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Pharmacology > Cholinergic Agonists and Antagonists > Flashcards

Cholinergic Agonists and Antagonists Flashcards

1
Q

Direct acting cholinergic agonists MOA

A

Bind to and activate muscarinic and nicotinic receptors –> many have effects on both receptors

Therapeutically useful drugs preferentially activate muscarinic receptors (located at parasympathetic effector organs and sweat glands)

Can be divided into choline esters (acetylcholine, methacholine, carbacol, bethanechol) and alkaloids

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2
Q

Direct effects of acetylcholine on cardiovascular system

Effect of small vs large doses of ACh on CVS

A

Vasodilation: endothelial M3 effect –> release of NO

Decrease in heart rate, rate of conduction in the SA and AV nodes and force of contraction - M2 effect

IV injection of small dose - vasodilation (M3) will cause fall in peripheral vascular resistance which will decrease the MAP –> will lead to reflex tachycardia (increased HR because the blood pressure is falling so the baroreceptors change the direct action of the drug)

IV injection in larger doses - vasodilation –> fall in PVR –> fall in MAP –> bradycardia M2 effect also occurs in addition to vasodilation and hypotension mediated by endothelial M3 receptors

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3
Q

Effect of acetylcholine on various organ systems (8)

A

Vasculature: release of NO and vasodilation –> decrease in BP (M3)

Iris: miosis

Ciliary muscle: accommodation of lens to near vision

Salivary, lacrimal and sweat glands: Increased secretions

Lungs: Bronchoconstriction and increased secretions

GI tract: Increased tone (M3), peristaltic activity and secretions and relaxation of sphincters

Urinary bladder: contraction of detrusor muscle and relaxation of sphincter –> voiding of urine

Heart: decreased heart rate, force of contraction and conduction velocity

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4
Q

Nicotinic effects of acetylcholine

A

If muscarinic effects are blocked by a muscarinic antagonist like atropine, last doses of ACh will produce nicotinic effects only (nothing will happen at low doses of ACh even when M receptors are blocked)

Increase in blood pressure and vasoconstriction due to stimulation of sympathetic ganglia and release of epinephrine from adrenal medulla

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5
Q

Choline Esters MOA and PK

A

Acetylcholine
Methacholine
Carbachol
Bethanechol

Are direct acting cholingeric agonists

Quaternary ammoniums –> poorly absorbed and distributed into CNS

Acetylcholine is rapidly hydrolysed by AChE but the other 3 are more resistant to hydrolysis by cholinesterase

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6
Q

Acetylcholine uses

A

No systemic therapeutic applications due to multiplicity of actions and rapid hydrolysis by both AChE and plasma BChE

Used to obtain rapid miosis after delivery of the lens in cataract surgery and other procedures where paid miosis is needed

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7
Q

Bethanechol MOA and uses

A

Direct acting muscarinic agonist

Used to treat

  • post-operative and postpartum urinary retention
  • atony of the urinary bladder
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8
Q

Carbachol MOA and uses

A

Direct acting muscarinic and nicotinic agonist

Used to treat miosis during surgery

Reduces intraocular pressure after cataract surgery

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9
Q

Methacholine MOA and uses

A

Direct acting muscarinic agonist

Used in diagnosis of bronchial airway hyperactivity in patients who do not have clinically apparent asthma –> It may be performed if a patient’s symptoms and spirometry do not clearly establish a diagnosis of asthma. The patient breathes in nebulized methacholine. The main result is the provocation concentration of methacholine that causes FEV1 to drop by 20%

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10
Q

Pilocarpine MOA and uses

A

Direct acting partial muscarinic agonist

Natural alkaloid and tertiary amine –> can enter the CNS

Stable to hydrolysis by AChE

Uses:

  • Second line agent for open angle glaucoma
  • Management of acute-angle closure glaucoma
  • Treatment of dry mount due to radiotherapy for cancer of head and neck
  • Treatment of dry mount caused by Sjogren’s syndrome
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11
Q

Adverse effects of muscarinic agonists

A

Increased sweating, salivation

Flushing (due to vasodilation of skin vessels)

Low blood pressure

Nausea

Abdominal pain and diarrhea

Bronchospasm

Pilocarpine can enter brain and cause CNS distrubances

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12
Q

Nicotine MOA and effects of different doses and uses

A

Natural alkaloid –> direct acting selective agonist of nicotinic receptor

Tertiary amine –> can enter brain

Use: smoking cessation therapy

Low dose: ganglionic stimulation by depolarisation. Response resembles simultaneous discharge of both parasympathetic and sympathetic nervous systems:

  • CVS: Mainly sympathomimetic effects. Increase HR and BP due to catecholamine release from nerve terminals and adrenal medulla
  • GI and urinary tracts: Mainly parasympathetic effects: nausea, vomiting, diarrhoea and voiding of urine
  • Secretions: stimulation of salivary and bronchial secretions

High doses: Ganglionic and neuromuscular blockage due to sensitisation of receptors by prolonged depolarisation –> paralysis

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13
Q

Acute nicotine poisoning

A

Nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental conduction and weakness

Decreased blood pressure and weak pulse

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

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14
Q

Differences in MOA of indirect acting cholinergic agents

A

All inhibit acetylcholinesterase and increase concentration of endogenous acetylcholine

Edrophonium:
Binds reversibly to active site of AChE –> Enzyme-inhibitor complex doesn’t involve a covalent bond and is short-lived (only 2 to 10 minutes)

Carbamates:
Form a colavent bond with AChE –> enzyme-inhibitor bond spontaneously hydrolyses within 30 minutes to 6 hours

Organophosphates:
Phosphorylate AChE –> covalent bond formed is extremely stable and hydrolyses very slowly –> phosphorylated enzyme may undergo a process called ageing –> strengths the phosphorous-enzyme bond so it becomes irreversible

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15
Q

Effects of cholinesterase inhibitors on CNS, NMJ, eyes, glands, GI and urinary tracts

A

CNS: In low concentrations, liposoluble cholinesterase inhibitors cause CNS activation. In higher concentrations, they cause convulsions which may be followed by coma and respiratory arrest

NMJ: Increase strength of skeletal muscle contraction (Nm receptors)

Eyes: miosis and accommodation of lens to near vision

Salivary, lacrimal and sweat glands: Increased secretions

Lungs: Bronchoconstriction and increased secretions

GI tract: Increased tone (M3), peristaltic activity and secretions and relaxation of sphincters

Urinary bladder: contraction of detrusor muscle and relaxation of sphincter –> voiding of urine

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16
Q

Effects of cholinesterase inhibitors on cardiovascular system

A

Can activate both sympathetic and parasympathetic ganglia supplying the heart

Heart: parasympathetic effects predominate –> decreased heart rate, contractility and conduction velocity –> cardiac output falls

Vascular smooth muscle: Minimal effect because vascular beds lack cholingeric innervation. At moderate doses, they cause an increase in systemic vascular resistance and blood pressure due to the activation of sympathetic ganglia and central sympathetic centers

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17
Q

Cardiovascular effects of moderate doses of cholinesterase inhibitors (4)

A

Modest bradycardia
Fall in cardiac output
Increased vascular resistance
Increase in blood pressure

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18
Q

Cardiovascular effects of toxic doses of cholinesterase inhibitors

A

The accumulation of acetylcholine at the ganglia is initially excitatory on nicotinic receptors, but at higher concentrations, ganglionic blockade ensues as a result of persistent depolarization

Causes marked bradycardia, significant decrease of cardiac output and hypotension

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19
Q

Edrophonium MOA and uses

A

Reversible acetylcholinesterase inhibitor –> indirect acting cholingeric antagonist

Quaternary ammonium - does not enter CNS

Uses:

  • Diagnosis of myasthenia gravis. Edrophonium IV leads to rapid increase in muscle strength
  • Used to reverse the neuromuscular block produced by non-depolarising muscular blockers
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20
Q

Physostigmine MOA and uses

A

Carbamate –> Form a colavent bond with acetylcholinesterase –> indirect acting cholingeric antagonist

Tertiary amine –> can enter and stimulate CNS

Used to treat overdoses of anticholinergic drugs (eg: atropine)

21
Q

Neostigmine MOA and uses

A

Carbamate –> Form a colavent bond with acetylcholinesterase –> indirect acting cholingeric antagonist

Quaternary ammonium - does not enter CNS

Uses:

  • Postoperative urinary retention
  • Reversal of effects of non-depolarizing neuromuscular blockers after surgery
  • Treatment of myasthenia gravis
22
Q

Pyridostigmine MOA and uses

A

Carbamate –> Form a colavent bond with acetylcholinesterase –> indirect acting cholingeric antagonist

Quaternary ammonium - does not enter CNS

Treatment of myasthenia gravis

23
Q

Echothiophate MOA and use

A

Organophosphate –> covalently bond forms via phosphorylation of acetylcholinesterase and inhibits enzyme –> indirect acting cholinergeric antagonist

Rarely used for glaucoma

24
Q

Malathion and Parathion

A

Organophosphate insecticides

Activated in the body by conversion to oxygen analogs.

Malathion is rapidly metabolized to inactive products in birds and mammals, but not
in insects. It is considered safe enough for sale to the general public.

Parathion is not detoxified effectively in vertebrates; thus it is considered more dangerous than malathion to humans and livestock and is not available for general public use.

Can lead to poisoning

25
Q

Sarin

A

Organophosphate nerve gas

Poisoning with these agents includes an important component of CNS toxicity.

26
Q

AChE inhibitors used in Alzeihmer Disease

A

Donepezil
Rivastigmine
Galantamine

Patients with Alzheimer disease have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function.

The mainstay of therapy for patients with Alzheimer disease is the use of centrally acting cholinesterase inhibitors to slow down progression of disease.

27
Q

Pralidoxime use

A

REactivator of AChE –> can be used as a cholinesterase regenerator for organophosphate insecticide poisoning

If given before ageing has occured, it can split the phosphorus-enzyme bond.

28
Q

Antidote to organophosphate insecticide poisoning

A

First give atropine to block the muscarinic receptors so the excess acetylcholine cannot act

Give pralidoxime to regenerate the cholinesterase. Need to give it before ageing because if it occurs, then it is irreversible

29
Q

Atropine MOA

A

Reversible competitive muscarinic receptor antagonist –> prevents acetylcholine from binding at the receptors

Tertiary amine - both a central and peripheral muscarinic blocker

30
Q

Atropine effects (5)

A

Eye: mydriasis and cycloplegia (loss of accommodation)

GI: Reduces gastric motility

Urinary system: Decreases hypermotility of the bladder

Cardiovascular system:

  • 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 may cause cutaneous vasodilation: “atropine flush”

Secretions: Sweat, salivary and lacrimal glands are blocked. Inhibition of sweat glands may cause high body temperature (due to inability to thermoregulate)

31
Q

Uses of atropine (4)

A

Antispasmodic - to relax GI tract and bladder

Antidote for cholinergic agonists

  • eg: To alleviate the muscarinic side effects of anticholinesterase drugs (eg
    neostigmine) used for reversal of neuromuscular blockade

To block respiratory tract secretions prior to surgery

To increase heart rate or decrease AV-block when bradycardia or AV-block are hemodynamically significant and thought to be due to excess parasympathetic tone.

32
Q

Atropine adverse effects (7)

A

Dry mouth

Blurred vision

Sandy eyes - due to decrease lacrimation

Tachycardia

Constipation

Urinary retention

CNS effect: Restlessness, confusion, hallucinations, delirium which pay progress to depression, collapse of circulatory and respiratory systems and death

33
Q

Scopolamine MOA and uses

A

Muscarinic receptor antagonist

Uses:

  • Prevents motion sickness (inhibits M1 receptors in the vomiting centres in the brain)
  • To block short-term memory: sometimes used in anaesthetic procedures
34
Q

Irpratropium and tiotropium MOA and uses

A

Quaternary ammonium muscarinic antagonists

Used as inhalation drugs in treatment of COPD and asthma

35
Q

Homatropine and tropicamide MOA and uses

A

Tertiary amine muscarinic antagonists

Used as mydriatic for fundoscopy.
Produces mydriasis with cycloplegia
Preferred to atropine because of shorter duration of action

36
Q

Benztropine and trihexyphenidyl MOA and uses

A

Tertiary amine muscarinic antagonists

Used to treat Parkinson’s disease and the extrapyramidal effects of antipsychotic drugs

In the basal ganglia, there is dopaminergic input and cholinergic input and there is a balance between these
two. In Parkinson’s the dopaminergic input starts to die so the cholinergic effects predominate –> tremors, tardive dyskinesia. Block the action of the extra cholinergic input using these drugs to stop these symptoms

37
Q

Glycopyrrolate MOA and uses

A

Muscarinic antagonist

Used orally to inhibit GI motility

Used parentally to prevent bradycardia during surgical procedures

38
Q

Tolterodine MOA and uses

A

Muscarinic antagonist

Used for overactive bladder

39
Q

Contraindications of antimuscarinic agents (3)

A

Contraindicated in patients with angle-closure glaucoma –> obstructs drainage of acqeous humour even more due to mydriasis

Should be used with caution in patients with prostatic hypertrophy - can cause even more stasis of urine in the bladder and it can lead to infections

Should be used in caution in the elderly –> can enter CNS –> 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).

40
Q

Nicotinic receptor antagonists that are ganglion blockers

A

Nicotine: ganglion blocker due to prolonged depolarisation of nicotinic receptors

Hexamethomium and mecamylamine: antagonism of nicotinic receptors

41
Q

Effects of ganglion blockers

A

Effect is to remove the predominant control

Arterioles (S)–> vasodilation and hypotension
Veins (S) –> ventilation
Heart (PS) –> increased heart rate
Iris (PS) –> Mydriasis
Ciliary muscle (PS) –> cycloplegia (focus for far vision)
GI tract (PS) –> reduced tone and motility, constipation and decreased secretions
Urinary bladder (PS) –> urine retention
Salivary glands (PS) –> Dry mouth
Sweat glands (S) –> Anhydrosis

42
Q

Tubocurarine MOA and uses

A

Competitive antagonist of Nm receptors –> prevent acetylcholine from binding –> non-depolarizing blockers –> prevent depolarization and inhibit muscular contraction

Adjuvant drugs in anaesthesia during surgery to relax skeletal muscle

43
Q

Reversing non-depolarizing blockade

A

Action can be overcome by increasing concentration of acetylcholine in synaptic cleft, for example with cholinesterase inhibitors such as neostigmine or edrophonium.

44
Q

Succinylcholine MOA and use

A

Depolarizing neuromuscular blocker –> Binds to nicotine receptor and depolarises the NMJ –> persists in the synaptic cleft and stimulates the receptor –> receptor desensitisation –> flaccid paralysis

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).

Uses:

  • Rapid endotracheal intubation
  • ECT: last line of treatment for patients with drug refractory depression
45
Q

Adverse effects of depolarising neuromuscular blockers

A

Malignant hyperthermia due to excessive release of Ca2+ from the DR –> high fever, muscle breakdown, acidosis

Most incidents due to combination of succinylcholine and a halogenated aesthetic

46
Q

Antidote to malignant hyperthermia

A

Dantrolene –> blocks release of Ca2+ from DR

Reversal of adverse effects caused by depolarisation blockers

47
Q

Hemicholinum-3

A

Blocks CHT –> Prevents uptake of choline required for acetylcholine synthesis

Used as a research tool

48
Q

Vesamicol

A

Blocks Ach-H+ antiporter (VAchT) –> prevents storage of acetylcholine

Used as a research tool

49
Q

Botulinum Toxin MOA and uses

A

A potent neurotoxin –> prevents synaptic vesicle fusion with the axon
terminal membrane –> inhibiting acetylcholine release.

Injected locally into muscles for treatment of several disease involving muscle spasms (torticollis, achalasia, strabismus,
blepharospasm, and other focal dystonias

Approved for cosmetic treatment of facial wrinkles

Pharmacology (20 decks)

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