Introduction to CVS – Shock, Blood & Urinary System Drugs
This unit continues cardiovascular pharmacology with drugs used in life-threatening shock and blood disorders. It covers Hematinics (iron, folic acid, B12 for anemia), the balance between Coagulation and Anticoagulation (Heparin, Warfarin), Fibrinolytics that dissolve clots in heart attacks, and Antiplatelet drugs. It also covers Plasma Volume Expanders for hemorrhagic shock, and the Diuretics/Antidiuretics that regulate urine output and fluid balance.
Syllabus & Topics
- 1Shock – Introduction: Acute circulatory failure → inadequate tissue perfusion → multi-organ damage → death. Types: Hypovolemic (hemorrhage, dehydration), Cardiogenic (MI, severe CHF), Septic/Distributive (endotoxins → massive vasodilation), Anaphylactic (IgE-mediated histamine release).
- 2Drugs for Shock: Vasopressors: Norepinephrine (drug of choice for septic shock – α1 vasoconstriction), Dopamine (dose-dependent: low = renal vasodilation; moderate = ↑cardiac contractility; high = vasoconstriction), Dobutamine (selective β1 → ↑contractility in cardiogenic shock). IV fluids (Normal saline, Ringer’s lactate). Corticosteroids (Hydrocortisone – for refractory septic shock).
- 3Hematinics – Iron: Ferrous sulfate (oral, most commonly used), Ferrous gluconate, Iron dextran/Iron sucrose (IV, for severe deficiency or malabsorption). Iron is essential for hemoglobin synthesis. ADRs: GI irritation, black stools, constipation. Acute iron poisoning (children) – treat with Deferoxamine (iron chelator).
- 4Hematinics – Folic Acid & Vitamin B12: Folic acid – essential for DNA synthesis (thymidylate synthesis). Deficiency → megaloblastic anemia. Cyanocobalamin (Vitamin B12) – essential for methionine synthase and methylmalonyl-CoA mutase. Deficiency → megaloblastic anemia + neurological damage (subacute combined degeneration of spinal cord). Must differentiate: B12 deficiency has neurological symptoms; folate deficiency does not.
- 5Coagulants – Vitamin K: Menadione (K3, synthetic), Phytomenadione (K1, natural). Essential cofactor for hepatic synthesis of clotting factors II, VII, IX, X (vitamin K-dependent). Used to reverse warfarin overdose and in hemorrhagic disease of newborn (neonates are vitamin K deficient).
- 6Anticoagulants – Heparin: Unfractionated Heparin (UFH) – activates Antithrombin III → inactivates thrombin (IIa) and Factor Xa. IV/SC, immediate onset. Monitored by aPTT. ADRs: bleeding, HIT (Heparin-Induced Thrombocytopenia). Antidote: Protamine sulfate. Low Molecular Weight Heparins (Enoxaparin) – selectively inhibit Factor Xa, SC, predictable dose, no monitoring needed.
- 7Anticoagulants – Oral: Warfarin – inhibits Vitamin K epoxide reductase (VKORC1) → ↓functional clotting factors II, VII, IX, X. Delayed onset (3-5 days, existing factors must be cleared). Monitored by PT/INR. Narrow therapeutic index. Multiple drug/food interactions (Vitamin K-rich foods antagonize). Teratogenic. Antidote: Fresh frozen plasma + Vitamin K.
- 8Fibrinolytic/Thrombolytic Drugs: Streptokinase (from Streptococcus – activates plasminogen indirectly, antigenic), Urokinase (from human kidney cells – direct plasminogen activator), Alteplase (t-PA – recombinant tissue plasminogen activator, fibrin-selective, drug of choice for acute MI and stroke). Dissolve already-formed thrombi. Window: most effective within 3-6 hours of MI/stroke. Risk: hemorrhage.
- 9Antiplatelet Drugs: Aspirin (low-dose 75-150 mg – irreversibly inhibits COX-1 → ↓TXA₂ → ↓platelet aggregation for the platelet’s 7-10 day lifespan). Clopidogrel (irreversibly blocks P2Y12 ADP receptor – used post-MI, post-stent). Dipyridamole (↑cAMP by PDE inhibition → ↓platelet aggregation). GP IIb/IIIa inhibitors (Abciximab – IV, most potent antiplatelet in acute coronary syndromes).
- 10Plasma Volume Expanders: Dextran 40 (low molecular weight – improves microcirculation), Dextran 70 (high MW – expands blood volume). Polygeline (Haemaccel), Hydroxyethyl starch (Hetastarch). Used in hypovolemic shock when blood is unavailable. ADRs: allergic reactions, interference with cross-matching.
- 11Diuretics – Carbonic Anhydrase Inhibitors: Acetazolamide – inhibits CA in proximal tubule → ↓HCO₃⁻ reabsorption → mild diuresis + metabolic acidosis. Used primarily for glaucoma (↓aqueous humor), altitude sickness, and as adjunct in epilepsy.
- 12Diuretics – Thiazides & Loop: Hydrochlorothiazide (DCT, Na⁺/Cl⁻ co-transporter, first-line antihypertensive). Furosemide (thick ascending LoH, Na⁺/K⁺/2Cl⁻ co-transporter – most potent diuretic, pulmonary edema, CHF). ADR: hypokalemia, hyponatremia, hyperuricemia (gout), hyperglycemia.
- 13Diuretics – Potassium-Sparing & Osmotic: Spironolactone (aldosterone antagonist), Amiloride, Triamterene (block ENaC). Weak alone but prevent K⁺ loss. Spironolactone also used in CHF (↓mortality). Mannitol (osmotic – IV for cerebral edema, acute glaucoma, forced diuresis in poisoning).
- 14Antidiuretics: Vasopressin (ADH – V2 receptors on collecting duct → aquaporin-2 insertion → water reabsorption). Desmopressin (synthetic analogue – longer acting, selective V2 → used for Diabetes Insipidus, nocturnal enuresis, Hemophilia A). ADRs: water intoxication (hyponatremia).
Learning Objectives
Frequently Asked Questions (FAQs)
Q1. Why Is Norepinephrine the Drug of Choice in Septic Shock?
Norepinephrine is the preferred vasopressor in Septic shock because this condition involves profound vasodilation and reduced systemic vascular resistance caused by inflammatory mediators such as nitric oxide and cytokines. Norepinephrine strongly stimulates α1-adrenergic receptors, producing vasoconstriction and restoring blood pressure, while its mild β1 activity helps maintain cardiac output. Compared with Dopamine, it causes fewer tachyarrhythmias.
Q2. What Is the Difference Between Heparin and Warfarin?
Heparin is administered intravenously or subcutaneously, has an immediate onset of action, and works by activating antithrombin III to inhibit thrombin and factor Xa. Its effect is monitored using activated partial thromboplastin time (aPTT), and the antidote is Protamine sulfate.
Warfarin is taken orally and has a delayed onset of 3–5 days because it inhibits synthesis of vitamin K–dependent clotting factors. Its effect is monitored by PT/INR, and reversal can be achieved with Vitamin K and fresh frozen plasma. Heparin is typically used for acute anticoagulation, whereas warfarin is used for long-term therapy.
Q3. How Does Low-Dose Aspirin Prevent Heart Attacks?
Low doses of Aspirin irreversibly inhibit cyclooxygenase-1 (COX-1) in platelets, preventing formation of thromboxane A₂, a molecule that promotes platelet aggregation and vasoconstriction. Because platelets lack nuclei and cannot synthesize new COX enzymes, this inhibition persists for the lifespan of the platelet (about 7–10 days), reducing formation of arterial thrombi that can cause myocardial infarction.
Q4. Why Does Furosemide Cause Hypokalemia?
Furosemide inhibits the Na⁺/K⁺/2Cl⁻ transporter in the thick ascending limb of the Loop of Henle, leading to increased sodium delivery to the distal nephron. This stimulates sodium reabsorption in exchange for potassium secretion in the collecting duct, causing increased urinary potassium loss and hypokalemia. For this reason, it is sometimes combined with potassium-sparing diuretics such as Spironolactone or Amiloride.
Q5. What Is Desmopressin Used For?
Desmopressin (DDAVP) is a synthetic analogue of vasopressin that selectively activates V2 receptors in the kidneys, promoting water reabsorption without significant vasoconstriction. It is used to treat Central diabetes insipidus, manage nocturnal enuresis in children, and treat bleeding disorders such as Hemophilia A and Von Willebrand disease by stimulating release of stored factor VIII and von Willebrand factor.