By Linda Self

Cholinergics PNSReceptorsAcetylcholineDirect and indirect acting cholinergic drugs

Direct acting cholinergicsUrecholineActions—indications

Indirect acting agentsAffect cholinesteraseNeostigmine ( prostigmine) is prototypeMestinon (pyridostigmine) is drug of

choice for MGTensilon (edrophonium)diagnostic agentAntilirium (physostigmine)only agent that

crosses blood brain barrierAricept (donepazil)—use in AD

Cholinergic and Myasthenic crisesDifficult to distinguishTreatments differMyasthenic crisis requires more medication,

cholinergic crisis requires lessDistinguished 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)

Organophosphate poisoningTabin, Sarin—nerve gasesInsecticides—malathion, parathionDecontaminate—clothing, flushing with

water, activated charcoal and lavageAtropine for muscarinic effects—

hypersalivation, urination, defecation, laryngospasm)

Protopam (pralidoxime) for nicotinic effects –causes poison to release enzyme cholinesterase

ADUse reversible indirect acting cholinergicsAricept (donepezil)does not cause liver

toxicity. Can cause n/v, bradycardia, PUD, exac. of asthma

Razadye (galantamine)-long actingExelon (rivastigmine)Cognex (tacrine)– more hepatototoxicity

AnticholinergicsMost affect muscarinic receptors in brain,

secretory glands, heart and smooth muscleFew affect nicotinic receptors, e.g., Robinul

(glycopyrolate)Effects of anticholinergics are diffuseIndications—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

AnticholinergicsAtropineAtroventScopolamine—antiemetic, motion sicknessSpiriva (tiotropium)Bentyl (antiscretory/antispasmotic)CogentinTrihexy (Parkinson’s)

Corticosteroids; Hematopoietic, Immunizing, immunosuppressive

agents and drugs used in oncology

ImmunityDefenseSpecificity, memory and inducibilityNormal immunity –ability to recognize self

and non-selfRecognition of epitopes (distinctive molecules

on non-self antigens)Underactive=immunodeficiencyOveractive=autoimmune diseases

ImmunityNaturalAcquired immunity—active or passive

(antibodies are transferred)Cellular—involving activated T cellsHumoral—involves B cells and antibodiesAll antigens elicit both types

ImmunizationsAdministration of antigen to induce antibody

formation (active) or serum from immune people (passive)

Regulated by US FDA

Active ImmunityVaccines and toxoidsVaccines are suspensions of microorganisms

or antigenic productsToxoids are bacterial toxins that have been

modified to retain antigenic properties, not permanent

Indications for active immunityGive before exposure to actual illnessDiphtheria,tetanus, pertussis, hemophilus

influenza (Hib) , inactivated polio vaccine, pneumococcal (PCV), hepatitis A and B, varicella, MMR, PPV, MC4, influenza

Some combinations

Contraindications to use of agents for active immunity

Febrile illnessesImmunosuppressedImmunodeficiency statesLeukemiaLymphoma In pregnancy If generalized malignancy

Passive ImmunityImmune serums are biologic products used

for passive immunityTemporaryAgents: cytomegalovirus immune globulin,

hepatitis B immune globulin, rabies immune globulin, rubella, tetanus immune globuline, varicella zoster, RSV immune globulin, tetanus immune globulin

Key Points in ImmunizationsWomen 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 vaccinesPneumococcal at 65; may repeat in five years if with

chronic conditionsAfter Varicella, avoid close contact with newborns,

pregnant women and immunocompromised personsAfter immunizations, stay in area 30 minutes

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

DefinitionsCytokines—substances produced by bone

marrow cells, regulate cellular activities; are the key components in producing hematopoietic and immunostimulant drugs

Interferons—glycoproteins w/antiviral activityInterleukins—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.

Hematopoietic and immunostimulant drugs

Very powerfulDifficult to maintain therapeutic dosing for

prolonged timeCan have untoward and unanticipated side

effectsCan act as antiproliferative and

immunoregulatory agents; can augment natural killer cells

ParenteralSignificant side effects decreasing compliance

Hematopoietic AgentsEpogen (epoetin alfa)=erythropoietinUse for anemiaHct 2x weekly, adjust as Hct increases to

36%

Colony stimulating factorsNeupogen (filgrastim) stimulate blood cell

production by marrow in patients with bone marrow transplantation or chemotherapy induced neutropenia

Leukine—angiogenetic, used in ischemic heart disease

InterleukinsProleukin (aldesleukin)—recombinant

version if IL-2Activates cellular immunity, produces TNF

and inhibits tumor growthFor metastatic renal cell CAToxicity can cause GI bleed, dysrhythmias,

resp. embarrassmentContraindicated in recent organ

transplantation

InterferonsAlfa -2a and 2b for hairy cell leukemia and

Kaposi’s sarcomaalfa n1 approved for chronic hepatitis CBeta for multiple sclerosis

CorticosteroidsDecrease inappropriate or undesirable

immune response. Examples include: RA, SLE, asthma or suppression of transplant rejection

GlucocorticoidsEffects—catabolism, decrease immune

response, decrease utilization and increase production of glucose, stabilize mast cells, affect gastric mucosa, muscle atrophy and adrenal cortex suppression

CorticosteroidsPrednisone is prototypeCelestone (betamethasone)Decadron (dexamethasone)Solucortef (methylprednisolone)Kenalog (triamcinolone)

Immunosuppressant DrugsUse in concert with steroidsUsed in autoimmune disordersNewer agents modify specific components of

immune response, fewer SEImuran-bone marrow depression is SESandimmune (cyclosporine)—monitor

renal and hepatic toxicity, CNS toxicityMethotrexate—bone marrow suppressionRemicade—infusion reactions, GI upset,

others

Cytotoxic, Antiproliferative AgentsUsed primarily in cancerImuran (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.

Antirejection AgentsSandimmune (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

Monoclonal AntibodiesRemicade (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.

Drugs affecting the Endocrine System

Review of Endocrine systemHypothalamus—releasing hormones that

affect both anterior and posterior pituitaryAnt. Pituitary---GH, ACTH, TSH, FSH, LH,

Prolactin, melanocyte stimulating hormonePost. Pituitary—ADH, oxytocinAdrenalsThyroidpancreas

Hypothalamic hormonesGenerally parenteral or intranasally, broken

down in GI systemEquivalent to gonadotropin releasing hormonesFactrel (gonadorelin)—used for diagnostic

testing of gonadotropin functionZoladex (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

Hypothalamic hormonesNone of the GnRH equivalents can be given

orallyFactrel (gonaderelin) diagnostic testing Lupron( leuprolide)decreases estrogen and

testosterone levelsZoladex (goserelin) decreases estrogen and

testosterone levelsSandostatin (octreotide)—somatostatin.

Decreases GH, decreases GI secretions and motility. Given in severe diarrhea as well as with acromegaly.

Anterior Pituitary HormonesCosyntropin (corticotropin)-diagnostic test of

adrenal functionProtropin (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.

Anterior Pituitary HormonesThytropar (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

Posterior Pituitary HormonesDDAVP (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.

Drugs used for Calcium and Bone Disorders

Bisphosphanates—Fosamax (alendronate), Actonel (risedronate) and Zometa (zoledronic acid)

Bind to bone, inhibit calcium resorptionTake on empty stomach, with water, 30

minutes before other intakeCalcimar, Miacalcin (calcitonin-salmon) for

hypercalcemia, Paget’s Disease, and osteoporosis. Slows bone resorption, may be helpful with bone pain.

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

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.

Calcium and bone disordersNolvadex (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

Lasix causes increased excretion of calcium

Adrenal AgentsAdrenal cortex produces glucocorticoids,

mineralocorticoids and adrenal sex hormonesHydrocortisone is prototypeFlorinef (fludrocortisone)—only

mineralocorticoid described in text

PearlsThiazide 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 supplementalMenopausal women should have 1000 mg of

calcium daily

PearlsVasopressin-watch for water intoxication,

chest pain, MIOxytocin can result in uterine ruptureOctreotide can cause arrhythmias,

bradycardia, hyperglycemia, injection site pain and symptoms of gallstones

Acute hypercalcemiaMedical emergencyFor severe s/s or level >12mg/dL. RehydrateIV salineLasixFosamax or ZometaMonitor serum calcium levelsCalcium channel not so effective

Thyroid and antithyroid drugsThyroid produces thyroxine, triidothyronine

and calcitoninThyroxine is called T4 (has 4 atoms of iodine)Triidothyronine has 3 atoms of iodine so is

called T3

ThyroidEssential for normal G&DCritical for brain development and

maturationIncreases rate of cellular metabolism and

oxygen consumptionIncreases heart rate, force of contraction and

cardiac outputIncreases fat metabolism including

cholesterolInhibition of pituitary secretion of TSH

Thyroid DisordersGoiter—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

HypothyroidismOccurs secondary to disease or destruction of

the thyroidCauses: Hashimoto’s thyroiditis, previous

exposure to radiation, treatment with amiodarone, lithium or iodine

HypothyroidismCongenital=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 thyroxineReplacement indicated if TSH is >10 microunits/L

HypothyroidismMyxedema comaCharacterized by hypothermia,

cardiovascular collapse, coma, hyponatremia, hypoglycemia, and lactic acidosis

Predisposing factors include: cold, infection, CNS depressants

Tx—synthetic levothyroxine is drug of choice.

In myxedema coma, Tx will be given IV.

HyperthyroidismCharacterized by excessive secretion of

thyroid hormoneMay be associated with overtreatment with

thyroid drugs, nodular goiter, thyroiditis, functioning thyroid cancer, pituitary adenoma resulting in excess TSH secretion

Subclinical hyperthyroidism is defined as reduced TSH (below 0.1 microunit/L) and normal T3 and T4 levels

Greatly increases the risk for atrial fibrillation

HyperthyroidismThyroid storm or thyrotoxic crisis is a severe

complication. Will result in: severe tachycardia, fever, dehydration, heart failure and coma

Tx depends on cause. May need surgery or radioactive iodine therapy

Antithyroid drugs include Propylthioruracil (PTU)and Tapazole (methimazole), and iodine preparations

Drugs used in hypothyroidismSynthroid, Levothyroid (levothyroxine)—

synthetic T4. Offers uniform dosing and potency.

Euthroid and Thyrolar (Liotrix) contains both levothyroxine and triiodothyronine in a 4:1 ratio approximating natural thyroid hormone

Drugs used in hyperthyroidismPTU is prototype of thioamide antithyroid

drugsCan be used alone or in combination with

thyroidectomy and in Tx of thyrotoxic crisesActs by inhibiting conversion of T4 to more

active T3. Does not affect thyroid stores. Short acting requiring TID dosing.

Drugs used in hyperthyroidismTapazole (methimazole)---similar to PTULugol’s (strong iodine solution) and

saturated solution of potassium iodide (SSKI)—these drugs inhibit release of thyroid hormone, causing them to accumulate in the gland

Lugol’s decreases the size and vascularity of the thyroid before thyroidectomy

Iodine preparations should not be followed by PTU, Tapazole or radioactive iodine. The latter drugs cause release of stored thyroid and can precipitate crisis.

Sodium Iodide 131Radioactive isotope of iodine. Thyroid picks up the

isotope from circulating blood. Act by emitting beta and gamma rays. Rays destroy thyroid tissue and decrease production of thyroid hormones. Also used for diagnosis and in the treatment of cancer.

Usually given in a single dose as outpatient. No special precautions. May be months before therapeutic effect. During this time, on maintenance medications.

Iodine preparations and thioamide antithyroid drugs are contraindicated during pregnancy. Can result in goiter and hypothyroidism in fetus or newborn.