isoniazid poisoning
TRANSCRIPT
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!