Lecture 6 - Cholinomimetics Flashcards
What type of drugs are cholinomimetics and which of the nervous systems do do they mimic?
Cholinomimetics are drugs that mimic the action of acetylcholine in the body
These are PARASYMPATHOMIMETIC drugs
The cycle by which acetylcholine is synthesised, released and metabolised is crucial for understanding the influence of different types of cholinomimetics. Summarise this cycle.
1) Acetyl CoA + Choline –> Acetylcholine. This is catalysed by Choline Acetyltransferase (CAT)
2) ACh is packaged into vesicles
3) Depolarisation causes opening of voltage sensitive calcium channels
4) Ca2+ ions enter the presynaptic neurone and stimulate movement and fusion of ACh vesicles to the presynaptic membrane
4) ACh is released into synaptic cleft and diffuses across to bind to receptors on postsynaptic membrane
5) ACh then broken down by acetylcholinesterase into choline and acetate
6) Choline is recycled into the presynaptic neurone to continue the cycle
What are muscarinic effects defined as, what can they be abolished by, what type of autonomic stimulation it corresponds to, and what effects do larger doses of acetylcholine induce similar to?
- Muscarinic effects - “Effects that can be replicated by MUSCARINE”
- Can be abolished by low doses of muscarinic antagonist ATROPINE
- Muscarinic actions correspond to PARASYMPATHETIC stimulation
- Larger doses of ACh can induce effects similar to those caused by NICOTINE
How are nicotinic and muscarinic receptors arranged within the PNS, the SNS, and motor neurones?
- Nicotinic in ganglia in both PNS and SNS as well as on the adrenal medulla. In motor neurones, found on the skeletal muscle, no muscarinic receptors in motor neurones.
- Muscarinic receptors are found in PNS on effector organs and on very specific SNS organs such as sweat glands.
Where are the 5 muscarinic subtypes and which are the main 3?
M1 - CNS, salivary glands, stomach M2 - Heart M3 - Salivary glands, bronchial/visceral smooth muscle, sweat glands, eye M4/5 - CNS M1/2/3 are the main important ones
Are muscarinic receptors generally excitatory or inhibitory and what is the exception?
- Generally excitatory
- M2 in the heart exception - inhibitory, reduces heart rate
What type (1/2/3 etc) of receptors are muscarinic receptors?
Type 2 - G protein linked
Which G proteins are each of the 5 muscarinic receptors linked to, what effects does this cause, and what is the rule for remembering which are linked to which?
M1,3,5 = Gq protein linked receptor - stimulates PLC to increase IP3 and DAG production
M2,4 = Gi protein linked receptor - inhibitory, reduces production of cAMP
Rule of remembrance
- Odds = Gq
- Evens = Gi
What type of receptor are nicotinic receptors?
Ligand gated ion channels - ion channels dependent on the binding of acetylcholine
What are the two main types of nicotinic receptor?
Muscular and Ganglionic (based on where they’re found)
What are the 5 subunits that make up the receptor, what does their combination determine about the receptor and what are the different combinations of the different types of nicotinic receptors?
- Alpha, beta, gamma, delta, epsilon
- Determines the ligand binding properties of the receptor
- Muscle = 2a, b, d, e
- Ganglion = 2a, 3b
Are the effects of acetylcholine stronger or weaker on nicotinic receptors compared with muscarinic?
Effects of acetylcholine are relatively weak on nicotinic compared to muscarinic
What are the 3 main muscarinic effects on the eye?
- Contraction of the ciliary muscle, accommodates for near vision
- Contraction of sphincter pupillae (circular muscle of the iris), constricts pupil (miosis) and increases drainage of intraocular fluid
- Lacrimation (tears)
Where is aqueous humour generated in the eye and what is its path into and out of the eye?
- Aqueous humour is generated by the capillaries of the ciliary body
- It’s generated and flows into the anterior chamber of the eye
- It provides oxygen and nutrients to the lens and cornea as they have no blood supply
- It diffuses forwards across the lens, then across the cornea and it drains through the CANALS OF SCHLEMM back into the venous system
Why is the path of aqueous humour important and what happens in angle-closure glaucoma?
- It is important if the drainage of the aqueous humour becomes impaired as it can lead to glaucoma.
- Glaucoma is an increase in intraocular pressure, angle-closure glaucoma is when the angle between the cornea and iris becomes narrowed and reduces the drainage of intraocular fluid via the Canals of Schlemm
- If the production rate remains the same and the drainage rate reduces, the humour builds up in the eye increasing intraocular pressure.
How can angle-closure glaucoma be treated and why does this treatment work?
Muscarinic agonist - stimulation of muscarinic receptors
- Causes contraction of the iris which OPENS UP THE ANGLE and increases the drainage of intraocular fluid through the Canals of Schlemm thus reducing the disparity between drainage and production so pressure in the eye returns to normal.
Where are M2 receptors found in the heart and what effects do they have when stimulated?
M2 receptors are INHIBITORY
- Found in the atria and the nodes
- Atria - decreases Ca2+ entry thus reducing cardiac output
- Nodes - decreases K+ efflux thus reducing heart rate
Reduced cardiac output and heart rate
