Endocrine Pharm

  1. Insulin release is increased by:
    • glucose
    • Sulfonylureas
    • M-agonists
    • B2-agonists
  2. Insulin is decreased by:
    alpha2 agonists
  3. Diabetic Drugs: Alpha Glucosidase Inhibitors
    • Drugs: acarbose, mitigol
    • Mechanism: inhibits intestinal brush boarder alpha-glucosidases, dealyed sugar hydrolysis & glu absorption (decreasing CHO absorption in gut)
    • Clinical Use: monotherapy in type II or in combo
    • Contraindications: malabsorption
    • Side effects: GI disturbances, no hypoglycemia, recently hepatotoxicity
    • Best option for: mild post-prandial hyperglycemia
  4. Diabetic Drugs: Sulfonylureas
    • 1st gen drugs: tolbtamine, chloropromide
    • 2nd gen drugs: glybunide, glipizide, glemipride; 2nd gen are more commonly used
    • Mechanism: closes K channels on the beta-cell mb = causes cell depolarization = insulin release via Ca channel influx
    • Clinical use: release of endogenous insulin, for type 2 DM, need some beta-cell function, not useful for type 1, tolbtamine can be used in renal dysfn
    • Contraindications: severe renal/hepatic dz bc it causes longer hypoglycemia
    • Side effects: 1st gen = disulfiram-like reaction), hypoglycemia, weight gain
    • Best option for: monotherapy or in combo with biguanides/TZD
    • Drug interactions: mostly 1st gen = hypoglycemia with cimetidine, insulin, salicylates, sulfonamides
  5. Diabetic Drugs: Biguanides
    • Drug: metformin
    • Mechanism: decreases gluconeogenesis, decreases serum glucose, overal insulin sensitizer
    • Clinical use: oral hypoglycemia, can be used in pts with no beta-cell function
    • Contraindications: creatinine >1.5, CHF, liver dz
    • Side effects: lactic acidosis, GI upset, weight loss, no hypoglycemia
    • Best option for: mono or combo therapy, synergistic with sulfonylureas
  6. Diabetic Drugs: Thiazolidinedione/Glitazone
    • Drug: pioglitazone, rosiglitazone
    • Mechanism: Peroxisome Proliferator-Activated Receptor (PPAR) agonist, receptor is expressed on adipose cells, muscle cells, vascular ep = promotes fat storage/redistribution, makes large insulin resistant cells --> smaller insulin sensitive cells causing a flux of FFA to subcutaneous tissue away from viscera = increased insulin sensitivity, increases peripheral BG tissue uptake
    • Contraindications: CHF severe liver dz
    • Side effects: fluid retention, weight gain, edema, CV/hepatoxocity
    • Best option for: mono or combo therapy
  7. Diabetic Drugs: Incretin Mimetics: GLP-1 Mimetics
    • Drug: Exenatide
    • Mechanism: gut detects BG, incretin hormones, increase secretion of insulin, decrease glucagon release
    • Contraindications: ESRD, gastric dz
    • Side effects: hypoglycemia (when used with sulfonylureas), GI disturbances, pancreatitis, weight loss
    • Best option for: combo w/ metformin, TZD, sulfonylureas, injectable
  8. Diabetic Drugs: DPP-Inhibitors (Dipeptidyl peptidase-4)
    • Drug: Sitagliptin
    • Mechanism: DPP-4 enzyme degrades GLP-1 = increases incretin hormone level = increased pancreatic secretion of insulin and decreases liver glucose production
    • Side effects: no weight gain, nasal congestion, rhinorrhea
    • Clinical use: DM in kidney dz
  9. Diabetic Drugs: Mimetics
    mimics amyline (peptide)
    • Drugs: Pramlintide
    • Mechanism: decreases post-prandial glucose, and slows GI transit
    • Side effects: hypoglycemia, nausea, diarrhea, weight loss
    • Contradindications: gastroparesis, hypoglycemia, unawareness
    • Clinical use: subQ injection, not used alone, but in combo therapy w/ insulin, for type I and II
  10. Mechanism of insulin release
    Glucose enters beta cell = increases intracellular ATP = closes K channels = membrane depolarization = increases Ca influx = insulin release

    Insulin = less glucagon released from pancreatic alpha cells
  11. Insulin Therapy: Short Acting
    • Drugs: Lispro, Aspart, Regular
    • Mechanism: bind insulin receptor (tyrosine receptor kinase activity). Liver: increased glu storage as glycogen. Muscle: increased glycogen and protein synthesis, K uptake. Fat: aids in TG storage
    • Clinical use: type I & II DM, life-threatening hyperkalemia and stress-induced hyperglycemia
    • Toxicity: hypoglycemia, hypersensitivity rxn (rare)
  12. Insulin Therapy: Long Acting
    • Drugs: NPH (intermediate), Glargine, Detemir
    • Mechanism: binds insulin receptor (tyrosine kinase activity). Liver: increased glu storage as glycogen. Muscle: increased glycogen and protein synthesis, K uptake. Fat: aids in TG storage, "peakless" insulin
    • Clinical use: type I & II DM, life-threatening hyperkalemia and stress-induced hyperglycemia
    • Toxicity: hypoglycemia, hypersensitivity rxn (rare)
  13. Hypoglycemia Reactions:
    Symptoms & Tx
    Symptoms: lip/tongue tingling, lethargy, confusion, sweats, tremors, tachycardia, coma, seizures

    Treatment: Oral glucose, IV dextrose if unconscious, or glucagom (IM/inhalation)
  14. Tx strategy for type I DM:
    • low-sugar diet
    • insulin replacement
  15. Tx strategy for type II DM:
    • dietary modification
    • exercise for weight loss
    • oral hypoglycemics
    • insulin replacement
  16. Type II DM tx: Repaglinide
    • Mechanism: stimulates insulin release from pancreatic beta cells
    • Use: adjunctive use in type II DM - administer right before meals due to short half-life
  17. Obesity Drug: Orlistat
    • Mechanism: alters fat metabolism by inhibiting pancreatic lipases
    • Clinical use: long-term obesity management (in conjunction w/ modified diet)
    • Toxicity: steatorrhea, GI discomfort, reduced absorption of fat-sol viatmins (A, D , E, K), headache

    OrliSTAT gets rid of FAT
  18. Obesity Drug: Sibutramine
    • Mechanism: sympathomimetic serotinin and NEp reuptake inhibitor
    • Clinical use: ST & LT obesity management
    • Toxicity: htn, tachycardia
  19. Thyroid drug: Propylthiouracil, Methimazole (thioamides)
    • Mechanism: inhibits organification of iodide and coupling of thyroid hormone synthesis, propylthriouracil also decreases the peripheral conversion of T4 --> T3, slow onset
    • Clinical use: hyperthyroidism,
    • Toxicity: skin rash, agranulocytosis (rare), aplastic anemia
    • Pregnancy: both drugs cross placenta, but propylthiouracil is safter bc it is extensive protein bound
  20. Thyroid drug: Levothyroxine, thriiodothyronine
    • Mechanism: thyroxine replacement
    • Clinical use: hypothyroidsm, myxedema
    • Toxicity: tachycardia, heat intolerance, tremors, arrhythmias
  21. Thyroid Drug: Iodide
    • Drug: K-I + Iodine (Lugol's solution)
    • clinical use: thyrotoxicosis, pre-operatively, decreases gland size, fragility, vascularity, no LT use bc thyroid gland 'escapes' from effects after 10 - 14 days
  22. Hypothalamic/Pit Drug: GROWTH HORMONE
    • Drug: somatrem, somatropin
    • Clinical use: GH deficiency, Turner's syndrome, osteoporosis
  23. Hypothalamic/Pit Drug: SOMATOSTATIN
    • Drug: octreotide
    • Clinical use: Acromegaly, carcinoid, gastrinoma, glucagonoma
  24. Carcinoid Syndrome
    release of vasoactive substances like 5HT (5-HIAA is a marker), histamine and PG

    Tx: octreotide, plus maybe serotinin receptor blocker (cyprohepatidine or methyseride)
  25. Hypothalamic/Pit Drug: OXYTOCIN
    Clinical use: stimulation of labour, uterine contractions, milk let-down; controls uterine hemorrhage
  26. Hypothalamic/Pit Drug: GnRH
    • Drugs: leuprolide, nafarelin
    • Clinical use: endometriosis, prostat carcinoma (repository form)
  27. Hypothalamic/Pit Drug: FSH/LH
    • Drugs: Urofollitropin (FSH), Placental HCG (LH), menotropins (FSH, LH)
    • Clinical use: hypogonadal states
  28. Hypthalamic/Pit Drug: DA
    • Drug: Bromocriptine
    • Clinical use: hyperPRLemia
  29. Hypothalamic/Pit Drug: ACTH
    • Drug: cosyntropin
    • Clinical use: infanitle spasms
  30. Hypothalamic/Pit Drug: ADH (desmopressin)
    • drug: desmopressin
    • Mechanism: V2 selective
    • clinical use: pituitary (central NOT nephrogenic) DI, hemophilia A (increases Factor 8 release from liver), vW dz (increases vW factor from endothelium), primary nocturnal enuresis
  31. Demeclocycline
    • Mechanism: ADH antagonist (member of the tetracycline family)
    • Clinical use: SAIDH
    • Toxicity: nephrogenic DI, photosensitivity, abnormalities in bone and teeth
  32. Glucocorticoids
    • Drugs: hydrocortisone, prednisone, tramcinolone, dexamethasone, beclomethasone
    • Mechanism: decrease the production of leukotrienes & PGs by inhibiting phospholipase A2 & expression of COX-2
    • Clinical use: Addisons, inflammation, immune suppression, astham
    • Toxicity: Iatrogenic Cushing's syndrome: buffalo hump, moon facies, truncal obesity, muslce wasting, thin skin, easy bruisability, osteoporosis, adrenaocortical atrophy, peptic ulcers, diabetes (if chronic)
  33. Adrenal Steroids: General
    • Endocrine uses: glucocorticoids (ie prednisone, dexamethasone), mineralocortoids (fludrocortisone)
    • Uses:
    • Addison disease: replacement
    • Adrenal insufficiency states: trauma, infection, shock, supplementation
    • Premature delivery: to prevent respiratory distress syndrome, supplementation
    • Adrenal hyperplasia: feedback inhibition of ACTH
  34. Adrenal Steroid Antagonists
    • Spironolactone
    • blocks aldosterone and androgen receptors
  35. Mifepristone (RU-486)
    • Mechanism: competitive inhibitor of progestins at progesterone receptors, blocks glucocorticoid receptors too!
    • Clinical use: termination of pregnancy, administered with misoprostol (PGE1)
    • Toxicity: heavy bleeding, GI effects (nausea/vomiting/anorexia), abdominal pain
  36. Estrogens: Ethinyl estradiol, DES, Mestranol
    • Mechanism: binds estrogen receptors, estridiol is the major natural estrogen, increases oral bioavailability, halflife, and feedback inhibtion of LH, FSH
    • Clinical use: hypogonadism, ovarian failure, menstrual abnormalities, HRT in post menopausal women; use in men with androgen-dep prostate cancer (palliative), contraception (FD of low gonadotropins), acne
    • Toxicity: increasd risk of endometrial cancer (hyperplasia), bleeding in post menopausal women, clear cell adenocarcinoma in vagina in females exposed to DES in utero, increased thrombi
    • Side effects: nausea, breast tenderness, endometrial hyperplasia, increased gall bladder disease, migrain, blood coagulation, cancer risk
    • Contraindications: ER-positive breast cancer, hx of DVT
    • Note: conjugated equine estrogens (premarin) - natural, ethinyl estradiol and mestranol (steroidal), DES (nonsteroidal)
  37. Anastrozole
    • Mechanism: aromatase inhibitor = decreases estrogen synthesis
    • Clinical use: estrogen-dependent, post menopausal breast cancer
  38. Estrogen Partial Agonists: SERMS (Selective Estrogen Receptor Modulators: CLOMIPHENE
    • Mechanism: partial agonist at estrogen receptors in hypothalamus, prevents nl feedback inhibition and increases release of LH and FSH from pit = stimulates ovulation
    • Clinical use: treat infertility and PCOS
    • Side effects: hot flashes, ovarian enlargement, multiple simultaneous pregnancies, visual disturbances
  39. Estrogen Partial Agonists: SERMS (Selective Estrogen Receptor Modulators: TAMOXIFEN
    • Mechansim: antagonist on breast tissue, actions vary depending on 'target' tissue
    • Tissue effects: E-receptor agonist (bone), antagonist (breast), partial agonist (endometrium)
    • Clinical use: treat and prevent recurrence of ER-positive breast cancer
    • Toxicity: increased endometrial cancer
  40. Estrogen Partial Agonist: SERMS (Selective Estrogen Receptor Modulators): RALOXIFENE
    • Mechanism: agonist on bone, antagonist on breast and uterus
    • Clinical use: reduces resorption of bone, tx of osteoporosis
    • Toxicity: if used in menopause - no increased cancer risk
  41. Ritodrine/Terbutaline
    • Mechanism: B2 agonists = uterine relaxation
    • Clinical use: reduces premature uterine contractions

    Ritodrine, allows the fetus to retrun to dreams; by preventing early delivery
  42. Progestin
    • Drugs: medroxyprogesterone, norethindrone, desogestrel (synthetic lacking androgenic & antiestrogenic activity)
    • Mechanism: progestin is a synthetic version of progesterone to increase oral bioavailability, increase feedback inhibition of gonadotorpins (especially LH)
    • Clinical use: contraception (w/ oral estrogens), depot contraception (mthoxyprogesterone q 3mo), HRT w/ estrogens to decrease endometrial cencer
    • Side effects: decreased HDL increased LDL, glu intolerance, breakthrough bleeding, androgenic (hirsuitism, acne), antiestrogenic (block lipid changes)
    • Antagonist: mifepristone - abortifacient (used w/ PGs)
  43. Oral Contraception: synthetic progestins, estrogen
    Mechanism: prevent the estrogen surge, LH surge does not occur = ovulation does not occur

    Advantages: reliable, decreased risk of endometrial/ovarian cancer, decreases ectopic pregnancy, decreased pelvic infections, regulation of menses

    Disadvantages: taken daily, no protection against STDs, increased TG, depression, weight gain, nausea, htn, hypercoagulability
  44. Antiandrogens: Finasteride
    • Drug: finasteride (propecia)
    • Mechanism: 5-alpha-reducatse inhibitor (decreases conversion of testosterone into DHT)
    • Clinical use: BPH, promotes hair growth (male-pattern baldness tx)
    • Toxicity: teratogenicity
  45. Antiandrogens: Fluatmide
    • Mechanism: nonsteroidal competitive inhibitor of androgens at the testosterone receptor
    • Clinical use: prostate carcinoma
  46. Antiandrogenic: Ketoaconazole
    • Mechanism: inhibits steroid synthesis (inhibits desmolase)
    • Clinical use: tx of PCOS to prevent hirsuitism
    • Side effects: gynecomastia and amenorrhea

    note: to prevent male pattern hair loss give a drug that will encourage female breast growth
  47. Antiandrogenic: Sprinolactone
    • Mechanism: inhibits steroid binding
    • clinical use: tx of PCOS to prevent hirsuitism
    • Side effects: gynecomastia and amenorrhea

    note: to prevent male pattern hair loss give a drug that will encourage female breast growth
  48. Sildenafil, Vardenafil
    • Mechanism: inhibits cGMP phosphodiesterase = increased cGMP = smooth muscle relaxation in corpus cavernosum = increased BF = penile erection
    • Sildenafil and vardenafil fill the penis

    Clincal use: tx of ED

    Toxicity: headache, flushing, impaired green-blue colour vision, life-threatening hypotension if pt is taking nitrates

    Hot and sweaty, but then Headache, Heartburn, Hypertension
  49. Bisphophonates
    • Drugs: etidronate, pamidronate, alendronate, risedronae
    • Mechanism: inhibits osteoclastic activity; reduces both formation resorption of hydroxyapetite
    • Clinical use: malignancy-associated hypercalemia, Paget's disease of bone, postmenopausal osteoporosis
    • Toxicity: Corrosive esophagitis, nausea, diarrhea
  50. Terapratide
    • Mechanism: recombinant DNA PTH analogue
    • Clinical use: once daily to stimulate the osteoblasts & new bone formation
    • Continuous infusion would stimulate osteoclast activity
    • has to be used for less than 2 years = bc of increased risk of osteosarcoma
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Endocrine Pharm
Endocrine Pharm