Cholinergic Mechanism Flashcards
Direct cholinergic responses are mediated by:
- Muscarinic receptors at❓
- Nicotinic receptors at❓
- Parasympathetic
Postjunctional
Neuroeffector sites - Parasympathetic ganglia
Sympathetic ganglia
NMJ of the somatic nervous system
Muscarinic receptors are:
- Members of seven transmembrane domain
- G-coupled receptors
- Functional and structurally unrelated to nicotinic receptors
True or false
True
Describe the nicotinic Ach receptor
- Ligand gated ion channel
- 5 subunits (2a, 1b, 1g, 1d)
- Receptor opens transmembrane ion channel when Ach bind on extracellular a-subunit sites
- Muscle, ganglionic and CNS types
Are M1, M3 and M5 receptors are generally excitatory or inhibitory in nature❓
How do they bring about this effect❓
M1, M3, M5 receptors are excitatory in nature
⬆️IP3/DAG activity
Are M2 and M4 receptors are generally excitatory or inhibitory in nature❓
How do they bring about this effect❓
Inhibitory
⬇️cAMP
Are N1 and N2 receptors are generally excitatory or inhibitory in nature❓
How do they bring about this effect❓
Excitatory
⬆️cation conductance
Acetylcholine is an ester of acetic acid and choline
True or false❓
What limits it utility physiologically❓
True
- Lack of selectivity (both M -Ach and N-Ach)
- Rapid degradation by cholinesterases
- What properties do direct acting agonist of Ach receptors have❓
- List some examples of choline esters
- List selective agonists of muscarinic receptors
- Carbacol can activate both receptors. True or false❓
- Acetyl group in Ach replaced by carbamoyl group
Substitution of methyl group of beta carbon
- Bethanecol
Carbacol
Methacoline - Bethanecol
Methacoline - True
At usual therapeutic doses, the effects of carbacol on ACh is dependent on the activation of muscarinic receptors
True or false❓
Why❓
True
Greater abundance and accessibility compared to NAch
List the choline non-esters you know
Pilocarpine
Muscarine
What do you know about Pilocarpine❓
- Crosses membranes easily
- Crosses BBB
- Rapidly absorbed by cornea of the eye
- Unaffected by cholinesterases
- Naturally occurring
- Cholinomimetic alkaloid
- Tertiary amine
Muscarine is an alkaloid with no therapeutic use, however, it can cause dangerous cholinomimetic stimulation after ingestion of some mushrooms
True or false
True
What is the effect of cholinesterase inhibitors❓
Prevent degradation of Ach/Prevent ACh binding
⬆️Ach in the system
⬆️Stimulation of muscarinic and nicotinic receptors
AchE can be inhibited by which mechanisms❓
- Binding to anionic site/Competitive binding
2. Binding to esteratic site (false substrate for cholinesterase)
What are the two major classes of AChE inhibitors❓
List a few examples
Carbamates/Carbamic Acid Esters: Physostigmine Neostigmine Pyridostigmine Rivastigmine (good brain penetration)
Organophosphate Esters: Echothiophate Parathion Malathion Isoflurophate
*Echothiophate is not lipid soluble
What is the mechanism behind carbamate inhibition of AChE❓
What is the mechanism behind organophosphate inhibition of AChE❓
- •A carbamylated intermediate is formed (instead of an acetylated one)
•carbamylated enzyme undergoes hydrolysis much more slowly
*Recovery time is in minutes or hours
2. Binding to esteratic site ⬇️ Stable bond btwn phosphate and AChE ⬇️ ”Irreversible inhibition”
*Recovery time is in days
Do you know any quaternary ammonium compounds closely related to carbamates❓
How do they inhibit AChE❓
- Edrophonium (monoquaternary)
Ambenonium (bisquaternary)
2. \+vely charged ⬇️ Bind to anionic site competitively ⬇️ Displaces ACh from active site without covalent modification
What is the duration of action of:
A) Endrophonium
B) Ambenonium
A) 5-10minutes
B) 4-8hours
List some organ responses to cholinergic agonists
1.
Heart:
AV node: ⬇️dromotropy
Atria/Ventricles: ⬇️inotropy
SA node: ⬇️chronotropy
2.
Eye:
Sphincter muscle: C: Miosis
Cilliary muscle: C: Accommodation
- Glands:
Lacrimal: ⬆️
Sweat: ⬆️
Salivary: ⬆️
- Lungs:
Bronchial muscle: C
Bronchial glands: ⬆️ secretion - Urinary bladder:
Detrusor muscle: C
Trigone and sphincter: R
- GIT:
Intestines: ⬆️motility
Sphincters: R
Glands: ⬆️
1.
List some AChE, CNS inhibitors you know
- Are they reversible or irreversible inhibitors❓
- Tacrine
Donepazil
Galantamine - They are reversible
Which ACh direct agonist would you use in initiating micturition in acute, non-obstructive urinary retention❓
Bethanecol
Which ACh direct agonist would you use in producing miosis in the treatment of glaucoma❓
Pilocarpine
ACh is used in causing miosis during cataract surgery of short duration
True or false
True
Carbacol is used for longer durations
Which ACh indirect agonist would you use in producing miosis in the treatment of glaucoma❓
Physiostigmine
Which ACh indirect agonist would you use in producing miosis in the diagnosis and treatment myasthenia gravis❓
Endrophonium
Ambenonium
Neostigmine
Which ACh indirect agonist would you use to counteract intoxication of anticholinergics❓
Physostigmine
Which ACh indirect agonist would you use to improve cognitive functions in AD patients❓
Tacrine
Galantamine
Rivastigmine
Which ACh indirect agonist would you use to treat paralytic ileus or cardiac tacharrythmias❓
Edrophonium
What are the adverse effects of cholinergic agonists❓
Congested conjunctiva
Myopic accommodation
Transient lenticular opacity
Headache
Syncope
Tremors
Nausea Vomiting Abdominal cramps Diarrhea Salivation
Bradycardia
Hypotension
Bronchospasm
Sweating
Lacrimation
Flushing
