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 discoveredGeneral overview of the three drugs currently available todayDiscuss the mechanism of actionDiscuss the use of each drug (dosing, duration of action, etc)List the side effects common and unique to all three drugsDiscuss the metabolism pathway(s) for each of the drugsDiscuss the interactions seen

History:Penile Implants (1973):

These are surgically implantedThey are still used in patients who have failed on other therapiesOverall 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

History

Vasoactive Intracavernosal pharmacotherapy (1995):

There are 2 products approved by the FDACaverject (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)

PDE 5 InhibitorsThree 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 activityMax frequency is once per dayMaybe 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 activityHigh 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 foodMaximum dosing frequency is once per day

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.

Side Effects

Sildenafil:Headache and flushing

Dyspepsia

Nasal congestion

Abnormal vision (blue halo around lights)

Side Effects

Vardenafil:Headache and flushing

Rhinitis

Dyspepsia

Flu syndrome

Side Effects

Tadalafil:Headache and flushing

Dyspepsia

Nasal congestion

Back pain--unique to Cialis

MyalgiaCan be very bad (can’t move). Pt will need to stop and use an alternative treatment.

Side Effects

Non-arteritic Ischemic Optic NeuropathyThis is the most common optic nerve disease for adults >50 years oldThe 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 diseaseHTNHypercholesterolemiaDiabetesAge

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

Drug-Drug Interactions for the PDE 5 Inhibitors

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.

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.

Interactions Already in the System:

Sildenafil:Drug-Class Interactions:

CYP3A4 potent Inhibitors >5 fold inc AUC

Potassium sparing diuretics

Loop diuretics

Antacids

Sildenafil cont’d:

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

Interactions Already in the System:

Vardenafil:Drug-Drug Interactions:

Atazanavir

Cimetidine

Darunavir/ritonavir

Erythromycin

Ketoconazole

Ritonavir (initially)

Interactions Already in the System:

Tadalafil:Drug Class Interactions:

CYP3A4 Potent Inhibitors >5 fold inc AUC

Angiotensin Receptor Blocker and Thiazide Combos

Antacids

Tadalafil cont’d:

Drug-Drug Interactions:

AmlodipineAspirinAtazanavirBendrofluazideDarunavir/ritonavirDoxazosinEnalaprilEthanol-acute

KetoconazoleLovastatinMidazolamRifampinS-warfarinTamsulosinTheophylline

Interactions I Added

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.

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.

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

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.

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

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.

Genelex Database

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.

Accuracy of the Algorithm

05

101520253035404550

TotalInteractions

AlgorithmRight

AlgorithmWrong

Counts

When it was Right

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

0

5

10

15

20

25

30

TotalTimesRight

Rightbut %Wrong

Counts

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.

02468

101214161820

TotalWrong

PD

Counts

References1. 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.

2. 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.

3. 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.

4. Kloner RA. Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on a-blocker interactions. Am J Cardiol 2005;96:42-46.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. Therapeutics (Pharm 562) Class Lecture notes from 5/23/2007

11. Product Insert: Sildenafil

12. Product Insert: Tadalafil

13. Product Insert: Vardenafil