32.2 Cardiovascular Pharmacology I: Cardiac Arrest and ACLS Drugs, Bradycardia and Complete Heart Block, Antiarrhythmics, Anticoagulation in Atrial Fibrillation, Antianginals, ACS Therapy and Fibrinolysis, Pericarditis and Endocarditis Regimens

Why this area matters

The TOS cardiovascular area asks you to:

• explain how drugs act in cardiac arrest, heart block, arrhythmias, ischemia, ACS and pericarditis;
• correlate drugs with pathophysiology;
• choose a regimen;
• predict adverse effects and interactions;
• plan monitoring.

Ischemic heart disease is the leading cause of death in the Philippines, so ACS pharmacology and secondary prevention are high-yield.

Drugs in cardiac arrest and resuscitation

• Shockable rhythms (VF, pulseless VT):
  • high-quality CPR and defibrillation come first;
  • epinephrine 1 mg IV or IO every 3 to 5 minutes after the second shock;
  • amiodarone 300 mg IV bolus, then 150 mg, for refractory VF or VT. Lidocaine 1 to 1.5 mg/kg is an alternative.
• Non-shockable rhythms (asystole, PEA): CPR and epinephrine as soon as possible. Search for and treat the reversible causes, the Hs and Ts:
  • hypovolemia, hypoxia, hydrogen ion (acidosis), hypo- or hyperkalemia, hypothermia;
  • tension pneumothorax, tamponade, toxins, thrombosis (pulmonary or coronary).
• Special situations:
  • calcium for hyperkalemia or calcium-channel-blocker overdose;
  • sodium bicarbonate for tricyclic overdose or severe hyperkalemia;
  • magnesium for torsades de pointes;
  • fibrinolytics for suspected massive PE.
• Bradycardia with poor perfusion:
  • atropine 1 mg IV, repeated every 3 to 5 minutes up to 3 mg;
  • if this fails, transcutaneous pacing, or an infusion of dopamine (5 to 20 mcg/kg/min) or epinephrine (2 to 10 mcg/min).
  • Complete (third-degree) heart block and Mobitz II often respond poorly to atropine, because the block is below the AV node, and need pacing.
  • Review drugs that cause block: beta-blockers, verapamil and diltiazem, digoxin, amiodarone.

Vaughan Williams Antiarrhythmic Classification

Antiarrhythmics alter cardiac electrophysiology by targeting transmembrane ionic currents.

Amiodarone Toxicity Profile

Amiodarone possesses properties of all four Vaughan Williams classes (Classes I, II, III, and IV). It is lipophilic, distributes extensively into adipose tissue ($V_d > 5,000\text{ L}$), and has an exceptionally long elimination half-life ($40\text{--}60\text{ days}$). Because each molecule is 37% iodine by weight, chronic amiodarone administration causes significant multi-organ toxicity:

1. Pulmonary Toxicity ($5\text{--}15\%$, most lethal): Chronic interstitial pneumonitis, organizing pneumonia, or acute respiratory distress syndrome with fatal pulmonary fibrosis (presents with insidious non-productive cough, progressive dyspnea, and bilateral diffuse interstitial infiltrates; pulmonary function testing reveals reduced DLCO).
2. Thyroid Dysfunction: Can cause Hypothyroidism ($15\text{--}20\%$, via the Wolff-Chaikoff effect blocking organification) or Hyperthyroidism (Type 1 via Jod-Basedow iodine-induced substrate effect in toxic nodular goiter; Type 2 via destructive thyroiditis). Baseline and serial TSH monitoring is mandatory.
3. Hepatotoxicity: Asymptomatic transaminase elevations in up to 25%; rare fulminant cirrhosis or hepatitis.
4. Ocular Microdeposits: Corneal epithelial microdeposits occur in virtually 100% of patients on therapy $> 6$ months (visual halos around lights); optic neuropathy can rarely lead to permanent blindness.
5. Dermatological: Severe photosensitivity and a striking blue-gray (slate-gray) skin pigmentation on sun-exposed areas due to cutaneous iodine-lipid deposition.

Unclassified Antiarrhythmics: Adenosine & Magnesium

• Adenosine:
  • Mechanism: Activates myocardial $A_1$ adenosine receptors, stimulating $G_i$, suppressing adenylyl cyclase, opening inward-rectifying $K^+$ channels ($I_{K,Ado}$), and inhibiting L-type $Ca^{2+}$ channels. This hyperpolarizes the AV node, producing transient complete AV conduction block.
  • Clinical Indication: First-line pharmacological therapy for the acute termination of stable Paroxysmal Supraventricular Tachycardia (PSVT / AVNRT).
  • Kinetics & Administration: Ultra-short half-life ($< 10\text{ seconds}$), rapidly taken up by erythrocytes and endothelial cells and degraded by adenosine deaminase. Must be administered as a rapid intravenous push (6 mg bolus over 1-2 seconds) followed immediately by a rapid 20-mL saline flush into a large peripheral vein with arm elevation.
  • Interactions: Antagonized competitively by methylxanthines (theophylline, caffeine; requiring higher doses); potentiated by dipyridamole.
• Magnesium Sulfate:
  • First-line intravenous agent for terminating polymorphic ventricular tachycardia associated with prolonged QT (Torsades de pointes), even in patients with normal baseline serum magnesium levels. Stabilizes cardiac membranes by blocking early afterdepolarizations (EADs).

Anticoagulants in atrial fibrillation and thrombosis

• Stroke prevention in atrial fibrillation: use the CHA2DS2-VASc score.
  • Direct oral anticoagulants (apixaban, rivaroxaban, dabigatran, edoxaban) are preferred in non-valvular AF.
  • Warfarin (target INR 2 to 3, or higher for mechanical mitral valves) is required for mechanical heart valves and moderate to severe rheumatic mitral stenosis.
• Warfarin:
  • inhibits vitamin K epoxide reductase, which lowers factors II, VII, IX and X and proteins C and S;
  • early warfarin skin necrosis occurs in protein C deficiency, so start with heparin overlap;
  • it is teratogenic;
  • it has many interactions: CYP2C9 inhibitors raise the INR, and inducers and vitamin K-rich foods lower it.
  • Reversal: vitamin K and prothrombin complex concentrate (or fresh frozen plasma).
• Heparins:
  • unfractionated heparin is monitored by aPTT, reversed by protamine and can cause heparin-induced thrombocytopenia;
  • enoxaparin is dosed by weight and renal function.
• Specific reversal agents: idarucizumab reverses dabigatran, and andexanet alfa reverses factor Xa inhibitors where available.

Antianginal and ACS pharmacology

Antianginal Therapeutics & Nitrate Physiology

Organic Nitrates (Nitroglycerin, Isosorbide Dinitrate, Isosorbide Mononitrate)

• Mechanism: Denitrated intracellularly in vascular smooth muscle cells by mitochondrial aldehyde dehydrogenase-2 (ALDH2), releasing Nitric Oxide (NO). NO activates soluble guanylyl cyclase, increasing cyclic GMP (cGMP), activating Protein Kinase G (PKG), dephosphorylating myosin light chains, and inducing vascular smooth muscle relaxation.
• Hemodynamic Selectivity: At therapeutic antianginal doses, nitrates act predominantly as systemic venodilators (capacitance vessels $\gg$ large conduit arteries $\gg$ arterioles). Venodilation markedly decreases venous return to the right heart, reducing left ventricular end-diastolic volume and wall tension (preload reduction). According to Laplace's Law ($\text{Wall Stress} = \frac{P \cdot r}{2h}$), reduced ventricular radius and pressure drastically lowers myocardial oxygen consumption ($MVO_2$), rapidly relieving angina.
• Nitrate Tolerance (Tachyphylaxis): Continuous 24-hour nitrate exposure leads to intracellular sulfhydryl group depletion, ALDH2 inactivation, and neurohormonal reflex counter-regulation. To prevent tolerance, patients must observe a daily nitrate-free interval of 8 to 12 hours (typically overnight when the patient is resting and myocardial oxygen demand is lowest).
• Absolute Contraindication: PDE-5 Inhibitors:
  • Co-administration of organic nitrates with Phosphodiesterase-5 (PDE-5) Inhibitors (Sildenafil, Vardenafil, Tadalafil) is an absolute, life-threatening contraindication.
  • PDE-5 breaks down cGMP. When a patient taking a nitrate (which generates massive cGMP) also takes a PDE-5 inhibitor (which halts cGMP degradation), intracellular cGMP surges exponentially. This triggers profound, uncontrolled systemic vasodilation, resulting in severe refractory hypotension, coronary hypoperfusion, acute myocardial infarction, and cardiovascular collapse.
  • Mandatory Safe Separation Windows: At least 24 hours after taking Sildenafil or Vardenafil, and at least 48 hours after taking Tadalafil (due to its prolonged 17.5-hour elimination half-life), before any nitrate may be administered.

Other antianginals:

• Beta-blockers reduce heart rate and contractility, lowering oxygen demand. They are first-line for stable angina and after MI.
• Calcium channel blockers are used for vasospastic (Prinzmetal) angina and when beta-blockers are not tolerated.
• Ranolazine inhibits the late sodium current.
• Trimetazidine is a metabolic agent.

Acute coronary syndrome:

• Antiplatelets:
  • aspirin 160 to 325 mg chewed at once (irreversible COX-1 inhibition, so less thromboxane A2), then 75 to 100 mg daily;
  • plus a P2Y12 inhibitor: clopidogrel (a prodrug activated by CYP2C19), ticagrelor (reversible; can cause dyspnea) or prasugrel (avoid with previous stroke);
  • dual antiplatelet therapy is given for 12 months after ACS in most patients.
• Anticoagulation: unfractionated heparin, enoxaparin or fondaparinux.
• Other drugs:
  • High-intensity statin (atorvastatin 40 to 80 mg) regardless of baseline LDL.
  • Beta-blocker within 24 hours unless there is heart failure, shock or heart block.
  • ACE inhibitor for reduced EF, diabetes or anterior MI.
  • Nitrates for pain, unless there is hypotension, right ventricular infarction (which depends on preload) or recent PDE-5 inhibitor use.
  • Avoid NSAIDs.
• Reperfusion in STEMI:
  • primary PCI is preferred if done promptly;
  • otherwise fibrinolysis within 12 hours of symptom onset (door-to-needle within 30 minutes), using streptokinase, alteplase or tenecteplase;
  • absolute contraindications: any previous intracranial hemorrhage, ischemic stroke within 3 months, intracranial neoplasm or vascular lesion, active bleeding, suspected aortic dissection, and significant head or facial trauma within 3 months;
  • streptokinase is antigenic, so it is not repeated, and it can cause hypotension.

Pericarditis and cardiovascular infections

• Acute pericarditis (viral or idiopathic):
  • aspirin or an NSAID (ibuprofen) with gastric protection;
  • plus colchicine for 3 months, which halves recurrences;
  • corticosteroids are reserved for contraindications or specific causes, because they increase recurrence.
  • Aspirin is preferred after MI, because NSAIDs impair scar healing.
  • Tuberculous pericarditis is treated with anti-TB drugs.
• Infective endocarditis (prolonged IV bactericidal therapy, usually 4 to 6 weeks):
  • viridans streptococci: penicillin G or ceftriaxone;
  • MSSA: oxacillin, nafcillin or cefazolin;
  • MRSA: vancomycin (or daptomycin);
  • Enterococcus: ampicillin plus gentamicin (or ceftriaxone);
  • empiric therapy covers staphylococci, streptococci and enterococci until cultures return.
  • Prophylaxis (amoxicillin 2 g before dental procedures) is limited to the highest-risk patients.
• Rheumatic fever: treat with penicillin to eradicate streptococci, aspirin for arthritis and carditis, and benzathine penicillin G for secondary prophylaxis.