Flashcards in thyroid pharmacology Deck (57):
Which drugs can cause hypothyroidism
lithium, amiodarone, cholestyramine, phenytoin, carbamazepine
Levothyroxine- time course
Resolution of symptoms begins within 2-3 weeks. Requires 6-8 weeks of maintenance dose to reach steady-state plasma levels . Thyroid function tests should be assessed at least 6-8 weeks after any dosage change
Hypothyroidism during pregnancy
Requires an increased dose (avg 25% increase) due to: 1. Increased levels of TBG (via estrogen) decreases free T4-T3. 2. Increased placental metabolism of T4-T3.
An extreme form of hypothyroidism, so severe as to readily progress to death unless diagnosed promptly and treated vigorously. Na and glucose drop, hypothermia, shock and possibly death.
Myxedema coma treatment
1. large doses of T4- IV loading dose followed by daily IV dosing. 2. hydrocortisone to prevent adrenal crisis b/c T4 may increase its metabolism
Thyroid hormones absorption
Best in ileum-colon. bioavailability - T4: 65-85%, T3: 95%. May be modified by binding proteins (T4), food or intestinal flora. Absorption is impaired in severe myxedema, so IV only.
Levothyroxine- instructions for usage
empty stomach with water, 30-60 min before breakfast or 4 hours after last meal in evening
Levothyroxine- drugs that can impair absorption
•Metal ions (antacids, calcium and iron supplements). Ciprofloxacin, bile acid sequestrants, raloxifene, sucralfate. Avoid interaction by spacing levothyroxine dose 2 hrs before or 4-6 hrs after interacting drug
amount of free T3 and T4 in plasma
free T4 = 0.04%, free T3 = 0.4%
Levothyroxine- drugs that affect protein binding
Increased binding: estrogens/SERMs, methadone, 5-fluorouracil, heroin. Decreased binding: glucocorticoids, androgens, salicylates, anticonvulsants (phenytoin-carbamazepine), furosemide
Activation of thyroid hormones
•T3 (80%) utilized by peripheral tissues is derived from T4 deiodination in liver via 5'-deiodinase. T3 in brain and pituitary derived by intracellular deiodination
Drugs that inhibit conversion of T4 to T3
glucocorticoids, Beta blockers, amiodarone, propylthiouracil
Conditions which inhibit conversion of T4 to T3
acute/chronic illness, caloric deprivation, malnutrition, fetal/neonatal period
Inactivation of T3
•Deiodination to reverse T3, Deamination, decarboxylation, conjugation to glucuronide or sulfate
Conditions which cause increased/decreased metabolic clearance of thyroid hormones
•Increased in hyperthyroidism and CYP450 induction - decreased by hypothyroidism
Half life of T3 and T4
T4: 7 days (due to protein binding). T3: 1 day.
When should Thyroid function tests be monitored for hypothyroidism
6-8 weeks after any change in levothyroxine
aka triiodothyronine. Synthetic T3.
NOT recommended for routine replacement due to short t1/2 (greater Cp fluctuations between doses), high cost.
cardiac disease- T3 activity has greater risk of cardiotoxicity. Also may increase risk of osteoporosis
Liotrix - MOA
4:1 mixture of T4 and T3.
No advantage b/c T4 conversion to T3 in periphery results in near normal ratio. Rarely required, not recommended.
Liotrix adverse outcomes
May increase incidence of low TSH concentrations and increase markers of bone turnover
Thyroid USP MOA
Dessicated porcine thyroid extract containing T3 and T4
Thyroid USP disadvantages
1. Variable T4/T3 ratio and content - unexpected toxicities. 2. protein antigenicity. 3. instability.
Thyroid USP uses
Less desirable than levothyroxine - current recommendation is use in hypothyroidism should be avoided
Adverse reactions of thyroid hormones in children and adults
Children: restlessness, insomnia, accelerated bone maturation. Adults: anxiety, heat intolerance, palpitations-tachycardia, tremors, weight loss, diarrhea. Also sympathetic overactivity: can precipitate arrhythmias, angina, or MI in patients with cardiac dz
Drug interactions with thyroid hormones
•Increased adrenergic effect of sympathomimetics: epi or decongestants (pseudoephedrine - phenylephrine)
In general, treatment of graves disease
1. interfere with hormone production (synthesis inhibitors): thionamides, idodides. 2. Modify tissue response (symptomatic improval): beta blockers, corticosteroids. 3. glandular destruction: radioactive iodine or surgery
Who responds best to methimazole- PTU
mild dz, small gland, young patients
Benefits of specific beta blockers in graves disease
Used for symptom relief until hyperthyroidism is resolved. Propranolol: blocks T4 to T3 conversion. Metoprolol-atenolol: B1 selective, longer T1/2.
Inhibits thyroid peroxidase blocking T4/T3 synthesis. Blocks iodine organification and iodotyrosine coupling. At high doses PTU blocks peripheral conversion of T4 to T3.
Time course of methimazole- PTU actions
requires 3-4 weeks to deplete T4
Methimazole- PTU uses
Only for thyrotoxicosis from excess production (Graves disease - high RAI) NOT excess release (low RAI)
methimazole- PTU absorption
rapid. PTU is incomplete. Methimazole is complete
Methimazole- PTU distribution
Both can cross placenta and are concentrated by fetal thyroid, so use with caution in pregnancy. PTU is more protein bound so it crosses the placenta less readily and has less secretion into breast milk.
Methimazole-PTU elimination/ half lives
Short half lives (PTU 1-2 hrs, methimazole 5-13 hrs) - but drugs accumulate in thyroid - thus clinical actions longer. PTU given 2-3 times per day. Methimazole once daily
Clinical resolution of thyrotoxicosis within 2 weeks. Biochemical resolution in about 6 weeks.
Situations where methimazole-PTU alone are effective in graves
small goiter, low level of anti-TSH receptor Ab, and mild-to-moderate hyperthyroidism
remission with methimazole-PTU for graves
•Remission within 12-18 months. 1/3 will have lasting remission. 60-70% will have recurrence of graves
Methimazol -PTU adverse rxns
Agranulocytosis is most dangerous. Pruritic rash, GI intolerance, arthralgias more common. For PTU only, hepatotoxicity is rare but serious.
Compare methimazole vs PTU
Methimazole generally preferred: efficacy at lower doses, once-daily dosing, and lower side effect incidence. PTU is safer to fetus - treatment of choice in pregnancy
SSKI (super saturated potassium iodide) and Lugols solution (potassium iodide/iodine)
SSKI- Lugols solution MOA
•Inhibit T4-T3 synthesis (via elevated intracellular [I-]). Inhibit T4-T3 release (via elevated plasma [I-]) > block Tg proteolysis
SSKI- Lugols uses
1. severe thyrotoxicosis-thyroid storm b/c rapid onset. 2. decrease size and vascularity of hyperplastic gland before surgery.
SSKI- Lugols disadvantages
variable effects, rapid reversal when withdrawn, potential to produce new T3 and worsen hyperthryoidism
SSKI- Lugols adverse rxns
acneform rash, rhinorrhea, metallic taste - swollen salivary glands (selective accumulation)
Radioactive iodine MOA
Administered orally- concentrates in thyroid. Beta radiation causes slow inflammatory process that destroys the parenchyma of gland over a period of weeks to months.
Radioactive iodine advantages
easy administration, effective, low expense, no pain
Radioactive iodine disadvantages
slow onset (2-6 months and 10% require second dose), radiation thyroiditis via release of preformed T3 may cause cardio complications in elderly, worsening of ophthlamopathy, causes hypothyroidism.
Who should not receive radioactive iodine
pregnant or nursing women, elderly
Use of surgery for graves dz
Less commonly used b/c radioactive iodine has better benefit to risk ratio. 50-60% require thyroid supplementation afterwards due to iatrogenic hypothyroidism. Can be used in 2nd trimester of pregnancy if needed
What is a thyroid storm
Sudden acute exacerbation of thyrotoxicosis causing fever, flushing, sweating, tachycardia-atrial fibrillation, delirium, coma. May occur if patients are non-compliant, incompletely treted, undiagnosed and have an acute stressor. Sx are due to hypermetabolism and excessive adrenergic activity