ORGANO PHOSPHORUS

AND CARBAMATE
POISONING

Prof. S.SHIVAKUMAR’S Unit

By
Dr.EMMANUEL BHASKAR.M
 INTRODUCTION
Most Common Poisoning In Tamilnadu
3 Million Cases, 20,000 Deaths /YR World
Wide.
23.38% Of Toxicology Cases At G.S.H
1930, Schrader, German, Studied Mech of
Toxicity
Weapon of Chemical Warfare.
 CLASSIFICATION
ORGANOPHOSPHATES

HIGHLY TOXIC MODERATELY TOXIC

Phosphamidon [Dimecron] Fenthion [Baytex, Entex] [Lipid soluble]

Ethyl Parathion [Folidol] Malathion [Finit]

Chlorthio Phos [Celathion] Fenitrothin [Tik-20]

Demeton [Systox] Diazinon [Spectacide]

Carbophenothion [Trithion] Temephos [Abate]

[Lipid – Soluble] Bromphos [Nexion]

Phoxim [Baythion]
 CARBAMATES
HIGHLY TOXIC MODERATELY TOXIC

Aldicarb [Temik] Propoxur [Baygon]

Aminocarb [Matacil] Carbaryl [Sevin]

Carbofuran [Furadan] Isolan [Isolan]

Methomyl [Lannate] Oxamyl [Vydate]

Dimetilan[Snip]

ROUTE OF EXPOSURE : Inhalational [Most Rap], Oral, Conjuctival,

Dermal [Least Rapid].
MECHANISM OF ACTION
ACETYL CHOLINE [Ach], Found At NMJ of
(i) Preganglionic Synapses – Sym & Para-Symp
(ii) Postganglionic Para-Sym [Mus] Terminals, Within
Brain
Binds Post Synaptic Receptors Via
(i) G Proteins [Muscarinic]
(ii) LIG - Linked Channels [Nicotinic]
Within Synaptic Cleft.
ChE
Acetyl Choline Acetic Acid +Choline
 BIN DING O F ACh TO ChE
ChE
Ach Binds To
Acyl Pocket
OH
ANIONIC SER
ACYL POCKET
N-C4H7O2 ACh

Binds Ser Active Site

Allosteric Change In
N-C4H7O2 OH Pocket Shape
ANIONIC SER
SHAPE CHANGES

CH3 COOH + CHOLINE Hydrolysis, Pocket Shape

Restored [Turnover T-
150µsec]
ANIONIC SER
SHAPE RESTORED
 Ot her Enzym es Inhi bi ted By Opc &
Car bamate
Chymotrypsin, PL & Hepatic Carboxyl Esterases.
Carbamate Spontaneously Dissociate in 4-24hrs
Phosphorylated Complex is Irreversible Naturally.
AGING - Overtime OPC Permanently Alter
Shape of Acyl Pocket, Acyl Gp is
Lost,
Enzyme Nonfunctional
- Dur 48-72hrs [Except War Gases]
- Carbamates Do Not Cause Aging
Lipophilic OPC Residues Stay for Dys To Weeks.
 ANS
Preganglionic Parasympathetic Sympathetic Somatic
Nerves
Ach Ach Ach Ach Ach
Ganglion
Epi Skeletal Muscle

Post Ganglionic Ach Ach Norepi

+Sweatgld Via
-Bloodvessel
+ Pupil Bld
[Some]
Effector -Heartrate
- Pupil
Organs +Exocrine Glands
+Heart Rate
+GIT Smooth Muscle
-Gastrointestinal SM
+Lung Smooth Muscle
-Lung SM
+Blood Vessels [Most]
Often The Parasympathetic Features Predominates
 CLINICAL FEATURES

Symptoms After Inhalation Occur Within Second.

Transdermal, Trans Conjuctival – Delayed Onset
[Except “Vx” Used in Chemical Warfare]
Delayed Onset (i) Parathion [Has To Be Conv To Paraoxon –
Liver] {ii) Lipophilic OPC [Stored In Adipose.T., Slowly
Leaches Out]
Features i) MUSCARIINIC
ii) NICOTINIC
iii) CENTRAL
MUSCARIINIC FEATURES :
[WADIA – TYPE I
SYNDROME]
“DUMBELS” “SLUDGE”
D - Diarrhea, Diaphoresis S – Salivation
U – Urinary Incont L – Lacrimation
M – Miosis U – Urinary Incontinence
B – Bronchorrhea, Bronchospasm, D – Diarrhea
Brady, Blurred Vision G – Gastro Intestinal
E – Emesis Distress
L – Lacrimation E – Emesis
S – Salivation
 NICOTINIC FEATURES: CENTRAL : LESS WITH
CARBAMATES

(i) Muscle Fasciculations (i) Unconsciousness

[Striated] (ii) Confusion, Fatigue
(iii) Paralysis (iii) Toxic Psychosis, Seizures
(iv) Muscle Weakness (iv) Resp. Depression
(v) Hypertension (v) Ataxia, Dysarthria
(vi) Tachycardia (vi) Extra Pyramidal Features.
(vii) Mydriasis [Rare]
 SEVERITY OF OPC POISONING [AFTER
NAMBA]
LATENT POISONING
Clinical Manif : None
S.Cholinesterase : > 50% of Normal Value [3000 – 6000 IU/L]

MILD MOD SEV

Clinical Man : (i) Fatigue, Headache (i) Miosis (i) Fasciculations

(ii) Numbness, N&Vom (ii) Genweakness, (ii) Mar.Miosis

(iii) Diaphoresis, Saliv (ii) Dysarthria, [- Pupillary Reflex]

(iv) Wheezing, Abdpain, (iv)Fascicul, + (iii) Flaccid Paralysis

Diarrhoea Symptoms of Mild (iv) Pulm. Rales.

Poisoning (v) Resp. Distress

(vi) Cyanosis

Able to Ambulate Pt- Unconscsious

20 – 50% Unable to Ambulate < 10%

Cholineste :
IMPORTANT DIFFERENTIAL
DIAGNOSIS
MIOSIS -(i) Clonidine
(ii) Opioids Should Lack MUs &
(iii) Meprobamate NIC Signs
(iv) Phenothiazine
(v) Pontine HAE

MUSCARINIC (i) Amanita, Inocybe,

Clitocybe Should Lack Nicotinic
(ii) Bethanecol Findings
(iii)Pilocarpine

NICOTINIC (i) Nicotine Should Not Have

(ii) Nicotiana Miosis [May Have
Sialorrhoea,
Lobelia
Bronchorhoea
 DELAYED COMPLICATIONS
INTERMEDIATE SYNDROME : [FIRST DESCRIBED IN 1987]
[WADIA TY-II]
Occurs 24-96hrs, Weakness of Ocular, Bulbar, Proximal Limb
Muscles, And Respiratory Failure.
Common With Dimethoate, Parathion, Malathion & Methly
Parathion
ChE Activity 20% or Less During Onset
Represent Final Partitioning of OPC From Serum To M.E.P.
EMG Studies Show Decremental Conduction With RNS.
Causative Factor – Inadequate Oxime Therapy / Premature DIS.
Recovery in 4 – 18 Days.
Incremental Conduction Improvement And Normalization of EMG
Occurs With Recovery.
 OPC INDUCED DELAYED
NEUROTOXICITY : [TRI-ORTHO
CRESYL PHOSPHATE]
Sensory – Motor Polyneuropathy, 1-3 wks, Involves NTE
Starts With Distal Motor Weakness – Lower Extremities And
Sensory Paresthesia
Progresses To Muscle Atrophy & Paralysis, Foot Drop
Ataxia Develops – Distal Tendon Reflexes Lost
May Involve – Upper Extremities And Produce Flaccid
Symmetric Paralysis
Large Distal Neurons – Axonal DEG – Myelin Degeneration
Some Recover 12 – 15 months, Permanent SpasticityAnd
Persistent UMN Signs Reported.
 INVESTIGATIONS
CHOLINESTERASE : (i) RBC [True ChE] (ii) Plasma [Pseudo ChE]
To Confirm Diagnosis, Decide Oxime Therapy
PLASMA CHOLINESTERASE [PSEUDO ChE] : N [3000 – 6000 IU/L]
 In Plasma, Liver, Heart, Pancreas, Brain
 Sensitive, First To Fall In Acute Exposure, Normal – Chronic Exp.
 Less Specific Than RBC ChE, Poor Correl With Neuronal.E.
 Response To Anti Dotal Therapy, Less Dramatic,
 Depressed In Genetic Def, Hepatic Dys, Alcoholics, Malnut,
Chronic Illness, Neoplasm, Infection
 Without Treatment Pl.ChE Improves Over 7-10 Days, Normalizes in
4 – 6 Weeks
4 – 6 wks.
RBC CHOLINESTERASE :
 Diagnostic In Chronic Exposure
 More Specific, Correlates With Neuronal Effects.
 Low Levels In Haemoglobinopathies & Thalasemia,
 Without Treatment, Improves 1 % /Dy, 3-4 Mths To Normalize

OTHER INVESTIGATIONS:
 Neutrophil Leucocytosis - 46% Hyperglycaemia - 7%
 Proteinuria - 19% ECG [TACH, BRAD, - 5%
VPD,TDP, HB,VT]
 Glycosuria, ↑ S.Amylase - 14%

EMG : (i) Decrement Increment Response To High Freq

[30-50 Hz] RNS
(ii) Decremental Response To High Rate RNS
[ 30 & 50 Hz]
 PRECAUTION FOR
PHYSICIAN
Clothing & Shoes Covered With Protective Water Impermeable
Materials, Masks With EYE Shields.
OPC Penetrates Normal Latex/Polyvinyl Gloves,
Nitrile/Neoprene Gloves Recommended
MANAGEMENT
ABC
Cloths Removed, Put In Chlorine Bleach Soln [4 –5 %
Hypochlorite]
Skin Washed With Soap & Water, Then With Ethanol & H2O.
Gastric Lavage & Activated Charcoal, Followed Along With A
Cathartic. If Unconscious Gastric Lavage After Placing a Cuffed
ET Tube.
ATROPINE
 Phys Antidote For Ach, Blocks Ach At Mus Not NIC Recep
 Onset Of Action 1- 4Mts, Peak Effects 8 Mts.
 Signs of Atropinization : Tachycardia, Flushing, Myrdriasis,
Hyperthermia, Drying of
Secretions.
 Drying of Secretion – Reliable Endpoint, Not – Tachy, Myrdriasis
 DOSE : Oxygenation Before Therapy.
Mild – 1-2 mg I.V. Every 15-30mts Until Signs of
Atropinization
Moderate To - 5mg I.V. If No Effect of Adminis Dose, Double
Severe Dose Every 5Mts Till Atropinization

As High as 1200mg – 1500 mg May Be Required In 24hrs.

Infusion –50mg in 250ml N.S. May Be Used When Large

Doses Given
Tachycardia And Dilated Pupils Are Not Contraindications
For Atropine Use.
Most Common Cause of Treatment Failure is Inadequate
Atropinization.
After Atropinization is Achieved Dose Adjusted To
Maintain A Dry Tracheo Bronchial Tree – For 24hrs.
Head To Foot Tepid Sponging – Decrease Body
Temperature.
Glyco Pyrolate [0.05mg /kg IV] May Be Given To Counter
Peripheral Muscarinic Effects [It has No CNS Action].
PARALIDOXIME : Nucleophilic Oxime
 Regenerate ChE by Removing The Phosphate Moiety
From Acyl Pocket.
 Scavenger For Non-Bound Organo-Phosphate.
 Endogenous Anti-Cholinergic Effect In Normal Doses.
ChE Levels Taken Before Therapy, Improvement
Monitored.
Dose : - Should Not Be Given Rapid I.V. – Neuro – MUS
Blockade
- 1-2 GM In 250 Ml N.S. – 30 Mts, Followed by
Similar Doses At 1-2Hrs And 6-12 Hrs.

No Improvement

500 Mg/Hr, 12 G/Dy

Clinical Therapeutical End Point Is Resolution of Muscle
Weakness, Fasciculations.

Contrary To Previous Belief, P2 AM Has Definitive Role

Even Beyond 24 hrs, Inspite of Enzyme Aging.

Reason – Highly Lipid Soluble OPC Leach Out From Fat

Store For Dys –Weeks [6 Wks], These Form New Comp.
Which Will Be Countered By P2 AM.

Subsequent P2 AM Therapy Based On ChE Monitoring.

Inadequate Oxime Therapy Results In Intermediate Syn.

Adverse Effects of High Dose of P2 AM
(i) Headache, Dizziness
(ii) Nausea & Vom
(iii) Hypertension

Even Though P2 AM Is Not Helpful In Carbamate Toxicity

It Is Not Contraindicated.

Other Oximes : (i) Obiodoxime : Superior To P2 AM

In Dimethyl
Phosphoryl
(ii) Trimedoxime

Hagedorn GP : (i) HI -6
(ii) HLO - 7
Drugs To Be Avoided In OPC
 Methyl Xanthines
 Amino Glycosides
 Succinyl Choline
Seizures – Treated With Diazepam/Lorazepam.
Ventilator Support
 Stupor With Abnormal Chest X-Ray
 Pao2 < 60 mmHg.
 Profound Muscle Weakness
 CONCLUSION
Cause of Death – Pulmonary Edema, Resp
Paralysis.
Should Be Classified Based On Severity.
Cholinesterase Levels Taken Initially, Subs
Monitored.
Complete Atropinization, As High as 1200mg –
1500mg in 24 hrs.
Earlyadequate Oxime Therapy, Upto 12G/DY, Follow
Up With ChE Levels.
Oxime Not Contraindicated In Carbamates, Although
Not Helpful.
Identify Patients Requiring Ventilatory Support.