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IC 1.0 > Cholinergic Pharmacology > Flashcards

Cholinergic Pharmacology Flashcards

1
Q

In what way does the location of action differ between direct-acting and indirect-acting cholinergic agonists?

A
  • direct acting are capable of acting anywhere there are cholinergic receptors
  • indirect acting are only capable of acting where there is already endogenous acetylcholine
  • for example, direct acting agonists could activate the muscarinic receptors on endothelial cells, but indirect acting agonists could not
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2
Q

Describe the structure of a muscarinic receptor.

A

it has seven transmembrane domains with the third cytoplasmic loop couple to a G protein

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3
Q

Describe the distribution of muscarinic and nicotinic receptors.

A
  • muscarinic are found in the CNS, in tissues targeted by the PNS, and on vascular endothelium
  • nicotinic are found on all ANS postganglionic cells, muscles innervated by somatic motor fibers (NMJ), and some CNS neurons
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4
Q

What are the two kinds of direct-acting cholinoreceptor agonists?

A
  • esters of choline

- alkaloids

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5
Q

What characteristics are shared by the direct-acting cholinoreceptor agonists that are esters of choline? List them and their individual differences.

A
  • they all have a quaternary ammonium group that renders them insoluble in lipids, thus they don’t cross the BBB well
  • acetylcholine is endogenous, is highly susceptible to AChE and shows no specificity for muscarinic or nicotinic receptors
  • methacholine has an additional methyl group that renders it only partly susceptible to AChE and converts some muscarinic specificity
  • carbachol has an additional amino group that renders it resistant to hydrolysis by AChE but has no specificity
  • bethanechol has both the additional methyl group and amino group; therefore, it is resistant to AChE and has selectivity for muscarinic receptors
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6
Q

What is methacholine?

A
  • a direct-acting cholinoreceptor agonist with a structure like ACh with the addition of a methyl group
  • that methyl group conveys specificity for muscarinic receptors
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7
Q

What is carbachol?

A
  • a direct-acting cholinoreceptor agonist with a structure like ACh with the addition of a second nitro group
  • that nitro group renders it resistant to acetylcholinesterase
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8
Q

What is bethanechol?

A
  • a direct-acting cholinoreceptor agonist with a structure like ACh with the addition of a methyl group and nitro group
  • the methyl group conveys specificity for muscarinic receptors
  • the nitro group renders it resistant to acetylcholinesterase
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9
Q

What characteristics are shared by the direct-acting cholinoreceptor agonist alkaloids? List them and their individual differences.

A
  • they are all non-polar which means they have CNS activity
  • nicotine and lobeline have nicotinic specificity
  • muscarine and pilocarpine have muscarinic specificity
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10
Q

What is the primary difference between direct-acting cholinoreceptor agonists that are choline esters versus alkaloids?

A
  • the choline esters are polar and have limited CNS activity

- the alkaloids are non-polar and have greater CNS activity

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11
Q

What is pilocarpine?

A

a direct-acting cholinoreceptor agonist that is an alkaloid and has muscarinic specificity

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12
Q

What is lobeline?

A

a direct-acting cholinoreceptor agonist that is an alkaloid and has nicotinic specificity

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13
Q

Activation of cholinoreceptors typically has what cellular effect?

A

trigger depolarization the nerve cell or neuromuscular end plate by increasing the potassium flux

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14
Q

In addition to the presence of an agonist, functioning of a nicotinic receptor depends on what other element?

A

the existence of a potassium gradient

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15
Q

Prolonged exposure to a nicotinic agonists can have what effect?

A

it can eliminate the existing gradient necessary for the effects of the receptor, leading to muscle paralysis

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16
Q

What are the effects of a muscarinic agonist in the CV, respiratory, GI, GU, and glands?

A

CV: indirect reduction of peripheral vascular resistance and direct slowing of heart rate
- activation of muscarinic receptors on endothelial cells triggers synthesis and release of NO, which causes vasodilation (the direct effect of muscarinic receptor activation here is actually vascular smooth muscle contraction but this is outweighed by NO)
- activation of muscarinic receptors in the SA node directly slow heart rate
- at high dose, these typically outweigh the SNS reflex that opposes the drop in peripheral resistance
Respiratory: contracts smooth muscle of the bronchial tree and activates glands of the mucosa to secrete, often exacerbating or inducing asthma-like symptoms
GI: increases salivary, gastric, pancreatic secretions and increases peristaltic activity by contracting longitudinal muscles and relaxing sphincters
GU: contracts detrusor and relaxes trigone and sphincter muscles, promoting voiding
Glands: stimulates secretion by thermoregulatory sweat glands

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17
Q

Acetylcholine-Induced vasodilation requires what apart from an agonist?

A

an intact endothelium because the vasodilation is mediated by NO production by those endothelial cells

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18
Q

Give at least one example where muscarinic receptors mediate a sympathetic response.

A

sympathetic postganglionics release ACh on muscarinic receptors to stimulate secretion by thermoregulatory sweat glands

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19
Q

What are the effects of a nicotinic agonist?

A
  • activates all autonomic ganglia, simultaneously triggering SNS and PNS discharge
  • the effect, then, is mediated by the predominant one
  • as such, SNS effects effects are seen in the peripheral vasculature but PNS effects are seen in most other tissues
  • recall that nicotine has a somewhat greater affinity for neuronal than skeletal muscle nicotinic receptors, so muscle fasciculations are more limited than other effects
  • and recall that prolonged activation, reduces the potassium gradient
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20
Q

How does the affinity of nicotine for skeletal muscle and neuronal nicotinic receptors differ?

A

it has a higher affinity for the neuronal subtype

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21
Q

How do the effects of low dose acetylcholine differ from those of high dose?

A
  • low dose typically only activates vascular muscarinic receptors because it stays in the vascular space, inducing vasodilation and a reflex tachycardia
  • high dose tends to leave the vascular space and hit all cholinergic receptors evoking vasodilation, bradycardia, and activation of nicotinic receptors at autonomic ganglia
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22
Q

Activation of cardiac muscarinic receptors has what effects?

A
  • slowed rate of diastolic depolarization of the SA node
  • slows AV conduction
  • reduces force of myocardial contractions
  • shortens the atrial refractory period leading to atrial flutter
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23
Q

What are the three types of indirect-acting cholinergic agonists?

A
  • alcohols bearing a quaternary ammonium
  • carbamates: carbonic acid esters of alcohols bearing quaternary or tertiary ammonium groups
  • organophosphates: organic derivatives of phosphoric acid
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24
Q

List the indirect-acting cholinergic agonists by group.

A
  • alcohols: edrophoium
  • carbamates: neostigmine, physostigmine, carbaryl
  • organophosphates: echothiophate, soman, sarin, malathion, parathion
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25
Q

What is edrophoium?

A
  • an indirect-acting cholinergic agonist (acting on ACh)

- has a very short half life and is polar with little CNS activity

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26
Q

How do indirect-acting cholinergic agonists function?

A
  • they primary function by inhibiting AChE

- they also inhibit butyrylcholinesterase

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27
Q

Which carbamates have greater cholinergic agonists effects in the CNS?

A

physostigmine and carbaryl more so than neostigmine because neostigmine is a quaternary amine where as the others are uncharged, tertiary amines

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28
Q

How do organophosphates differ from the other indirect-acting cholinergic agonists?

A

they are well absorbed topically and distribute to all parts of the body, including the CNS

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29
Q

How do carbamate esters tend to increase cholinergic activity?

A

they undergo a two-step hydrolysis and a covalent bond is formed, so the inhibition of AChE is longer than that of the quaternary alcohol edrophonium

30
Q

How do organophosphates tend to increase cholinergic activity?

A

they bind and are hydrolyzed by AChE, resulting in the phosphorylation of the AChE active site, a covalent interaction that is extremely stable and gets stronger with time (called “aging”)

31
Q

Explain the half lives of the edrophonium, carbamates, and organophosphates.

A
  • edrophonium reversibly binds the active site of AChE and therefore has a short half-life of minutes
  • carbamates form a covalent bond and thus last hours
  • organophosphates form an incredible stable phosphorylated enzyme that experiences “aging” and inhibition lasts hundreds of hours, the lifetime of the protein
32
Q

What is organophosphate aging?

A

the idea that it creates a phosphorous-enzyme bond that strengthens with time

33
Q

What is pralidoxime?

A
  • called 2-PAM
  • it is a weak AChE inhibitor with very strong affinity
  • as such, it can be used to outcompete organophosphates if given before aging occurs and maintain enzyme function
34
Q

Where do cholinesterase inhibitors have their most prominent effects?

A
  • in the CV and GI/GU systems as well as the eye (glaucoma) and skeletal muscle
  • they have little effect on vascular smooth muscle and BP
35
Q

Give some examples of clinical uses for cholinesterase inhibitors.

A
  • glaucoma
  • GI/GU disorders related to smooth muscle inactivity: post-op ileus, urinary retention, reflux esophagitis, insufficiency salivary secretion
  • myasthenia gravis diagnosis (edrophonium) and treatment
  • atropine or other pure anticholinergic intoxication
  • limited effects on Alzheimer’s through an unknown mechanism
36
Q

What is the primary clinical use of edrophonium?

A

as a diagnostic test for myasthenia gravis

37
Q

Describe the symptoms cholinesterase toxicity. What is the main concern?

A

“SLUDGE”

  • salivation
  • lacrimation
  • urinary incontinence
  • diarrhea
  • GI cramps
  • emesis

the primary cause of death is paralysis of the diaphragm and respiratory arrest

38
Q

How is cholinesterase toxicity treated?

A
  • atropine, a muscarinic antagonist
  • respiratory maintenance
  • decontamination to prevent further absorption
  • pralidoxime to rescue “un-aged” enzyme in the presence of organophosphates
39
Q

Describe Nicotinic Toxicity

A
  • requires only 40 mg of nicotine (found in two regular cigarettes but most destroyed by burning and absorption is usually limited by vomiting afterwards)
  • CNS stimulation causes convulsions, coma, respiratory arrest
  • CV: hypertension and cardiac arrhythmias
40
Q

List the direct muscarinic agonists.

A 
choline esters
- acetylcholine
- bethanechol
- carbachol
- cevimeline
alkaloids
- muscarine
- pilocarpine
41
Q

List the direct nicotinic agonists.

A

alkaloids

  • nicotine
  • varencline
  • lobeline
42
Q

List the cholinesterase inhibitors.

A
  • simple alcohol: edrophonium
  • carbamates: neostigmine, physostigmine, pyridostigmine, rivastigmine, ambenonium, demecarium, carbaryl
  • organophosphates: echothiophate, soman, sarin, parathion, malathion, isoflurophate, DFP
  • other: donepezil, tacrine, galantamine
43
Q

Tertiary amine antimuscarinic drugs are used for their effects where? What about quaternary amine antimuscarinic drugs?

A
  • tertiary cross the BBB: eye and CNS

- quaternary do not: peripheral effects

44
Q

What is the prototypic muscarinic antagonist?

A

atropine

45
Q

Describe the mechanism of atropine.

A

it is a competitive muscarinic antagonist without any selectivity for M1, M2, or M3

46
Q

How does a muscarinic antagonist like atropine affect the CNS? What is it’s primary clinical use in the CNS?

A
  • it has minimal stimulant effects
  • toxic disease can cause agitation, hallucinations, and coma
  • its main use is when it is given alongside a dopamine precursor in the treatment of Parkinson’s
47
Q

How does a muscarinic antagonist like atropine affect the eye? How do we use these effects clinically? In what condition would it be contraindicated?

A
  • it causes mydriasis (dilation of the pupil) and paralysis of the ciliary muscle (called cycloplegia), which are necessary for ophthalmic exam
  • contraindicated in those with acute glaucoma, especially cases of narrow anterior chamber angle glaucoma
48
Q

How does a muscarinic antagonist like atropine affect the CV system?

A
  • the SA node is under PNS tone and sensitive to muscarinic blockade, so it will produce tachycardia
  • few hemodynamic effects because endothelial cells don’t have any PNS innervation to begin with
49
Q

How does a muscarinic antagonist like atropine affect the respiratory system? How is this used clinically?

A
  • bronchodilation and reduction of secretion

- can be used to treat asthma, but not as useful as B-adrenoceptor stimulants

50
Q

How does a muscarinic antagonist like atropine affect the GI and GU systems? What are the clinical applications?

A
  • reduces GI motility and secretions; therefore, it is useful as a pre-op adjuvant before abdominal surgery
  • can produce urinary retention, and is used in cases of BPH
51
Q

How does a muscarinic antagonist affect the sweat glands?

A

suppresses thermoregulatory sweating and can elevate the body temperature (known as “atropine fever”) - don’t forget this is a sympathetic system

52
Q

Summarize the basic effects of a muscarinic antagonist on the CNS, eye, CV system, respiratory system, GU and GI tracts, and sweat glands.

A
  • CNS: mild stimulant, toxic doses cause agitation, hallucinations, and coma - used in Parkinson’s
  • Eye: mydriasis and cycloplegia - used for ophthalmic exam and contraindicated in those with glaucoma
  • CV: tachycardia without effects on peripheral vasculature
  • Respiratory: bronchodilator with reduced secretion - not as beneficial for asthma as B-adrenergic agonists
  • GI: reduce GI motility - pre-op adjuvant for abdominal surgery
  • GU: induce urinary retention, especially in those with BPH
  • Sweat: loss of thermoregulatory sweating known as “atropine fever”
53
Q

List the major therapeutic applications of atropine and other muscarinic antagonists.

A
  • Parkinson’s disease
  • ophthalmoscopic examination
  • relieves bronchoconstriction of asthma and COPD
  • relief of vagal syncope
  • treatment for sinus bradycardia
  • cardiopulmonary resuscitation
  • suppress traveler’s diarrhea
  • limit urinary urgency, frequency, or incontinence
  • reverse cholinergic poisoning
  • relief of hyperhidrosis
54
Q

How does atropine poisoning manifest and how is it treated.

A
  • atropine poisoning manifests with dry mouth, mydriasis, tachycardia, flushed skin, and delirium
  • known as “dry as a bone, blind as a bat, red as a beet, and mad as a hatter”
  • treat with physostigmine
55
Q

In what cases are muscarinic antagonists like atropine contraindicated?

A
  • glaucoma, especially angle-closure glaucoma

- prostatic hyperplasia

56
Q

List the muscarinic antagonists

A
  • tertiary amines: atropine, scopolamine, homatropine, pirenzepine, tropic amide, tolterodine, dicyclomine, fesoteridine, mepenzolate, solifenacin, oxybutynin, darifenacin, trospium
  • quaternary amines: atropine methyl nitrate, methscopolamine, ipratropium, propantheline, glycopyrrolate
57
Q

What is Tolterodine?

A

a tertiary muscarinic antagonist with M3 selectivity, making it particularly useful for patients with urinary urgency, frequency, or incontinence

58
Q

What are ganglion-blocking drugs?

A

synthetic amines that block the actions of ACh and other agonists at nicotinic receptors, particularly at PNS and SNS autonomic ganglia

59
Q

Why do nicotinic antagonists have few side effects?

A

because they don’t show selectivity for the PNS or SNS system and tend to suppress both

60
Q

What is the primary complication of nicotinic antagonists?

A
  • they block sympathetic output to peripheral vasculature and there is no PNS output, so there is a decrease in vascular resistance and the ability of the body to increase it when necessary
  • the result is orthostatic hypotension
61
Q

List the important nicotinic antagonists and their important differences.

A
  • hexamethonium
  • trimethaphan (lacks a CNS effect)
    mecamylamine (readily enters the CNS)
62
Q

How do nicotinic antagonists affect the CNS?

A
  • only mecamylamine has CNS effects as it is a tertiary amine
  • produces sedation, tremor, choreiform movements, and mental aberrations
63
Q

How do nicotinic antagonists affect the eye?

A
  • cycloplegia (since PNS tone predominates in the ciliary muscle)
  • moderate dilation of the pupil (since PNS tone predominates)
64
Q

How can we predict the effects of a nicotinic antagonist?

A
  • their effects are predicted by the predominant ANS tone at each particular end-organ
  • thus PNS effects tend to predominate except in the peripheral vasculature
65
Q

How do nicotinic antagonists affect the CV system?

A
  • SNS tone predominates in the peripheral vasculature, so there is a decrease in blood pressure and orthostatic hypotension
  • moderate tachycardia due to removal of PNS tone at the SA node
66
Q

Describe the cholinergic regulation of heart rate.

A
  • recall that the heart tends to contract quickly
  • it is slowed by PNS tone at the SA node
  • changes in blood pressure are often met by a reflex that slows or increases heart rate to compensate
67
Q

How do nicotinic antagonists affect the GI and GU systems?

A
  • GI: reduced secretion and motility, producing constipation
  • GU: hesitancy or urinary retention, particularly in those with prostatic hyperplasia
  • GU: sexual function is impaired
68
Q

How do nicotinic antagonists affect the sweat glands?

A

it suppresses thermoregulatory sweating

69
Q

Summarize the basic effects of a nicotinic antagonist on the CNS, eye, CV system, respiratory system, GU and GI tracts, and sweat glands.

A
  • CNS: tertiary amine antagonists produce sedation, tremor, choreiform movements, and mental aberrations
  • Eye: cycloplegia with moderate dilation fo the pupil
  • CV: reduced vascular resistance and BP with moderate tachycardia
  • GI: constipation
  • GU: poor sexual functioning and hesitancy or urinary retention, particularly with prostatic hyperplasia
  • Glands: suppressed thermoregulatory sweating
70
Q

How does a nicotinic antagonist affect the administration of other cholinergic drugs?

A

it eliminates or suppresses the homeostatic reflexes that are normally seen after administering a cholinergic drug, thereby dramatically altering responsiveness

IC 1.0 (24 decks)

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