cholinomimetics

Question 1

muscarinic and nicotinic effects

Answer 1

replicated by muscarine, but is abolished by a small dose of antagonist atropine once this blockade occurs, larger doses of ACH are needed to cause the effects of nicotine

Question 2

location and types of muscarinic receptors

Answer 2

M1 is present in salivary glands (produce saliva), stomach (produce acid) and CNS M2 is in heart (slows it down) M3 is in salivary glands, bronchi, sweat glands and eye

Question 3

comparing muscarinic subtypes and general rule

Answer 3

apart from M2, they are excitatory- they are all G protein coupled M1/3 stimulate GQ, which increases IP3 and DAG, but M2 stimulates the inhibitory Gi, which lowers cAMP

Question 4

nicotinic receptors and

Answer 4

ligand gated ion channels with 5 subunits- ACH arrives and causes Na+ influx- large DOSE of ACH needed

Question 5

different types of nicotinic receptors and clinical relevance

Answer 5

two main types are those on skeletal muscles, and on PNS organds, they have different subunit combinations, so can be targeted by different drugs ganglion has 2 alpha 3 beta, muscle has epsilon and delta

Question 6

main location of muscarinic receptors

Answer 6

eye, salivary glands, lungs, heart, sweat glands, gut, bladder and vasculature

Question 7

muscarinic effects of eye

Answer 7

contraction of ciliary muscle- causes lens to buldge to allow near vision contraction of sphincter pupillae- constricts pupil (miosis) and supports drainage of intraocular fluid lacrimation (tears)

Question 8

aqueous humour production and glaucoma DIAGRAM

Answer 8

aqueous humour is produced by ciliary bodys, which moves forward to iris when sphincter pupillae contracs, and into canal of schlemm where it drains back into venous system in glaucoma the iris is ruffled, so less drainage occurs, increasing intra-ocular pressure, which could cause blindness

Question 9

muscarinic effects of heart

Answer 9

M2 ACHr receptors in atria and nodes, decreasing cAMP, decreasing Ca2+ entry (= lower CO ie negative inotropic effect, and decreasing K+ (=lower HR ie negative chonotropic effect)

Question 10

muscarinic effects of vasculature

Answer 10

most blood vessles don’t have direct PNS innervation, although they have muscarinic receptors, so can be targeted by drugs ACH acts of M3 receptors on endothelial cells, NOT VCSM, causing NO production= muscle relaxation= lower TPR

Question 11

overall effect on CVS

Answer 11

lower BP due to lower CO, HR and TPR

Question 12

muscarinic effects on non-vascular muscles

Answer 12

this muscle does not have PNS innervation, so it contracts: lungs (bronchoconstriction), gut (more peristalsis/motility) and bladder (emptying)

Question 13

muscarinic effects on exocrine glands

Answer 13

more salivation, bronchial secretions, GI secretions (acid) and sweating (SNS) can lead to difficulty breathing (constriction of airways) and GI pain

Question 14

types of directly acting cholinomimetics

Answer 14

agonists at muscarinic receptors are choline esters (bethanechol) and alkaloids (pilocarpine), whuch are similar in structure to ACH bethanecol has an extra methyl group, enhancing its selectivity compared to ACH

Question 15

pilocarpine: selectivity, use and side effects, and half life

Answer 15

non selective against muscarinic subtypes, so affects M1-3 useful for glaucoma as it flattens the iris however can cause blurred vision, GI pain, hypotension, although it is only applied locally to eye, hence low doses suffice half life of 3-4hrs

Question 16

bethanechol (compárison with pilocarpine)

Answer 16

unlike pilocarpine, it’s selective for M3, and is resistance to degradation unlike ACH supports bladder emptying and gastric motility, with a similar half life to pilocarpine side effects include bradycardia, respiratory problems and sweating (like ACH would do), and are more serious as applied systemically, not locally like pilocarpine

Question 17

indirectly acting cholinomimetic drugs

Answer 17

they don’t directly act on muscarinic receptor, but act on acetylcholineterases, increasing ACH ie NORMAL PNS stimulation

Question 18

types of indirect drugs

Answer 18

reversible anticholinesterase eg physostigmine irreversible include ecothiopate

Question 19

cholinesterase enzymes types

Answer 19

they make ACH go to choline and acetate there is acetylcholinesterase (true) and butyrylcholinesterase (pseudo)

Question 20

acetylcholinesterase

Answer 20

found in all cholingergic synapses with a rapid reaction, and is very selective to ACH OH group attached to serine helps break ACH

Question 21

butyrylcholinesterase

Answer 21

buty is found in plasma and tissues but not cholinergic synapses, and has a broad specificity, so hydrolyses other esters as well it makes sure there is low ACH, although there is genetic variation between people

Question 22

effects of cholinesterase inhibitors (doses)

Answer 22

low dose enhances muscarinic activity, moderate dose even more as well as increasing transmission of all ganglia high dose is toxic and causes depolarising block at ganglia, where receptors desensitised= respiratory failure

Question 23

reversible anticholinesterases

Answer 23

compete with ACH for active site by donating carbamyl group to enzyme, preventing ACH from binding carbamyl group is removed by slow hydrolysis and ACH broken down, but done in minutes rather than ms, increasing ACH duration

Question 24

physostigmine- half life, where it acts, uses

Answer 24

acts on post ganglionic PNS synapse, NOT effector organ, and has a short half life treats glaucoma by supporting circular muscle contraction to allow intraocular fluid drainage also treats atropine poision- this is a competitive antagonist of ACH, so by increasing ACH, inhibition is less

Question 25

irreversible anticholinesterases and nonhuman use

Answer 25

phosphorylate enzyme active site, leaving a large blocking group which is resistant to hydrolysis, so recovery takes weeks can be used as insectidies

Question 26

ecothiopate

Answer 26

treats glaucoma like physostigmine, but with a longer duration has systemic side effects by overstimulate of PNS: sweating, bradycardia, respiratory problems, blurred vision, GI pain

Question 27

anticholinesterases and CNS

Answer 27

they are non polar so can cross blood brain barrier low doses cause excitation, high can cause unconciousness and even death

Question 28

treatment of organophosphate poisoning

Answer 28

organophosphates in insecticides/nerve agents can be very toxic and cause CNS failure treatment involves atropine, artificial respiration, and pralidoxime (unblocks the enzyme)