Cholinergics

Question 1

Where are Cholinergic receptors found?

Answer 1

• Nicotinic (N1/Nm) found on Skeletal Muscle
• Nicotinic (N2/Nn) found on post-ganglionic neurons of the ANS (both sympathetic and parasympathetic)
• Muscarinic (M1-M3) found on parasympathetic end organs

Question 2

Are Nicotinic receptors G-coupled protein receptors or Ligand-gated receptors? Describe the appropriate receptor type.

Answer 2

Nicotinic Ligand-gated receptors: Bind 2 ACh molecules causing Na+ channel to open and causing Excitatory Postsynaptic Potential (EPP) to be evoked and Action Potential generated when threshold reached

Question 3

Are Muscarinic receptors G-coupled protein receptors or Ligand-gated receptors? Describe the appropriate receptor type.

Answer 3

Muscarinic G-coupled protein receptors
M1 and M3 receptors are Gq receptors: leads to release of Ca2+ and Contraction of smooth muscle/glands
M2 receptor is a Gi receptor (inhibitory): inhibition of cAMP leads to decreased heart function

Question 4

What is the rate limiting factor in ACh synthesis?

Answer 4

Choline uptake

Question 5

What enzyme catalyzes the synthesis of ACh?

Answer 5

Choline Acetyltransferase (ChAT)

Question 6

What enzyme inactivates ACh in the synaptic cleft?

Answer 6

Cholinesterase (ChE): Acetylcholinestase and Plasma Cholinesterase (aka Pseudocholinesterse)

Question 7

What class of drugs are seen below?
Bethanechol
Methacholine
Carbachol

Answer 7

Cholinergic Agonists: Directly stimulates the PNS

Question 8

Bethanechol

1) Receptor targeted?
2) Susceptible to Cholinesterase?
3) Use?

Answer 8

1) Muscarinic Selective
2) NO=Longer Half-life
3) Post-op ileus, Congenital megacolon, Urinary retention

Question 9

Methacholine

1) Receptor targeted?
2) Susceptible to Cholinesterase?

Answer 9

1) Muscarinic Selective

2) YES=Shorter Half-life

Question 10

Carbachol

1) Receptor targeted?
2) Susceptible to Cholinesterase?
3) Use?

Answer 10

1) Non-selective, activates Muscarinic and Nicotinic
2) NO=Longer Half-life
3) Glaucoma

Question 11

What class of drugs are seen below?
Muscarine
Pilocarpine
Nicotine
Varenicline

Answer 11

Natural Alkaloid Cholinergic Agonists: Directly stimulate the PNS

Question 12

Which of the following are muscarinic selective? Which are nicotinic selective?
Muscarine
Pilocarpine
Nicotine
Varenicline

Answer 12

Muscarine, Pilocarpine=Muscarinic Selective

Nicotine, Varenicline=Nicotinic Selective

Question 13

Pilocarpine

1) Uses
2) Mechanism of Action

Answer 13

1) Dry Mouth, Acute cases of Glaucoma

2) Cholinergic Agonist- Muscarinic receptor selective to stimulate the PNS

Question 14

Does Nicotine stimulate the Sympathetic or Parasympathetic Nervous System?

Answer 14

Stimulates BOTH via Nn receptors on the postganglionic neurons

Question 15

Varenicline

1) Uses
2) Mechanism of Action

Answer 15

1) Quit Smoking

2) Cholinergic Agonist- Nicotinic receptor selective

Question 16

Describe the signs/symptoms of Cholinergic Toxicity

Answer 16

N/V/D, Urinary Urgency, Salivation, Sweating, Skin vasodilation (Flushing), Bronchial constriction

Question 17

In what patients would Cholinergic Agonists be contraindicated?

Answer 17

Asthma, Coronary Insufficiency, Peptic Ulcer Disease, Hyperthyroidism

Question 18

Where is Acetylcholinesterase primarily located?

Answer 18

Neuromuscular junctions

Question 19

Where is Plasma cholinesterase primarily located?

Answer 19

Plasma and Liver

Question 20

Name the Competitive Cholinesterase Inhibitors.

What is their Mechanism of Action?

Answer 20

-Edrophonium (VERY short acting)
-Neostigmine
-Pyridostigmine
-Physostigmine
MOA: binds REVERSIBLY to the active site on Cholinesterase to indirectly stimulate the PNS (SHORT/Moderate-acting)

Question 21

What are some common uses of Cholinesterase INhibitors?

Answer 21

Myasthenia Gravis, Ileus, Glaucoma

Neostigmine used for neuromuscular blockade reversal

Question 22

Name the Non-Competitive Cholinesterase Inhibitors.

What is their Mechanism of Action?

Answer 22

-Organophosphates: Diisopropylfluorophosphate (DFP), Echothiophate
-Insecticides: Carbaryl, Malathion, Parathion
-Nerve Gases: Sarin, Soman
MOA: IRREVERSIBLY phosphorylates the active site on Cholinesterase causing “aging” and indirectly stimulating the PNS (LONG-acting)

Question 23

Organophosphate Intoxication can lead to ______ ___.

Answer 23

Cholinergic Crisis

• Think ‘SLUD’-Salivation, Lacrimation, Urination, Defication
• Also causes Bradycardia, Bronchoconstriction, Miosis

Question 24

What therapy is used for Organophosphate Intoxication?

Answer 24

1st: Atropine (Muscarinic Antagonist)- competitively binds Muscarinic receptors
2nd: Pralidoxime [aka 2-PAM] (AChE Re-activator)- MUST be given before AChE “aging” occurs

Question 25

What is the Mechanism of Action of Cholinergic Antagonists?

Answer 25

MOA: Competitively bind Muscarinic receptors blocking ACh from binding to Muscarinic receptors *Therefore inhibiting the PNS (leads to Sympathetic symptoms/actions)

Question 26

How are these drugs related? What is their Use? Atropine Homotropine Tropicamide

Answer 26

- Cholinergic Antagonists - Eyes: Mydriasis (Pupil Dilation), Cycloplegia (Far Vision)- Used for Eye Exams, Eye Inflammation * Think about Sympathetic (Flight/Fight) Functions* * ALL are tertiary amines=able to cross the BBB*

Question 27

How are these drugs related? What is their Use? Glycopyrrolate Ipratropium Tiotropium

Answer 27

- Cholinergic Antagonists - Lungs: Decreased Secretions, Bronchodilation- Used to lessen bronchial secretions and laryngospasm before inhalant anesthetics

Question 28

How are these drugs related? What is their Use? Atropine Glycopyrrolate

Answer 28

- Cholinergic Antagonists - Heart: Block Vagal Response, Prevent Bradycardia - GI: Decrease Smooth Muscle motility and GI secretions- Used for Peptic Ulcer Disease, Diarrhea d/t diverticulitis * Atropine NO longer used for GI d/t CNS effects w/high doses*

Question 29

``` How are these drugs related? What is their Use? Darifenacin Oxybutynin Tolterodine Solifenacin ```

Answer 29

- Cholinergic Antagonists - GU: Relaxes Smooth Muscle of the Bladder- Used for Bladder Spasms, Mild Inflammation, Neurologic condition * M3 receptor Selective

Question 30

How are these drugs related? What is their Use? Trihexyphenidyl Scopalamine Methscopalamine

Answer 30

- Cholinergic Antagonists - CNS: Anti-Parkinsonism, Anti-Motion Sickness * Trihexyphenidyl (Parkinson's) and Scopalamine (Motion Sickness)=Tertiary amines= Crosses BBB(CNS effects) * Methscopalamine is Quanternary=NO crossing BBB

Question 31

What are the Central side effects of Cholinergic Antagonists?

Answer 31

Hallucinations, Amnesia, Sedation, Excitement * Only occur in tertiary amine agents* * THINK of Sympathetic effects*

Question 32

What are the Peripheral side effects of Cholinergic Antagonists?

Answer 32

Excessive Mydriasis (Pupil dilation), Cycloplegia (Far vision), Photophobia, Dry eyes, Dry mouth (Xerostomia), Tachycardia, Red Skin (aka "atropine fever" d/t reduced sweating)

Question 33

True/False | Ganglionic Nicotinic Agonists stimulate the Sympathetic Nervous System.

Answer 33

FALSE, Ganglionic Nicotinic Agonists stimulate both Sympathetic and Parasympathetic Nervous System. * The organ system determines which ANS division (Sympathetic or Parasympathetic) will give the predominate actions/functions. * For example, the heart is predominately controlled by the SNS, therefore the actions/functions produced by the drug will be sympathetic in nature. (Except HR, that is controlled by PNS/Vagal Nerve)

Question 34

Name one Ganglionic Nicotinic Agonist

Answer 34

Nicotine: binds to Nn receptors at ALL ganglionic sites (PNS and SNS), even the adrenal medulla *Has MANY side effects

Question 35

Describe the Symptoms of Nicotine Toxicity

Answer 35

Nausea, excessive Salivation, Abdominal Pain, Diarrhea, Cold Sweats, HTN, Dizziness Possible seizures, respiratory arrest (d/t muscle paralysis), and cardiac arrhythmias

Question 36

Name one Ganglionic Nicotinic Antagonist

Answer 36

Mecamylamine: non-depolarizing competitive antagonists that bind irreversibly to Nn receptors at ALL ganglionic sites Uses: HTN emergencies, Severe PVD **NOT 1st choice therapy d/t MANY side effects *The organ system determines which ANS division (Sympathetic or Parasympathetic) will be blocked and give the predominate actions/functions of that division

Question 37

Transmission of action potentials at the neuromuscular junction can be facilitated/improved by ________ ____.

Answer 37

Acetylcholinesterase Inhibitors (like Neostigmine)

Question 38

True/False Denervation of skeletal muscle results in muscle atrophy, while denervated smooth muscle does not result in muscle atrophy.

Answer 38

TRUE

Question 39

Describe the Mechanism of Action of Non-Depolarizing Neuromuscular Antagonists.

Answer 39

Competes w/ACh for binding to Nm receptors, blocks Na+ channel opening inhibiting depolarization of the muscle cell * Starts with motor weakness until total paralysis occurs * AChE inhibitors will allow ACh to compete off the non-depolarizing agent

Question 40

Name 4 Non-Depolarizing Neuromuscular Antagonists

Answer 40

CURare CisatraCURium MivaCURium RoCURonium*Vagal blockade, be careful of tachycardia **ALL are contraindicated in Myasthenia gravis

Question 41

Succinylcholine 1) Mechanism of Action 2) Use 3) Metabolizing Agent 4) Contraindications

Answer 41

1) Depolarizing Neuromuscular Antagonist- act non-competitively at Nm receptors, opening Na+ channels, depolarization occurs (Phase 1), membrane unable to repolarize initially but w/prolonged exposure membrane repolarizes (Phase 2) but is now resistant to depolarization d/t desensitization 2) Muscle Relaxant, Adjunct for Anesthesia 3) Rapid hydrolysis by Plasma Cholinesterase 4) Plasma Cholinesterase gene mutations (causes prolonged action), Conditions of high K+ (depolarization of skeletal muscle releases LOTS of K+ and risk for cardiac arrest)