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
Nicotine effect
-where does it act
-acts on both parasympathetic and sympathetic ganglia
Parasympathetic –> cardiac and smooth muscle, gland cells, nerve terminals
Sympathetic –>. sweat glands, cardiac and smooth muscle, gland cells, nerve terminals, renal vascular smooth muscle
Nicotine effect
- what does it do
- activation effects
- clinical use
CNS: stimulation
Cardiovascular: tachycardia and hypertension
Respiratory: increase bronchial secretion
GI: nausea, vomiting, increase motility
Salivary glands: increase secretion
Sweat glands: increase secretion
- more parasympathetic system and less sympathetic system –> more parasympathetic effects (except vascular system)
- assists giving up smoking
Ganglion-blocking drugs
-where does it act
-both parasympathetic and sympathetic
Parasympathetic –> cardiac and smooth muscle, gland cells, nerve terminals
Sympathetic –>. sweat glands, cardiac and smooth muscle, gland cells, nerve terminals, renal vascular smooth muscle
Ganglion-blocking drugs
- what does it do
- inhibitory effects
LOOK AT THE TABLE IN THE SUMMARY
Neuro-muscular blocking drugs
-classification
-block the cholinergic transmission between motor nerve endings and nicotinic receptors on the skeletal muscle
Non-depolarizing drugs
- Long action (tubocurarine)
- Intermediate action (rocuronium)
Depolarizing drugs - succinylcholine
Malignant hyperthermia
-massive release of calcium from the sarcoplasmic reticulum, leading to uncontrolled contraction and stimulation of metabolism in skeletal muscle
Neuromuscular blocking drugs: nondepolarizing & depolarizing blockers
- Acetylcholine (normal agonist) –> opens the sodium channel
- Nondepolarizing blocker –> competitive antagonists –> bind to the receptor to prevent opening of the channels
- Depolarizing blockers –> they mimic acetycholine but they are much more resistant to acetylcholinesterase –> producing persistent depolarization
Fasciculation (phase I) –> desensitization (phase II) –> muscle relaxation
Neuromuscular blocking drugs
- Names
- Side effects
- Depolarizing: succinylcholine
- Non-depolarizing: atracurium, pipecuronium, mivacurium, tubocurarine
Succinylcholine unwanted effects –> bradycardia, arrhythmias, increased intraocular pressue, prolonged paralysis
Non-depolarizing unwanted effects –> hypotension (due to ganglion block and histamine release)
Neuromuscular blocking drugs
-reversal blockade
- action of nondepolarizing blockers is reversed by increasing ACh concentration (by cholinesterase inhibitors)
- paralysis produced by the depolarizing blocker is increased by cholinesterase inhibitors during phase I; during phase II, the block produced by succinylcholine is usually reversible by cholinesterase inhibitors
Ganglion blocking drugs
- Name
- Clinical use
- Trimetaphan
2. ganglionic blocker in hypertension, as an adjunct to anesthesia, and to induce hypotension during surgery.
How parasympathetic system works in the eye? (3)
- Pupil contracts
- Ciliary muscle constriction
- Constrictor pupillae contracts –> lens bulges more and reduces focal length
Signs or symptoms that are consistent with the diagnosis of botulinum poisoning? (2)
- Inhibits the vesicle fusion with the surface membrane
- Cycloplegia (paralysis of accommodation)
Sympathetic vs. Parasympathetic system
- Sympathetic –> reaction to stress –> second neuron is in a specific ganglion
- Parasympathetic –> activated when body is in rest state –> two neurons in the loop, one in the CNS and one next to the organ
Pralidoxime
cholinesterase regenerator
Atropine – indications (6)
- We need it because it increases the amount of acetylcholine in general
- Blocks M receptors
- non selective
- It is an antimuscarinic drug
- Stimulation of M receptors –> bradycardia
- too much acethylcholine –> tachycardia
