PCOL Block 7: Antiemetics
Name exampled of Parkisonism
Shuffling gate Unusual hand or finger movements (eg pill rolling)
What other receptors can Droperidol antagonize? (3)
Similar to haloperidol: 5HT GABA NE
What is one off-label use for prochlorperazine?
Migraines
Classes of antiemetics (7)?
1. 5-HT3 antag 2. Corticosteroids 3. Neurokinin-R antag 4. Olanzapine 5. D2 antag 6. Cannabinoids 7. BZDs 8. H1 antag / M1 antag
Uses of antiemetics (4)?
1. Cancer chemo & radiation therapy (CINV, RINV) 2. Post-op N/V (PONV) 3. Motion sickness 4. Morning sickness (hyperemesis gravidarum) Can use prophylactic & acutely Antiemetics don't always help for motion sickness
When do we administer anti-emetics for chemo? What do we administer it with? (2)
30 min prior to chemo Corticosteroid or NK1 antagonists (cortico with chemo)
Which receptors are present in GIT?
5-HT3
Which of the following is a second line for CINV: 1. 5-HT3 antag 2. Corticosteroids 3. Neurokinin-R antag 4. Olanzapien 5. D2 antag 6. Cannabinoids 7. BZDs 8. H1 antag / M1 antag
5. D2 antag
Which of the following is used for motion sickness: 1. 5-HT3 antag 2. Corticosteroids 3. Neurokinin-R antag 4. Olanzapien 5. D2 antag 6. Cannabinoids 7. BZDs 8. H1 antag / M1 antag
8. H1 antag / M1 antag
Name examples of a dyskinesias: (5)
= Movement problems Tongue, arms, finger, leg movements "flailing" Lip smacking Bilnking Akthiasa (can't remain motionless) Akinesia (can't initiate movement) ^^ EPS
Name examples of dystonias: (2)
= Muscle tension problems that are painful Extreme muscle contractions Unusual twisting of body parts like neck and eyes
Metoclopramide is clinically used when? (5)
- CINV - CINV proph - PONV - PONV prophylaxis - GI uses (radiology, diabetic gastroparesis, radiology, intestinal intubation)
For CINV and PONV what are indicated for prophylaxis? acute treatment?
- all setron rx acute: dolesetron + granisetron (DG is a cute sorority)
Define the following ADRs of chemo: Acute emesis Delayed emesis Anticipatory emesis
Acute emesis: w/in 1-2 hours of chemo, peaks 4-6 Delayed emesis: more than 24 hrs after chemo Anticipatory emesis: prior to chemo due to past experience
What are the off-label uses of ondansetron?
Alcohol dependence Cyclic vomiting syndrome Gastroenteritis Hyperemesis gravidarum Morning sickness Pruritis
There were several reports of death due to this drug
Alosetron
This drug is indicated for Tx of severe, chronic diarrhea-predominant IBS in women for whom conventional therapy has failed
Alosteron
What are the 5 H1 and M1 Antagonists to know? Which has fewer anti-cholinergic effects?
Antihistamines: Promethazine Diphenhdryamine Dimenhydrinate (Dramamine) Meclizine: No anti-cholinergic effects --> less sedating Anticholingeric = Scopolamine NOTE: Dramamine Less Drowsy
What are 2 interactions with Metoclopramide?
Antipsychotics Metabolized by 2D6 so inducers and inhibitors effect it Opioids Digoixin Antidiabetic drugs
What are four neurokinin 1 receptor (NK1) antagonists in the USA?
Aprepitant <-- oral Fosaprepitant <-- IV (participants) Roalapitant NEPA (netupitant & palonstetron)
What are some ADRs of Droperidol? (3)
Arrhythmias EPS Prolonged QT These are severe, which is why this is last line!!
What are FDA recommendation in monitoring Dalosetron and cardiac toxicity?
Assessment of K+ and Mg+ levels before taking ECC monitoring CI'd in pts. w/ congenital QT syndrome Avoid drugs that prolong QT (verapamil) or QRS internal (flecainide, quinidine)
We usually place the granisetron patch under the shirt why?
B/c it can irritate the skin when exposed to sunlight
Why are dose reductions necessary when NK antagonists are taken w/ glucocorticoids?
Bc they inhibit 3A4 and glucocorticoids are metabolized by that
For CINV and RINV, antiemetics are best to be given when?
Before start of therapy for prophylaxis
What is the MOA of the NK1s?
Block the endogenous effects of substance P by blocking the NK1 receptor
MOA of 5-HT3 antagonists
Blocks 5-HT3 receptors on intestinal vagal and spinal afferent nn. This is partly mediated via 5-HT3 receptors in vomiting center and CTZ
Antiemetic mechanism of dronabinol?
CB1 receptor in vomiting center
Dronabinol uses: (2) Dosages?
CINV (high dose) Anorexia (low dose)
Anticipatory vomiting occurs with input from which area?
CNS
While not clinically reported all the 5HT3's have a potential for what?
CYP interactions
Metabolism & elimination of 5-HT3 antags?
CYP met (except for dolasetron) Liver & renal elimin
This drug class interacts w/ other CNS depressing drugs
Cannabinoids
This drug class is highly protein bound
Cannabinoids
The NTS receives input from: (4). What receptors are located at each site?
Chemoreceptor trigger zone (CTZ = area postrema) -- multiple (NK1, D2, opioids, etc) (posture bar) Vestibular system via CN 8 -- H1, M1 (rowers) GI Tract via Vagus/spinal afferents -- 5-HT3 (Las Vagus & the serotonin shotput) CNS
Severe ADRs of Alosteron?
Constipation Ischemic colitis
What can be administered w/ Palonsetron to make it more efficacious?
Corticosterois and/or NK1 antagonist More recently Olanzapine
This drug is indicated for morning sickness
Doxylamine:pyridoxine Other H1 and M1 are used off-label
Which 3 receptors are present in the CTZ? Where is it located?
D2 NK1 Opioid located @ 4th ventricle but outside BBB <-- so can reach CTZ w/o having to cross BBB (important for drugs)
What are some off label effects of Metoclopramide?
D2 antagonism can augment ACh effect in gut and increase prolactin release to aid in lactation PROKINETIC EFFECT (judge with milk coming out of nose)
What is the MOA of Metoclopramide?
D2 antagonism, some 5HT3 antagonism, & 5-HT4 stimulation
What is the main MOA of Droperidol?
D2 antagonist
What corticosteroid is often used with other anti-emetics?
Dexamethasone
Which corticosteroid is mainly given for emesis?
Dexamethasone
Which of the following H1 and M1 Antagonists can be used to prevent EPS: Dimenhydrinate Diphenhydramine Doxylamine:pyridoxine Meclizine Promethazine Scopolamine
Diphenhydramine
Which drug would you want to combine w/ D2 receptor antagonists?
Diphenhydramine Helps prevent EPS
What cannabinoid is commonly used? Which THC receptor?
Dronabinol (delta-9-THC)
Another D2 receptor antagonist that works for PONV prophylaxis and general N/V, but mostly as a last line drug
Droperidol
What ADRs are associated with cannabinoids? (6)
Dysphoria/euphoria Dizziness Paranoia Drowsiness Impaired cognition GI effects - abdominal pain, N/V
What are ADRs for the 5HT3 antagonists?
Headache (hammer hitting head) Diarrhea/constipation (tight hammer belt) Dizzyness Fatigue Sleepy Cramps Nervousness 5-HT syndrome normally well-tolerated
What are 2 ADRs of Metoclopramide?
EPS and sedation
Use for Olanzapine?
Effective for blocking N/V
What other effects does prochlorperazine have?
Extra pyramidal symptoms & NMS Also sedation, muscle relaxation, hypotension, reflex tachycardia
T or F 5-HT3 antagonists are useful in motion sickness
FALSE
What are some ADRs for NK1s?
Fatigue dizziness diarrhea constipation HS rxns, infusion rxns Stevens-Johnson syndrome and TEN rare
Which drug class and drug has a potential QT prolongation?
First gen 5-HT3 antagonists Esp. Dolasetron
This drug class is used pre-op to dry airways
H1 and M1 antagonists
What is a concern of prochlorperazine long term?
Irreversible tardive dyskinesia
How is 5-HT3 recpetor unique w/ regards to all other 5-HT receptors?
It is ionotropic All others are metabotropic (GPCR)
5HT3 antagonists are preferred over other antiemetics due to: (2)
Less sedation + EPS effects ** huge benefit
Which 2 receptors are present in the vestibular system?
M1 muscarinic and H1 distamine (bee swatter and M1 parking spot near rowing boats)
Which of the following Antihistamine drugs has the least amount of anticholinergic activity and is, therefore, less sedating: Dimenhydrinate Diphenhydramine Doxylamine:pyridoxine Meclizine Promethazine
Meclizine
What drug interactions does dronabinol have?
Metabolized by CYP 2C9 and CYP3A4 (C for cannabinoid)
This drug is used for GI preps like radiology, diabetic gastroparesis, radiology, intestinal intubation
Metoclopramide
What is the most common D2 receptor that is a substituted benzamide?
Metoclopramide
Stimulation of the vestibular system can result in?
Motion sickness
What is the main clinical use of H1 and M1 antagonists?
Motion sickness
What are the clinical indications for prochlorperazine? (3)
N/V Anxiety Schizo If you're crazy but low-key a little pukey, then this is your girl
Thalidimide is also an antiemetic, but is not used due to S/E What class does it fall under?
NK antagonists
What is the "vomiting center"?
Nucleus tractus solitarius (track & field sketch)
Name the suffix for 5-HT3 antagonists:
Odansetron <-- Zofran (bae) (dancer)
This drug is known to cause more somnolence and fatigue and doesn't appear to be as effective if it replaced one of the 3 main classes for CINV
Olanzapine
What is indicated for radiation induced N/V?
Ondansetron
What are the 4 drugs in the 5-HT3 antagonist class? Which is given in patch for? Which is a prodrug? Which has the longest half-life and highest affinity for 5-HT3 receptors?
Ondansetron Palonosetron <- longest half-life & highest affinity --- "paleo = dino = ancient [long living]" Dolasetron <- prodrug --- reduced to hydrodolasestron (via carbinyl reductase) Granisetron <- patch
What drug can we not complex 5HT3 antagonists with? Which drug is the worse for this?
Other cardiotoxic drugs b/c 5HT3 will elongate the QT interval (dolasetron is the worst especially when given with a corticosteroid, D for death) Drugs include: Verapamil, Flecainide, Quinidine
Which of the following is a second-gen 5-HT3 antagonist: Dolasetron Granisetron Ondansetron Palonosetron
Palonosetron All others are first gen
CI of D2 antag (metoclopramide)?
Parkinsons disease Small bowel obstruction
IV antiemetics are given during:
Pregnancy to prevent morning sickness (hard to feed baby if mom keeps on throwing up)
This is a D2 receptor antagonist that is also a phenothiazine antipsychotic
Prochlorperazine
Irritation of GI mucosa by chemo, radiation, distension or infection occurs via:
Release of 5HT in the gut and binding to 5-HT3 receptors
Why is dolasetron CI'd in CINV?
Risk of abnormal cardiac activity
Which NK antagonist inhibits CYP2D6?
Rolapitant The rest will inhibit 3A4
What anticholinergic is commonly prescribe for emesis and motion sickness?
Scopolamine
The M1 and H1 ADRs include what? (3)
Sedation Dry mouth Blurred vision
T or F Prophylaxis antiemeis can prevent anticipatory emesis from occuring
TRUE
What drug interactions with CYPs will NKs have? (2)
These are met by 3A4 ; can inhibit 3A4 -- so careful w/ any drug that affects/uses 3A4
What effect does Metoclopramide have with opioids?
They oppose each other as Metoclopramide pushes peristalsis while opioids inhibit it
When are NK antagonists indicated?
Used with corticosteriods and 5HT3 antagonists for CINV prophylaxis
The Setron (5HT3 antagonists) are useful in treating what?
Vagaly induced nausea and vomiting
What is the MOA of prochlorperazine? (2)
antiemetic: block D2 and M1 - also block α-adrenoreceptors