Anabolic Steroids And Androgens

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Steroidal hormones secreted from the testes

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Androgens

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The major androgen

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Testesterone

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Part of testes that secretes testesterone

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Leydig cells(interstitial cells)

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Precursors of Testesterone

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Androstenedione and Dehydroepiandrosterone

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What stimulates the release of Testesterone in males

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Adrenal cortex

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What stimulates the release of Testesterone in females

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LH stimulates the corpus luteum to secrete testosterone

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Metabolites of Testesterone

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Active steriods- Estradiol and Dihydrotestosterone (DHT)

Inactive compounds- Androsterone and etiocholanolone

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Metabolism of Testesterone

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5-alpha reductase enzymes converts testosterone to DHT. DHT is MORE ACTIVE THAN TESTOSTERONE. DHT is metabolized to Androsterone, Androstenedione, and Androstenediol.

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MOA of androgens

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Testesterone and DHT act by binding to androgen receptors called NR3A receptors. This is a nuclear receptor.

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Aromatase converts Testesterone to

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Estradiol

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Pharmacokinetics of Testesterone

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Testosterone is inactive orally due to high firstpass metabolism in liver.The duration of action after i.m.injection is also very short.The major metabolic products of testosteroneare androsterone and etiocholanolone.

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Examples of Testesterone ester

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Testesterone enanthate, Testesterone cypionate and Testesterone undecanoate

CUE

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What are Testesterone esters

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17 alpha hydroxyl esters of Testesterone. They are lipophilic drugs.

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Use of Testesterone esters

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Given to hypogonadal man( produce little or no Testesterone)

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Examples of Transdermal delivery system of Testesterone

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Testoderm

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Method of delivery of Transdermal delivery system

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Given through the skin as a patch attached to the scrotal sac

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Examples of 17 alpha alkylated androgens

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Danazol, methyltestosterone, stanazolol and oxandrolone( Dan Met Stan the Ox)

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Clinical uses of androgens

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1) Testesterone is used in male hypogonadism

2) they are used to enhance athletic performance

3)they are used to treat short stature by improving bone formation

4) they are used to treat anaemia by causing erythropoiesis

5) Used to treat endometriosis

6) uses to treat osteoporosis (alone or combined with estrogens)

7) used to treat angio-necrotic edema

8) used to treat muscle wasting diseases( AIDs, tuberculosis and terminal cancer)

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What is hypogonadism

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Testosterone insufficiency

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Androgens used to enhance athletic performance

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Androstenedione and tetrahydrogestrinone

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Androgen used to treat endometriosis

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Danazol

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Androgen used to treat angio-necrotic edema

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Danazol

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Adverse effects of Androgens

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1) In females, they can cause muscularization, facial hair growth, shrinkage of breasts, deepening of voice, uterine atrophy and baldness.

2) It causes hirsutism (abnormal hair growth in females)

3) it can lead to azoospermia (complete absence of sperm production) after prolonged use

4) they can cause oedema(because they are steriods)

5) They can cause liver cirrhosis

6) They can cause acne

7)Some are hepatotoxic

8) they can cause testicular atrophy from prolonged use

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Adverse effects of Androgens

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1) In females, they can cause muscularization, facial hair growth, shrinkage of breasts, deepening of voice, uterine atrophy and baldness.

2) It causes hirsutism (abnormal hair growth in females)

3) it can lead to azoospermia (complete absence of sperm production) after prolonged use

4) they can cause oedema(because they are steriods)

5) They can cause liver cirrhosis

6) They can cause acne

7)Some are hepatotoxic

8) they can cause testicular atrophy from prolonged use

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Major divisions of anti-androgens

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1) inhibitors of Testesterone biosynthesis

2) inhibitors of androgen action

3) 5 alpha reductase inhibitors

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Inhibitors of Testesterone biosynthesis

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1) Gonadotropin releasing hormone analogue (GRHA)

2) Gonadotropin releasing hormone receptor antagonist (GRHRA)

3) Estradiol and some other Estrogens

4) Imidazole anti-fungal drugs

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MOA of GRHA

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They inhibit Testesterone biosynthesis by inhibiting the secretion of LH and FSH resulting in the suppression of Testesterone and spermatogenesis.

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Uses of GRHA

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They are used to treat prostrate cancer. Remember that Testesterone increases cell proliferation in the prostrate (for spermatogenesis) which can worsen cancer.

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Examples of GRHA

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Goserelin

Leuprolide

Tetrahydogestrinone

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Examples of GRHRA

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Abarelix and Setrorelix

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MOA of GRHRA

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They block the action of gonadotropin releasing hormone at the receptors.

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Action of estrogens as inhibitors of Testesterone biosynthesis

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Estradiol, Diestystitesterone(DES), etc inhibit synthesis of Testesterone and are used to treat prostate cancers.

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Example of imidazole anti-fungal drugs

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Ketoconazole

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MOA of ketoconazole

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It blocks the biosynthesis of all steriods in the body(both in the animal cells and fungal cells). It's action is non-selective. It will block the synthesis of Estrogen, Testesterone and other steriods in the body. It can cause gynocomaestia

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Inhibitors of Androgen action

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Androgen receptor antagonists

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Examples of Androgen receptor antagonists

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Flutamide, bicalutamide, spirinolactone, cyproterone acetate

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Potent Androgen receptor antagonists

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Flutamide and bicalutamide

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Why is bicalutamide preferred to flutamide

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It is less hepatotoxic

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Androgen receptor antagonists that can be used to manage hirsutism

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Spirinolactone and cyproterone acetate

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MOA of spirinolactone

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It is a weak antagonist at Androgen receptors. It can also inhibit the biosynthesis of Testesterone.

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It is a progestin as well as a weak Androgen receptor antagonist

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Cyproterone

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Examples of 5 alpha reductase inhibitors

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Finasteride and Dutasteride

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Antagonist of type 2 5-alpha reductase

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Finasteride

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Antagonist of an antagonist of both Type1 and type2 5 alpha reductase enzymes

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Dutasteride

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Uses of the 5 alpha reductase inhibitors

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They are used to treat prostate Cancer. Finasteride is used to treat male baldness.

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Actions of testesterone

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1.Sex organs and secondary sex characters (Androgenic)

Testosterone isresponsible for all the changes that occur in aboy at puberty:Growth of genitals,Growth of hair, Thickening of skin which becomes greasy due to proliferation and increased activity of seba-ceous glands—especially on the face.The ductoften gets blocked and infection occurs resulting in acne. Subcutaneous fat is lost and veins lookprominent.Larynx grows and voice deepens.Behavioral effects are—increased physical vigour,aggressiveness, penile erections.Male libido appears to be activated by testosterone directly

2.Testes

Moderately large doses cause testicular atrophy by inhibiting Gn secretion from pituitary.Still larger doses have a direct sustaining effect and atrophy is less marked.Testosterone is needed for normal spermatogenesis and maturation of spermatozoa.

3.Skeleton and skeletal muscles(Anabolic)

Testosterone is responsible for the pubertal spurt of growth in boys and to a smaller extent in girls.There is rapid bone growth, both in thickness as well as in length.After puberty,the epiphyses fuse and linear growth comes to a halt.Estradiol produced from testosterone, and not testosterone itself, is responsible for fusionof epiphyses in boys as well as in girls.

4.Erythropoiesis Testosterone accelerateserythropoiesis by increasing erythropoietin pro-duction and probably direct action on haemesynthesis.Men have higher hematocrit than women.

5) they stimulate protein anabolism

6) they maintain sexual behaviour, libido and reproduction function

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Drugs that can be used to correct erectile dysfunction

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Phosphodiesterase type 5 inhibitors

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Examples of phosphodiesterase type5 inhibitors

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Sildenafil and tadalafil

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Which phosphodiesterase type5 inhibitors is longer acting

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Tadalafil

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Which phosphodiesterase type5 inhibitors is contraindicated in patients with hereditary retinal disorders

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Sildenafil

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MOA of phosphodiesterase type5 inhibitors

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Erectile dysfunction (ED) refers to the inability of men to attain and maintain an erect penis with sufficient rigidity to allow sexual intercourse. Sexual arousal increases blood flow to the penis and relaxes the cavernosal sinusoids so that they fill up with blood, making the penis rigid,elongated and erect. Nitric oxide (NO) releasedfrom parasympathetic nonadrenergic noncholi-nergic (NANC) nerves and vascular endotheliumis the major transmitter causing relaxation of smooth muscle in corpus cavernosum and the blood vessels supplying it. The phosphodiesterase type5 inhibitors cause the release of NO that diffuses into the smooth muscle cells where it activates guanilate cyclase. This results in increase in cyclospamic CGMP that mediates vasodilation via activation of protein kinase G.

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Side effects of the phosphodiesterase type5 inhibitors

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1) hypotension

2) flushing

3) headache

4) visual disturbances

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Pharmacokinetics of phosphodiesterase type5 inhibitors

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Absorption of sildenafil is delayed by food. Peak plasma concentrations is attained 30-120minutes after an oral administration. It is metabolized by cytochrome 3A4 isozymes which is induced by barbiturate, rivafecin, carbemezepin and inhibited by cimetidine, anti viral drugs(ritonavir) and microlide antibiotics such as grape fruit juice.