By Dr. Magdy M. Awny. (nerve agent)

Transcription

1 By Dr. Magdy M. Awny (nerve agent)

2 Pesticides Is any chemical substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest are a group of insecticides or Organophosphorous compounds (OPCs) nerve- agents which act at acetyl-cholinesterase chemical warfare agents (nerve gases e.g. Sarin)

3 Organophosphates and carbamates insecticides (nerve agents) -Are potent cholinesterase inhibitors severe cholinergic toxicity following Cutaneous exposure, Inhalation, or Ingestion. -Acute OPC poisoning is common in children.. (Accidental) adult (Occupation farmers, unskilled workers or suicide attempts via ingestion -Each cpd differ in its relative toxicity, reversibility of binding to esterases & lethality as shown in the next table

4 Relative toxicities of organophosphates Compound Relative toxicity Tetra ethyl pyro phosphate 1000 Parathion 500 Methyl parathion 333 Trithion 80 Diazinon 2 Chlorthion 1 Malathion 1 Acute toxicity is highly variable: Parathion, sarin (nerve gas) very toxic, malathion much less

5 PHYSIOLOGY: NORMAL Electrical impulse goes down nerve Ach release stimulates receptor site on organ organ action ACh is destroyed by AChE No more organ activity

6 Types of Ach esterases: True Ach esterase 2 Types of esterases exist Plasma (Pseudo)-Ach esterase Located within nervous tissue, RBCs Degrades Ach in synapse, RBCs Specific to Ach Serve as more reliable index of OPC poisoning Found in the liver and serum Degradation of Ach, other cholines at liver and serum i.e. at any area of the body None specific not correlate well with the severity of poisoning Routine detection of enzyme conc in poisoned pts is not recommended where there are a wide inter, intra individual variation in both types of esterase. So diagnosis of OPC poisoning should be based on history and pts S& S not on lab analysis of esterase conc. administration of atropine, pralidoxime should not be delayed for detection of Ach esterase.

7 By time (24-48 hrs) Mode of OP Action Organophosphate conformational change (aging) Carbamate AChE irreversibly inactive (resistant to reactivation due to initial stimulation stable later paralysis binding) of cholinergic synapses Acetylcholine Choline + Acetate Treatment: Atropine Affecting: Cholinergic 2-PAM Nerve impulse transmission In CNS, NMJ, autonomic ganglia *Brain growth and development Carbamate compounds unlike organophosphates, are transient AChE Muscarinic Synaptic cleft Nicotinic cholinesterase inhibitors.

8 Exposure to Nerve Agent AChE ACh NERVE AGENTS 9

9 Exposure to Nerve Agent AChE ACh NERVE AGENTS 10

10 Effects on Striated (Skeletal) Muscle AChE ACh NERVE AGENTS 11

11 Effects on Smooth and Cardiac Muscle AChE ACh NERVE AGENTS 12

12 Effects on Exocrine Glands AChE ACh NERVE AGENTS 13

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14 Symptoms of Pesticide Poisoning Are due to effects of the increased amount of acetylcholine (M, N & CNS manifestation) Onset of symptoms may appear within minutes of exposure or delayed for up to 12 hrs (dermal absorption) depending on quantity and route of exposure The initial manifestation often reflect the exposure route e.g. after oral ingestion...git complaints appear first after inhalation...pulmonary symptoms are first after dermal exposure.muscle fasciculation exist first

15 Clinical Features (Acute OP poisoning) Generally manifests in minutes to hours 1-Muscarinic manifestations: Are best remembered by the mnemonic SLUDGE & SLUDGE = Salivation Lacrimation Urination Defecation Gastric Emptying DUMBLES DUMBLES=. Diaphoresis, Diarrhea Urination, Miosis Bradycardia, Bronchospasm, Bronchorrhea Lacrimation Emesis Salivation

16 A-Muscarinic effects of acetylcholine 1-pulmonary Acetylcholine increases bronchial secretions and constricts the sphincter muscles of air passages Dyspnea, wheezing, cough, pulmonary edema & cyanosis Fatality usually result from sever respiratory distress due to diaphragmatic or intercostal muscle paralysis, bronchorrhea, bronchoconstriction Chemical pneumonitis from aspiration of petroleum distillate vehicles may complicate OPC poisoning after oral ingestion 2-cardiovascular 3-GIT & urinary bladder 4-Glandular effects 5-eye VPHY8300/Spring 04 Bradycardia & hypotension N,V,D, abdominal pain & urinary incontinence Diaphoresis, salivation & lacrimation Miosis & blurred vision

17 VPHY8300/Spring 04 B-Nicotinic effects of acetylcholine Acetylcholine is a universal neurotransmitter in all ganglia and therefore increases tone and activity Generalized hyperactivity, tremors 1-Striated muscle (NMJ) Muscular twitching (fasciculations), cramping, weakness & paralysis If respiratory muscle is involved respiratory effort (failure), dyspnea & cyanosis asphyxiation & death 2-Sympathetic ganglia Tachycardia hypertension pallor mydriasis sweating

18 VPHY8300/Spring 04 C- Central effects of acetylcholine Acetylcholine is a universal neurotransmitter in CNS and autonomic ganglia. Its accumulation will cause increased firing of neurons General hyperactivity& seizures Anxiety, restlessness, insomnia, confusion Ataxia, slurred speech, coma with decreased reflexes, depression of respiratory & circulatory centers

19 Signs and Symptoms of Acute OP Poisoning Site and receptor affected Exocrine glands (M) Eyes (M) Gastrointestinal tract (M) Respiratory tract (M) Manifestations Increased salivation, lacrimation, perspiration Miosis, blurred vision Abdominal cramps, vomiting, diarrhea Increased bronchial secretion, bronchoconstriction Bladder (M) Cardiovascular system (M) Cardiovascular system (N) Skeletal muscles (N) Urinary frequency, incontinence Bradycardia, hypotension Tachycardia, transient hypertension Muscle fasciculations, twitching, cramps, generalized weakness, flaccid paralysis Central nervous system (M, N) Dizziness, lethargy, fatigue, headache, mental confusion, depression of respiratory centers, convulsions, coma

20 (OPIDN). May resolve spontaneously, but can result in permanent neurologic dysfunction. Organophosphate Induced Delayed Neuropathy result from damage of nerve axon as OPC inhibit neuropathy target esterase (NTE) rather than AchE axonal injury It occurs with specific organophosphorous agents. Usually occurs 1-4 weeks after exposure, due to slow release of OP from body fat. Symptoms: sensory targets (tingling, cramping muscle pain in legs.demyelination) and motor targets fatigue, weakness, paralysis).. Mostly affect the pelvic limbs (flaccid weakness of lower extremities muscles i.e. leg drop), may ascends to involve upper extremities (arm & forearm) following severe exposure. Sensorimotor degeneration exposure to OPC may lead to OPIDN even in absence of acute toxicity symptoms.

21 Carbamate insecticides e.g. aldicarb & methomyl They differ from organophosphates in: 1) Reversible inhibitors of AchE activity (returns to normal with in 24 hrs) 2) less toxic, their effects are not reversed by pralidoxime 3) Highly metabolized 4) Atropine only used as antidote If pt presents with Unkn pesticide exposure and S&S of AchE inhibition, pralidoxime should be administered

22 1-Pt resuscitation, stabilization 4-benzodiazepines Management 2-decontamination 3-Antidotes

23 Do not delay the treatment until laboratory confirmation is obtained. Since death mostly due to respiratory arrest so initial management is keeping a patent airways & ventilatory support. we give 100 % oxygen via facemask or intubation as patients who appear mildly poisoned may rapidly develop respiratory failure. Clearness of airways by suction of copious secretions from oropharynx &upper airways if dermal exposure is significant..remove the contaminated clothes, place it in plastic bag & discarded, then pt washed thoroughly with soap & water. If poisoning due to inhalation..remove the victim from! source Consider volume resuscitation with normal saline or ringer to treat Bradycardia and hypotension.?

24 1-Emesis not recommended as vomiting may already exist, pt may develop coma, seizures so aspiration of the organic vehicle of OPC pneumonitis 2-Gastric lavage can be considered & the airways should be protected at first by using cuffed endotracheal tube to prevent aspiration as pt may be unconscious 3-Activated charcoal (1-2g/kg) should be considered within one hour although its usefulness is uncertain 4-Cathartic not done as pts. may have diarrhea

25 3-Treatment of cholinesterase inhibition (Antidotes) ATROPINE for muscarinic effects 2-PAM only for organophosphates shortly after poisoning Wash contaminated surfaces Endotracheal tube (provide unobstructed respiration) Intravenous feeding

26 Used in order to Atropine - reverse the cholinergic effects (M, CNS not nicotinic), dry bronchial secretions - Reverse bronchospasm so facilitate ventilation and oxygenation Atropinisation targets: (SBP > 90 mm Hg, HR about 110/min & Clear lung fields) Initial dose: 0.05 mg/kg IV bolus, if no sign of atropinism (flushing, dryness of mucus membranes, mydriasis, tachycardia) appears, it indicates a diagnosis of OPC poisoning Doubled every 5 min until bronchial secretions and wheezing stop. pt is atropinized then give infusion of 10 20% of the total dose required to atropinize the patient each hour in 0.9% saline chloride to keep pt free from cholinergic symptoms until all absorbed organophosphate metabolized Severe poisoning requires very large doses given quickly e.g. up to 100 mg over several hrs).

27 Tachycardia and mydriasis are not appropriate markers for therapeutic improvement, as they may indicate continued hypoxia, hypovolemia, or sympathetic stimulation. Fever, muscle fibrillation, no bowel sound, urine retention and delirium are the main signs of atropine toxicity that indicate that atropine administration should be discontinued for 30 min and then start again at a 20% lower dose What if you give too much Atropine Anticholinergic Syndrome: Hot as hell Blind as a bat Red as a beet Dry as a bone Mad as a hatter

28 Cholinesterase reactivation by removing the phosphoryl group deposited by the organophosphate. effective in treating both muscarinic and nicotinic symptoms. Use within 48 hours after poisoning. Used in concurrent with atropine. Use only for moderate to severe Organophosphate poisoning and not carbamate. Use if neuromuscular dysfunction is present e.g. muscle fasciculation, weakness, and paralysis

29 Dose mg/kg IV over 30 min. Repeated after 1-2 hours, then every 10 to 12 hr interval for 48hr In sever cases with sk. muscle paralysis (continuous infusion of 0.5g/hr is initiated) Adverse effects: Nausea, headache, dizziness, drowsiness, Blurred vision, diplopia, Muscle rigidity weakness, Hyperventilation may occur.

30 loading dose of 250 mg over 30 min Then give a continuous infusion of 750 mg /24 h until clinical recovery Prophylactic diazepam has been shown to decrease neurocognitive dysfunction after poisoning. Diazepam mg/kg IV, repeat as necessary if seizures occur. phenytoin has no effect on organophosphate agent-induced seizures.

31 ????????? Thank you