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.

Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs) part 1

Eicosanoids

Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs)
- Eicosanoids are oxygenation products of polyunsaturated long-chain (20 Catom) fatty acids. - There are considered "local hormones" They have specific effects and they are multiple subfamilies   of eicosanoids, e.g. Prostaglandins (PGs), Thromboxanes (TXs) and Leukotrienes (LTs). - The PGs and TXs are collectively identified as Prostanoids. - Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from   platelets (thrombocytes) and leukotrienes from leukocytes, hence the derivation of their names. - The eicosanoids produce a wide range of biological effects on inflammatory responses, on the   intensity and duration of pain and fever, and on reproductive function. They also play important   roles in inhibiting gastric acid secretion, regulating blood pressure through vasodilation or   constriction, and inhibiting or activating platelet aggregation and thrombosis.
Bio Synthesis	- Eicosanoids are not stored within cells, but are synthesized as required. - Two main pathways are involved in the biosynthesis of eicosanoids. - The prostaglandins and thromboxanes are synthesized by the cyclic pathway, the   leukotrienes by the linear pathway. - Eicosanoids biosynthesis steps; 1) 20-carbon atoms fatty acid (arachidonic acid; AA) formation: - Eicosanoid biosynthesis begins when a cell is activated by mechanical trauma,   cytokines, growth factors or other stimuli. - This triggersà release of a phospholipase at the cell membrane. - The phospholipase catalyzes ester hydrolysis of phospholipid (by phospholipase A2;    PLA) - This frees a 20-carbon fatty acid (arachidonic acid; AA). 2) Prostanoids formation (cyclooxygenase pathway): - The cyclic pathway is initiated through the action of prostaglandin  G/H  synthase (also called prostaglandin-endoperoxide synthase). - This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase. - There are two forms of COX activity in humans, COX-1 and COX-2. - COX-1 (prostaglandin synthase-1; PGS-1) is expressed constitutively in gastric mucosa, kidney, platelets, and vascular endothelial cells. - COX-2 (prostaglandin synthase-2; PGS-2) is inducible and is expressed in macrophages and monocytes in response inflammation. - Both COX-1 and COX-2 catalyse the 2-step conversion of arachidonic acid to prostanoids, including prostaglandins (PGs), prostacyclin (PGI2) and thromboxane (TXA2) 3) Leukotrienes formation (Leukotriene pathway): - The linear pathway is initiated through the action of lipoxygenase (LOX) enzymes of   which there are three forms, 5-LOX, 12-LOX and 15-LOX. - The most actively investigated leukotrienes are those produced by the 5-LOX. The   leukotrienes are synthesized by several different cell types including white blood   cells (leukocytes), mast cells, lung, spleen, brain and heart. - The enzyme 5-lipoxygenase (5-LOX) uses 5-lipoxygenase activating convert   arachidonic acid into protein hydroperoxyeicosatetraenoic acid (5-HPETE), which   spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). - The enzyme LTA synthase acts on 5-HPETE to convert it into leukotriene A4 (LTA4), which may be converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase. - Leukotriene C4 synthase to conjugate glutathione with LTA4 to make LTC4, which is   transported outside the cell, where a glutamic acid (FLAP) moiety is removed from   it to make LTD4. The leukotriene LTD4 is then cleaved by dipeptidases to make   LTE4. The leukotrienes LTC4, LTD4 and LTE4 all contain cysteine and are collectively   known as the cysteinyl leukotrienes.
Inhibition Of Eicosanoid Synthesis	- Corticosteroids block all the known pathways of eicosanoid synthesis. - Non-steroidal anti-inflammatory drugs (NSAIDS) e.g. Aspirin, Indomethacin, block   both prostaglandin and thromboxane formation by reversibly inhibiting COX   activity. - Aspirin is an irreversible non-selective COX inhibitor. - NSAIDS are not selective for COX-1 or COX-2. - Selective COX-2 inhibitors (e.g. Celecoxib), which were developed more recently. - 5-LOX inhibitor (e.g. Zileuton) and selective antagonists of the CysLT1 receptor for leukotrienes (LTC4, LTD4 and LTE4) (Zafirlukast, Montelukast and Pranlukast, are used clinically in mild to moderate asthma.

 

 

 

 

 

 

Eicosanoid Receptors

- Each of the eicosanoids functions via interactions with cell-surface receptors that are members of   the G-protein coupled receptor (GPCR) family. - There are at least ten characterized prostaglandin receptors. Receptors that bind the prostaglandin   D family of lipids are called the DP receptors, those that bind E family prostaglandins are called the   EP receptors, those that bind F family prostaglandins are called the FP receptors, those that bind   prostacyclin (PGI:) are called the IP receptors, and those that bind the thromboxanes are called the   TP receptors. - There are at least four leukotriene receptors. Two receptors have been characterized that bind LTB4 called BLT1 and BLT2 and two receptors that bind the peptidoleukotrienes (cysteinyl leukotrienes) called CysLT1 and CysLT2.

 

 

 

 

 

Eicosanoid	Major Site of Synthesis	Major Biological Activities
PGI2 (Prostacyclin)	Heart and vascular endothelial cells	- Inhibit platelet aggregation. - Induce vasodilation. - decrease T-cell proliferation and lymphocyte migration.
PGE1		- Induce vasodilation. - Inhibit platelet aggregation.
PGE2	Kidney, spleen and heart	- Induce vasodilation - Induce platelet aggregation. - Induce uterine contractions. - Maintaining the open passageway of the fetal ductus   arteriosus.
PGD2	Mast cells, eosinophils and brain	- It is a major prostaglandin produced by mast cells. - Induce inflammatory response. - Induces vasodilation. - Induce bronchoconstriction. - Involved in androgenetic alopecia, inhibitors of PGD2 being   studied to treat male pattern baldness.
PGF2α	Kidney, spleen and heart	- Induce vasoconstriction. - Induce bronchoconstriction. - Induce smooth muscle contraction.
TXA2	Platelets	- Induce platelet aggregation. - Induce vasoconstriction. - Induce bronchoconstriction.
LTB4	Monocytes, basophils, eosinophils, mast cells epithelial cells	- Powerful inducer of leukocyte chemotaxis and TXA2 Platelets LTB4 aggregation, vascular permeability, T-cell proliferation and secretion of INF-y (Interferon gamma), IL-1 and IL-2 (Interleukin 1 and 2).
LTC4  LTD4		- Component of slow-reactive substance of anaphylaxis and   (SRS-A). - Induce vasoconstriction. - Induce bronchoconstriction. - Secretion of INF-y.
LTE4	Mast cells and basophils

N.B: SRS-A; is a mixture of the leukotrienes LTC4, LTD4 and LTE4. Mast cells secrete it during the anaphylactic reaction, inducing inflammation.

 

 

 

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