Aspirin and Paracetamol PDF

Analgesic, antipyretic and anti-inflammatory drugs Salicylate poisoning is potentially life-threatening ingestion. Most households have enough aspirin in the medicine cabinet to produce life-threatening ingestion. Available preparations: 1. Aspirin (acetyl salicylic acid). 2. Various cold preparat...

Analgesic, antipyretic and anti-inflammatory drugs Salicylate poisoning is potentially life-threatening ingestion. Most households have enough aspirin in the medicine cabinet to produce life-threatening ingestion. Available preparations: 1. Aspirin (acetyl salicylic acid). 2. Various cold preparations. 3. Topical preparations such as Methyl salicylate “oil of wintergreen” (counter irritant) and salicylic acid (topical keratolytic). Conditions of poisoning: * Accidental: - In children occurs due to accidental ingestion by the child himself or accidental intoxication during treatment because pyrexia due to aspirin overdose may be mistaken for fever of infection with further administration of aspirin. - The elderly patient may suffer chronic toxicity following a gradual alteration in the patient’s metabolic elimination processes. * Suicidal: by young adolescents, it leads to morbidity rather than mortality due to large fatal dose. Mechanism of action: 1- Therapeutic action: Therapeutic salicylate levels result in anti-inflammatory, analgesic and antipyretic effects primarily through inhibition of prostaglandin biosynthesis. 2- Toxic action and clinical presentations: a. GIT irritation manifested by: Burning pain in mouth and throat. Nausea and vomiting Gastric erosion and ulceration leading to GIT bleeding especially hematemesis. b. Hematology: bleeding tendencies due to: inhibition of prothrombin synthesis (↑prothrombin time). Inhibition of platelet function (↑bleeding time). c. Hypersensitivity reaction (Allergy): Urticaria and skin rash. Precipitation of bronchial asthma. Angioneurotic edema. d. CNS: Salicylates cause central stimulation: Restlessness, excitability, delirium, and convulsions (due to increased Co2). Coma occurs in severe cases with inhibition of vasomotor and respiratory centers. e. Kidney : renal compromise occurs due to: Direct effect of aspirin →renal tubular necrosis → uremia. Indirect effect due to decreased renal perfusion due to dehydration. f. Hyperthermia: due to Uncoupling of oxidative phosphorylation with subsequent increase in cellular metabolic rate. Dehydration secondary to fluid loss by sweating and vomiting. g. Salicylism: high pitched tinnitus, vertigo, deafness may occur with therapeutic and toxic doses. This effect is due to 8th cranial nerve involvement. It is reversible. h. Liver: mild liver necrosis may occur. i. Metabolic disorders: Initially there is short period of hyperglycemia (due to glycolysis) followed by hypoglycemia either late in acute toxicity or in chronic toxicity (due to depletion of glycogen stores). j. Fluid and electrolyte disturbances: 1. Dehydration due to increased metabolic rate and hyperthermia (sweating). Vomiting and hyperventilation are other contributing factors. 2. Hypokalemia due to K loss in urine.  k- Acid-base imbalance: * It is one of the most common manifestations of salicylate poisoning. * Respiratory alkalosis is the predominant early acid-base disturbance and it is due to CNS and respiratory center stimulation → increased depth and rate of respiration’ increased CO2 expired by the lungs less plasma CO2 → less carbonic acid is formed →↑ HCO3/H2CO3 ratio and pH of the blood (respiratory alkalosis).  Fatal dose: 390 mg/kg BW. (Adult aspirin tablet contains 320 mg of acetyl salicylic acid. Therefore, 60-70 tablets are needed for fatal outcome) Fatal serum level: >100 mg %. Causes of death 1. Early (12-24hrs): central respiratory failure and cardiac arrhythmias (acidosis). 2. Delayed (few days): renal failure and hemorrhage.  Investigations: 1. Blood salicylate level: to assess severity of poisoning (not before hours). 2. Coagulation profile: prothrombin time and concentration and bleeding time. 3. Arterial pH, CO2, HCO3, and potassium (K) to assess acid base disturbance 4. Kidney an4. liver function tests. 5. X-Ray: aspirin concretions may be visualized in the stomach.  Treatment: 1- Supportive measures: ABCs (see general toxicology) Establish adequate airway, cardiovascular and respiratory support. 2- GIT decontamination: - Emesis by syrup of ipecac. - Gastric lavage using sodium bicarbonate. - Activated charcoal and MDAC to prevent on going absorption of salicylate. - Whole bowel irrigation is more effective in elimination. - Saline cathartics. 3- Excretion of the poison from the blood: - Forced alkaline diuresis: effective in metabolic acidosis and moderate toxicity. - Hemodialysis is indicated in severe cases and / or renal dysfunction. 4- Symptomatic: a. Metabolic acidosis → IV. Na HCO3. b. GIT irritation demulcents. c. Dehydration → IV fluids. d. seizures → diazeparn. e. bleeding tendencies →Vit. K or blood transfusion. f. Hyperthermia → cold foments and ice enema. g. Hypoglycemia → add glucose to IV fluids.  Acetaminophen (paracetamol) Acetaminophen (paracetamol) (APAP), N-acetyl-p- aminophenol, one of the coal tar analgesics, is a major active metabolite of phenacetin and acetanilide. It follows aspirin as a major cause of poisoning. Conditions of poisoning - Accidental: most common especially in children. - Suicidal (rare)  Mechanism of action: 1. Therapeutic action: It has the same analgesic and antipyretic actions as aspirin due to its potent inhibitory effect on synthesis of central prostaglandin (PG): On the contrary, the anti- inflammatory action is very weak due to its weak inhibitory action on synthesis of peripheral PG. 1. Toxic action: - The liver: The main hazard of APAP is liver damage. Mechanism: In therapeutic dose, acetaminophen is rapidly absorbed from the stomach and upper GIT to be metabolized in the liver through: * Major pathway: 90% of APAP is conjugated with glucuronide and sulfate → non toxic conjugate. * Minor pathway: 4% of APAP is metabolized via cytochrome P 450 mixed function oxidase system → toxic metabolite that is subsequently reduced by sulfhydryl (- SH) group of glutathione → non toxic compound. In overdose: APAP saturates conjugation pathways and produces an increase in toxic metabolite that overwhelms the glutathione detoxification mechanism (depletion of glutathione stores).The toxic metabolite then will bind to —SH group of hepatic cellular protein → centri-lobular necrosis. - The kidneys: Tubular necrosis. Clinical presentations: The clinical course passes into four phases that may overlap. Phase 1:30 min- 24 hrs. (GIT symptoms) - Malaise and diaphoresis. - Nausea and vomiting. - Drowsiness (no loss of consciousness). Phase II: 24-72 hrs. (Apparent recovery & blood chemistry changes) - Pain and tenderness in the right hypochondrium. - Altered liver function tests: Elevation in serum enzymes (AST, ALT, LDH) and bilirubin. Prolongation of prothrombin time may occur. Phase III: 72-96 hrs. (Fulminant liver failure) - Liver failure (jaundice, coagulation defects and encephalopathy and altered conscious level). - The condition is potentially reversible. Phase IV: 7-10 days (Prognosis) - Recovery: resolution of hepatic dysfunction and complete hepatic recovery occurs within 3-6 months. - Death: in severe cases due to multi-organ failure. Fatal dose: 15 g (a tablet contain 325-500 mg) Investigations: 1- Serum level of acetaminophen to assess degree of toxicity. 2- Liver function tests and prothrombin time. 3- Kidney function tests.  Treatment: 1- Supportive measures: ABCs (see general toxicology) 2- GIT decontamination: - Emesis by syrup of ipecac. - Gastric lavage - Activated charcoal and MDAC to prevent ongoing absorption of APAP and are given after antidote therapy to prevent adsorption of NAC. - Saline cathartics. Are preferred to enhance elimination from GIT. 3- Excretion of the poison from the blood: hemodialysis for renal failure. 4- Specific antidotes: i. N- acetyl Cysteine (NAC): - Mechanism: * It is metabolized by the hepatocyte to a glutathione precursor (cysteine) that provides protective levels of glutathione to detoxify the hepatotoxic metabolite by providing — SH group (minor pathway). * Enhance sulfation conjugation by providing sulfur (major pathway). - Forms and dose: Oral (mucomyst). Intravenous (parvolex) not approved in USA as it may cause anaphylactic reaction.  Should be initiated as early as possible because it is the only method to prevent hepatic necrosis. Initial loading dose (140 mg/kg), followed by maintenance doses (70 mg/kg/4hours for 3days). ii. No other antidotes proven to be effective as NAC. The suggested antidotes include, cimetidine (cytochrome antagonist) and methionine. 5- Symptomatic: Liver support: dextrose, sorbitol, etc.