ORGANOPHOSPHOROUS

POISONING

PRESENTOR Dr. S.PRIYA

MODERATOR Lt.Col A.K. GHOSH
(Classified specialist Medicine &
Cardiology)

INTRODUCTION
Acute organic insecticide poisoning is
a major health problem all over the
world, particularly in the developing
countries, where organophosphates
(OPs) are the most common suicidal
poisons with high morbidity and
mortality

The OP compounds are popular

insecticides because of their effectiveness
and nonpersistence in the environment
owing to their unstable chemical nature.
They do not persist in the body or
environment as do organochlorides and
have become the insecticide group of
choice replacing DDT, an organochloride
compound

PHARMACOLOGY

CLASSIFICATION
1. Agricultural insecticides (high toxicity)
Paration
phorate
mevinphos
disulfoton.
2. Animal insecticides (intermediate toxicity)
chlorpyrifos.
3. Household use or use in golf courses (low toxicity)
malathion
dichlorvos.

PHARMACOKINETICS

Skin
Oral mucosa
Conjunctival mucosa
G.I.T
Respiratory routes
Organophosphate compounds block
ACETYLCHOLINEACETICACID &
CHOLINE
Increased acetylcholine at synapses
Most common cause of toxic effect of
o.p.poisoning

PATHOPHYSIOLOGY

OPs bind to the active serine residue

of acetyl cholinesterase irreversibly
Convert the enzyme into an inactive
protein complex
Result in accumulation of acetyl
choline at the receptors

Etiology of OP Poisoning

Suicidal
Accidental poisoning
Occupational exposure such as
farming
Large proportion(68%) suicidal
attempts
Young patients <30 yrs with male
preponderance

CLINICAL FEATURES

Cardiovascular: Bradycardia, hypotension.

Respiratory Rhinorrhea, bronchorrhea,
bronchospasm, cough.

Gastrointestinal: Increased salivation, nausea

and vomiting, abdominal pain, diarrhea, fecal
incontinence.
Ocular: Blurred vision, increased lacrimation,
miosis.

CLINICAL FEATURES(CONTD..)

Nicotinic Effects
Cardiovascular: Tachycardia,
hypotension.
Musculoskeletal: Weakness,
fasciculations, cramps, paralysis

Central Receptor Stimulation

Anxiety, restlessness, ataxia, absent

reflexes, convulsions, insomnia,
tremors, dysarthria, coma,
hyperreflexia, Cheyne Stokes
breathing, respiratory depression,
and circulatory collapse come under
this

Multisystem Manifestations

The end-result may be involving the

gastrointestinal tract, respiratory
system, cardiovascular system,
nervous system, skeletal muscles, as
well as metabolic effects such as
hypo- or hyperglycemia.

Neurological Manifestations
THREE
TYPE
TYPE
TYPE

types of paralyses recognized

I
II
III

Type-I Paralysis or Acute Paralysis

Initial cholinergic crisis

Persistent depolarization at NMJ
Blockade of acetylcholinesterase
Develops within 24-48 h.
FEATURES- muscle fasciculations,
cramps, twitching, and weakness
Respond to atropine

Type I (Contd)

Muscle paralysis
Upper motor neuron lesion
Muscle paralysis - respiratory
muscles--->respiratory failure
requiring ventilation
Acute respiratory failure in 33% of
patients who presented with OP
poisoning

Type-II Paralysis or Intermediate

Syndrome

Wadia as Type-II paralysis

Senanayake as intermediate
syndrome
24-96 h after the poisoning
Majority of patients, respiratory
insufficiency
Cranial nerve palsies
Proximal muscle weakness

TYPE II(CONTD..)

Relative sparing of the distal muscle

groups
Incidence varies - 8% and 49%
Earliest manifestations
Weakness of neck flexion
Inability to lift the head from the pillow
Test to assess if patient is likely to develop
respiratory muscle weakness
Cranial nerves involved are those
supplying the extraocular muscles

TYPE II(CONTD..)

VII and X are less frequent.

Syndrome persists for approx 4-18
days
Most patients survive this with
ventilatory support unless infections
complicate the course
There is a myopathy evidenced by
significant elevation of muscle
enzymes

TYPE III PARALYSIS

OP-induced delayed polyneuropathy

(OPIDP) is a sensory-motor distal
axonopathy
Occurs after the ingestion of large doses ,
chronic exposure
One being pure motor polyneuropathy
Other having a mild sensory component
with a more prominent motor component.

Other Neurologic Manifestations

Impaired memory, confusion,

irritability, lethargy
Extrapyramidal manifestations
Developing for 4-40 days following
poisoning and lasting for approx 1-4
weeks, including dystonias, resting
tremor, cog-wheel rigidity

Other Neurologic
Manifestations(contd)

optic atrophy, degeneration of retina,

defective vertical smooth pursuit
movements, myopia owing to spasm,
or paresis of accommodation.
Rare neurological Guillian-Barr
syndrome, sphincter involvement,
isolated bilateral recurrent laryngeal
nerve paralysis, and ototoxicity

Cadiovascular Manifestations

Prolonged Q-T corrected (QTc) interval (67%);

Elevated ST segment (24%);
Inverted T-waves (17%);
Prolonged PR interval (9%);
Rhythm abnormalities such as sinus tachycardia
(35%), sinus bradycardia (28%), extra systoles ,
atrial fibrillation, ventricular tachycardia ;
Other manifestations noncardiogenic pulmonary
edema (43%), hypertension (22%), and
hypotension (17%).

CARDIAC TOXICITY

Phase 1: A brief period of increased

sympathetic tone
Phase 2: Prolonged periodof increased
parasympathetic activity, including
atrioventricular block.
Phase 3: QT prolongation followed by
torsade de points , ventricular tachycardia,
and development of ventricular fibrillation.

CARDIAC TOXICITY (contd..)

Recent study QTc prolongation at

admission respiratory failure and
higher mortality
Mech of toxicitydirect toxic effect
on the myocardium, overactivity of
cholinergic or nicotinic receptors,
hypoxemia, acidosis, electrolyte
abnormalities

Respiratory Manifestations

Muscarinic effects of bronchorrhea,

bronchospasm and laryngeal spasm result
in airway obstruction.
The nicotinic effects ->weakness and
paralysis of respiratory and oropharyngeal
muscles
Central depression ->respiratory arrest
Intermediate syndrome develop
respiratory failure- mechanical ventilation

Gastrointestinal Manifestations

GI manifestations are the first to

appear
They respond well to atropine
therapy

Management

Decontamination of the skin is very

important. The patient should be stripped
and washed with soap and water
Forced emesis if the patient is fully awake
or through a gastric lavage
0.5-1 g/kg activated charcoal every 4 h
Serotonin adipinate that enhances the
propulsive function of git resulted in
shortening of the toxicogenic phase and a
3.5-fold reduction of mortality.

Airway and Respiration

Adequate oxygenation should be ensured

(a) Symptoms of ocular muscle
involvement (e.g.; diplopia), (b) neck
muscle weakness, (c) respiratory rate, (d)
tidal volume or vital capacity
(e) Single breath count, and (f) arterial
blood gas estimation or pulse oximetry.
Respiratory infections should be
anticipated and treated appropriately

Cardiac Monitoring

Hemodynamic and electrocardiographic

monitoring
Hypoxemia and electrolyte abnormalities
contribute to cardiac complications. Some
of these may revert with atropine.
Ventricular tachycardia with a prolonged
QTc is best treated with electrical pacing
SVT can be treated with IV bolus of shortacting -blockers.

Specific Therapy

Anticholinergic Agents Atropine can

be started initially as a 2-mg
intraventricular (IV) bolus
Then at doses of 2-5 mg IV bolus
every 5-15 min until atropinization is
achieved.
No longer necessary to achieve total
atropinization i.e full mydriasis, heart
rate more than 150/min, and absent
bowel sounds.

At approx 100/min,
Pupils' midsize,
Bowel sounds just present,
maintains adequately atropinization
without risks of hyperexcitability,
restlessness, hyperpyrexia and
cardiac complications that are seen
with total atropinization.

The dose of atropine required is

maximal on day 1 and tends to
decrease over the next few days.

Oximes

Reactivate the phosphorylated

acetylcholinesterase by binding to the
organophosphorus molecule.
Report by de Silva et al found that P2AM
did not maker any difference to the
outcomes.
Reactivation has been shown to be
complete when oximes are given 1 hr after
exposure

Randomized control trials

(Indian Journal of Pharmacology, Vol39, No2, Mar-Apr07)

TRIAL 1

moderately severe group,6-> placebo arm

5-> treatment group.
In the severe group, 5-> the placebo
group 5-> treatment group.
While 12 g PAM infusion/day was used for
severe cases for three days
4 g/day was used for moderate cases also
for 3 days.
Placebo group was given saline infusion.

Conclusion

Treatment with PAM did not make

any difference in OP poisoning
The more useful treatment options
are anticholinergic drugs like
atropine and supportive ventilation.

Trial 2

A 1 g bolus of pralidoxime (termed

'low dose') was compared with 12 g
given as a reducing infusion over 4
days without a loading dose (termed
'high dose').
This RCT reported an increased
mortality rate (22% vs 14%;
.

Conclusion

The authors argued that 'high-dose'

pralidoxime was therefore
'associated with a worse outcome'
and should have 'no role in op
poisoning management
Increased requirement for ventilation
among patients who received the
infusion as compared to those who
received the bolus dose.

Trial 3

It compared 'high-dose' pralidoxime

(i.e., 12 g by continuous infusion
without loading dose) with the
placebo saline infusion
'high-dose' regimen was associated
with a significantly higher risk of
death

Nonrandomized Clinical Trials

Trial 1

One group (group I) received atropine

alone
Other group (group II) received atropine
&PAM
PAM neither improved the atropine
profile in group II patients as compared to
group I nor did it significantly change the
ventilatory profile in the two groups.
Mortality was negligible in both the
groups

Trial 2

Atropine was given intravenously to all patients in

amounts sufficient to maintain the pulse rate >
120/minute and to keep the pupil fully dilated.
Patients in the control group were also given a
median of 4 g PAM intravenously during the first
24 h of treatment.
Thereafter PAM was given intravenously at a 1 g
daily dose for up to five days.
There were no significant differences between
the study and control groups with regard to any
of the outcomes such as median atropine
requirement in first 24 hours, patient with
intermediate syndrome and median hospital stay
(days) or the patient needing intensive care
treatment or ventilation,

Discussion

There was no statistically significant

association of oxime therapy with
mortality ventilator requirements or the
incidence of intermediary syndrome
Increased need for intensive care therapy
Oximes in OP poisoning was associated
with either a null effect or possible harm

concluded that use of oximes in OP

poisoning was associated with either
a null effect or possible harm

Discussion (contd)

Studies have given following results

De Silva et al:- No benefit from
pralidoxime was found
Johnson and Vale:-(a) failure of treatment
is usually a function of inadequate dosing
(b) Emphasized that dosage should be
maintained continuously until clear,
irreversible, clinical improvement is
achieved

Discussion(contd..)

Current WHO guidelines

:-Recommend giving a 30 mg/kg
loading dose of pralidoxime over 1020 minutes followed by a continuous
infusion of 8-10 mg/kg/h until clinical
recovery or seven days have
elapsed, whichever is later .

Toxicol Rev. 2003;22(3):165-90

These studies impressively demonstrated

that any generalisation regarding an
effective oxime concentration is
inappropriate
pralidoxime plasma concentrations of
around 80 mumol/L (13.8 mg/L
pralidoxime chloride) should be attained .
These concentrations should be
maintained as long as circulating poison is
expected to be present, which may require
oxime therapy for up to 10 days

The most appropriate consists of a

bolus short infusion followed by a
maintenance dosage. For pralidoxime
chloride, a 1 g bolus over 30 minutes
followed by an infusion of 0.5 g/h
appears appropriate to maintain the
target concentrtion of about 13 mg/L
(70 kg person).

THANK YOU