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Endocrine Drugs - Comprehensive Pharmacology

(Based on KDT, Padmaja Udaykumar, Katzung, Goodman & Gilman, Lippincott, and Harrisons)

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PART I: THYROID AND ANTITHYROID DRUGS

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A. THYROID HORMONES (Replacement Therapy)

1. Levothyroxine (L-T4, Synthroid, Eltroxin)

• Enters cells via specific transporters (MCT8, OATP1C1)
• Converted peripherally to active T3 by deiodinases (mainly Type 1 in liver/kidney, Type 2 in brain/pituitary)
• T3 binds nuclear thyroid hormone receptors (TRα, TRβ) → heterodimerizes with RXR → binds thyroid response elements (TREs) on DNA → regulates gene transcription
• Effects: increased basal metabolic rate, protein synthesis, cardiac output, CNS development, thermogenesis, growth hormone sensitization

• Oral bioavailability: 70-80% (tablet form); improved with Tirosint (liquid gel cap) formulation
• Absorption: mainly duodenum and ileum; reduced by food, calcium, iron, antacids, cholestyramine
• T1/2: ~7 days (allows once-daily dosing)
• Highly protein-bound (TBG, TBPA, albumin); only ~0.03% free
• Converted to T3 (active) and reverse T3 (inactive) in periphery

1. Primary hypothyroidism (drug of choice)
2. Secondary/tertiary hypothyroidism
3. Hashimoto thyroiditis
4. Congenital hypothyroidism (cretinism) - start within 2 weeks of birth
5. Myxedema coma - IV levothyroxine
6. TSH suppression in differentiated thyroid carcinoma
7. Goiter (simple, non-toxic)

• Adults: 1.6-1.8 mcg/kg/day
• Elderly/cardiac patients: Start low (25-50 mcg/day), titrate slowly
• Full replacement dose in healthy adults: typically 100-125 mcg/day
• Maximum effect seen after 6-8 weeks of therapy

• Decreased absorption: calcium, iron, antacids, bile acid sequestrants, sucralfate, proton pump inhibitors, food
• Increased metabolism (enzyme inducers): rifampin, phenobarbitone, carbamazepine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibitors
• Drugs increasing TBG: estrogens, tamoxifen, raloxifene, heroin, methadone, 5-FU, perphenazine
• Drugs decreasing TBG: androgens, glucocorticoids, danazol, L-asparaginase, nicotinic acid
• Drugs displacing T3/T4 from TBG (transient hyperthyroxinemia): salicylates, mefenamic acid, IV furosemide, heparin

• Palpitations, tachycardia, arrhythmias
• Angina, worsening heart failure
• Tremor, nervousness, insomnia
• Heat intolerance, sweating, weight loss
• Diarrhea, menstrual irregularity
• Osteoporosis (long-term excess)
• Accelerated bone age in children

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2. Liothyronine (L-T3, Cytomel)

• Oral bioavailability: ~95% (near-complete absorption)
• T1/2: ~1 day (shorter than T4 - requires 2-3x/day dosing)
• Faster onset and offset of action
• Not preferred for routine replacement (produces supraphysiologic peaks)

1. Myxedema coma (IV form) - some protocols use IV T3 or combination
2. Diagnostic testing (T3 suppression test)
3. Short-term use when rapid thyroid hormone action needed
4. Some cases of depression refractory to antidepressants (as augmentation)
5. Screening for thyroid cancer recurrence (brief withdrawal)

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3. Thyroid Extract (Desiccated thyroid)

• Older preparation from porcine/bovine thyroid gland
• Contains both T4 and T3 in fixed ratio (4:1)
• Variable potency, largely replaced by synthetic preparations
• Still used by some patients preferring "natural" treatment

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B. ANTITHYROID DRUGS

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4. Thioamides: Methimazole (MMI) & Propylthiouracil (PTU)

• Block oxidation of iodide to iodine (I⁻ → I⁰)
• Block organification - inhibit iodination of tyrosyl residues on thyroglobulin
• Block coupling - prevent formation of T3 and T4 from monoiodotyrosine (MIT) and diiodotyrosine (DIT)

• PTU at doses >400 mg/day inhibits Type 1 deiodinase
• Blocks peripheral conversion of T4 to T3
• Clinically important in thyroid storm

• Both drugs reduce thyroid antibody (TRAb) levels
• Methimazole more potent immunosuppressant
• May induce remission by suppressing autoimmune process in Graves' disease

• Both concentrated in thyroid gland
• PTU: 80% protein-bound, shorter half-life
• Methimazole: minimal protein binding, long intrathyroidal duration
• Both secreted in breast milk (MMI more so, but both considered acceptable)

1. Hyperthyroidism - Graves' disease (first line in many centers)
2. Toxic multinodular goiter
3. Toxic adenoma
4. Preparation before thyroid surgery (to render euthyroid)
5. Thyroid storm (PTU preferred - also blocks T4→T3 conversion)
6. Pregnancy-associated hyperthyroidism

• Common (3-5%): nausea, GI distress, urticaria, rash, arthralgia, fever
• Serious (0.3-0.5%): Agranulocytosis (most serious - patient should stop drug immediately if sore throat/fever and get WBC count)
• PTU: Fulminant hepatic necrosis (rare but fatal - black box warning from FDA); now avoided in children
• Methimazole: Cholestatic hepatitis (rare); aplasia cutis (scalp defect in neonate)
• Both: hypothyroidism (dose-dependent), vasculitis (PTU-associated ANCA-positive vasculitis)
• Both: hypoprothrombinemia (rare), lupus-like syndrome

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5. Iodine and Iodides (Lugol's Solution, Potassium Iodide)

• Large doses of iodide acutely inhibit thyroid hormone synthesis (Wolff-Chaikoff effect)
• Mechanism: high intrathyroidal iodide inhibits organification
• Normal thyroid "escapes" in 10-14 days by downregulating NIS (sodium-iodide symporter)
• In Graves' disease, this escape mechanism may be impaired → prolonged suppression

• Inhibits thyroid hormone release (most rapid effect - within hours)
• Reduces thyroid vascularity, size, and firmness (crucial for pre-surgical preparation)
• Blocks thyroidal radioiodine uptake (used for radiation protection)

• Lugol's solution: 5% iodine + 10% KI (contains ~8 mg iodine/drop)
• Saturated solution of potassium iodide (SSKI): 38-50 mg iodide/drop
• Potassium iodide tablets

1. Pre-operative preparation for thyroid surgery (given 10-14 days before surgery to reduce vascularity and bleeding risk)
2. Thyroid storm (large doses - adjunct to thioamides)
3. Radiation emergency prophylaxis (KI protects thyroid from radioactive iodine uptake after nuclear accidents)
4. Expectorant (SSKI - older use)
5. Sporotrichosis (SSKI - antifungal)

• Metallic taste, burning in mouth/throat
• Sore teeth and gums, excessive salivation
• Coryza, sneezing, frontal sinus pain
• Skin rash (iododerma - acneiform eruption)
• Parotitis, sialadenitis
• Goiter and hypothyroidism with prolonged use (paradoxical goiter)
• Hyperthyroidism in susceptible individuals with underlying autonomy (Jod-Basedow effect)
• Hypersensitivity reactions

• Iodides alone are NOT used for long-term therapy - gland escapes and may become more active
• Must be given AFTER thioamides in thyroid storm (PTU/MMI given first, then iodide 1 hour later, to prevent iodide from being used to synthesize more hormone)

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6. Radioactive Iodine (¹³¹I)

• ¹³¹I is concentrated in thyroid by NIS (same as stable iodide)
• Emits beta particles (main therapeutic effect - tissue range 0.5-2 mm)
• Also emits gamma rays (used for imaging with ¹²³I)
• Beta radiation destroys thyroid follicular cells → gradual reduction in thyroid mass
• No significant damage to surrounding structures

• Half-life: 8.1 days
• Effective half-life in thyroid: ~5 days
• Full effect: 6-12 months

1. Graves' disease (most definitive treatment - preferred in USA)
2. Toxic multinodular goiter
3. Toxic adenoma
4. Thyroid carcinoma (post-thyroidectomy ablation of remnant/metastases) - higher doses
5. Iodine uptake scan: ¹²³I (not ¹³¹I - less radiation)

• Pregnancy (absolute) - crosses placenta, destroys fetal thyroid
• Breastfeeding (excreted in milk)
• Age <5 years (relative) - pediatric thyroid more sensitive to radiation-induced cancer
• Unable to comply with radiation safety measures
• Large obstructive goiter (surgery preferred)
• Moderate-severe active Graves ophthalmopathy (may worsen eye disease)

• Hypothyroidism (nearly universal eventually - considered a predictable outcome, not complication per se)
• Radiation thyroiditis (transient worsening, 5-10 days after)
• Sialadenitis
• Worsening of Graves ophthalmopathy (can be prevented with concomitant glucocorticoids)
• Theoretical increased malignancy risk (data not conclusive for thyroid doses)
• Chromosomal abnormalities in gonads at very high doses

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7. Perchlorate, Thiocyanate (Older, rarely used)

• Mechanism: compete with iodide for NIS transport - block iodide uptake
• Perchlorate: associated with aplastic anemia (limited use)
• Thiocyanate: dietary goitrogens (cassava, cabbage, broccoli contain goitrogenic thiocyanates)

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PART II: ANTIDIABETIC DRUGS

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A. INSULIN

Types and Preparations:

• Given 30 minutes before meals
• Only insulin approved for IV use
• Used in DKA, HHS, perioperative management

• Neutral Protamine Hagedorn
• Protamine (a protein) precipitates insulin as suspension - must NOT be given IV
• Cloudy suspension - needs mixing before injection

1. Binds α-subunit of insulin receptor (tyrosine kinase receptor)
2. Receptor autophosphorylates on β-subunit at tyrosine residues
3. Activates IRS-1, IRS-2 (insulin receptor substrates)
4. Downstream: PI3K→Akt pathway (metabolic effects); Ras-MAPK pathway (mitogenic effects)

• Glucose transport: translocates GLUT-4 to cell surface in muscle and fat
• Glycogen synthesis (activates glycogen synthase, inhibits glycogen phosphorylase)
• Glycolysis (phosphofructokinase activation)
• Inhibits gluconeogenesis and glycogenolysis in liver
• Promotes triglyceride synthesis; inhibits lipolysis
• Promotes protein synthesis; inhibits protein catabolism
• Promotes K⁺ uptake into cells (used in hyperkalemia treatment)

1. Type 1 DM (absolute requirement)
2. Type 2 DM (when OHAs fail)
3. DKA, HHS (regular insulin IV)
4. Hyperkalemia (regular insulin IV + dextrose)
5. Gestational diabetes
6. Perioperative diabetes management
7. Critical illness hyperglycemia

• Hypoglycemia (most common, most serious)
• Lipodystrophy at injection sites (lipoatrophy/lipohypertrophy)
• Weight gain
• Insulin edema (fluid retention)
• Allergic reactions (rare with recombinant human insulin)
• Somogyi effect: rebound hyperglycemia after nocturnal hypoglycemia
• Dawn phenomenon: early morning hyperglycemia due to nocturnal GH surge
• Insulin resistance (rare high-dose)

• Basal insulin (glargine/detemir): Start 10 units/day at bedtime
• Basal-bolus: Long-acting + rapid-acting before meals
• Premixed insulin (e.g., 70/30 NPH/Regular): Twice daily

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B. ORAL ANTIDIABETIC AGENTS (OADs)

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1. Biguanides - Metformin (Drug of Choice for T2DM)

• Primary: Inhibits complex I of mitochondrial electron transport chain → ↓ ATP/AMP ratio → activates AMPK (AMP-activated protein kinase)
• Inhibits hepatic gluconeogenesis (main effect - reduces fasting glucose 25-30%)
• Increases peripheral glucose uptake and utilization
• Decreases intestinal glucose absorption
• Reduces VLDL and LDL cholesterol
• Improves insulin sensitivity
• Does NOT stimulate insulin secretion → no hypoglycemia alone

• Oral bioavailability: ~55%
• Not protein-bound; not metabolized
• Eliminated unchanged by kidneys (tubular secretion)
• T1/2: ~6 hours
• No active metabolites

1. Type 2 DM - first-line drug (WHO, ADA, RSSDI guidelines)
2. Prediabetes (prevention)
3. Polycystic ovary syndrome (PCOS) - improves insulin resistance, restores ovulation
4. Non-alcoholic fatty liver disease (NAFLD)
5. Metabolic syndrome

• No weight gain (often causes modest weight loss)
• No hypoglycemia as monotherapy
• Cardioprotective (UKPDS showed reduced CV events/mortality)
• Improves lipid profile
• Inexpensive

• GI effects (most common): nausea, diarrhea, metallic taste, abdominal discomfort (take with meals to reduce)
• Lactic acidosis (rare but potentially fatal, particularly in renal impairment, hepatic failure, hypoxic states)
• Vitamin B12 deficiency (long-term use - inhibits ileal absorption)
• Reduces intestinal absorption of glucose and B12

• eGFR <30 mL/min (hold if eGFR 30-45; contraindicated <30) - lactic acidosis risk
• Hepatic failure
• Cardiac/respiratory failure (tissue hypoxia)
• Alcoholism
• IV contrast use - hold 48 hours before and after
• Surgery - hold perioperatively
• Pregnancy (used in PCOS; some guidelines accept in gestational DM)

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2. Sulfonylureas (SUs)

1. Bind SUR1 subunit of ATP-sensitive K⁺ channel (K_ATP channel) on pancreatic β-cells
2. Close K_ATP channel → membrane depolarization
3. Opens voltage-gated Ca²⁺ channels → Ca²⁺ influx
4. Ca²⁺ triggers insulin exocytosis from secretory granules
5. Require functional β-cells (do NOT work in T1DM)

• All highly protein-bound
• Glibenclamide: long-acting (T1/2 10-16 h), active metabolites, highest hypoglycemia risk
• Glipizide: short-acting (T1/2 ~3-7 h), inactive metabolites, less hypoglycemia
• Gliclazide: intermediate, active metabolites, modified-release form available
• Glimepiride: long-acting once daily, lowest hypoglycemia risk, some insulin-sensitizing properties

1. Type 2 DM (second-line after metformin failure or intolerance)
2. MODY (maturity-onset diabetes of the young - especially MODY 2 and 3)
3. Persistent hyperinsulinemic hypoglycemia of infancy (diazoxide - related SUR mechanism)

• Hypoglycemia (most serious - especially chlorpropamide, glibenclamide)
• Weight gain (stimulate insulin → anabolic effect)
• GI effects (nausea, vomiting - less common)
• Chlorpropamide-specific:
  • SIADH (syndrome of inappropriate ADH) → hyponatremia
  • Disulfiram-like reaction with alcohol
  • Photosensitivity
  • Prolonged action - not used in elderly
• Cardiovascular risk: block K_ATP channels in cardiac muscle (may impair ischemic preconditioning)

• Type 1 DM
• Pregnancy (glyburide used in some protocols for gestational DM but has transplacental transfer)
• Severe renal failure (accumulation → hypoglycemia)
• Severe hepatic failure
• Sulfa allergy (relative contraindication for sulfonyl-based SUs)

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3. Meglitinides (Glinides) - "Short-Acting Insulin Secretagogues"

• Taken with each meal (3x/day)
• Excellent control of postprandial hyperglycemia
• Less hypoglycemia risk than SUs (short-acting)
• Useful in irregular meal schedules
• Repaglinide: metabolized by liver (CYP2C8, CYP3A4), safe in renal failure
• Nateglinide: D-phenylalanine derivative, even faster onset

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4. Thiazolidinediones (TZDs) / Glitazones

• Bind PPARγ (peroxisome proliferator-activated receptor gamma) in nucleus of adipocytes, muscle, liver
• PPARγ activation regulates gene transcription → adipocyte differentiation and fat redistribution
• Increases production of adiponectin → improves insulin sensitivity in muscle, liver, adipose
• Decreases free fatty acid release from visceral fat
• Reduces hepatic gluconeogenesis
• No direct effect on insulin secretion

• Pioglitazone: T1/2 ~3-7 h, active metabolites T1/2 16-24 h
• Metabolized by CYP2C8 (pioglitazone), CYP2C8/2C9 (rosiglitazone)
• Once-daily dosing
• Onset of glucose-lowering: 4-12 weeks (slow - need for patience)

1. Type 2 DM (monotherapy or combination)
2. NAFLD/NASH (pioglitazone - improves liver histology)
3. Lipodystrophy-associated insulin resistance

• Fluid retention/edema (Na⁺ and water retention) - contraindicated in heart failure
• Weight gain (fat redistribution + edema)
• Anemia (dilutional)
• Bone fractures (increased risk especially in women - distal limb fractures)
• Pioglitazone: possible risk of bladder cancer (use >1 year - FDA black box in some countries)
• Rosiglitazone: increased myocardial infarction risk (controversial - led to restriction/withdrawal in many countries)
• Hepatotoxicity (rare, class effect - monitor LFTs)
• Macular edema (rare)
• Ovulation induction in anovulatory women (use contraception)

• Heart failure (NYHA Class III-IV)
• Liver disease
• Active bladder cancer (pioglitazone)
• Pregnancy

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5. Alpha-Glucosidase Inhibitors

• Competitive inhibition of intestinal alpha-glucosidases (maltase, sucrase, glucoamylase) at brush border
• Slows digestion and absorption of complex carbohydrates → reduces postprandial glucose rise
• Does NOT affect fasting glucose significantly
• Does NOT cause hypoglycemia as monotherapy

• Acarbose: minimally absorbed (~2%), acts locally in gut lumen
• Miglitol: ~100% absorbed (but acts locally)
• Must be taken with first bite of each meal

• Flatulence, bloating, abdominal distension, diarrhea (fermentation of undigested carbohydrates in colon by bacteria)
• GI effects worsen with high-carb diet
• Hepatotoxicity (rare, mainly with high-dose acarbose - FDA warning)
• Anemia (iron malabsorption - long-term)

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6. DPP-4 Inhibitors (Gliptins)

• Inhibit DPP-4 (dipeptidyl peptidase-4) enzyme
• DPP-4 normally degrades incretin hormones GLP-1 and GIP (half-life ~2 min → increased to ~7 min)
• Preserved GLP-1/GIP → glucose-dependent insulin secretion ↑ (safe - no hypoglycemia in hypoglycemic state)
• GLP-1 also: ↓ glucagon, ↓ gastric emptying, ↑ satiety
• "Glucose-dependent" action: only active when blood glucose is high → minimal hypoglycemia risk

• Most: once daily oral dosing
• Sitagliptin: 80% renally excreted (dose adjust in CKD)
• Linagliptin: unique - primarily biliary/fecal excretion; no dose adjustment needed in renal/hepatic failure
• Vildagliptin: twice daily

• Generally well-tolerated ("weight-neutral")
• Nasopharyngitis, upper respiratory tract infections
• Pancreatitis (rare but noted - FDA warning; causal link debated)
• Joint pain (arthralgia - FDA safety communication)
• Saxagliptin/Alogliptin: increased risk of heart failure hospitalization (SAVOR-TIMI, EXAMINE trials)
• Bullous pemphigoid (rare but reported class effect)
• No weight gain, no hypoglycemia

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7. GLP-1 Receptor Agonists (Incretin Mimetics)

• Short-acting: Exenatide (twice daily), Lixisenatide (once daily)
• Long-acting: Liraglutide (once daily), Dulaglutide (once weekly), Semaglutide (once weekly oral/SC), Albiglutide (once weekly, discontinued in USA), Tirzepatide (dual GLP-1/GIP agonist - once weekly)

• Mimic endogenous GLP-1 (but resistant to DPP-4 degradation due to structural modifications)
• Bind GLP-1 receptors on β-cells → glucose-dependent insulin secretion ↑
• Suppress glucagon (α-cell effect)
• Delay gastric emptying → reduce postprandial glucose peaks
• Central satiety effects → reduced appetite and food intake
• Promote β-cell proliferation and inhibit apoptosis

• Subcutaneous injection (except oral semaglutide)
• Long half-lives allow once-weekly administration
• Not metabolized by liver/kidney - degraded by proteases

1. Type 2 DM - add-on after metformin failure
2. Obesity (liraglutide 3 mg - Saxenda; semaglutide 2.4 mg - Wegovy) - FDA-approved
3. Cardiovascular risk reduction (liraglutide: LEADER trial; semaglutide: SUSTAIN-6; dulaglutide: REWIND)
4. CKD with T2DM (favorable)

• Nausea, vomiting, diarrhea (most common, usually transient, worse with short-acting)
• Weight loss (beneficial side effect)
• Pancreatitis (rare - FDA warning; causal link debated)
• Medullary thyroid carcinoma concern (rodent data; avoid in MTC personal/family history, MEN 2)
• Injection site reactions
• Gallstones (rapid weight loss)
• Tachycardia (liraglutide)
• Retinopathy worsening (rapid HbA1c reduction - semaglutide; monitor)

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8. SGLT-2 Inhibitors (Gliflozins)

• Inhibit SGLT-2 (sodium-glucose cotransporter-2) in proximal convoluted tubule of kidney
• Normally SGLT-2 reabsorbs ~90% of filtered glucose
• Inhibition → glycosuria (excretion of 60-100 g glucose/day) → reduces blood glucose
• Osmotic diuresis → reduces blood pressure, body weight
• Reduces plasma volume → favorable hemodynamic effects in heart failure
• Increases ketone production (mild ketonemia - beneficial in heart failure/CKD)
• Reduces intraglomerular pressure → renoprotective

• EMPA-REG OUTCOME (empagliflozin): 38% reduction in CV death in T2DM with established CVD
• CANVAS (canagliflozin): similar CV benefits; increased amputations
• DAPA-HF (dapagliflozin): reduced CV death/heart failure hospitalization in HFrEF (with and without DM)
• CREDENCE (canagliflozin): reduced ESRD and renal outcomes
• DAPA-CKD (dapagliflozin): kidney and CV protection in CKD (with and without DM)

• Genital mycotic infections (candidiasis in women and men - most common)
• Urinary tract infections
• Polyuria, volume depletion, orthostatic hypotension
• Euglycemic DKA (rare but serious - occurs even with near-normal glucose; higher risk in T1DM, surgery, starvation)
• Lower limb amputations (canagliflozin - FDA black box)
• Bone fractures (canagliflozin)
• Fournier's gangrene (rare - necrotizing fasciitis of genitalia - FDA warning)
• Hyperkalemia (mild)
• Hypoglycemia only when combined with SU or insulin

1. T2DM (glucose lowering - 2nd or 3rd line)
2. Heart failure with reduced ejection fraction (HFrEF) - regardless of DM status
3. Chronic kidney disease (CKD) - dapagliflozin, canagliflozin
4. Obesity with T2DM

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9. Amylin Analogues - Pramlintide

• Synthetic amylin analogue (amylin = co-secreted with insulin from β-cells, deficient in DM)
• Suppresses glucagon, slows gastric emptying, induces satiety
• Reduces postprandial glucose

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10. Bile Acid Sequestrants - Colesevelam

• Lowers glucose by unclear mechanism (possible gut GLP-1 stimulation, altered bile acid signaling)
• Also lowers LDL cholesterol
• Given as tablet; very rarely used as antidiabetic

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11. Dopamine Agonist - Bromocriptine (Cycloset)

• Fast-release formulation; FDA-approved for T2DM
• Mechanism: resets circadian rhythms in hypothalamus → improves insulin resistance
• Modest HbA1c reduction (~0.5%)
• Advantage: may reduce CV events (Cycloset Safety Trial)
• Adverse effects: nausea, dizziness, orthostatic hypotension

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PART III: CORTICOSTEROIDS (Adrenocortical Drugs)

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A. Glucocorticoids

• Bind intracellular glucocorticoid receptor (GR) → translocation to nucleus
• GR-DNA complex binds GRE (glucocorticoid response elements) → transactivation of anti-inflammatory genes (lipocortin/annexin A1, IL-10, IL-1RA)
• Transrepression: inhibit NF-κB, AP-1 → suppress pro-inflammatory genes (COX-2, PLA2, cytokines, adhesion molecules)

1. Adrenal insufficiency (Addison's disease) - replacement: hydrocortisone + fludrocortisone
2. Adrenal crisis - hydrocortisone IV 100 mg stat, then 50-100 mg every 6-8 h
3. Congenital adrenal hyperplasia (CAH) - suppress ACTH with glucocorticoid
4. Cushing syndrome (diagnosis) - dexamethasone suppression test

1. Asthma, COPD exacerbations
2. Rheumatoid arthritis, SLE, vasculitides
3. Nephrotic syndrome
4. IBD (Crohn's, UC)
5. Organ transplant rejection prophylaxis
6. Cerebral edema (dexamethasone)
7. Anaphylaxis (second-line after epinephrine)
8. Bacterial meningitis (dexamethasone - adjunct)
9. Anti-emesis (dexamethasone with chemotherapy)
10. Fetal lung maturity (betamethasone or dexamethasone 24-34 weeks preterm labor)
11. Leukemia, lymphoma (part of chemotherapy protocols - CHOP, MOPP)
12. Duchenne muscular dystrophy (deflazacort or prednisone - slow progression)

• Cushing syndrome (iatrogenic): moon face, central obesity, buffalo hump, purple striae, skin thinning
• Osteoporosis and vertebral fractures (give prophylactic calcium + vitamin D + bisphosphonates)
• Hyperglycemia / steroid-induced diabetes
• Hypertension
• Peptic ulceration (especially with NSAIDs) - give PPI prophylaxis
• Infections (bacterial, fungal, viral - reactivation of TB, CMV, PCP)
• Growth retardation in children
• HPA axis suppression → adrenal insufficiency on sudden withdrawal
• Myopathy (proximal muscle weakness)
• Glaucoma and posterior subcapsular cataracts
• Avascular necrosis of femoral head
• Psychological effects (euphoria, depression, psychosis)
• Hypokalemia

• Never stop abruptly after >2-3 weeks of use
• Taper gradually to allow HPA axis recovery
• Stress dosing during illness or surgery required

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B. Mineralocorticoids

Fludrocortisone (Florinef)

• Primary mineralocorticoid used therapeutically
• Mechanism: Binds mineralocorticoid receptors in renal collecting duct → activates aldosterone-responsive genes → ↑ Na⁺ channels (ENaC), ↑ Na-K-ATPase → Na⁺ retention, K⁺ excretion, water retention
• Uses: Addison's disease (combined with hydrocortisone), congenital adrenal hyperplasia (21-hydroxylase deficiency), salt-wasting states, orthostatic hypotension
• ADRs: Hypertension, hypokalemia, edema, cardiac failure

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C. Adrenal Steroid Synthesis Inhibitors

Metyrapone

• Inhibits 11β-hydroxylase → blocks cortisol synthesis (accumulation of 11-deoxycortisol)
• Use: Cushing syndrome diagnosis (metyrapone test), treatment of Cushing syndrome, ectopic ACTH syndrome

Ketoconazole

• Antifungal azole that inhibits adrenal and gonadal steroidogenesis (CYP17, CYP11A1)
• Use: Cushing syndrome (off-label), prostate cancer (high-dose)
• ADRs: Hepatotoxicity, gynecomastia, adrenal insufficiency

Aminoglutethimide

• Inhibits CYP11A1 (cholesterol side-chain cleavage) - blocks all steroidogenesis
• Also blocks aromatase (CYP19)
• Use: Cushing syndrome, breast cancer (older agent)

Mifepristone (RU-486)

• Competitive GR antagonist (also progesterone receptor antagonist)
• Use: Cushing syndrome (unresectable/metastatic) - FDA-approved for hyperglycemia of Cushing
• Also: Medical abortion (antiprogestogenic effect), emergency contraception

Etomidate (IV)

• Primarily an anesthetic agent but potently inhibits 11β-hydroxylase
• Use: Severe/rapid control of Cushing syndrome (IV, continuous infusion in critical patients)

Mitotane (o,p'-DDD)

• Adrenolytic drug - selectively destroys adrenocortical cells
• Also inhibits steroidogenesis (multiple enzyme inhibition)
• Use: Adrenocortical carcinoma (primary treatment), Cushing syndrome
• ADRs: Significant GI toxicity, CNS effects, adrenal insufficiency (supplement glucocorticoids)

Osilodrostat, Levoketoconazole (newer agents)

• Newer selective 11β-hydroxylase inhibitors for Cushing syndrome

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PART IV: PITUITARY AND HYPOTHALAMIC HORMONES

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Anterior Pituitary Hormones & Analogues

Growth Hormone (Somatropin)

• Recombinant human GH (Genotropin, Humatrope, Norditropin)
• Mechanism: Binds GH receptor (class I cytokine receptor family) → JAK2/STAT5 signaling → IGF-1 production in liver
• Effects: Linear growth, protein anabolism, lipolysis, hyperglycemia (diabetogenic), Na⁺ retention
• Uses: GH deficiency in children (primary indication), Turner syndrome, Prader-Willi syndrome, HIV wasting, adult GH deficiency, short bowel syndrome
• ADRs: Edema, arthralgia, carpal tunnel syndrome, slipped capital femoral epiphysis, pseudotumor cerebri, insulin resistance, potential cancer risk (theoretical)
• Contraindications: Active malignancy, diabetic retinopathy, closed epiphyses (for growth use)

Somatostatin Analogues (Octreotide, Lanreotide, Pasireotide)

• Mimic somatostatin (inhibit GH, TSH, insulin, glucagon secretion)
• Octreotide: T1/2 2 h; LAR (long-acting repeatable) monthly injection
• Lanreotide: Monthly deep SC injection
• Pasireotide: Broader receptor binding (SSTR1-3, 5); used in Cushing disease
• Uses:
  • Acromegaly (when surgery fails/contraindicated) - primary pharmacological therapy
  • Carcinoid syndrome and tumors (GEP-NETs)
  • VIPoma, glucagonoma
  • TSH-secreting pituitary adenomas
  • Esophageal variceal bleeding (reduces portal pressure)
  • Acute pancreatitis (controversial)
  • Diarrhea in dumping syndrome
• ADRs: GI effects (nausea, diarrhea, steatorrhea), gallstones (reduced bile flow - most important ADR), bradycardia, hyperglycemia (pasireotide - high rate), injection site reactions

Pegvisomant

• GH receptor antagonist (blocks GH action, increases IGF-1 in acromegaly? No - reduces IGF-1)
• Blocks GH receptor dimerization → no JAK2 activation → reduces IGF-1
• Use: Acromegaly refractory to somatostatin analogues
• ADRs: Liver enzyme elevation, injection site reactions; GH levels rise (can't use GH as monitoring - use IGF-1)

Prolactin Inhibitors / Dopamine Agonists

• Mechanism: D2 receptor agonists → inhibit lactotroph secretion of prolactin
• Cabergoline preferred (once or twice weekly, better tolerated)
• Uses: Hyperprolactinemia, prolactinoma (first-line), acromegaly (adjunct), Parkinson's disease (bromocriptine), suppression of lactation (bromocriptine)
• ADRs: Nausea, vomiting, orthostatic hypotension, nasal stuffiness; cabergoline: cardiac valvulopathy at high doses (seen in Parkinson's patients), pulmonary fibrosis

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Gonadotropins and Related Drugs

FSH and LH Preparations

• Urofollitropin (urinary FSH), Follitropin-α, Follitropin-β, Corifollitropin alfa (long-acting FSH)
• hCG (human chorionic gonadotropin) - acts like LH
• Uses: Ovulation induction, controlled ovarian hyperstimulation (IVF), male hypogonadism (hCG), cryptorchidism

GnRH (Gonadorelin) and Analogues

• Pulsatile GnRH: treats hypogonadotropic hypogonadism
• GnRH Agonists (continuous administration): Leuprolide, Goserelin, Triptorelin, Buserelin, Nafarelin
  • Mechanism: Initial stimulation → downregulation of GnRH receptors → suppression of FSH/LH → "medical castration"
  • Flare effect: first 2 weeks of therapy - transient rise in LH/FSH/sex steroids (cover with antiandrogen in prostate cancer)
  • Uses: Prostate cancer, endometriosis, uterine fibroids, precocious puberty, breast cancer (premenopausal), IVF (downregulation protocols)
• GnRH Antagonists: Cetrorelix, Ganirelix, Degarelix
  • Mechanism: Direct competitive antagonism of GnRH receptor → immediate suppression of LH/FSH (no flare)
  • Uses: IVF protocols (prevents premature LH surge), prostate cancer (degarelix)

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PART V: SEX HORMONES AND RELATED DRUGS

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A. Estrogens

1. HRT (menopausal symptoms - hot flushes, vaginal atrophy; always combine with progestogen if uterus intact)
2. Osteoporosis prevention/treatment
3. Oral contraceptives (combined with progestogen)
4. Hypogonadism (ovarian failure)
5. Dysmenorrhea, endometriosis
6. Prostate cancer (DES - now rarely used)
7. Atrophic vaginitis (topical)
8. Delayed puberty

• Nausea, breast tenderness, weight gain
• VTE (deep vein thrombosis, pulmonary embolism) - especially oral estrogen
• Breast cancer risk (with long-term combined HRT)
• Endometrial hyperplasia/cancer (unopposed estrogen)
• Cholestasis, gallstones
• Hypertension
• Thrombophlebitis
• Migraine exacerbation
• DES-specific: vaginal clear cell adenocarcinoma in daughters (in utero exposure)

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B. Progestogens (Progestins)

1. Combined oral contraceptives (with estrogen)
2. Progestogen-only pill (mini-pill)
3. HRT (with estrogen - protects endometrium)
4. Dysfunctional uterine bleeding
5. Endometriosis
6. Endometrial cancer (MPA)
7. Threatened abortion
8. Contraception (Depo-Provera injection, LNG-IUS)
9. Luteal phase support in IVF

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C. Combined Oral Contraceptives (COCs)

1. Inhibit ovulation (suppress LH surge via hypothalamic-pituitary feedback)
2. Cervical mucus thickening (reduces sperm penetration)
3. Endometrial atrophy (inhibit implantation)
4. Altered tubal motility

• VTE history or DVT/PE
• Ischemic heart disease, stroke
• Valvular heart disease with complications
• Migraine with aura
• Breast cancer
• Active liver disease, hepatic adenoma
• Age >35 with smoking (≥15 cigarettes/day)
• Uncontrolled hypertension (>160/100)
• Prolonged immobilization

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D. Androgens

1. Hypogonadism (male)
2. Delayed puberty
3. Anemia (aplastic, myelofibrosis)
4. Wasting conditions (HIV, cancer)
5. Endometriosis and uterine fibroids (danazol)
6. Hereditary angioedema (danazol - increases C1 esterase inhibitor)
7. Female hypoactive sexual desire disorder (low-dose testosterone)

• Virilization in women (acne, hirsutism, clitoromegaly, voice deepening)
• Premature epiphyseal closure in children
• Salt and water retention (hypertension, edema)
• Polycythemia (erythrocytosis)
• Gynecomastia (aromatization to estrogen)
• Hepatotoxicity (17α-alkylated compounds - methyltestosterone, stanozolol)
• Lipid changes: ↑LDL, ↓HDL
• Testicular atrophy, azoospermia (exogenous testosterone)
• Aggression (high doses)

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E. Antiandrogens

• Inhibits 5α-reductase type II → blocks conversion of testosterone to DHT
• Uses: Benign prostatic hyperplasia (BPH), male pattern baldness (androgenetic alopecia)
• ADRs: Decreased libido, erectile dysfunction, ejaculatory problems, gynaecomastia, depression (reported)

• Uses: Prostate cancer (combined with GnRH agonist - prevents flare), hirsutism (women), PCOS (hirsutism/acne)
• Flutamide ADRs: Hepatotoxicity (potentially fatal), diarrhea, gynecomastia, hot flashes
• Bicalutamide: Better tolerated than flutamide

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PART VI: PARATHYROID AND CALCIUM-REGULATING DRUGS

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Parathyroid Hormone (PTH) and Analogues

• Teriparatide (PTH 1-34): Recombinant human PTH; subcutaneous daily injection
  • Mechanism: Intermittent PTH administration → anabolic bone effect (stimulates osteoblasts > osteoclasts)
  • Use: Severe osteoporosis (especially with fractures, high fracture risk)
  • ADRs: Nausea, dizziness, transient hypercalcemia, osteosarcoma risk in rats (FDA black box - avoid in Paget's disease, prior radiation to bone, children, high bone turnover)
  • Duration: Maximum 2 years (cumulative)
• Abaloparatide: PTHrP analogue; similar uses, possibly less hypercalcemia

Vitamin D and Analogues

• Cholecalciferol (D3), Ergocalciferol (D2): Prodrugs requiring hydroxylation
• Calcitriol (1,25-(OH)₂D₃): Active form; used in hypoparathyroidism, renal osteodystrophy, CKD
• Alfacalcidol (1α-OHD3): Requires only 25-hydroxylation (liver); used in renal failure
• Calcipotriol: Vitamin D analogue for psoriasis (topical)
• Paricalcitol, Doxercalciferol: Used in secondary hyperparathyroidism of CKD (selectively suppress PTH)

Bisphosphonates

• Esophageal irritation/ulceration (oral - must be taken with full glass of water, remain upright for 30-60 min)
• Osteonecrosis of the jaw (ONJ) - especially with IV bisphosphonates in cancer patients
• Atypical subtrochanteric femur fractures (long-term use >5 years)
• Acute phase reaction (flu-like illness with IV doses)
• Hypocalcemia (especially IV)
• Renal impairment (zoledronic acid - avoid if CrCl <35 mL/min)

Denosumab

• Fully human monoclonal antibody against RANK-L (receptor activator of NF-κB ligand)
• Blocks RANK-L → prevents RANK-L/RANK binding on osteoclast precursors → inhibits osteoclast formation and activity
• Uses: Postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, male osteoporosis, bone metastases (cancer), giant cell tumor of bone
• ADRs: Hypocalcemia (supplement calcium + vitamin D), ONJ (less than bisphosphonates), atypical femur fractures, infections, rebound bone loss on discontinuation (risky)
• Advantage: No renal dose adjustment needed

Calcitonin

• Naturally from parafollicular C-cells of thyroid
• Salmon calcitonin (more potent): SC/IM injection or nasal spray
• Mechanism: Binds calcitonin receptor on osteoclasts → ↓ bone resorption; ↑ renal calcium excretion
• Uses: Paget's disease of bone, hypercalcemia (acute), osteoporosis (nasal - second line), analgesic effect in vertebral fractures
• ADRs: Nausea, facial flushing, rhinitis (nasal form), tachyphylaxis (antibody formation)

Cinacalcet (Calcimimetic)

• Allosteric activator of calcium-sensing receptor (CaSR) on parathyroid gland
• Increases receptor sensitivity to Ca²⁺ → suppresses PTH secretion
• Uses: Secondary hyperparathyroidism in CKD on dialysis, primary hyperparathyroidism (inoperable), parathyroid carcinoma
• ADRs: Hypocalcemia, nausea, vomiting, QT prolongation (rare)

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PART VII: ANTIDIURETIC HORMONE (ADH/VASOPRESSIN) - Related Drugs

Vasopressin (ADH) and Analogues

• Vasopressin (Pitressin): Acts on V2 receptors in collecting duct (water reabsorption - aquaporin-2) and V1 receptors in vessels (vasoconstriction)
• Desmopressin (DDAVP):
  • Synthetic V2 selective agonist (minimal V1 effects - no vasoconstriction)
  • Uses: Central DI (diabetes insipidus), nocturnal enuresis, von Willebrand disease type 1, Hemophilia A (mild-moderate - releases VWF and FVIII from endothelium), platelet dysfunction in uremia
  • Routes: Intranasal, oral, IV/SC
  • ADRs: Hyponatremia (dilutional - restrict fluid intake), headache, nasal irritation

Vasopressin Antagonists (Vaptans)

• Tolvaptan (V2 selective), Conivaptan (V1+V2), Satavaptan, Lixivaptan
• Mechanism: Block V2 receptor → "aquaresis" (free water excretion without Na⁺ loss)
• Uses: SIADH (dilutional hyponatremia), hyponatremia in heart failure, cirrhosis
• ADRs: Rapid correction of Na⁺ (osmotic demyelination syndrome risk - must correct Na⁺ slowly ≤10-12 mEq/L/24h), thirst, dry mouth, hepatotoxicity (tolvaptan - black box; avoid in hepatic impairment)

Drugs for Nephrogenic DI

• Thiazide diuretics (paradoxically reduce urine output in NDI by causing volume depletion → proximal tubule Na⁺/water reabsorption increases)
• Indomethacin (prostaglandin inhibition → increases ADH action)
• Amiloride (lithium-induced NDI)

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PART VIII: DRUGS FOR PHEOCHROMOCYTOMA

• Phenoxybenzamine (irreversible α-blocker): Given for 10-14 days pre-operatively
• Phentolamine (reversible α-blocker): For hypertensive crises
• β-blockers: Only after adequate α-blockade (never before - prevents vasoconstriction → hypertensive crisis)
• Metyrosine (α-methyl-p-tyrosine): Inhibits tyrosine hydroxylase → reduces catecholamine synthesis; used in pheochromocytoma

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PART IX: OXYTOCIN AND RELATED DRUGS

Oxytocin

• Synthesized in hypothalamus, released from posterior pituitary
• Mechanism: Binds Gq-coupled oxytocin receptor → PLC → IP3 → ↑ intracellular Ca²⁺ → uterine contractions; stimulates milk ejection
• Uses: Induction of labor, augmentation of labor, postpartum hemorrhage prevention/treatment (IV infusion), incomplete abortion
• ADRs: Uterine hyperstimulation → fetal distress; water retention (V2 receptor effects - antidiuretic); hypotension (rapid IV bolus), neonatal hyperbilirubinemia

Tocolytics (Stop Preterm Labor)

• Ritodrine, Salbutamol, Terbutaline (β2 agonists): Relax uterine smooth muscle
• Nifedipine (calcium channel blocker): Often preferred - similar efficacy, less maternal side effects
• Atosiban (oxytocin receptor antagonist): Selective, less maternal side effects; expensive; approved in Europe
• Indomethacin (NSAID): Inhibit prostaglandin synthesis; risk of premature ductus arteriosus closure (avoid >32 weeks)
• Magnesium sulfate: Neuroprotection of fetus (preterm <32 weeks); also used in preeclampsia

Ergot Alkaloids (Oxytocics)

• Methylergonovine (Methergine), Ergometrine:
  • Mechanism: Partial agonist at α and serotonin receptors → sustained uterine contraction
  • Uses: Postpartum hemorrhage (after delivery of placenta), postpartum uterine atony
  • ADRs: Hypertension (vasoconstriction - contraindicated in hypertension/preeclampsia), nausea, vomiting
• Carboprost (15-methyl PGF2α), Misoprostol (PGE1):
  • Prostaglandin uterotonic agents
  • Uses: Refractory PPH, abortion, cervical ripening

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Summary Table: Key Drug Comparisons

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Endocrine Drugs - 3 Marks Questions & Answers

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THYROID & ANTITHYROID DRUGS

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• Inhibits thyroid peroxidase (TPO) → blocks oxidation of iodide, organification, and coupling reactions → ↓ T3 and T4 synthesis
• Inhibits peripheral conversion of T4 → T3 (Type 1 deiodinase inhibition) - unique to PTU
• Reduces thyroid autoantibody levels (immunosuppressive effect)

• Agranulocytosis (0.3-0.5%) - most serious; patient must report sore throat/fever immediately
• Fulminant hepatic necrosis (black box warning - rare but fatal)
• ANCA-positive vasculitis
• Rash, urticaria, arthralgia
• Hypothyroidism (dose-dependent)
• Crosses placenta → neonatal goiter/hypothyroidism

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• Graves' disease (most definitive treatment)
• Toxic multinodular goiter
• Toxic adenoma
• Post-thyroidectomy remnant ablation in thyroid carcinoma

• Hypothyroidism (nearly universal eventually)
• Radiation thyroiditis (transient, 5-10 days after)
• Sialadenitis
• Worsening of Graves ophthalmopathy
• Contraindicated in pregnancy (destroys fetal thyroid)

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• Large doses of iodide acutely inhibit thyroid hormone synthesis
• High intrathyroidal iodide inhibits the organification of iodide (blocks TPO-mediated reactions)
• This is an autoregulatory mechanism to prevent excess hormone synthesis
• Normal thyroid "escapes" in 10-14 days by downregulating NIS (sodium-iodide symporter), reducing iodide transport into gland
• In Graves' disease, escape may be impaired → prolonged suppression (exploited therapeutically)
• Basis for use of Lugol's iodine pre-operatively and in thyroid storm

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• Rapidly inhibit thyroid hormone release (fastest action - within hours)
• Reduce thyroid vascularity
• Block thyroidal uptake of radioiodine

• Thioamide (PTU/MMI) must be given FIRST (at least 1 hour before iodide)
• If iodide given first, it acts as substrate → more hormone synthesis
• Sequence: PTU/MMI → β-blocker → iodide (Lugol's) → steroids

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• Oral bioavailability: 70-80% (improved with liquid gel formulations)
• Absorption: duodenum and ileum; reduced by food, Ca²⁺, Fe²⁺, antacids, cholestyramine
• Plasma protein binding: >99% (TBG > TBPA > albumin); only 0.03% free
• T1/2: ~7 days (allows once-daily dosing)
• Converted peripherally to T3 (active) by deiodinases
• Eliminated by hepatic metabolism and fecal/urinary excretion
• Enzyme inducers (rifampin, phenytoin, carbamazepine) increase metabolism → may need higher dose

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ANTIDIABETIC DRUGS

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• Inhibits Complex I of mitochondrial respiratory chain → ↓ ATP production → ↑ AMP/ATP ratio → activates AMPK
• AMPK activation → inhibits hepatic gluconeogenesis (primary effect)
• Increases peripheral glucose uptake and utilization
• Decreases intestinal glucose absorption
• Improves insulin sensitivity

• No hypoglycemia as monotherapy
• No weight gain (often modest weight loss)
• Cardioprotective (UKPDS - reduces CV mortality)
• Improves lipid profile (↓ LDL, VLDL)
• Inexpensive; oral once/twice daily
• Drug of first choice in T2DM (ADA/WHO guidelines)

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• Bind SUR1 subunit of K_ATP channel on pancreatic β-cells
• Close K_ATP → membrane depolarization → open voltage-gated Ca²⁺ channels → Ca²⁺ influx → insulin exocytosis
• Require functional β-cells (ineffective in T1DM)

• Type 2 DM (second-line after metformin)
• MODY (maturity-onset diabetes of young)

• Hypoglycemia (most serious - especially glibenclamide, chlorpropamide)
• Weight gain
• Chlorpropamide: SIADH, disulfiram-like reaction with alcohol, photosensitivity
• Cardiovascular risk (block cardiac K_ATP - impair ischemic preconditioning)

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• Inhibit SGLT-2 in proximal convoluted tubule → block reabsorption of ~90% filtered glucose → glycosuria
• Osmotic diuresis → ↓ BP, ↓ weight
• Reduce intraglomerular pressure → renoprotective
• Hemodynamic benefits → useful in heart failure

• EMPA-REG: 38% ↓ in CV death
• DAPA-HF: Reduced HF hospitalizations (with and without DM)
• DAPA-CKD: Kidney protection in CKD

• Genital mycotic infections (most common)
• Urinary tract infections
• Euglycemic DKA (rare but serious)
• Fournier's gangrene (rare)
• Lower limb amputations (canagliflozin)

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• Bind PPARγ (nuclear receptor) in adipocytes, muscle, liver
• Regulate gene transcription → ↑ adiponectin → improves insulin sensitivity
• Redistribute fat from visceral to peripheral
• ↓ free fatty acid release; ↓ hepatic gluconeogenesis
• Do NOT stimulate insulin secretion

• Type 2 DM (mono or combination)
• NAFLD/NASH (pioglitazone - improves liver histology)
• Insulin resistance states

• Fluid retention and edema
• Weight gain
• Bone fractures (distal limb - especially women)
• Bladder cancer (pioglitazone - long-term use)
• Rosiglitazone: increased MI risk
• Hepatotoxicity (monitor LFTs)
• Contraindicated in heart failure

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• Competitively inhibit intestinal alpha-glucosidases (maltase, sucrase, glucoamylase) at brush border
• Delays digestion and absorption of complex carbohydrates
• Reduces postprandial glucose rise (no effect on fasting glucose)
• No hypoglycemia as monotherapy

• Flatulence, bloating, abdominal distension (most common - due to colonic fermentation of undigested carbs)
• Diarrhea
• Hepatotoxicity (rare, high-dose acarbose)

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CORTICOSTEROIDS

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• Lipid-soluble → cross cell membrane → bind intracellular glucocorticoid receptor (GR) in cytoplasm
• GR-drug complex translocates to nucleus
• Binds GRE (glucocorticoid response elements) on DNA

1. Transactivation: ↑ anti-inflammatory genes → lipocortin (annexin A1) synthesis → inhibits PLA2 → ↓ arachidonic acid → ↓ prostaglandins + leukotrienes; also ↑ IL-10, IL-1RA
2. Transrepression: Inhibit NF-κB and AP-1 transcription factors → ↓ COX-2, iNOS, cytokines (IL-1, IL-6, TNF-α), adhesion molecules

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• Hyperglycemia → steroid-induced diabetes
• Hyperlipidemia, central obesity
• Cushing syndrome (moon face, buffalo hump, purple striae)

• Osteoporosis, vertebral fractures (give Ca²⁺ + Vit D + bisphosphonate prophylaxis)
• Proximal myopathy
• Avascular necrosis of femoral head

• HPA axis suppression → adrenal insufficiency on sudden withdrawal
• Growth retardation in children

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1. Cerebral edema (tumor, post-operative) - drug of choice
2. Bacterial meningitis (adjunct - reduces inflammation and hearing loss)
3. Fetal lung maturity (24-34 weeks preterm labor)
4. Anti-emesis with chemotherapy
5. Diagnostic: dexamethasone suppression test (Cushing syndrome diagnosis)
6. Acute mountain sickness / cerebral edema
7. Leukemia/lymphoma chemotherapy protocols (CHOP, R-CHOP)
8. COVID-19 (RECOVERY trial - reduced mortality in severe disease requiring oxygen)
9. Spinal cord compression (malignant)
10. Croup in children

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PITUITARY / HYPOTHALAMIC DRUGS

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• Binds SSTR2 and SSTR5 preferentially
• Inhibits GH, TSH, insulin, glucagon secretion
• Reduces splanchnic blood flow (portal pressure ↓)

1. Acromegaly (when surgery fails) - most important use
2. Carcinoid syndrome (diarrhea, flushing)
3. VIPoma, glucagonoma (GEP-NETs)
4. Acute variceal bleeding (reduce portal pressure)
5. TSH-secreting pituitary adenoma
6. Dumping syndrome
7. Refractory diarrhea (chemo-induced, HIV)

• GI: nausea, diarrhea, steatorrhea
• Gallstones (most important long-term ADR - reduced bile flow and motility)
• Bradycardia
• Hyperglycemia (high doses)
• Injection site reactions

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• Initially (first 2 weeks): stimulate pituitary GnRH receptors → ↑ LH, FSH → ↑ sex steroids ("flare effect")
• With continuous administration: downregulate GnRH receptors → ↓ LH, FSH → ↓ testosterone/estrogen to castration levels ("chemical castration")

1. Prostate cancer (medical castration) - cover flare with antiandrogen (bicalutamide)
2. Endometriosis (↓ estrogen → regression of implants)
3. Uterine fibroids (preoperative shrinkage)
4. Precocious puberty (continuous suppression)
5. Breast cancer (premenopausal women)
6. IVF/ART (downregulation protocols)
7. Female infertility (pulsatile mode = stimulation)

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CALCIUM-REGULATING DRUGS

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• Bind hydroxyapatite at bone resorption sites
• Ingested by osteoclasts during bone resorption
• Inhibit farnesyl pyrophosphate (FPP) synthase in mevalonate pathway
• ↓ geranylgeranyl pyrophosphate → impairs osteoclast cytoskeletal function, promotes osteoclast apoptosis
• Net result: ↓ bone resorption

• Osteoporosis (postmenopausal, steroid-induced, male)
• Paget's disease of bone
• Malignant hypercalcemia (IV zoledronate - drug of choice)
• Bone metastases (reduce skeletal events - breast, prostate, myeloma)

• Esophageal erosion/ulceration (oral; must remain upright 30-60 min after taking)
• Osteonecrosis of jaw (ONJ) - especially IV bisphosphonates in cancer patients
• Atypical subtrochanteric femur fractures (long-term use >5 years)
• Acute phase reaction (fever, myalgia - IV doses)
• Hypocalcemia (supplement Ca²⁺ + Vit D)
• Renal impairment (zoledronate - avoid if eGFR <35)

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• Binds and neutralizes RANK-L (receptor activator of NF-κB ligand)
• Prevents RANK-L from binding RANK on osteoclast precursors
• Inhibits osteoclast formation, function, and survival → ↓ bone resorption

1. Postmenopausal osteoporosis (Prolia - 60 mg SC every 6 months)
2. Male osteoporosis
3. Glucocorticoid-induced osteoporosis
4. Bone metastases from solid tumors (Xgeva - 120 mg SC monthly)
5. Giant cell tumor of bone
6. Multiple myeloma

• Hypocalcemia (supplement Ca²⁺ + Vit D before and during therapy)
• Osteonecrosis of jaw (ONJ)
• Atypical femur fractures
• Infections (cellulitis)
• Severe rebound bone loss on discontinuation (consider transitioning to bisphosphonate)

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MISCELLANEOUS / SHORT NOTES

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• Type: Calcimimetic agent (type II calcimimetic)
• Mechanism: Allosteric activator of calcium-sensing receptor (CaSR) on parathyroid chief cells → increases receptor sensitivity to extracellular Ca²⁺ → suppresses PTH secretion even at low/normal Ca²⁺ levels
• Uses:
  • Secondary hyperparathyroidism in CKD patients on dialysis (drug of choice)
  • Primary hyperparathyroidism (inoperable/surgical risk)
  • Parathyroid carcinoma
• Adverse Effects: Hypocalcemia (main concern), nausea, vomiting, myalgia, QT prolongation (rare)
• Monitoring: Serum Ca²⁺, PTH levels

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• Binds V2 receptors on renal collecting duct → activates adenylyl cyclase → ↑ cAMP → inserts aquaporin-2 channels → water reabsorption
• Also binds V2 on endothelium → releases vWF and Factor VIII from Weibel-Palade bodies

1. Central diabetes insipidus (drug of choice)
2. Primary nocturnal enuresis in children
3. von Willebrand disease type 1 (mild bleeding)
4. Hemophilia A (mild-moderate) - raises FVIII levels
5. Platelet dysfunction in uremia (before surgery)

• Hyponatremia (dilutional - must restrict fluid intake)
• Headache, nausea
• Nasal irritation (intranasal form)
• Facial flushing

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1. Drug binds SUR1 subunit (sulfonylur receptor) of K_ATP channel
   • SUs bind permanently (long duration)
   • Glinides bind transiently (short duration)
2. K_ATP channel closes → K⁺ cannot leave cell → membrane depolarization
3. Depolarization opens voltage-gated L-type Ca²⁺ channels
4. Ca²⁺ influx into β-cell
5. Ca²⁺-calmodulin complex → activates kinases → phosphorylation of secretory proteins
6. Insulin-containing granules fuse with plasma membrane → exocytosis → insulin release

• Sulfonylureas: long-acting, bind with higher affinity → sustained insulin release → risk of prolonged hypoglycemia
• Meglitinides: short-acting, bind different site → rapid, brief insulin release → better postprandial control, less hypoglycemia

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1. Hypoglycemia - most common and dangerous (tachycardia, sweating, tremor, confusion, coma)
2. Weight gain (anabolic effect of insulin)
3. Lipodystrophy:
   • Lipoatrophy (fat loss at injection site - less common with recombinant insulin)
   • Lipohypertrophy (fat accumulation from repeated injections at same site)
4. Insulin edema (sodium and water retention - start of therapy)
5. Local allergy: Redness, swelling at injection site
6. Systemic allergy: Rare with recombinant human insulin
7. Somogyi phenomenon: Nocturnal hypoglycemia → rebound morning hyperglycemia (counter-regulatory hormones); treat by reducing evening insulin dose
8. Dawn phenomenon: Early morning hyperglycemia due to nocturnal GH/cortisol surge (no hypoglycemia preceding it); treat by increasing evening insulin
9. Insulin resistance: Rare, requires very high doses (>200 units/day)
10. Insulin neuritis: Paradoxical worsening of peripheral neuropathy with rapid glucose control

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