Cholinometics Flashcards
What are cholinomimetic drugs?
Drugs that mimic the action of ACh in the nervous system
Diagram showing synthesis, release and metabolism of ACh.
Outline the stages of neurotransmitter action (numbered 1-4)
What are muscarinic effects and how can they be abolished?
Effects that can be replicated by muscarine. Abolioshed by antagonist atropine.
What branch of the ANS are muscarinic acitons related to?
Parasympathetic stimulation.
How can nicotinic effects be induced by atropine?
atropine blockade of muscarinic receptors allow large doses of ACh to induce nicotinic effects.
How do PNS and SNS fibres differ?
PNS - long pre-ganglionic, ACh pre-ganglionic and post-ganglionic.
SNS - short pre-ganglionic, ACh pre-ganglionic, NA post-ganglionic.
Outline 2 unique SNS effector routes.
Adrenal medulla releasing Adrenaline and NA as neurohormones into the blood stream.
Ach post-ganglionic neurotransmitter to sweat glands instead of NA.
What neurotransmitter do motor neurones to skeletal muscle use?
Ach
Where are muscariniuc receptors located?
Post-ganglionic ACh receptors in PNS effector organs (including sweat glands)
Where are nicotinic Ach receptors found?
PNS and SNS pre-ganglionic receptors.
How many muscarinic receptor types are there?
5
Where are M1, M2 and M3 receptors found?
M1 - salivory glands, stomach, CNS
M2 - heart.
M3 - salivory glands, bronchial/visceral SM, sweat glands, eyes.
What type of receptor are Muscarinic receptors?
G protein - type 2 receptors.
7 transmembrane segments with a loop on the inside that activates the trimer G protein.
How do M1 and M3 receptors differ from M2 receptors.
M1 and M3 are linked to stimulatory G protein, Gq - increase IP3 and DAG production.
M2 - linked to inhibitory Gi prtoein - reduction in cAMP
What type of receptors are nicotinic receptors?
Ligand gated ion channels - type 1 receptors.
How many subunits do nicotinic receptors have?
5 - alpha, beta, gamma, delta, epsilon.
What is the significance of nicotinic receptor subunit combinations?
Subunit combination determines ligand binding properties.
What nicotinic receptors subunits exist at muscle and ganglionic type receptors?
Muscle - 2 alpha, beta, gamma, epsilon.
Ganglion - 2 alpha, 3 beta.
How do nicotinic receptor effects compare to that of muscarinic receptors?
Effect of Ach is relatively weaker in nicotinic.
What ion moves through nicotinic receptors to give an effect?
Na+
List potential target systems of mucarinic cholingeric receptors.
Eye, sweat glands, lung, heart, sweat glands, bladder, gut, vasculature.
What are the 3 main muscarinic effects on the eye?
- ciliary muscle contraction - accomodation for near vision (more convex lens)
- contraction of sphincter pupillae (iris circular muscle) - constricts pupil and improves intraocular drainage.
- lacrimation.
Label diagram of eye.
Outline function of the sphincter pupillae.
open pathway for aqueous humour, allowing drainage via the canals of Schlemmand reducing intra-ocular pressure (since cornea and iris don’t receive blood supply)
How can glaucoma occur?
Ruffling of the iris reduces angle of canal of Schlemm, inhibiting drainage of fluid.
Outline muscarinic effects on the heart.
Receptors focused in atria, SA and AV nodes.
Reduced cAMP due to binding of M2 receptor –> reduced Ca2+ entry and increased K+ efflux –> reducded contractility and heart rate.
Why can vasculature be targeted by ACh related drugs despite not receiving PNS innervation?
Ach acts on vascular endothelial cells to stimulate NO release via M3 receptor, inducing vasodilation –> reduced TPR.
(NO diffuses into VSMC from vascular endothelium)
Give 4 muscarinic effects on exocrine glands.
salivation
increased bronchial secretions
increased gasto-intestinal secretions
increased sweating.
Give an overview of muscarinic effects on the cardiovascular system.
Decreased heart rate
decreased CO
vasodilation
overall: sharp drop in blood pressure.
How does non-vascular smooth muscle respond to muscarinic PNS innervation.
Excitatory responses.
Lung - bronchoconstriction.
Gut - increased peristalsis
Bladder - increased bladder emptying.
Overview potential muscarinic effects on the body (7 things)
- Decreased heart rate
- Decreased blood pressure
- Increased sweating
- Difficulty breathing
- Bladder contraction
- Gastrointestinal pain
- Increased salivation and tears
Draw bethanechol and pilocarpine muscarinic receptor agonists.
What kind of compounds are bethanechol and pilocarpine?
choline esters and alkaloids.
Is pilocarpine a selective muscarinic agonist?
No (between types of muscarinic receptor)
What is the half life of pilocarpine in the body?
3-4hr
Is pilocarpine lipid soluble?
Yes
What is the primary use of pilocarpine?
Local treatment for closed angle glaucoma.
List some side effects of pilocarpine.
Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress.
Is bethanechol a selective muscarinic agonist?
Yes, for M3 receptors.
Give some characteristics of bethanechol.
Resistant to degradation. Orally active. Limited access to brain. Half life - 3-4hr.
What are the primary uses of bethanechol?
bladder emptying, gastric motility.
Give some side effects of bethanechol.
sweating, impaired vision, bradycardia, hypotension, respiratory difficulty.
What is the method of action of indirectly acting cholinomimetic drugs?
inhibit the action of acetylcholinesterase - increase effect of normal PNS stimulation.
Give some examples of reversible and irreversible anticholinesterases.
Reversible - physostigmine, neostigmine, donepezil.
Irreversible - ecothiopate, dyflos, sarin
What do cholinesterases do?
What two types are there?
metabolise acetylcholine to choline and acetate.
acetylcholinesterase (specific)
butyrylcholinesterase (pseudocholinesterase)
Outline the distribution, selectivity and speed of acetylcholinesterase.
Outline its method of action (diagram)
Found in all cholinergic synapses.
Very rapid (> 10,000 reactions/second)
Highly selective for ACh
What is the role of butyrylcholinesterase?
Maintain low plasma ACh and metabolise other esters (broad substrate specificity).
Not found in cholinergic synapses.
What are the effects of cholinesterate inhibitors.
Low dose - enchanced muscarinic activity,
Moderate dose - further enhancement + increased transmission at all autonomic ganglia
High doe - toxic. Depolarising block at autonomic ganglia.
How to reversible anticholinesterase drugs work?
Compete with ACh.
Donate Carbamyl group, blocking active site, preventing ACh binding.
Carbamyl group removed by slow hydrolysis.
Give the half life and location of action of physostigmine.
Half life - 30 mins.
Primarily acts at postganglionic PNS synapse.
What is physostigmine used for?
treatment of glaucoma and atropine poisoning.
How do irreversible anticholinesterases work?
React with enzyme to leave large stable blocking group resistant to hydrolysis - new enenzymes must be made.
What is ecothiopate used for?
Glaucoma. Prolonged duration of action.
What are the side effects of ecothiopate?
sweating, blurred vision, GI pain, bradycardia, hypotension, resp. difficulty.
What are the effecvts of anticholinesterases on the CNS?
Low doses - excitation, possible convulsions.
High doerses - unconsciousness, repiratory depression, death.
How can organophosphate poisoning be treated?
Artificial respiration, atropine (IV), pralidoxime (IV).
Nb. phosphorylated enzyme ages within a few hours.
