1. STATINS - HMG-CoA Reductase Inhibitors (KDT Pharmacology - 2nd MBBS)

Definition / What Are Statins?

• Lovastatin (first statin; prodrug - inactive lactone)
• Simvastatin (prodrug - inactive lactone)
• Pravastatin
• Fluvastatin
• Atorvastatin (most potent, longest half-life ~14h)
• Rosuvastatin (most potent, t½ ~19h)
• Pitavastatin

2. HMG-CoA REDUCTASE - Role in Cholesterol Synthesis

HMG-CoA → Mevalonate (using NADPH as cofactor)

• Cholesterol
• Dolichols
• Ubiquinone (CoQ10)
• Isoprenoids (farnesyl, geranylgeranyl pyrophosphate)

MECHANISM OF ACTION (MOA) of Statins

1. Statins bind HMG-CoA reductase competitively → block conversion of HMG-CoA to mevalonate → ↓ hepatic cholesterol synthesis
2. ↓ intrahepatic cholesterol → liver senses cholesterol deficiency → ↑ upregulation (transcription) of LDL receptor genes (SREBP-2 pathway)
3. ↑ LDL receptors on hepatocyte surface → ↑ clearance of LDL-C, IDL, and VLDL remnants from blood
4. Result: Significant fall in plasma LDL-C (20-60% reduction depending on dose and agent)

• ↓ VLDL production → ↓ TG levels
• Modest ↑ HDL-C (5-10%)
• ↓ IDL by enhanced removal

• Anti-inflammatory (↓ CRP)
• Stabilize atherosclerotic plaques (↓ macrophage content, ↓ lipid core)
• Antithrombotic (↓ platelet aggregation)
• Improve endothelial function (↑ NO production)
• These effects partly explain the cardiovascular benefit beyond LDL reduction

PHARMACOKINETICS (ADME)

THERAPEUTIC EFFECTS (Uses)

• Drug of choice for elevated LDL-C
• ↓ LDL-C by 25-60%

• Primary prevention: Patients with high 10-year ASCVD risk, age 40-75, LDL ≥70 mg/dL
• Secondary prevention: All patients with established CAD, stroke, peripheral artery disease
• Reduce: myocardial infarction, stroke, cardiovascular death, need for revascularization

• Patients aged 40-75 with known clinical ASCVD
• Diabetes mellitus (type 1 or 2), age 40-75
• LDL-C ≥190 mg/dL (severe hypercholesterolemia)
• Primary prevention with high ASCVD risk score

• Atorvastatin/Rosuvastatin reduce elevated TG along with LDL

• Statins are mainstay; may combine with ezetimibe or PCSK9 inhibitors

• High-intensity statin started immediately regardless of baseline LDL

• Chronic kidney disease with proteinuria
• Non-alcoholic fatty liver disease (investigational)
• Post-transplant dyslipidemia

ADVERSE EFFECTS

1. Myopathy (Most Important)

• Myalgia (muscle pain/weakness) - most common (5-10%)
• Myositis (muscle inflammation with ↑ CK)
• Rhabdomyolysis (rare but severe) - massive muscle breakdown → myoglobinuria → acute renal failure → can be fatal
• Risk increased by:
  • High doses
  • CYP3A4 inhibitors (azole antifungals, macrolides, grapefruit juice, ciclosporin, HIV protease inhibitors)
  • Combination with fibrates (especially gemfibrozil) - most dangerous combination
  • Combination with niacin
  • Hypothyroidism, renal failure, elderly

Monitor: CK levels if symptomatic; stop statin if CK >10x upper limit of normal

2. Hepatotoxicity

• Transient, mild ↑ in serum transaminases (AST/ALT) - dose-related
• Occurs in ~1-3% patients
• Clinically significant hepatitis is rare
• Monitor LFTs at baseline and if symptoms develop
• Contraindicated in active liver disease

3. New-onset Type 2 Diabetes Mellitus

• Small but significant increased risk (~10-20%)
• Mechanism: statins ↓ glucose transporter expression in pancreatic β-cells, reduce insulin secretion
• Risk > benefit calculation still favors statin use in most patients

4. Immune-mediated Necrotizing Myopathy (IMNM)

• Rare autoimmune condition
• Anti-HMGCR antibodies develop even after stopping the statin
• Requires immunosuppressive therapy (steroids, IVIG)

5. CNS Effects

• Rare reports of cognitive impairment, memory loss (FDA warning)
• Generally reversible on discontinuation
• More common with lipophilic statins (simvastatin, atorvastatin)

6. Gastrointestinal

• Nausea, constipation, dyspepsia, diarrhea (mild, usually transient)

7. Headache, insomnia

PRECAUTIONS AND CONTRAINDICATIONS

• Pregnancy (Category X) - cholesterol needed for fetal development; statins are teratogenic
• Lactation - excreted in breast milk
• Active liver disease or unexplained persistent elevations in hepatic transaminases

• Patients on CYP3A4 inhibitors (dose-limit simvastatin to 20 mg/day with amlodipine; avoid >10 mg simvastatin with strong inhibitors)
• Elderly patients (higher risk of myopathy)
• Renal impairment (adjust dose)
• Hypothyroidism (correct before starting statin - risk of myopathy)
• Heavy alcohol use (hepatotoxicity)

• Gemfibrozil + statin → ↑ statin plasma levels (inhibits glucuronidation and OATP1B1) → ↑ rhabdomyolysis risk
• CYP3A4 inhibitors (ketoconazole, erythromycin, clarithromycin, ritonavir, diltiazem) → ↑ levels of atorvastatin/simvastatin/lovastatin
• Warfarin → statins may potentiate anticoagulant effect (monitor INR)
• Cyclosporin → ↑ statin levels → myopathy risk
• Bile acid sequestrants → reduce statin absorption (take statin 1-2h before or 4h after)
• Grapefruit juice → CYP3A4 inhibition → ↑ lovastatin/simvastatin levels

• Baseline LFTs, CK, fasting lipid panel
• Repeat lipid panel at 4-12 weeks after initiation or dose change
• CK only if myopathy symptoms develop

3. PLASMA EXPANDERS

Definition

• Also called plasma volume expanders or plasma substitutes or colloid solutions
• They are used when plasma volume is reduced but red cell replacement is not immediately needed

Classification of Plasma Expanders

A. Natural/Semi-natural

1. Human Albumin (4-5% or 20-25% solutions)
2. Fresh Frozen Plasma (FFP)
3. Whole blood / Plasma

B. Synthetic Colloids (True Plasma Expanders)

1. Dextrans - polysaccharide derivatives
   • Dextran 40 (MW 40,000) - low molecular weight
   • Dextran 70 (MW 70,000) - high molecular weight
2. Hydroxyethyl Starch (HES / Hetastarch)
   • Hetastarch (MW ~450,000)
   • Pentastarch (MW ~200,000)
   • Tetrastarch (MW ~130,000)
3. Gelatins
   • Haemaccel (polygeline)
   • Gelofusine (succinylated gelatin)
4. Polyvinylpyrrolidone (PVP) - largely obsolete

Individual Plasma Expanders

1. Dextran

• Source: Polysaccharide produced by Leuconostoc mesenteroides bacteria acting on sucrose
• Types:
  • Dextran 70 (MW 70,000): Volume expander; 1g draws ~20-25 mL water from interstitium; effect lasts 12-24h
  • Dextran 40 (MW 40,000): Improves microcirculation; antithrombotic; used in vascular surgery; excreted faster in urine
• Uses:
  • Hypovolemic shock (burns, hemorrhage, surgery)
  • Prevention of postoperative DVT (Dextran 70)
  • Improvement of microcirculation in peripheral vascular disease (Dextran 40)
  • Priming fluid in extracorporeal circulation (Dextran 40)
• Adverse effects:
  • Anaphylactoid reactions (1-2%) - most dangerous
  • Coagulation abnormalities (impairs platelet function, ↓ Factor VIII activity)
  • Rouleaux formation (interferes with cross-matching - blood sample must be taken before infusion)
  • Osmotic diuresis (Dextran 40)
  • Renal failure (dextran 40 at high doses)
  • Volume overload, pulmonary edema
• Contraindication: Hypersensitivity, severe renal failure, bleeding disorders

2. Hydroxyethyl Starch (HES / Hetastarch)

• Source: Amylopectin (corn starch) modified with hydroxyethyl groups to slow degradation
• Types: Hetastarch (450 kDa), Pentastarch (200 kDa), Tetrastarch/Voluven (130 kDa)
• Action: Expands plasma volume effectively; newer tetrastarches have better safety profiles
• Uses:
  • Hypovolemic shock (surgical, trauma, burns)
  • Perioperative volume replacement
• Adverse effects:
  • Pruritus (severe, prolonged, difficult to treat) - HES deposits in skin
  • Coagulopathy (↓ Factor VIII, von Willebrand factor)
  • AKI (Acute Kidney Injury) - HES now contraindicated in critically ill/septic patients (EMA withdrawal)
  • Anaphylaxis (less common than dextran)

3. Gelatin Solutions

• Types: Haemaccel (polygeline, 35,000 Da), Gelofusine (succinylated gelatin, 30,000 Da)
• Source: Degraded bovine collagen
• Duration of action: Short (~2-3h, small MW → faster renal excretion)
• Uses:
  • Hypovolemia, surgery, trauma
  • Less effect on coagulation than dextran/HES
• Adverse effects:
  • Anaphylactic reactions (slightly higher than HES)
  • Haemaccel contains Ca²⁺ - should not be infused with blood (may cause clotting)
  • Volume overload

4. Human Albumin

• Source: Human plasma (pooled, pasteurized)
• Concentrations: 4-5% (iso-oncotic) and 20-25% (hyperoncotic)
• Half-life: ~20 days
• Uses:
  • Hypovolemic shock (when synthetic colloids not available)
  • Hypoalbuminemia with edema
  • Large volume paracentesis (>5 L) - albumin preferred over other expanders (more effective than dextran-70 or saline in preventing paracentesis-induced circulatory dysfunction)
  • Hepatorenal syndrome (with terlipressin)
  • Spontaneous bacterial peritonitis
• Adverse effects:
  • Volume overload
  • Risk of viral transmission (minimized by pasteurization)
  • Expensive

USES of Plasma Expanders (Summary)

COMPARISON TABLE

Sources:

• Goodman & Gilman's Pharmacological Basis of Therapeutics, 13e
• Pye's Surgical Handicraft (Plasma substitutes section)
• Miller's Anesthesia 10e
• Goldman-Cecil Medicine (Statin therapy)

Note for 2nd MBBS exam: For KDT (KD Tripathi Essentials of Medical Pharmacology), the core exam points are: MOA (competitive HMG-CoA reductase inhibition → ↑LDL receptors → ↓LDL-C), adverse effects (myopathy/rhabdomyolysis is the most tested), contraindications (pregnancy, liver disease), and drug interactions (gemfibrozil + statin = dangerous). For plasma expanders: Dextran types, uses, and the key adverse effect of anaphylaxis + coagulation interference are most exam-relevant.