What are the common medications used to manage endocrine disorders, including those affecting the hypothalamus, pituitary, adrenal cortex, and reproductive systems, as well as those used in cancer treatment?

Board-Relevant Pharmacology: Endocrine and Chemotherapy Agents

Hypothalamus and Pituitary Agents

Propylthiouracil (PTU)

• Mechanism: Inhibits thyroid peroxidase (blocks iodine organification and T4→T3 conversion peripherally) 1
• Key adverse effects: ANCA-associated vasculitis (29.84-fold increased risk vs methimazole), rapidly progressive glomerulonephritis (6.44-fold), pulmonary alveolar hemorrhage (7.77-fold), agranulocytosis (0.1-0.5% incidence) 1, 2
• Critical indication: Preferred in first trimester pregnancy (methimazole causes congenital malformations) 1
• Monitoring: CBC for agranulocytosis, renal function for ANCA vasculitis 2

Methimazole (MMI)

• Mechanism: Inhibits thyroid peroxidase (blocks iodine organification only) 1
• Key adverse effects: Agranulocytosis (4.01-fold increased risk vs PTU), aplasia cutis congenita (123.22-fold), exomphalos (22.17-fold), skin rash (3-5% of patients) 1, 2
• Contraindication: First trimester pregnancy due to congenital malformations 1
• Advantage: Once-daily dosing, lower vasculitis risk than PTU 1
• Treatment of agranulocytosis: Granulocyte colony-stimulating factor 2

Levothyroxine (L-T4)

• Dosing: 1.6 mcg/kg/day average replacement dose; administer on empty stomach 30-60 minutes before breakfast 3, 4
• Goal: Normalize TSH while avoiding suppression below 0.2 mIU/L (atrial fibrillation and bone loss risk with TSH ≤0.1) 4
• Pregnancy: TSH increases during pregnancy; monitor and adjust dose upward; return to pre-pregnancy dose immediately postpartum 3
• Pediatric: Immediate initiation in congenital hypothyroidism to prevent cognitive impairment; monitor for cardiac overload in first 2 weeks 3
• Drug interactions: Administer ≥4 hours apart from interfering medications (calcium, iron, PPIs) 3
• Contraindication: Uncorrected adrenal insufficiency (precipitates adrenal crisis) 3
• Hypophysitis management: Start corticosteroids several days before levothyroxine; follow free T4 (not TSH) for dose titration 5
• Adverse effects with overtreatment: Atrial fibrillation (especially elderly), decreased bone mineral density, cardiovascular changes 2, 4

Adrenal Cortical Pharmacology

Glucocorticoids (Hydrocortisone, Prednisone)

Replacement Therapy Dosing

• Primary adrenal insufficiency: Hydrocortisone 10-20 mg AM, 5-10 mg early afternoon; add fludrocortisone 0.1 mg/day for mineralocorticoid replacement 5
• Secondary adrenal insufficiency: Hydrocortisone 10-20 mg AM, 5-10 mg early afternoon (no fludrocortisone needed—aldosterone production intact) 5
• Pediatric replacement: Weight-based dosing; double doses for 24-48 hours during illness 5

Perioperative Stress Dosing

• Major surgery (adults): Hydrocortisone 100 mg IV at induction, then continuous infusion or divided doses 5
• Major surgery (pediatric): Hydrocortisone 2 mg/kg at induction, then continuous IV infusion: 25 mg/24h (≤10 kg), 50 mg/24h (11-20 kg), 100 mg/24h (prepubertal >20 kg), 150 mg/24h (pubertal >20 kg) 5, 6
• Minor surgery with GA: Hydrocortisone 2 mg/kg IV/IM at induction; double oral doses for 24 hours postop 5
• Minor procedure without GA: Double morning dose pre-procedure 5

Critical Management Points

• Adrenal crisis treatment: Dexamethasone 4 mg IV if diagnosis uncertain (allows subsequent ACTH stimulation test); hydrocortisone 100 mg IV if diagnosis confirmed 5
• Post-adrenalectomy for Cushing: Tertiary adrenal insufficiency occurs; requires stress-dose coverage until HPA axis recovery (temporary in adrenal adenoma) 6, 7
• Patient education: Stress dosing instructions, medical alert bracelet mandatory 5
• Pitfall: Never start levothyroxine before corticosteroids in combined deficiencies (precipitates adrenal crisis) 5

Indications (Prednisone)

• Primary/secondary adrenal insufficiency, congenital adrenal hyperplasia, hypercalcemia of malignancy, inflammatory conditions (rheumatologic, dermatologic, respiratory, hematologic) 8

Adverse Effects

• Hyperglycemia (monitor diabetics closely), hypertension, hypokalemia, osteoporosis, immunosuppression, HPA axis suppression 5
• Iatrogenic adrenal insufficiency: All routes (oral, inhaled, topical, intranasal, intra-articular) can suppress HPA axis; 7 in 1000 people on long-term oral steroids 5

Reproductive Pharmacology

SERMs (Selective Estrogen Receptor Modulators)

• Mechanism: Tissue-selective estrogen receptor agonist/antagonist activity 5
• Reproductive effects: Can affect hypothalamic-pituitary-gonadal axis; monitor for menstrual irregularities 5

Aromatase Inhibitors

• Mechanism: Block conversion of androgens to estrogens 5
• Endocrine effects: Reduce estradiol levels; can cause hyperandrogenism in women 5

Chemotherapy Agents: Genome Synthesis, Stability, and Maintenance

Antimetabolites

Methotrexate

• Mechanism: Dihydrofolate reductase inhibitor (blocks purine/pyrimidine synthesis)
• Rescue agent: Leucovorin (folinic acid) bypasses DHFR block

5-Fluorouracil (5-FU)

• Mechanism: Thymidylate synthase inhibitor (blocks DNA synthesis)

Hydroxyurea

• Mechanism: Ribonucleotide reductase inhibitor (blocks DNA synthesis)

Azathioprine & 6-Mercaptopurine

• Mechanism: Purine analogs (incorporate into DNA/RNA, inhibit purine synthesis)
• Metabolism: Metabolized by thiopurine methyltransferase (TPMT); test TPMT activity before dosing

Mycophenolate Mofetil

• Mechanism: Inosine monophosphate dehydrogenase inhibitor (blocks purine synthesis)

Cladribine

• Mechanism: Purine analog (accumulates in lymphocytes, causes DNA strand breaks)

Cytarabine (Ara-C)

• Mechanism: Pyrimidine analog (inhibits DNA polymerase)

Gemcitabine

• Mechanism: Pyrimidine analog (inhibits ribonucleotide reductase)

Alkylating Agents

Cyclophosphamide & Ifosfamide

• Mechanism: Cross-link DNA strands
• Toxicity: Hemorrhagic cystitis (prevent with mesna), SIADH

Busulfan

• Mechanism: Alkylates DNA
• Toxicity: Pulmonary fibrosis, seizures (prevent with phenytoin during conditioning)

Nitrosoureas (Carmustine, Lomustine)

• Mechanism: Alkylate and cross-link DNA; lipophilic (cross BBB)
• Toxicity: Delayed myelosuppression (4-6 weeks)

Platinum Compounds

Cisplatin, Carboplatin, Oxaliplatin

• Mechanism: Cross-link DNA (intra-strand and inter-strand)
• Cisplatin toxicity: Nephrotoxicity (dose-limiting), ototoxicity, peripheral neuropathy, severe nausea
• Carboplatin toxicity: Myelosuppression (dose-limiting, less nephro/ototoxic than cisplatin)
• Oxaliplatin toxicity: Cold-induced peripheral neuropathy

Amifostine

• Mechanism: Cytoprotective agent (free radical scavenger); reduces cisplatin nephrotoxicity and radiation toxicity

Antitumor Antibiotics

Bleomycin

• Mechanism: Induces DNA strand breaks via free radicals
• Toxicity: Pulmonary fibrosis (dose-limiting; avoid supplemental O2), minimal myelosuppression

Doxorubicin & Daunorubicin (Anthracyclines)

• Mechanism: Intercalate DNA, inhibit topoisomerase II, generate free radicals
• Toxicity: Dose-dependent dilated cardiomyopathy (monitor cumulative dose), myelosuppression, red urine (not hematuria)

Actinomycin D (Dactinomycin)

• Mechanism: Intercalates DNA, inhibits RNA polymerase
• Toxicity: Myelosuppression, radiation recall

Topoisomerase Inhibitors

Etoposide & Teniposide

• Mechanism: Topoisomerase II inhibitors (cause DNA strand breaks)
• Toxicity: Myelosuppression, secondary leukemias (11q23 translocations)

Topotecan & Irinotecan

• Mechanism: Topoisomerase I inhibitors (prevent DNA religation)
• Irinotecan toxicity: Early diarrhea (cholinergic, treat with atropine), late diarrhea (treat with loperamide); metabolized by UGT1A1 (dose reduce in Gilbert syndrome)

Microtubule Inhibitors

Vincristine & Vinblastine (Vinca Alkaloids)

• Mechanism: Bind tubulin, prevent microtubule polymerization (M-phase arrest)
• Vincristine toxicity: Peripheral neuropathy (dose-limiting), SIADH, constipation; fatal if given intrathecally
• Vinblastine toxicity: Myelosuppression (dose-limiting), less neurotoxic than vincristine

Paclitaxel (Taxane)

• Mechanism: Stabilizes microtubules, prevents depolymerization (M-phase arrest)
• Toxicity: Myelosuppression, peripheral neuropathy, hypersensitivity reactions (premedicate with steroids/antihistamines)

Targeted Therapy

Tyrosine Kinase Inhibitors

Imatinib

• Target: BCR-ABL (CML), c-KIT (GIST), PDGFR
• Toxicity: Fluid retention, myelosuppression, hepatotoxicity

Erlotinib

• Target: EGFR (NSCLC with EGFR mutations)
• Toxicity: Acneiform rash, diarrhea, interstitial lung disease

Sorafenib & Sunitinib

• Target: Multi-kinase inhibitors (VEGFR, PDGFR, RAF)
• Toxicity: Hand-foot syndrome, hypertension, hypothyroidism, hepatotoxicity

Vemurafenib

• Target: BRAF V600E mutation (melanoma)
• Toxicity: Photosensitivity, cutaneous squamous cell carcinoma, QT prolongation

Monoclonal Antibodies

Rituximab

• Target: CD20 (B-cell lymphomas)
• Toxicity: Infusion reactions, tumor lysis syndrome, progressive multifocal leukoencephalopathy (PML)

Cetuximab

• Target: EGFR (colorectal cancer, head/neck cancer; only if KRAS wild-type)
• Toxicity: Acneiform rash (correlates with response), hypersensitivity, hypomagnesemia

Bevacizumab

• Target: VEGF (anti-angiogenesis)
• Toxicity: Hypertension, proteinuria, bleeding, impaired wound healing, GI perforation, thromboembolism

Alemtuzumab

• Target: CD52 (CLL, T-cell lymphomas)
• Toxicity: Severe immunosuppression (opportunistic infections including CMV, PCP), infusion reactions

Trastuzumab

• Target: HER2/neu (breast cancer, gastric cancer)
• Toxicity: Reversible cardiomyopathy (monitor LVEF), infusion reactions; do NOT combine with anthracyclines (synergistic cardiotoxicity)