Intravenous (IV) anesthetics are commonly used for the induction and maintenance of general anesthesia and for sedation. The rapid onset and offset of these drugs is attributable to their physical translocation into and out of the brain. After a bolus IV injection, lipid-soluble drugs such as propofol, thiopental (not available in the United States), and etomidate rapidly distribute into the vessel-rich group of highly perfused tissues (eg, brain, heart, liver, and kidneys), causing an extremely rapid onset of effect. Plasma concentrations decrease as the drug is taken up by the less well-perfused tissues (eg, muscle and fat), and the drug rapidly leaves the brain. This redistribution from the brain is responsible for the termination of effects; the clearance of the active drug occurs mainly by hepatic metabolism and renal elimination. Elimination half-life is defined as the time required for the plasma concentration of a drug to decrease by 50% during the elimination phase of clearance. Context-sensitive half-time (CSHT) is defined as the time required for a 50% decrease in the central compartment drug concentration after a steady-state infusion of specified duration (duration is the “context”).

1. Propofol (2,6-diisopropylphenol) is used for the induction or maintenance of general anesthesia and for procedural sedation. In the United States, it is marketed as a 1% isotonic oil-in-water emulsion, which contains 10% soybean oil, 2.25% glycerol, and 1.2% purified egg phosphatide. Bacterial growth is inhibited by ethylenediaminetetraacetic acid, diethylenetriamine pentaacetic acid, sulfite, or benzyl alcohol depending on the manufacturer. Fospropofol is an aqueous formulation of propofol available in other countries for procedural sedation. It is a prodrug of propofol, and its aqueous nature negates undesirable effects of the emulsion such as pain on injection and lipid disorders.
   1. Mode of action. Facilitates inhibitory neurotransmission by enhancing the function of γ-aminobutyric acid type A (GABA_A) receptors in the central nervous system (CNS). The modulation of glycine receptors, N-methyl-D-aspartate (NMDA) receptors, cannabinoid receptors, and voltage-gated ion channels may also contribute to propofol’s actions.
   2. Pharmacokinetics
      1. Hepatic and extrahepatic metabolism to inactive metabolites that are renally excreted.
      2. CSHT remains below 15 minutes following 2-hour infusion, making propofol infusions useful for the maintenance of anesthesia, but CSHT may rise well above 30 minutes for infusions lasting over 8 hours.
   3. Pharmacodynamics
      1. CNS
         1. Induction doses rapidly produce unconsciousness (30-45 seconds), followed by a rapid termination of effect due to redistribution. Emergence is rapid and often accompanied by mood elevation. Low doses produce sedation and amnesia.
         2. Weak analgesic effects at hypnotic concentrations.
         3. Decreases intracranial pressure (ICP) and also cerebral perfusion pressure (CPP) due to markedly decreased mean arterial pressure (MAP). Cerebral autoregulation, as well as vasoconstriction in response to hyperventilation, are unaffected.
         4. Anticonvulsant properties raise the seizure threshold.
         5. Propofol-induced anesthesia is associated with frontal alpha oscillations (8-12 Hz), delta oscillations (1-4 Hz), and slow oscillations (0.1-1 Hz) electroencephalogram (EEG). Higher doses cause burst suppression and isoelectric EEG.
         6. Depresses somatosensory-evoked potentials (SSEPs) and motor-evoked potentials (MEPs), but little effect on brainstem auditory–evoked potentials (BAEPs).
         7. Has antiemetic effects, even at subhypnotic doses. Postoperative nausea and vomiting (PONV) occurs less frequently after a propofol-based anesthetic compared with other techniques.
      2. Cardiovascular system
         1. Dose-dependent decreases in preload, afterload, and contractility lead to decreases in blood pressure (BP) and cardiac output. Hypotension may be marked in hypovolemic, elderly, or hemodynamically compromised patients.
         2. Heart rate (HR) is minimally affected, and baroreceptor reflex is blunted.
      3. Respiratory system
         1. Dose-dependent decreases in respiratory rate (RR) and tidal volume (TV).
         2. Ventilatory responses to hypoxia and hypercarbia are diminished.
   4. Dosage and administration (Table 12.1)
      1. Titrate with reduced incremental doses in hypovolemic, elderly, or hemodynamically compromised patients or if administered with other anesthetics.

         Table 12-1 Dosages of Commonly Used IV Anesthetics and Induction Dose Onset and Duration

         Drug Dose Onset (s) Induction Dose Duration (min) Induction (mg/kg) Maintenance (μg/kg/min) Sedation (Titrate to Effect) Propofol IV 1-3 100-150 25-75 μg/kg/min <30 3-8 Midazolam IV 0.2-0.4 0.5-1.5 0.5-1.0 mg 30-60 15-30 Midazolam IM — — 0.07-0.1 mg/kg — — Ketamine IV 1-2 15-90 0.1-0.8 mg/kg 45-60 10-20 Ketamine IM 5-10 — 2-4 mg/kg — — Etomidate IV 0.2-0.4 10a 5-8 μg/kg/mina <30 4-8 Dexmedetomidine IV — — 0.2–0.7 μg/kg/hb — — Methohexital IV 1-1.5 — 0.5 mg/kgc <30 4-7

         IM, intramuscular; IV, intravenous.

         ^a Off-label use, avoided due to risk of adrenal suppression.

         ^b After loading dose of 0.5 to 1.0 μg/kg over 10 minutes.

         ^c Off-label use, following initial loading dose of 0.75 to 1 mg/kg, redose every 2 to 5 minutes as needed.

      2. Relatively larger induction and maintenance doses are required in infants and small children.
      3. Propofol emulsion supports bacterial growth despite the addition of antimicrobials; prepare drug under sterile conditions, label with date and time, and discard unused propofol after 6 to 12 hours to prevent inadvertent bacterial contamination.
      4. Target-controlled infusion pumps have been developed, which, based on the patient’s age and body weight, can titrate an initial bolus and variable infusion rate to achieve a desired plasma concentration (not available in the United States).
      5. Systems have also been developed to measure propofol concentration by mass spectrophotometry in exhaled gas or by IV electrodes, but these modalities are not used in common practice.
   5. Adverse effects
      1. Venous irritation. May cause pain during IV administration, which can be reduced by administration in a large vein or by adding lidocaine to the solution (eg, 20 mg of lidocaine to 200 mg of propofol). The most effective method to reduce pain is to give lidocaine (0.5 mg/kg, IV) 1 to 2 minutes before propofol injection with a tourniquet proximal to the IV site.
      2. Lipid disorders. Propofol is a lipid emulsion and should be used cautiously in patients with disorders of lipid metabolism (eg, hyperlipidemia and pancreatitis).
      3. Myoclonus and hiccups can occur after induction doses, although less frequently than with methohexital or etomidate.
      4. Propofol infusion syndrome is a rare and often fatal disorder that occurs in critically ill patients (usually children) subjected to prolonged, high-dose propofol infusions. Typical features include rhabdomyolysis, metabolic acidosis, cardiac failure, and renal failure.
2. Barbiturates such as thiopental (not available in the United States) and methohexital rapidly produce unconsciousness (30-45 seconds) after IV administration, followed by rapid termination of effects due to redistribution. Barbiturate preparations for IV administration are highly alkaline (pH > 10) and are usually prepared as dilute solutions (1.0%-2.5%).
   1. Mode of action. Similar to propofol, barbiturates facilitate inhibitory neurotransmission by enhancing GABA_A receptor function, binding it at an allosteric site and increasing the amount of time Cl⁻ ions are open. At higher concentrations, they can cause direct stimulation of GABA_A receptors. They also inhibit excitatory neurotransmission via glutamate and nicotinic acetylcholine receptors.
   2. Pharmacokinetics
      1. Hepatic metabolism. Methohexital has a much higher clearance than thiopental. Thiopental is metabolized to pentobarbital, an active metabolite with a longer half-life.
      2. Multiple doses or prolonged infusions may produce prolonged sedation or unconsciousness due to the reduced rate of redistribution, the return of the drug to the central compartment, and slow hepatic metabolism. The CSHT of thiopental is long, even after short infusions.
   3. Pharmacodynamics
      1. CNS
         1. Dose-dependent CNS depression ranging from sedation to unconsciousness. Much higher doses are required to suppress responses to painful stimuli.
         2. Dose-dependent cerebral vasoconstriction and decrease in cerebral metabolic rate (CMRO₂) cause reductions in ICP and cerebral blood flow (CBF). Cerebral autoregulation remains unaffected.
         3. At high doses, thiopental will produce an isoelectric EEG. In contrast, methohexital can elicit seizure activity. This characteristic of methohexital, in addition to its favorable pharmacokinetic profile, makes it a suitable anesthetic agent for electroconvulsive therapy.
         4. Minimal effects on SSEPs or MEPs, but dose-dependent depression of BAEPs.
      2. Cardiovascular system
         1. Cause venodilation and depress myocardial contractility, leading to a dose-dependent decrease in BP and cardiac output, especially in patients who are preload dependent. Decrease in BP is less pronounced than with propofol.
         2. Baroreceptor reflexes remain largely intact; therefore, HR may increase in response to hypotension.
      3. Respiratory system
         1. Dose-dependent decreases in RR and TV. Ventilatory responses to hypoxia and hypercarbia are markedly depressed. Apnea may result 30 to 90 seconds after an induction dose.
         2. Laryngeal reflexes remain more intact relative to propofol; therefore, the incidence of cough and laryngospasm is higher.
   4. Dosage and administration (Table 12.1)
      1. Doses should be reduced in hypovolemic, elderly, or hemodynamically compromised patients.
      2. May precipitate when mixed with drugs in lower pH solution (eg, succinylcholine) and cause the precipitation of other drugs (eg, vecuronium). Therefore, it is prudent to use a free-running IV and avoid simultaneous injection with other drugs.
   5. Adverse effects
      1. Allergy. True allergies are unusual. Thiopental occasionally causes anaphylactoid reactions (ie, hives, flushing, and hypotension) due to histamine release.
      2. Porphyria
         1. Absolutely contraindicated in patients with acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria.
         2. Barbiturates induce porphyrin synthetic enzymes such as δ-aminolevulinic acid synthetase; patients with porphyria may accumulate toxic heme precursors and suffer an acute attack.
      3. Venous irritation and tissue damage
         1. May cause pain at the site of administration due to venous irritation.
         2. Thiopental can cause severe pain and tissue necrosis if injected extravascularly or intra-arterially. If intra-arterial administration occurs, phentolamine (α-blocker), heparin, vasodilators, and regional sympathetic blockade may be helpful in treatment.
      4. Myoclonus and hiccups are often seen during induction with methohexital.
3. Benzodiazepines include midazolam, lorazepam, and diazepam. They are often used for sedation, amnesia, anxiolysis, or as adjuncts to general anesthesia. Midazolam is prepared in a water-soluble form at pH 3.5, while diazepam and lorazepam are dissolved in propylene glycol and polyethylene glycol, respectively.
   1. Mode of action. Enhance inhibitory neurotransmission by increasing the affinity of GABA_A receptors for GABA. In contrast to other agents (ie, barbiturates), benzodiazepines are unable to activate the GABA_A receptor in the absence of GABA. Different clinical effects (eg, amnesia, sedation, and anxiolysis) appear to be mediated by different GABA_A receptor subtypes.
   2. Pharmacokinetics
      1. After IV administration, the onset of CNS effects occurs in 2 to 3 minutes for midazolam and diazepam (slightly longer for lorazepam). Effects are terminated by redistribution; therefore, durations of a single dose of diazepam and midazolam are similar. The effects of lorazepam are somewhat more prolonged.
      2. All three drugs are metabolized in the liver. Elimination half-lives for midazolam, lorazepam, and diazepam are approximately 2, 11, and 20 hours, respectively. The active metabolites of diazepam last longer than the parent drug and accumulate with repeated dosing. Hydroxymidazolam can accumulate and cause sedation in patients with renal failure.
      3. Diazepam clearance is reduced in the elderly, but this is less of a problem with midazolam and lorazepam. Obese patients may require higher initial doses of benzodiazepines, but clearance is not markedly different.
   3. Pharmacodynamics
      1. CNS
         1. Amnestic, anticonvulsant, anxiolytic, muscle relaxant, and sedative-hypnotic effects in a dose-dependent manner. Amnesia may last for up to 1 hour following a single premedication dose of midazolam. Sedation may sometimes be prolonged.
         2. Unless combined with other agents, benzodiazepines are unable to inhibit the response to noxious stimulus sufficiently for surgical anesthesia to be achieved.
         3. Do not produce significant analgesia.
         4. Dose-dependent reduction of CBF and CMRO₂.
         5. Do not produce burst suppression or isoelectric EEG pattern, even at very high doses.
      2. Cardiovascular system
         1. Mild systemic vasodilation and decrease in cardiac output. HR is usually unchanged.
         2. Hemodynamic changes may be pronounced in hypovolemic or critically ill patients if rapidly administered in a large dose or with an opioid.
      3. Respiratory system
         1. Mild dose-dependent decreases in RR and TV. Some decrease in hypoxic ventilatory drive.
         2. Respiratory depression may be pronounced if administered with an opioid, in patients with pulmonary disease or in debilitated patients.
   4. Dosage and administration (see Table 12.1 for midazolam)
      1. Incremental IV doses of diazepam (2.5 mg) or lorazepam (0.25 mg) may be used for sedation.
      2. Appropriate oral doses are 5 to 10 mg of diazepam or 2 to 4 mg of lorazepam.
   5. Adverse effects
      1. Drug interactions. Administration of a benzodiazepine to a patient receiving the anticonvulsant valproate may precipitate a psychotic episode.
      2. Pregnancy and labor
         1. May be associated with a slightly increased risk of cleft lip and palate when administered during the first trimester.
         2. Cross the placenta and may lead to CNS depression in the neonate.
      3. Superficial thrombophlebitis and injection pain may be produced by the vehicles in diazepam and lorazepam.
   6. Flumazenil (imidazobenzodiazepine) is a competitive antagonist at the benzodiazepine binding site of GABA_A receptors in the CNS.
      1. Reversal of benzodiazepine-induced sedative effects occurs within 2 minutes; peak effects occur at approximately 10 minutes. It does not completely antagonize the respiratory depressant effects of benzodiazepines.
      2. Half-life is shorter than the benzodiazepine agonists, thus repeated administration may be necessary.
      3. Metabolized to inactive metabolites in the liver.
      4. Dose of 0.3 mg IV every 30 to 60 seconds (to a maximum dose of 5 mg).
      5. Contraindicated in patients with tricyclic antidepressant (TCA) overdose (thought to be due to unmasking TCA-induced seizure activity) and in those receiving benzodiazepines for the control of seizures or elevated ICP. Use cautiously in patients who have had long-term treatment with benzodiazepines because acute withdrawal may be precipitated.
4. Etomidate is a benzylimidazole sedative-hypnotic agent most commonly used for IV induction of general anesthesia. It is supplied in a solution containing 35% of propylene glycol.
   1. Mode of action. Facilitates inhibitory neurotransmission by enhancing GABA_A receptor function.
   2. Pharmacokinetics
      1. After an induction dose, times to loss of consciousness and return of consciousness are similar to that for propofol. Effects of a single bolus dose are terminated by redistribution.
      2. Very high clearance in the liver and by circulating esterases to inactive metabolites.
   3. Pharmacodynamics
      1. CNS
         1. No analgesic properties.
         2. CBF, CMRO₂, and ICP decrease, while CPP is usually maintained. Cerebral vasoconstriction in response to hyperventilation is preserved.
         3. Induces burst suppression at high doses.
         4. Less depression of evoked potentials compared to that with propofol or thiopental. BAEPs are unaffected, while SSEPs are enhanced.

            Increases EEG activity in epileptogenic foci potentially precipitating with seizures.

      2. Cardiovascular system
         1. Minimal changes in HR, BP, and cardiac output. Often chosen to induce general anesthesia in hemodynamically compromised patients.
         2. Does not affect the sympathetic tone or the baroreceptor function. Will not effectively suppress hemodynamic responses to pain.
         3. Decreases myocardial oxygen consumption.
      3. Respiratory system
         1. Dose-dependent decreases in RR and TV; transient apnea may occur.
         2. The respiratory depressant effects of etomidate are less pronounced than those of propofol or barbiturates.
   4. Dosage and administration (Table 12.1)
   5. Adverse effects
      1. Myoclonus may occur after administration, particularly in response to stimulation. Can be avoided by premedication with benzodiazepines or opiates.
      2. Nausea and vomiting occur more frequently in the postoperative period than with other anesthetic agents.
      3. Venous irritation and superficial thrombophlebitis may be caused by the propylene glycol vehicle. Minimized by administration into a free-flowing IV carrier infusion. Pain at injection site has been described in 30% to 80% of patients.
      4. Adrenal suppression. Inhibits 11β-hydroxylase; a single induction dose suppresses adrenal steroid synthesis for up to 24 hours in elderly or debilitated patients. May not be clinically significant after a single dose, but repeated doses/infusions have been associated with increased mortality in the ICU.
      5. Hiccups and nystagmus are also relatively common side effects following induction with etomidate.
5. Ketamine is an arylcyclohexylamine (related to phencyclidine) sedative-hypnotic agent with potent analgesic properties. It is used for the induction of general anesthesia and for sedation and analgesia in the perioperative setting. It is a mixture of R+ and S− isomers. The S− isomer has higher potency and produces fewer side effects.
   1. Mode of action. Anesthetic effects are mainly attributed to noncompetitive antagonism of NMDA receptors in the CNS, although effects on opioid receptors, acetylcholine receptors, and voltage-gated sodium and calcium channels also have been reported.
   2. Pharmacokinetics
      1. Produces unconsciousness in 30 to 60 seconds after an IV induction dose. Effects are terminated by redistribution in 15 to 20 minutes. After intramuscular (IM) administration, the onset of CNS effects is delayed for approximately 5 minutes, with peak effect at approximately 15 minutes.
      2. Metabolized rapidly in the liver to multiple metabolites, some of which have modest activity (eg, norketamine). Elimination half-life is 2 to 3 hours.
      3. Repeated bolus doses or prolonged infusions result in accumulation.
   3. Pharmacodynamics
      1. CNS
         1. Produces a “dissociative” state accompanied by amnesia and profound analgesia. Analgesia occurs at much lower concentrations than hypnosis, so analgesic effects persist after the return of consciousness.
         2. Increases CBF, ICP, and CMRO₂; cerebral vasoconstriction in response to hyperventilation is preserved.
         3. Enhancement of SSEPs; depression of BAEPs and visual-evoked potentials.
         4. Dose-dependent EEG changes that differ from other anesthetics; high doses do not produce an isoelectric EEG. Gamma oscillations (25-40 Hz) are often observed.
      2. Cardiovascular system
         1. Increases HR, cardiac output, and BP of systemic and pulmonary arteries by triggering the release of endogenous catecholamines.
         2. Often used for inducing general anesthesia in hemodynamically compromised patients, particularly those for whom HR, preload, and afterload should remain high. Should be used cautiously in patients with CAD or pulmonary hypertension.
         3. It has direct negative inotropic and vasodilation effects, usually outweighed by a potent sympathomimetic effect, but may act as a direct myocardial depressant in patients with maximal sympathetic nervous system stimulation or in patients with autonomic blockade.
      3. Respiratory system
         1. Usually depresses RR and TV only mildly and has minimal effect on CO₂ response.
         2. Potent bronchodilator due to sympathomimetic effects.
         3. Laryngeal protective reflexes are relatively well maintained, although aspiration can still occur.
   4. Dosage and administration (Table 12.1)
      1. Useful for IM induction in patients with no IV access (eg, children).
      2. A concentrated 10% solution is available for IM use only.
   5. Adverse effects
      1. Oral secretions are markedly stimulated. The coadministration of an antisialagogue (eg, glycopyrrolate) may be helpful.
      2. Emotional disturbance. May cause agitation and unpleasant hallucinations during the early postoperative period. Incidence is higher with increased age, female gender, and dosages greater than 2 mg/kg but may be greatly reduced with the coadministration of a benzodiazepine or propofol. Children seem to be less troubled than adults by the hallucinations. Alternatives should be considered in patients with psychiatric disorders.
      3. Muscle tone. May lead to random myoclonic movements, especially in response to stimulation. Muscle tone is often increased.
      4. Increases ICP and is relatively contraindicated in patients with head trauma or intracranial hypertension.
      5. Ocular effects. May lead to mydriasis, vertical nystagmus, diplopia, blepharospasm, and increased intraocular pressure.
      6. Anesthetic depth may be difficult to assess. Common clinical signs of anesthetic depth (eg, HR, BP, and RR) as well as EEG-based monitors of anesthetic depth are less reliable when ketamine is used.
      7. PONV
6. Dexmedetomidine. Dexmedetomidine is a sedative agent with analgesic properties. It is used as an adjunct to general anesthesia and for sedation in the ICU and the OR. It is also used in regional anesthesia, in combination with local anesthetics to prolong the duration of the regional block, and for premedication of pediatric patients (nasal or oral). In some centers, it is also used routinely for awake craniotomies (off-label).
   1. Mode of action. Highly selective α₂-adrenergic receptor agonist (α₂/α₁ 1600:1). Clonidine is a less-selective and longer-acting α₂ agonist (α₂/α₁ 200:1) with similar sedating and analgesic properties. Sedative effect mimics the mechanism of sleep. It decreases the inhibitory outflow from the locus coeruleus, causing an increase in the GABAergic outflow from the ventrolateral preoptic nucleus in the hypothalamus.
   2. Pharmacokinetics
      1. Undergoes rapid redistribution after IV administration. Elimination half-life is approximately 2 hours.
      2. Metabolized extensively in the liver.
   3. Pharmacodynamics
      1. CNS
         1. Elicits a sedated but arousable state similar to natural sleep.
         2. Potentiates CNS effects of propofol, volatile anesthetics, benzodiazepines, and opioids.
         3. Opioid sparing effect intraoperatively.
         4. Weak amnestic, lacking anticonvulsant properties.
            1. Low doses produce spindles on the EEG that are similar to those observed during non–rapid eye movement (REM) stage 2 sleep. Higher doses produce delta and slow oscillations similar to non-REM stage 3 sleep.
            2. Decreases the likelihood of emergence delirium in pediatric population.
      2. Cardiovascular system
         1. Decreases HR and BP, α_2A receptor–mediated decrease in catecholamine release.
         2. Transient hypertension may occur after an IV bolus, thought to be secondary to peripheral α_2B receptor activation.
         3. Baroreflex is well preserved.
      3. Respiratory system
         1. Minimal respiratory depression, although it may contribute to respiratory depressant effects of other anesthetics.
         2. Airway reflexes remain intact, making it useful for awake fiberoptic intubation.
      4. Endocrine system. May decrease adrenal response to adrenocorticotropic hormone after prolonged infusions, although clinical significance is unclear.
   4. Dosage and administration (Table 12.1)
      1. Decreased dosage should be considered in patients with significant hepatic dysfunction. Because the activity of dexmedetomidine metabolites has not been studied, decreased dosage may be prudent for patients with severe renal dysfunction.
      2. Indicated only for infusions of less than 24 hours.
   5. Adverse effects. Antimuscarinic effects (eg, dry mouth and blurred vision) may occur due to α₂ adrenal receptor–mediated inhibition of acetylcholine release.
7. Opioids.Morphine, meperidine, methadone, hydromorphone, fentanyl, sufentanil, alfentanil, and remifentanil are opioids commonly used in general anesthesia. Their primary effect is analgesia; they are used to supplement other agents during the induction or maintenance of general anesthesia. In high doses, opioids are occasionally used as the primary anesthetic (eg, cardiac surgery). Opioids differ in their potencies, pharmacokinetics, and side effects.
   1. Mode of action. Bind to specific receptors in the brain, spinal cord, and on peripheral neurons. The opioids listed above are all relatively selective for μ-opioid receptors, and most of the analgesic and side effects of opioid medications are mediated by μ-opioid receptors. Additional mechanism of action for specific opioids include NMDA antagonism, in the case of methadone, and inhibition of serotonin reuptake and α2b agonism, in the case of meperidine.
   2. Pharmacokinetics
      1. Pharmacokinetic data are presented in Table 12.2.

         Table 12-2 Dose, Time to Peak Effect, and the Duration of Analgesia for Intravenous Opioid Agonists and Agonist-Antagonists^a

         Opioid Dose (mg)b Peak (minute) Duration (hour)c Morphine 10 30-60 3-4 Meperidine 80 5-7 2-3 Hydromorphone 1.5 15-30 2-3 Oxymorphone 1.0 15-30 3-4 Methadone 10 5-10 — Fentanyl 0.1 3-5 0.5-1 Sufentanil 0.01 3-5 0.5-1 Alfentanil 0.75 1.5-2 0.2-0.3 Remifentanil 0.1 1.5-2 0.1-0.2 Pentazocine 60 15-20 2-3 Butorphanol 2 15-20 2-3 Nalbuphine 10 15-20 3-4 Buprenorphine 0.3 <30 5-6

         ^a Data for fentanyl derivatives are derived from intraoperative studies, the remainder from postoperative pain studies.

         ^b Approximately equianalgesic doses (see text).

         ^c Average duration of first single dose.

      2. After IV administration, the onset of action is within minutes for the fentanyl derivatives; hydromorphone and morphine may take 20 to 30 minutes for peak effect due to their lower lipid solubilities. The termination of effects for all opioids except remifentanil is by redistribution.
      3. Elimination is primarily by the liver and depends on hepatic blood flow. Remifentanil is metabolized by nonspecific esterases in tissues (primarily skeletal muscle). Morphine and meperidine have active metabolites, whereas hydromorphone and the fentanyl derivatives do not.
      4. Metabolites are primarily excreted in the urine. In patients with renal failure, the accumulation of morphine-6-glucuronide may cause prolonged narcosis and respiratory depression. Renal failure may also cause the accumulation of normeperidine, an active meperidine metabolite associated with seizure activity.
      5. CSHT of fentanyl derivatives: fentanyl > alfentanil > sufentanil > remifentanil
   3. Pharmacodynamics
      1. CNS
         1. Produce sedation and analgesia in a dose-dependent manner; euphoria is common. Very large doses may produce amnesia and loss of consciousness, but opioids are not reliable hypnotics.
         2. Reduce the minimum alveolar concentration (MAC) of inhalational anesthetics and the requirements for IV sedative-hypnotic drugs.
         3. Decrease CBF and CMRO₂.
         4. Produce miosis by the stimulation of the Edinger-Westphal nucleus of the oculomotor nerve.
      2. Cardiovascular system
         1. All opioids except meperidine produce minimal changes in cardiac contractility. Baroreceptor reflexes are preserved.
         2. Systemic vascular resistance (SVR) usually is moderately reduced because of reduced medullary sympathetic outflow. Bolus doses of meperidine or morphine may reduce SVR secondary to histamine release.
         3. Produce bradycardia in a dose-dependent manner by the stimulation of the central vagal nuclei. Meperidine has a weak atropine-like effect and does not cause bradycardia.
         4. The relative hemodynamic stability offered by opioids often leads to their use in sedation or anesthesia for hemodynamically compromised or critically ill patients.
      3. Respiratory system
         1. Produce dose-dependent respiratory depression. RR decreases initially; TV decreases with larger doses. The effect is accentuated in the presence of sedatives, other respiratory depressants, or preexisting pulmonary disease.
         2. Decrease ventilatory response to hypercapnia and hypoxia. Effects are markedly increased if the patient falls asleep.
         3. Opioids dose dependently decrease the cough reflex. Higher doses suppress tracheal and bronchial foreign body reflexes, so endotracheal intubation and mechanical ventilation are better tolerated.
      4. Gastrointestinal system
         1. Decrease gastric emptying and intestinal secretions. Colonic tone and sphincter tone increase and propulsive contractions decrease, resulting in constipation.
         2. Increase biliary pressure and may produce biliary colic; the spasm of the sphincter of Oddi may prevent cannulation of the common bile duct. The incidence is lower with agonist-antagonist opioids.
   4. Dosage and administration. Opioids are usually administered IV, either by bolus or by infusion. Appropriate dosages are presented in Table 12.2. Clinical dosing must be individualized and based on the patient’s underlying condition and clinical response. Larger doses may be required in patients chronically receiving opioids. Opioids are also routinely utilized in neuraxial anesthesia techniques to optimize pain control.
   5. Adverse effects
      1. Allergic reactions are rare, although anaphylactoid reactions may occur with morphine and meperidine secondary to histamine release.
      2. Drug interactions. The administration of meperidine or tramadol is contraindicated in patients taking monoamine oxidase inhibitor, as it may precipitate serotonin syndrome (clonus, hyperthermia, agitation).
      3. Nausea and vomiting can occur because of the direct stimulation of the chemoreceptor trigger zone. Nausea is more likely if the patient is moving.
      4. Muscle rigidity may occur, especially in the chest, abdomen, and upper airway, resulting in the inability to ventilate the patient. The incidence increases with drug potency, dose, rate of administration, and presence of nitrous oxide. Rigidity may be reversed by administering neuromuscular relaxants or opioid antagonists and is less likely after pretreatment with a benzodiazepine or propofol.
      5. Urinary retention may occur because of increased tone in the vesical sphincter and inhibition of the detrusor (voiding) reflex. May also decrease awareness of the need to urinate.
   6. Naloxone is a pure opioid antagonist used to reverse unanticipated or undesired opioid-induced effects such as respiratory or CNS depression.
      1. Mode of action. Competitive antagonist at opioid receptors in the brain and spinal cord.
      2. Pharmacokinetics
         1. Peak effects are seen within 1 to 2 minutes; a significant decrease in its clinical effects occurs after 30 minutes because of redistribution.
         2. Metabolized in the liver.
      3. Pharmacodynamics
         1. Reverses the pharmacologic effects of opioids such as CNS and respiratory depression.
         2. Crosses the placenta; administration to the parturient before delivery will decrease opioid-induced respiratory depression in the neonate.
      4. Dosage and administration. Perioperative respiratory depression in an adult can be treated with 0.04 mg IV every 2 to 3 minutes as needed. Repeated administration may be necessary due to short duration of action.
      5. Adverse effects
         1. May lead to the abrupt onset of pain as opioid analgesia is reversed. This may be accompanied by sudden hemodynamic changes (eg, hypertension and tachycardia).
         2. May precipitate pulmonary edema and cardiac arrest in rare cases.