Summary

These lecture notes cover the topic of Androgens. They discuss the different types of androgens, their biosynthesis, and their effects on the body. The notes also detail the various methods for treating androgen-related illnesses.

Full Transcript

PHM: 2110- MEDICINAL CHEMISTRY 1 ANDROGENS Lecturer: Katherine Prasad School of Pharmacy College of Medical Sciences University of Guyana ANDROGENS ❑The male sex hormones known as androgens ❑Has C19 s...

PHM: 2110- MEDICINAL CHEMISTRY 1 ANDROGENS Lecturer: Katherine Prasad School of Pharmacy College of Medical Sciences University of Guyana ANDROGENS ❑The male sex hormones known as androgens ❑Has C19 steroids and usually contains a ketone at C3 and a hydroxyl at C17 ❑The primary androgen found in the blood is testosterone, with the active metabolite 5α-dihydrotestosterone. ❑All three classes of endogenous steroids are present in both sexes, but the production and circulating plasma levels of testosterone are substantially higher in males. ANDROGENS-TESTOSTERONE Androgenic activity Anabolic activity ✓ Development of male ✓ Growth of muscle, bone characteristics Secreted by: ✓ Testis ✓ Adrenal cortex ANDROGENS Major disorders affecting the male reproductive system are: ❑ Aging-related androgen insufficiency (hypogonadism and andropause), ❑ Prostate and testicular cancer, ❑ Benign prostatic hyperplasia (BPH), ❑ Erectile dysfunction (ED) Majority of the disorder is caused by a deficiency or excess of testosterone in the body DISCOVERY ❑ 1889- French physiologist Charles Brown-Séquard administered an extract to himself and reported that he felt an increased vigor and capacity for work ❑ 1911- Pézard showed that extracts of testicular tissue increase comb growth in capons. Early attempts to isolate pure male hormones from the testes failed, because only small amounts are present in this tissue. ❑ 1931-Butenandt isolated 15mg of crystalline androsterone from 15,000 L of human male urine. ❑ 1934- Butenandt and Dannenberg isolated second crystalline compound, dehydroepiandrosterone, which has weak androgenic activity. During the following year, testosterone was isolated from bull testes( 6-10 times more active). ❑ Many steroids with androgenic activity have subsequently been synthesized TESTOSTERONE C-19 Androstane nucleus Known as androgens Δ4-3Keto group No side chain at 17th position β-hydroxyl group at 17th position BIOSYNTHESIS BIOSYNTHESIS PHYSIOLOGY The effects of endogenous androgens are contributed by testosterone and its active metabolites, DHT. Dihydrotestosterone Testosterone ❑Circulating testosterone is essential for the differentiation and growth of male accessory reproductive organs (e.g prostate and seminal vesicles) ❑Control of male sexual behavior ❑Maintenance of male secondary characteristics (muscle, bone, larynx, and hair) PHYSIOLOGY ❑GnRH is released due to low circulating testosterone. ❑LH production is increased by the pituitary gland ❑Testosterone production is increased by the Leydig cells. ❑FSH stimulates the Sertoli cells controlling spermatogenesis and development of the testis. PHYSIOLOGY EFFECTS OF TESTOSTERONE-ANDROGENIC ❑Growth of penis and scrotum in boys ❑ Increase the growth of pubic, axillary, and beard hair ❑ The larynx grows and the vocal cord become thicker, leading to a lower pitched voice ❑Stimulating and maintaining sexual function in men ❑Sebum secretion ❑Reduction of hormone binding and increase liver synthesis of clotting factors, triglycerides and lipase. ❑Growth of prostate and stimulate erythropoietin production EFFECTS OF TESTOSTERONE-ANABOLIC Increase in: ✓Muscle mass ✓Skeletal growth ✓Protein synthesis Causes retention of nitrogen by increasing the rate of protein synthesis and muscle mass and decreases protein catabolism PHARMACOKINETICS ❑Testosterone when administered orally, is rapidly converted to inactive metabolites and only about one sixth of the dose administered is available in active form. ❑Testosterone can be administered through parenteral route, but it has a prolonged absorption time and a greater activity in the propionate ester form. ❑The major metabolic products of testosterone are androsterone and etiocholanolone which are excreted in urine, as conjugates with glucuronic acid and sulphate. METABOLISM ❑ Testosterone can be metabolized in either its target tissues or the liver. ❑ In androgen target tissues, testosterone can be converted to physiologically active metabolites: ❑ Prostate gland, skin, liver testosterone is reduced to DHT by 5α-reductase ❑ Adipose tissues testosterone is converted to estradiol by aromatase through cleavage of the C-19 methyl group and aromatization of ring A. ❑ Liver testosterone is inactivated through reduction and oxidation, followed by glucuronidation (Glucuronide conjugates and sulfate conjugates) and renal excretion. MECHANISM OF ACTION Testosterone, DHT, and other androgens execute their actions predominantly through the AR. These receptors are mainly found in:. Prostate Skeletal Liver muscle CNS Adrenal Bone gland MECHANISM OF ACTION ❑Testosterone is responsible for initiation of AR action in muscle, bone, brain, and bone marrow. ❑DHT plays a major role in genitalia, prostate, skin, and hair follicles due to their higher expression of 5α-reductase enzymes. ❑AR is a soluble protein that functions as an intracellular transcriptional factor. ❑It is regulated by the binding of androgens, which initiates sequential conformational changes of the receptor that affect receptor–protein interaction and receptor–DNA interactions. DRUGS USED IN AGE-RELATED ANDROGEN INSUFFICIENCIES ❑Male Hypogonadism- inability of the testes to produce sufficient testosterone to maintain sexual function, muscle strength, bone mineral density and fertility. ❑Testosterone and structurally related steroidal androgens are used to treat male hypogonadism DRUGS USED IN AGE-RELATED ANDROGEN INSUFFICIENCIES Andropause ❑ Sex hormone fluctuations later in life ❑ Andropause affects men between the ages of 40 and 55 years. Men’s “transition” may be much more gradual and expand over many decades, and men will very likely experience andropausal symptoms including ED, loss of muscle mass, irritability, generalized fatigue, and even problems with memory and cognition. HORMONE REPLACEMENT THERAPY Benefits Risks Improves sexual performance and desire Stimulated growth of preexisting cancer Increased energy and QOL Increase chance of BPH Increase bone mineral density Issues with voiding Increase bone mass strength Increase potential for liver toxicity via oral route Decrease irritability and depression Gynecomastia Thickened body hair and skin Testicular shrinkage Pain, soreness and burning from injection HORMONE REPLACEMENT THERAPY Formulations of testosterone: ❑Injectable formulations of testosterone esters ❑Transdermal delivery formulations (scrotal or non-scrotal patches or gels), ❑Buccal or oral testosterone. INJECTIONS ❑IM injections bypass the first-pass metabolism. ❑IM injections are depot formulations of testosterone esters- ❑Esters are hydrolyzed to release free testosterone over a period of time ❑Administered IM once every 2-4 weeks ESTERS OF TESTOSTERONE 17β-propionate 17β -enanthate 17 β -cyclopentylpropionate Esterification of the Increase duration of 17β-hydroxyl group action with heptanoic acid, IMPLANTS ❑Subcutaneous implantation of testosterone pellets (Testopel) ❑Pellets contains 75mg of testosterone ❑Administered subcutaneously on the anterior abdominal wall or buttocks to deliver testosterone over a 3- to 4-month period. TRANSDERMAL ❑Most common route- bypass first pass metabolism ❑Skin irritation is more common ❑Pretreatment with corticosteroid creams can reduce the severity and incidence of skin irritation without affecting testosterone absorption from the formulation. GELS ❑Testosterone gel (AndroGel, Testim) is a 1% testosterone hydroalcoholic gel that provides continuous transdermal delivery of testosterone for 24 hours once the gel is rubbed into the skin on the lower abdomen, upper arm, or shoulder. ❑ It should not be applied to scrotal tissue. ❑Side effect- possibility of transferring the medication to a partner; skin-to-skin contact should be avoided either until the gel is completely dry or by covering the area after an application. ORAL PREPARATIONS To increase bioavailability and duration of action- block the metabolism of 17β-hydroxyl group with substituents in the 17α-position Side effect- liver toxicity due to the 17α-alkyl group. Fluoxymesterone 17α-methyltestosterone Thus, these oral androgens are generally considered to be obsolete STRUCTURE-ACTIVITY RELATIONSHIPS A substance must contain a steroid skeleton to have androgenic activity. Oxygen functional groups normally occurring at positions 3 and 17 of the steroid ring system are not essential for activity. STRUCTURE-ACTIVITY RELATIONSHIPS ❑Introduction of a 3-ketone function or a 3a-OH group enhances androgenic activity. ❑ Longer-acting esters of the 17β-OH compounds are hydrolyzed in vivo to the free alcohol (active form) STRUCTURE-ACTIVITY RELATIONSHIPS ❑The 17β-oxygen atom is important for attachment to the receptor site, while 17α-alkyl groups are important for preventing metabolic changes. ❑Such 17a-substituents render the compounds orally active. STRUCTURE-ACTIVITY RELATIONSHIPS Increasing the length of the alkyl side chain at the 17α-position, however, resulted in decreased activity. Addition of an ethynyl group produces compounds with progestin activity e.g. ethisterone. Attaching an isoxazole ring to ethisterone produces danazol Has antigonadotropic properties, weak androgen and anabolic properties; use for endometriosis STRUCTURE-ACTIVITY RELATIONSHIPS ❑ Halogen substitution produces compounds with decreased activity except when inserted into positions 4 or 9 (e.g., Fluoxymesterone). ❑ Introduction of double bond at C-1 position increases the anabolic activity e.g. – methandrostenolone is more active than methyltestosterone. ❑ Replacement of carbon atom at C-2 position by oxygen (e.g. oxandrolone) gives the oral anabolic activity APPLICATIONS ❑ Androgen replacement therapy in Men: Androgens are used to replace or augment endogenous androgen secretion in hypogonadal men ❑ Protein anabolic agents: Androgens and anabolic steroids have been used in conjunction with dietary measures and exercises in an attempt to reverse protein loss after trauma, surgery. ❑ Anemia: refractory anemias such as aplastic anemia, sickle cell anemia, and hemolytic anemias. Recombinant erythropoietin has largely replaced androgens for this purpose. ❑ Growth stimulator: stimulate growth in boys with delayed puberty. ❑ Osteoporosis: treatment of osteoporosis, either alone or in conjunction with estrogens. ADVERSE EFFECTS ❑ Females: masculinization, acne, growth of facial hair, deepening of the voice, male pattern baldness, excessive muscle development and menstrual irregularities ❑ Males: priapism, impotence, decreased spermatogenesis, and gynecomastia ❑ Children: abnormal sexual maturation and growth disturbances resulting from premature closing of the epiphyseal plates. ❑ General effects: increase serum LDL and lower serum high-density lipoprotein levels, fluid retention. ❑ The adverse effects from oral testosterone include stomach upset, headache, acne, increased hair growth on the face or body, jaundice (liver toxicity), anxiety, change in sex drive, sleeplessness ANABOLIC AGENTS Anabolic steroids are similar to those of androgens. Dehydrogenation 17α-methyltestosterone 1,4-diene analog, methandrostenolone,(more potent) These effects are thought to result from estrogenic metabolites. ANABOLIC AGENTS SAR Androgens, having no methyl group in position 10 of the steroid nucleus, are referred to as the 19-norandrogens. More anabolic activity Less androgenic activity Orally inactive Nandrolone Removing the methyl group at C10 decreases androgenic activity SAR Nandrolone can be orally active via the incorporation of methyl group at C-17 position Used as esters and given IM SAR Replacement of C2 with oxygen increases anabolic activity Oxandrolone- 2-oxasteroid analog of 17a-methyltestosterone, containing a lactone in the A ring. It has three times the anabolic activity of 17a-methyltestosterone but exhibits slight androgenic activity Oxandrolone SAR 17α alkyl substitution offers greater anabolic activity and oral bioavailability ❑ Oxymetholone (Anadrol) was used to stimulate production of erythropoietin in the treatment of anemias resulting from bone marrow failure. Now rarely used ❑ Testolactone (Teslac), an-oxasteroid, six- membered lactone ring. It was used in the treatment of breast cancer as a noncompetitive irreversible inhibitor of aromatase to suppress the formation of estrogens that would stimulate the growth of breast tissue. Testolactone was discontinued in 2008 Testolactone BENIGN PROSTATIC HYPERPLASIA ❑ BPH is the noncancerous proliferation of the prostate gland. The major problem associated with BPH is lower urinary tract symptoms. ❑ This is due to increase conversion of testosterone to DHT by 5α reductase. ❑ The symptoms of BPH stem from obstruction of the urethra by an enlarged prostate and the gradual loss of bladder function, which results in incomplete emptying of the bladder. BENIGN PROSTATIC HYPERPLASIA poor urine stream, dribbling, large urine volume Obstructive hesitancy, increase frequency, nocturia Irritative TREATMENT ❑The α1 adrenergic antagonists treat the increased adrenergic tone of the sympathetic nervous system by relaxing the muscles at the neck of the bladder and in the prostate, thereby reducing the pressure on the urethra and increasing the flow of urine. ❑They do not cure BPH. TREATMENT ❑Drug in this class are: Alfuzosin, tamsulosin, and silodosin which are used as first-line α1 adrenergic antagonists for the treatment of BPH, while doxazosin and terazosin have also been used to treat high blood pressure. ❑Adverse effects: related to abnormal ejaculation and orthostatic hypotension, with vasodilation, dizziness, headache, and tachycardia also occurring in some patients during the first 2 weeks of treatment. TREATMENT ❑The 5α-reductase inhibitors work by suppressing the production of DHT, thereby reducing the size of the prostate. ❑The critical enzyme targeted for DHT inhibition is 5α-reductase, which converts testosterone to DHT. ❑Treatment of BPH: finasteride, a selective inhibitor, and dutasteride, a nonselective inhibitor of type 1 and 2 5α-reductase ❑Take 6-12 months to see effect ❑SE: impotence, sexual dysfunction, decrease libido PROSTATE CANCER ❑ The incidence of prostate cancer increases with age. ❑ Traditional treatments for localized prostate cancer include watchful waiting, surgery and external- beam radiation, whereas surgical and pharmacologic approaches to induce androgen deprivation are used for advanced prostate cancer. ❑ Marked reductions in serum testosterone caused metastatic prostate cancer to regress ❑ Gonadotropin-releasing hormone agonists, antagonists, antiandrogens, and chemotherapy for advanced cases. ❑ The goal of LHRH therapy for advanced prostate cancer is to suppress the production of testosterone in the testis by shutting down the production of LH by the pituitary. ❑ The LHRH agonists such as leuprolide acetate and goserelin acetate ❑ Degarelix (Firmagon) is the only LHRH antagonist approved for use in the treatment of advanced prostate cancer. ANTIANDROGENS ❑ Treatment for advanced prostate cancer also involves the use of hormone-blocking drugs called antiandrogens. ❑ The goal of antiandrogen therapy is to block the actions of testosterone and DHT on ARs. ❑ Nonsteroidal antiandrogens such as flutamide, nilutamide, and bicalutamide, are referred to as pure antiandrogens, because they bind exclusively to AR. ANTIANDROGENS Flutamide ❑ Competitive inhibitor of androgen receptor ❑ Rapidly metabolize in human ❑ Side effect: gynecomastia and occasionally cause reversible hepatotoxicity ❑ Uses: Cancer of prostate along with GNRH Female hirsutism ANDROGEN RECEPTOR INHIBITOR Bicalutamide, nilutamide and enzalutamide are potent orally active antiandrogens that can be administered as a single daily dose. Use in treatment of metastatic carcinoma of prostate ERECTILE DYSFUNCTION ❑ ED is the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Phosphodiesterase Inhibitors ❑ Sildenafil, tadalafil, and vardenafil, have emerged as the first-line treatment for ED ❑ The introduction of the first PDE5 inhibitor, sildenafil citrate (Viagra), revolutionized the treatment of men with ED ❑ During sexual stimulation, parasympathetic neurons and vascular endothelial cells release NO, which activates soluble guanylate cyclase, thereby increasing the level of cGMP in the corpus cavernosum and relaxation (vasodilation) of vascular smooth muscle. SIMILARITY Heterocyclic ring Adverse Effects Nausea, indigestion, cutaneous flushing, headache, and retinal effects, including a bluish haze and increased light sensitivity. Name a specific class of medication that cannot be used together with Phosphodiesterase Inhibitors Other alternative drugs currently available for the treatment of ED include ❑ Prostaglandin E1 which is given by injection at the base of the penis or by suppository into the tip of the penis ❑ α1 adrenergic blocker ❑ Nonselective PDE inhibitor papaverine. KETOCONAZOLE Used primarily in the treatment of fungal disease, but also an inhibitor of adrenal and gonadal hormone. Displaces estradiol and dihydrotestosterone from sex hormone binding protein and increase the estradiol: testosterone ratio in plasma. USES: Used experimentally to treat prostatic carcinoma. Side effect: Reversible gynecomastia SPIRONOLACTONE Competitive inhibitor of aldosterone Competes with DHT for the androgen receptor in target tissues. Reduces 17alpha -hydroxylase activity. Side effects: Hirsutism gynecomastia END OF LECTURE

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