Clinical toxicology Salicylates Department of Biopharmaceutics and Clinical Pharmacy

SALICYLATES Salicylate poisoning is a potentially life-threatening conditions ! Availability in many OTC oral preparations, various cold preparations; topical keratolytic preparations (methyl salicylate) ! Lack of discrete toxidromes…confusion, dehydration, and metabolic acidosis are often attributed to sepsis, pneumonia, or gastroenteritis

SALICYLATES Aspirin poisoning may affect people of all ages Children are most susceptible: fatal outcome enhanced with dehydration and/or febrile Elderly: chronic toxicity due to alterations in the elimination process and simultaneous ingestion of other drugs

Side effects Gastrointestinal ulceration and intolerance Blockage of platelet aggregation Inhibition of prostaglandin-mediated renal function Inhibition of uterine motility Hypersensitivity reactions Reye’s syndrome in children with viral infections Reye’s syndrome: BRAIN damage & LIVER dysfunction & hypoglycemia…..rash, vomiting, liver damage; fatty liver, encephalopathy LEXICOMP: Pediatric: When used for self-medication (OTC labeling): Children and teenagers who have or are recovering from chickenpox or flu-like symptoms should not use this product. Changes in behavior (along with nausea and vomiting) may be an early sign of Reye's syndrome; patients should be instructed to contact their healthcare provider if these occur. Influenza Virus Vaccine (Live/Attenuated): May enhance the adverse/toxic effect of Salicylates. Specifically, Reye's syndrome may develop. Risk X: Avoid combination

SALICYLATES….PK ACETYLATED SALICYLIC ACID (aspirin) & NONACETYLATED SALICYLIC ACID (sodium salicylate, choline salicylate, magnesium salicylate…) Aspirin pKa 3.5…..nonionized in the stomach…..rapid absorption Absorption depends on formulation: enteric coated tablets…..absorbed slowly Highly ionized in blood stream….any decrease in the blood pH…..nonionized form….tissue absorption (CNS)….Vd increase in case of acidemia Buffered preparations.…form salts upon disintegration which enhance absorption Pharmacokinetics. Salicylates are well absorbed from the stomach and small intestine. Large tablet masses and enteric-coated products may dramatically delay absorption (hours to days). The volume of distribution of salicylate is about 0.1–0.3 L/kg, but this can be increased by acidemia, which enhances movement of the drug into cells.

SALICYLATES….PK Effervescent tablets rapidly absorbed Other factors: rate of gastric emptying, concurrent ingestion of food and drugs, GI diseases ELIMINATION: mostly by hepatic metabolism at therapeutic doses, but renal excretion becomes important with overdose …..saturation of hepatic enzyme….zero-order elimination kinetics Furosemide….inhibit salicylate excretion; Acetazolamide: enhance the ability of nonionized form to penetrate CNS

Aspirin - Pharmacokinetics Rapidly absorbed from GI tract through passive diffusion  80-90% is bound to plasma proteins, mainly albumin  Can displace several other drugs from plasma protein resulting in higher effective plasma concentrations  Rapidly hydrolyzed in blood and liver to salicyclic acid

Aspirin Toxicity: changes in acid-base balance Salicylates directly stimulate the respiratory center in the medulla resulting in hyperventilation Uncoupling of oxidative phosphorylation…. the cell becomes dependent upon anaerobic metabolism, resulting in accumulation of lactate + - CO + H O H C O H + HCO 2 2 3 3 2 (respiratory alkalosis) 3. Compensated by renal excretion of bicarbonate (compensated metabolic acidosis)

Respiratory alkalosis CNS effects of salicylate intoxication Salicylate level increases in the brain Stimulate respiratory center hyperventilation PCO2 Respiratory alkalosis Uncouple oxidative phosphorylation Inh kreb’s cycle enz Inhibition a.a metabolism periph glu demand Renal compensation ATP Inc organic acids, a-ketogluterate Aminoaciduria glycolysis Stim lipid met Metabolic acidosis Inc lactic and pyruvic acid ketone bodies

SALICYLATES  The major early toxic manifestations of salicylate poisoning result from stimulation of the CNS These include nausea, vomiting, tinnitus, headache, hyperapnea, and neurological abnormalities (confusion, slurred speech, convulsions) Another serious effect of salicylates is dehydration?? Uncouple oxidative phosphorylation in the mitochondria; this generates heat and may increase body temperature Renal compensated respiratory alkalosis results in loss of carbonate, followed by Na and K and water

SALICYLATES  This dehydration is more common in children and usually associated with moderate to severe levels of salicylate toxicity A useful means of evaluating the degree of potential following an acute oral ingestion of salicylate is to correlate the blood concentration with the clinical status of the patient

Blood level range (mg/dl) Single oral dose ingested (mg/kg) NB: daily therapeutic dose is 40–60 mg/kg/d Range of toxicity S &S Blood level range (mg/dl) Single oral dose ingested (mg/kg) Approximate n. of tab Baby aspirin Adult aspirin Asymptomatic <45 mild N,V,mild hyperpnea, tinnitus 45-65 150-200 Up to 37 Up to 9 Moderate Hyperpnea, hyperthermia, sweating, dehydration 65-90 200-300 37-74 9-18 Sever Sever Hyperpnea, coma, convulsion, pulmonary edema, cyanotic, CV collapse 90-120 300-500 74-123 18-30 lethal Coma, death 120 >500 >123 >30

ASPIRIN Complications Electrolyte Disturbance Hypokalemia and deranged Na+ levels Glucose (hypo) Cerebral and pulmonary edema may occur due to unknown reason Salicylates alter platelet function and may also prolong the prothrombin time Significant GI bleeds secondary to gastritis or PUD

Management Treatment of salicylate toxicity should involve: GI decontamination Correct Dehydration Correction of metabolic acidosis Hyperthermia control Hypokalemia control Hypoglycemia control Hypocalcemia control Hypoprothrombinemia control Seizure control Hemodialysis

Management Treatment of salicylate toxicity should involve: GI decontamination Correct Dehydration Correction of metabolic acidosis Hyperthermia Hypokalemia Hypoglycemia

G.I decontamination Not necessary for patients with chronic intoxication If acute….within 1-2 hr post ingestion (no if > 12hrs): Administration of oral activated charcoal and if necessary gastric lavage Whole-bowel irrigation is recommended to help move the pills and charcoal through the intestinal tract Enhanced elimination by sodium bicarbonate (PH 7.5) or hemodialysis are very effective methods

Extracorporeal methods Hemodialysis is required for any of the following: Seum levels >100mg/dl in acute intoxication, Serum levels > 60mg/dl in chronic intoxication Persistent/progressive acidosis Deteriorating level of consciousness Renal insufficiency   

Correct Dehydration Dehydration is common with salicylate poisoning Due to hyperthermia, electrolyte imbalance and kidney shutdown and vomiting Usually treatment with parenteral fluids Important to keep the patient hydrated to maintain kidney function (renal excretion) Not overhydrated as it may contribute to pulmonary edema

Correct Dehydration Note: if patient has pulmonary edema will not tolerate fluids load and must be considered for dialysis

Management Treatment of salicylate toxicity should involve: G.I decontamination Correct Dehydration Correction of metabolic acidosis Hyperthermia Hypokalemia Hypoglycemia

Correction of metabolic acidosis Sodium bicarbonate is added to the i.v. fluids to correct metabolic acidosis associated with moderate to sever toxicity This will also rise the PH of the urine, so enhance salicylate elimination Do not use acetazolamide for urine alkalinization (acidify the serum)

Management Treatment of salicylate toxicity should involve: G.I decontamination Correct Dehydration Correction of metabolic acidosis Hyperthermia Hypokalemia Hypoglycemia

Hyperthermia Rectal temp must be obtain coz oral route may be falsely low (tachypnea) Hyperthermia is a problem with moderate-severe poisoning Begin external cooling with tepid (lukewarm) sponging and fanning. This evaporative method is the most efficient method of cooling

Management Treatment of salicylate toxicity should involve: G.I decontamination Correct Dehydration Correction of metabolic acidosis Hyperthermia Hypokalemia Hypoglycemia

Hypokalemia Potassium chloride is added to the IV fluids to correct hypokalemia Serum K levels should be closely monitored…arrhythmias

Management Treatment of salicylate toxicity should involve: G.I decontamination Correct Dehydration Correction of metabolic acidosis Hyperthermia Hypokalemia Hypoglycemia

Hypoglycemia Glucose is added to i.v. fluids to correct the hypoglycemia and ketosis Note: Salicylate-poisoned patients may have low brain glucose levels despite normal measured serum glucose.

Other procedures Diazepam for seizures Calcium supplement for hypocalcemic tetany Vitamin K1 for coagulation defects