34.3 Endocrine Pharmacology II: Pituitary Disorders (GH Deficiency, Acromegaly, Prolactinoma, Diabetes Insipidus, Panhypopituitarism), Thyroid Drugs and Thyroid Storm, Calcium and Parathyroid Disorders, Adrenal Disorders and Corticosteroids

Why this area matters

The TOS endocrine area asks you to:

• explain drug action in pituitary, thyroid, calcium and adrenal disorders;
• plan therapy;
• anticipate adverse effects;
• monitor treatment.

Corticosteroids are among the most prescribed drugs, and their adverse effects and withdrawal risks are tested often.

Pituitary disorders

• Growth hormone deficiency (dwarfism):
  • recombinant GH given daily by subcutaneous injection;
  • monitor growth, IGF-1, glucose and thyroid function;
  • adverse effects are intracranial hypertension, slipped capital femoral epiphysis and edema.
• Acromegaly and gigantism (GH excess):
  • transsphenoidal surgery first;
  • then somatostatin analogs (octreotide, lanreotide), which cause gallstones and GI upset;
  • pegvisomant, a GH-receptor antagonist;
  • dopamine agonists, or radiotherapy.
• Hyperprolactinemia and prolactinoma:
  • dopamine agonists first: cabergoline, which is better tolerated and given weekly, or bromocriptine, preferred when pregnancy is planned;
  • adverse effects are nausea, orthostatic hypotension and impulse-control problems; high-dose cabergoline is linked to valvulopathy;
  • always exclude drug causes: antipsychotics, metoclopramide, verapamil, opioids.
• Diabetes insipidus:
  • central DI: desmopressin (a V2 agonist), given intranasally, orally or by injection. Watch for hyponatremia from water retention;
  • nephrogenic DI: thiazides, a low-salt diet and NSAIDs (indomethacin); amiloride for lithium-induced DI.
• Panhypopituitarism:
  • replace hydrocortisone first, then levothyroxine (judged by free T4, not TSH), then sex steroids and GH;
  • giving thyroxine before steroids raises cortisol demand and can precipitate adrenal crisis.

Thyroid Therapeutics: Levothyroxine vs. Thionamides

• Levothyroxine (Synthetic $T_4$):
  • Drug of choice for primary and central hypothyroidism. Converted peripherally by 5'-deiodinases to active $T_3$.
  • Administration Rule: Must be ingested in the morning on an empty stomach with a full glass of plain water at least 30 to 60 minutes before breakfast. Co-ingestion of calcium carbonate, ferrous sulfate, cholestyramine, or proton pump inhibitors profoundly impairs oral absorption.
  • Monitoring: Half-life is 7 days. Serum TSH must be measured 6 to 8 weeks after initiating or altering a dose to evaluate steady-state response.
• Thionamides: Methimazole vs. Propylthiouracil (PTU):
  • Shared Mechanism: Both drugs inhibit Thyroid Peroxidase (TPO), blocking the organification of iodide and the coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT) to synthesize $T_3$ and $T_4$.
  • Unique PTU Mechanism: PTU possesses an additional mechanism: it inhibits peripheral 5'-deiodinase, blocking the peripheral conversion of $T_4$ to the active $T_3$.
  • Pregnancy Trimester Rules:
    • First Trimester of Pregnancy: Propylthiouracil (PTU) is the drug of choice. Methimazole is teratogenic during organogenesis, causing aplasia cutis congenita (congenital scalp defect), choanal atresia, and esophageal atresia.
    • Second and Third Trimesters of Pregnancy & General Maintenance: Methimazole is preferred. PTU carries an FDA boxed warning for severe, unpredictable, fulminant hepatic necrosis and liver failure.
    • Thyroid Storm: PTU is preferred over methimazole because of its rapid blockade of peripheral $T_4$-to-$T_3$ conversion, combined with high-dose propranolol, Lugol's iodine (given at least 1 hour after the thionamide so that the iodine is not used to make new hormone), and IV hydrocortisone.
  • Agranulocytosis ($0.2\text{--}0.5\%$): The most feared idiosyncratic adverse effect of both thionamides. Manifests within the first 3 months of therapy with sudden fever and sore throat (pharyngitis). Patients must be warned to immediately stop the drug and obtain a STAT complete blood count (CBC). An Absolute Neutrophil Count (ANC) $< 500/\mu\text{L}$ confirms agranulocytosis, requiring immediate hospitalization, broad-spectrum antibiotics, and G-CSF support.

Other thyroid drugs:

• Radioactive iodine: used for Graves disease and toxic nodules. It is contraindicated in pregnancy and breastfeeding, may worsen Graves eye disease, and often leads to hypothyroidism.
• Beta-blockers (propranolol): control adrenergic symptoms.
• Thyroid storm treatment, in order:
  • a thionamide (PTU preferred);
  • iodine at least 1 hour after the thionamide;
  • propranolol;
  • hydrocortisone;
  • cooling with paracetamol, not aspirin, which displaces T4;
  • treatment of the precipitant.
• Myxedema coma: IV levothyroxine (with or without T3) after IV hydrocortisone, plus supportive care.

Calcium and parathyroid disorders

• Hypercalcemia (malignancy, primary hyperparathyroidism):
  • IV normal saline to restore volume and promote calciuria;
  • calcitonin, which acts within hours but loses effect in 48 hours (tachyphylaxis);
  • IV zoledronic acid or pamidronate, which take effect in 2 to 4 days and last weeks (risks: acute-phase reaction, renal toxicity);
  • denosumab in renal impairment;
  • glucocorticoids for vitamin D-mediated hypercalcemia (granulomatous disease, lymphoma);
  • loop diuretics only after volume repletion;
  • dialysis if severe.
• Primary hyperparathyroidism: parathyroidectomy. Cinacalcet (a calcimimetic) is used when surgery is not possible, and in secondary hyperparathyroidism of CKD.
• Hypocalcemia:
  • symptomatic hypocalcemia (tetany, seizures, prolonged QT) is treated with IV calcium gluconate and magnesium if low;
  • chronic hypoparathyroidism is treated with oral calcium and calcitriol (active vitamin D), avoiding hypercalciuria.
• Vitamin D deficiency is treated with cholecalciferol. Calcitriol is needed when renal 1-alpha-hydroxylation is impaired, as in CKD.
• Osteoporosis drugs (bisphosphonates, denosumab, teriparatide, raloxifene) are covered with musculoskeletal pharmacology.

Adrenal disorders and corticosteroids

• Addison disease (primary adrenal insufficiency):
  • hydrocortisone in 2 to 3 daily doses, plus fludrocortisone;
  • sick-day rules: double or triple the dose during fever or illness, and use injectable hydrocortisone if vomiting;
  • stress doses for surgery;
  • a medical alert bracelet.
• Adrenal crisis:
  • IV hydrocortisone 100 mg at once, then 50 mg every 6 hours (or an infusion);
  • normal saline with dextrose;
  • do not wait for test results.
• Secondary adrenal insufficiency from stopping long-term steroids (more than about 3 weeks of supraphysiologic doses) is prevented by tapering.
• Adverse effects of long-term corticosteroids:
  • Cushingoid features;
  • hyperglycemia;
  • hypertension;
  • osteoporosis (give calcium, vitamin D and a bisphosphonate);
  • myopathy;
  • cataracts and glaucoma;
  • peptic ulcer (with NSAIDs);
  • infections, including reactivated TB and strongyloidiasis;
  • mood changes;
  • poor wound healing;
  • growth suppression in children;
  • HPA axis suppression.
• Cushing syndrome:
  • surgery for adenomas;
  • medical therapy with steroidogenesis inhibitors: ketoconazole (hepatotoxic), metyrapone, osilodrostat, or mifepristone (a receptor antagonist);
  • exogenous Cushing syndrome is treated by tapering the steroid.
• Primary hyperaldosteronism (Conn syndrome): unilateral adenomas are removed. Bilateral hyperplasia is treated with spironolactone (gynecomastia) or eplerenone, which correct hypokalemia and BP.
• Pheochromocytoma:
  • alpha-blockade first (phenoxybenzamine or doxazosin) for 10 to 14 days, with liberal salt and fluids;
  • then a beta-blocker for tachycardia;
  • then surgery.
  • A beta-blocker alone leaves alpha-receptors unopposed and can cause a hypertensive crisis.
  • Phentolamine or nitroprusside treats intraoperative crises.