Thyroid Pharmacology Flashcards
Control of Thyroid Function
- Hypothalamic-pituitary-thyroid axis can be activated by circadian rhythms, prolonged cold exposure or acute psychosis; severe stress can suppress activation
- Pituitary release of TSH stimulated by hypothalamic TRH and inhibited by somatostatin, dopamine and glucocorticoids
Biosynthesis of Thyroid Hormones
a. Major regulated step: Uptake of I- (iodide ion) into thyroid gland is stimulated by TSH via a G-protein coupled receptor (increase in cAMP levels).
i. This process can be blocked by anions of similar size such as SCN-, ClO4-, and I- itself (high concentrations > 6 mg, autoregulatory action via decreased expression of transporter).
ii. The generation of cAMP is inhibited by lithium ions and can result in symptoms of hypothyroidism when lithium is used as anti-manic therapy.
b. Iodide organification. I- oxidized and incorporated into tyrosine residues on thyroglobulin [Tg] molecules (mono-[MIT] and di-iodinated [DIT] tyrosine) via thyroid peroxidase
c. Coupling of precursors occurs on Tg (T4 / T3 ratio of 5:1 on thyroglobulin molecule); also mediated via thyroid peroxidase. MIT + DIT—> T3 and DIT + DIT–>T4
d. Retrieved from storage in lumen (large capacity) by pinocytosis; slowly released from gland by proteolysis (in T4/T3 ratio of 12-14:1)
Hypothalamic - Pituitary Hormones
1) Thyrotropin-Releasing Hormone [TRH, aka Protirelin]
a. Structure / Pharmacokinetics: Tripeptide; administered IV, t1/2 about 4-5 min
b. Pharmacodynamics. Activation of phospholipase C—> increse IP3—> increase intracellular Ca++
c. Stimulates pituitary production of TSH (and prolactin)–> stimulates thyroid to produce T4
d. TRH stimulation of TSH blocked by T3 (and somatostatin), potentiated by lack of T3
e. Uses
i. Test for pituitary reserve of TSH in suspected hypothyroidism and for hyperthyroidism
ii. Unlabelled: Antisedative effect (CNS action) for phenobarbital, diazepam, ethanol overdose situations; high-dose TRH may improve outcome of spinal cord injuries
iii. Orphan drug for prevention of infant respiratory distress syndrome in premature infants
f. Side Effects. Duration only a few minutes: urge to urinate, metallic taste, nausea, light-headedness
2) Thyroid-Stimulating Hormone [TSH, aka Thyrotropin]
a, Structure / Pharmacokinetics: Glycoprotein, consists of alpha and beta subunits. MW: 28,000-30,000. Therapeutic TSH prepared from bovine source. Administered IM or SC; t1/2 about 1 hr.
b. Pharmacodynamics: Stimulates cAMP production (via activation of adenylyl cyclase) resulting in increased uptake of iodine and production of thyroid hormones. Lithium blocks this action of TSH.
c. Uses. Role in therapy of metastatic thyroid carcinoma (enhances uptake of radioactive 131I into thyroid gland which is subsequently destroyed)
d. Side Effects: Nausea / vomiting, thyroid tenderness, allergic symptoms, hyperthyroid symptoms
Thyroid Hormones
a. Mechanism of Action. Free T4 and T3 enter cell via active transport (T4 converted to T3 in cells), T3 then enters nucleus and binds to receptor.
i. Most of thyroid hormone effects mediated by subsequent increase in RNA and then protein synthesis: increased formation of Na+-K+-ATPase—> Increased ATP turnover and O2 consumption–> calorigenic effect; also increases in myosin ATPase and sarcoplasmic reticulum Ca++-ATPase.
ii. Metabolic actions include increased fat / carbohydrate / protein consumption and metabolism.
b. Effects
• Responsible for optimal growth (via control of protein synthesis), development, function, and maintenance of all body tissue
• Critical for development of nervous (myelination), skeletal (ossification in epiphyses), and reproductive tissues. Thyroid deprivation results in irreversible mental retardation and dwarfism
• Thyroid hormones influence secretion and degradation rates of virtually all other hormones (including cortisol, estrogen, testosterone, insulin, catecholamines)
• Sympathetic nervous system activity increased via thyroid hyperactivity, especially cardiovascular system (increased number of β-adrenergic receptors and adenylyl cyclase activity)
Management of Hypothyroidism
Summary
a. Etiologies
• Most common cause is autoimmune thyroiditis (Hashimoto’s disease) with glandular destruction due to cell- and antibody-mediated damage
• Other causes include radiation exposure, surgery, iodine deficiency, enzyme defects, pituitary disease (low TSH), or rare hypothalamic disease (low TRH, low TSH)
b. Symptoms. Presents as a multisystem disorder of reduced metabolic rate.
• Manifested by reversible slowing of all body functions in adults and striking retardation of growth and development in children
• Common clinical findings include: weight gain, lethargy / weakness / fatigue, goiter, pale and puffy dry skin, bradycardia, decreased appetite, fluid retention, cold intolerance, constipation, hyperlipidemia, depression
c. Treatment
• Replacement therapy is appropriate; use of levothyroxine (T4) most satisfactory. For adults, generally start with 50-100 mcg, working up to 1.6-1.8 mcg/kg/day
- Infants / children require more T4 / kg (10 mcg/kg) - should be monitored for normal growth and development as well as TSH and free thyroxine index. Greater urgency to achieve full thyroid replacement, increase at weekly intervals
- For elderly patients the optimum dose may be as low as 0.5 mcg/kg
- Resolution of symptoms begins within 2-3 weeks of initiating therapy, but requires 6-8 weeks after starting with given dose to reach steady-state plasma levels. Thyroid function tests (TSH levels) should be assessed 6-8 weeks after dosage adjustments are made and then every 6-12 months after euthyroid state obtained
- Pregnancy may require increased dose due to increased levels of TBG (via elevated estrogen) and increased placental metabolism of T4-T3.i. Check levels upon pregnancy confirmation to guide potential dose change, monitor every 1-3 months
ii. Average dose increase about 25% - Use caution in initiating therapy if underlying cardiac disease exists (smaller initial doses: 12.5-25 mcg, increase every 4-6 weeks) or in elderly patients who might have clinically silent cardiac disease
- Myxedema coma (end state of untreated hypothyroidism) is an acute medical emergency (hyponatremia, hypoglycemia, hypothermia, shock, death possible)i. Large doses required with IV loading dose of T4 followed by daily IV dosing (oral absorption is poor). May also be treated with both T4 and T3 or T3 alone
ii. Hydrocortisone may be required to prevent adrenal crisis as thyroid hormone may increase its metabolism
Treatment of Hypothryroidism
- Replacement therapy is appropriate; use of levothyroxine (T4) most satisfactory. For adults, generally start with 50-100 mcg, working up to 1.6-1.8 mcg/kg/day
i. *Know levothyroxine (T4) - Infants / children require more T4 / kg (10 mcg/kg) - should be monitored for normal growth and development as well as TSH and free thyroxine index.
i. Greater urgency to achieve full thyroid replacement, increase at weekly intervals
ii. *know that chi;ldren need T4 - For elderly patients the optimum dose may be as low as 0.5 mcg/kg
- Pregnancy may require increased dose due to increased levels of TBG (via elevated estrogen) and increased placental metabolism of T4-T3.
i. Check levels upon pregnancy confirmation to guide potential dose change, monitor every 1-3 months
ii. Average dose increase about 25% - Use caution in initiating therapy if underlying cardiac disease exists (smaller initial doses: 12.5-25 mcg, increase every 4-6 weeks) or in elderly patients who might have clinically silent cardiac disease
- Myxedema coma (end state of untreated hypothyroidism) is an acute medical emergency (hyponatremia, hypoglycemia, hypothermia, shock, death possible)
i. Large doses required with IV loading dose of T4 followed by daily IV dosing (oral absorption is poor). May also be treated with both T4 and T3 or T3 alone
ii. Hydrocortisone may be required to prevent adrenal crisis as thyroid hormone may increase its metabolism
Thyroid Hormone Preparations
a. Preparations are of synthetic or animal origin, containing T4 only, T3 only, or combinations of T4 and T3.
* NOTE: Levothyroxine, the drug of choice for thyroid hormone replacement therapy, has a narrow therapeutic index. Thus, its pharmacokinetics and drug-drug interactions take on added importance.
b. Pharmacokinetics of Levothyroxine (T4) and Triiodothyronine (T3)
Absorption. Best in ileum and colon (bioavailability - T4: 65-85%, T3: 95%).
i. Modified by binding-proteins (T4), food, intestinal flora; absorption may be impaired in severe myxedema (requiring use of parenteral formulation)
ii. Levothyroxine should be taken alone on an empty stomach, with a full glass of water, at least 30 minutes before breakfast
iii. Drugs that can impair absorption of levothyroxine include: metal ions (antacids-Ca++-Fe++), ciprofloxacin, bile acid sequestrants, raloxifene, sucralfate, dietary fiber, soy. Managed by spacing levothyroxine dose 2 hours before or 4-6 hours after interacting drug.
c. Peripheral Transport
i. Reversibly bound in plasma to thyroid-binding globulin (TBG) (free T4 = 0.04%, free T3 = 0.4%). Only the unbound hormone has metabolic activity.
ii. Thus, changes in either the concentrations of binding proteins OR binding affinity of hormone for protein will have major effects on TOTAL serum hormone levels. Drug effects on protein binding:
NOTE: Laboratory tests that measure only TOTAL hormone levels can be misleading since the pituitary gland responds to and regulates only circulating FREE hormone levels. I.e., levels of free hormone are minimally changed when total levels of hormone are altered by changes in binding to proteins, IF the hypothalamic-pituitary-thyroid axis is intact.
Peripheral Metabolism of T3 and T4
a. Activating step: T3 is the biologically active thyroid hormone. Most circulating T3 (80%) that is utilized by peripheral tissues is derived from deiodination of T4 in the liver via 5’-deiodinase. T3 in brain and pituitary is derived locally. The activity of this activating enzyme can be inhibited by various drugs and conditions.
b. Inactivating reactions: Include deiodination to reverse T3, deamination, decarboxylation, and conjugation to glucuronide or sulfate
c. Metabolic clearance rates may be increased in hyperthyroidism and with P450 enzyme induction [carbamazepine, digoxin, phenytoin, rifampin]; decreased by hypothyroidism
d. Half-life of T4 = 7 days; T3 = 1 day. Degree of protein binding is major factor accounting for pharmacokinetic differences between T3 and T4
e. Long half-life of T4 allows once-daily dosing and maintenance of a steady state despite occasional missed doses; fluctuation in plasma levels is less than 15% between doses
Levothyroxine
a. Synthetic T4 is preparation of choice for thyroid replacement
b. Advantages include:
i. Stability, content uniformity, lack of allergenic foreign protein (relative to Thyroid USP)
ii. Low cost and long t1/2 allowing once-daily dosing (relative to T3)
c. Can be given orally or IV
d. Generic formulations
i. No evidence to support superiority of any brand name product over any generic formulation and FDA allows pharmacists to switch patient from one product to another unless prescriber indicates “dispense as written”
ii. *However, in clinical practice, it is advisable to use the same levothyroxine product (whether brand or generic) throughout the treatment for any individual patient.
- Could be as much as 10% difference between “equivalent” products.
- Thyroid function tests should be checked 6 weeks after any change in levothyroxine product formulation.
Liothyronine
Synthetic T3.
a. Well absorbed, rapid action, but shorter duration of effect that permits quicker dosage adjustments (at 1-2 weeks intervals)
b. *NOT recommended for routine replacement due to short t1/2 (hence greater fluctuations in plasma levels between doses), high cost
c. Reasonable option to add if symptoms persistent on optimal levothyroxine therapy. Optimal T4 / T3 ratio is ~ 10:1
d. Should be avoided in patients with cardiac disease (increased thyroid hormone activity associated with greater risk of cardiotoxicity)
e. Used in T3 suppression test (differentiate hyperthyroidism from euthyroidism)
Levothyroxine and Liothyronine
- Levothyroxine
a. Synthetic T4 is preparation of choice for thyroid replacement
b. Advantages include:
i. Stability, content uniformity, lack of allergenic foreign protein (relative to Thyroid USP)
ii. Low cost and long t1/2 allowing once-daily dosing (relative to T3)
c. Can be given orally or IV
- Liothyronine
a. Well absorbed, rapid action, but shorter duration of effect that permits quicker dosage adjustments (at 1-2 weeks intervals)
b. *NOT recommended for routine replacement due to short t1/2 (hence greater fluctuations in plasma levels between doses), high cost
c. Reasonable option to add if symptoms persistent on optimal levothyroxine therapy. Optimal T4 / T3 ratio is ~ 10:1
d. Should be avoided in patients with cardiac disease (increased thyroid hormone activity associated with greater risk of cardiotoxicity)
e. Used in T3 suppression test (differentiate hyperthyroidism from euthyroidism)
Liotrix
4: 1 mixture of T4 and T3.
a. More expensive, no advantage since T4 conversion to T3 in periphery results in near normal ratio. Rarely required, not recommended
b. Combination therapy may cause increased incidence of low TSH concentrations and increased markers of bone turnover
Thyroid USP
Thyroid Strong (50% stronger) a. Dessicated porcine thyroid extract containing thyroxine and liothyronine; absorption characteristics and half-lives of T4 and T3 are same as in non-combination products
b. Disadvantages include:
i. Variable T4/T3 ratio and content that may produce unexpected toxicities (generally higher T3:T4 ratio in swine than is desirable in humans)
ii. Protein antigenicity
iii. Product instability
c. Less desirable than levothyroxine, use in hypothyroidism is not recommended
d. Adverse reactions. Toxicity due to excessive T4 directly related to plasma hormone level, thus is equivalent to signs and symptoms of hyperthyroidism
• Children: Restlessness, insomnia, accelerated bone maturation and growth
• Adults: Anxiety, heat intolerance, palpitation/tachycardia, tremors, weight loss and increased bowel movements. Can precipitate cardiac arrhythmias, angina pectoris, or myocardial infarction in patients with cardiac disease
• Drug interaction with thyroid hormones: Will see increased adrenergic effect of sympathomimetics like epinephrine or decongestants
Hyperthyroidism (thyrotoxicosis)
a. Etiologies
• Most common form of hyperthyroidism is Graves’ disease that results from thyroid stimulation by autoantibodies (thyroid-stimulating antibody [TSAb]) that mimic stimulation by TSH
• Other forms of hyperthyroidism result from TSH receptor-independent release of thyroid hormone including toxic uninodular and multinodular goiter (benign neoplasias that are autonomous from normal TSH regulation)
b. Symptoms. Multisystem clinical syndrome, predominant signs of metabolic and CVS hyperactivity
- Weight loss (with hyperphagia), heat intolerance, insomnia, nervousness / anxiety, smooth-warm moist skin, muscle weakness, weakness
- Signs of autonomic nervous system overactivity include: β-adrenergic (atrial tachycardia, tremor), sympathetic cholinergic (increased sweating), and parasympathetic (increased GI motility)
- Subclinical hyperthyroidism associated with increase in bone and cardiovascular disease incidence
Treatment of Graves’ Disease
a. General Treatment Strategies: Reduction of thyroid activity and hormone effects accomplished by:
i. Modifying tissue response (symptomatic improvement) (beta-blockers, corticosteroids)
ii. Interfering with hormone production (thionamides, iodides)
iii. Glandular destruction (surgery, radioactive iodine)
b. Thionamides. Methimazole (Propylthiouracil (PTU) - declining use)
Overview: Best if mild diseases, small gland, or young patient. Frequent relapses.
i. Leaves gland intact (some patients avoid permanent hypothyroidism), but 60-70% relapse
ii. Methimazole until remission (1-15 yrs)
iii. Beta-blocker for symptomatic relief until hyperthyroidism is resolved. Propranolol has advantage of blocking T4T3 conversion; metoprolol/atenolol are 1 selective, longer t1/2
c. Pharmacokinetics
i. Absorption: Rapid, PTU incomplete (50-80%), methimazole 100% absorbed
ii. Distribution: Both cross placenta and are concentrated by fetal thyroid requiring caution if used in pregnancy; PTU more protein-bound, so crosses placenta less readily and less secretion into breast milk (higher amounts with methimazole)
iii. Elimination: Relatively short half-lives (PTU 1-2 hrs, methimazole 5-13 hrs), but drugs are accumulated in thyroid and durations of action are longer (PTU: 12-24 hrs; methimazole: 40 hrs). Thus, PTU can be given 2-3 times daily and methimazole once daily.
d. Mechanism of Action
i. Prevent T4 / T3 synthesis by blocking iodine organification and coupling of the iodotyrosines
ii. High doses of PTU will block peripheral conversion of T4 to the more active T3
iii. Synthesis (not release) inhibited so requires 3-4 weeks to deplete T4 stores. Beta-blockers can be used to alleviate symptoms (esp. palpitations and tachycardia) until thionamide takes effect
• NOTE: These agents only work in thyrotoxicosis [high RIU] due to excess thyroid hormone production (NOT thyroiditis [low RIU])
Thionamides. Methimazole (Propylthiouracil (PTU) - declining use)
Clinical Use and Toxicity
a. Clinical Use
• Some clinical resolution of thyrotoxicosis within 2 weeks and biochemical resolution in about 6 weeks. Follow-up testing of thyroid function at 4-6 week intervals until stabilized
• Patients with small goiters, low levels of anti-TSH receptor antibodies, and mild-to-moderate hyperthyroidism, achieve remission within 12-18 months on thionamide alone. About one-third of patients experience lasting remission, but overall recurrence rate of Graves’ hyperthyroidism is 50-60%.
b. Toxicity
• Adverse reactions (3-12%); most common pruritic rash, gastric intolerance, arthralgias
• Most dangerous is agranulocytosis (0.3-0.6%). Routine measurement of complete blood counts (CBC) is controversial, but should be obtained if sore throat / fever are present
• Hepatotoxicity with PTU is rare (1:1000 in children and adults) but severe enough (deaths and liver transplants [3rd leading drug cause]) to raise concerns about routine use
• If allergies occur, cross-sensitivity to the agents is 50%, thus switching is not recommended
c. SUMMARY: Methimazole generally preferred because of efficacy at lower doses, once-daily dosing, and lack of serious hepatotoxicity). Thionamides are treatment of choice for hyperthyroidism in pregnancy. Both drugs cross placenta but PTU is thought to be safer in pregnancy (increased protein-binding) and has not been associated with teratogenic effects.
Iodide (I-) in Hyperthyroidism treatment
a. Iodide (I-): SSKI [potassium iodide], Lugol’s solution [potassium iodide and iodine]. Used since 1920’s, but rarely used as sole therapy today.
b. Mechanism of action. Complex action, transient effect.
• High doses (> 6 mg daily) inhibit hormone synthesis (via elevated intracellular [I-]) and hormone release (via elevated plasma [I-]) through inhibition of thyroglobulin proteolysis
• Effect occurs rapidly, thus iodide is useful in patients with severe thyrotoxicosis and in thyroid storm
• Disadvantages include: variable effects (some patients show no response), rapid reversal of inhibitory effect when withdrawn, and potential that the iodide may be used to produce new thyroid hormone and worsen hyperthyroidism
c. Clinical use
• Should not be used alone, gland “escapes” iodide block in 2-8 weeks and can see exacerbation of thyrotoxicosis upon withdrawal
• Can delay onset of thionamide therapy (due to initial action to increase intraglandular stores), so initiate I- therapy after onset of thionamide effect occurs
• Also used to decrease size and vascularity of hyperplastic gland prior to surgery (given for 10 days prior to surgery)
d. Toxicity. Uncommon, reversible (acneiform rash, rhinorrhea, metallic taste, swollen salivary glands). Selective accumulation in salivary glands
Radioactive Iodine (131-I)
a. Preferred in patients over 21 and becoming more common in patients < 20 y/o
• Administered orally (capsule or liquid), rapidly absorbed, concentrated in thyroid. β-radiation causes a slow inflammatory process that destroys parenchyma of gland over weeks to months
• Advantages include easy administration, effectiveness, low expense, absence of pain. Results in permanent resolution of hyperthyroidism.
b. Disadvantages include:
Slow onset and time to peak effect (2-6 months after therapy to reach euthyroid state)
2nd dose required in some patients (10%)
Radiation thyroiditis can occur with release of preformed thyroid hormone and can result in cardiovascular complications in elderly or susceptible patients
May cause worsening of opthalmopathy
Major complication is hypothyroidism (80% require replacement therapy) that is more serious in children. Does NOT appear to produce radiation-induced genetic damage, leukemia or neoplasia.
c. *Should not administer to pregnant or nursing women
Surgery - Thyroidectomy
TX for Hyperthyroidism
- Rarely used today because radioactive iodine works so well that the risks of general anesthesia and parathyroid / recurrent laryngeal nerve damage become relatively great. Advantage of rapid, permanent cure of hyperthyroidism
- Treated with antithyroid drugs until euthyroid (6 weeks) plus iodine several days prior to surgery
- 50-60% of patients require thyroid supplementation after surgery (iatrogenic hypothyroidism)
- Can be utilized in 2nd trimester of pregnancy if needed
Treatment of Thyroid Storm
a. Thyroid Storm: Sudden, acute exacerbation of thyrotoxicosis; may occur in a non-compliant, incompletely treated, or undiagnosed patient with hyperthyroidism who experiences an acute stress (infection, surgery, or trauma).
b. Symptoms include fever, flushing, sweating, tachycardia / atrial fibrillation, high output heart failure, delirium, coma. Reflected in hypermetabolism and excessive adrenergic activity
c. Treatment aimed at: control of symptoms, inhibition of release of preformed thyroid hormone, and block of conversion of T4 to T3
1. *Propranolol, IV or po, controls cardiovascular manifestations (also blocks T4 to T3 conversion)
- Release of hormones slowed by sodium iodide IV, potassium iodide drops orally
- Synthesis of hormones blocked by PTU as well as T4 to T3 conversion (but not by methimazole)
- *Hydrocortisone protects against shock, blocks conversion of T4 to T3, and may modulate the immune response that lead to exacerbation of thyrotoxicosis
Etiology of Hypothyroidism
Major Causes
a. Primary Hypothyroidism—> decreased thyroid
1. Chronic autoimmune (Hashimoto’s) thyroiditis
2. Drugs
i. Antithyroid drugs, lithium, amiodarone, tyrosine kinase inhibitors, iron, cholestyramine, phenytoin, carbamazepine
b. Central Hypothyroidism (2˚/3˚)—> due to pituitary or hypothalamus
Pituitary tumor
Trauma
Postpartum pituitary necrosis (Sheehan’s syndrome)
Hypophysitis
Biochemical Diagnosis- Hypothyroidism
Overt Hypothyroidism:
1) Increased TSH
2) Decreased Free T4
Subclinical:
1) Increased TSH
2) nl Free T4
