Cholinergic Pharmacology Flashcards
What are cholinergic nerves?
Nerves that release acetylcholine and are found in all divisions of the nervous system
What divisions of the nervous system release acetylcholine?
Somatic motor nerves parasympathetic pre and post ganglionic neurones sympathetic preganglionic neurones Enteric CNS
What is a major pathway to drug discovery?
Toxins!!
Berries of deadly nightshade - dilate pupils
Calabar bean - Potentiates the effects of the parasympathetic stimulation.
What is muscarine?
Active compound that mimicked the activation of the parasympathetic nervous system found in poisonous fungi (fly agaric)
What is cholinergic transmission?
Nerves which use acetylcholine as a neurotransmitter
how is acetylcholine supplied?
Choline comes from the diet and liver since nerves cannot make enough choline.
Uptake into nerve endings via high affinity carrier Na dependent transport proteins.
What is Hemicholinum?
A competitive inhibitor of the choline carrier.
How is acetylcholine synthesised?
Choline + acetylCoA catalysed by choline acetyltransferase (ChAT)
This occurs in the nerve cytoplasm
ChAT inhibitors are not used clinically.
How is acetylcholine stored?
Store is maintained by energy dependent pumps into synaptic vesicles.
What happens when there is inhibition of pumps storing ACh?
Drugs such as Vesamicol leads to the depletion of stores by inhibiting the pumps
What is Acetyltriethylcholine?
Formed from triethylcholine by ChAT, which can also be taken up and stored.
Then it can be released as a false neurotransmitter.
(has weak effect on the postsynaptic receptors)
How is acetylcholine released?
Always requires Ca entry into nerve endings.
Occurs by exocytosis where the vesicle membrane fuses with the cell membrane
What drugs affect the release of acetylcholine?
Massive release and depletion of vesicle evoked by alpha-latrotoxin (black widow spider venom)
Release can be blocked by the botulinum toxin.
How is ACh removed from the synaptic cleft and inactivated?
Diffusion is not important unless cholinesterase is inhibited.
Hydrolysis of ACh by AChE in a non-reversible reaction
what is Sarin?
A neurotoxin developed as a chemical weapon in the 1950s
An acetylcholinesterase inhibitor which hence blocks skeletal neuromuscular transmission and augments parasympathetic effects
How is acetylcholine fedback?
Cholinergic nerves have presynaptic or prejunctional receptors:
- ACh(muscarinic) inhibits release of ACh (enteric)
- ACh (nicotinic) increases the release of ACh probably less functionally important)
- ATP is converted to adenosinewhich inhibits release (A1 receptors)
- Morphine (opioids)inhibit release (µ-receptors), leading to constipation
- Noradrenalineinhibits release (a2-adrenoceptors); ‘sympathetic cross-inhibition’ in tissues
What are the main receptors for ACh?
Nicotinic receptors
Muscarinic receptors
How are receptors classified?
Anatomical
Chemical/pharmacological
Molecular
How can we determine between pharmacological or molecular receptors?
Pharmaxological - Potency series of agonists or specific antagonists
Molecular - Well suited to knockout and expression systems
Where are nicotinic receptors found?
Skeletal muscle
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Autonomic ganglia
Not the same type of nicotinic receptor though
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What are nicotinic receptor agonists?
Nicotine
Transiently stimulate ganglia and motor end-plate if given briefly at very high concentrations.
What are some nicotinic receptor antagonists?
Selectively antagonised by autonomic ganglia (and CNS)
Hexamethonium
Non-specific antagonist - d-tubicurarine
What is Hexamethonium and what is it used to treat?
Nicotinic antagonist which blocks the autonomic ganglia.
Used to treat high blood pressure.
What is the mechanism of action of hexamethonium?
Blocks the ion channel
What is the unusual mechanism of action of galantamine?
- Found in the Snowdrop (Galanthus sp.)
- Act on nicotinic receptors to increase their activity (allosteric potentiating ligand or ‘positive allosteric modulator)
- Also has anticholinesterase activity
- Used for the treatment of Alzheimer’s disease (central action)
- Peripheral side effects include an changes in gut motility.
What are muscarinic cholinoceptors?
a relative potency seriesfor agonists (when cholinesterase is inhibited): methacholine, muscarine > carbachol»_space;> nicotine
What are some muscarinic antagonists?
M1 (Pirenzepine) - stomach, salivary glands
M2 (Gallamine) - cardiac muscle
M3 - smooth muscle
Less specific antagonists - atropine, hyoscine, cyclopentolate
What are some clinical uses of antimuscarinic drugs?
- Asthma (ipratropium)
- To treat bradycardia (atropine)
- To decrease gut motility; decrease secretions (pirenzapine)
- During operations: decrease secretions, decrease AChEI side-effects (atropine)
- To dilate pupils (tropicamide)
- Urinary incontinence (oxybutynin)
- Motion sickness (hyoscine)
What are some muscarinic agonists?
Parasympathomimetics
ACh
Carbachol
Muscarine
Pilocarpine
What are the effects of parasympathomimetics?
Cardiovascular - decreased heart rate, cardiac output
Smooth muscle -contracts, vascular dilates via endothelium (EDRF = NO)
Exocrine glands -secrete -sweating, lacrimation, salivation, bronchial secretion
What are some uses of parasympathomimetics?
Rarely used to widespread side effects
May be used for the treatment of glaucoma
What are the nicotinic Cholinoceptors agonists?
Nicotine Carbachol DMPP Methacholine Muscarine
What are the relative potency series of nicotinic cholinoceptor agonists at skeletal muscle?
Nicotine > Carbachol»_space;DMPP»>methacholine/muscarine
What are the relative potency series of nicotinic cholinoceptor agonists at autonomic ganglia and CNS?
Nicotine, DMPP > Carbachol»_space;>methacholine/muscarine
What are the problems with hexamethonium?
Poorly absorbed (requires Injection) Blocks both sympathetic and parasympathetic ganglia so unpredictable side effects
What are the muscarinic Cholinoceptor agonists?
Methacholine
Muscarine
Carbachol
Nicotine
What is the relative potency series of muscarinic chonlinoceptor agonists (when cholinesterase is inhibited)
Methacholine, Muscarine > Carbachol»_space;> Nicotine
