Medical Pharmacology Chapter 12: Anxiolytics and Sedative-Hypnotics
Preoperative Medication: Sedative Hypnotics and Other Agents and Issues
Reasons for administration include the following:
Pain management preoperatively
Management of hypertension associated with tracheal intubation
Sedation (not for anxiety as opioids are not effect in anxiolytics in adults)
Control of shivering in the OR or in the post anesthesia care unit (PACU): here meperidine (Demerol) may be effective, although morphine and fentanyl (Sublimaze) are unlikely to help
For children, opioids administered in lozenge form (fentanyl (Sublimaze)) is effective for:
Reduction of anxiety
Improved induction quality
Fentanyl (Sublimaze), administered in lozenge form, would still be expected to have effects on respiration-namely respiratory depression reflected in reduced respiratory rate and oxygen saturation.
Accordingly,oxygen saturation should be monitored.
Having the child breathe deeply can reverse the respiratory depression effect (lozenge induced)
Opioid side effects also include nausea, vomiting, and itching.
Fentanyl (Sublimaze) administration preoperatively does not prolong PACU stay and post-operative analgesic drugs are required to a lesser extent (vomiting can delay hospital release, if the child is required to drink fluids before discharge)
Opioids and hemodynamic effects:
Opioids administered preoperatively reduce hypertension that can occur during tracheal intubation; however, following intubation blood pressure may decrease below baseline (systolic, diastolic and mean arterial pressure all may decrease below starting values).
Preoperative pain management: options
Both opioids and nonsteroidal anti-inflammatory agents are used to control preoperative pain.
Comparing several agents used preoperatively (laparoscopy) to manage pain, i.e. ketorolac (Toradol) 60 mg, fentanyl (Sublimaze) 100 ug, or dezocine (Dalgan) 6 mg:
In the PACU post-surgery--
About 60% of the fentanyl (Sublimaze) patient group required additional analgesia
About 35% of the ketorolac (Toradol) group required additional analgesia
About 25% of the dezocine (Dalgan) group required additional analgesia (nausea greatest after dezocine (Dalgan))
Other reports conclude that preoperative administration of diclofenac (Voltaren) or naproxen (Naprosyn, Aleve) to patients undergoing laparoscopy reduced postoperative pain, including the need to add supplemental analgesia.
Note that for children, ibuprofen (Motrin, Advil) which has analgesic and anti-inflammatory properties, may be given rectally preoperatively.
Overview: Propofol (Diprivan) has many uses including induction and anesthesia maintenance; however, propofol (Diprivan) is effective also in providing sedation and anxiety relief
Propofol (Diprivan) and management of anxiety:
Considering propofol (Diprivan) along with midazolam (Versed) and methohexital (Brevital) for anxiety reduction/sedation for retrobulbar and peribulbar block, all agents appears similar.
Evaluation of the different group of patients who received enflurane (Ethrane), nitrous oxide, and oxygen for anesthesia maintenance but received either propofol (Diprivan) or thiopental (Pentothal) for induction, post surgery anxiety increased only in the patient group receiving thiopental (Pentothal).
Patients seen 24 hours before surgery: If anxiety is not managed by "comforting" or if the patient explicitly requests medication to relieve anxiety, diazepam (Valium), at an appropriated dosage might be administered orally the night before and at 6 a.m. on the surgical day appears appropriate.
For patients seen in the preoperative holding area who need anxiety management several approaches are available including:
IV midazolam (Versed) or
IV propofol (Diprivan)
Note that for children oral midazolam (Versed) is appropriate, administered in the holding area, and an appropriate dosage.
6Predisposing factors for aspiration
Obesity (morbidly obese), patients with hiatal hernia (anatomical predisposition due to loss of diaphragmatic contribution to sphincter tone and more nearly straight angle between the esophagus and stomach), pregnancy. In general, desperation risk in the ambulatory setting is comparable to that in the inpatient setting.
6Drugs useful for controlling the risk and consequences of aspiration:
H2 receptor antagonists: these agents reduce the acidity and gastric volume.
The mechanism of action is by competitive antagonism of histamine interaction with the H2 receptor type.
Principal H2 receptor antagonists: cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid)
The onset of action is about 60-90 minutes following administration and the duration of action is at least three hours.
8Cimetidine (Tagamet) inhibits a cytochrome P450 isoform, CYP2D6 which is responsible for the metabolism of the number of agents including commonly prescribed antidepressants, antipsychotics, beta-blockers, and some narcotics notably codeine and tramadol (Ultram). CYP2D6 exhibits genetic polymorphism indicating that distinct population differences are reflected in the extent of the enzyme's expression and activity. For example, and 7%-10% of Caucasians are poor metabolizers is of drugs usually metabolize by CYP2D6.
This observation is the basis of ethic differences since Asians and blacks are less likely than Caucasians to be poor metabolizers.
Individuals who are poor metabolizers of drugs which are CYP2D6 substrates may be at risk for orthostatic hypotension and antipsychotic side effects including over sedation.
Because of the number of cytochrome P450 isoforms and the extent of genetic polymorphism, testing of individuals for presence and extent of expression of isoforms may someday be required to predict with greater accuracy an individual's response to medication.
Cimetidine (Tagamet) reduces hepatic blood flow between 25% and 33% depending on whether cimetidine (Tagamet) administration is acute or chronic.
Therefore, drugs which are cleared by the liver, such as propranolol (Inderal), may be eliminated more slowly its administered in combination with cimetidine (Tagamet).
Finally, cimetidine (Tagamet) can cause mental confusion which is mainly observed in elderly patient populations typically within 2 days of the first dose.
6Ranitidine (Zantac), famotidine (Pepcid)
Ranitidine (Zantac) is more potent than cimetidine (Tagamet) by factor of between 4 and 6.
Famotidine (Pepcid) is about 7 times more potent than ranitidine (Zantac) and about 20 times more potent than cimetidine (Tagamet)
6Proton Pump Inhibitor (omeprazole (Prilosec):
Omeprazole (Prilosec) and lansoprazole (Prevacid) inhibit the H+-K+-ATPase responsible for producing HCl by the gastric parietal cells
Although the omeprazole (Prilosec) half-life ranges from 0.3-2.5 hours, omeprazole's (Prilosec) metabolite covalently bonds with H+-K+-ATPase, permanently inactivating the enzyme. Ultimately synthesis of new enzyme is required to reestablish the basal condition.
Omeprazole (Prilosec) also inhibits cytochrome P450 drug metabolizing systems (CYP2C19,CYP2C9,CYP2D6,CYP3A); therefore drug-drug interactions may occur. Lansoprazole (Prevacid) exhibits similar cytochrome P450 interactions.
Ambulatory care setting:
Dosage: 80 mg given the night before the scheduled procedure
Following omeprazole (Prilosec) administration in this manner, gastric volume is unchanged; however gastric flu pH increases.
To avoid adverse pulmonary effects which may occur upon aspiration of particulate antacids, soluble antacids such as sodium citrate or Bicitra may be preferable
Dosage: The usual dose is about 30 ml which will increase gastric pH but may also increase gastric volume. An alternative is a use of small amounts (1.6 ml) of sodium bicarbonate permitting increase in gastric pH without influencing gastric volume appreciably.
6Metoclopramide (Reglan), dopamine receptor antagonist:
Metoclopramide (Reglan) beneficial effects in the ambulatory setting include:
Reduces gastric emptying time (speeds gastric emptying)
Increases lower esophageal sphincter pressure
Reduces and sometimes prevents nausea/vomiting
Further reduction of gastric volume can be accomplished by combining cimetidine (Tagamet) and metoclopramide (Reglan). The combination increased gastric pH and decrease gastric volume to an extent greater than that observed with either drug alone.
To achieve optimal antiemetic effects with metoclopramide (Reglan) adequate dosing is required.
For example, doses typically used in the preoperative setting (0.15-0.3 mg/kg) were not effective in blunting cisplatin (Platinol)-mediated emetic effects, which could be prevented by significantly higher doses.
For patients at risk for aspiration (e.g. patients with hiatal hernia, morbidly obese patients, parturients, patients with duodenal ulcer history) could be pretreated with the combination of sodium citrate with metoclopramide (Reglan) and H2 receptor blocker in preparation for ambulatory surgery.
Rationale: Nausea +/- vomiting not only may be the most important factor which delays patient discharge from the ambulatory center but also contributes to unscheduled admissions of both children and adults following ambulatory surgery.
Risk factors for postoperative vomiting/nausea include:
Previous post-anesthesia emesis
Motion sickness history
Surgical procedure within from one to seven days of the menstrual cycle
Certain procedures including laproscopy; lithotripsy; ENT surgery
Use of opioids as part of preoperative medication protocols
Promethazine (Pherergan), a phenothiazine-class antipsychotic drug, is used in children to manage postoperative nausea and vomiting
Dosage: 0.5-1 mg/kg
Promethazine (Pherergan) (0.5 mg/kg, IV and IM) appeared more effective than droperidol (Inapsine) in managing postoperative vomiting in patients (children) undergoing strabismus surgery.
FDA has recommended that Droperidol not be used due to risk for Q-T prolongation and resultant serious arrhythmias.
Droperidol (Inapsine) has been classified as variably successful in management of emesis.
Lower doses (0.25-0.5 mg) may be more effective than higher doses in terms of anti-emetic effects and are less likely to delay anesthesia recovery.
For children, dosages of 50-75 ug/kg is probably effective in managing postoperative nausea that may delay discharge.
When droperidol (Inapsine) and propofol (Diprivan) were compared, postoperative nausea management appeared similar.
Serotonin antagonists: Major drug in this category is ondansetron (Zofran), with a half-life of about 3.5 hours in adults (shorter in children and significantly longer, about eight hours for elderly patients)
Effective dosage: The dose range for ondansetron (Zofran) that provides effective management of emesis is between 4 and 8 mg [4 mg may not be less effective than 8 mg]
4 mg ondansetron (Zofran) was better for control a postoperative nausea/vomiting than metoclopramide (Reglan). Furthermore, 8 mg dose was superior to droperidol (Inapsine) at 1.25 mg and to metoclopramide (Reglan) at 10 mg
Generally, ondansetron (Zofran) will be most effective is given at the end of surgery.
Primary adverse effect: headache
Other adverse effects include:
Elevation in liver function test results
Following placement of an intravenous catheter, a fluid bolus of 10 ml/kg may diminish postoperative dizziness, drowsiness and thirst compared to reduced initial fluid administration, e.g. 2 ml/kg.
Since many patients do not exhibit postoperative nausea and vomiting, routine use of antiemetics is problematic.
Acceptable approaches include:
Induction agent: propofol (Diprivan) with metoclopramide (Reglan) and low-dose droperidol (Inapsine) (early in the case)
Yes, despite the above protocol, patients experience nausea and vomiting in the PACU, ondansetron (Zofran) can be added
For those children thought to be at risk for emesis, after inhalation induction, the anesthesia provider may change to propofol (Diprivan) infusion.
1Preoperative Medication in Basis of Anesthesia, 4th Edition, Stoelting, R.K. and Miller, R., p 119- 130, 2000)
Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives; Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, pp. 364-367 (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc., 1996.
3Sno E. White The Preoperative Visit and Premedication in Clinical Anesthesia Practice pp. 576-583 (Robert Kirby and Nikolaus Gravenstein, eds) W.B. Saunders Co., Philadelphia, 1994
4John R. Moyers and Carla M. Vincent Preoperative Medication in Clinical Anethesia, 4th edition, 551-565, (Paul G. Barash, Bruce. F. Cullen, Robert K. Stoelting, eds) Lippincott Williams and Wilkins, Philadelphia, PA, 2001
5Gertler, R., Brown, H. C, Mitchell, D.H and Silvius, E.N Dexmedetomidine (Precedex): a novel sedative-analgesic agent, BUMC Proceedings 2001; 14:13-21 (http://www.baylorhealth.com/proceedings/14_1/14_1_gertler.htm)
6J. Lance Lichtor Anesthesia for Ambulatory Surgery in Clinical Anethesia, 4th edition, 1217-the1238, (Paul G. Barash, Bruce. F. Cullen, Robert K. Stoelting, eds) Lippincott Williams and Wilkins, Philadelphia, PA, 2001
7J. S. Gravenstein, and R. R. Kirby "General Anesthesia: Induction, Maintenance, and Emergence" in Clinical Anesthesia Practice pp. 585-596 (Robert Kirby and Nikolaus Gravenstein, eds) W.B. Saunders Co., Philadelphia, 1994
8Cupp, M. J. and Tracy, T.S. Cytochrome P450: New Nomenclature and Clinical Implications, in American Family Physician, January 1, 1998 (http://www.aafp.org/afp/980101ap/cupp.html)