Phosphodiesterase-5 (PDE-5) inhibitors like sildenafil revolutionized erectile dysfunction treatment by inhibiting the PDE-5 enzyme and increasing cGMP levels. They work by enhancing smooth muscle relaxation in the penis during sexual stimulation. Common side effects include headache, flushing and stomach pain. Use with nitrates is dangerous and may cause low blood pressure or heart attack. Proper dosing and not exceeding one pill per day is important. PDE-5 inhibitors have been safely used to treat other conditions like pulmonary hypertension as well.

1. Phosphodiesterase -5 inhibitors
Halim maher
Lecturer of Andrology, sexology & STD’s
Suez Canal University

2. Contents
• I. Introduction
• II. Pharamacodynamics
• III. Pharmacokinetics
• IV. Therapeutic Indications
• V. Precautions & Adverse Reactions
• VI. Drug Interactions
• VII. Summary

3. Introduction
 The introduction of the first phosphodiesterase (PDE)-5inhibitor,
sildenafil (Viagra), in 1998 revolutionized the treatment of the major
sexual dysfunction affecting men as erectile disorder.
 They are also being misused as recreational drugs that are believed to
enhance sexual performance.
 These drugs have been used by more than 20 million men, if not
more, around the world.
 Sildenafil was originally developed to treat angina pectoris but later on
was recognized as novel treatment option for impotence. To date,
sildenafil has been the most extensively studied PDE-5 inhibitor.

4. Robert Francis Furchgott, Ferid Murad & Louis J. Ignarro
made a revolutionary invention that, no doubt,
contributed to Viagra history.

5. Pharamacodynamics
 The development of sildenafil provided important
information about the physiology of erection.
 Sexual stimulation causes the release of the
neurotransmitter nitric oxide (NO), which increases the
synthesis of cyclic guanosine monophosphate (cGMP),
causing smooth muscle relaxation in the corpus
cavernosum that allows blood to flow into the penis
and that results in turgidity.
 The concentration of cGMP is regulated by the enzyme
PDE-5, which, when inhibited, allows cGMP to increase
& enhance erectile function.

6. • Because sexual stimulation is required to
cause the release of NO, PDE-5 inhibitors have
no effect in the absence of such stimulation

8. Pharmacokinetics
Absorption - Phosphodiesterase-5 Inhibitors
are rapidly absorbed from the gastrointestinal
(GI) tract, with maximal plasma concentrations
reached in 30 to 120 minutes. Because it is
lipophilic, concomitant ingestion of a high-fat
meal delays the rate of absorption
Excretion - Excretion of 80 % of the dose is via
feces, and another 13 % is eliminated in the
urine. Elimination is reduced in persons over age
65 years & in the presence of severe renal or
hepatic insufficiency.

9. Remember
Concomitant ingestion of a high-fat meal delays the
rate of absorption of Phosphodiesterase-5 Inhibitors

10. Half life -The mean half-lives of sildenafil &
vardenafil are 3 to 4 hours & that of tadalafil is
about 18 hours.
Tadalafil can be detected in the bloodstream
5 days after ingestion, & because of its long
half-life, it has been marketed as effective for
up to 36 hours.

11. Therapeutic Indications
1- Erectile dysfunction

12.  Erectile dysfunctions have traditionally been classified as
organic, psychogenic, or mixed.
 Over the last 20 years, the prevailing view of the cause of
erectile dysfunction has shifted away from psychological
causes toward organic causes.
 Organic causes include :
 DM (diabetes) , hypertension, smoking, peripheral vascular
disease, pelvic or abdominal surgery (especially, prostate
surgery), multiple sclerosis, peripheral neuropathy
&Parkinson`s disease

13. 2-Pulmonary Hypertension
Because PDE5 is also present in the arterial wall
smooth muscle within the lungs, they have also
been explored for the treatment of pulmonary
hypertension.
Sildenafil is more selective for pulmonary
circultaion than vardenafil, and is the only PDE 5
inhibitor shown to improve arterial oxygenation
in PAH

14. 3-Other uses
 PDE-5 inhibitors are emerging as novel therapeutic tools with
a potential to protect or enhance endothelial function in humans & to
selectively improve regional blood flow.
 The FDA has recently approved a reformulation of sildenafil for the
Treatment of :
 Raynaud's phenomenon
 Respiratory disorders with ventilation/perfusion mismatch,
 Congestive cardiac failure,
 Hypertension & stroke are the other conditions in which PDE-5
inhibitors are being tried.

15. Side effects
Common adverse effects:-
• Headache, flushing & stomach pain.
Less common adverse effects :-
• Nasal congestion
• Urinary tract infection
• Abnormal vision, increased sensitivity to light, or
blurred vision
• Diarrhea
• Dizziness
• Rash

16. Use of PDE-5 inhibitors is contraindicated in
persons who are taking organic nitrates in any
form
The combination of organic nitrates & PDE
inhibitors can cause a precipitous lowering of
blood pressure (BP) & can reduce coronary
perfusion to the point of causing MI & death.

17. Don`t forget
The combination of organic nitrates & PDE inhibitors
can cause MI & death.

18. Non arteritic anterior ischemic optic neuropathy
 Recently there have been 50 reports & 14 verified cases
of a serious condition in men taking Sildenafil called non
arteritic anterior ischemic optic neuropathy (NAION).
 This is an eye ailment that causes restriction of blood flow to the optic
nerve & can result in permanent vision loss.
 The first symptoms appear within 24 hours after use of
Sildenafil & include blurred vision & some degree of vision loss.
 The incidence of this effect is very rare.
 In the reported cases, many patients had preexisting eye
problems which may have increased their risk.

19. Dosage & Clinical Guidelines
Sildenafil - Sildenafil is available as 25-, 50-, &
100- mg tablets.
The recommended dose of sildenafil is 50
mg taken by mouth 1 hour prior to intercourse.
The duration of the effect is usually 4 hours,
Based on effectiveness & adverse effects, the
dose should be titrated between 25 & 100 mg.
Sildenafil is recommended for use no more than
once a day.

20. Vardenafil - Vardenafil is supplied in 2.5-, 5-, 10-,
& 20-mg tablets.
The initial dose is usually 10 mg taken with or
without food about 1 hour before sexual activity.
 The dose can be increased to a maximum of
20mg or decreased to 5 mg based on efficacy &
side effects.

21. Tadalafil -The recommended dose of tadalafil
is 10 mg before sexual activity, which may be
increased to 20 mg or decreased to 5 mg,
depending on efficacy & side effects.
Because of its long half-life, it should probably
not be used more than once every 36 hours

22. Remember

23. Drug Interactions
 The major route of PDE-5 metabolism is through
CYP450 ,(CYP) 3A4, & the minor route is through CYP
2C9.
 Inducers or inhibitors of these enzymes, therefore, will
affect the plasma concentration & half-life of sildenafil.
 for example, 800 mg of cimetidine, a nonspecific CYP
inhibitor, increases plasma sildenafil concentrations by
56% .
 Erythromycin (E-mycin) increases plasma sildenafil
concentrations by 182 %.

24. Summary
PDE 5 inhibitors are effective regardless of the
baseline severity of erectile dysfunction, race, or
age.
PDE 5 inhibitors increase cGMP to enhance erectile
function
Sildenafil is more selective for pulmonary
circultaion than vardenafil, & is the only PDE 5
inhibitor shown to improve arterial oxygenation in
PAH

25. The most important potential adverse effect
associated with use of these drugs is
myocardial infarction (MI).
Use of PDE-5 inhibitors is contraindicated in
persons who are taking organic nitrates
Sildenafil is recommended for use no more
than once a day. Dosage is between 25 mg
100mg

26. Don`t forget