When using sildenafil (Viagra), is there an increased risk of a hemorrhagic/ischemic stroke in a pa

Fråga: When using sildenafil (Viagra), is there an increased risk of a hemorrhagic/ischemic stroke in a patient that has already gone through an ischemic stroke? Is there any risk of a pharmacodynamic or pharmacokinetic interaction between sildenafil and warfarin (Waran)?

Sammanfattning: There are case reports of both hemorrhagic and ischemic stroke following sildenafil intake, but confounding factors, such as pre-existing arterial disease and the strain of sexual activity, make it difficult to establish a casual relation. Stroke patients have been excluded from clinical studies.

No interactions between sildenafil and warfarin have been reported in the literature. A pharmacodynamic interaction cannot be excluded, as sildenafil has been suggested to inhibit platelet aggregation.

Svar: Sildenafil exerts its effect by modulating the effect of nitric oxide in corpus cavernosum after sexual stimulation (1). Nitric oxide activates guanylate cyclase, which leads to increased levels of cyclic guanosine monophosphate (cGMP). The increased cGMP causes smooth muscle relaxation and increased blood flow. Sildenafil inhibits the degradation of cGMP by inhibiting phosphodiesteras type 5 (PDE5).

A thorough literature search in Drugline, Medline, Embase and common pharmacological literature has been performed. Two published case reports of intracerebral hemorrhage after sildenafil use have been found (2, 3). The first case involves a probable overdose of sildenafil followed by intercourse, causing a spontaneous intracerebral hemorrhage resulting in death (2). The second case concerns a man with intracerebral hemorrhage after taking two tablets of sildenafil (25 mg) within an hour, without being able to perform sexual intercourse (3). We also found two cases with patients affected by ischemic events after taking sildenafil (4, 5). One man experienced weakness and sensation disturbances in his right body part during four hours, starting a couple of hours after intake of 50 mg sildenafil. Six days later he took 100 mg sildenafil and again developed the same symptoms, but this time they did not resolve. On neither occasion did he engage in sexual intercourse. The authors suggest that sildenafil should be used with caution in patients with stroke (which is the manufacturers recommendation). The second patient developed a stroke in the optic nerve head after ingesting 50 mg of sildenafil (5).

A few reports of other hemorrhagic disorders after sildenafil use have been found (6,7,8). Cases of nose-bleeding and hemorrhoidal bleeding have been published. PDE5, the enzyme inhibited by sildenafil, leading to smooth muscle relaxation and increased blood flow, is located not only in the corpus cavernosum, and can therefore cause smooth muscle relaxation in other parts of the body. The authors think that sildenafil may cause vasodilatation and trigger bleeding in susceptible patients (6, 8). Ex vivo studies have also shown that sildenafil may inhibit PDE5-induced platelet aggregation. A dose of 100 mg increased the bleeding time significantly, whereas the lower dose of 50 mg did not (9).

In the Swedish Catalogue of Approved Medical Products (FASS), sildenafil is contraindicated in patients with a recent stroke. This recommendation is based on the lack of studies in this group of patients (1). According to the manufacturer, they have not included patients in their studies who have had a stroke within the past six months (10). The manufacturer has not seen any tendencies of increased stroke risk after treatment with sildenafil.

In the files of SADRAC (the Swedish Adverse Drug Advisory Committee) there is one report of a cerebral infarction (out of a total of 50 reports) (11). The WHO adverse drug reaction-monitoring centre has received reports of a total of 95 cases of hemorrhage or infarction in the brain after sildenafil use. In addition, there are 19 reports of subarachnoidal hemorrhage (12). The WHO reports are not evaluated as to the cause relationship.

There are two possible confounders to consider when discussing sildenafil as a possible cause of cerebrovascular incidents. The first is that arterial disease predisposes the patient to both erectile dysfunction and cerebrovascular incidents. The second is that sexual activity is a risk factor in itself for cerebrovascular incidents (13).

Sildenafil is metabolised by CYP3A4 (major route) and CYP2C9 (minor route) (14). Sildenafil is a weak inhibitor of the cytochrome isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 in vitro. The racemic mixture of warfarin is metabolised by different pathways (15). R-warfarin is metabolised by CYP1A2, CYP3A4 and carbonylreductase and S-warfarin by CYP2C9. Theoretically, since sildenafil and warfarin are partly metabolised by the same enzyme system, there could be a pharmacokinetic interaction between the two substances. However, no interactions have been found in common pharmacological literature or databases. Data from clinical trials have shown that inhibitors of CYP2C9 (eg warfarin) do not affect the pharmacokinetics of sildenafil (14). Other in vivo studies indicate that sildenafil does not show clinical significant interactions with warfarin, even though it inhibit CYP2C9 (15, 16).