- synthetic T3 - Well absorbed, rapid action, but shorter duration of effect that permits quicker dosage adjustments (at 1-2 weeks intervals)

Thyroid Pharmacology Flashcards by Soliman Oushy

Drugs leading to Primary hypothyroidism

lithium, 
amiodarone*
cholestyramine, 
phenytoin,
 carbamazepine

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Treatment of Hypothyroidism

Replacement therapy: Levothyroxine (T4) children get highest dose, seniors get lowest dose.

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Tx of hypothyroidism resolves Sx when?

Resolution of symptoms begins within 2-3 weeks

Requires 6-8 weeks of maintenance dose to reach steady-state plasma levels

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Contraindication of hypo Tx

heart disease (use caution)

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Hypothyroidism Treatment - Pregnancy considerations

Usually requires increase in dose due to:

Increased levels of TBG (via  estrogen) decreases free T4-T3 - no intact gland to increase production
Increased placental metabolism of T4-T3

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Myxedema coma: derangement and Tx

Acute medical emergency (low Na+, low glucose, hypothermia, shock, death)

Large doses of T4 required: IV loading dose followed by daily IV dosing
Hydrocortisone to prevent adrenal crisis as T4 may increase its metabolism

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Levothyroxine pharmacokinetics

empty stomach with water, 30-60 min before breakfast or 4 hours after last meal in evening

Drugs that can impair absorption of levothyroxine include:

Metal ions
bile acid sequestrants,
Avoid interaction by spacing levothyroxine dose 2 hrs before or 4-6 hrs after interacting drug

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T of F: Changes in TBG levels or binding affinity will affect TOTAL serum levels

True, - NOT FREE

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Drugs increasing thyroid hormone binding

Estrogens / SERMs

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Drugs decreasing thyroid hormone binding

Anticonvulsants (phenytoin-carbamazepine)

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Drugs that inhibit thyroid hormone activation

Glucocorticoids
Beta-blocke
Amiodarone
Propylthiouracil (higher doses)

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Thyroid hormone Metabolic clearance rates

Increased in hyperthyroidism and CYP450 induction - decreased by hypothyroidism
Half-life of T4 = 7 days & Half-life of T3 = 1 day
Degree of protein binding major factor for difference
Long t1/2 T4: once-daily dose - Cp fluctuation 10%

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Advantages of levothyroxine

Stability, content uniformity, lack of allergenic protein (vs Thyroid USP)
Low cost
Once-daily dosing – minimal fluctuation
Can be given orally or IV

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Liothyronine

synthetic T3
Well absorbed, rapid action, but shorter duration of effect that permits quicker dosage adjustments (at 1-2 weeks intervals)

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Liothyronine contraindications

NOT recommended for routine replacement due to short t1/2 (greater Cp fluctuations between doses), high cost
Should be avoided in patients with cardiac disease (increased T3 activity  greater risk of cardiotoxicity)
May increase risk of osteoporosis

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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

Thyroid USP disadvantages

Variable T4/T3 ratio and content unexpected toxicities
Protein antigenicity
Product instability
Less desirable than levothyroxine - current recommendation is use in hypothyroidism should be avoided

Thyroid hormone replacement ARS and DDI

-Toxicity: directly related to plasma hormone level equivalent to signs and symptoms of hyperthyroidism
Drug interaction with thyroid hormones
-Increased adrenergic effect of sympathomimetics: epi or decongestants (pseudoephedrine - phenylephrine)

Tx of Graves

Medications
-Antithyroid drugs (methimazole, propylthiouracil)- Inhibit synthesis of thyroid hormone
-Beta blockers- Reduce systemic hyperadrenergic symptoms and effects (primarily tremor, palpitations, etc.)
Radioactive Iodine (131I)
Surgery

Thionamides:

Methimazole - PTU (propylthiouracil)

Thionamides use in graves`

Methimazole until remission (1-15 yrs)
β-blocker for symptom relief until hyperthyroidism resolved
-Propranolol has advantage of blocking T4->T3 conversion
-Metoprolol-atenolol are beta1 selective, longer t1/2

Thionamides MOA

Inhibit thyroid peroxidase: prevent T4 / T3 synthesis

use of thionamides in hyperthyroidism

Only for thyrotoxicosis from excess production (Graves disease - high RAI) NOT excess release (low RAI)

Does Methimazole - PTU Both cross placenta and are concentrated by fetal thyroid?

yes, Requires caution if used in pregnancy. PTU less readily b/c protein bound.

Methimazole - PTU Effective alone IF:

small goiter, low level of anti-TSH receptor Ab, and mild-to-moderate hyperthyroidism

Thionamides: Methimazole - PTU adverse effects

- rash - Most dangerous is agranulocytosis (0.3-0.6% - obtain baseline CBC) - PTU: Hepatotoxicity is rare, but serious enough

Thiionamides SUMMARY

- 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

Iodide ion medications

- SSKI [super-saturated potassium iodide] | - Lugol’s solution [potassium iodide / iodine]

Iodide ion MOA

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

SSKI and Lugol's Solution use, and adverse reactions

-Decrease size and vascularity of hyperplastic gland prior to surgery -Adverse Reactions Reversible: acneform rash, rhinorrhea, metallic taste - swollen salivary glands (selective accumulation) -Potential to produce new T3  worsen hyperthyroidism

Radioactive Iodine (131I) MOA

concentrates in thyroid | β-radiation causes slow inflammatory process that destroys parenchyma of gland over a period of weeks to months

Radioactive Iodine (131I) disadvantages

- Slow onset and time to peak effect (2-6 months to euthyroid state) - 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 in hyperthyroidism

Less commonly used today as 131I has much greater benefit:risk ratio Requires treatment with antithyroid drugs-iodide prior to surgery iatrogenic hypothyroidism Can be utilized in 2nd trimester of pregnancy if needed

Thyroid Storm Sx

fever, flushing, sweating, tachycardia-atrial fibrillation, delrium, coma -Caused by acute exacerbation of thyrotoxicosis (non-complient patient Symptoms reflect hypermetabolism and excessive adrenergic activity

Tx of thyroid storm

- Propranolol - controls CVS symptoms plus blocks T4->T3 - Hormone release slowed by NaI IV - KI drops orally - Hormone synthesis blocked by PTU plus block of T4->T3 - Hydrocortisone protects against shock plus blocks T4->T3 - plus modulates immune response