Pharm: thyroid and antithyroid drugs Flashcards
what is the precursor for thyroid hormone
tyrosine
T4
thyroxine
prohormone
T3
3,5,3 triiodothyronine
active hormone
reverse T3
3,3,5 triiodothyronine
inactive***
how is T4 converted to T3
type 1 (D1) and type 2 (D2) deiodinases
D1 expressed where
liver and kidney
~24% T4-T3 conversion
D2 expressed where
CNS, pituitary, thyroid, heart, adipose, skeletal muscle
~60% T4-T3 conversion
Type 3 (D3) deiodinase
predominantly expressed in the brain and skin in healthy adults
functions to INACTIVATE T3 - converts to T2 and reverse T3
how is iodide transported into thyroid
sodium-iodide symporter
what are the diseases caused by defective sodium-iodide symporter
- symporter gene mutation (congenital hypothyroidism)
- autoimmune (Hasimoto’s) thyroiditis (autoantibodies against the symporter)
what enzyme leads to the synthesis of thyroid hormone from tyrosine
thyroid peroxidase (adds iodine and couples tyrosines)
what transports thyroid hormone to target cells in blood?
thyroxin-binding globulin (TBG)
how is thyroid hormone transported from colloid to blood?
endocytosed, fuse with lysosome, free thyroid hormone released
how is thyroid hormone transported into the target cells?
- simple diffusion
- MCT (monocarboxylate transporter family)
- OATP (organic anion transporting polypeptides)
where are MCT and OATP expressed? what are they important for?
expressed in liver, kidney, brain, heart
maintain intracellular concentrations of thyroid hormone
regulation of thyroid function (hypothalamus, anterior pituitary)
hypothalamus: TRH
anterior pituitary: TSH
TSH and T4 levels in: hyperthyroidism, hypothyroidism primary, hypothyroidism secondary
hyperthyroidism: TSH low and T4 high
hypothyroidism primary: TSH high and T4 low
hypothyroidism secondary: TSH low and T4 low
what does binding of T3 to thyroid hormone receptor lead to?
transcriptional regulation (activation or suppression) of thyroid hormone regulated genes
what hormone is released from the thyroid?
80% T4 and 20% T3
symptoms of hypothyroidism
fatigue, depression, sensitivity to cold (lower metabolism), weight gain, goiter, muscle weakness, coarsening of the skin, dry or brittle hair, constipation, muscle cramps, increased risk of miscarriage
hypothyroid diseases
- hashiimoto’s thyroiditis: autoimmune antibodies against thyroid peroxidase or sodium-iodide symporter or TSH receptor
- iodine deficiency
- thyroid ablation
- secondary (central) hypothyroidism (pituitary or hypothalamus)
myxedema
severe form of hypothyroidism, mostly adult onset
cretinism
infancy/childhood hypothroidism. causes mental retardation and dwarfism
treatment for hypothyroidism
thyroid hormone replacement therapy
- levothyroxine sodium T4
- liothyronine sodium T3
- liotrix mixture of T4:T3
what is the preferred drug for use in the treatment of hypothyroidism? how is it administered?
levothyroxine sodium (T4) - longer half life and can be converted to T3 in peripheral tissues oral administration - IV or IM for people with GI diseases
which drug is for more acute scenarios of hypothyroidism
IV liothyronine - more rapidly effective (2-4 hr)
*it is also more potent than levothyroxine)
side effects of thyroid replacement drugs
dose related and more quickly occur with liothyronine
- heart palpitations
- nervousness
- heat intolerance
- excessive sweating
- insomnia
- tremor
- frequent bowel movements
- excessive weight loss
in which patients should thyroid hormone replacement be used with caution
angina, coronary artery disease, hypertension pregnant women (need adequate doses)
what is the most common preventable cause of mental handicap in the world?
iodine deficiency
iodine sources
soil and water
symptoms of hyperthyroidism
- rapid heart beat
- weight loss
- nervousness and alertness
- heat intolerance
- fatigue
- increased bowel frequency
- loss of sleep
- tremors
- excessive sweating
- exophthalmus
grave’s disease
MCC hyperthyroidism
autoimmune thyroid-stimulating antibodies causing overproduction of thyroid hormone
what are the causes of hyperthyroidism
- graves disease
- nodular goiter (most are benign)
- thyroiditis
- thyroid cancer
lab findings for hyperthyroidism
serum TSH decreased
T3 and free T4 elevated
hyperthyroid treatment strategies
- subtotal thyroidectomy + replacement of T4
- irradiate thyroid gland (radioactive iodine 131I) + replacement of T4
- inhibit thyroid peroxidase activity with antithyroid drugs (propylthiouracil, methimazole, carbimazole)
- interfere with thyroid hormone facilitation of sympathetic activite (beta blocker propranolol)
what are the antithyroid drugs
propylthiouracil, methimazole, carbimazole (prodrug of methimazole)
what is the mechanism of action of the antithyroid drugs propylthiouracil, methimazoke, carbimazole?
inhibits the organification of iodide and coupling of iodotyrosine causing inhibition of thyroid hormone synthesis (blocks thyroid peroxidase enzyme)
which antithyroid drug has additional activity and what is it?
propylthiouracil also reduces the deiodination of T4 to T3 by inhibiting D1 deiodinase activity
methimazole and propylthiouracil severe side effects
agranulocytosis, hepatitis, lupus-like syndrome
which antithyroid drug is safer with respect to agranulocytosis?
methimazole
which drug is the choice for pregnant women?
propylthiouracil
people developing one of the severe side effects from antithyroid drugs are then treated with what?
131I or surgery since agranulocytosis, hepetitis, and SLU Like syndrome are absolute contraindications
131 I
thyroid specific 131 I isotope is used to destroy sufficient thyroid tissue to restore euthyroid
what does 131 I emit
gamma rays and beta particles
how are patients with severe hyperthyroidism looking to use 131 I treated?
combination with antithyroid drugs or a beta blocker because effects are not seen for over 4 weeks
contraindications for radioiodine
pregnancy and breast feeding
mechanism for beta-adrenergic-antagonist drugs
which ones are used?
propranolol, metoprolol, atenolol, nadolol
used as adjunctive agents in patients with graves’ hyperthyroidism to control symptoms such as tremor, anxiety, palpitations
