Anti cholinergics-2, aimst

• DR BADAR UDDIN UMAR

DRUGS ACTING ON THE ANS

ANTICHOLINESTERASE POISONING ANTICHOLINERGIC DRUGS

LECTURE - 2

LEARNING OBJECTIVES:

At the end of this session the we shall be able to –• Discuss the clinical features and drug treatment

of organophosphorus poisoning• Explain the role of enzyme reactivators in

organophosphorus poisoning• List and explain the adverse effects and

contraindications of atropine• Discuss the aspects of pharmacokinetics, routes and

dosage of clinically important/ commonly used drugs

ORGANOPHOSPHORUS POISONING

• Poisoning with organophosphorus compounds (OPCs) may occur by –

• Accidental exposure during spraying insecticides or in industry

• Suicidal poisoning

• Homicidal poisoning (rare)

• War gas exposure

OPC POISONING

• Acetylcholine esterase enzymes (AChE) of the body will be destroyed

• Covalent phosphorus-enzyme bond

• Phosphorylation

• There will be massive (Acetylcholine) ACh accumulation in the body…….ACh toxicity

ORGANOPHOSPHORUS COMPOUNDS

• Organophosphates are pentavalent phosphorus compounds containing a labile group such as -

• Fluoride (in dyflos) or an

• Organic group (in parathion and ecothiopate)

• This group is released, leaving the serine hydroxyl group (-SH) of the enzyme phosphorylated

ORGANOPHOSPHORUS COMPOUNDS

• The inactive phosphorylated enzyme is usually very stable

• When phosphorylated by OPCs, AChE have no ability to hydrolyze ACh and

• Recovery of enzymatic activity depends on the synthesis of new enzyme molecules

• This may take weeks

• With ecothiopate, slow hydrolysis occurs over the course of a few days, so that their action is not strictly irreversible

ORGANOPHOSPHORUS COMPOUNDS

• Dyflos and parathion are volatile non-polar substances of very high lipid solubility

• Are rapidly absorbed through mucous membranes and even through unbroken skin and insect cuticles

• Due to this they can be used as war gases or insecticides

Organophosphate Insecticide Action.mp4

SIGNS AND SYMPTOMS OF OPC POISONING:

All s/s are due to ….excessive level of Ach in the body

Muscarinic actions will lead to-

Eye - Constricted pupils (Miosis), blurred vision, eye ache, conjunctival congestion, brow ache

Glands - Profuse Sweating, Salivation, Rhinorrhea & Lacrimation

GIT movement… Nausea, Vomiting, Diarrhea with abdominal cramps

S/S OF OPC POISONING CONT.….DUE TO MUSCARINIC ACTIONS…..

Genito urinary - Urgency for urination and spontaneous voiding and penile erection (in severe case)

Bronchospasm, bronchial secretion Difficulty in breathing

Pulse rate/ Bradycardia

Hypotension

Collapse

SIGNS AND SYMPTOMS OF OPC POISONING CONT.….

Nicotinic effects

• Fasciculation (early)

• Weakness (late)

• Paralysis

• Adrenomedullary discharge (sympathetic, early and transient)

CNS Effects

• Anxiety• Insomnia• Nightmares• Confusion• Tremors• Convulsions• Respiratory depression• Circulatory collapse

S/S OF OPC POISONING FOR EASY REMEMBERING:

DUMBBELLS…… stands for

• Diarrhea• Urgency for Urination • Miosis• Bradycardia • Bronchospasm • Emesis• Lacrimation • Laxation and • Salivation

MANAGEMENT OF OPC POISONING:

The therapy of organophosphate poisoning is known by the catchy acronym - AFLOP:

Atropine

Fluids

Oxygen

Pralidoxime

MANAGEMENT OF OPC POISONING:

General measures:

Termination of exposure by - Removal of clothes etc. that are contaminated

Washing the whole body

Gastric lavage

Cleaning the airways for easy respiration

Oxygen therapy and artificial respiration if needed

IV fluid for correction of dehydration and shock

IV Diazepam for convulsion

MANAGEMENT OF OPC POISONING:

Drugs used in OPC poisoning:

A) Atropine:

It is the antagonist of Ach

It will block the MR &

Will prevent the effects of Ach

MANAGEMENT OF OPC POISONING:

Dose of atropine:1-2 mg IM or IV immediatelyRepeated 5-15 min…..until signs of atropinization

Dryness of mouth Reversal of miosis (mydriasis) HR: above 70/min

MANAGEMENT OF OPC POISONING:

B) Enzyme reactivator / regenerator

Reactivate or regenerate AChE enzyme

So AChE will be free again and metabolize ACh

Oximes -

PAM (Pralidoxime) &

DAM (Diacetylmonoxime)

MANAGEMENT OF OPC POISONING:

Oximes The oxime group (=NOH) has a high affinity for

phosphorous atom

So, can hydrolyze the phosphorylated AChE enzyme

Should be given within 12 hrs. of poisoning, after that can’t be reversed (stabilized by ‘aging’)

AGING OF

ACETYLCHOLINESTERASE

LOSS OF AN ALKYL GROUP FROM PHOSPHORYLATED ACHE “AGES” THE ENZYME

AChE, phosphorylated and inhibited by DFP

“Aged” AChE

“AGING” OF PHOSPHORYLATED- ACHE

ADVERSE EFFECTS OF ATROPINE

ANTICHOLINERGIC DRUG

ADVERSE EFFECTS OF ATROPINE

• Dry mouth

• Blurred vision

• Tachycardia

• Constipation

• Urinary hesitancy and retention

• Atropine poisoning

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CONTRAINDICATIONS OF ATROPINE….

• Glaucoma

• Elderly males with enlarged prostate

• Paralytic ileus

• Ulcerative colitis

• Gastroesophageal reflux

• Tachycardia

• Cardiac insufficiency

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ATROPINE-LIKE DRUGS

• Atropine has got wide-spread effect• So, it produces many side-effects

• There are some Atropine-like synthetic drugs • which are used clinically for different conditions

Atropine-like synthetic drugs

• These drugs have got more effect in that specific purpose &

• has less side-effects than atropine

ATROPINE-LIKE SYNTHETIC DRUGS

• Atropine-like Mydriatic drugs

• Atropine-like antispasmodic drugs

• Atropine-like antiasthmatic drugs

• Atropine-like antiparkinsonic drugs

ATROPINE-LIKE MYDRIATICS:

• Homatropine

• Eucatropine

• Cyclopentolate

• Tropicamide

ATROPINE-LIKE MYDRIATICS:

• Atropine-like synthetic drug

• Duration of action: shorter than atropine

• Effect of atropine lasts for about 1 week

• Effects are like atropine but less side effects

ATROPINE-LIKE MYDRIATICS:

Used in eye for …..• Mydriasis for Funduscopic examination

• Accurate measurement of refractory error…. Specially for un-cooperative patients & young children (ciliary paralysis is required)

• Prevention of synechia (adhesion) formation in uveitis & iritis

ATROPINE-LIKE MYDRIATICS:

Homatropine

Duration : duration about 2-3 days

Cyclopentolate• Duration : duration about 1 day

Tropicamide• More shorter duration of action: 6 hrs.

ATROPINE-LIKE MYDRIATICS:

• Now-a-days, antimuscarinics are less used for opthalmoscopic examination if there is no need of long lasting effect

• Alpha-adrenergic stimulants (e.g., phenylephrine) are used for their short-lasting mydriatic effect, specially for funduscopic examination

ATROPINE-LIKE ANTISPASMODICS:

• Dicycloverine (Dicyclomine)• Oxybutynin

• Propantheline • Hyoscine butylbromide

ATROPINE-LIKE ANTISPASMODICS:

Dicycloverine (Dicyclomine)

• Tertiary amine• More lipid soluble• More absorbed• More CNS effect• Has some direct action on smooth muscle

ATROPINE-LIKE ANTISPASMODICS:

Propantheline

Hyoscine butylbromide

• Quaternary ammonium compound• Less lipid soluble• Less absorbed• Less CNS effect• More appropriate as GIT antispasmodics

ATROPINE-LIKE ANTISPASMODICS:

These are selective … less side-effects

Mainly used for….

• Traveler's diarrhea• Peptic ulcer disease• Spasmodic pain in GIT• IBS (irritable bowel syndrome)

ATROPINE-LIKE ANTIASTHMATIC:

• Ipratropium• Tiotropium (longer duration of action)

Selective effect in bronchus

• Used in bronchial asthma• Given by inhalation in bronchial Asthma

ATROPINE-LIKE ANTIPARKINSONIC DRUGS:

• Benztropine• Orphenadrine• Procyclidine

Selective effect in brain

• Decreases Ach effect in basal ganglia• Decreases tremor, rigidity in parkinsonism

LEARNING OUTCOMES:

• At the end of this session the students will be able to –• Discuss the clinical features and drug treatment of

insecticide (organophosphorus) poisoning• Explain the role of enzyme reactivators and the

importance of ‘aging’ in organophosphorus poisoning• List the adverse effects and contraindications of

atropine and explain the reasons of the same• Discuss the aspects of pharmacokinetics, routes and

dosage of clinically important/ commonly used drugs like atropine

Thank You