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 
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

 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
 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

1. Salicylates directly stimulate the respiratory center in

the medulla resulting in hyperventilation
+
CO + H 2O H 2C O 3 H + HCO -3
2
(respiratory alkalosis)

2. Uncoupling of oxidative phosphorylation…. the cell

becomes dependent upon anaerobic metabolism,
resulting in accumulation of lactate

3. Compensated by renal excretion of bicarbonate

(compensated metabolic acidosis)

 CNS effects of salicylate intoxication

Salicylate level increases in the brain

Stimulate respiratory center

hyperventilation

PCO2

Respiratory alkalosis
Uncouple oxidative periph glu Inh kreb’s cycle Inhibition a.a
phosphorylation demand enz metabolism Renal
compensation
ATP Inc organic Aminoaciduria
acids, a-
glycolysis ketogluterat
Stim lipid met
e

ketone bodies
Metabolic acidosis
Inc lactic and pyruvic acid
 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
 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
NB: daily therapeutic dose is 40–60 mg/kg/d

Range of S &S Blood Single Approximate

toxicity level oral n. of tab
range dose Baby Adult
(mg/d ingeste aspiri aspiri
l) d n n
(mg/kg
)

Asymptomatic <45
mild N,V,mild hyperpnea, 45-65 150-200 Up to Up to 9
tinnitus 37

Moderate Hyperpnea, 65-90 200-300 37-74 9-18

hyperthermia,
sweating, dehydration
Sever Sever Hyperpnea, 90-120 300-500 74-123 18-30
 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