450: Cholinergics

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1

Ionization removes ____________ solubility

Lipid

2

Ionization imparts ____________ solubility

Water

3

In order to excrete a drug, it must be _________philic in the kidney

Hydro

4

Acids are ionized in a more ________pH

Basic

5

Bases are ionized in a more ________pH

Acidic

6

The percentage at which a drug is 50/50 ionized is its ______

PKA

7

Good H bond donor examples

O-H, N-H

8

Good H bond acceptor examples

O., N.

9

What is responsible for synthesizing ACh

ChAT

10

Choline is a ____________ ammonium alcohol

Quaternary

11

What is the rate limiting step of ACh synthesis?

Choline reuptake

12

Which receptor:

  • located throughout the CNS and Exocrine glands
  • Involved in memory, learning, Alzheimer's

M1

13

Which receptor:

  • Primarily postgang neurons: Heart, smooth muscle, exocrine glands
  • Decrease HR and force of contraction
  • Presynaptic autoreceptor

M2

14

Which receptor:

  • In brain, smooth muscle (contraction), secretory glands (secretion)
  • Decrease NT release

M3

15

Where is M4 located

Smooth muscle and secretory glands

16

What drives binding of ACh to the GPCR?

Ionic bond b/w Asp and ACh on #3

17

What functional groups are known to interact with ACh and how?

  • Asp; Ionic bond to amine
  • Thr; H bond to ester
  • Tyr; H bond to ester
18

What event activates GPCR signaling?

ACh binding to receptor pocket

19

List endogenous examples of ionizable amines

  • ACh
  • E
  • NE
  • Serotonin
  • His
  • DA
  • Trace elements
20

T/F: Drugs that are ionized or lipophyllic can easily pass through membranes.

False

21

T/F: Nicotinic receptors are Pentameric GPCRs.

False

22

What are the subunits of nicotinic channels?

α2, β, γ (or ε), and δ

23

T/F: ACh gates the passage of Na+ and Ca2+ through nicotinic channels.

False

24

Where does ACh bind on a nicotinic receptor?

α2

25

Why is ACh a poor therapeutic agent?

  • Ester hydrolyzed rapidly
  • Quat. ammonium salt = ↑H2O solub. = ↓absorption
  • Nonselective for M1-5 and nicotinic receptors
26

List the SAR for muscarinic selective agonists

  • N capable of + charge (pref. quat ammonium salt)
  • For max potency, size of N substituents should not exceed a methyl group
  • O capable of H bonding (pref. ester)
  • No more than 2 C b/w O and N
27

Adding a methyl group on the β carbon of ACh creates what?

Methacholine, a semi-selective M agonist

28

What is the Methacholine challenge?

Inhalation of methacholamine as a diagnostic agent for asthma; triggers asthma attack and lung fxn measured after repeated doses

29

List the SAR rules for Muscarinic antagonists

  1. R1 and R2 should be cyclic / heterocyclic rings for max antagonism
  2. R3 can be H, OH, CH3O (increases binding via H bonds)
  3. X substituents which are esters are most potent
  4. N substituents that are quat ammonium salts are most potent (tert amines also antagonistic)
  5. Distance b/w ester and N can vary b/w 2-4, w/ 2 being most active
30

Introduction of β-CH3 creates what within the molecule?

Optically active chiral center

31

T/F: The S form of methacholamine is equipotent w/ ACh at antagonism fo the receptor.

False

32

How is the S form of methacholamine hydrolyzed compared to ACh?

1/2 the rate

33

T/F: The R form of methacholamine is 20x less potent as ACh at agonism of the receptor.

True

34

T/F: R methacholamine is hydrolyzed by AChE and is a weak competitive inhibitor of AChE.

False

35

Where is ACh hydrolyzed by AChE?

Ester group

36

T/F: Ocular administration of Carbachol lasts 12 hrs because carbachol is not as readily hydrolyzed.

False

37

Carbamate is more stable than carboxylic ester bc the carbonyl carbon is ______(more/less) electrophilic

less

38

T/F: Carbachol/carbamate is not as readily absorbed from the GI

True

39

Why is carbachol's use limited to ocular indications?

Activates muscarinic and nicotinic receptors = more side effects

40

What is carbachol used for?

  • Miotic for cataract surgery
  • decrease IOP for glaucoma (increase aq outflow)
41

What is the affect of adding an amine group (modifying acyloxy group) for a muscarinic agonist (like we see with Carbachol)?

Increase duration of the drug

42

What is the affect of adding a β-CH3 group for a muscarinic agonist (like we see with Methacholine)?

Increase muscarinic specificity

43

What unique properties does bethanechol have?

  • β-methyl = muscarinic specific
  • Carbachol amine = increase duration
44

What is bethanechol's MOA?

Selective M agonist

45

What happens if bethanechol is administered IV or IM?

Cholinergic crisis

46

T/F: The S enantiomer of bethanechol exhibits greater binding than the R enantiomer.

True

47

How is bethanechol administered?

Orally

48

Competitive, reversible blockers of M receptors are known as

M antagonists

49

What effects in the body are caused by M antagonists?

  • Decrease smooth muscle contraction, GI, UT
  • Dilation of pupils
  • Decrease sweat/saliva
  • Decrease gastric secretion
50

Why are M antagonists contraindicated in pts with glaucoma?

Potent effects on IOP; Iris dilated = drainage blocked = increase in P

51

Earliest antimuscarinics were ____________ extracted from plants such as deadly nightshade

Alkyloids

52

Name two drug examples of belladonna alkaloids isolated from Atropa belladonna

  • Atropine
  • Scopolamine
53

How do drugs like Atropine and scopolamine mimic ACh to block M receptors?

Tropine ring folds like an accordion and allows the drug to compress and fit into the ACh binding site

54

T/F: Atropine and Scopolamine allow for a change in the conformation of the receptor, thereby inhibiting its effects.

False

55

Is the tropine ring required for drugs like atropine and scopolamine to work?

Yes; it allows the distance b/w N and O to be similar to the distance b/w N and O of ACh

56

What is homatropine used for?

GI spasms (via ganglionic blocking)

57

How is homatropine different from atropine?

  • Addition of methyl group (increases potency bc quat amine)
  • Reduction of CH2-OH to OH group
58

What is Clidinium used for?

  • Has antispasmodic and antisecratory effect on GI
  • Peptic ulcer disease
  • ab/stomach cramps/spasms due to colicky ab pain, diverticulitis, and IBS
59

What is Ipratropium used for?

  • COPD
  • Bronchitis/rhinitis associated w/ cold or allergies
60

Will Ipratroium or Tiotropium have CNS activity? why?

No. Ionized.

61

T/F: Tiotropium is more selective for M1 and M4 receptors.

False

62

What drug is a spasmolytic flavone derivative that acts by relaxing the smooth muscle in the UT?

Flavoxate

63

T/F: Flavoxate is a competitive M agonist for overactive bladder

False

64

How does Curare cause paralysis in the muscles?

alkaloid acting as NM blocking agent

65

What is the AI of Curare?

D-Tubocurarine (non-depolarizing NMJ blocker)

66

What are some AE associated w/ Curare and other NM blocking agents and what causes them?

  • Hypotension
  • Bronchospasm
  • Cardiac issues
  • Caused by: His release
67

T/F: Many NM blocking agents cause depolarization at the motor end plate.

True

68

What is the max number of methylene groups allowed by SAR for M antagonists?

10-12

69

Why are bis-quaternary ammonium ions useful for blocking nAChR?

Bc N receptors have a dianionic binding site

70

T/F: Decamethonium and Succinyl choline block the NMJ and causes depolarization of the postjxnl membrane.

True

71

What drug is 2 molecules of ACh connected at carbons alpha to carbonyl of acetate?

Succinyl choline

72

T/F: Succinyl choline is useful for procedures such as intubation because it is slowly deactivated by esterase in the plasma, causing long durations of relaxation (>10min).

False

73

List examples of steroid NM blocking agents

  • Pancuronium
  • Vecuronium
  • Pipercuronium
  • Rocuronium
74

Describe Pancuronium

  • Bis-quat ammonium
  • Long acting (120-180 min)
  • 3-6 min onset
  • CV effects, contraindicated
  • Stimulates His release
75

Describe Vecuronium

  • Tert-quat ammonium
  • Intermediate acting (30-40 min)
  • 3-6 min onset
  • No CV effects
  • No His release
76

Describe Pipecuronium

  • Bis-tert/quat ammonium
  • Long acting (80-100 min)
  • 3-6 min onset
  • No CV, His. effects
77

Describe Rocuronium

  • Tert-quat ammonium
  • Intermediate acting (30-40 min)
  • 1 min onset
  • No CV effects
  • No His. effects