Drugs Modulating Androgen Activity & Drugs Acting on the Bladder PDF

Drugs Acting on Androgen Receptors  Testosterone Undergoes extensive first-pass metabolism Available as i.m. injection, transdermal patches Replacement therapy in male hypogonadism  Anabolic effects Skeletal muscle hypertrophy (protein synthesis) Increased muscl...

Drugs Acting on Androgen Receptors  Testosterone Undergoes extensive first-pass metabolism Available as i.m. injection, transdermal patches Replacement therapy in male hypogonadism  Anabolic effects Skeletal muscle hypertrophy (protein synthesis) Increased muscle size & strength Disproportionately large upper-body mass  Anabolic effects Increased collagen synthesis in connective tissue ↑ bone density (suppression of osteoclast activity) ↑ erythropoietin production Structural modification of testosterone to increase anabolic activity  Anabolic:androgenic ratio Testosterone (1) Nandrolone (10) Stanozolol (30)  Anabolic steroids & doping in sports Used as a performance enhancing agent by athletes Significant adverse effects Banned by World Anti-Doping Agency (WADA)  Anabolic steroids: adverse effects Supraphysiologic doses can have effects on other steroid receptors Testicular atrophy, gynaecomastia in males Virilisation in females (hirsutism, amenorrhoea, hoarse voice, clitoral hypertrophy) Acne, male pattern baldness, striae Peliosis hepatis (hemorrhagic liver cysts)  Androgen antagonists Steroidal Non-steroidal 1. Supraphysiologic Doses and Steroid Receptor Effects: When anabolic steroids are taken at doses far exceeding natural levels, they not only bind to androgen receptors but may also interact with other types of steroid receptors, such as glucocorticoid or mineralocorticoid receptors, leading to unintended side effects. For example, the interaction with glucocorticoid receptors may influence metabolism and immune function, while interaction with mineralocorticoid receptors may cause fluid retention and hypertension. 2. Testicular Atrophy and Gynecomastia in Males: Testicular Atrophy: High levels of exogenous anabolic steroids suppress the hypothalamic-pituitary-gonadal (HPG) axis, reducing the natural production of testosterone. As a result, the testes shrink due to decreased stimulation (reduced luteinizing hormone). Gynecomastia: Supraphysiologic levels of anabolic steroids can lead to excess conversion of testosterone to estradiol (via the enzyme aromatase). Elevated estrogen levels in men cause the development of breast tissue (gynecomastia). 3. Virilization in Females: Women who use anabolic steroids may experience virilization, the development of male characteristics: Hirsutism: Excessive facial and body hair growth, particularly in areas typical of male hair distribution (beard, chest). Amenorrhea: Disruption of the menstrual cycle, leading to the absence of periods. Hoarse Voice: Thickening of the vocal cords, leading to a deeper voice, which may be irreversible. Clitoral Hypertrophy: Enlargement of the clitoris, a male-like feature resulting from androgen exposure. 4. Acne, Male Pattern Baldness, Striae: Acne: Anabolic steroids increase the production of sebum (skin oil), leading to clogged pores and acne. This is particularly common on the back, shoulders, and chest. Male Pattern Baldness (Androgenic Alopecia): Supraphysiologic doses of steroids can accelerate hair loss in individuals predisposed to male pattern baldness, due to the action of dihydrotestosterone (DHT) on hair follicles. Striae (Stretch Marks): Rapid increases in muscle size and skin stretching can lead to stretch marks (striae), particularly in areas like the chest, shoulders, and arms. 5. Peliosis Hepatis (Hemorrhagic Liver Cysts):  Steroidal androgen antagonists Cyproterone acetate (progesterone agonist) Drospirenone (progesterone agonist & mineralocorticoid antagonist) Spironolactone (mineralocorticoid antagonist) Used in androgen-dependent conditions (acne, hirsutism, androgenetic alopecia)  Non-steroidal androgen antagonists 1. Cyproterone Acetate (Progesterone Agonist) Cyproterone acetate is a synthetic steroid with anti-androgenic and progestogenic (progesterone- like) effects. It blocks androgen receptors, preventing androgens like testosterone and dihydrotestosterone (DHT) from binding to their receptors in tissues like skin and hair follicles. Flutamide Additionally, it has a progestogenic effect that suppresses the release of luteinizing hormone (LH) from the pituitary gland, leading to a decrease in testosterone production. Uses: It is commonly used in the treatment of severe acne, hirsutism (excess hair growth), and androgenetic alopecia in women. It can also be used to reduce sexual drive in men and in hormone therapy for transgender women. Bicalutamide 2. Drospirenone (Progesterone Agonist & Mineralocorticoid Antagonist) Drospirenone is a synthetic progestin that also acts as a mineralocorticoid receptor antagonist (similar to spironolactone), meaning it has anti-androgenic effects and reduces the action of aldosterone, a hormone involved in salt and water retention. Nilutamide Like cyproterone acetate, it works as a progesterone agonist, providing anti-androgenic effects by inhibiting testosterone’s actions. It also helps reduce fluid retention, which is beneficial for certain hormonal therapies. Uses: Drospirenone is a component of some oral contraceptives, such as those used to treat acne and hirsutism in women. Its anti-androgenic properties make it useful in conditions associated with androgen excess. Enzalutamide 3. Spironolactone (Mineralocorticoid Antagonist) Spironolactone is primarily a potassium-sparing diuretic that works as a mineralocorticoid antagonist (blocking aldosterone), but it also has anti-androgenic effects because it can block androgen receptors. It inhibits androgen synthesis and blocks androgen receptors in tissues like hair follicles and sebaceous glands, reducing the effects of excess androgens. Uses: It is frequently used to treat acne, hirsutism, and androgenetic alopecia in women by reducing androgen action in the skin and hair follicles. It is also used in conditions like polycystic ovary syndrome (PCOS), which is often characterized by elevated androgens. Used in prostate cancer Drugs acting on the urinary system  Muscarinic receptor antagonists Treatment of overactive bladder Selective (M3) – darifenacin , solifenacin Non-selective (M2 – also present in salivary glands, cardiovascular system, brain, GIT) – trospium, oxybutynin, tolterodine, festosterodine  Phosphodiesterase-5 inhibitors Smooth muscle relaxation, antiproliferative effects in prostatic & bladder smooth muscle Tadalafil  Drugs for benign prostatic hyperplasia (BPH) Bladder outlet obstruction → LUTS Obstruction has static & dynamic components Drugs – α1 adrenoceptor antagonits – 5α-reductase inhibitors  α1adrenoceptor antagonits Non-selective – Prazosin – Terazosin – Doxazosin Selective (α1A) – Tamsulosin – Silodosin  α1adrenoceptor antagonits First-dose hypotension (esp. prazosin) 1. Intraoperative floppy iris syndrome Role of Dihydrotestosterone (DHT): DHT is a potent androgen (male sex hormone) derived from testosterone. It plays a significant role in the development of male characteristics. However, DHT also has a strong affinity for androgen receptors in hair follicles, particularly those located on the scalp. In genetically predisposed individuals, DHT binds to androgen receptors in hair follicles, causing the follicles to shrink (a process known as miniaturization), which leads to a shorter hair growth phase and, ultimately, hair thinning and loss. 2. Function of 5-Alpha Reductase Enzyme: 5-alpha reductase is an enzyme found in various tissues, including the scalp, skin, and prostate. It converts testosterone into DHT by removing a hydrogen molecule from testosterone. There are two main types of 5-alpha reductase enzymes: Type 1 and Type 2. Type 2 is predominantly found in hair follicles and the prostate and is primarily responsible for DHT production in the scalp. 3. Inhibition of 5-Alpha Reductase: 5-alpha reductase inhibitors, such as finasteride and dutasteride, work by blocking the activity of the 5-alpha reductase enzyme. Finasteride primarily inhibits the Type 2 enzyme, while dutasteride inhibits both Type 1 and Type 2 enzymes. By inhibiting this enzyme, these medications reduce the conversion of testosterone to DHT. Lower levels of DHT in the scalp result in a decreased binding of DHT to androgen receptors in hair follicles. 4. Prevention of Hair Follicle Miniaturization: With reduced DHT levels, the hair follicles are less affected by the hormone’s miniaturizing effects. This helps in maintaining normal hair growth cycles, preventing the thinning of hair follicles, and promoting hair regrowth. Over time, this process can slow down hair loss, reduce hair thinning, and, in some cases, even reverse some degree of hair loss by allowing miniaturized hair follicles to recover.  Intraoperative floppy iris syndrome Intraoperative miosis, flaccid iris, prolapse of the iris during cataract surgery in patients taking α1 adrenoceptor antagonits (esp. tamsulosin) Discontinuation of medication does not decrease the incidence of the syndrome Those planning to undergo cataract surgery should not initiate treatment until after the surgery  5α-reductase inhibitors 5α-reductase present in prostate, hair follicles  5α-reductase inhibitors Finasteride (inhibits type-I) Dutasteride (inhibits type-I & type-II) Reduce the size of the prostate Treatment for several months needed Adverse effects 1. Role of Dihydrotestosterone (DHT) in BPH: DHT is an androgen (a male hormone) derived from testosterone by the action of the enzyme 5-alpha-reductase. DHT plays a significant role in the growth and development of the prostate gland. In BPH, elevated levels of DHT cause excessive growth of the prostate – Reduced libido tissue, particularly in the transition zone, which surrounds the urethra. This enlargement compresses the urethra, leading to obstructive urinary symptoms like weak urine flow, difficulty starting and stopping urination, and incomplete bladder emptying. 2. Inhibition of 5-Alpha Reductase: – Breast tenderness 5-alpha-reductase inhibitors, such as finasteride and dutasteride, work by blocking the conversion of testosterone into DHT. By reducing DHT levels, these drugs shrink the prostate gland, alleviate pressure on the urethra, and improve urinary symptoms. The reduction in prostate size can take several months to become evident, but the long-term effects lead to a significant decrease in urinary obstruction and the need for surgery.