Pharmacology of Finasteride

1. Introduction/Overview

Finasteride represents a cornerstone therapeutic agent in the management of androgen-dependent conditions, specifically benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). Its development marked a significant advancement in pharmacotherapy by introducing a targeted, mechanism-based approach to modulating androgen activity without directly antagonizing the androgen receptor. The clinical importance of finasteride stems from its ability to provide a medical alternative to surgical intervention for BPH and to offer a treatment for a common dermatological condition with significant psychosocial impact. Understanding its pharmacology is essential for healthcare professionals to optimize therapeutic outcomes and manage potential risks.

Learning Objectives

• Describe the molecular mechanism of action of finasteride as a selective inhibitor of the type II 5α-reductase isoenzyme.
• Outline the pharmacokinetic profile of finasteride, including its absorption, distribution, metabolism, and elimination characteristics.
• Identify the approved clinical indications for finasteride and explain the rationale for its use in each condition.
• Analyze the spectrum of adverse effects associated with finasteride therapy, with particular attention to sexual dysfunction and post-finasteride syndrome.
• Evaluate important drug interactions, contraindications, and special population considerations relevant to the safe prescribing of finasteride.

2. Classification

Finasteride is classified primarily as a 5α-reductase inhibitor. This classification is based on its specific enzymatic target rather than a broader therapeutic category. From a chemical perspective, finasteride is a synthetic 4-azasteroid compound. It is a competitive inhibitor that bears structural similarity to the natural substrate of the enzyme, testosterone, but contains a nitrogen substitution in the A-ring, which confers its inhibitory properties. Therapeutically, it is categorized as an agent for the treatment of symptomatic BPH and as a hair growth stimulant for male pattern hair loss. It is distinct from other antiandrogens, such as receptor antagonists like flutamide or bicalutamide, as it reduces the synthesis of a potent androgen rather than blocking its receptor.

3. Mechanism of Action

The pharmacodynamic action of finasteride is highly specific and centers on the inhibition of the steroid metabolic enzyme 5α-reductase.

Detailed Pharmacodynamics

Finasteride exerts its effects by selectively and competitively inhibiting the type II isoenzyme of 5α-reductase. This enzyme is responsible for the irreversible conversion of testosterone, the primary circulating androgen, into dihydrotestosterone (DHT). DHT is a significantly more potent androgen than testosterone, with an affinity for the androgen receptor approximately 2.5 to 10 times greater. The formation of DHT is a critical step in androgen action within specific tissues, notably the prostate gland, hair follicles, and sebaceous glands.

Molecular and Cellular Mechanisms

At the molecular level, finasteride acts as a mechanism-based inhibitor. It competes with testosterone for binding to the active site of the 5α-reductase enzyme. Upon binding, finasteride is metabolized by the enzyme to form a stable, covalent adduct with the enzyme-cofactor complex (NADPH), leading to irreversible inhibition. This results in a profound and sustained reduction in intracellular and serum DHT levels. In the prostate, DHT is the principal androgen mediating cellular proliferation and hypertrophy. Its reduction leads to involution of the epithelial component of the prostate, a decrease in prostate volume (by approximately 20-30% after 6-12 months of therapy), and a consequent improvement in urinary flow parameters. In the context of androgenetic alopecia, DHT is implicated in the miniaturization of susceptible hair follicles. By reducing scalp DHT concentrations, finasteride can slow, halt, or partially reverse this miniaturization process, leading to increased hair count and thickness.

The selectivity for the type II isoenzyme is a key feature. Type II 5α-reductase is predominantly located in the prostate, seminal vesicles, epididymides, and hair follicles, as well as in liver tissue. The type I isoenzyme, which is not inhibited by finasteride at therapeutic doses, is found primarily in sebaceous glands and the liver. This selectivity explains the drug’s targeted tissue effects and its relatively specific adverse effect profile related to reproductive tissues.

4. Pharmacokinetics

The pharmacokinetic profile of finasteride is characterized by good oral bioavailability, extensive metabolism, and elimination primarily via the hepatobiliary route.

Absorption

Finasteride is well absorbed following oral administration, with an average bioavailability of approximately 63% (range 26-170%), unaffected by food intake. The time to reach peak plasma concentration (t_max) is typically 1-2 hours post-dose. The extent of absorption is not dose-proportional at very high doses, but within the therapeutic range (1-5 mg), linear pharmacokinetics are generally observed.

Distribution

Finasteride is widely distributed throughout the body. Its volume of distribution is estimated to be 76 liters, indicating distribution into tissues beyond the plasma compartment. The drug is approximately 90% bound to plasma proteins, primarily albumin. Finasteride crosses the blood-brain barrier to a limited extent and has been detected in semen. Importantly, it can cross the placenta, which is a critical consideration for its contraindication in pregnancy.

Metabolism

Hepatic metabolism is the principal route of finasteride biotransformation, primarily via the cytochrome P450 3A4 (CYP3A4) isoenzyme system. The major metabolites are the ω-hydroxy and ω-carboxylic acid derivatives of finasteride, which are considered pharmacologically inactive. The parent compound and its metabolites undergo extensive enterohepatic recirculation.

Excretion

Elimination occurs predominantly through the feces (approximately 57% of an oral dose), with urinary excretion accounting for about 39%. The majority of the excreted material in both routes consists of metabolites, with less than 1% of an oral dose excreted unchanged in the urine. The terminal elimination half-life (t_1/2) of finasteride in men is approximately 6-8 hours. However, due to its mechanism of irreversible enzyme inhibition, the pharmacodynamic half-life (the time for DHT levels to return to baseline) is much longer, typically 14-21 days after discontinuation of therapy.

Dosing Considerations

The standard dosing regimens are 5 mg once daily for the treatment of symptomatic BPH and 1 mg once daily for the treatment of male pattern hair loss. The difference in dose is related to the need for a more profound suppression of DHT in the prostate gland compared to the hair follicle. Steady-state plasma concentrations are achieved within 5-7 days of daily dosing. The prolonged pharmacodynamic effect allows for some forgiveness in missed doses, but consistent daily administration is required for optimal clinical efficacy.

5. Therapeutic Uses/Clinical Applications

Finasteride is approved for two distinct clinical indications, each with a specific dosing regimen.

Approved Indications

Benign Prostatic Hyperplasia (BPH): Finasteride 5 mg/day is indicated for the treatment of symptomatic BPH to improve symptoms, reduce the risk of acute urinary retention, and decrease the need for surgical intervention such as transurethral resection of the prostate (TURP). Clinical trials have demonstrated that treatment leads to a mean increase in urinary flow rate, a significant reduction in prostate volume (by 20-30%), and a corresponding decrease in symptom scores as measured by tools like the International Prostate Symptom Score (IPSS). The maximal effect on prostate size is typically observed after 6-12 months of continuous therapy. It is often used in combination with an α₁-adrenergic receptor antagonist (e.g., tamsulosin) for additive symptomatic relief, as the two drugs work via complementary mechanisms.

Androgenetic Alopecia (Male Pattern Hair Loss): Finasteride 1 mg/day is indicated for the treatment of this condition in men only. Efficacy is most pronounced in the vertex and anterior mid-scalp areas. Clinical studies show that after 12 months of treatment, approximately 48% of men demonstrate increased hair growth, 42% have no further hair loss, and 10% may continue to lose hair. Continued treatment is necessary to sustain benefit; cessation of therapy leads to a reversal of effect within 12 months.

Off-Label Uses

Several off-label applications exist, though evidence and support vary:

• Hirsutism in Women: Used at doses of 2.5-5 mg daily, often in combination with oral contraceptives, for the management of idiopathic or polycystic ovary syndrome (PCOS)-related hirsutism. Its use is limited by teratogenicity risk and is absolutely contraindicated in women who are or may become pregnant.
• Female Pattern Hair Loss: Studies have shown mixed results, and it is not FDA-approved for this indication. Use is highly restricted due to the risk of fetal exposure.
• Prostate Cancer Chemoprevention: The Prostate Cancer Prevention Trial (PCPT) demonstrated that finasteride 5 mg/day reduced the incidence of prostate cancer by approximately 25% over 7 years. However, an observed increase in the proportion of high-grade tumors (Gleason score 7-10) among those who did develop cancer has limited its widespread adoption for this purpose.

6. Adverse Effects

The adverse effect profile of finasteride is primarily related to its intended antiandrogenic effects on tissues dependent on DHT.

Common Side Effects

Sexual dysfunction is the most frequently reported class of adverse effects. In clinical trials for BPH, the incidence includes:

• Decreased libido (3.1-5.4%)
• Erectile dysfunction (4.9-8.1%)
• Ejaculation disorder (2.1-3.7%, primarily reduced ejaculate volume)

These effects are often dose-dependent, may diminish with continued treatment in some individuals, and are generally reversible upon discontinuation of the drug, although persistent cases have been reported. Other common effects include breast tenderness and enlargement (gynecomastia).

Serious/Rare Adverse Reactions

Post-Finasteride Syndrome (PFS): A controversial and poorly understood constellation of persistent sexual, neurological, and physical symptoms reported by a subset of patients after discontinuing finasteride. Symptoms may include persistent sexual dysfunction (loss of libido, erectile dysfunction), depression, anxiety, cognitive fog, and muscular atrophy. The pathophysiology remains unclear, and its incidence is not well-defined, leading to ongoing research and debate.

Hypersensitivity Reactions: Rare cases of angioedema, involving swelling of the lips, tongue, throat, and face, have been reported.

Psychological Effects: Some studies suggest a potential association with depression and suicidal ideation, though a definitive causal relationship has not been firmly established.

High-Grade Prostate Cancer: As noted in the PCPT trial, there is an observed association with a higher relative risk of detecting high-grade prostate cancer, though the absolute risk remains low.

Black Box Warnings

Finasteride carries a Boxed Warning regarding the risk of exposure during pregnancy. The drug is contraindicated in women who are or may become pregnant due to the risk of causing abnormalities of the external genitalia in a male fetus. Women of childbearing potential should avoid handling crushed or broken tablets if they are pregnant or may become pregnant, due to potential absorption through the skin.

7. Drug Interactions

Formal pharmacokinetic drug interaction studies with finasteride are limited, but several considerations are important.

Major Drug-Drug Interactions

• Inhibitors of CYP3A4: Concomitant administration with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) may decrease the metabolic clearance of finasteride, potentially increasing its plasma concentration. The clinical significance of this increase is likely minimal given finasteride’s wide therapeutic index, but monitoring for enhanced adverse effects could be considered.
• Inducers of CYP3A4: Agents such as rifampin, carbamazepine, and phenytoin may increase the metabolism of finasteride, potentially reducing its plasma concentration and therapeutic efficacy. Dose adjustment may be necessary.
• Other 5α-Reductase Inhibitors: Concurrent use with dutasteride (which inhibits both type I and II isoenzymes) is not recommended due to overlapping mechanisms and an increased risk of adverse effects without established additive benefit.
• Herbal Supplements: Saw palmetto (Serenoa repens) is sometimes used for BPH and may have weak 5α-reductase inhibitory activity. The clinical impact of combining it with finasteride is unknown but may theoretically increase the risk of side effects.

Contraindications

• Pregnancy (Category X): Absolute contraindication due to risk of teratogenicity (ambiguous genitalia in male fetuses).
• Hypersensitivity: Contraindicated in patients with known hypersensitivity to finasteride or any component of the formulation.
• Pediatric Use: Not indicated for use in children. Safety and efficacy have not been established.
• Women: The 1 mg formulation is contraindicated in women. The 5 mg formulation is contraindicated in women who are or may become pregnant.

8. Special Considerations

Use in Pregnancy and Lactation

As a Category X drug, finasteride is absolutely contraindicated in pregnancy. Animal studies have demonstrated that inhibition of 5α-reductase in utero can cause development of ambiguous genitalia (hypospadias) in male offspring. It is not known whether finasteride is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from a drug that inhibits a critical steroidogenic enzyme, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Finasteride is not indicated for use in women.

Pediatric and Geriatric Considerations

Finasteride is not indicated for use in pediatric patients. Its safety and efficacy in children have not been established. In geriatric patients, no dosage adjustment is generally required based on age alone. However, elderly patients may have a higher incidence of concomitant conditions (e.g., renal or hepatic impairment) or be on multiple medications, necessitating careful review.

Renal Impairment

No dosage adjustment is necessary in patients with renal impairment, including those on dialysis. This is because less than 1% of the drug is excreted unchanged in the urine, and the metabolites eliminated renally are considered inactive. Pharmacokinetic studies have shown no significant impact of renal impairment on finasteride clearance.

Hepatic Impairment

Caution is advised in patients with severe hepatic impairment (Child-Pugh class C). Since finasteride is extensively metabolized in the liver, severe hepatic dysfunction could potentially alter its clearance. However, specific dosage recommendations for hepatic impairment are not provided in the prescribing information, suggesting that the wide therapeutic index may mitigate risk. In patients with mild to moderate hepatic impairment, no adjustment is typically required, but monitoring for adverse effects is prudent.

9. Summary/Key Points

• Finasteride is a selective, irreversible inhibitor of the type II isoenzyme of 5α-reductase, the enzyme that converts testosterone to the more potent androgen dihydrotestosterone (DHT).
• Its primary therapeutic actions are a reduction in prostate volume (with 5 mg dose) for the management of BPH and the inhibition of hair follicle miniaturization (with 1 mg dose) for the treatment of male pattern androgenetic alopecia.
• The pharmacokinetic profile includes good oral bioavailability, metabolism primarily by CYP3A4, and elimination via feces and urine with a terminal plasma half-life of 6-8 hours, though its pharmacodynamic effect on DHT levels persists for weeks.
• The most common adverse effects are sexual in nature, including decreased libido, erectile dysfunction, and reduced ejaculate volume. A Boxed Warning exists for fetal toxicity if used during pregnancy.
• Significant drug interactions may occur with potent inhibitors or inducers of the CYP3A4 enzyme system.
• Finasteride is contraindicated in women who are or may become pregnant and requires careful consideration in special populations, though no dose adjustment is typically needed for renal impairment or mild-moderate hepatic impairment.

Clinical Pearls

• Patients should be counseled that therapeutic effects on BPH symptoms or hair growth may take 6-12 months to become fully apparent and that continuous therapy is required to maintain benefit.
• Clear and emphatic counseling regarding the risk of teratogenicity is mandatory when prescribing to men whose female partners are of childbearing potential, as the drug is present in semen.
• Persistent sexual side effects, sometimes referred to as post-finasteride syndrome, are a subject of ongoing clinical concern and research; patients should be informed of this potential risk.
• In BPH, prostate-specific antigen (PSA) levels are reduced by approximately 50% during finasteride therapy. When monitoring for prostate cancer, PSA values should be doubled for interpretation, or a new baseline should be established after 6 months of treatment.
• Discontinuation of therapy results in a return to pretreatment DHT levels and a gradual reversal of clinical benefits over several months.

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