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Pharmacology > Cholinergics and Anticholinergics > Flashcards

Cholinergics and Anticholinergics Flashcards

1
Q

What are the two types of cholinergic receptors?

A

Muscarinic and Nicotinic

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2
Q

What are the important muscarinic receptors and what do they mediate?

A

M1: stomach
M2: heart
M3: lungs, glands, GIT
All mediate CNS effects

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3
Q

What kind of receptors are muscarinic receptors?

A

G-protein coupled receptors, sensitive to muscarine

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4
Q

What are the important nicotinic receptors and what do they mediate?

A

n1/nm: skeletal muscles at neuromuscular junctions
n2/nn: ganglia in the CNS

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5
Q

What kind of receptors are nicotinic receptors?

A

Ionotropic, most sensitive to nicotine

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6
Q

What is the effect of activating M3 receptors?

A

bronchoconstriction, increased GIT motility and secretions, increased secretions from glands

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7
Q

What is the effect of activating M2 receptors?

A

decreased HR, decreased contractility, increased GIT activity

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8
Q

Explain Alzheimer’s briefly and the role of cholinergics

A

Alzheimer’s is a neurodegenerative disease associated with cognitive decline and dementia.

The cholinergic neurons in the basal forebrain are the most damaged.

Increasing the availability of Ach can improve the symptoms

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9
Q

Explain Parkinson’s disease briefly and the role that cholinergics play.

A

It is a neurodegenerative disease associated with progressive loss of initiation and control of voluntary movements.

The dopaminergic cells of the substantia nigra are the first to die.

Cholinergic interneurons oppose the effect of dopamine in the striatum.

Blocking Ach can relieve symptoms

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10
Q

What are the three types of direct cholinergic agonists?

A

Muscarinic agonists: structurally similar to Ach, can be broken down by enzymes

Choline esters

Alkaloids: more resistant to being broken down

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11
Q

What is the mechanism of indirect cholinergic drugs?

A

Anti-cholinesterases: inhibiting enzymes that break down Ach –> increases availability of Ach

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12
Q

Describe the adverse effects of cholinergic agents

A

Diarrhoea: parasympathetic overstimulation of the GIT (motility and secretion)

Nausea: parasympathetic overstimulation of the GIT, effect on nausea and vomiting pathways in the CNS, overstimulation of M1 receptors

Diaphoresis: sweating, sympathomimetic effect in eccrine sweat glands

Miosis: parasympathetic effect on eye

Urinary urgency: parasympathetic effect on the bladder

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13
Q

What are the general contraindications of cholinergic agents?

A

Asthma: as activation of M3 receptors causes bronchoconstriction and increased secretion in the airways

Peptic ulcer: as activation of M1 receptors stimulates gastric acid secretion

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14
Q

What is an alkaloid muscarinic drug?

A

Pilocarpine

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15
Q

What is a muscarinic choline ester?

A

Carbamate choline esters: bethanechol, carbachol

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16
Q

What are carbamate choline esters susceptible and resistant to?

A

Resistant to acetylcholinesterases but susceptible to choline esterase

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17
Q

What is a nicotinic alkaloid?

A

Nicotine

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18
Q

What is a partial nicotinic agonist?

A

Varenicline

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19
Q

What is a non-selective cholinergic agent?

A

Acetylcholine

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20
Q

Describe the mechanism of action of pilocarpine and its effects

A

It is an alkaloid non-selective muscarinic acetycholine receptor agonist
It activates M3 receptors

It contracts the sphincter muscles in the eye, freeing up Schlemm’s canal for intra-ocular fluid to drain, while causing miosis.

it strengthens the trabecular meshwork

it contracts ciliary muscles for near vision accommodation

It promotes salivation

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21
Q

What are the clinical uses and side effects of pilocarpine?

A

glaucoma and xerostomia (dry mouth)

topical opthalmic: minimal systemic absorption, mostly local stinging/irritation

oral administration: sweating, blurred vision, worsens asthma and COPD

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22
Q

What is the MOA of Bethanechol and its effects?

A

It is a quartenary choline ester M3 agonist

Urinary system: increases detrusor tone, decreases outlet resistance of the internal sphincter

GIT: increases motility and secretion

Has little M2 activation so little cardiac effect

Quartenary structure means it doesn’t cross the BBB so no CNS effects

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23
Q

What are the clinical uses and adverse effects of Bethanechol?

A

Used to treat gastric atony after vagotomy

Used to treat urinary retention

Adverse effects include diarrhoea, nausea, vomiting or cramps.

There is also pulmonary bronchoconstriction and increased secretion in the airway

There is also miosis

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24
Q

What is the effect of Nicotine at the neuromuscular junction?

A

it causes skeletal muscle contraction, spasms, and fasciculations

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25
Q

What is the effect of nicotine at neuronal receptors?

A

It induces the release of adrenaline from the adrenal medulla

HR increases (symp > para)

GIT motility and secretion increase (para > symp)

RR increases

Peripheral vasoconstriction (symp)

Medullary emetic chemoreceptors: vomiting and nausea

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26
Q

What is a clinical use for nicotine and its adverse effects?

A

Smoking cessation

Adverse effects: dependence due to dopaminergic reward pathway activation

low doses increase HR, RR, BP etc but they reduce appetite

27
Q

What is the mechanism of action of physostigmine?

A

It is a reversible carbamate AChE inhibitor – this means it’s a tertiary amine that crosses the BBB.

28
Q

What is myasthenia gravis?

A

An autoimmune disease where antibodies attack Nm nicotinic receptors

Depletion of these receptors leads to muscle weakness

29
Q

What are the two classifications of anticholinesterases?

A

Reversible and irreversible/poorly-reversible

30
Q

What are the clinical uses and adverse effects of physostigmine?

A

Used in Alzheimer’s disease (since cholinergic receptors in the basal forebrain are affected) and since it crosses the BBB. It’s also used for atropine poisoning.

Adverse effects: nausea, diarrhoea, vomiting, bradycardia, hypotension. basically overstimulation of parasympathetic system

31
Q

What is the mechanism of neostigmine?

A

It is also a carbamate inhibitor of AChE, like physostigmine.

It activates M3 receptors, contracting the GIT and GU smooth muscle, reducing sphincter tone and increasing secretions.

Unlike physostigmine, it is a quartenary structure and so cannot cross the BBB

*It is resistant to hydration (not soluble in water)

32
Q

What are the clinical uses and adverse effects of neostigmine?

A

It is used to reverse non-depolarising nm blockades, by increasing availability of ACh and allowing for firing at NMJ. It does not reverse depolarising blockades

It is used to treat myasthenia gravis

Increases motility in a neurogenic paralytic ileus e.g. post-surgery

It can treat urinary retention secondary to bladder atony

Adverse effects: sweating, diarrhoea, urinary incontinence

33
Q

What are some organophosphates?

A

Sarin, soman, tabun, parathion, malathion

34
Q

What is the mechanism of action for poisons like sarin?

A

They are absorbed through the skin, GIT, and lungs

They are suicide inhibitors of AChE –> increases ACh at NM junctions and neuronal synapses

Sarin, soman, tabun are nerve agents

parathione and malathion are used in insecticides

35
Q

What are the clinical manifestations of poisoning from nerve agents like sarin?

A

CNS: coma, respiratory depression, seizures, nausea, vomiting

Bradycardia, sweating, salivation, lacrimation may also occur. Basically parasympathetic overstimulation occurs as well.

Has somatic nicotinic effects as well: muscle twitching, fasciculation, weakness, flaccid paralysis

36
Q

What are possible antidotes for nerve agents?

A

Cholinesterase regenerators to prevent inhibition from becoming irreversible

muscarinic receptor blockers to reverse muscarinic effects like bradycardia

37
Q

What is the mechanism of action of Pralidoxime?

A

It regenerates AChE as it has a higher affinity for phosphate than AChE –> removes the phosphate from AChE

38
Q

What is the clinical use of pralidoxime?

A

Acute treatment of organophosphate poisoning

39
Q

What are some examples of muscarinic antagonists drugs?

A

atropine, benzatropine, scopolamine, ipratropium, oxybutynin

40
Q

What are some common adverse effects of muscarinic antagonists?

A

Basically parasympatholytic effects

Blurred vision (reduced ability to accommodate), confusion, sedation mydriasis, constipation (decreased GIT motility), urinary retention, glaucoma, tachycardia, dry mouth

41
Q

What is the mechanism of action of Atropine?

A

It is a non-selective muscarinic receptor antagonist.

Basically the reverse of all parasympathetic actions.

Note that in the CNS, this leads to confusion/delirium

42
Q

What are the clinical uses and adverse effects of Atropine?

A

Treatment of bradycardia

Treatment of anticholinesterase overdose

For ophthalmic examination: by paralysing the ciliary muscle and causing mydriasis

used to treat diarrhoea as an anti-motility agent

Adverse effects: “red as beet, blind as bat, dry as bone, hot as a hare, mad as a hatter” lolz

Superficial vasodilation, blurred vision, reduced secretions, hyperthermia (due to reduced sweating), delirium and hallucinations

43
Q

What is the mechanism of action of benzatropine?

A

It is also a non-selective muscarinic receptor antagonist.

It is a tertiary amine alkaloid so is more lipophilic and crosses the BBB better than atropine, has stronger CNS effects.

maintains the dopaminergic-cholinergic balance in the striatum

44
Q

What are the clinical uses of benzatropine and its adverse effects?

A

used to treat parkinson’s as a second or third line treatment

used to treat parkinsonism as an adverse effect of treatment with typical antipsychotics that block dopaminergic D2 receptors

side effects similar to atropine, with risk of glaucoma as well

45
Q

What is the mechanism of action of Scopolamine?

A

It is also a “non-selective” muscarinic acetylcholine receptor antagonist.

But it actually targets mainly M2 (blockade, induces tachy), M3 (decrease secretions and relaxes smooth muscles) and CNS

Notable CNS effects are its antiemetic and amnesic effects

46
Q

What are the clinical uses and adverse effects of scopolamine?

A

Used to treat motion sickness

Used as an adjunct for anaesthesia: reduces secretions, decreases nausea, causes amnesia

Adverse effects similar to benzatropine

47
Q

What is the mechanism of action of Ipratropium?

A

Also a “non-selective” muscarinic acetylcholine receptor antagonist.

Difference is that is a quartenary amine, so poor systemic absorption and minimal CNS effects

It does have some preference for M3 receptors –> decreases bronchoconstriction and bronchial secretions

48
Q

What are the clinical uses and adverse effects of ipratropium?

A

First line treatment for COPD (targets hyperactivity of para system in COPD)

Second line treatment for asthma

Generally administered by inhalation w minimal systemic absorptions so few side effects

Causes dry mouth, and sedation (despite being quaternary amine)

49
Q

What is the mechanism of action of oxybutynin?

A

Tertiary amine, distributes widely with dose-dependent effects

Mainly targets M3 and M1 (reduces gastric secretions) receptors

50
Q

What are the clinical uses and adverse effects of oxybutynin?

A

Treat urinary incontinence (antagonism of M3 receptors relaxes smooth muscle and increases sphincter tone)

Used to reduce gastric acid and treat peptic ulcers, but better tolerated drugs like omeprazole and cimetidine are now used.

Adverse effects similar to the others

51
Q

What is a contraindication for most direct anticholinergic drugs, except ipratropium?

A

narrow angle glaucoma – as relaxation of the constrictor muscles in the iris obstructs the schlemm’s canal and increases intraocular pressure

52
Q

What is an additional contraindication for oxybutynin, besides narrow angle glaucoma?

A

Pyloric obstruction and retentive bladder

53
Q

What are non-depolarizing neuromuscular blocking agents?

A

They block Nm acetylcholine receptors and neurotransmission at the NMJ. This leads to paralysis of skeletal muscles.

54
Q

What is the order of onset of paralysis for non-depolarizing NMBAs?

A

Fingers/eyes –> limbs/trunk –> diaphragm

Order of recovery is the opposite

55
Q

Describe the absorption and distribution of non-depolarizing NMBAs

A

Poor oral absorption, low lipid solubility, no penetration of the BBB, small volume of distribution

56
Q

What is the mechanism of Pancuronium?

A

It is a non-depolarizing neuromuscular blockade inducer

It is a competitive antagonist of Nm nicotinic acetylcholine receptors

IV administration: rapid onset of duration and short half life

57
Q

What is rocuronium?

A

Similar to pancuronium but shorter acting

58
Q

What is actracurium?

A

Similar to pancuronium but preferred in multiorgan system failure as its metabolism is independent of renal and hepatic function!

59
Q

What are the clinical uses and adverse effects of pancuronium, rocuronium, and actracurium?

A

Induction of paralysis for surgery or ventilation

Histamine release at high doses: causes flushing, oedema, erythema (abnormal redness of skin and mucous membranes due to capillary congestion), hypotension, tachycardia

Has a weak anti-muscarinic effect: increases HR and cardiac output

60
Q

What is the mechanism of succinycholine?

A

Nm nicotinic ach receptor agonist

Not inactivated by acetylcholinesterase, but hydrolysed by plasma/liver pseudocholinesterases

Causes a depolarizing blockade: irreversible by tectanic stimulation or cholinesterase inhibitors

Phase I: opening of Na channels due to binding of succinylcholine –> depolarization –> transient twitching.

Phase II: membrane repolarizes, but desensitized to the action of acetylcholine

61
Q

What are the clinical uses and adverse effects of succinylcholine?

A

Paralysis for surgery

Adverse effects: Malignant hyperthermia, common in people with deficient or atypical plasma cholinesterase

Prolonged apnea due to paralysis of the diaphragm

Hypotension, arrhythmias, respiratory collapse

Increased intraocular pressure

62
Q

What is the mechanism of the botulinum toxin?

A

Taken from clostridium botulinum

Cleaves SNARE proteins – prevents the exocytosis of ACh containing vesicles – prevents them from acting at the NMJ to cause muscle contraction

63
Q

What are the clinical uses and adverse effects of the botulinum toxin?

A

Used in cervical dystonia, migraines, upper limb spasticity for cosmetic purposes, for blepharospasm (excessive blinking) and strabismus (squints)

Adverse effects include paralysis of the wrong muscle groups or allergic reactions

64
Q
A

Pharmacology (6 decks)

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