Isoniazid ( INH ) overdose

Khaled A. Alrasheedi

PharmD, Clinical Toxicologist

objectives

• At end of this lecture you will able to know :

• Definitions and pharmacology of Isoniazid

• Toxicology characteristic of Isoniazid

• How to diagnosis of Isoniazid toxicity

• How to Management

Definition

• Isoniazid (INH) was introduced in 1952 and remains the antibiotic most commonly used in the treatment of tuberculosis.

• It is first-line treatment for both latent tuberculosis and in combination with other agents for active tuberculosis.

PHARMACOLOGY

• Dosage : 5 mg / kg/ day , Up to 10 mg/kg/day

• Absorption : rapidly absorbed from gastrointestinal tract GIT

• Peak serum concentrations : 3 – 5 µg / ml within 1 – 2 hrs.

• Half life is about 1 – 3 hrs.

• Metabolism in liver via acetylation.

• Hydrazine a component of rocket fuel that is also touted as an alternative treatment for cancer, and monomethylhydrazine, the toxic component of Gyromitra mushrooms, are derivatives of INH.

• They produce neurotoxicity and hepatotoxicity in a similar manner.

• INH is an inhibitor of several cytochrome P-450– mediated functions, particularly demethylation, oxidation, and hydroxylation.

• Significant drug interactions exist with INH.

• INH has a significant effect on several biochemical pathways.

CLINICAL TOXICOLOGY

• Adverse Events

• The most common :

1. Rash

2. Neuropsychiatric abnormalities,

3. Abnormal liver function with the appearance of jaundice

Risk factor for induce hepatotoxicity

• INH-induced liver enzyme elevation occurs in up to 20% of patients and in most cases is asymptomatic.

• 1- Older patients and in slow acetylators

• 2- Alcoholism and active hepatitis B infection

• 3- Multidrug antitubercular regimens

• Acute pancreatitis has also been associated with INH use but is rare.

• Approximately 25% of those taking INH develop antinuclear antibodies

• Peripheral neuritis has been observed in up to 20% of those taking INH at doses greater than 6 mg/kg. (patients with poor nutritional status, alcoholism, pregnancy, or hemodialysis-requiring renal disease at greater risk)

Acute Intoxication

• Acute ingestion of 2 to 3 g of INH leads to toxicity.

• whereas ingestion of more than 10 to 15 g or 80 mg/kg is usually fatal without aggressive treatment.

• Severe INH toxicity correlates with serum INH concentrations of greater than 30 mg/L.

• Clinical manifestations appear as early as 30 minutes after ingestion

signs and symptoms

• Nausea,

• Vomiting

• Slurred Speech

• Dizziness

• Mydriasis

• Tachycardia

• A subsequent cascade of biochemical events soon leads to the striking clinical features that characterize INH intoxication, namely, recurrent seizures, severe metabolic acidosis, and coma.

• Seizures after INH overdose are episodic and tend to occur at regular intervals.

• Once they begin, seizures are difficult to control despite the administration of anticonvulsants.

• Seizures refractory to conventional anticonvulsant therapy are a hallmark of INH intoxication

Severe metabolic acidosis is another prominent feature of INH overdose.

• surviving victims may present with a systemic pH as low as 6.49.

Coma may be protracted after overdose (lasting more than 24 hours) and may continue after seizures have abated and metabolic acidosis has been corrected.

Other clinical effects of acute INH intoxication :

• severe hypotension, hyperglycemia, acetonuria,

• abnormal results of liver function tests, and renal failure

DIAGNOSIS

• In the absence of a history of overdose, INH overdose may be suspected in patients who present with the characteristic symptom complex.

• Only INH overdose has recurrent seizures as its hallmark

• 1- The differential diagnosis of severe metabolic acidosis

• Diabetic ketoacidosis and the ingestion of cyanide, methanol,

• ethylene glycol, iron, ibuprofen, or salicylates.

laboratory tests

1. An Arterial Blood Gas Determination

2. Electrocardiogram,

3. Electrolyte Measurements,

4. Liver Function Tests,

5. Creatine Phosphokinase Determination,

6. Urinalysis

MANAGEMENT

• The initial management of INH intoxication :

• Stabilization of vital signs with provision

• of a patent airway, oxygen,

• cardiovascular

• support with intravenous fluids,

• and administration of sodium

• bicarbonate to treat metabolic acidosis

• Activated charcoal with a cathartic is indicated when patient arrive emergency department within 1 hour of ingestion.

• Ipecac-induced emesis is contraindicated owing to the potentially rapid onset of seizures and risk for airway compromise.

• Intravenous pyridoxine has been shown to be highly effective for INH intoxication and should be administered to all symptomatic patients.

• The milligram dose of pyridoxine should equal the ingested dose of

• INH.

• When the quantity of ingested INH is unknown, a pyridoxine dose of 5 g (75 mg/kg in children) should be administered.

• Repeated doses of pyridoxine may be required based on the resolution of signs and symptoms.

• Pyridoxine is commonly dispensed

• as 100 mg/mL solution with a pH ranging from 2 to 3.8.

• Anticonvulsants remain important in the early treatment of seizures

• ( The benzodiazepines are agents of choice ).

• Prophylactic administration of benzodiazepines has no proven efficacy.

• INH has a small volume of distribution and low protein binding, pharmacokinetic features that make it amenable to hemodialysis and peritoneal dialysis.

References

• Haddad and Winchester's clinical management of poisoning and drug overdose 4th edition.

• THANK YOU