Cholinomimetics Flashcards Preview

Year 2 - LCRS - Pharmacology > Cholinomimetics > Flashcards

Flashcards in Cholinomimetics Deck (52)
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1
Q

What are the two major groups of Cholinomimetics drugs?

A

Directly acting and indirectly acting Cholinomimetics drug

2
Q

What are the two categories of directly acting Cholinomimetics?

A

Choline esters (i.e. bethanecol)

Alkaloids (i.e. pilocarpine)

=> agonists at muscarinic AChR

3
Q

What are the 2 categories of indirect Cholinomimetics?

A

Reversible (physostigmine, neostigmine) and irreversible (organophosphate like ecothiopate, dyflos, parathion,sarin) Acetylcholinesterase drugs.

4
Q

What are muscarinic effects?

A
  • bradycardia
  • hypotension
  • increased sweating
  • increased lacrimation
  • difficulty breathing
  • GI pain
  • bladder contractions
  • increased salvation
5
Q

Where is Acetylcholinersterase found and how fast does it work?

A
  • Found in all cholinergic synapses (peripheral and central)
  • highly selective for ACh (has much less effect on other choline esters)
  • > 10 000 reactions / second (hydrolysis) - very rapid action!
  • in synaptic cleft
  • serine residue on the active site of the enzyme
  • ACh binds
  • hydroxyl group on the serine residue hydrolyses the acetate away from the choline
  • immediately inacitvates ACh
6
Q

What are the effects of cholinesterase inhibitors based on their dose?

A

Low dose: enhanced muscarinic activity
Moderate dose: further enhanced muscarinic activity, increased transmission at all autonomic ganglia
High dose: toxic! Depolarising block at autonomic gamglia and NMJ.

7
Q

Where are muscarinic receptors found?

A
  • on PNS effector organs

- on sweat glands in the SNS

8
Q

Where are nicotinic receptors found?

A
  • at autonomic ganglia
  • where motor neurones synapse with muscle at the NMJ
  • ligand gated ion channels with 5 subunits (alpha - epsilon)
9
Q

What are the muscarinic receptor subtypes?

A
M1:	Salivary glands, Stomach, CNS
M2:	Heart
M3:	Salivary glands, Bronchial/visceral SM, Sweat glands, Eye
M4:	CNS
M5:	CNS

1,3,5 are Gq, IP3 DAG (excitatory, increases IP3, DAG, PLC)
2,4 are Gi cAMP (inhibitory, reduction in ic cAMP)

10
Q

What is the difference between muscarinic and nicotinic receptors?

A
  • muscarinic receptors are G-protein linked receptors
  • nicotinic receptors are ligand gated ion channels (5 subunit, subunit combination determines the ligand binding properties of the receptor
11
Q

What is the difference between muscle type and ganglion type nicotinic receptors?

A
  • Muscle type have 2alpha, 1 beta, 1 delta and 1 epsilon subunit
  • ganglion type have 2alpha and 3 beta subunits (CNS similar)
  • The effects of ACh are relatively weak -> you need higher amounts of ACh to stimulate these (e.g. compared to muscarinic)
    the subunits determines its ligand binding properties.
  • Also: the different subunits allow for the use of different drugs that target e.g. muscle type or ganglion type and have different effects.
12
Q

What are muscarinic effects on the eye?

A
  • contraction of the ciliary muscle: accomodation for near vision
  • contraction of the sphincter pupillae (circular muscle of the iris) -> constricts pupil (miosis) and improves drainage of intraocular fluid; Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage via the canals of Schlemm and reducing intra-ocular pressure
  • lacrimation (tears)
13
Q

Where is muscarine from?

A

Can be isolated from a mushroom called Amanita muscaria

14
Q

Muscarinic vs nicotinic effects

A
  • muscarinic effects can be replicated by muscarine (a selective agonist of ACh muscarinic receptors)
  • the msucarinic effects can be diminished by the actions of atropine (a competitive muscarinic cholinoceptor antagonist)
  • if you block the muscarinic receptors with atropine you can see nicotinic actions, however you need higher ACh to stimulate the receptors -> similar to the effects caused by nicotine
15
Q

Where can nicotine itself be isolated from?

A

The tobacco plant (nicotiana tabacum)

16
Q

Muscarinic effects on the heart

A
  • M2 Receptors are inhibitory
  • can be found in the atria and in the nodes
  • they cause a decrease in cAMP
  • this in turn causes
    a) decreased Ca2+ entry -> decreased CO
    b) increased K+ efflux which causes decreased HR
17
Q

What are the 2 muscarinic effects on the heart?

A
  • decreased CO

- deceased HR

18
Q

What are the msucarinic effects on vasculature?

A
  • most BV do not have PS innervation
  • ACh acts on vascular endothelial cells to stimulate NO release via M3 AChR
  • NO induces vascular smooth muscle relaxation
  • Result is a decrease in TPR

This is more relevant to the clinical use of cholinomimetics rather than normal physiology.

19
Q

General rule regarding the effect of muscarinic receptors

A
  • generally they are excitatory, e.g. increased secretions

- odd one out is M2 which is inhibitory and causes decreased contractility and HR

20
Q

Are there currently therapeutically useful drugs for M4 and M5 muscarinic receptors?

A

No!

  • we are still not sure what their function is, we know that they are in the CNS
21
Q

What are the muscarinic effects on the cardiovascular system?

A
  • decreased HR (Bradycardia)
  • Decreased CO (due to decreased atrial contraction)
  • Vasodilatation (stimulation of NO production)

All of these combined can lead to a sharp drop in blood pressure!!

22
Q

What are the muscarinic effects on non-vascular smooth muscle?

A
  • Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle – i.e. it contracts
  • > Lung: Bronchoconstriction
  • > Gut: Increased peristalsis (motility)
  • > Bladder: Increased bladder emptying
23
Q

What are muscarinic effects on exocrine glands?

A
  • Salivation
  • Increased bronchial secretions
  • Increased gastro-intestinal secretions (including gastric HCl production) -> this is because MAChR on parietal cells stimulation causes increased gastric HCl secretion
  • Increased sweating (SNS-mediated)
24
Q

Pilocarpine

A
  • DIRECLTY acting cholinomimetic drug (alkaloid)
  • Derived from the leaves of a South American shrub Pilocarpus
  • Non-selective muscarinic agonist (there are structural similarities between pilocarpine and ACh which allow it to work on that receptor (incl. methyl group, carbon chain, oxygen, nitrogen)
  • selectivity at the muscarinic receptors, much less at nicotinic.
  • good lipid solubility
  • t1/2 ≈ 3-4h
  • Particularly useful in ophthalmology as a local treatment for glaucoma
  • SE: Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress
25
Q

What is pilocarpine used for? What are its side effects?

A
  • Particularly useful in ophthalmology as a local treatment for glaucoma
  • pilocarpine causes pupil constriction
  • Side effects: Blurred vision, sweating, gastro-intestinal disturbance and pain, hypotension, respiratory distress
26
Q

Bethanecol

A
  • DIRECLTY acting cholinomimetic drug (choline ester)
  • Minor modification of ACh, produces an M3 AChR selective agonist
  • only structural difference to ACh is a methyl group -> small change makes it selective to muscarinic receptors
  • Resistant to degradation
  • orally active and with limited access to the brain
  • t1/2 ≈ 3-4h
  • Mainly used to assist bladder emptying and to enhance gastric motility
  • Side effects: sweating, impaired vision, bradycardia, hypotension, respiratory difficulty
  • [Cevimeline – newer M3-selective cholinomimetic]
27
Q

What are the clinical uses and the side effects of bethanecol?

A
  • Mainly used to assist bladder emptying and to enhance gastric motility
  • Side effects: sweating, impaired vision, bradycardia, hypotension, respiratory difficulty
28
Q

What are indirectly acting cholinomimetic drugs?

A
  • They increase the effect of normal PS nerve stimulation.

- there are reversible and irreversible anticholinesterases

29
Q

What do cholinesterase enzymes do?

A
  • Metabolise acetylcholine to choline and acetate
  • Two types which differ in distribution, substrate specificity and function:
    - Acetylcholinesterase (true or specific cholinesterase)
    - Butyrylcholinesterase (pseudocholinesterase)
30
Q

Butyrylcholinesterase

A
  • Found in plasma and most tissues but not cholinergic synapses
  • Broad substrate specificity - hydrolyses other esters e.g. suxamethonium
  • Is principal reason for low plasma acetylcholine
  • Shows genetic variation
31
Q

What are the effects of cholinesterase inhbitors?

A
  • Low dose -> Enhanced muscarinic activity (see above)
  • Moderate dose -> Further enhancement of muscarinic activity; Increased transmission at ALL autonomic ganglia (nAChRs)
  • High dose -> toxic (Depolarising block at autonomic ganglia & NMJ (see PT9 NMJ lecture))
32
Q

Name Reversible Anticholinesterase Drugs

A
  • Physostigmine

- neostigmine

33
Q

What are reversible anticholinesterase drugs?

A
  • e.g. Physostigmine, neostigmine
  • Compete with ACh for active site on the cholinesterase enzyme
  • Donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding
  • Carbamyl group removed by slow hydrolysis (mins rather than msecs) -> these drugs are longer acting than ACh
  • Increase duration of ACh activity in the synapse -> increase concentration in the synapse.
34
Q

Physostigmine

A
  • Naturally occurring tertiary amine from Calabar beans (Physostigma venenosum)
  • reversible anticholinesterase drug
  • Primarily acts at the postganglionic parasympathetic synapse (t1/2 ≈ 30 mins)
  • Used in the treatment of glaucoma, aiding intraocular fluid drainage
  • Also used to treat atropine poisoning, particularly in children
35
Q

What drug is used in atropine poisoning?

A

Physostigmine (particularly in children)

36
Q

Irreversible anti cholinesterase drugs

A
  • Organophosphate compounds: ecothiopate, dyflos, parathion and sarin
  • Rapidly react with the enzyme active site, leaving a large blocking group
  • This is stable and resistant to hydrolysis - recovery may require the production of new enzymes (days/weeks)
  • Only ecothiopate in clinical use, but the others are commonly used as insecticides (and as nerve gas!)
37
Q

Which is the only irreversible anticholinesterase drug used clinically?

A

Ecothiopate (the others are commonly used as insecticides and as nerve gas)

38
Q

Ecothiopate

A
  • Potent inhibitor of ACh-esterase
  • Slow reactivation of the enzyme by hydrolysis takes several days
  • Used as eye drops in treatment of glaucoma, acting to increase intraocular fluid drainage with a prolonged duration of action
  • Systemic side effects: sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
39
Q

Anticholinesterase drugs and the CNS

A
  • Non-polar anticholinesterases (e.g. physostigmine; nerve agents) can cross the blood brain barrier
  • Low doses: Excitation with possibility of convulsions
  • High doses: Unconsciousness, respiratory depression, death
40
Q

How do you treat organophosphate poisoning?

A
  • can cause severe toxicity (muscarinic activity; CNS excitation; depolarising NM block)
  • Treatment: atropine (iv); artificial respiration; pralidoxime (iv)
  • NB: Phosphorylated enzyme ‘ages’ within few hours -> after a few hours it becomes irreversible
  • pralidoxime: It is the only drug that can reverse the organophosphate block but it has to be given within a few hours. Interacts with blocked ACh-esterase and unblocks it (only within a few hours) -> works on muscarinic and nicotinic receptors.
  • atropine: acts on muscarninc receptors -> blocks muscarnic receptors and reduce the response at them.
41
Q

Where do clinically relevant cholinomimetics act?

A

At muscarnic receptors

42
Q

SBA 1: Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system?

A: All autonomic synapses
B: Pre- and post-ganglionic parasympathetic synapses
C: Pre- and post-ganglionic sympathetic synapses
D: Post-ganglionic parasympathetic synapses only
E: Pre-ganglionic sympathetic synapses only

A

B

43
Q

SBA 2: Anticholinesterase drugs can be used to treat which of the following conditions?

A: Asthma
B: Glaucoma
C: Hypotension
D: Motion Sickness
E: Peptic Ulcer Disease
A

B

44
Q

Nicotinic receptors

A
  • made from 5 subunits (alpha, beta, gamma, delta, epsilon)
  • subunit combination determines ligand binding porperties
  • this is useful to us because we can develop more selective drugs that i.e. rather bind to muscle type (at nmj) or ganglion type receptors
  • ligand gated ion channels
  • effects of ACh are relatively weak, you need higher concentrations of ACh to stimulate these receptors than muscarnic receptors
  • opening of channel due to ACh binding causes Na+ influx into the cell (also some K+ out and some Ca2+ in) snaps shut after a millisecond or 2 -> mainly an inwards sodium current
45
Q

Ganglion type nicotinic receptor subunit composition

A

2 alpha

3 beta

46
Q

muscle type nicotinic receptor subunit composition

A

2 alpha
1 beta
1 delta
1 epsilon

47
Q

Nicotinic receptors in the CNS

A
  • similar to the ganglion type but not the same

- CNS contains quite a lot of nicotinic receptors which tend to be presynaptic

48
Q

What is the function of acquesous humour in the eye?

A
  • the lens and cornea don’t have their own blood supply
  • the aqueous humour provides these tissues with oxygen and nutrients
  • bathes the lens and cornea
49
Q

How is aqueous humour produced and drained in the eye?

A
  • produced by the ciliary body
  • this flows to the anterior chamber of the eye
  • it then drains through the canals of schlemm at the margin of the iris
  • then drainage into the venous system
  • constant production and drainage
50
Q

Closed angle glaucoma

A
  • in some people and especially with age the iris can become folded or ruffled
  • this changes (closes) the angle at the canals of schlemm
  • this causes reduced drainage
  • this causes increased intra-ocular pressure
  • increased IOP can be damaging to the retina, optic nerve and in severe cases can cause blindness
  • muscarinic drugs act on the circular muscles and flatten the iris which opens the angles and provides the access to the canals.
51
Q

Acetylcholinesterase

A
  • found in all cholinergic synapses (peripheral
52
Q

What are the effects of organophosphate poisoning?

A
  • severe toxicity!!
  • increased muscarnic activity
  • CNS excitation
  • depolarising NM block -> cessation of respiration
  • some organophosphates can be very lipid soluble to cross the skin and gain enough access to systemic circulation to cause some nasty side effects.