9 Anti-Emetics Flashcards
Following this lecture you should be able to …
Demonstrate an understanding of the physiological basis for emesis from signal detection to the central processing of information.
Describe the key molecular aspects of signal sensing in the central nervous system with specific reference to receptor subtypes.
Demonstrate an understanding of the applied pharmacology for emesis and the relationship to signal recognition and transduction
Identified Applied Pharmacology
To Review:
Histamine H1-receptor antagonists (e.g. cylizine, cinnarizine, promethazine )
Serotonin or 5-HT3 receptor antagonists (e.g. ondansetron )
Muscarinic (mACh) receptor antagonists (e.g hyoscine, scopolaimine)
D2-receptor antagonists (e.g. phenothiazines, chloropromazine, perphenazine, metoclopramide, domperidone)
Cannabinoids (e.g. nabilone)
Neurokinin-1 antagonist (e.g. aprepitant)
Corticosteroids & Dexamethasone
Emesis – Overview
Emesis
Physical event; forceful evacuation of gastric contents through mouth; A protective physiological mechanism in response to something harmful being ingested
Stages: Feeling of nausea Retching Vomiting Emetic – agent which causes vomiting Anti-emetic – agent which prevents vomiting Occurs in motion sickness, and vestibular disorders…
Emesis – Overview
Accompanies Numerous Disease States
e.g. migraine, bacterial and viral infections, etc
Accompanies Changes in Physiological Status
e.g. pregnancy; motion sickness
An Unwanted Side Effect of Clinically-Used Drugs
Anti-cancer agents: Chemotherapy-Induced
Nausea & Vomiting (CINV)
Anaesthetics: Post Operative Nausea & vomiting (PONV)
Opioids
70- 80% of cancer patients treated with anti-neoplastic agents experience emesis; 10-44% have anticipatory emesis
Integrated Physiology of Emesis
The Vomiting Reflex is regulated by the CNS (medulla)
The mechanism of emesis is a complex process dependent on multiple biological, chemical, and neural pathways.
Emesis is controlled and centralized within the brainstem in a neural network on the dorsal surface of the medulla oblongata.
This region is referred to as the “brainstem emetic (vomiting) control center” or dorsal vagal complex.
Integrated Physiology of Emesis
There are three major inputs to the dorsal vagal complex which cause nausea and vomiting:
The Chemoreceptor Trigger Zone (located in the dorsal vagal complex),
The Vagal Pathway
The Vestibular Pathway
Integrated Physiology of Emesis
The rational therapeutic approach to the pathophysiology of emesis (inc CINV) includes blockade of the neurotransmitters involved in the triggering the response…
Blockade of the neurotransmitters
Signal Integration and Drugs
Endogenous mediators of emesis - Antagonists i.e. anti-emetics
Serotonin - 5HT3 ACh - M Dopamine - D2 Substance P - NK1 Histamine - H1 Enkephalin - δ
General Antiemetic Drugs
Choice of drug will be based upon the stimulus causing nausea and vomiting which determines which receptors are activated
Several classes of drugs are effective and available
Used for specific conditions, but there is overlap
Many histamine, muscarinic & serotonin receptor antagonists exhibit clinically useful activity
Different classes of anti-emetics have different side effect profiles
Anti-Emetic Histamine Receptor Antagonists
H1 Antagonists / Antihistamines Anti-Emetics Histamine Antagonists Motion Sickness Vestibular disease GI irritants Anti-Emetics Histamine Antagonists cyclizine promethazine cinnarizine
Cyclizine - motion sickness
Cinnarizine - motion sickness, vestibular disorders (e.g. Meniére´s disease, vertigo)
Promethazine - severe morning sickness of pregnancy
Of limited use against substances that act directly on CTZ
Side effects: Drowsiness and sedation; but these do contribute to efficacy
Histamine Receptor Agonists
H3 Agonists
Betahistine hydrochloride / anti-vertigo drug Serc®.
Mode of action:
Activates H-receptors on blood vessels in the inner ear
→ local vasodilation
→ increased permeability
→ reverses the underlying problem of endolymphatic hydrops
Side-effects: gastro-intestinal disturbances; headache, rashes, pruritus
Anti-Emetic Muscarinic Receptor Antagonists
Good “general purpose” antiemetics
Hyoscine, Scopolaimine
- non-selective antagonists
- motion sickness (drug of choice)
- oral and / or transdermal patch application
Side-effects:
- dry mouth, blurred vision,
- less sedative actions than antihistamines
Anti-Emetics Acetylcholine Antagonists
Motion Sickness
hyoscine
scopolaimine
Anti-Emetic Dopamine Receptor Antagonists
D2 receptors have a strong representation in the in CTZ
D2 Antagonists have a powerful anti-emetic action, and will antagonise muscarinic and histamine receptors too…
Anti-Emetic Dopamine Receptor Antagonists
D2 receptor antagonist
Phenothiazines
Severe morning sickness of pregnancy
Administered orally, i.v. or suppository
Inexpensive
Side-effects: sedative, hypotension,
dystonia (especially children), dyskinesia
Prochlorpromazine - tablet or intramuscular injection.
Perphenazine – tablet, & trifluoperazine (tablet) are less sedative than chloropromazine (tablet or deep intramuscular injection)
Dopamine Antagonists Ureamia Opioid-induced emesis CINV GI disorders Viral Gasteroent-eritis phenothiazines perphenazine prochloropromazine metoclopramide domperidone
Anti-Emetic Dopamine Receptor Antagonists
D2 receptor antagonist
Metoclopramide
Penetrates blood brain barrier
Acts on GIT; increasing GI motility
Oral administration/injection (i.m./i/v.)
Side-effects: movement disorders (esp. children), fatigue, motor restlessness, spasmodic torticollis, occulogyric crises, menstruation disorders (via effect on prolactin release), Rare Reactions; QT prolongation
Anti-Emetic Dopamine Receptor Antagonists
D2 receptor antagonist
Domperidone (Motilium, Motillium)
Does not penetrate BBB; has reduced central effectiveness, but fewer side effects
Used for migraine & cytotoxic therapy-induce emesis; emesis due to emergency hormonal contraception
Oral administration/i.v./suppositories
Anti-Emetic Serotonin Receptor Antagonists
Ondansetron
Drug of choice for CINV and PONV
Oral, suppositories, i.v. or intramuscular administration
Side-effects: gastro-intestinal disturbances; headache (not common)
Granisetron (Oral, i.v.), palonosetron (i.v.), tropisetron (Oral, i.v.)
Serotonin Antagonists
Chemotherapy (CINV) Anesthetics (PONV) Radiation Induced Vomiting ondansetron
Anti-Emetic NK1R Antagonists
Neurokinin-1 antagonist
Active in late phase emesis with cytotoxic drugs
Aprepitant
Substance P antagonist
Used for CINV and PONV
Oral / i.v. admin
Anti-Emetic NK1R Antagonists
Neurokinin-1 antagonist
Active in late phase emesis with cytotoxic drugs
Aprepitant
Substance P antagonist
Used for CINV and PONV
Oral / i.v. admin
Side Effects: fatigue, listlessness, constipation / diarrhea, loss of appetite, hiccups Rare Side Effects: dizziness, ringing in the ears, hiccups, dyspepsia, diarrhoea, constipation, anorexia; asthenia, headache..
Fosaprepitant (a prodrug of aprepitant), Casopitant, Maropitant (motion sickness)
Anti-Emetic Action of Cannabinoids
Nabilone (Cesamet)
Mimetic of the main chemical component of cannabis (HTC)
Valuable in the treatment of CINV ; FDA approval in 1985, marketed 11 years later
Thought to act via opioid receptors in CTZ
Adjunct therapy for chronic pain management
Nabilone (Cesamet)
Mimetic of the main chemical component of cannabis (HTC)
Valuable in the treatment of CINV ; FDA approval in 1985, marketed 11 years later
Thought to act via opioid receptors in CTZ
Adjunct therapy for chronic pain management
Oral Administration
Side effects: drowsiness, dizziness, dry mouth, mood changes, postural hypotension Rare Side Effects:, hallucinations, psychotic reactions
Other cannabinoid mimetics: Marinol (Dronabinol)
Corticosteroids & Antiemetics
Corticosteroids
Dexamethasone
‡ vomiting caused by cytotoxics (chemotherapy)
‡ mechanism of action not fully understood
‡ used in combination with D2 or 5HT3 antagonists → improved actions
Summary of Key Anti-Emetics
Morning sickness - Promethazine / phenothiazines
Motion sickness - Hyoscine / Promethazine / cyclizine
PONV - Phenothazines / metoclopramide
CINV - Ondansetron / phenothiazines
Opioids - Haloperidol / metoclopramide
Gastroenteritis - Metoclopramide
Anticipatory Emesis - Benzodiazepines
Therapeutic Uses of Emetics
Used for
Poisonous substance ingested
Drug overdose
Alcohol intoxication
Not for
Ingestion of corrosive substances
CNS stimulant, morphine overdose
Kerosene poisoning
Patient must be fully conscious
Therapeutic Uses of Emetics
Syrup of ipecac. (ipecacuanha)
Comprises two alkaloids emetine & cepheline
Oral administration, works within ~15mins
Irritates gastric mucosa and activates CTZ directly
Apomorphine
Directly stimulate CTZ & VC
Administered IM or SC and acts within 5-10mins
Activated charcoal
Most commonly used; adsorbant – binds toxins
Following this lecture you should be able to…
Demonstrate an understanding of the physiological basis for emesis from signal detection to the central processing of information.
Describe the key molecular aspects of signal sensing in the central nervous system with specific reference to receptor subtypes.
Demonstrate an understanding of the applied pharmacology for emesis and the relationship to signal recognition and transduction
