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ASPIRIN-MOA, Therapeutic uses and Adverse effects ****(rationale of usage in MI)

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aspirin AND myocardial infarction

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American Heart Association acute coronary syndrome guideline aspirin recommended loading dose 2025

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Aspirin

Aspirin (acetylsalicylic acid) is an NSAID with analgesic, antipyretic, anti-inflammatory, and, at low doses, antiplatelet actions.

Mechanism of action

Aspirin irreversibly acetylates and inhibits cyclooxygenase (COX-1 and COX-2). This prevents conversion of arachidonic acid to prostaglandin H2, thereby reducing formation of:
  • Prostaglandins: pain, fever, inflammation
  • Prostacyclin (PGI₂): vasodilator and inhibitor of platelet aggregation
  • Thromboxane A₂ (TXA₂): platelet aggregation and vasoconstriction

Antiplatelet action at low dose

  • Platelets mainly use COX-1 to form TXA₂.
  • Aspirin irreversibly blocks platelet COX-1, causing decreased TXA₂ synthesis.
  • Therefore: decreased platelet aggregation and decreased arterial thrombus formation.
  • Platelets lack a nucleus, so they cannot make new COX. The antiplatelet effect continues for the platelet lifespan, about 7-10 days.
  • Endothelial cells can regenerate COX and restore PGI₂ production. Thus low-dose aspirin preferentially reduces platelet TXA₂ relative to endothelial PGI₂.
Lippincott Illustrated Reviews: Pharmacology, p. 438-439; Katzung's Basic and Clinical Pharmacology, 16th ed., p. 1008.

Therapeutic uses

1. As an antiplatelet drug, low dose

Used for prevention and treatment of arterial thrombotic disorders:
  • Acute coronary syndrome, including unstable angina, NSTEMI, and STEMI
  • Acute myocardial infarction
  • Secondary prevention after MI
  • Prevention of ischemic stroke and transient ischemic attack
  • After coronary angioplasty and stent placement, usually with a P2Y12 inhibitor such as clopidogrel, prasugrel, or ticagrelor
  • After coronary artery bypass grafting
  • Peripheral arterial disease

2. Analgesic

For mild to moderate pain:
  • Headache
  • Toothache
  • Musculoskeletal pain
  • Dysmenorrhea

3. Antipyretic

Reduces fever by lowering prostaglandin-mediated hypothalamic temperature set point.

4. Anti-inflammatory

At higher doses, may be used in inflammatory conditions, though it is now less commonly chosen because other NSAIDs are generally better tolerated.

5. Other uses

  • Kawasaki disease: high-dose aspirin initially, followed by antiplatelet-dose aspirin.
  • Pre-eclampsia prevention: low-dose aspirin in selected high-risk pregnant patients.

Rationale for aspirin use in myocardial infarction

What causes an acute MI?

Most acute MIs occur when an atherosclerotic coronary plaque ruptures or erodes. This exposes thrombogenic material, leading to:
  1. Platelet adhesion
  2. Platelet activation
  3. TXA₂ release
  4. Platelet aggregation
  5. Formation and enlargement of a platelet-rich coronary thrombus
  6. Coronary artery occlusion and myocardial ischemia/necrosis

How aspirin helps

Aspirin irreversibly inhibits platelet TXA₂ production, so it:
  • Reduces platelet activation and aggregation
  • Limits propagation of the coronary thrombus
  • Reduces recurrent coronary occlusion and reinfarction
  • Lowers risk of death and major adverse cardiovascular events
It does not directly dissolve an established thrombus. Reperfusion is achieved by primary PCI or, where appropriate, fibrinolysis. Aspirin prevents further platelet-mediated thrombus growth and recurrent ischemic events.

In acute MI / acute coronary syndrome

In patients without an absolute contraindication, aspirin should be given promptly as a loading dose, followed by low-dose daily therapy. The 2025 ACC/AHA ACS guideline recommends an initial oral loading dose of 162-325 mg, then daily low-dose aspirin, to reduce death and major adverse cardiovascular events.
Aspirin is usually combined with a P2Y12 inhibitor in acute coronary syndrome. This is called dual antiplatelet therapy (DAPT), because the two drugs inhibit platelet activation through different pathways.
Katzung's Basic and Clinical Pharmacology, 16th ed., p. 1008. Aspirin decreases coronary thrombosis with MI and is used in unstable angina and TIA.

Adverse effects

1. Gastrointestinal effects

  • Dyspepsia, nausea, epigastric pain
  • Gastritis
  • Peptic ulceration
  • Upper GI bleeding and perforation
Mechanism: inhibition of COX-1 decreases protective gastric prostaglandins, causing reduced mucus and bicarbonate secretion and reduced mucosal blood flow.

2. Bleeding

  • Prolonged bleeding time
  • GI bleeding
  • Intracranial hemorrhage, rarely
  • Increased perioperative bleeding
Risk rises with anticoagulants, other antiplatelet drugs, corticosteroids, SSRIs, alcohol, and other NSAIDs.

3. Hypersensitivity / aspirin-induced asthma

  • Bronchospasm
  • Rhinitis
  • Urticaria
  • Angioedema
  • Rarely anaphylactoid reactions
Mechanism: COX inhibition diverts arachidonic acid toward leukotriene production. This is particularly relevant in aspirin-exacerbated respiratory disease.

4. Salicylism

Usually with high doses:
  • Tinnitus, hearing impairment
  • Dizziness
  • Headache
  • Nausea and vomiting
  • Sweating
Tinnitus is a typical early warning feature of salicylate toxicity.

5. Salicylate poisoning

May cause:
  • Hyperventilation and respiratory alkalosis initially
  • Metabolic acidosis later
  • Hyperthermia
  • Dehydration
  • Confusion, seizures, coma
  • Pulmonary edema

6. Renal effects

  • Reduced renal blood flow and GFR
  • Sodium and water retention
  • Edema
  • Acute kidney injury, especially in dehydration, heart failure, chronic kidney disease, or concurrent ACE inhibitor/ARB plus diuretic use

7. Reye syndrome

Aspirin can cause Reye syndrome in children or adolescents with viral infections, particularly influenza or varicella.
Therefore, aspirin should generally not be given to children with viral fever.

8. Effects on uric acid

  • Low doses reduce urate excretion and may precipitate gout.
  • High doses are uricosuric, but are not routinely used for this purpose.

Important contraindications / precautions

Avoid or use only under specialist direction in:
  • Active bleeding or bleeding disorders
  • Active peptic ulcer disease or recent GI hemorrhage
  • Aspirin allergy or aspirin-induced asthma
  • Children/adolescents with viral illness
  • Severe renal or hepatic dysfunction
  • Concomitant anticoagulant use, unless benefit clearly outweighs bleeding risk
  • Late pregnancy, except when specifically prescribed at low dose for an obstetric indication
The principal clinically important toxicity of antiplatelet-dose aspirin is bleeding, especially upper GI bleeding. Risk is lower with 75-100 mg daily than with higher doses and is higher with DAPT or in patients with prior ulcer/GI bleed, coagulopathy, thrombocytopenia, kidney/liver disease, or uncontrolled hypertension. Goldman-Cecil Medicine, Aspirin section.

Proton pump inhibitors pharmacology short note

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proton pump inhibitors adverse effects

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FDA proton pump inhibitors drug safety long term use fracture hypomagnesemia C difficile

Proton Pump Inhibitors (PPIs): Short Note

Examples

  • Omeprazole
  • Esomeprazole
  • Pantoprazole
  • Lansoprazole
  • Dexlansoprazole
  • Rabeprazole

Mechanism of action

PPIs are prodrugs that become activated in the acidic secretory canaliculi of gastric parietal cells. They irreversibly inhibit the gastric H⁺/K⁺-ATPase proton pump, the final common step in gastric acid secretion.
This produces profound suppression of both basal and meal-stimulated acid secretion. Since inhibition is irreversible, acid secretion resumes only after synthesis of new proton pumps.
Administration: Give 30-60 minutes before food, preferably before breakfast. If twice daily, give before breakfast and evening meal.
Tintinalli's Emergency Medicine, Proton Pump Inhibitors section.

Pharmacokinetics

  • Acid-labile drugs, hence usually formulated as enteric-coated tablets/capsules.
  • Short plasma half-life but prolonged pharmacological effect due to irreversible pump inhibition.
  • Metabolized mainly in the liver through CYP2C19 and CYP3A4.
  • Rabeprazole and pantoprazole have fewer clinically important CYP-mediated interactions than omeprazole.

Therapeutic uses

  1. Peptic ulcer disease, including gastric and duodenal ulcers
  2. GERD and erosive esophagitis
  3. Part of Helicobacter pylori eradication regimens
  4. Prevention and treatment of NSAID-induced ulcers
  5. Stress-ulcer prophylaxis in selected high-risk hospitalized/ICU patients
  6. Zollinger-Ellison syndrome and other hypersecretory states
  7. Upper GI bleed due to peptic ulcer, usually high-dose IV PPI after endoscopic therapy
  8. Gastroprotection in patients receiving antiplatelets such as aspirin, especially if GI-bleeding risk is high

Adverse effects

Common
  • Headache
  • Nausea, abdominal pain
  • Diarrhea or constipation
  • Flatulence
Long-term / important adverse effects
  • Vitamin B12 deficiency
  • Hypomagnesemia
  • Reduced calcium absorption and possible fracture risk in susceptible persons
  • Increased risk of enteric infections, including Clostridioides difficile associated diarrhea
  • Acute interstitial nephritis and, rarely, chronic kidney injury
  • Rebound acid hypersecretion after sudden discontinuation following prolonged treatment
  • Fundic gland polyps and hypergastrinemia with prolonged use
The FDA advises considering magnesium monitoring in patients expected to receive prolonged therapy, particularly those also taking digoxin or diuretics, because long-term PPI use can cause hypomagnesemia. The FDA safety communication reports that this usually occurs after prolonged use, often more than one year.

Drug interactions

  • Omeprazole and esomeprazole inhibit CYP2C19 and may reduce conversion of clopidogrel to its active metabolite.
  • If a PPI is needed with clopidogrel, pantoprazole is often preferred because of less CYP2C19 inhibition.
  • PPIs can reduce absorption of drugs requiring an acidic gastric pH, such as ketoconazole, itraconazole, and atazanavir.
  • They may increase methotrexate concentrations, especially with high-dose methotrexate.
Goodman & Gilman's The Pharmacological Basis of Therapeutics, Therapeutic Uses and Adverse Effects section.
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