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Pharmacology > Anticholinergics (LJ Chp 8) > Flashcards

Anticholinergics (LJ Chp 8) Flashcards

1
Q

Why use anticholinergics

A
  • Treat +/- prevent ax/preax bradycardia
  • Decrease airway/salivary secretions
  • Dilate pupil
  • Block vagally-mediated reflexes (viscerovagal, oculocardiac, Branham)
  • Block effects of parasympathomimetic drugs
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2
Q

Why historically used as part of standard premed protocol

A
  • Inhalant anesthetics (eg diethyl ether) produced profound parasympathetic effects –> hypersalivation, bradycardia
  • Used consistently preop to counter effects
  • Modern inhalants have lesser effects on the autonomic NS –> indiscriminate use of anticholinergic drugs less popular
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3
Q

Plants that contain naturally-occurring tropane alkaloids (atropine, hyoscyamine, scopolamine)

A

Deadly nightshade - Atropa belladonna
Henbane - Hyoscyamus niger
Mandrake - Mandragora officilianis
–> plants contain concentrations that are potentially toxic to most species
–> extracts from these plants have been used since ancient times for their anesthetic, mydriatic, antidiarrheal, analgesic properties

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4
Q

When and from what was atropine isolated?

A

1830s

Deadly nightshade/Atropa belladonna

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5
Q

When and from what was hyoscine isolated?

A

1880s

Henbane/Hyoscyamus niger

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6
Q

General pharmacology of Anticholinergics

A

Competitively antagonize ACh at postganglionic muscarinic cholinergic R in the PNS
–Use of “antimuscarinics” to differentiate drugs that only act as antagonists @ muscarinic R from some naturally occurring compounds that can non-specifically antag both muscarinic and nicotinic ACh R

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7
Q

Muscarinic R

A

5 subtypes –> M1-M5 (based on order in which cloned)

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8
Q

Mechanism of Muscarinic R

A

Intracellular signaling by activation of different subtypes occurs via coupling to multiple G proteins
–Single receptor subtypes capable of activating more than 1 GPCR in the same cell
Tissue-specific anatomic distribution/physiological response

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9
Q

M1, M3, M5 R

A

Couple with Gq/11-type proteins

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10
Q

M2, M4 R

A

Couple with Gi/o-type proteins

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11
Q

Which muscarinic R couple with Gq/11-type proteins?

A

M1, M3, M5

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12
Q

Which muscarinic R couple with Gi/o-type proteins?

A

M2, M4

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13
Q

T/F: atropine and glycolic are relatively unselective in binding to muscarinic R types

A

True!

Different tissues types have different responses to clinically administered doses of these drugs

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14
Q

T/F: receptors in the salivary, cardiac, and bronchial tissues more sensitive than those in the urinary and GIT

A

True

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15
Q

Which anticholinergic has greater antisialagogue effects?

A

Glyco > atropine

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16
Q

Which anticholinergic has greater HR increase?

A

Atropine > glycolic

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17
Q

Which anticholinergic has greater smooth muscle relaxation?

A

Atropine = glyco

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18
Q

Which anticholinergic has greater ophthalmic effects/pupil dilation?

A

Atropine

Glyco doesn’t affect ocular tissue

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19
Q

Location of M1

A

CNS, Stomach

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20
Q

Location of M2

A

Lungs, Heart (SA/AV node, atrial myocardium)

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21
Q

Location of M3

A

CNS, Salivary glands, airway SM; also vascular endothelium

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22
Q

Location of M4

A

CNS, Heart

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23
Q

Location of M5

A

CNS

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24
Q

Effect of binding to M1

A

CNS –> neuron depolarization

Stomach –> H+ secretion

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25
Q

Effect of binding to M2

A

Lungs –> bronchoconstriction
SA/AV nodes –> bradycardia, AV block
Atrial myocardium –> decreased inotrophy

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26
Q

Effect of binding to M3

A

CNS –> ?
Salivary glands –> salivation
Airway SM –> BC, increased secretions
Vascular endothelium –> VD

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27
Q

Effect of binding to M4

A

UNK

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28
Q

Effect of binding to M5

A

UNK

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29
Q

Other roles of M1, M2, M3 receptors?

A

Cause actions via non-G protein mechanisms such as protein kinase

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30
Q

What are the two anticholinergics used in veterinary medicine?

A
  • Atropine
  • Glycopyrrolate

Relatively unselected in their binding to receptor subtypes

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31
Q

Cellular response at the M1

A

PLC activated

Increased IP3, DAG. Ca2+, PKC, cAMP

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32
Q

Cellular response at the M2

A

PLC activated, increased/decreased adenylyl cyclase

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33
Q

Cellular response at the M3

A

PLC activated
Increased IP3, DAG, Ca2+
Increased NO

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34
Q

Cellular response at the M4

A

Decreased adenylyl cyclase

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35
Q

Cellular response at the M5

A

PLC activated
Increased IP3, DAG, Ca2+
Decreased PKA, cAMP

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36
Q

AC

A

adenylyl cyclase

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37
Q

DAG

A

Diacylglycerol

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38
Q

IP3

A

Inositol triphosphate

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39
Q

PKC

A

Protein kinase C

40
Q

PKA

A

Protein kinase A

41
Q

PLC

A

Phospholipase C

42
Q

Anticholinergic effects in the heart

A

-Mediateed by pre/post synaptic M2 receptors located in the SA, AV nodes; atrial myocardium

43
Q

Cardiac effects of systemic anticholinergic drug administration

A
  • Increase in sinus rate
  • Acceleration of AV nodal conduction
  • Increased atrial contractility
44
Q

Downside of increased HR with anticholinergic administration

A

Tachycardia/tachydysrhythmias - may be unwanted, particularly if changes result in decreased CO or significantly increased myocardial oxygen consumption,

45
Q

Contraindications for anticholinergic use

A
  • Hypertrophic CM

- Restrictive CM

46
Q

Mechanism of a paradoxical bradycardia following atropine administration

A
  • DT more rapid blockade of presynaptic M1 R that inhibits negative feedback mechanism –> transient increase in ACh release, further slowing HR
  • Wait few minutes or repeat dose –> induction of blockade of postsynaptic M2 receptors –> increased HR
47
Q

Anticholinergic administration effects: bronchodilator, reduced airway secretions

A
  • via M2, M3 R antagonism
  • Can decrease airway resistance, likelihood of airway obstruction
  • Can contribute to hypoventilation –> theoretically decreased arterial oxygen tension as a result of increased anatomic dead space
48
Q

Effect of anticholinergic administration on reduction of airway secretions

A

Viscosity of the airway secretions increases as the volume is decreased following an anticholinergic administration –> potentially offsets any benefit with respect to reducing airway secretions

49
Q

Ophthalmic Effects

A
  • Cholinergic fibers originating from CN III innervate circular m (sphincter papillae) of the iris that control pupil diameter
  • Also ciliary m that controls shape of lens, facilitating accommodation
  • Topical administration to cornea blocks actions of ACh at both of these sites –> mydriasis, cyclopegia
  • Atropine in cats, horses, sheep, goats; glyco in rabbits
50
Q

Effects on IOP

A
  • Acutely increase caused by drainage angle closure in cats (not in sheep, horses)
  • Mixed findings –> ROA avoided in patients with preexisting elevations of IOP or those predisposed to developing angle-closure glaucoma
51
Q

Ranking ocular effects (when administered systemically)

A

Scopolamine > atropine > glycopyrrolate

52
Q

T/F: the potential to induce mydriatic, cyclopegia effects with systemic (ie either IV or IM) administration of anticholinergics is lower than with topical administration

A

True

Probably also dose and drug dependent

53
Q

Negative ophthalmic effects of anticholinergic administration

A

-Decreased tear production –> corneal drying

54
Q

Effect of systemic anticholinergic administration on patients with glaucoma

A

-Few data for any species to suggest that systemic administration of atropine or glycopyrrolate at clinically relevant doses for treatment of reflex or drug-induced bradycardia would cause adverse effects in patients with glaucoma

55
Q

Which anticholinergics that cross BBB?

A

Atropine

Scopolamine

56
Q

Effects of anticholinergics that cross the BBB

A
  • Potential to induce sedation, prolong anesthetic recovery when administered systemically via M1 R antagonism
  • Atropine: sedative potential when clinically relevant doses administered is negligible
57
Q

Anticholinergics (M3) as Effective Antisialogogues

A
  • Effective antisialogogues in monogastrics
  • Ruminants: salivation is not inhibited completely –> saliva becomes more viscous to the point where thickened, ropy saliva may post a risk of causing airway obstruction
  • Routine use not recommended in ruminants except for treating intraoperative bradycardia
58
Q

Anticholinergics and GI Ileus

A
  • Dose required to decrease GI motility via blockade of M3 R higher than that required to treat bradycardia
  • Some risk of GI ileus following administration
  • May lead of symptoms of colic in horses –> avoided except in instances of bradycardia
59
Q

Effects of anticholinergics in monogastrics

A

-Decrease lower esophageal sphincter function –> increased risk GER +/- associated complications (asp pneumonia, esophagitis, esophageal stricture

60
Q

Atropine

A

-Racemic mixture L/D-hyoscyamide

61
Q

Which isomer of atropine is responsible for its activity?

A

L-isomer

62
Q

Atropine Structure

A

Lipid-soluble tertiary amine structure
Tropic-acid ester linked to organic base
Easily crosses BBB, blood-placental barrier

63
Q

Atropine Onset: IV

A

1min

64
Q

Atropine Onset: IM

A

5min

65
Q

How long does atropines increase in HR last?

A

Increase in HR should last approximately 30min

66
Q

How long does atropine’s effects on other systems last?

A

generally affected for one to several hours

Mydriasis after topical administration can last for up to several hours

67
Q

Atropine Metabolism

A
  • Varies btw species
  • Rapidly cleared from the central compartment via hydrolysis to inactive metabolites
  • Some excreted unchanged by kidneys in dogs and people
68
Q

Atropine in Rabbits

A
  • Normally eat leaves of deadly nightshade without issue –> have ability to metabolize atropine-like compounds rapidly via plasma esterase (atropinase)
  • May render typical clinical doses ineffective
  • Large amt of enzyme not possessed by all rabbits so full MOA yet to be elucidated
69
Q

Atropine metabolism in cats

A

Hepatic and renal esterases contribute to clearance from plasma

70
Q

Atropine Clinical Use

A
  • Prevent/treat bradycardia associated with ax

- IM, IV preferred over SQ to maximize absorption, minimize onset time

71
Q

Atropine Dose: Dogs, Cats

A

0.02-0.04mgkg

72
Q

Atropine Dose: Horses

A

0.02-0.04mgkg

73
Q

Atropine Dose: Ruminants

A

0.04-0.08mgkg

74
Q

Atropine Dose: Pigs

A

0.04-0.08mgkg

75
Q

Glyco Dose: Dogs, Cats

A

0.005-0.01mgkg

76
Q

Glyco Dose: Horses

A

0.0025-0.005

77
Q

Glyco Dose: Ruminants

A

0.0025-0.005

78
Q

Glyco Dose: Pigs

A

0.0025-0.005

79
Q

Other Clinical Uses: Atropine

A
  1. Reversal from NMB prior to administration of cholinergic drugs (neostigmine, edrophonium)
  2. CPR - if no IV access, can be administered via ETT @ 2-3x IV doses
80
Q

Atropine Effects: Dose-Dependent Tachycardia

A
  • Mean dose required to increase HR by 50% in conscious dogs ~0.04mgkg IV
  • Greater increases in HR may be observed in patients with high pre-existing vagal tone –> “excess tachycardia”
  • Occasionally see VPCs but not necessarily proportional to the magnitude of the tachycardia
  • Transient tachycardia generally well-tolerated in most patient populations
81
Q

Atropine’s Tachycardia: Which subset of patients to use with caution?

A

-Those which may be adversely impacted by tachycardia ie restrictive/hypertrophic forms of cardiomyopathy

82
Q

What are the two parasympathomimetic effects that often occur with lower doses of atropine?

A
  1. Transient bradycardia

2. Second-degree AV block

83
Q

MOA of Parasympathomimetic Effects of Atropine Administration

A
  • Initial blockade of of presynaptic peripheral M1 receptors that normally inhibit ACh release
  • Causes transient increase in ACh prior to onset of atropine-induced postsynpatic M2 blockade
  • Resulting bradycardia +/- AV block typically resolves spontaneously with establishment of postsynaptic blockade or upon administration of a supplemental dose
84
Q

Glycopyrrolate Structure

A
  • Synthetic quaternary ammonium
  • Poorly lipid soluble –> difficult to cross BBB, placental-blood barrier.
  • Mandelic acid ester linked to organic base
  • 4x potency of atropine
85
Q

Glycopyrrolate Duration of Action

A
  • Onset of action slightly slower compared to atropine –> usually occurs within several minutes
  • In conscious dogs CV effects lasted for approximately 1hr –> longer than those for atropine
86
Q

Glycopyrrolate Metabolism

A
  • Cleared from plasma relatively rapidly

- Excreted unchanged in the urine

87
Q

Ocular Effects of Topical Glycopyrrolate

A

Rabbits: persistant mydriasis, cycloplegia

Systemic administration in dogs of clinically relevant doses reported to have minimal effects on ocular parameters

88
Q

Why is glycopyrrolate preferred in people over atropine?

A
  • People: improved CV parameters with less risk of tachycardia
  • Not the case in dogs: drug effects on CV system similar btw the two anticholinergics
89
Q

Effect of Glyco on GI Motility

A
  • motility decreased for up to 30min in dogs
  • Duration of decreased motility was dose-dependent, lasting for over 6hr following 0.005mgkg IV dose
  • Development of postop colic in horses is multifactorial - in one study, only 1/17 horses that received glyco colicked after surgery
90
Q

Clinical use of glyco

A
  • Tx/prevent bradycardia in perioperative period
  • Used to counteract cholinergic effects when reversing NMBA with cholinergic drug
  • Not used as emergency drug in CPR DT longer onset times
91
Q

Are anticholinergics water-soluble or fat-soluble?

A

Water Soluble

92
Q

Historical use(s) of anticholinergics

A
  • Premixed premed combos in SA ax –> “BAG” (butor, Acepromazine, glyco), “superBAG” (buprenorphine, ace, glyco)
  • Often selected to counteract bradycardia associated with a2 agonists
93
Q

Use of anticholingerics to treat bradycardia

A

-Important to determine whether bradycardia is a baroreceptor-response to increased arterial BP secondary to peripheral VC or due to centrally mediated suppression of sympathetic output with accompanying low BP

94
Q

Consequences of increasing HR in face of increased ABP

A

Has the potential to decrease CO further while significantly increasing myocardial oxygen consumption

95
Q

T/F: minimal improvement in CO when dogs sedated with dexmed + atropine vs dexmed alone

A

True

96
Q

Use of an anticholinergic following a2

A
  • If ABP is low, admin of anticholinergic may be considered to counter bradycardia and improve BP
  • If bradycardia is actually secondary to decreased sympathetic nervous system activity, antagonism of PS influence on the sinus node may not cause improvement in HR
  • In those cases, administration of sympathomimetic agent (ie ephedrine) or reversal of alpha 2 may be beneficial

Pharmacology (7 decks)

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