Anti-emetics Flashcards by Greg Poyser

What are the major classes of anti-emetics?

Mixed receptor antagonists
Dopamine type 2 receptor antagonists
Muscarinic receptor antagonists
Serotonin (5HT3) receptor antagonists
Cannabinoids

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What is the definition of nausea?

Subjective, unpleasant sensation in throat and stomach, often precedes vomiting

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What is the definition of vomiting?

Forceful propulsion of stomach contents out of the mouth

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What often precedes both nausea and vomiting?

Salivation
Sweating
Tachycardia

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What happens in the process of vomiting?

Stomach, oesophagus and associated sphincters are relaxed
Tension in gastric and oesophageal muscles trigger afferent nerve impulses
Contraction of upper small intestine, pyloric sphincter and pyloric region of stomach
Contents of upper jejunum, duodenum and pyloric region of stomach move into body and fundus of stomach
Lower and upper oesophageal sphincters and oesophagus relax
Retching/vomiting then may occur

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What are the consequences of acute nausea?

Interferes with mental and physical activity

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What are the consequences of severe vomiting?

Very debilitating
Dehydration
Loss of gastric hydrogen and chloride ions may lead to hypochloraemic metabolic alkalosis (raised blood pH)
Contributes to reduction in renal bicarbonate exertion and increase in bicarbonate reabsorption
This is accompanied by increased sodium reabsorption in exchange for potassium leading to hypokalaemia

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What is the vestibular system particularly important in for children?

Motion sickness

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What is the result of lots of CNS inputs into the emetic pathway?

If you see something disturbing or smell something disgusting it could induce vomiting- several cortical inputs that influence vomiting

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What in the stomach is responsible for feeding back to vomiting centre and triggering nausea and vomiting?

Mechanoreceptors and chemoreceptors

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How can vomiting be a life saving protection system?

The vomiting centre and CTZ sit in a location in the brain that has a very porous BBB so vomiting centre and CTZ act as an early warning system to protect brain from toxin damage as these toxins will stimulate vomiting centre and CTZ and trigger vomiting before they have a chance to cross BBB and affect CNS

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What are the targets for anti-emetic drugs?

Vestibular system
Cortex
CTZ
Peripheral pathways

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What is an example of a mixed receptor antagonist?

Promethazine- phenothiazine derivative

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What is promethazine’s mode of action?

Competitive antagonist at following receptors in order of potency:
Histaminergic (H1)
Cholinergic (Muscarinic, M)
Dopaminergic (D2)

It acts centrally (vestibular nucleus, CTZ and vomiting centre) to block activation of vomiting centre

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What is the difference between promethazine and other phenothiazines which are used as neuroleptic drugs?

Different oder of potency with greater antagonistic effects at D2 receptors

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When is promethazine used as an anti-emetic?

Motion sickness- used prophylactically but some benefit may be gained if it’s taken after onset of nausea and vomiting
Disorders of the labyrinth e.g. Meniere’s disease
Hyperemesis gravidarium
Pre and post operatively

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What else is promethazine used for?

Because of its effect in histamine blockade and its sedative effects, it’s also useful for:
Relief of allergic symptoms
Anaphylactic emergency
Night sedation, insomnia

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What is hyperemesis gravidarium?

Complication of pregnancy characterised by severe nausea and vomiting

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What are the pharmacokinetics of promethazine like?

Administered orally
Onset of action 1-2 hours so need to give relatively in advance to someone that is travelling
Maximum effect at around 4 hours
Duration of action 24 hours

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What unwanted effects of promethazine are there?

Dizziness
Tinnitus
Fatigue
Sedation
Excitation in excess
Convulsions
Anti-muscarinic side effects

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Give two examples of dopamine (D2) receptor antagonists

Metoclopramide and domperidone

What is the order of potency of dopamine receptor antagonists?

D2>H1>Muscarinic receptors

Where do dopamine receptor antagonists work?

Centrally especially at CTZ

What effect do dopamine receptor antagonists have?

Prokinetic effects in GI tract:
Increases smooth muscle motility (from oesophagus to small intestine)
Accelerated gastric emptying
Accelerates transit of intestinal contents (from duodenum to ileo-caecal valve)

What causes pro kinetic effects on GI tract of dopamine receptor antagonists?

Antagonism of inhibitory effect of dopamine on myenteric neurones

Why are dopamine receptor antagonists not very good at treating motion sickness?

Only blocking the dopamine receptors in CTZ and not blocking rest of signals going directly from vestibular system to vomiting centre

What are metoclopramide and domperidone used to treat?

Treat nausea and vomiting associated with: Uraemia Radiation sickness GI disorders Cancer chemotherapy (high doses) Parkinson's disease treatments that stimulate dopaminergic transmission

Why can you give domperidone to Parkinson's patients who are having bad nausea and vomiting because of Parkinson's drugs?

It will only block dopamine receptors in CTZ and won't interfere with dopamine transmission elsewhere that the anti-Parkinson's drugs are working on

How are dopamine receptor antagonists given?

Orally- rapidly absorbed but extensive first pass metabolism | IV

What is the difference between metoclopramide and domperidone in terms of BBB?

Metoclopramide can cross the BBB- it has potential CNS side effects They can also cross the placenta

Why must care be taken with bioavailability of coadminstered drugs with dopamine receptor antagonists?

Because of the pro-kinetic effects of these drugs- they increase the rate of transit through GI tract so could reduce chance of some drugs being sufficiently absorbed Furthermore nutrient supply may be compromised which is important in conditions like DM

What are the unwanted effects of dopamine receptor antagonists?

In the CNS (metoclopramide only): -Drowsiness -Dizziness -Anxiety -Extrapyrimidial reactions- children are more susceptible Parkinsonian like syndrome- rigidity, tremor and motor restlessness In the endocrine system: Dopamine exerts negative influence on prolactin release so there is: -Hyperprolactinaemia -Galactorrhea -Disorders of menstruation

Give an example of muscarinic receptor antagonist

Hyoscine

What is the antagonist potency of hyoscine?

Muscarinic>>>D2=H1

Where does hyoscine act?

Centrally, especially in vestibular nuclei, CTZ and vomiting centre to block activation of vomiting centre

What is hyoscine used for?

Anti-emetic: Prevention of motion sickness (only works prophylactically) In operative pre-medication

What are the targets of hyoscine?

Direct actions on vestibular system and some weak action on dopamine receptors

Why are muscarinic receptor antagonists very good anti-emetics?

There is decreased feed from projections from vestibular system to the CTZ and there are muscarinic receptors in vomiting centre as well, you also inhibit pathways coming into the vomiting centre

How are muscarinic receptor antagonists administered?

Orally or via transdermal patch

What are the unwanted effects of muscarinic receptor antagonists?

``` Typical anti-muscarinic side effects: Drowsiness Dry mouth Cycloplegia Mydriasis Constipation ```

Give an example of a serotonin (5-hydroxytryptophan) receptor antagonists (5-HT1)

Ondansetron

What is ondansetron's mode of action?

It blocks transmission in visceral afferents and CTZ

What is ondansetron used for?

Anti-emetic: Main use in preventing anti-cancer drug induced vomiting (especially cisplatin) Radiotherapy induced sickness Post operative nausea and vomiting

Where are 5HT receptors found?

Driving a lot of pathways coming from periphery to trigger felling of nausea and vomiting within the CTZ Within the CTZ itself that respond to a lot of drugs that cause nausea and vomiting particularly chemotherapy type compounds- blocks 2 pathways hence why it's so effective

What are the pharmacokinetics of ondansetron?

Orally administered Well absorbed Excreted in the urine

What are the unwanted effects of ondansetron?

Headache Sensation of flushing and warmth Increased large bowel transit time (constipation)

What is ondansetron commonly used in combination with?

5-HT receptor antagonists may be used for low emetogenic chemotherapy but they may be used in combination with corticosteroids for high or moderately high emetogenic chemotherapy- improved efficacy may be due to anti-inflammatory properties of corticosteroids

What common drug can also be used as an anti-emetic?

Cannabinoids-THC | Effective at treating emesis from anti-cancer drugs which other antiemetics aren't effective against

How do cannabinoids act as an anti-emetic?

It acts at a number of sites within CNS via CB1 receptors which are located presynaptically and decrease release of neurotransmitters associated with triggering vomiting process

What else do cannabinoids do post emesis?

Inhibits prostaglandin synthesis which has been implicated in emesis from anti-cancer drugs