Organophosphorous compounds

poisoning

Introduction Organophosphate (OP) compounds are a

diverse group of chemicals used in both

domestic and industrial settings.

Examples of organophosphates include

1-insecticides (malathion, parathion, diazinon,

fenthion)

2- nerve gases (sarin)

3- ophthalmic agents (echothiophate,

isoflurophate)

Exposure to organophosphates is also possible

via intentional or unintentional contamination of

food sources.

,

Mechanism of toxicity The primary mechanism of action of

organophosphate is inhibition of

acetylcholinesterase (AChE).

Phosphate radical of organophosphates

interacts with active enzyme site forming a

covalent bond leading to increase of Ach at

the synapses and neuro-muscular junction.

Once AChE has been inactivated, ACh

accumulates throughout the nervous system,

resulting in overstimulation of muscarinic and

nicotinic receptors.

Clinical effects are manifested via activation of

the autonomic and central nervous systems

and at nicotinic receptors on skeletal muscle.

Once an organophosphate binds to AChE, the

enzyme can undergo one of the following:

1. Endogenous hydrolysis of the phosphorylated

enzyme by esterases

2. Reactivation by a strong nucleophile such as

pralidoxime (2-PAM)

3. Irreversible binding and permanent enzyme

inactivation (aging)

Types of cholinesterases

two types of cholinesterase. Both are inhibited

by organophosphates, but RBCs

cholinesterase may serve as a reliable index of

organophosphate poisoning as it contains true

cholinesterase and reflects the status of the

CNS.type True cholinesterase Pseudo cholinesterase

substrate acetylcholine

Ach and other

choline esters as

succinyl choline

Site of existenceCNS

RBCs

Plasma

liver

Routes of intoxification

Organophosphates can be absorbed

cutaneously, ingested, inhaled, or injected.

Although most patients rapidly become

symptomatic, the onset and severity of

symptoms depend on the specific compound,

amount, route of exposure, and rate of

metabolic degradation, duration.

Mortality

About 3-22%

Mortality rates depend on:

the type of compound used, amount ingested,

general health of the patient, delay in discovery

and transport, insufficient respiratory

management, delay in intubation.

Complications include severe bronchorrhea,

seizures, weakness, and neuropathy.

Respiratory failure is the most common cause

of death.

Signs and syymptoms Signs and symptoms of organophosphate

poisoning can be divided into 3 broad

categories, including (1) muscarinic effects,

(2) nicotinic effects, and (3) CNS effects.

1. CNS manifestations:

Ach is an excitatory neurotransmitter (NT). CNS

manifestations include:

Anxiety, restlessness, confusion, slurred speech,

ataxia and seizures.

2. Muscarinic manifestations:

Can be summarized as DUMBELS:

(diaphoresis and diarrhea; urination; miosis;

bradycardia, bronchospasm, bronchorrhea;

emesis; lacrimation; and salivation and sweating).

Muscarinic effects by organ systems include the

following:

a) CVS: bradycardia, hypotention. [at last?]

b) Respiratory - Rhinorrhea, bronchorrhea,

bronchospasm, cough, severe respiratory

distress

c) Gastrointestinal - nausea and vomiting,

abdominal pain, diarrhea, fecal incontinence

d- Genitourinary- incontinance

e- Ocular - Blurred vision, miosis

f- Glands - Increased lacrimation, diaphoresis

3- Nicotinic manifestations:

a- NMJ (NM) : muscle twitching, cramping,

weakness, decrease in respiratory effort,

cyanosis and paralysis due to prolonged

stimulation of muscles.

b- Sympathetic ganglia [Nn]: tachycardia, HTN

[initially WHY??] due to stimulation of adrenal

medulla.

Nicotinic manifestations are symbolized as

MATCH

(Muscle weakness / Adrenal hyper activity +

Ataxia/ Tachycardia/ Cramps/ HTN)

Managment

– For confirmed diagnosis measure RBCs level of

AChE.

1. Prevent any further exposure.

Remove all clothing and gently cleanse patients

suspected of organophosphate exposure with

soap and water because organophosphates are

hydrolyzed readily in aqueous solutions with a

high pH. Consider clothing as hazardous waste

and discard accordingly.

Health care providers must avoid contaminating

themselves while handling patients.

Irrigate the eyes of patients who have had

ocular exposure using isotonic sodium chloride

solution or lactated Ringer's solution.

2. History and physical examination of the patient

3. Symptomatic and supportive treatment:

ensure patent airways and ventilatory support.

Copious secretions may necessitate their

suction from oropharynx and upper airways.

4. gastric evacuation by ipecac or lavage.

5 -Continuous cardiac monitoring should be

established;

an ECG should be performed.

Torsades de Pointes should be treated in the

standard manner. The use of intravenous

magnesium sulfate has been reported as

beneficial for organophosphate toxicity. The

mechanism of action may involve

acetylcholine antagonism or ventricular

membrane stabilization.

6. The mainstays of medical therapy

in organophosphate poisoning include atropine,

pralidoxime (2-PAM), and benzodiazepines (eg,

diazepam).

A-Initial management must focus on adequate use

of atropine. Intravenous diphenhydramine may

provide an alternative centrally acting

anticholinergic agent used to treat muscarinic

toxicity if atropine is unavailable or in limited

supply.

It is capable of reversing CNS and Muscarinic

manifestations.

It may serve as a diagnostic tool for

organophosphate poisoning.

Dose: 1-4 mg I.V. dose repeated every 5-60 mins

until the patient demonstrates the S&S of mild

atropinism [mydriasis], then widen the interval

to 2-6 hrs for 48 hrs to keep the patient free of

cholinergic symptoms.

B- Pralidoxime

MOA: it reactivates acetylcholinesterase by

cleaving the covalent bond

Indications: the presence of nicotinic mediated

symptoms as muscle fasciculations, weakness

and paralysis.

Dose: initial dose 1 gm infused over 15-30 mins.

If weakness persists after one hr the dose may be

repeated.

Additional doses may be required at intervals for up

to 48 hrs to maintain relief of S & S.

.

It must be administered within 48 hrs of

intoxication, otherwise, the binding became

irreversible, the enzyme is destroyed and re-

synthesis must occur to replenish enzyme

stores [it takes about 4 weeks]

Because it does not significantly relieve

depression of respiratory center or decrease

muscarinic effects of AChE poisoning,

administer atropine concomitantly to block

these effects of OP poisoning