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Therapeutics > Exam 1 Cholinergic Antagonists/Anticholinergics > Flashcards

Exam 1 Cholinergic Antagonists/Anticholinergics Flashcards

1
Q

What do muscarinic antagonists (antimuscarinics) do?

A

they are competitive antagonists for muscarinic receptors (M1, M2, M3) located in the smooth muscle, cardiac muscle, and exocrine glands

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2
Q

Where does acetylcholine bind?

A

binds to cholinoceptors on the postsynaptic cell and is directly acting → binds to muscarinic and nicotinic receptors

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3
Q

What is atropine?

A

the oldest and most well known antimuscarinic agent that is an antagonist at M1, M2, and M3 receptors → has CNS access and can only bind to muscarinic receptors

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4
Q

What is the basis of anticholinergics?

A

they bind to the receptor and disrupt acetylcholine binding

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5
Q

Overactive bladder and COPD can be treated with what kind of agents?

A

antagonists

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6
Q

What are the effects of antimuscarinic agents?

A
  1. muscarinic receptor blockade → competitive antagonism at the muscarinic receptor (M1, M2, M3) mediated actions of acetylcholine on autonomic effectors innervated by postganglionic cholinergic nerves as well on smooth muscles that lack cholinergic innervation
  2. ganglia → antimuscarinic agents have little effect on the actions of acetylcholine at the nicotinic receptor & autonomic ganglia (where transmission primary involves ACh binding to nicotinic receptors) → atropine can produce partial block (M1) only at high doses
  3. CNS → widespread distribution of muscarinic receptors throughout brain & therapeutic doses are attributable to their central muscarinic blockade
  4. prototype drug is atropine
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7
Q

How does atropine have a dose dependent effect?

A
  1. 0.5 mg → slight cardiac slowing, some mouth dryness, inhibition of sweating
  2. 1 mg → definite mouth dryness, thirst, heart acceleration, mild pupil dilation
  3. 2 mg → rapid heart rate, palpitation, marked mouth dryness, dilated pupils, some blurring of near vision
  4. 5 mg → difficulty in speaking/swallowing, restlessness and fatigue, headache, dry/hot skin, reduced intestinal peristalsis, difficulty peeing
  5. greater than 10 mg → rapid/weak pulse, obliterated iris, blurred vision, flushed skin, ataxia, restlessness, excitement, hallucinations, delirium, coma

red as a beet, dry as a bone, blind as a bat, hot as a firestone, and mad as a hatter

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8
Q

What is the most common anticholinergic side effect?

A

dry mouth

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9
Q

What are the effects of atropine according by dose on the exocrine glands?

A

effect → decreased secretions and sweating
therapeutic → preanesthetic, OTC cold remedies, peptic ulcer
adverse/toxic → dry mouth, hyperthermia in children

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10
Q

What are the effects of atropine according by dose on the eye?

A

effect → mydriasis, cycloplegia (blurred vision)
therapeutic → ophthalmic examination or procedures
adverse/toxic → acute exacerbation of glaucoma

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11
Q

What are the effects of atropine according by dose on the cardiovascular system?

A

effect → increased heart rate
therapeutic → treatment of bradyarrhythmia, heart block, sinus arrest
adverse/toxic → tachycardia, increased risk of VF in acute MI

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12
Q

What are the effects of atropine according to dose on the respiratory tract?

A

effect → block of vagal, bronchoconstriction

therapeutic → treatment of COPD and asthma

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13
Q

What are the effects of atropine according to dose on urinary bladder?

A

effect → decreased tone and constricted sphincter
therapeutic → reduce urinary frequency in certain settings
adverse/toxic → urinary retention, especially for elderly

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14
Q

What are the effects of atropine according to dose on the GI smooth muscle?

A

effect → decreased motility and tone
therapeutic → treatment of hypermotility (caused by antihypertensive drugs)
adverse/toxic → constipation, especially in elderly

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15
Q

What are the effects of atropine according to dose on the CNS?

A

effect → block of all muscarinic receptors
therapeutic → anti-motion sickness, anti-Parkinson’s
adverse/toxic → confusion, delirium, depression, coma

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16
Q

What is the major mechanism of antimuscarinics?

A

competitive and reversible inhibition of muscarinic receptor activation by preventing the binding of acetylcholine

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17
Q

What are the two classes of antimuscarinics based on their structure?

A
  1. tertiary amines → mainly used in ocular and CNS applications since it has no charge (example is atropine)
  2. quaternary amines → mainly used in GI tract and peripheral application since it is charged (example is anisotropine)
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18
Q

What are the three main classes of muscarinic antagonists?

A
  1. tertiary amines (3 bond to nitrogen) that has good CNS access → belladonna alkaloids like atropine and scopolamine
  2. tertiary amine derivatives for anti-Parkinson use → benztropine (Cogentin) and trihexyphenidyl (Artane)
  3. quaternary (+ charge) derivatives of belladonna alkaloids → ipratropium (Atrovent) and tiotropium (Spiriva)
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19
Q

What are important things to note about long lasting tertiary amine antimuscarinics?

A
  1. M1/M2/M3 non-selective
  2. treats GI/urinary conditions, motion sickness, adjunct for Parkinsons
  3. can affect the CNS → scopolamine has higher CNS penetration so it induces greater drowsiness (low doses) or hallucinations (high doses)
  4. naturally occurring → belladonna used to dilate the eyes in Italy, deadly nightshade, historically used as a hallucinogen with side effects of confusion, dilated pupils, and tachycardia
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20
Q

What is the difference in duration of effect between atropine and scopolamine?

A

atropine lasts 7-10 days while scopolamine lasts 3-7 days → atropine has longer duration

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21
Q

Why does scopolamine have higher CNS access than atropine?

A

it has an epoxide group that atropine lacks making it more lipophilic and thus greater CNS access

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22
Q

What is the action, clinical use, and side effects of scopolamine (Maldemar)?

A
  1. action → antimuscarinic with relatively more CNS action than atropine (highly lipophilic)
  2. clinical use → effective treatment of motion sickness (oral or transdermal)
  3. side effects → dry mouth, blurred vision, sedation, high doses: confusion and psychosis
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23
Q

What are examples of long lasting tertiary amine antimuscarinics?

A

atropine and scopolamine

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24
Q

What are examples of short acting tertiary amine antimuscarinics?

A

homatropine and tropicamide

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25
Q

What are things to know about short acting tertiary amine antimuscarinics?

A
  1. used in optical applications (cycloplegia and mydriasis) → due to short duration of action
  2. action of this drug is similar to atropine/scopolamine
  3. homatropine is less toxic but tropicamide has a shorter duration of action
26
Q

What is the difference in duration of effect for homatropine and tropicamide?

A

homatropine lasts 1-3 days while tropicamide lasts 0.25 days → homatropine has a longer duration

27
Q

What is a tertiary amine used for Parkinson’s Disease?

A

benztropine (Cogentin) → 2 aromatic groups, binds to muscarinic receptor, has more CNS access since it is more lipophilic because of the aromatic rings, is a derivative of alkaloids

28
Q

How is benztropine used for Parkinson’s?

A

has sedative activity and is used as an adjunct therapy with L-DOPA in PD patients (to achieve better balance between dopaminergic and cholinergic neurotransmission) → has a similar potency to atropine

29
Q

What is another drug used for Parkinson’s?

A

trihexyphenidyl

30
Q

What is a quaternary amine used for COPD?

A

ipratropium (Atrovent) → quaternary nitrogen so it has less CNS access which is why it is used more for peripheral uses

31
Q

What is the action, clinical use, and problems associated with ipratropium (Atrovent)?

A
  1. action → antimuscarinic with receptor activity similar to atropine, an M3 antagonist that blocks acetylcholine mediated constriction and open the airways
  2. clinical use → treatment of COPD, occasionally for asthma → less effective as a monotherapy but enhances the therapeutic effect of beta-adrenergic agonists in COPD
  3. problems → few because of poor absorption, toxic doses may cause hypotension (ganglionic blockade) and muscle weakness (neuromuscular blockade)
32
Q

What is Combivant or Duoneb (trade name)?

A

the combination of ipratropium and albuterol which is effective in treating COPD

33
Q

What is a longer acting analog similar to ipratropium?

A

tiotropium (Spiriva)

34
Q

What are some examples of quaternary amines used to treat GI disorders?

A

glycopyrrolate and propantheline bromide (Probanthine) → used to treat gastric disorders (GI spasms, peptic ulcers)

glycopyrrolate is used during pre-op to reduce secretions since the charged nitrogen makes crossing the gut difficult

35
Q

What is the action, clinical use, and problems associated with tolterodine (Detrol)?

A
  1. action → no apparent selectivity for different muscarinic receptor subtypes but therapeutically seems to act somewhat selectively on M3 receptor
  2. clinical use → overactive bladder (OAB)
  3. problems → still causes typical anticholinergic effects but significantly lower than with previous antimuscarinic drugs
36
Q

What are examples of newer M3 receptor selective muscarinic antagonists used to treat OAB?

A
  1. solifenacin (Vesicare)
  2. darifenacin (Enablex)
  3. oxybutynin

advantages: lower incidence of constipation and confusion

37
Q

What are common side effects with antimuscarinic drugs used to treat overactive bladder?

A

constipation and confusion

38
Q

What are important things to know about antimuscarinic poisoning?

A
  1. over 600 medications contain drugs with antimuscarinic properties → H1 receptor antagonists (diphenhydramine), older antipsychotics (chlorpromazine), tricyclic antidepressants (amitriptyline)
  2. often see antimuscarinic effects at therapeutic doses (like dry mouth)
  3. treatment → change medicine or decrease dose, supportive care (sodium bicarbonate is prolonged QRS or arrhythmias, benzodiazepines for agitation/delirium), can also treat with physostigmine which is an acetylcholinesterase inhibitor
  4. identify potentially inappropriate medications for the elderly → 30-60% of elderly nursing home residents receive medications with significant antimuscarinic effects → Beers criteria and STOPP
39
Q

What are the most common side effects of anticholinergics?

A

dry mouth and constipation

40
Q

What are neuromuscular blocking drugs?

A

neuromuscular blocking agents look like acetylcholine that binds to muscarinic and nicotinic receptors and to acetylcholinesterase → sites include preganglia and CNS

41
Q

What are some examples of neuromuscular blocking drugs?

A

acetylcholine, succinylcholine (is a dimer so can’t be hydrolyzed by acetylcholinesterase because it doesn’t have the acetyl CH3), and tubocurarine

42
Q

What is the normal mechanism of nicotine receptors?

A

nerve action potential → ACh release → ACh binds to the nicotinic receptor → depolarization → open fast Na+ channels → action potential in neuron or muscle

43
Q

What is an alternative pathway of nicotinic receptors?

A

open fast Na+ channels → fast Na+ channels close (INACTIVE) → ACh degrades and the endplate is repolarized → reset fast Na+ channels to ACTIVE STATE → depolarization → open fast Na+ channels → action potential

44
Q

What are the stimulation effects of nicotine on muscle?

A

normal operation of nicotinic receptors is the rapid degradation of synaptically released acetylcholine → allows the neuronal membrane or muscle endplate to repolarize and fast Na+ channels to reset → the next ACh release causes another depolarization which triggers the opening of the rested Na+ channels and action potential

45
Q

What are the desensitization effects of nicotine on the muscle?

A

nicotinic receptors are specifically adapted to the transient nature of acetylcholine as a neurotransmitter

depolarizing blockade: agonist binds to nicotinic receptor → depolarization → open fast Na+ channels → action potential in neuron (or muscle)

46
Q

What happens if the agonist remains bound to the receptor?

A

persistent depolarization means fast Na+ channels CANNOT reset to the active state to induce another action potential → desensitization

47
Q

What are two ways to block the nicotinic receptor?

A
  1. non-depolarizing blockade (normal antagonist) → tubocurarine
  2. depolarizing blockade (first activates, then blocks) → succinylcholine
48
Q

What is the action, clinical use, and problems associated with tubocurarine (Curare)?

A
  1. action → nicotinic receptor competitive antagonist producing non-depolarizing blockade
  2. clinical use → skeletal muscle relaxation during anesthesia → particularly useful for intubation
  3. problems → minor
49
Q

What is the mechanism of action of succinylcholine (Suxamethonium) aka SUX?

A
  1. binds to the nicotinic acetylcholine receptor (structure is two linked ACh molecules)
  2. agonist nicotinic receptor, initial depolarization allows ion flow
  3. persistent depolarization makes the muscle fiber resistant to further stimulation by ACh by preventing the resetting of voltage gated Na+ channels
  4. metabolized to choline by plasma butyrylcholinesterase → slower than acetylcholinesterase, choline increases BP, muscle fasciculation precedes paralysis of the arm, neck, leg then respiratory muscles
  5. has a rapid onset of 30-60 seconds but a short duration (5-10 minutes)
50
Q

What is the clinical use of succinylcholine?

A

skeletal muscle relaxation during anesthesia (particularly useful for intubation) and is also used for electro-convulsant therapy

51
Q

What are the problems associated with succinylcholine?

A
  1. muscle soreness → avoid in hyperkalemia, cause of cardiac arrest (has cardiac side effects since it increases BP)
  2. malignant hyperthermia
  3. prolonged paralysis can result in people with atypical plasma cholinesterase
52
Q

What is the action, clinical use, and problems associated with botulinum toxin?

A
  1. action → inhibit release of acetylcholine by inhibiting fusion and release of ACh from the synaptic cleft → indirect acting
  2. clinical use → dystonias (uncontrolled muscle spasms), cerebral palsy, spasm of ocular muscles, anal fissure, hyperhidrosis (excessive sweating)
  3. problems → spread from injection site
53
Q

What is the action and use of hexamethonium?

A
  1. action → antagonist at nicotinic receptors in autonomic ganglia thus blocking all SNS and PSNS activity (is a ganglionic nicotinic receptor antagonist)
  2. use → originally developed to treat hypertension but not used clinically due to adverse effects
54
Q

What are the problems associated with hexamethonium?

A

blocking basal tone of SNS and PSNS resulting in:

  1. blood vessels (SNS) → hypotension
  2. swat glands (SNS) → decreased perspiration
  3. other glands (PSNS) → dry mouth, decreased secretions
  4. heart rate (PSNS) → tachycardia (usually but sometimes if SNS is active will see bradycardia)
  5. eye (PSNS) → pupillary dilation and blurred vision
  6. gut (PSNS) → decreased tone and motility, constipation
  7. bladder (PSNS) → urinary retention
55
Q

What are the examples of muscarinic agonists?

A
  1. acetylcholine
  2. muscarine
  3. pilocarpine
  4. bethanechol
  5. carbachol
  6. methacholine
56
Q

What are examples of acetylcholinesterase inhibitors?

A
  1. edrophonium
  2. neostigmine
  3. physostigmine
  4. pyridostigmine
  5. echothiophate
  6. sarin
  7. malathion
57
Q

What are examples of muscarinic antagonists?

A
  1. atropine
  2. scopolamine
  3. ipratropium
  4. tolterodine
58
Q

What are examples of acetylcholinesterase poisoning antidotes?

A
  1. atropine

2. pralidoxime (2-PAM)

59
Q

What are examples of nicotinic agonists?

A
  1. nicotine

2. varenicline (partial)

60
Q

What are examples of nicotinic NMJ antagonists?

A
  1. succinylcholine (depolarizing)

2. tubocurarine (non-depolarizing)

61
Q

What is an example of a ganglionic antagonist?

A

hexamethonium

62
Q

What is an example of a drug that blocks the release of acetylcholine?

A

botulinum toxin

Therapeutics (15 decks)

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