Cholinomimetics Flashcards
What are the main subtypes of muscarinic receptors?
M1: Neural - Salivary glands - Stomach - CNS M2: Cardiac - Heart M3: exocrine glands and smooth muscle - Salivary glands - Bronchial/visceral SM - Sweat glands - Eye M4: Periphery - CNS M5: Striatal dopamine release - CNS
General rule - muscarinic receptors are excitatory apart from M2 receptors in the heart which are inhibitory
What type of receptor are muscarinic receptors?
Type 2 - G protein coupled
Distinguishing feature of type 2 receptors are the 7 transmembrane segments (alpha helices)
What are the M1 and M3 subtype receptors linked to?
Gq protein –> increases IP3 and DAG
What is M2 subtype receptor linked to?
Gi protein (inhibitory) –> decreases the production of cAMP
How many subunits are there in nicotinic receptors and what subunits are in the different types of nicotinic receptors
5 subunits - alpha, beta, gamma, delta, epsilon
Muscle type: 2 alpha, beta, epsilon
Ganglion type: 2 alpha, 3 beta (CNS similiar)
The effect of ACh is relatively weak - you need more ACh to stimulate nicotinic than muscarinic receptors
Where are muscarinic cholingeric receptors found?
Eye Salivary glands Lungs Bladder Gut Heart Vasculature (most vessels don't have parasympathetic innervation) Sweat glands (sympathetic)
What are the muscarinic effects of the eye?
Contraction of ciliary muscle: bulging of the lense accommodation for near vision
Contraction of the sphincter pupillae (circular muscle of the iris): Miosis and improves drainage of intraocular fluid
Lacrimation (tears)
How does the contraction of the sphincter pupillae improve intraocular drainage?
AH is produced in the ciliary bodies, bathes the lens and cornea. Contraction opens the pathway for aqueous humour to drain into via the the canals of Schlemm and reducing intraoccular humour.
What are the muscarinic effects on the heart?
M2 receptors in the atria and nodes:
Stimulation = decreased production of cAMP
Decreased Ca2+ –> decreased CO
Increased K+ efflux –> decreased HR
What are the muscarinic effects on the vasculature?
Most blood vessels do not have parasympathetic innervation but they do have muscarinic receptors.
ACh acts on the M3 AChR on the vascular endothelial cells (not smooth muscle cells) to stimulate NO release.
NO induces vascular smooth muscle relaxation = decrease in TPR
See diagram
Summarise the muscarinic effects on the CVS?
Decreased HR
Decreased CO (due to decreased atrial contraction)
Vasodilation (stimulation of NO production)
= Sharp drop in BP. (be careful when using muscarinic agonists)
Muscurinic effects on non-vascular smooth muscle?
Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular smooth muscle. i.e it contracts
Lung: Bronchoconstriction
Gut: Increased peristalsis (motility)
Bladder: Increased bladder emptying
What are the muscarinic effects on the exocrine glands?
Salvation
Increased bronchial secretion
Increased gastro-intestinal secretions (including gastric HCL)
Increased sweating (SNS-mediated)
Summarise the muscarinic effects on the body?
See slides
What are the two types of cholinomimteic drugs?
Directly acting
Indirectly acting
What are the typical directly acting cholinomimetic drug agonists at muscarinic receptors?
1) Choline esters (bethanechol) (some degree of selectivity of M3 receptors)
2) Alkaloids (pilocarpine) (only targets muscarinic receptors)
Describe pilocarpine
Non-selective muscarinic agonist
Good lipid solubility (good for eye use. Given locally)
Plasma half life; 3-4hrs
What is pilocarpine useful for?
Effective local treatment of glaucoma - useful in opthalmology
What are the side effects on pilocarpine?
If it does get into the systemic system you will see.
- blurred vision (effect on the lens)
- sweating
- GI disturbance and pain
- hypotension
- respiratory distress
Describe bethanochol
Very similar to ACh
M3 selective agonist
Resistant to degradation, orally active and with limited access to the brain
Plasma half life; 3-4hrs
What is the main use of bethanochol?
Assist bladder emptying and to enhance gastric motility post op
What are the side effects of bethanochol?
- impaired vision
- sweating
- bradycardia
- hypotension
- respiratory difficulty
What are the indirectly acting cholinomimetic drugs?
increase effect of normal parasympathetic nerve stimulation - effectively using ACh
What are the types of indirectly acting cholinomimetic drugs?
Reversible anticholinesterases: physostigmine, neostigmine, donepezil (aricept)
Irreversible anticholinesterases: ecthiopate, dyflos, sarin
What are the cholinesterase enzymes?
Metabolise ACh to choline and acetate
Acetylcholinesterase Butyrylcholinesterase (pseudocholinesterase)
Describe acetylcholinesterase
Found in all cholinergic synapses
Very rapid action (hydrolysis; >10000 reactions per second)
Highly selective for ACh - active site has a serine residue.
Describe butyrylcholinesterase
Found in the plasma and most tissues but not in cholinergic synapses.
Broad substrate specificity - hydrolyses other esters such as suxamethonium
This is reason why we gave low plasma ACh
Shows genetic variation
Describe the effects o cholinesterase inhibitors
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)
What is the mechanism of action of revesible anticholinesterase drugs?
Physostigmine
Competes with ACh for the active site on the cholinesterase enzyme to prevent ACh from binding.
The carbamyl group is removed by slow hydrolysis (mins rather than msecs) which increases the duration of ACh activity in the synapse
Describe physostigmine?
Primarily acts at the postganglionic PS synapse
Plasma half life; 30 mins
What is physostigmine used for?
Treatment of glaucoma (aids in intraocular fluid drainage)
Also used to treat atropine poisoning (particularly in children)
Describe the irreversible anticholinesterase drugs?
Organophosphate compounds - ecothiopate
What is the mechanism of action of irreversible anticholinesterase drugs?
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)
Describe ecothiopate
Potent inhibitor of ACh
Slow reactivation of the enzyme by hydrolysis takes several days
What are the uses of ecothiopate?
Used as eye drops in treatment of glaucoma –> prolonged duration of action
What are the side effects of ecothiopate?
Systemic side effects:
- sweating
- blurred vision, GI pain
- bradycardia
- hypotension
- respiratory difficulty
ALL PREDICTABLE SIDE EFFECTS OF THE STIMULATION OF MUSCARINIC RECEPTORS
Describe antichoinesterase 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
Describe the treatment of organophosphate poisoning?
Accidental exposure to organophosphates used in insecticides, or deliberate use as nerve agents can cause severe toxicity ( muscarinic activity; CNS excitation; depolarising NM block)
Treatment: atropine (iv); artificial respiration; pralidoxime (iv) (only compound which can reverse irreversible inhibitors within the first coupe of hours)
NB: Phosphorylated enzyme ‘ages’ within few hours
See diagram
