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  • Permissive effects are those that require glucocorticoid presence such that the function becomes deficient when the glucocorticoid is absent (e.g., vascular and bronchial smooth muscle response to catecholamines diminish when cortisol is absent and are restored by cortisol treatment).
  • the basic structure, actions, and effects of synthetic corticosteroids resemble that of the natural glucocorticoid hydrocortisone (a.k.a. = cortisol) synthetic corticosteroids are usually synthesized from cattle cholic acid or plant steroid sapogenins
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • are very many, diverse, and unrelated
  • are very many, diverse, and unrelated
  • Permissive effects are those that require glucocorticoid presence such that the function becomes deficient when the glucocorticoid is absent (e.g., vascular and bronchial smooth muscle response to catecholamines diminish when cortisol is absent and are restored by cortisol treatment).
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • Permissive effects are those that require glucocorticoid presence such that the function becomes deficient when the glucocorticoid is absent (e.g., vascular and bronchial smooth muscle response to catecholamines diminish when cortisol is absent and are restored by cortisol treatment).
  • Neutrophils are increased by increased influx into blood from blone marrow and decreased migration from the blood vessels; this results in reduction of the number of cells at the site of inflammation. Reduction in lymphocutes, monocytes, eosinophils, and basophils results from their movement from the vascular bed to lymphoid tissues. The ability of macrophages and other antigen-presenting cells to respond to antigens and mitogens is reduced.
  • the basic structure, actions, and effects of synthetic corticosteroids resemble that of the natural glucocorticoid hydrocortisone (a.k.a. = cortisol) synthetic corticosteroids are usually synthesized from cattle cholic acid or plant steroid sapogenins
  • Potency relative to cortisol Glucocorticoids with significant antiinflammatory activity in blue Mineralocorticoids with significant sodium retaining activity in red
  • are very many, diverse, and unrelated
  • are very many, diverse, and unrelated
  • the basic structure, actions, and effects of synthetic corticosteroids resemble that of the natural glucocorticoid hydrocortisone (a.k.a. = cortisol) synthetic corticosteroids are usually synthesized from cattle cholic acid or plant steroid sapogenins
  • are very many, diverse, and unrelated

Transcript

  • 1. PHCL 766 BLOOD-ENDOCRINE Pharmacology
  • 2. Drugs Used in the Treatment of Hypothalamic, Pituitary, Thyroid, and Adrenal Disorders
    • General Considerations
      • A hormone is a substance secreted by one tissue or gland that is transported via the circulation to a site where it exerts its effects on different tissues.
      • Uses for hormones and synthetic analogues
        • Diagnostic tools in endocrine disorders
        • Replacement therapy in endocrine disorders
        • Treatment of nonendocrine disorders
  • 3. Interactions among the hypothalamic, pituitary, and peripheral glands (+) = stimulant; (-) = inhibitor Breast Prolactin (+) Dopamine (-) PRH (+) Estrogen Progesterone Testosterone Gonads FSH (+) LH (+) GnRH or LHRH (+) T 4 , T 3 Thyroid TSH (+) TRH (+) Glucocorticoids, Mineralcorticoids Androgens Adrenal cortex ACTH (+) CRH (+) Somatomedins Liver GH (+) GHRH (+); SRIH (-) Target Organ Hormone Target Organ Pituitary Hypothalamic
  • 4. Hypothalamic Hormones and Related Drugs
    • Sermorelin (growth hormone–releasing hormone)
      • Mechanism of action: causes rapid elevation of growth hormone in the blood
      • Use: assessment of responsiveness and treatment of growth hormone deficiency
    • Somatostatin (growth hormone–inhibiting hormone)
      • Octreotide (synthetic analogue)
      • Mechanism of action: inhibits release of pituitary and gastrointestinal hormones
      • Uses
        • Symptomatic treatment of hormone-secreting tumors, including pituitary tumors, carcinoid tumors, insulinomas, vasoactive intestinal peptide tumors (VIPomas)
        • Esophageal varices ( octreotide )
      • Adverse effects: abdominal pain, diarrhea, nausea and vomiting
    The ending –relin indicates a hypothalamic-related hormone
  • 5. Hypothalamic Hormones and Related Drugs
    • Protirelin (thyrotropin-releasing hormone; TRH)
      • Mechanism of action: stimulates synthesis and release of thyrotropin and prolactin from the anterior pituitary
      • Use: assessment of thyroid function in patients with pituitary or hypothalamic dysfunction
    • Corticotropin-releasing hormone (CRH; corticorelin )
      • Mechanism of action: stimulates release of corticotropin and  -endorphin from the anterior pituitary
      • Use: differentiation between hypothalamic and pituitary causes of corticotropin deficiency or excess
  • 6. Hypothalamic Hormones and Related Drugs
    • Gonadotropin-releasing hormone (GnRH)–related preparations
      • Examples: leuprolide, nafarelin, gonadorelin
      • Mechanism of action
        • Stimulate secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH): pulsatile intravenous administration every 1–4 hours
        • Inhibit gonadotropin release: continuous administration of longer-lasting synthetic analogues
      • Uses
        • Shorter-acting preparations : treatment of delayed puberty, induction of ovulation in women with hypothalamic amenorrhea, stimulation of spermatogenesis in men with hypogonadotropic hypogonadism (infertility)
        • Long-acting GnRH analogues : suppression of FSH and LH in polycystic ovary syndrome, endometriosis, precocious puberty, prostate cancer
        • May be effective in endometriosis, uterine fibrinoids in women, and prostate cancer in men.
      • Adverse effects: menopausal symptoms, amenorrhea, testicular atrophy
      • GnRH antagonist: ganirelix, cetrorelix
        • Used to prevent premature surges of LH during controlled ovarian hyperstimulation.
  • 7. Anterior Pituitary Hormones and Related Drugs
    • Growth hormone –related preparations
      • Somatropin, somatrem , recombinant human growth hormone (rhGH)
      • Growth hormone is required for stimulating normal growth in children and adolescents as well as for controlling metabolism in adults.
      • Disorders characterized by an excess of growth hormone include gigantism ( before puberty) and acromegaly ( after fusion of epiphyseal plates of the long bones).
      • Disorders characterized by a deficiency of growth hormone include dwarfism .
      • Mechanism of action
        • Increase production of somatomedins in the liver and other tissues
          • Insulin-like growth factor ( IGF-1 )
        • Oppose the actions of insulin
      • Uses: hypopituitary dwarfism, cachexia, Turner’s syndrome (single X chromosome)
      • Adverse effects
        • Impaired glucose tolerance may develop over long periods.
        • Only synthetic growth hormone is used today (Creutzfeldt-Jakob disease resulted from the use of cadaveric growth hormone).
        • Excess growth hormone production results in gigantism and acromegaly; deficiency results in dwarfism .
  • 8. Mecasermin
    • Mechanism of action
      • Insulin-like growth factor ( IGF-1 ) produced by using recombinant DNA technology
      • It is a recombinant IGF-1 product that promotes growth
    • Uses
      • Growth failure in children with severe primary insulin-like growth factor-1 deficiency ( IGF-1 deficiency )
      • Treatment of patients with GH gene deletions who have developed neutralizing antibodies to GH
    • Adverse effects
      • Cardiac murmur
      • Hyper/hypoglycemia
      • Iron-deficiency anemia
  • 9. Pegvisomant
    • Mechanism of action
      • A protein of recombinant DNA origin covalently bound to polyethylene glycol (PEG) polymers
      • GH analogue that selectively binds GH receptors
      • Blocks the binding of endogenous GH
      • Leads to decreased serum concentrations of IGF-I and other GH-responsive proteins
    • Use
      • Acromegaly (patients resistant to or unable to tolerate other therapies)
    • Adverse effects
      • Pain
      • Abnormal liver function tests
  • 10. Anterior Pituitary Hormones and Related Drugs
    • Thyrotropin (thyroid-stimulating hormone; TSH)
      • Mechanism of action
        • Stimulates growth of thyroid gland
        • Stimulates the synthesis and release of thyroid hormones
      • Use: diagnosis of hypothyroidism
  • 11. Anterior Pituitary Hormones and Related Drugs
    • Adrenocorticotropin (ACTH)–related preparations
      • Examples: corticotropin, ACTH 1–24 , cosyntropin
      • Regulation of secretion
        • Corticotropin levels undergo daily cyclic changes (circadian rhythms).
          • Peak plasma levels occur about 6:00 am, and the lowest levels occur about 12:00 am.
      • Stress increases the release of corticotropin.
      • Mechanism of action
        • Stimulate growth of the adrenal gland
        • Stimulate the production and release of glucocorticoids, mineralocorticoids, and androgens from the adrenal cortex
      • Use: differentiation between primary (adrenal malfunction) and secondary (pituitary malfunction) adrenocortical insufficiency
      • Adverse effects (corticotropin or glucocorticoids): Cushing’s syndrome
        • General: weight gain, cushingoid appearance (“moon face”), sodium retention, edema
        • Musculoskeletal: osteoporosis, myopathy, growth retardation (children)
        • Ophthalmic: cataracts, glaucoma
        • Other: diabetes mellitus, peptic ulcer disease, psychosis, decreased resistance to infection
    Stress markedly affects multiple hormonal systems
      • ACTH and glucocorticoids cause iatrogenic Cushing’s syndrome
    Know
  • 12. Anterior Pituitary Hormones and Related Drugs
    • Prolactin and related preparations
      • Prolactin
        • Regulation of secretion
          • Stress, suckling, phenothiazines ( dopamine antagonists ), and TRH stimulate the release of prolactin.
          • Dopamine and dopamine agonists in the central nervous system (CNS), such as bromocriptine, tonically inhibit the release of prolactin.
      • Mechanism of action: stimulates milk production
        • Oxytocin stimulates milk ejection (“let-down”)
      • Use: not available for clinical use
      • Inhibitors of prolactin release ( bromocriptine, Cabergoline )
        • Uses: prevention of breast tenderness and engorgement in women who are not breastfeeding; inhibition of lactation; treatment of amenorrhea and galactorrhea associated with hyperprolactinemia due to pituitary adenomas
  • 13. Anterior Pituitary Hormones and Related Drugs: Follicle-stimulating hormone (FSH)
    • Examples
      • Uro follitropin
      • Follitropin alfa
      • Follitropin beta
    • Sources
      • Urofollitropin is a preparation of highly purified FSH extracted from the urine of postmenopausal women
      • Follitropin alfa and follitropin beta are recombinant preparations of FSH
    • Mechanism of action
      • Stimulates ovarian follicle growth (females)
      • Also, stimulates granulosa cell synthesis of aromatase for conversion of testosterone synthesized in the theca interna to estradiol
      • Stimulates spermatogenesis (males)
    • Uses
      • Infertility
      • Polycystic ovarian syndrome
    • Adverse effects
      • Multiple births
      • Ovarian enlargement
    -follitropin = FSH
  • 14. Anterior Pituitary Hormones and Related Drugs: Luteinizing hormone (LH)
    • Examples and sources
      • Menotropins
        • Extracted from urine of postmenopausal women (both FSH and LH activity)
      • Chorionic gonadotropin (human)
        • LH obtained from the urine of pregnant women
      • Chorionic gonadotropin (recombinant)
        • LH analogue produced by recombinant DNA techniques
      • Lutropin alfa
        • LH prepared using Chinese hamster cell ovaries
    • Mechanism of action
      • Increases follicular estradiol secretion
      • Required for FSH induced follicular development
      • Preparations containing FSH and LH activity are used in various fertility paradigms.
  • 15. Anterior Pituitary Hormones and Related Drugs: Luteinizing hormone (LH)
    • Uses
      • Menotropins
        • In conjunction with chorionic gonadotropins (human) to induce ovulation and pregnancy in infertile women
        • Stimulation of multiple follicle development in ovulatory patients as part of an assisted reproductive technology (ART)
        • Stimulation of spermatogenesis in primary or secondary hypogonadotropic hypogonadism in males
      • Lutropin
        • Stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency
        • Given in combination with follitropin alfa
      • Chorionic gonadotropin (recombinant)
        • As part of an ART program, induces ovulation in infertile females who have been pretreated with FSH
        • To induces ovulation and pregnancy in infertile females when the cause of infertility is functional
  • 16. Posterior Pituitary Hormones and Related Drugs
    • These hormones are produced in the hypothalamus and are transported to the posterior pituitary (neurohypophysis), where they are stored and released into the circulation
      • Vasopressin (antidiuretic hormone; ADH)
      • Oxytocin
        • This substance, which is secreted by the supraoptic and paraventricular nuclei on the hypothalamus, is used to induce labor and stimulate uterine contractions
  • 17. Vasopressin
    • General considerations
      • The synthetic analogue is desmopressin (preferred for treating neurogenic diabetes insipidus).
      • Disorders characterized by an absence of ADH include diabetes insipidus (severe polyuria, hypernatremia).
      • Disorders characterized by an excess of ADH include syndrome of inappropriate antidiuretic hormone ( SIADH ), water retention, hyponatremia, and possible pulmonary disease.
    • Regulation of secretion
      • Increases in plasma osmolality (e.g., dehydration) result in increased secretion of ADH.
      • Decreases in blood pressure (e.g., due to hemorrhage) increase ADH secretion.
    • Mechanism of action
      • Modulates renal tubular reabsorption of water, increasing permeability of the distal tubule and collecting ducts to water
      • This effect is mediated by an increase in cAMP associated with stimulation of the V 2 receptor.
      • At high concentrations, causes vasoconstriction (helps maintain blood pressure during hemorrhage)
      • This effect occurs via the stimulation of the V 1 receptor coupled to the polyphosphoinositide pathway.
  • 18. Vasopressin
    • Uses
      • Central ( neurogenic ) diabetes insipidus
        • Thiazide diuretics are used to treat nephrogenic diabetes insipidus because:
        • They cause a reduction in the polyuria of patients with diabetes insipidus by causing volume depletion, hence reducing glomerular filtration rate and volume of urine.
      • Esophageal variceal bleeding and colonic diverticular bleeding (some cases)
      • Ventricular fibrillation or pulseless ventricular tachycardia
    • Adverse effects: overhydration, hypertension
    • Drugs that affect the secretion or action of ADH
      • Diuretics, carbamazepine, morphine, tricyclic antidepressants increase ADH release.
      • Ethanol decreases ADH release.
      • Lithium and demeclocycline , which reduce the action of ADH at the collection ducts of the nephron, are used to treat SIADH .
    Excess ADH results in SIADH, water retention, hyponatremia, and possible pulmonary disease; absence of ADH results in diabetes insipidus .
  • 19. Ovarian Function
    • In human females the ovaries are quiescent during childhood
    • Ovarian function begins when the ovaries respond to pituitary gonadotropins ( FSH and LH ) at puberty ( menarche or gonadarche )
    • Menarche is followed by 30-40 year period of menstrual cycles manifested as episodes of bleeding caused by ovarian secretion of estrogen and progesterone
    • At menopause cyclic bleeding stops when the ovaries fail to respond to the pituitary gonadotropins .
  • 20. Regulation of Menstruation
    • Menstrual cycles are automatically reactivated every 28-30 days by a neuronal ‘clock’ (hypothalamic arcuate nucleus) serving as a pulse generator that fires at regular intervals 
    • Releases GnRH periodically into the hypothalamic-pituitary portal vasculature 
    • GnRH acts on anterior pituitary to release LH & FSH 
    • LH & FSH stimulate ovaries to secrete estrogen & progesterone
    • Negative feedback regulation :
    • (A) estrogen acts on pituitary to decrease FSH and LH
    • (B) progesterone acts on hypothalamus to decrease GnRH
  • 21. Menstrual Cycles
    • As each cycle starts, vesicular follicles become larger  after 5-6 days a dominant follicle develops more rapidly  theca and granulosa cells multiply to release estrogens  estrogen secretion peaks just before midcycle  brief surge in LH and FSH release  ovulation
    • After ovulation, the follicular cavity fills with blood  luteinized theca and granulosa cells proliferate to form the corpus luteum which then produces estrogen and progesterone for the rest of the cycle
    • Normal ovulatory menstrual cycles are maintained by the pulsatile release of hormones (constant infusions of GnRH will stop LH and FSH release  decrease estrogen and progesterone  amenorrhea)
  • 22. Estrogen Biosynthesis and Metabolism
    • Three major estrogens normally secreted are:
      • Estrone (E1)
      • Estradiol (estradiol-17b; E2)
      • Estriol (E3)
    • Secretion of estradiol the major estrogen, varies widely during the menstrual cycle with the highest peak occurring at ovulation
    • Ovaries also produce some estrone, but estrone and estriol are mostly formed in the liver
    • Estradiol in the circulation is bound to sex hormone-binding globulin and albumin, converted in the liver to hydroxylated derivatives and conjugated metabolites which are excreted in bile
    • Stallions are the most prolific natural source of estrogens producing more than pregnant mares or women  
  • 23. Estrogen Mechanism of Action
    • Estrogen receptors are nuclear receptors (same superfamily that includes steroid, sterol, retinoic acid, and thyroid receptors) found mainly in the uterus, vagina, and ovary
    • Estrogen binds to two receptors ( ER  and ER   on heat shock proteins in the nucleus 
      • Releases hormone-receptor complex to form homodimers that bind to estrogen response elements (EREs) 
      • EREs regulate gene transcription 
      • mRNA edited to form protein  estrogen effects
  • 24. Estrogen Effects
    • Female maturation - estrogens stimulate:
      • Development of the vagina, uterus, and fallopian tubes
      • Breast enlargement by stromal and ductal growth
      • Closing of epiphyses of long bones at puberty
      • Growth of axillary and pubic hair
      • Body fat distribution to produce female body contour
      • Skin pigmentation of nipples, areolae, and genitals
      • Growth of uterine muscle and development of endometrial lining
      • Continuous estrogen exposure 
      • endometrial hyperplasia  abnormal bleeding
  • 25. Estrogen Effects
    • Cardiovascular and metabolic effects –
      • Increased risk of thromboembolism
      • Metabolic changes in the liver causing increased circulating protein levels ( TBG, angiotensinogen, fibrinogen , clotting factors , etc)
      • Increased serum triglycerides and free & esterified cholesterol
      • On the contrary, some lipid effects are beneficial:
        •  HDL and  LDL  beneficial ratio!
      • Lipid effects together with direct vasodilation may be protective 
        • Cardiovascular diseases in older women reduced by 35-50%
        • This so-called protective effect has recently been contradicted
    • Blood coagulation – enhanced by increasing coagulation factors and plasminogen, and decreasing antithrombin and platelet adhesiveness
  • 26. Compounds with Estrogenic Activity
    • Natural estrogens - from which synthetic estrogens were derived
      • Estradiol, estrone, estriol
    • Synthetic estrogens - most commonly used in OCs
      • Ethinyl estradiol, mestranol , quinestrol
    • Synthetic nonsteroidal compounds with estrogenic activity - also have been used some clinically
      • Diethylstilbestrol, chlorotrianisene, methallenestril
  • 27. Commonly Used Estrogens
    • Are among the most commonly prescribed drugs in the US because of use for:
    • oral contraception (OC) and
    • estrogen (ERT) or hormone (HRT) replacement therapy
    • High ratio of hepatic to peripheral effects when given orally because significant amounts are excreted in bile and reabsorbed in the intestine
    • Hepatic effects are minimized by vaginal, trans-dermal, or parenteral administration
    Table 40–1 Commonly Used Estrogens. 3–9 mg/d Methallenestril 12–25 mg/d Chlorotrianisene 0.1–0.2 mg/week Quinestrol Patch    Transdermal 0.2–2 mg/d    Injectable 0.3–1.25 mg/d    Oral Conjugated, esterified, or mixed estrogenic substances: 1.25–2.5 mg/d Estropipate 2–20 mg every other week Estradiol valerate 2–5 mg every 3–4 weeks Estradiol cypionate 1–2 mg/d Micronized estradiol 0.005–0.02 mg/d Ethinyl estradiol Average Replacement Dosage Preparation
  • 28. Clinical Uses of Estrogens
    • Primary hypogonadism –
      • For replacement therapy in estrogen-deficiencies due to undeveloped ovaries, premature menopause, castration or menopause
      • Treatment attempts to mimic physiology of puberty
      • Estrogen treatment usually starts at 11-13 years of age in order to
        • Stimulate development of secondary sex characteristics and menses
        • Prevent osteoporosis
        • Avoid psychologic effects of delayed puberty and estrogen deficiency
    • Postmenopausal hormonal therapy –
      • The main therapeutic indications are to prevent hot flushes and osteoporosis
      • Only the lowest possible doses should be used because of increased risks for breast and endometrial cancer
      • The so-called “protective effect against cardiovascular disease” is now contradicted by recent studies
    • Other uses – combined with progestins to:
      • Suppress ovulation in intractable dysmenorrhea
      • Suppress ovarian function for treatment of hirsutism and amenorrhea caused by excessive ovarian secretion of androgens
  • 29. Adverse Estrogen Effects
    • Postmenopausal uterine bleeding – to avoid confusion with vaginal bleeding caused by endometrial cancer, use the smallest amounts of estrogen cyclically
    • Increased risks for breast and endometrial cancer
    • Nausea, breast tenderness, hyperpigmentation, migraine, cholestasis, gall bladder disease, and hypertension
    • Contraindicated in patients with:
      • Breast or endometrial cancer
      • Undiagnosed genital bleeding
      • Liver disease
      • Thromboembolic disorders
      • Heavy smokers
  • 30. The PROGESTINS
    • Progesterone , the natural progestin, is the most important human progestin
    • Aside from important hormonal effects, it serves as a precursor for estrogens, androgens, and adrenocortical steroids
    • It is synthesized from circulating cholesterol in the ovary, testis, adrenals, and placenta
    • It is produced  primarily by the corpus luteum in the ovary
      • Plasma levels are elevated to peak in the third trimester of pregnancy
  • 31. Progesterone Pharmacokinetics
    • Progesterone is rapidly absorbed from any route of administration with a plasma half-life of about 5 min and small amounts stored in body fat
    • Oral preparations are ineffective because it is completely metabolized after one passage through the liver where it forms pregnanediol, is conjugated with glucuronic acid, and then excreted in urine as pregnanediol glucuronide
    • Urinary pregnanediol is used as an index of progesterone secretion
    • Many synthetic progestins are commercially available and some are active when given orally (e.g., megestrol, dimethisterone, medroxyprogesterone )
    • Third-generation progestins used primarily in oral contraceptives are 19-nortestosterone derivatives like desogestrel, norethynodrel, norethindrone, or norgestimate
  • 32. Progesterone Action and Effects
    • Mechanism of action - like other steroid hormones;
      • It enters the cell
      • Binds to nuclear and cytoplasmic receptors
      • Forms a ligand-receptor complexinds to a progesterone response element (PRE)
      • Activates gene transcription
    • It stimulates lipoprotein lipase to favor fat deposition
    • Effects on carbohydrate metabolism are more marked:
      • It increases insulin and the insulin response to glucose
      • It promotes hepatic glycogen storage
    • It competes with aldosterone for mineralocorticoid receptors in renal collecting tubules to decrease Na + reabsorption which in turn increases adrenal secretion of aldosterone
    • It also increases body temperature, respiratory responses to CO 2 , development of breast secretory mechanisms, endometrial maturation, etc
  • 33. Clinical Uses of Progestins
    • Therapeutic – mainly for:
      • Hormone replacement therapy (HRT)
      • Oral contraception (OC)
      • Long-term ovarian suppression - injected in large doses IM medroxyprogesterone results in anovulation and amenorrhea
      • Treatment of dysmenorrhea, endometriosis, and bleeding disorders for which estrogen is contraindicated
    • Diagnostic – to test for estrogen secretion; after treatment with progesterone or medroxyprogesterone in amenorrheic women, withdrawal bleeding occurs only when there has been endometrial stimulation by estrogen
  • 34. ORAL CONTRACEPTIVES (OCs)
    • Two types of preparations are used:
      • Combinations of estrogens and progestins
      • Continuous progestin without concomitant estrogen
    • OCs taken properly are 97-98% effective in reducing the risk of conception
    • Contraceptive failures occur when one or more doses are missed
    • Most commonly used estrogens are ethinyl estradiol or mestranol
    • Progestin-only contraceptives avoid adverse effects due to the estrogen component but are slightly less effective (96-97.5%) in reducing conception risk; some examples are:
      • Oral norethindrone or norgestrel
      • Etonogestrel implantation
      • Medroxyprogesterone for IM injection
  • 35. GONADAL HORMONES AND INHIBITORS ANDROGENS DANAZOL FLUOXYMESTERONE METHYLTESTOSTERONE NANDROLONE OXANDROLONE TESTOLACTONE TESTOSTERONE ESTROGEN AND PROGESTIN COMBINATION Drospirenone and Estradiol (HRT; oral) Estradiol and Levonorgestrel (HRT; patch) Estradiol and Norethindrone (HRT; patch) Estradiol and Norgestimate (HRT; oral) Estrogens (Conjugated/Equine) and Medroxyprogesterone (HRT; oral) Estrogens (Esterified) and Methyltestosterone (HRT; oral) Ethinyl Estradiol and Desogestrel (OC) Ethinyl Estradiol and Drospirenone (OC) Ethinyl Estradiol and Ethynodiol Diacetate (OC) Ethinyl Estradiol and Etonogestrel (VRC) Ethinyl Estradiol and Levonorgestrel (OC) Ethinyl Estradiol and Norelgestromin (PC) Ethinyl Estradiol and Norethindrone (OC) Ethinyl Estradiol and Norgestimate (OC) Ethinyl Estradiol and Norgestrel (OC) Mestranol and Norethindrone (OC) ANTIPROGESTINS Mifepristone Danazol ESTROGEN DERIVATIVES ESTRADIOL ESTROGENS (CONJUGATED A/SYNTHETIC) ESTROGENS (CONJUGATED B/SYNTHETIC) ESTROGENS (CONJUGATED/EQUINE) ESTROGENS (ESTERIFIED) ESTROPIPATE
  • 36. Monophasic OCs
    • Fixed amounts of estrogen and progestin
    • Taken daily for 21 days
    • Followed by 7-day “pill-free” period
    • 28 day packs with last 7 pills inert
    • The FDA approved Yasmin® for routine contraception.
    • Then the FDA approved for YAZ™, a low-estrogen formulation, for routine contraception. YAZ™ contains 3 mg of drospirenone, but only 20 mcg of ethinyl estradiol, compared to 30 mcg in Yasmin®; the dosage regimen of YAZ™ is unique in that it contains 24 days of active therapy, followed by 4 days of placebo, which may offer patients fewer hormone fluctuations than the traditional 21 days of active pills per 28 day cycle.
    Norethindrone Mestranol Norinyl 1/50 Ortho-Novum 1/50 Drospirenone Ethinyl estradiol Yasmin® YAZ™ Norgestrel Ethinyl estradiol Ovral 28 Desogestrel Ethinyl estradiol Desogen Norethindrone Ethinyl estradiol Loestrin, Brevicon, Modicon, Norinyl, Ortho-Novum, Ovcon Progestin Estrogen Preparation
  • 37. Triphasic OCs
    • Three different pills each taken daily for 7 days
    • Reduces steroid amounts
    • Approximates menstrual estrogen to progestin ratio more closely
    Norethindrone Ethinyl estradiol Estrostep 21, Ortho-Novum 7/ 7/ 7 Tri- Norinyl Norgestimate Ethinyl estradiol Ortho-Tri-Cyclen L-norgestrel Ethinyl estradiol Triphasil Tri-Leven Progestin Estrogen Preparation
  • 38. Oral Combination Contraceptives
    • Monophasic combination tablets
      • Same combination of estrogen and progestin given for 21 days and stopped for 7 days each month
    • Biphasic combination tablets
      • Same estrogen dose for 21 days, with a higher progestin dose in the last 10 days of each month
    • Triphasic combination tablets
      • Generally the same estrogen dose for 21 days, with a varying progestin dose over the 3 weeks of administration
    • 24 Day pill regimen
      • Loestrin 24 Fe; Ethinyl estradiol 0.02 mg and norethindrone acetate 1 mg for 24 days and ferrous fumarate for 4 days
    • Extended cycle oral contraceptives
      • One active tablet/day for 84 consecutive days, followed by 1 inactive tablet/day for 7 days
      • If all doses have been taken on schedule and one menstrual period is missed, pregnancy should be ruled out prior to continuing therapy.
  • 39. Transdermal (patch) Estrogen-Progestin Contraceptive
    • Ethinyl estradiol and norelgestromin
    • Procedure
      • Apply one patch each week for 3 weeks (21 total days)
      • Then one week patch-free
      • Apply each patch on the same day each week
      • Only one patch should be worn at a time
      • No more than 7 days patch-free interval
    • FDA posted concerns that use of the ethinyl estradiol and norelgestromin transdermal patch may increase the risk of blood clots in some women
      • The contraceptive patch may increase blood clots in some women since the area-under-the curve (AUC) is high in some women due to more extensive dermal absorption.
  • 40. Vaginal Ring (NuvaRing)
    • Vaginal ring (NuvaRing) made of ethylene vinyl acetate provides 0.015 mg ethinyl estradiol and 0.12 mg etonogestrel daily,
    • Applied for 21 days and removed for one week ; does not interfere with intercourse
    • Mechanism of action, risks and failure rate similar to OCs
  • 41. Intrauterine Devices
    • Two types of IUDs are currently used in the US :
      • Copper (TCu-380A) IUD
        • A T-shaped device that is mostly spermicidal due to the sterile inflammatory reaction created secondary to a foreign body in the uterus
        • Copper salts are released to alter the endometrium and cervical mucus
        • White blood cells are attracted to kill the spermatozoa by phagocytosis and sperm transport is significantly impaired,
      • Two hormone-containing IUDs :
        • Progesterone-releasing device (Progestasert) releases progesterone released at a rate of 65 mg/d (approved for 1 year) to diffuse into the endometrial cavity, and cause decidualization and atrophy of the endometrium
        • Levonorgestrel-releasing device (Mirena) releases levonorgestrel gradually at a rate of 20  g/d (approved for 5 years)
    • The IUD should be placed within 7 days after onset of the menstrual cycle. Protection begins immediately after insertion and failure rates after the first year of use are for copper IUD 0.5–0.8%, Progestasert 1.3–1.6%, and Mirena 0.1–0.2%.
  • 42. OC Multiple Mechanisms of Action
    • Main action is selective inhibition of pituitary function to depress ovarian function and prevent ovulation
      • Minimal follicular development
      • Corporea lutea, larger follicles, stromal edema, and other features of ovulation are absent
      • Ovaries usually become smaller
    • Decrease likelihood of implantation and conception by changing cervical mucus, endometrium, and tubal motility and secretion
    • Uterine effects after prolonged OC use may include cervical hypertrophy and polyp formation
  • 43. OC Pharmacologic Effects
    • Ovarian depression – causing minimal follicular development, loss of corpora lutea, large follicles, stromal edema, and smaller ovaries
      • Normal menstrual patterns resume when OCs are discontinued:
      • 75% ovulate in the first post-treatment cycle and 97% by third cycle
    • Uterine effects –after prolonged use:
      • Cervical hypertrophy and polyp formation,
      • Cervical mucus thicker and less copious
    • Breast stimulation –
      • Breast enlargement with suppressed lactation
  • 44. Other OC effects (after prolonged use)
    • CNS effects on mood and behavior
    • Endocrine effects may alter adrenal steroids, renin/angiotensin system, aldosterone, thyroxine, and androgens
    • Thromboembolism from changes in clotting factors and blood coagulation
    • Hepatic effects may alter drug excretion and metabolism
    • Lipid metabolism increases in serum triglycerides, phospholipids, and cholesterol
    • Carbohydrate metabolism reduced GI sugar absorption, increase in basal insulin
    • Cardiovascular effects : increases in BP, HR , and cardiac output
    • Skin effects : increase in pigmentation (chloasma) and decreased sebum formation, acne, and terminal hair growth
  • 45. OC Adverse Effects
    • Low incidence of serious toxicity but mild adverse effects are frequent
      • Adverse effects are greatly reduced with use of smaller doses
      • With current low-dose OCs the risks of hypertension, myocardial infarction, or stroke are almost nil
    • Mild effects include nausea, edema; transient headaches and worsened migraine
    • Moderate effects include:
      • Breakthrough bleeding (especially when progestational agents are used alone),
      • Weight gain, increased skin pigmentation, ureteral dilation, vaginal fungal infections , galactorrhea, and amenorrhea
      • Acne and hirsutism may be aggravated by androgenic activity of many 19-nortesterone derivatives ( norethynodrel, norethindrone, norgestrel )
    • Severe effects include:
      • Thromboembolism – 3X higher risk related to estrogen
      • Myocardial infarction - especially in obese, hypertensive, diabetic, or hyperlipidemic women; smoking markedly increases this risk (i.e., annual number of cases per 100,000 is 4 for non-smokers vs 40-44 for smokers)
      • Increased risk of strokes – especially over age 35
      • GI disorders - cholestatic jaundice, gall bladder disease, hepatic adenomas
      • Depression
      • Cancer
  • 46. Beneficial Effects of Low dose OCs compared to women not on OCs
      • Lower risks of :
        • Ovarian cysts
        • Ovarian and endometrial cancer
        • Benign breast disease
      • Lower incidence of :
        • Ectopic pregnancy
        • Iron deficiency
        • Rheumatoid arthritis
      • Ameliorate :
        • Premenstrual symptoms
        • Dysmenorrhea
        • Endometriosis
  • 47. Continuous Progestins
    • Daily progestin (norethindrone) tablets
      • For patients whom estrogen administration is undesirable
    • Etonogestrel implantation
      • Implant 1 rod in the inner side of the upper arm; remove no later than 3 years after the date of insertion
    • Continuous progestins are preferred as contraceptives in women who should not take estrogens (e.g., heavy smokers)
    • Progestin contraceptive mechanisms
      • Thickening of cervical mucus
      • Inhibition of ovulation (but not always)
      • Inhibition of implantation
      • Not effective once the implantation process has occurred
  • 48. EMERGENCY CONTRACEPTION
    • Postcoital contraception is used when a woman who believes she is at risk for unintended pregnancy because the contraceptive method has failed or she had unprotected intercourse.
    • High-dose OCs approved by FDA for postcoital contraception in 1997.
    • Combination method uses 2 doses of two tablets (Ovral: 50 μ g ethinyl estradiol, 0.5 mg norgestrel) 12 hours apart (total: 200 μ g ethinyl estradiol, 2 mg norgestrel).
    • Progestin-only method involves two doses of ten pills (Ovrette 0.075 mg) 12 hours apart
    • Maximum efficacy is achieved if the first dose is taken within 72 hours after intercourse and repeated in 12 hours.
    • The failure rate with combination formulas is 2–3% and with progestin only 1%.
  • 49. Selective Estrogen Receptor Modulators (SERMS)
    • SERMS are compounds with tissue-selective estrogenic activities acting only in tissues where their actions would be beneficial (as in bone, brain, or liver during postmenopausal hormone replacement) but not in tissues where estrogenic actions would be harmful (as in breast or endometrium)
    • Tamoxifen and toremifene are partial agonist inhibitors of estradiol
      • For treatment of breast cancer in postmenopausal women
      • Inhibit breast cancer cells and tumor size, but stimulate endometrial proliferation and thickening, and may increase the risk of endometrial cancer
      • Prevent loss of bone density and reduce risk of atherosclerosis
    • Raloxifene is a partial estrogen agonist-antagonist at some but not all target tissues
      • Has beneficial effects on bone but without affecting the endometrium or breast
      • Used for preventing postmenopausal osteoporosis
      • Does increase the risk of thromboembolism
  • 50. OVULATION-INDUCING AGENT: Clomiphene
    • Clomiphene is a partial estrogen agonist that acts by blocking estrogen receptors
    • Because estrogen normally inhibits the pituitary, by blocking estrogen >>>> clomiphene will:
      • Reduce the negative feedback by estradiol 
      • Thus, increase FSH and LH secretion
    • Used for stimulating ovulation in amenorrheic women who want to become pregnant
    • Ovarian stimulation usually results in enlarged ovaries
    • Most common adverse effects are: hot flushes; occasional eye symptoms, headache, constipation, skin allergies, and reversible hair loss
    • Stimulation of ovulatory menstrual cycles may cause nausea and vomiting, increased nervous tension, depression, fatigue, breast soreness, weight gain, urinary frequency, and heavy menses
  • 51.
    • A 30-year-old sexually active woman who has used combination oral contraceptives for 10 years and smokes two packs of cigarettes daily, would be at high risk for which of the following?
    • A. Ectopic pregnancy
    • B. Iron deficiency
    • C. Ovarian cancer
    • D. Rheumatoid arthritis
    • E. Myocardial infarction
    Ans = E Note the other foils are beneficial effects og OCs
  • 52.
    • For hormonal replacement therapy in postmenopausal women, which of the following estrogen preparations is least likely to elevate angiotensinogen?
    • Estradiol oral tablets
    • Esterified estrogen oral tablets
    • Ethinyl estradiol oral tablets
    • Diethylstilbestrol oral tablets
    • Estradiol vaginal cream
    Ans = E Because no first Pass through liver
  • 53. TESTOSTERONE Synthesis & Secretion
    • Testosterone, the principal androgen in men, is secreted mostly by Leydig cells in the testis (95%) and partly by the adrenal cortex (5%)
    • Testosterone secretion is much higher in males than in females and it accounts for most gender differences
    • Plasma testosterone levels of about 0.6 mg/dL in males after puberty, decline after
    • age 50
    • In women the much lower plasma levels of 0.03 mg/dL are secreted by the adrenal cortex and corpus luteum
    • In men about 8 mg is produced daily from plasma cholesterol along with small amounts of two weak androgens: androstenedione and dehydroepiandrosterone (DHEA) )
  • 54. Testosterone Metabolism
    • In target tissues, testosterone is converted into active and inactive metabolites
    • Two active steroids are formed:
      • Dihydroxytestosterone
      • Estradiol
    • Dihydrotestosterone (DHT) is the major active androgen in most tissues
    • Various tissue effects can be mediated by testosterone, dihydrotestosterone, or estradiol
    • In the liver, testosterone is metabolized to androsterone and etiocholanolone which are both biologically inactive
  • 55. Physiologic Effects
    • Testosterone and dihydrotestosterone cause many changes at puberty:
      • General growth-promoting properties
      • Penile and scrotal growth: phallus enlarges in length and width, scrotum becomes rugated, and prostatic secretions begin
      • Thicker and oilier skin with more active sebaceous glands
      • Appearance of public, axillary, and beard hair
      • Laryngeal growth, thicker vocal cords  lower-pitched voice
      • Accelerated skeletal growth and epiphysial closure
      • Growth of prostate and seminal vesicles
      • Stimulating and maintaining male sexual function
    • In early adulthood and midlife:
      • Gradual development of male pattern baldness; begins with recession of hair at temples and vertex
      • Development of benign prostatic hyperplasia or prostatic cancer
    • Serum testosterone declines gradually as men age so that by age 80 free testosterone concentration is about 40% of that at age 20
      • May be related to decreases in energy, libido, muscle mass/strength, and bone mineral density
  • 56. SYNTHETIC ANDROGENS
    • Oral testosterone is rapidly absorbed but ineffective because it is catabolized in the liver ( high 1 st pass effect )
    • Synthetic preparations as lipophilic esters dissolved in oil, bypass hepatic catabolism and in hypogonadal males are injected IM every 2-4 weeks
    • Propionate, enanthate, undecenoate, or cypionate esters with more prolonged and greater activity release free testosterone at injection sites
    • Used for:
      • Anabolic effects
      • Treating testosterone deficiency
    • All synthetic androgens that are used to improve athletic performance have potent androgenic effects and the increase in muscle strength is always accompanied by adverse effects
  • 57. Pharmacologic Effects
    • Bind to intracellular androgen receptors that initiate a series of events similar to those for estradiol and progesterone.
    • In adult males, large doses suppress gonadotropin secretion  testicular atrophy
    • Can produce secondary male characteristics in women
    • Use with great caution because of masculinizing effects
    • Urinary nitrogen excretion is reduced due to increased protein synthesis or decreased protein breakdown
  • 58. Clinical Uses
    • Androgen replacement therapy in hypogonadal males
    • Growth stimulator in boys with delayed puberty
    • Treatment in women of:
      • Postpartum breast engorgement
      • Endometriosis
      • Endometrial bleeding (and to enhance libido) after menopause
      • Postmenopausal osteoporosis ( alone or combined with estrogens)
      • Chemotherapy of premenopausal breast tumors ( not much today)
  • 59. Clinical Uses
    • As protein anabolic agents to reverse protein loss after trauma, surgery, or prolonged immobilization
    • Anabolic steroid abuse - athletes use doses 10-200 X higher than endogenous testosterone levels to improve competitive performance by increasing strength and aggressiveness;
      • Will suppress endogenous testosterone and sperm production;
      • May cause gynecomastia and virilization
    • Aging – to replace low androgen levels in elderly males:
      • May worsen benign prostatic hyperplasia
      • Increase risk of prostatic cancer
  • 60. Adverse Effects
    • Largely due to masculinizing actions that are most pronounced in women and prepubertal children
    • In women:
      • Acne, hirsutism, amenorrhea, clitoral enlargement, deep voice; also alter serum lipids to increase atherosclerotic susceptibility
    • In men:
      • Acne, sleep apnea, erythrocytosis, gynecomastia, azoospermia, decreased testicular size
  • 61. Androgen Suppression and Antiandrogens
    • Gonadotropin-releasing hormone analogs like goserelin and leuprolide are used for gonadal suppression in treatment of prostatic cancer
    • Ketoconazole (antifungal agent) is used to inhibit adrenal and gonadal steroid synthesis in situations of over-production
    • Finasteride & Dutasteride inhibit 5 α -reductase to reduce conversion of testosterone to dihydrotestosterone (DHT) and is used to reduce prostatic size in benign prostatic hyperplasia
      • Infrequently causes impotence
    • Flutamide, bicalutamide, and nilutamide are antiandrogens used for treatment of prostatic carcinoma
  • 62. THYROID PHYSIOLOGY
    • The thyroid gland maintains metabolic homeostasis by regulating:
      • Growth and development ,
      • Body temperature
      • Energy levels
    • These multiple functions are accomplished through two hormones:
      • Triiodothyronine or T 3
      • Tetraiodothyronine or T 4
  • 63. Iodinated Thyroid compounds
  • 64. Two Thyroid Hormones MIT= monoiodotyrosine DIT= diiodotyrosine 5 1 Thyroglobulin ratio 65 59 Iodine content (%) two DIT one MIT plus one DIT Molecular composition T 4 or thyroxine T 3 Alias Tetraiodothyronine Triiodothyronine Hormones
  • 65. Thyroid Hormone Biosynthesis
    • Iodide (I - ) absorbed in the GIT enters an extracellular pool from which the thyroid gland removes 75 mg daily
    • Thyroid hormone synthesis proceeds as:
    • I - is taken up by thyroid follicular cells via a membrane Na + /I - transporter 
    • I - is coupled to tyrosine residues on the thyroglobulin molecule (organification) 
    • Formation of monoiodo- (MIT) and diiodo-tyrosine (DIT) 
    • Thyroid peroxidase catalyzes coupling of two molecules of DIT to form T 4 , and one molecule each of MIT and DIT to form T 3 
    • Thyroglobulin stored as colloid in the lumen 
    • TSH signals secretion to hydrolyze thyroglobulin to free MIT, DIT, T 3 & T 4 
    • MIT and DIT are deiodinated to recycle while T 3 & T 4 are released by exocytosis
  • 66. Peripheral Metabolism of Thyroxine
    • Plasma T 3 & T 4 are reversibly bound to thyroxine-binding globulin (TBG)
    • Thyroid hormone released mostly as T 4 because T 4 to T 3 ratio in thyroglobulin is 5:1
    • Peripheral metabolism of T 4 is mainly by deiodination to form:
      • T 3 which is 3-4 times more potent than T 4 , or
      • Reverse T 3 which is metabolically inactive
    • Total serum levels for T 4 are higher because more of it is released and metabolic clearance of T 3 is much higher
  • 67. Summary of Thyroid Hormone Kinetics 7 1 Half Life (days) 80 95 Oral absorption (%) 1 3-4 Biologic potency 64-132 1.5-2.9 Total Serum levels (nmol/L) 1.1 24 Daily Metabolic clearance (L) 75 25 Daily production (mg) T 4 T 3 Thyroid Hormones
  • 68. Mechanisms for Thyroid Regulation
      • Hypothalamic-Pituitary Regulation
      • paraventricular nuclei in the hypothalamus secrete TRH 
      • TRH stimulates the anterior pituitary to release TSH  
      • TSH acts on the thyroid to release T 3 & T 4 
      • T 3 & T 4 act by negative feedback to inhibit formation of TRH and TSH
      • Autoregulation within the thyroid modifies thyroid hormone synthesis through blood iodine levels:
      • high iodine levels 
      • inhibit iodide organification 
      • reduced T 3 & T 4 synthesis 
      • hypothyroidism
  • 69. Hormonal Mechanisms in Thyroid Disease
    • Normal hypothalamic-pituitary axis
    • Stimulatory autoantibody in Graves’ disease causing increased thyroid hormone secretion and suppression of TRH and TSH
    • Destructive autoantibody in Hashimoto’s disease causing decreased thyroid hormone secretion, no negative feedback, and increased TRH and TSH
  • 70. Thyroid Hormone Mechanism of Action
      • T 3 & T 4 are dissociated from thyroid-binding proteins ( TBPs ) 
      • Enter target cells by diffusion or transport 
      • In the cytoplasm 5’-deiodinase converts T 4 to T 3 
      • T 3 enters the nucleus to bind to T 3 receptors 
      •  Corepressor is released & coactivator bound
      • Gene expression is turned on
      • T 3 receptors belong to a superfamily of nuclear receptors (c- erb includes receptors for steroid hormones and vitamins A and D)
      • many T 3 receptors are found in responsive tissues like pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine
  • 71. Circulating Thyroid Hormone
    • Circulating iodine is 95% organic iodine and 5% free iodide; of the organic iodine 95% is T 4 and 5% is T 3
    • To protect circulating T 3 and T 4 they are mostly bound to thyroxin binding globulin (TBG)
    • Amounts of free or unbound hormones are minimal: 0.03% T 4 and 0.3% T 3
    • Only the unbound hormones have metabolic activity
    • In peripheral tissues T 4 is converted to T 3 by iodothyronine 5’-deiodinase found mainly in liver, thyroid, and kidneys
    • The active hormone in most target tissues is T 3
  • 72. T 3 Mechanism of Action
    • T 3 acts on intracellular thyroid hormone receptors (TRs) located in all cells of the body
    • TR monomers interact with retinoic acid X receptor (RXR) to form heterodimers
    • In the absence of T 3 the TR:RXR heterodimer associates with a corepressor complex that binds to DNA to inhibit gene expression
    • In the presence of T 3 , the corepressor complex dissociates, coactivators form to stimulate gene expression
    • Binding to TR dimers thus serves as a molecular switch from inhibition to activation of gene expression
  • 73. Thyroid Hormone Effects
    • Are generally responsible for optimal growth, development, function, and energy levels in all tissues
      • Excess  hyperthyroidism (thyrotoxicosis)
      • Inadequacy  hypothyroidism (myxedema)
    • Main effects include:
      • Nervous, musculoskeletal, and reproductive tissues: nervousness, emotional lability, muscle weakness and fatigue, osteoporosis, menstrual irregularities
      • Calorigenic effect : increased oxygen consumption, sweating
      • Sympathetic hyperactivity due to increased  -adrenergic sensitivity  dramatic cardiovascular effects including: tachycardia, increased stroke volume and cardiac output, high-output heart failure, arrhythmia, angina
      • Metabolic effects : decreased cholesterol and triglycerides; increased basal metabolic rate, hyperglycemia, and appetite
  • 74. Thyroid Preparations
    • Major clinical use of T 3 & T 4 is for hormone replacement therapy in hypothyroidism or cretinism
    • Four preparations now used clinically are:
      • Synthetic levothyroxine [T 4 ] is the preparation of choice for replacement and suppression therapy because of its stability, uniform content, low cost, long half-life (7 days), and conversion to produce both T 3 & T 4
      • Desiccated thyroid, though inexpensive, is not recommended for replacement therapy because of its antigenicity, instability, and variable hormone content
      • Liothyronine, [T 3 ], is 3-4 times more active than levothyroxine, but not recommended for routine replacement therapy because of its higher cost, shorter half-life (24 hours), and greater potential for cardiotoxicity
      • Liotrix , a 4:1 combination of synthetic T 4 and T 3 , is also expensive with the same disadvantages as liothyronine
  • 75. Antithyroid Drugs
    • [1] Thioamides :
    • Methimazole
    • Propylthiouracil
    • [2] Iodides : potassium iodide solution
    • [3] Radioactive Iodine (RAI)
    • [4] Other Drugs :
    • anion inhibitors
    •  -adrenergic blockers
  • 76. Thioamides : Methimazole & Propylthiouracil
    • Both accumulate readily in the thyroid gland for treatment of thyrotoxicosis
    • Methimazole is 10X more active that propylthiouracil
    • Plasma half-lives: 6 hr for methimazole and 1.5 hr for propylthiouracil
    • Slow onset of action requiring 3-4 weeks to deplete T 4 stores
    • Multiple mechanisms of action including:
      • Major action to prevent hormone synthesis by inhibiting peroxidase reactions to block iodine organification
      • Block iodotyrosine coupling
      • Inhibit peripheral deiodination of T 3 & T 4
    • Adverse reactions occur in 3-12% of treated patients:
      • Most common: maculopapular pruritic rash
      • Rarely: urticarial rash, vasculitis, arthralgia, lupus-like reaction, jaundice, hepatitis hypothrombinemia
      • Most dangerous – agranulocytosis
  • 77. Iodides : Potassium Iodide Solution
    • Many thyroid actions including:
      • Inhibition of hormone release by reducing thyroglobulin proteolysis
      • Decrease in size and vascularity of the hyperplastic gland
    • Thyrotoxic symptoms improve within 2-7 days , but should not be used alone because the gland “escapes’ from iodide block after 2-8 weeks and withdrawal may result in severe thyrotoxicosis
    • Chronic use in pregnancy should be avoided as iodides cross the placenta and can cause fetal goiter
    • Advantages are: simplicity, inexpensive, relatively nontoxic, and absence of glandular destruction
    • Adverse reactions, though uncommon, include: acneiform rash, swollen salivary glands, mucous membrane ulceration, conjunctivitis, rhinorrhea, metallic taste, drug fever, bleeding disorders, anaphylaxis
    • Disadvantages are: “escape”, aggravation of thyrotoxicosis, allergic reactions, and increased intraglandular iodine which can delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks
  • 78. Radioactive Iodine (RAI)
    • RAI is the only isotope used for treatment of thyrotoxicosis
    • RAI is given as oral solution, 131 I is rapidly absorbed and concentrated in the thyroid gland
    • Thyroid parenchymal destruction becomes evident within weeks in form of epithelial swelling, necrosis, follicular disruption, edema, and leukocyte infiltration
    • The therapeutic effect depends on emission of beta rays with:
      • Penetration range of 400-2000  m
      • Effective half-life of 5 days
    • Advantages include easy administration, effectiveness, low expense, and absence of pain
    • Major disadvantage is induction of hypothyroidism
    • Main contraindication is pregnancy as RAI crosses the placenta and is excreted in breast milk
  • 79. Anion Inhibitors &  -adrenergic Blockers
    • Monovalent ions as perchlorate (ClO4-), pertechnetate (TcO4-), and thiocyanate (SCN-) block iodide uptake through competitive inhibition of the iodide transport mechanism, but their effectiveness is unpredictable
    • Potassium perchlorate is no longer used clinically because it causes aplastic anemia
    • Iodinated contrast media ( diatrizoate by mouth, or iohexol; IV or oral ) though not FDA approved, act by inhibiting conversion of T 4 to T 3 in liver, kidney, pituitary, and brain
    • Since many symptoms of thyrotoxicosis result from sympathetic hyperactivity,  -adrenergic blockers are also used for treatment
  • 80. Drugs Affecting T 3 -T 4 Synthesis
    • Anions (perchlorate, pertechnetate, and thiocyanate ) compete with I - uptake
    • RAI causes selective thyroid destruction
    • Iodide (high levels) reduce T 3 -T 4 release by inhibiting thyroglobulin proteolysis
    • Thioamides inhibit peroxidase to block organification
  • 81.
    • A 25-year-old woman complains of heat intolerance, excessive sweating, tremors, palpitations, difficulty in swallowing, and muscular weakness. Oral treatment with which of the following will produce relief within 2-7 days?
    • A. Dessicated thyroid
    • B. Levothyroxine
    • C. Methimazole
    • D. Propylthiouracil
    • E. Potassium iodide
    Ans = E Potassium iodide inhibits proteolysis and decreases TH levels in a couple of days; Takes 3 to 4 weeks to lower TH Levels with PTU
  • 82. ADRENOCORTICAL SECRETIONS
    • Endogenous adrenocortical hormones are steroid molecules normally produced and secreted from the adrenal cortex
    • The adrenal cortex has two functionally discrete compartments, which secrete distinctly different hormones:
      • Outer zona glomerulosa secretes the mineralocorticoid  aldosterone
        • Aldosterone secretion from the outer zona glomerulosa is regulated mainly by extracellular K + through angiotensin receptors
      • Inner zonae fasciculata/reticularis secretes the glucocorticoid  cortisol , and adrenal androgens
        • Inner zones do not have angiotensin receptors, but are regulated mainly by ACTH and glucocorticoid production is catalyzed by two enzymes:
          • - 17 α -hydroxylase (P45017 α )
          • - 11 β -hydroxylase(P45011 β )
  • 83. Adrenocortical Hormones *dehydroepiandrosterone Androgenic-estrogenic DHEA* Androgen Salt-retaining Aldosterone Mineralo corticoid Intermediary metabolism Cortisol Gluco corticoid Activity Hormone Class
  • 84. Adrenocorticoid Biosynthesis
    • Synthesis from cholesterol proceeds along three pathways:
      • Mineralocorticoid
      • Glucocorticoid
      • Andro-estrogen
    • Produce 3 major hormones (underlined):
      • Aldosterone
      • Cortisol
      • Dehydroepi-androsterone (DHEA)
  • 85. CORTISOL (hydrocortisone)
    • It is the naturally-occurring glucocorticoid
    • It comes from cholesterol
    • Synthesis and secretion are tightly regulated by the CNS which is very sensitive to negative feedback by:
      • Circulating cortisol
      • Exogenous (synthetic) glucocorticoids
    • 10-20 mg secreted daily following a circadian rhythm regulated by ACTH
    • Half-life 60-90 min
    • 90% bound by corticosteroid binding globulin (CBG) synthesized by the liver; 5-10 % free or loosely bound to albumin
    • Mostly inactivated in the liver:
      • About 20% is converted to cortisone
      • Only 1% is excreted in urine
  • 86. Mechanism of Glucocorticoid Action - 1
    • Act on glucocorticoid receptors
    • There are two types:
      • Type I – mineralocorticoid receptor ; expressed mainly in organs of excretion as kidney, colon, salivary glands, sweat glands
      • Type II – glucocorticoid receptor ; broader tissue distribution
    • Glucocorticoid receptors are primarily cytoplasmic, in form of oligomeric complexes with two molecules of heat shock proteins (Hsp90); shown on next slide
  • 87. Steroid-Receptor Interaction S = Steroid R = Receptor Hsp90 = Heat shock protein 90
    • Free steroid enters cell cytoplasm to release receptor from Hsp90 
    • Steroid-receptor receptor complex enters the nucleus 
    • Binds to the glucocorticoid response element (GRE) 
    • Regulates transcription by RNA polymerase and other factors 
    • mRNA edited and exported to cytoplasm to form protein
  • 88. Mechanism of Glucocorticoid Action - 2
    • Most effects are mediated by widely distributed glucocorticoid receptors that regulate transcription of target genes
    • Glucocorticoids regulate 10-20% of the expressed genes in a cell
    • Glucocorticoid effects are mainly due to proteins synthesized from mRNA transcribed by their target genes
    • Glucocorticoids have anti-growth, anti-inflammatory, and immunosuppressive effects because the transcription factors affected have broad actions on growth factors and proinflammatory cytokines
    • These transcription factors represent targets for new drugs, glucocorticoid agonists or antagonists, that are response or tissue selective
  • 89. Corticosteroid Effects
    • Have many widespread effects on all tissues and organs because almost all cells in the body are affected
    • Most effects are direct while others are “permissive”
    • Major groups of effects are:
        • Anti-inflammatory and immunosuppressive
        • Metabolic
        • Catabolic and antianabolic
        • CNS
  • 90. Anti-inflammatory & Immunosuppressive Effects
    • Manifestations of inflammation are dramatically reduced by:
      • Increasing neutrophils
        • Inactivates neutrophil adhesion molecules causing marginating pool (pool normally adhering to endothelium) to become part of circulating pool
      • Decreasing lymphocytes, monocytes, eosinophils, and basophils
      • Affecting concentration, distribution, and function of leukocytes
      • Suppressing cytokines, chemokines, and other lipid and glucolipid mediators of inflammation
      • Reducing synthesis of prostaglandins and leukotrienes
      • Suppressing mast cell degranulation to reduce histamine release to decrease capillary permeability
    • These changes are responsible for not only for their major therapeutic use but also for serious adverse effects
  • 91. Metabolic Effects
    • These effects contribute to supply adequate glucose to the brain in the fasting state by:
      • Increasing glucose from gluconeogenesis
      • Increasing amino acids from muscle catabolism
      • Inhibiting peripheral glucose uptake
      • Stimulating lipolysis
    • These changes are generally beneficial, but can also cause serious adverse effects even when therapeutic doses are used.
    • Important dose-related effects on carbohydrate, protein, and fat metabolism are to:
      • Stimulate gluconeogenesis and glycogen synthesis ,
      • Release of amino acids during muscle catabolism ,
      • Stimulate hormone-sensitive lipase and lipolysis ,
      • Elevate serum glucose to stimulate insulin release and inhibit glucose uptake by muscle cells:
        • The increased insulin secretion stimulates lipogenesis and inhibits lipolysis to cause increased fat deposition and release of fatty acids and glycerol into the circulation
  • 92. Catabolic & Antianabolic Effects
    • Occur in lymphoid and connective tissues, muscle, fat, and skin
    • Supraphysiologic amounts reduce muscle mass causing weakness and skin thinning
    • Bone effects cause osteoporosis in Cushing’s syndrome and limit long-term therapeutic use
    • Reduced growth in children can be partly prevented with high doses of growth hormone
  • 93. CNS Effects
    • Marked slowing of EEG alpha rhythm and depression
    • Behavioral disturbances initially as insomnia and euphoria followed by depression and/or psychosis
    • Large does may increase intracranial pressure (pseudotumor cerebri)
    • Suppressed pituitary release of ACTH, GH, TSH, and LH ; thus, multiple endocrine effects
  • 94. Other Effects
    • Development of peptic ulcer by suppressing local immune response to H. pylori
    • Promote fat redistribution to increase visceral, facial, nuchal (nape), and supraclavicular fat
    • Antagonize Vitamin D effect of calcium absorption
    • Increase numbers of platelets and erythrocytes
    • Cortisol deficiency impairs renal function and augments vasopressin secretion resulting in an inability to excrete a water load normally
    • Stimulate structural and functional development of fetal lungs including the production of pulmonary surface-active (surfactant) materials required for air breathing
  • 95. Commonly Used Glucocorticoids
  • 96. Synthetic Corticosteroids
    • Traditionally grouped as:
      • Glucocorticoids - affect glucose metabolism and inflammation
      • Mineralocorticoids - affect Na + retention
    • The two groups of effects are usually not closely related and reflect distinct actions at two distinct receptors
    • Separation between classes is not perfect because many steroids classified as glucocorticoids (e.g., cortisol and prednisone) also have some mineralocorticoid activity, while others classified as mineralocorticoids (e.g., fludrocortisone) also affect glucose metabolism
    • Ratios of glucocorticoid to mineralocorticoid potency differ:
      • Betamethasone & dexamthasone have strong anti-inflammatory but no salt-retaining activity
      • Desoxycorticosterone has salt-retaining but no anti-inflammatory activity
    • Because glucocorticoids are widely used for treating various inflammatory, allergic, hematologic, and other disorders, many synthetic steroids with anti-inflammatory and immunosuppressive activity have been developed
    • Corticosteroids without salt-retaining activity should be used whenever electrolyte abnormalities are present
  • 97. Synthetic Corticosteroid Potencies 250 10 Fludrocortisone 20 0 Desoxycorticosterone 0 30 Dexamethasone 0 25-40 Betamethasone 0 5 Triamcinolone 0 5 Methylprednisolone 0.3 5 Prednisolone 0.3 4 Prednisone 0.8 0.8 Cortisone 1 1 Cortisol Na + retention antiinflammatory corticosteroid
  • 98. Therapeutic Uses of Corticosteroids I. Diagnosis and Treatment of Adrenal Disorders
    • Adrenocortical insufficiency (Addison’s disease) –
      • Requires life-long combined glucocorticoid and mineralocorticoid treatment; use hydrocortisone plus a mineralocorticoid like fludrocortisone
      • Do not use glucocorticoids that have no salt-retaining activity
    • Bilateral adrenal hyperplasia (Cushing’s disease) –
      • From an ACTH-secreting pituitary adenoma
      • Main characterics are rounded plethoric face, trunk obesity, muscle wasting, purple striae, skin bruising, and osteoporosis
      • Treat with large doses of hydrocortisone following surgical removal of the tumor
    • Aldosteronism – aldosterone excess resulting from adrenal adenoma
      • treat with spironolactone
    • Dexamethasone suppression test –for diagnosis of Cushing’s syndrome characterized by high cortisol levels that are reduced to 50% by dexamethasone
  • 99. Therapeutic Uses of Corticosteroids II. Treatment of Nonadrenal Disorders Atopic dermatitis, seborrheic dermatitis Skin Prevent rejection Organ transplant Allergic conjunctivitis, uveitis Ocular Inflammatory bowel disease, ulcerative colitis Gastrointestinal Lupus erythematosus, rheumatoid arthritis Collagen-vascular Cerebral edema CNS Angioneurotic edema, anaphylactic & drug reactions, bronchial asthma, hay fever, urticaria Allergy Examples Disorder
  • 100. Nonadrenal Disorders
    • Are very many, diverse, and unrelated
    • Glucocorticoids are not curative in nonadrenal disorders and whenever possible, should be used only to supplement specific treatment for the disease
    • Most commonly used glucocorticoids include: betamethasone, dexamethasone, hydrocortisone, prednisolone, methylprednisolone, and triamcinolone
    • For chronic use proceed carefully with low doses, intermittent administration (i.e., alternate day) and do not discontinue abruptly ; taper doses when stopping
    • Local administration can minimize systemic adverse effects as when using hydrocortisone enemas for ulcerative colitis or inhaled steroids for asthma
  • 101. Toxicity of Synthetic Glucocorticoids
    • When used for < 2 weeks serious adverse effects are infrequent but insomnia, behavioral changes, and acute peptic ulcers may occur occasionally
    • When given for longer periods major adverse effects include:
      • Metabolic adverse effects resulting from the hormonal actions  iatrogenic Cushing’s syndrome manifested in form of moon facies, fat redistributed from extremities to trunk, punctate acne, obesity, muscle wasting, skin thinning, osteoporosis, diabetes, impaired wound healing, etc
      • Other complications include: peptic ulcer, myopathy, acute psychosis, depression, glaucoma, hypertension, fluid retention and edema, etc
      • Adrenal suppression resulting in anorexia, nausea or vomiting, weight loss, lethargy, headache, fever, joint pains, and postural hypotension
    • Should be used with great caution in patients with peptic ulcer, heart disease, hypertension, psychoses, infections, diabetes, osteoporosis, glaucoma, etc
  • 102. MINERALOCORTICOIDS
    • Aldosterone , the most important mineralocorticoid in man, is synthesized in the zona glomerulosa
    • It binds to mineralocorticoid receptors in the distal convoluted and proximal collecting tubules to promote sodium reabsorption
    • Deoxycorticosterone , the precursor of aldosterone, is also normally synthesized and secreted
    • Synthetic fludrocorticosterone , the most commonly prescribed, has potent mineralocorticoid activity that is used for treating adrenocortical insufficiency associated with mineralocorticoid deficiency
  • 103. ADRENOCORTICAL ANTAGONISTS
    • Consisting of various unrelated agents:
      • Metyrapone - a selective inhibitor of steroid synthesis commonly used for testing adrenal function;
      • Ketoconazole – an antifungal agent, which is also, a nonselective inhibitor of adrenal and gonadal steroid synthesis used for treatment of Cushing’s syndrome
      • Mifepristone (RU 486) - a glucocorticoid antagonist with strong antiprogestin activity and has been used as an abortifacient
      • Spironolactone - an aldosterone antagonist, widely used to prevent hypokalemia in treatment of hypertension and congestive heart failure
        • Used to treat hirsutism in women (androgen antagonist)
  • 104.
    • In a 30-year-old woman with a long history of lupus erythematosus, oral treatment with dexamethasone tablets for 4 weeks may aggravate which of the following?
    • A. Anaphylactic reactions
    • B. Bronchial asthma
    • C. Inflammatory bowel disease
    • D. Seborrheic dermatitis
    • E. Diabetes mellitus  
    Ans = E Steroid-induced diabetes
  • 105.
    • For treatment of a 20-year-old asthmatic man who complains of chest tightness and shortness of breath when he exercises, which of the following is a corticosteroid that has no salt-retaining activity?
    • A. Cortisone
    • B. Desoxycorticosterone
    • C. Fludrocorticosterone
    • D. Prednisolone
    • E. Triamcinolone
    Ans = E Given by inhalation for asthma
  • 106. Adverse Effects Adrenal suppression Growth inhibition Diabetes Muscle wasting Osteoporosis Salt retention Psychosis Cataracts
    • Gluconeogenesis
    • Fat deposition
    • Muscle protein catabolism
    • Immunosuppression
    • Anti-inflammatory
     11- β -hydroxylase
    • Lipocortin
    •  COX-2
  • 107. Which of the following proteins is expected to be up-regulated when a 49-year-old woman with rheumatoid arthritis is treated with dexamethasone?
    • Cyclooxygensae-2
    • IgE
    • Lipocortin
    • Phospholipase A 2
    • Thromboxane A 2
    Answer: C Lipocortin inhibits phospholipase A2; Thus, decreasing arrachidonic acid levels  decreasing production of Inflammatory mediators
  • 108. Which of the following is appropriate to reduce the signs and symptoms of Cushing’s syndrome in a 45-year-old man with an adrenal tumor?
    • Betamethasone
    • Fludrocortisone
    • Hydrocortisone
    • Ketoconazole
    • Triamcinolone
    Answer: D Inhibits mammalian synthesis of glucocorticoids and steroid hormones by inhibiting the cytochrome P-450 system and 11 β -hydroxylase
  • 109. ENDOCRINE PANCREAS
    • The pancreas in adult humans
    • Consists of 1 million islets of Langerhans
    • Contains 4 cell types that synthesize and secrete a distinct hormone
    Facilitate digestion Pancreatic polypeptide < 2 F (PP) Inhibit secretory cells Somatostatin 3-5 D (delta) Storage and anabolic hormone Unknown INSULIN C-peptide amylin 75 B (beta) Mobilize glycogen Glucagon 20 A (alpha) Function Hormone % Islet Cell Cell type
  • 110. HUMAN PROINSULIN
    • Insulin comes from proinsulin synthesized in pancreatic B cells
    • Proinsulin is hydrolyzed to release:
      • Insulin
      • C-peptide (no known function)
    • Removal of C-peptide forms insulin, a small protein consisting of 51 amino acids arranged in two chains:
      • A chain = 21 amino acids
      • B chain = 30 amino acids
    • Insulin crystals are stored in secretory granules inside B cells
    • The human pancreas normally contains 8 mg (200 U)
  • 111. Insulin Secretion
    • Upon stimulation by hyperglycemia or insulin secretagogues
      • Intracellular ATP increases to close K + channels in B cell
      • Opens voltage-gated Ca ++ channels
      • Ca ++ enters to increase intracellular Ca ++
      • Insulin is secreted
    • Secretion is increased by various stimuli (sugars, amino acids, secretagogues)
    • Glucose is the principal stimulus
    At rest , B cells have low ATP levels, ATP-gated K + channels are open, K + diffuses out to keep the cell fully polarized (negative) and insulin secretion is minimal
  • 112. Circulating Insulin
    • Blood levels detected by radioimmunoassay in normal subjects are:
      • Basal values of 5-15 mU/mL (30-90 pmol/L)
      • Peak rise to 60-90 mU/mL (360-540 pmol/L) during meals
    • Circulating insulin binds to specialized receptors located on cell membranes of:
      • Liver
      • Muscle
      • Adipose tissues
    • Circulating insulin has a half-life of 3-5 minutes
    • Removed from circulation by insulinase (glutathione insulin transhydrogenase) action in:
      • Liver 60%
      • Kidney 35-40%
  • 113. Insulin Receptor IRS = insulin receptor substrate Tyr = tyrosine P = phosphate
    • Consists of two covalently linked heterodimers each containing:
      •  subunit – extracellular
      •  subunit - spans cell membrane
    • Insulin binds to the  subunit, which sticks out like an antenna, to activate the receptor and bring the catalytic loops of the cytoplasmic  subunit closer together to facilitate tyrosine kinase activity 
    • Activated tyrosine kinase phosphorylates the docking proteins IRS to translate the insulin signal  
    • The phosphorylation network causes translocation of glucose transporters (GLUT4) to the cell membrane 
    • Increase glucose uptake, glycogen formation, and multiple effects of protein synthesis, lipolysis, and lipogenesis
  • 114. Major Target Tissues: Liver, Fat, and Muscle
  • 115. INSULIN EFFECTS
    • Four main sites of action:
    • Glucose transporters to facilitate glucose movement across cell membranes; GLUT 4 is most important for hypoglycemia
    • Liver to increase storage of glycogen and decrease postabsorptive catabolism
    • Muscle to promote protein and glycogen synthesis
    • Adipose tissue to reduce free fatty acids and promote triglyceride storage
    • hypoglycemia results mainly from: inhibition of hepatic glucose production, and stimulation of glucose uptake & metabolism in liver, adipose tissues, and skeletal muscle
  • 116. Outcomes of Diabetes Glycation of proteins     Type 1   Type 2 obesity 
  • 117. INSULIN Preparations
    • Usually injected SC with onset, peak, and duration of action dose related
    • Short-acting or ultrashort acting mimic the post-prandial rise in insulin and given IV for hyperglycemic emergencies or diabetic ketoacidosis
    • NPH, long, and ultra-long acting preparations mimic basal insulin
    • Mixtures used to produce desired times of onset, peak, and duration of action
    • Glargine and detemir are ultra-long-acting, produces a sustained “peakless” absorption profile, and can provide once-daily effective 24-hr plasma levels
  • 118. Five Main Types of Insulin > 24 Glargine & detemir Ultralong-acting 18-24 NPH Intermediate-acting 5-7 Regular Short-acting 3-4 Lispro (Humalog) Aspart (Novolog) Glulisine Ultra-short-acting Duration (hrs) Preparations Insulin Type
  • 119. Types of Diabetes Mellitus Heterogeneous, obesity related, reduced B cells Autoimmune disease of B cells Etiology Insulin resistant Lack of insulin Basic defect 90 (increases with age) 5-10 Incidence (%) Adult < 30 years Age group Type 2 (NIDDM) Type 1 (IDDM)
  • 120. Insulin Therapy
    • Insulin is currently the mainstay treatment in:
      • All type 1 diabetics and
      • Type 2 diabetics not adequately controlled by diet and/or oral hypoglycemic drugs (20%)
    • Injected subcutaneously (abdomen, buttock, anterior thigh, or dorsal arm) for long-term treatment, but may also be given IM or IV
    • Insulin injected SC differs from endogenously secreted insulin in two ways:
      • Does not reproduce the rapid rise and fall occurring when insulin is secreted due to stimulation by ingested food, and
      • Diffuses into the systemic circulation instead of being secreted into the portal circulation (eliminates direct hepatic effects)
    • Ideal goal - to normalize blood glucose and all aspects of glucose metabolism, but this is difficult to achieve
  • 121. Insulin Hypoglycemia
    • Most common complication resulting from delayed meals, unusual physical exertion, or insulin overdose
    • Main signs occurring with plasma glucose of 60-80 mg/dL:
      • Neuroglycopenic - CNS impairment manifested as mental confusion, bizarre behavior, convulsions, or coma
      • Autonomic hyperactivity -
        • Sympathetic (tachycardia, palpitations, sweating, tremors)
        • Parasympathetic (nausea, hunger)
    • Rapidly relieved by giving glucose
      • In patients who can swallow -orange juice or any sugar-containing food or beverage
      • In unconscious patients - IV 50% glucose, 20-50 mL over 2-3 min; last resort glucagon
  • 122. ORAL ANTIDIABETIC DRUGS
    • Used alone or with insulin for type 2 diabetes:
    • Four categories based on hypoglycemic mechanism:
      • Insulin Secretagogues
        • Sulfonylureas
        • Meglitinides
      • Biguanides
        • Metformin
      • Thiazolidinediones (TZDs); -glitazones
        • Rosiglitazone
        • Pioglitazone
      • Alpha-glucosidase inhibitors
        • Acarbose
        • Miglitol
  • 123. Insulin Secretagogues
    • Stimulate insulin release through closing K + channels in pancreatic B cells
    • Chemically may be either
      • Sulfonylureas or
      • A meglitinide (repaglinide) 
  • 124. Sulfonylureas
    • Bind to high-affinity receptors for K + channels in pancreatic B cells 
    • Inhibit K + efflux to cause depolarization  
    • Open voltage-gated Ca ++ channel 
    • Increase Ca ++ influx 
    • Release insulin
    Glyburide Tolbutamide Glipizide Tolazamide Gliclazide Chlorpropamide Glimepiride Acetohexamide Second generation First generation
  • 125. Sulfonylurea Characteristics
    • Also reduce serum glucagon levels
    • Used mainly for treating type 2 diabetics whose hyperglycemia cannot be controlled by diet alone
    • Second generation sulfonylureas are:
      • More effective and cause fewer adverse effects; but more profound hypoglycemia
      • Should be used with caution in diabetics who are elderly or have cardiovascular disease
    • Tolbutamide is safest for elderly diabetics because:
      • Its duration of action is relatively short
      • Severe hypoglycemic episodes are unlikely
  • 126. Meglitinides
    • Increase insulin release from B cells by regulating K + efflux through the K + channel
    • Those available are repaglinide and nateglinide
    • Their site of action includes:
      • A unique binding site and
      • Two other sites in common with the sulfonylureas
    • Used mainly for controlling postprandial glucose levels
    • Use cautiously in the presence of hepatic dysfunction
    • Can be used in type 2 diabetics who are allergic to sulfonylureas because the repaglinide & natglinide structures does not contain a sulfonamide moiety
  • 127. Biguanides: Metformin
    • Mechanism of action uncertain, but does not depend on functioning B cells; proposed mechanisms include:
      • Direct stimulation of tissue glycolysis
      • Reduced hepatic gluconeogenesis
      • Reduced GI glucose absorption
      • Reduced plasma glucagon
    • It is “euglycemic” or antihyperglycemic; does not cause hypoglycemia but reduces fasting or postprandial blood glucose levels
    • Used mainly in:
      • Obese patients with ‘insulin resistance syndrome’
      • Type 2 diabetics who do not respond to sulfonylureas alone
    • Most frequent adverse effects (20% of patients) are gastrointestinal : anorexia, nausea, vomiting, abdominal discomfort, diarrhea
    • Increases the risk of lactic acidosis
    • Contraindicated in patients with renal or hepatic disease, alcoholism, or chronic cardiopulmonary dysfunction
  • 128. Thiazolidinediones (Tzds): Rosiglitazone & Pioglitazone
    • Diminish insulin resistance by enhancing the tissue sensitivity to insulin (i.e., increased glucose uptake and metabolism in muscle and adipose tissues)
      • The –glitazones are insulin sensitizers
    • TZDs are agonists of PPAR-  (peroxisome proliferator-activated receptor-gamma) nuclear receptors found in muscle, fat, and liver
    • PPAR-  activates insulin-responsive genes that regulate carbohydrate and lipid metabolism
    • The major site of TZD action in diabetics are adipose tissues
    • Some beneficial effects may be due to redistribution of body fat causing reduced visceral fat mass and loss of central obesity
    • Also “euglycemic” rather than hypoglycemic; restore normal blood glucose levels without causing hypoglycemia
    • The first one, troglitazone , was withdrawn because of liver damage
    • Rosiglitazone & pioglitazone are clinically effective in type 2 diabetes without producing hepatotoxicity
    • Adverse effects are: edema, anemia, expanded plasma volume; rosiglitazone has been associated with an increased risk of heart failure
  • 129. Sitagliptin (Januvia™)
    • An orally effective dipeptidyl-peptidase-IV (DPP-IV) inhibitor used in the treatment of type 2 diabetes mellitus
    • Potentiates the effects of the incretin hormones, glucagon-like peptide-1 ( GLP-1 ) and glucose-dependent insulinotropic peptide (GIP), by inhibiting their breakdown by DPP-IV
    • Additionally, may improve beta-cell function
    • Indications include:
      • Use as initial combination therapy with metformin in drug-naive patients
      • As add-on therapy to a sulfonylurea
      • As add-on therapy to a sulfonylurea plus metformin
  • 130. Exenatide (Byetta®)
    • An incretin mimetic:
      • Incretins are endogenous compounds, such as glucagon-like peptide-1 ( GLP-1 ), that improve glycemic control once released into the circulation via the gut
    • A 39-amino acid GLP-1 agonist isolated from the salivary gland venom of the lizard Heloderma suspectum (Gila monster)
    • It mimics the enhancement of glucose-dependent insulin secretion and other antihyperglycemic actions of incretins
    • Indicated for the adjunct treatment of type 2 diabetes mellitus inadequately managed by the use of metformin, a sulfonylurea, a thiazolidinedione, or a combination of metformin plus a sulfonylurea or metformin plus a thiazolidinedione
    • It is given via subcutaneous administration
    • Can cause hypoglycemia especially when used with other hyoglycemic agents
    • Pancreatitis
      • The FDA issued information on reports of acute pancreatitis occurring in patients taking exenatide.
  • 131. Pramlintide (Symlin®)
    • It is a synthetic analog of amylin, a hormone co-secreted with insulin from pancreatic beta cells
    • Amylin secretion is absent in patients with type 1 diabetes mellitus and decreased in patients with type 2 diabetes mellitus
    • Amylin affects glucose concentrations by:
      • Slowing of gastric emptying without altering the overall absorption of nutrients
      • Suppression of postprandial glucagon secretion
      • Centrally-mediated modulation of appetite leading to decreased caloric intake
    • Indicated for:
      • Adjunct treatment of type 1 diabetes mellitus in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy
      • Adjunct treatment of type 2 diabetes mellitus in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin
    • Common adverse effects of pramlintide are:
      • Hypoglycemia
      • Nausea
      • Cause weight loss rather than weight gain
    • It is administered by subcutaneous injection
  • 132.
    • In a 26-year old woman with type 1 diabetes, treatment with which of the following insulin preparations has the longest duration of action?
    • A. Aspart
    • B. Glargine
    • C. Lispro
    • D. Regular
    • E. Ultralente
    Ans = B Glargine often referred to as “peak-less” insulin
  • 133.
    • A 65-year-old woman is 5’4”, weighs 120 kg, and has lab values of: fasting blood glucose = 225 mg/dL (normal < 115), glycosylated hemoglobin or HbA1 = 17% (normal 4-6%), and plasma triglycerides = 370 mg/dL (normal 35-160). Oral treatment with which of the following would reduce insulin resistance without damaging the liver in this patient?
    • A. Metformin
    • B. Miglitol
    • C. Proinsulin
    • D. Pioglitazone
    • E. Troglitazone
    Ans = D The –glitazone’s are “ insulin sensitizers”; Troglitazone removed from market because of hepatotoxicity
  • 134.  Disulfiram effect Lactic acidosis Insulin sensitizers PPAR γ
    • Risk of
    • Heart failure
    Repaglinide Nateglinide Pramlintide (Symlyn) = synthetic amylin; multiple effects including anorectic Exenatide (Byetta) GLP-1 from saliva of Gila monster; used when difficult to attain glycemic control Sitagliptin is an orally effective dipeptidyl-peptidase-IV (DPP-IV) inhibitor used in the treatment of type 2 diabetes mellitus
  • 135. A 12-year-old boy with type 1 diabetes mellitus is brought to the Emergency Department complaining of dizziness. Laboratory findings revealed severe, hyperglycemia, ketoacidosis and a blood pH of 7.1. Which of the following medications is most appropriate to treat this boy?
    • Glyburide
    • Metformin
    • Pioglitazone
    • Regular insulin
    • Ultralente insulin
    Answer: D IV regular insulin for this patient
  • 136. Metformin is contraindicated in a alcoholic 49-year-old obese woman with type 2 diabetes mellitus because it may increase the risk of the following?
    • A disulfiram-like effect
    • Excessive weight gain
    • Lactic acidosis
    • Severe hepatotoxicity
    • Severe hypoglycemia
    Answer: C Metformin can cause lactic acidosis when given to patients with: Liver disease Renal disease Cardio/pulmonary disease Alcoholics
  • 137. BONE MINERAL HOMEOSTASIS
    • Major mineral constituents of bone are calcium and phosphate with the largest amounts of both found in bone: of total amounts in the body, bones contain
      • 98% of calcium and
      • 85% of phosphate
    • Average American diets contain about the same amounts of both constituents, but intestinal absorption of phosphate is much higher than that of calcium
    • Renal reabsorption of both constituents is highly efficient averaging
      • 98% for calcium
      • 85% for phosphate
  • 138. General Features of Calcium and Phosphate Homeostasis
    • Total body content and amounts in US diet are almost the same
    • Bone serves as the principal reservoir through constant remodeling and mineral exchange with extracellular fluid
    • Larger amounts of calcium are present in bone and reabsorbed by the kidneys
    • Phosphate is more efficiently absorbed in the intestines
    85 98 Renal tubular reabsorption 70-90 15-25 Intestinal absorption (%) 600-1000 600-1000 Dietary amount (mg/day) 85 98 Body content in bone (%) 1 1-2 Total body content (kg) Phosphate Calcium Constituent Amounts
  • 139. Daily Calcium Turnover
    • Ca ++ enters the body only through the intestine resulting in daily absorption of about 300 mg
    • An obligatory loss of 150 mg/day occurs in mucosal and biliary secretions, and in sloughed intestinal cells; this plus the residual 500 mg remaining from unabsorbed intake adds to a total fecal loss of 650 mg/day
    • Urinary excretion of Ca ++ is determined by tubular reabsorption which is highly efficient: more than 98% of the 9 g filtered daily is reabsorbed
    • The principal regulators of bone homeostasis are:
      • Parathyroid hormone
      • Vitamin D
      • Calcitonin
  • 140. The affects of Vit D, PTH & CT on Calcium & Phosphate Note: Vit D inhibits renal P excretion PTH promotes renal P excretion Vit D & PTH inhibit renal Ca excretion CT promotes both P & Ca excretion
  • 141. The Hormonal Interactions Controlling Bone Mineral Homeostasis
  • 142. Parathyroid Hormone (PTH)
    • Primary function is to keep Ca ++ concentration in the extracellular fluid constant
    • PTH secreted by the parathyroid glands has a plasma half-life of 2-5 min and is rapidly removed by hepatic and renal clearance
    • PTH secretion is determined mainly by plasma Ca ++ concentration: it increases whenever plasma Ca ++ is low, and decreases whenever plasma Ca ++ concentration is high
    • PTH increases plasma Ca ++ concentration by acting on:
      • Bones to increase bone resorption (increase Ca ++ mobilization), and
      • Kidneys to increase reabsorption of Ca ++ ( decrease Ca ++ excretion)
      • But small intestine Ca ++ absorption is unaffected
  • 143. Teriparatide (a PTH analog)
    • Uses
      • Osteoporosis in postmenopausal women at high risk of fracture
      • Primary or hypogonadal osteoporosis in men at high risk of fracture
      • Teriparatide, a PTH analog, is given subcutaneously
    • Adverse effects
      • Hypercalcemia
      • Hyperuricemia
      • Arthralgia
      • Respiratory effects
  • 144. Vitamin D: calcifediol, carcitriol, cholecalciferol, dihydrotachysterol, doxycalciferol, ergocalciferol
    • Formed in skin by ultraviolet irradiation and also found in certain foods
    • Intrinsic and dietary forms of vitamin D are inactive precursors that have to converted to active metabolites of which calcitriol is the most active
    • The primary function is the regulation of Ca ++ homeostasis which it does by acting on:
      • Bones to  bone resorption (  Ca ++ mobilization),
      • Kidneys to  tubular reabsorption (  Ca ++ excretion),
      • Small intestines to  Ca ++ absorption
    • Is the only regulator affecting intestinal Ca ++ absorption
    • Deficiency in children causes rickets resulting in abnormal and retarded bone growth
  • 145. Vitamin D
    • Uses
      • Treatment of vitamin D deficiency
      • Prophylaxis against Vitamin D deficiency
      • Rickets prevention
        • Given with calcium to supplement the diet of infants
      • Hypoparathyroidism (with calcium supplements)
      • Osteoporosis
        • Prevention and treatment
      • Chronic renal disease
        • Calcitriol
        • Paricalcitol (Oral and I.V.)
    • Calcitriol is the preferred drug for management of hypocalcemia in dialysis-dependent renal failure patients
    • Hypervitaminosis D
      • Hypercalcemia
      • Hyperphosphatemia
      • Nephrocalcinosis
        • Calcification of collecting tubule basement membrane
      • Calcification of soft tissues (e.g., skin)
  • 146. Principal Regulators of Ca ++ Homeostasis
    • Both PTH and vitamin D increase
      • Bone resorption
      • Tubular reabsorption
    • Intestinal absorption is increased by vitamin D but unaffected by PTH
    Increase No effect Intestinal absorption Increase Increase Renal reabsorption Increase Increase Bone resorption Vitamin D PTH
  • 147. Secondary Regulators of Mineral Homeostasis
    • Calcitonin = hypocalcemic hormone secreted by parafollicular cells in the thyroid
      • Effects are generally opposite to those of PTH
      • Lowers serum calcium and phosphate by:
        • Inhibiting osteoclastic bone resorption
        • Reducing tubular reabsorption of calcium and phosphate
      • used for treatment of Paget’s disease, hypercalcemia, osteoporosis
    • Glucocorticoids generally inhibit mineral homeostasis by:
      • Antagonizing vitamin D-stimulated intestinal Ca ++ absorption
      • Stimulating renal Ca ++ excretion
      • Blocking bone collagen synthesis
      • Used for reversing hypercalcemia in lymphomas, sarcoidosis, or vitamin D intoxication
    • Estrogens can prevent accelerated bone loss
      • Act by decreasing PTH-induced bone resorption
      • More effective in preventing rather than restoring bone loss
      • Used for treatment or prevention of postmenopausal osteoporosis
      • When prescribing estrogens solely for the prevention of osteoporosis, use only for women at significant risk of osteoporosis; nonestrogen drugs should always be considered as alternatives.
  • 148. Bisphosphonates
    • Pyrophosphate analogs that include alendronate, Clondronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, and zoledronic acid
      • Act by retarding formation and dissolution of hydroxyapatite crystals in the skeleton
      • Bind to hydroxyapatite in bone, inhibiting osteoclast activity
    • Cause gastric irritation and <10% of oral doses is absorbed; jaw osteonecrosis
    • Used clinically for treatment of hypercalcemia associated with malignancy, osteoporosis, syndromes of ectopic calcification, and Paget's disease
    • Alendronate and risedronate given once a week; ibandronate given once a month; must remian in upright position for 30 minutes and take with plenty of water prior to the first meal of the day
    • A once-yearly dosage of zoledronic acid (Reclast®) 5 mg via intravenous infusion reduced the incidence of bone fracture in women with postmenopausal osteoporosis at the most common fracture sites (e.g., hip, spine, and select non-spine sites)
  • 149. Uses of Bisphosphonates
    • Postmenopausal bone loss
      • Alendronate (oral; once a week)
      • Risedronate (oral; once a week)
    • Osteoporosis and compression fractures
      • Alendronate (oral; once a week)
      • Risedronate (oral; once a week)
      • Ibandronate (oral; once a month)
      • Zoledronic acid (I.V.; once a year)
    • Hypercalcemia due to malignancy
      • Clodronate
      • Etidronate
      • Tiludronate
      • Zoledronic acid
    • Paget’s disease
      • Clodronate
      • Etidronate
      • Tiludronate
      • Zoledronic acid
  • 150. Adverse effects of Bisphophonates
    • Reflux esophagitis (gastroesophageal reflux disease; GERD) when taken orally; avoid this by:
      • Taking these drugs on an empty stomach, with at least 8oz water, immediately upon awakening
      • Remaining in an upright position for at least 30 minutes after taking the drug
      • Avoid drinking or eating anything for 30 minutes after taking the drug
    • Bisphosphonates irritate the stomach and esophagus
    • Musculoskeletal pain
    • Hypocalcemia
    • Hypophosphatemia
    • Osteonecrosis (jaw)
  • 151. Other Nonhormonal Agents that affect Bone Mineral Homeostasis
    • Thiazides –are diuretics used in treatment of hypercalciuria
      • Act by: blocking sodium reabsorption in the distal tubule 
      • Increase calcium-sodium exchange in the basolateral membrane 
      • Increase calcium reabsorption 
      • Reduced renal calcium excretion
      • Loop diuretics like furosemide increase calcium excretion but should not used for this purpose
    • Plicamycin (mithramycin) – cytotoxic antibiotic used for treatment of Paget’s disease and hypercalcemia
      • Unknown mechanism of action
  • 152. Osteoporosis
    • Abnormal bone loss predisposing to fractures; most common in postmenopausal women but also occurs in older men
    • Aside from menopause or aging, osteoporosis can result from:
      • Chronic treatment with glucocorticoids or other drugs
      • Endocrine disorders like thyrotoxicosis or hyperparathyroidism
      • Malabsorption syndrome
      • Alcohol abuse
      • Idiopathic (without obvious cause)
    • Postmenopausal osteoporosis is due to estrogen deficiency and best treated with cyclic doses of estrogen
    • Raloxifene is a partial estrogen agonist used to prevent postmenopausal osteoporosis; it has beneficial effects on bone but without affecting the endometrium or breast
    • Idiopathic osteoporosis in elderly men is usually treated with vitamin D together with dietary calcium
  • 153.
    • A 70-year-old woman has a history of repeated fractures and bone mineral density measurement –2.45 SD below the mean reference. Which of the following can be used to increase intestinal Ca ++ absorption in this patient?
    • A. Parathyroid hormone
    • B. Calcitonin
    • C. Ibandronate
    • D. Raloxifene
    • E. Dihydrotachysterol  
    Ans = E Only, Vitamin D preparations directly increase intestinal absorption of ca lcium
  • 154.
    • Treatment with testosterone enanthate in a 60-year-old woman is likely to produce which of the following?
    • Breast engorgement
    • Endometrial bleeding
    • Endometriosis
    • Hirsutism
    • Postmenopausal osteoporosis
    Ans = D Testosterone masculinizes the female
  • 155. -relin = hypothalamic Osteoporosis Malignancy
  • 156. Which of the following is appropriate for thyroid involution induction prior to thyroidectomy in a 24-year-old woman with hyperthyroidism?
    • Levothyroxine
    • Potassium iodide
    • Propylthiouracil
    • Protirelin
    • Thyrotropin
    Answer: B Give KI a few days before surgery to shrink the gland and reduce bleeding due to surgery
  • 157. Which of the following is appropriate for the inhibition of uterine contraction during premature labor in a 27-year-old woman?
    • Albuterol
    • Dinoprostone
    • Ergonovine
    • Magnesium sulfate
    • Oxytocin
    Answer: D Magnesium sulfate delays labor
  • 158.  FSH secretion  LH secretion 5 α -reductase BPH -utamide
  • 159. Which of the following is appropriate for the treatment of a locally confined Stage C prostate cancer in combination with leuprolide and radiation therapy in a 59-year-old man?
    • Anastrozole
    • Finasteride
    • Flutamide
    • Methyltestosterone
    • Tamoxifen
    Answer: C Flutamide is an adrogen blocker; Antagonizes the results of the initial surge of LH & FSH secretion prior to their inhibition when leuprolide is given continuously
  • 160. Which of the following is recommended as adjuvant therapy for axillary node-positive breast cancer in 55-year-old postmenopausal woman who has had segmental mastectomy, axillary dissection, and breast irradiation to decrease the incidence of developing a contralateral breast cancer?
    • Clomiphene
    • Flutamide
    • Leuprolide
    • Mifepristone
    • Tamoxifen
    Answer: E Tamoxifen used both to prevent and treat breast cancer
  • 161. AGENTS TO TREAT ANEMIA
    • Anemia may arise from failure to make sufficient red blood cells or to synthesize adequate quantities of hemoglobin
    • Types of anemia
      • Microcytic
      • Macrocytic
      • Other anemia’s
  • 162. Drugs Used to Treat Anemia
    • Microcytic anemia
      • Ferrous sulfate
      • Ferrous gluconate
      • Ferrous fumarate
      • Iron dextran
      • Iron Antidote
        • Deferoxamine
    • Macrocytic anemia
      • Folic acid
      • Leucovorin
      • Cyanocobalamin
      • Hydroxocobalamin
    • Other anemia
      • Epoetin alfa (Erythropoietin)
      • Sargramostim (GM-CSF)
      • Filgrastim (G-CSF)
      • Oprelvekin (IL-11)
  • 163. Anemia
    • Symptoms:
      • Paleness
      • Fatigue
      • Shortness of breath
      • Exercise intolerance
      • Increased heart rate
    • Causes of anemia: Abnormally low level of hemoglobin resulting from:
      • A decrease in the amount of hemoglobin per RBC
    • Microcytic, hypochromic anemia
      • A decrease in the number of circulating RBC’s
    • Megaloblastic, hyperchromic anemia
      • A decrease in hemopoietic growth factors, especially erythropoietin
    • Normocytic anemia or mixed
  • 164. MICROCYTIC HYPOCHROMIC ANEMIA Iron deficiency  Impaired hemoglobin synthesis  Small red cells with insufficient hemoglobin  Microcytic hypochromic anemia MEGALOBLASTIC ANEMIA Vitamin B 12 or folic acid deficiency  Impaired DNA synthesis  Impaired production and maturation of erythroid precursors  Macrocytic hyperchromic anemia
  • 165. Iron
    • Physiological functions of iron:
      • Required for hemoglobin synthesis
      • Co-factor in such enzymes as the cytochromes
      • Required for myoglobin synthesis
  • 166. Pharmacokinetic Properties of Iron
    • Absorption: in duodenum and proximal jejunum
      • Involves active transport of ferrous iron , which is oxidized to ferric iron in the intestinal mucosa
      • Ferric iron can be stored as ferritin in the intestinal mucosa, or it can be transported by transferrin to other sites
      • Only 5-10% of dietary elemental iron (10 to 15 mg/day) is absorbed (mucosal block)
      • Heme-iron from meat can be absorbed with iron in ferric state
      • Low iron stores ( ferritin in intestinal mucosal cells) increase iron absorption and the rate of erythropoiesis
      • Absorption is decreased by food, metal chelators, antacids, fluoroquinolones, and tetracycline
      • Absorption is increased by hydrochloric and large amounts of ascorbic acid
      • Gastric resection or surgical removal of the upper region of the small intestine impairs iron absorption
  • 167. Pharmacokinetic Properties of Iron
    • Distribution:
      • Transferrin is a specific ferric iron transport protein
      • Erythroid cells have transferrin receptors , thus, iron is actively transported into hemoglobin-synthesizing cells in the bone marrow
      • Ceruloplasmin converts ferrous iron to the ferric state, and this copper-containing, plasma protein appears to be important for cellular uptake of iron
      • 10-20% total iron stored in ferritin and hemosiderin, which are stored in macrophages in liver, spleen and bone marrow
      • 70% in hemoglobin (red cells)
      • 10% in myoglobin (muscles)
      • 1% in cytochromes and transferrin
  • 168. Pharmacokinetic Properties of Iron
    • Excretion:
      • There is no specific mechanism for excreting iron
      • Iron balance is regulated by intestinal absorption
      • About 1 mg of iron is lost daily by such processes as exfoliation of mucosal cells, which contain ferritin
  • 169. Causes of Iron Deficiency
    • Inadequate dietary intake: rare in USA
    • Malabsorption
    • Increased requirements: growth, pregnancy, and menstruation
    • Blood loss (bleeding, cancer)
    • Iron deficiency
    • Storage iron decreases then disappears
    • e.g., loss of hemosiderin granules in bone marrow
    • Serum ferritin decreases (< 10  g/L)
    • Good indicator of iron status
    • Serum iron decreases (< 40  g/dL)
    • Total iron-binding capacity of transferrin increases (> 400  g/dL)
    • due to decreased saturation (< 10%)
    • Onset of anemia
    40/400 = 10 %
  • 170. Treatment of Iron-deficiency Anemia
    • Oral: ferrous salts are DOC for iron deficiency anemia:
      • Ferrous sulfate
      • Ferrous gluconate
      • Ferrous fumarate
      • Treatment results in a rapid increase in reticulocytosis, and a measurable response to iron therapy should be detectable within one week
      • Normal hemoglobin levels should be reached in 1-3 months
        • Normal hemoglobin levels:
          • 14-18 g/dL for men
          • 12-16 g/dL for women
      • Treatment should last 3-6 months or longer if the dose of iron was decreased due to intolerance
    • Parenteral iron : Iron dextran >>>> should be used rarely
      • Patients with gastric or small bowel resections
      • Patients with inflammatory bowel disease involving the proximal small intestine
  • 171. Adverse Effects of Iron
    • G astrointestinal irritation
    • Acute toxicity from oral iron : seen as acute poisoning in children; treat with iron-chelating drug, deferoxamine
      • Symptoms: G.I. irritation; necrosis; nausea, cyanosis; hematemesis; green and tarry stools; cardiovascular collapse; metabolic acidosis
    • Acute toxicity from iron dextran : Headache, Light headedness, Fever, Arthralgia, Nausea, Vomiting, Back pain, Flushing, Urticaria, Bronchospasm, Anaphylaxis (rare)
    • Small doses of iron dextran should be given first to check for signs of immediate hypersensitivity
    Can cause death
  • 172. Chronic Toxicity of Iron
    • Men with high meat diet?
    • Hemochromatosis : Excessive iron absorption (inherited disorder)
    • Hemosiderosis: Result of numerous blood transfusions
    • Iron overload may also occur in the presence of anemia other than that caused by iron deficiency, such as the anemia of chronic disease or hemolytic anemia.
    • Excess iron deposited in heart, liver, pancreas and other organs.
    • In the absence of anemia, iron overload is treated by phlebotomy . One unit of blood removes 250-mg iron.
  • 173. Folic Acid
    • Physiological functions :
      • Essential for normal synthesis of DNA and normal mitosis of proliferating cells
      • Conversion of folic acid to cofactors required for purine and pyrimidine synthesis
    • Folate (F)
    • Dihydrofolate reductase (DHFR)
    • Dihydrofolate (FH 2 )
    • Dihydrofolate reductase (DHFR)
    • Tetrahydrofolate (FH 4 )
    • 1-carbon donors
    • 5-CH 3 -FH 4 5-CHO-FH 4 10-CHO-FH 4 5,10-CH 2 -FH4 5,10-CH+=FH 4
    Dietary Folate Requires B-12 for Utilization   Folate supplements
  • 174. Folic Acid
    • Sources: Diet (not synthesized) from plants and animals.
      • Yeast, liver, kidney and green vegetables
    • Pharmacokinetic properties:
      • Absorption:
      • Readily and completely absorbed from small intestine by active transport system
      • 50-200  g folate absorbed daily (10-25% of folate in diet)
      • Absorption is increased in pregnancy, but so is demand
    • Polyglutamate forms of folate (5-CH 3 -FH 4 )
    • Conjugase (glutamyl transferase)
    • Monoglutamate forms of 5-CH 3 -FH 4
    • Active and passive transport in proximal jejunum
    • Requires B-12 for
    • utilization
  • 175. Folic Acid
    • Distribution:
      • Liver and other tissues store 5-20 mg of folate
      • Major dietary and storage form is 5-CH 3 -FH 4
      • Because the body stores relatively little folic acid (relative to the high demand), megaloblastic anemia can develop in 1-6 months following folate deficiency
    • Excretion:
      • Folates are metabolized and excreted in urine and feces.
      • Serum levels decline within days when intake is diminished.
    Deficiency can occur relatively fast
  • 176. Deficiency
    • Inadequate dietary intake
      • Alcoholics
    • Increased requirement:
      • During pregnancy
      • Renal dialysis (blood folates are removed by dialysis)
      • Proliferative disorders (e.g., cancer, leukemia, certain chronic diseases and skin disorders)
      • Hemolytic anemia
    • Interference with utilization by other drugs: anticonvulsant drugs such as: phenytoin, primidone, and mephobarbital, also oral contraceptives and isoniazid
    • Malabsorption syndromes: patients with high rates of cell turnover (hemolytic anemia); alcoholism/poor liver function
     Occurs frequently
  • 177. Therapeutic Use
    • Treatment of folate deficiency
    • Give during pregnancy -- maternal folate deficiency is associated with neural tube defects (spina bifida)
    • Coronary heart disease:
      • Hyperhomocystinemia (high levels of homocysteine) is a possible risk factor
      • Conversion of homocysteine to methionine requires folic acid and vitamin B 12
      • Thus, low methionine levels with folic acid or B 12 deficiency
      • Clinical studies are ongoing to determine whether folic acid and/or vitamin B 12 supplements reduce the risk of coronary heart disease
  • 178. Vitamin B 12
    • Physiological function: essential for normal synthesis of DNA and for maintenance of myelin throughout the nervous system
      • DNA synthesis : vitamin B 12 is required to convert 5-CH 3 -FH 4 (the dietary form) to FH 4 ; FH 4 (more specifically its derivative 5,10-CH 2 -FH 4 ) is required to convert dUMP to dTMP
      • Lipid synthesis : vitamin B 12 is required to convert methylmalonyl-CoA to succinyl-CoA
      • Amino acid synthesis: vitamin B 12 and folate are required to convert homocysteine to methionine
  • 179. Vitamin B 12 Deficiency and the Methylfolate Trap
    • 5-CH 3 -FH 4
    • (Major dietary and storage form)
    •  vitamin B 12
    • Tetrahydrofolate (FH 4 )
    • Other 1-carbon donors
    • Nucleotides (dUMP & dTMP)
    • In vitamin B 12 deficiency, levels of 5-CH 3 -FH 4 increase (trapped) with a decrease in the other forms of folate required for nucleotide synthesis
    • This defect can be circumvented by administration of folic acid, which can be reduced to tetrahydrofolate by dihydrofolate reductase (DHFR)
    • Thus, the defects in nucleotide synthesis caused by vitamin B 12 deficiency can be corrected by folic acid treatment
  • 180. Structure of Vitamin B 12
    • Porphyrin-like ring system complexed with cobalt
    • Different ligands attached to cobalt produce several forms of cobalamin
      • Active form: R = 5’-deoxyadenosyl or methyl group
      • Drugs: R = Cyano (CN-) or hydroxy (OH-)group
      • Food: R = various ligands
    • Drugs and dietary cobalamins are converted to active forms in the body
  • 181. Vitamin B 12
    • Sources:
      • Food (microbial origin); meat (liver), eggs and dairy products
      • Not synthesized in humans (Extrinsic factor)
    • Pharmacokinetic properties:
      • Absorption: requires intrinsic factor (IF):
        • Glycoprotein synthesized by parietal cells of stomach
        • IF binds vitamin B 12 , and this complex is absorbed in ileum
        • Intrinsic factor is not used as a drug
      • Distribution:
        • Transported via transcobalamin II, a plasma glycoprotein
        • Excess stored in liver: thus it takes 3-6 years to deplete stores from body (since it has long half-life, only given once a month in patients who cannot absorb it from diet)
      • Excretion: occurs in bile but undergoes enterohepatic circulation and most is reabsorbed from small intestine; when transcobalamin II is saturated excess is excreted in urine
    IF is never used as a drug Deficiency occurs very very slow
  • 182. Causes of Vitamin B 12 Deficiency
    • Lack of intrinsic factor: pernicious anemia
    • Treat with Vitamin B 12 not with intrinsic factor
    • Lack of receptors for IF/B 12 complex in ileum
    • Fish tapeworm infections
    • Patients with gastrectomy
  • 183. Therapeutic Uses
    • Therapeutic uses :
      • Only approved use is treatment of vitamin B 12 deficiency
      • Usually given by intramuscular injection
      • Vitamin B 12 is nontoxic even in large amounts
    • Preparations :
      • Cyanocobalamin :
        • Available nasally, orally, and parenterally, usually given parenterally
        • Unlike hydroxocobalamin, cyanocobalamin does not cause an antibody response to hydroxocobalamin-transcobalamin II complex
        • Preferred agent for long-term use
      • Hydroxocobalamin :
        • Is highly protein bound and remains in circulation longer
        • Some patients produce antibodies against hydroxocobalamin-transcobalamin II complex
        • Also, now used for treatment of cyanide poisoning (known or suspected)
  • 184. Vitamin B 12 versus Folic Acid Deficiency
    • It is important to diagnosis the cause of megaloblastic anemia so that corrective therapy can be initiated appropriately with either vitamin B 12 or folic acid .
    • Clinical tests:
      • Red cell levels of folic acid (more reliable than serum levels)
      • Serum levels of vitamin B 12
    Since folic acid can reverse the hematological damage due to vitamin B 12 deficiency but not the neurological changes, one must differentiate between folate deficiency and vitamin B 12 deficiency
  • 185. Two-stage Schilling Test
    • Used to determine the cause of vitamin B 12 deficiency.
      • The test involves the oral administration of radioactive vitamin B 12 with and without pig intrinsic factor, after which the presence of radioactivity in the urine is determined (a positive result proving that vitamin B 12 was absorbed).
      • A negative result ( i.e., impaired absorption) of both free vitamin B 12 and vitamin B 12 complexed with pig intrinsic factor indicates malabsorption in the distal ileum (perhaps due to inflammatory bowel disease or small bowel resection).
      • A negative result ( i.e., impaired absorption) of just vitamin B 12 indicates malabsorption due to lack of intrinsic factor (perhaps due to gastrectomy or pernicious anemia).
  • 186. (Addisonian) Pernicious Anemia
    • Megaloblastic anemia due to B 12 deficiency resulting from lack of production of intrinsic factor by the parietal cells of the gastric mucosa.
    • Accompanied by achlorhydria.
    • Generally observed in older men and women of northern European extraction ( e.g., Scandinavians).
    • Five years or more may elapse between loss of intrinsic factor and the development of megaloblastic anemia, which is how long it takes to deplete liver stores of vitamin B 12 .
    • Treatment with parenteral vitamin B 12 should not be delayed after gastrectomy (or surgical procedures and diseases that would impair B 12 absorption), and should be continued for life.
     Often seen first
  • 187. Other Anemias
    • Bone marrow failure, causing decreased red cell production, may result from:
      • Myelofibrosis and Multiple myeloma: affect bone marrow directly
      • Myelosuppressive chemotherapy: antitumor agents; drugs used to treat AIDS; immunosuppressive agents
      • Deficiency of hematopoietic growth factors: chronic renal failure (erythropoietin deficiency)
  • 188. Drugs Used to Treat Bone Marrow Failure
    • Epoetin alpha (Erythropoietin):
      • A glycoprotein that stimulates red cell production
      • Derived from genetically modified cells of Chinese hamster ovary
      • Used in treatment of anemia patients with chronic renal failure and in cancer patients receiving chemotherapy
    • Sargramostim (GM-CSF):
      • Recombinant granulocytic-macrophage colony stimulating factor
      • Promotes myeloid recovery in patients with non-Hodgkin's lymphoma, acute lymphoblastic leukemia, and Hodgkin's disease who are undergoing bone marrow transplantation
      • Promotes myeloid recovery after standard-dose chemotherapy
      • Treats drug-induced bone marrow toxicity or neutropenia associated with AIDS
    • Filgrastim (G-CSF):
      • Recombinant colony stimulating factor
      • Prevents and treats chemotherapy-related febrile neutropenia, for promotion of myeloid recovery in patients undergoing bone marrow transplantation
    • Oprelvekin (IL-11)
      • Promotes megakaryopoiesis
      • See Immunopharmacological Agents
  • 189. Summary on Agents Used to Treat Anemia
    • Cause Inadequate iron Inadequate globin synthesis Inadequate
    • RBC synthesis
    • Deficiency Iron Folic acid Vitamin B 12 Erythropoietin
    • Low stores, Large stores,
    • quick onset slow onset
    • Differential Microcytic Megaloblastic Megaloblastic plus Normocytic/normochromic
    • Diagnosis Hypochromic neurologic defects Mixed-type anemia
    • Low iron, ferritin Low folic acid Low vitamin B 12 Low erythropoietin
    • Schilling test
    • Major factors Blood loss Decrease intake Decreased intake Kidney failure
    • Dietary insufficiency No intrinsic factor Chronic disease
    • Malabsorption Malabsorption Cancer
    • Impaired metabolism Infection
    • DHFR inhibitors Inflammation
    • Increased utilization Cytotoxic drugs
    • Pregnancy
    • Malignancy
    • Hemolytic anemia
    • Renal dialysis
    • Treatment Ferrous iron Folic acid Cyanocobalamin Erythropoietin
  • 190. Folate vs. B-12 deficiency
  • 191. Which of the following would be most appropriate for the treatment of normocytic anemia in a 62-year-old woman with chronic renal failure?
    • Erythropoietin
    • Ferrous sulfate
    • Folic acid
    • Oprelvekin
    • Vitamin B-12
    Answer: A Erythropoietin is made in the kidney; lack of it causes normocytic anemia
  • 192. A 25-year-old pregnant woman in her 4 th month of pregnancy was diagnosed with macrocytic anemia. Which of the following would her infant have a higher than normal risk of?
    • Cardiac abnormality
    • Congenital neutropenia
    • Liver damage
    • Limb deformity
    • Neural tube defect
    Answer: E Folic acid deficiency leads to neural tube defects
  • 193. Drugs Used in Disorders of Coagulation
    • Platelet inhibitors
    • Anticoagulants
    • Drugs for bleeding disorders
    • Thrombolytic drugs
  • 194. Platelet Inhibitors
    • COX-1 -> TXA 2
      • Aspirin
      • NSAIDs
    • ADP antagonists
      • Ticlodipine
      • Clopidogrel
    • Platelet-receptor glycoprotein inhibitors
      • Abciximab
      • Tirofiban
      • Eptifibatide
    • Miscellaneous
      • Dipyridamole
      • Cilostazol
      • Anagrelide
  • 195. Anticoagulants
    • Accelerate ATIII activity
      • Heparin (UFH)
      • LMWH
        • Enoxaparin
        • Dalteparin
        • Tinzaparin
      • Fondaparinux
    • Thrombin inhibitors
      • Hirudin (The rudin’s)
      • Lepirudin
      • Desirudin
      • Bivalirudin
      • Argatroban
    • Vitamin K epoxide reductase inhibitor
      • Warfarin
    Note all names contain PAR
  • 196. Thrombolytic Drugs
    • Streptokinase
    • Urokinase
    • Alteplase
    • Reteplase
    • Tenecteplase
  • 197. Drugs Used for Bleeding Disorders
    • Vitamin K
      • Warfarin antidote
    • Antihemophillic factor
    • Plasma clotting factors
    • Fibrinolytic inhibitors
      • Aminocaproic acid
    • Protamine sulfate
      • Heparin antidote
  • 198. Physiological Hemostasis (platelets) Vessel damage ( injury to endothelial cell wall)  Vasospasm (vessel constriction )  Platelet adhesion (platelets bind to damaged vessel via GP Ia, which binds to collagen, and GP Ib, which binds von Willebrand factor)  Platelet aggregation (platelets bind to themselves via GP IIb/IIIa, which also binds fibrinogen and other macromolecules)  Viscous metamorphosis (loss of individual platelet membranes to form a gelatinous mass)  Temporary hemostasis endothelin Phase 1 Platelet Plug
  • 199. Physiological Hemostasis (clot formation)  Coagulation triggered by damaged vessels (collagen and platelet factors)  Thrombin formation  Thrombin-induces release of platelet ADP and serotonin , and prostaglandin synthesis from platelet arachidonic acid  Increased thromboxane synthesis in platelet (pro-thrombogenic) with decreased prostacyclin synthesis in damaged vessel wall (anti-thrombogenic)  Thrombin-induced conversion of fibrinogen to fibrin  Reinforcement of thrombus with fibrin for long-lasting hemostasis Phase 2 Fibrin Plug TXA 2 PGI 2
  • 200. Blood Coagualtion
    • Cascade of enzymatic reactions leading to a fibrin clot (see Fig on next slide)
    • Zymogen -> Active Protease
    • Prothrombin (II) -> Thrombin (IIa)
    • Activation of both intrinsic & extrinsic systems leads to the conversion of prothrombin (II) to thrombin (IIa)
    • Prothrombin is bound by calcium to phospholipids on the platelet surface, whereas thrombin is released into the circulation
     Example
  • 201. Coagulation Cascade Greatest effect  of heparin Greatest effect  of LMWH
  • 202. Intrinsic Coagulation
    • All required factors are present in blood and coagulation is initiated by collagen from damaged blood vessel
    • Factors II, VII, IX, and X are not limiting
    • This system is slow
    • Measured by partial thromboplastin time (PTT)
    • Used to monitor heparin therapy
  • 203. Extrinsic Coagulation
    • Requires tissue factor (tissue thromboplastin, factor III)
    • Factors II, VII, IX, and X are limiting
    • This system is fast
    • Measured by one-stage prothrombin time (PT)
    • Used to monitor warfarin therapy
  • 204. Risk Factors for Thromboembolism Abnormalities of blood flow
    • Atrial fibrillation
    • Left ventricular dysfunction
    • Ischemic/idiopathic myocardiopathy
    • Congestive heart failure
    • Bed rest/immobilization/paralysis
    • Venous obstruction from tumor/obesity or pregnancy
  • 205. Risk Factors for Thromboembolism Abnormalities of surface in contact with blood
    • Vascular injury/trauma
    • Heart valve disease
    • Heart valve replacement
    • Atherosclerosis
    • Acute myocardial infarction
    • Indwelling catheters
  • 206. Risk Factors for Thromboembolism Abnormalities of clotting factors
    • Endogenous anticoagulants
      • Protein C deficiency
      • Protein S deficiency
      • Antithrombin III deficiency
    • Antiphospholipid antibody syndrome
    • Estrogen therapy
    • Pregnancy
    • Malignancy
    Vitamin K-dependent ↑ clotting factors 
  • 207. Arterial Thrombosis Platelets > fibrin (white thrombus) High Pressure
    • Local ischemia
    • Myocardial infarction
    • Unstable angina
    • Stroke
    • Prophylaxis
      • Antiplatelet Therapy
  • 208. Venous Thrombosis Fibrin > platelets (red thrombus) Low Pressure
    • Deep venous thrombosis (DVT)  pulmonary embolism
    • Prophylaxis
      • Anticoagulant therapy
  • 209. Antithrombotic Drugs    Clopidogrel COX-1
  • 210. Aspirin (Acetylsalicylic acid)
    • Inhibits the synthesis of thromboxane A 2 (TXA 2 ) by irreversible acetylation of cyclooxygenase (COX-1) in platelets
    • TXA 2 increases the PIP 2 pathway in platelets causing aggregation (reduced by aspirin)
    • TXA 2 is a potent stimulator of platelet activation and vasoconstriction
    • COX-1 is in platelets and is inhibited by low doses of aspirin
    • COX-2 is in endothelial cells -> PGI 2 (inhibited by high doses of aspirin and COX-2 inhibitors); causes platelet inhibition and vasodilatation
  • 211. Aspirin (as an antiplatelet drug)
    • Useful in preventing or reducing the risk of myocardial infarction and recurring transient ischemic attacks (TIAs) due to its antithrombotic effects
    • Antithrombotic effects on platelets are seen 1 to 2 days after administration and lasts for the duration of the platelets life-span (7 to 10 days)
    • Stop aspirin 1 week before surgery
    • Stop other NSAIDs 2-3 days before surgery
  • 212. Ticlopidine (Ticlid)
    • Interferes with ADP-induced binding of fibrinogen to platelet membrane at specific receptor sites
    • Inhibits platelet adhesion and platelet-platelet interactions
    • Indicated as alternative to aspirin to prevent an initial or recurrent thromboembolic stroke
    • Also useful for myocardial reinfarction prophylaxis
    • Administered orally
    • Rapidly and well (>80%) absorbed
    • Extensively metabolized
    ADP antagonist
  • 213. Ticlopidine (Ticlid)
    • Rare cases of severe bone marrow toxicity limits use to patients who are intolerant or unresponsive to aspirin
    • Increases liver functional enzymes
    • Drug interactions
      • Increased bleeding occurs when given with:
        • Warfarin
        • Heparin
        • Other antiplatelet drugs
        • NSAID drugs
      • Cimetidine decreases its clearance
      • It decreases the clearance of theophylline
    • Usually clopidogrel is preferred over ticlodipine
    Less drug-drug interactions than clopidogrel
  • 214. Clopidogrel (Plavix)
    • Similar mechanism to ticlopidine but has a lower incidence of adverse cutaneous, gastrointestinal, or hematologic reactions than ticlopidine
    • It is used to reduce atherosclerosis in patients with a history of recent stroke, recent MI, or established peripheral vascular disease
    • It inhibits the activity of CYP2C9 and therefore may increase the plasma concentrations of drugs such as:
      • Fluvastatin
      • Many NSAIDs
      • Phenytoin
      • Tamoxifen
      • Tolbutamide
      • Warfarin
    • Ticlodipine is only preferred over clopidogrel if drug-drug interactions are difficult to manage
    Many drug-drug interactions
  • 215. Abciximab (ReoPro)
    • A member of a class of drugs called platelet-receptor glycoprotein inhibitors
    • Given IV to high-risk patients undergoing coronary angioplasty and patients undergoing angioplasty, atherectomy and stent placement often with clopidogrel
    • Inhibits platelet aggregation by preventing binding of fibrinogen, von Willebrand factor, and other adhesive molecules to glycoprotein receptor IIb/IIIa on activated platelets
    • Bleeding is most common adverse effect
    Expensive
  • 216. Other Platelet-Receptor Glycoprotein Inhibitors
    • Tirofiban (Aggrast)
      • a non-peptide
    • Eptifibatide (Integrilin)
      • a cyclic peptide
    • These are intravenous platelet glycoprotein IIb/IIIa inhibitors similar to abciximab, but they are not monoclonal antibodies
  • 217. Dipyridamole (Persantin)
    • A coronary vasodilator that also inhibits platelet aggregation
    • In combination with aspirin, reduces thrombosis in patients with thrombotic disease
    • In combination with warfarin, inhibits embolism from prosthetic heart valves (main use)
    • Mechanism not clear >>> but in part due to increase in cAMP because of inhibition of phosphodiesterase
  • 218. Cilostazol (Pletal)
    • Antithrombotic, antiplatelet and vasodilatory action
    • Inhibits phosphodiesterase type III, and thereby, increases cAMP levels
    • Used for intermittent claudication and peripheral vascular disease
  • 219. Anagrelide (Agrylin)
    • Reduces elevated platelet counts in patients with essential thrombocytosis (too many platelets)
    • Inhibits megakaryocyte development in the late postmitotic stage
    • Approved for the treatment of thrombocytocytosis secondary to myeloproliferative disorders, such as, polycythemia vera and chronic myelogenous leukemia to reduce the risk of stroke and myocardial infarction
    Inhibits formation of platelets
  • 220. General Mechanisms of Anticoagulation
    • Calcium chelators : inhibit blood coagulation in vitro (oxalic acid; sodium citrate; disodium edetate [EDTA])
    • Heparins : accelerates the action of antithrombin III to neutralize thrombin & other coagulation factors
    • Rudins : direct thrombin inhibitors
    • Coumarin derivatives: interfere with the hepatic synthesis of functional vitamin K-dependent clotting factors
  • 221. Standard Heparin (UFH)
    • Source : Porcine intestinal mucosa and bovine lung
    • Structure: Sulfated mucopolysaccharide (acidic molecule)
    • Formulations : Standard, unfractionated heparin (UFH) polymer (3,000 – 30,000)
      • Average = 12,000 to 15,000 g/mol
    • Route of administration:
      • Continuous (infusion pump)
      • Intermittent (subcutaneous)
      • Not oral due to lack of absorption
      • Not IM due to risk of hematoma at injection site
    • Onset of action : Immediate
  • 222. Standard Heparin (UFH)
    • Endothelial cell/protein binding:
      • Extensive (sticky molecule)
      • Clearance is dose-dependent because plasma levels of heparin increase considerably once binding sites are saturated
      • Dose-dependent pharmacokinetics
    • Therapeutic goal: Prolong Partial Thromboplastin time (PTT) to 1.5 to 2.5 times normal (measured just before next dose for intermittent therapy)
    Most drugs are dose-independent
  • 223. Standard Heparin (UFH) Mechanism of action
    • The protease inhibitor, antithrombin III , forms a 1:1 complex with clotting factor proteases
    • This interaction is slow, but is stimulated 1000 fold by heparin, which binds to antithrombin III
    • The heparin-antithrombin III complex inactivates factor IIa (thrombin); main mechanism
    • The heparin-antithrombin III complex also inactivates factor Xa, which occurs earlier in the cascade
    • During active thrombosis, the anticoagulant effect of heparin is primarily due to inactivation of thrombin (IIa)
    • With little or no thrombosis, the anticoagulant effect is largely due to inactivation of factor Xa
  • 224. Standard Heparin (UFH) Contraindications
    • Bleeding disorders and disorders that predispose to bleeding (e.g., hemophilia, thrombocytopenia), hemorrhage and several other diseases
    • Patients with advanced liver or kidney disease, severe hypertension and certain infections (active tuberculosis, infective endocarditis)
    • Preferable to other anticoagulants during pregnancy due to lack of placental transfer (contrast to warfarin)
  • 225. Standard Heparin (UFH) Adverse Effects
    • Bleeding/hemorrhage
    • Bleeding is minimized with careful monitoring of PTT and platelet counts
    • Allergic reaction (heparin is an animal product)
    • Osteoporosis (long-term therapy)
    • Transient and occasionally severe thrombocytopenia:
      • Type I = immediate, transient and reversible heparin-induced platelet sequestration.
      • Type II = delayed, severe, immune (IgG)-mediated heparin-induced thrombocytopenia (HIT)
    • Thromboembolism - a paradoxical effect related to heparin-induced thrombocytopenia (HIT)
  • 226. Standard Heparin (UFH) Antidote
    • Protamine sulfate
      • Protamine is a basic peptide that binds to heparin (acid/base or anion/cation interaction)
      • Excessive antidote must be avoided because protamine itself is an anticoagulant
      • Administer 1 mg protamine sulfate IV for each 100 units of heparin remaining in the patient
      • Protamine is much less capable of reversing the effects of LMWH
     Disadvantage of LMWH
  • 227. Low Molecular Weight Heparins (LMWH)
    • Enoxaparin = low MW (2,000 – 6,000)
    • Dalteparin = low MW (2,000 – 9,000)
    • Tinzaparin = low MW (3,000 – 8,000)
  • 228. Low Molecular Weight Heparins (LMWH) Properties
    • LMWH’s were first approved for primary prevention of deep vein thrombosis after hip replacement therapy
    • LMWH’s are being evaluated and used for the treatment of other thromboembolic diseases
    • LMWH’s have some advantages over UFH:
      • Pharmacokinetics (dose-independent)
      • Pharmacodynamic
      • Safety
    • Also contraindicated in HIT
    • Not readily reversed with protamine sulfate
    • Monitored by anti-Xa activity assay , when needed
  • 229. Comparison of Unfractionated Heparin (UFH) and LMWH’s 3 to 6 hours 50 to 90 min Elimination half-life NO YES Dose-dependent clearance Minimal Extensive Endothelial cell/ Protein binding NO YES Increases vascular permeability ++ +++++ Inhibition of platelet function Not required or anti-Xa assay Required PTT Monitoring From 2:1 to 4:1 1:1 Anti-Xa vs IIa activity LMWH UFH Property
  • 230. Fondaparinux (Arixtra)
    • It is a synthetic pentasaccharide anticoagulant
    • Unlike UHF or LMWHs, it has no effect on thrombin (factor IIa)
    • It exerts antithrombotic activity as a result of ATIII-mediated selective inhibition of factor Xa
    • Elimination half-life of 18 hours; allows once-daily dosing; given subcutaneously
    • In contrast to heparin anticoagulants, fondaparinux does not require laboratory monitoring and lacks a specific antidote in the event of excessive anticoagulation.
    • Should not cause HIT >> because it does not bind to platelet factor 4 >> however, clinical trials are needed to determine if it is a safe alternative to heparin in patients at risk for HIT
  • 231. Fondaparinux (Arixtra) Uses
    • Venous thromboembolism prophylaxis following orthopedic surgery
    • Treatment of pulmonary embolism (PE)
    • Treatment of deep venous thrombosis (DVT)
    • Treatment of coronary artery thromboembolism; promising but still under study
  • 232. Direct Thrombin Inhibitors
    • Hirudin : the rudin’s
      • 65 amino acid peptide
      • This is a specific thrombin inhibitor obtained from leeches
    • Lepirudin (Refludan) is a recombinant yeast-derived form of hirudin
      • It is approved for anticoagulation in patients with heparin-induced thrombocytopenia (HIT)
    • Desirudin (Ipivask) and Bivalirudin (Angiomax) are new recombinant hirudin analogs that may be used instead of heparins in the future
    • Argatroban (Acova) is the 2nd agent (1st is lepirudin) approved for HIT
      • unlike lepirudin, it is cleared by liver and can be used in patients with end-stage renal disease
  • 233. Warfarin (the oral) Anticoagulant
    • Coumarin derivative
    • Hemorrhagic substances found in spoiled sweet clover used as rodenticides
    • 100% oral bioavailability
    • Plasma protein binding :
      • Extensive (>99%), which accounts for:
        • Low volume of distribution (albumin space)
        • Long half-life (36 h)
        • Lack of urinary excretion of unchanged drug
    • Metabolism : Metabolized to inactive metabolites by cytochrome P450 (CYP2C9) in liver; site of numerous drug interactions
    S isomer >> most active 
  • 234. Warfarin Mechanism of Action Reproduced with permission from Elsevier Sciences “Mosby’s Ace the Boards: Pharmacology” by Enna, Gordon & Pazdernik, Copyright © 1996, Figure 8.3, p. 285. Zymogen Oxidative/Carboxylation  Binds Calcium Warfarin receptor Ca 2+
  • 235. Warfarin
    • Target: Vitamin K epoxide reductase (warfarin receptor)
    • Resistance: Mutations in vitamin K epoxide reductase confers heritable resistance to warfarin in humans (loss of anticoagulation) as well as rats (loss of rodenticidal activity)
    • Speed of onset: slow
      • Warfarin half-life = 1.5 days
      • Eight to 12 h for initial anticoagulant effect, several days to reach maximum hypoprothrombinemia.
      • The delay represents the time to replace normal clotting factors with incompletely γ -carboxylated factors, and the time to reach steady-state levels of drug
    • Antidote :
      • Discontinue drug and administer large doses of vitamin K (phytonadione) and fresh, frozen plasma or factor IX concentrates containing prothrombin complex.
     pharmacokinetic  pharmacodynamic
  • 236. Warfarin Drug-drug interactions
    • Drugs that diminish the response to oral anticoagulants:
      • Inhibition of oral warfarin absorption:
        • Cholestyramine; (also affects Vit K absorption)
      • Induction of hepatic microsomal enzymes:
        • Barbiturates
        • Carbamazepine
        • Phenytoin
        • Primidone
        • Rifampin
        • St. John’s Wort
      • Stimulation of clotting factor synthesis
        • Vitamin K ↔ diet & bacteria
        • Estrogens
    Anticonvulsants
  • 237. Warfarin Drug-drug interactions
    • Drugs that enhance the response to oral anticoagulants (can be very serious):
      • Displacement form plasma albumin:
        • Sulfonamides
      • Inhibition of anticoagulant metabolism
        • Amiodarone
        • Allopurinol
        • Cimetidine
        • Ciprofloxacin
        • Erythromycin
        • Co-trimoxazole
        • Metronidazole *
        • Fluconazole *
      • Reduction in availability of vitamin K
        • Broad-spectrum antibiotics
    * Selective for S-warfarin
  • 238. Warfarin Uses
    • Heparin and warfarin are both used to treat both arterial and venous thrombi
    • Heparin is used for the first 7-10 days, with a 3-5 day overlap with warfarin, which may be continued for up to 6 months
    • Warfarin is also used to prevent blood clots in patients with chronic atrial fibrillation
  • 239. Warfarin Therapeutic goal
    • Prolongation of Prothrombin Time (PT) above normal
    • 1.2-1.5 fold if rabbit tissue thromboplastin is used (basis of the old North America test)
    • 1.5-3.5 fold if human tissue thromboplastin is used [basis of the INR (international normalized ratio of test/control]
      • Low-intensity anticoagulation (INR 1.5—2); long-term
      • Moderate-intensity anticoagulation (INR 2—3); initially
      • High-intensity anticoagulation (INR 2.5—3.5); mechanical prosthetic heart valves
    • Therapeutic goal achieved in about one week
    • Slow onset
  • 240. Warfarin Limitations
    • Adverse effect: serious and possibly fatal bleeding occurs in brain, pericardium, stomach and intestine
    • Pregnancy:
      • Warfarin is contraindicated (category X)
      • Fetal warfarin syndrome (FWS)
      • Teratogen 1st trimester
      • In utero fetal hemorrhage throughout pregnancy
    • Contraindications:
      • Pregnancy (risk of fetal hemorrhage/malformation)
      • Patients with bleeding disorders
      • Liver disease (impaired drug metabolism)
  • 241. Comparisons Between Heparin and Warfarin Prevention & treatment of throboembolic disorders Prevention & treatment of throboembolic disorders Clinical uses Vit K; fresh frozen plasma Protamine sulfate Treatment of overdose PT (INR) PTT Monitoring 2 to 5 days 4 hours Duration Gradual (1 to 3 days) Immediate Onset oral Parenteral Route No Yes Activity in vitro ↓ ↓ Vitamin-K dependent clotting factors Accelerates the action of ATIII to neutralize thrombin Mechanism Warfarin Heparin Property
  • 242. Indications for Anticoagulant Therapy
    • Myocardial infarction
    • Rheumatic heart disease
    • Cerebrovascular disease
    • Venous thrombosis
    • Pulmonary embolism
    • Disseminated intravascular coagulation (DIC)
  • 243. Thrombolytic Drugs Lyse thrombi by catalyzing formation of serine protease ( plasmin ) from its precursor zymogen ( plasminogen) Reprinted from “Rapid Review Series: Pharmacology,” by Pazdernik, Kerecsen, & Shaw, Figure 16-4, p. 108, © 2003 Mosby, with permission from Elsevier.  Alteplase 
  • 244. Thrombolytic Drugs
    • Thrombolytic therapy is directed toward the conversion of plasminogen to plasmin, which degrades fibrin and lyses thrombi
    • Circulating antiplasmins preclude the possibility of using plasmin itself for thrombolytic therapy
    • Plasma does not contain inhibitors of urokinase (human kidney protease) or the complex formed between plasminogen and streptokinase (streptococcal enzyme)
    • These activators convert plasminogen to plasmin inside the thrombus, where plasmin is protected from the inhibitory effects of circulating antiplasmins
    • Preferential conversion of fibrin-bound plasminogen to plasmin also occurs with tissue plasminogen activator (t-PA)
    • t-PA is more efficacious than streptokinase or anistreplase for thrombolytic therapy in myocardial infarction, but it carries a higher risk of hemorrhagic stroke.
    More expensive
  • 245. Specific Thrombolytic Agents
    • Streptokinase:
      • Nonenzymatic protein produced by group C beta-hemolytic streptococci
      • Facilitates thrombolysis through formation of activator complex with plasminogen results in formation of plasmin
      • Plasmin degrades fibrin, fibrinogen, and procoagulant factors V and VIII
      • Hypersensitivity to streptokinase may occur
      • No longer on USA market
  • 246. Specific Thrombolytic Agents
    • Urokinase:
      • Parenteral thrombolytic agent (from human cultured kidney cells)
      • Indicated for lysis of pulmonary emboli, lysis of coronary artery thrombi associated with evolving transmural myocardial infarction
      • Hypersensitivity reactions occur less frequently than with streptokinase
  • 247. Recombinant Thrombolytic Agents
    • Alteplase: biosynthetic recombinant form of human tissue plasminogen activator (t-PA)
      • Considerably more expensive than streptokinase
      • Alteplase is not associated with hypersensitivity reactions
    • Reteplase
      • Recombinant plasminogen activator
      • Longer half-life than alteplase
    • Tenecteplase, TNK-t-PA
      • Modified human t-PA
      • Compared to Alteplase, it has a prolonged half-life, increased specificity for fibrin and increased resistance to plasminogen activator inhibitor-1
  • 248. Uses of Thrombolytic Agents
    • Thrombolytic drugs were only used for deep-vein thrombosis and serious pulmonary embolism
    • Today they are used for the treatment of acute peripheral arterial thrombosis (including myocardial infarction patients who meet certain criteria) and emboli, and for unclogging catheters and shunts
    • In 1996, approved for treatment of acute ischemic stroke
    • Rule out intracranial bleeding (CT scan)
    • September 2001, approved for the restoration of function to central venous access devices
    • Thrombolytic therapy should be followed with anticoagulant therapy with heparin (rapid onset) and then warfarin (orally effective)
    • For myocardial infarction, aspirin may be an adjuvant therapy because of its anti-platelet effect.
  • 249. Contraindications to Thrombolytic Therapy
    • Surgery within 10 days
    • Serious G.I. bleeding within 3 months
    • History of hypertension (diastolic pressure > 110 mm Hg)
    • Active bleeding or hemorrhagic disorder
    • Previous cerebrovascular accident or active intracranial process
    • Aortic dissection
    • Acute pericarditis
  • 250. Drugs Used in Bleeding Disorders
    • Vitamin K:
      • Fat soluble vitamin from green leafy vegetables
      • Produced by bacteria colonizing human intestine; needs bile salts for absorption
      • Required for γ -carboxylation of glutamate residues in prothrombin and factors VII, IX and X
      • Treats warfarin excess and vitamin K deficiency
      • Prevents hemorrhagic disease of vitamin K deficiency in newborns
  • 251. Drugs Used in Bleeding Disorders
    • Plasma Fractions/Clotting Factors; Deficiencies in plasma coagulation factors can cause bleeding (e.g., hemophilia):
      • Concentrated plasma fractions treat these deficiencies
      • Threat of AIDS and viral hepatitis discourages use of plasma fractions in treatment of patients with hemophilia
    • Recombinant factors are preferred; Antihemophilic factor (AHF; Factor VIII): commercially prepared using genetically altered mammalian cells to secrete human factor VIII
  • 252. Drugs Used in Bleeding Disorders
    • Fibrinolytic Inhibitors:
      • Aminocaproic acid treats:
        • Systemic or urinary hyperfibrinolysis ( e.g., aplastic anemia, abruptio placentae, hepatic cirrhosis)
        • Bleeding associated with neoplastic diseases (carcinoma of the prostate, lung, stomach, or cervix)
        • Bleeding following cardiac surgery
  • 253. Summary Know the pharmacology and uses of:
    • Platelet inhibitors
    • Anticoagulants
    • Drugs for bleeding disorders
    • Thrombolytic drugs
  • 254. -parin = LMWH -rudin = thrombin inhibitor Arterial thrombosis = anti-platelets Venous thrombosis = anticoagulants HIT
  • 255. A 33-year-old pregnant woman with antiphospholipid syndrome is treated with aspirin and heparin, 5,000 International Units, subcutaneously every 12 hours. Which of the following best describes the mechanism of action of heparin in this patient?
    • Antithrombin III accelerator
    • Thrombin inhibitor
    • Thromboxane synthase inhibitor
    • Thrombolytic inhibitor
    • Vitamin K epoxide reductase inhibitor
    Answer: A Heparin & LMWH
  • 256. Which of the following would be most appropriate to give by injection for deep venous thrombosis prophylaxis in a 65-year-old woman undergoing elective hip replacement surgery who has previously experienced severe heparin-induced thrombocytopenia (HIT)?
    • Argatroban
    • Clopidogrel
    • Enoxaparin
    • Reteplase
    • Warfarin
    Answer: A -rudns & argatroban can be used for HIT; argatroban preferred in patients with renal disease
  • 257. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
    • Salicylates
      • Aspirin
      • Salicylic acid
    • Other NSAIDs
      • Ibuprofen
      • Indomethacin
      • Ketorolac
      • Naproxen
      • Oxaprozin
      • Piroxicam
      • Sulindac
    • COX - 2 Inhibitors
      • Celecoxib
      • Rofecoxib (discontinued)
      • Valdecoxib (discontinued)
    • Analgesic/Antipyretic (only)
      • Acetaminophen
    These agents are: Analgesic Antipyretic Antiinflammatory
  • 258. Antiarthritic Agents
    • NSAIDs
    • Corticosteroids
    • Disease Modifying Antirheumatic Drugs (DMARDs)
      • Immunosuppressive Agents
        • Methotrexate, Cyclophosphamide, Azathioprine, Cyclosporine, Leflunomide
      • Antimalarials
        • Hydroxychloroquine
      • Gold compounds
        • Aurothioglucose, Auranofin
      • Anti-TNF  Drugs
        • Adalimumab, Infliximab, Etanercept
      • IL-1 Antagonist
        • Anakinra
      • Others
        • Penicillamine, Sulfasalazine
  • 259. Agents Used in Gout
    • Acute Treatment:
      • Colchicine
      • NSAIDs
        • Indomethacin
        • Naproxen
        • Sulindac
      • Corticosteroids (rarely)
    • Prevention:
      • Uricosuric agents
        • Sulfinpyrazone
        • Probenecid
      • Xanthine oxidase Inhibitor
        • Allopurinol
    Never Aspirin
  • 260. NSAIDs
    • Effects are due to inhibition of eicosanoid synthesis from arachidonic acid (See next slide)
    • The prostaglandins are involved in:
      • Pain
      • Fever
      • Inflammation
      • Platelet aggregation
  • 261. Arachidonic Acid Pathway Reprinted from “Rapid Review Series: Pharmacology,” by Pazdernik, Kerecsen, & Shaw, Figure 18-1, p. 115, © 2003 Mosby, with permission from Elsevier . COX-1 COX-2
  • 262. Aspirin and other NSAIDs
    • Mechanism of action:
      • Aspirin and most other NSAIDs are weak acids.
      • They inhibit prostaglandin and thromboxane biosynthesis (but generally not leukotriene biosynthesis).
      • The target is cyclooxygenase (COX) (prostaglandin synthase).
        • COX-1. Present in most cells,
    • -- also platelets -> TXA 2
        • COX-2. Present in cells involved in inflammation,
    • -- also endothelial cells -> PGI 2
      • Aspirin and most other approved NSAIDs appear to inhibit both enzymes although not necessarily to the same extent.
      • Celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) are new NSAIDs that selectively inhibit COX-2.
      • Aspirin blocks eicosanoid formation by binding irreversibly to COX.
      • All other NSAIDs, including salicylate, are reversible inhibitors of COX.
  • 263. Differential Effects between Aspirin and NSAIDs
    • NSAIDs differ in their anti-inflammatory, analgesic and antipyretic effects. The effects of salicylates are also dose dependent:
      • Low doses for analgesia and antipyresis
      • High doses for anti-inflammatory effects
    • Reasons for differential effects:
      • Differential inhibition of various forms of cyclooxygenase.
        • COX-1 present in a variety of tissues
        • COX-2 present in cells involved in inflammation (induction is blocked by anti-inflammatory glucocorticoids)
      • Differential inhibition of cyclooxygenase and lipoxygenase .
        • Most NSAIDs inhibit only COX, but ketoprofen and indomethacin inhibit both.
      • Inhibition of COX by acetaminophen is blocked by peroxides (formed during inflammation).
        • For this reason, acetaminophen exerts analgesic and antipyretic effects, but is a relatively ineffective anti-inflammatory agent.
      • Differential effects on other mediators of pain and inflammation.
  • 264. NSAID Side Effects
    • The NSAIDs also differ in their side effects, some of which are an extension of their pharmacological effects ( i.e., a consequence of COX inhibition).
    • This provided the impetus to develop selective COX-2 inhibitors.
  • 265. Aspirin (Acetylsalicylic Acid)
    • Pharmacokinetics:
      • Orally administered; rapidly absorbed from G.I. tract
      • Significant amount is hydrolyzed to salicylic acid in blood;
      • salicylic acid is a reversible inhibitor of cyclooxygenase
      • Rapidly distributed to all tissues
      • Bound to plasma proteins (80%; site of drug interactions)
      • Acetylsalicylic acid (t ½ = 15 min.) is enzymatically and rapidly metabolized to salicylic acid
      • Salicylic acid is extensively conjugated with glucuronic acid and glycine
      • Dose-dependent pharmacokinetics: when conjugation pathways become saturated, small increases in the dose of aspirin can produce relatively large increases in plasma salicylate levels
        • Low dose of aspirin (600 mg) gives first-order kinetics, t ½ = 3-5 h (salicylate) Analgesic, antipyretic
        • High dose of aspirin (> 4000 mg) gives zero-order kinetics, t ½ > 12 h (salicylate) Anti-inflammatory
      • Excreted in urine as salicylic acid, salicyluric acid, glucuronic acid conjugates
  • 266. Aspirin (Acetylsalicylic Acid)
    • Pharmacodynamics: Many effects due to inhibition of prostaglandin synthesis through irreversible inhibition of the enzyme cyclooxygenase; the enzyme is acetylated
      • Anti-inflammatory effects :
        • Due to inhibition of cyclooxygenase (COX-2)
        • Prostaglandin synthesis is inhibited
        • Inhibits macrophage and leukocyte migration to site of inflammation
      • Analgesic effects:
        • Effective against pain of mild to moderate intensity
        • Most effective for pain with muscular, vascular or inflammatory conditions
      • Antipyretic effects:
        • Lowers body temperature when fever is present
        • Blocks production of prostaglandins in the CNS to &quot;reset&quot; temperature control at hypothalamus, facilitating heat dissipation by vasodilatation
        • Fall in temperature due to dilation of superficial blood vessels, often accompanied by profuse sweating
      • Antiplatelet effects:
        • Aspirin prolongs bleeding time
        • Antithrombotic effect due to inhibition of thromboxane synthesis via irreversible inhibition of platelet cyclooxygenase (COX-1); this effect, even after low doses, lasts for life-span of platelets (about 8 days)
      • Effects on uric acid:
        • Large doses of aspirin are uricosuric (decrease uric acid levels)
        • Lower doses increase uric acid levels
  • 267. Aspirin (Acetylsalicylic Acid)
    • Adverse effects:
      • Gastrointestinal effects:
        • Main adverse effect of usual dosages is gastric upset
        • Taking aspirin with food or milk can minimize discomfort
        • GI irritation due in part to direct irritant effects of drug; aspirin inhibits synthesis of prostaglandins, which are protective in the gut
        • Patients taking large doses of any NSAID for prolonged period may be given PGE 1 analog (misoprostol) or proton pump inhibitors (omeprazole) to prevent peptic ulcers
        • Large doses: nausea and vomiting (see below, overdose toxicity)
      • Hepatic and renal toxicity:
        • May cause mild, usually asymptomatic hepatitis
        • Aspirin (worse when given with other NSAIDs) may decrease kidney function, especially in patients with underlying renal disease (prostaglandins (PGE 2 & PGI 2 ) increase renal blood flow)
      • Other adverse effects:
        • Usual doses have a negligible effect on glucose tolerance, but large doses given to a diabetic should be administered with caution
        • Hypersensitivity reactions may occur
  • 268. Aspirin (Acetylsalicylic Acid)
    • Contraindications:
        • Aspirin is contraindicated in hemophiliacs
        • Patients with aspirin-induced nasal polyps or with allergic reactions (e.g. urticaria) to aspirin are at risk of developing bronchoconstriction or anaphylaxis and should not receive aspirin
        • Aspirin should not be given to children with viral infections (e.g. influenza, chicken pox) because of the associated increased incidence of Reye's syndrome
  • 269. Aspirin Overdose Toxicity
    • Common cause of poisoning in young children
    • Symptoms:
      • Salicylism (tinnitus, vertigo, deafness)
      • Hyperthermia
      • Hyperpnea
      • Initially, respiratory alkalosis
      • Later, respiratory and metabolic acidosis
    • Treatment:
      • If seen early, gastric lavage
      • Maintain temperature
      • Intravenous fluids
      • NaHCO 3 plus K +
      • Hemodialysis or hemoperfusion, in severe cases
  • 270. Aspirin: Pharmacotherapeutics
    • Uses:
      • Antipyresis
      • Acute rheumatic fever
      • Mild pain, especially associated with inflammation (headache, myalgia, arthritis, dysmenorrhea)
      • Prophylaxis:
        • Platelet hyperaggregation
        • Coronary artery disease
        • Myocardial infarction
        • Postoperative deep-vein thrombosis
  • 271. Aspirin: Drug interactions
    • Displacement of other drugs from albumin binding sites is potential mechanism for interactions between aspirin and:
      • Oral hypoglycemic drugs
      • Other NSAIDs
      • Methotrexate
      • Phenytoin
      • Oral anticoagulants (warfarin)
  • 272. Other Nonselective NSAIDs
    • Antipyretic, analgesic, and anti-inflammatory effects similar to aspirin
    • Adverse effects of aspirin are shared by other NSAIDs, but most NSAIDs produce milder GI side effects
    • All agents alter platelet function and prolong bleeding time
    • Treats mild to moderate pain, fever, and rheumatoid arthritis when patients cannot tolerate aspirin
    • Major differences are duration of action and potency
    Examples of other NSAIDs: Ibuprofen; Naproxen; Sulindac; Piroxicam; Indomethacin
  • 273. Pharmacokinetic Differences Among NSAIDs
    • Ibuprofen Short half-life ( 2 h) 4 x 600 mg for RA
    • Naproxen Long half-life (14 h) 2 x 375 mg for RA
    • Piroxicam Long half-life (45 h) 1 x 20 mg for RA
  • 274. Pharmacodynamic Differences Among NSAIDs
    • COX selectivity:
      • Some newer NSAIDs (celecoxib, rofecoxib, valdecoxib) are selective COX-2 inhibitors, and exert anti-inflammatory effects with fewer side effects.
      • Aspirin inhibits COX irreversibly
      • All other NSAIDs inhibit reversibly.
    • Cyclooxygenase versus lipoxygenase: Ketoprofen, diclofenac and indomethacin inhibit both cyclooxygenase and lipoxygenase.
    Rofecoxib & valdecoxib: removed from the market because Increased cardiac events; likely due to inhibition of PGI 2 formation All nonselective NSAIDs except aspirin have a Black Box Warning of Increased cardiovascular risks; likely due to inhibition of renal prostaglandins
  • 275. Ketorolac (Toradol)
    • Given IV, IM, or PO for moderate pain
    • Systemic use should not be more than 5 days
    • Eye preparation available for ocular pain
    Often used in the hospital by injection
  • 276. Indomethacin
    • Not suggested as a general use analgesic, but particularly effective for pain at night
    • Produces numerous G.I. effects and several severe hematopoietic reactions
    • Treats acute gout, useful in special situations such as ankylosing spondylitis and osteoarthritis of the hip
    • Used for patent ductus arteriosus (PDA) in premature infants
    • Adverse effects: headache, indigestion, and CNS effects such as vertigo, dizziness and confusion
    • With the exception of newborns with patent ductus arteriosus, indomethacin is not given to children. Nor is it given to pregnant women.
  • 277. Celecoxib (Celebrex)
    • Selective antagonist of cyclooxygenase type 2 (COX-2)
    • Does not inhibit platelet function and does not cause gastropathy
    • Contraindicated in patients with known celecoxib hypersensitivity or sulfonamide hypersensitivity (celecoxib contains a sulfonamide side chain)
    • Approved to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis.
    • The use of celecoxib is being studied in patients with sporadic adenomatous polyps of the colon, Barrett's esophagus, actinic keratosis, and superficial bladder cancer.
  • 278. Rofecoxib (Vioxx)
    • Removed from the market (9/27/04)
    • A selective cyclooxygenase-2 (COX-2) inhibitor
    • Shifts TXA 2 /PGI 2 balance to an unfavorable ratio
    • Increased risk for cardiovascular events; only with prolonged use and high doses
    • A NSAID which was indicated:
      • To relieve the signs and symptoms of osteoarthritis
      • For the treatment of dysmenorrhea or acute pain
    • Compared to celecoxib, it lacks a sulfonamide chain and thus is not contraindicated in patients allergic to sulfonamides
    • It is not primarily dependent on CYP450 enzymes for metabolism
  • 279. Valdecoxib (Bextra)
    • A selective COX-2 inhibitor
    • Withdrawn from market (04/07/05)
    • Was indicated for:
      • Dysmenorrhea
      • Osteoarthritis
      • Rheumatoid arthritis
    • Dysmenorrhea is caused by excessive prostaglandin synthesis
    • Contraindicated in patients with sulfonamide hypersensitivity
    • Shifts TXA 2 /PGI 2 balance to an unfavorable ratio
    • Increased risk for cardiovascular events
  • 280. Acetaminophen (Tylenol)
    • Possesses analgesic and antipyretic effects similar to aspirin but has no anti-inflammatory activity
    • Does not affect platelet function or uric acid levels
    • Does not produce gastric irritation
    • Extensively used in children
    • Most serious adverse effect of acute overdose is hepatic necrosis (See Figure on next slide for mechanism)
    • Some evidence that it exerts its action on COX-3 in the CNS
    • CYP2E1 causes bioactivation (induced by alcohol, isoniazid)
    • Can cause acute hemolytic anemia, especially in primaquine-sensitive individuals
    • Can cause neutropenia, pancytopenia, and leukopenia (rare)
  • 281. Acetaminophen Hepatotoxicity Reproduced with permission from Elsevier Sciences “ Mosby’s Ace the Boards: Pharmacology” by Enna, Gordon & Pazdernik, Copyright © 1996, Figure 8.6, p. 295  CYP2E1 Acetaminophen-induced hepatotoxicity is synergistic with alcohol consumption Acetylcysteine is used to prevent hepatotoxicity after an acute overdose of acetaminophen      N-acetylcysteine  EtOH; Isoniazid
  • 282. Antiarthritic Agents Reprinted from “Rapid Review Series: Pharmacology,” by Pazdernik, Kerecsen, & Shaw, Figure 22-1, p. 143, © 2003 Mosby, with permission from Elsevier . Pathogenesis of rheumatoid arthritis and sites of action of drugs
  • 283. Antiarthritic Agents
    • NSAIDs (First line)
    • Corticosteroids:
      • Cause dramatic improvement in rheumatoid arthritis
      • Do not arrest the disease process itself
      • Adverse effects limit long-term use
    • Disease Modifying Antirheumatic Drugs (DMARDs):
      • These drugs have a slow onset of action (6 weeks to 6 months)
      • Mechanisms of action are not well understood
  • 284. DMARDs
    • Immunosuppressive Agents : See section below.
    • Antimalarial drugs: Hydroxychloroquine & Chloroquine:
      • Mechanism of action is unclear
      • Hydroxychloroquine is similar to chloroquine but more commonly used to treat rheumatoid arthritis and lupus erythematosus
      • Contraindicated in psoriatic arthritis because of possible development of exfoliative dermatitis
      • Can cause irreversible retinal damage (less of a problem with hydroxychloroquine than chloroquine)
  • 285. DMARDs
    • Gold compounds:
      • Should not be given with penicillamine because it chelates gold.
      • Contraindications:
        • Previous gold toxicity
        • Pregnancy
        • Liver or kidney impairment
        • Blood dyscrasia
      • Adverse effects:
        • Dermatitis and diarrhea
        • Eosinophilia and other hematological disturbances
        • Proteinuria may lead to nephrotic syndrome
        • Aplastic anemia (rare but fatal)
      • Aurothioglucose:
        • Adjunctive treatment of early active cases of adult and juvenile rheumatoid arthritis
        • Administered IM
        • Cutaneous reactions such as erythema and exfoliative dermatitis may occur; more serious side effects include blood dyscrasias and kidney toxicity
      • Auranofin:
        • Only gold compound available for oral administration
        • Treats early active cases of both adult and juvenile types of rheumatoid arthritis
  • 286. DMARDs
    • Penicillamine: oral chelating agent treats patients with:
      • Wilson's disease,
      • Cystinuria
      • Resistant cases of rheumatoid arthritis
    • Sulfasalazine: used for treatment of:
      • Rheumatoid arthritis
      • Ankylosing spondylitis
      • Ulcerative colitis
    • Leflunomide (Arava):
      • Orally active
      • Converted to an active metabolite that inhibits dihydroorotic acid dehydrogenase , an enzyme involved in ribonucleotide synthesis
      • Leads to a translocation of P53 to the nucleus
      • Stimulated cells are arrested in G1 phase
      • Inhibits autoimmune T-cell proliferation
      • Inhibits production of autoantibodies by B-cells
      • First agent for RA indicated for both symptomatic improvement and retardation of structural joint damage
      • Cause, alopecia, rash and diarrhea
  • 287. DMARDs
    • Anti-TNF  compounds (See immune section; PHCL 761)
      • Infliximab
      • Etanercept
      • Adalimumab
    • Anakinra (Kineret):
      • Interleukin-1 (IL-1) receptor antagonist
      • Reduces the signs and symptoms and slows the progression of structural damage of moderate to severe active rheumatoid arthritis in patients who failed one or more DMARDS.
      • Given subcutaneously once a day
  • 288. GOUT
    • Disease caused by increase in amount of uric acid in body
    • Causes:
      • Primary: overproduction or under-excretion of uric acid
        • Under-excretion of uric acid occurs in diabetes and in starvation
        • Overproduction of uric acid results from an increase in de novo synthesis
      • Secondary: accumulation of uric acid due to another disease such as leukemia
    • Drugs that may cause under-excretion and/or accumulation of uric acid include:
      • Diuretics (thiazides, furosemide, ethacrynic acid)
      • Antituberculosis drug (pyrazinamide, ethambutol)
      • Salicylates (low doses);
      • Nicotinic acid
      • Ethanol
      • Cytotoxic drugs
    • Symptoms: inflammatory reaction mediated by prostaglandins and cells of immune system due to phagocytosis by synoviocytes of uric acid crystals deposited in peripheral joints; subsequent inflammation causes severe pain
  • 289. Urate crystals in joints (Acidic due to high production of lactic acid in synovial tissue)  Phagocytosis by synoviocytes  Prostaglandins, lysosomal enzymes, IL-1  Infiltration of polymorphonuclear leukocytes  Amplification of inflammatory response (Release of prostaglandins and leukotriene B4)  Infiltration of mononuclear phagocytes (macrophages) (Increased urate crystallization due to acidification of synovial tissue)  Phagocytosis of urate crystals  Amplification of inflammatory response
  • 290. GOUT Site of Drug Action Reprinted from “Rapid Review Series: Pharmacology,” by Pazdernik, Kerecsen, & Shaw, Figure 22-2, p. 145, © 2003 Mosby, with permission from Elsevier. Avoid Salicylates Blood
  • 291. GOUT Treatment of Acute Symptoms
    • Colchicine:
      • Reduces pain and inflammation of an acute attack of gouty arthritis
      • Produces anti-inflammatory effect by inhibiting leukocyte migration and phagocytosis
      • Adverse effects include: diarrhea, nausea and vomiting
    • NSAIDs (Indomethacin):
      • Very effective for inflammation with acute gouty arthritis
      • Indomethacin is primary NSAID used to treat severe gout
      • Other NSAIDs also used
        • Ibuprofen
        • Naproxen
        • Sulindac
    • Corticosteroids: anti-inflammatory properties make them useful in treatment of acute gout; but adverse effects associated are significant with prolonged use
  • 292. GOUT Prophylaxis Therapy
    • Uricosuric agents:
      • Probenecid:
        • Oral uricosuric agent to treat hyperuricemia associated with chronic gout or secondary to other causes (drug-induced hyperuricemia)
        • Not effective for acute attacks of gout and can aggravate inflammation if administered during initial stages
    • Allopurinol:
      • Inhibits xanthine oxidase and thus inhibits synthesis of uric acid
      • Effective in both primary and secondary forms of gout
      • Serious side effects including vasculitis, agranulocytosis, hypersensitivity reactions
      • Allopurinol inhibits the conversion of mercaptopurine and azathioprine to their inactive metabolites.
      • If allopurinol needs to be used with these two antimetabolites, their doses must be reduced.
     Do not use if GFR < 50/mL/min
  • 293.  COX-1 = platelets COX-2 = endothelial cells Vasculature & kidney
  • 294. A 16-year-old girl with severe cramping pain that begins a few hours prior to the start of her menstrual flow complains of headache and very heavy bleeding during menstruation. Which of the following medications with appropriate analgesic and anti-inflammatory activity to relieve dysmenorrhea without inhibiting platelet aggregation could be used for the treatment of this patient?
    • Acetaminophen
    • Celecoxib
    • Ibuprofen
    • Indomethacin
    • Valdecoxib
    Answer: B Severe cramping is from inflammatory prostanoids produce in uterus
  • 295. A 60-year old-man has excruciating pain in his left big toe. Examination of the foot reveals that the first metatarsophalangeal joint is swollen, hot red and very tender. Which of the following medications is most appropriate to relieve symptoms in this patient?
    • Acetaminophen
    • Allopurinol
    • Aspirin
    • Colchicine
    • Probenecid
    Answer: D Colchicine & Indomethacin best to treat severe symptoms from an acute attack of gouty arthritis