Walters-Androgens

Front 1

describe the modification of testosterone for therapeutic use

Back 1

a) alkylation of 17-α position; protects molecule against 1st pass metabolism and permits oral use of certain androgens
b) esterification of 17-β position; increases lipid solubility of certain androgens permitting formulation in oil for IM use; also prolongs duration of action; longer carbon chains have greater lipid solubility and duration of action

Front 2

describe uses of 17-alpha substituted androgens

Back 2

1. FLUOXYMESTERONE
USES
MEN-replacement therapy for hypogonadism
WOMEN:
a. inoperable breast cancer in premenopausal women who have had oophorectomy (i.e. can't convert testosterone to estrogen)
b. prevent postpartum breast pain and engorgement
2. METHYLTESTOSTERONE
USES:
MEN-hypogonadism, impotence, cryptorchism
WOMEN-breast cancer, postpartum breast pain and engorgement
3. DANAZOL-by inhibiting release of gonadotropins, used to treat endometriosis and angioedema

Front 3

describe 17-alpha substituted anabolic androgens

Back 3

Anabolism involved in construction of new compounds and tissues; anabolic steroids assimilate nutrients for synthesis of new tissues
1. OXYMETHOLONE-used to stimulate RBC production by bone marrow in treating anemias; stimulates production of EPO by kidneys-->stimulates production of RBCs by marrow
2. OXANDROLONE-causes N retention-->stimulates synthesis of amino acids and proteins-->muscle growth and weight gain
used to promote weight gain after surgery, severe infection or following chronic use of glucocorticoids (to reverse protein wasting and loss of N as urea)

Front 4

describe the side effects of 17-alphs substituted androgens

Back 4

1. ↑ LDLs & decreases HDLs--> ↑ risk of coronary heart disease, particularly w/ anabolics in large doses
2. CHOLESTATIC HEPATITIS-JAUNDICE main clinical feature w/ chronic treatment (yellowish color to skin from accumulation of bile pigments)
3. PELIOSIS HEPATIS, characterized by small, blood-filled cysts throughout liver; generally asymptomatic but cysts can rupture-->liver failure
4. HEPATIC CARCINOMA
5. high doses of anabolic androgens (to increase athletic perfomance) lead to:
a. cardiovascular-MI, myocarditis, cardiomegaly, CVAs, PE)
b. liver-hepatomegaly and fatal hepatitis
c. MSK- tendon rupture and avulsions (tears)
note-ALL androgens classified by DEA as C-III controlled substances

Front 5

describe 17-Beta esterified androgens

Back 5

safer than 17-α-substituted androgens, but given IM; long acting forms used as replacement therapy for hypogonadism, delayed puberty and breast cancer
1. TESTOSTERONE ENANTHATE
2. TESTOSTERONE CYPIONATE

Front 6

describe nandrolone

Back 6

17-β ESTERIFIED ANABOLIC ANDROGEN; parenteral for various anemias to stimulate renal production of EPO

Front 7

describe other formulations of testosterone (not modified at 17C)

Back 7

1. TESTOSTERONE PELLETS-implanted in skin
a) can’t adjust dose (calculate carefully)
b) to discontinue, must remove pellets
c) pellets can slough out
2. TESTOSTERONE TRANSDERMAL SYSTEM-placed on scrotum
a) scrotum more permeable
b) scrotum high in 5-α-reductase activity; enzyme converts testosterone to DHT which is form required by testes
3. TESTOSTERONE GEL-for hypogonadism; apply to shoulders, arms, abdomen inner thigh (NOT APPLIED TO GENITALS)
4. TESTOSTERONE 2% TOPICAL SOLUTION-applied underarm by metered- dose pump

Front 8

describe the side effects of all adrogens

Back 8

A. MEN
1. decreases spermatogenesis (azoospermia)-->impotence from conversion of testosterone to estradiol
2. priapism
3. gynecomastia (including milk ejection)
B. WOMEN (can be permanent)
1. increased facial hair growth
2. deepening of voice
3. menstrual irregularities from decreased gonadotropin release due to (-) feedback inhibition on anterior pituitary
4. DON'T USE ANDROGENS DURING PREGNANCY (easily cross placenta and can masculinize female fetus)
C. Other side effects
EDEMA from Na+ retention; aldosterone-like effect on distal tubules from mineralocorticoid activity or stimulation of synthesis of angiotensinogen (significant only w/ high doses if patient has CHF or renal insufficiency)

Front 9

Describe GnRH analogs

Back 9

1. LEUPROLIDE
USES
a. prostate cancer
b. precocious puberty
c. endometriosis
MOA-initial increase in LH/FSH which (worsen symptoms of prostate cancer initially); repeated use downregulates GnRH receptors in anterior pituitary-->decreases LH release-->shuts down testosterone synthesis
Pregnancy category X-major fetal abnormalities & mortality
2. NAFARELIN-administered as nasal solution; used to treat precocious puberty and endometriosis

Front 10

describe 5-alpha-reductase inhibitors

Back 10

inhibit conversion of testosterone to DHT; advantage over GnRH analogs is they don't cause an initial LH or testosterone surge
1. FINAZTERIDE-inhibits Type II 5-α-reductase in urogenital tissue in men & genital skin in men & women
2. DUTASTERIDE-inhibits Types I & II 5-α-reductase; treats benign prostatic hypertrophy (BPH)

Front 11

describe androgen receptor antagonists

Back 11

used to treat prostate cancer (androgen-dependent tumor)
1. FLUTAMIDE-inhibits binding of DHT to androgen receptor; its metabolite, hydroxyflutamide has 20x> affinity for receptor and is active form
2. BICALUTAMIDE
3. NILUTAMIDE

Front 12

describe phosphodiesterase inhibitors

Back 12

Inhibition of PDE increases cGMP levels in smooth muscles of corpus cavernosum -->activation of protein kinase that phorphorylates (inactivates) myosin light-chain kinase-->prevents smooth muscle contraction-->vasodilation and increased blood flow to penis (facilitates erection)
ineffective in absence of sexual stimulation which causes release of NO that initiates vasodilation
PDE 5 found mainly in erectile smooth muscle; small amounts found throughout systemic vasculature
1. SILDENAFIL
2. VARDENAFIL-more selectivity for PDE 5
3. TADALAFIL

Front 13

describe the side effects of PDE inhibitors

Back 13

1. impaired blue-green color discrimination; due to inhibition of PDE 6 involved in phototransduction in retina; sildenafil 10x more selective for PDE 5 than PDE 6
2. Permanent blindness in patients w/ diabetes or HTN
3. Rx-induced migraine due to increased cerebral blood flow
(caution in patients w/ Hx of migraine)
4. severe refractory hypotensionn
5. facial flushing (vasodilatory effect)

Front 14

describe alprostadil

Back 14

protaglandin (PGE1)-used for erectile dysfunction; relaxes smooth muscle and dilates cavernosal arteries

Front 15

describe alpha antagonists

Back 15

BLOCK α1A RECEPTOR IN PROSTATE; TREATs BENIGN PROSTATIC HYPERTROPHY (BPH)
1. Tamsulosin
2. silodosin

Front 16

describe tamsulosin

Back 16

contains sulfa moiety (allergic rxns reported)
Side effects:
1. Retrograde ejaculation-fluid goes to urinary bladder; by blocking sphincter α1A receptors, bladder sphincter muscles relax permitting ejaculate to enter bladder
2. ↓ BP -->dizziness or fainting
3. Headache, dizziness, nasal congestion, palpitations

Front 17

describe silodosin

Back 17

doesn't contain sulfa; doesn't cause orthostatic hypotension (potential is there)
Side effects-retrograde ejaculation
Rx interactions
1. inhibitors of CYP3A4 (ketoconazole, itraconazole, ritonavir et al) ↑ plasma silodosin levels (don't give together)
2. Use w/ PDE5 inhibitors increases the of orthostatic hypotension