Antiemetics PDF

ANTIEMETICS ROGERS OMAE – KRNA KIJABE HOSPITAL/KCHS DEPARTMENT OF ANESTHESIOLOGY  INTRODUCTON Post‐operative nausea and vomiting (PONV) continues to be one of the most common complaints following surgery. Without prophylaxis it occurs in more than 30% of surgeri...

ANTIEMETICS ROGERS OMAE – KRNA KIJABE HOSPITAL/KCHS DEPARTMENT OF ANESTHESIOLOGY  INTRODUCTON Post‐operative nausea and vomiting (PONV) continues to be one of the most common complaints following surgery. Without prophylaxis it occurs in more than 30% of surgeries, or as high as 80% in high risk populations. Serious medical consequences may result Including dehydration, electrolyte imbalance, bleeding, suture dehiscence, esophageal rupture and aspiration In some high risk surgeries it an lead to severe injury or death. Mandible fracture with wired jaws Cervical spine fusion with risk of spinal cord injury Neurosurgical procedures  Introduction Nausea and vomiting has many causes including drugs, motion sickness, fear, pregnancy, vestibular disease and migraine. In previous decades anesthesia was almost synonymous with vomiting, but with the advent. However, even the latest agents have failed to eradicate this troublesome symptom encountered in the perioperative period.  DEFINATIONS Vomiting/emesis: Forceful expulsion of gastric contents Nausea: Unpleasant sensation in the throat and epigastrium associated with the urge to vomit. VOMITING PATHOPHYSIOLOGY  EFFECTS OF THE VOMITING CENTER 1. Relaxation of lower esophageal sphincter 2. Contraction of diaphragm and abdominal muscles 3. Increase in intraabdominal pressure 4. Autonomic changes (e.g tachycardia) causes increase in peristalsis. 5. Vomiting reflexes causes the epiglottis to close Role of antiemetics in anesthesia practice PONV may occur in ~1/3 of pts undergoing GA (high-risk pts can reach 70%-80%). Emetogenic agents include volatile anesthetics, opiates, N2O, and anesthetic duration. PONV frequently ↑PACU stays and causes unanticipated admission PONV can result in aspiration, surgical dehiscence, electrolyte imbalances, ↑ICP  RISK FACTORS Assessment of patient risk factors is a key component in guiding antiemetic prevention and management strategies. Several predictive models have been developed to stratify a risk for PONV A simplified scoring system by Apfel and colleagues continues to be one of the most popular scoring systems  RISK FACTORS FOR PONV In a 2 center inpatient study, Apfel identified highly predictive risk factors for PONV: Female gender, history of motion sickness or PONV, non smoker and use of perioperative opioids. The presence of 0, 1, 2, 3 or 4 of these factors correspond to a PONV incidence of 10%, 21%, 39%, 61% and 79% respectively.  RISK FACTORS OF PONV In 1999 study by Sinclair and colleagues involving more than 17,000 patients, a comprehensive exam of PONV risk factors was studied in ambulatory surgery patients. In addition to the 4 factors identified by Apfel, duration of anesthesia longer than 30 minutes, general anesthesia and type of surgery. Adults – Cholecystectomy, Gyn procedures, laparascopy Children – Strabismus surgery, Adenotonsillectomy  PONV RISK FACTORS Patient risk factors: Female gender, young, history of PONV or motion sickness, and nonsmoker status. Surgical risk factors: Ear, breast, abdomen, gynecological surgeries  ANTIEMETICS Most antiemetic's act on the neurotransmitter receptor types found in the anatomic site responsible for emesis. To date there is no single agent that can block all receptor types, nor is there any single drug that is completely effective against PONV in all cases.  CLASSIFICATIONS Histamin 1 receptor antagonist. Meclizine, Cinnarizine, Cyclizine, Diphenhydramine. Muscarinic receptor antagonist Hyosin (Scopolamine) Selective 5-HT3 antagonist Ondansetrone, Granisetron, Palonosetrone, Dolasetron CLASSIFICATION CONT.. Dopamin 2 receptor antagonist Substituted Benzamides Ie. Metoclopramide, Trimethobenzamide Butyrophenones Ie. Domperidone, Droperidol Phenothiazines Ie. Prochlorperazine, Promethazine  CLASSIFICATION CONT.. Neurokinin 1 antagonist Aprepitant (oral formulation), Fosaprepitant ( IV formulation) Cannabinoids Dronabinol, Nabilone Adjuvants – Glucorticoids, Benzodiazepins Dexamethasone, Methylprednisolone, Diazepam, Lorazepam  SEROTONIN ANTAGONISTS Since their introduction the early 1990’s to treat chemotherapy induced nausea and vomiting, serotonin antagonists have become one of the conerstones of modern antiemetic prophylaxis and therapy. The 5-HT3 receptor antagonists include ondansentron, granisetrone, ramosetron, tropisetron and palosetron, all act by inhibiting the action of serotonin in 5-HT3 receptor rich areas of the brain. All have similar effect profiles: with most common being headache, dizziness, constipation and diarrhea.  SEROTONIN ANTAGONISTS Selective 5-HT3 antagonists, including ondansentron, have been associated with a number of dose-dependent increases in ECG intervals (eg PR, QRS duration) usually occurring 1-2 hours after I.V administration. In general this changes are not clinically relevant. When used in conjuction with other agents that prolong these intervals, arrhythmia may occur.  SEROTONIN ANTAGONISTS All of the 5-HT3 antagonists are equally effective for the treatment of PONV. Ondansentron (Zofran) as the prototypical antagonist has been the most studied. A Conchrane systematic review found that ondansetrone reduces the risk of nausea by 32% and vomiting by 45% over placebo. The review also reported that no evidence exists that the risk of PONV differed for groups based on timing of administration.  SEROTONIN ANTAGONISTS In clinical practice the usual recommended dose for ondansentron is 4mg IV, administered at the end of the surgery. Unlike ondansentron, the other 5-HT3 antagonists exhibit a linear dose-response curve, with increasing doses achieving a greater clinical effect until the maximal effective dose is reached.  STEROIDS Dexamethasone has been shown to be useful in the management of PONV. Corticosteroids act centrally to inhibit prostaglandin synthesis and to control endorphin release. A study by Wang, et al concluded that: dexamethasone is most effective for PONV prophylaxis when administered immediately after induction rather than at end of surgery. Onset takes 2-3 hours.  STEROIDS SAMBA guidelines recommend a prophylactic dose of dexamethasone 4 to 5 mg IV at induction. A study by Elhakim, et al concluded that dexamethasone 8mg (early – immediately after induction) combined with ondansentrone 4mg (late – within 30 minutes of closure) provided maximal prophylaxis.  CHOLINERGIC ANTAGONISTS The anticholinergic agents are among the oldest antiemetics. Both scopolamine and atropine block muscarinic cholinergic emetic receptors in the cerebral cortex and the pons. Atropine has weaker antiemetic effects than scopolamine and is generally not used in the post – op period  CHOLINERGIC ANTAGONISTS Most studies of scopolamine have investigated the transdermal scopolamine (TDS) patch, which is designed to release 1.5 mg of scopolamine over 3 days. Scopolamine may be most useful as an adjunct to other antiemetics, especially when combined with ondansentrone.  DOPAMINE ANTAGONISTS The dopamine receptor antagonist act at the D2 receptors in the chemoreceptor trigger zone and area postrema to suppress nausea and vomiting. There are 3 types of dopamine antagonists commonly used: butyrophenones, benzamides and phenothiazines. Dopamine Antagonists: Butyrophenones Butyrophenones are D2 receptor blockers in addition to alpha blockers. Their adverse effects include sedation and extrapyramidal symptoms. The 2 primary antiemetic agents in this group are haloperidol and droperidol.  Dopamine Antagonists: Butyrophenones In 2001, the FDA issued a “black box” warning for droperidol, citing reports of severe cardiac arrhythmias (torsades de pointes) and cases of sudden cardiac death with the use of droperidol. The use of droperidol has declined significantly since that ruling.  Dopamine Antagonists: Phenothiazines The phenothiazines include: promethazine, chlorpromazine, prochlorperazine, perphenazine and thiethylperazine. Their use has declined because of their high incidence of adverse effects including: sedation, restlessness, diarrhea, agitation, CNS effects, hypotension, neuroleptic syndrome and supraventricular tachycardia Phenothiazines are not currently recommended as first line antiemetic agents.  Dopamine Antagonists: Benzamides The most commonly used antiemetic in this group is metoclopramide. Metoclopramide is a procainamide derivative that blocks D2 receptors both centrally at the CTZ and the postrema and peripherally in the GI tract. Metoclopramide increases lower esophageal tone and promotes gastric motility.  Dopamine Antagonists: Benzamides Metoclopramide can also cause sedation, dysphoria, extrapyramidal syndrome and spastic torticollis (treat with Benadryl – Diphenhydramine) Metoclopramide has received a black box warning from the FDA due to irreversible tardive dyskinesia with higher dosing and long term use.  METOCLOPRAMIDE MOA: Dopamine D2 receptors antagonist It is potent Antiemetic & Prokinetic agent As Antiemetic It has potent Antiemetic & antinausea effect. Blocks D2 receptors in CTZ of the medulla (area postrema) As Prokinetic agent It can selectively stimulate gut motor function. Blocks D2 receptor in GIT & blocks the normal inhibitory effect of Dopamine on cholinergic smooth muscle stimulation--- ↑ motility.  The Uses - Metoclopramide Potent antiemetic controls / reduces vomiting due to: Uremia Radiation Viral gastro enteritis, hepatic-biliary disease Anticancer drugs Migraine Post operatively & pre-operatively  ANTIHISTAMINES The antiemetic properties of antihistamines such as diphenhydramine, dimenhydrinate, cyclizine, doxylamine and promethazine are due to blockade of the histamine H1 receptor at the Nucleus Tractus Solitarius, at the vomiting center and vestibular system. Their anticholinergic activity is responsible for their most common side effects: Sedation, dry mouth, blurred vision and urinary retention.  MANAGEMENT STRATEGY No single intervention can completely prevent or treat PONV One should come up with a multimodal approach to maximize clinical efficacy while minimizing risks to the patient. In an effective strategy, consider: 1. Assessment of risk for developing PONV and baseline risk reduction 2. Prophylaxis and cost effectiveness 3. Combination therapy 4. Rescue treatment.  MANAGEMENT STRATEGY Combination therapy is recommended for patients at moderate to high risk for PONV. Combination antiemetic therapy can be used with other pharmacologic and non-pharmacological techniques. This approach is often called “multimodal approach” A multimodal approach can often include preoperative anxiolysis, aggressive hydration, droperidol and dexamethasone at induction, ondansetron at the end of surgery, TIVA with propofol and ketorolac or IV acetaminophen, with no use of nitrous oxide or neuromuscular blockade.  MANAGEMENT STRATEGY In rescue treatment, patients who had not previously received antiemetic prophylaxis should be given a 5-HT3 antagonist. Patients who had already received prophylaxis should be given a rescue antiemetic from a different treatment class than the prophylactic drug. In patients who received a 5-HT3 antagonist for prophylaxis, no further benefit is achieved from repeat doses in the 6 hour after the initial dose.  MY PERSONAL MANAGEMENT STRATEGY Give anxiolytic early - Midazolam 1-2 mg Dexamethasone 6- 8 mg early (immediately following induction) and ondansetron 4mg late (within last 30 minutes of case) Induce with propofol (maintain with TIVA?) Avoid N2O Avoid NMBA (and reversal) if possible  MY PERSONAL MANAGEMENT STRATEGY Maintain euvolemia Pain relief with LA if possible Rescue in PACU with: One additional dose (4mg) of ondansentron A different class of agent (droperidol, metoclopramide)