later.

• A 67-year-old man developed toxic epidermal necrolysis, having during the previous 48 hours taken sildenafil between 300 and 400 mg (partly as a commercially available drug and partly in a Chinese aphrodisiac herbal medicine) [ ]. He had also been taking eight different medicines for diabetes, hypertension, hyperlipidemia, heart failure, gout, and osteoarthritis. The serum concentration of tumor necrosis factor was initially raised. He was given infliximab and recovered.

Acute widespread urticaria was reported after vardenafil consumption in a 48-year-old man with no other identifiable causative factors [ ].

Sexual function

Whereas priapism has not been reported with sildenafil in controlled clinical trials, it is being mentioned in postmarketing drug surveillance programs, and two case reports have appeared in a healthy young man and a patient with sickle cell trait [ , ].