2. Cholinergics & anticholinergics

Question 1

Types of cholinergic receptors

Answer 1

1. Muscarinic: 
M1: stomach, CNS (nausea and vomiting pathways) 
M2: heart, CNS
M3: lungs, glands, GI tract, CNS
M4, M5: CNS

2. Nicotinic:
   N1 or Nm: skeletal muscle
   N2 or Nn: ganglion, CNS

Question 2

Common adverse effects of cholinergic agonists

Answer 2

diarrhoea, diaphoresis, miosis, nausea, urinary urgency

Question 3

General contraindications of cholinergic drugs

Answer 3

1. asthma (they cause bronchoconstriction)

2. peptic ulcer (they enhance gastric acid secretion)

Question 4

Types of direct cholinergic drugs

Answer 4

Muscarinic: pilocarpine, bethanechol
Nicotinic: nicotine, varenicline (partial agonist)
Muscarinic & nicotinic: acetylcholine

Question 5

Does acetylcholine cross membranes or BBB?

Answer 5

No, it is a quaternary ammonium

Question 6

MOA and uses of pilocarpine

Answer 6

1. Alkaloid nonselective muscarinic acetylcholine receptor agonist
2. M3 receptor activation
3. Treatment of glaucoma (both narrow- and wide-angle) by freeing entrance to Schlemm’ canal for narrow-angle and enhancing tone of the trabecular meshwork for wide-angle
4. Treatment of xerostomia (dry mouth) by promoting salivation

Question 7

Adverse / side effects of pilocarpine

Answer 7

1. topical ophthalmic administration → minimal systemic absorption but local stinging and irritation
2. oral administration → sweating, blurred vision, and other cholinergic adverse effects + worsens asthma and COPD

Question 8

MOA and uses of bethanechol

Answer 8

1. quaternary choline ester muscarinic acetylcholine receptor agonist (M3)
   - GU: increase detrusor tone and decrease outlet resistance of internal sphincter
   - GI: increase motility and secretion
   - weak agonist at M2 → minimal cardiac effects
   - crosses BBB poorly → minimal CNS effects
2. Treatment of gastric atony by increasing motility and secretion in the GI
3. Treatment of urinary retention by increasing detrusor tone and decreasing outlet resistance of internal sphincter

Question 9

Adverse / side effects of bethanechol

Answer 9

1. pulmonary: bronchoconstriction, increase secretions
2. GI: nausea, vomiting cramps and diarrhoea
3. ophthalmic: miosis

Contraindicated in asthma!

Question 10

MOA & uses of nicotine

Answer 10

1. Nm (neuromuscular) nicotinic acetylcholine receptor agonist
   - Skeletal muscle contraction, fasciculations, spasms
   - High dose → depolarising blockade
2. Nn (neuronal) nicotinic acetylcholine receptor agonist
   - Adrenal medulla: adrenaline release
   - Cardiac: increase HR
   - Vascular: peripheral vasoconstriction
   - GI: increase gut motility, increase secretions
   - Carotid bodies: increase RR
   - medullary emetic chemoreceptors: nausea & vomiting
3. Clinical uses: aid to smoking cessation

Question 11

Adverse / side effects of nicotine

Answer 11

1. dependence due to activation of brain dopaminergic reward pathways
2. low dose: increase HR, RR, BP, decrease appetite
3. high dose: medullary depression, bradycardia, neuromuscular blockade

Question 12

MOA & uses of varenicline

Answer 12

1. partial nicotinic agonist

2. highly effective in smoking cessation

Question 13

Adverse / side effects of varenicline

Answer 13

associated with psychiatric symptoms, including suicide ideation

Question 14

Types of indirect cholinergic drugs

Answer 14

1. Acetylcholinesterase (AChE) inhibitors

2. Low does nicotine

Question 15

MOA of AChE inhibitors

Answer 15

Increase the availability of acetylcholine

Question 16

Classification of AChE inhibitors

Answer 16

1. Reversible
   - Short acting: Edrophonium
   - Long-acting: Neostigmine, Pyridostigmine, Physostigmine (carbamates) + Donepezil
2. Irreversible or poorly reversible
   - Very long-acting: Sarin, malathion, parathion

Question 17

MOA and uses of donepezil / physostigmine

Answer 17

1. noncovalent acetylcholine esterase inhibitor
2. crosses BBB readily (in contrast to neostigmine)
3. physostigmine: carbamate AChE inhibitor that is tertiary amine → crosses BBB readily
4. clinical use for donepezil → produces modest cognitive improvement → Alzheimer’s disease
5. clinical use for physostigmine → antidote for atropine poisoning

Question 18

Adverse/side effects of donepezil / physostigmine

Answer 18

diarrhoea, nausea, vomiting and other common cholinergic side effects

Question 19

MOA & uses of neostigmine

Answer 19

1. carbamate inhibitor of AChE
2. M3: contracts GI and GU smooth muscles, decreases sphincter tone and increase secretions
3. clinical uses for neostigmine:
   - reversal of nondepolarising neuromuscular blockade
   - myasthenia graves
   - increase GI motility on post op or neurogenic ileus
   - treatment of urinary retention secondary to bladder atony

Question 20

Adverse/side effects of neostigmine

Answer 20

1. peripheral cholinergic adverse effects: diarrhoea, sweating, urinary urgency
2. quaternary carbamate: poor absorption, do not penetrate into CSF

Question 21

MOA of sarin, parathion, malathion

Answer 21

potent suicide inhibitor of AChE → increase ACh at NM and neuronal synapses

Question 22

Clinical manifestation of sarin acute poisoning

Answer 22

Cholinergic crisis:
SLUD
S - Salivation 
L - Lacrimation 
U - Urination 
D - Defecation 

+ abdominal cramps, miosis, hypotension, bradycardia

Question 23

Antidote for sarin acute poisoning

Answer 23

1. Cholinesterase regenerator: Pralidoxime

2. mACh receptor blockers: Atropine

Question 24

MOA / uses for Pralidoxime

Answer 24

1. cholinesterase regenerator
2. higher affinity for phosphate than AChE
3. clinical use: acute treatment of organophosphate poisoning

Question 25

Limitations of pralidoxime

Answer 25

1. Must be administered within a few hours before "ageing" occurs 2. Only effective in organophosphate poisoning 3. Not effective if AChE is carbamylated (e.g. by neostigmine)

Question 26

Types of direct anticholinergic drugs

Answer 26

1. Receptor antagonists: - Muscarininc: atropine, benzatropine, scopolamine, ipratropium, oxybutynin - Non-depolarising neuromuscular blocking agents (NMBAs) 2. Ganglionic blockers: High dose nicotine

Question 27

Adverse effects of anticholinergic drugs

Answer 27

blurred vision, confusion, mydriasis, constipation, urinary retention

Question 28

MOA / uses of atropine

Answer 28

1. nonselective muscarinic acetylcholine receptor antagonist - M1 block → decrease gastric acid secretion; CNS confusion/delirium - M2 block → increase HR - M3 block → decrease saliva, decrease bronchial secretions; decrease sweat; mydriasis; cycloplegia; inhibit micturition; decrease GI tone and motility; decrease GI secretions - M4/M5 block → contribute to CNS effects 2. treatment of bradycardia 3. treatment of anti cholinesterase overdose 4. GI antimotility agent to treat diarrhoea (with diphenoxylate) 5. for ophthalmic examination - cycloplegia and mydriasis

Question 29

Adverse / side effects / contraindications of atropine

Answer 29

"red as a beet, blind as a bat, dry as a bone, hot as a hare, and mad as a hatter" 1. red as a beet → superficial vasodilation 2. blind as a bat → blurred vision 3. dry as a bone → decrease secretions 4. hot as a hare → hyperthermia (decrease sweat) 5. mad as a hatter → delirium and hallucinations Contraindicated in narrow-angle glaucoma!

Question 30

MOA / uses of benzatropine

Answer 30

1. Nonselective muscarinic acetylcholine receptor antagonist 2. Tertiary amine alkaloid → crosses the BBB better and has stronger CNS effects 3. dopaminergic-cholinergic balance in striatum 4. treatment of Parkinson's disease and Parkinsonism

Question 31

Adverse / side effects / contraindications of benzatropine

Answer 31

hyperthermia (decrease sweat), glaucoma, urinary retention, dry mouth, constipation, blurred vision, sedation, amnesia, delirium, hallucinations Contraindicated in narrow-angle glaucoma!

Question 32

MOA / uses of scopolamine

Answer 32

1. Nonselective muscarinic acetylcholine receptor antagonist - M3 block → inhibits secretions and relaxes smooth muscles - M2 block → tachycardia - CNS → antiemetic and amnesic 2. treatment of motion sickness, urinary incontinence, adjunct for anaesthesia (amnesia, decrease secretions, decrease nausea)

Question 33

Adverse / side effects / contraindications of scopolamine

Answer 33

dry mouth, constipation, urinary retention, blurred vision, sedation, glaucoma Contraindicated in narrow-angle glaucoma!

Question 34

MOA / uses of ipratropium

Answer 34

1. Nonselective muscarinic acetylcholine receptor antagonist - M3 block → decrease bronchoconstriction and decrease bronchial secretions 2. Quaternary amine → poorly absorbed systematically and minimal CNS effects 3. treatment of COPD (1st line therapy) & asthma (via inhalation as a 2nd line therapy)

Question 35

Side effects of ipratropium

Answer 35

1. minimal due to poor systemic absorption 2. dry mouth 3. sedation (administration with bromide which can cross BBB to cause sedation) 4. bradycardia (rarely)

Question 36

MOA / uses of oxybutynin

Answer 36

1. Nonselective muscarinic acetylcholine receptor antagonist - M3 block → relaxes smooth muscle walls, increase sphincter tone and decrease secretions - M1 block → decease gastric acid production (via action on enterochromaffin-like cells) 2. tertiary amine 3. treatment for urinary incontinence 4. reduction of gastric acid secretion and treatment of peptic ulcer (better tolerated drugs are used for this indication)

Question 37

Adverse effects / side effects/ contraindications of oxybutynin

Answer 37

Parasympatholytic effects: mydriasis (pupillary dilation), tachycardia, decrease GI motility, decrease secretions Contraindications: 1. pyloric obstruction; retentive bladder 2. narrow-angle glaucoma

Question 38

What are non-depolarising NMBAs?

Answer 38

1. Block Nm nicotinic ACh receptors 2. Block neurotransmission at Nm junctions 3. Paralysis of skeletal muscles

Question 39

Characteristics of non-depolarising NMBAs

Answer 39

1. Poor oral absorption 2. Low lipid solubility → do not penetrate BBB 3. Small Vd

Question 40

Types of non-depolarising NMBAs

Answer 40

Short-acting: Rocuronium (0.5-3mins) Intermediate-acting: Pancurorium, Atracurium (2-5mins) Long-acting: Tubocurarine (2-13mins)

Question 41

MOA & uses of Pancuronium

Answer 41

1. competitive antagonists of Nm nicotinic acetylcholine receptor 2. non-depolarising blockade results in skeletal muscle paralysis 3. IV → rapid onset of action and short half-life 4. clinical uses: indication of paralysis for surgery

Question 42

Side effects of pancuronium

Answer 42

1. Histamine release at higher doses: flushing, oedema, erythema, hypotension, tachycardia 2. Weak antimuscarinic activity: increase HR, increase CO due to vagolytic effects

Question 43

Types of indirect anticholinergic drugs

Answer 43

1. depolarising neuromuscular blocking agents (NMBAs): succinylcholine 2. presynaptic toxin: botulinum toxin

Question 44

MOA and uses of succinylcholine

Answer 44

1. Nm nicotinic acetylcholine receptor agonist Phase 1 → opens sodium channels associated with nAChR → depolarisation → fasciculations Phase 2 → continuous depolarisation → gradual repolarisation as the sodium channels close or is blocked → resistance to depolarisation → flaccid paralysis (depolarising blockade) 2. clinical use: paralysis for brief surgical procedures

Question 45

Adverse effects of succinylcholine

Answer 45

1. Malignant hyperthermia 2. Apnea 3. Hypotension, arrhythmias, respiratory collapse

Question 46

MOA and uses of botulinum toxin

Answer 46

1. Cleaves SNARE proteins preventing exocytosis of ACh containing synaptic vesicles 2. clincial uses: cervical dystonia, blepharospasm, strabismus, migraine and other headache disorders, upper limb spasticity

Question 47

Side effects of botulinum toxin

Answer 47

1. paralysis of wrong muscle group | 2. allergic reactions