Cholinergics I Flashcards by Uche PM

What is the major difference between the muscarinic and nicotinic cholinoreceptors?

The muscarinics are GPCRs while the nicotinics are ion channels

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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

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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

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What is the mechanism of action of the nicotinic cholinoreceptors?

Cause depolarization by activating sodium and potassium channels

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The nicotinic receptor is activated by _ molecules of Ach. It causes _

2 molecules

Sodium channel opening, excitatory post-synap. potential

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In addition to the sympathetic and parasymp ganglia, the adrenal medulla contains what subtype of nicotinic receptor?

The N1/Nn subtype

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What is the effect of cholinergics on the parasympathetic NS?

Activation, cholinergics are parasympathomimetics

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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

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Muscarine and pilocarpine are _

Cholinergics that are selective for the muscarinic type AchR

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Nicotine and varenicline are _

Cholinergics that are selective for the nicotinic type AchR

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Muscarine, pilocarpine, varenicline and nicotine all fall under the class of _

Natural alkaloids

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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

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What is the effect of muscarinic receptor activation of the lung?

Broncho-constriction

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The major factor determining the synthesis of Ach is _. What type of co-transporter is this?

Choline uptake

Sodium - choline

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What is the enzyme that catalyzes the synthesis of Ach?

Choline acetyl-transferase

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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

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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

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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

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The 2 major enzymes that hydrolyze Ach are _

Acetylcholinesterase and plasma cholinesterase (aka pseudocholinesterase and butyrylcholinesterase)

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What are the major locations of acetylcholinesterase (3)?

Cholinergic synapses
Neuromuscular junctions
RBCs

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What are the major locations of plasma cholinesterase (2)? What are 2 major functions?

Plasma and Liver

Hydrolyze escaped ACh
Hydrolyze ingested plant esters

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Succinylcholine, a neuromuscular blocker is inactivated by _

Plasmacholinesterase

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Organophosphate insecticides are more likely to react with _ while organophosphate nerve gases are more likely to react with _

Plasma cholinesterase

AchE

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What is the net effect of AchE inhibitors?

They (indirectly) stimulate the parasymp NS, same as the cholinergic drugs

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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