Phosphodiesterase V Inhibitors

1
Phosphodiesterase V Inhibitors

• By Lydia Zou
• lzou_at_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 (its 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
• Its 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)

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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

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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)

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Side Effects

• Vardenafil
• Headache and flushing
• Rhinitis
• Dyspepsia
• Flu syndrome

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Side Effects

• Tadalafil
• Headache and flushing
• Dyspepsia
• Nasal congestion
• Back pain--unique to Cialis
• Myalgia
• Can be very bad (cant move). Pt will need to
  stop and use an alternative treatment.

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Side Effects

• Non-arteritic Ischemic Optic Neuropathy
• This is the most common optic nerve disease for
  adults gt50 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

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Metabolism Pathways

• Sildenafil
• Major pathway 3A4 (79)
• Minor pathways 2C9 (20)
• 2C19 and 2D6 (lt2)
• Vardenafil
• Major pathway 3A4
• Minor pathways 3A5 and 2C9
• Tadalafil
• Major pathway 3A4

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Drug-Drug Interactions for the PDE 5 Inhibitors
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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.

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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.

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Interactions Already in the System

• Sildenafil
• Drug-Class Interactions
• CYP3A4 potent Inhibitors gt5 fold inc AUC
• Potassium sparing diuretics
• Loop diuretics
• Antacids

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Sildenafil contd

• 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

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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 gt5 fold inc AUC
• Angiotensin Receptor Blocker and Thiazide Combos
• Antacids

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Tadalafil contd

• Drug-Drug Interactions
• Amlodipine
• Aspirin
• Atazanavir
• Bendrofluazide
• Darunavir/ritonavir
• Doxazosin
• Enalapril
• Ethanol-acute

• Ketoconazole
• Lovastatin
• Midazolam
• Rifampin
• S-warfarin
• Tamsulosin
• Theophylline

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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 contd

• 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 vardenafils
  plasma levels. Patients did experience an
  additional systolic/diastolic BP decrease of 6/5
  mmHg when on both medications.

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Vardenafil contd

• 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

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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
  vardenafils 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, its suggested that patients on potent
  3A4 inhibitors should take no more than 10mg of
  tadalafil per 72 hours.

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Genelex Database
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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.

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Accuracy of the Algorithm
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When it was Right

• There were instances where the algorithm was
  correct but it didnt 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 wouldnt have expected
  the algorithm to get it since it focuses on
  pharmacokinetics. Although they were counted as
  part of the total Wrong, I dont think it was
  actually wrong. In actuality, the number of
  pharmacokinetic interactions that were Wrong
  was 7.

32
References

1. Hedaya MA, El-Afify DR, El-Maghraby GM. The
   effect of ciprofloxacin and clarithromycin on
   sildenafil oral bioavailability in human
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2. Jetter A, Kinzig-Schippers M, Walchner-Bonjean M,
   et al. Effects of grapefruit juice on the
   pharmacokinetics of sildenafil. Clin Pharmacol
   Ther 20027121-29.
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
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4. Kloner RA. Pharmacology and drug interaction
   effects of the phosphodiesterase 5 inhibitors
   focus on a-blocker interactions. Am J Cardiol
   20059642-46.
5. Mehrotra N, Gupta M, Kovar A, et al. The role of
   pharmacokinetics and pharmacodynamics in
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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 200611251-257.
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 20061762551-2556.
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 20057763-75.
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
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10. Therapeutics (Pharm 562) Class Lecture notes from
    5/23/2007
11. Product Insert Sildenafil
12. Product Insert Tadalafil
13. Product Insert Vardenafil