7 - Prokinetics & Antiemetics

What are the targets of drugs used in nausea & vomiting?

• vestibular pathways (H1 & M1)

• central antiemetic targets (5-HT₃, NK₁, H1)

What agents are H1 antagonists?

• promethazine

• doxylamine

• meclizine

• diphenhydramine

What agents are M1 antagonists?

• hyoscine (scopolamin)

• dicyclomine

What agents are serotonin 5-HT₃ antagonists?

• ondansetron

• granisetron

• dolasetron

• palonosetron

What agents are NK1 antagonists?

• aprepitant

• fosapitant

• rolapitant

What agents are D2 receptor antagonists?

• metoclopramide

• domperidone

• haloperidol

• chlorpromethazine

What are the indications of scopolamine (hyoscine)?

• motion sickness

• post-op n/v

• also used for treatment of excessive salivation, UI, & IBS

What is the MOA of scopolamine?

non-specific antimuscarinic (M1-4)

• interferes with the transmission of nerve impulses by ACh in the parasympathetic nervous system

What are the metabolism/excretion characteristics of scopolamine?

CYP3A4, renal elimination

What is the half-life of scopolamine?

~5hr

What are the routes of admin of scopolamine?

• oral

• SQ

• ophthalmic

• IV
  transdermal patch

What are the toxicity characteristics of scopolamine?

• tachycardia

• arrhythmia

• blurred vision

• photophobia

• urinary retention

What agent is used in scopolamine toxicity?

physostigmine

• cholinergic drug that readily crosses the BBB

gastric lavage & induced emesis can also be used

What is the antiemetic use of diphenhydramine?

• motion sickness

• acute dystonic reactions

What are the characteristics of meclizine?

longer acting & less sedating

What is the antiemetic use of cyclizine?

motion sickness

What are the characteristics of promethazine?

potent H1 blockade

What is the antiemetic use of doxylamine + pyridoxine?

n/v in pregnancy

What are class effects of H1 antihistamines?

• sedation

• dizziness

• dry mouth

• blurred vision

• urinary retention

• constipation

• confusion

Which serotonin 5-HT₃ antagonists are effective in n/v and in what causes?

• ondansetron

• granisetron

caused by CINV, post radiation, post-op n/v, & gastroenteritis

Which class is the most potent antiemetic & why?

5-HT₃ antagonists

• mediated through central & peripheral region by 5-HT₃ blockade

What are the bioavailability characteristics of ondansetron (zofran) & granisetron (kytril)?

~60%

What are the metabolism characteristics of ondansetron (zofran) & granisetron (kytril)?

• ondanestron → liver (CYP3A4/5, 1A2, 2D6), p-gp interaction

• granisetron → liver (CYP3A3/4/5)

What are the excretion characteristics of ondansetron (zofran) & granisetron (kytril)?

• ondansetron → renal

• granisetron → renal & fecal

What are the routes of admin of ondansetron (zofran) & granisetron (kytril)?

• ondansetron → PO, rectal, IV, IM, thin film

• granisetron → PO, IV, transermal

What is the interaction focus of ondansetron?

strong enzyme inducers → reduce exposure

What are the common ADE of serotonin 5-HT₃ antagonists?

• headache

• dizziness

• constipation

What are the cardiac ADE of serotonin 5-HT₃ antagonists?

QT interval prolongation requires attention to dose & patient risk

What is the maximum IV dose of ondansetron?

16mg one-time dose

What is the interaction of serotonin 5-HT₃ antagonists?

serotonin syndrome risk with serotonergic drugs (SSRI, SNRI, MAOI, TCA)

Why is IV dolasetron contraindicated for chemotherapy-induced n/v?

cardiac safety

What is the indication of neurokinin 1 (NK1) receptor antagonists?

chemotherapy-induced n/v

What are the uses of aprepitant (emend/cinvanti)?

• prophylaxis of post-op n/v

• prevention of acute & delay chemotherapy-induced n/v

How is fosaprepitant (emend) administered?

IV prodrug of aprepitant

What are the uses of rolapitant (varubi)?

long-acting option for delayed chemotherapy-induced n/v

What is the MOA of NK1 receptor antagonists?

it works by blocking/antagonizing substance P from attaching to the NK1 receptors

• also boosts the efficacy of 5-HT₃ antagonists

What is the cause of post-op n/v?

when a patient is stimulated surgically, substance P is produced via central & peripheral pathways & binds to NK-1 receptor

Which NK-1 receptor antagonists are used in chemotherapy-induced and post-op n/v?

• aprepitant

• fosarepitant

Which NK-1 receptor antagonist is used in chemotherapy-induced only?

rolapitant

What are the metabolism characteristics of aprepitant/fosarepitant?

liver

• main CYP3A4

• minor CYP2C19 & 1A2

What are the metabolism characteristics of rolapitant?

• hepatic CYP3A4 → active metabolite M19

• minor CYP2D6

• inhibits p-gp BCRP transporters

What is the key inhibition pathway of NK1 receptor antagonists?

CYP3A4

What is the PK contrast between aprepitant & rolapitant?

rolapitant has a much longer half-life than aprepitant

How are aprepitant & fosarepitant excreted?

fecal

How is rolapitant excreted?

• feces

• urine

What are the ADR of aprepitant?

generally safe & well tolerated

• fatigue

• dizzy

• hiccups

• GI symptoms (abdominal pain, diarrhea)

not recommended for long-term use in n/v

What is an important consideration for CYP3A4 interactions of aprepitant?

most chemotherapy patients are taking dexamethasone, review this dose before aprepitant administration

What are the ADR of rolapitant?

• neutropenia

• hiccups

• decreased appetite

• dizziness

What interactions should be reviewed before administration of rolapitant?

• CYP2D6 interactions with substrates (thioridazine contraindicated)

• QT risk

Which agent is a NK1 and 5-HT₃ antagonist and what is it’s indication?

netupitant + palonosetron (akynzeo) (+dexamethazone)

• chemotherapy-induced n/v

How is akynzeo efficacious?

inhibits serotonin binding to 5-HT₃ and substance P binding to NK1

• inhibits the synergistic cross-talk between receptors

What agents are FDA-approved cannabinoids?

• nabilone (analog of dronabinol)

• dronabinol (synthetic THC)

• cannabidol

• THC

What is the indication of dronabinol (marinol, syndros)?

• anorexia associated with weight loss in patients with AIDs

• chemotherapy-induced n/v in pts who have failed to respond adequately to conventional treatment

What is the indication of nabilone (casamet)?

chemotherapy-induced n/v in pts who have failed to respond adequately to conventional treatment

What is the MOA of cannabinoids?

• Agonists at CB1 receptor (Gi/o) in brainstem emetic circuits

• ↓ adenylyl cyclase→ ↓ cAMP→ ↓ Ca+ influx at presynaptic terminals → release of excitatory neurotransmitters (dopamine, glutamate, substance P) → ↓ activation of emetic pathways → vomiting.

Which cannabinoid has the longer duration of action & half-life?

nabilone

• 35hr half life of metabolites

Which cannabinoid has lower oral bioavailability?

low due to extensive first-pass metabolism

What are the metabolism characteristics of metabolism?

liver (CYP2C9, CYP3A4)

What are the metabolism characteristics of nabilone?

multiple CYP450 isoforms

• weak moderate inhibition CYP2E1, 3A4, 2C8, 2C9

What are the excretion characteristics of dronabinol & nabilone?

fecal & renal

What is the DEA schedule of dronabinol?

• schedule II as syndros

• schedule III as marinol

What is the DEA schedule of nabilone?

schedule II

What are the ADR of cannabinoids?

• Dysphoria, dizziness, sedation, orthostatic HTN

• Psychiatric effects can limit tolerability

• Chronic heavy cannabis use can cause cannabinoid hyperemesis

What is the mechanism of metoclopramide?

antiemetic action mechanism:

• D₂ receptor blockade

• 5-HT₃ antagonism contributes at higher doses

prokinetic action mechanism (upper GI):

• D₂ receptor blockade

• 5-HT₄ antagonism enhances ACh release

increases lower esophageal sphincter tone, antral contractions, & gastric emptying

What is the indication of metolopramide?

gastroparesis

What are the absorption characteristics of metoclopramide/domperidone?

rapid oral absorption

What are the metabolism/excretion characteristics of metoclopramide?

hepatic, renal

What are the half-life characteristics of metoclopramide?

4-6hrs

What is the BBW of metoclopramide?

tardive dyskinesia often irreversible → limit treatment to 12wks

What are the contraindications of metoclopramide?

• mechanical obstruction

• perforation

• GI hemorrhage

What is the MOA of domperidone?

antiemetic & upper-GI prokinetic actions

• peripherally selective D₂R & D₃R antagonist

• D₂R blockade promotes upper-GI transit

Which agent crosses the BBB (domperidone/metoclopramide)?

metoclopramide

What are the metabolism/excretion characteristics of domperidone?

• hepatic, CYP3A4

• feces/urine

What are the half-life characteristics of domperidone?

7hr

What are the ADR of domperidone?

• hyperprolactinemia, galactorrhea, gynecomastia

• QT prolongation, sudden cardiac death

• dry mouth & GI symptoms

What are the routes of administration of metocloperamide?

oral & iv

What is the route of administration of domperidone?

oral

What are the uses of metoclopramide?

• chemotherapy-induced n/v

• reflux & hepatobiliary disorders

What are the uses of domperidone?

• acute chemotherapy-induced n/v

• post-op n/v

What agent & doses are the adjunct for CINV, PONV, & radiation-induced n/v?

dexamethasone

• PONV: 4-10mg

• CINV: 12-20mg

What is the MOA of tegaserod (zelnorm)?

• partial 5-HT₄ receptor agonist → activates enteric neurons, enhancing GI motility, peristaltic reflexes, and intestinal transit

• 5-HT₂B receptor antagonist → may reduce visceral pain

What is the indication of tegaserod?

women <65yrs with IBS-C

What are the ADR of tegaserod?

• common: headache, abdominal pain, nausea, diarrhea

• severe diarrhea → volume depletion, hypotension, syncope

• review patients renal, hepatic, & CV function

What are the warnings of tegaserod?

• avoid with bowel obstruction or relevant ischemic cardiovascular history

• cardiovascular ischemic events are a safety concern

What is the MOA of prucalopride (motegrity)?

highly selective 5-HT₄ agonist → enhances enteric ACh release & peristaltic reflex

What is the indication of prucalopride?

CIC in adults

What are the ADR of prucalopride?

• headache

• abdominal pain

• n/v/d

• headache

• suicidal ideation warning

• depression

What are the contraindications of prucalopride?

• intestinal perforation/obstruction

• obstructive ileus

• inflammatory GI conditions (ulcerative colitis, crohn’s)

Why is prucalopride safe where cisapride is not?

selectivity for 5-HT4 over hERG & 5-HT1B

Which 5-HT₄ agonist has the longer half-life?

prucalopride (~24hr)

What are the metabolism characteristics of tegaserod/prucalopride?

• tegaserod: hydrolysis & direct glucuronidation

• prucalopride: CYP3A4