Paul (Cholinergic pharmacology) Flashcards
Loewi’s experiment
Stimulate vagus in donor heart. Heart rate slows. Remove fluid sample.
Add fluid to recipient heart. Heart rate slows
Cholinergic history
Muscarine
- resembled vagus stimulation
- muscarine like substance released from frogs heart after vagal stimulation
Atropine- blocked effects of muscarine and acetylcholine
- abolished muscarinic actions
- larger doses of ACh increased heart rate and BP
Nicotine
- also produced increased heart rate and BP
Two different ‘receptors’ for endogenous ACh
(Type 1) Nicotinic receptors
(Type 2) Muscarinic receptors
Functional differences based on
- agonist selectivity
- antagonist selectivity
(Type 1) Nicotinic receptors
Agonist-gated channel receptor.
Ionotropic receptors.
Act very quick, ion channel closed until bound
(Type 1) Muscarinic receptors
G protein-coupled receptor/metabotropic/7 Trans-membrane
Slower than nicotinic
3 types functionally
- M1 (neural and gastric)
- M2 (cardiac muscle)
- M3 (exocrine glands, smooth muscle)
Autonomic nerve terminals
General process we can influence with drugs.
Neurotransmitter synthesised in nerve terminal.
Parasympathetic cholinergic nerve terminal
Hemicholinium blocks the re-uptake of choline.
Botulinum blocks the release of ACh.
Vesamicol blocks the uptake of ACh. Build up of ACh in junction causes contraction and paralysis.
Acetylcholinesterase breaks down ACh into acetyl and choline
Cholinesterases- breakdown acetylcholine
There are 2 forms of cholinesterases. These are acetylcholinesterase (AChE) and plasma cholinesterases (aka pseudo or butyrykchokinesterase (BuChE)).
They are serine hydrolases that catalyse the hydrolysis of acetylcholine to choline and acetic acid.
The active centre of cholinesterases have 2 areas that interact with ACh. These are the anionic and esteratic site.
Choline is liberated during this reaction and an acetylated enzyme is produced. The enzyme is rapidly regenerated and acetic acid is formed.
Anticholinesterases
Inhibition of AChE slows or prevents the degradation of ACh released at synapses.
There are three classes of anticholinesterases. The difference between the groups is their duration of action and this depends on how they interact with AChE.
The three groups are short acting, medium acting and irreversible (long acting) anticholinesterases
Short acting anticholinesterases
e.g. Edrophonium
Monoquaternary ammonium alcohols.
they bind to the anionic site of cholinesterases and competitively displace acetylcholine from the active site. Edrophonium has a 5 minute duration (used diagnostically)
Medium acting anticholinesterases
These interact with the serine hydroxyl of the esteractic site to give a carbamylated product. The carbamylated enzyme is hydroxylated more slowly.
E.g. physostigmine, neostigmine, and pyridostigmine - eserine.
Neostigmine, and pyridostigmine have direct agonist activity.
Long acting anticholinesterases
These irreversibly phosphorylate he serine hydroxyl group of the esteractic site. The regeneration of the phosphorylated enzyme takes days. Most are organophosphorus compounds. The organophosphates are much less selective in that they phosphorylate other enzymes that contain a serine molecule at an active site. They are used as insecticides and chemical weapons.
Uses of anticholinesterases
Used for treating myasthenia gravis (muscle weakness) and for the reversal of non-depolarising neuromuscular junction block.
They are also used for treating Alzheimer’s disease (done-evil- centrally acting).
Reversible for dementia. Irreversible for Nerva agent (Novichok)
Myasthenia gravis (muscle weakness)
Circulating antibodies block ACh (nicotinic receptors) at the neuromuscular junction
Nicotinic receptors
Ionotropic
Embedded in the cell membrane. It is a protein with 5 subunits- 2a, b, g, e.
Found at neuromuscular junctions in skeletal muscle and in autonomic ganglia. At both sites these receptors are post- synaptic.
Drugs acting on nicotinic receptors
Agonists
- Neuromuscular junction (depolarising neuromuscular blockers)
-Suxamethonium
- Decamethonium
- Autonomic ganglia and CNS
- Nicotine
- Varenicline
Antagonists
- Neuromuscular junction (non-depolarising neuromuscular blockers can be reverse using ACh)
- Tubocurarine
- Atracurium
- Pancuronium
- Vecuronium
- Autonomic ganglia and CNS
- Timethaphan (rarely used)
Both agonist and antagonist are neuromuscular blockers as the agonist cause contraction and then antagonist causes relaxation.
Neuromuscular blocking agents
Depolarising blockers:
These drugs activate the nicotinic receptor and therefore produce initial contraction of the muscle fibres. The maintained depolarisation produced by these drugs eventually lead to an inactivation of the sodium channels in the muscle membrane adjacent to the end plate. This prevents the end-plate potential from producing a propagated action potential.
Non-depolarising blockers:
These drugs act as competitive antagonists at the nicotinic receptor sites. They compete with acetylcholine at the neuromuscular junction and thereby reduce the size of end plate potential this blocking transmission. the effects of non-depolarising blockers ca be reversed by an increase in acetylcholine concentration (e.g. by administration of anticholinesterases)
Most of the neuromuscular blocking drugs are quaternary ammonium compounds which penetrate cell membrane poorly. These drugs are therefore given intravenously.
Ganglion blocking drugs
No longer used.
These drugs have widespread effects due to the fact that they block sympathetic and parasympathetic ganglia e.h. hypotension due to sympathetic ganglia blockade, dry mouth and tachycardia due to parasympathetic blockade.
Among the ganglion blocking drugs are trimetaphan which competitively blocks ganglionic nicotinic receptors, and ehexamethonium which is a direct channel blockers.
Excessive amount of nicotine may also produce a depolarising block at the ganglion.
Muscarinic receptors
They are embedded in the cell membrane.
They are members of the GPCR family (Metabotropic) having 7 transmembrane segments in their amino acid sequence.
5 muscarinic receptor subtypes (m1-m5) have so far been clones but only 3 are well characterised.
M1 (neural) and M3 (glandular) couple to Gq protein and increase the concentration of inositol triphosphate and diacylglycerol concentration.
M2 (cardiac) couple to Gi protein and inhibit adenylate cyclase and open K+ channels. M1 receptors can also inhibit K+ channels opening.
Actions of muscarinic receptor agonists
Drugs stimulating muscarinic receptors cause:
1. Smooth muscle contractions (gut, bladder) (m3)
2. Pupillary constriction, ciliary muscle contraction (old medicine used to treat glaucoma)
3. Decreased rate and force of contraction of the heart
4. Increased glandular secretion (salivary, sweat, pancreas) (m3)
5. Increased gastric acid secretion (m3)
6. vasodilation through the release of endothelial nitrous oxide (m3)
7. Inhibition of neurotransmitter release
We don’t use muscarinic agonists therapeutically as there is no need to cause the effects
Muscarinic antagonists
These antagonists act as competitive antagonists and they show mostly no selectivity between receptor subtypes.
Blockade of muscarinic receptors causes:
1. Inhibition of secretion (e.g. dry mouth)- can help in travel sickness
2. Increase heart rate
3. Paralysis of accomodation
4. Pupillary dilation- used for eye exams
5. Relaxation of smooth muscles- bronchiole smooth muscle relaxation to treat asthma
6. Inhibition of gastric acid secretion- treat stomach ulcers in olden days
7. CNS excitation (atropine, a competitive antagonist for the muscarinic acetylcholine receptor)
8. CNS depression (scopolamine, a competitive antagonist at the muscarinic acetylcholine receptors)
9. Anti-parkinsonian action
10. Anti-emetic action
Examples of drugs acting on muscarinic receptors
Agonists
- Bethanechol
- Pilocarpine
Antagonists
- Atropine
- Scopolamine
- Ipratropium/Tiotropium
- Oxybutynin
- Tropicamide
- Darifenacin
