Westminster Anticholinergics

Front 1

scopalamine origin

Back 1

henbane

Front 2

atropine/belladonna found in

Back 2

Datura plant (jimson)

Front 3

anticholinergic effect?

Back 3

Lowers the “rest and digest” of the parasympathetic by antagonizing acetylcholine receptor

acetylcholinesterase inhibitors.

Front 4

anticholinergic uses?

Back 4

Treatment for reflex-mediated bradycardia
Prophylaxis against anticholinesterase toxicity,(treatment for cholinergic crisis, cholinergic adjunct for curariform block)
Antisialagogue preanesthetic medication (not atropine)
Prophylaxis against arrhythmias induced by succinylcholine for intubation
Anesthesia adjunct (preanethesia) with an opioid
reduce excitement,
produce amnesia
protect against opioid-induced respiratory depression.
Prophylaxis against aspiration
Postoperative nausea and vomiting
Sedation

Front 5

local anesthetics block the?

Back 5

Na channel

Front 6

Parenteral ___________ is also indicated in conjunction with analgesics in cardiopulmonary bypass patients who cannot be deeply anesthetized because of the risk of severe hypotension or circulatory collapse

Back 6

scopolamine

Front 7

Other anticholinergic uses...

Back 7

Antidote
Anticholiesterase (cholinergic crisis), muscarine, organophosphate overdose
Resuscitation
Opthalmic (mydriasis/cycloplegia)
Urinary Incontinence treatment - Darifenacin, M2 antagonist
Peptic Ulcer Treatment Adjunct
Irritable bowel syndrome
Motion Sickness
Asthma - ipratropium and tiotropium
Antidiarrheal (constituent of Lomotil)
Antivertigo
Allergies (better options)
Constituent of nonprescription cold remedies
Management of Parkinson's Disease – Benzotropine
Treat antidopaminergic effects of metoclopramide
Hiccups

Front 8

what causes mydriasis/cycloplegia?

Back 8

anticholinergics

Front 9

anticholinergic for asthma?

Back 9

ipratropium and tiotropium

Front 10

anticholinergic for Management of Parkinson's Disease –

Back 10

Benzotropine

Front 11

what can treat the antidopaminergic effects of metoclopramide?

Back 11

anticholinergics

Front 12

Metoclopramide is a dopamine _____?

Back 12

antagonist

Front 13

anticholinergics effect on lactation

Back 13

inhibition

Front 14

Parasympathetic Effects of anticholinergics on eye, salivary gland, heart, lungs, pancreas, intestine and bladder

Back 14

Eye: Contraction to give miosis and near vision
Salivary Glands: Secretion
Heart: Decreased HR, conduction velocity, contraction
Lungs: Bronchoconstriction
Pancreas: Increased insulin secretion
Intestine: Increased Motility and tone
Bladder: Sphincter relaxation and Detrosor contraction

Front 15

Anti-cholinergic vs. Antimuscarinic?

Back 15

The anticholinergics are anti-muscarinics more specifically

Front 16

anticholinergic for COPD

Back 16

Ipratropium – isopropyl atropine analog

Front 17

The _____ is the natural occurring and the active compound but given as racemic mixture

Back 17

levorotary

Front 18

anticholinergic SAR facts

Back 18

These have the ester again – recognized by the acetylcholine receptor. Not recognized by acetylcholinesterase or any other esterase.
These structures have a chiral carbon.

Front 19

tropic acid is in?

Back 19

atropine (hyoscyamine) pka 9.9

Front 20

mandelic acid is in?

Back 20

glycopyrolate (robinul)

Front 21

scopolamine pka

Back 21

7.5-7.8

Front 22

2 naturally occurring anticholinergics

Back 22

scopolaine and atropine

Front 23

2 synthetic anticholinergics

Back 23

glycoryrrolate and ipratropium

Front 24

are anticholinergis acids?

Back 24

NO, even though they have an acidic portion

Front 25

As bases, _________ are often formulated as water soluble conjugate acids at slightly acidic pHs.

Back 25

anticholinergics

Front 26

Parasympathetic Muscarinic Postganglionic (effector) receptor sites: [4]

Back 26

autonomic effector cells (smooth muscle)
cardiac muscle
Sinoatrial/atrioventricular nodes
exocrine glands.

Front 27

anticholinergics....

non-comp or comp?

Back 27

Competitive antagonists

Block acetylcholine from binding.

G- protein will not be released and will not activiate second messenger

Front 28

anticholinergic effect on pre synaptic neruon...

Back 28

Have no effect on the pre-synaptic neuron. Acetylcholine will continue to be released

Front 29

M1 receptor....
location
2nd messenger effect
clinical effect
clinically selective drug?

Back 29

CNS,Stomach
Phospholipase C Stimulation
H+ secretion
Yes

Front 30

M2 receptor....
location
2nd messenger effect
clinical effect
clinically selective drug?

Back 30

Heart,CNS,Airway Smooth Muscle
Adenylate Cyclase Inhibition
Bradycardia
No*

Front 31

M3 receptor....
location
2nd messenger effect
clinical effect
clinically selective drug?

Back 31

CNS
Salivary Glands
Airway Smooth Muscle
Vascular Endothelial Cells
Phospholipase C Stimulation,Salivation
Bronchodilation
Vasodilation
No

Front 32

M4 receptor....
location
2nd messenger effect
clinical effect
clinically selective drug?

Back 32

CNS, Heart

Adenylate Cyclase Inhibition
?
No

Front 33

M5 receptor....
location
2nd messenger effect
clinical effect
clinically selective drug?

Back 33

CNS
Phospholipase C Stimulation
?
No

Front 34

the anticholinergic/antimuscarinics that we use affect what M recoptors?

Back 34

all M types

Front 35

Dose variability

Back 35

Lower dose

Bronchial/salivary secretions (M3)
heart and eye effects (M2)
control GI and genitourinary tract
inhibition of H+ secretions (M1)

Higher dose

So If giving higher doses to control H+ then will have side effects of the other lower concentrations. If giving low dose to minimize salivary secretions, might not see other effects

Front 36

Atropine dose variablity examples.....from low to high dosage

same trend with all 3 compounds

Back 36

Atropine
0.5 mg slight cardiac slowing/some dryness of mouth/inhibition of sweating
1.0 mg dryness of mouth/thirst/acceleration of heart/mild dilation of pupils
2.0 mg rapid heart rate/palpitation/marked dryness of mouth/dilated pupils/blurring of near vision
5.0 mg all above worse/difficulty is speaking and swallowing/restlessness and fatigue/headache/dry and hot skin/ reduced intestinal peristalsis
10+ mg all above worse/ pulse rapid and weak/iris obliterated/vision very blurred/skin flushed, hot and dry and scarlet/ataxia/restlessness and excitement/hallucinations/delirium
COMA

Front 37

What would govern between atropine, glycopyrolate or scopolamine?

Back 37

unwanted side effect or speed of onset

Front 38

most sedative

least

Back 38

most scopalamine

no sedative effects with glycopyrolate

Front 39

most antisialogogue?

least?

Back 39

most scopolamine

least atropine

Front 40

most HR effect?

least?

Back 40

most-atropine

least scoplomine

Front 41

most smooth muscle relaxation?

least?

Back 41

most atropine/glycopyrolate

least glycopyrolate

Front 42

most mydriasis/cycloplegia?

least?

Back 42

most-scopolamine

least-non with glycopyrolate

Front 43

motion sickness tx most?

least?

Back 43

most-scopolamine

least-none with glycopyrolate

Front 44

gastric acid reduction-most?

least?

Back 44

all equal

Front 45

agent with fetal HR effect

Back 45

maybe scopolamine- only

Front 46

agent for glaucoma patient?

Back 46

must be careful with scopolamine dosage so atropine maybe better choice

Front 47

agent for pregnant pt?

Back 47

Although atropine and scopolamine can both cross placenta, no change for atropine (scopolamine has not been tested) also no change for glycopyrrolate – expected since not very lipophylic.

Front 48

why does scopolamine have more sedative effects?

Back 48

higher PKA

Although scop and atropine are tertiary amines, at physiological pH, more of atropine is ionized so less concentration to CNS.

Front 49

agent for bradycardia tx?

Back 49

atropine because faster onset.

This increased heart rate is an anticholinergic effects but remember for later chapters, this is also an adrenergic agonist effect (same effect observed for epinephrine)

Front 50

what causes scopolamine/MS sedative effects?

Back 50

Depress RAS to give sedation
Depress other areas of brain to give amnesia

Front 51

Antisialagogue effects

Back 51

Scopalamine w/ sedation Glycopyrrolate w/o
Added to nonprescription cold remedies to stop upper airway secretions

Front 52

Increased Heart Rate, Tachycardia (Atropine-fast onset))

Back 52

Treatment for reflex-mediated bradycardia
Effect primarily at sinoatrial node
Less change at extremes of age
Lower dose with volatile anesthetic
Glycopyrrolate may be best choice for patients at risk for cardiovascular complications (faster offset)

Front 53

most potent?

Back 53

scopolamine, then glyco

Front 54

how does atropine the HR?

Back 54

Block Ach binding at sinoatrial node. Higher doses for those with lower vagal tone. Young adults with high vagal tone show most effect. Volatile anestheics depress vagal center so need less drug

Front 55

Relax Smooth Muscle (Glycopyrrolate)

Back 55

Bronchodilation
Decrease airway resistance/increase dead space
Biliary and ureteral Smooth Muscle Relaxation
Modest antispasmodic
wont overcome opioid effects on sphincter of Oddi but will on ureteral contraction.
Reduces tone of funcus of bladder giving urinary retention
Gastrointestinal Tract
Descrease peristalsis increases transit time
High drug concentration required

Front 56

Mydriasis /Cycloplegia

Back 56

Block constriction of pupil and contraction of ciliary muscles.
7-14 day recovery time
Care must be taken with Glaucoma patients (acute angle effects)

End result is dilated pupils – reputed to be why Cleopatra and Renaissance women used belladonna on their eyes to look more alluring. I was give Ipratropim bromide and instructed to thoroughly wash my hands after using inhaler because if I touched by eyes, I would be unable to see clearly for a week.

Front 57

choice for NO CNS effects?

Back 57

glycopyrolate

no cardiac effects if arelolized

Front 58

Alternative is Ipratropium bromine (N-isopropyl derivative) which is often used for COPD. Ipratropium could also be used against brochoconstriction due to tracheal intubation since this seems to be an acetylcholine mediated response. Ipratropium and a b-agonuist such as albuterol is good treatment for COPD

Back 58

xxxxx

Front 59

Gastric H+ Secretion notes

Back 59

Requires high doses and will see other effects

Front 60

Prevention of Motion Sickness
best choice?

Back 60

Transdermal scopalamine is best choice

Transdermal – low dose minimizes other effects that might see like sedation. Must apply at least 4 hours ahead of time. Blocks trasmission of signals to the medulla that come from overstimulation of the vestibular apparatus. Some say because lowers salivation. Need again be careful of any transfer to eye after handeling of the patch

Front 61

Presynaptic inhibitory M1 receptor (feedback blocker) (antagonistic effect)

Back 61

vagal nerve endings
Sympathetic effects (allows more ach to be released)
Adrenergic neurons
Sympathomimetic effects (we can cause the release of nor-epi, which is the natural ligand for adrenergic neurons)

Inhibition of this presynaptic receptor prevents the feedback inhibition of acetylcholine release. More acetylcholine is released and my in fact see paradoxical slowing of the heart rate.

Also can cause release of norepiniphrine so can get sympathetic effects (fight and flight)

This response can happen with low doses (parasympathetci) paradoxical lowering

Front 62

Absorption/Distribution

Back 62

Tertiary amines rapidly absorbed/distributed
shown to cross placenta (tachycardia in fetus)
Can cross BBB (CNS effects)
Quaternary amines poor absorption/distribution

Tertiary amines oral absorption in GI (not stomach why?) can be absorbed through mucosa
Quat amines (glycopyrrolate) – if given orally, only about 10 – 25% absorbed

Quaternary amines do not cross BBB but tertiary can. This means the teriary amines can have some CNS activity. At different doses see sedation and excitation.

Front 63

Protein Binding

Back 63

Atropine - Moderate (
Scopalamine – Low (BEST DISTRIBUTED)
Glycopryrolate - (worst distributed/absorbed)

Front 64

% ionization of Glycopyrolate?

Back 64

100% ionized at ANY ph

Scop is more unionized at phys PH, therfore more will cross the BBB.
Glyco 15-20% bioavail with PO

Front 65

Metabolism

Back 65

99% Scopalamine/80% Atropine/20% Glycopyrolate
Hepatic Metabolism
Atropine hydrolyzed to Tropine and Tropic Acid (ester bond-hydrolysis in liver)

Although atropine is hydrolyzed, this cannot be done with plasma esterases in humans though animals have the correct esterase.
Scopolamine is the least ionized

The purpose of metabolism is to make things more water soluble

Front 66

The dose of glycopyrolate is about ______ that of atropine and scopolamine

Back 66

half

Front 67

Atropine facts

Back 67

dose 0.01 – 0.02

onset comparable to Glycopyrollate

duration Oral: 4–6 hrParenteral: Brief

elimination 2.5 hr
Renal
(~20% unchanged)

Front 68

scopolamine facts

Back 68

dose 0.01 – 0.02

onset Oral: 30–60 Parenteral: 30

duration Oral: 4–6 hrParenteral: 4 hr 8 hr

elimination Renal
(1% unchanged)

Front 69

glycopyrolate facts

Back 69

dose 0.005-0.001
*about _

onset IM/SC: 14-30 IV: 1
Duration Antisialagogue:
Up to 7 hrVagal blocking:
2–3 hr

elimnation 1.7 hr
*Renal
(80% unchanged)

Front 70

Side Effects

Back 70

CNS – Central Anticholinergic Syndrome
Low doses atropine mild stimulating
Higher doses are depressant
Gastroesophageal Reflux
Decreasing tone of lower esophageal sphincter decreases barrier.

Sopalamine>atropine have seen glycopyrrolate with IV before induction of anesthesia
Restlessness, confusion, hallucinations, combative (children), somnolence, unconsciousness especially in elderly but also those under age 13

Front 71

Overdose (Central and Peripheral Anticholinergic Syndrome)

mostly seen in extremes of age

Back 71

Blurred vision, continuing, or changes in near vision clumsiness or unsteadiness confusion difficulty in breathing dizziness drowsiness, severe dryness of mouth, nose, or throat, severe fast heartbeat fever “atropine fever” (sweat inhibition) hallucinations muscle weakness, severe Seizures slurred speechtiredness, severe unusual excitement, nervousness, restlessness, or irritability unusual warmth, dryness, and flushing of skin 
Respiratory paralysis with quaternary compounds due to curare-like effects

Front 72

atropine fever from?

Back 72

inhibition of sweating

Front 73

Overdose Treatment

Back 73

Physostigmine (Antilirium)
sometimes Neostigmine
Barbiturate/Benzodiazepine
Norepinephrine

Physostigmine/neostigmine – these acetylcholinesterase inhibitors will allow for the increase of acetylcholine at the receptor sites. This will increase concentration at the muscaric receptor and cause a reversal.
Physostigmine best for CNS effects because physo can cross BBB. Neostigmine cannot as well.
Low dose IV and repeated doses since pysostigmine is metabolized fairly rapidly

Barb or benzo for the delirium
Norepinephrine for increasiing blood pressure

Front 74

Other Drugs/same receptor

Back 74

Edrophonium – M2/M3 competitive antagonist
Antihistamines

* Remember, the depolarizing and non-depolarizing muscle relaxants do block acetylcholine receptors but the nicotinic receptors

Edrophonium was acetylcholinesterase inhibitor but also seems to have some mild anti-muscarinic effects as well.

Antihistimines have anticholinergic and that is why helpful in cold remedies.