Muscarine acts almost exclusively at muscarinic receptor sites. Arecoline acts at muscarinic and nicotinic receptors. Pilocarpine has mainly a muscarinic action. Present clinical use of the natural alkaloids is largely restricted to pilocarpine as a sialagogue and miotic agent. USES Glaucoma Second line agent for open angle glaucoma. (Pilocarpine was the most widely used anti-glaucoma drug before timolol was introduced). Management of acute angle-closure glaucoma. Treatment includes several drugs: timolol, pilocarpine, apraclonidine, acetazolamide and an osmotic agent, such as oral glycerol and IV mannitol. ADVERSE Can enter brain and cause CNS disturbances. Stimulates sweating and salivation.

Not hydrolyzed by acetylcholinesterase Inactivated by other esterases. Little or no nicotinic actions. Strong muscarinic activity. Treatment of acute postoperative and postpartum urinary retention. Neurogenic atony of the urinary bladder with retention. Adverse Effects Sweating Salivation Flushing Low blood pressure Nausea Abdominal pain Diarrhoea Bronchospasm

Both muscarinic and nicotinic agonist. Poor substrate for acetylcholinesterase. Biotransformed by other esterases at much slower rate. Uses Miosis during surgery. Reduces intraocular pressure after cataract surgery.

Predominantly muscarinic agonist. Hydrolyzed by acetylcholinesterase at considerably slower rate than acetylcholine. Almost totally resistant to hydrolysis by nonspecific cholinesterase or butyrylcholinesterase. USES: Dx of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma.

MOA: binds reversibly to the active site of the enzyme; enzyme-inhibitor complex doesn’t involve a covalent bond and is short- lived. Used in diagnosis of myasthenia gravis. Edrophonium IV leads to rapid increase in muscle strength. Also used to reverse the neuromuscular block produced by non-depolarizing muscular blockers.

MOA: form a covalent bond with the enzyme; Can enter and stimulate CNS. USES: Treatment of overdoses of anticholinergic drugs; Many drugs have anti-cholinergics (side) effects NOTE: Physostigmine should not be given to a patient with suspected TCA overdose because it can aggravate depression of cardiac conduction.

The carbamate-cholinesterase bond spontaneously hydrolyzes within 30 minutes - 6 hours. Clinical recovery occurs in several hours; only rarely in more than 24 hours. includes physostigmine, neostigmine, pyridostigmine

Quaternary ammonium Doesn’t enter CNS. USES To stimulate bladder and GI tract. Antidote for competitive blockers of the NMJ. Symptomatic treatment of myasthenia gravis

Treatment of myasthenia gravis. Most commonly used anticholinesterase for this indication.

Lecture 12: Cholinergic Drugs Flashcards by Minh Lam

Direct effects of ACh on CARDIOVASCULAR SYSTEM

DIRECT EFFECS OF ACETYLCHOLINE

Vasodilation (M3 effect).
Decrease in cardiac rate (M2 effect).
Decrease in rate of conduction in the SA and AV nodes (M2 effect).
Decrease in force of contraction (M2 effect).
Some of these direct effects can be obscured by baroreceptor reflexes.
IV injection of a small dose of acetylcholine produces a fall in blood pressure due to vasodilation (M3 effect) usually accompanied by reflex tachycardia.
Larger doses of acetylcholine cause hypotension (M3 effect) and bradycardia (M2 effect).

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NICOTINIC EFFECTS OF ACH

If muscarinic effects are blocked by atropine, large doses of acetylcholine produce nicotinic effects:
Increase in blood pressure and vasoconstriction due to stimulation of sympathetic ganglia and release of epinephrine from the adrenal medulla.

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ACETYLCHOLINE as a drug

No systemic therapeutic applications due to multiplicity of actions, and rapid hydrolysis by both acetylcholinesterase and plasma butyrylcholinesterase.
USES: Used to obtain rapid miosis after delivery of the lens in cataract surgery and other anterior procedures where rapid miosis is required.

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NATURAL ALKALOIDS

Muscarine acts almost exclusively at muscarinic receptor sites.
Arecoline acts at muscarinic and nicotinic receptors.
Pilocarpine has mainly a muscarinic action.
Present clinical use of the natural alkaloids is largely restricted to pilocarpine as a sialagogue and miotic agent.

USES Glaucoma

Second line agent for open angle glaucoma. (Pilocarpine was the most widely used anti-glaucoma drug before timolol was introduced).
Management of acute angle-closure glaucoma. Treatment includes several drugs: timolol, pilocarpine, apraclonidine, acetazolamide and an osmotic agent, such as oral glycerol and IV mannitol.

ADVERSE

Can enter brain and cause CNS disturbances.
Stimulates sweating and salivation.

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Bethanecol

Not hydrolyzed by acetylcholinesterase
Inactivated by other esterases.
Little or no nicotinic actions.
**Strong muscarinic activity. **
Treatment of acute postoperative and postpartum urinary retention.
Neurogenic atony of the urinary bladder with retention.

Adverse Effects

Sweating
Salivation
Flushing
Low blood pressure
Nausea
Abdominal pain
Diarrhoea
Bronchospasm

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CARBACHOL

Both muscarinic and nicotinic agonist.
Poor substrate for acetylcholinesterase.
Biotransformed by other esterases at much slower rate.

Uses

Miosis during surgery.
Reduces intraocular pressure after cataract surgery.

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METHACHOLINE

Predominantly muscarinic agonist.
Hydrolyzed by acetylcholinesterase at considerably slower rate than acetylcholine.
Almost totally resistant to hydrolysis by nonspecific cholinesterase or butyrylcholinesterase.
USES: Dx of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma.

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NICOTINIC RECEPTOR AGONISTS

GANGLION STIMULANTS
NICOTINE: Affects the NMJ in concentrations only slightly greater than those that affect ganglia.
- Low doses: ganglionic stimulation by depolarization
- CV system: Mainly sympathomimetic effects. Increase in HR and BP due to catecholamine release from adrenergic nerve terminals and from adrenal medulla.
- GI & urinary tracts: Mainly parasympathomimetic effects: nausea, vomiting, diarrhea, voiding of urine.
- Secretions: Stimulation of salivary and bronchial secretions.
High doses: ganglionic blockade and neuromuscular blockade.

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Nicotine: Acute poisoning

nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental confusion and weakness.

BP falls; pulse is weak.

Death may occur from paralysis of respiratory muscles and/or central respiratory failure.

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INDIRECT-ACTING CHOLINERGIC AGENTS (ANTICHOLINESTERASES)

Simple alcohols bearing a quaternary ammonium
* Edrophonium
Carbamates
* Physostigmine, neostigmine, pyridostigmine.
Organophosphates

Echothiophate, parathion, malathion
covalent bond formed is extremely stable and hydrolyzes very slowly.

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ANTICHOLINESTERASES: ORGAN SYSTEM EFFECTS

Cholinesterase inhibitors have less marked effects on blood pressure than direct-acting muscarinic agonists.

Few vascular beds receive cholinergic innervation.

There fore the effects of cholinesterase inhibitors on vascular smooth muscle are minimal.

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Edrophonium

MOA: binds reversibly to the active site of the enzyme; **enzyme-inhibitor complex doesn’t involve a covalent bond and is short- lived. **
Used in diagnosis of myasthenia gravis. Edrophonium IV leads to rapid increase in muscle strength.
Also used to reverse the neuromuscular block produced by non-depolarizing muscular blockers.

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Physostigmine

MOA: form a covalent bond with the enzyme; Can enter and stimulate CNS.
USES: Treatment of overdoses of anticholinergic drugs; Many drugs have anti-cholinergics (side) effects
NOTE: Physostigmine should not be given to a patient with suspected TCA overdose because it can aggravate depression of cardiac conduction.

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Carbamates

The carbamate-cholinesterase bond spontaneously hydrolyzes within 30 minutes - 6 hours. Clinical recovery occurs in several hours; only rarely in more than 24 hours.
includes physostigmine, neostigmine, pyridostigmine

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NEOSTIGMINE

Quaternary ammonium
Doesn’t enter CNS.

USES

To stimulate bladder and GI tract.
Antidote for competitive blockers of the NMJ.
Symptomatic treatment of myasthenia gravis

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Pyridostigmine

Treatment of myasthenia gravis.
Most commonly used anticholinesterase for this indication.

Echothiphate

organophospates
Used for chronic open-angle glaucoma, subacute or chronic angle-closure glaucoma after iridectomy or where surgery is refused or contraindicated.

Malathion & Parathion

insecticides
Exam q: Farmer poisoned by malathion/parathion
must be activated in the body by conversion to oxygen analogs.

AChE inhibitors used to treat Alzheimer’s disease

Tacrine
Donepezil
Rivastigmine
Galantamine

Pralidoxime

synthetic compound that can reactivate inhibited acetylcholinesterase.
If given before ageing has occurred, pralidoxime is able to split the phosphate-enzyme bond and can be used as cholinesterase regenerator drug for organophosphate insecticide poisoning.
Because of its positive charge, it doesn’t enter the CNS and is ineffective in reversing the central effects of organophosphate poisoning.

Atropine: Actions

Prototype muscarinic receptor antagonist; tertiary amine
Many antihistaminic, antipsychotic, and antidepressant drugs have similar structures and predictably significant antimuscarinic effects
Binds competitively to muscarinic receptors, preventing acetylcholine from binding.
Tertiary amine: both central and peripheral muscarinic blocker.

Actions

Eye: Mydriasis. Cycloplegia.
GI: Reduces gastric motility.
Urinary system: Decreases hypermotility of urinary bladder.
CVS
- Low doses: bradycardia. Due to blockade of presynaptic M2 receptors that normally inhibit ACh release.
- Moderate to high therapeutic doses: Blockade of atrial M2 receptors: tachycardia.
- High doses of antimuscarinic agents may cause cutaneous vasodilation. This is called ‘atropine flush’. The mechanism is unknown.
Salivary, sweat and lacrimal glands are blocked.

Atropine: Uses

Mydriasis and cycloplegia.
Antispasmodic: to relax GI tract and bladder.
Antidote for cholinergic agonists.
Antidote for mushroom poisoning due to muscarine, found in Amanita muscaria and other fungi.
**Anti-sialogogue: **To block respiratory tract secretions prior to surgery.

PHARMACOKINETICS

Readily absorbed, partially metabolized by liver, eliminated primarily in urine. Half-life 4 hours.

Atropine: Adverse Effects

Dry mouth, blurred vision, sandy eyes, tachycardia, constipation.
Effectson CNS: restlessness, confusion, hallucinations, delirium, which may progress to depression, collapse of the circulatory and respiratory systems and death.

Scopolamine: Uses

Prevention of motion sickness.
To block short-term memory: sometimes used in anaesthetic procedures.
In contrast to atropine, it produces sedation; at higher doses can produce excitement.
For some pre- and postoperative states when a mydriatic and cycloplegic is needed in treatment of iridocyclitis

SYNTHETIC & SEMISYNTHETIC DRUGS

* QUATERNARY AMMONIUM MUSCARINIC ANTAGONISTS * TERTIARY AMINE MUSCARINIC ANTAGONISTS

IPRATROPIUM AND TIOTROPIUM

* QUATERNARY AMMONIUM MUSCARINIC ANTAGONISTS * Used as inhalational drugs in the treatment of chronic obstructive pulmonary disease (COPD). * Also used as inhalational drugs in asthma.

HOMATROPINE CYCLOPENTOLATE TROPICAMIDE

* TERTIARY AMINE MUSCARINIC ANTAGONISTS * For use in ophthalmology. * **Produce mydriasis with cycloplegia (loss of accommodation)** * Preferred to atropine because of shorter duration of action.

BENZTROPINE TRIHEXYPHENIDYL

* TERTIARY AMINE MUSCARINIC ANTAGONISTS * Used to treat **parkinsonism and the extrapyramidal effects of antipsychotic drugs.**

GLYCOPYRROLATE

* blocks muscarinic receptors * Used orally to inhibit GI motility. * Used parenterally to prevent bradycardia during surgical procedures.

TOLTERODINE

* anti-muscarinic (M2 & M3) * Used for over active bladder.

CONTRAINDICATIONS OF ANTIMUSCARINIC AGENTS

* Contraindicated in patients with **angle-closure glaucoma.** * Should be used with caution in patients with **prostatic hypertrophy** and in the **elderly. **

ADVERSE EFFECTS OF ANTICHOLINERGIC AGENTS IN GERIATRIC & COGNITIVELY IMPAIRED PATIENTS

* Anticholinergic adverse effects are potentially hazardous to elderly patients, especially those with cognitive impairment. * Many common drugs possess some anticholinergic activity, and the elderly (and especially the cognitively impaired elderly) are very sensitive to cholinergic blockade (due to central cholinergic hypofunction and dysfunction in ageing and dementia, respectively). * Adverse effects caused by anticholinergic drugs in the elderly may include acute encephalopathy (delirium, confusional state), falls, urinary retention, constipation, and exacerbation and decompensation of underlying cognitive, functional, and behavioral deficits (particularly in patients with dementia).

ANTINICOTINIC AGENTS: GANGLION BLOCKERS

* Ganglion blockade may occur by the following mechanisms: * By **prolonged depolarization.** Example: Nicotine. * By **antagonism of nicotinic receptors.** Examples: Hexamethonium, mecamylamine, trimethaphan; used for hypertension in the past but had too many adverse effects * Effects of ganglion-blockers can be predicted by a knowledge of which division of the autonomic nervous system exercises dominant control of various organs.

NMJ Blocker classes

* COMPETITIVE ANTAGONISTS (NONDEPOLARIZING BLOCKERS) * AGONISTS (DEPOLARIZING BLOCKERS) * Used during surgery to produce complete muscle relaxation.

Tubocurarine

MOA: Competitive antagonists/non-depolarizing blocker USES: As adjuvant drugs in anaesthesia during surgery to relax skeletal muscle. PHARMACOKINETICS Given IV. Oral absorption is minimal. Penetrate membranes very poorly. Don’t cross blood-brain barrier. ADVERSE Autonomic effects: some agents are moderate blockers of muscarinic receptors. Histamine release: tubocurarine may cause histamine release.

Succinylcholine

* MOA: binds to the nicotinic receptor and depolarizes the junction. Persists in the synaptic cleft, stimulating the receptor: receptor desensitizes. * leads to flaccid paralysis. USES * Useful when rapid endotracheal intubation is needed. * During ECT PHARMACOKINETICS Given IV by continuous infusion. Rapidly hydrolysed by plasma cholinesterase. Extremely brief duration of action (5-10 min) and rapid onset (1-1.5 min). Adverse effects * **Malignant hyperthermia**: Due to excessive release of Ca2+ from the SR. * **Most incidents due to combination of succinylcholine and an halogenated anesthetic.** * Treatment: **dantrolene**. Blocks release of Ca2+ from SR.

HEMICHOLINIUM-3

* Blocks the CHT; INHIBITORS OF ACETYLCHOLINE SYNTHESIS * Prevents uptake of choline required for ACh synthesis. * Research tool.

VESAMICOL

* INHIBITORS OF ACETYLCHOLINE STORAGE * Vesamicol blocks the ACh-H+ antiporter that is used to transport ACh into vesicles, thereby preventing the storage of ACh. * Research tool.

BOTULINUM TOXIN

* Inhibits acetylcholine release. * Injected locally into muscles for treatment of several diseases involving muscle spasms. * Also approved for cosmetic treatment of facial wrinkles. Uses treatment of torticollis, achalasia, strabismus, blepharospasm, and other focal dystonias.