Thyroid Pharmacology (review with handout) Flashcards
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
MOA of SSKI and Lugol’s
Complex action, transient effect of high doses (> 6 mg daily)
Inhibit T4-T3 synthesis (via elevated intracellular [I-])
Inhibit T4-T3 release (via elevated plasma [I-]): block Tg proteolysis
Rapid onset: used in severe thyrotoxicosis - thyroid storm
Disadvantages include: Variable effects (some patients show no response)
Rapid reversal of inhibitory effect when withdrawn
Potential to produce new T3: worsen hyperthyroidism
Clinical use of SSKI and Lugol’s and adverse reactions
decrease size and vascularity of hyperplastic gland prior to surgery
Adverse reactions:
reversible: acneform rash, rhinorrea, metallic taste, swollen salivary glands (selective accumulation)
Clinical consideration in medical management of Graves disease
- Concern for agranulocytosis with use of thionamides
- More rapid achievement of euthyroid state with methimazole vs PTU
- Beta-blockers are used to control cardiovascular symptoms while euthyroidism is being achieved
- PTU has a greater level of binding to plasma proteins than methimazole which may be advantageous in pregnant patients
Radioactive Iodine: Admin, advantages, disadvantages
Admin orally, rapid abs, concentrates in thyroid
-Beta radiation causes slow inflammatory process that destroys parenchyma of gland over weeks to mo
Advantages: easy admin effective low expense absence of pain
Disadvantages of I131:
Disadvantages include:
Slow onset and time to peak effect (2-6 months to euthyroid state) - 10% require 2nd dose
Radiation thyroiditis via release of preformed T3: cardiovascular complications in elderly
May cause worsening of opthalmopathy
Major complication is hypothyroidism
Should not administer to pregnant or nursing women
NO radiation-induced genetic damage, leukemia or neoplasia
surgery
less common today (131I has greater benefit:risk ratio)
need thryoid supp after surgery in 50-60%
2nd tri of preg if needed
Thyroid storm
sx:fever, flushing, sweating, tachycardia-atrial fibrillation, delirium, coma
Sudden, acute exacerbation of thyrotoxicosis may occur if patients are:
Non-compliant
Incompletely treated
Undiagnosed with hyperthyroidism experiencing an acute stressor (infection-surgery-trauma)
Symptoms reflect hypermetabolism and excessive adrenergic activity
Treatment of thyroid storm
aim to control sx
inhibit release of preformed thyroid hormones
block T4 to T3 conversion
Medical therapy:
Propranolol - IV or po - controls CVS symptoms plus blocks T4 toT3
Hormone release slowed by NaI IV - KI drops orally
Hormone synthesis blocked by PTU plus block of T4 to T3
Hydrocortisone protects against shock plus blocks T4 to T3 - plus modulates immune response
Meds most effective in blocking release of preformed thyroid hormone from gland in thryroid storm
Potassium iodide (also protects thyroid gland from exposure to radioactive iodine following a nuclear meltdown)
Sodium iodide
