Cholinergic transmission Flashcards
Cholinergic receptors (2)
- type of receptors that get activated when they bind acetycholine
- Muscarinic (slow) and nicotinic (fast)
Nicotinic receptor sub-types
- “Name”
- Location
- Mechanism
- Major functions
Nn –> ANS ganglion, Na+-K+ ion channels, depolarizes and evoke an action potential
Nm –> neuromuscular end plate, Na+-K+ ion channels, depolarizes and evoke an action potential
Muscarinic receptor sub-types
- “Name”
- Location
- Mechanism
- Major functions
M1 –> activation, nerve endings, Gq-coupled, increase IP3 and DAG cascade
M2 –> inhibition, heart and some nerve endings, Gi-coupled, decrease cAMP and activates K+ channels
M3 –> activation, effector cells: smooth muscles/glands/ ednothelium, Gq-coupled, increase IP3 and DAG cascade
M4 –> Gi- coupled, enhanced locomotion
M5 –> Gq
Nicotinic signalling (4)
- receptor sub-types: Nn and Nm
- made of 5 subunits
- ligand-gated ion channels
- Acetylcholine binds to the alpha subunit, causes conformational changes, channel is open, Na+ in and K+ out, depolarization, response
Muscarinic signalling (5)
- 7 transmembrane proteins, one end binds acetylcholine and the other end activates intracellular proteins
- G-protein coupled receptors
- G- proteins are made up of 3 subunits (alpha, beta, gamma)
- bound to GDP when it is inactive, bound to GTP when it is active
- When the alpha subunit is bound to GTP, it separates from the others and then it is free to interact with other proteins. But, by doing that it used energy and then GTP is converted back to GDP and the subunits come back together.
Cholinergic junction (9)
- Choline is transported into the pre-synaptic nerve by sodium dependent choline transporter (inhibited by hemicholiniums)
- Choline + acetyl coA –> acetylcholine (enzyme: choline acyl transferase)
- Acetylcholine is transported to the vesicle by VAT (inhibited by vesamicol)
- Release of transmitters
- Voltage-sensitive Ca2+ channels open
- Increase intracellular Ca2+
- Vesicle fuses with surface membrane (inhibited by botulinium toxin)
- Acetylcholine is released
- Acetylcholine function is terminated by acetylcholinesterase
Cholinergic drugs
-types
Direct acting
- Muscarinic: choline esters –> acetylcholine and alkaloids –> pilocarpine
- Nicotinic
Indirect acting
- Organophosphates –> long acting –> ex: parathion
- Carbamates –> intermediate to long acting –> ex: neostigmine
- Edrophonium –> short acting
Clinical use of muscarinic agonists
- name
- what do they do
-acetilcholine and pilocarpine
Eye: accomodation for near vision (increase tension in the ciliary muscle), miosis, increase outflow
GI tract: increase secretion and peristalsis, decrease sphincter tone
Bladder: decrease sphincter tone and increase detrusor
Drugs use in open-angle glaucoma
- name
- what do they do
Pilocarpine - ciliary muscle contraction, opening of trabecular meshwork: increased outflow
Timolol - decreased aqueous secretion from ciliary epithelium
Anticholinesterase drugs (3)
- acetycholinesterase is inhibited –> increase acetylcholine
- stimulate:
1. Parasympathetic: cardiac and smooth muscle, gland cells and nerve terminals
2. Sympathetic: glands
3. Somatic: skeletal muscle - Neostigmine, donepezil, edrophonium, dyflos, pralidoxin
Clinical uses of anticholinesterase drugs (indirect-acting agonists)
- Names
- Actions, indications, side effects duration of action
-Neostigmine, donepezil, edrophonium
CNS: alzheimer’s disease - donepezil
Eye: glaucoma
GI: increase motility
Anesthesiology: reverse action of non-depolarising neuromuscular blocking drugs
Myasthenia gravis: diagnosis (short acting), treatment (long acting)
Unwanted effects: excessive secretions, bradycardia, hypotension, bronchoconstriction, muscle fasciculations
Irreversible anticholinesterases
- Names
- Actions, indications, side effects duration of action
- organophosphates
- Dyflos, Pralidoxin
- in agriculture, used as insecticides and antihelminthic agents
- Dyflos –> used in the treatment of chronic glaucoma
- Unwanted effects: hypotension, bronchoconstriction, bradycardia, muscle fasciculations, CNS stimulation (convulsions), excessive secretions
Anticholinergic drugs
-classification
Antimuscarinic
- M1- selective (pirenzepine)
- Non-selective (atropine)
Antinicotinic
- Ganglion blockers (hexamethonium)
- Neuromuscular blockers (tubocurarine)
Antimuscarinic drugs
-stimulate
Parasympathetic: cardiac and smooth muscle, gland cells and nerve terminals
Sympathetic: sweat glands
Clinical uses of muscarinic antagonists (antimuscarinic drugs)
- Names (7)
- Actions, indications, side effects duration of action
-Atropine, Scopolamine, Oxybutynin, Tropicamide, Pirenzepine, Benztropine, Ipratropium
CNS: motion sickness (Scopolamine), Parkinson’s disease (Benztropine)
Eye: dilates the pupil (tropicamide)
Respiratory: asthma, COPD (Ipratropium)
Cardiovascular: bradycardia (atropine)
GI: peptic ulcer (pirenzepine), antispasmodic action (oxybutynin)
Anesthesiology: premedication (atropine)
Unwanted effects: sedation, blurred vision, dry mouth, urinary retention