Cholinergics I Flashcards
What is the major difference between the muscarinic and nicotinic cholinoreceptors?
The muscarinics are GPCRs while the nicotinics are ion channels
There are 3 types of muscarinic receptors, M1, M2 and M3. Where are they found?
M1 - Postganglionic neurons
M2- Cardiac, smooth muscle
M3 - Glands, smooth muscles, endothelium
There are 2 types of nicotinic cholinoreceptors (N1/N2) Where are they found?
N1 / Nn - Postganglionic autonomic (symp and parasymp) neurons
N2/ Nm - Skeletal muscle neuromuscular junction
What is the mechanism of action of the nicotinic cholinoreceptors?
Cause depolarization by activating sodium and potassium channels
The nicotinic receptor is activated by _ molecules of Ach. It causes _
2 molecules
Sodium channel opening, excitatory post-synap. potential
In addition to the sympathetic and parasymp ganglia, the adrenal medulla contains what subtype of nicotinic receptor?
The N1/Nn subtype
What is the effect of cholinergics on the parasympathetic NS?
Activation, cholinergics are parasympathomimetics
Acetylcholine, bethanechol, carbachol and methacholine are all AchR agonist. How are the latter 3 related to Ach?
The latter 3 are synthetic Ach derivatives that are more selective and have longer duration of action
Muscarine and pilocarpine are _
Cholinergics that are selective for the muscarinic type AchR
Nicotine and varenicline are _
Cholinergics that are selective for the nicotinic type AchR
Muscarine, pilocarpine, varenicline and nicotine all fall under the class of _
Natural alkaloids
When AchR agonists mimic the parasymp NS, this is accomplished by activating what type of receptor? Where are these receptors located (3)
The muscarinic receptors
Smooth muscle, glands, heart
What is the effect of muscarinic receptor activation of the lung?
Broncho-constriction
The major factor determining the synthesis of Ach is _. What type of co-transporter is this?
Choline uptake
Sodium - choline
What is the enzyme that catalyzes the synthesis of Ach?
Choline acetyl-transferase
Methacholine is an Ach derivative that has a methyl group. What is the significance of this group?
It has greater selectivity for muscarinic type receptors
Carbachol is an Ach derivative that has an amino (NH2) group. What is the significance of this group?
It has a longer duration of action as it binds poorly to AchE and pseudoAchE
Bethanechol is an Ach derivative that has a methyl group and an amino group. What is the significance of these groups?
It is long lasting and it is selective for the muscarinic type receptor
The 2 major enzymes that hydrolyze Ach are _
Acetylcholinesterase and plasma cholinesterase (aka pseudocholinesterase and butyrylcholinesterase)
What are the major locations of acetylcholinesterase (3)?
Cholinergic synapses
Neuromuscular junctions
RBCs
What are the major locations of plasma cholinesterase (2)? What are 2 major functions?
Plasma and Liver
- Hydrolyze escaped ACh
- Hydrolyze ingested plant esters
Succinylcholine, a neuromuscular blocker is inactivated by _
Plasmacholinesterase
Organophosphate insecticides are more likely to react with _ while organophosphate nerve gases are more likely to react with _
Plasma cholinesterase
AchE
What is the net effect of AchE inhibitors?
They (indirectly) stimulate the parasymp NS, same as the cholinergic drugs
The 4 examples of AchE inhibitors provided are _
– edrophonium
– neostigmine
– pyridostigmine
– physostigmine
Edrophonium, neostigmine, pyridostigmine and physostigmine are all [long/short] acting. Their main function is as _
Short acting, reversible
competitive inhibitors of AchE
Organophosphate derivative, nerve gases and insecticides are all examples of _
Non-competitive inhibitors of AchE
Edrophonium and ambemonium are both _
Reversible short acting inhibitors of AchE
Neostigmine, physostigmine and pyridostigmine are all _
Reversible short acting inhibitors of AchE
Sarin, soman and VX are all examples of _. They function as _
Nerve gases
Irreversible inhibitors of AchE
Carbaryl and tetraethylpyrophosphate are both examples of _. They function as _
Insecticides
Irreversible inhibitors of AchE
Malathion and parathion are both examples of _. They function as _
Insecticides
Irreversible inhibitors of AchE
Di-isopropylfluorophosphate (DFP) and echothiophosphate are both examples of _. They function as _
Organophosphate derivatives
Irreversible inhibitors of AchE
AchE inhibitors fall into 3 groups (alcohols, carbamates and organophosphates). Edrophonium is a _. It crosses the BBB [true/false]. Why?
Simple alcohol
False
It has a quaternary ammonium group (charged)
AchE inhibitors fall into 3 groups (alcohols, carbamates and organophosphates). Neostigmine, physostigmine, carbaryl and pyridostigmine are all _. Which crosses the BBB?
Carbamates
Physostigmine
AchE inhibitors fall into 3 groups (alcohols, carbamates and organophosphates). Di-isopropylfluorophosphate (DFP) and echothiophosphate are both _
Organophosphates
Ach is hydrolyzed by AchE in _ steps. The intermediates of this reaction are _ (2). The final product is AchE and _
Two
Choline (free) and Acetylated AchE
Acetate and AchE
The AchE intermediate from the hydrolysis of neostigmine is _. How long does this take compared to Ach hydrolysis?
Carbamylated AchE (more resistant to hydration) 0.5 - 2 hrs Much longer than Ach (100 microseconds)
Di-isopropylfluorophosphate (DFP) can interact with AchE to form _. This is “rescue-able” until the formation of _
Phosphoryl AchE
Aged AchE
Edrophonium, neostigmine, pyridostigmine and ambemonium can all be used for the treatment of which disease? They are all intermediate in duration except for _ which is very short acting?
Myesthenia gravis
Edrophonium
Edrophonium and neostigmine are both used for the treatment of _. Which is longer in duration?
Ileus
Neostigmine
In addition to myesthenia gravis and ileus, what type of heart condition can edrophonium be used for?
Arrythmias
Physostigmine, demecarium and echothiophate can all be used for the treatment of what eye disease? Which of this is of long duration?
Glaucoma
Echothiophosphate
Organophosphates like herbicides and insecticides are lipid soluble drugs that act as _. What are the major routes involved in O-P poisoning?
AchE inhibitors
Dermal and Pulmonary
The clinical marker for degree of organophosphate intoxication is _. What is the acronym?
Parasymp. stimulation
SLUD
If organophosphate intoxication first results in occular and respiratory symptoms, what is the most likely route of intoxication?
Respiratory
If organophosphate intoxication first results in GI symptoms, what is the most likely route of intoxication?
Oral
The 2 drugs used for the treatment of organophosphate poisoning are _
Atropine and Pralidoxime (2-PAM)
What are the effects of atropine? Why is it administered in large doses at first?
Atropine competitively binds muscarinic receptors (blocks parasymp symptoms)
High doses help cross BBB
What are the effect of pralidoxime (2-PAM)? What is the temporal consideration for its administration? Where is it most effective?
It is an AchE reactivator (removes phosphoryl group)
It has to be administered before aging
Neuromuscular synapses
Acute closed angle glaucoma (vs. chronic) is a medical emergency. What two drugs are usually administered to treat this? What are their mechanism of action?
Pilocarpine (muscarinic agonist)
Physostigmine (AchE inhibitor)
Cause ciliary body ctx, opens canal of schlemm
Postoperative ileus, congenital megacolon, urinary retention and reflux esophagitis are treated using _ (2)
Bethanechol and neostigmine
Salivary secretions can be increased using _, while dry mouth assoc. with Sjogren syndrome can be treated using _
Pilocarpine
Cevimeline
For the treatment of myesthenia gravis, what 4 AchE inhibitors are usually employed?
MG - NAPE Neostigmine Ambemonium Pyridostigmine Edrophonium
Why are cholinergic agonists not administered IV or IM?
Increased toxicity, loss of selectivity
Cholinergic agonists used for the treatment of occular conditions are usually [secondary, tertiary or quaternary] compounds
Tertiary
Four conditions contraindicated for the use of cholinergic agonists are _
Asthma
Coronary insufficiency
Hyperthyroidism
Peptic acid disease
Flushing, sweating, cramping, belching, urinary bladder tightness, reduced visual accomodation, headache and salivation are all _
Side effects of cholinergic agonists
Atropine and homatropine are selective for _
muscarinic selective antagonists
Scopolamine and methscopolamine are selective for _. Which is a quaternary amine?
muscarinic selective antagonists
Methscopolamine
Trihexyphenidyl, Cyclopentolate and tropicamide are selective for _
muscarinic selective antagonists
Ipratropium and tiotropium are selective for _
muscarinic selective antagonists
Darifenacin, solifenacin and tolterodine are examples of _
M3 selective cholinergic antagonists
Mecamylamine and trimethaphan are examples of _
Nicotinic selective cholinergic antagonists
The example of depolarizing cholinergic nicotine selective drug provided is _ This is metabolized by _
Succinylcholine
Pseudocholinesterase
Curare is an example of _. It causes _
non-depolarizing nicotine specific cholinergic antagonist
Paralysis
Atracurium, cisatracurium and mivacurium are all examples of _
non-depolarizing nicotine specific cholinergic antagonist
Pancuronium and vecuronium are examples of _
non-depolarizing nicotine specific cholinergic antagonist
What are the direct and indirect means by which muscarinic receptors mimic parasymp NS?
Direct - AchR agonist
Indirect - AchE antagonists
Quaternary alcohol, carbamates and organophosphate derivative are [competitive/noncompetitive] cholinesterase inhibitors
Alcohols and carbamates - competitive
OP - non-competitive
Among organophosphates, the only one with clinical use us _. It is used for treatment of _
Malathion
Head lice
To stimulate smooth muscle post-op (increase GI motil, increase bladder emptying, increase saliva) you would use _. It acts as a _
Bethanechol
Muscarinic agonist
To test the function of muscarinicreceptors, slow the heart and test for bronchial hyperactivity, you would use _
Methacholine
Corneal application of _ and _ are used in acute wide angle glaucoma
Pilocarpine and carbachol
To increase GI motility and bladder emptying following surgery, and to reverse neuromuscular blockade (curare), you’d use _
Neostigmine
To treat mysethenia gravis, block effect of nerve gases, reverse neuromuscular blocade you’d use _
Pyridostigmine
The N1 or Nn subtype of nicotinic receptor is usually found in synapses between _
Nerve and Nerve - Think peipheral ganglia of autonomics
The N2 or Nm subtype of nicotinic receptor is usually found in synapses between _
Nerve and muscle - Think neuromuscular junction of somatic NS
What are the 2 broad categories of cholinergic drugs that mimic the parasympathetics via muscarinic receptors?
ACh and synthetic choline esters (analogues of ACh) Natural Alkaloids (more selective for muscarinic receptors)
What are the 4 muscarinic receptor agonists that directly stimulate the parasympathetic NS? Which 2 are muscarinic selective?
Acetylcholine
Methacholine (Selective)
Carbachol
Bethanechol (Selective)
What are the 2 AChE inhibitors that are also quaternary ammoniums?
Edrophonium
Neostigmine
Atropine is a great first drug for the treatment of _. What will it not affect / rescue? Why?
organophosphate intoxication
Neuromuscular synapse hyperactivity and resulting paralysis
It is a muscarinic (not nicotinic) blocker
In situations of cholinergic agonist overdose, what 2 drugs can be used?
Atropine
Norepinephrine
Effector sites of the muscarinic receptor antagonists include (4) _
Smooth muscle
Cardiac muscle
Glands
CNS
Under what conditions will muscarinic antagonists cause partial blockade at the autonomic ganglia or neuromuscular junctions?
Extremely high doses
When Mydriasis and cycloplegia are both required for an eye exam, what 5 antimuscarinic drugs can be used? (in order of desending duration of action)
ASHCT Atropine Scopolamine Homatropine Cyclopenolate Tropicamide
In cases of myocardial infarct, what is the use of muscarinic antagonists? Which one specifically?
MI causes reflex slowing of the heart because of vagal inputs
Atropine can block this slowing. Only used in ICU
What are the 2 effects of the antimuscarinic drugs on the airway? Which is not beneficial? Why?
Bronchodilation and decreased secretions
Decreased secretion - increased microbe stasis and growth
What 2 antimuscarinic drugs are essentially topical agents that can be used to elicit bronchodilation without decreased secretion? Why? What disease can they be used for?
Ipratropium and Tiotropium
Quaternary amine, don’t cross the mucus membranes to get systemic to cause decreased secretion
COPD
