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Core Problem 71- Vomiting, anorexia, nausea Basic Medical Sciences Vomiting: forceful expulsion of the contents of the stomach and upper intestinal tract through the mouth. It is a complex reflex coordinated by a region in the brainstem medulla oblongata known as the ‘vomiting centre’. Vomiting Centre: In the lateral reticular formation of the medulla at the level of the olivary nuclei. Receives afferents from: Limbic cortex. CTZ (chemoreceptor trigger zone) Nucleus solitarius- afferents complete the arc for the gag reflex. Spinal cord- involved in the nausea that accompanies physical injury. Vestibular system- nausea and vomiting caused by vestibular disease and motion sickness. A key source of stimulation is the CTZ in the area postrema of the brain, which is outside the blood brain barrier, and is sensitive to toxins in the blood and can initiate vomiting. NB: the CTZ possesses many dopamine (D2) receptors, which explains why dopaminergic drugs used in the treatment of Parkinson’s cause nausea and vomiting. Emetics can stimulate vomiting via receptors in the: stomach, duodenum, or brain. Vomiting centre projects to the vagus nerve and to the spinal motor neurones supplying the abdominal muscles. Benefits: Removal of ingested toxic substances before they can be absorbed. Nausea that accompanies may condition you to avoid future ingestion of foods containing such toxic substances. Vomiting Process: Increased salivation, sweating, increased heart rate, pallor and nausea. Deep breath, closure of glottis and elevation of the soft palate. Abdominal muscles contract, increasing abdominal pressure, which is transmitted to stomach’s contents. Lower oesophageal sphincter relaxes and high abdo pressure forces contents of stomach into the oesophagus. Core Problem 71- Vomiting, anorexia, nausea This is known as ‘retching’ (can occur multiple times without expulsion via mouth). Vomiting occurs when abdominal contractions become so strong that increased intrathoracic pressure forces contents of oesophagus through upper oesophageal sphincter. Causes of Nausea and Vomiting: 1. Drug-induced vomiting Cytotoxic drugs vary in their emetic potential, but some, e.g. cisplatin, cause severe vomiting in most patients. Emetic action seems to involve the CTZ. Dopamine antagonists are often effective antiemetics. Pharmacology Anti-emetics: Transmitters involved in the pathways concerned with emesis are not fully known. CTZ is rich in D2 dopamine and 5HT3 receptors. Cholinergic and histaminergic synapses are involved in transmission from the vestibular apparatus to the vomiting centre. Core Problem 71- Vomiting, anorexia, nausea Examples of Dopamine antagonists: Name of drug Class of drug MOA Use Adverse effects Prochlorperazine Phenothiazi ne (antipsychot ic agents) Blocks dopamine receptors. Alleviate symptoms of vertigo. Antiemetic, particularly for: chemotherapy, radiotherapy and pre/post-op. Sedative. Neurolepticsblock dopamine receptors in the basal ganglia resulting in extrapyramidal effects i.e. parkinsonism, acute dystonic reactions, akathisia and tardive dyskinesia. RARE: Neuroleptic malignant syndrome. Metoclopramide D2 antagonist. D2 antagonist and prokinetic action on gut and increases absorption of many drugs. Nausea and vomiting e.g. chemotherapy, post-op. Facilitate gastric emptying in those with gastricparesis. Mild adverse effects. Severe dystonic reaction may occur, mainly in young and female. Useful in migraine in combo with paracetamol (acetaminophen) Domperidone D2 antagonist. Similar to metoclopra mide but doesn’t cross blood-brain barrier. Nausea and vomiting. Promotes lactation as results in increased Rarely causes sedation or extrapyramidal sideeffects. Core Problem 71- Vomiting, anorexia, nausea prolactin secretion due to dopamine inhibition. Gastroparesis. 5HT3 antagonists examples: Name of drug MOA Use Adverse effects Ondansetron Serotonin 5-HT3 receptor antagonist Primary drugs used to treat chemotherapyinduced nausea and vomiting. Constipation, dizziness and headache. Reduces activity of vagus nerve, which deactivates the vomiting centre and blocks serotonin receptors in the CTZ. Post-op and post radiation, nausea and vomiting. NB: combo of ondansetron and dexamethasone will prevent cisplatininduced emesis in most patients. Motion Sickness Dopamine antagonists and 5HT3 antagonists are ineffective in reducing the nausea and vomiting of motion sickness. Antimuscarinic drugs or antihistamines, which act directly on the vomiting centre, may be effective, although side-effects are common. Symptoms and signs of this develop gradually but eventually culminate in vomiting or retching, after which there is often a temporary lessening of malaise. Motion sickness is believed to be a response to conflicting sensory information (i.e. signals from the eye and vestibular systems do not agree). Treatments: Antimuscarinic- Hyoscine: one of the most effective agents for motion sickness. Muscarinic receptor antagonist and frequently causes drowsiness, dry mouth and blurred vision. Core Problem 71- Vomiting, anorexia, nausea Antihistamine- Cinnarizine- interferes with the signal transmission between vestibular apparatus of the inner ear and the vomiting centre of the hypothalamus. Produces fewer side-effects than hyoscine, namely: drowsiness and blurred vision. NB: must be taken 2 hours before provocative stimulation. Vestibular disease The labyrinths generate a continuous input to the brainstem. Any pathological process that alters the balance of this ‘tonus’ may cause dizziness. Major symptom is vertigo, which is a false sense of rotary movement, associated with sympathetic overactivity, nausea and vomiting. Acute labyrinthitis: Often presents abruptly with nausea and vomiting. Frequently regarded as viral or postviral syndrome. Meniere’s disease- results from increased pressure in the membranous labyrinth. Attacks of severe vertigo associated with nausea and vomiting, deafness and tinnitus occur several times, followed by long periods of remission. Between attacks, the deafness and tinnitus persist and gradually worsen. Treatment: 1. Antihistamines: cinnarizine, cyclizine Cyclizine: Piperazine derivative with histamine H1- receptor antagonist activity. May have direct effects on the labyrinthine apparatus and on the CTZ. Exerts a central anticholinergic action. Caution: patients with- glaucoma, urinary retention or prostatic enlargement. 2. Phenothiazines i.e. promethazine and prochlorperazine. 3. Betahistine: Drug used specifically for meniere’s. Has a very strong affinity as an antagonist for histamine H3 receptors and a weak affinity as an agonist for histamine H1 receptors. Two modes of action: Core Problem 71- Vomiting, anorexia, nausea 1. Direct stimulating effect on H1 receptors located on blood vessels in the inner ear. Gives rise to local vasodilation and increased permeability, which helps to reverse the problem of endolymphatic hydrops. 2. Powerful antagonist effects at H3 receptors, and increases the levels of neurotransmitters released from the nerve endings. This explains the potent vasodilatory effects. Side-effects: headache, digestive-related side-effects. NB: In pregnancy, anti-emetics should only be used for intractable vomiting because of possible, but undefined, risk to the fetus. Limited evidence suggests that promethazine is safe. Behavioural Sciences Eating disorders (anorexia nervosa and bulimia): Please see core problem 27: addictive behaviour. Index Conditions Many conditions cause vomiting, nausea or anorexia (or all three!). All the conditions are covered in other core clinical problems.