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Phosphodiesterase V Inhibitors

Phosphodiesterase V Inhibitors. By Lydia Zou lzou@u.washington.edu Doctor of Pharmacy Candidate Class of 2008. Goals:. Historical treatments for Erectile Dysfunction before the PDE5 inhibitors were discovered General overview of the three drugs currently available today

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Phosphodiesterase V Inhibitors

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  1. Phosphodiesterase V Inhibitors By Lydia Zou lzou@u.washington.edu Doctor of Pharmacy Candidate Class of 2008

  2. Goals: • Historical treatments for Erectile Dysfunction before the PDE5 inhibitors were discovered • General overview of the three drugs currently available today • Discuss the mechanism of action • Discuss the use of each drug (dosing, duration of action, etc) • List the side effects common and unique to all three drugs • Discuss the metabolism pathway(s) for each of the drugs • Discuss the interactions seen

  3. History: • Penile Implants (1973): • These are surgically implanted • They are still used in patients who have failed on other therapies • Overall patient-partner satisfaction is 90% • Vascular Surgery (1973): • Not done very much these days (it’s a last resort) • Vacuum Pump (1983): • They work by creating a negative vacuum pressure. There is a constriction ring that is placed at the base of the penis to prevent venous drainage and maintain rigidity. • Good in theory but not in reality b/c it was clumsy to use

  4. History • Vasoactive Intracavernosal pharmacotherapy (1995): • There are 2 products approved by the FDA • Caverject (alprostadil injection) • Edex (alprostadil injection) • Transurethral alprostadil (1997): • MUSE: Medicated Urethral System for Erection • It’s a small stick with aprostadil (PGE1) at the end that is stuck into the urethra. A release button is pushed to release the medication. • Oral PDE-5 Inhibitors (1998)

  5. PDE 5 Inhibitors • Three drugs are currently approved: • Sildenafil (Viagra) • Doses: 25mg, 50mg, 100mg • Most patients start at 50mg and it can be taken anytime from 1/2 to 4 hours before sexual activity • Max frequency is once per day • Maybe best to take it on an empty stomach • Vardenafil (Levitra) • Doses: 2.5mg, 5mg, 10mg, and 20mg • Most patients start at 10mg taken ~60minutes before sexual activity • High fat meals can reduce the plasma concentration by 18-50% (on an empty stomach is not a bad idea) • Tadalafil (Cialis) • Doses: 5mg, 10mg, 20mg • Most patients start on 10mg and it can be taken without regard to food • Maximum dosing frequency is once per day

  6. Mechanism of Action • They inhibit phosphodiesterase V, which is responsible for the breakdown of cGMP • cGMP relaxes the smooth muscle and increases blood flow to the corpus cavernosum. • Note: These drugs do not cause a chemical erection. Sexual stimulation is still needed to cause the initial release of nitric oxide, which stimulates the synthesis of cGMP.

  7. Side Effects • Sildenafil: • Headache and flushing • Dyspepsia • Nasal congestion • Abnormal vision (blue halo around lights)

  8. Side Effects • Vardenafil: • Headache and flushing • Rhinitis • Dyspepsia • Flu syndrome

  9. Side Effects • Tadalafil: • Headache and flushing • Dyspepsia • Nasal congestion • Back pain--unique to Cialis • Myalgia • Can be very bad (can’t move). Pt will need to stop and use an alternative treatment.

  10. Side Effects • Non-arteritic Ischemic Optic Neuropathy • This is the most common optic nerve disease for adults >50 years old • The onset is sudden and patients usually experience decreased vision in one eye • Occurs most frequently in the morning when first waking up • Risk Factors: • Ischemic heart disease • HTN • Hypercholesterolemia • Diabetes • Age

  11. Metabolism Pathways • Sildenafil: • Major pathway: 3A4 (79%) • Minor pathways: 2C9 (20%) • 2C19 and 2D6 (<2%) • Vardenafil: • Major pathway: 3A4 • Minor pathways: 3A5 and 2C9 • Tadalafil: • Major pathway: 3A4

  12. Drug-Drug Interactions for the PDE 5 Inhibitors

  13. Contraindications for PDE 5 Therapy • Nitrates: • Patients using nitrates regularly or intermittently should not use any of the PDE-5 Inhibitors. • Applies for any form of nitrates (sublingual, transdermal, etc) • Patients can get extreme hypotension • Hypersensitivity to any of the components of the tablet.

  14. Use with Caution: • Alpha-Blockers: • In the past these drugs were contraindications, but recent evidence suggests that they can be used together • Patients should be stabilized on either the alpha-blocker or the PDE-5 inhibitor first before the other is added on at the lowest possible dose.

  15. Interactions Already in the System: • Sildenafil: • Drug-Class Interactions: • CYP3A4 potent Inhibitors >5 fold inc AUC • Potassium sparing diuretics • Loop diuretics • Antacids

  16. Drug-Drug Interactions: Amiodarone Amlopdipine Aspirin Atazanavir Bosentan Cimetidine Ciprofloxacin Clarithromycin Darunavir/ritonavir Delavirdine Erythromycin Fluvoxamine Grapefruit juice Indinavir Nelfinavir Ritonavir (initially) S-warfarin Saquinavir Saquinavir/ritonavir tacrolimus Sildenafil cont’d:

  17. Interactions Already in the System: • Vardenafil: • Drug-Drug Interactions: • Atazanavir • Cimetidine • Darunavir/ritonavir • Erythromycin • Ketoconazole • Ritonavir (initially)

  18. Interactions Already in the System: • Tadalafil: • Drug Class Interactions: • CYP3A4 Potent Inhibitors >5 fold inc AUC • Angiotensin Receptor Blocker and Thiazide Combos • Antacids

  19. Drug-Drug Interactions: Amlodipine Aspirin Atazanavir Bendrofluazide Darunavir/ritonavir Doxazosin Enalapril Ethanol-acute Ketoconazole Lovastatin Midazolam Rifampin S-warfarin Tamsulosin Theophylline Tadalafil cont’d:

  20. Interactions I Added

  21. Sildenafil • Drug-Class Interactions: • Beta-Blockers: • The product insert states that the AUC of the active metabolite, N-desmethylsildenafil, was increased by 102% when taken with non-specific beta-blockers • Drug-Drug Interactions: • Ambrisentan: • A negative trial, cited in the product insert of ambrisentan, on healthy volunteers showed that sildenafil and ambrisentan did not have a clinically relevant effect on each others’ pharmacokinetics. No dose adjustments are needed when they are co-administered.

  22. Vardenafil cont’d • Drug-Drug Interactions: • Nifedipine: • According to the product insert, co-administration of vardenafil 20mg and slow-release nifedipine 30mg or 60mg daily did not affect the Cmax or AUC of nifedipine. Nifedipine also did not change vardenafil’s plasma levels. Patients did experience an additional systolic/diastolic BP decrease of 6/5 mmHg when on both medications.

  23. Vardenafil cont’d • Drug-Drug Interactions: • Ranitidine: • According to the product insert, there is no pharmacokinetic interaction between these 2 drugs. • S-warfarin: • According to the package insert, no pharmacokinetic reactions occur between these two drugs. Vardenafil does not seem to have an effect on prothrombin time or other pharmacokinetic factors when taken with warfarin

  24. Vardenafil • Drug-Drug Interactions: • Digoxin: • According to the product insert, there is no pharmacokinetic interaction between these two drugs. • Glyburide: • According to the product insert, there is no pharmacokinetic interaction between these two drugs • Indinavir: • According to the package insert, patients on indinavir (800mg TID) should not exceed 2.5mg of vardenafil per 24 hours. Indinavir increased vardenafil’s AUC by 16-fold, Cmax by 7-fold, and half-life by 2-fold.

  25. Tadalafil • Drug-Class Interactions: • H2-Antagonists: • According to the package insert, there was no significant pharmacokinetic effect on tadalafil when stomach pH was increased • Drug-Drug Interactions: • Alfuzosin: • A randomized, double-blind, placebo-controlled, crossover study in 18 healthy normotensive adults studied the effects of tadalafil 20mg and alfuzosin 10mg daily. The mean standing and supine BP were slightly lower in those taking tadalafil compared to placebo, but these differences were not statistically significant

  26. Tadalafil • Drug-Drug Interactions: • Ritonavir (initially): • According to the PI, patients at steady state on ritonavir 500mg or 600mg twice per day had a 32% increase in exposure (AUC) and a 30% decrease in Cmax when given a single dose of tadalafil compared to tadalafil 20mg alone. Patients on ritonavir 200mg BID experienced a 124% increase in AUC with no change in Cmax. Based on these results, it’s suggested that patients on potent 3A4 inhibitors should take no more than 10mg of tadalafil per 72 hours.

  27. Genelex Database

  28. The Genelex Database • It lists the current drug interactions available in the literature. • Accounts for individual genotypes when metabolizing drugs. • Lists a severity rating. • Predicts interactions based on metabolism information when studies are not available. • It also lets users know when an interaction is based on literature and when it is based on the algorithm.

  29. Accuracy of the Algorithm

  30. When it was Right • There were instances where the algorithm was correct but it didn’t predict the right percentage of change.

  31. When it was Wrong • In many instances, the interaction I put in was a pharmacodynamic one so I wouldn’t have expected the algorithm to get it since it focuses on pharmacokinetics. Although they were counted as part of the total “Wrong,” I don’t think it was actually wrong. In actuality, the number of pharmacokinetic interactions that were “Wrong” was 7.

  32. References • Hedaya MA, El-Afify DR, El-Maghraby GM. The effect of ciprofloxacin and clarithromycin on sildenafil oral bioavailability in human volunteers. Biopharm Drug Dispos 2006;27:103-110. • Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 2002;71:21-29. • Kloner RA, Jackson G, Emmick JT, et al. Interactions between the phosphodiesterase 5 inhibitor, talalafil and 2 a-blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol 2004;172:1935-1940. • Kloner RA. Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on a-blocker interactions. Am J Cardiol 2005;96:42-46. • Mehrotra N, Gupta M, Kovar A, et al. The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy. Int J Impot Res 2007; 19:253-264. • Bank AJ, Kelly AS, Kaiser DR, et al. The effects of quinapril and atorvastatin on the responsiveness to sildenafil in men with erectile dysfunction. Vasc Med 2006;11:251-257. • Nieminen T, tammela TL, Koobi T, et al. The effects of tamsulosin and sildenafil in separate and combined regimens on detailed hemodynamics in patients with benign prostatic enlargement. J Urol 2006;176:2551-2556. • Ring BJ, Patterson BE, Mitchell MI, et al. Effect of tadalafil on cytochrome p450 3A4-mediated clearance: studies in vitro and in vivo. Clin Pharmacol Ther 2005;77:63-75. • Giuliano F, Kaplan SA, Cabanis M, et al. Hemodynamic interaction study between the alpha1-blocker alfuzosin and the phosphodiesterase-5 inhibitor tadalafil in middle-aged healthy male subjects. Urology 2006;67:1199-1204. • Therapeutics (Pharm 562) Class Lecture notes from 5/23/2007 • Product Insert: Sildenafil • Product Insert: Tadalafil • Product Insert: Vardenafil

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