Phosphodiesterase inhibitors. By Nashwa Naeem Elfar Ass. lecturer. Phosphodiesterase enzymes (PDE).
PDE family: 11 isoenzymes families (PDE 1-PDE 11) with over 50 isoforms
A) Nonselective phosphodiesterase inhibitors
They act as competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMP, activate PKA, inhibit TNF-alpha and leukotriene synthesis, and reduce inflammation and innate immunity and nonselective adenosine receptor antagonists
B) Selective phosphodiesterase inhibitors
PDE1 selective inhibitors
PDE2 selective inhibitors
PDE3 selective inhibitors
PDE4 selective inhibitors
Mechanism of action:
In response to sexual stimulation,
Nitric oxide released from nonadrenergic-noncholinergic neurotransmission and the endothelium of the cavernous smooth muscle is probably the principal neurotransmitter for penile erection.
Within the muscle, nitric oxide activates a guanylylcyclase that raises intracellular concentrations of cyclic guanosinemonophosphate (GMP).
Cyclic GMP in turn activates a specific protein kinase which results in the opening of the potassium channels and hyperpolarization and causes sequestration of intracellular calcium and blocks calcium influx. As a result of this drop in cytosolic calcium, smooth muscle relaxation occurs leading to erection.
PDE-5 inhibitorsdo not increase the nitric oxide level, but they potentiatethe nitric oxide effect to stimulate erection. Without sexualarousal, this effect activates the nerve-nitric oxide pathway,these inhibitors are ineffective
Vardenafil(10 times more potent than sildenafil)
and the newer:
Nonselectivity of PDE5 inhibitors with respect to all PDE1 subtypes may induce vasodilatation, flushing, and tachycardia.
Inhibition of this enzyme can induce visual disturbances, which have occurred at the highest clinically applied dose of sildenafil and to a lesser extent with vardenafil.
No visual disturbances have been reported with tadalafil use.
Musculoskeletal pain, in particular back pain, more significant with tadalafil than with sildenafil or vardenafil AStadalafil presented a five fold higher selectivity for PDE11A.
According to the 2006 American Urological Association
Oral Phosphodiesterase-5 Inhibitor therapy as medically necessary in males for the treatment of erectile dysfunction when ANY of the following criteria are met:
1- Age 60 or older
2- Hormonally-induced erectile dysfunction with EITHER of the following:
3- Neurogenic erectile dysfunction such as resultant from spinal cord injury, multiple sclerosis, pituitary microadenoma with hyperprolactinemia, cerebral vascular accident (CVA), diabetes, radical prostatectomy or surgically induced impotence
4- Vasculargenic erectile dysfunction such as resultant from aortic aneurysm, atherosclerosis, hypertension, hyperlipidemia, or peripheral vascular disease (PVD)
5- Pelvic trauma-induced erectile dysfunction such as resultant from compression injuries or radiation.
6- Pharmacologic-induced erectile dysfunction where the patient has tried ONE alternate, non-erectile dysfunction-causing medication and erectile dysfunction persists, OR there is a contraindication to making medication changes.
These concerns have however been ameliorated as studies have not shown an increased rate of myocardial infarction, ischemic heart disease or mortality.
BUT..Treatment of ED in a patient with cardiovascular disease is complicated by a small increase in risk of myocardial infarction related to sexual activity.
Patients who have failed to respond to a PDE5 inhibitor will not necessarily fail to respond to other drugs in the class.
Patients should not be deemed true treatment failures until they have failed to respond to maximum dose medication on at least eight occasions.
Non-responding patients may derive benefit from a regular dosing schedule, suggesting that in some patients reversal of ED may result from more continuous exposure to PDE5 inhibitors.
Some patients also fail to respond to ED treatment for other reasons, such as associated androgen deficiency. This may be overcome by instituting treatment with androgen replacement therapy
The concomitant use of SSRIs and sildenafil may represent an appropriate approach for PE.
The possible mechanism may be that an improved erection (firmness, duration or both) resulting from the PDE-5 inhibitor provides inhibition of ejaculation via down-regulation of receptors involved in somatosensory latency times.
A reduction in performance anxiety may exist on a subconscious level.
PDE5 is expressed in clitoral corpus cavernosum and in vaginal smooth muscle and epithelium. Therefore it is possible that PDE5 inhibitors could affect female sexual arousal disorder.
Increased levels of cGMP have been shown to occur in human-cultured vaginal smooth muscle cells treated with a PDE5 inhibitor suggesting involvement of the NO/cGMP axis in the female sexual response.
SSRI antidepressants commonly produce iatrogenic sexual dysfunction. Sildenafil (100 mg) and vardenafil (10 mg) have been used to reverse SSRI-induced anorgasmia in women.
Pulmonary hypertension is the result of upregulation of PDE5 gene expression, causing vasoconstriction in the lung.
PDE5 inhibitors are used as potent pulmonary vasodilators reducing Pulmonary hypertension and inhibiting vascular remodelling.
Sildenafil has been shown to be effective in treating severe Raynaud's phenomenon associated with systemic sclerosis and digital ulceration.
Sildenafil has shown promise in the treatment of congestive cardiac failure.
It has also been shown to reduce aortic pressure through vasodilation, reduced arterial stiffness and wave reflection and could be used in the management of systemic hypertension.
Sildenafil has been shown to significantly improve neurovascular coupling without affecting overall cerebral blood flow by increasing brain levels of cGMP. This data suggest that PDE5 inhibitors may have a role in promoting recovery from stroke.