1. Clinical toxicology Salicylates Department of Biopharmaceutics and Clinical Pharmacy

2. Properties of Prostaglandins

3. 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

4. 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

5. Side effects 1.Gastrointestinal ulceration and intolerance 2.Blockage of platelet aggregation 3.Inhibition of prostaglandin-mediated renal function 4.Inhibition of uterine motility 5.Hypersensitivity reactions 6.Reye’s syndrome in children with viral infections

6. 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

7. 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

8. 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

9. Aspirin Toxicity: changes in acid-base balance 1.Salicylates directly stimulate the respiratory center in the medulla resulting in hyperventilation 2.Uncoupling of oxidative phosphorylation…. the cell becomes dependent upon anaerobic metabolism, resulting in accumulation of lactate 2 CO H O 2 + H C O 23 H + +HCO 3 - (respiratory alkalosis) 3. Compensated by renal excretion of bicarbonate (compensated metabolic acidosis)

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

11. 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?? 1.Uncouple oxidative phosphorylation in the mitochondria; this generates heat and may increase body temperature 2.Renal compensated respiratory alkalosis results in loss of carbonate, followed by Na and K and water

12. 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

13. Range of toxicity S &SBlood level range (mg/d l) Single oral dose ingeste d (mg/kg ) Approximate n. of tab Baby aspiri n Adult aspiri n Asymptomatic<45 mildN,V,mild hyperpnea, tinnitus 45-65150-200Up to 37 Up to 9 ModerateHyperpnea, hyperthermia, sweating, dehydration 65-90200-30037-749-18 SeverSever Hyperpnea, coma, convulsion, pulmonary edema, cyanotic, CV collapse 90-120300-50074-12318-30 lethalComa, death120>500>123>30 NB: daily therapeutic dose is 40–60 mg/kg/d

14. 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

15. 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

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

17. 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

18. 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

19. 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

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

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

22. 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)

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

24. 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

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

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

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

28. 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.

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