Endocrine pharm – HY mixed drugs

Thionamides

• Propylthiouracil (PTU)
• Methimazole

MOA of PTU methimazole?

• Both inhibit thyroperoxidase.
• PTU has a second MOA: inhibits 5-deiodinase.
• Thyroperoxidase converts iodide to iodine within the thyroid gland so that it can be added to thyroglobulin for thyroid hormone synthesis.
• 5-deiodinase converts T4 to T3 peripherally.

PTU inhibits peripheral conversion of T4 to T3 by inhibiting 5-deiodinase. Methimazole does not have this added MOA. Both inhibit thyroperoxidase.

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Thyroperoxidase converts iodide to iodine within the thyroid gland so that it can be added to thyroglobulin for thyroid hormone synthesis.

5-deiodinase converts T4 to T3 peripherally.

T3 and T4 will go down. TSH will go up (less suppression).

In Graves, T3 and T4 are normally high, and TSH is low (suppressed by high T3 and T4).

NSAIDs before steroids

Neutropenia due to PTU or methimazole.

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Major side-effects of PTU and methimazole?

• Agranulocytosis (neutropenia) –> presents as mouth ulcers, sore throat, fever.
  • 38F + treated four days ago for hyperthyroidism in hospital + now has WBCs 3500; why? –> answer = “drug-induced neutropenia” (PTU or methimazole). This is on 2CK IM form.
• Hepatotoxicity (PTU > methimazole).
• Methimazole is teratogenic in first trimester (causes aplasia cutis congenita).
• In pregnant woman with Graves, PTU is used first trimester; methimazole is then used 2nd and 3rd trimester to spare the patient from PTU’s greater risk of hepatotoxicity with continued use.

PTU in first trimester; methimazole in 2nd + 3rd trimesters.

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Major side-effects of PTU and methimazole?

• Agranulocytosis (neutropenia) –> presents as mouth ulcers, sore throat, fever.
  • 38F + treated four days ago for hyperthyroidism in hospital + now has a fever and a mouth ulcer; why? –> answer = “drug-induced neutropenia” (PTU or methimazole). This is on 2CK IM form.
• Hepatotoxicity (PTU > methimazole).
• Methimazole is teratogenic in first trimester (causes aplasia cutis congenita).
• In pregnant woman with Graves, PTU is used first trimester; methimazole is then used 2nd and 3rd trimester to spare the patient from PTU’s greater risk of hepatotoxicity with continued use.

Propranolol

• Beta-blockade decreases peripheral conversion of T4 to T3.
• Propranolol the classic beta-blocker used to treat tachycardia in hyperthyroidism.

Increase by 50% (factoidy but on Step 3)

Subclinical hypothyroidism (↑ TSH,  normal T3 + T4).

Normally we don’t treat. But give levothyroxine if:

1) Anti-Hashimoto antibodies

2) Pregnant, or

3) TSH >10 mIU/L (NR 0.5-5.0).

Don’t stop the drug. Keep the dose the same + add levothyroxine.

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Drug-hypothyroidism (e.g., due to lithium or amiodarone).

• 25F + started on medication for bipolar disorder + cold intolerance + weight gain  + TSH is high + serum lithium levels within normal limits; what do we do? –> answer = keep dose of lithium the same + commence levothyroxine.

↓TSH, ↑ T3, ↑ T4; these arrows are the mere changes in the patient’s serum values as a result of the T4 administration.

Untreated (or insufficiently treated) Hashimoto will have (↑ TSH, ↓ T3, ↓ T4).

↓TSH, ↑ T3, ↓ T4. These arrows are the mere changes in the patient’s serum values as a result of the T3 administration.

Student says, “Wait, what? Why is T4 down.” Because T4 is converted to T3 peripherally, but not the other way around. If we give thyroxine (T4), of course T4 is high, but so is T3 because it’s converted T4 → T3. However if we give T3, it’s not converted to T4, so T4 (which is already low) will go down further because the T3 induces negative feedback on TSH secretion, and the lower TSH will mean the thyroid gland is suppressed.

a) Vasopressin analogue.

b)

• Central diabetes insipidus (replaces vasopressin).
• von Willebrand disease (stimulates vWD production + release from vascular endothelium).
• Hemophilia A (stimulates factor VIII production + release from the liver and vascular endothelium).

a) Conivaptan, Tolvaptan

b) SIADH (usually caused by small cell bronchogenic carcinoma or head trauma).

a) Technically a tetracycline antibiotic, but not used for antimicrobial purposes because it causes nephrogenic diabetes insipidus (i.e., antagonizes vasopressin receptors). However this side-effect is advantageous and capitalized upon in order to treat SIADH.

b) Treats SIADH. Can also use the -vaptan agents (conivaptain, tolvaptan for SIADH –> vasopressin receptor antagonists).

a) Aldosterone receptor antagonists.

b)

1) Spironolactone or eplerenone used as potassium-sparing diuretic in patients already on furosemide (the latter causes potassium wasting).

• 44M + liver failure + peripheral edema + already taking furosemide; what drug could be added to help with this patient’s edema? –> answer = spironolactone.
• (It should be noted that triamterine and amiloride, which are ENaC inhibitors, are correct answers for this Q as well; I’ve seen this Q with numerous answers).

2) Hyperaldosteronism due to adrenal hyperplasia or Conn syndrome (aldosterone-secreting tumor).

3) Spironolactone is used in heart failure when patient has low ejection fraction despite already being on an ACEi/ARB and a beta-blocker.

Gynecomastia (HY for USMLE); eplerenone has much lesser risk.

Hyperkalemia (potassium-sparing diuretic, but can inadvertently cause hyperkalemia in some patients).

a) MOA of cinacalcet?

• Calcimimetic (i.e., sensitizes calcium-sensing receptor on the parathyroid glands).
• Causes a decrease in serum PTH, thereby reducing serum calcium levels.

b) When is cinacalcet used?

• Secondary hyperthyroidism due to renal failure in patients on dialysis (i.e., once electrolytes are stabilized in patients with renal failure, cinacalcet can help lower the PTH levels).
• Primary hyperparathyroidism refractory to surgery.

c) What do I need to know for USMLE?

• USMLE is way more likely to ask what effect giving cinacalcet would have on a patient versus why it’s used –> answer = ↓ PTH; ↓ serum Ca²⁺.

Sevelamer

MOA of sevelamer?

• Phosphate-binder that binds phosphate in the small bowel and prevents its absorption.
• Decreases phosphate levels in patients with chronic renal disease.

Spironolactone, Eplerenone

Demeclocycline, Conivaptan, Tolvaptan

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Conivaptan, Tolvaptan

MOA of conivaptan and tolvaptan?

• Vasopressin receptor antagonists.

When are they used?

• SIADH (usually caused by small cell bronchogenic carcinoma or head trauma).

Demeclocycline

MOA of demeclocycline?

• Technically a tetracycline antibiotic, but not used for antimicrobial purposes because it causes nephrogenic diabetes insipidus (i.e., antagonizes vasopressin receptors). However this side-effect is advantageous and capitalized upon in order to treat SIADH.
• For USMLE, demeclocycline and the -vaptan agents are both used for SIADH.

Desmopressin (DDAVP) first. Then do factor VIII replacement.

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Desmopressin (DDAVP)

• Vasopressin analogue.

When is it used?

• Central diabetes insipidus (replaces vasopressin).
• von Willebrand disease (stimulates vWD production + release from vascular endothelium).
• Hemophilia A (stimulates factor VIII production + release from the liver and vascular endothelium).

PTU, methimazole

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Major side-effects of PTU and methimazole?

• Agranulocytosis (neutropenia) –> presents as mouth ulcers, sore throat, fever.
  • 38F + treated four days ago for hyperthyroidism in hospital + now has a fever and a mouth ulcer; why? –> answer = “drug-induced neutropenia” (PTU or methimazole). This is on 2CK IM form.
• Hepatotoxicity (PTU > methimazole).
• Methimazole is teratogenic in first trimester (causes aplasia cutis congenita).
• In pregnant woman with Graves, PTU is used first trimester; methimazole is then used 2nd and 3rd trimester to spare the patient from PTU’s greater risk of hepatotoxicity with continued use.