ORGANO PHOSPHORUS AND CARBAMATE POISONING

Prof. S.SHIVAKUMAR’S Unit

By

Dr.EMMANUEL BHASKAR.M

INTRODUCTION

Most Common Poisoning In Tamilnadu3 Million Cases, 20,000 Deaths /YR World Wide.23.38% Of Toxicology Cases At G.S.H1930, Schrader, German, Studied Mech of ToxicityWeapon of Chemical Warfare.

CLASSIFICATION

HIGHLY TOXIC MODERATELY TOXIC

Phosphamidon [Dimecron]

Ethyl Parathion [Folidol]

Chlorthio Phos [Celathion]

Demeton [Systox]

Carbophenothion [Trithion]

[Lipid – Soluble]

Fenthion [Baytex, Entex] [Lipid soluble]

Malathion [Finit]

Fenitrothin [Tik-20]

Diazinon [Spectacide]

Temephos [Abate]

Bromphos [Nexion]

Phoxim [Baythion]

ORGANOPHOSPHATES

CARBAMATES

HIGHLY TOXIC MODERATELY TOXIC

Aldicarb [Temik]

Aminocarb [Matacil]

Carbofuran [Furadan]

Methomyl [Lannate]

Dimetilan[Snip]

Propoxur [Baygon]

Carbaryl [Sevin]

Isolan [Isolan]

Oxamyl [Vydate]

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

BINDING OF ACh TO ChE

ChE

N-C4H7O2 ACh

SER

ACYL POCKET

ANIONIC

N-C4H7O2 OHSER

SHAPE CHANGES

CH3 COOH + CHOLINE

ANIONIC

ANIONIC SER

SHAPE RESTORED

Ach Binds To Acyl Pocket

Binds Ser Active Site Allosteric Change In Pocket Shape

Hydrolysis, Pocket Shape Restored [Turnover T-150sec]

OH

Other Enzymes Inhibited By Opc & Carbamate

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.

ANSPreganglionic Parasympathetic Sympathetic Somatic

Nerves

Ach Ach Ach Ach Ach

Ganglion

Epi Skeletal Muscle

Ach Ach Norepi

Via

Bld

Effector

Organs

+ Pupil

-Heartrate

+Exocrine Glands

+GIT Smooth Muscle

+Lung Smooth Muscle

+Sweatgld

-Bloodvessel

[Some]

- Pupil

+Heart Rate

-Gastrointestinal SM

-Lung SM

+Blood Vessels [Most]

Often The Parasympathetic Features Predominates

Post Ganglionic

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 – SalivationU – Urinary Incont L – LacrimationM – Miosis U – Urinary IncontinenceB – Bronchorrhea, Bronchospasm, D – Diarrhea

Brady, Blurred Vision G – Gastro IntestinalE – Emesis DistressL – Lacrimation E – EmesisS – Salivation

NICOTINIC FEATURES: CENTRAL : LESS WITH CARBAMATES

(i) Muscle Fasciculations

[Striated]

(i) Paralysis

(ii) Muscle Weakness

(iii) Hypertension

(iv) Tachycardia

(v) Mydriasis [Rare]

(i) Unconsciousness

(ii) Confusion, Fatigue

(iii) Toxic Psychosis, Seizures

(iv) Resp. Depression

(v) Ataxia, Dysarthria

(vi) Extra Pyramidal Features.

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 :

Cholineste :

(i) Fatigue, Headache

(ii) Numbness, N&Vom

(iii) Diaphoresis, Saliv

(iv) Wheezing, Abdpain,

Diarrhoea

Able to Ambulate

20 – 50%

(i) Miosis

(ii) Genweakness,

(ii) Dysarthria,

(iv)Fascicul, +

Symptoms of Mild

Poisoning

Unable to Ambulate

10 – 20%

(i) Fasciculations

(ii) Mar.Miosis

[- Pupillary Reflex]

(iii) Flaccid Paralysis

(iv) Pulm. Rales.

(v) Resp. Distress

(vi) Cyanosis

Pt- Unconscsious

< 10%

IMPORTANT DIFFERENTIAL DIAGNOSIS

MIOSIS -(i) Clonidine

(ii) Opioids

(iii) Meprobamate

(iv) Phenothiazine

(v) Pontine HAE

Should Lack MUs & NIC Signs

MUSCARINIC (i) Amanita, Inocybe,

Clitocybe

(ii) Bethanecol

(iii)Pilocarpine

Should Lack Nicotinic Findings

NICOTINIC (i) Nicotine

(ii) Nicotiana

Lobelia

Should Not Have Miosis [May Have

Sialorrhoea, Bronchorhoea

DELAYED COMPLICATIONS

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.

INTERMEDIATE SYNDROME : [FIRST DESCRIBED IN 1987] [WADIA TY-II]

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

CONCLUSIONCause 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.