Muscarinic cholinergics Flashcards
What are the cholinergic drugs of clinical use which are primarily muscarinic agonists?
- Pilocarpine
- Methacholine
- Bethanecol
What are the cholinergic drugs of clinical use which are both nicotinic and muscarinic agonists?
Carbachol, acetylcholine
What cholinergic drugs bind only the nicotinic receptors?
Nicotine - all nicotinic
Varenicline - partial nicotinic
What does black widow spider venom do?
Promotes sustained continuous release of ACh - causing muscle twitching locally, or systemic cholinergic signs (sweating, bradycardia, etc)
What are indirectly-acting cholinomimetics?
Anticholinesterase -> augment cholinergic activity
What are the reversible anticholinesterases which act by slow removal from the enzyme?
Physostigmine, neostigmine, rivastigmine, pyridostigmine
What are the reversible competitive inhibitor anticholinesterases?
Edrophonium, tacrine, donepezil, galantamine
What are the irreversible anticholinesterases (require enzymatic turnover)?
Echothiophate
Sarin - nerve gas
Malathion, parathion - organophosphate insecticides
What are the reversible anti-muscarinic compounds (competitive antagonists)?
Atropine, tropicamide, ipratropium, tiotropium, scopolamine, tolterodine (urinary urgency), oxybutynin, benztropine, propantheline (GI hypermotility)
What are the reversible anti-nicotinic competitive antagonists?
d-tubocurarine, cisatracurium, pancuronium, vecuronium, rocuronium, mecamylamine (ganglion blocker not used)
How do hemicholinium and vesamicol work?
Hemicholinium - blocks choline reuptake into the presynaptic terminal
Vesamicol - blocks vesicle packaging of ACh
What are the initial features of botox poisoning?
Diplopia and blurred vision are initial symptoms, followed by skeletal muscle paralysis
What are two competitive inhibitors of calcium influx into the presynaptic terminal which can block ACh release?
- Aminoglycosides - inhibit calcium movement
2. Mg+2 - competitive interference (may be due to magnesium sulfate treatment for seizures in eclampsia)
What is depolarizing blockage and what agent is known for causing this?
Excessive cholinergic agonist NMJ causes a constant depolarization of motor end plate so contraction cannot occur -> paralysis
Succinylcholine is known for causing this
What type of amines are most muscarinic agonists and why?
Most are quaternary amines -> so they do not cross the blood brain barrier.
CNS symptoms can occur during muscarine poisoning
What are the two main muscarinic antagonists which are tertiary amines? How do they function?
Atropine and scopolamine
-> competitive inhibitors of muscarinic ACh receptor
What is the toxicity of atropine?
“Red as a beet, dry as a bone, blind as a bat, mad as a hatter”
Red as a beet -> cutaneous vasodilation
Dry as a bone -> loss of secretions, i.e. salivary and sweating
Blind as a bat -> cycloplegia (loss of accommodation) and loss of pupillary constriction (produces mydriasis)
Mad as a hatter -> delirium, CNS depression
Between Scopolamine and Atropine, which is more likely to produce CNS effects?
Scopolamine - much more active effect in reticular activating system. Will produce amnesia and delirium even at therapeutic levels
What are the clinic uses of atropine? When is it contraindicated?
- Treatment of organophosphate poisoning
- Long-term dilation of eye
- Infant colic -> causes constipation
Contraindicated in patients with glaucoma due to increased ICP
What is Scopolamine primarily used for? Contraindication?
Anti-motion sickness drug - applied as a patch behind ear for its CNS effects - M1 receptors
Think of the otter holding a scope in sketchy!
Contraindication: Glaucoma
What is the MoA of benztropine? What it is used for?
Parkinsonian tremor and rigidity, and management of parkinsonian symptoms produced by antipsychotics
Muscarinic antagonist (of central M1 receptors), reduces ACh levels in basal ganglia down to comparable of dopamine levels
What is “anti-cholinergic burden”
The cumulative effects of anti-histamines, anti-depressants, and anti-psychotics which also have muscarinic antagonist activity and reduce cognitive function in elderly patients in particular.
These are associated with dementia
What are the primary actions of muscarinic antagonists in the eye?
Primary actions: Pupillary sphincter relaxation (mydriasis), ciliary muscle relation (cycloplegia)
What is the MoA of Pilocarpine, amine type, and what is it used for?
Tertiary amine which is a muscarinic AGONIST
Used for causing miosis of the eye -> allows easier drainage of Canal of Schlemm to reduce IOP
1st line: emergency therapy of acute glaucoma
2nd line: chronic glaucoma (beta blocker better)
Also: used to treat dry mouth in cancer patients or those with Sjogren’s syndrome (increases salivation and sweating)
Think of Pile of Carpine
What is the MoA of Carbachol, amine type, and what is it used for?
Quaternary amine which is a muscarinic agonist AND nicotinic agonist
- > it is basically acetylcholine
- > only used as a miotic during cataract surgery
What is a shorter-acting muscarinic antagonist used for corrective lens exams?
Tropicamide
What are the three actions of muscarinic agonists on the heart?
- Slows heart rate - negative chronotropic (hyperpolarization via K+)
- Decreases force of contraction - negative inotropic (Reduction of AP duration and less Ca+2)
- Suppresses AV conduction speed - negative dromotropic
Where are M3 receptors present in the cardiovascular system and how do they function?
They are on most vascular beds, and will work through Gq mechanism to cause release of intracellular calcium, triggering release of endothelial-derived relaxing factor (NO), which relaxes the vascular bed
How do low vs high levels of muscarinic agonists affect the heart rate and why?
Low levels - reflex tachycardia due to drop in blood pressure from stimulation of M3 receptors on vascular system
High levels - directly stimulate cardiac M2 receptors to cause a cardiac depression
When are systemic muscarinic agonists contraindicated?
In patients with cardiovascular problems due to their propensity to cause vasodilation and reflex tachycardia
How can acetylcholine be used diagnostically?
Can be injected into coronary arteriesin patients with vasospastic angina pectoris -> will cause spasm only in diseased vessels
What do low and high levels of atropine do to the heart?
- Low levels - bradycardia due to binding of presynaptic M2 receptors
- High levels - tachycardia and increased AV conduction due to blocking of M2 receptors (used in life threatening situations of heart block, like isoproterenol)
Why does atropine cause cutaneous vasodilation?
Due to hyperthermic effect of not being able to sweat -> more of a problem in children
How does muscarinic agonist activity differ between the GI motility and the sphincters? What is the exception?
GI tract -> hypermotility due to depolarization of membrane and increased AP firing (M3 -> Gq mechanism)
Sphincters -> stimulate the enteric nervous system to release dilatory peptides.
However, the lower esophageal sphincter will contract in response to cholinergic agonsts.
How do muscarinic agonists increase secretory activity in the GI tract?
Increase secretion of digestive enzymes from pancreas, and release of HCl and pepsinogen from stomach wall
When is bethanechol used and when is it contraindicated? Is it tertiary or quaternary?
It is quaternary but is acting in GI tract and thus can be administered orally
Muscarinic agonist used to treat stasis conditions of GI tract and urinary bladder, especially post-surgery or childbirth. GET MOVING “BETH”!
Contraindicated in mechanical obstruction
Why is atropine not used to treat peptic ulcer anymore?
- Delays emptying of stomach
2. Only blocks ACh secretion component of HCl, not histamine and gastrin
When is propantheline used? Is it tertiary or quaternary?
Quaternary amine. Muscarinic antagonist, kind of the opposite of bethanechol -> Spasmolytic agent
Used in treating spasms (hypermotility) of GI tract, biliary tract, and urinary bladder
How does acetylcholine effect urination?
Higher ACh levels -> detrussor muscle is more depolarizable, will want to empty bladder at lower volumes.
Muscarinic antagonists are used in the treatment of urinary urgency, and can cause a side effect of urinary bladder retention
What is the structure of oxybutynin, how is it metabolized, and what is it used for?
Tertiary amine, CYP3A4 metabolized
Used for: post-operative bladder spasm (muscarinic antagonist)
Think of ox butler slowly pouring water from bladder
What is the structure of tolterodine, and what is it used for?
Tertiary amine. It’s basically the same as oxybutynin.
Muscarinic antagonist, used for the treatment of urinary urgency.
Think of the turtle receiving the drink from the ox butler
What is methacholine used for?
Diagnosis of bronchial airway hyper-reactivity, it is a muscarinic agonist which is a quaternary amine applied to lungs.
Asthma = acute respiratory distress upon application
What two agents are used to treat COPD, and how do the differ? Are they tertiary or quaternary?
Quaternary amines which are inhaled, they are muscarinic antagonists
Ipratropium and tiotropium
Tiotropium has a longer half-life, and less M2-antagonist activity (good because it allows ACh to bind presynaptic receptor, limiting release)
Other than pilocarpine, what other drug is used for xerostomia (dry mouth)?
Cevimeline -> another muscarinic agonist
What is the DUMBELS pneumonic for acetylcholineesterase inhibitory toxicity?
Diarrhea Urination Miosis Bronchospasm / Bradycardia Lacrimation Salivation
