Anti-Emetics and Prokinetics

Moderator: Dr. D.A.RizviPresentor: Dr. Roohana Hasan

Emesis and its causesPathophysiology of EmesisEmeticsAnti emeticsTherapeutic uses of Anti-emeticsSpecial topics Motion sicknessEmesis in pregnancyChemotherapy induced vomitingPost operative nausea and vomiting

Vomiting (Emesis) is the forceful expulsion ofcontents of the stomach and often, the proximalsmall intestine

Vomiting is a complex reflex involving both autonomic and somatic neural pathways.

Vomiting is a complex process that consists of

(gastric relaxation and retroperistalsis),

(rhythmic action of respiratory muscles preceding vomiting and consisting of contraction of abdominal and intercostal muscles and diaphragm against a closed glottis),

(intense contraction of the abdominal muscles and relaxation of the upper esophageal sphincter).

Pre-ejection Phase

Retching

Ejection

The “chemoreceptor trigger zone” or area postrema is located at the caudal end of the fourth ventricle.

This is outside the blood-brain barrier but is accessible to emetogenic stimuli in the blood or cerebrospinal fluid.

The chemoreceptor trigger zone is rich in dopamine D 2 receptors and opioid receptors, and possibly serotonin 5-HT 3 receptors and NK 1 receptors.

These are drugs used to evoke vomiting.

Act on CTZ : Apomorphine

Act reflexly and on CTZ : Ipecacuanha

EMETICS

Poisoning Acute cases of poisoning (except in corrosive

substances poisoning or if patient is not fully conscious)

Alcoholic intoxication Removal of foreign bodies from the

oesophagus

Indications

Apomorphine

Semi synthetic derivative of morphine

• Given IM or SC, act centrally;

• Dose is 6 mg (2-8mg)

• Induces vomiting in 5 -10 min

• Respiratory and CNS depressant

Contraindicated

Respiratory depression

Ipecacuanha

Dried root of Cephaelis ipecacuanha

Contains alkaloid - emetine

Used as syrup ipecac.

Produces effect in 15 min.

Acts by irritating gastric mucosa & through CTZ centre.

Dose = 5ml in infants

= 10-15ml in children

= 15-20ml in adults

Contraindications

Corrosive poisoning

CNS stimulant drug poisoning

Kerosene poisoning

Unconscious patients

Morphine poisoning

A group of drugs which are used to control nausea and vomiting

Provide symptomatic relief Removal of causative factor to have ultimate relief

Classification

Hyoscine (0.2–0.4 mg oral, i.m.) is the most effective drugfor motion sickness.

It has a brief duration of action;

Mechanism of Action Acts by blocking conduction of nerveimpulses across a cholinergic link in the pathway leading fromthe vestibular apparatus to the vomiting centre.

Side effects sedation, dry mouth and other anticholinergic sideeffects; suitable only for short brisk journies.

Dicyclomine (10–20 mg oral) has been used

for prophylaxis of motion sickness and for morning sickness.

H1 ANTIHISTAMINICS

Useful mainly in motion sickness and to a lesser extent in morning sickness, postoperative and some other forms of vomiting.

Their antiemetic effect appears to be based on anticholinergic, antihistaminic, weak antidopaminergic and sedative properties

Promethazine, diphenhydramine, dimenhydrinate

These drugs afford protection of motion sickness for 4–6 hours, but produce sedation and dryness of mouth.

By their central anticholinergic action they block the extrapyramidal side effects of metoclopramide while supplementing its antiemetic action.

Doxylamine- It is a sedative H1 antihistaminic

with prominent anticholinergic activity.

Pharmacokinetics- Oral absorption of doxylamine is slow, and its t½ is 10 hr.

Side effects -drowsiness, dry mouth, vertigo and abdominal upset.

Dose: 10–20 mg at bed time.

Cinnarizine It is an antivertigo drug having

antimotion sickness property.

Mechanism of Action- acts by inhibiting influx of Ca2+ from endolymph into the vestibular sensory cells which mediates labyrinthine reflexes.

Theraputic Uses

Vestibular system is important in motion sickness viacranial nerve VIII - rich in Cholinergic M1 &Histamine H1receptors

Most effective drugs for motion sickness

Vestibular disorders ( Meniere’s disease)

Meclizine is long acting so useful in sea sickness

Cinnarizine also has antivertigo effect. Act byinhibiting influx of calcium to vestibular sensorycells from endolymph

NeurolepticsPhenothiazines:

Prochlorperazine

Promethazine

Triflupromazine

Phenothiazines are antipsychotics with potent antiemetic property due

to D2 antagonism and anti-muscarinic properties H1 and

antihistaminic property.

Side Effects- produce significant degree of sedation. Acute

muscle dystonia may occur

Therapeutic Uses:

Broad spectrum antiemetic action effective in:

Drug induced and postoperative nausea andvomiting (PONV).

Disease induced vomiting: gastroenteritis,

Uraemia, liver disease, migraine, etc.

Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting.

Radiation sickness vomiting (less effective).

Prokinetic Drugs

Drugs that promote gastrointestinal transit and speed gastric emptying by enhancing coordinated propulsive motility.

Effective antiemetic agents

Two clinically important drugs:

Metoclopramide

Domperidone

Metoclopramide

Mechanism of Action: acts through dopaminergic and serotonergic receptors

D2 antagonism: Central antidopaminergic (D2) action of metoclopramide on CTZ is responsible for its anti emetic activity

5-HT4 agonism: It acts in the GIT to enhance Ach release from the myenteric motor neurons and thereby enhance the contractile activity.

5HT3 antagonism: At higher concentrations it blocks 5HT3 receptors in the inhibitory myentric interneurons and in the CTZ

D2 antagonism:

Central

antidopaminergic

(D2) action of

metoclopramide on

CTZ

5-HT4

agonism: It

acts in the GIT to

enhance Ach

release from the

myenteric motor

neurons

5HT3 antagonism:

At higher

concentrations it

blocks 5HT3

receptors in the

inhibitory myentric

interneurons and in

the CTZ

Pharmacokinetics

Rapidly absorbed from GIT after oral administration.

Undergoes a high degree first pass metabolism.

It is excreted in the urine as free and as metabolites.

It is also excreted in the breast milk.

DOSE: 10-20mg orally or IV every 6 hrs.

As Antiemetic

effective in postoperative, drug induced, disease associated (especially migraine), radiation sickness, etc,

It has potent Antiemetic & antinausea effect.

Blocks D2 receptors in CTZ of the medulla (area postrema)

As Prokinetic agent

It can selectively stimulate gut motor function.

Blocks D2 receptor in GIT & blocks the normalinhibitory effect of Dopamine on cholinergic smoothmuscle stimulation--- ↑ motility.

Therapeutic Uses:

Used in emesis due to

Uremia

Radiation

Viral gastro enteritis, hepatic-biliary disease

Anticancer drugs

Migraine

Post operatively & pre-operatively

Used as a gastro kinetic agent

GERD

Dyspepsia

Adverse Effects -

Extrapyramidal reactions with facial and skeletalmuscle spasms- Restlessness, Dystonias ,Parkinsonian symptoms.

More common in young and very old. Usually occurshortly after staring treatment and subside with in 24hours of stopping the drug.

Diarrhea

Drowsiness and fatigue, dizziness, restlessness andanxiety.

Galactorrhoea, Gynecomastia, impotence and menstrual disorders – due to increased prolactin levels (blocks the action of PIH)

Domperidone- It is a D2 receptor antagonist.

It crosses blood-brain barrier poorly.

Extrapyramidal side effects are rare, but hyperprolactinaemia can occur.

Pharmacokinetics- absorbed orally, but bioavailability is only ~15% due to first pass metabolism.

It is completely biotransformed and metabolites are excreted in urine.

Plasma t½ is 7.5 hr.

Dose- 10-40mg

Adverse effects

Dry mouth

Loose stools

Headache

Rashes

Galactorrhoea

Cisapride

Mechanism of Action

The prokinetic action is exerted mainly through

5-HT4 agonism which promotes ACh release from myenteric neurones, aided by

weak 5-HT3 antagonism which suppresses inhibitory transmission in myenteric plexus.

Enteric neuronal activation via 5-HT4 receptor also promotes cAMP-dependent Cl– secretion in the colon, increasing water content of stools.

Safety of cisapride was challenged by reports of serious ventricular arrhythmias and death.

At high concentrations, cisapride blocks delayed rectifying K+ channels in heart—prolongs Q-Tc interval and predisposes to ventricular fibrillation.

Following such reports, cisapride was suspended from marketing in most countries several years back, but was available in India till it was banned in March 2011.

5-HT4 agonist

The drug functions as a motility stimulant, achieving its desired therapeutic effects through activation of the 5-HT4 receptors of the enteric nervous system in the gastrointestinal tract.

It also stimulates gastrointestinal motility and the peristaltic reflex, and allegedly reduces abdominal pain.

Approved by the FDA in 2002, it was subsequently removed from the market in 2007 due to FDA concerns about possible adverse cardiovascular effects.

TEGASEROD

SELECTIVE 5-HT3

ANTAGONISTS

Mechanism of Action:

Blocks-the depolarization action of 5-HT exertedthrough blockage of 5-HT3 receptors in the vagalafferents of the GIT as well as in the NTS andCTZ

It has weak 5-HT4 antagonist activity

Pharmacokinetics:

Oral bioavailability is 60-70%

t1/2 is 3-5hrs

No significant drug interactions have been noted.

Adverse effects:

Excellent safety profile

Headache, Dizziness & constipation

All three drugs cause prolongation of QT interval, but

more pronounced with dolasetron.

Therapeutic Uses:

Chemotherapy and Radiation therapy induced nausea and vomiting

Post operative nausea and vomiting

Advisable to administer Ondansetron(4-8 mg IV) 4 hours before surgery is advisable.

Drug induced vomiting

Vomiting due to GI disorders

Uraemia and neurological injuries induced vomiting

Hyperemesis Gravidarum

Granisetron: 10 times more potent than ondansetron and effective in repeated cycles of chemotherapy.

Polonosetron: Longest acting (t1/2 is 40 hrs)

Approved by the FDA in delayed cancer induced nausea and vomiting-occurring between 2nd to 5th day

Romosetron: Similar to ondansetron and is marketed only in few countries

NEUROKININ-1 (NK1)ANTAGONISTS

AprepitantFosaprepitant

Given orally BA = 65% , Crosses BBB.t ½ : 11 hrs, Metabolized by hepatic CYP3A4.

MOA• Act as Antiemetic: Selectively block NK1 receptor in

area postrema. • Blocks the emetic action of Substance P

Uses

Used in combination with 5HT3 antagonists &Corticosteroids for prevention of acute & chronicnausea and vomiting from Cancer chemotherapy

Tetrahydrocannabinol (THC) main psychoactive chemicalin marijuana

It probably acts through the CB1 subtype ofcannabinoid receptors located on neurones in theCTZ and/ or the vomiting centre itself.

Pharmacokinetics: complete absorption on oraladministration, significant 1st pass effect, metabolitesexcreted slowly over days to weeks in faeces & urine

CannabinoidsDronabinol

Nabilone

GLUCOCORTICOIDS

Dexamethasone

Methylprednisolone

Antiemetic MOA not clear

Enhance action of 5HT3 antagonists in Cancer

chemotherapy induced Nausea & vomiting

Benzodiazepines

Diazepam

Lorazepam

The weak antiemetic property of BZDs is primarily based on the sedative action, relieving psychogenic component.

Used as adjuvant to metoclopramide/ondansetron,

Used prior to Cancer chemotherapy to reduce anticipatory vomiting

Vomiting caused by anxiety

TYPES OF EMESIS

MOTION SICKNESS

MORNING SICKNESS (VOMITING DURING PREGNANCY)

CHEMOTHERAPY/ RADIATION INDUCED NAUSEA AND EMESIS (CIE)

POST OPERATIVE EMESIS

Emesis and Pregnancy

Nausea and vomiting of pregnancy (NVP) is the most common medical condition of pregnancy, affecting up to 80% of all pregnant women to some degree

Etiology:Exact pathogenesis is unclear

Elevated levels of human chorionic gonadotropin (hCG)

Chronic infection with Helicobacter pylori may play a role in hyperemesis gravidarum.

Delayed gastric motility caused by progesterone may be responsible for the condition

Psychologic factors

Doxylamine/pyridoxine:

• The only FDA-approved drug for treating nausea and vomiting in

pregnancy

• A greater form of reduction in Hyperemesis gravidarum

• No teratogenic potential

Ondansetron :

• Class B safety in pregnancy

• Most common parenteral and oral antiemetic used due to its

efficacy

Anticholinergics may be used as supportive drugs.

Ginger capsules: 250 mg taken 4 times a day have been

demonstrated to be effective against nausea and vomiting of

pregnancy

Contraindicated Drugs

Domperidone (X)

The combination of pyridoxine 10 mg and

doxylamine 10 mg was withdrawn from the

market due to increased risk of birth defects

with the combination.

MOTION SICKNESS

Result during space flights, taking off and landing of an aeroplane etc.

It is a labyrinthine vomiting via stimulation of vestibular nuclei.

Drugs used:H1 ANTAGONIST/ CENTRAL

ACTINGANTICHOLINERGIC.Hyoscine.Side effects of hyoscine: anticholinergic

Blurred vision, dryness of mouth, cyclopelgia, sedation and sleepiness.

DIPHENHYDRAMINE, CYCLIZINE, MECLIZINE – prevents motion sickness and treatment of vertigo due to labyrinth dysfunction.

CINNARAZINE-Anti vertigo drug. Used in prevention of motion sickness.

Acts as antihistaminic, anticholinergic, antiserotonin & Ca2+ channel blocker.

Inhibits influx of Ca2+ from endolymph into vestibular apparatus.

Chemothrapy Induced Emesis

• Anti-cancer drugs induce emesis by direct activation of 5HT3 receptors in CTZ / may activate vagal and splanchnic 5HT3 receptors to send emetogenic signals to vomiting center through neurotransmitters.

ONDANSETRON GRANISETRON DOLASETRON TROPISETRON PALONOSETRON RAMOSETRON

Some Anti-emetic Regimens Used in Cancer Chemotherapy

POST OPERATIVE VOMITING

• Complications in patients receiving general anaesthesia.

• 5HT3 ANTAGONIST- preferred

• PROCHLORAZINE- blocks Dopamine 2 and muscarinic receptors.

• PROMETHAZINE- potent anticholinergic and antihistaminic.

Elevated cholecystokinin levels slow gastric emptying andmotility and are associated with feed intolerance in criticallyill patients

☆Dexloxiglumide

Selective and highly potent CCK-1 receptor antagonist

Inhibits gall bladder contraction

Improves lower oesophageal sphincter function

Hastens colonic transit

☆Alvimopan

High affinity for μ receptors

Does not cross the blood–brain barrier

No effect on gastric emptying

hastened gut recovery and shortened time tohospital discharge in patients after bowelresection or hysterectomy

μ-opioid antagonist

Summary

References Hasketh PJ: Chemotherapy-induced nausea and

vomiting. N Engl J Med 2008;358:2482.

Le TP et al: Update on the management of postoperative nausea and vomiting and postdischarge nausea vomiting in ambulatory surgery. Anesthesiol Clin 2010;28:225.

Roila F et al; Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: Results of the Perugia consensus conference. Ann Oncol 2010;21(Suppl 5):v232.

DeMaeyer JH et al: 5-HT 4 receptor agonists: Similar but not the same. Neurogastroenterol Motil2008;20:99.

Patrick A et al: Review article: Gastroparesis. Aliment Pharmacol Ther 2008;27:724.

Reddymasu SC et al: Severe gastroparesis: medical therapy or gastric electrical stimulation. ClinGastroenterol Hepatol 2010;8:117.

Borison H L et al. 1981 J Clin Pharmacol 21: 235-295.) Goodman and Gillman Davidson Guyton physiology KD Tripathi pharmacology Katzung