Penile Erectile Dysfunction Drugs

Penile erectile dysfunction is a condition in which the corpus cavernosum does not fill with blood to allow for penile erection.

Approved drugs for treatment of penile erectile dysfunction include prostaglandin alprostadil and phosphodiesterase type 5 (PDE5) receptor inhibitor sildenafil.

Therapeutic Action

• The desired and beneficial actions of drugs for treatment of penile erectile dysfunction are as follows:
• Alprostadil acts locally to relax the vascular smooth muscle and allow filling of the corpus cavernosum, causing penile erection.
• PDE5 receptor inhibitors act to increase nitrous oxide levels in the corpus cavernosum. Nitrous oxide activates the enzyme cyclic guanosine monophosphate (cGMP) to cause smooth muscle relaxation and increased flow of blood.

Indications

Prostaglandin and PDE5 receptor inhibitors are indicated for the following medical conditions:

•Treatment of penile erectile dysfunction.

Pharmacokinetics

Here are the characteristic interactions of drugs affecting the male reproductive system and the body in terms of absorption, distribution, metabolism, and excretion:

Contraindications and Cautions

The following are contraindications and cautions for the use of these drugs:

• Presence of any anatomical obstruction or condition that might predispose to priapism. The risk could be exacerbated by these drugs.
• Penile implants.
• Bleeding disorders, CV diseases, optic neuropathy, severe hepatic and renal disorders. 

Adverse Effects

Use of these drugs may result to these adverse effects:

• Local effects associated with alprostadil: pain at injection site, infection, priapism, fibrosis, rash.
• Effects associated with PDE5 inhibitors: headache, flushing, dyspepsia, urinary tract infection, diarrhea, dizziness, possible eight cranial nerve toxicity and loss of hearing.
• A potentially life-threatening effect that has been documented is hepatocellular cancer.

Interactions

The following are drug-drug interactions involved in the use of these drugs:

• Organic nitrates, alpha-adrenergic blockers. Serious CV effects, including death, have occurred.
• Ketoconazole, itraconazole, erythromycin. Increased sildenafil levels

Name of the Penile Erectile Dysfunction Drugs

1. Alprostadil
2. Sildenafil
3. Tadalafil
4. Vardenafil

Mechanism of Action:

Alprostadil causes penile erection by increasing blood flow to the penis through relaxation of trabecular smooth muscles and dilation of cavernosal arteries (upper right). A naturally occurring prostaglandin, alprostadil interacts with specific membrane-bound receptors in the corpora cavernosa cells of the penis.

This action activates intracellular adenyl cyclase (lower right), which in turn converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). Increased intracellular levels of cAMP activate protein kinase, an enzyme that activates other enzymes to initiate a cascade of chemical reactions.

These chemical reactions cause the trabecular smooth muscles to relax and the cavernosal arteries to dilate. Blood flow to the penis is then increased, which distends the penile lacunar spaces and compresses the veins, trapping blood in the penis and causing it to become enlarged and rigid.

Indications:

oErectile Dysfunction

oPatent Ductus Arteriosus – in pediatrics

Contraindications and Cautions

•Anuria

•Balanitis (inflammation of head of penis)

•Cavernosal fibrosis

•Hypersensitivity to alprostadil or its components

•Hyperviscosity syndrome

•Indwelling urethral catheter

•Leukemia

•Men for whom sexual activity is contraindicated

•Multiple myeloma

•Penile angulation​

•Penile implants​

•Peyronie’s disease​

•Polycythemia​

•Severe hypospadius (urethral opening on underside of penis)​

•Sickle cell anemia or trait​

•Tendency to develop venous thrombosis, thrombocythemia, urethral obstruction or stricture, urethritis​

Metabolism and Half- Life :

Half-Life: 5-10 min

Onset: ED (intraurethral; muse): 30-60 min; Protein bound: 81%

Metabolism: chiefly in lungs via enzymatic oxidation (plasma levels may be higher in patients with pulmonary disease)

Metabolites: Prostanoid metabolites (inactive)

Excretion: Mainly in urine 90%, small amount in lung

Drug Interactions :

Anticoagulants: possibly increased risk of bleeding

Cyclosporine: possibly decreased blood cyclosporine level

Side- Effects :

•CNS: Dizziness, headache, syncope

•CV: Hypertension, hypotension, tachycardia, vasodilation

•EENT: Nasal congestion, sinusitis

•GU: Pelvic pain; penile disorders, including edema, fibrosis, pain, and rash; priapism; prolonged erection; prostatic pain or enlargement; urethral abrasions; urethral bleeding

•MS: Back pain

•RESP: Cough, upper respiratory tract infection

•Other: Flulike symptoms, injection site bruising or hematoma, needle breakage

Nursing Considerations

•Reconstitute solution with 1 ml diluent, for a concentration of 5, 10, 20, or 40 mcg/ ml, depending on vial strength. Gently swirl contents of reconstituted vial. Use reconstituted solution within 24 hours when stored at room temperature. Don’t use vials that contain precipitate or discolored solution. Discard unused reconstituted solution.

•Using a 1⁄2-inch 27G to 30G needle, inject drug at a 90-degree angle into proximal third of spongy tissue that runs the length of the dorsolateral aspect of penis, avoiding any visible veins. Rotate injection sites by alternating sides of the penis.

•Carefully examine penis for evidence of penile fibrosis. Expect to discontinue treatment if patient develops cavernosal fibrosis, penile angulation, or Peyronie’s disease (hardening of the corpora cavernosa, which causes penis to become distorted when erect) during therapy.

•Watch for prolonged erection after giving drug. Notify prescriber and be prepared to treat patient for priapism if erection lasts longer than 4 hours.

•If patient is receiving an anticoagulant, such as warfarin or heparin, watch for bleeding at injection site because drug may inhibit platelet aggregation

Patient teaching

•Inform patient that initial therapy must be performed in the office setting. Teach him how to correctly administer intracavernous injections or urethral suppositories. Inform him that the goal of treatment is to produce an erection that lasts no longer than 1 hour.

•Advise patient to use alprostadil for injection no more than three times/week and to separate doses by 24 hours. Inform patient using urethral suppositories not to exceed two doses in a 24-hour period.

•Tell patient to inform prescriber immediately about nodules or hard tissue in the penis; an erection that persists for more than 4 hours; new or worsened penile pain; or persistent curvature, redness, swelling, or tenderness of the erect penis.

•Inform patient that common adverse reactions include mild to moderate pain immediately after injection and burning after suppository insertion. Also, needle may break. Advise patient to avoid it by following prescriber’s instructions exactly and by handling injection device properly. If needle breaks during injection and he can see and grasp broken end, he should remove it and contact prescriber. If he can’t see or grasp broken end, he should seek medical care.

•Instruct patient using suppository form to urinate just before inserting suppository and to insert it with applicator supplied with drug. Tell patient to hold penis upright after insertion and to roll it firmly between his hands to distribute drug.

2. Sildenafil

Mechanism of Action:

Inhibits PDE5, enhancing the effects of nitric oxide released during sexual stimulation. This action inactivates cyclic guanosine monophosphate (cGMP), which then increases cGMP levels in corpus cavernosum. Resulting smooth muscle relaxation promotes increased blood flow and subsequent erection. Also relaxes pulmonary vascular smooth muscle cells and, to a lesser degree, vasodilation in systemic circulation.

Indications:

• Erectile Dysfunction
• Pulmonary Arterial Hypertension

Contraindications and Cautions:

• Hypersensitivity to drug
• Concurrent use of nitrates (nitroglycerin, isosorbide mononitrate or dinitrate)

Use cautiously in:​

Serious cardiovascular disease (such as​ history of myocardial infarction,​ cerebrovascular accident, or serious​ arrhythmia within past 6 months);​ coronary artery disease (current or previous)​ with unstable angina; resting​ blood pressure below 90/50 mm hg or​ above 170/110 mm hg (current or previous);​ heart failure (current or previous);​ renal or hepatic impairment (current​ or previous); bleeding disorder;​ active peptic ulcer; anatomic penile​ deformity; retinitis pigmentosa; conditions​ associated with priapism (sickle​ cell anemia, multiple myeloma, leukemia);​ pulmonary veno-occlusive disease;

Use not recommended for any of​ these conditions​

• History of uncontrolled hypertension​ or hypotension​
• Concurrent use of alpha blockers and​ antihypertensives (particularly​ bosentan)​
• Concurrent use of potent CYP3A​ inhibitors such as erythromycin, ketoconazole,​ itraconazole, ritonavir, or​ saquinavir (use not recommended)​
• Patients older than age 65​
• Pregnant or breastfeeding patients​
• Children (safety and efficacy not​ established).​

Metabolism and Half- Life:

Absorption: Bioavailability: 40%

Peak plasma time: 30-120 min

Metabolism: Metabolized in liver by CYP3A4 and (in minor amounts) CYP2C9

Metabolites: N-desmethyl metabolite (active; possesses 50% of sildenafil’s PDE-5-inhibiting activity)

Elimination: Half-life: Parent drug, 3-4 hr; active metabolite, 10-70 min

Excretion: Feces (80%), urine (13%)

Drug Interactions:

• Alpha blockers, Antihypertensives, nitrates: increased risk of hypotension
• Enzyme inducers, rifampin: reduced sildenafil blood level
• Hepatic isoenzyme inhibitors (such as cimetidine, erythromycin, itraconazole, ketoconazole), protease inhibitors (such as indinavir, nelfinavir, ritonavir, saquinavir): increased sildenafil blood level and effects
• High-fat diet: reduced drug absorption, decreased peak level

Side- Effects :

• CNS: headache, dizziness, anxiety, drowsiness, vertigo, transient global amnesia, insomnia, paresthesia, seizures, cerebrovascular hemorrhage, transient ischemic attack
• CV: hypertension, hypotension, myocardial infarction (MI), cardiovascular collapse, ventricular arrhythmias, sudden death
• EENT: transient vision loss, blurred or color-tinged vision, increased light sensitivity, ocular redness, retinal bleeding, vitreous detachment or traction, photophobia, hearing loss, epistaxis, rhinitis, sinusitis nasal congestion
• GI: diarrhea, dyspepsia, gastritis
• Musculoskeletal: myalgia
• Respiratory: exacerbation of dyspnea
• GU: hematuria, urinary tract infection, priapism
• Skin: flushing, rash, erythema, pyrexia
• Other: hypersensitivity including anaphylactic reactions (rare)

Nursing Considerations

• Monitor cardiovascular status carefully.
• Evaluate patient’s vision and hearing.
• Assess for drug efficacy.
• Use sildenafil cautiously in patients with renal or hepatic dysfunction, elderly patients, and men with penile abnormalities that may predispose them to priapism.
• Also use cautiously in patients with left ventricular outflow obstruction, such as aortic stenosis and idiopathic hypertrophic subaortic stenosis, and those with severely impaired autonomic control of blood pressure because these conditions increase patient’s sensitivity to vasodilators such as sildenafil.
• Monitor patient’s blood pressure and heart rate and rhythm before and often during therapy.
• Monitor vision, especially in patients over age 50; who have diabetes, hypertension, coronary artery disease, or hyperlipidemia; or who smoke because sildenafil rarely may cause non- arteritic anterior ischemic optic neuropathy that may lead to decreased vision or permanent vision loss.

Patient teaching

• Advise patient taking drug for erectile dysfunction to take 30 minutes to 4 hours before sexual activity.
• Tell patient not to exceed prescribed dosage or take more than one dose daily.
• Instruct patient to stop sexual activity and contact prescriber immediately if chest pain, dizziness, or nausea occurs.
• Teach patient to recognize and immediately report serious cardiac and vision problems and sudden decrease in or loss of hearing.
• Inform patient that drug can cause serious interactions with many common drugs. Instruct him to tell all prescribers he is taking it.
• Caution patient never to take drug with nitrates, because of risk of potentially fatal hypotension.
• Instruct patient not to take other PDE5 inhibitors.
• Instruct patient to report priapism (persistent, painful erection) or erections lasting more than 4 hours.
• Tell patient that high-fat diet may interfere with drug efficacy.
• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration and alertness.
• Explain that sildenafil used to treat erectile dysfunction may be taken up to 4 hours before sexual activity but that taking it 1 hour beforehand provides the most effective results.
• Warn patient not to take sildenafil if he also takes any form of organic nitrate, either continuously or intermittently, because profound hypotension and death could result. Also caution patient taking sildenafil for erectile dysfunction not to take more than 25 mg within 4 hours of an alpha blocker, such as doxazosin, because symptomatic orthostatic hypotension can occur.
• Tell patient to stop taking drug and contact prescriber if vision decreases suddenly in one or both eyes or if he has a loss of hearing, possibly with tinnitus and dizziness.
• Advise patient taking sildenafil for erectile dysfunction to seek sexual counselling to enhance the drug’s effects.
• To avoid possible penile damage and permanent loss of erectile function, urge patient to notify prescriber immediately if erection is painful or lasts longer than 4 hours.
• Instruct diabetic patient to monitor his blood glucose level frequently because drug may affect glucose control.

3.Tadalafil

Mechanism of Action:

Inhibits PDE5, increasing cyclic guanosine monophosphate level and enhancing erectile function; also relaxes pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.

Indications:

• Erectile dysfunction
• Benign Prostatic Hyperplasia
• Pulmonary Arterial Hypertension

Dosage adjustment

Mild to moderate hepatic impairment or renal impairment

Administration with alpha blockers or potent CYP3A4 inhibitors such as ketoconazole or ritonavir

Contraindications and Cautions:

• Hypersensitivity to drug or its components
• Concurrent use of organic nitrates (regularly or intermittently)

Use cautiously in:

• Mild to moderate hepatic or renal impairment
• Severe renal impairment (avoid adcirca use; once-daily cialis use not recommended)
• Severe hepatic impairment (cialis use not recommended; avoid adcirca use )
• Cardiac risk that makes sexual activity inadvisable, left ventricular outflow obstruction, myocardial infarction within last 90 days, unstable angina or angina occurring during sexual intercourse, new york heart association class II or greater heart failure in last 6 months, uncontrolled arrhythmias, blood pressure below 90/50 mm hg, uncontrolled hypertension (blood pressure above 170/100 mm hg), stroke within last 6 months, pulmonary veno-occlusive disease), erectile dysfunction whose cause hasn’t  been evaluated, conditions that increase risk of priapism (use not recommended)
• Concurrent use of potent CYP450- 3A4 inhibitors or inducers, or other PDE5 inhibitors (avoid use)
• Concurrent use of alpha blockers (except tamsulosin 0.4 mg/day), antihypertensives, or alcohol
• Pregnant or breastfeeding patients
• Children (safety and efficacy not established).

Metabolism and Half- Life:

Absorption

• Duration: ≤36 hr
• Peak plasma time: Erectile dysfunction, 0.5-6 hr; PAH, 2-8 hr

Distribution

• Protein bound: 94%
• Vd: Erectile dysfunction, 63 L; PAH, 77 L

Metabolism

Metabolized in liver by CYP3A4

Elimination

• Half-life: Erectile dysfunction, 15-17.5 hr; PAH (not on bosentan), 35 hr
• Total body clearance: Erectile dysfunction, 2.5 L/hr; PAH (not on bosentan), 1.6 L/hr
• Excretion: Feces (61%), urine (36%)

Drug Interactions:

• Alpha-adrenergic blockers (except tamsulosin 0.4 mg/day): marked blood pressure decrease
• Angiotensin receptor blockers, enalapril, metoprolol: decreased blood pressure
• CYP450-3A4 inducers (such as carbamazepine, phenobarbital, phenytoin, rifampin): decreased tadalafil blood level
• CYP450-3A4 inhibitors (such as erythromycin, itraconazole, ketoconazole, ritonavir): increased tadalafil blood level
• Theophylline: slight increase in heart rate
• Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase, uric acid: increased levels
• Grapefruit juice: increased drug blood level
• Alcohol use: decreased blood pressure

Side- Effects:

• CNS: headache, fatigue, dizziness, insomnia, hyperesthesia, paresthesia, drowsiness, vertigo, asthenia, transient global amnesia
• CV: angina pectoris, chest pain, hypertension, hypotension, orthostatic hypotension, palpitations, syncope, tachycardia, myocardial infarction
• EENT: blurred vision, color vision changes, conjunctivitis, eye pain, increased lacrimation, eyelid swelling, epistaxis, nasal congestion, pharyngitis
• GI: nausea, vomiting, diarrhea, dyspepsia, esophagitis, gastroesophageal reflux, gastritis, upper abdominal pain, dysphagia, dry mouth
• GU: increased or spontaneous erection
• Musculoskeletal: myalgia; back, neck, limb, and joint pain
• Respiratory: dyspnea
• Skin: pruritus, rash, sweating
• Other: facial edema, pain

Nursing Considerations

• Monitor for drug efficacy
• Know that patients with hereditary degenerative retinal disorders, including retinitis pigmentosa, should not receive tadalafil because of the risk of serious ophthalmic adverse reactions.
• Patients with severe hepatic or renal impairment should not receive tadalafil because its effects in these patients are unknown.
• Use tadalafil cautiously in patients with left ventricular outflow obstruction, such as aortic stenosis and idiopathic hypertrophic subaortic stenosis, and those with severely impaired autonomic control of blood pressure because these conditions increase sensitivity to vasodilators such as tadalafil.
• Use tadalafil cautiously in patients with conditions that may predispose them to priapism, such as sickle cell anemia, multiple myeloma, leukemia, or penile deformities (such as angulation, cavernosal fibrosis, or Peyronie’s disease).
• Monitor blood pressure and heart rate and rhythm before and during therapy.

Patient teaching

• Advise patient taking Cialis for erectile dysfunction on an as-needed basis to take before anticipated sexual activity.
• Instruct patient that when taking Cialis on a daily basis he should take tablet at approximately the same time every day, without regard to sexual activity.
• Instruct patient to take Adcirca tablets one after the other every day and not to split the dose.
• Caution patient never to take concurrently with nitrates.
• Instruct patient to stop sexual activity and contact prescriber immediately if chest pain, dizziness, or nausea occurs.
• Advise patient to seek immediate medical attention if sudden loss of vision or sudden decrease in or loss of hearing occurs.
• Instruct patient not to take other PDE5 inhibitors.
• Tell patient drug can cause serious interactions with many common drugs. Instruct him to tell all prescribers he is taking it.
• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration and alertness.
• Inform patient that drug may cause temporary blood pressure drop, leading to light-headedness if he stands up suddenly. Advise him to rise slowly and carefully.​
• Explain that, when used as needed to treat erectile dysfunction, tadalafil should be taken 1 hour before sexual activity to provide the most effective results. Alternatively, if the patient chooses to take a smaller dose of tadalfil daily, encourage him to take it at about the same time every day regardless of the timing of sexual activity.
• Tell patient not to take tadalafil if he takes any form of organic nitrate, either continuously or intermittently, because profound hypotension and death could result. Tell him to seek immediate medical attention if he has a sudden loss of vision or hearing.
• If patient takes tadalafil to treat erectile dysfunction, advise him to obtain sexual counselling to help enhance the drug’s effects.
• To avoid possible penile damage and permanent loss of erectile function, urge patient to notify prescriber immediately if erection is painful or lasts longer than 4 hours.
• Advise patient to limit alcohol consumption while taking tadalafil.

4.Vardenafil

Mechanism of Action:

Sexual stimulation causes nitric oxide to be released in corpus cavernosum, and nitric oxide activates guanylate cyclase, which in turn increases cyclic guanosine monophosphate (cGMP), thus causing smooth-muscle relaxation; PDE-5 inhibitors enhance smooth muscle-relaxing effects of nitric oxide in corpus cavernosum by inhibiting degradation of cGMP

Indications:

Erectile dysfunction

Dosage adjustment

• Patients older than age 65
• Concurrent use of CYP450-3A4 inhibitors
• Concurrent HIV therapy (except highly active antiretroviral therapy)

Contraindications and Cautions:

• Hypersensitivity to drug
• Concurrent use of nitrates or nitrate patches to treat angina
• Concurrent use of alpha-adrenergic blockers

Use cautiously in:

cardiovascular disease, retinitis pigmentosa, hepatic or renal impairment, reduced hepatic blood flow.

patients at increased risk for priapism (as from sickle-cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).

Metabolism and Half- Life:

Absorption

• Rapidly absorbed. Bioavailability: 15%
• Onset: 60 min;  Peak plasma time: 30-120 min
• Peak plasma concentration: 8-19% lower for ODT than for film-coated tablet

Distribution

Protein bound: 95% ;  Vd: 208 L

Metabolism

• Metabolized in liver by CYP3A4 and (in minor amounts) CYP2C9
• Metabolites: M1 (active; plasma concentration 26% of parent compound)

Elimination

• Half-life: 3-6 hr
• Total body clearance: 56 L/hr
• Excretion: Feces (95%), urine (5%)

Drug Interactions :

• Alpha-adrenergic blockers, nitrates: hypotension
• Erythromycin, itraconazole, ketoconazole, protease inhibitors: increased vardenafil blood level
• Creatine kinase: increased level

Side- Effects:

• CNS: headache
• CV: hypotension
• EENT: blurred vision, altered color perception, light sensitivity, rhinitis
• GI: dyspepsia
• Skin: flushing
• Other: flulike symptoms

Nursing Considerations

• Monitor blood pressure and heart rate, particularly if patient has cardiovascular disease.
• Vardenafil shouldn’t be used by men taking class IA (procainamide, quinidine) or class III (amiodarone, sotalol) antiarrhythmics or by men who have congenital prolonged QT interval. Drug may potentiate prolonged QT interval.
• Use vardenafil cautiously in men with renal or hepatic dysfunction, in elderly men, and in men with penile abnormalities that may predispose them to priapism.
• Also use cautiously in patients with left ventricular outflow obstruction, such as aortic stenosis, and those with severely impaired autonomic control of blood pressure. These conditions increase sensitivity to vasodilators, such as vardenafil.
• Monitor blood pressure and heart rate before and after giving drug, especially if patient takes an alpha blocker, because of increased risk of symptomatic hypotension.
• Monitor patient’s vision, especially if he’s over age 50; has diabetes, hypertension, coronary artery disease, or hyperlipidemia; or smokes, because vardenafil rarely leads to nonarteritic ischemic optic neuropathy and decreased vision, possibly permanent.
• Monitor patient’s hearing. Sudden decrease or loss, possibly with tinnitus and dizziness, may occur with vardenafil use. Report such changes immediately and expect drug to be discontinued.

Patient/ Family Teaching

• Tell patient he may take with or without food.
• Instruct patient to take one tablet about 1 hour before anticipated sexual activity.
• Tell patient not to take vardenafil if he takes an organic nitrate, continuously or intermittently, or within 4 hours of taking an alpha blocker because profound hypotension and death could result.
• Caution patient not to take vardenafil more than once daily or to exceed 20 mg daily.
• Tell patient to stop taking vardenafil and notify prescriber if he has a sudden loss of vision in one or both eyes, sudden hearing loss, seizures, or trouble remembering.
• Advise patient to seek sexual counselling to enhance drug’s effects.
• To avoid possible penile damage and permanent loss of erectile function, urge patient to notify prescriber at once if erection is painful or lasts longer than 4 hours.

REFERENCES

1. Robert Kizior, Keith Hodgson, Saunders Nursing Drug handbook,1st edition 2024, Elsevier Publications. ISBN-9780443116070
2. McGraw Hill- Drug Handbook, Seventh Edition, 2013, McGraw Hill Education Publications,9780071799430.
3. April Hazard, Cynthia Sanoski, Davi’s Drug Guide for Nurses -Sixteenth Edition 2019, FA Davis Company Publications,9780803669451.
4. Jones and Bartlet, Pharmacology for Nurses, Second Edition, 2020, Jones and Bartlet Learning Publications, ISBN 9781284141986.
5. Nursebro.com, Search – Nursebro

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