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Monday, August 11, 2025

Impotence agents


1. Definition

  • Pharmacological agents used in the treatment of erectile dysfunction (ED) in men

  • Aim to improve the ability to achieve and/or maintain an erection sufficient for satisfactory sexual activity

  • Act on vascular, neurological, hormonal, or psychological mechanisms involved in penile erection

  • Also referred to as erectogenic agents

2. Mechanism of Action – General

  • Normal erection physiology involves sexual stimulation triggering nitric oxide (NO) release from nerve endings and endothelial cells in the corpus cavernosum

  • NO activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) → relaxation of smooth muscle in penile arteries and cavernosal tissue → increased blood inflow and restricted outflow → erection

  • Impotence agents typically work by:

    • Enhancing NO-cGMP pathway (e.g., PDE5 inhibitors)

    • Directly supplying vasoactive substances

    • Replacing deficient hormones

    • Modifying neural signals involved in erection

3. Main Pharmacological Classes

A. Phosphodiesterase Type 5 (PDE5) Inhibitors

  • Block breakdown of cGMP by PDE5 → prolong smooth muscle relaxation and erection

  • Examples: sildenafil, tadalafil, vardenafil, avanafil

  • Require sexual stimulation to be effective

B. Prostaglandin E1 (PGE1) Analogs

  • Directly relax cavernosal smooth muscle by increasing cAMP and cGMP

  • Example: alprostadil

  • Routes: intracavernosal injection, intraurethral suppository

C. Combination Intracavernosal Therapy

  • Mix of PGE1, papaverine (nonspecific PDE inhibitor), and phentolamine (α-adrenergic antagonist)

  • Used when monotherapy fails

D. Hormonal Agents

  • Testosterone replacement therapy (TRT) for hypogonadism-related ED

  • Available as injections, transdermal gels/patches, oral formulations

E. Dopaminergic Agents

  • Apomorphine (sublingual; less commonly used) – stimulates central dopamine receptors involved in sexual arousal

F. Experimental/Adjunctive

  • Stem cell therapy, low-intensity shockwave therapy, melanocortin receptor agonists (e.g., bremelanotide – more for hypoactive sexual desire disorder but under investigation for ED)

4. Indications

  • Erectile dysfunction from vascular, psychogenic, hormonal, or neurogenic causes

  • ED secondary to chronic illnesses (e.g., diabetes, hypertension)

  • ED after prostate surgery or pelvic trauma

  • Off-label:

    • Pulmonary arterial hypertension (sildenafil, tadalafil)

    • Raynaud’s phenomenon (sildenafil in some cases)

5. Contraindications

  • Absolute:

    • Concomitant use of nitrates or nitric oxide donors (risk of severe hypotension)

  • Relative/Caution:

    • Severe cardiovascular disease where sexual activity is inadvisable

    • Recent stroke or myocardial infarction

    • Retinitis pigmentosa (rare genetic retinal disorder)

    • Hypersensitivity to drug or formulation components

6. Adverse Effects

PDE5 Inhibitors

  • Common: headache, flushing, nasal congestion, dyspepsia, visual disturbances (sildenafil), back pain (tadalafil)

  • Rare but serious: priapism, sudden hearing loss, non-arteritic anterior ischemic optic neuropathy (NAION), severe hypotension

Alprostadil

  • Penile pain, fibrosis at injection site, priapism, urethral burning (with suppository)

Testosterone

  • Acne, oily skin, polycythemia, gynecomastia, prostate enlargement, mood changes

7. Drug Interactions

PDE5 Inhibitors

  • Potentiated hypotension with nitrates and α-blockers (dose separation required)

  • Metabolized by CYP3A4 – interactions with strong inhibitors (ketoconazole, ritonavir) and inducers (rifampin)

Testosterone

  • May enhance effects of oral anticoagulants

  • Interacts with corticosteroids (fluid retention risk)

Alprostadil & Combination Intracavernosal Therapy

  • Minimal systemic interactions due to local administration

8. Precautions

  • Assess underlying cause of ED before starting pharmacotherapy

  • Monitor cardiovascular risk prior to initiating PDE5 inhibitors in patients with known heart disease

  • Evaluate testosterone levels before TRT; monitor PSA, hematocrit during therapy

  • Educate patients on proper administration of injectable or intraurethral therapies to avoid injury or priapism

9. Advantages and Limitations

Advantages

  • High efficacy rates, especially with PDE5 inhibitors

  • Oral options widely available and convenient

  • Multiple alternatives for patients unresponsive to first-line agents

Limitations

  • Require sexual stimulation (PDE5 inhibitors)

  • Variable onset and duration across agents

  • Possible side effects, cost, and psychological factors affecting adherence

10. Common Agents and Duration of Action

  • Sildenafil – onset 30–60 min; duration ~4 hours

  • Tadalafil – onset ~30 min; duration up to 36 hours (“weekend pill”)

  • Vardenafil – onset ~30 min; duration 4–5 hours

  • Avanafil – fastest onset (~15 min); duration up to 6 hours

  • Alprostadil injection – onset 5–15 min; duration ~30–60 min




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