Pharmacology > Thyroid > Flashcards

Thyroid Flashcards

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1
Q

What stimulates and inhibits TSH release

A

Stimulates:

  1. hypothalamic TRH**
  2. circadian rhythm
  3. prolonged exposure
  4. acute pyschosis

Inhibits:

  1. Somatostatin
  2. dopamine
  3. glucocorticoids
  4. severe stress
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2
Q

Describe the biosynthesis of TH and the targets for therapry

A
  1. Uptake of iodide into thyroid gland stimulated by TSH (blocked by high [I] and lithium)
  2. I oxidized and incorporated into tyrosine residues (DIT, MIT) on Tg via peroxidase (inhibited by thioamides)
  3. Coupling of precursors occur on Tg via thyroid peroxidase (peroxidase inhibited by Iodides and thioamides)
  4. retrieved from storage by pinocytosis and released from gland by proteolysis (inhibited by iodides in blood)
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3
Q

Describe the MOA of thyroid hormone

A

free T3 and T4 enter cell via active transport–> T4 converted to T3–> T3 enters nucleus and binds to receptors–> increase in mRNA/protein

Results:

  1. calorgenic effect via increased Na/K ATPase
  2. increase myosin ATPase and SR Ca2+ ATPase
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4
Q

Describe the effects of thyroid hormone

A
  1. Responsible for optimal growth, development, function, and
    maintenance of all body tissues
  2. Critical for development of nervous (myelination), skeletal (ossification in epiphyses), and reproductive tissues–Thyroid deprivation results in irreversible mental retardation and dwarfism
  3. Increase secretion and degradation rates of other hormones
  4. SNS activity increased via thyroid hyperactivity–
    Especially cardiovascular system - increased number of β-adrenergic receptors and adenylyl cyclase activity
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5
Q

Thyroid hormone increases secretion and degradation rates of what hormones

A
  1. Cortisol
  2. Estrogen
  3. Testosterone
  4. Insulin
  5. Catecholamines
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6
Q 
A 40-year-old woman presents for an annual physical. Examination reveals a slightly elevated HR and BP. Palpation of her neck revealed a complaint of tenderness, and an enlarged thyroid was felt. Laboratory testing showed elevated TSH, decreased T4 levels, and elevated thyroglobulin antibodies. Which of the following is the most likely diagnosis? 
A.  Grave’s disease 
B.  Hashimoto’s disease 
C.  Nontoxic goiter 
D.  Pituitary adenoma 
E.  Thyroid cancer
A

B.  Hashimoto’s disease

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7
Q

Causes of hypothyroidism

A
  1. Hashimoto’s (MC-autoimmune)
  2. radiation exposure
  3. surgery
  4. iodine deficiency
  5. Enzyme defects
  6. pituitary dz (low TSH)
  7. Rare: hypothalamic dz (low TRH, low TSH)
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8
Q 
When initiating T4 therapy for an elderly patient with long-standing hypothyroidism, it is important to begin with small doses to avoid which of the following? 
A.  A flare-up of exophthalmos 
B.  Acute renal failure 
C.  Hemolysis 
D.  Overstimulation of the heart 
E.  Seizures
A

D.  Overstimulation of the heart

*Use caution in initiating therapy if underlying cardiac disease exists

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9
Q

Describe the clinical use of levothyroxine

A

replacement therapy to tx hypothyroidism (T4)

Adult: 1.6-1/8mcg/kg

kids: up to 10mcg/kg
elderly: as low as 0.5mcg/kg

  • resolutiono f sx begins within 2-3 weeks
  • requires 6-8 weeks of maintenance dose to reach steady state plasma levels

*reassess Thyroid fxn tests in 6-8 weeks after any dose change

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10
Q

Describe how tx for hypothyroidism is changed for pregnancy

A

usually requires an increased dose (~25%) due to:

  1. increased levels of TBG (via increased estrogen)
  2. Increased placental metabolism of T4-T3
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11
Q

What is Myxedema coma?

A

end state of untreated hypothyroidism

  • acute medical emergency w/
    1. hyponatremia
    2. hyoglycemia
    3. hypothermia
    4. shock
    5. death
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12
Q

what is the tx of myxedema coma

A
  1. large doses required with IV loading dose of T4 followed by daily IV dosing (poor oral absorption)
  2. Hydrocortisone to prevent adrenal crisis as T4 may increase its metabolism
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13
Q

Describe the absorption of levothyroxine (T4) and Triiodothyronine (T3)

A
  1. best absorption in ileum-colon (T3>T4)
  2. Modified by binding proteins (T4), food, intestinal flora
  3. impaired w/ severe myxedema (use IV)
  4. Levo- take on EMPTY stomach w/ water 3-60 min before breakfast
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14
Q

What are drugs that can impair absorption of levothyroxine

A
  1. metal ions (antacids, Ca, Fe supplements)
  2. Ciprofloxacin
  3. bile acid sequestrants
  4. raloxifene
  5. Sucralfate

*avoid interactions by spacing levo dose 2 hrs before or 4-6hrs after interacting drug

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15
Q

Changes in TBG levels or binding affinity will affect ___ not ___

A

TOTAL serum levels - NOT FREE

*IF HPT axis intact –> free T4/T3 will change minimally

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16
Q

What are drugs that INCREASE thyroid hormone plasma-protein binding

A
  1. Estrogen/SERMs/Tamoxifen**
  2. Methadone
  3. Clofibrate
  4. 5-fluorouracil
  5. Heroin
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17
Q

What are drugs that DECREASE thyroid hormone plasma-protein binding

A
  1. Glucocorticoids
  2. Androgens
  3. Salicylates*
  4. Furosemide
  5. Antiseizure meds* (phenytoin and carbamazepine)
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18
Q

__ is biologically active thyroid hormone and most is derived from __

A

T3

*most circulating T3 (80%) that is utilized by peripheral tissues is derived from deiodination of T4 in the liver via 5’-deiodinase

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19
Q

What drugs can inhibit 5’-deiodinase which converts T4 into T3

A
  1. Glucocorticoids
  2. Beta-adrenergic receptor antagonists (BB)
  3. Amiodarone
  4. Propylthiouracil (HDs)
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20
Q

What conditions can inhibit 5’-deiodinase which converts T4 into T3

A
  1. Acure and chronic illness
  2. caloric deprivation
  3. Malnutrition
  4. fetal/neonatal period
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21
Q

Inactivating reactions of 5’-deiodinase

A
  1. deiodination to reverse T3 deamination
  2. decarboxylation
  3. comjugation to glucuronidate or sulfate
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22
Q

Describe the metabolic clearance rates of T3 and T4

A

T3: half life=1 day
T4: half life = 7 days (allows for 1x dosing)

  • Degree of protein binding major factor for difference
  • increased in hyper and CYP450 induction and decreased in hypo
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23
Q

What are CYP450 inducers that increase thyroid hormone metabolism

A
  1. carbamazepine
  2. digoxin
  3. phenytoin
  4. rifampin
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24
Q 
A 62-year-old woman presents with complaints of fatigue, sluggishness, and weight gain. She needs to nap several times a day, which is unusual for her. She has been taking T4 for the past 15 years without significant problems regarding her energy level. Her recent history is significant for diagnosis of arrhythmia. What is the most likely cause of her current condition? 
A.  Amiodarone 
B.  Lidocaine 
C.  Verapamil 
D.  Metoprolol 
E.  Propranolol
A

A. Amiodarone

E.  Propranolol*** (inhibits 5-deiodinase activating enzyme)

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25
T3 in brain and pituitary derived by __
intracellular deiodination (locally)
26
___ is the preparation of choice for thyroid hormone replacement
synthetic T4 (levothyroxine)
27
Describe the advantages of Levothyroxine
1. Stability/content uniformity 2. lack allergenic protein (vs Thyroid USP) 3. low cost 4. once daily dosing w/ minimal fluctuations (t1/2=7 days) 5. can be given PO or IV
28
Why is it advised to use the same levothyroxine produce (whether brand or generic) throughout the treatment for any individual patient?
could be as much as 10% difference btwn "equivalent" products
29
check thyroid function tests ____ after ANY change in levothyroxine product formulations
6-8 weeks
30
What is the drug for synthetic T3
Liothyronine (aka Triiodothyronine or Cytomel)
31
Describe the absorption, DOA, and onset of Liothyronine
- well absorbed - rapid action - shorter duration of effect that permits quicker dosage adjustments (at 1-2 week intervals)
32
When is Liothyronine used
(synthetic T3) -reasonable option to add if sx persistent on optimal levo therapy (Optimal T4/T3 ratio is 10:1) -used in T3 suppression tests to differentiate hyperthyroid from euthyroid
33
When is Liothyronine avoided/ its ADE
1. NOT recommended for routine replacement due to short t1/2 (greater Cp fluctuations btwn doses) 2. AVOID is pts w/ cardiac dz (increased T3 activity--> risk of cardiotoxicity) 3. May increase risk of osteoporosis
34
Describe the use of Liotrix
(4: 1 mixture of T4 and T3) - no advantage since T4 conversion to T3 in periphery results in near normal ratio * rarely required, NOT recommended
35
Describe disadvantages of Liotrix
1. may increase incidence of low TSH concentrations 2. increase markers of bone turnover 3. more expensive
36
What is Thyroid USP (Armour Thyroid)
* dessicated porcine thyroid extract containing T3 and T4 | - absorption characteristics and t1/2 of T3 and T4 are same as in non-combination products
37
What are disadvantages of Thyroid USP
1. Variable T4/T3 ratio and content--> unexpected toxicities 2. Protein antigenicity 3. product instability *less desirable than levothyroxine---> current recommendations is to AVOID use in hypothyroidism
38
What are adverse reactions of thyroid hormone
**toxicity related to excessive T4 plasma level --> same as sx of hyperthryoidism Children: restless, insomnia, accelerated bone maturation Adults: anxiety, heat intolerance, paplitations, tachycardia, tremors, wt. loss, diarrhea SNS over activity--> arrhythmias, angina, MI
39
What are DDI w/ thyroid hormone
See increased adrenergic effect of sympathomimetics like epi or decongestants (pseudoephedrine or phenylephrine)
40
Relative to levothyroxine (T4), triiodothyronine (T3): A.  Has greater oral bioavailability B.  Has a longer duration of action C.  Has a greater affinity for thyroid hormone receptors D.  Is considered a prohormone for levothyroxine E.  Is required for most patients to adequately reduce symptoms of hypothyroidism F.   Has a greater potential for cardiovascular side effects during initiation of therapy G.  Is more expensive
A.  Has greater oral bioavailability (95% vs 65%) C.  Has a greater affinity for thyroid hormone receptors (10X) F.   Has a greater potential for cardiovascular side effects during initiation of therapy G.  Is more expensive
41
A 40-year-old woman presents for an annual physical. Examination reveals a slightly elevated HR and BP. Palpation of her neck revealed a complaint of tenderness, and an enlarged thyroid was felt. Laboratory testing showed elevated TSH, decreased T4 levels, and elevated thyroglobulin antibodies. Which of the following is the most likely diagnosis? A.  Grave’s disease B.  Hashimoto’s disease C.  Nontoxic goiter D.  Pituitary adenoma E.  Thyroid cancer
B.  Hashimoto’s disease
42
Causes of Hyperthyroidism
1. Grave's disease 2. toxic Uninodular goiter 3. toxic multinodular goiter
43
Signs of autonomic nervous system overactivity
1. B-adrenergic (atrial tachycardia, tremor) 2. sympathetic cholinergic (increased sweating) 3. parasympathetic (increased GI motility)
44
____ is associated with increased incidence in bone and CV disease
subclinical hyperthyroidism
45
another name for hyperthyroidism
Thyrotoxicosis
46
Describe general treatment strategies for Graves disease
1. Decrease synthesis/interfere w/ hormone production (thiionamides and iodides) 2. modifying tissue response- for sx (BB and corticosteroids) 3. Glandular destruction (radioactive Iodine 131, surgery)
47
When are thyroid hormone synthesis inhibitors best used
1. mild dz 2. small gland 3. young pt *leaves gland intact but 60-70% relapse
48
What BB are used for sx relief in hyperthyroidism
Propranolol- advantage of blocking T4--> T3 conversion (use in thyroid storm) Metoprolol-Atenolol-- B1 selective, longer t1/2
49
Compare and contrast PTU vs MET for (thionamides) pharmacokinetics including absorption, distribution, and elimination
Absorption: Met>PTU Distribution: both cross placenta and are concentrated by fetal thyroid but PTU is more protein bound so crosses placenta LESS readily and less in breast milk Elimination: Met: t1/2= 5-13 hrs, QD PTU: t1/2= 1-2hrs, 2-3x/day **accumulate in thyroid
50
What are the MOA of thionamides
inhibit thyroid peroxidase --> prevent T4/T3 synthesis by blocking iodine organification and coupling of the iodotyrosine * HDs of PTU also blocks peripheral conversion of T4 to active T3 * Synthesis is inhibited NOT release so it take 3-4 weeks to deplete T4 (since it is stored in the thyroid)
51
When are Thionamides best used
Only for thyrotoxicosis from excess PRODUCTION (Graves disease - high RAI) NOT excess release (low RAI ie. thyroiditis)
52
Clinical resolution of thyrotoxicosis is in ___ and biochemical resolution is in ___
w/in 2 weeks w/in 6 weeks * remission w/in 12-18 months - About 1/3 of patients experience lasting remission - Recurrence rate of Graves hyperthyroidism is 50-60%
53
Thionamides are effective alone if:
1. small goiter 2. low levels of anti-TSH receptor Ab 3. mild-moderate hyperthyroidism
54
What are adverse reactions of Thionamides
1. Pruritic rash 2. GI intolerance 3. Arthralgias (MC) 4. Agranulocytosis (most dangerous)-- sore throat/fever 5. Hepatotoxicity w/ PTU (rare but serious to cause death and liver transplant) *50% cross sensitivity with Met-PTU
55
Why is Metimazole preferred over PTU
1. efficacy at lower doses 2. once daily dosing 3. lower side effect incidence **PTU is safer to fetus and tx of choice in preg. (increased protein binding)
56
A 24-year-old woman was found to have mild hypothyroidism due to Graves disease and it is decided to begin treatment with methimazole. Methimazole reduced serum concentrations of T3 primarily by: A.  Accelerating the peripheral metabolism of T3 B.  Inhibiting the proteolysis of thyroglobulin C.  Inhibiting the secretion of TSH D.  Inhibiting the uptake of iodide by cells in the thyroid E.  Preventing the addition of iodine to tyrosine residues on thyroglobulin
E.  Preventing the addition of iodine to tyrosine residues on thyroglobulin
57
Clinical considerations in medical management of Graves disease include: A.  Concern for agranulocytosis with use of thionamides B.  More rapid achievement of euthyroid state with methimazole vs PTU C.  Possibility of life-threatening hepatotoxicity with methimazole D.  Thionamides are more effective in patients with low uptake (RAIU) E.  Beta-blockers are used to control cardiovascular symptoms while euthyroidism is being achieved F.   PTU has a greater level of binding to plasma proteins than methimazole which may be advantageous in pregnant patients
A.  Concern for agranulocytosis with use of thionamides B.  More rapid achievement of euthyroid state with methimazole vs PTU E.  Beta-blockers are used to control cardiovascular symptoms while euthyroidism is being achieved F.   PTU has a greater level of binding to plasma proteins than methimazole which may be advantageous in pregnant patients
58
What is SSKI and Lugol's solution
SSKI-- super-saturated potassium iodide Lugol's-- potassium iodide/iodine *used for severe hyperthryoidism and thyroid storm
59
Describe the MOA of SSKI and Lugol's solution
Complex, transient effect of HDs (>6mg daily) - Inhibits T4, T3 synthesis via elevated INTRACELLULAR [I-] - inhibits T4, T3 RELEASE via elevated plasma [I-]--> blocks Tg proteolysis
60
What are disadvantages of SSKI and Lugol's solution
1. Variable effects (some pts show no response) 2. rapid reversal of inhibitory effects when withdrawn 3. potential to produce new T3--> worsen w/ hyperthyroidism
61
What are the clinical uses of SSKI and Lugol's solution
1. Decrease size and vascularity of hyperplastic gland prior to surgery (given 10 days prior) 2. initiate I- therapy AFTER onset of thionamide effect occurs *storm, severe hyper and prior to surg.
62
Describe adverse reactions of SSKI and Lugol's solution
``` *uncommon Reversible: 1. Acneform rash 2. rhinorrhea 3. metallic taste 4. swollen salivary glands (selective accumulation in salivary glands) ```
63
``` A 25-year-old woman presents with insomnia and fears she may have “something wrong with her heart”. She describes “her heart jumping out of her chest”. She feels healthy otherwise and reports she has lots of energy. Lab tests confirm hyperthyroidism. Which of the following is a drug that produces a permanent reduction in thyroid activity? A.  Propranolol B.  Propylthiouracil C.  131I D.  Potassium iodide E.  Hydrocortisone ```
C.  131I
64
Describe the MOA of radioactive iodine (131I)
administered orally, rapidly absorbed, concentrates in thyroid -B-radiation causes slow inflammatory process that destroys parenchyma of gland over a period of weeks to month
65
Describe the advantages of radioactive iodine (131I)
1. Easy administration (PO QD) 2. effectiveness 3. low expense 4. absence of pain 5. results in permanent resolution of hyperthyroidism
66
Describe the disadvantages of radioactive iodine (131I)
1. Slow onset and time to peak effect (2-6 months to euthyroid state) 2. 10% require 2nd dose 3.  Radiation thyroiditis can occur w/ release of preformed T3 and cause cardiovascular complications in elderly 4. Worsening of opthalmopathy 5.   Major complication is hypothyroidism 6. Should not administer to pregnant or nursing women *NO radiation-induced genetic damage, leukemia or neoplasia
67
Describe the use of surgery for hyperthyroidism
1. tx of choice if large gland 2. less commonly used today as 131-I has much greater benefit:risk ratio 3. requires tx w/ antithyroid drugs and iodine prior to surgery * 50-60% of patients require thyroid supplementation after surgery due to iatrogenic hypothyroidism * can be utilized in 2nd trimester of pregnancy if needed
68
Sx of thyroid storm
1. fever 2. flushing 3. sweating 4. tachycardia-atrial fibrillation 5. delirium 6. coma *Sudden, acute exacerbation of thyrotoxicosis reflected in hypermetabolism and excessive adrenergic activity
69
Thyroid storms can occur if pts are:
1. non-compliant 2. incompletely treated 3. undiagnosed w/ hyperthyroidism experiencing an acute stressor (infection-surgery-trauma)
70
``` A 56-year-old woman presented to the ED with tachycardia, shortness of breath, and chest pain. She had shortness of breath and diarrhea for the last 2 days and was sweating anxious. A relative reported that the patient had run out of methimazole 2 weeks earlier. A TSH measurement revealed a value of < 0.01 mIU/L (nl: 0.4-4.0 mIU/L) and a diagnosis of thyroid storm was made. Which of the following is a drug that is a useful adjuvant in the treatment of thyroid storm? A.  Amiodarone B.  Epinephrine C.  Propranolol D.  Radioactive iodine E.  Hydrocortisone ```
C.  Propranolol E.  Hydrocortisone
71
``` Multiple medications are utilized in the management of thyroid storm. Which agent is most effective in blocking the release of preformed thyroid hormone from the gland? A.  Hydrocortisone B.  Metoprolol C.  Potassium Iodide D.  Propranolol E.  Propylthiouracil F.   Sodium Iodide ``` Which of the above is utilized to “protect” the thyroid gland from exposure to radioactive iodine following a nuclear plant “meltdown”?
C.  Potassium Iodide F.   Sodium Iodide C. potassium iodide
72
What is the treatment of thyroid storm
1. Propranolol (IV or PO)- controls CVS sx AND blocks T4--> T3 2. slow release of hormones by sodium iodide (IV), potassium iodide drops orally 3. Inhibit synthesis of hormones by PTU PLUS block of T4-->T3 conversion (NOT BY MET) 4. Hydrocortisone protects against shock PLUSE blocks T4--> T3 PLUS modulates immune reponse that can lead to exacerbation of thyrotoxicosis
73
Tx of Thyroid storm is aimed at:
1. control of sx 2. inhibition of release of performed thyroid hormones 3. block of conversion of T4 to T3
Pharmacology
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