Cholinergic pharmacology Flashcards
Where are the cholinergic nerves found?
• Cholinergic nerves: i.e those releasing Ach, are found in all divisions of the nervous system:
o Somatic motor nerves
o Parasympathetic pre- and postganglionic
o Sympathetic preganglionic
o Enteric
o CNS (particularly onto pre-synaptic receptors)
Pathway to drug discovery: Toxins!
Berries of deadly nightshade: found to dilate the pupils, found to block the effects of muscarine, active ingredients: Atropine
Calaber bean: a long known poison, potentiates the effects of parasympathetic stimulation. Active ingredient: Physostigmine
Poisonous fungi: Muscarine
• Poisonous Fungi: Fly agaric, Amanita muscaria (red and white spotted toadstool)
o Stimulates parasympathetic NS activation by mimicking the activation of PSN’s
o Active ingredient called “mucarine”
Cholinergic transmission
Nerves which use Ach as a neurotransmitter
Supply
• Nerves cannot make enough Choline
• Choline has to be taken up from blood
• Choline comes from diet and from liver
• Uptake into nerve endings via a high-affinity carrier, Na+ dependent process.
o Hemicholinum: Competitive inhibitor of choline carrier
o Causes activity dependent block of cholinergic transmission, due to depletion of Ach stores.
o If terminal very active, will run down its stores of Ach very quickly
o No clinical use (as its actions are widespread)
Synthesis
a. Choline + acetylCoA acetylcholine + CoA catalysed by choline acetyltransferase (ChAT)
b. ChAT occurs in nerve cytoplasm
c. Triethylcholine is also a substrate and this gives acetyltriethylcholine
d. ChAT inhibitors are not used clinically
Storage
a. Storage is maintained by energy-dependent pump (vesicular Ach transporter)
b. Uptake mechanism is not very specific (will package other substances into the vesicle if they look sufficiently like Ach)
c. Acetyltriethylcholine, formed from triehtylcholine by ChAT, can also be taken up and stored
d. It Is then released as a ‘false transmitter’
e. It has a weak effect on postsynaptic receptors.
f. Illustrates an unusual type of drug action: feed a precursor that is not itself active: it is converted into a false transmitter, stored and released from nerves. Its functional effect depends on how potent it is at postsynaptic receptors compared with natural transmitter
g. Inhibition of pump by vesamicol leads to depletion of stores
Release?
• Release
a. Always requires entry of Ca2+ into nerve ending
b. Occurs by exocytosis: Fusion of vesicle membrane will cell membrane
c. Drugs that affect the release of acetylcholine:
i. Massive release and depletion of vesicles evoked by: black widow spider venom (alpha-latrotoxin)
ii. Release blocked by botulinum toxin. Used clinically to treat blepharospasm, salivary drooling axillary hyperhidrosis, achalasia (oesophageal spasm) and for cosmetic reasons; but it is also a biological warfare agent.
Inactivaton
• Inactivation
• How is Ach removed from the synaptic cleft?
• Diffusion is not important, unless cholinesterase is inhibited
• Main mechanism is hydrolysis by tissue (acetlcholinesterase)
a. Once the Ach is released, it is broken down by Ach esterases.
b. An example of an Ach esterase affecting autonomic function is Sarin.
Sarin: A ‘neurotoxin’ developed as a chemical weapon in the 1950’s; an Ach inhibitor, which hence blocks skeletal neurotransmitter transmission and augments parasympathetic effects. (Amplifying PNS); cramping abdominal pains, bronchoconstriction, secretion into airways, constricting pupils
Feedback
a. Once the vesicles fuse with the membrane, they release their neurotransmitter
b. This Ach will act on its target
c. Ach can also act on receptors found on nerve terminals themselves: feedback inhibition.
d. ATP can also act as neurotransmitter; can react with adenosine which can inhibit further release
Prejunctional modulators for Ach
Ach (muscarinic) inhibits the release of Ach (enteric)
Ach (nicotinic) inhibits the release of of Ach
ATP is converted into adenosine which inhibits release (A1 receptors)
Morphine (opiods) inhibits release (u receptors), leading to constipation
NA inhibits release (a-adrenoceptors)
Methods of classification of receptors
- Anatomical (e.g skeletal, cardiac, ganglionic)
- Chemical/ Pharmacological (sensitivity to specific drugs)
- Molecular (M1, nAchR)
- At present, the receptors are characterised by a mixture of pharmacological and molecular nomenclature.
Nicotinic cholinoceptors (relative potencies of agonists)
Skeletal muscle:
Nicotine, carbachol, DMPP, Metacholine muscarine
Autonomic ganglia (and CNS): Nicotine, DMPP, carbachol, metacholine muscarine
Nicotinic receptor agonists
Transiently stimulate ganglia and MEP, if given briefly at high concentrations
Example Nicotine: However, receptors rapidly desensitise and so these agonists can end up inhibiting ganglionic transmission if given at a low concentration for a long time
Nicotinic receptor antagonists
• Slectively antagonised by:
o Autonomic ganglia (and CNS): hexamethonium
o Non specific antagonist: d-tubocuraine
