Salicylates and Their Effects

Analgesic, Antipyretic, and Anti-inflammatory Drugs

• Salicylates are a group of drugs with analgesic, antipyretic, and anti-inflammatory properties.
• Salicylate poisoning is potentially life-threatening, often occurring from accidental ingestion of aspirin or other preparations containing salicylates.
• Common household aspirin can lead to dangerous levels in the body.

Salicylates: Available Preparations

• Aspirin (acetyl salicylic acid)
• Various cold preparations
• Topical preparations such as methyl salicylate ("oil of wintergreen") and salicylic acid

Salicylates: Conditions of Poisoning

• Accidental poisoning in children can occur due to accidental ingestion or mistaking a medicinal dose of aspirin for a fever remedy.
• Elderly patients may experience chronic toxicity due to altered metabolic elimination processes.
• Suicide attempts, commonly by young adolescents, often result in morbidity rather than immediate mortality.

Salicylates: Mechanism of Action

• Therapeutic levels of salicylates result in anti-inflammatory, analgesic, and antipyretic effects primarily due to inhibition of prostaglandin biosynthesis.
• Toxic actions manifest as gastrointestinal (GIT) irritation, characterized by burning sensations, nausea, vomiting, and gastric erosion with possible bleeding, particularly hematemesis.

Salicylates: Toxic Actions and Clinical Presentations

• Hematology: Bleeding tendencies caused by inhibition of prothrombin synthesis and platelet function which lead to increased bleeding time.
• Hypersensitivity Reactions: Urticaria, skin rashes, and bronchial asthma may occur.
• Central Nervous System (CNS): Salicylates can cause central stimulation, resulting in restlessness, excitability, delirium, convulsions, and coma in severe cases. These symptoms are often due to increased CO2 levels and inhibition of vasomotor and respiratory centers.
• Kidney: Renal compromise results from direct effects of aspirin leading to renal tubular necrosis and uremia; and indirect effects due to decreased renal perfusion from dehydration.
• Hyperthermia: Uncoupling of oxidative phosphorylation leads to increased metabolic rate and subsequent hyperthermia, often accompanying dehydration due to fluid loss by sweating and vomiting. Salicylism can happen with high doses and may include tinnitus, vertigo and hearing loss.
• Metabolic Disorders: Initially, there might be a period of hyperglycemia followed later by hypoglycemia, due to depletion of glycogen stores.

Salicylates: Acid-base Imbalance

• Respiratory alkalosis is the most common acid-base imbalance in salicylate poisonings. This is caused by the stimulation of the central nervous system and respiratory centers which cause increased rate and depth of respiration, resulting in increased expiration of CO2, leading to decreased plasma CO2 and causing decreased levels of carbonic acid. This results in an increased HCO3/H2CO3 ratio and an increase in the pH of the blood.

Salicylates: Fatal Dose and Causes of Death

• Fatal dose: 390 mg/kg body weight (BW)
• Fatal serum level: >100 mg %
• Early death (12-24 hrs): Central respiratory failure and cardiac arrhythmias (acidosis)
• Delayed death (days after): Renal failure and hemorrhage

Salicylate: Investigations

• Blood salicylate level to assess the severity of poisoning
• Coagulation profile (prothrombin time, concentration, and bleeding time)
• Arterial pH, CO2, HCO3, and potassium (K) to assess acid-base disturbance
• Kidney and liver function tests
• X-ray to visualize aspirin concretions in the stomach

Salicylate: Treatment

• Supportive measures (establishing adequate airway, cardiovascular, and respiratory support)
• Gastrointestinal decontamination (inducing vomiting, gastric lavage, using sodium bicarbonate, activated charcoal, MDAC and whole bowel irrigation)
• Forced alkaline diuresis (effective for moderate toxicity)
• Hemodialysis (indicated for severe cases and/or renal dysfunction)
• Symptom management

Paracetamol: Introduction

• Acetaminophen (paracetamol) is a commonly used analgesic and antipyretic.
• A major active metabolite of phenacetin and acetanilide;
• It follows aspirin as the second most common cause of poisoning.

Paracetamol: Conditions of Poisoning

• Accidental poisoning is most common, especially in children
• Suicidal attempts are less frequent

Paracetamol: Mechanism of Action

• Therapeutic: Same analgesic and antipyretic effects as aspirin, due to its inhibitory effect on the synthesis of central prostaglandins. However, its anti-inflammatory activity is minimal.
• Toxic: Liver damage is a major concern in overdose. Acetaminophen is rapidly absorbed and metabolized in the liver. The major pathway is conjugation with glucuronide and sulfate groups to form non-toxic conjugates.

Paracetamol: Toxic Action

• In overdose, acetaminophen saturates conjugation pathways, leading to an increase in toxic metabolites.
• Toxic metabolites overwhelm the glutathione detoxification mechanism, leading to depletion of glutathione stores.
• Toxic metabolites bind to sulfhydryl (-SH) groups of hepatic cellular proteins, resulting in centrilobular necrosis.
• Renal: Tubular necrosis can also occur in the kidneys.

Paracetamol: Clinical Presentation

• The clinical course of paracetamol poisoning typically involves four stages that may overlap.
• Phase 1 (30 min-24 hrs): gastrointestinal symptoms (malaise, diaphoresis, nausea, vomiting, drowsiness).
• Phase 2 (24-72 hrs): apparent recovery and blood chemistry changes (pain, tenderness in the right hypochondrium, elevated serum liver enzymes, AST, ALT, LDH, bilirubin, possible prolongation of prothrombin time). Phase 3 (72-96 hrs): Fulminant liver failure (jaundice, coagulation defects, and altered conscious level). This phase can potentially be reversed.
• Phase 4 (7-10 days): Prognosis (resolution of hepatic dysfunction; complete hepatic recovery may occur in 3-6 months, but in severe cases death due to multi-organ failure can occur).

Paracetamol: Fatal Dose

• 15 g (a tablet usually contains 325-500 mg)

Paracetamol: Investigations

• Serum level of acetaminophen
• Liver function tests
• Prothrombin time
• Kidney function tests

Paracetamol: Treatment

• Supportive measures: ABCs (general toxicology)
• Gastrointestinal decontamination (emesis by syrup of ipecac, gastric lavage, activated charcoal to prevent ongoing absorption of APAP) – these are given after antidote therapy to prevent NAC adsorption.
• Saline cathartics (to enhance elimination)
• Excretion of the poison from the blood: hemodialysis for renal failure
• Specific antidote: N-acetylcysteine (NAC) to prevent hepatic necrosis. Initial loading dose is 140 mg / kg, followed by maintenance doses of 70 mg/kg every 4 hours for 3 days.

Test your knowledge on analgesic, antipyretic, and anti-inflammatory drugs, specifically focusing on salicylates. This quiz covers their mechanisms, preparations, and the dangers of poisoning, particularly in children and the elderly. Evaluate your understanding of both therapeutic uses and potential risks associated with these medications.