ISONIAZID

POISONING
Presented by
Group 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 OUT
Seizures
CNS infections  Fever  No headache
Meningitis  Altered mental status  No neck stiffness
Cerebral abscess  Vomiting  Not photophobic
 Rapid breathing  Not phonophobic
 Seizures  No rashes
 No speech difficulties
 No inflammation
 No headache
Structural Lesion  Seizures  No atherosclerotic plaque
Infarct  Coma  No thrombus
Hemorrhage  Increase heart rate  No embolus
 Altered mental status  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  No cerebral edema
 Seizures  No skull fracture
 Depression  No cerebral contusion(bruise in
 Confusion thr brain)
 Altered mental status  No subdural hemorrhage ( bet.
The dura and the archnoid)
 No epidural hemorrhage (bet.
The skull and the dura)
Toxic
Tricyclic and Tetracyclic Anti-  Seizures  No delirium
depressants e.g. carbamazepine,  Coma  No QRS prolongation, A-V
amitriptyline, Imipramine,  Tachycardia block, hypotension
amoxapine  Diaphoresis  No decreased bowel sounds
 Hyperthermia and motility
 Acidosis  No urinary retention
Cocaine and other stimulants  Tachypnea  (-)hyperactive bowel sound
 Seizures  (-)chest pain
 Diaphoresis  (-)palpitations
 Nausea and vomiting  (-)hallucinations
 Hyperthermia  (-)psychosis
 Increased BP
 Suicidal ideations
Theophylline  Nausea and vomiting
 Tachypnea  (-)wide pulse pressure
 Seizures  (-)respiratory acidosis
Lithium  Nausea and vomiting  (-)anorexia
 Seizures  (-)hypotension,
 Coma  (-)thyroid goiter,
hypothyroidism,
hyperthyroidism,
hyperglycemia, hypercalcemia
 (-)diarrhea
 (-)weight gain
 (-)aplastic anemia
Organophosphate
 Seizure  (-)tearing, drooling
 Comatose with gargling sound  (-)urinary and fecal
 Confusion incontinence
 Profuse diaphoresis  (-)gastrointestinal cramping
 Emesis  (-)bronchospasm and
 Respiratory difficulty bronchorrhea
 Suicidal ideation  (-)respiratory arrest
 (-)diaphragmatic
 weakness

Withdrawal Symptoms –  Nausea and vomiting  Abnormal movements

alcohols, sedative-hypnotic drugs ,  Seizures  Tremor of the hands
barbiturates  Coma  Involuntary, abnormal
movements of the eyelids
Agitation
Metabolic Acidosis

Uremia  Seizure  (-)peripheral neuropathy

 Vomiting  (-)hypotension
 Coma  (-)arrhythmias
 (-)ascites and peritonitis
Hypoperfusion  Tachycardia  Normal level of glucose
level
Status Epilepticus  Toxicologic etiology,  Patient doesn’t exhibit
seizure without return to tachycardia,RBS is
full consciousness normal(it should be
between seizure, hyperglycemia)
hypertension
Toxins: salicylates,ethylene  Same as above  Same as above
glycol, methanol, carbon
monoxide,cyanides,touluene,
acetaminophen
CNS  Same as above  Same as above
Clinical Presentation of Isoniazid
Poisoning
 Acute Chronic
 Rash
 Nausea and
 Fever
vomiting
 Hepatitis
 Seizures,
 Peripheral neuropathy
including status
 Optic neuritis
epilepticus
 Arthritis, vasculitis, lupus-like
 Lactic acidosis
syndrome
 Obtundation,
 Pellagra-like syndrome
coma
(diarrhea, dementia, dermatitis)
Laboratory Diagnosis
 serum INH concentration
 greater than 10 mg/L 1 hour post-ingestion
 greater 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 levels

 10 mL oxalated or heparinized blood

 Urine
 200 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  Liver Function

 Na+, K+, Cl-
 Protime
 Metabolic Acidosis
 Arterial Blood Gas  Aspartate
 Random Blood aminotransferase
Sugar,
 Urine pH  Alanine aminotransferase
 Alkaline phosphatase

Laboratory Diagnosis
 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:

 nicotinicacid (niacin or vitamin B3)

 nicotinamide adenine dinucleotide (NAD)
 pyridoxine (vitamin B6)
 pyridine ring
 important for its anti-tuberculous activity.
Pharmacodynamics
 Mostpopular use is as an anti-TB drug
 Mechanism 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

Pharmacodynamic
s
 Absorption
 Rapid and complete
 Rate can be slowed with food
 Distribution
 Allbody tissues and fluids including CSF
 Crosses placenta
 Enters breast milk
 Protein binding
 10% to 15%

Pharmacodynamic
s
 Metabolism
 Hepaticwith decay rate determined
genetically by acetylation phenotype

 Half-life elimination
 Fastacetylators: 30-100 minutes
 Slow acetylators 2-5 hours
 May be prolonged with hepatic or severe
renal impairment

Pharmacodynamic
s
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
 Isoniazid
N- P450 oxidation
acetyltransferase

Acetylisoniazid Hydrazine
+
Isonicotinic Acid
hydrolysis (non-toxic)

P450 oxidation
Acetylhydrazine Hepatotoxic
+ Metabolite
Isonicotinic Acid
(non-toxic)
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
Toxicokinetics
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.

Toxicokinetics
 Increased
Pyridoxine 1 Pyridoxine
excretion

Pyridoxine
phophokinase Tryptophan
2
Glutamate
decarboxylase Kynureninase 5

Decreased
Pyridoxal-5’-phosphate NAD+

Glutamate decreased SEIZURES Lactate Pyruvate

GABA 4 6
3

Acidosis
 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 Slow
acetylators acetylators
Metabolism 5-6 times slow
faster
Plasma 30-50% lower high
concentration
s
Elimination approximatel 180 minutes
half-life y 70 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
2.Prevent complications of isoniazid
toxicity
 Correction of GABA deficiency by
pyridoxine replacement

3. Prevent recurrence of suicidal attempts

 Referral 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!