Review Article: A review of phosphodiesterase type 5 inhibitors A review of phosphodiesterase type 5 inhibitors Schellack N, BCur, BPharm, PhD(Pharmacy), Senior Lecturer Agoro A, BPharm, Academic Intern Department of Pharmacy, Faculty of Health Sciences, University of Limpopo (Medunsa Campus) Correspondence to: Natalie Schellack, e-mail: [email protected] Keywords: phosphodiesterase type 5 inhibitors, erectile dysfunction, cardiac failure, pulmonary hypertension Abstract Currently, three phosphodiesterase type 5 (PDE5) inhibitors are available for clinical use in South Africa; sildenafil, vardenafil and tadalafil. The PDE inhibitors are used in males to treat erectile dysfunction. However, sildenafil is also registered for use in the treatment of pulmonary hypertension. Newer studies are investigating the use of these drugs for other conditions, including hypertension, ischaemia or reperfusion injury, myocardial infarction, cardiac hypertrophy, heart failure and other peripheral circulatory conditions, e.g. Raynaud’s disease. The article provides a broad overview of the mechanism of action, indications, pharmacokinetics and side-effects of these agents. © Medpharm S Afr Fam Pract 2014;56(2):96-101 Introduction The first oral medication in the PDE5 inhibitor class resulted in an additional choice in ED therapy, and obviously Indications for the use of phosphodiesterase (PDE) inhibitors brought about therapeutic outcomes that were desired are not limited to erectile dysfunction (ED) only. They have from the previous forms of treatment.6 Initially, sildenafil was also showed effectiveness in pulmonary hypertension and developed as an antihypertensive and antianginal agent by 1,2 other cardiovascular diseases (CVD). Their effects on Pfizer, but was ultimately approved by the US Food and the improvement of cardiac function, exercise capacity Drug Administration (FDA) for the primary indication of ED and increased cardiac output have been proven by several because of its lack of efficacy in terms of the original clinical studies.3 Also, their vasodilative effects can yield a decrease trial outcomes and the “beneficial” side-effect of causing in arterial blood pressure that can be highly beneficial to erections. Vardenafil and tadalafil received FDA approval patients with CVD.2 These benefits are made possible by to be used in ED five years after the initial approval of the fact that the enzyme, phosphodiesterase, is present in sildenafil.5 various parts of the human body, such as the hypertrophied ED is the persistent failure, for a period of at least six myocardium, and the pulmonary and systemic blood months, to acquire and maintain an erection for the purpose vessels.4 of satisfactory sexual performance.5,7 More than 150 million Prior to the roll-out of effective PDE type 5 (PDE5) inhibitors, men are affected by ED worldwide, which may increase to over 320 million by 2025.6 Although the prevalence of ED ineffective and unsafe medications, such as yohimbine, varies among countries, other factors, such as age, poor apomorphine, phentolamine and trazadone, were health and decreased exercise levels, also increase the risk considered for the management of ED. Instead of these of acquiring ED.7 medications, invasive therapies, such as penile prosthetic surgery, intracorporeal injectable medication and urethral Men have suffered ED as a result of various neurological, suppositories, were used in the management of ED.5,6 neurovascular, endocrinological, psychological and cardio- These therapies were not only invasive, but also unsafe and vascular defects. The risks of acquiring ED have increased 5 deficient because unpleasant techniques were involved.6 in smokers and patients with diabetes over the years. Psychological factors that cause ED are stress, depres- Although nonselective PDE inhibitors, such as caffeine, sion and anxiety.5 However, some medicines that are used proved to have minimal vasculogenic activity, papaverine, to manage depression and hypertension, as well as neuro- an injectable PDE5 inhibitor, was used widely used until leptics, are known culprits in terms of causing ED.5,7 Low its side-effect profile caused the restriction of its use as a quality of life, low levels of testosterone, obstructive sleep monotherapy in ED.5 apnoea syndrome and obesity relate to a higher risk of ED.7 S Afr Fam Pract 2014 96 Vol 56 No 2 Review Article: A review of phosphodiesterase type 5 inhibitors 1 3 NANC ACh binds to Cholinergic neuron nerve cell post-synaptic M3 releasing ACh receptors 2 Vascular endothelial cells nNOS eNOS Nitric oxide release Vascular smooth muscle cells NO Nucleus (+) 4 Guanylyl cyclase PDE5 Cytoplasm (+) (+) GTP cGMP 5’-GMP Cell membrane ↓ Intracellular (Second (Inactive) [Ca2+] messenger) Enlargement of a vascular smooth Vascular muscle cell smooth muscle relaxation 5’-GMP: 5’-guanosine monophosphate (inactivated guanosine monophosphate), ACh: acetylcholine, cGMP: cyclic guanosine monophosphate (the second messenger that sets a biochemical cascade in motion, which results in decreased levels of intracellular calcium ions and resultant relaxation of the vascular smooth muscle), eNOS: endothelial cell-derived nitric oxide synthase, GTP: guanosine triphosphate, M3 receptors: post-synaptic muscarinic receptors of the M3 subtype, from which receptor stimulation leads to increased production and the release of nitric oxide, NANC: non-adrenergic and non-cholinergic, nNOS = neuronal nitric oxide synthase, NO: nitric oxide, PDE5: phosphodiesterase type 5 (the enzyme that catabolises cyclic guanosine monophosphate) Nitric oxide is derived from (1) non-adrenergic and non-cholinergic nerves via the action of neuronal nitric oxide synthase, and (2) endothelial cells, via the action of endothelial cell-derived nitric oxide synthase. The production and release of nitric oxide by the endothelial cells is augmented by the stimulation of postsynaptic M3 receptors (3) by acetylcholine and the site of action of the phosphodiesterase type 5 inhibitors (4)5,6,8 Figure 1: The mechanisms involved in vascular smooth muscle relaxation, thereby facilitating normal penile erection Mechanism of action concentration of cGMP in the corpus cavernosum of the penis. This action results in vasodilation and an PDE5 inhibitors potentiate the vasodilative effect of antiproliferative effect on the smooth muscle cells.8,9 acetylcholine, which is released from sacral parasympathetic neurons, causing an increase in blood flow to the penis, and Figure 1 shows the mechanisms involved in vascular smooth muscle relaxation, thereby facilitating normal penile thereby facilitating penile erection during sexual stimulation. function. The penile erection results when the muscarinic receptors in the endothelial cells are activated by acetylcholine. This Both cGMP and cyclic adenosine monophosphate (cAMP), activation leads to an increased production and release i.e. the cyclic nucleotides, play vital roles in the regulation of nitric oxide. The diffusion of nitric oxide into vascular of cardiovascular functioning in cardiac disorders. cGMP smooth muscle cells activates guanylyl cyclase and the facilitates the effect of nitric oxide, as well as that of atrial resultant increase in the synthesis of cyclic guanosine natriuretic peptide, while cAMP facilitates the effects of adrenaline on the heart and other tissue.10 There is a large monophosphate (cGMP), leading to muscle relaxation and distribution of PDE5 in the pulmonary tissue, vascular vasodilation of the penis.8 smooth muscle, heart, renal tubules and platelets,3 hence PDE5 inhibitors act by hampering the breakdown of cyclic the vasodilatory effect will not be restricted to the penis, but GMP by PDE5, causing an increase in the intracellular also to other sites where the enzyme is present. The inhibition S Afr Fam Pract 2014 97 Vol 56 No 2 Review Article: A review of phosphodiesterase type 5 inhibitors of PDE5 by the highly selective PDE inhibitors catalyses the plasma levels of these agents. Known inhibitors of the hydrolysis of cGMP to its inactive form, 5’-guanosine both CYP3A4 and CYP2C9, e.g. bosentan, cimetidine, monophosphate, and also facilitates an increase in the erythromycin, clarithromycin, ketoconazole, ritonavir, vasodilatory effect of endogenous nitric oxide, thereby saquinavir, fluvoxamine and amiodarone, as well as known yielding positive cardiovascular and pulmonary effects inducers of CYP3A4, e.g. rifampicin and carbamazepine, in conditions such as hypertension, pulmonary arterial might alter the plasma levels of these agents.9 1,11 hypertension and coronary artery disease. Therefore, it is advised that the dosage of sildenafil and other related agents should be decreased by 50% in Indications men who are taking a CYP3A4 inhibitor as concomitant Sildenafil, vardenafil and tadalafil are equally efficacious therapy.8,13 Concomitant use of PDE5 inhibitors and nitrates in mild to moderate ED. They are usually considered to be potentiate the hypotensive effects of the latter. Therefore, first-line therapy for ED. Nevertheless, the choice of drug PDE5 inhibitors are contraindicated in patients receiving is based on side-effect profile and patient requirements.12,13 organic nitrate therapy.16 The co-administration of PDE5 Currently, the PDE5 inhibitors are undergoing further inhibitors and antihypertensive agents, especially the investigations beyond ED, including myocardial a-adrenergic blockers, may cause an additional decrease infarction, cardiac hypertrophy, heart failure, strokes,