Cholinomimetics

Question 1

Define cholimemetics

Answer 1

Drugs that mimic the action of ACh in the body, they are important PNS drugs and binds to both muscarinic and nicotinic receptors.

Question 2

Describe the synthesis, release and metabolism of ACh

Answer 2

1. ACh is synthesised via acetyl co A and choline (in presynaptic and carried out via CAT enzyme which is specific to cholinergic neurones)
2. Depolarisation causes the opening of the VGCCs which in turn causes the exocytosis of ACh
3. Then it is metabolised via ACh esterase which is bound to the basement membrane

Question 3

Describe the role of muscarinic receptors and their effects

Answer 3

Muscarinic effects can be replicated by muscadine and be abolished by antagonist, Atropine. It corresponds to parasympathetic stimulation and is stimulated by ACh quickly.

1. M1: CNS excitation, salivary glands, stomach releases HCL (parietal cells).
2. M2: heart decreases the HR via SAN
3. M3: salivary gland, bronchial and visceral, eye

M1 and M3 : Gq proteins = IP3 + DAG = secondary messenger = excitatory
M2: Gi protein = cAMP = secondary messenger = inhibitory.

Question 4

Describe the difference muscarinic effects on eye, heart, CVS, non-vascular smooth muscle and exocrine glands

Answer 4

Eye: 1. Contraction of ciliary muscle (accomadtion of near vision), 2. Contraction of sphincter pupillae (miosis and increase drainage of interocular fluid). 3. Lacrementation (tears)

Heart: M2 in atria is inhibitory and therefore decrease cAMP, decreased Ca+ entry and decreased cardiac output, also decrease in K+ effluent and decrease in HR = decreased BP

CVS: bradycardia, decreased CO and vasodilation via NO via M3 and thus decreased BP

Non vascular smooth muscle: responds in the opposite way to vascular smooth muscle - contraction, eg lungs bronchocontriction, increased but parastalsis, increased iron production in bladder

Exocrine glands: increase salivary, bronchial secretion, GInsecretion, increased sweating.

Question 5

Summarise the directly acting cholinomimetics and indirectly acting cholinomimetics

Answer 5

Directly acting on muscular:
1. Alkaloids (pilocarpine): non selective and acts on all muscarinic game receptors, lipid soluble, good in ophthalmology but causes blurred vision, sweating, GI pain, hypotension and resp distress

2. Choline esters (bethanecol): minor modification of acetylcholine, produces as M3 selective agonist. And is resistant to ACh esterase, assistance in bladder opening and enhanced gastric motility. (Less side effective because selective)

Indirect: inhibit ACh esterase and increase build up of ACh and therfore increase effect of PNS

1. Reversible anti choline-esterase: physostigmine, neostigmine, donepezil, compete with ACh and donate a carbonyl group to binding site (removed via slow hydrolysis)
2. Irreversible anti choline esterase: ecothiopate, dyflos, sarrin. Rapidly react leaving large blocking group, stable and resistant recovery via production of new enzyme.

Non-polar physostigmine in BBB, low dose causes excitation and high dose causes unconsciousness and resp depression