L73: Drugs Acting On Parasympathetic NS

Question 1

Nicotinic receptor vs Muscarinic receptor

Answer 1

Nicotinic:

• Gated channels
• Short-lived excitation
• in both sympathetic and parasympathetic NS
• PNS and SNS Ganglion
• NMJ
• Brain
• **- SNS: Sympathetic Vasoconstriction
• **- PNS: same as Muscarinic agonist
• **- NMJ: increase muscle tension / contraction
• **- Brain: CNS stimulation —> tremor, convulsion, stimulate respiratory centre

Muscarinic:

• GPCR
• longer-lasting effect
• excitation/inhibition
• only in parasympathetic NS
• Sweat gland

***- M1: CNS
—> CNS excitation, memory, cognition, locomotor activity, tremor, hypothermia, salivary secretion, gastric acid

***- M2: Heart
—> Decrease rate, force, AV conduction

***- M3: Smooth Muscle + Exocrine gland
—> Smooth muscle contraction except Vasodilation, ocular accommodation (ciliary muscle + constrictor pupillae muscle), glandular secretion

Question 2

Acetylcholinesterase and ACh

Answer 2

AChE:
Anions site (glutamate): bind choline of ACh
Catalytic site (esteratic): histidine + serine

ACh: acetyl (acidic) + choline (basic) —> linked by Ester bond

Acetyl-group is transferred from ACh to serine hydroxyl group (in catalytic site) of AChE —> breaking Ester bond of ACh —> acetylated AChE and free choline

Question 3

Drugs enhance PNS transmission

Answer 3

1. Nicotinic agonist (experimental tools)
   - Nicotine
   - Lobeline
   - Epibatidine

• **2. Muscarinic agonist
• Pilocarpine (glaucoma)
• Bethanechol (bladder and GI hypotonia)
• Cevimeline (M3 agonist: Sjogren’s syndrome)

***3. AChE inhibitor
—> Short acting (quaternary ammonium compound)
- Edrophonium (affect NMJ: diagnosis)

—> Medium-acting (carbamyl ester):

• Neostigmine, pyridostigmine (affect PNS: glaucoma)
• Physostigmine (affect NMJ: myasthenia gravis)

—> Long-acting (phosphorus compound):
- Dyflos, Parathion, Ecothiophate (affect PNS: glaucoma)

Question 4

AChE poisoning

Answer 4

Initial excitation due to accumulation of ACh —> convulsion, muscle twitching
Followed by depression —> depolarisation block, unconsciousness, respiratory failure
Treated by Pralidoxime (AChE reactivation): nucleophile group lure away phosphate group from AChE but must be given early before chemical change of AChE

Question 5

Drugs inhibit PNS transmission

Answer 5

1. Nicotinic antagonist (ANS / NMJ / CNS)
   - Trimetaphan (hypertension)
   - Mecamylamine (CNS sedation)

• **2. Muscarinic antagonist
• Atropine (bradycardia)
• Hyoscine (Antiemetic, motion sickness, GI relaxation, antispasmodic in IBD)
• Benztropine (Reduce involuntary movement, Parkinsonism)
• Tropicamide (eye drops)
• Ipratropium (bronchodilator)
• Pirenzepine (M1 antagonist: reduce gastric acid secretion)
• Darifenacin (M3 antagonist: relax bladder for urinary incontinence)

3. Inhibitor of ACh release and synthesis
   - Hemicholinium (inhibit ACh synthesis: block transport of choline back to nerve terminal)
   - Vesamicol (inhibit ACh vesicular transport into nerve terminal)
   ***- Botulinum toxin (inhibit ACh release: forehead wrinkles, blepharospasm, urinary incontinence, hyperhidrosis, sialorrhoea)
   —> poisoning: muscle paralysis, dry mouth, blurred vision, respiratory paralysis
   - Beta-bungarotoxin (inhibit ACh release)

Question 6

Anticholinergic SE

Answer 6

M1: CNS
- CNS excitation, memory, cognition, locomotor activity, tremor, hypothermia, salivary secretion, gastric acid
—> Dry mouth
—> Drowsiness / Sedation
—> Memory problems
—> Delirium

M2: Heart
- Decrease rate, force, AV conduction
—> Fast HR
—> Flushing + Warm skin

M3: Smooth Muscle + Exocrine gland
- Smooth muscle contraction except Vasodilation, ocular accommodation (ciliary muscle + constrictor pupillae muscle), glandular secretion
—> Blurred vision
—> Urinary retention
—> Constipation
—> Decreased sweating