By Nashwa Naeem Elfar Ass. lecturer Phosphodiesterase enzymes (PDE) • Phosphodiesterases are a diverse family of enzymes that degrade the phosphodiester bond of cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messengers cAMP and cGMP, and hence cell function. • PDEs are therefore important regulators of signal transduction mediated by these second messenger molecules. PDE family: 11 isoenzymes families (PDE 1-PDE 11) with over 50 isoforms PDE Main tissue localization 1 2 3 Brain, heart, vascular smooth muscle 4 5 Lung, mast cells, vascular smooth muscle 6 7 8 Retina 9 10 11 Adrenal cortex, brain, heart, corpus cavernosum Heart, corpus cavernosum, vascular smooth muscle, platelets, liver pancreas Corpus cavernosum, lung, vascular smooth muscle, platelets, brain, esophagus Skeletal muscle, T cells Testis, thyroid Broadly expressed, not well characterized Brain, testes Skeletal muscle, prostate, liver, kidney, pituitary, testis Phosphodiesterase Inhibitors Drugs that block subtypes of the enzyme phosphodiesterase (PDE), therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). They are classified into non-selective PDE inhibitors and selective PDE Classification: A) Nonselective phosphodiesterase inhibitors caffeine aminophylline IBMX (3-isobutyl-1-methylxanthine) paraxanthine pentoxifylline, Theobromine, Theophylline. 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 Vinpocetine PDE2 selective inhibitors EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine) Anagrelide PDE3 selective inhibitors Enoximone and milrinone, used clinically for short-term treatment of cardiac failure. These drugs mimic sympathetic stimulation and increase cardiac output. PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. PDE4 selective inhibitors Mesembrine, Rolipram, Ibudilast, Piclamilast, Luteolin, Drotaverine, PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells, have proven potential as antiinflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD, and rhinitis. They suppress the release of cytokines and other inflammatory signals, and inhibit the production of reactive oxygen species. PDE4 inhibitors may have antidepressive effects and have also recently been proposed for use as antipsychotics. PDE5 selective inhibitors PDE5 has only one subtype, PDE5A, of which there are 4 isoforms in humans called PDE5A1-4. PDE5 enzyme is specific for cGMP which means it only hydrolyzes cGMP but not cAMP, the selectivity is mediated through network of hydrogen bonding which is favorable for cGMP but unfavorable for cAMP in PDE5. PDE5 is responsible for the degradation of cGMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis, which leads to erectile dysfunction (ED). 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 guanylyl cyclase that raises intracellular concentrations of cyclic guanosine monophosphate (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 leading to erection. occurs Activation of the NO-cGMP pathway results in trabecular smooth muscle relaxation, leading to increased blood flow into the penis with pooling of blood in sinuses; and increase in corpus cavernosum pressure, resulting in penile erection. On return to the flaccid state, cyclic GMP is hydrolyzed to guanosine monophosphate by phosphodiesterase type 5. PDE-5 inhibitors do not increase the nitric oxide level, but they potentiate the nitric oxide effect to stimulate erection. Without sexual arousal, this effect activates the nerve-nitric oxide pathway, these inhibitors are ineffective Examples of PDE5 Inhibitors Sildenafil, Tadalafil, Vardenafil (10 times more potent than sildenafil) and the newer: Udenafil , Avanafil, Lodenafil parameter Sildenafil Vardenafil Tadalafil Doses available 25 mg, 50 mg, 100 mg 5 mg, 10 mg, 20 mg 5 mg once daily, 20 mg Administration Take 60 minutes prior to sexual activity Take 60 minutes prior to sexual activity Take from 16 min to 30 min prior to sexual activity Food interaction Yes, with high fat foods Yes, with high fat. Not affected by a normal meal foods. None Mean time to peak concentration Cmax (min.) 60 60 120 T1/2 3–5hr 4–5hr 17.5hr Metabolism Cytochrome P450 3A4 Cytochrome P450 3A4 Cytochrome P450 3A4 > 65 yrs of age Half life increased, dose adjustment should be considered Half life increased, dose adjustment required, recommend lower starting dose Half life increased, no dose adjustment recommended Selectivity For PDE1: Nonselectivity of PDE5 inhibitors with respect to all PDE1 subtypes may induce vasodilatation, flushing, and tachycardia. PDE5 inhibitors may also indirectly inhibit PDE3, thereby elevating heart rate and vasodilation while inhibiting platelet aggregation. For PDE6: 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. For PDE11: Musculoskeletal pain, in particular back pain, more significant with tadalafil than with sildenafil or vardenafil AS tadalafil presented a five fold higher selectivity for PDE11A. Adverse reactions Tadalafil Vardenafil Sildenafil Headache Flushing Headache Dyspepsia Headache Flushing Dizziness Dyspepsia Dizziness Flushing Nausea Dyspepsia Nasal congestion Dizziness Nasal congestion Back pain, myalgia Rhinitis Altered vision PDE5 Inhibitors & ED According to the 2006 American Urological Association (AUA) Guidelines: PDE5 inhibitors are considered to be the first line of therapy in the management of ED, unless contra-indicated. the management of ED begins with the identification of organic comorbidities and psychosexual dysfunctions; both should be appropriately treated. For patients with a definite endocrinopathy, endocrine therapy for hypogonadism, hyperprolactinemia, and thyroid disorders is an appropriate intervention. Indications 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: erectile dysfunction persists despite correction of an abnormal testosterone, prolactin, or thyroid level correction of the hormonal deficiency is contraindicated due to comorbidity (e.g., a low testosterone in a man with prostate cancer) 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 dysfunctioncausing medication and erectile dysfunction persists, OR there is a contraindication to making medication changes. Contraindications& drug interaction The PDE5I can potentiate the hypotensive effects of nitrates. Therefore, PDE5I are contraindicated in patients who are using any form of organic nitrate, either regularly and/or intermittently because of the risk of severe hypotension. PDE5 inhibitors can potentiate the vasodilatation of nitrates and result in potentially dangerous hypotension. Caution is advised when PDE5I are co-administered with alpha blocking agents and/or anti- hypertensives because both have vasodilatory effects and an additive effect on blood pressure lowering may be anticipated. The longer half-life of tadalafil imposes increased risk for drug interactions in patients taking potent cytochrome P450 erythromycin, ketoconazole, protease inhibitors. (CYP450) inhibitors cimetidine or e.g: the safety concerns This has been the area of primary concern due to reports of myocardial infarction and death. 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. In some cases, the sudden hearing loss was accompanied by tinnitus and/or dizziness. Non-arteritic anterior ischemic optic neuropathy (NAION) has been reported rarely in temporal relationship with the use of PDE5I. rare reports of prolonged erections more than four hours and priapism (painful erections more than six hours in duration) for this class of compounds Patients Failing to Respond to their Initial PDE5 Inhibitor 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 Recommendations for treatment optimisation with PDE5- inhibitors Control medical and lifestyle risk factors. Emphasize the need for sexual stimulation. Titrate dose if lower doses are not effective. Counsel patients on how to take the drug properly. Explain that excessive use of alcohol should be avoided, as this can have a negative impact on erectile function. Manage expectations and inform patient that most patients respond to treatment after one or two doses; some patients may need seven or eight attempts before they are successful. The first few attempts at intercourse may be emotionally charged for both the patient and partner, especially if patients have not been sexually active for a long time. Discuss side effects. Uses of PDE-5 inhibitors beyond ED Premature ejaculation (PE): 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. Anorgasmia in women: 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 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. Raynaud's phenomenon Sildenafil has been shown to be effective in treating severe Raynaud's phenomenon associated sclerosis and digital ulceration. with systemic Heart failure 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. Vascular disease 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. Irritable bowel syndrome (IBS) NO is a major inhibitory neurotransmitter in gastrointestinal tract. Sildenafil causes relaxation of smooth muscles in various organs by increasing levels of NO.