Anti-emetic Drugs and Prokinetic Drugs Flashcards
What are Anti-emetic Drug physiology?
High concentrations of M1, H1, and Neurokinin 1 and serotonin (5-HT3) receptors have been identified in vomiting center.
How is vomiting controlled?
Chemoreceptor trigger zone (CTZ) and vomiting center is where stimuli are integrated.
Stimulation from higher centers, distension of the stomach and GI tract, and vestibular feedback
Pathophysiology Aspects of Chemotherapy Induced Nausea and Vomiting
Chemotherapy agents act on Entero-chromaffin cell of the GI tract. Which then causes there to be serotonin release. Serotonin binds to the 5-HT3, which then causes vomiting.
Chemotherapy then causes area postrema -> causes there to be substance P release that attaches to NK1.
Anti-histamine anticholinergic antagonists
weak anti-emetic activity.
work on muscarinic and histamine receptors in the vomiting center and the vestibular system –> stimulates nausea and vomiting.
What are the Anti-histamine and anticholinergic antagonists ?
scopolamine, meclizine, and dimenhydrinate.
Scopolamine
Muscarinic receptor antagonist.
Blocking the M1 receptors in the CNS.
Prevents motion sickness.
Clinical Applications of Scopolamine
Post-operative nauea/vomiting, motion sickness.
Adverse Reactions
Exacerbate psychosis and somnolence, and xerostomia `
Meclizine
MOA: H1 antihistaminic agent with minimal anticholinergic properties that causes less sedation.
Inhibits histamine and anti-cholinergic pathways
Clinical Applications
Nausea/vomiting
Pregnancy
motion sickness
Dimenhydrinate
MOA: inhibits histamine and anti-cholinergic pathways.
Clinical Applications: chemotherapy-induced nausea/vomiting
H1 anti-histamine agent do not have —-
significant action at CTZ
Dopamine receptor antagonists
anti-psychotics
strong anti-emetics
D2 receptor antagonists
What are dopamine receptor antagonists?
Prochlorperazine promathazine droperidol metoclopramide domperidone
Prochlorperazine + Promethazine
Blocks Dopaminergic D1 and D2 receptors in the brain.
Inhibit peripheral transmission to the vomiting center.
anti-cholinergic and antihistamine activity
Adverse Reactions of Prochlorperazine + Promethazine
Extrapyrimidal effects.
Promethazine
D1 and D2 receptors in the brain, including CTZ –> inhibits peripheral transmission to the vomiting center.
anti-cholinergic and anti-histaminic activity
Droperidol MOA, Clinical Applications, Adverse Reactions, Contraindications
Blocks dopaminergic receptors in the CTZ.
Clinical Applications: post-operative nausea/vomiting. Has not been/limited use for chemotherapy induced also.
Metoclopramide
D2 receptor antagonist without antipsychotic activity
Enhancing action of acetylcholine at muscarinic nerve endings in the gut
Metoclopramide Clinical Applications
Nausea/vomiting and gastric gastroparesis
Adverse Reactions of Metoclopramide
Fatigue, somnolence, Extrapyrimidal side effects, headache
Contraindications of Metoclopramide
Tardive dyskinesia
Domperidone
MOA: D2-receptor antagonist without anti-psychotic activity
Act centrally by blocking dopamine D2 receptor in the CTZ
Clinical Applications: Prevention of GI symptoms.
Serotonin 5-HT3 receptor anagonists are:
Ondansetron, dolasetron, granisetron, palonosetron
What are serotonin 5-HT3 receptors antagonists useful for?
They are useful acute pahse chemotherapy induced vomiting. Post-operative nausea/vomiting, and radiation induced nausea/vomiting
5-HT3 serotonin receptor antagonists are combined with:
they are combined with cortico-steroids
Ondansetron:
MOA: Blocks serotinin by acting peripherally on vagal nerve terminals and centrally on CTZ.
Clinically Applications:
chemotherapy induced
nausea/vomiting,
post-operative
nausea/vomiting
acute radiation induced nausea/vomiting
Ondanserton adverse effects:
QT interval prolongation
Dolasetron and Granisetron
Dolasetron +
MOA: Peripherally acts on vagal nerve and centrally on CTZ.
Clinical Applications: Chemotherapy induced nausea/vomiting
QT interval prolongation is the main side effect for dolasetron.
For granisetron, it is constipation, headache, fatigue, progressive ileus, ect
Palonosetron
Palonosetron is same basically as all serotonin inhibitors.
It is useful in prevention of PONV, CINV, increased efficacy in preventing acute and delayed CINV.
better than ondansetron and dolasetron.
petter than granisetron.
Adverse effect: less effect on QT interval
What is cannabinoid hyperemesis syndrome?
hyper-emesis due to chronic cannabis use
Dronabilol and nabilone are
synthetic analogs of THC that are used as second line agents to CINV
Dronabilol MOA and Clinical Applications
breakthrough CINV
chemotherapy induced nausea and vomiting
Nabilone
Inhibits the vomiting center through the stimulation of CB1 subtype of cannabinoid receptors
chemotherapy induced nausea/vomiting.
Breakthrough CINV
Benzodiazepines
Weak anti-emetics and are used to prevent anxiety or anticipatory nausea/vomiting
Alprazolam and Lorazepam
MOA: binds to GABA receptors and causes calming effect and lowers level of anxiety
GABA-A receptors.
Clinical applications of of Alprazolam and Lorazepam
high level of anxiety and anticipatory nausea/vomiting
Neurokinin 1 -receptor antagonists
Substance P is the principal NT that activates neurokinin 1 receptors in the CNS.
Acute phase of CINV is thought to be mediated by serotonin and Substance P, where Substance P is believed to be primary mediator of delayed phase.
No affinity for serotonin, dopamine, corticosteroid receptors
Useful for delayed phase of CNV
combined with dexamethasone and a 5-ht3 receptor antagonist , N1 receptor antagonists
Standard care for prevention of CINV in both adults and children receiveing highly emetogenic chemotherapy
Useful in prophylaxis treatment of chemotherapy induced nausea/vomiting and post-operative nausea.
All may be given before chemotherapy Day 1
Apretitant,
Aprepitant
MOA: inhibits the neurokinin 1 receptor, augmenting the anti-emetic activity of 5 -HT3 receptor antagonists and corticosteroid to inhibit the acute and delayed phase of chemo induced emesis
Clinical Application of Apretitant
used for CINV and post-operative nausea/vomiting (PONV)
What is Fosaprepitant
Fosaprepitant is IV formulation of aprepitant.
What are apretitant and fosaprepitant inhibitors of:
CYP3A4
Dose of dexamethasone should be —— when used concurrently as an anti-emetic
should be decreased when used concurrently as an anti-emetic
Netupitant is—- inhibitor
Rolapitant is —— inhibitor
Neutpitant is a CYP-450 inhibitor (dexamethasone should be decreased)
Rolapitant is a —- CYP-2D6 inhibitor, and dexamethasone shoudn’t be decreased
Prokinetic Agents Purpose
Promote the GI transit and speed gastric emptying by enhancing coordinated propulsive motility.
Release of excitatory neurotransmitters at nerve muscle junction.
Used to pre-op the empty gut, gastroparesis, GERD as anti -emetic .
Bethanechol
MOA: not hydrolyzed by AChE
Strong muscarinic receptor antagonist (M2 and M3)
no nicotinic actions.
Pharmacological Effects: increase motility, limited distribution to the CNS
Clinical Applications: Stimulate GI smooth musclemotor activity
Neostigmine
MOA: Indirect gastric stimulant/inhibits AChE–> increases ACh, stimultes peristalsis via M2 receptors
Clinical Applications: colonic pseudo obstruction.
Metoclopramide
Dopamine has inhibitory effect on motility, resulting from suppresses ACh releaser from myenteric motor neurons. These are D2 receptor antagonists.
Accelerate gastric emptying (emergency surgery, ect), dyspepsia, GERD
Adverse Effect: tardive dyskinesia
Domperidone
same as metoclopramide
Motilin and Macrolide Antibiotics
Macrolide antibiotics are motilin receptor agonists.
Clinical: IV pre-op to empty gut for gastroparesis
Prucalopride and Tegaserod
5-HT4 receptor agonists.
Stimulate peristaltic reflex, intestinal secretions, and GI motility
Prucalopride is used to treat Chronic Idiopathic Constipation in adults, and OIC in chronic pain patients
Tegaserod is for IBS-C
