Cholinergic Pharmacology

Question 1

2 types of cholinergic receptors

focus on muscarinic

Answer 1

Muscarinic and Nicotinic

Question 2

Location of muscarinic receptors

Answer 2

M1: CNS neurons, sympathetic postganglionic neurons, some presynaptic neurons
M2: MYOCARDIUM (heart)
M3: Exocrine glands, vessels (smooth muscle & endothelium)
M4: CNS neurons
M5: Vascular endothelium; cerebral vessels

Question 3

A muscarinic receptor associated with the heart

Answer 3

M2

Question 4

Examples of direct-acting cholinergic drugs

Direct-acting: Binds directly to Ach receptors

Answer 4

Alkaloids: Pilocarpine, Muscarine, Nicotine, Arecoline

Choline esters: Acetylcholine, Bethanechol, Carbachol, Methacholine

Question 5

Examples of indirect-acting cholinergic drugs

Indirect-acting: Inhibit degradation of Ach

Answer 5

All are cholinesterase inhibitors:
-Anticholinesterases

Reversible:
Carbamates: Neostigmine
Acridine: Tacrine

Irreversible:
Organophosphates: Malathion, Parathion, Sarin
Carbamates: Carbaryl

Question 6

Neurotransmitter of cholinergic

Answer 6

-Acetylcholine
(All preganglionic autonomic fibers, all postganglionic parasympathetic fibers, and a few postganglionic sympathetic fibers)

Question 7

The action of the M2 receptor decreases the contractility of the atrial.

Why it does not decrease the contractility of vesicles?

Answer 7

There is no muscarinic receptor on vesicles. The receptors only involve atrial.

NO RECEPTOR, NO EFFECT!

Question 8

Which is muscarinic receptor causing contraction of bronchiolar smooth muscle (bronchoconstriction)?

Answer 8

M3 receptor

Question 9

Which receptors are inhibitory and stimulatory?

Answer 9

M1, M3, M5: Stimulatory (increased intracellular calcium)

M2, M4: Inhibitory (Inhibition of adenylyl cyclase)

Question 10

Nicotinic

Answer 10

NN: Postganglionic neurons, some presynaptic cholinergic terminals
NM: Skeletal muscle neuromuscular endplates

[Opening of Na+, K+ channels, depolarization]

Question 11

Cholinergic receptor type primarily localized at skeletal muscle neuromuscular junctions:

Answer 11

Nicotinic N*M

Question 12

Cholinergic drugs mimic or

block the action of _____.

Answer 12

Acetylcholine

Question 13

Acetylcholine is rapidly inactivated by synaptic

_____.

Answer 13

Acetylcholinesterase

Question 14

Anticholinesterases

Answer 14

Reversible:

• Short-acting (ionic binding to the anionic site)
• Medium-acting (carbamylated enzyme is much slower to hydrolyzed)

Irreversible:

• Phosphorylation of the serine group
• Long-acting as the phosphorylated enzyme is very stable

Question 15

Ileus

Answer 15

The inability of the intestine to contract normally leading to a build-up of food material.

Symptoms:

• Inability to fart
• Nausea
• Vomiting
• Abdominal discomfort
• Constipation
• Loss of appetite

Question 16

List 4 Indirect Cholinergic agonists
(REVERSIBLE inhibitors of ChE)

ChE = cholinesterase which breaks down ACh

Answer 16

Reversible inhibitors of ChE: 
neostigmine
physostigmine
pyridostigmine
edrophonium

P/S: 3 ends with “stigmine”

Question 17

What are the clinical effects at the PNS, CNS, and NMJ?

NMJ: neuromuscular junction
CNS: central nervous system
PNS: peripheral nervous system

Answer 17

Eye:
Sphincter muscle of IRIS- contraction (miosis)
Ciliary muscle- contraction for near vision

Miosis: Reduction in pupil size caused by the contraction of the pupillary constrictor muscle (muscarine receptor-mediated)

Heart:
SA- decrease in the rate (-ve chronotropy)
Atria- decrease in contractile strength (-ve inotropy), decrease in refractory period
Ventricles- small decrease in contractile strength
AV- decrease in conduction velocity (-ve dromotropy), increase in refractory period

Question 18

cont;

What are the clinical effects at the PNS, CNS, and NMJ?

Answer 18

Blood vessels:
Arteries, veins- dilation (via EDRF), constriction (high-dose direct effect)

Lung:
Bronchiol muscle- contraction (bronchoconstriction)
Bronchiol glands- stimulation

GIT:
Motility: increase
Sphincters: relaxation
Secretion: stimulation

Question 19

cont;

What are the clinical effects at the PNS, CNS, and NMJ?

Answer 19

Urinary bladder:
Detrusor- contraction
Trigon & sphincter- relaxation

Glands:
Sweat, salivary, lacrimal, nasopharyngeal- secretion

Question 20

NEOSTIGMINE

Answer 20

Used to reverse neuromuscular blockade induced by certain neuromuscular blocking agents.

Pharmacokinetics:-
Bioavailability: 1-2% (PO)
Onset: 1-20 mins (IV), 20-30 mins (IM)
Duration: 2.5-4H (IM), 1-2H (IV)
Protein bound: 15-25% to albumin (PO)
t1/2: 47-60 mins (IV), 51-90 mins (IM), 42-60 mins (PO)

Question 21

Arrange the duration of action of indirect ACh agonists

longest to shortest

Answer 21

Longest duration:

1. Physostigmine
2. Pyridostigmine
3. Neostigmine
4. Edrophonium; shortest duration

Question 22

True/ False:

Both Neostigmine & Physostigmine effective given orally, but Neostigmine easily penetrates BBB (causes CNS effects).

Answer 22

FALSE!!!

Both Neostigmine & Physostigmine effective given orally, but PHYSOSTIGMINE easily penetrates BBB (causes CNS effects).

Question 23

BETHANECHOL

Direct-acting choline esters

Answer 23

• Pure muscarinic agonist
• Used as treatment of bladder and gastrointestinal hypotonia

Pharmacokinetics:
Oral & parenteral, duration: 30 mins
Not enter CNS
Toxicity: Excessive parasympathomimetic effects, especially bronchospasm in asthmatics
Interactions: Additive with other parasympathomimetics

Question 24

​BETHANECHOL

Mechanism of action, Effects

Answer 24

Muscarinic agonist; negligible effect at nicotinic receptors

Effects:

• Activates M1 through M3 receptors in all peripheral tissues
• Causes increased secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate

Question 25

CARBACHOL

Answer 25

Nonselective muscarinic and nicotinic agonist; otherwise similar to bethanechol Used tropically almost exclusively for GLAUCOMA

Question 26

PILOCARPINE | Mechanism of action, Effects

Answer 26

Partial muscarinic agonist; negligible effect at nicotinic receptors Effects: - Activates M1 through M3 receptors in all peripheral tissues - Causes increased secretion, smooth muscle contraction (except vascular smooth muscle relaxes), and changes in heart rate

Question 27

PILOCARPINE | Clinical use, Pharmacokinetics

Answer 27

- Treat Glaucoma (A condition where the eye’s optic nerve, which provides information to the brain, is damaged with or without raised intraocular pressure) - For xerostomia in Sjogren's syndrome Pharmacokinetics: -Oral lozenge and topical Toxicity: Excessive parasympathomimetic effects, especially bronchospasm in asthmatics Interactions: Additive with other parasympathomimetics

Question 28

Xerostomia

Answer 28

Dry mouth, a condition in which the salivary glands in your mouth don't make enough saliva to keep your mouth wet

Question 29

Name naturally occurring alkaloid which is a directly-acting cholinergic agonist -producing all parasympathomimetic effects -used topically to reduce intraocular pressure in canine glaucoma therapy.

Answer 29

PILOCARPINE!!! - topically to reduce intraocular pressure in canine glaucoma therapy. - primarily a muscarinic agonist

Question 30

What do these compounds have in common? - Muscarine - Arecoline - Pilocarpine

Answer 30

All naturally occurring, direct-acting cholinergic AGONISTS | MAP "Directs u to nature's cholon" ine

Question 31

ATROPINE

Answer 31

Non-selective antagonist Well absorbed orally CNS stimulant Clinical uses: Adjunct for anesthesia (reduced secretions, bronchodilations) Anticholinesterase poisoning Bradycardia Gastrointestinal hypermobility (antispasmodic)

Question 32

ATROPINE

Answer 32

Main side effects: urinary retention, dry mouth, blurred vision Dicycloverine (dicyclomine) is similar and used mainly as an antispasmodic agent Belladonna alkaloid t1/2: 4 hours

Question 33

ATROPINE (Opthalmology)

Answer 33

Mechanism of action: Competitive antagonism at all M receptors Effects: Causes mydriasis and cycloplegia Clinical uses: Retinal examination Prevention of synechiae after surgery Pharmacokinetics: Uses as drops; long (5-6 days) action Toxicity: increased intraocular pressure in closed-angle glaucoma Interaction: with other antimuscarinics

Question 34

PIRENZIPINE

Answer 34

Pharmacokinetics: - Selective for M1 receptors - Inhibits gastric secretion by action on ganglion cells - Little effect on smooth muscle or CNS Clinical use: Peptic ulcer treatment * Fewer side effects than other muscarinic antagonists * Largely superseded by other antiulcer drugs

Question 35

Name 2 synthetic anti-muscarinic drugs (atropine-like agents)

Answer 35

Pirenzepine | Telenzepine

Question 36

IPRATROPIUM

Answer 36

- Derivative of atropine - Produce bronchodilation, tachycardia & inhibition of secretion similar to atropine but with less inhibitory effect on mucociliary clearance - Side effect: dry mouth - Administered as an aerosol or solution for inhalation - Maximal responses: 30-90 mins - Effects: 4-6 hours

Question 37

IPRATROPIUM | Respiratory; asthma, COPD

Answer 37

- Competitive, nonselective antagonist at M receptors Mechanism of action: reduces/ prevents bronchospasm Effects: prevention & relief of acute episodes of bronchospasm Pharmacokinetics: Aerosol canister, up to qid *qid: quarter in die, 4 times a day Toxicity: Xerostomia, cough Interactions: with other muscarinic

Question 38

PRALIDOXIME

Answer 38

Mechanism of action: very high affinity for phosphorus atom but does not enter CNS Effects: - Regenerates active AChE (acetylcholinesterase) - Can relieve skeletal muscle & plate block Clinical use: Usual antidote for early-stage (48 hours) cholinesterase inhibitor poisoning Pharmacokinetics: * Intravenous every 4-6 hours * Toxicity: Can cause muscle weakness in overdose