Thyroid and Anti-Thyroid Drugs Flashcards
4 Thyroid Drugs
- Levothyroxine [T4]
- Liothyronine [T3]
- Liotrix [4:1 ratio of T4:T3]
- Thyroid desiccated
Anti-Thyroid Drugs
- Thioamides: Methimazole & PTU (propylthiouracil))
- Iodides: Potassium Iodide
- Radioactive Iodine (131I) sodium
- B-blockers: Metoprolol, propranolol, atenolol
Thioamides (Anti-thyroid agent)
- Methimazole
- Propylthiouracil (PTU)
Iodides (Anti-thyroid agent)
- Potassium Iodide
B-Blockers (Anti-thyroid drugs)
- Metaprolol
- Propanolol
- Atenolol
How are thyroid hormones made? (steps)
- NIS (Na+/iodide symporter) moves [iodide] into the thyroid follicular cells from blood.
- Pendrin, a iodide transporter enzyme, transports iodide from [across the apical membrane of follicular cell => colloid].
- @ apical cell membrane:
- TPO (thyroid peroxidase): [iodide => iodine] via oxidation.
- In thyroglobulin molecule (gylcoprotein w a shit ton of tyrosine):
- Iodide organification: iodine undergoes iodination of tyrosine resides => DIT and MIT
- [DIT + DIT] => T4 (thyroxine); [MIT + DIT] => T3 (triiodothyronine)
- T3/T4, MIT and DIT go from colloid => apical membrane of the follicular cell via proteolysis and exocytosis,
- Released into blood in 5:1 T4:T3 ratio, bound to TBG (thyroxine-binding globulin) in plasma.
- T4 deiodinated to T3 (4x more portent than T4) or reverse T3 (metabollically inavtive)
How is T4 inactivated?
- Deamination
- Decarboxylation
- Conjugation
Bioavailability and 1/2-life of thyroid hormones (T3/4)
-
T4
- Bioavailability = 80% (best in duodenum and ileum)
- 1/2 life = 7 days
-
T3
- Bioavailability = 95%
- 1/2 life = 1 day
What thyroid drug is given for [thyroid replacement therapy] and why?
T4 (Levothyroxine)
- Longer 1/2 half = once a day administration
- More stable
- Cheap
- Lack of allergic foreign protein
- Easy to measure
Even though T3 is more potent (bioavailability of 95% vs 80%), why is it not recommended for replacement therapy?
- Shorter 1/2 life = 3/4x/day
- More expensive
- Difficult to monitor
Where is oral T4 best absorbed within the GI tract?
Duodenum and ileum
Absorption of T4 and T3 may be affected by what underlying condition?
Myxedema w/ ileus but NOT by mild hypothyroidism
1/2-life and clearance of T3/4 in a Hyperthyroid vs. Hypothyroid state
- Hyperthyroid = T4/T3 clearance is ↑ and half-life ↓
- Hypothyroid = T4/T3 clearance is ↓ and half-life ↑
Which 6 agents prevent peripheral conversion of T4 =>T3 by inhibiting 5’-deiodinase => [↑ reverse T3 levels and decrease in T3], and what is their purpose?
Agents that inhibit [T4 => T3 conversion] are given to patients with thyroid storm [thyrotoxic crisis] => reduce T3 levels.
- Radiocontrast agents: iopanoic acid and ipodate
- Amiodarone
- β-blockers
- Corticosteroids
- PTU
- Flavanoids
List 9 drugs/agents that ↓ T4 absorption
- Antacids (aluminum hydroxide, calcium carbonate)
- Ferrous sulfate
- Cholestyramine
- Colestipol
- Ciprofloxacin
- PPI’s
- Bran, Soy, and Coffee
7 drugs that (+) liver CYP450s and ↑ the metabolism of T4 and T3?
- Rifampin
- Rifabutin
- Phenobarbital
- Phenytoin
- Protease inhibitors
- Carbamazepine
- Imatinib
5 drugs that cause AI thyroid disease w/ hypo- or hyperthyroidism.
- Interferon-α / Interferon-β
- IL-2
- Lithium
- Amiodarone
How do drugs/conditions that change the clearance in patients with a NL thyroid react?
Thyroid starts to hyperfunction = maintain NL hormone concentration
MOA of Thyroid Hormone
- T3/T4 enter cell via active transport
- T4 => converted to T3 via 5’-deiodinase
- T3 enters nucleus => binds to TR (thyroid receptor)
- Corepressor is released and coactivator binds
- TR homodimer separtaes
- TR binds to RXR (retanoid X receptor)
- transciption
In the absence of hormone, what is the structure of the TR (thyroid receptor)?
- TR (homodimer) bound to corepressor protein, which is bound to DNA on the TRE (thyroid hormone response element)
How long after administering thyroid hormone does it take to see the effects and why?
Lag time of hours or days due effects at the level of gene transcription
What are T3 preparations best used for clinically?
Short-term suppression of TSH
How can we ↓ thyroid activity and hormones?
- Block synthesis of TH
- Modify the tissues response to TH
- Destroy thyroid w/ radiation or surgery
Thiomides
- Drugs
- MOA (general)
- Methimazole and PTU (propylthiouracil)
- Block synthesis of thyroid hormone
PTU
Bioavailability, absorption,, metabolism, half-life, and dosing
-
BA of 50-80% that is rapidly absorbed, peaking in our serum at 1 hour => vitually all metabolites are excreted in 24 hours
- BA is low d/t incomplete absorption and large 1st-pass effect.
- 1/2 life = 1.5 hour
- Dose = 3- 4x/ day
Methimazole
Bioavailability, absorption, metabolism, half-life, and dosing
- BA is 100% (completely absorbed) and excreted slower (65% in 48 hours)
- 1/2 life = 6 hours
- Dosing = 1x day
Thiomides in pregnancy and when breastfeeding
-
Pregnancy: cross placental barrier and concentrates in thyroid = n_ot recommended_
- If must give = give PTU in 1st trimester and methimazole in 2nd/3rd trimerst
- Breastfeeding: safe (secreted in milk at low concentrations)
If you must give thiomides during pregnancy, what is recommended?
- 1st trimester = PTU
- 2nd/3rd = Methimazole
MOA of Thioamides (Methimazole and PTU)
Block synthesis of TH => thus, takes 3-4 weeks before stores are depleted
- Inhibit thyroidal peroxidase (TPO) catalyzed rxns
- Blocks iodide organification
- Inhibits coupling of MIT and DIT to form T3 and T4
- *****PTU ALSO BLOCKS PERIPHERAL CONVERSION OF T4=> T3, DROPPING T3 LEVELS EVN MORE
- Does NOT block thyroid gland uptake of iodide
How does the fall in T3 concentration with PTU + iodine differ from that of Methimazole + iodine?
FALL EVEN MORE bc PTU blocks peripheral conversion of T4 –> T3;
What effect to PTU and Methimazole have on thyroid gland iodide uptake?
- Do NOT block thyroid gland iodide uptake
- Inhibit hormone synthesis, rather than release
AE’s PTU or Methimazole?
Which is most severe? ***
- Maculopapular pruritic rash, at times accompanied by: Fever + nausea + GI distress
-
Agranulocytosis (granulocyte count < 500 cells/mm3) ****
- Reverse by DQing drug or CSF
Risk of agranulocytosis in ppl taking Thiomides is higher for who?
- Risk ↑ in older pt’s and those receiving high-dose methimazole
Potassium Iodide (Anti-thyroid) MOA
Prevents the release of TH.
- Inhibits organification and hormone release
- ↓ size and vascularity of hyperplastic thyroid gland
3 clinical uses of Potassium Iodide?
Treats:
- 1) Thyroid storm and sx’s improve within 2-7 days (rapidly)
- 2) Pre-op reduction of hyperplastic thyroid
- 3) Block uptake of radioactive isotopes of iodine in a radiation emergency or other exposure to radioactive iodine
AE’s Potassium Iodide?
AE = uncommon
- Acneiform rash
- Swollen salivary glands
- Mucous membrane ulcerations
- Conjunctivitis
- Metallic taste
Potassium Iodide in Pregnancy
Avoid: crosses placental barrier and cause goiter in BB
Radioactive Iodione
- TX
- MOA
- Administartion
- CI
- TX: thyrotoxicosis
- Destroys thyroid parenchyma (epithlium swells and necrosis, follicle disrupts, edema and leukocyte infiltartaion)
- Orally; rapidly absortbed => concentrated in thyroid and foollicles
- DO NOT GIVE TO PG W or BREASTFEEDING
Radioactive Iodine in PG and Breastfeeding
CI IN W WHO ARE PG OR BREASTFEEDING
Advanages of Radioactive Iodine
- Easy to adminiter (oral)
- Effective
- Cheap
- No pain
Which β-blockers are effective adjunctive agents in the management of thyrotoxicosis and which is most commonly used?
Those w/o sympathomimetic activity (i.e., metoprolol, propranolol, and atenolol)
- Propranolol is most commonly use
What effect do β-blockers have on thyroid levels?
- Improve hyperthyroid sx’s, but typically do not alter levels
- High doses of propranolol have been shown to reduce T3 through blockade of peripheral conversion of T4 –> T3
Treatment of Hypothyroidism
- Levothyroxine (T4) on empty stomach; effects seen in 6-8 weeks
What is a myxedema coma?
End state of untreated hypothyroidism = progressive weakness, stupor, hypothermia, hypoventillation, hypoglycemia, shock and death.
Management of hypothyroidism in someone with myxedema coma
- Large loading dose of IV T4 (bc poor absorption) followed by smaller IV dosing
Management of hypothyroidism in someone with myxedema + CAD
Correction of myxedema with T4 must be done cautiously to avoid provoking arrhythmia, angina, or acute MI (sx’s of elevated T4)
Why is tx of hypothyroidism in pt’s _trying to get pregnan_t and those currently pregnant so important?
- Trying to get pregnant & hypothyroidism = infertile
- Pregnant = decelopment of brain depends on moms T4
When is anti-thyroid drug therapy most useful for Grave’s disease and what are the preferred agents?
- Most useful in young pt’s w/ small glands and mild disease
- Methimazole or PTU administered until remission (12-18 mo. of tx)
- Methimazole is preferable to PTU (EXCEPT in pregnancy) due to once-daily dosing
When is a thyroidectomy the preferred tx for Grave’s disease and what % of these pt’s will require thyroid supplementation?
- pt’s w/ very large glands or multinodular goiter
- 80-90% will require thyroid supplementation
When is radioactive iodine the preferred tx for Grave’s disease; what about in pt’s w/ underlying heart disease, severe toxicosis, and the elderly?
- Preferred tx for most pt’s >21 years of age
- In pt’s w/ underlying heart disease, severe thyrotoxicosis, or elderly tx w/ anti-thyroids until pt is euthyroid is preferable
- 80% will develop hypothyroidism and require replacement therapy
What are the adjunct drugs which can be added to anti-thyroid therapy in pt with Graves?
- β-blockers w/o intrinsic sympathomimetic activity may be helpful in controlling tachycardia, HTN, and a-fib
- If β-blocker is CI can give the CCB, diltiazem, for management of tachycardia
Thyroid storm (Thyrotoxic crisis) treatment
- B-blockers => control arrhythmia
- K+ iodide => prevent release of thyroid
- PTU/methimazole => prevent production of TH
- IV hydrocortisone => prevent shock and block conversion of T4=> 3 in peripheral tissue
- Supportive therapy
