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CHOLINOMIMETICS

Dr Igor Khalin

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• Parasympathomimetics Sympathomimetics

(cholinomimetics) (adrenomimetics)

• Parasyimpatholythics Sympatholythics

(cholinoblockers) (adrenoblockers)

Druds acting on ANS

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• Parasympathomimetics

(cholinomimetics)

• Sympatholythics

(adrenoblockers)

Drugs acting on ANS

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• Sympathomimetics

(adrenomimetics)

• Parasympatholythics

(cholinoblockers)

Drugs acting on ANS

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Cholinomimetics• Eye accommodation for near vision, miosis, IOP • Saliva copious, liquid

• Bronchi constriction, secretion

• Heart rate, blood pressure

• GIT secretion, peristalsis sphincter tone• Bladder detrusor sphincter tone

 

 

   

   

 

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Cholinergic neuron

ATP

ATP

negative feedback

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Cholinergic receptors

MUSCARINIC NICOTINIC

M1 M2 M3 M4 M5 NMNN

EyeHeartSmooth musclesExocrine glandsCNS

GanglionsCarotid sinusSkeletal musclesAdrenal glandsCNS

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Muscarinic receptors

• High affinity for muscarine• M1 – gastric parietal cells, saliva, CNS

• M2 - cardiac cells, smooth muscle,

CNS• M3 - bladder, exocrine glands, smooth muscle, eye, CNS

• M1&M3 – Gq

• M2 - Gi

Amanita muscaria

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Muscarinic receptors

M1

M3

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Cholinergic Agonists

Direct acting Indirect acting

AcetylcholineBethanecolCarbacholPilocarpine

EdrophoniumPhysostigmine

Neostigmine

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Direct acting cholinergic agonists

ACETYLCHOLINE - Pharmakokinetics

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Direct acting cholinergic agonists

1. Decrease in heart rate and cardiac output 2. Decrease in blood pressure

ACETYLCHOLINE - Effects

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Organ system effects

• 3. Eye– Contraction of sphincter (Miosis)– Contraction of cilliary muscle (Myopia)

ACETYLCHOLINE

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Direct acting cholinergic agonists

ACETYLCHOLINE

4. Other actionsdiarrheasweatingnausea

4. Clinical use very rare: eye drops to obtain miosis

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Direct acting cholinergic agonists

1. Stimulation of atonic bladder2. Nonobstructive urinary retention3. Neurogenic atony4. Megacolon

Ophthalmology-glaucoma-surgery

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Direct acting cholinergic agonists

PILOCARPINE - PK

1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB

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Direct acting cholinergic agonists

Jaborandi (Pilocarpus pennatifolius)

1. Secretagoge (sweat, tears, saliva)

• Jaborandi - what causes slobbering

1. Sjögren’s syndrome• Dry mouth, lack tears

2. Glaucoma

PILOCARPINE - Effects

PILOCARPINE – Clinical usage

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Direct acting cholinergic agonistsPILOCARPINE open-angle vs. closed angle glaucoma

posterior synechiae

anterior synechiae

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Mushroom poisoning

Miosis Hyper salivation Excessive sweating, lacrimation Cold, wet skin Bradycardia Polyuria Diarrhea Convulsions

Atropine

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Nicotinic receptors• High affinity to nicotine• NM- neuro-muscular junction

• NN – ganglion, adrenal gland

CNS, carotid sinus

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Indirect acting cholinergic agonists

Reversible Irreversible

EdrophoniumNeostigmine

PhysostigmineRivastigmineGalantamine

EchothiophateOrganophosphates

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Mechanism of action

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Mechanism of action

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Mechanism of action

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Reversible

Physostigmine

Calabar Bean

1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB

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Reversible

Physostigmine

1. Atony of intestine2. Atony of bladder3. Glaucoma4. Overdose of ATROPINE, ANTIPSYCOTICS, ANTIDEPRESSANTS

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Reversible

Physostigmine

1. Convulsions2. Bradycardia3. Paralysis of skeletal muscle

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Reversible

Neostigmine

1. Quatenary nitrogen2. Poor adsorbtion3. Not penetrate BBB

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Reversible

Neostigmine

1. Paralyzes2. Myastenia gravis3. Antidote of neuro-muscular blocker

TUBOCURARINE

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Reversible

Neostigmine

1. Salivation2. Flushing3. Decreased BP4. Abdominal pain5. Diarrhea6. Bronchospasm

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Reversible

Neostigmine

1. Bronchial asthma2. Intestinal inflammation,

obstruction3. Bladder obstruction4. Peritonitis

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Reversible

Edrophonium

1. Quatenary nitrogen2. Poor adsorbtion3. Not penetrate BBB 4. Fast elimination5. Duration 10-20 min

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Reversible

Edrophonium

1. Diagnosis of myasthenia gravis2. Antidote of neuro-muscular

blocker

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Reversible

Rivastigmine

1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB

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Reversible

Rivastigmine

Alzheimer disease

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Irreversible

Echothiophate

Glaucoma

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Toxicology

Organophosphates

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Toxicology

SalivationLacrimationUrinationDefecationGastrointestinal motility EmesisMiosis

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Toxicology

1. Reactivation of acetylcholinesterase• PRALIDOXIME

Not enter BBB2. M-cholinoblocker

• ATROPINE Antimuscarinic only

3. Anticonvulsant• DIAZEPAM

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SUMMARY