Cholinergic Agonists

“Parasympathomimetic” Agents

and “Cholinomimetic Agents”

Cholinergic Agonists aka

Cholinergic Agonists

Drugs that mimic acetylcholine

Direct acting

directly binds to receptors

Indirect acting

increases acetylcholine level by inhibiting acetylcholinesterase

Choline Esters

Poorly absorbed & distributed in the CNS.

Choline Esters

charged with quaternary ammonium group renders them insoluble in lipid

Choline Esters

Hdrolyzed in the GIT (acetylcholinesterase)-- Betanechol and

Metacholine are resistant

ACETYLCHOLINE

is a quaternary ammonium compound that cannot penetrate membranes.

-rapidly hydrolyzed

ACETYLCHOLINE

large IV bolus injection has brief effects of 5-20 seconds compared to IM or SC which has a local effect.

acetyl-B-methylcholine

METACHOLINE chemical name

METACHOLINE

more resistant to enzymatic hydrolysis than

Ach.

METACHOLINE

Clinical Use: not used clinically

Muscarinic actions =Ach.

-No nicotinic actions

METACHOLINE

Pharmacological Actions

CARBACHOL

very potent choline ester having both muscarinic and nicotinic effects

CARBACHOL

Act predominantly on GIT, UB

⏤ nicotinic actions>Muscarinic actions

Use: Glaucoma

(Urecholine)

BETANECHOL aka

carbamoyl-B-methylcholine

BETANECHOL chemical name

BETANECHOL

Not hydrolyzed by cholinesterases

1. Treatment of gastric retention

2. Treatment of postoperative abdominal distention

3. Treatment of nonobstructive urinary retention

4. Prevention of paralytic ileus

USES OF BETANECHOL:

Alkaloids

Natural (derived from natural sources)

tertiary amine- well absorbed orally except: Muscarine

Cholinomimetics

stimulate receptor of Acetylcholine

Pilocarpus jaborandi

PILOCARPINE

- from leaves of

PILOCARPINE

Action: Muscarinic action similar to Ach

PILOCARPINE

Glaucoma- *stimulates M3 in the pupil → miosis-- > drains aqueous humor and ⬇ decrease ocular pressure

Nicotiana tabacum

NICOTINE From

NICOTINE

component of cigarette smoke

40mg (1 drop of pure nicotine liquid) -fatal dose of nicotine

NICOTINE

Acute Toxicity:

Nicorette gum or patch

Use in smoking cessation:

CNS action-convulsion, coma & respiratory arrest

⏤ Skeletal Muscle endplate depolarization-respiratory paralysis, depolarization blockade

⏤ Hypertension & cardiac arrhythmias

Dangerous Effects of Nicotine:

(Lobelia inflata)

LOBELINE

plant derivative similar to nicotine

Amanita muscaria

MUSCARINE from mushroom

MUSCARINE

A quaternary ammonium salt

MUSCARINE

Action: Muscarinic action similar to Ach; No nicotinic action

Mushroom Poisoning (mimic Ach)

MUSCARINE causes

(Areca catechu)

ARECOLINE From Areca nut

Indirect acting Agonists

Acetylcholinesterase inhibitors

Increases acetylcholine in the synaptic cleft by inhibiting acetylcholinesterase

Indirect acting Agonists

Produce their primary effects by inhibiting acetylcholinesterase which hydrolyzes acetylcholine.

Ach binds to the enzyme’s active site & hydrolyzed yielding free choline & acetylated enzyme.

“All of the cholinesterase inhibitors increase the concentration of endogenous Ach at cholinoceptor by inhibiting acetylcholinesterase.

Indirect acting Agonists MOA

REVERSIBLE INHIBITORS

IRREVERSIBLE INHIBITORS

Indirect acting Agonists types

REVERSIBLE INHIBITORS

Attach to the ACHE enzyme and are only slowly hydrolyzed.

IRREVERSIBLE INHIBITORS-

Reacts to form a stable, phosphorylated enzyme, which is essentially not hydrolyzed

QUATERNARY ALCOHOLS

15-30 mins duration of action

QUATERNARY ALCOHOLS

Don’t form a covalent bond and bind reversibly at the active site. The action is therefore very short-lived

Edrophonium (Tensilon)

Short-acting; for diagnosis of Myasthenia gravis

Myasthenia gravis

An autoimmune disease (Antibodies disrupt Nm receptors)

CARBAMATES

intermediate- long acting

CARBAMATES

2-8 hrs duration of action

eserine

PHYSOSTIGMINE aka

PHYSOSTIGMINE (aka eserine)

highly lipid soluble , crosses blood brain barrier

Ophthalmic uses

Treatment of poisonings with anticholinergic agents

CARBAMATES

Pharmacological Action similar to Ach

Uses:

NEOSTIGMINE (Prostigmin)

not lipid soluble, does not cross BBB

Post-operative ileus

Urinary retention ü Reverse NMJ block from curare-like drugs

Myasthenia Gravis

NEOSTIGMINE (Prostigmin)

Pharmacological Action similar to Ach

Uses:

(Prostigmin)

NEOSTIGMINE aka

Pyridostigmine (Mestinon)

Ambenonium (Mytelase)

CARBAMATES ex

(Mestinon)

Pyridostigmine BN

(Mytelase)

Ambenonium BN

CARBAMATES

used for the treatment of muscle weakness and fatigue in people with myasthenia gravis

(Humorsol)

DEMECARIUM aka

DEMECARIUM (Humorsol)

Ophthalmic Solution

A cholinesterase inhibitor used to treat glaucoma by lowering the pressure inside the eye.

Inc. Ach-- > stimulates M3 in the pupils → miosis-- > drains aqueous humor and decrease ocular pressure

Tacrine (Cognex®)

- Donepezil (Aricept®)

- Galantamine

- Rivastigmine

Reversible inhibitors used in Alzheimer’s Disease

(Cognex®)

Tacrine BN

(Aricept®)

Donepezil BN

Alzheimer’s

a progressive disease, where dementia symptoms gradually worsen over a number of years.

Acetylcholine (ACh)

is essential for processing memory and learning= decreased in both concentration and function in patients with Alzheimer's disease.