Cholinergic system Flashcards
What are the two groups that drugs affecting the ANS are divided into?
- Cholinergic (act on ACh-activated receptors)
- Adrenergic (norephinephrine/epinephrine-stimulated receptors)
Where are ACh receptors found?
- Postganglionic sympathetic and parasympathetic neurons
- Effector cells
Use of ACh
- Released from pre-ganglionic neurons in both sympathetic and parasympathetic ganglia.
- Released from post-ganglionic neurons in parasympathetic system to stimulate effectors (eg. glands, smooth & cardiac muscles, fat & xliver cells)
- Released from somatic efferents at NMJ to stimulate skeletal muscle (end-plate potential + action potential)
Function of ACh
- Stimulates skeletal muscle
- Stimulates parasympathetic input at low concentrations
- Stimulates sympathetic input at high concentrations.
What are cholinomimetic drugs?
Substances that stimulate the PNS - also called cholinergic drugs
How can cholinergic drugs act?
- Directly by stimulating nicotinic/muscarinic receptors (mimicking ACh)
- Indirectly by inhibiting cholinesterase, promoting ACH release
2 types of cholinergic receptors
- Muscarinic receptors
- Nicotinic receptors
What type of receptors are muscarinic?
Slow-acting metabotropic receptors i.e. 2nd messenger GPCR
Where are muscarinic receptors located?
On effect tissue
Where do muscarinic receptors receive transmission signals from?
Postsynaptic parasympathetic nerve terminals
What effects are muscarinic receptors responsible for?
Parasympathetic-like effects in effector tissue such as heart, smooth muscles, brain and exocrine glands.
What are the 5 subtypes of mAChR?
- M1 (CNS & autonomic ganglia): excitatory signals in CNS & glandular tissues (eg. gastrc acid secretion)
- M2 (cardiac): ↑ parasympathetic effects of heart (eg. cardiac depression)
- M3 (glandular & smooth muscular): ↑ parasympathetic effects (eg. bronchoconstriction, GIT stimulation, eye accommodation & vasodilation)
- M4 (CNS): inhibitory effects in CNS
- M5 (CNS): excitatory effects in CNS
What do M1, M3 and M5 receptors act through to activate?
They act through GqPCR to activate IP3 pathway
What do M2 and M4 receptors act through and function?
They act through GiPCR, to inhibit adenylyl cyclase & ↑ K+ conductance
What type of receptors are nicotinic receptors?
Fast-acting ionotropic receptor channel i.e. ligand-gated
Where are nicotinic receptors found?
- CNS
- Sympathetic synapses with adrenal medulla
- Autonomic ganglia
- NMJ
What are the 2 subtypes of nAChR?
- Muscle subtype, Nm (found in skeletal muscle endplate region at NMJ)
- found in neuronal membranes at ANS post-synaptic ganglia and CNS
What happens where nicotinic receptors are located?
Depolarising waves trigger postsynaptic firing and skeletal muscle contraction respectively.
What are nicotinic receptors composed of?
Different subunits, with combinations varying depending on main 3 classes of nAChR: Muscular, Ganglionic and CNS types
What is the structure of ACh?
A choline ester with a positively charged quaternary ammonium group and a negatively charged ester group.
Which compounds partially mimic the structural characteristics of ACh? and what does this allow?
Nicotine and muscarine - allows them to bind to cholinergic receptors
What are the side effects of agonists due to overstimulation of cholinergic receptors?
DUMBELS
- Diarrhea
- Urination
- Miosis/muscle weakness
- Bronchorrhea
- Emesis
- Lacrimation
- Salivation/Sweating
What are muscarinic receptors affinities for cholinomimetic agents?
Muscarine > ACh > nicotine
(opposite for nicotinic receptors)
Direct-acting cholinomimetics characteristics?
- Mimic ACh binding
- Some have receptor specificity or decreased tendency to be metabolised by cholinesterases.
7 direct-acting cholinomimetics?
BBM CAMP
- Butyrylcholine
- Bethanecol
- Muscarine
- Carbachol
- ACh
- Methacholine
- Pilocarpine
About acetylcholine as a direct-acting cholinomimetic
- Equal affinity for muscarinic & nicotinic receptors
- Produces non-specific cholinergic effects, and rapidly broken down by AChE
About butyrylcholine as a direct-acting cholinomimetic.
Choline-based ester similar to ACh
About methacholine as a direct-acting cholinomimetic.
- More muscarinic than nicotinic
- Broken down by AChE
About carbachol as a direct-acting cholinomimetic.
More nicotinic than muscarinic
About muscarine as a direct-acting cholinomimetic. (3))
- Higher affinity for muscarinic receptors
- Parasympathetic effects: cardiac depression, bronchoconstriction, miosis, acid & salivary secretion, sphincter relaxation, vasodilation
- In muscarine poisoning, bradycardia with marked hypotension & vasodilation results in circulatory shock. It can be avoided completely by prompt diagnosis & treatment with atropine.
About bethanecol as a direct-acting cholinomimetic.
- Parasympathomimetic choline carbamate
- Stimulate muscarinic receptors only
About pilocarpine as a direct-acting cholinomimetic.
– Parasympathomimetic alkaloid
Stimulate M3 receptors
- Pilocarpine stimulates the secretion of large amounts of saliva and sweat. It is used to treat dry mouth (xerostomia).
- Treatment of chronic open-angle glaucoma & acute angle-closure glaucoma. It acts on M3 receptor found on the iris sphincter muscle, causing the muscle to contract, leading to miosis.
- Acts on the ciliary muscle and causes it to contract, opening the trabecular meshwork to facilitate rate that aqueous humor leaves the eye to decrease IOP.
- Diagnosis of CF by stimulating sweat glands in a sweat test to measure [Cl-] & [Na+] that is excreted in sweat
Where do indirect-acting reversible cholinomimetics bind?
Bind to enzyme transiently instead of ACh
Function of AChE
Cleaves ACh to acetate and choline to terminate its actions.
Where is AChE located?
Pre and postsynaptically in nerve terminal where it is membrane bound
What do inhibitors of AChE indirectly provide and how?
Cholinergic action by preventing degradation of ACh.
Where do inhibitors of AChE bind to? and what does this cause?
To anionic and esteric site of cholinesterase, which reversibly blocks its active site so it can no longer hydrolyse ACh before they reach the postsynaptic receptors.
What does accumulation of ACH in synaptic space provoke?
A responde at all cholinoreceptors in body (ANS receptors, NMJ and brain)
Give 3 indirect-acting cholinomimetics
- Physostigmine
- Neostigmine
- Donepezil
Write about physostigmine
Tertiary amine naturally found in plants. It forms carbamoylated intermediate with AchE.
Indirectly stimulates both NN & muscarinic receptors in ANS
Can also enter & stimulate cholinergic sites in CNS
Action lasts 30mins – 2hrs
Enhance smooth muscle contraction (eg. GI) & pupil diameter
Used in treatment of overdoses of drugs with anticholinergic actions eg. atropine as it can antagonize the central effects of atropine on muscarinic receptors.
Write about neostigmine
Indirectly stimulates both NM & muscarinic receptors
More polar, hence does not penetrate BBB, hence low propensity to cause CNS effects & does not absorb well from GIT
Stimulate bladder & GIT
Reverse anesthesia from neuromuscular blocking agents
Improve muscle tone in people with myasthenia gravis
Write about donepezil
The precise mechanism of action of donepezil in patients with Alzheimer’s disease is not fully understood. Certainly Alzheimer’s disease involves a substantial loss of the elements of the cholinergic system and it is generally accepted that the symptoms of Alzheimer’s disease are related to this cholinergic deficit, particularly in the cerebral cortex and other areas of the brain. It is noted that the hippocampal formation plays an important role in the processes of control of attention, memory and learning. Just the severity of the loss of cholinergic neurons of the central nervous system (CNS) has been found to correlate with the severity of cognitive impairment.
How do indirect-acting irreversible cholinomimetics bind?
Bind to the enzyme covalently; long lasting
Example of indirect-acting irreversible cholinomimetics
Poisonous organophosphates – dyflos, sarin gas
Write about poisonous organophosphates – dyflos, sarin gas
Effects: bind to similar sites to ach but phosphyrylate esteric site and it’s “irreversible. Act soon enough can give a drug that will reactivate enzyme.
Oxime reactivators, Pralidoxime (2-PAM), is typically used in organophosphate poisoning to remove anticholinesterases from the enzyme, by binding to it and decreasing its affinity for the cholinesterase.
Pralidoxime is often used with atropine (a muscarinic antagonist) to help reduce the parasympathetic effects of organophosphate poisoning. Pralidoxime is only effective in organophosphate toxicity (i.e. it does not have an effect if the acetylcholinesterase enzyme is carbamylated, as occurs with neostigmine or physostigmine). Pralidoxime has an important role in reversing paralysis of the respiratory muscles but due to its poor BBB penetration, it has little effect on centrally-mediated respiratory depression. This is why atropine, which has excellent BBB penetration, is concomitantly administered with Pralidoxime during the treatment of organophosphate poisoning.
Cholinergic antagonists subtypes
- Anti-muscarinic agents
- Ganglionic blockers
- Neuromuscular blockers
4 Anti-muscarinic agents
- Atropine (atropa belladonna)
- Pirenzepine
- Methoctramine
- Solifenacin
What is atropine?
A tertiary amine belladonna alkaloid that binds competitively with cholinergic receptors, preventing ACh from binding to those sites.
What is a common phenomenon of atropine?
Low doses will cause a paradocical slowing of the heart, but the predominant effect will be to speed up the heart.
What is atropine still available to treat, but why is it not preferable?
To treat GIT but not as effective due to better proton-pump inhibitors available.
Affinity of atropine
High affinity for muscarinic receptors
Mneumonic for anticholinergic toxidrome
Hot as a hare, blind as a bat, dry as a bone, red as a beet & mad as a hatter
Atropine effects on PNS parasympathetic
Tachycardia, bronchodilation, constipation, inhibit acid & saliva secretions
What is the predominant effect of atropine at low doses? and why?
Slight ↓HR due to blockade of M1 receptors on inhibitory presynaptic neurons, permitting ↑ACh release.
What is the effect of atropine at high doses? and why?
Progressive ↑HR by blocking M2 receptors on SA node.
What is atropine used to treat?
- Organophosphate poisoning
- Bradycardia (neostigmine)
- Bladder incontinence
- Produce mydriasis and cycloplegia prior to refraction
- Suppress respiratory secretions prior to surgery
What is atropine commonly used in combination with and why?
in combination with β2-agonists & inhaled corticosteroids for asthmatic patients
Pirenzepine info (2)
- M1 selective antagonist
- Does not cross BBB
When is pirenzepine prescribed and why?
- In treatment of peptic ulcers
- It reduces gastric acid secretion and reduces muscle spasm
Where does methoctramine bind?
To pre-synaptic M2 receptors
Name an anti-muscarinic agent that isn’t used clinically
Methoctramine
Where does solifenacin bind?
To M3 receptors
What is solifenacin used in the treatment of?
Overactive urinary bladder
Where do ganglionic blockers specifically act? and effect
On nicotinic receptors of both sympathetic and parasympathetic autonomic ganglia and block the entire output of the ANS at the nicotinic receptor.
What is nicotine?
It is a component of cigarette smoke without therapeutic benefit & delirious to health.
What does nicotine lead to?
- Postsynaptic neurons depolarisation and firing
- Adrenal medulla activatino
What is the initial stimulatory response of nicotine?
↑BP & HR, ↑ peristalsis & secretions
What do high doses of nicotine result in?
↓BP, ↓ activity in both GIT & ceasing of bladder musculature
What is the general effect of nicotine?
First causes stimulation due to release of transmitter from adrenergic terminal and adrenal medulla, followed by paralysis of all ganglia due to ganglionic blockade.
Tubocurarine and hexametonium ‘effect’
non depolarising effect
Where does hexamethonium act?
On pre-ganglionic sites in both sympathetic and parasympathetic NS
Effect of atropine on arterioles and system
Sympathetic - vasodilation and dilation
Parasympathetic - tachycardia
Effect of atropine on muscle and system
Parasympathetic - mydriasis and cycloplegia
Effect of atropine on GIT and system
Parasympathetic - relaxation (constipation)
Effect of atropine on urinary bladder and system
Parasympathetic - urinary retention
Effect of atropine on salivary glands and system
Parasympathetic - dry mouth
Effect of atropine on sweat glands and system
Sympathetic - anhidrosis
What was hexamethonium formally used to treat and why is it not anymore?
- Previously used to treat hypertension
- Discontinued due to non-specificity and combined sympatholytic and parasympatholytic effects
Trimetaphan effect
- Non-depolarising
- Short action, for controlled hypotension during surgery
What is mecamylamine
Non-selective, non-competitive antagonist of nAChR
What is Mecamylamine used as and why
Used as a research tool for addiction and neuropsychiatric disorders as it easily crosses BBB
What is varenicline used for?
Smoking cessation
What type of agonist is varenicline?
Partial agonist
Function of neuromuscular blockers
Block cholinergic transmission between motor nerve endings and the nicotinic receptors on the skeletal muscle.
Where do neuromuscular blockers act?
On receptors at the endplate of NMJ
Why are neuromuscular blockers important clinically?
- During surgery to facilitate tracheal intubation and provide complete muscle relaxation at lower anaesthetic doses -> more rapid recovery from anaesthesia
- Reduces postoperative respiratory depression
How do neuromuscular blockers act at low doses?
As competitive antagonist (can be overcome by anticholinesterases)
How do neuromuscular blockers act at high doses?
As channel blocker at motor endplate (ability of anticholinesterases reduced)
