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
