Term
nausea: the imminent need to vomit, associated with gastric stasis
retching: the labored movement of abdominal and thoracic muscles
vomiting: the forceful expulsion of gastric contents (GI retroperistalsis) |
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Definition
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Term
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Definition
located in the lateral reticular formation of the mid-brainstem (medulla)
receives information from the:
gut (vagus nerve)
splanchic afferents (spinal chord)
cerebral cortex (anticipatory nausea or vomiting; see something that makes you sick)
vestibular apparatus (motion sickness) |
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Term
| chemoreceptor tigger zone (CTZ) |
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Definition
located in the area postrema of the 4th ventricle of the brain
LACK OF A BLOOD-BRAIN-BARRIER ALLOWS THIS TO MONITOR BLOOD AND CSF CONSTANTLY FOR TOXINS, AND RELAY THE INFO TO THE VOMITING CENTER |
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Term
cholinergic
histaminergic
dopaminergic
opiate
serotinergic
neurokinin
benzodiazepine |
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Definition
| numerous neurotransmitter receptors are located in the vomiting center, chemoreceptor trigger zone, the solitary tract nucleus (STN), and throughout the GI tract including: |
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Term
input: sensory afferents and CNS pathways
integration: higher centres -> vomiting center (mACh receptors)
output: nerves to somatic and visceral receptors |
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Definition
stimulus: pain, repulsive sights and smells, emotional factors
what is the imput, integration, and output? |
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Term
imput: labyrinth -> vestibular nulei (H1 and mACh receptors)
integration: chemoreceptor trigger zone (D2 and 5-HT3 receptors) -> vomiting center (mACh receptors)
output: nerves to somatic and visceral receptors |
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Definition
stimulus: motion sickness
what is the imput, integration, and output? |
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Term
input: blood
integration: chemoreceptor trigger zone (D2 and 5-HT3 receptors) -> vomiting center (mACh receptors)
output: nerves to somatic and visceral receptors
input: release of emetogenic agents (5-Ht, prostanoids, free radicals
integration: chemoreceptor trigger zone (D2 and 5-HT3 receptors) -> vomiting center (mACh receptors)
out put: nerves to somatic and visceral receptors
input: release of emetogenic agenst (5-HT, prostanoids, free radicals) -> visceral afferents (5-HT3 receptors?)
integration: chemoreceptor triggering zone (D2 and 5-HT3 receptors) -> vomiting center (mACh receptors)
output: nerves to somatic and visceral receptors
input: release of emetogenic agents (5-HT, prostanoids, free radicals) -> visceral afferents (5-HT3 receptors?)
integration: nucleus of the solitary tract (mACh and H1 receptors) -> vomiting center (mACh receptors)
output: nerves to somatic and visceral receptors |
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Definition
stimulus: endogenous toxins, drugs
what is the input, integration, and output? |
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Term
input: visceral afferents (5-HT3 receptors?)
integration: chemoreceptor trigger zone (D2 and 5-HT3 receptors) -> vomiting center (mACh receptors)
output: nerves to somatic and visceral receptors
input: visceral afferents (5-HT3 receptors?)
integration: nucleus of the solitary tract (mACh and H1 receptors) -> vomiting center (mACh receptors)
output: nerves to somatic and visceral receptors |
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Definition
stimulus: stimuli from pharynx and stomach
what is the input, integration, and output? |
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Term
1) 5-hydroxytryptamine (5-HT3): principal mediators; antagonists act as antiemetics
2) dopaminergic (D2): agonists produce emesis; antagonists block emesis
3) histaminergic (H1, H2): histamine receptor blockade results in antiemetic activity limited to vestibular causes
4) cholinergic (muscarinic): agonists cause motion sickness
5) substance P: neuropeptide; antagonists (aprepitant) act as antiemetics |
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Definition
| neurochemical control of emesis: 5 neurotransmitters |
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Term
5-HT3 antagonists
ondansetron
granisetron
dolasetron
ramosetron
palonosetron |
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Definition
| the gold standard for treatment of chemotherapy and radiation induced nausea and vomiting (can be prevented in ~80% of patients) |
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Term
these agents have central and peripheral effects
5-HT3 receptors are present in vagal afferents, the STN (receives signals from vagal afferrents) and the area postrema itself (CTZ)
ECL cells release serotonin in the small intestine in response to chemo and may stimulate vagal afferents (via 5-HT3) to initiate the vomit reflex
5-HT3 receptors are critical to emesis are found in the CTZ, the STN and the stomach and small intestine
pharmacophore model:
[image] |
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Definition
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Term
5-HT3 receptor antagonist
carbazole derivative
acts primarily on CTZ
no dopamine, muscarinic activity
metabolism:
[image]
metabolism by CYP1A2, 2D6, 3A4, 2E1; followed by glucuronide or sulfate conjugation
hydroxylation in 7- 8- positions
demethylation |
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Definition
MOA and metabolism of ondansetron
[image] |
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Term
antiemetic 5-HT3 receptor antagonist
indazole derivative
metabolism:
[image]
metabolized by CYP3A4 (inhibited by ketoconazole) and CYP1A1
hydroxylation in 5- 6- positions
demethylation |
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Definition
MOA and metabolism of granisetron
[image] |
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Term
antiemetic 5-HT3 receptor antagonist
indole derivative
metabolism:
[image]
rapidly converted by plasma carbonyl reductase to its ACTIVE METABOLITE, hydrodolasetron
1/3 excreted unchanged in urine
metabolized by CYP3A4 and 2D6
hydroxylation in 5- 6- positions
FDA WARNING for injectable form: QT prolongation arrhythmia potential (oral form is still available) |
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Definition
MOA and metabolism of dolasetron
[image] |
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Term
antiemetic 5-HT3 antagonist
imidazole derivative |
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Definition
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Term
antiemetic 5-HT3 antagonist
isoquinoline derivative
highest affinity for 5-HT3 in this class
metabolism:
by CYP1A2, 2D6, 3A4
N-oxide and 6-S-hydroxy
[image]
metabolite 9 and 4 are the major metabolites |
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Definition
MOA and metabolism of palonosetron
[image] |
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Term
D2 receptor antagonists are promiscuous drugs.
their principal mode of action as antiemetics is on D2 receptors at the CTZ but they have numerous other activities |
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Definition
| MOA of antiemetic D2-receptor antagonists |
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Term
antiemetic D2 receptor antagonist
benzamid class
does not penetrate BBB (less central side effects)
D2, weak 5-HT3 antagonist
gastric prokinetic agent
metabolism:
[image]
rapid rist pass metabolism
hydroxylation (pink) and N-deakylation |
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Definition
MOA, class, and metabolism of domperidone
[image] |
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Term
antiemetic D2 receptor antagonist
benazmide class
penetrates BBB (more central side effects)
D2, weak 5-HT3 antagonist
gastric prokinetic agent
ADR: tardive dyskinesia
metabolism:
[image]
hepatic metabolism
substrate and inhibitor of CYP2D6
de-ethylation of side chain |
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Definition
MOA, class, and metabolism of metoclopramide
[image] |
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Term
antiemetic D2 receptor antagonist
butyrophenone class
D2, weak 5-HT3, H1 activity
post operative nausea
adjunct to anesthesia |
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Definition
MOA and class of droperidol
[image] |
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Term
antiemetic D2-receptor antagonist
butyrophenone class
D2, weaker H1, ACh activities
prokinetic activity
metabolism:
by CYP1A2, 2D6 (N-dealkylation, ketone reduction)
[image]
[image]
haloperidol is associated with a high incidence of tardive dyskinesia
HPP+ is a neurotoxin that sequesters in mitochondria and disrupts electron transport |
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Definition
MOA, class, and metabolism of haloperidol
[image] |
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Term
[image]
need tertiary amine attached to 4th carbon
most potent D2 antagonists have para F |
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Definition
| SAR of antiemetic D2-receptor antabonists (butyrophenone class) |
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Term
antiemetic D2 receptor antagonist
phenothiazine class
typical antipsychotic used for schizophrenia
many CNS activities: D2,3,5 also D1,4 and 5-HT1,2 and H1,2 and M1,2 and alpha1,2 receptors |
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Definition
MOA and class of chlorpromazine
[image] |
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Term
antiemetic D2 receptor antagonist
phenothiazine class
piperazine subclass (potent)
typical antipsychotic
D2, muscarinic, H1 activity |
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Definition
MOA and class of fluphenazine
[image] |
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Term
antiemetic D2 receptor antagonist
phenothiazine class
piperazine subclass (potent)
typical antipsychotic
D2, muscarinic, H1, 5-HT activity
used off label for hyperemesis gravidarum (not teratogenic; when pregnancy women experience violent vomiting severe enough to endanger the fetus) |
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Definition
MOA and class of perphenazine
[image] |
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Term
antiemetic D2-receptor antagonist
phenothiazine class
piperazine subclass (potent)
typical antipsychotic
D2, muscarinic, H1, 5-HT activity |
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Definition
MOA and class of prochlorperazine
[image] |
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Term
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Definition
| SAR of antiemetic D2 receptor antagonists (phenothiazine class) |
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Term
H1 receptor antagonists
their principal mode of action as antiemetics on H1 receptors at the STN and the vestibular nuclei
primarily for motion sickness and vertigo |
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Definition
| MOA of antiemetic antihistamines |
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Term
antiemetic H1 antihistamine
benzydryl class
piperzine subclass
H1, muscarinic, weak D2 activity
metabolism:
[image]
hepatic metabolism
demethylated to norcyclizine, inactive |
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Definition
MOA, class, and metabolism of cyclizine
[image] |
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Term
antiemetic H1 antihistamine
benzyhydryl class
H1, muscarinic, weak D2 activity
metabolism:
[image]
metabolism by CYP2D6: de-methylation, deamination to carbosylate, conjugation
CYP3A4
mainly renal excretion |
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Definition
MOA, class, and metabolism of diphenhydramine
[image] |
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Term
antiemetic H1 antihistamine
benzhydryl class
salt of diphenhydramine and chlorotheophylline
chlorotheophylline is a stimulant |
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Definition
MOA and class of dimenhydrinate
[image] |
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Term
antiemetic H1 antihistamine
benzhydryl class
piperzine subclass
H1, muscarinic, weak D2 activity
metabolism:
[image]
hepatic metabolism
N-dealkylation to norchlorcyclazine |
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Definition
MOA, class, and metabolism of meclizine
[image] |
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Term
antiemetic H1 antihistamine
phenothiazine class
H1, muscarinic, D2 activity |
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Definition
MOA and class of promethazine
[image] |
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Term
muscarinic receptor antagonists
their principal mode of action as antiemetics is on mACh receptors at the STN, the vestibular nuclei, and the VC
primarily for motion sickness |
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Definition
| MOA of antiemetic antimuscarinics |
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Term
antiemetic antimuscarinic
muscarinic, weak D2, H1 activity
metabolism:
[image]
conjugation of hydroxy
demethylation
hydroxyaryl
distance between amine and carbonyl is similar to ACh (natural agonist) due to conformation |
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Definition
MOA and metabolism of scopolamine
[image] |
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Term
neurotransmitter that activates the neruokinin-1 (NK1) receptor, a GPCR
has physiological roles in inflammation, pain, GI, respiratory functions, stress response, and emesis
5-HT neurons coexpress SP and the firing of NE neurons is modulated by SP |
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Definition
actions of substance P
[image] |
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Term
antiemetic NK-1 receptor antagonist
acts on NK1 receptors located in the VC and CTZ to oppose the actions of substance P
very promising taret - performed better than most commonly used antiemetic ondansetron in trials
metabolism:
[image]
extensively metabolized
primarily by CYP3A4: O-dealkylation
CYP2C19: O- and N-dealkylations |
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Definition
MOA and metabolism of aprepitant
[image] |
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Term
antiemetic cannabinoid
mechanism related to stimulation of CB1 receptors on neurons in the VC
highly lipophilic and well absorbed
[image]
11-OH THC is the MAIN ACTIVE METABOLITE
parent drug and metabolites are highly bound to plasma proteins
excreted via the biliary-fecal route
useful in patients receiving cancer chemo when other drugs fail
ADRs: prominent central sympathomimetic activity, abstinence syndrom, displacement of other drugs from plasma proteins |
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Definition
MOA and metabolism of dronabinol
[image] |
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Term
glucocorticoids, most often dexamethasone, are useful adjuncts to antiemetic therapy in cancer patients
recognized that patients who received prednisone as a result of their Hodgkin disease protocol developed less nausea than those who didn't
mode of action is unclear but most likely involves suppression of cancer, radiation, or chemotherapy induced inflammation and prostaglandin production
used as an adjunct with 5-HT antagonists like ondansetron, also with metoclopramide, the phenothiazines, aprepritant, and cannabinoids |
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Definition
| MOA of glucocorticoids as antiemetics |
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Term
not antiemetics themselves but their anxiolytic and sedating properties are useful for reducing anticipatory nausea and vomiting
most useful in combination with other antiemetics |
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Definition
| MOA of benzodiazepines as antiemetics |
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Term
benzodiazepine
anxiolytic, amnesic, sedative/hypnotic
GABA-A receptor
metabolism:
[image]
glucuronidation is major |
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Definition
MOA and metabolism of lorazepam
[image] |
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Term
benzodiazepine
anxiolytic, amnesic, sedative/hypnotic
GABA-A receptor
metabolism:
[image]
CYP3A4: 4-hydroxy (blue)
also alpha-hydroxy (pink) |
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Definition
MOA and metabolism of alprazolam
[image] |
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