primary intensive course sg buloh 2012

7/30/2019 primary intensive course sg buloh 2012

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PHARMAC: ANTIEMETICS LEEML281112

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ANTIEMETICSANTIEMETICSANTIEMETICSANTIEMETICS

PHYSIOLOGY OF VOMITINGPHYSIOLOGY OF VOMITINGPHYSIOLOGY OF VOMITINGPHYSIOLOGY OF VOMITING

Vomiting/Emesis: Forceful expulsion of gastric contents through the mouth

Act of Vomiting

1. Salivation and nausea (ass with pallor, rapid breathing, sweating and tachycardia)

2. Breath held in mid-inspiration

3. Glottis closes

4. Reverse peristalsis empties material from upper part of small intestines into stomach

5. Abdominal wall contract Intra-abdominal pressure

6. Lower esophageal sphincter and esophagus relax

7. Gastric content ejected

Pressure of 40 cm H2O is required to lift gastric content to esophagus and mouth

Cardia elevated during vomiting Abdominal part of esophagus rises to the chest


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CONTROL OF VOMITING

Vomiting Center present in the lateral reticular formation of the medulla

VC can be stimulated by different afferent pathways:

1. Chemoreceptor Trigger Zone

Located in the floor of the 4th

ventricle of the brain and constitutes the area postrema (a

circumventricular organ which is functionally outside the BBB)

Substances such as drugs and toxins carried in the blood can directly reach it (explains why some

drugs cause or stop vomiting)

Contains dopamine D2, serotonin 5-HT3, opioid, acetylcholine and substance P receptors whose

activations results in different pathways, the end result of all of which includes substance P

2.

Vagus Nerve The 10th CN gets activated when pharynx is activated causing the gag reflex

3. Vestibular system

Control the balance and sends its input to the CNS via the vestibular nerve (8th

CN)

Any disturbances of balance (eg Motion sickness) can cause vomiting

Rich in Cholinergic and Histamine H1 receptors

4. Vagal and Enteric Nervous System from GIT

GIT can be irritated by chemotherapy, radiation, certain drugs, severe distension and infection

Stimulate the VC directly via vagal afferents (cholinergic receptors) and sympathetic afferents

from the GIT (NA receptors)

Can also stimulate the CTZ to cause vomiting via the 5HT3 receptors and Dopamine D2

receptors present in the GIT

5. The periphery via sensory nerves

GIT irritation, myocardial infarction, renal or biliary stones via the pain receptors (H1 Receptors)


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6. Chemoreceptors and baroreceptors (5HT3 and H1 receptors)

7. CNS(Higher center cortex, limbic system)

Can be affected by stress, certain psychiatric conditions, nauseating smells or sights

Ideal Properties Of Antiemetics

1. Effective (different type of nausea and vomiting)

2. Reliable

3. Fast onset

4. Predictable / long duration of action (good compliance)

5. Minimal side effects

6. No drug interaction

7. No allergic reaction

8. Available oral or parenteral

ANTIEMETICSANTIEMETICSANTIEMETICSANTIEMETICS

ANTIHISTAMINES

Eg. Ethanolamines Diphenhydramine, Dimenhydrinate 1-2mg/kgPiperazines Cyclizine (NNT 4-5), Hydroxyzine, Meclizine

Uses: Prevention or treatment of motion sickness

MOA: First generation H1 receptor antagonists. Ethanolamines drugs have more anticholinergic and

sedating effect compared to the piperazines

SE: sedation, dizziness, confusion, dry mouth, cycloplegia, and urinary retention

ANTICHOLINERGICS

Eg. Scopolamine Transdermal patch 1.5mg applied behind the ear (NNT 6)

Uses: Prevention or treatment of motion sickness (Need to apply 4 hours before op ends or evening

before)

MOA: Blocks muscarinic receptor in the cerebral cortex

SE: drowsiness, dry mouth, blurred vision, tachycardia, constipation

CI: Pt with glaucoma dt dilation of pupils


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PHENOTHIAZINES

Eg. Promethazine (Phenergan) 12.5-25mg

Chlorpromazine (Thorazine)Prochlorperazine edisylate (Compazine) 5-10mg

Perphenazine (Trilafon)

Uses

1. Chemotherapy-induced vomiting

2. Radiotherapy-induced vomiting

3. PONV

MOA: Inhibition of central dopamine D2, muscarinic and H1 histamine receptors in CTZ

SE : dry mouth, drowsiness, dizziness, hypotension, EPS (tremors, mask face, rigidity, shuffling gait)

DI: CNS depression when taken with ETOH, narcotics, sedative-hypnotics and general anesthetics

BUTYROPHENONES (antipsychotic agents)

Eg Haloperidol (Haldol)

Droperidol (Inapsine) 0.625-1.25mg (NNT 4-6)

MOA: Inhibition of central dopamineD2 receptors in the CTZ

Uses: Rx of PONV & emesis induced by toxins, chemo and radiation therapy

1. Chemotherapy-induced vomiting

2. Radiotherapy-induced vomiting3. PONV

SE: EPS if used over extended time, hypotension

Droperidol may prolong the QT interval (FDA black box warning)

BENZAMIDES

Eg. Metoclopramide 10-50mg

Domperidone

Uses:

1. Symptomatic treatment of nausea and vomiting from any cause

2. Prokinetic agents

MOA:

1. Antagonize dopamine D2 receptors in the CTZ to relieve N, V

2. Antagonize the inhibitory effect of dopamine on myenteric motor neurons Enhance

coordinated GIT propulsive motility in the upper digestive tract


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3. High doses also blocks serotonin receptors

Metoclopramide Domperidone

Oral: tablets 10mg, Capsule SR 15mg, Syrup 1mg/ml

IV/IM: solution for injection 5mg/ml

Crosses BBBSE:

1. EPS (esp children and young adults at higher doses)

2. Galactorrhea by blocking the inhibitory effect of

dopamine on prolactin release (infrequent)

Oral: Tablets 10mg, Syrup 1mg/ml

Rectal supp: 30mg

Does not cross BBBSE: no EPS

1. Galactorrhea

BENZODIAZEPINES

Eg. Lorazepam (Ativan), Diazepam

Uses: Given prior to the initiation of chemotherapy to reduce anticipatory vomiting or vomiting

caused by anxiety

SEROTONIN 5HT3 ANTAGONIST

Eg. Ondansetron (Zofran) 4-8 mg (t 4-6hrs)

Granisetron (Kytril) 0.35-1.5mg (t 5-8 hrs)

Dolasetron 12.5 mg (t 7h)

Tropisetron 2mg (t 7hrs)

Palonosteron (t 40hrs)

MOA

Potent antiemetics

Causes peripheral 5-HT3 receptor blockade on intestinal vagal afferents and central 5-HT3 receptor

blockade in the VC and CTZ

Main antiemetic action is against emesis mediated by vagal stimulation (eg postoperative and

chemotherapy)

Does not cause EPS

Uses1. Chemotherapy induced nausea & vomiting given 30 min. before chemotherapy.

2. Postradiation nausea & vomiting

3. PONV (Vomiting NNT 6, Nausea NNT 7)

PK

High first pass metabolism


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Excreted by liver & kidney

No dose reduction in renal insufficiency but needed in hepatic insufficiency

SE

Excellent safety profile

Headache, dizziness, constipation, elevated liver enzymes Prolongation of QT interval, but more pronounced with dolasetron

CORTICOSTEROIDS

Eg. Dexamethasone (Decadron) 4-5mg (NNT=4)

Methylprednisolone (Solu-Medrol)

MOA: Various theories?

o Central inhibition of PG synthesiso Decrease turnover of 5HT in the CNS

Uses: Enhance efficacy of 5HT3 receptor antagonists in the treatment of chemotherapy-induced

vomiting and PONV

SE: Flushing, perineal itching (usually one dose not ass with SE)

CANNABINOIDS - active ingredient in marijuana

Eg. Dronabinol (Marinol)

Nabilone (Cesamet)

Uses: For the prevention of chemotherapy-induced nausea and vomiting (unresponsive to other

antiemetics)

MOA: not known

PK

o Readily absorbed after oral administration

o Extensive first-pass metabolism with limited systemic bioavailability after single doses

o Metabolites are excreted primarily via the biliary-fecal route

SE

o Euphoria or dysphoria, sedation and hallucinations

o Withdrawal syndrome with abrupt withdrawal (restless, insomnia and irritability)

o Autonomic effects (sympathetic) in the form of tachycardia, palpitation, conjunctival

injection, and orthostatic hypotension


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NK1 RECEPTOR ANTAGONIST

Eg. Aprepitant 40mg POCasopitant

Uses: 1. Preventing chemotherapy-induced nausea and vomiting

2. Aprepitant approved for PONV

MOA: Blocks NK1 receptors in the central and peripheral nervous systems thus preventing emesis

Phase 3 trial recently completed better than ondasetron for up to 48h for vomiting but same

nausea rate and rescue equipments

SE: Headache, fatigue, dizziness, elevated liver enzymes

Expensive

EMETICSEMETICSEMETICSEMETICS

Drugs for Emetics Given when an individual has consumed certain toxic substances that must be expelled before

absorption

Dont induce vomiting if caustic substances have been ingested (eg ammonia, chlorine bleach, lye,toilet cleaners, or battery acid) Activated charcoal is given when emesis is CI

1. Ipecac

Stimulates the CTZ in the medulla and acts directly on the gastric mucosa

Take with water (not milk or carbonation)

Onset in 15 to 30 min (Repeat Rx if needed)

Toxic if absorbed give charcoal

SE: diarrhea, sedation, lethargy

Toxicity: Hypotension, tachycardia, chest pain

2. Apomorphine A morphine derived emetic

Given SC/IM

Onset 15 min

primary intensive course sg buloh 2012

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