Thyroid Pharmacology (review with handout) Flashcards
(32 cards)
Thyroid hormone absoprtion
- best in ileum, colon (bioavail 65%-85% T4, 95% T3)
- Modified by binding-proteins (T4), food, intestinal flora
- absorp impaired in severe myxedema
Levothyroxine (when.how to take)
Drugs that can impair absorp
-take on empty stomach w/ water 30-60 mins before breakfast or 4 hours after last meal in evening
Drugs that impair levo:
Metal ions (antacids, Ca and iron supp)
Ciprofloxacin, bile acid sequestrants
Avoid interaction by spacing levothyroxine dose 2 hrs before or 4-6 hours after interacting drug
thyroid hormone distrib
-bound to plasma in TBG
-only unbound active
Changes in TBG levels or binding affinity will affect total, not free lvls
-Drugs that increase binding:
estrogens/SERMS (others too)
-Drugs that decrease binding:
anticonvulsants (phenytoin, carbamazepine) and others
Activation of thyroid hormones
T4 to T3 is active hormone
- T3 utilized by peripheral tissues derived from T4 deiodination in liver via 5’ deiodinase
- T3 in brain and pit derived by intracellular deiodination
Activating enzyme inhibited by: Drugs glucocorticoids beta blockers amiodarone propylthiouracil and Conditions: acute and chronic illness caloric deprivation Malnutrition Fetal/neonatal period
Metabolic clearance rates
increased in hyperthyroidism and CYP450 induction, decreased by hypothyroidism
-half-life of T4 = 7 days, T3= 1 day (degree of protein binding is major difference)
Long T1/2 of T4– once daily dose Cp fluctation about 10%
Tx of hypothyroidism
Levothyroxine (T4)
Resolution of sx begins in 2-3 weeks:
6-8 weeks to reach steady state
USE CAUTION in starting therapy if cardiac disease exists
Tx of hypothyr in pregnancy
Req increased dose due to:
increased levels of TBG (via increased estrogen) decreases free T4, T3 no intact gland to increase production
-increased placental metabolism of T4-T3
Monitor TSH levels
Avg dose increase by 25%
Myxedema Coma
End state of untreated hypothyroidism:
Acute medical emergency (decreased Na, decreased glucose, hypothermai, shock death)
Large doses of T4: IV loading w/ IV daily dosing followed
Hydrocortisone to prevent adrenal crisis as T4 may increase metab
Advantages of Levothyroxine
Stability, content uniformity, lack of allergenic protein (vs Thyroid USP)
Low cost
Once-daily dosing – minimal fluctuation in Cp peak-trough
Can be given orally or IV
*advise to use the SAME T4 product (brand or generic) throughout tx
Relative to levothyroxine T4, T3 has
- greater oral bioavail
- greater affinity for thyroid hormone receptors (10X)
- greater potential for CV SE
- is more expensive
Liothyronine
synthetic T3
-well absorbed, rapid action, shorter duration of effect allows quicker dosage adjustments (1-2 weeks intervals)
NOT good for routine replacement due to short t1/2 and high cost
Avoid with pts with cardiac disease
May increase risk of osteoporosis
Liotrix
4:1 mixture of T4 and T3
No advantage since T4 conversion to T3 in periphery results in near normal ratio
More expensive
Rarely required, not recommended
May increase incidence of low TSH concentrations and increase markers of bone turnover
Thyroid USP
-Dessicated porcine thyroid extract containing T3 and T4
Absorption characteristics and half-lives of T4 and T3 are same as in non-combination products
Disadvantages include:
Variable T4/T3 ratio and content; unexpected toxicities (T3:T4 ratio higher than generally desirable)
Protein antigenicity
Product instability
Less desirable than levothyroxine - current recommendation is use in hypothyroidism should be avoided***
Adverse Rxns
- toxicity related to plasma hormone level, equivalent to signs and sx of hyperthyroidism
- Children: restlessness, insomnia, accelerated bone maturation
- Adults: anxiety, heat intolerance, palpitations-tachycardia, tremors, weight loss, diarrhea
- Sympathetic overactivity: can precipitate arrhythmias, angina, or MI in patients with cardiac disease
Drug interaction with thyroid hormones:
Increased adrenergic effect of sympathomimetics: Epi or decongestants (pseudoephedrine - phenylephrine)
General Treatment of Graves Disease (hyperthyroidism)
-interfering w/ hormone production– synthesis inhibitors:
thionamides
iodides
Modifying Tissue response: symptomatic improvement:
beta blockers
corticosteroids
Glandular destruction:
radioactive iodine
surgery
Methimazole
-a thionamides
-In Graves:
best if mild dis, small gland, young pt
-leaves gland intact
Methimazole until remission (1-15 yrs)
Beta blocker in Graves
-symptom relief until hyperthyroidism resolved
Propranolol also block T4 to T3 conversion
Metoprolol, atenolol are beta 1 selective, long t1/2
Methimazole, PTU MOA
Inhibit thyroid peroxidase (prevent T4/T3 synth)
Block iodine organification and iodotyrosine coupling
High doses of PTU also block peripheral conversion of T4 to active T3
Synthesis (not release) inhibited - requires 3-4 weeks to deplete T4
*** only for thyrotoxicosis from excess PRODUCTION not excess release
True hyperthryoid state
(Scan) “normal” or elevated iodine uptake in the setting of a low TSH is abnormal and indicates autonomous production of thyroid hormone.
-if uptake is low then thyroid hormone excess due to high release of preformed thyroid hormone
Absorption, Distribution, Elimination of thionamides
(Methimazole, PTU)
Absorption
Rapid, PTU incomplete (50-80%), methimazole 100%
Distribution
Both cross placenta and are concentrated by fetal thyroid
Requires caution if used in pregnancy
PTU more protein-bound, so crosses placenta less readily and less secretion into breast milk than methimazole
Elimination
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 daily and methimazole once daily
When is use of thionamides effective ALONE?
small goiter, low level of anti-TSH receptor Ab, and mild-to-moderate hyperthyroidism
Remission within 12-18 months
About 1/3 of patients experience lasting remission
Recurrence rate of Graves hyperthyroidism is 60-70%
Adverse rxns of thionamides
3-12% incidence: pruritic rash, GI intolerance, arthralgias
Most dangerous is agranulocytosis (0.3-0.6% - obtain baseline CBC), cross-sensitivity is 50%
PTU: Hepatotoxicity is rare, but serious enough (deaths and liver transplants) for concerns about routine use
Which is preferred, methimazole or 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
Lugol’s solution
SSKI: super saturated potassium iodide
Lugol’s solution: potassium iodide/iodine
