Cholinergic Pharmacology

Question 1

Muscarinic Receptors

Answer 1

• Ligand = acetylcholine
• G-protein coupled receptors
  
  • agonist or antagonist can chagne ratio of monomeric to oligomeric receptors
    
    • form dimers or oligomers when activated
• M1-5
  *

Question 2

M1

Answer 2

• Location: Nerves
• muscarinic
• increased congition function (learning and memory)
• increased seizure activity
• Relevant Disease:
  
  • Alzheimer’s
  • cognitive dysfunction
  • Schizoprhrenia

Question 3

M2

Answer 3

• Location: nerves, heart and smooth muscle
• muscarinic
• Heart:
  
  • SA node: slowed spontaenous depolarization; hyperpolarization = lower BP
  • AV node: decrease in conduction velocity
  • Atrium: decrease refractory period, decrease contraction
  • ventricle: decrease contraction
• Smooth muscle:
  
  • increase contraction
• Peripheral Nerves:
  
  • neural inhibition via autoreceptors and heteroreceptors → decreased ganglionic transmission

Question 4

M3

Answer 4

• Location: Glands, endothelium, and smooth muscle
• muscarinic
• Smooth muscle:
  
  • increase contraction (mostly bladder)
• Glands:
  
  • increased secretion (mostly salivary gland)
  • increased food intake
  • increased body weight
  • increased fat deposit
  • inhibition of DA release
• Relevant Disease:
  
  • COPD
  • Urinary incontinence
  • irritable bowel syndrome

Question 5

M4

Answer 5

• Location: CNS
• Muscarinic
• Autoreceptor and heteroreceptor-mediated inhibition of transmitter relase in CNS and periphery
• analgesia: catapletic activty
• faciliation of DA release
• Relevant Disease:
  
  • Parkinson Disease
  • Schizophrenia
  • Neuropathic Pain

Question 6

M5

Answer 6

• Location: CNS
• muscarinic
• Mediator of dilation in cerebral arteries
• Facilitates DA release
• augmentation of drug-seeking behavior and reward (opiates, cocaine)
• Relevant Disease:
  
  • Parkinsons
  • Drug Dependence
  • Schizophrenia

Question 7

Nicotinic Receptors

Answer 7

• Ligand = acetylcholine
• Nm and Nn
• ligand-gated receptors: allow exchange of Na and K → cell membrane depolarization

Question 8

Nm

Answer 8

Nicotinic Receptor

Location: Neuromuscular junction

skeletal muscle contraction

Question 9

Nn

Answer 9

Nicotinic receptor

Location: postganglionic bodies and dendrites

depolarization and secretion of caetcholamines

Question 10

“nium” ending of drug

Answer 10

non-depolarizing blocking agent

antagonist at the Nm receptors → loss of sketelal contractility

Question 11

adrenergic receptors in the CNS

Answer 11

Alpha 2: prejunctional control of transmitter release

increased permeability of Ca²⁺

Question 12

Acetylcholine half life

Answer 12

VERY SHORT

1. broken down by acetycholine esterase
   
   1. those that arent broken down in the synaptic cleft diffuse into the plasma where they are broken down by butylyl choline esterase

Question 13

Esters of Choline

Answer 13

• direct cholinomimetics
• charged
• poor lipid solubility → poorly distributed into CNS
• all hydrolized in the GI → less active
• examples: Acetylcholine
  
  • methacholine
  • carbachol
  • bethanecol

Question 14

Alkaloids

Answer 14

• directing acting cholinomimetics
• (non-ester)
• tend to act on muscarinic receptors
• examples: “ine”
  
  • pilocarpine (isopto carpine)
  • Salagen → more saliva for Sjogren syndrome
  • Vareniclince (Chantix) →smoking cessation
  • Cevimeline →saliva production stimulator

Question 15

Sjogren Syndrome

Answer 15

• autoimmune disease that attacks glands: can have dry eye and dry mouth
• can use a cholinomimetic → alkaloids (non-ester choline) → Salagen and cevimeline (Evoxac)

Question 16

Side effects & Toxicity of Muscarinic Agents

Answer 16

• SA:
  
  • diaphoresis
  • N/V/D
  • abd cramps
  • sensation of tightness in the bladder
  • difficulty in visual accomodation
  • hypotension
• Toxicities:
  
  • NVD
  • urinary urgency
  • salivation
  • sweating
  • cutaneous vasodilation
  • bronchiol constriction

Question 17

Nicotine

Answer 17

• direct acting cholinergic drug
• lipid soluble
  
  • SE/toxicity: depression, suicidal ideation
• can be abosrbed across skin

Question 18

Cholinesterase inhibitors

Answer 18

• increase levels of acetylcholine
• end in “stigmine”
  
  • Neostigmine:
    
    • reversal of non-depolarizing neuromuscular blocking agents (reversal of durg induced muscle paralysis: Atracurium, Rocuronium, Vecuronium)
  • Physostigmine
    
    • same action, not yet approved
• Edrophonium : short acting
• Neostigmine: medium acting
• Echothiophate ( an organophosphate): long acting
• Rivastigmine, galantium, and donepezil: alzheimer’s treatment (lipophilic so can cross BBB)

Question 19

Non-depolarizing vs depolarizing blockers

Answer 19

• non-depolarizing neuromuscular blockers
  
  • competitively bind to nichotinic receptors
    
    • competing with Ach = Rocuronium
• Depolarizing neuromuscular blockers
  
  • binds to the nicotinic receptors which cause an initial depolarization but then lead to paralysis due to depolarization
    
    • ex: succinylcholine does not allow repolarization

Question 20

Muscarinic Antagonists

Answer 20

• parasympatholytic
• naturally occuring alkaloids:
  
  • atropine
    
    • deadly nightshade, belladonna
  • Scopolamine
    
    • used to treat vertigo
• Synthetic
  
  • Dicyclomine: gut antispasmotic → IBS
  • Ipratroprium: bronchodilator
  • Oxybutynin overactive bladder

Question 21

Cholinesterase Regenerator

Answer 21

Pralidoxime (2PAM) – antitode for excessive nicotinic stimulation (insecticide toxicity)

Question 22

Antimuscarinic Agent Toxicity and Contraindications

Answer 22

• Toxicity:
  
  • dry mouth
  • mydriasis (pupil dilation)
  • tachycardia
  • hot and flushed skin
  • agitation
  • delirium that may last up to one week
• Cautions:
  
  • glaucoma → increase intraocular pressure
  • BPH (benign prostatic hyperplasia) → urinary retention
  • PUD (peptic ulcer disease) → slow gastric emptying

Question 23

Botulinum toxin

Answer 23

• irreversibly block acetylcholine vesicle release → muscle paralysis
• indications: migraine, excessive sweating, eye muscle spasms

Question 24

Black Widow venom (alpha latrotoxin)

Answer 24

• stimulates relase of ACh→ muscle contration
• when Ach becomes depleted leads to muscle paralysis

Question 25

Cevimeline

Answer 25

cholinomimetic

treatment for sjogren syndrome

Question 26

nicotinic blockers

Answer 26

• TEA and C6
• effects:
  
  • CNS: sedation, tremor, and mental aberrations
  • Eyes: pupil dilation
  • CV: orthostatic hypotension, reduced cardiac contractility
  • GI: reduced secretion, reduced motility, and constipation
  • GU: hesitancy in urination, and urinary retention

Question 27

Succinylcholine

Answer 27

depolarizing blocker → used during intubation to prevent gag reflex

• binds to the nicotinic rreceptors which causes an initial muscle contraction then paralysis due to depolarization and lack of repolarization
• first have fasciculations then followed by muscle paralysis

Question 28

Rocuronium

Answer 28

• non-depolarizing neuromuscular blockers
• competitively bind to nicotinic receptors and block the action of acetylcholine

Question 29

Bethanecol

Answer 29

Ester of choline

• urinarty tract: increase detrusor muscle tone
• GI: stimulates peristalsis
• SE: bradycardia, hypotension, seizure
• CI: asthma, COPD, urinary or GI obstruction , CVD

Question 30

Isopto Carpine

Answer 30

• alkaloid (non-etser) choline
• treatment: glaucoma, miotic agent → mydriasis reversal

Question 31

SE and toxicity of muscarinic agonists

Answer 31

• diaphoresis
• NVD
• abd cramps
• sensation of bladder tightness
• hypotension

Treatment: Atropine (anticholinergic)

Question 32

Lobeline

Answer 32

• direct acting alkaloid (nonester chline)
• used for smoking cessation
• mixed agnonist-antagonist at nicotinic receptor

Question 33

Nicotine

Answer 33

Direct acting alkaloid (non-ester) choline

Lipid soluble

• acute toxicity = vomiting, CNS stimulation, respiratory paralysis, arrythmias

Question 34

Dicyclomine

Answer 34

anticholinergic drug

used to treat IBS