Antiemetic drugs. Prokinetic agents. Drugs for irritable bowel disease (IBS) Flashcards
factors influencing emesis
Emetic pathways represent a complex mechanism with a final effect on the vomiting center. Involve interaction with multiple mediators, including Ach, dopamine, 5-HT, histamine, endogenous opioids, endogenous cannabinoids, and neurokinins.
- Pain receptors (via GI afferents) -> release of substance P -> NK1-R spinal cord
- Vestibular system
- CHemoreceptor trigger zone (CTZ) area postrema - D2, 5HT3, CB1(-)
all three act on vomiting center, M1
Antagonists: 5HT3 D2 M1 NK1
Agonists:
CB1
Antiemetic agents
- Dimenhydrinate - H1 histamine blockers
- Scopolamine - Antimuscarinic agents
- Ondansetron - 5-HT3 receptor blockers
- Palonosetron - 5-HT3 receptor blockers
- Metoclopramide - D2 dopamine receptor blockers
- Droperidol - D2 dopamine receptor blockers
- Aprepitant - NK1 receptor antagonists
- Dronabinol - CB1 cannabinoid agonist
Further agents with potential antiemetic effects: 1. Benzodiazepines (lorazepam, alprazolam) 2. Corticosteroids (dexamethasone, methylprednisolone)
Dimenhydrinate
H1 histamine blockers
- In addition to their central and peripheral H1 blockade effect, exert muscarinic blockade
- Inhibition of muscarinic receptors in the vomiting center → inhibitory effect on emetic pathways
Combination drug of diphenhydramine and theophylline derivative (intend to reduce sedative effect and abuse liability due to H1 blockade)
kinetics:
- Oral, parenteral
- Metabolism by hepatic P450 enzymes
indication:
- Motion sickness, Meniere’s disease (vestibular nausea)
- Antiemetic (chemotherapy-induced vomiting)
- vomiting due to irradiation
Side effects: - CNS effects - Atropine-like effects - α-blockade (orthostatic hypotension) - Abuse liability+ seddation, \+ consequences of M/D-receptor blockade
Scopolamine
Antimuscarinic agents- muscarinic antagonsit
Inhibit muscarinic receptors in the vomiting center → inhibitory effect on emetic pathways
non-selective for receptor
Lipid-soluble – enter CNS
prevention of motion sickness (vestibular nausea) (but short T1/2 - 3 h)
orally , parenterally
better tolerated as a transdermal patch
SE: very high incidence of anticholinergic effects
Ondansetron
and
Palonosetron
5-HT3 receptor blockers
Blocking of 5HT3 receptors in CNS and GIT
on the terminals of enteric cholinergic neurons inhibits colonic motility, especially in the left colon
Most potent antiemetics in chemotherapy, radiation therapy, after surgery
Block serotonin receptors (excitatory) in the chemoreceptor trigger zone and enteric nervous system
kinetics: - Ondansetron (oral, IV, daily admin) - Palonosetron (IV, 40 h half life) - Highly-potent antiemetic effect - Duration of action 3-6 h' - Metabolism by hepatic P450 enzymes (consider dose reduction in patients with hepatic insufficiency)
Indications:
- Chemotherapy-induced nausea and vomiting
- Post-operative nausea and vomiting
Side effects:
- Constipation
- headache
- QT prolongation, arrhythmias
- Serotonin syn. (milder risk compared to SSRI’s or TCA’s)
Metoclopramide
D2 dopamine receptor blockers, 5HT3-antagonist and 5HT4-agonist
Not effective in nausea of vestibular origin
- Central effects → inhibition of dopamine D2-receptor in the chemoreceptor trigger zone (area postrema) results in potent anti-nausea and antiemetic action
- Peripheral effects → in the GI, dopamine acts as an inhibitor of Ach release; reducing this inhibitory effect results in prokinetic effect (mediated by Ach)
- Within the GI tract, activation of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect produces prokinetic effect
- Inhibition of dopamine D2-receptor in the chemoreceptor zone of the medulla (area postrema) results in potent anti-nausea and antiemetic action
Antiemetic in chemo and or radiation therapy, acute migraine
Prokinetic: increases peristalsis in stomach: GERD, gastroparesis, paralitic ileus
- Oral, parenteral
- Antidopaminergic side effects limit its high dose required to achieve potent antiemetic effect; in use more commonly as a prokinetic agent (low doses required)
- Freely enters CNS
- Agonist activity at 5-HT4 receptors (peristaltic motility ↑), antagonist activity at 5-HT3 receptors (sensory nerve – vomiting ↓)
- Prokinetic effect (gastric paresis)
- Anti-emetic effect (achieved only at high doses)
Indications:
- GERD (increase lower esophageal sphincter tone)
- Conditions with delayed gastric emptying
(post-operative, diabetic gastroparesis)
- Non-ulcer (chronic) dyspepsia
- Anti-emetics
- Given as preparation to upper GI endoscopy (clearance
of blood and clots – improves endoscopic visualization)
- Post-partum lactation stimulation
Side effects:
1. CNS effects: restlessness, drowsiness, insomnia, anxiety
2. Extrapyramidal symptoms (drug-induced parkinsonism)
3. Hyperprolactinemia (PRL ↑) – galactorrhea,
gynecomastia, impotence, menstrual disorders
Droperidol
D2 dopamine receptor blockers
- Central effects → inhibition of dopamine D2-receptor in the chemoreceptor trigger zone (area postrema) results in potent anti-nausea and antiemetic action
- Peripheral effects → in the GI, dopamine acts as an inhibitor of Ach release; reducing this inhibitory effect results in prokinetic effect (mediated by Ach)
*Antipsychotic agent with general properties similar to those of haloperidol (management of acute psychosis)
Not effective in nausea of vestibular origin
- Oral, parenteral
- Metabolism by hepatic P450 enzymes
- Antiemetic (used in surgical and diagnostic procedures)
- Anti-emetic use (with potent sedative effect)
- Used in combination with fentanyl in neuroleptanalgesia
- Potential use in general anesthesia regimens
- Acute migraine attack
Side effects:
- CNS depression (additive effect)
- α-blockade (orthostatic hypotension)
- H1-blocks
- 5-HT blocks
Aprepitant
NK1 receptor antagonists
- Neurokinin receptors in the spinal cord and area postrema – play a role in pain transmission; ligands include neurokinin, substance-P, substance-A, bradykinins
- Inhibition of NK1 receptors → reduce pain-induced vomiting
central blockade in the area postrema
Combined therapy with aprepitant, a 5-HT 3 –receptor antagonist, and dexamethasone prevents acute emesis in 80–90% of patients
kinetics: - Oral - Metabolism by hepatic P450 enzymes - Inhibitor of cytochrome P450 CYP3A4 (reduces serum half-life of warfarin)
indications:
- Chemotherapy-induced nausea and vomiting
- Post-operative nausea and vomiting
- Usually given in combination with dexamethasone and
palonosetron
Side effects:
- Fatigue, dizziness
- Diarrhea
vertigo, diarrhea
saturates the CYP3A4 enzyme
Several chemotherapeutic agents are metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vinblastine, and vincristine
Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant plasma levels (eg, ketoconazole, ciprofloxacin, clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine)
decreases the international normalized ratio (INR) in patients taking warfarin.
Dronabinol
CB1 cannabinoid agonist
Inhibitory CB receptors, act to inhibit presynaptic release of conventional transmitters, including dopamine
*Controlled substance formulation of THC (tetrahydrocannabinol)
appetite stimulant and antiemetic
kinetics:
- Oral
- Biliary elimination
- Peak effect in 2-4 h’, psychoactive effects may last up to 6 h’,
appetite-stimulant effects may persist for 24 h’
Indications:
- Chemotherapy-induced nausea and vomiting
- AIDS wasting syndrome (appetite stimulant)
- chemotherapy-induced nausea and vomiting per os, combined with D2-antagonist - phenotiazins
Side effects:
- Tachycardia, hypotension
- euphoria/dysphoriasteroids
- Hallucination
- Reddening of the conjunctiva
lorazepam, alprazolam
Benzodiazepines
(lorazepam, alprazolam)
Antiemetic potency is low by itself; beneficial effect may be due to their sedative, anxiolytic and amnesic properties (beneficial in treating anxiety-induced vomiting)
dexamethasone, methylprednisolone
corticosteroids
Monotherapy, effective against mild to moderate emetogenic chemotherapy
Most frequently used in combination with other agents
-In combination enhances the efficacy of 5-HT3 -receptor antagonists or D2-antagonist (metoclopramid)
-Benzodiazepins –
lorazepam or diazepam are used to reduce vomiting caused by anxiety
Chemotherapy-induced nausea and vomiting – commonly used combination drug regimen:
- Aprepitant
- Ondansetron
- Dexamethasone/methylprednisolone
Prokinetic agents
Drugs that selectively stimulate gut motor function → prokinetic agents
*all prokinetic agents are contraindicated if obstructive ileus is suspected (risk of toxic megacolon and intestinal perforation)
Metoclopramide -
D2 dopamine receptor blockers (5-HT4-receptor agonistseffect!!!)
(Domperidone) -> no CNS penetration, rest like metoclopramide (5-HT4-receptor agonists effect!!!)
Erythromycin - Macrolide antibiotics
Neostigmine - Cholinomimeti indirect
Bethanechol- Cholinomimetic direct
Agents that increase lower esophageal sphincter pressures
- GERD
Drugs that improve gastric emptying
- Gastroparesis and post-surgical gastric emptying delay
Agents that stimulate the small intestine
- Postoperative ileus or chronic intestinal pseudo-obstruction.
Agents that enhance colonic transit
- constipation
Erythromycin
Macrolide antibiotics
Directly stimulate motilin receptors on GI smooth muscle cells
Act on motilin receptors
- Oral, parenteral
indications:
- Gastroparesis (IV)
- Given as preparation to upper GI endoscopy (clearance
of blood and clots – improves endoscopic visualization)
Side effects:
- GI symptoms (potential risk for severe diarrhea)
- Skin rash
- Eosinophilia
- QT prolongation
Neostigmine
Cholinomimetics - Carbamates (non-competitive, reversible inhibition)
Bind cholinesterase and undergo hydrolysis (alcohol portion released) → acidic portion (carbamate ion) is released much more slowly from the enzyme active site → preventing binding and hydrolysis of endogenous acetylcholine
Acetylcholine-esterase inhibitor (indirect-acting sympathomimetic)
Kinetics:
- Oral, parenteral
- Duration of action 2-4 h’
- Quaternary amine – does not enter CNS
Indications:
- Myasthenia gravis
- Non-obstructive ileus (post-operative/neurogenic)
- Urinary retention
- Reversal of NM block (due to curare-like overdose)
*Clinical use is limited (due to strong contractile effect, may induce intense abdominal cramps and pain)
AchE inhibitor poisoning ("DUMBBELS")
- Diarrhea
- Urination
- Miosis
- Bradycardia
In the management of myasthenia gravis, AchE-inhibitors are given together with a selective muscarinic antagonist (glycopyrrolate, hyoscyamine) – control muscarinic side effects (abdominal pain, nausea, vomiting, sweating).
- Bronchoconstriction
- Excitation (CNS, muscles)
- Lacrimation
- Secretion (sweating, salivation)
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
