ORGANOPHOSPHATEPOISONING

Dr.U.P.RathnakarMD.DIH.PGDHM

www.scribd.comwww.pharmacologyfordummies.blogspot.com

What is the link?• Cholinergic drugs

[Agonists of Ach Rec.]Cholinomimitics OR

Directly acting cholinergics OR

Indirectly acting Cholinomimitics

Musc.Rec.Antagonists

Antagonists at N.M.Junction

Anti-Cholinesterases

Antagonists Anti-cholinergics

N.M.Blockers

Ganglion blockers

Anticholinesterases[Indirectly acting cholinergics]

Reversible anticholinesterases Carbamates Acridine

Tacrine.• Physostigmine• Neostigmine• Pyridostigmine• Edrophonium• Ambenonium• Demecarium• Rivastigmine, • Donepezil, • Galantamine.

Organophosphates: Carbamates:• Echothiophate Carbaryl*• Parathion* Propoxur*• Malathion*• Diazinon*• Tabun#• Sarin#• Soman#

*Insecticides # Nerve gases-chemical warfare

Irreversible anticholinesterases

Anticholinesterases[Indirectly acting cholinergics]

Carbamylation [Therapeutic] and Phosphorylation [Poisoning]

ReactionVery Slow

Orirreversible

REVERSIBLE ANTICHOLINESTERASES-USES

MIOTIC

• Glaucoma• Reverse the effect of mydriatics• Alternated with mydriatics-to

break irido-corneal adhesions

REVERSIBLE ANTICHOLINESTERASES-USES

• Postoperative paralytic ileus/urinary retension

[Neostigmine]• Postoperative decurarization [Neostigmine

preceded by Atropine]• Cobra bite [Neostigmine+Atropine]• Belladona [Atropine] poisoning-Physostigmine• Alzheimer’s disease-Tacrine, rivastgmine,

donepezil, galantamine [cerebroselective]• Drug over dosage-e.g. TCA

• Myasthenia gravis

Irreversible anticholinesterases

Organophosphates• Echothiophate –used in glaucoma• Parathion • Malathion• Diazinon• Tabun• Sarin • Soman

Insecticides

Nerve gases

Entry into body

• Transdermal• Inhaled• Ingested

Mechanism Of Action

Organophosphorous compounds bind to acetylcholinesterase overabundance of acetylcholine in the synapse Compound undergoes a conformational change

(aging) renders the enzyme irreversibly resistant to reactivation.

Carbamate Compounds unlike organophosphates, are transient

cholinesterase inhibitors.

OP Poisoning

• Occupational• Accidental• Homicidal• Suicidal• Chemical warfare

Clinical Features (Acute Toxicity)

Paralysis

Types of toxicity

• Acute cholinergic syndrome• Intermediate syndrome• Delayed Neurotoxicity• Warfare

Clinical Features (Acute Toxicity)

• Generally manifests in minutes to hours • Evidence of cholinergic excess• Parasympathetic-Sympathetic-Nicotinic

SLUDGe =Salivation, Lacrimation, Urination, Defecation, Gastric Emptying.

BBB= Bradycardia, Bronchorrhea,

Bronchospasm.

DUMBELLS= Diarrhea , Diaphoresis

UrinationMiosis Bradycardia Emesis LacrimationLethargySalivation

TREATMENT

A - B – C

• Airway: Bronchoconstriction• Breathing: Paralysis of resp.muscles• Circulation: Hypotension Vs Hypertension

TREATMENTAcute

• General supportive measures: • Termination of exposure, copious washing , airway,

respiration , oxygen, DIAZEPAM, tt shock• Anticholinergics Atropine i.v.

- Sufficent doses i.v. [For muscarinic effects]-till atropinization-maintained for 1-2 weeks

• Cholinesterase reactivators• Pralidoxime - Sufficiently early i.v.

[For Nicotinic effects]

Oximes-MOA

ReactionVery Slow

Orirreversible

Oximes attach to anionic site

Oxime + Phosphorous

Oxime –phosphate diffuses

Pralidoxime[2-PAM]ObidoximeDiacetyl-monoxime[DAM]

[Cholinesterase reactivators]

Oximes

• Ineffective against carbamates-Anionic site is not free

• Contra indicated-intrinsic anti-ChE activity• More effective at nicotinic • Poor in muscarunic sites• Not at all in CNS-does not cross BBB• Not effective after phosphorylated enzyme under

goes aging• Atropine is the DOC-Oxime is secondary drug

Chronic OP poisoning

• Fluorine compounds• Polyneuritis and demyelination of nerves• Sensory loss → Motor loss → LMN palsy →

Spasticity → Upper motor neurone paralysis• Mechanism → not inhibition of ChE• Takes years to recover

Nerve agents [Nerve gases]

•These chemicals are liquid at room temperature,

•Phosphorus-containing• organic chemicals (organophosphates)•Weapons of mass destruction

Nerve gases[Anticholinesterases]

Gulf war syndrome

• Approximately 250,000 of the 697,000 veterans who served in the 1991 Gulf War are afflicted with enduring chronic multi-symptom illness,

• A wide range of acute and chronic symptoms have included fatigue, loss of muscle control, headaches, dizziness and loss of balance, memory problems, muscle and joint pain, indigestion, skin problems, immune system problems, and birth defects.

• Nerve Gas??• Pyridostigmine??

Nerve gases

• Miosis, profuse salivation, convulsions, involuntary urination and defecation and eventual death by asphyxiation

• Nerve agents can also be absorbed through the skin

• Or portal of entry into the body is the respiratory system

• Protection-full body suit in addition to a respirator.

Dr.U.P.RathnakarMD.DIH.PGDHM

www.scribd.comwww.pharmacologyfordummies.blogspot.com

Anticholinergics[Cholinoceptor antagonists]

What is the link?• Cholinergic drugs

[Agonists of Ach Rec.]Cholinomimitics OR

Directly acting cholinergics OR

Indirectly acting Cholinomimitics

Musc.Rec.Antagonists

Antagonists at N.M.Junction

Drugs act like ACh Act at sites & receptors

Where Ach acts

Ganglia-NNSk.muscles-NMHeart,Lungs,

Int.]MuscEye, Sweat

glands]M12345Inhibit degradation of AchBy AChE[Cholinesterase] Anti-Cholinesterases Increase duration of

Action of ACh

Antagonists Anti-cholinergics

N.M.Blockers

Ganglion blockers

ANTICHOLINERGICS

Competitive antagonists of acetylcholine at cholinergic sites

Site of action of anti-cholinergics

Antimuscarinics

Ganglionic blockers

NM Blockers

Semisynthetic derivatives

•Homatropine•Atropine methonitrate•Hyoscine butyl bromide•Ipratropium bromide•Tiotropium bromide

Synthetic compounds

•MydriaticsCycclopentolate& Tropicamide

•Antisecretory-antispasmodicsQuaternaryPropatheline, Glycopyrrolate

TertiaryDicyclomine, Pirenzepine

•AntiparkinsonianTrihexyphenydyl, Biperiden, Benztropine

•VasicoselectiveOxybutynin, Flavoxate

Natural alkaloids

•Atropine•Scopolamine[Hyoscine]

Anticholinergic drugs[Classification]

SOURCE AND CHEMISTRY

• Atropine -Atropa belladonna Or Datura stramonium-tertiary amine

• Scopolamine  (hyoscine) -Hyoscyamus niger, • Tertiary derivatives- used -effects on the eye or the

CNS[mydriatrics or antiparkinsonians]• Quaternary amines -more peripheral effects with

reduced CNS effects[Antispasmodics]• Antihistaminic -antipsychotic -antidepressant - have

similar structures • Hence antimuscarinic side effects.• .

Pharmacokinetics

ABSORPTION • Natural alkaloids and most tertiary

antimuscarinic drugs are well absorbed from the gut and conjunctival membranes.

• Even absorbed across the skin (transdermal route-scopolamine).

• Only 10–30% of a dose of a quaternary drug is absorbed after oral administration,

Pharmacokinetics

• DISTRIBUTION • Atropine and tertiary agents are widely distributed in the body.

• Significant levels –in CNS within 30 minutes to 1 hour, and this can limit the dose tolerated when the drug is taken for its peripheral effects.

• Scopolamine is rapidly and fully distributed into the CNS where it has greater effects than most other antimuscarinic drugs.

• Quaternary derivatives are poorly taken up by the brain and therefore are relatively free—at low doses—of CNS effects.

Pharmacokinetics

• METABOLISM AND EXCRETION • Atropine-Rapid phase is 2 hours and that of the slow phase

is approximately 13 hours. • About 50% of the dose is excreted unchanged in the urine.

• The drug's effect on parasympathetic function declines rapidly in all organs except the eye. Effects on the iris and ciliary muscle persist for 72 hours.

Pharmacodynamics

• Atropine causes reversible (surmountable) blockade of cholinomimetic actions at muscarinic receptors;

• Muscarinic antagonists not just neutral compounds that occupy the receptor and prevent agonist binding.

• Muscarinic receptors are constitutively active,• Drugs that block the actions of acetylcholine are inverse

agonists • Shift the equilibrium to the inactive state of the receptor. • Muscarinic blocking drugs that are inverse agonists

include atropine, pirenzepine, trihexyphenidyl,

Tissue selectivity

• Most sensitive to atropine are the salivary, bronchial, and sweat glands.

• Secretion of acid by the gastric parietal cells is the least sensitive.

• Atropine is highly selective for muscarinic receptors. • Its potency at nicotinic receptors is much lower, • Atropine does not distinguish among the M1, M2, and M3

subgroups of muscarinic receptors. • Quaternary- Poor absorption, do not cross BBB, more

nicotinic and ganglionic actions, longer acting• Differences between Atropine and Scopolamine????

Systemic Effects

CNS

• Medullary-Excitation• Vestibular-depression• Basal ganglion-↓Cholinergic

activity• High doses-Disorientation,

hallucination, coma

Eye

• Passive mydriasis• Cycloplegia• Reduce lacrimal secretion

• Belladona!!!• The name belladonna derives from the alleged

use of this preparation by Italian women to dilate their pupils

• Modern-day fashion models are known to use this same device for visual appeal

• WHEN A ADRENERGIC STIMULANT IS GIVEN- THE DILATOR PUPILLAE MUSCLE CONTRACTS LEADING TO

• MYDRIASIS.• ACTIVE MYDRIASIS.• [No cycloplegia]• [Light reflex ++]

• ANTICHOLINERGICS-UN-OPPOSED ACTION OF THE DILATOR PUPILLAE

- MYDRIASIS. - PASSIVE MYDRIASIS• [Cycloplegia++]• [No light rehlex]

Active and PassiveMydriasis

ActiveMydriasis

PassivePassive mydriasis

Drug Adrenergic Anticholinergic

Muscles Contraction of dilator

Paralysis of constrictor

Cycloplegia Absent Present

Light reflex Present Absent

Conjuctival vessels

Constricted No effect

IOT Decreased or no change

Increased

Systemic EffectsCVS

• Tachycardia-M2 blockade

• Transient initial bradycardia- [Not central action]

• Most blood vessels receive no direct innervation from the parasympathetic system.

• All vessels contain endothelial muscarinic receptors that mediate vasodilation

• These receptors are blocked by antimuscarinic drugs.

[Efect of injected esters]

• At toxic doses, and in some individuals at normal doses, antimuscarinic agents cause cutaneous vasodilation, especially in the upper portion of the body. The mechanism is unknown.

• Cholinergic system not involved in vascular tone

• Tachycardia Vs Direct vasodilation=Net effect

Systemic EffectsRS

• Bronchodilation and decreased secretions

• COPD and preanesthesia

• Can not completely abolish activity[Enteric nervous system]

• Salivary secretion effectively blocked

• Gastric-only basal secretion• Not intestinal and

pancreatic secretions[Hormonal control]

GIT

Systemic EffectsGUT

• Relaxes smooth muscle of the ureters and bladder wall and slows voiding

• Can precipitate urinary retention in men who have prostatic hyperplasia

• Atropine suppresses thermoregulatory sweating

• Body temperature is elevated-therapeutic doses in children

Sweat glands

Atropine toxicity

• Hot as a hare, • Blind as a bat, • Dry as a bone, • Red as a beet,

• Mad as a hatter.

Anticholinergics –Clinical applications

• Mydriatic & Cycloplegic• Respiratory disorders-COPD• CVS disorders• GIT disorders• Disorders of urinary system• Parkinsonism• Motion sickness• Preanesthetic

Drug Onset Duration Remarks

Atropine 30-40 Mts 1 week Useful in childrenHigh ciliary tone

Homatropine 45-60 Mts 1-3 days Unsatisfactory in children

Cyclopentolate 30-60 Mts 1 day Behavioral abnormalities in children[Absorption]

Tropicamide 20-40 Mts 3-6 H Unreliable cycloplegic

Mydriasis-Anticholinergics

Mydriasis• To test errors of refraction• For fundoscopy• Iritis, iridocyclitis, keratitis• Rest to iris, anodyne, reduces spasm• To prevent/break adhesions[Synechiae]

Respiratory disorders[Ipratropium & Tiotropium]

• COPD & Bronchitis• Less effective in B.Asthma• Orally-dries secretions, • Mucociliary clearance is affected• Inhalational route• Combined with adrenergic agonists

Cardiovascular disorders

• Increased vagal tone- Bradycardia- MI, Digitalis toxicity

• Chaga’s disease-Antibodies to M2 rec.

GIT & Genito-urinary disorders[Antispasmodic]

• Peptic ulcer-not common[Propantheline, oxyphenonium]

• Traveller’s diarrhoea• Intestinal colic, dysmenorrhoea

[Dicyclomine]• Urinary incontinence

[Oxybutynin, Darifenacin , solifenacin, Tolterodine and fesoterodine ]

• Valethamate-Cx dialation

Preanesthetic

• Prior admin.with irritant GA[Ether]• To reduce secretions & prevent

laryngospasm [????]• With Halothane[Sensitizes the heart]• To prevent arrhythmias• To reduce vasovagal reflexes• Atropine & Glycopyrrolate

Atropine

CNS action

Motion sickness• Hyoscine-oral & Transdermal• Prophylactically• Not effective in other vomiting

Parkinsonism• Trihexyphenydyl, procyclidine,Biperiden• In mild cases

Toxicity and DI

Management of Toxicity• Gastric lavage [if ingested] with KMNO4• Cold sponging• Dark room• Physostigmine i.v.• Diazepam

DI

Delays gastric emptying-delays absorption

Antihistaminics, TCA-additive effects