Cholinomimetics Flashcards
03.10.2019
What are the two major groups of Cholinomimetics drugs?
Directly acting and indirectly acting Cholinomimetics drug
What are the two categories of directly acting Cholinomimetics?
Choline esters (i.e. bethanecol)
Alkaloids (i.e. pilocarpine)
=> agonists at muscarinic AChR
What are the 2 categories of indirect Cholinomimetics?
Reversible (physostigmine, neostigmine) and irreversible (organophosphate like ecothiopate, dyflos, parathion,sarin) Acetylcholinesterase drugs.
What are muscarinic effects?
- bradycardia
- hypotension
- increased sweating
- increased lacrimation
- difficulty breathing
- GI pain
- bladder contractions
- increased salvation
Where is Acetylcholinersterase found and how fast does it work?
- 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
What are the effects of cholinesterase inhibitors based on their dose?
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.
Where are muscarinic receptors found?
- on PNS effector organs
- on sweat glands in the SNS
Where are nicotinic receptors found?
- at autonomic ganglia
- where motor neurones synapse with muscle at the NMJ
- ligand gated ion channels with 5 subunits (alpha - epsilon)
What are the muscarinic receptor subtypes?
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)
What is the difference between muscarinic and nicotinic receptors?
- 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
What is the difference between muscle type and ganglion type nicotinic receptors?
- 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.
What are muscarinic effects on the eye?
- 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)
Where is muscarine from?
Can be isolated from a mushroom called Amanita muscaria
Muscarinic vs nicotinic effects
- 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
Where can nicotine itself be isolated from?
The tobacco plant (nicotiana tabacum)
Muscarinic effects on the heart
- 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
What are the 2 muscarinic effects on the heart?
- decreased CO
- deceased HR
What are the msucarinic effects on vasculature?
- 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.
General rule regarding the effect of muscarinic receptors
- generally they are excitatory, e.g. increased secretions
- odd one out is M2 which is inhibitory and causes decreased contractility and HR
Are there currently therapeutically useful drugs for M4 and M5 muscarinic receptors?
No!
- we are still not sure what their function is, we know that they are in the CNS
What are the muscarinic effects on the cardiovascular system?
- 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!!
What are the muscarinic effects on non-vascular smooth muscle?
- 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
What are muscarinic effects on exocrine glands?
- 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)
Pilocarpine
- 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
What is pilocarpine used for? What are its side effects?
- 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
Bethanecol
- 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]
What are the clinical uses and the side effects of bethanecol?
- Mainly used to assist bladder emptying and to enhance gastric motility
- Side effects: sweating, impaired vision, bradycardia, hypotension, respiratory difficulty
What are indirectly acting cholinomimetic drugs?
- They increase the effect of normal PS nerve stimulation.
- there are reversible and irreversible anticholinesterases
What do cholinesterase enzymes do?
- Metabolise acetylcholine to choline and acetate
- Two types which differ in distribution, substrate specificity and function:
- Acetylcholinesterase (true or specific cholinesterase)
- Butyrylcholinesterase (pseudocholinesterase)
Butyrylcholinesterase
- 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
What are the effects of cholinesterase inhbitors?
- 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))
Name Reversible Anticholinesterase Drugs
- Physostigmine
- neostigmine
What are reversible anticholinesterase drugs?
- 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.
Physostigmine
- 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
What drug is used in atropine poisoning?
Physostigmine (particularly in children)
Irreversible anti cholinesterase drugs
- 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!)
Which is the only irreversible anticholinesterase drug used clinically?
Ecothiopate (the others are commonly used as insecticides and as nerve gas)
Ecothiopate
- 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
Anticholinesterase drugs and the CNS
- 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
How do you treat organophosphate poisoning?
- 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.
Where do clinically relevant cholinomimetics act?
At muscarnic receptors
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
B
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
B
Nicotinic receptors
- 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
Ganglion type nicotinic receptor subunit composition
2 alpha
3 beta
muscle type nicotinic receptor subunit composition
2 alpha
1 beta
1 delta
1 epsilon
Nicotinic receptors in the CNS
- similar to the ganglion type but not the same
- CNS contains quite a lot of nicotinic receptors which tend to be presynaptic
What is the function of acquesous humour in the eye?
- 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
How is aqueous humour produced and drained in the eye?
- 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
Closed angle glaucoma
- 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.
Acetylcholinesterase
- found in all cholinergic synapses (peripheral
What are the effects of organophosphate poisoning?
- 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.
