Cholinergic Agonists ‘Cholinomimetic agents’

Pharmacology ILecture 2

Dr. Hiwa K. Saaed HD, M.Sc. PhDDepartment of Pharmacology & Toxicology

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1. Direct acting: are drugs that mimic ‘look like’ Ach

2. Indirect acting: potentiate the actions of Ach by inhibition of cholinesterase

Cholinergic Agonists2

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Cholinergic Agonists

Classification

A. Pharmacologically: by their spectrum of action.

1. Muscarinic agonists:

Bethanechol

methacholine

pilocarpine.

2. Nicotinic agonists:

nicotine

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B. mode of action 1. Direct-acting: bind directly to and

activate muscarinic or nicotinic receptors,

Also subdivided chemically:A. Esters of choline (including

acetylcholine, bethanechol, methacholine and carbachol)

B. Alkaloids (such as muscarine, pilocarpine and nicotine).

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Classification

2. Indirect-acting: by inhibiting the hydrolysis of endogenous

acetylcholine. also subdivided to

A. Reversible:neostigmine, physostigmine, pyridostigmine,

ambenomium, edrophonium, donepezil,

galantamine, rivastigmine, tacrine.

B. Irreversibleechothiophate, isoflurophate

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Classification

Cholinergic Agonists 7

Indirect and direct

Some quaternary cholinesterase inhibitors also have a modest DIRECT action as well,

example, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase.

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Basic Pharmacology

Muscarinic and Nicotinic agentsAcetylcholine & Carbachol: have effects on

both receptors. muscarinic agents; ‘Pilocarpine and Bethanechol’

preferentially bind to muscarinic receptors.

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Pharmacokinetics

All the direct-acting cholinergic drugs have longer durations of action than Ach.

Choline esters are poorly absorbed and poorly distributed into the CNS because they are hydrophilic.

The tertiary cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration.

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Pharmacokinetics

Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route).

they differ markedly in their susceptibility to hydrolysis by cholinesterase.

1. Acetylcholine is very rapidly hydrolyzed.2. Methacholine 3 times more resistant to

hydrolysis3. Carbachol & Bethanechol are extremely

resistant to hydrolysis.

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Pharmacology of Ach-like agonist

Although, it affects almost every system within the body. it is therapeutically of no importance!!!! because of

1. its multiplicity of actions, 2. and its rapid inactivation by the

cholinesterases.

A. Acetylcholine (Ach)13

Acetylcholine (Ach)

CVS: it ↓s heart rate, contractility, and blood pressure.

GIT: it ↑s motility of the GIT and bladder. Pulmonary system: it ↑s secretions of the

bronchioles Eye: miosis and accommodation. PNS: contraction of skeletal muscle CNS: it affects neurotransmission Endocrine system: it causes release of

epinephrine from the adrenal medulla (via Nn receptors).

And it stimulates sweat gland secretions.

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Response mediated by Muscarinic receptors

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Response mediated by Nicotinic receptors

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Adverse effects:

excessive generalized cholinergic stimulation DUMBLES: • Diarrhea and decreased BP, • Urination,• Miosis, • Bronchoconstriction, • Lacrimation, • Excitation of skeletal muscle, • Salivation and Sweating

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B. Bethanechol

It has duration of action of about one hour. Its major action on the smooth musculature

of the bladder and GIT, causing increased intestinal motility and tone.

(BBB- Bethanechol stimulates the Bladder and Bowel)

Therapeutic Uses: to stimulate the atonic bladder in

postoperative, non-obstructive urinary retention.

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C. Carbachol actions:

Systemically: Carbachol has profound effects on both the CVS and the GIT

because of its ganglion (Nn receptor) stimulating activity, and it may first stimulate and then depress these systems.

It can cause release of epinephrine from the adrenal medulla by its nicotinic action.

Locally instilled into the eye, it mimics the effects of Ach, causing miosis and a spasm of accommodation.

is rarely used therapeutically except in the eye to treat glaucoma. Because of its high potency, and relatively long duration of action.

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Act on muscarinic receptors Used in diagnosis of asthma

and bronchial hyperreactivity

D. Methacholine20

E. Pilocarpine (an alkaloid)

The pilocarpine is a tertiary amine, and is stable not hydrolyzed by AchE.

It is far less potent compared with Ach and its derivatives.

Pilocarpine exhibits muscarinic activity and is used primarily in ophthalmology.

topically produces a rapid miosis and contraction of the ciliary muscle; a spasm of accommodation; the vision is fixed at some particular distance, making it impossible to focus.

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E. Pilocarpine action

Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva,

but its lack of selectivity (adverse effects) limited its use:

1. can enter the brain and causes CNS disturbances.

2. It stimulates profuse sweating and salivation.

Pilocarpine actions:23

Sjogren syndrome

Sjogren syndrome, immunologic disorder with destruction of the exocrine glands leading to the mucosal dryness (dry mouth and lack of tears)

is usually treated with cevimeline, a cholinergic drug that also has the drawback of being nonspecific.

Recent studies have shown that mouth sprays of Pilocarpine are beneficial in promoting salivation in patients with Xerostomia (dryness of the mouth).

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is the DOC in the emergency lowering of IOP of both narrow-angle and a wide-angle glaucoma.

Therapeutic use in glaucoma:25

is extremely effective in opening the trabecular meshwork around Schlemm canal result in an increased drainage of aqueous humor

Organ system effects of cholinergic agonists

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