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Foundations 2 > Cholinergic Agents > Flashcards

Cholinergic Agents Flashcards

1
Q

muscarine

A

a poisonous substance found a a mushroom that mimics the effects of ACh

results in smooth muscle contractions, secretion, decreased heart rate, fall in blood pressure

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2
Q

atropine

A

blocks muscarinic response to ligand

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3
Q

nicotine

A

increases heart rate and blood pressure, mimics the effects of ACh in large doses or when injected with atropine, which blocks the muscarinic receptors

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4
Q

tubocurarine

A

blocks nicotinic receptors

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5
Q

structure-activity relationship (SAR) for acetylcholine

A

has nicotinic and muscarinic sides

the more substituents added to the molecule, the more muscarinic it becomes

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6
Q

acetylcholine as a direct-acting parasympathomimetic agent

A

mimics the effects of parasympathetic stimulation

slows heartrate through SA node

G-protein receptors opens potassium channels and generates the outward potassium currents to hyperpolarize the membrane

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7
Q

SA node pacemaker

A

driven by the funny current (pacemaker potential)

calcium channels activated by hyperpolarization and a potassium curve repolarizes the cells

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8
Q

three ways that vagal stimulation can decrease the heart rate

A

activation of potassium channels

inhibition of funny current

inhibition of L-type calcium currents

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9
Q

parasympathetic function at the AV node

A

ACh decreases AV conduction by an increase in gK (potassium conductance)

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10
Q

effect of ACh on blood vessels

A

even though there is no parasympathetic innervation on blood vessels, ACh can cause dilation through receptors that are in the endothelium

results in EDRF (NO) release and relaxation of smooth muscle

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11
Q

effect of a low dose of ACh alone

A

produces vasodilation and a reflex tachycardia in response to the decrease in blood pressure when injected IV

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12
Q

effect of ACh and neostigmine

A

much larger fall in blood pressure due to vasodilation and decrease in heart rate when injected IV

high doses in the vicinity of muscarinic receptors may be able to overcome the reflex

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13
Q

effects of ACh and neostigmine and atropine (a muscarinic blocker)

A

only increases blood pressure and heart rate are observed

removal of the muscarinic link leaves only the sympathetic division, which is then activated by the direct action of ACh on sympathetic ganglia

sustained effects eventually are produced from epinephrine after norepinephrine effects terminate

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14
Q

Why isn’t acetylcholine used clinically?

A

non-specific

rapid hydrolysis

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15
Q

methacholine

A

methyl group on beta carbon atom of ACh, making it more resistant to ACh and more specific for muscarinic receptors

metacholine challenge used to detect bronchial asthma

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16
Q

bethanechol

A

combines structural features of methacholine and carbachol

specific for muscarinic receptors and resistant to hydrolysis by esterases

therapeutic uses - treatment with disorders of low bowel tone (adynamic ileus) and urinary retention problems

contraindications - effect on heart can produce shock, asthmatics, hyperhtroid patients susceptible to arrhythmias, peptic ulcers, intestinal or bladder obstruction

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17
Q

adynamic ileus

A

absence of motility due to decreased activity of the autonomic nervous system - GI tract

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18
Q

pilocarpine

A

mimics the effects of acetylcholine - muscarinic activator

tertiary amine with the important part of its structure following the structure-activity relationship (SAR) for muscarainic receptors

natural alkaloid and not hydrolyzed by cholinesterases

therapeutic use - glaucoma therapy, dry mouth - sjogren’s syndrome (autoimmune disease of exocrine glands)

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19
Q

cevimeline

A

acetylcholine mimic

newer agent with more efficacy than pilocarpine to treat symptoms of Sjogren’s syndrome

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20
Q

glaucoma

A

disease associated with increased intraocular pressure resulting in blindness

increased pressure can be caused by increased synthesis and/or decreased outflow of aqueous humor

AH synthesis in ciliary body -> AH in anterior chamber -> AH to trabecular meshwork to canal of Schlemm -? AH out of the eye through the venous system

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21
Q

narrow angle glaucoma

A

acute, congestive

filtration angle is markedly reduced, impairing the exit of AH, drug pretreatment is required prior to surgery

pilocarpine contracts circular muscle fibers, pulls iris toward the center of the eye and uncrowds the angle

other agents prior to surgery are anti-cholinesterases, acetazolamide or methazolamide or dichlorphenamide, mannitol

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22
Q

open angle glaucoma

A

no physical obstructrion, but the trabecular meshwork has poor tone and is misaligned

tone is improved by pilocarpine and helps add tone and open the pores

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23
Q

surgical treatments for glaucoma

A

narrow angle - laser iridotomy

open angle - laser trabeculoplasty

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24
Q

anti-cholinesterases

A

indirect-acting parasympathomimetic agents (drugs which potentiate the action of endogenous ACh at muscarinic receptors)

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25
Q

two types of cholinesterases

A

true, specific or acetylcholinesterase - localized to cholinergic synapses and red blood cells

pseudo, non-specific or butyryl cholinesterases - all over

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26
Q

general symptoms of poisoning with anticholinesterase agents

A

Salivation

Lacrimation

Urination

Defecation

“SLUD syndrome”

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27
Q

toxicity of irreversible cholinesterase inhibitors

A

ACh is released in unphysioligically high amounts due to activation of presynaptic nicotinics - high calcium permeability

this causes the nerve to fire and increase the ACh concentration even more

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28
Q

CNS symptoms of cholinesterase poisoning

A

anxiety, headache, tremors, conusion, violent activity, convulsions, coma, depression of respiratory and CV centers, cyanosis, fall in blood pressure

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29
Q

-stigmine

A

reversible cholinesterase inhibitor

30
Q

physiostigmine

A

reversible cholinesterase inhibitor

tertiary amine, can cross the blood brain barrier

duration about 1-2 hours

oral or parenteral administration

therapeutic uses - glaucoma therapy, as an antidote

31
Q

neostigmine

A

reversible cholinesterase inhibitor

quaternary so no CNS effects

duration 2-4 hours

oral or parenteral administration

32
Q

therapeutic uses of neostigmine

A

treat myasthenia gravis

reverse non-depolarizing block at the end of surgery

miotic

glaucoma therapy

treat urinary retention

treat GI stasis, most common autonomic use

33
Q

pyridostigmine bromide

A

reversible cholinesterase inhibitor

same as neostigmine except available in slow release form for long-lasting 4-12 hour oral effect, useful at bedtime

34
Q

edrophonium

A

duration only 5-15 minutes

generally IV but you can give IM

therapeutic uses - to test for MG and distinguish from cholinergic chrisis

35
Q

contraindications of reversible cholinesterase inhibitors

A

asthma, hyperthyroid patients, ulcers, GI or bladder obstruction similar to those of bethanecol

other features - all are hydrolyzed by liver cholinesterase

quaternary agents have direct stimulatory action on the ACh receptor in addition to inhibiting cholinesterase

36
Q

mechanism of ACh hydrolysis by ChE

A

ACh anchors at the anionic site of ChE, enzyme activity is at the esteratic site

interaction of ACh with the esteratic site causes a rearrangement of the complex leaving an acetylated enzyme and a free choline

the acetylated enzyme then reacts with water to free the acetic acid and regenerate the enzyme

37
Q

mechanism of reversible icholinesterase inhibitorsn

A

molecules have slower hydrolysis after the conformational change of the enzyme to cleave the molecule

usually leaves the enzyme carbamylated and is hydrolyzed very slowly

38
Q

mechanism of edrophonium

A

combines electrstatically at theanionic site of ChE and hydrogen bonds to the imidazole of histidine at the esteradic site

transient inhibition

39
Q

DFP mechanism

A

reacts only with the serine residue of the steratic site to fomr a phosphorylated enzyme which does not hydrolyze at all

resynthesis of the enzyme is necessary to restore ChE, a process which takes 3-6 weeks

40
Q

DFP

A

diisopropyl phosphorofluroidate

prototype agent used as nerve gas by British and Americans in WWII

oily liquid that is absorbed by every route, including skin

effects similar to those of physostigmine

41
Q

Tabun and Sarin

A

both synthetic nerve gasses made in Germany during WWII as insecticides

SARIN is structurally DFP minus one isopropyl group

irreversible inhibition of cholinesterases

42
Q

parathion

A

agricultural insecticide

metabolized to paraoxon, the toxic form that inhibits ChE

responsible for many poisonings and deaths

43
Q

malathion

A

insecticide

slightly safer than parathion because higher animals can metabolize this faster than parathion

44
Q

chlorpyrifos

A

extremely popular insectiside in garden products and in pet flea collars for many years

45
Q

VX

A

the deadliest of nerve gases, 2.5 million tons in Newport still being cleared, terrorism in Japan, Gulf War, etc.

46
Q

treatment of toxicity

A

1) decontaminate (remove from skin)
2) block excess muscarinic activity with atropine (a lot is needed)
3) treat skeletal muscle effects through artificial respiration or reactivation of the enzyme
4) yridostigmine (not good!)
5) anticonvulsants if severe (diazepam)

47
Q

2-PAM and mechanism

A

aka pralidoxime

designed on theoretical bases, reactivates ChE by first attaching to anionic site and then binding to the P atom of the inhibitor and removing the inhibitor from the esteratic site

predominant effect is at skeletal neuromuscular junction with much less effect occurring at muscarinic neuro-effector sites

48
Q

anticholinergic agents

A

muscarinic antagonists - agents that block actions of ACh at cholinergic neuro-effector sites

ganglionic blockers - block nicotinic receptors on autonomic ganglia

49
Q

atropine

A

a belladonna alkalid from deadly nightshade

prototype drug

acts as a competitive inhibitor at muscarinic receptors

effects are opposite to those of parasympathetic stimulation

causes pupillary dilation, bronchiolar dilation, constipation, urinary retention, decreased secretions, etc.

decreased sweating as well, increases heartrate at clinical doses

50
Q

therapeutic uses for atropine

A
  • mydriatic and cycloplegic for eye exam
  • COPD treatment
  • GI and urinary bladder spasms
  • blockade of secretions
  • increase heart rate
  • antidote for cholinesterase poisoning
  • Parkinsonium

effect of atropine is generally too long to be practical and other derivatives are employed instead

may precipitate an attack of narrow angle glaucoma

51
Q

accommodation

A

object moves toward eye -> CNS reflex -> parasympathetic firing is increased -> lens is allowed to round into its natural shape to focus on the approaching object

52
Q

cycloplegia

A

paralysis of accommodation, lens fixed for distant vision

53
Q

cyclospasm

A

spasm of ciliary muscle and blurred vision

54
Q

atropine treatment of bronchioles

A

treat COPD

can also treat asthma with atropine-like agents such as ipratropium and tiotropium

55
Q

atropine treatment of GI spasms

A

spasms of smooth muscle cause pain known as cholic, relieved by atropine

current drug of choice

can also treat enuresis in children

56
Q

atropine treatment of blockade of secretions

A

respiratory secretions

acid secretions, may be used synergeistically with antibiotics and proton pump inhibitors

adjunct to surgical procedures such as intubation

57
Q

atropine to increase heart rate

A

during stage 2 of anesthesia

during spinal anesthesia

58
Q

Parkinsonism

A

atropine was a popular treatment in the past, superseded by L-dopa

symptoms of parkinsonism can be alleviated by blocking the ACh effects or increasing hte effects of dopamine

59
Q

homatropine

A

derivative of atropine with a shorter duration of action

60
Q

scopolamine

A

similar to atropine but has an additional oxygen on one of the rings, more CNS depressant effects at usual therapeutic doses

has been used int he past for sedative hypnotic effects in conjunction with opiod analgesics

not effective when severe pain is present

very effective against motion sickness

61
Q

effects of muscarinic receptor blockers

A

anti-emetic - targets muscarinic receptors in the vestibular nucleus and the vomiting center

seadation - blocks the muscarinic receptors int he cholinergic basal forebraine and mesopontine cholinergic nuclei associated with the reticular activating system

amnesia - blocks muscarinic receptors in the septo-hippocampal projection

62
Q

symptoms of belladonna toxicity from atropine and scopolamine

A

Dry as a bone -decreased secretions, urinary retention

Red as a beet - cutaneous vasodilation due to histamine and/or compensatory effect due to increased body temeprature

Mad as a hatter - delierium, hallucinations, eventually coma

Hot as a stove - increased body temperature (decreased sweating)

Blind as a bat - mydriasis, cycloplegia

63
Q

treatment of atropine toxicity

A

emesis if mental status is not severely impaired

gastric lavage even as late as 24-48 hours after ingestion

activated charcoal after gastric emptying

if anticholinergic effects are severe use an antidote - physostigmine

64
Q

drugs for overactive bladder

A

tolterodine

fesoterodine

oxybutynin

solifenacin

darifenacin

65
Q

drugs for ocular defects

A

cyclopentolate

tropicamide

homatropine

66
Q

drugs for Parkinson’s disease

A

benztropine

trihexyphenidyl

67
Q

drugs for bronchiolar dilation in asthmatics and COPD

A

ipratropium - quaternary, blocks ganglia, produces effective bronchiolar dilation without impairing mucilliary clearance

tiotropium - treats COPD, superior to ipratropium because it does not block presynaptic inhibitory muscarinic receptors as ipratropium does

68
Q

drugs for spasms of GI tract

A

atropine

lomotil

glycopyrrolate

69
Q

ganglionic blocking drugs

A

basic processes involved are essentialyl the same as the processes for skeletal neuromuscular junctions

block the action of ACh at autonimc ganglia

both sympatetic and parasympathetics are blocked

particular effect observed depedns on whcih system controls ther esting tone of a particular organ

predominatn tone is muscarinic cholinergic, mediated largely by the parasympathetic division

70
Q

ganglionic blocking drugs

A

Foundations 2 (33 decks)

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