1. Clinical toxicology Salicylates
Department of Biopharmaceutics and Clinical Pharmacy

2. 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

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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)

9. 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

10. 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

11. 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

12. 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
Up to 37
Up to 9
Moderate
Hyperpnea, hyperthermia, sweating, dehydration
65-90
37-74
9-18
Sever
Sever Hyperpnea, coma, convulsion, pulmonary edema, cyanotic, CV collapse
90-120
74-123
18-30
lethal
Coma, death
120
>500
>123
>30

13. 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

14. 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

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

16. 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

17. 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   

18. 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

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

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

21. 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)

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

23. 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

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

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

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

27. 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.

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