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muscurinic Flashcards

1
Q

cholinergic synapse overview

A

Ach is like the carrier of choline goes into the synapse and the vesicle holds it until it is released by a NT autoreceptors reside on the synapse (M2 off switch) on the post synaptic cell there are cholinesterase inhibitors, cholinoceptors (G protein coupled M)

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2
Q

what is ach hydrolyzed by at the synapse

A

AChE

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3
Q

why can’t you give Ach as a drug

A
  • rapidly hydrolyzed - bad absorption because of the positive charge - buteryl cholinesterase (rapidly broken down int he plasma to hydrolyze)
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4
Q

heteroreceptor and autoreceptor

A

hetero- alpha 2 auto - M2 they both cause an effect on parasymp activity (chlonidine causes dry mouth)

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5
Q

BuChE

A

Ach and other choline-based esters can by hydrolyzed by plasma esterase such as butylrylcholinesterase - important for drugs who are based on Ach

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6
Q

muscurinic recptors

A

G-protien coupled receptors - contains an ester and a charge like Ach

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7
Q

nicotinic

A

ligand gated cation channels (primarily sodium)

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8
Q

M1 location

A

CNS, gastric, salivary, autonomic ganglia, enteric nerves

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9
Q

M1 G protein

A

Gq

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10
Q

M1 response

A

inc IP3, inc DAG, inc Ca- depolarization and excitation, inc AA

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11
Q

M1 function

A

inc cognitive function, inc siezure activity, inc secretions, inc autonomic ganglia depolarization, dec dopamine release and locomotion (alzehiemers not enough Ach)

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12
Q

M2 G protien

A

Gi

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13
Q

M2 location

A

autonomic nerve terminals, CNS, heart, smooth muscle

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14
Q

M2 cellular response

A

inhibition of cAMP and VGCC

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15
Q

M2 function

A

dec heart rate, inc smooth muscle contraction via auto/hetero receptors, inc tremors, hypothermia, and analgesia,

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16
Q

M3 G protein

A

Gq

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17
Q

M3 tissue location

A

CNS, smooth muscle, glands, heart

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18
Q

M3 cellular response

A

same as M1

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19
Q

M3 function

A

increased smooth muscle contraction (bladder), inc salivary gland, inc food intake, body fat deposits inhibit dopamine release, synthesis of NO

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20
Q

structure of muscurinic agonists - ammonium group

A
  1. ammonium group: nitrogen capable of bearing a positive charge (quat amine), can have no charge (tertiary amine), can’t be a secondary amine - biggest sub on nitrogen can be a methyl (if ethyl the activity dec on agonist)
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21
Q

structure of muscurinic agonists (3)

A
  1. ammonium 2. ethylene 3. acyloxy group do not want drugs to be too big! made after ach 2 molecules between N and ester
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22
Q

structure of muscurinic agonists- ethylene bridge

A

2 carbon atoms between nitrogen and oxygen INGs rule of 5 - longer or shorter than 5 atoms between N and C terminal will not work

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23
Q

structure of muscurinic agonists- acyloxy group

A

ester, ether, or ketone - really only needs to be an oxygen!

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24
Q

methacholine

A

M>>N methyl on the beta carbon which makes it much better M than N - slows down the metabolism hydrolysis by AchE and has some nicotinic activity

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25
carbachol
no methyl group on B carbon (not selective for M and can activate M or N) has a carbamate that can be broken down by acetyl cholenesterase much less - increases resistance to hydrolysis - lots of nicotinic activity because no methyl
26
adding a methyl group on the B carbon of a muscurinic agonist
increases the selectivity for M over N and slows down the metabolism - survives the cholinesterase better
27
carbamate on the end of the muscurinic agonist
N + ester broken down by AchE much less - increases resistance to hydrolysis
28
bethanechol
like methacholine and carbachol having a baby ! has a carbamate and a methyl group! hydrolysis resistant AChE, no nicotinic activity
29
pilocarpine
plant derived alkaloid - would eat it for dry mouth doesnt fit the mold - has a lactone ring but it still works! hydrolysis resistant AChE, no nicotinic activity
30
cevimeline
pharmacologically muscurinic agonist- does not look like it would fit the mold hydrolysis resistant by AChE, no nicotinic activity
31
INGs rule of 5
5 atoms starting from the alpha carbon (C right next to N) all the way to the terminal
32
off-label uses of muscurinic agonists
- acute urinary retention (non-obstructive) - treatment of disabling anticholinergic side effects from meds such as tricyclic antidepressent - bronchial airway hyper-reactivity (no asthma) - lowering of intraocular pressure in glaucoma (mydriasis in symp and constrict in parasymp) - miosis induction after opthalmoscopic exam -xerostomia and sjogren's syndrome - COPD - bradycardia
33
CNS (M,N)
stimulatory, N small doses elevation of mood, alerting, addiction (nausea), large doses, seizures; coma; convulsions
34
sphincter muscle of iris (M)
contraction (miosis)
35
ciliary muscle of eye (M)
contraction, accommodation for near vision
36
heart (M)
decrease in heart rate
37
bronchi (M)
contraction
38
blood vessel (M)
dilation and release of EDRF from endothelium
39
motility in GI (M)
inc perstalisis
40
sphincters in GI (M)
dec tone, relaxation (exception: contracts the gastroesophageal sphincter)
41
urinary bladder (M)
inc contraction and inc secretion
42
skeletal muscle (N)
activation of NM end plates, contraction
43
glands (M)
inc secretion
44
what do muscurinic antagonists violate to not make them agonists
- attached to nitrogen a lot bigger than methyl group - not 5 molecules between N and ester
45
muscurinic antagonist- N
nitrogen is either a tertiary amine or quaternary ammonium- can't get into the brain if it is charged
46
muscurinic antagonist- R1, R2
R1 and R2 are carbocyclic or heterocyclic rings
47
muscurinic antagonist- R1, R2
R1 and R2 are carbocyclic or heterocyclic rings the other is usually saturated (but not required) sometimes these rings fuse together, rings can't be too large or else the drug can't bind
48
R3 on muscurinic antagonists
usually a hydrogen, hydroxyl, or component of R1 or R2 - or can be other small groups
49
"X" on muscurinic antagonists
usually an ester but this is not required- can also be an ether or even absent altogether - just part of the aliphatic chain
50
length between ring-substituted carbon and the nitrogen on muscurinic antagonists
usually 2-4 atoms - more potent agents have 2 methylene units in this chain
51
muscurinic antagonists used for the following disease states
COPD, parkinson's disease, overactive bladder, mydriatics/cycloplegics (opthalmic exams), IBS-D
52
peripheral M antag adverse effects
xerostomia, dry eyes, blurred visions, dry skin, tachycardia
53
central M antag adverse effects
confusion, hallucinations (jimson weed), delerium, coma
54
what structural features would limit the CNS effects on an antimuscurinic drug
ionized nitrogen on a quaternary ammonium - can't pass the BBB
55
what are potential drug interactions with antimuscurinic
cautious when using with other antimuscurinics benydryl + amitryptiline
56
relaxation of sphincter muscle of the iris
mydriasis- dialating
57
relaxation of ciliary muscle of the iris
loss of accommodation and blurred vision "paralyze" cycloplegia - accommodates for long range of vision
58
pilocarpine
glaucoma - need to find a different way to dilate, stimulates the alpha 1 instead
59
drugs for opthalmic
atropine, tropicamide, cyclopentolate
60
drugs for COPD
Tiotropium (Spiriva), Ipratropium (Atrovent), Glycopyrrolate (Seebri), Aclidinium (Tudorza), Umeclidinium (Incruse Ellipta)
61
COPD SAR M antagonists
all quaternary ammonium - little central effects - bad for oral absorption - all have an ester and aromatic rings
62
parkinsons disease - MOA
deficiency of dopamine in the nigrostriatal tract - leads to an imbalance between dopamine and ach in motor control areas - treated with drugs that can reduce ach activity
63
would a quat ammonium be good for drugs to fight parkinsons?
NO, they do not want a charge so they can get in the brain
64
parkinsons drugs
benztropine (cogentin), trihexphenydil (artane)
65
IBS drugs have the potential for adverse CNS effects
no, they do not
66
IBS drugs
dicyclomine (bentyl)
67
muscurinic receptors and nausea / vomiting
M1 mainly participate in vestibular nasea/vomiting aka motion sickness, M1 also on the nucleus of tractus solitarius (vomiting center)
68
what drug is given for motion sickness
scopolamine
69
sudden urge to urinate
miturition- stretch on receptor, parasymp fire and motor neuron stop firing, smooth muscle contracts, internal sphincter passively pulled open, external sphincter relaxes, higher CNS input facilitates or inhibits reflexes
70
why does oxytrol have less side effects
antimuscurinic drugs - less side effects because it has a greater AUC- used to treat over active bladder
71
what do all quat ammoniums have in common?
they all end i n -ium
72
advantage of M3 selectivity
no cardiovascular effects - cardioselective for M3, still get constipation/ dry mouth, dec in CNS effects
73
functional tissue selectivity M3 for urinary
"functional" means we do not know why- may be a different subtype, slight differences of the receptor, environment may cause 1 receptor over another and may be pH environment
74
how does this metabolize
p450 because of the ester - it is an ium because of the + charge
75
functional tissue selectivity for bladder M3 - solifenacin- CYP 314 metabolized
76
Darifenacin- 2d6 and 3a4- cause dry mouth and selective m3
77
oxybutinin- ## Footnote Most lipophilic of all agents for OAB - goes into brain so do not use for elderly phase 2 conjunction, replace functional group with OH Refer to previous page for discussion of formulation- dependent ADR profiles. Active metabolite: desethyloxybutynin
78
What side effects would you predict in someone who was a CYP2D6 poor metabolizer when compared to an ultra-rapid metabolizer?
more parent drug and less metabolite,
79
Tolterodine and Fesoterodine
fesoterone- prodrug of 5-HMT, more predictable and much cleaner tolerodine- no esterase, less predictable

pharm sci (12 decks)

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