Tadalafil

Introduction Overview

Generic Name

tadalafil

Brand Name

Cialis, Adcirca

Dosage Form

Oral tablets

Drug Class

Agents for pulmonary hypertension, Impotence agents (Phosphodiesterase type 5 inhibitors)

Pharmacokinetics

Absorption:
Tadalafil is rapidly absorbed following oral administration, with peak plasma concentrations typically achieved within 30 minutes to 6 hours, averaging about 2 hours post-dose. The absolute bioavailability is approximately 80%, indicating efficient absorption from the gastrointestinal tract. Food does not have a significant impact on the rate or extent of tadalafil absorption, allowing it to be taken with or without meals. The prolonged half-life of approximately 17.5 hours supports once-daily dosing and accounts for the drug's extended duration of action, which can last up to 36 hours after a single dose.

Distribution:
Tadalafil exhibits a large volume of distribution (approximately 63 L), reflecting extensive tissue penetration. It is highly bound to plasma proteins, primarily albumin, with about 94% bound, which limits its free fraction in plasma. The drug's distribution includes the vascular smooth muscle of the corpus cavernosum, pulmonary vasculature, as well as other peripheral tissues. The distribution characteristics enable tadalafil to exert its pharmacologic effects at target sites responsible for erectile function, Benign Prostatic Hyperplasia (BPH), and pulmonary arterial hypertension (PAH).

Metabolism:
Tadalafil is predominantly metabolized in the liver via the cytochrome P450 enzyme CYP3A4 isoform. The principal metabolic pathway involves demethylation followed by oxidation to form a catechol metabolite, which is subsequently conjugated to glucuronides. This metabolite has no significant pharmacological activity. The metabolism of tadalafil is susceptible to interactions with potent CYP3A4 inhibitors (such as ketoconazole and ritonavir), which can increase plasma tadalafil concentrations and impact safety. Conversely, CYP3A4 inducers (such as rifampin) may decrease its levels, potentially reducing efficacy.

Elimination:
Elimination of tadalafil primarily occurs via fecal (approximately 61%) and renal (approximately 36%) excretion of metabolites. The terminal elimination half-life averages 17.5 hours, facilitating once-daily dosing. Renal impairment may moderately increase tadalafil exposure, while hepatic impairment can significantly increase plasma concentrations, requiring caution or dose adjustment. Its clearance is decreased in patients with hepatic or severe renal impairment, and dosage modifications are recommended. The drug is not efficiently removed by hemodialysis.

Dosage Forms

Available Dosage Forms:
- Oral tablets: 2.5 mg, 5 mg, 10 mg, 20 mg

Dosages for Adults and Adolescents:
- Erectile Dysfunction (ED):
- On-demand dosing: 10 mg orally prior to anticipated sexual activity; may be increased to 20 mg or decreased to 5 mg based on efficacy and tolerability.
- Daily dosing: 2.5 mg once daily at approximately the same time each day, with potential increase to 5 mg daily if necessary.
- Benign Prostatic Hyperplasia (BPH) or ED with BPH:
- 5 mg once daily at the same time each day.
- Pulmonary Arterial Hypertension (PAH):
- 40 mg once daily (two 20 mg tablets) orally, with or without food.

Specific Patient Populations:
- Elderly: No dosage adjustment required solely based on age.
- Hepatic Impairment: Use caution; avoid in severe hepatic impairment (Child-Pugh Class C); moderate impairment may require dose adjustment.
- Renal Impairment: For severe renal impairment (creatinine clearance <30 mL/min), use with caution and consider dose adjustments.
- Pediatric patients: Safety and efficacy not established; tadalafil is not approved for use under 18 years old.

Clinical Guidelines:
- Do not exceed one dose per day for on-demand dosing.
- For PAH treatment, do not use tadalafil for ED concurrently.
- Tablets should be swallowed whole; do not break, split, or chew. Can be administered with or without food.

Mechanism Of Action

Tadalafil is a selective, reversible inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells lining blood vessels. By inhibiting PDE5, tadalafil enhances the effects of nitric oxide (NO) released during sexual stimulation or physiological vasodilation processes, increasing cGMP levels and leading to smooth muscle relaxation.

In erectile tissue, elevated cGMP causes relaxation of the corpus cavernosum's smooth muscle, resulting in increased blood flow and facilitating an erection in response to sexual stimulation. Unlike nonspecific vasodilators, tadalafil’s PDE5 inhibition targets the enzyme predominantly found in the corpus cavernosum, leading to localized vascular effects without systemic hypotension at therapeutic doses.

In the pulmonary vasculature, PDE5 inhibition results in vasodilation of pulmonary arteries, reducing pulmonary vascular resistance and pressure. This action improves exercise capacity and functional status in patients with pulmonary arterial hypertension (PAH) by decreasing right ventricular workload and enhancing cardiac output.

Tadalafil’s longer half-life compared to other PDE5 inhibitors, such as sildenafil, provides prolonged therapeutic plasma concentrations, allowing efficacy up to 36 hours post-dosing. This extended duration results in increased flexibility for sexual activity timing and sustained pulmonary vascular effects in PAH. Clinical studies have demonstrated its efficacy and safety in treating erectile dysfunction, benign prostatic hyperplasia symptoms, and PAH by leveraging this pharmacodynamic profile.

Pharmacological Actions

Selective inhibition of phosphodiesterase type 5 (PDE5) enzyme.
Increase of cyclic guanosine monophosphate (cGMP) levels in smooth muscle cells.
Relaxation of vascular smooth muscle in the corpus cavernosum promoting penile erection.
Vasodilation of pulmonary arterial smooth muscle reducing pulmonary vascular resistance.
Improvement of blood flow to specific areas such as penile tissue and pulmonary circulation.
Prolonged pharmacological effect due to long half-life (~17.5 hours).
No significant effect on phosphodiesterase type 6 (PDE6), minimizing visual side effects compared to sildenafil.
Enhancement of exercise capacity in patients with pulmonary arterial hypertension.

Therapeutic Or Clinical Uses

Treatment of erectile dysfunction (impotence) in adult men.
Management of benign prostatic hyperplasia (BPH) symptoms, including lower urinary tract symptoms.
Treatment of pulmonary arterial hypertension to improve exercise capacity in adults.
Off-label use in improving endothelial function-related conditions due to vasodilatory properties.
Potential use in combination therapy for refractory pulmonary hypertension cases.
Improving quality of life in men with concomitant ED and BPH.
Alternative to other PDE5 inhibitors for patients with inadequate response or tolerability.

Side Or Adverse Effects

Headache, commonly reported and dose-related.
Flushing characterized by warmth, redness, or tingly sensation.
Dyspepsia and nausea including upset stomach.
Nasal congestion or stuffy nose due to vasodilation.
Myalgia and back pain, potentially delayed onset several hours post-dose.
Pain in arms, legs, or back reported occasionally.
Visual disturbances, including blurred vision or color tinge changes, though rare.
Prolonged and sometimes painful erection (priapism); medical emergency if lasting more than 4 hours.
Sudden vision loss (non-arteritic anterior ischemic optic neuropathy), rare but serious.
Sudden hearing loss or ringing in the ears reported infrequently.
Hypotension, particularly when combined with nitrates or other vasodilators.
Dizziness or light-headedness, possibly related to blood pressure changes.
Allergic reactions including rash, hives, and swelling of face, lips, or throat.
Chest pain or cardiac symptoms during sexual activity requiring urgent assessment.
Rare reports of stroke or myocardial infarction temporally related to use.

Precautions

Contraindicated with concurrent nitrate therapy due to risk of severe hypotension.
Use caution in patients with cardiovascular disease, such as angina, heart failure, or arrhythmias.
Evaluate risk-benefit before prescribing to patients with history of stroke or myocardial infarction.
Use cautiously in patients with hypertension or hypotension.
Monitor patients with renal or hepatic impairment due to altered pharmacokinetics.
Avoid concurrent use with riociguat or other drugs affecting nitric oxide pathways.
Inform patients about the signs of priapism and the need for urgent medical care if erection lasts >4 hours.
Advise against alcohol use with tadalafil due to additive hypotensive effects.
Patients with anatomical deformation of the penis or conditions predisposing to priapism require careful assessment.
Not recommended for use in pediatric patients under 18 years of age.
Women should generally avoid tadalafil; safety and efficacy not established in females except PAH use.
Evaluate patients for risk factors of non-arteritic anterior ischemic optic neuropathy before treatment.
Should not be started during pregnancy without medical guidance due to potential maternal-fetal risks.
Warn patients about avoiding grapefruit products that may increase tadalafil plasma concentrations.
Close monitoring for hearing or vision changes during therapy.

Warnings

Do not use tadalafil concomitantly with nitrate medications to avoid life-threatening hypotension.
Sudden loss of vision has been reported; discontinue immediately and seek emergency medical attention.
Prolonged erections lasting longer than 4 hours (priapism) may cause permanent damage.
Risk of sudden hearing loss, and tinnitus has been associated with use; discontinue if symptoms occur.
Patients should seek emergency care if chest pain, dizziness, or nausea occur during sexual activity.
Use with caution in patients with heart disease; sexual activity itself may pose risk.
Avoid coadministration with riociguat, which may cause excessive hypotension.
Not for use in patients with pulmonary veno-occlusive disease unless otherwise indicated.
Potential interaction with CYP3A4 inhibitors or inducers that affect serum tadalafil levels.
Use caution when engaging in activities requiring alertness until individual response is known.
Monitor blood pressure during treatment, especially in patients on antihypertensives.
Post-marketing reports of stroke and myocardial infarction temporally related to tadalafil use exist.
Not recommended during breastfeeding due to lack of safety data.
The extended pharmacodynamic effect can last more than 36 hours, requiring caution in dosing.
Drug should be stored away from moisture and heat to maintain efficacy.

Contraindication

Known hypersensitivity to tadalafil or any component of the formulation.
Concurrent use of nitrate medications including nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate.
Use of recreational nitrate-related drugs (e.g., amyl nitrite 'poppers').
Strong CYP3A4 inhibitors coadministered without dose adjustment (e.g., ketoconazole) in some cases.
Patients with severe hepatic impairment (Child-Pugh Class C).
Patients with severe renal impairment on dialysis.
Use in females for erectile dysfunction; safety and efficacy not established.
Patients with a history of non-arteritic anterior ischemic optic neuropathy connected to PDE5 inhibitor use.
Concurrent use with riociguat for pulmonary hypertension.
Patients in whom sexual activity is inadvisable due to cardiovascular status.
Use in children and adolescents under 18 years of age.
Patients with anatomical deformation of the penis (e.g., Peyronie's disease), which predispose to priapism.

Drug Interactions

Nitrate medications (e.g., nitroglycerin, isosorbide dinitrate): Risk of severe hypotension.
Riociguat: additive hypotensive effects and contraindicated combination.
CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin): May increase tadalafil plasma levels and risk of adverse effects.
CYP3A4 inducers (e.g., rifampin, carbamazepine): May decrease tadalafil effectiveness by reducing plasma levels.
Alpha-blockers (e.g., doxazosin, tamsulosin): Potential additive blood pressure lowering effects causing symptomatic hypotension.
Antihypertensive agents: Possible enhanced hypotensive effect.
Antiretroviral drugs for HIV/AIDS: Potential CYP-mediated interactions altering tadalafil levels.
Antifungal agents (e.g., itraconazole, fluconazole): May increase tadalafil exposure.
Certain antibiotics (e.g., clarithromycin, erythromycin): Can elevate tadalafil serum concentration.
Seizure medications (e.g., phenytoin): Potential interactions via metabolism induction or inhibition.
Alcohol: May exacerbate hypotensive effects and dizziness.
Grapefruit juice: Can increase plasma levels of tadalafil by CYP3A4 inhibition.
Other PDE5 inhibitors (e.g., sildenafil, vardenafil): Avoid concurrent use due to additive effects.
Use caution with other vasodilators or agents that affect blood pressure.
Medications affecting platelet aggregation may theoretically increase bleeding risk.

Preparations Of The Drug

Oral tablet formulations: 2.5 mg, 5 mg, 10 mg, and 20 mg tablets.
Available under brand names Cialis (for erectile dysfunction and BPH) and Adcirca (for pulmonary arterial hypertension).
Tablets supplied for once-daily or as-needed dosing regimens depending on indication.
Packaged in various unit counts to accommodate different treatment plans.
Tablets are film-coated for ease of swallowing and to protect stability.
Preserved in blister packs or bottles to protect from moisture and heat.
Cialis tablets are typically round, biconvex and film-coated, with distinct imprinting.
Adcirca tablets similar in appearance with appropriate branding differentiation.
No injectable or topical formulations officially approved; administration is exclusively oral.
Generic formulations available with bioequivalence to branded products.
Stability requires storage at room temperature away from excess moisture and heat.
Prescribed only under physician supervision with specific dosing instructions provided.
Patient education materials available with packaging to ensure proper usage.
Counseling on adherence and avoidance of contraindicated substances included in preparation guidelines.
Dispensed with warnings about potential interactions and adverse effects.