A32. Antiemetic drugs. Prokinetic agents. Drugs for irritable bowel disease (IBS). Flashcards
Why is Eryhtromycin used as a prokinetic agent?
Erythromycin which is a macrolide, promotes motility by stimulating motilin receptors.
Which cholinomimetic is used as prokinetic agent?
Bethanechol is a cholinomimetic used for non-obstructive GI dysmotility (like in post up ileus, neurogenic ileus). Remember the major effects of cholinomimetics (BP ↓, bronchoconstriction, all GI secretions (e.g. saliva,acid))… similar to the ACE-I effect w/ DUMBBELSS [diarrhea, urination, miosis, bronchospasm, bradycardia, lacrimation, emesis, salivation, sweating]. It is also contraindicated with peptic ulcer, hyperthyroidism, obstructive ileus, asthma.
List the D2 antagonists that can be used as a prokinetic agent.
- Metoclopramide
- Domperidone: D2 receptor blocking in area postrema → GI motility ↑.
What are prokinetic agents and their indications?
Prokinetic agents/drugs stimulate upper GI motility and are helpful for gastroparesis, post-surgical gastric emptying. Also GERD patients can benefit (helps LES pressure ↑). Previously cholinomimetic agents were used, but less-so now.
List the prokinetic agents.
- D2 antagonists: Metoclopramide, Domperidone.
- Cholinomimetics: Bethanechol
- Erythromycin (Macrolide)
List the serotonin agonists.
- Lorcaserin
List the Anorexiants/ Appetite suppressants.
- Diethylpropion
- Phentermine
(Riba said all of these are no longer indicated for obesity.)
What lipase inhibitor is used for Weight loss and what is it’s MOA?
Orlistat (only licensed one for now)
MOA: inhibits gastric and pancreatic lipases → decreased breakdown of dietary fat into smaller molecules → less absorption. fat absorption ↓ by ~30% → less calories → weight loss.
What can be given in obesity?
- Lipase inhibitors (most important) 2. Anorexiants/ “appetite suppressants” 3. serotonin agonists
Name the receptors modified pharmacologically. ***
- Muscarinic receptor antagonists: scopolamine is best against motion sickness. 2. H1-antagonists (+ additional muscarinic ATG). 3. D2 antagonists. 4. 5-HT3 Antagonists / Serotonin receptor blockers 5. Substance P/ NK-1 Antagonists: drugs = Aprepitant, Fosaprepitant 6. Cannabinoids: CB-1 agonists 7. Vitamin B6: glucocorticoids
How are glucocorticoids used in this category/topic?
Glucocorticoids can enhance antiemetic action (less important). Dexamethasone and Methylprednisone are moderate-mild in effect. More likely used in combo with others.
When can Vitamin B6 be used in this category of drugs?
Vitamin B6/ pyridoxine can be used to reduce pregnancy-related nausea.
How can cannabinoids be used in this regard?
Cannabinoids: CB-1 agonists have excellent anti-emetic action. Original idea of using cannabinoids as medicine was not nausea, but pain or loss of appetite. first licensed indication was AIDS in terminal phase. now in some countries, cancer is an indication. It increases appetite, decreases nausea, decreases pain. THC/dronabinol as medicinal name. more expensive than a joint. The “problem” is the psychoactive effects. Nabilone: synthetic cannabinoid agonist.
Name some Substance P/Nk-1 antagonists.
Substance P / NK-1 Antagonists: 1. Aprepitant 2. Fosaprepitant.
What is the MOA and purpose of 5-HT3 antagonists/Serotonin receptor blockers as an antiemetic agent.
5-HT3 antagonists / serotonin receptor blockers act in the GI, cause constipation. It is the most potent antiemetics. Primarily anti-cancer drug nausea, also for post-op nausea.
D2 Antagonists
D2 antagonists block dopamine in area postrema CTZ. It’s a very efficient anti-emetics. Practically any anti-psychotic can be used as antiemetic, but obviously don’t use haloperidol etc for this. Droperidol is indicated for post-op nausea, even in children. Dose is way less than antipsychotic dose (parenterally given). May however prolong QT. o selective D2: mainly peripherally-acting, don’t really act on other receptors • metoclopramide: more or less enters brain • domperidone: doesn’t penetrate brain, but there’s no BBB in area postrema so it still has antinausea effect. Doesn’t have extrapyramidal side effects like metoclopramide. • pro-kinetic effect, actually opens the pylorus and stomach emptying is easier → increase propulsion. block nauseating reflexes. Occurs via 5-HT4 (not D2! Asked on midterm) • used for post-op nausea, IBS, ↓ nausea in cancer patients (esp metoclopramide).
How and why are H1 antagonists used as antiemetics?**
H1-antagonists (+ additional muscarinic ATG): Typical selective H1 antagonist anti-allergic drugs are not good for nausea, but H1 + muscarinic antagonism can help. Not as strong as scopolamine, but still have some anticholinergic action. Dimenhydrinate also used for motion sickness. Most important side effect is sedation
How can Muscarinic receptor antagonists be used as an anti-emetic?
Muscarinic receptor antagonists such as scopolamine is best against motion sickness.
Physiology: Nausea reflex**
nausea reflex o efferent: parasympathetic (smooth muscle) + motoneurons (skeletal muscle) o afferent: • reticular formation: collects impulse from gut, chemoreceptor zone, labyrinthic fibers/nuclei. decides whether there will be nausea or not. at least 3 receptors + neurotransmitters ▪ Muscarinicreceptors (M1probably),H1histamine,D2dopamine • area postrema: chemoreceptor trigger zone (CTZ) ▪ found in 4th ventricle. no BBB here, any chemical agent can enter here and sense the chemical structures to induce nausea. nauseating chemicals can be toxins or drugs or some foods ▪ dopamine 2 and serotonin 3 receptors can be activated then go to reticular formation • GI: anything we digest appears there. may send information upward. ▪ involves serotonin 3, dopamine 2, others – very complicated. neurokinin-1 receptor probably ▪ enteralstimulusgoestosolitarytractnucleusandacts. • labyrinthic reflex: important in motion sickness. ▪ mostlymuscarinicreceptorstimulation,H1too ▪ any drug which enhances labyrinthic reflex, e.g. opioids, can cause nausea. morphine often provokes vomiting • note that any sensory input may lead to nausea. smell, taste, see, feel something disgusting, even just thinking.
What are antiemetics?
Antiemetics: inhibit nausea/vomiting.
What are the adverse effects of taking serotonin agonists?
Adverse effects: 1. GI symptoms: Nausea, Constipation 2. H/A 3. Dry mouth 4. Dizziness 5. Lethargy. 6. Possibility of serotonin syndrome / NMS. avoid combination with SSRIs, MAOIs, etc. 7. Not recommended in severe renal impairment, excreted in urine.
What is the MOA of anorexiants/appetite suppressants.
MOA: Increases release of norepinephrine and dopamine from nerve terminals + inhibiting reuptake. The higher sympathetic response lowers the appetite.
Pharmacokinetics of anorexiants/appetite suppressants.
Tolerance: Develops within weeks, causing plateau of weight loss. Increased dose doesn’t benefit much, so discontinuation is recommended at this point. Administration: oral Half-life: about 4-8 hours. Dependency: potential for abuse/dependence (similar to amphetamines, which were also used as anorexients).
What are the side effects that accompany anorexiants/appetite suppressant use and when is it contraindicated?
Side effects: - Dry mouth - Headache - Insomnia - Constipation - ↑ HR - ↑ BP (avoid in patients with hypertension, heart disease, arrhythmias) CI: if taking MAOIs, other sympathomimetics
Pharmacokinetics of lipase inhibitors?
Administered: orally w/ each meal that contains fat. Absorption: minimal systemic absorptioni
What are the side effects of taking lipase inhibitors ?
Adverse effects: 1. mostly GI problems (steatorrhea, flatulence, increased defecation. can decrease this problem w/ concomitant intake of the bile-acid binding resin cholestyramine). Decreased absorption of fat- soluble vitamins (should take supplements) 2.Rarely pancreatitis
Contraindications of lipase inhibitors?
CI: in pregnancy, malabsorption syndromes, cholestasis. Also interferes with absorption of other medications, e.g. amiodarone, cyclosporine, levothyroxine.
Name the drugs in the antiemetic pharmacon category.
- 5-HT3 blockers 2. D2 blockers 3. H2 blockers 4. Antimuscarinics 5. Corticosteroids 6. Cannabinoids 7. Neurokinin receptor antagonists
Pharmacokinetics of substance P/NK(Neurokinin) -1 antagonists.
Only available in pills. Aprepitant usually given orally w/ dexamethasone and a 5-HT3 antagonist. Strong CYP3A4 metabolism, and may affect other drugs like warfarin and oral contraceptives.
What are the indications of substance P/NK-1 antagonists?
Indications: only cancer-drug nausea
What are the side effects of taking Substance P/NK-1 antagonists?
Diarrhea
Name the 5-HT3 blockers.
5-HT3 blockers: a) ondansetron (most important) b) granisetron c) tropisetron d) dolasetron e) alosetron (not only anti-emetic, but also for diarrheal form of irritable bowel syndrome)
Name the D2 blockers.
D2 blockers a) prochlorperazine b) droperidol c) metoclopramide d) domperidone
Name the H2 Blockers used as antiemetics.
- H2 blockers: a) diphenhydramine/dimenhydrinate
Name the neurokinin receptor antagonists.
Neurokinin receptor antagonists: a) aprepitant b) fosaprepitant
Name the cannabinoids used as antiemetics.
Cannabinoids: a) dronabinol b) nabilone
Name the corticosteroids used as antiemetics.
Corticosteroids: a) Dexamethasone
Name the antimuscarinics used as antiemetic agents.
Antimuscarinics: a) Scopolamine
What are the adverse effects of 5HT Antagonist /Serotonin receptor blockers.
SE: 1. QT prolongation may occur w/ dolasetron or high dose ondansetron. (so dolasetron is used less often) 2. May impair B12 absorption. 3. Combo with other serotonergic drugs may possibly → serotonin syndrome.
What are the side effects and contraindications of D2 antagonists?
SE: A little bit goes through BBB → acute dystonia. CI: in Parkinson’s (EPS observed)
Physiology: importance of nucleus tractus solitarius?
The nucleus tractus solitarius (NTS) is the vomiting center, located in medulla oblongata. This nucleus recieves inputs from the GI tract (directly via the vagus nerve), vestibular system and area postrema. The NTS project neurons to other medullary nuclei to coordinate the vomiting response.
What is Ondansetron and it’s indication of use?**
MOA: Ondansetron antagonizes 5HT-3 receptor on vagal afferents in the GI tract. ** Indication: Treats chemo-induced or post-op vomiting
Ondansetron can cause what side effects?
- GI symptoms: constipation 2. CNS symptoms: a) headache and dizziness b) Serotonin syndrome: symptoms include rigidity, tremor, hyperthermia, confusion (although these symptoms are more common in SSRIs) 3. Cardiac: prolong the QT interval and induce torsades de pointes.
What are the side effects of metoclopramide?
- GI symptoms: diarrhea 2. CNS symptoms: a) Depression (central d2 blockade) b) Extrapyramidal symptoms (central d2 blockade): dystonia, akathisia, parkinsonian features (chronic use can cause parkinsonism). c) Neuroleptic malignant syndrome: symptoms include fever, rigidity, mental status changes, autonomic instability, rhabdomyolysis. 3. Hyperprolactinemia (central d2 blockade ): gyncomastia, impotence, menstrual disorders, galactorrhea. 4. Cardiac: Prolonged QT and induce torsades de pointes.
phenotiazines?**
phenothiazines: prochlorperazine (mentioned a lot in Lippincott, but not by Riba). very effective
Why is domperiodone better when it comes to side effects than metoclopramide?
Domperidone doesn’t cross BBB and so has less CNS toxicity.
pharmacokinetics of serotonin receptor blockers
Administration: available parenterally or pills.
What is the MOA of Lorcaserin?
Lorcaserin is a selective 5-HT2C receptor agonism stimulates POMC neurons → melanocortin → decrease in appetite.
What are the indications for Locarserin and possible side effects of this drug?
It is used in chronic weight management, however drugs of this class were pulled from the market due to potentially fatal adverse effects (esp valvulopathy, due to 5-HT2B effect).
