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It is licensed for acute postoperative, postpartum and neurogenic urinary retention but its use has largely been superseded by catheterisation.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
the long duration of LAMAs stems from their ,……
the long duration of LAMAs stems from their slow dissociation from the M3 receptors whilst they dissociate from M2 receptors much faster
what mAChRs are used to treat urinary incontinence
M3 selective antagonists such as solifenacin and darifenacin can be used in the treatment of urinary incontinence through their selective inhibition of M3 receptors that mediate contraction of the detrusor muscle in the urinary bladder.
what is often a problem associated with the use of mAChR antagonists?
salivary secretion is particularly sensitive to inhibition by muscarinic
antagonists ® dry mouth is often a common problem with use of such agents
what is glycopyrronium used for>
glycopyrronium ® to reduce excessive salivation (drooling) associated with use of some drugs, heavy metal poisoning or Parkinson’s disease. Can also be used to manage hyperhidrosis (= excessive sweating).
some antimuscarinic agents ®are used as pre-anaesthetic medication —– but why?
some antimuscarinic agents ® as pre-anaesthetic medication to reduce salivary and bronchial secretions during ether or ketamine-induced anaesthesia
summarise uses of mAChR agonsits?
- to reduce intraocular pressure (in some glaucoma)
- to promote salivary and lacrimal secretion (in xerostomia, Sjögren’s syndrome).
Notable agent: pilocarpine
sumarise the uses of mAChR antagonists:
- to reduce vagal tone and bronchoconstriction (specially in COPD). Notable agents: ipratropium and triotropium.
- to promote mydriasis and clycloplegia (for eye inspection). Notable agent: tropicamide
- to reduce detrusor contractility in overactive bladder. Notable agent: solifenacin
- to promote heart rate (in bradycardia due to b blocker overuse, acute myocardial infarction). Notable agent: atropine
- to counteract poisoning associated with long-lasting, irreversible inhibition of AChE. Notable agent: atropine
- to control muscarinic side effects of an antiChE (e.g. neostigmine) in reversal of non-depolarising neuromuscular block. Notable agent: atropine, glycopyrronium
There are two types of cholinesterase;
There are two types of cholinesterase; acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).
both AChE and BuChE are ….
both are serine hydrolases:
a nucleophilic Serine within the active centre plays the key role for ACh hydrolysis
describe How AChE hydrolyses ACh
- ACh recognised by PAS
- ACh pushed down gorge
- ‘catalytic anionic site’ (CAS) traps the ACh and places it against the catalytic triad (Glu334-His447-Ser203) for
the actual hydrolysis to take place
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
give a short acting reversible AChE inhibitor
edrophonium
give a medium acting reversible AChE ingibitor
Stigmines
physostigmine, neostigmine etc
give some long acting irreversible AChE inhibitors
- Irreversible
- (organophosphates such as dyflos, parathion, ecothiophate, nerve gases etc.)
is edrophorium covalent or non covalent?
non-covalent
describe edrophonium
- too short-acting to be therapeutically useful
- charged, so can’t cross the membranes ® don’t reach CNS
mainly used in diagnosis of myasthenia gravis (MG)
describe the covalent reversible, medium-acting AChE inhibitors
These are esters of carbamic acid (instead of acetic acid as with ACh) and have the suffix ‘stigmine’ and include physostigmine, neostigmine, pyridostigmine and rivastigmine
interact with the anionic site of AChE and transfer carbamyl group to the hydroxy group of Ser 203. Carbamylated AChE is more stable than acetylated AChE and takes minutes to hydrolyze.
which Covalent, reversible, medium acting anti-cholinesterases (carbamates) can cross the BBB
use of Neostigmine
Neostigmine is used intravenously to reverse neuromuscular blockade after surgery and orally to treat myasthenia gravis.
use for Pyridostigmine
Pyridostigmine is also an oral treatment for myasthenia gravis with a longer action than neostigmine.
T or F
Some anticholinesterases (e.g. rivastigmine, donepizil) that can cross the BBB have been FDA approved for Alzheimer’s patients
T
Some anticholinesterases (e.g. rivastigmine, donepizil) that can cross the BBB have been FDA approved for Alzheimer’s patients
describe aging relating to AChE inhibitors
as ‘aging’, in which oxygen–phosphorus bonds within the inhibitor undergo spontaneous rearrangement in favour of stronger bonding between the enzyme and the inhibitor. Once aging occurs, the duration of AChE inhibition is increased even further
Ecothiophate used to be locally used in….
Ecothiophate used to be locally used in glaucoma.
Acute poisoning by irreversible anti-AChEs results in…..
Acute poisoning by irreversible anti-AChEs results in excessive salivation, severe bradycardia, hypotension and difficulty in breathing.
Combined with a depolarising neuromuscular block and central effects, the outcome can be fatal
treatment for Acute poisoning by irreversible anti-AChEs
Standard treatment involves the use of atropine in large doses which can reach the brain in sufficient concentrations to suppress the central and peripheral cholinergic symptoms associated with the poisoning.
Atropine is virtually without effect against the peripheral neuromuscular compromise, which can be reversed by pralidoxime (2-PAM), a AChE reactivator
what is by pralidoxime (2-PAM),
by pralidoxime (2-PAM), a AChE reactivator. The cationic group of pralidoxime interacts with the anionic site of AChE, which brings the oxime group into close proximity with the phosphorylated serine. The oxime group is a very strong nucleophile and lures the phosphate group away from the Ser hydroxyl of the enzyme. The effectiveness of AChE reactivation is however limited to within a few hours of exposure as the phosphorylated AChE undergoes the ‘aging’ that renders the phosphorylated group no longer being susceptible to nucleophilic attack.
one problem with 2-PAM
2-PAM doesn’t cross the BBB ® not useful in treating the CNS
effects associated with organophosphate poisoning
- 2-PAM can be used as an adjunct to atropine in the treatment of poisoning by organophosphorus insecticide or nerve agent
current clinical uses of AChE inhibitors
• to treat myasthenia gravis (_______ or ________)
current clinical uses of AChE inhibitors
• to treat myasthenia gravis (neostigmine or pyridostigmine)
current clinical uses of AChE inhibitors
• to reverse the action of non-depolarising NMJ blockers after surgery (_________). A muscarinic antagonist is usually given to limit cholinergic effects.
• to reverse the action of non-depolarising NMJ blockers after surgery (neostigmine). A muscarinic antagonist is usually given to limit cholinergic effects.
how are AChE inhibitos used int hte diagnosis of Myasthenia gravis
edrophonium
injected
decrease in facial paralysis within 10 mins
fat
mamba
