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
