Clinical toxicology Salicylates

Salicylate

• is used as an analgesic agent for the treatment of mild to moderate pain.

• Aspirin is used as an anti-inflammatory agent for the treatment of soft tissue and joint inflammation and vasculitides such as acute rheumatic fever .

• antipyretic drug.• Low-dose aspirin helps to prevent thrombosis

SALICYLATES

• Salicylate poisoning is a potentially life-threatening conditions

• ! Availability in many OTC oral preparations, various cold preparations; topical keratolytic preparations (methyl salicylate)

• Toxidromes (a syndrome caused by a dangerous level of toxins in the body)…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 (GI)

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 (is a syndrome has effect tomany organs unknown cause associated aspirin and viral infection in children==rash , vomiting and liver damage

SALICYLATES….PK• ACETYLATED SALICYLIC ACID (aspirin) &

NONACETYLATED SALICYLIC ACID (sodium salicylate, choline salicylate, magnesium salicylate…)

• are readily absorbed from the stomach Absorption depends on formulation: enteric coated tablets…..absorbed slowly

• . 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 (metabolic acidosis).

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

• Phase 1 of the toxicity is characterized by hyperventilation resulting from direct respiratory center stimulation, leading to respiratory alkalosis

• In phase 2 aciduria in the presence of continued respiratory alkalosis occurs when sufficient potassium has been lost from the kidneys

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

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

Range of toxicity

S &S Blood level range (mg/dl)

Single oral dose ingested (mg/kg)

Approximate n. of tabBaby 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

NB: daily therapeutic dose is 40–60 mg/kg/d

ASPIRIN Complications • E lyctrolyte 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 (peptic ulcer disease).

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)

• (Caution is advised for patients receiving concomitant high-dose aspirin and Diamox, as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported.

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.

• (hypoglycemia may ensue from impaired gluconeogenesis and increased utilization In addition, salicylate intoxication may decrease CNS glucose levels despite a normal peripheral glucose level if CNS glucose utilization exceeds blood supply)

Other procedures

• Diazepam for seizures• Calcium supplement for hypocalcemic

tetany• Vitamin K1 for coagulation defects