Pharmacology of Drugs for Myocardial Infarction

Introduction / Overview

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Rapid pharmacologic intervention is essential to limit myocardial damage, preserve ventricular function, and reduce long‑term adverse outcomes. Contemporary therapeutic strategies involve reperfusion, antithrombotic, anti‑ischemic, and neurohumoral modulation. A systematic understanding of drug mechanisms, pharmacokinetics, and safety profiles is indispensable for clinicians and pharmacists involved in acute cardiac care.

Learning objectives:

• Identify the primary pharmacologic classes employed in the management of acute MI.
• Explain the molecular and cellular mechanisms underlying the therapeutic actions of these agents.
• Describe the pharmacokinetic properties that influence dosing regimens in the acute setting.
• Recognize common adverse effects and potential drug–drug interactions pertinent to MI therapy.
• Apply knowledge of special patient populations to optimize pharmacologic care in MI.

Classification

Reperfusion‑Related Agents

• Thrombolytic agents: recombinant tissue plasminogen activator (tPA), streptokinase, urokinase.
• Antithrombotic adjuncts: glycoprotein (GP) IIb/IIIa inhibitors (e.g., eptifibatide, tirofiban).

Antiplatelet Therapy

• Thienopyridines: clopidogrel, prasugrel, ticagrelor.
• Direct oral anticoagulants (DOACs) are occasionally considered in specific scenarios.

Neurohumoral Modulators

• Beta‑adrenergic blockers: metoprolol, atenolol, bisoprolol.
• Angiotensin‑converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).
• Statins: high‑intensity atorvastatin, rosuvastatin.
• Potassium‑sparing diuretics (e.g., spironolactone) in selected patients.

Analgesic and Anti‑ischemic Agents

• Opioids: morphine, fentanyl.
• Non‑steroidal anti‑inflammatory drugs (NSAIDs) are generally avoided.
• Calcium channel blockers and nitrates may be used for chest pain control.

Other Supporting Agents

• Anticoagulants: unfractionated heparin, low‑molecular‑weight heparin (enoxaparin).
• Plasma‑derived products: cryoprecipitate, fresh frozen plasma in bleeding scenarios.

Mechanism of Action

Thrombolytic Agents

Recombinant tissue plasminogen activator binds fibrin and converts plasminogen to plasmin, initiating fibrinolysis and clot dissolution. Streptokinase forms a complex with plasminogen, stimulating its conversion to plasmin without requiring fibrin. Urokinase directly activates plasminogen independent of fibrin. The net effect is rapid restoration of coronary blood flow, contingent upon timely administration.

Glycoprotein IIb/IIIa Inhibitors

These agents competitively inhibit the GP IIb/IIIa receptor on activated platelets, preventing fibrinogen cross‑linking and platelet aggregation. The blockade is reversible, resulting in a transient antiplatelet effect that is particularly valuable during percutaneous coronary intervention (PCI).

Antiplatelet Thienopyridines and Ticagrelor

Clopidogrel, prasugrel, and ticagrelor inhibit the P2Y₁₂ receptor on platelets, thereby impeding ADP‑mediated activation. Clopidogrel and prasugrel require hepatic biotransformation to active metabolites; ticagrelor binds reversibly and exerts a more immediate effect. The inhibition of platelet aggregation reduces the risk of stent thrombosis and recurrent ischemic events.

Beta‑Blockers

Beta‑adrenergic antagonists block β₁‑adrenergic receptors in the heart, diminishing sympathetic stimulation. This reduces heart rate, myocardial contractility, and oxygen demand, while also attenuating arrhythmogenic potential. The net result is a reduction in infarct size and mortality when initiated early.

ACE Inhibitors and ARBs

ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, lowering vasoconstriction, aldosterone secretion, and sympathetic tone. ARBs block the angiotensin II type 1 receptor, producing similar hemodynamic effects. The neurohumoral blockade mitigates remodeling and preserves ventricular function post‑MI.

Statins

Statins competitively inhibit 3‑hydroxy‑3‑methyl‑glutaryl‑coenzyme A reductase, decreasing endogenous cholesterol synthesis. The downstream effect is up‑regulation of LDL receptors and reduction of circulating LDL cholesterol. Beyond lipid lowering, statins exhibit pleiotropic actions: plaque stabilization, anti‑inflammatory effects, and improvement of endothelial function.

Morphine and Opioids

Opioids activate mu‑opioid receptors in the central nervous system to alleviate chest pain. The analgesic effect also reduces sympathetic tone, indirectly lowering myocardial oxygen demand. However, potential respiratory depression and hypotension must be monitored.

Unfractionated Heparin

Heparin potentiates antithrombin III, leading to inhibition of thrombin and factor Xa. The anticoagulant effect limits further thrombus propagation within coronary arteries, complementing reperfusion strategies.

Calcium Channel Blockers and Nitrates

Calcium channel blockers inhibit L‑type calcium channels, reducing myocardial contractility and vasodilating coronary arteries. Nitrates release nitric oxide, causing venous and arterial dilation, thereby decreasing preload and afterload. Both classes can relieve ischemic pain but are used selectively depending on patient hemodynamics.

Pharmacokinetics

Thrombolytic Agents

Recombinant tPA is administered intravenously, achieving peak plasma concentrations within minutes. Its half‑life (t_1/2) is approximately 4–5 minutes, necessitating continuous infusion or bolus dosing. Streptokinase and urokinase are similarly administered IV, with t_1/2 values of 7–10 minutes and 2–3 minutes, respectively. Renal excretion is minimal; hepatic metabolism predominates. Dose adjustments are generally not required in mild renal impairment but should be considered in severe hepatic dysfunction.

GP IIb/IIIa Inhibitors

Eptifibatide and tirofiban are given as IV bolus followed by continuous infusion. Their half‑lives are 30–60 minutes, with renal elimination accounting for 60–70% of clearance. Dose reduction is recommended for creatinine clearance <30 mL/min to avoid excessive platelet inhibition.

Thienopyridines and Ticagrelor

Clopidogrel and prasugrel are orally administered; absorption peaks at 90 minutes and 1 hour, respectively. Clopidogrel requires hepatic biotransformation via CYP2C19; genetic polymorphisms may impair activation. Prasugrel is metabolized by CYP3A4 and CYP2B6, providing more consistent antiplatelet effects. Ticagrelor is absorbed rapidly, with a half‑life of 7–11 hours, and does not require metabolic activation. Renal excretion is modest; hepatic impairment may prolong action.

Beta‑Blockers

Metoprolol undergoes first‑pass hepatic metabolism; its half‑life ranges from 3–7 hours. Atenolol is primarily renally excreted, with a half‑life of 6–7 hours. Bisoprolol is metabolized hepatically, half‑life 10–12 hours. Dose adjustments are necessary in renal or hepatic dysfunction, depending on the specific agent.

ACE Inhibitors and ARBs

Lisinopril is renally cleared; its half‑life is 12–18 hours. Enalapril is prodrug, converted to enalaprilat; half‑life 12–17 hours. Losartan is metabolized to EXP3174; half‑life 2–3 hours (parent) and 6–9 hours (active metabolite). ARBs are largely renally excreted; dose reductions are advised in advanced kidney disease.

Statins

Atorvastatin and rosuvastatin have long half‑lives (12–20 hours) due to hepatic metabolism via CYP3A4. Pravastatin and fluvastatin are less dependent on CYP metabolism, offering safer profiles in drug–interaction‑prone patients. Renal or hepatic impairment may necessitate dose adjustments, particularly for lipophilic statins.

Morphine

Morphine is absorbed orally with a bioavailability of 20–40%. Peak plasma concentrations occur within 30–60 minutes. The half‑life is 3–4 hours, with metabolites (morphine‑6‑glucuronide) contributing to analgesic effect. Hepatic impairment prolongs action; renal dysfunction may accumulate active metabolites.

Unfractionated Heparin

Heparin binds to antithrombin III, with a rapid onset of action and a half‑life of 1–2 hours. It is largely cleared by the reticuloendothelial system; renal function has limited impact on clearance. Monitoring via activated partial thromboplastin time (aPTT) guides dosing.

Calcium Channel Blockers and Nitrates

Verapamil: oral half‑life 3–7 hours; hepatic metabolism. Diltiazem: oral half‑life 1–2 hours; hepatic clearance. Nitrates: sublingual nitroglycerin has a half‑life of 1–3 minutes; intravenous nitroglycerin 3–5 minutes. Metabolism is primarily hepatic, with renal excretion of metabolites.

Therapeutic Uses / Clinical Applications

Reperfusion Therapy

• Intravenous thrombolysis is indicated for patients presenting within 12 hours of symptom onset when percutaneous coronary intervention (PCI) is not immediately available.
• GP IIb/IIIa inhibitors are administered during PCI to reduce ischemic complications.

Antiplatelet Regimens

• Dual antiplatelet therapy (DAPT) with aspirin plus a thienopyridine or ticagrelor is standard after PCI or stent placement.
• Clopidogrel is often used when cost or availability of newer agents is limiting; prasugrel or ticagrelor are preferred in high‑risk patients due to superior platelet inhibition.

Neurohumoral Modulation

• Beta‑blockers are initiated early in MI to reduce mortality, especially in anterior infarcts or left ventricular dysfunction.
• ACE inhibitors or ARBs are started within 24 hours post‑MI to attenuate remodeling, particularly in patients with reduced ejection fraction.
• High‑intensity statins are recommended within 24 hours to stabilize plaque and reduce recurrent events.

Analgesia and Anti‑ischemia

• Morphine is used for severe chest pain refractory to nitrates and beta‑blockers, with caution for hypotension and respiratory depression.
• Calcium channel blockers and nitrates provide supplemental analgesia and ischemia relief; nitrates also lower preload.

Anticoagulation

• Unfractionated heparin is combined with antiplatelet therapy during PCI to prevent stent thrombosis.
• Low‑molecular‑weight heparin may be used in selected patients with contraindications to unfractionated heparin.

Adverse Effects

Thrombolytics

• Bleeding: intracranial hemorrhage, gastrointestinal bleeding.
• Allergic reactions: anaphylaxis, urticaria.
• Reperfusion injury: arrhythmias, ventricular fibrillation.

GP IIb/IIIa Inhibitors

• Bleeding: mucosal, gastrointestinal, intracranial.
• Thrombocytopenia: immune‑mediated, dose‑dependent.
• Hypotension: due to vasodilation.

Thienopyridines and Ticagrelor

• Bleeding: increased risk of major hemorrhage.
• Gastrointestinal disturbances: nausea, dyspepsia.
• Ticagrelor: dyspnea, bradyarrhythmias.

Beta‑Blockers

• Bradycardia, hypotension, fatigue.
• Respiratory depression in asthmatic or COPD patients.
• Worsening heart failure in decompensated states.

ACE Inhibitors / ARBs

• Hypotension, cough (ACE inhibitors), angioedema.
• Hyperkalemia, renal impairment.
• Withdrawal reactions: rebound hypertension.

Statins

• Myopathy, rhabdomyolysis (rare).
• Liver function test elevations.
• Diabetes mellitus exacerbation.

Morphine

• Respiratory depression, hypotension, nausea.
• Potential for opioid dependence.

Unfractionated Heparin

• Bleeding, heparin‑induced thrombocytopenia (HIT).
• Hypocalcemia due to calcium chelation.

Calcium Channel Blockers / Nitrates

• Headache, flushing (nitrates).
• Peripheral edema, hypotension (verapamil, diltiazem).
• Drug interactions: CYP3A4 inhibition (verapamil).

Drug Interactions

Thienopyridines

• Clopidogrel: reduced activation by CYP2C19 inhibitors (e.g., fluconazole, omeprazole).
• Prasugrel: interaction with CYP3A4 inhibitors/inducers (e.g., ketoconazole, rifampin).
• Ticagrelor: minimal metabolism; caution with CYP3A4 inhibitors but effect is less pronounced.

Beta‑Blockers

• Verapamil and diltiazem inhibit CYP3A4, increasing plasma levels of certain beta‑blockers (e.g., carvedilol).
• Combined use with calcium channel blockers may potentiate bradycardia and hypotension.

ACE Inhibitors / ARBs

• Potassium‑sparing diuretics (spironolactone) increase hyperkalemia risk.
• NSAIDs reduce antihypertensive efficacy and may impair renal function.

Statins

• Simvastatin, lovastatin: potent CYP3A4 inhibitors (ketoconazole) can increase myopathy risk.
• Pravastatin: less interaction with CYP3A4; suitable in polypharmacy.
• Drug interactions with CYP3A4 inhibitors (e.g., clarithromycin) raise serum statin concentrations.

Unfractionated Heparin

• Interaction with warfarin: additive anticoagulation; monitor INR.
• Concomitant antiplatelet agents (aspirin, clopidogrel) increase bleeding risk.

Morphine

• Combining with benzodiazepines or other CNS depressants may potentiate respiratory depression.
• Opioid antagonists (naloxone) reverse analgesic effect but may precipitate withdrawal.

Special Considerations

Pregnancy and Lactation

Thrombolytics and antiplatelet agents are generally contraindicated in pregnancy due to bleeding risk and lack of safety data. Beta‑blockers are category C; ACE inhibitors and ARBs are contraindicated (category D) in the third trimester. Statins are category X. Morphine is category C but may be used if benefits outweigh risks. Lactation: most agents are secreted in milk; caution is advised.

Pediatric Considerations

Drug dosing in children is derived from adult data adjusted for weight and maturation. Thrombolytics have limited pediatric use; dosing is weight‑based. Antiplatelet therapy is employed in pediatric MI, though rare. Beta‑blockers and ACE inhibitors are used cautiously, with monitoring for growth and development effects.

Geriatric Considerations

Older adults exhibit altered pharmacokinetics: reduced hepatic metabolism, increased plasma protein binding, and diminished renal clearance. Dose reductions and careful monitoring for hypotension, bradycardia, and renal function are advised. Polypharmacy increases interaction risk.

Renal Impairment

GP IIb/IIIa inhibitors require dose adjustment for creatinine clearance <30 mL/min. Unfractionated heparin clearance is unaffected but monitoring remains essential. ACE inhibitors and ARBs should be initiated cautiously in chronic kidney disease; serum creatinine and potassium should be monitored. Statins: pravastatin is preferred in renal dysfunction due to minimal hepatic metabolism.

Hepatic Impairment

Thienopyridines require dose adjustment in severe hepatic dysfunction due to reduced activation. Beta‑blockers with hepatic metabolism (metoprolol, carvedilol) should be dose‑reduced. Statins: pravastatin and fluvastatin are safer; lipophilic statins may accumulate. ACE inhibitors: lisinopril may accumulate; dose adjustment is necessary.

Summary / Key Points

• Early reperfusion, antithrombotic, and neurohumoral modulation constitute the cornerstone of MI therapy.
• Drug selection is guided by clinical presentation, time from symptom onset, and patient comorbidities.
• Pharmacokinetic properties influence dosing intervals, especially in renal or hepatic impairment.
• Adverse effect profiles demand vigilant monitoring, particularly for bleeding and metabolic complications.
• Drug‑drug interactions are common; therapeutic drug monitoring and dose adjustments can mitigate risk.
• Special patient populations require tailored regimens, with particular attention to pregnancy, pediatrics, geriatrics, and organ dysfunction.

Adherence to evidence‑based pharmacologic protocols in acute MI remains essential for optimizing patient outcomes and reducing long‑term morbidity.

References

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