книга / 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Learning Objectives

Describe clinical situations requiring the use of adrenal steroids, estrogens, and progestin

Solve problems concerning oral contraceptives

List the common complications of steroid hormone use

ADRENAL STEROIDS

λNonendocrine uses: For use in inflammatory disorders (and accompanying adverse effects), see Section VI, Drugs for Inflammatory and Related Disorders.

λEndocrine uses of glucocorticoids (e.g., prednisone, dexamethasone, hydrocortisone) and the mineralocorticoid (fludrocortisone) include:

–Addison disease replacement therapy

–Adrenal insufficiency states (infection, shock, trauma) supplementation

–Premature delivery to prevent respiratory distress syndrome supplementation

–Adrenal hyperplasia feedback inhibition of ACTH

λAdrenal steroid antagonists:

–Spironolactone

–Blocks aldosterone and androgen receptors (see Section III, Cardiac and Renal Pharmacology)

λMifepristone:

–Blocks glucocorticoid and progestin receptors

λSynthesis inhibitors:

–Metyrapone (blocks 11-hydroxylation)

–Ketoconazole

ESTROGENS

λPharmacology: Estradiol is the major natural estrogen. Rationale for synthetics is to ↑ oral bioavailability, ↑ half-life, and ↑ feedback inhibition of FSH and LH.

λDrugs:

–Conjugated equine estrogens (Premarin)—natural

–Ethinyl estradiol and mestranol—steroidal

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Section VIII λ Endocrine Pharmacology

λClinical uses:

–Female hypogonadism

–Hormone replacement therapy (HRT) in menopause →↓ bone resorption (↓ PTH)

–Contraception—feedback ↓ of gonadotropins

–Dysmenorrhea

–Uterine bleeding

–Acne

–Prostate cancer (palliative)

λSide effects:

–General

ºNausea

ºBreast tenderness

ºEndometrial hyperplasia

º↑ gallbladder disease, cholestasis

ºMigraine

ºBloating

–↑ blood coagulation via ↓ antithrombin III and ↑ factors II, VII, IX, and X (only at high dose)

–Cancer risk

º↑ endometrial cancer (unless progestins are added)

º↑ breast cancer—questionable, but caution if other risk factors are present

ºDES given during breast feeding →↑ vaginal adenocarcinoma cancer in offspring

λOther drugs:

–Anastrozole

ºMode of action: aromatase inhibitor →↓ estrogen synthesis

ºUse: estrogen-dependent, postmenopausal breast cancer

Anastrozole

Figure VIII-2-1. Mechanism of Action of Anastrozole

–Clomiphene (fertility pill)

ºMode of action: ↓ feedback inhibition →↑ FSH and LH →↑ ovulation → pregnancy

ºUse: fertility drug

ºAdverse effect: ↑ multiple births

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Chapter 2 λ Steroid Hormones

λSelective estrogen-receptor modulators (SERMs):

–Tamoxifen

ºVariable actions depending on “target” tissue

ºE-receptor agonist (bone), antagonist (breast), and partial agonist (endometrium)

ºPossible ↑ risk of endometrial cancer

ºUsed in estrogen-dependent breast cancer and for prophylaxis in highrisk patients

–Raloxifene

ºE-receptor agonist (bone), antagonist breast and uterus

ºWhen used in menopause, there is no ↑ cancer risk

ºUse: prophylaxis of postmenopausal osteoporosis, breast cancer

Table VIII-2-1. Comparison of Tamoxifen and Raloxifene in Various Tissues

PROGESTIN

λPharmacology: Progesterone is the major natural progestin. Rationale for synthetics is ↑ oral bioavailability and ↑ feedback inhibition of gonadotropins, especially luteinizing hormone (LH).

λDrugs:

–Medroxyprogesterone

–Norethindrone

–Desogestrel is a synthetic progestin devoid of androgenic and antiestrogenic activities, common to other derivatives

λClinical uses:

–Contraception (oral with estrogens)—depot contraception (medroxyprogesterone IM every 3 months)

–Hormone replacement therapy (HRT)—with estrogens to ↓ endometrial cancer

λSide effects:

–↓ HDL and ↑ LDL

–Glucose intolerance

–Breakthrough bleeding

–Androgenic (hirsutism and acne)

–Antiestrogenic (block lipid changes)

–Weight gain

–Depression

λAntagonist: mifepristone—abortifacient (use with prostaglandins [PGs])

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Section VIII λ Endocrine Pharmacology

ORAL CONTRACEPTIVES

λPharmacology:

–Combinations of estrogens (ethinyl estradiol, mestranol) with progestins (norgestrel, norethindrone) in varied dose, with mono-, bi-, and triphasic variants

–Suppress gonadotropins, especially midcycle LH surge

λSide effects:

–Side effects are those of estrogens and progestins, as seen previously

λInteractions: ↓ contraceptive effectiveness when used with antimicrobials and enzyme inducers

λBenefits:

–↓ risk of endometrial and ovarian cancer

–↓ dysmenorrhea

–↓ endometriosis

–↓ pelvic inflammatory disease (PID)

–↓ osteoporosis

ANDROGENS

λPharmacology: include methyltestosterone and 17-alkyl derivatives with increased anabolic actions, e.g., oxandrolone, nandrolone

λUses:

–Male hypogonadism and for anabolic actions →↑ muscle mass, ↑ RBCs, ↓ nitrogen excretion

–Illicit use in athletics

λSide effects:

–Excessive masculinization

–Premature closure of epiphysis

–Cholestatic jaundice

–Aggression

–Dependence

λAntagonists:

–Flutamide: androgen receptor blocker—used for androgen-receptor– positive prostate cancer

–Leuprolide: GnRH analog—repository form used for androgen-receptor– positive prostate cancer

–Finasteride

º5-Alpha reductase inhibitor, preventing conversion of testosterone to dihydrotestosterone (DHT)

ºDHT is responsible for hair loss and prostate enlargement

ºUses: BPH, male pattern baldness

ºCaution: teratogenicity

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Chapter 2 λ Steroid Hormones

Finasteride

Figure VIII-2-2. Mechanism of Action of Finasteride

Chapter Summary

Adrenal Steroids

λThe nonendocrine uses in inflammatory disorders were discussed in the previous chapter.

λThe glucocorticoids are used to treat Addison disease and adrenal insufficiency states, as a supplement in infantile respiratory distress syndrome, and in adrenal hyperplasia.

Estrogens

λSynthetic estrogens are used to increase the oral bioavailability and half-life relative to that obtained with estradiol and to induce feedback inhibition of FSH and LH.

λThe uses and adverse affects of estrogens are listed.

λThe clinical uses of anastrozole (decreases estrogen synthesis), danazol (decreases ovarian steroid synthesis), clomiphene (decreases feedback inhibition), and the selective estrogen-receptor modulators tamoxifen and raloxifene are considered.

Progestin

λSynthetic progestins are used to increase oral bioavailability and half-life relative to progesterone and to induce feedback inhibition of gonadotropins, especially LH.

λThe progestin-like drugs, their use in contraception and in hormonal replacement therapy, and their adverse effects are considered.

λMifepristone is an antagonist used with PG as an abortifacient.

λThe pharmacology of oral contraceptives and their adverse effects, drug interactions, and benefits are pointed out.

Androgens

λClinically useful androgen analogs include methyltestosterone and 17-alkyl derivatives. Their clinical and illicit uses and side effects are presented.

λClinically useful drug antagonists are flutamide (an androgen-receptor blocker used to treat prostate cancer), leuprolide (a GnRH analog used to treat prostate cancer), and finasteride (a 5-α-reductase inhibitor used to treat benign prostatic hyperplasia and male pattern baldness).

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Learning Objectives

Describe the short-term effect of iodine on the thyroid and the most commonly used thioamides

Table VIII-3-1. The Synthesis of Thyroid Hormone and Action and Effects of Antithyroid Agents

Definition of abbreviations: MIT, monoiodotyrosine; DIT, diiodotyrosine; T3, triiodothyronine; T4, thyroxine. *Thyroid storm management may include the use of any or all of these agents.

Figure VIII-3-1. Thyroid Hormone Synthesis

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Section VIII λ Endocrine Pharmacology

λThioamides: propylthiouracil and methimazole

–Use: uncomplicated hyperthyroid conditions; slow in onset

–High-dose propylthiouracil inhibits 5′ deiodinase

–Common maculopapular rash

–Both drugs cross the placental barrier, but propylthiouracil is safer in pregnancy because it is extensively protein bound

λIodide

–Potassium iodide plus iodine (Lugol’s solution) possible use in thyrotoxicosis: used preoperatively →↓ gland size, fragility, and vascularity

–No long-term use because thyroid gland “escapes” from effects after 10 to 14 days

λI131: most commonly used drug for hyperthyroidism

Chapter Summary

λThe steps in thyroid hormone synthesis and the antithyroid agents’ effects upon them are summarized in Table VIII-3-1. The clinical uses and their potential complications are presented in greater detail for the thioamides (propylthiouracil and methimazole) and iodine.

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