NC Hwang 2008

Antiemetic agents
Postoperative nausea and vomiting •estimated 25-40% of all surgical patients at risk of experiencing PONV •risk factors: •surgical procedures – orchidectomy, strabismus correction, inner ear operations •anaesthesia related – type of premedication and anaesthetic agent •female gender •younger age, with children at greater risk than adults •obesity •concomitant gastrointestinal disease Vomiting reflex •a complex integration of somatic and autonomic functions •considered in 3 components •afferent receptors •central integration •efferent pathway Afferent components •peripheral receptors •mechanoreceptors in gut wall, which respond to distension •abdominal visceral afferents and the abdominal course of vagus nerve, which are involved in detection of stimuli •chemoreceptors located in the mucosa of the upper gastrointestinal tract, which monitors intraluminal environment and include enterochromaffin cell in intestine, and serotonin receptors at vagal nerve endings •cranial nerves •taste, smell can provoke emesis •mechanical stimulation of pharynx afferents (via glossopharyngeal nerve to brainstem) •central receptors 1. area postrema / chemoreceptor trigger zone (CTZ) •a U-shaped structure, a few mm long, located at the base/floor of the 4th ventricle •capable of detecting emetic agents and subsequently triggering the vomiting reflex •permeable to polar molecules in the blood and cerebrospinal fluid •D2, μ, 5HT3, α1 and α2 receptors present, which responds to chemical stimuli such as chemotherapeutic agents (D2 and 5HT3 receptors), opioids (m receptors), catecholamine (a1 and a2 receptors) 2. vestibular system •the vestibular apparatus sends impulses to the area postrema and then to the nucleus tractus solitarius •cholinergic and H1 receptors present •labyrinthine stimulation causes emesis and nausea •anaesthetic agents may lower trigger threshold for emesis, perhaps by acting at both the area postrema and the vestibular apparatus 3. Other Centres •higher centres appear to have a facilitatory role in modulating brainstem emetic mechanism •input from limbic system can induce nausea and vomiting Central integration •vomiting centre •tractus solitarius, and reticular formation in the medulla •5-HT3, D2, μ, H1, Ach receptors present •receives •chemical input from CTZ •neural input from frontal lobe and limbic system, vestibular apparatus, cerebellum, vagal and sympathetic inputs, glossopharyngeal and trigeminal afferents, gastrointestinal tract Efferent pathway •stimulation of vomiting centre causes hypomotility and reverse motility of gastrointestinal tract •diaphragm presses down on stomach and abdominal wall tightens in tone, forcing the stomach contents out through the oesophagus •as this happens, epiglottis closes glottis preventing vomit from entering larynx
Higher centre

Emotional input (Memory, fear, anxiety, anticipation) Vomiting centre at medulla Tractus solitarius nucleus Cerebellum (5-HT3, D2, μ, H1) CNS area postrema / CTZ (H1, μ) (5-HT3, D2, μ, α1, α2) BBB apomorphine, digoxin Periphery Vagal and copper sulphate Inner ear sympathetic (Ach, H1) effects motion Stomach, small aminoglycosides intestines Glossopharyngeal (5-HT3) and trigeminal Sensory input Blood-borne Local irritants afferents emetics (pain, smell, cytotoxic cytotoxic drugs sight) drugs opioids radiation pharynx cholinomimetics bacteria (gagging) digoxin viruses L-DOPA bromocriptine apomorphine

Sites of action of anti-emetic agents •central D2 receptors antagonised by •substituted benzamide (metoclopramide) •phenothiazines (chlorpromazine, prochlorperazine, promethazine) •benzimidazole derivatives (domperidone), •butyrophenones (haloperidol, droperidol) •peripheral D2 receptors antagonised by metoclopramide •mu opioid receptors antagonised by nalaxone •serotonin 5HT3 receptors antagonised by •ondansetron, granisetron •in high dose, metoclopramide antagonises 5HT3 receptors in the gastrointestinal tract •alpha2 receptors •clonidine (agonist) •muscarinic acetylcholine receptors antagonised by •centrally acting anticholinergic agents (hyoscine) and antihistamine agents (promethazine) •histamine receptors antagonised by antihistamine agents (promethazine) •GABA receptors in cortex •anxiolytic drugs (benzodiazepines)

Receptor site affinity Muscarinic H1 5HT3 Drug D2 Antihistamines diphenhydramine + ++ ++++ promethazine ++ ++ ++++ Phenothiazines fluphenazine ++++ + ++ chlorpromazine ++++ ++ ++++ + prochlorperazine ++++ Antiserotonin ondansetron ++++ granisetron ++++ Benzamides metoclopramide +++ + ++ Benzimidazole domperidone ++++ Butyrophenones droperidol ++++ + + Anticholinergic hyoscine hydrobromide + ++++ + Tricyclic antidepressants amitriptyline +++ +++ ++++ nortriptyline +++ ++ +++ -

Phenothiazines •block D2 receptors in CTZ •antimuscarinic effect at vomiting centre and vestibular apparatus •has antihistamine effect •examples: prochlorperazine, promethazine •side effects •sedation limits their use as antiemetic •extrapyramidal symptoms, especially dystonia (can be reversed by intravenous diphenhydramine 50mg) •hypotension Butyrophenone – droperidol •acts at area postrema by blocking D2 receptors, capable of blocking apomorphine induced emesis •at high doses, nearly as effective as metoclopramide in preventing emesis due to cisplatin •side effects •sedation, delayed dystonia, less than phenothiazines •mild alpha blocking effects giving rise to postural hypotension, less than phenothiazines •QT prolongation (production discontinued effect 31st March 2001) Domperidone •benzimidazole derivative •D2 antagonism, but its effects are confined to the periphery as it does not penetrate well into the central nervous system •rarely causes extrapyramidal effects •antiemetic effects less than metoclopramide •beneficial effects •enhancement of coordinated antral-duodenal motility, accelerating gastric emptying •acceleration of transit in the small intestine •pharmocokinetics •rapidly absorbed after oral administration •bioavailability 15% •t½β about 7-8 hours •mainly excreted in bile •side effects •headache •elevation of serum prolactin (breast engorgement, galactorrhoea, amenorrhoea) •dosage: 20mg-40mg Antihistamine agents •antiemetic effect related to antimuscarinic effect at vomiting centre and vestibular apparatus •suppression of conduction in the vestibulocerebellar pathway •good for motion sickness •sedation is common side effect •agents •diphenhydramine, hydroxyzine, promethazine

Metoclopramide •substituted benzamide, related to procaine •hastens gastric emptying and increases lower oesophageal sphincter tone •central action: •blocks D2 receptors at CTZ •peripheral action: •hastens gastric emptying probably through central action on brainstem nuclei controlling gastric motility (prokinetic effects); •at high dosages, reduces the sensitivity of visceral nerves to locally acting emetic agents, probably via 5-HT3 blockade •pharmacokinetics •rapidly and completely absorbed after oral administration •75% bioavailability after oral administration •40% bound to plasma protein •distributed rapidly into most tissues and readily crosses BBB and placenta, also secreted in breast milk •pharmacokinetics •clearance 6 ml/kg/min, decreased in ureamia and cirrhosis •t½β is 4-6 hours, may be 24 hours in patients with impaired renal function •30% excreted unchanged in urine •rest is excreted in urine and bile after conjugation with sulphate or glucuronic acid •side effects •dystonia (8%), children prone to this •dosing: 0.5 mg/kg per 24 hours, not for below 5 years old

Serotonin receptor antagonists •receptor sites •located peripherally on vagal nerve endings, •located centrally on presynaptic nerve endings in area postrema and nucleus tractus solitarius •examples of 5-HT3 antagonists •ondansetron, granisetron, tropisetron, dolasetron •Ondansetron •prototype selective 5-HT3 receptor blocker, structurally related to serotonin •ondansetron binds competitively with 5HT3 receptors and may be displaced by presence of serotonin •no extrapyramidal effects •indications •chemotherapy induced emesis •especially cisplatin which is associated with the release of serotonin from small intestine enterochromaffin cells •postoperative nausea and vomiting •pharmacokinetics •administered orally or intravenously •0.1-0.15 mg/kg IV •oral bioavailability of 60% •75% bound to plasma proteins •peak plasma concentrations within 30-60 minutes •clearance 6 ml/kg/min, decreased in elderly, cirrhosis, increased in children •t½β 3-4 hours •metabolised extensively by liver •5% excreted unchanged in urine •side effects •headache, lightheadedness, dizziness, •warm sensation in epigastrium, flushing and constipation •Granisetron •5HT3 receptor antagonists with high receptor specificity and affinity •binds non-competitively to vagal afferent 5HT3 receptors, may continue to maintain effective 5HT3 receptor blockade when it is no longer detectable in plasma •pharmacokinetics •administered orally or intravenously •60% bioavailability after oral administration •65% bound to plasma protein •VD 2-4L/kg •clearance 11 ml/kg/min, decreased in elderly and cirrhosis, no change in uraemia •metabolised extensively by CYP3A, by Ndemethylation, aromatic ring oxidation, subsequent conjugation •t½β 10 hours, increased in elderly and cirrhosis •12% of administered dose excreted unchanged in urine, the rest eliminated as metabolites in urine and bile

•side effects •headache (15.7%) •fatigue (11.3%) •diarrhoea (7.7%) •anorexia (6.3%) •dizziness (5.2%) •constipation (5.1%) •abnormal vision (0.4%) •dosage •10 mg/kg IV for chemotherapy induced vomiting •40 μg/kg IV before induction of anaesthesia to reduce incidence of PONV Antimuscarinic agents •antimuscarinic effect at vomiting centre and vestibular apparatus •hyoscine hydrobromide is proven drug for motion sickness Other agents with antiemetic property •Glucocorticoids •dexamethasone, methylprednisolone •unknown mechanism •usage has reduced since report of bilateral subcapsular cataracts following high dose steroid therapy •Ephedrine •possibly acts by preventing postural hypotension in ambulant patients, and correcting the imbalance of vagal tone •dosage: 0.5 mg/kg •Lignocaine •2 mg/kg significantly reduce the incidence of nausea and vomiting after squint correction surgery in children •unknown mechanism •Propofol •as an infusion only, 1 mg/kg/min postanaesthesia •plasma concentration of 300-500ng/ml for antiemetic effect •Benzodiazepines •action via GABA receptor to decrease anxiety •block the re-uptake of adenosine, leading to enhanced adenosine effect •evidenced by presence of adenosine uptake sites, and aminophylline, an adenosine antagonist, is capable of causing vomiting •adenosine has been shown to modulate dopaminergic effects centrally, by depressing dopamine synthesis and release, and by postsynaptic inhibition of dopamine action

•Marijuana (cannabis) derivatives •tetrahydrocannabinol •effective antiemetic agents when other antiemetic agents are ineffective •mechanism of action •involves receptors in the chemoreceptor trigger zone •alteration of fluidity and ion transport in neuronal membrane •use is limited by side effect of sleepiness, blurred vision, dry mouth, depression •Ginger root •given preoperatively is useful treatment for motion sickness •Aprepitant •a selective high-affinity antagonist of human substance Plneurokinin 1 (NK1) receptors •acts centrally to block chemotherapy-induced emesis by augmenting the antiemetic activities of ondansetron and dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis •has little or no affinity for 5-HT3, dopamine, and corticosteroid receptors •pharmacokinetics •after oral administration, mean absolute oral bioavailability ≈ 60 to 65%; mean peak plasma concentration (Cmax) ≈ 4 hours (Tmax) •mean Vdss ≈ 70 L •more than 95% bound to plasma proteins •crosses BBB •elimination by •CYP3A4 (major pathway): drug interactions with dexamethasone and oral contraceptives •CYPlA2 and CYP2C19 (minor pathway) •apparent t½β ≈ 9 to 13 hours •not excreted by kidneys Incidence of PONV after •granisetron (17%) •haloperidol 2mg and dexamethasone 5mg (19%) •droperidol 1.25mg or haloperidol 2mg (36-7%) •dexamethasone 5mg (38%) •metoclopramide 10mg (43%) •placebo (50%)

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