Erectile Dysfunction

Other Drugs Used in Erectile Dysfunction (Not Act on α2 Receptors)
A) Phosphodiesterase Type-5 (PDE5) Inhibitors
Sildenafil (Viagra)
About The Drug	- Sildenafil is a phosphodiesterase type-5 (PDE5) Inhibitor. - Early 1990s: Pfizer completes several early trials of sildenafil citrate for its use as a heart   disease treatment. But volunteers in the clinical trials are About the Drug reporting  increased erections several days after taking a dose of the drug. - In 1998 the FDA approved Viagra (Blue pill) to treat erectile dysfunction (ED) and pulmonary arterial hypertension (PAH).
Mechanism Of Action	- During sexual stimulation Stimulate release of nitric oxide (NO) in the   corpus cavernosum in the penis. - NO release à  Activate guanylate cyclase (GC)à  ↑ cyclic guanosine   monophosphate (cGMP) à decrease Ca2+ influx à Relaxation of blood     vessels smooth muscleà vasodilatationà Erection. - Phosphodiesterase type-5 responsible for degradation of cGMP into GMP. - Sildenafil is a selective phosphodiesterase type-5 (PDE5) Inhibitorà   accumulation of cGMP Erection. - Sildenafil has no effect in absence of sexual stimulation.
Phosphodiesterases Enzymes	PDE enzyme types: PDE-1, 2, 3, 4, 5, 6, 7, 8, 9, 10 & 11.
	Type	Main function and location
	PDE-3	- Control cardiac contractility.
	PDE-5	- Control contractility of pulmonary vascular smooth muscle and the corpus cavernosum.
	PDE-6	- Control photo-transduction pathway of the retina
	- Sildenafil effect is more potent on PDE-5 than other   phosphodiesterases. - The approximately 4,000 fold selectivity for PDE-5 versus PDE-3. - The approximately 10 fold selectivity for PDE-5 versus PDE-6.
Pharmacokinetics	Absorption and Distribution: - It is rapidly absorbed (orally). - Maximum plasma concentrations are reached within 30 - 120 minutes.                              Metabolism and Excretion: - It is metabolized predominantly by CYP450 (CYP3A4) hepatic -microsomal isoenzymes. - It is excreted predominantly in the feces (80%) and in the urine (13%).
Therapeutic uses	- Treatment of erectile dysfunction (ED). - Treatment of pulmonary arterial hypertension (PAH):       It relaxes the arterial wall, leading to decreased pulmonary arterial       resistance and pressure.
Dose	-Usual Adult Dose for Pulmonary Hypertension:    20 mg orally three times a day. -Usual Adult Dose for Erectile Dysfunction:    50 mg - 100 mg orally once a day, needed, 1 hour prior to sexual    activity. - Dose Adjustments (erectile dysfunction):   Geriatric: 25 mg 1 hour prior to sexual activity.   Mild to moderate renal dysfunction: No adjustment recommended.      Severe renal dysfunction (CrCl less than 30 mL/min): 25 mg.   Hepatic impairment (any degree): 25 mg.    With alpha blockers or with CYP450 3A4 inhibitors (ketoconazole or    erythromycin): 25 mg.
Side effects	Most common adverse effects:  - Headache, flushing, dyspepsia, abnormal vision, nasal congestion,   back pain, myalgia, nausea, dizziness and rash. - Abnormal vision: due to inhibition of PDE-6.                                              In Details   - Common: (10% or more):       Headache (28%) dyspepsia (17%), abnormal vision (11%) {green       vision/blue vision} Diarrhea (10%), myalgia/back pain (10%),       flushing (10%), nasal congestion (10%) and rash (10%). - Uncommon (0.1% to 1%):       Tachycardia and hypotension transient decreases in supine blood       pressure in healthy volunteers (maximum decrease of 8.4/5.5       mmHg).
Contraindication	- In patients who taking organic nitrites and nitrates. - Severe hepatic impairment or severe renal impairment. - Hypotension, recent stroke or heart attack. - Retinal disorders (genetic disorders of retinal phosphodiesterases).
FDA Warning	- Patients should stop Sildenafil if a sudden loss of vision occurs in   one or both eyes, which could be a sign of non arteritic anterior   ischemic optic neuropathy (NAION).  - Patients should stop Sildenafil in the event of sudden decrease or      loss of hearing.

 

Tadalafil (Cialis®)	Vardenafil (Levitra®)
- Vardenafil and Tadalafil  are selective PDE-5 inhibitors used for erectile dysfunction. - Structurally Vardenafil is similar to Sildenafil, while Tadalafil is very different. - Vardenafil is may be effective in the treatment of premature ejaculation - Tadalafil used for in treatment of pulmonary arterial hypertension and symptoms of     benign prostatic hyperplasia (BPH). - Vardenafil is more selective than Sildenafil and Tadalafil to PDE-5.
Avanafil (Stendra®)
- Avanafil is a selective is a PDE5 inhibitor approved for erectile dysfunction by FDA on April 27, 2012.  - Onset of action: 15 minutes (Fast onset of action).  - Duration of action: up to 6 hours.  - Dosage form: Tablets: 50, 100 and 200 mg.  - Side effects same as Sildenafil.

 

 

Brief comparison:	Sildenafil	Vardenafil	Tadalafil
FDA approval date	March 27, 1998	August 19, 2003	November 21, 2003
Dosage form	25mg, 50mg, 100mg tablets	2.5mg, 5mg, 10mg, 20mg tablets	5mg, 10mg, 20mg tablets
Efficacy	82-84%	80%	81%
Onset of action	30 minutes(effect delayed by food)	25 minutes(effect delayed by fatty meal)	16-45 minutes (effect NOT delayed by food)
Recommended dose	50 mg, may be adjusted to 100 mg or 25 mg	10 mg, may be adjusted to 20 mg	10 mg, may be adjusted to 20 mg
Duration of action	4 to 5 hours	4 to 5 hours	36 hours
	- Less effective after Food Interactions high-fat meal	- Less effective after high-fat meal- Moderate-fat meal does not reduce its effectiveness	- Works without regard to what eat,
Most common side effects	Facial flushing, indigestion,Headache	Facial flushing, headache	indigestion headache
Less common side effects	Altered vision, dizziness, nasal congestion	Indigestion, nausea,  dizziness nasal congestion	Back pain, muscle aches, nasal congestion, facial flushing dizziness,

 

B) Prostaglandin E1 analogue

Alprostadil (Caverject®)

- To understand what prostaglandin meaning; see Autacoids chapter (next chapter). - Alprostadil is a prostaglandin E1 (PGE1) analogue used in the continuous treatment of   erectile dysfunction due to vasodilatation properties. - Dosage form: urethral suppositories and in injectable form. - Penile suppository inserted into the urethra. - injected by syringe directly into the corpus cavernosum of the penis. - Onset of action: 5 to 10 minutes. - Duration of action: Injection 1 to 3 hours, supp. 30 to 60 minutes. - Most common side effects: pain at place of injection or pain of urethra (suppository only)                                                     and painful erection.

 

C) Other

Papaverine (Papacon®)

- Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of  visceral spasm, vasospasm and in the treatment of erectile dysfunction.