Cholinergic Pharmacology Flashcards
2 types of cholinergic receptors
focus on muscarinic
Muscarinic and Nicotinic
Location of muscarinic receptors
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
A muscarinic receptor associated with the heart
M2
Examples of direct-acting cholinergic drugs
Direct-acting: Binds directly to Ach receptors
Alkaloids: Pilocarpine, Muscarine, Nicotine, Arecoline
Choline esters: Acetylcholine, Bethanechol, Carbachol, Methacholine
Examples of indirect-acting cholinergic drugs
Indirect-acting: Inhibit degradation of Ach
All are cholinesterase inhibitors:
-Anticholinesterases
Reversible:
Carbamates: Neostigmine
Acridine: Tacrine
Irreversible:
Organophosphates: Malathion, Parathion, Sarin
Carbamates: Carbaryl
Neurotransmitter of cholinergic
-Acetylcholine
(All preganglionic autonomic fibers, all postganglionic parasympathetic fibers, and a few postganglionic sympathetic fibers)
The action of the M2 receptor decreases the contractility of the atrial.
Why it does not decrease the contractility of vesicles?
There is no muscarinic receptor on vesicles. The receptors only involve atrial.
NO RECEPTOR, NO EFFECT!
Which is muscarinic receptor causing contraction of bronchiolar smooth muscle (bronchoconstriction)?
M3 receptor
Which receptors are inhibitory and stimulatory?
M1, M3, M5: Stimulatory (increased intracellular calcium)
M2, M4: Inhibitory (Inhibition of adenylyl cyclase)
Nicotinic
NN: Postganglionic neurons, some presynaptic cholinergic terminals
NM: Skeletal muscle neuromuscular endplates
[Opening of Na+, K+ channels, depolarization]
Cholinergic receptor type primarily localized at skeletal muscle neuromuscular junctions:
Nicotinic N*M
Cholinergic drugs mimic or
block the action of _____.
Acetylcholine
Acetylcholine is rapidly inactivated by synaptic
_____.
Acetylcholinesterase
Anticholinesterases
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
Ileus
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
List 4 Indirect Cholinergic agonists
(REVERSIBLE inhibitors of ChE)
ChE = cholinesterase which breaks down ACh
Reversible inhibitors of ChE: neostigmine physostigmine pyridostigmine edrophonium
P/S: 3 ends with “stigmine”
What are the clinical effects at the PNS, CNS, and NMJ?
NMJ: neuromuscular junction
CNS: central nervous system
PNS: peripheral nervous system
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
cont;
What are the clinical effects at the PNS, CNS, and NMJ?
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
cont;
What are the clinical effects at the PNS, CNS, and NMJ?
Urinary bladder:
Detrusor- contraction
Trigon & sphincter- relaxation
Glands:
Sweat, salivary, lacrimal, nasopharyngeal- secretion
NEOSTIGMINE
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)
Arrange the duration of action of indirect ACh agonists
longest to shortest
Longest duration:
- Physostigmine
- Pyridostigmine
- Neostigmine
- Edrophonium; shortest duration
True/ False:
Both Neostigmine & Physostigmine effective given orally, but Neostigmine easily penetrates BBB (causes CNS effects).
FALSE!!!
Both Neostigmine & Physostigmine effective given orally, but PHYSOSTIGMINE easily penetrates BBB (causes CNS effects).
BETHANECHOL
Direct-acting choline esters
- 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
BETHANECHOL
Mechanism of action, Effects
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
CARBACHOL
Nonselective muscarinic and nicotinic agonist; otherwise similar to bethanechol
Used tropically almost exclusively for GLAUCOMA
PILOCARPINE
Mechanism of action, Effects
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
PILOCARPINE
Clinical use, Pharmacokinetics
- 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
Xerostomia
Dry mouth, a condition in which the salivary glands in your mouth don’t make enough saliva to keep your mouth wet
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.
PILOCARPINE!!!
- topically to reduce intraocular pressure in canine
glaucoma therapy. - primarily a muscarinic agonist
What do these compounds have in common?
- Muscarine
- Arecoline
- Pilocarpine
All naturally occurring, direct-acting cholinergic AGONISTS
MAP “Directs u to nature’s cholon”
ine
ATROPINE
Non-selective antagonist
Well absorbed orally
CNS stimulant
Clinical uses:
Adjunct for anesthesia (reduced secretions, bronchodilations)
Anticholinesterase poisoning Bradycardia
Gastrointestinal hypermobility (antispasmodic)
ATROPINE
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
ATROPINE (Opthalmology)
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
PIRENZIPINE
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
Name 2 synthetic anti-muscarinic drugs (atropine-like agents)
Pirenzepine
Telenzepine
IPRATROPIUM
- 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
IPRATROPIUM
Respiratory; asthma, COPD
- 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
PRALIDOXIME
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
