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Pharmacology > Cholinergic Drugs > Flashcards

Cholinergic Drugs Flashcards

1
Q

2 types of Ach receptors

A

Muscarinic (heart, smooth muscles, exocrine glands)

Nicotinic (ganglion and skeletal muscles)

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2
Q

What do direct-acting cholinergic drugs affect?

A

Muscarinic and nicotinic receptors (direct binding)

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3
Q

What do indirect-acting cholinergic drugs affect?

A

Mainly acetylcholinesterase

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4
Q

Examples of direct-acting cholinergic drugs

A

Choline esters: acetylcholine, metacholine
Carbamoyl esters: carbachol, bethanechol
Natural alkaloids: pilocarpine, muscarine

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5
Q

Difference between tertiary and quaternary agents

A

Tertiary: Neutral, therefore lipid soluble, can pass BBB
Quaternary: (+) charge, water soluble, CANNOT cross BBB

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6
Q

Examples of tertiary agents

A

Alkaloids (pilocarpine), Physostigmine

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7
Q

Examples of quaternary agents

A

Choline esters, muscarine (??), simple alcohols (edrophonium), carbamates

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8
Q

2 divisions of direct-acting cholinomimetics

A

Choline esters and Alkaloids

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9
Q

Cholinomimetic choline ester groups

A

1) Acetic acid esters (Acetylcholine, methacholine)

2) Carbamic acid esters (carbachol, bethanechol)

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10
Q

Acetylcholine profile

A 
Susceptability to AchE: +++
Muscarinic action: +++
Nicotinic action: +++
Antagonized by atropine: +++
Does not cross BBB, very short half-life
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11
Q

Methacholine profile

A 
Susceptability to AchE: +
Muscarinic action: +++
Nicotinic action: +
Antagonized by atropine: +++
More resistant to hydrolysis
NO LONGER USED
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12
Q

Carbachol profile

A 
Susceptability to AchE: -
Muscarinic action: ++
Nicotinic action: +++
Antagonized by atropine: +
Mitotic drug for glaucoma
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13
Q

Bethanechol profile

A

Susceptability to AchE: -
Muscarinic action: +++
Nicotinic action: -
Antagonized by atropine: +++

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14
Q

The muscarinic receptor is highly stereoselective. Which isomer of bethanechol does it have more affinity?

A

S-bethanechol is 1000x more potent than R-bethanechol

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15
Q

Examples of natural cholinomimetic alkaloids

A 
Pilocarpine (tertiary)
Muscarine (quaternary)
Nicotine
Labeline (tertiary)
Arecholine
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16
Q

Which is the only cholinomimetic alkaloid with therapeutic use?

A

Pilocarpine

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17
Q

Examples of synthetic cholinomimetic alkaloids

A

dimethylphenylpiperazinium (DMPP)
Oxotremorine
**Both used for research

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18
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: CVS

A

Decrease HR = (-) chronotrophy
Decrease SA & AV node conduction = (-) dromotrophy
(-) ionotrophy
Generalized vasodilation (from NO formation in endothelial walls/blood vessels)
LARGE doses: depressed AV conduction

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19
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: GIT

A 
Stimulation of GI smooth muscles, tone and motility
Increased secretions
Relaxation of sphincters
=DIARRHEA!!!! cha cha cha!!! =D 
Hi baby!
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20
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: GUT

A

Contraction of detrussor muscle

Relaxation of trigone and external sphincter

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21
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: Respiratory system

A

Contraction of bronchial smooth muscles

Increased tracheobronchial secretions

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22
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: Eyes

A

Miosis - contraction of pupillary sphincter

Cyclospasm - contraction of ciliary muscles

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23
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: Exocrine glands

A

Increased secretions of ALL glands: lacrimal, salivary, eccrine, sweat, nasopharyngeal, gastric, intestinal

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24
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: CNS

A

For tertiary only: tremors, hypothermia, locomotor activity, improved cognition

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25
Q

Pharmacologic nicotinic actions of cholinomimetic drugs: NMJ

A

Disorganized fasiculations or strong contractions of the entire muscle
“depolarization blockade” - stimulation and then flaccid paralysis d/t persistent depolarization at NMJ

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26
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: CNS

A

High concentrations: emesis, tremor, stimulation of respiratory center
Higher concentration: convulsions to coma

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27
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: Autonomic ganglia

A

Will depend on the dominant division of that organ
CVS: sympathiomimetic (hypertension, tachycardia, followed by bradycardia)
GIT, GUT: parasympathetic (nausea, emesis, diarrhea, voiding of urine)

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28
Q

Pharmacologic muscarinic actions of cholinomimetic drugs: Adrenal medulla

A

Increase Epi and Norepi release

Plus Dopa, VIP, Ach

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29
Q

Clinical uses of cholinomimetic drugs: Opthalmology

A

Glaucoma (pilocarpine, carbachol)
Iritis, keratitis
Accomodative esotropia - strabismus, hyperemetropic accomodative error

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30
Q

Clinical uses of cholinomimetic drugs: GI d/o

A 
To increase GI motility
Postop gastric distention, gastric atony
Congenital megacolon
Ileus
**Bethanechol
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31
Q

Clinical uses of cholinomimetic drugs: Xerostomia

A

In head and neck radiation
Sjogren’s syndrome
**Pilocarpine, bethanechol, Cevimaline (new drug)

32
Q

Clinical uses of cholinomimetic drugs: CNS

A

Dementia

**Taclifenasine, Xanomeline

33
Q

Major Contraindications of cholinomimetic drugs

A 
Asthma
Hyperthyroidism
Coronary insufficiency
Acid Peptic disease
GIT obstruction
34
Q

Adverse effects of cholinomimetic drugs

A 
Flushing
Sweating
Salivation
Abdominal cramps
Belching
Sensation of tightness in urinary bladder
Difficulty in visual accommodation
Bronchospasm
Hypotension
Bradycardia
35
Q

Cholinomimetic Poisoning and treatment

A

Exaggeration of parasympathetic effects
Treat with competitive blockers: atropine Epinephrine
Supportive therapy

36
Q

Treatment of mushroom poisoning: Mycetism

A

Dependent on species

Fast, without delay

37
Q

Mushroom species: Inocybe & Clitocybe

A

High muscarine concentration
Symptoms in 30-60 mins
Treatment: Atropine

38
Q

Mushroom species: Amantia

A

Contains muscarine, muscimol, ibotenic acid, etc
S/Sx: irritability, restlesness, ataxia, hallucination, delirium, drowsiness, sedation
Treatment: Mainly supportive, Benzodiazapines (restlessness)

39
Q

Mushroom species: Psilocybe & Panaeolus

A

Contains psitocybin and tryptamine derivatives

S/Sx: hallucinations

40
Q

Mushroom species: Gyromitra

A

Toxic substance: acetylaldehyde methylformyl hydrazone

S/Sx: GI d/o, delayed hepatotoxicity

41
Q

Mushroom species: Amantia phalloides, leptiota, galerina

A

Worst of all the mushrooms (50% of fatal cases)
Toxic substance: Amatoxins
S/Sx: diarrhea, abdominal cramps, symptom free for 24 hours, hepatic/renal malfunction
Treatment: Supportive, penicillin, thioctic acid, silbinin

42
Q

MOA of indirect acting cholinomimetics

A

Inhibit hydrolysis of Ach by Acetylcholinesterase (AchE)

43
Q

What are the steps for degradation of Ach by AchE

A

1) Ach binds to active site of AchE
2) It is then hydrolyzed to yield free choline and the acetylated enzyme
3) The COVALENT acetyl bond is split by hydration
* *All this in 150 microseconds

44
Q

What does an indirect acting cholinomimetic do?

A

It attaches to AchE and is consequently hydrolysed = Ach is spared from being degraded

45
Q

2 Types of Cholinesterases

A

Acetylcholinesterase (specific for Ach)

Pseudocholinesterase or Butyrylcholinesterase (non-selective)

46
Q

Examples of reversible anti-cholinesterases

A

1) Non-covalent inhibitors: Edrophonium, Tacrine, donepezil

2) Carbamate inhibitors

47
Q

Examples of carbamate inhibitors

A 
Tertiary: Physostigmine
Quaternary: 
Pyridostigmine
Neostigmine
Rivastigmine
Propoxur (Baygon)
Ambenomium
Benzpyrinium
Demecarium
Carbaryl
Distigmine
48
Q

What are the uses of Edophorium?

A 
For diagnosis (not treatment!!!) of Myasthenia Gravis
For differential diagnosis between Myasthenia crisis vs cholinergic crisis
49
Q

Drugs used as anti-curare (for reversal of NM blockade: PANE

A 
Mnemonic: PANE
Pyridostigmine
Ambenomium
Neostigmine
Edrophonium
50
Q

In abdominal surgeries, PANE drugs are given with what anti-muscarinic drug and why is it given?

A

Atropine, to block muscarinic receptors while reversing the neuromuscular blockade

51
Q

Use for Rivastigmine

A

Alzheimer’s

**Cross BBB

52
Q

Uses for Physostigmine (tertiary)

A

Atropine intoxication

53
Q

Use for Neostigmine (quaternary)

A

Curare intoxication

54
Q

Use for Pyridostigmine (quaternary)

A

Chronic management of Myasthenia gravis
Stimulation of bladder and GIT
Has direct action at nicotinic NMJ

55
Q

Examples of irreversible anticholinesterases:

A 
Organophosphates:
Echothiophate (more stable than others)
Malathion
Parathion
Fenthion
Chloropyrifos
Dimpylate
Nerve gas: Sarin, soman, tabun, cyclosarin
56
Q

What does aging involve? (in organophosphate poisoning)

A

Breaking of the oxygen-phosphorus bonds of the inhibitor which further strengthens the phosphorus enzyme bond

57
Q

What are the 2 active sites of AchE and what part of Ach do they bind?

A 
Anionic site (glutamate)- choline (basic) moiety
Esteratic site (histidine & serine)
58
Q

Which active site of AchE do organophosphates bind to? Is it reversible or irreversible?

A

Only to esteratic sites (via serine residues)

It is irreversible especially after aging

59
Q

What is the management for organophosphate poisoning? When do they need to be given?

A

Enzyme regenerators:
Pralidoxime
Obidoxime
Need to be given before aging

60
Q

Examples of AchE inhibitors that bind to both active sites of AchE

A

Physostigmine

Neostigmine

61
Q

Examples of AchE inhibitors that bind to anionic active site of AchE

A

Edrophorium

62
Q

Examples of AchE inhibitors that bind to esteratic active site of AchE

A

Dyflos

63
Q

What are the 3 steps to Ach degradation

A

1) Bind to enzyme via electrostatic bond
2) Initial hydrolysis: acetyl group transfer to serine group = acetylated enzyme + free choline
3) Spontaneous hydrolysis of acetylated enzyme

64
Q

What is the MOA of cholinesterase reactivators

A

Breaks the phosphorus-enzyme bond formin a phosphoxime

65
Q

Pharmacologic actions/effects of AchE inhibitors: Eyes

A

Miosis, contraction of ciliary muscles
Decrease elevated IOP
DRUGS: Physostigmine, Demecarium, Echothiophate

66
Q

Pharmacologic actions/effects of AchE inhibitors: GIT and GUT

A

Increased GIT motility and secretions
Increase contraction of detrusor muscle and relaxation of trigone and sphincter
DRUG: Neostigmine

67
Q

Pharmacologic actions/effects of AchE inhibitors: NMJ

A

Therapeutic conc: Moderately prolongs actions of released Ach
Higher conc: fasiculations followed by flaccid paralysis
“depolarization block”

68
Q

Pharmacologic actions/effects of AchE inhibitors: CNS

A

Initial excitation followed by convulsions and coma and respiratory failure
Can be antagonized by atropine
DRUGS (Alzheimers): Donepezil, Rivastigmine, Galantamine

69
Q

Pharmacologic actions/effects of AchE inhibitors: CVS

A

Effects of parasympathetic limb dominate
Mimic vagal nerve activation of the heart
Decreased BP, CO, HR
Large, toxic doses: Marked decrease in HR, CO and BP

70
Q

Adverse effects of Anticholinesterase drugs

A 
Exaggerated Parasympathetic activity
GI distress
Salivation and sweating
Bradycardia
Bronchospasm
Difficulty of visual accomodation
Flushing
71
Q

What is DUMBELS in organophosphate poisoning?

A 
Diarrhea
Urinary frequency
Miosis and muscle weakness
Bronchospasm, bradycardia
Emesis, excitation
Lacrimation
Salivation, sweating, seizures
72
Q

Therapeutic uses of AchE inhibitors: Opthalmology

A

Glaucoma: Acute angle closure
Direct: Pilocarpine
Indirect: Physostigmine, demecarium, echotiophate

73
Q

Therapeutic uses of AchE inhibitors: NMJ

A

Myasthenia gravis (diagnosis (edrophonium) and treatment (pyridostigmine, neostigmine, ambenomium))
Curare or curare-like OD
Adjunct to surgical anesthesia

74
Q

Therapeutic uses of AchE inhibitors: GIT and GUT

A 
Postop ileus
Congenital megacolon
Urinary retention
DRUGS: bethanechol, neostigmine
Xerostomia (pilocarpine, cevimaline)
75
Q

Therapeutic uses of AchE inhibitors: Antimuscarinic drug intoxication

A

Physostigmine (only if necessary) of atropine poisoning

76
Q

Therapeutic uses of AchE inhibitors: CNS

A

Alzheimer’s
DRUGS: Donepezil, Rivastigmine, Galantamine
Note: Memantine (N-methyl-D-aspertate receptor inhibitor) is still the #1 drug used but it is NOT an anticholinesterase drug

Pharmacology (14 decks)

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