Phosphodiesterase Inhibitors
Examples
- Sildenafil
- Tadalafil
- Vardenafil
Indications
- Erectile dysfunction
- (pulmonary hypertension)
Contraindications
Contraindications
- Patients receiving nitrates
- Hypotension, recent stroke, unstable angina and myocardial infarction
- Previous history of non-arteritic anterior ischaemic optic neuropathy
- Cardiovascular disease
- Hypotension
- Left ventricular outflow obstruction
- Anatomical deformation of the penis / risk of priapism
- Hepatic impairment and renal impairment (half dose)
Mechanism
Nitric oxide (NO) is synthesised from L-arginine by nitric oxide synthase (NOS) in endothelial cells. The NO diffuses into smooth muscle cells where it binds and activates Guanylate cyclase, which synthesises cyclic GMP (cGMP) from Guanosine trisphosphate (GTP).
Sildenafil works by inhibiting phosphodiesterase 5 (PDE5). This prevents inactivation of cGMP. The increased concentration of cGMP increases smooth muscle relaxation, vasodilation occurs and results in penile erection as blood flows to the erectile tissue following activation of nitrergic nerves activated by sexual stimulation.
Administration
Oral.
Adverse Reactions
- Dyspepsia, nausea and vomiting
- Headache
- Flushing
- Hypotension
- Cardiovascular events
- Painful red eyes
Interactions
- Nitrates (and Nicorandil) - risk of severe hypotension
- Drugs that inhibit cytochrome P450 enzymes (e.g. erythromycin, ritonavir, cimetidine) - increase plasma concentration of sildenafil
Education
- Avoid grapefruit juice - it can increase plasma concentration
- Drug to be taken one hour before intercourse and not repeated within 24 hours
- Food may delay onset of action
- Warn patients to whom nitrates are prescribed not to take sildenafil
Pharmacokinetics
Plasma concentrations peak 30-120 minutes after administration.
Metabolism is by cytochrome P450 in the liver.
Metabolism is by cytochrome P450 in the liver.
