Anti-Emetics Flashcards
Emesis
Emetic – agent which causes vomiting
Anti-emetic – agent which prevents vomiting
forceful evacuation of gastric contents through mouth; A protective physiological mechanism in response to something harmful being ingested
Stages:
Feeling of nausea
Retching
Vomiting
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.
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.
Signal Integration and Drugs
Endogenous mediators of emesis
Serotonin Ach Dopamine Substance P Histamine Enkephalin
Anatagonist i.e. anti emetics
5HT3, M, D2, NK1, H1, Omega
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
Targets for Anti-Emetics - Chemoreceptor trigger zone
Dopamine: D2
Substance P/Neurokinin: NK1
Serotonin or 5HT3 Receptors: 5HT3
Targets for Anti-Emetics - Vagal pathway
Serotonin or 5HT3 Receptors: 5HT3
Targets for Anti-Emetics - Vestibular pathway
Histamine: H1
Muscarinic: M
Targets for Anti-Emetics - Vomiting Centre
Histamine: H1
Muscarinic: M
Substance P/Neurokinin: NK1
Serotonin or 5HT3 Receptors: 5HT3
H1 Antagonists / Antihistamines
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
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
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-Emetic Dopamine Receptor Antagonists
D2 receptors have a strong representation in the in chemoreceptor trigger zone
D2 Antagonists have a powerful anti-emetic action, and will antagonise muscarinic and histamine receptors too
Phenothiazines
D2 receptor antagonist Severe morning sickness of pregnancy Administered orally, i.v. or suppository Inexpensive Side-effects: sedative, hypotension, dystonia (especially children), dyskinesia
dystonia
a state of abnormal muscle tone resulting in muscular spasm and abnormal posture, typically due to neurological disease or a side effect of drug therapy
Metoclopramide
D2 receptor antagonist
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
Domperidone (Motilium, Motillium)
D2 receptor antagonist
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
BBB
BLOOD BRAIN BARRIER
Ondansetron
Drug of choice for CINV (chemotherapy) and PONV (anesthetics)
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.)
Aprepitant
Neurokinin-1 antagonist
Active in late phase emesis with cytotoxic drugs
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..
CINV
Chemotherapy-induced nausea and vomiting
PONV
Postoperative nausea and vomiting
Anti-Emetic Action of Cannabinoids
Mode of action:
Acts as an agonist of the CB receptors, but mechanism of action an an entiemetic is unknown.
CB1 found in the brainstem, but may act thought to act via opioid receptors in CTZ
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
Adjunct therapy for chronic pain management
Thought to act via opioid receptors in CTZ
Oral Administration
Side effects: drowsiness, dizziness, dry mouth, mood changes, postural hypotension Rare Side Effects:, hallucinations, psychotic reactions
Corticosteriods - Dexamethasone
‡ vomiting caused by cytotoxics (chemotherapy)
‡ mechanism of action not fully understood
‡ used in combination with D2 or 5HT3 antagonists → improved actions
