1. thyroid hormones
   1. normalize growth & development, body temp, & energy levels
      1. triiodothyronine (T3)
      2. Tetraiodothyronine (T4, thyroxine)
   2. regulates calcium metabolism
      1. calcitonin
2. thyroid drugs (HYPO)
   1. naturally occuring L isomers ( synthetic D isomer of thyroxine "dextrothyroxine" has 4% activ
   2. levothyroxine (Synthroid)
      1. DOC for thyroid replacement & supression therapy (stability, content uniformity, low cost, no allergenic foriegn protien, easy serum level measurement, t1/2 of 7 days
      2. once daily QD (30 min b4 or 1 hr after meal)
      3. T4 is converted to T3 intracellularly...admin of T4 produces both hormones
      4. 6-8 wks to reach ss
   3. liothyroxine (Cytomel)
      1. 3 to 4x more potent than levothyroxine
      2. short 1/2 life (<24 hrs)
      3. multiple daily doses
      4. higher cost
      5. ↑ risk of cardiac tox
   4. pharmacokinetics
      1. thyroxine is best absorbed in the duodenum/ileum
      2. abs is modified by food, drugs, gastric acidity, intestinal flora
      3. oral bioavailability of T4 is 80%, T3 95%
      4. abs affected by severe myxedema w/ ileus, but not mild hypothyroidism
      5. IV preferred for parenteral route
      6. in hyperthyrodism the clearance of T3/T4 are ↑ and t1/2 ↓, opposite for hypo
      7. P450 inducers ↑ metab of T3/T4
         1. clearance is maintained in euthyroid pts (bc compensatory hyperfunction of the thyroid)
         2. pts recieving T4 may require ↑ dosage to keep effectiveness
      8. if binding sites are altered...
         1. TBG sites are ↑ by preg, estrogens, BC's therefore causing the hormone to shift from free to bound & a ↓ in elim rate (conc of total+bound hormone will ↑, but conc of free hormone & ss will be normal
   5. precautions
      1. elderly- the heart is sensitive to circulating thyroxine...if arrythmias/angina devel...stop or reduce dose
      2. in younger pts/ mild disease pts- full replacemtn therapy may be started stat
   6. toxicity
      1. directly related to hormone level
      2. children: restlessness, insomnia,accel bone growth
      3. elderly: overtx of T4 can inc risk of A-fib and accelerated osteoporosis
3. Effects of hormones
   1. tyroid deprevation in early life results in irreversible mental retardation and dwarfism (congenital cretinism?)
   2. the secretion/ degradation rates of catecholamines, cortisol, estrogens, testosterone, insulin are affected by thyroid status
   3. thyroid hyperactivity resembles sympathetic nervous system overactivity although catecholamine levels are not increased
4. Antithyroid hormones (HYPER)
   1. reduction of thyroid activity & hormone effects by agents that...
      1. interfere with the production of thyroid hormones
      2. modify the tissue response to thyroid hormones
      3. glandular destruction with radiation or surgery
   2. goitrogens
      1. agents that supress T3/T4 secretion to subnormal levels, increasing TSH and produces glandular enlargement(goiter)
   3. thioamides
      1. short t1/2 has little influence on the DOA or dosing interval bc drugs are accumulated by the thyriod gland
      2. safe for nursing mothers
      3. tx: thryrotoxicosis
      4. thiocarbamide group is essential for antithyroid activity
      5. MOA
         1. block coupling of iodotyrosines
         2. inhibit synthesis by acting against iodide organification
         3. drugs affect synthesis of I so the onset is 3-4 wks before T4 stores are depleted
      6. drugs
         1. methimazole
            1. 10x more potent than propylthiouracil
            2. t1/2 6 hrs
            3. dosed 1x/day
            4. pharmacokinetics
            5. completely absorbed at variable rates
            6. slower excretion than proylthiouracil
            7. 65-70% of drug is recovered in urine in 48 hrs
            8. toxcity
            9. altered taste/ smell
            10. cholestatic jaundice
         2. propylthiouracil (PTU)
            1. add'l MOA
            2. Blocks peripheral conversion of T4 to T3
            3. t1/2 1.5 hrs
            4. dosed 3-4x/day
            5. pharmacokinetics
            6. rapidly absorbed
            7. peak after 1 hr
            8. bioavailability 50-80 %
            9. excreted as the inactive glucuronide w/in 24 hrs
            10. toxcity
            11. hepatitis
      7. toxicity
         1. GI distress
         2. nausea
         3. maculopapular pruritic rash & fever
         4. lupus-like rxn
         5. acute arthralgia
         6. AGRANULOCYTOSIS (grandulocyte ct <500 cells/mm3
         7. cross sensitivity for allergic rxns
      8. contraindications
         1. preg cat D
            1. PTU is pref'd bc its highly protien bound & doesnt cross placenta readily
            2. methimazole assoc with congenital malformations
   4. anion inhibitors
      1. monovalent anions
         1. pertechnetate (TcO4-)
         2. perchlorate (ClO4-)
            1. K ClO4- is used to block thyrodial reuptake of I in pts with iodide induced hyperthyroidism
            2. rarely used...SE: aplastic anemia
         3. thiocyanate (SCN-)
      2. MOA
         1. block the uptake od iodide by the gland through competitive inhibition of the iodide transport mechanism
            1. these effects can be overcome by lg doses of iodides...there effectiveness is unpredictable
   5. iodides
      1. Subtopic 3
      2. MOA
         1. inhibit organification and hormone release and decrease the size and vascularity of the hyperplastic gland
            1. valuable as preoperative prep for surgery
         2. @ pharmacologic doses (>6mg/d) they inhibit hormone release (inhibit thyroglobulin proteolysis)
            1. improvement in thyrotoxic sx w/in 2-7 days
            2. valued in iodide therapy of thyroid storm
      3. SE
         1. in susceptible indiv they can induce hypothyrodism or precipitate hypothyrodism
      4. disadvantage
         1. inc of intraglandular stores of iodine (delays onset of thioamide therapy/prevent radiactive I therpay for wks
            1. intiate therapy after thiamides and avoid radiactive therapy
            2. in radiation emergencies KI can protect the gland from subsequent damage if admin b4 radiation exposure
         2. should not be used alone bc the gland will escape from the iodide block in 2-8 wks and w/d can severly exacerbate thyrotoxicosis in an iodine-enriched gland
         3. avoid in pregnancy (causes fetal goiter)
   6. radioactive iodine I (131)
      1. tx: thyrotoxicosis
      2. rapidly absorbed and concentrates in thyroid
      3. therapeutic effect depends on emission of B rays with an effective t1/2 of 5 days and penetration range of 400-2000 mcm
         1. within a few weeks destruction of the thyroid parenchyma is evidenced by epithelial swelling and necrosis, follicular disruption, edema, and leukocyte infiltration
      4. do not ise in pregnant or nursing mothers
   7. B-blockers
      1. w/o ISA
      2. may cause clinical improvement of hyperthyroid sx but do not typically alter hormone levels
         1. propranolol (>160 mg/d) may dec T3 levels approx 20% by inhib peripheral conv of T4 to T3
5. Hypothyrodism
   1. syndrome resulting from defiency of thyroid hormones
   2. manifested by a reversible slowing down of all body functions
      1. in infants/ children: dwarfism & irreversible mental retardation
   3. lab diagnosis shows low free thyroxine and elevated serum TSH
      1. normal TSH 0.5-2.5 mU/L
   4. most common cause is Hashimoto's thyroiditis- immunologic disorder in genetically predisposed indiv
   5. DOC is levothyroxine
      1. infants/children req more T4/ kg than adults (10-15 mcg/kg/d vs 1.7 mcg/kg/d)
   6. special problems
      1. myxedema & CAD
         1. low levles of circulating thyroid hormones protect the heart form increasing demands that lead to angina & MI
         2. if coronary artery surgery is indicated, it should be done before correction of myexedema by thyroxine admin (will provoke angina & MI)
      2. myxedema coma
         1. end state of un-tx hypothyroidism
            1. assoc with weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, h20 intox, shock & death
         2. medical emergency
            1. may req technical intibation and mech ventilation
            2. may have infection & heart failure
         3. tx of choice- levothyroxine
            1. LD 300-400 mcg IV
            2. MD 50-100 mcg daily
            3. IV T3 can be used but cardiotoxic and diff to monitor
            4. hydrocortisone- if pt has assoc adrenal/ pituitary insuf
            5. opoids/ sedatives- use extreme caution
      3. hypothyrodism & pregnancy
         1. anovulatory cycle -> infertile
         2. pregnant hypothyroid pts needs adequate doeses of thyroxine bc fetel brain devel
            1. incr 30-50% in thyroxine does is req to normalize serum TSH during preg
      4. subclinical hypothroidism
         1. therapy considered if TSH > 10 mIU/L
         2. rate inc in women > 50 y.o.
         3. defined as elevated TSH level & normal thyroid hormone levels
      5. drug induced hypo
         1. amiodarone- induced hypothyroidism, levothyroxine may be necc even after d/c amiodarone (long t1/2)
6. hyperthyroidism (thyrotoxicosis)
   1. graves disease
      1. autoimmune disease where T lympocytes stimulate Beta lympocytes to make antibodies to thyroid agents
         1. antibodies: TSH-R Ab [stim]- directed against TSH receptor site in thyroid cell membrane
      2. lab diag
         1. inc T3, T4,FT4,FT3, and dec TSH
         2. radioacive uptake inc
         3. antithyroglobulin, thyroxine perioxidase, TSH-R Ab [stim] antibodies are present
      3. management
         1. antithyroid drug therapy
            1. methimazole/ PTU req 12-18 mo therap
            2. has a 50-68% relapse rate
            3. methimazole pref...PTU if pregnant
            4. PTU dec thyroid hormone faster bc it inhibits conversion of T4 to T3
            5. best clinical guide to remission is reduction in size of the goiter
            6. lab tests to monitor : FT3, FT4, TSH
         2. thyroidectomy
            1. TOC for lg glands & multinodular goiters
            2. pts get antithyrod drugs until euthyroid ( 6 wks), 10-14 days pre-op take saturated KI (to diminish vascularity of the gland & simplify surgery)
            3. about 80-90% of pts will req thyroid supplementation
         3. radioactive iodine
            1. TOC for pts >21 y.o.
            2. if pt w/ heart disease, severe thyrotoxicosis, & elderly tx w/ methimazole first, then d/c x 5-7 days, then I(131) given
            3. 6-12 wks after admin of I(131) the gland will shrink and pt will bc euthyroid or hypothyroid (tx w/ levothyroxine)
         4. adjuncts to therapy
            1. BB w/o ISA
            2. propranolol will control tachycardia, HTN, and A fib
            3. Diltiazem can be used if BB is contraindicated(ie asthma)
            4. adequate nutrition & vitamin supplements are essential
            5. barbituates accel T4 breakdown (good for sediative & lowering T4 levels)
            6. bile acid sequesterants rapidly dec T4 by incr fecal excretion of T4
   2. toxic uninodular goiter & toxic multi nod goiter
      1. occur in older women w/ nodular goiters
      2. FT4 is inc or normal, but FT3 or T3 is strikenly elvated
      3. single toxic adenomas can be excised or radioiodine therapy
      4. toxic multinod goiter is tx with methimazole /PTU then ectomy