Peripheral nerve transmission L3 Flashcards
why is developing specific Msubtype mAChR drugs important?
so there specificand have few sideeffects
describe PAMs vs NAMs for M type mAChRs
Positive allosteric modulators (PAMs) enhance orthosteric activity, while negative allosteric modulators (NAMs) inhibit it.
These allosteric modulators lead to the development of new therapeutic agents with increased efficacy and reduced side effects.
Agonists of mAChRs
give some exmaples:
- choline esters
- ACh
- Carbachol
- Bethanechol
- naturally occurring cholinomimetic alkaloids
- Pilocarpine
describe bethanechol
hybrid of methacholine and carbachol
lacks nicotinic actions but non-selectively activate mAChR subtypes.
It stimulates the detrusor muscle of the bladder (via M3 receptor), whereas the trigone and sphincter muscles are relaxed.
These effects produce urination and thus bethanechol can help in improving bladder function.
It is licensed for acute postoperative, postpartum and neurogenic urinary retention but its use has largely been superseded by catheterisation.
describe pilocarpine
is stable to hydrolysis by AChE.
mAChR agonist
what is pilocarpine used to treat?
- glaucoma - ontracts ciliary muscle ® improves drainage of aqueous humour ® reduce intraocular pressure
- increases salivation
- increases lacrimal secretions
mAChR antagonists or antimuscarinics - give some exmaples
contain ester and basic groups like ACh, but bulky aromatic group replacing the acetyl moiety
They include:
a) the naturally occurring alkaloids – atropine and scopolamine;
b) their semi-synthetic derivatives (e.g. homatropine, methscopolamine, ipratropium) and
c) synthetic agents (e.g. tropicamide, cyclopentolate, pirenzepine, darifenacin, solifenacin etc.
mAChR antagonists non selelctive?
most are non selective. but some are selective:
pirenzepine is M1 selective
darifenacin and solifenacin are M3 selective.
Venom of the African green mamba contains a toxin - MT7 that selectively targets M1.
describe benzilylcholine mustard
irreversible antagonist, not used clinically but in experiments
Eye (M3 stimulation -> ciliary muscle contracts; miosis)
why might mAChR antagonists be useful?
anti-muscarinics ® dilate the pupil (mydriasis) and paralyse the ciliary muscle (cycloplegia) ® help in eye inspection (fundoscopy) & in anterior uveitis
Short-acting, relatively weak mydriatics, such as tropicamide (action lasts for 4–6 hours) and cyclopentolate (action up to 24 hours), are typically preferred over atropine (action may last up to 7 days).
agents vary in potency and duration of action:
- tropicamide,
- cyclopentolate
- atropine
what are these 3 used to treat?
- tropicamide* = preferred, action lasts for 4-6 hrs
- cyclopentolate* = action lasts up to 24hrs
- atropine* action lasts up to a week
help dialte the pupil for fundoscopy (theyre mydriatics)
what si atropine used to treat>
Atropine in large doses is used as the standard treatment of poisoning by irreversible, long-acting inhibitors of AChE
M2 stimuation in the heart icnreases / decreases HR?
decrease
describe atropines effect on heart rate
- The main effect of antimuscarinic agents such as atropine on the heart is to alter the rate.
Although the dominant response is tachycardia, there is often a transient bradycardia with average clinical doses.
Larger doses of atropine cause progressive tachycardia by blocking M2 receptors on the SA nodal pacemaker cells, thereby antagonizing parasympathetic (vagal) tone to the heart.
The effect is more prominent in healthy young adults, in whom the vagal tone is considerable.
Atropine can be clinically useful to manage bradycardia associated with the excessive use of the ‘beta blockers’ (see later) and acute myocardial infarctions.
M3 and
GI tract (M3, M2 stimulation ® GI smooth muscle contractility)
howc an atropine be used to treamt GI diarrhoea
atropine -> inhibits GI motility at higher doses -> useful in diarrhoea
associated with irritation of the lower bowel, also as anti-spasmodic
hyoscine butylbromide - whats it used to tratm
anti-spasmodic (with no CNS side effects) - for GI motility issues
how can muscarinic receptor antagonists be used to treamt COPD?
Blocking the M3 receptors in bronchial smooth muscle tissue results in a decrease in smooth muscle tone causing bronchodilation. The effect is small in normal airways but significant in airways from COPD patients.
what si ipratropium used for?
short-acting muscarinic antagonists (SAMAs) such as ipratropium - used to treamt COPD by blocking M3 - causing relaxation
what are tiotropium and glycopyrronium used to treat>
long-acting muscarinic antagonists (LAMA) such as tiotropium and glycopyrronium block M3 mAChRs in airway to cause smooth muscle relaxation
These medications include short-acting muscarinic antagonists (SAMAs) such as ipratropium, and long-acting muscarinic antagonists (LAMA) such as tiotropium and glycopyrronium. All have higher selectivity for ………
These medications include short-acting muscarinic antagonists (SAMAs) such as ipratropium, and long-acting muscarinic antagonists (LAMA) such as tiotropium and glycopyrronium. All have higher selectivity for M3 receptors than for M2 receptors
mechanism of ACh hydrolysis details:
- carbonyl carbon (as in the acetyl group of ACh) is electrophilic
- the –OH of the Ser 203 can readily loose its H to the His 447, producing Ser-O- which is a nucleophile ® attacks the >C=O of the ACh, forming an intermediate complex
- the ACh bond is broken, releasing choline & leaving acetylSer-the enzyme
- serine-acetate bond is then spontaneously hydrolysed to release acetate and to regenerate the enzyme
which Covalent, reversible, medium acting anti-cholinesterases (carbamates) can cross the BBB
