organo phosphorus poisning(op) is a common type of poisning due to consumption of highly toxic organophosphorus usually available in agriculture pesticides and herbicides. it may lead to high toxic effects when consumed for the suicide purpose.

1. BY: Shaik. Shaheera
pharm. D Student.
Vignan pharmacy college.
ORGANOPHOSPHORUS
POISONING

2. INTRODUCTION
 Organophosphorus compounds are chemical agents in wide-spread use
throughout the world, mainly in agriculture.
 They are also used as nerve agents in chemical warfare (e.g. Sarin gas), and as
therapeutic agents, such as ecothiopate used in the treatment of glaucoma.
 They comprise the ester, amide or thiol derivatives of phosphoric acid
and are most commonly used as pesticides in commercial agriculture,
field sprays and as household chemicals.

3. • Organophosphorus compounds also known as cholinesterase inhibitors, and are
widelyusedpesticidesthatmaycause poisoningsafteraccidentalor suicidalexposure.
• AChEisanenzymethat degrades the neurotransmitter acetylcholine (A
Ch) into
cholineandaceticacid.
• PhysicalAppearance:Availableasdusts,granules,or liquids
• Someproducts need to be diluted with water before use, and some are burnt to make
smokethatkillsinsects

4.  There are no rules and regulations governing the purchase of these
products, and they are therefore readily available “over the counter”,
despite them being a major cause of morbidity and mortality.
 Exposure to organophosphates in an attempt to commit suicide is a
key problem, particularly in the developing countries, and is a
more common cause of poisoning than the chronic exposure
experienced by farmers or sprayers in contact with pesticides.

5. CLASSIFICATION
 There are more than a hundred organophosphorus compounds in common use.
These are classified according to their toxicity and clinical use:
 1. Highly toxic organophosphates: (e.g. tetra-ethyl
pyrophosphates, parathion). These are mainly used as agricultural
insecticides.
 2. Intermediately toxic organophosphates: (e.g. coumaphos, clorpyrifos,
trichlorfon). These are used as animal insecticides.
 3. Low toxicity: (e.g. diazinon, malathion, dichlorvos). These
are used for household application and as field sprays.

6. GENERALMECHANISMOF
AChE

7. MECHANISM OF ACTION OF
ORGANOPHOSPATE POISONING
Irreversibly bind to serine-OH group at the active site of
acetylcholinesterase (AChE)  establish covalent bond
(phosphorylation)
↓
AGING:loss of alkyl group + strengthening of covalent
bond
↓
Phosphorylated AChE is very stable
↓
Inhibition of enzyme activity  accumulation ofACh in the
synapse and NMJ
↓
Overstimulation of cholinergic receptors 6

8. • AChisfoundinthecentralandperipheralnervoussystem,neuromuscular
junctions, andredbloodcells(RBCs).
• OnceA
ChEhasbeeninactivated,A
Chaccumulates throughout thenervous
system, resultingin overstimulation of muscarinic and nicotinic
receptors.
• Acetylcholine stimulates muscarinic and nicotinic receptors
to cause muscle contraction and glandular secretions.

9. Absorption route
Cutaneous
Ingestion(Accidental Or Suicidal)
Inhalation
Injection

10. Pharmacokinetics
o Most organophosphates are highly lipid soluble
compounds and are well absorbed from intact skin,
oral mucous membranes, conjunctiva and the
gastrointestinal and respiratory tracts.
o They are rapidly redistributed to all body tissues.
o The highest concentrations are found in the liver and
kidneys.

11. .
 This high lipid solubility means that they easily cross
the blood/brain barrier and therefore produce potent
effects on the CNS.
 Metabolism occurs principally by oxidation in the liver
with conjugation and esterase hydrolysis
producing a half-life of minutes - hours.

12. .
 The oxidative metabolites of malathion and
parathion (malaoxon and paraoxon) are active forms
and are subsequently hydrolyzed into inactive
metabolites.
 Elimination of organophosphorus compounds and
its metabolites occur mainly via urine, bile and
faeces

13. Clinical features of Organophosphorus Poisoning
 Following exposure to organophosphorus compounds, the
toxic features are usually obvious within 30 minutes to 3
hours.
 This may be delayed in some cases depending on the rate
and amount of systemic absorption.
 The majority of patients give a history of intentional or
accidental ingestion of organophosphorus compounds.
 Toxicity is produced by the rapid absorption of the
compound through the gastrointestinal, respiratory tracts
and skin.

14. Cont…
 The clinical symptoms and signs are non-specific and will
depend on the specific agent, the quantity and the route of
entry.
 Some patients present with vomiting, diarrhoea and
abdominal pain, whilst others may be unconscious on arrival
at the hospital. A high index of suspicion is therefore needed to
make an early diagnosis.
 The clinical features can be broadly classified as secondary to
the
(a) muscarinic effects
(b) nicotinic effects and
(c) central receptor stimulation.

15. Cont…
 Early cases present predominantly with
parasympathetic over-activity, and a characteristic
garlic smell.
 The end result may be a multi-system manifestation
involving the gastrointestinal, respiratory,
cardiovascular and nervous systems, as well as
involvement of skeletal muscle, other organs and
metabolic effects such as hypo- or hyperglycemia.
 Most fatalities occur within 24 hours and those who
recover usually do so within 10 days.

16. Symptoms and signs

17. Cardiac manifestations
 The commonest cardiac manifestations following
poisoning are hypotension (with warm, dilated
peripheries), and bradycardia. Patients seldom present
with tachycardia and hypertension due to predominant
nicotinic receptor stimulation.
 Cardiac manifestations are often the cause of serious
complications and fatality.
 Electrocardiographic manifestations include prolonged Q-
Tc intervals, elevation of the ST segment, inverted T waves
and a prolonged PR interval. There may also be rhythm
abnormalities such as sinus bradycardia , ventricular extra-
systoles, ventricular tachycardia and fibrillation.

18. .
 Ludomirsky et al described three phases of cardiac
toxicity following organophosphate poisoning:
 Phase I: A brief period of increased sympathetic
tone
 Phase II: A prolonged period of parasympathetic
activity including AV node blockade
 Phase III: Q-T prolongation followed by torsade
de pointes, ventricular tachycardia and
ventricular fibrillation

19. Respiratory manifestations
 Respiratory manifestations of acute
organophosphorus poisoning include
bronchorrhoea, rhinorrhoea, bronchospasm and
laryngeal spasm.
 This is due to the action of the organophosphate on
muscarinic receptors.
 The integrity of the airway may be compromised by
excessive secretions.

20. .
 The nicotinic effects lead to weakness and
subsequent paralysis of respiratory and
oropharyngeal muscles.
 This increases the likelihood of both airway
obstruction and aspiration of gastric contents.
 Finally, central neurological depression may lead to
respiratory arrest

21. .
 Three different types of paralysis are recognized
based largely on the time of occurrence and their
differing pathophysiology:
 Type I paralysis or acute paralysis
 Type II paralysis or Intermediate syndrome
 Type III paralysis or Organophosphate- induced
delayed polyneuropathy
Neurological manifestations

22. Type I paralysis or acute paralysis
 is seen during the initial cholinergic phase.
 This is when large numbers of both muscarinic and
nicotinic receptors are occupied by acetylcholine,
leading to persistent depolarization at the
neuromuscular junction.
 Clinical features include muscle fasciculation,
cramps, twitching and weakness.
 At this stage the patient may require ventilatory
support due to the weakness of the respiratory
muscles leading to respiratory depression and arrest.

23. Type II Paralysis/Intermediate syndrome
 The intermediate syndrome is a distinct clinical entity that
occurs 24 to 96 hours after the ingestion of an OP compound.
 Approximately 10-40% of patients treated for acute poisoning
develop this illness.
 The onset of the IMS is often rapid, with progression of muscle
weakness from the:
 ocular muscles
 neck muscle (the patient cannot raise their head from the
pillow)
 proximal limbs
 respiratory muscles (intercostals and diaphragm) over the
course of 24 hours.

24. Type III paralysis or organophosphate- induced
delayed polyneuropathy. (OPIDP)
 is a sensory-motor distal axonopathy that usually
occurs after ingestion of large doses of an
organophosphorus compound.
 The neuropathy presents as weakness and ataxia
following a latent period of 2-4 weeks.
 Initial stimulation causes excitatory fasciculation,
which then progresses to an inhibitory paralysis. The
cardinal symptoms are distal weakness of the hands
and feet.

25. .
 This is often preceded by calf pain, and in some
cases, parasthesia of the distal part of the limbs.
Delayed CNS signs include tremor, anxiety and
coma.

26. SEVERITY OF POISONING

27. WHO classification for severity
MILD MODERATE SEVERE
Serum/rbc cholinesterase
level 2-8 u/l
0.8-2 u/l <0.8 u/l
Walks and talks
Abd pain nausea vomit
headache
Salivation sweating
Talks with soft voice
Cannot walk
Fasiculations present
Miosis restlessness
anxiety
Coma convulsions
profuse bronchial
secretions

28. • Peradeniya Organophosphorous Poisoning (POP)
Scale
• Severity based onAChEinhibition

29. PERADENIYA ORGANOPHOSPHOROUS
POISONING (POP) SCALE

31. • Ascore of 0 to 3 is considered as mild poisoning,
• 4 to 7 as moderate poisoning and
• 8 to 11 as severe poisoning

32. SEVERITY BASED ON AChE INHIBITION
Grade Acetylcholinesterase activity (%)
Mild 50-90
Moderate 10-50
Severe <10

33. DIAGNOSIS
1. History of exposure from familymembers or friends
2. Empty container can be good source of information for
diagnosis if available at site of accident.
3. Estimation of plasma or RBC cholinesterase
level(RBC cholinesterase level is less than 50% of
normal.)
4. P-Nitrophenol is a metabolite of many OP’s which is
excreted in urine and can be used as aqualitative test.

34. 5. Ancillaryinvestigation include:-
• a. Leukocytosis
• b. High Hematocrit
• c.Anion gap acidosis
• d. hyperglycemia
• Chest radiograph mayrevealpulmonary edema but
typically adds little to the clinical management of apoisoned
patient.
• CT-scan

35. Treatment
 Airway , Breathing , Circulation(ABC)analysis.
 Decontamination and Supportive therapy.
 Blockade of Muscarinic activity with ATROPINE.
 Reversal of cholinesterase inhibition with OXIME.
 Correction of Metabolic abnormalities.
 Prevention of infection.
 Management of complication.

36. • Emergency and supportive care :
• Endotracheal intubation and mechanical
ventilation maybe necessaryin patients with
organophosphate poisoning for airwayprotection and
management of bronchorrhea and seizures.
Airway , Breathing , Circulation(ABC)analysis.

37. DECONTAMINATION
• Patient washed thoroughly with soap and water if skin
spillage
• W
ashwith cold water for 5 minutes and then with
hot water from head to toe using non-germicidal soap
• Ocular exposure-irrigation with normal saline or
Ringer’ssolution.

38. • Gastric lavage is the most common form of
decontamination for OP poisoning despite the absence of
randomized controlled trials to confirm benefit.
• Lavage should be considered onlyif the patient arrives
within 1 hour of ingestingpoison
• Ipecacuanha-induced emesis should not be used in
OP poisoning.
• Patients poisoned with OP can rapidly become unconscious,
risking aspiration if ipecacuanha hasbeen given.

39. SUPPORTIVE MEASURES
• Maintain airwaypatency
• Control of blood glucose
• Endotracheal intubation and mechanical ventilation maybe
necessary
• Monitor pulse oximetry or arterial blood gases to determine
need for supplemental oxygen.
• Oxygenation
• Administer IVfluids to replace losses
• Patient shouldbe placed in the left lateral position, with
the neck extended.
• This position reduces risk of aspiration;helps keep the airway
patent, and could decrease pyloric emptying and absorption of
poison

40. ANTIDOTE

41. The mainstays of medical therapy in organophosphate
(OP) poisoning include :
1.Atropine,
2. Pralidoxime (2-P
AM), and
3. Benzodiazepines (eg, diazepam)
Intravenous Glycopyrrolate or Diphenhydramine may
provide an alternative centrallyacting anticholinergic agent
used to treat muscarinic toxicity if atropine is unavailable or in
limited supply.

42. ATROPINE
• Atropine :Atropine—Itisacompetitive antagonist of acetylcholine at the
muscarinicpostsynapticmembrane andinthe CNS.
Diagnostic dose:
• Adult: 1 mgIVor IM
;
• Child—0.25 mg(about 0.01 mg/kg IVor IM
Therapeutic dose:
• Adult :1 to 2 mgIVor IM
• Child:0.05mg/ kgIV(child);
Every15 minutesuntil the endpoint isreached
• Endpoint: Dryingup oftracheobronchialsecretions

43. • Once the endpoint has been reached, the dose should be
adjusted to maintain the effect for at least 24 hours
• Atropinisation must be maintained until all of the absorbed
organophosphate has been metabolised.
• This mayrequire administration of 2 to 2,000 milligrams of
atropine over several hoursto weeks

44. • Atropine therapy must be withdrawn slowly to prevent
recurrence or rebounding of symptoms, often in the
form of pulmonaryedema
• Effects of atropine overdosing-fever, warm dry skin,
irritability,and dilated and unresponsivepupils
• Adverse effects : Atrial arrhythmias,A
Vdissociation,
multiple ventricular ectopics,photophobia,raised intraocular
pressure,hallucinations

45. PRALIDOXIME (PYRIDINE-
2-
ALDOXIME METHIODIDE; 2-PAM)
• Pralidoxime competes for the phosphate moiety of the
organophosphorus compound and releases it from the
acetylcholinesterase enzyme, therebyliberating the latter and
reactivating it
• This reactivation is clinically most apparent at skeletal
neuromuscular junctions, with less activity at muscarinic
sites.
• Current recommendation is administration within 48 h of OP
poisoning.

46. • Because it does not significantly relieve depression
of respiratory center or decrease muscarinic
effects ofAChEpoisoning,
• Need to administer atropine concomitantly to block
these effects of OP poisoning.

47. DIAZEPAM
• Diazepamprevents convulsions and cardiac damage
• Addition of diazepam to atropine and 2-PAMimproves
survival
• it prevent the late effects causedbyseizure-inducedbrain
damage
• Dose:For adults—5 to 10 mg IVslowly,every 15 minutes,
upto amaximum of 30 mg
• Forchildren—0.25 to 0.4 mg/kg IVslowly,every5 to 10
minutes, upto amaximum of10 mg
• Ifdiazepam is ineffective, phenytoin or phenobarbitone can be
used instead

48. FOR INTERMEDIATE SYNDROME
• Managed bysupportive measures,since it does not respond
to oximes or atropine.
• Consideration of artificial respiration are recommended.

49. FOR OPHOSPHATE-INDUCED
DELAYED
• This syndrome also does not respond to either oximes or
atropine
• There is no known treatment for OPIDN
• Standard therapy should be accompanied with neuroprotective
drugs like corticosteroids for prevention
• Protease inhibitors havebeen usefulin protecting the
neuropathy target esterase and preventing the establishment
of delayed neuropathy
NEUROPATHY

50. OTHER THERAPIES
Magnesium Sulfate
• Blocks calcium channels and thus reduces acetylcholine
release
• Reduces CNS overstimulation resulting from N-methyl
D-aspartate receptor (NMDAR)
• Intravenous MgSO4 (4 g) given in the first dayafter
admission havebeen shown to decrease hospitalization
period and improve outcomes

51. Advanced Neuroprotective Drugs
• Ketamine, anoncompetitive NMDAR antagonist, can
be used until 1 hour following nerve agent-induced seizures
• Tezampanel, another glutamate receptor antagonist
useful against soman-induced seizures and neuropathy