Isoniazid Poisoning

ISONIAZID POISONING

Presented byGroup I

DE LEON. DUMAYAG. DIONISIO. HASAN. KESIP. LAGRIMAS. LAI.PABILONIA. PARCON. POCONG. RAMOS. SOTOZA. YOUNG

Poison

Any agent capable of Producing deleterious response in a

biological system Seriously injuring function Producing death

“What is there that is not a poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison.”

-Paracelcus (1493-1541)

The Case

This is a case of Mariela, 16 years old, was brought to PGH at 11:00 pm because of generalized seizures.

Salient Features

16 year-old female Generalized seizures Depressed when she came home 6 hours PTA Convulsing in bed 1 hour PTA with vomitus

consisting of tablets recognized as Isoniazid (used by her older sister 3 years ago), approximately 40 tablets ingested (300mg/tab)

On the way to the hospital, 4 other generalized seizures lasting for 1-2 minutes occurred

Salient features

At the ER, was non-responsive to pain, comatose with gargling sounds

Vital signs increased: BP of 140/90 mmHg, HR and PR of 96/min, T = 39°C, RR = 40/min

Fairly developed and nourished No cyanosis Positive for diaphoresis (perspiration

beads covered her face and neck)

Salient features

Heart, lungs, and abdominal examination were normal

Neurologic exam negative for localizing signs

Pulse Oximetry= 80% O2 saturation (LOW)

RBS = 100 mg/dL (NORMAL) Medical and Family history negative

for diabetes, CVDs, and epilepsy

Salient features

Working Diagnosis

Acute Isoniazid Toxicity

Differential Diagnosis

Differential Diagnosis Rule IN Rule OUTSeizures CNS infections Meningitis Cerebral abscess

Fever Altered mental status Vomiting Rapid breathing Seizures

No headache No neck stiffness Not photophobic Not phonophobic No rashes No speech difficulties No inflammation No headache

Structural Lesion Infarct Hemorrhage

Seizures Coma Increase heart rate Altered mental status

No atherosclerotic plaque No thrombus No embolus No petechial or debilitating

blood loss No hematemesis No hematochezia No hematuria No aneurysm or arteriovenous

malformation No vaginal bleeding No hematoma No contusion(brusing of brain

tissue)Trauma Coma

Seizures Depression Confusion Altered mental status

No cerebral edema No skull fracture No cerebral contusion(bruise in

thr brain) No subdural hemorrhage ( bet.

The dura and the archnoid) No epidural hemorrhage (bet.

The skull and the dura)

Toxic Tricyclic and Tetracyclic Anti-depressants e.g. carbamazepine, amitriptyline, Imipramine, amoxapine

Seizures Coma Tachycardia Diaphoresis Hyperthermia Acidosis

No delirium No QRS prolongation, A-V

block, hypotension No decreased bowel sounds

and motility No urinary retention

Cocaine and other stimulants Tachypnea Seizures Diaphoresis Nausea and vomiting Hyperthermia Increased BP Suicidal ideations

(-)hyperactive bowel sound (-)chest pain (-)palpitations (-)hallucinations (-)psychosis

Theophylline Nausea and vomiting Tachypnea Seizures

(-)wide pulse pressure (-)respiratory acidosis

Lithium Nausea and vomiting Seizures Coma

(-)anorexia (-)hypotension, (-)thyroid goiter,

hypothyroidism, hyperthyroidism, hyperglycemia, hypercalcemia

(-)diarrhea (-)weight gain (-)aplastic anemia

Organophosphate Seizure Comatose with gargling sound Confusion Profuse diaphoresis Emesis Respiratory difficulty Suicidal ideation

(-)tearing, drooling (-)urinary and fecal

incontinence (-)gastrointestinal cramping (-)bronchospasm and

bronchorrhea (-)respiratory arrest (-)diaphragmatic weakness

Withdrawal Symptoms – alcohols, sedative-hypnotic drugs , barbiturates

Nausea and vomiting Seizures Coma

Abnormal movements Tremor of the hands Involuntary, abnormal

movements of the eyelidsAgitation

Metabolic Acidosis

Uremia Seizure

Vomiting Coma

(-)peripheral neuropathy (-)hypotension (-)arrhythmias (-)ascites and peritonitis

Hypoperfusion

Tachycardia Normal level of glucose level

Status Epilepticus

Toxicologic etiology, seizure without return to full consciousness between seizure, hypertension

Patient doesn’t exhibit tachycardia,RBS is normal(it should be hyperglycemia)

Toxins: salicylates,ethylene glycol, methanol, carbon monoxide,cyanides,touluene,acetaminophen

Same as above Same as above

CNS Same as above Same as above

Clinical Presentation of Isoniazid Poisoning

Acute Chronic

Nausea and vomiting

Seizures, including status epilepticus

Lactic acidosis Obtundation,

coma

Rash Fever Hepatitis Peripheral neuropathy Optic neuritis Arthritis, vasculitis, lupus-

like syndrome Pellagra-like syndrome

(diarrhea, dementia, dermatitis)

Laboratory Diagnosis

serum INH concentrationgreater than 10 mg/L 1 hour

post-ingestiongreater than 3.2 mg/L 2 hours

post-ingestion greater than 0.2 mg/L 6 hours

post-ingestion

Takes a lot of time

Laboratory Diagnosis

Toxicological Examinations

Plasma INH levels10 mL oxalated or heparinized

blood

Urine200 mL for metabolite

Laboratory Diagnosis

Bedside Toxicologic Test 10% KCN, 10% Chloramine-T

To 4 drops of urine add 4 drops KCN and 10 drops Chloramine-T

Positive test: RED color

Laboratory Diagnosis

General Examinations

Electrolytes Na+, K+, Cl-

Metabolic Acidosis Arterial Blood Gas Random Blood

Sugar, Urine pH

Laboratory Diagnosis

Liver Function

Protime

Aspartate

aminotransferase

Alanine aminotransferase

Alkaline phosphatase

Kidney Function Blood Urea nitrogen Creatinine Myoglobin

Rhabdomyolysis Creatine phosphokinase MM fraction Complete Blood Count

Laboratory Diagnosis

Isoniazid: A closer look

Pharmacology also known as INH and isonicotinic

hydrazide structurally related to:

nicotinic acid (niacin or vitamin B3)nicotinamide adenine dinucleotide (NAD)pyridoxine (vitamin B6)

pyridine ring important for its anti-tuberculous activity.

PharmacodynamicsMost popular use is as an anti-TB drugMechanism of action:

inhibition of fatty acid synthetase 2 (FAS2) which catalyzes the linkage fatty acids to form mycolic acids.

Bactericidal against growing M. tuberculosis and bacteriostatic against dormant organisms

Pharmacodynamics

AbsorptionRapid and completeRate can be slowed with food

DistributionAll body tissues and fluids including CSFCrosses placentaEnters breast milk

Protein binding10% to 15%

Pharmacodynamics

MetabolismHepatic with decay rate determined

genetically by acetylation phenotype

Half-life eliminationFast acetylators: 30-100 minutesSlow acetylators 2-5 hoursMay be prolonged with hepatic or

severe renal impairment

Pharmacodynamics

Pharmacokinetics Forms:

Tablet Syrup Intramuscular injection

Rapidly absorbed in the small intestine Peak serum level within 2 hours of administration volume of distribution similar to that of total

body water at 0.6 L/kg and is minimally protein

bound

Pharmacokinetics

Metabolized through the cytochrome p450 enzyme system

75-95% excreted by the kidneys within 24 hours post administration

75% is metabolized through N-acetylation (hepatocytes and gut mucosa) and hydrolysis

Pharmacokinetics

Transformed to acetylhydrazine and isonicotinic acid, or directly to hydrazine

Crosses the blood-brain-barrier

Its concentration in the CNS is 20% of the serum concentration

Pharmacokinetics

IsoniazidN-

acetyltransferaseP450 oxidation

Acetylisoniazid

Acetylhydrazine+

Isonicotinic Acid(non-toxic)

hydrolysis

Hydrazine+

Isonicotinic Acid(non-toxic)

HepatotoxicMetabolite

P450 oxidation

Acetylation Diacetylhydrazine(non-toxic)

Pharmacokinetics

Toxicokinetics

Isoniazid induces toxicity by:directly

by inducing hypersensitivity (hepatitis, rash, fever)

Indirectly by depleting pyridoxine (vitamin B6) and niacin Toxicokinetic

s

INH-induced GABA deficiency occurs by 3 different mechanisms:

1. INH is converted to hydrazones, which block pyridoxine phosphokinase, the enzyme that activates pyridoxine to pyridoxal-5’-phosphate.

2. INH metabolites directly inhibit the activity of pyridoxal-5’-phosphate

3. INH increases the excretion of pyridoxine through the formation of isonicotinylhydrazide complexes, which are eliminated by the kidneys.Toxicokinetic

s

Glutamate

PyridoxineIncreased Pyridoxineexcretion

decreasedGABA

SEIZURES Lactate

Acidosis

Pyruvate

Tryptophan

Kynureninase

DecreasedNAD+

Pyridoxine phophokinase

Glutamate decarboxylase

Pyridoxal-5’-phosphate

1

2

3 4

5

6

Common Toxicologic Manifestations

Seizures Metabolic acidosis Neuropathy Hepatitis Renal failure

Toxicokinetics

Hydrazine Metabolites

Up to 5x more toxic than INH Prolong polyneuropathy Tubular necrosis Hepatitis

Characterizing Slow and Fast Acetylators

Fast acetylators

Slow acetylators

Metabolism 5-6 times faster

slow

Plasma concentrations

30-50% lower

high

Elimination half-life

approximately 70 minutes

180 minutes

90% of Filipinos are FAST ACETYLATORS

Therapeutic Objectives

1. Improve signs and symptoms and maintain vital signs

– Control and prevent reoccurrence of seizures

– Secure airway, breathing and circulation

– Gain intravenous access and administer appropriate intravenous fluids

– Address specific problems such as acidosis

– Do appropriate emergency evacuation of the ingested drug, if applicable

2.Prevent complications of isoniazid toxicityCorrection of GABA deficiency

by pyridoxine replacement

3. Prevent recurrence of suicidal attemptsReferral for psychiatric therapy

Drug Inventory

drug inventory

Management

Algorithm of Management Algorithm for Specific Complications

• A secure airway and breathing should be established and maintained. Give oxygen through ventori mask.

• Intravenous access should be obtained, and D5 0.9 NaCl 1 Liter x 8 hrs should be administered.

Administer Diazepam 2. 5 mg slow IV push as an initial approach to seizure control.

May shift to lorazepam IV 2.5 mg/dose at intervals 15-20 mins as needed.

Give antidote pyridoxine.

The Antidote

Pyridoxine

It rapidly terminates seizures, corrects metabolic acidosis, and reverses coma.

It provides the substrate to replenish pyridoxal-5′-phosphate, which in turn facilitates increased GABA production.

Pyridoxine Replacement

Pyridoxine should be administered in a dose equivalent to the suspected maximum amount of isoniazid ingested (i.e., gram-per-gram replacement).

If the amount of ingested isoniazid is unknown, 5 g of pyridoxine is given intravenously over 5 to 10 minutes.

Repeat dosing may be needed for persistent seizure activity and may also be used to reverse deep coma.

If the intravenous form of pyridoxine is not available, the drug using crushed tablets in a similar gram-per-gram replacement dose can also be utilized.

Since the patient ingested approximately 12 g of INH (300mg/tab x 40 tabs), on a gram to gram basis, 12 g of IV pyridoxine should be given as slow IV in a rate of 1g/min sufficient to counteract the neurotoxic effects

of isoniazid in most cases

Maintenance

Oral Vitamin B6 10mg/kg/day in three divided doses for 3-6 weeks

Referral

Refer for psychiatric help

Thank you!