Muscarinic Receptor Agonists/Antagonists

Question 1

Muscarinic Agonist Effect: Eye

Answer 1

1. ) Accommodation (near sight adjustment)

2. ) Pupil constriction

Question 2

Muscarinic Agonist Effect: Heart

Answer 2

1. ) HR REDUCTION

2. ) Contraction force REDUCTION

Question 3

Muscarinic Agonist Effect: Glands + Blood Vessels

Answer 3

1. ) Increase sweat
2. ) increase salivation
3. ) increase tearing
4. ) VASODILATION

Question 4

Muscarinic Agonist Effect: Lung

Answer 4

1. ) BronchoCONSTICTION (avoid in asthmatics)

2. ) INCREASED secretions

Question 5

Muscarinic Agonist Effect: Urinary Bladder

Answer 5

1. ) Detrusor muscle CONTRACTION

2. ) Relax urinary sphincter

Question 6

Muscarinic Agonist Effect: GI Tract

Answer 6

1. ) Increased peristalsis
2. ) Increased secretions (i.e. acid)
3. ) DECREASE sphincter tone

Question 7

Muscarinic Receptors: Brain/CNS

Answer 7

M1 - M5 (all 5 classes)

Question 8

Muscarinic Receptors: Heart

Answer 8

M2

Question 9

Muscarinic Receptors: Glands/Smooth Muscles

Answer 9

M3

Question 10

Muscarinic Receptor: GPCR or Ion Channel?

Answer 10

GPCR
Regulate Enzymes Fx: AC, PLC, MAPK
Regulate Ion Channels: K+, Ca++

Question 11

Four Major Cholinergic Groups (CNS)

Answer 11

1. ) Nucleus Basalis of Meynert*** (cortical innervation)
   
   • expands from ~hippocampus outwards
2. ) Medial Septal Nucleus (hippocampus)
3. ) Brainstem: thalamus
4. ) Basal ganglia: interneurons

Question 12

Acetylcholine:
Cholinesterase activity
Muscarinic Activity
Nicotinic Activity

Answer 12

Quaternary Amine
CEA: ++++
M: +++
N: +++

Question 13

Methacholine:
Cholinesterase activity
Muscarinic Activity
Nicotinic Activity

Answer 13

Quaternary Amine + CH3
CEA: +
M: +++
N: –

Question 14

Cabachol:
Cholinesterase activity
Muscarinic Activity
Nicotinic Activity

Answer 14

Quaternary Amine + NH2
CEA: –
M: ++
N: +++

Question 15

Bethanechol:
Cholinesterase activity
Muscarinic Activity
Nicotinic Activity

Answer 15

Quaternary Amine + CH3 + NH2
CEA: –
M: ++ (not subtype-selective)
N: –

Question 16

MUSCARINE

Answer 16

Quaternary Amine
No BBB Cross
No longer used clinically

Question 17

PILOCARPINE

Answer 17

Secondary Amine
CROSSES BBB (therefore psychostimulant)

Treat: xerostomia, glaucoma (sometimes)

Question 18

ARECOLINE

Answer 18

Betel nut extract (stimulant/recreational drug)
Tertiary amine (crosses BBB)

Question 19

Muscarinic Agonist Uses (5)

Answer 19

1. ) Recreational (arecoline)
2. ) Glaucoma
3. ) Urinary retention (post-op)
4. ) Gastrointestinal atony (post-op/neurogenic ileus)
5. ) Xerostomia

Question 20

Open Angel Glaucoma

Answer 20

90% Cases

• clogged intratrabecular network prevents outflow of intraocular fluid (increased intraocular pressure)
• contracts cilliary muscles –> frees exit via Schlemm

M3 stimulation

Question 21

Closed Angel Glaucoma

Answer 21

10% Cases (rare)
-lens + iris contact

M3 stimulation

Question 22

Xerostomia: 2 Causes + 2 Treatments

Answer 22

1. ) Neck/head irradiation
2. ) Sjogren’s Sx
3. ) Pilocarpine
4. ) Cevimeline

Question 23

Urinary Retention (musc. agon.) Treatment

Answer 23

Bethanechol

Question 24

GI Atony Treatment

Answer 24

Bethanecol

Question 25

Glaucoma (sometimes)

Answer 25

Pilocarpine

Question 26

Muscarinic AGONIST: Contraindications

Answer 26

1. ) SEVERE ASTHMA ***** 2. ) Severe bradycardia 3. ) Parkinson's disease 4. ) Urinary/bowel obstruction

Question 27

Muscarinic AGONIST: ADEs

Answer 27

1. ) Diarrhea 2. ) Excessive salivation/tears/sweating - "Sweating mushroom" 3. ) Miosis/accomdation (no far vision) 4. ) N/V 5. ) Urinary urgency 6. ) Bronchoconstriction (no asthma) 7. ) Hypotension/bradycardia 8. ) Seizures/tremor/hypothermia

Question 28

Muscarinic ANTAGONIST Effect: Eyes

Answer 28

1. ) NO accommodation (no near-sight) | 2. ) Dilated pupils

Question 29

Muscarinic ANTAGONIST Effect: Heart

Answer 29

1. ) TACHYcardia | 2. ) Increased contractile force

Question 30

Muscarinic ANTAGONIST Effect: Glands

Answer 30

1. ) Decreased salivation | 2. ) Decreased sweating

Question 31

Muscarinic ANTAGONIST Effect: Lungs

Answer 31

1. ) Bronchodilation | 2. ) Decreased secretions

Question 32

Muscarinic ANTAGONIST Effect: Urinary Bladder

Answer 32

1. ) Relaxation | 2. ) Loss of sphincter tone

Question 33

Muscarinic ANTAGONIST Effect: GI Tract

Answer 33

1. ) Decreased peristalsis | 2. ) Decreased secretions (acids, etc.)

Question 34

ATROPINE

Answer 34

NO BBB CROSSING -lacks oxygen bridge (on base ring) M1, M2, M3 Little to no affinity for nicotinic receptors

Question 35

Atropine: Problems

Answer 35

1. ) Side-effects 2. ) Non-selective for M3 (off-target effects) 3. ) Some BBB-crossing 4. ) LONG duration of action

Question 36

SCOPOLAMINE

Answer 36

``` Crosses BBB -possess base oxygen bridge -lacks oxygen bridge (on base ring) M1, M2, M3 Little to no affinity for nicotinic receptors ```

Question 37

Ipatropium vs. Atropine

Answer 37

Ipatropium has fewer ADEs *Quaternary amine prevents entrance into bloodstream *Some xerostomia due to minimal systemic absorption See also: tiotropium, aclidinium

Question 38

Solifenacin: Indication and advantages

Answer 38

*Urinary incontinence * M3-selective TERTIARY amine * Limited M2 affinity * Good bioavailability * great for elderly patients

Question 39

Muscarinic Receptor Antagonist: Ophthalmology

Answer 39

``` Tropicamide 15-60min Cyclopentolate 3-6hr Homatropine 12-24hr Scopolamine 3-7d Atropine 5-6d ```

Question 40

Muscarinic ANTAGONIST: ADEs

Answer 40

1. ) Blurred vision, mydriasis 2. ) Urinary retention 3. ) Constipation 4. ) Tachycardia 5. ) Reduced sweating 6. ) Confusion, hallucinations ***THINK OVER-ACTING ACH EFFECTS***

Question 41

"Dry as a...." Phrase from Slide Set 3 (Muscarinic Antagonists)

Answer 41

DRY as a bone BLIND as a bat RED as a beet MAD as a hatter

Question 42

Muscarinic Antagonist: Contraindications

Answer 42

1. ) GLAUCOMA 2. ) Benign prostatic hyperplasia 3. ) Gastric ulcer

Question 43

Acetylcholinesterase Inhibitor Mechanism

Answer 43

1. ) ACH binds active site 2. ) Nucleophilic attack of active site serine on ester oxygen (release of choline) 3. ) Hydrolysis of acetyl group (regenerate serine)

Question 44

Edrophonium

Answer 44

Competitive acetylcholinesterase inhibitor -binds choline site + prevents binding *quaternary amine strucutre SHORT HALF LIFE (rare)

Question 45

Carbamate ACE Inhibitors

Answer 45

1. ) Physostigmine 2. ) Pyridostigmin (quat amine) 3. ) Neostigmine (quat amine) MOA: catalysis conjugates serine residue. slow hydrolysis (~mins) temporarily inactivate enzymes

Question 46

Organophosphate AChEs

Answer 46

1.) Oxygen binds phosphate group 2.) Leaving group (halide) facilitates Sn2 binding mechanism 3.) SLOW (~days) hydrolysis inactivates AChE "permanent inactivation" Example: diisopropyl fluorophosphate (DFP)

Question 47

Acute Organophosphate Toxicity: SLUDGEM

Answer 47

``` Salivation Lacrimation Urination Defecation GI motility Emesis Miosis ```

Question 48

Acute Organophosphate Toxicity: BBB

Answer 48

Bronchospasm Bronchial secretion Bradycardia

Question 49

Organophosphate Toxicity: Antedotes

Answer 49

1.) 2-PAM (pralidoxime) 2.) Atropine [**atropine toxicity --> O.P. pyridostigmin**]

Question 50

2-PAM

Answer 50

Pralidoxime *strips organophosphate moiety from active site serine (ineffective if OP-enzyme bond has aged) Uses: - reverses effects at nicotinic receptors (NMJ) - muscarinic receptors (controversial) - no BBB travel (quaternary amine)

Question 51

Malathion

Answer 51

Pesticide (old) Mammals (LD50 1.2g/kg) --> metabolizes into inactive/inert metabolite Insects/Fish (LD50 0.5mcg/bee)--> metabolized into highly toxic metabolite (MALAOXON)

Question 52

Acetylcholine Esterase Inhibitor (AChE In.) Uses (4)

Answer 52

1. ) Glaucoma (echothiophate) 2. ) GI/Urinary tract effects 3. ) Myasthinea Gravis (NMJ effects) 4. ) CNS Effects (Alzheimers disease)

Question 53

Myasthinea Gravis Treatments (3)

Answer 53

1. ) Immune suppressants 2. ) Pyridostigmine 3. ) Neostigmine

Question 54

Myasthinea Gravis Characteristics (3)

Answer 54

1. ) autoimmune disease (antibodies are made vs. nicotinic receptors at NMJ) 2. ) Abs block ACh binding with nicotinic receptors 3. ) Abs initiate complement --> destroys post-synaptic membrane

Question 55

Pyridostigmine (ADEs)

Answer 55

1. ) GI issues (diarrhea) 2. ) Salivation 3. ) Sweating 4. ) Urinary urgency 5. ) Bronchiole secretions

Question 56

AChE Inhibitors: AD (3)

Answer 56

1. ) Rivastigmine (carbamate (reversible)) 2. ) Donepezil (competitive) 3. ) Galantamine (competitive) * *effective for BOTH NICOTINIC + MUSCARINIC**

Question 57

Rivastigmine (AD)

Answer 57

1. ) Effective in MILD and MODERATE disease 2. ) High ADE potential (esp N/V) 3. ) Have not been compared to Quat amine compounds (i.e. pyridostigmine)

Question 58

Inhibitor: VAT

Answer 58

VAT = vesicle-associated transporter (H+-mediated) Vesamicol

Question 59

Inhibitor: Presynaptic Vesicle Binding

Answer 59

Botulinum Toxin | -cleaves SNAPs + VAMPs preventing fusion and release of neurotransmitters

Question 60

Inhibitor: CHT

Answer 60

Sodium-dependent Choline Transporter (CHT) Hemicholiniums