Cholinergics / anticholinergics and drugs affecting the endocrine system

1. Cholinergics/anticholinergics and drugs affecting the endocrine system By Linda Self

2. Cholinergics • PNS • Receptors • Acetylcholine • Direct and indirect acting cholinergic drugs

3. Direct acting cholinergics • Urecholine • Actions— • indications

4. Indirect acting agents • Affect cholinesterase • Neostigmine ( prostigmine) is prototype • Mestinon (pyridostigmine) is drug of choice for MG • Tensilon(edrophonium)diagnostic agent • Antilirium (physostigmine)only agent that crosses blood brain barrier • Aricept (donepazil)—use in AD

5. Cholinergic and Myasthenic crises • Difficult to distinguish • Treatments differ • Myasthenic crisis requires more medication, cholinergic crisis requires less • Distinguished by the timing of s/s—within one hour of anticholinesterases, likely cholinergic excess. If within three hours, myasthenic problem. • Cholinergic crisis-Tx supportively, atropine, decrease anticholinesterase med • Myasthenic-Supportive treatment and increase of anticholinesterase med • (testing may require intubation and ventilator assist)

6. Organophosphate poisoning • Tabin, Sarin—nerve gases • Insecticides—malathion, parathion • Decontaminate—clothing, flushing with water, activated charcoal and lavage • Atropine for muscarinic effects—hypersalivation, urination, defecation, laryngospasm) • Protopam (pralidoxime) for nicotinic effects –causes poison to release enzyme cholinesterase

7. AD • Use reversible indirect acting cholinergics • Aricept (donepezil)does not cause liver toxicity. Can cause n/v, bradycardia, PUD, exac. of asthma • Razadye (galantamine)-long acting • Exelon (rivastigmine) • Cognex (tacrine)– more hepatototoxicity

8. Anticholinergics • Most affect muscarinic receptors in brain, secretory glands, heart and smooth muscle • Few affect nicotinic receptors, e.g., Robinul (glycopyrolate) • Effects of anticholinergics are diffuse • Indications—GI (gastritis, UC, irritable bowel; GU antispasmotic in overactive bladder; ophthalmology for exams, glaucoma; respiratory for bronchodilation; cardiology to increase heart rate • Antilirium for overdose of anticholinergics

9. Anticholinergics • Atropine • Atrovent • Scopolamine—antiemetic, motion sickness • Spiriva (tiotropium) • Bentyl (antiscretory/antispasmotic) • Cogentin • Trihexy (Parkinson’s)

10. Corticosteroids; Hematopoietic, Immunizing, immunosuppressive agents and drugs used in oncology

11. Immunity • Defense • Specificity, memory and inducibility • Normal immunity –ability to recognize self and non-self • Recognition of epitopes (distinctive molecules on non-self antigens) • Underactive=immunodeficiency • Overactive=autoimmune diseases

12. Immunity • Natural • Acquired immunity—active or passive (antibodies are transferred) • Cellular—involving activated T cells • Humoral—involves B cells and antibodies • All antigens elicit both types

13. Immunizations • Administration of antigen to induce antibody formation (active) or serum from immune people (passive) • Regulated by US FDA

14. Active Immunity • Vaccines and toxoids • Vaccines are suspensions of microorganisms or antigenic products • Toxoids are bacterial toxins that have been modified to retain antigenic properties, not permanent

15. Indications for active immunity • Give before exposure to actual illness • Diphtheria,tetanus, pertussis, hemophilus influenza (Hib) , inactivated polio vaccine, pneumococcal (PCV), hepatitis A and B, varicella, MMR, PPV, MC4, influenza • Some combinations

16. Contraindications to use of agents for active immunity • Febrile illnesses • Immunosuppressed • Immunodeficiency states • Leukemia • Lymphoma • In pregnancy • If generalized malignancy

17. Passive Immunity • Immune serums are biologic products used for passive immunity • Temporary • Agents: cytomegalovirus immune globulin, hepatitis B immune globulin, rabies immune globulin, rubella, tetanus immune globuline, varicella zoster, RSV immune globulin, tetanus immune globulin

18. Key Points in Immunizations • Women of childbearing age should not get pregnant for three months after receiving Rubella immunization • Influenza-may start at 6 months; annually in those over 65 • Tetanus toxoid—after initial immunization, give every ten years • Children with HIV—should not receive live vaccines • Pneumococcal at 65; may repeat in five years if with chronic conditions • After Varicella, avoid close contact with newborns, pregnant women and immunocompromised persons • After immunizations, stay in area 30 minutes

19. Hematopoietic and Immunostimulant Drugs • Cytokines or biologic response modifiers given to restore normal function or increase ability of the immune system • Examples: certain interferons and interleukins, colony stimulating factors

20. Definitions • Cytokines—substances produced by bone marrow cells, regulate cellular activities; are the key components in producing hematopoietic and immunostimulant drugs • Interferons—glycoproteins w/antiviral activity • Interleukins—cytokines that enable communication between leukocytes and other cells involved in inflammation or cell-mediated response. Result—maximized response to a given pathogen or foreign antigen.

21. Hematopoietic and immunostimulant drugs • Very powerful • Difficult to maintain therapeutic dosing for prolonged time • Can have untoward and unanticipated side effects • Can act as antiproliferative and immunoregulatory agents; can augment natural killer cells • Parenteral • Significant side effects decreasing compliance

22. Hematopoietic Agents • Epogen (epoetin alfa)=erythropoietin • Use for anemia • Hct 2x weekly, adjust as Hct increases to 36%

23. Colony stimulating factors • Neupogen (filgrastim) stimulate blood cell production by marrow in patients with bone marrow transplantation or chemotherapy induced neutropenia • Leukine—angiogenetic, used in ischemic heart disease

24. Interleukins • Proleukin (aldesleukin)—recombinant version if IL-2 • Activates cellular immunity, produces TNF and inhibits tumor growth • For metastatic renal cell CA • Toxicity can cause GI bleed, dysrhythmias, resp. embarrassment • Contraindicated in recent organ transplantation

25. Interferons • Alfa -2a and 2b for hairy cell leukemia and Kaposi’s sarcoma • alfa n1 approved for chronic hepatitis C • Beta for multiple sclerosis

26. Corticosteroids • Decrease inappropriate or undesirable immune response. Examples include: RA, SLE, asthma or suppression of transplant rejection • Glucocorticoids • Effects—catabolism, decrease immune response, decrease utilization and increase production of glucose, stabilize mast cells, affect gastric mucosa, muscle atrophy and adrenal cortex suppression

27. Corticosteroids • Prednisone is prototype • Celestone (betamethasone) • Decadron (dexamethasone) • Solucortef (methylprednisolone) • Kenalog (triamcinolone)

28. Immunosuppressant Drugs • Use in concert with steroids • Used in autoimmune disorders • Newer agents modify specific components of immune response, fewer SE • Imuran-bone marrow depression is SE • Sandimmune (cyclosporine)—monitor renal and hepatic toxicity, CNS toxicity • Methotrexate—bone marrow suppression • Remicade—infusion reactions, GI upset, others

29. Cytotoxic, Antiproliferative Agents • Used primarily in cancer • Imuran (azathioprine) antimetabolite that targets rapidly proliferating cells including T and B lymphocytes • Rheumatrex (methotrexate) folate antagonist. Used for cancer and for autoimmune or inflammatory disorders.

30. Antirejection Agents • Sandimmune (cyclosporine)—inhibits synthesis of IL- 2 necessary for activation of T cells and B cells. • Rapamune (sirolimus) affects T cell activation and proliferation secondary to several interleukins • Prograf (tacrolimus)—prevents rejection of transplanted organs by inhibiting T lymphocytes

31. Monoclonal Antibodies • Remicade (infliximab). Inhibits TNF from binding to receptors. Used in RA and Crohn’s. • Enbrel (etanercept) TNF receptor binder. RA. • Arava (Leflunomide) antiproliferative and anti-inflammatory activities. Inhibits pyrimidines needed for RNA and DNA synthesis. RA.

32. Drugs affecting the Endocrine System Review of Endocrine system • Hypothalamus—releasing hormones that affect both anterior and posterior pituitary • Ant. Pituitary---GH, ACTH, TSH, FSH, LH, Prolactin, melanocyte stimulating hormone • Post. Pituitary—ADH, oxytocin • Adrenals • Thyroid • pancreas

33. Hypothalamic hormones • Generally parenteral or intranasally, broken down in GI system • Equivalent to gonadotropin releasing hormones • Factrel (gonadorelin)—used for diagnostic testing of gonadotropin function • Zoladex (goserelin)—reduces hormonal levels so useful in metastatic breast cancer, prostate cancer and in endometriosis • Lupron (leuprolide)-advanced prostate cancer, central precocious puberty, endometriosis, uterine fibroids

34. Hypothalamic hormones • None of the GnRH equivalents can be given orally • Factrel (gonaderelin) diagnostic testing • Lupron( leuprolide)decreases estrogen and testosterone levels • Zoladex (goserelin) decreases estrogen and testosterone levels • Sandostatin (octreotide)—somatostatin. Decreases GH, decreases GI secretions and motility. Given in severe diarrhea as well as with acromegaly.

35. Anterior Pituitary Hormones • Cosyntropin (corticotropin)-diagnostic test of adrenal function • Protropin (somatrem)—synthesized growth hormone. Promotes growth in those deficient in GH or in renal failure. Tissue wasting with AIDS. • Chorex (HCG)—synthetic LH. Diagnostic test of testosterone production, cryptorchidism • Pergonal (menotropins)—preparation containing both LH and FSH. Usually combined with HCG to induce ovulation.

36. Anterior Pituitary Hormones • Thytropar (thyrotropin)—used as diagnostic agent to distinguish between primary and secondary hypothyroidism • Humatrope (somatropin) for children with GH deficiency. Not effective in epiphyseal closure. Tissue wasting of AIDs

37. Posterior Pituitary Hormones • DDAVP (desmopressin) and Pitressin (vasopressin) are synthetic equivalents of ADH. Useful in diabetes insipidus. • Parenteral desmopressin used as hemostatic agent in hemophilia and Von Willebrand’s Disease. Tx of bleeding esophageal varices. • Pitocin (oxytocin) promotes uterine contractility. Used in induction of labor and to control postpartum bleeding.

38. Drugs used for Calcium and Bone Disorders • Bisphosphanates—Fosamax (alendronate), Actonel (risedronate) and Zometa (zoledronic acid) • Bind to bone, inhibit calcium resorption • Take on empty stomach, with water, 30 minutes before other intake • Calcimar, Miacalcin (calcitonin-salmon) for hypercalcemia, Paget’s Disease, and osteoporosis. Slows bone resorption, may be helpful with bone pain.

39. Drugs used for calcium and bone disorders • Symptomatic hypocalcemia, calcium gluconate • Oral calcium preparations for osteopenia or nutritional deficiency • Corticosteroids—inhibit cytokine release by cytolytic effects of some bone tumors, inhibit calcium absorption from intestine and by increasing calcium excretion in urine. Used in hypercalcemia due to malignancies or Vitamin D intoxication

40. Drugs used for calcium and bone disorders • Estrogens most beneficial immediately after menopause. Decrease bone breakdown, increase calcium absorption from gut and increase calcitriol. • Evista (raloxifene) and Nolvadex (tamoxifen) act like estrogen in some tissues and prevent the action of estrogen in other body tissues • Evista is classified as a selective estrogen receptor modulator and is approved for postmenopausal osteoporosis.

41. Calcium and bone disorders • Nolvadex (tamoxifen) is classified as an antiestrogen. Used to prevent and treat breast cancer. Also has estrogenic effects so can be used to prevent osteoporosis • Forteo (teriparatide)—recombinant DNA version of parathormone. Increases bone formatin by increasing osteoblasts. Increases serum levels of calcium and calcitriol. Not known to cause deposition of calcium in soft tissues • Vit D 400 IU for 6months to 24 years; 200IU/day 25 years and older • Lasixcauses increased excretion of calcium

42. Adrenal Agents • Adrenal cortex produces glucocorticoids, mineralocorticoids and adrenal sex hormones • Hydrocortisone is prototype • Florinef (fludrocortisone)—only mineralocorticoiddescribed in text

43. Pearls • Thiazide diuretics contraindicated in hypercalcemia as decrease urinary excretion of calcium • Look at albumin levels when examining calcium levels • Children on growth hormone, ht. and wt. chart weekly, follow epiphyseal closure • Dietary calcium is superior to supplemental • Menopausal women should have 1000 mg of calcium daily

44. Pearls • Vasopressin-watch for water intoxication, chest pain, MI • Oxytocin can result in uterine rupture • Octreotide can cause arrhythmias, bradycardia, hyperglycemia, injection site pain and symptoms of gallstones

45. Acute hypercalcemia • Medical emergency • For severe s/s or level >12mg/dL. Rehydrate • IV saline • Lasix • Fosamax or Zometa • Monitor serum calcium levels • Calcium channel not so effective

46. Thyroid and antithyroid drugs • Thyroid produces thyroxine, triidothyronine and calcitonin • Thyroxine is called T4 (has 4 atoms of iodine) • Triidothyronine has 3 atoms of iodine so is called T3

47. Thyroid • Essential for normal G&D • Critical for brain development and maturation • Increases rate of cellular metabolism and oxygen consumption • Increases heart rate, force of contraction and cardiac output • Increases fat metabolism including cholesterol • Inhibition of pituitary secretion of TSH

48. Thyroid Disorders • Goiter—enlargement of thyroid due to lack of iodine in diet; thyroiditis, tumors, hyper or hypo function of the thyroid • Compensate for iodine deficiency, pituitary secretes more TSH; thyroid enlarges producing more hormone, possibly effecting a normal hormone level • Correction of goiter involves replacing iodine; replacement of thyroid hormone. May have regression or may need excision

49. Hypothyroidism • Occurs secondary to disease or destruction of the thyroid • Causes: Hashimoto’s thyroiditis, previous exposure to radiation, treatment with amiodarone, lithium or iodine

50. Hypothyroidism • Congenital=Cretinism; may occur with lack of iodine in mother’s diet. S/S in infancy, can result in severe mental retardation • Hypothyroidism may be subclinical but may progress. • S/S initially vague but become more pronounced: cold intolerance, fatigue, aches and pains, puffy appearance, mental sluggishness, anemia, bradycardia • Tx-exogenous thyroxine • Replacement indicated if TSH is >10 microunits/L