Block 4 Lecture 2 -- Pharmacotherapy of Thyroid Diseases Flashcards
What does lack of thyroid hormone produce in children?
cretinism
mental retardation, dwarfism, listlessness
What does lack of thyroid hormone produce in adults?
1) weight gain
2) fatigue
3) cold intolerance
Where and how is T3 produced?
deiodination of T4
80% from the periphery!
– especially liver
Compare the half-lives of T3 and T4.
T3: 1 day
T4: 6-8 days
Thyroxine-binding globulins (TBG) is upregulated by:
1) estrogens
2) clofibrate
3) tamoxifen
4) opiates
5) pregnancy
6) liver disease
7) HIV infection
Thyroxine-binding globulins are downregulated by:
1) glucocorticoids
2) androgens
3) anti-epileptics
4) furosemide
What proteins bind TH?
T3 and T4: TBG
– T4 with higher affinity; 1 molecule per TBG
T4: albumin, transthyretin
What proportion of bound TH is T4? What proportion of T4 is free?
90% of bound TH is T4
.03% of T4 is free
How are T3 and T4 eliminated?
conjugation in liver
- glucuronidation
- sulfation
Describe the TSH receptor and its effects
Gs
- increase T4 release
- increase I uptake
- increase thyroglobulin synthesis and proteolysis
- cause thyroid hyperplasia and hypertrophy
Describe the structure of TRH
tripeptide, released from the HT
What is the daily iodine requirement? Where is iodine found?
150 ug (1-2 ug/kg) -- fish, dairy, iodized salt
What happens in moderate iodine deficiency?
1) increased TSH
2) increased T3
3) decreased T4
4) hypertrophy to better extract I
- - simple “nontoxic” goiter
– hypothyroidism
What happens in severe iodine deficiency?
hypothyroidism
cretinism
What are the common causes of hypothyroidism?
- iodine deficiency (most common)
- - if iodine sufficient, chronic autoimmune thyroiditis (Hashimoto’s disease)
What is Hashimoto’s disease?
chronic autoimmune thyroiditis
– circulating Abs to thyroid peroxidase or thyroglobulin
What are risk factors for hypothyroidism?
1) age
2) post-partum woman
3) pre-existing autoimmune disorder
4) f/h autoimmune disease
What is the most common thyroid disorder?
hypothyroidism
What are signs/symptoms of hypothyroidism?
1) +/- goiter
2) expressionless puffy face, cold dry skin, scaly scalp, brittle hair/fingernails, SQ thickening and edema
3) slow and low-pitched speech, impaired cognition
4) depression, weight gain, lethargy, fatigue, cold intolerance, muscle weakness
5) poor appetite, constipation
What are signs/symptoms of cretinism?
1) dwarfism
2) mental retardation
3) lethargy
4) puffy expressionless face
5) protruding tongue
6) dry yellow skin
7) poor appetite
8) umbilical hernia
How is hypothyroidism BEST diagnosed?
free T4 level
How is myxedema coma treated?
emergency. ..
1) synthetic T3
2) levothyroxine
4) corticosteroids
What are the forms of synthetic T3?
1) liothyronine
2) cytomel
3) triostat
What are signs/symptoms of myxedema coma?
1) profound hypothermia
2) respiratory depression
3) bradycardia
4) hyponatremia
5) dry skin
6) coma
How is myxedema coma precipitated?
infection or CVD in long-standing hypothyroidism
– usually in elderly during the winter
Describe the bioavailability of levothyroxine.
50-80%
– reduced by food, binding resins, Fe, Ca, AlOH
What is the t1/2 of levothyroxine? How long till steady state?
7 days
6 weeks to steady state; even after a dose change
What is the goal of therapy in hypothyroidism treated with levothyroxine?
achieve normal TSH
– titrate via TSH level
Describe dosing of levothyroxine.
start with 112ug
– lower in elderly and heart disease patients
How does pregnancy affect levothyroxine dose? Why?
need to increase dose
- estrogens make more TBG
- transplacental passage of thyroxine
Why is hypothyroidism in pregnancy bad? What is an important recommendation?
associated with fetal distress and impaired neuromotor development
– take an Iodine supplement (AAP) if pregnant or breastfeeding
How is congenital hypothyroidism treated?
levothyroxine, 10-15 ug/kg
– prompt treatment = no long term effects
Why is thyroxine important in infants?
thyroxine needed for proper myelination post-natally
What is the most common endocrinopathy?
nodular thyroid disease
How is nodular thyroid disease treated?
1) levothyroxine suppression therapy
+/- surgery
What is thyrotoxicosis?
elevated levels of T4 and T3
What is the most common cause of thyrotoxicosis?
Graves disease
– aka “toxic diffuse goiter”
What is Graves disease?
autoimmune disorder
– IgG activates TSH receptor
What are signs/symptoms of thyrotoxicosis?
1) exophthalmos
2) excessive heat generation/motor activity
- - warm/flushed/moist skin
- - weak/tremulous muscles
- - muscle wasting and osteoporosis
3) forceful tachycardia, angina, arrhythmia
4) appetite, weight loss, insomnia, anxiety
What causes exophthalmos in thyrotoxicosis? How prevalent is it?
inflammation of periorbital tissues
– 50% of patients
How is thyrotoxicosis treated?
thioureylenes
- propylthiouracil (PTU)
- methimazole (MMI)
What is the MoA of thioureylenes?
1) inhibit thyroid peroxidase
- - generates thiocyanide, which inhibits I- uptake
2) block incorporation of iodine into Tyr’s of thyroglobulin
3) inhibits iodotyrosine coupline to iodothyronines
- iodinated thyroglobulin stores slowly depleted
- decreases immunosensitivity in Graves
What is the most-sensitive step to anti-thyroid drugs in TH synthesis?
coupling of iodotyrosines into iodothyronines
When is PTU preferred and why?
in severe disease
– addl MoA: inhibits peripheral conversion of T4 to T3
in nursing moms
How is thyrotoxicosis in pregnancy treated?
minimal dose to minimize risk of hypothyroidism to fetus
PTU preferred in nursing moms
What are adjuvant therapies to thioureylenes in thyrotoxicosis?
1) b-blocker: propranolol, atenolol
2) Ca-channel blockers: diltiazem
3) dexamethasone
Why are b-blockers adjuvants to thioureylenes?
antagonize sympathetic/adrenergic effects
– tachycardia, palpitations, tremor, anxiety
Compare propranolol to atenolol in thioureylene adjuvant therapy.
- propranolol crosses BBB, atenolol does not
- propranolol weakly inhibits peripheral T4 to T3 conversion
- both given BID
Why is diltiazem used as an adjuvant to thioureylenes in thyrotoxicosis? How often is it dosed?
decreases tachycardia and arrhythmias
QID
Why is dexamethasone used as an adjuvant in thyrotoxicosis?
- suppresses immunoreactivity
- - suppresses T4 to T3 conversion
What remedies other than thioureylenes and adjuvants are used for thyrotoxicosis?
1) subtotal thyroidectomy
2) radioactive iodine
3) ionic inhibitors
4) iodide
What ionic inhibitors are used in thyrotoxicosis?
1) thiocyanate (SCN-)
2) perchlorate (ClO4-)
3) fluoborate (BF4-)
4) lithium
How do the ionic inhibitors work for thyrotoxicosis?
- monovalent anions of similar size
- interfere with iodide uptake
lithium:
– decreases thyroxine and T3 secretion
Where is thiocyanate generated?
1) plant glycosides (cabbage)
2) cigarette smoke
- - smoking worsens hypothyroidism
What are concerns for perchlorate?
1) dose over 2 g/day causes fatal aplastic anemia
2) water supply contamination
3) 10x more potent than thiocyanate
When is iodide usually used for thyrotoxicosis?
prior to thyroid surgery after initial PTU/MMI
- shrink the thyroid
- avoid “thyroid escape”
What are the effects of iodide therapy?
1) resolves non-toxic goiter
2) suppresses thyrotoxicosis
at high concentrations…
– decrease I- uptake
– inhibits synthesis of iodotyrosines and iodothyronine
– inhibits release of thyroxine
At high concentrations, iodide suppresses all aspects of iodine metabolism. What is the Wolff-Chaikoff effect?
inhibiting the synthesis of iodotyrosines and iodothyronine
Describe the response to iodide therapy.
24h: metabolic rate falls
– comparable to thyroidectomy
– rapid block to release and synthesis of TH
– vascularity, gland size decreases
10-15 days: max effect
15+ days: hyperthyroidism returns, more severe
How is iodide supplied?
- Lugol’s solution (strong iodide solution); 3-5 drops = 18-30mg
- saturated solution of potassium iodide (SSKI); 1-3 drops
How is iodide used to protect against radioactive fallout?
1) protect thyroid against radioactive iodine
2) diminish incidence of thyroid cancer
How much iodide is needed to suppress thyroid function?
6 mg/day
What are the ADRs of iodide?
1) hypersensitivity
- - angioedema, laryngeal edema
2) cutaneous hemorrhage, serum sickness, anemias
3) iodism
- - metallic taste, burning sensation in mouth/throat, head cold, cough, HA, salivation
4) skin lesions
In what other drugs is iodine found?
1) amiodarone
2) topical antiseptics
3) radiology contrast agents
What are the signs/symptoms of thyroid storm?
1) fever (101+)
2) severe tachycardia
3) n/v
4) agitation/confusion
coma/death in 20% of patients
What causes thyroid storm?
precipitated by secondary illness in thyrotoxic patients
- infection
- stress
- trauma
- DKA
- labor
- heart disease
How is thyroid storm treated?
treat the symptoms
1) IV fluid
2) antipyretics
3) sedatives
4) dexamethasone
5) beta-blocker
suppress thyroid
6) large-dose PTU
7) oral iodides after PTU
What isotopes of oral radioactive iodide are used?
131 I- most common
– NaI (131) is the choice treatment for hypothyroidism
123 I
– used for thyroid scans
Compare 131 I- to 123 I-
131 I-
- t1/2 = 8 days
- gamma rays and beta particles
123 I-
- t1/2 = 13 h
- gamma rays
How do beta particles and gamma rays differ?
betas cause tissue damage
– pyknosis, necrosis of follicular cells
gammas pass thru tissues for quantification
How do oral radioactive iodides work in hyperthyroidism?
taken up by thyroid, incorporated into thyroglobulin
- damage tissue (beta)
- uptake can be quantified (gamma)
When is radioactive iodide therapy preferred in hyperthyroidism?
older patients
heart disease
toxic nodular goiter
Why is radioactive iodide preferred in thyrotoxicosis?
1) no surgery
2) no parathyroid loss
3) no risk of death or cancer
4) easy to treat hypothyroidism
Describe dosing of radioactive 131 NaI for thyrotoxicosis.
1) calculate dose to destroy thyroid; treat over 2-3 months
- - condition abates
2) further treatment possible for 6-12 months
Describe outcomes of radioactive iodide therapy in thyrotoxicosis.
- transient hyperthyroidism in 50% of patients during treatment
- delayed hypothyroidism (intentional or due to overtreatment) in 80% of patients over 10 years
How does hyperthyroidism present in pregnancy?
- often improves as pregnancy progresses
- - often returns after birth
What are ADRs of PTU/MMI?
1) agranulocytosis (1:500)
- - most serious
- - usually in first few months
2) urticarial reaction
- - most common
- - no cross-sensitivity
What to look for in agranulocytosis reaction from PTU/MMI?
sore throat, fever, gingivitis
- immediately report
- reversible if caught early
Compare PTU and MMI in PK/PD.
PTU: 1-4 doses -- t1/2 = 75min MMI: 1-2 doses -- t1/2 = 4-6h -- 10x more potent
both equally cross placenta, are secreted in milk, and concentrate in thyroid
Where are thioureylenes found?
cruciferous veggies (cabbage, brussel sprouts, broccoli)
What do brassica plants contain?
- thioureylenes
- - thiocyanate-generating compounds and goitrogens
How is thyrotoxicosis diagnosed?
increased iodine uptake into thyroid
– 24h radioactive iodine uptake test (RAIU)
TSH usually low except in pituitary adenoma
Describe epidemiology of nodular thyroid disease.
- ) 50% by age 60
- 4-7% incidence
- risk increased by ionizing radiation
- ) 4x more common in women
- ) often undiagnosed, generally benign
- ) 5% develop hypothyroidism
- ) 10% develop thyroid cancer
What tests are used to find TH levels to diagnose hypothyroidism?
1) total TH concentration
- - may not accurately reflect thyroid function (TBG amount or affinity)
2) TSH level
- - most common
- - sensitive indicator of free T4
- - elevated in primary, decreased in secondary
How is response to TSH measured?
recombinant TSH (Thyrogen) -- measures the uptake of radiolabeled iodine
When is cretinism usually recognized?
3-5 months of age
What is primary hypothyroidism?
failure of thyroid to make thyroxine
What is secondary hypothyroidism?
loss of pituitary function and TSH
What is congenital hypothyroidism?
severe iodine deficiency or genetic thyroid/pituitary defects
– leads to cretinism
Compare T4 and T3. Which is predominant, which is active?
T4 predominant (100x more than T3) T3 is active
What is the function of TH?
essential for development and metabolic homeostasis
In what patients is remission most likely in thyrotoxicosis after PTU/MMI treatment?
1) older patients
2) smaller goiters
3) prompt treatment
4) no history of relapse
When is PTU/MMI treatment effective?
when goiter size is reduced
How is thyrotoxicosis relapse treated?
RAI therapy
Describe treatment timeline for thyrotoxicosis. What’s the remission rate?
once effective…
- taper dose; update monthly;
- maintenance dose (50-300mg/day) x 1-2 years
- monitor yearly after ceasing therapy
remission rate = 40-50%
Describe the epidemiology of Graves’ disease.
- 4% incidence in US
- - 5-7x more common in women
- - usually age 20-50
- - usually associated with other autoimmune diseases
