Anesthesia Drugs

Naloxone is a competitive antagonist at opioid receptors, particularly the mu class. There is no significant agonist activity. Naloxone is indicated in cases of narcotic overdose. Respiratory depression secondary to narcotic overdosage is rapidly reversed with naloxone (1–2 minutes). Care should be taken to titrate low doses as abrupt reversal of analgesia can result in abrupt sympathetic stimulation and acute withdrawal symptoms in those who are opioid dependent. Naloxone has a short duration of action (30–40 minutes) and redosing is usually required when reversing long-acting opioids.

Dosing: 0.5–1 ␮g/kg every 5–10 minutes; maximum total dose of 10 mg ◆

Benzodiazepines

Benzodiazepines interact with specific receptors in the CNS that enhance the action of specific neurotransmitters ( Table 1.13 ). In particular, the action of gabapentin (GABA), an inhibitory neurotransmitter, is enhanced. As a result, benzodiazepines produce amnesia, anxiolysis, sedation, and prevent seizures. Benzodiazepines have no direct analgesic properties. Like barbiturates, benzodiazepines are highly protein-bound and rely on redistribution for their offset of action. Biotransformation of benzodiazepines occurs in the liver and metabolites are excreted mainly in the urine. Duration of action may be prolonged in patients with renal failure as metabolites are pharmacologically active.

Table 1.12 Opioid Receptors

Receptor Physiological Characteristics

Mu ␮1 receptor is responsible for producing analgesia, miosis, nausea/

vomiting, urinary retention, and pruritus.

The endogenous stimulus for ␮1 receptors are enkephalins.

␮2 receptor activation leads to euphoria, respiratory depression, sedation, bradycardia, ileus, and physical dependence.

Delta Activation leads to analgesia and contributes to physical dependence.

These receptors are highly selective for endogenous enkephalins.

Kappa Activation leads to analgesia, sedation, dysphoria, and psychomi- metic effects.

Pure Kappa agonists do not lead to respiratory depression.

Stimulation leads to vasopressin release and subsequent diuresis.

Sigma Activation leads to dysphoria, hallucinations, tachypnea, and mydriasis.

Diazepam

Diazepam is insoluble in water and requires propylene glycol, which may cause venous irritation. Diazepam has a long duration of action secondary to slow hepatic extraction and a large volume of distribution. The elimination half-life is nearly 30 hours.

Dosing: 5–20 mg orally (PO), 2–10 mg IV Midazolam

At low pH, midazolam is water soluble. At physiologic pH, midazolam becomes more lipid soluble resulting in fast onset of action. Midazolam has the shortest elimination half-life (2 hours) because of a high hepatic extraction ratio. Mida- zolam’s high potency and steep dose response curve require careful titration and close monitoring of respiration as even small doses can lead to apnea.

Dosing: Adult 3–5 mg IM, 0.5–5 mg IV; pediatric 0.025–0.1 mg/kg IV;

0.25–0.5 mg/kg PO 30 minutes before procedure Lorazepam

Like diazepam, lorazepam is insoluble in water and requires propylene glycol, which may cause venous irritation when administered. Because of Table 1.13 Benzodiazepine Effects on Organ Systems

Organ System Physiologic Response

Cardiovascular Minimal depression of the cardiovascular system even at high doses.

Slight decreases in arterial blood pressure, cardiac output, and peripheral vascular resistance are often observed.

Midazolam decreases arterial blood pressure and peripheral vascular resistance more than lorazepam or diazepam.

Variability in heart rate during administration suggests that Midazolam has vagolytic properties.

Respiratory Ventilatory response to CO₂ is reduced with benzodiazepine administration. This response is particularly pronounced when administered with other respiratory depressants, such as opioids.

Neurologic Benzodiazepines are very effective in seizure prophylaxis.

Cerebral oxygen consumption and cerebral blood flow are reduced.

Drug interactions When administered with opiates, benzodiazepines work synergistically to depress ventilation.

When administered with heparin, diazepam is displaced from its protein binding sites causing an increased free drug concentration.

The MAC of volatile anesthetics is reduced up to 30%. CNS depressants such as alcohol and barbiturates potentiate the sedative effects of benzodiazepines.

Abbreviations: CNS, central nervous system; MAC, minimum alveolar concentration.

its moderate lipid solubility lorazepam has a slower onset of action secondary to slower brain uptake. The lower lipid solubility of lorazepam limits its volume of distribution and decreases its elimination half-life (15 hours) despite the same hepatic extraction ration of diazepam.

Dosing: Adult 1–4 mg PO/IM/IV; pediatric 0.05 mg/kg PO/IM/IV preoperatively

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Benzodiazepine Reversal

Flumazenil

Flumazenil is a specific benzodiazepine receptor antagonist that reverses most of the effects of benzodiazepines. Onset is rapid (⬍1 minute) for the hypnotic effects of benzodiazepines. The amnestic effect is less reliably reversed. This agent is a competitive inhibitor at the benzodiazepine receptor.

Elderly patients in particular are prone to resedation and should be observed for respiratory depression after flumazenil administration.

Dosing: 0.2 mg (titrate every minute until desired degree of sedation reversal is observed). Sedation reversal typically requires 0.6–1.0 mg. Infusions at 0.5 mg/h are indicated for overdoses of long-acting benzodiazepines.

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Alpha-2 Agonists

Dexmedetomidine

Dexmedetomidine (brand name Precedex, Hospira, Inc., Lake Forest, IL) is an ␣2 agonist with 8 to 10 times greater receptor affinity than clonidine. It has sym- patholytic, analgesic, and sedating properties. The effect on the cardiovascular system is to lower heart rate and blood pressure, blunting the typical surgical response. ␣2 Agonists have minimal respiratory depression. Head and neck surgeons will find this drug useful for conscious sedation cases, augmented sleep studies, and fiberoptic intubations and tracheotomy placement. Also of interest to the otolaryngologist who employs the use of topical cocaine intra- operatively, recent research has suggested dexmedetomidine to be an effective treatment for the dangerous cardiovascular symptoms of cocaine intoxication.

Dosing: Loading dose of 1 ␮g/kg over 10 minutes followed by IV infusion at 0.2–0.7 ␮g/kg per hour

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Anesthesia Induction Medications

Propofol

Propofol is a rapidly acting induction agent, which produces unconsciousness within 30 seconds of dosing and effects last between 2 to 8 minutes ( Table 1.14 ). Propofol enhances the inhibitory action of GABA. Propofol is metabolized in the liver; however, offset of action results from redistribution, which is rapid secondary to high lipid solubility. Compared with other induction agents, propofol provides a faster recovery with less “hangover”

than barbiturates or etomidate. Additionally, this agent has antiemetic, antipruritic and anticonvulsion properties. At low (subhypnotic) doses (10–15 mg) propofol can ameliorate nausea and vomiting. Propofol does not provide analgesia, but does enhance the analgesic effects of narcotics.

Careful titration is advised in hypovolemia or coronary vascular disease, as propofol can lead to a profound decrease in blood pressure secondary to decreased systemic vascular resistance. Venous irritation with administration can be avoided with concomitant administration of lidocaine (20–80 mg).

Because propofol is an emulsion it should be avoided in patients with disor- ders in lipid metabolism.

Dosing: Induction 2–2.5 mg/kg IV (pediatric dosing: 2.5–3.5 mg/kg); infusion 100–200 ␮g/kg per minute; sedation 25–75 ␮g/kg per minute Etomidate

Etomidate depresses the reticular activation system by binding to the GABA receptors and enhancing the inhibitory effects of this neurotransmitter ( Table 1.15 ). Etomidate is dissolved in propylene glycol leading to pain on injection. This can be reduced by injecting lidocaine prior to induction.

Myoclonic movements are common after etomidate induction. Etomidate is characterized by a rapid onset secondary to high lipid solubility at physiologic pH. Etomidate is metabolized into inactive end products by hepatic microsomal enzymes and plasma esterases. Metabolites are excreted in the urine. Etomidate has very little effect on the cardiovascular system and is therefore the induction agent of choice in cardiovascular disease and severe hypovolemia.

Dosing: induction 0.2–0.6 mg/kg Ketamine

Ketamine has multiple effects through the CNS and has been demonstrated to be an N -methyl- ^D-aspartate (NMDA) antagonist ( Table 1.16 ). By ef- fectively “disconnecting” the thalamus from the limbic system, a state of

“dissociative anesthesia” results. In this state the patient appears conscious, Table 1.14 Effects of Propofol on Organ Systems

Organ System Physiologic Response

Cardiovascular Increased peripheral vasodilatation, decreased cardiac contractility, and decreased preload combine to cause hypotension.

The normal vagal response to hypotension is also impaired.

The hypotension with propofol is greater than that produced by barbiturates.

Respiratory Respiratory depression

Central nervous system Reduced intracranial pressure by reducing cerebral blood flow

but is unable to process or respond to sensory stimulation. Ketamine is a structural analogue to phencyclidine (PCP), and as with PCP, hallucinations can ensue even at low doses. Ketamine is metabolized in the liver, resulting in pharmacologically active metabolites (norketamine). Products of hepatic metabolism are renally excreted.

Dosing: 1–2 mg/kg IV; 3–5 mg/kg IM

Table 1.15 Effects of Etomidate on Organ Systems Organ System Physiologic Response

Cardiovascular Slight decrease in peripheral vascular resistance leads to slight decrease in arterial blood pressure.

Myocardial contractility and cardiac output are unchanged.

Respiratory Ventilation is reduced less than with other induction agents.

Even at induction doses, apnea usually does not occur unless opioids are also administered.

Central nervous system Cerebral metabolic rate, cerebral blood flow, and intracranial pressure are reduced.

Due to cardiovascular stability, cerebral perfusion pressure is maintained.

Etomidate lacks analgesic properties.

Endocrine Transient inhibition of enzymes responsible for cortisol and aldosterone synthesis occurs with intubation doses.

Long-term infusions lead to adrenocortical suppression.

Table 1.16 Effect of Ketamine on Organ Systems Organ System Physiologic Response

Cardiovascular Increased cardiac output, heart rate, and blood pressure secondary to increased sympathetic outflow Respiratory Minimally effects ventilatory drive

Ketamine is a potent bronchodilator and has benefits to patients with asthma.

Increased salivation can be resolved by pretreatment with anticholinergic medications.

Central nervous system Increased cerebral blood flow, cerebral oxygen consumption, and intracranial pressure Hallucinations, delirium, and disturbing dreams are decreased in children and those who receive benzodiazepines prior to ketamine.

Ketamine produces analgesia, amnesia, and unconsciousness.

Barbiturates

Barbiturates have several sites of action resulting in suppression of excit- atory neurotransmitters and activation of the inhibitory effects of GABA.

The result is inhibition of the reticular activation system. Methohexital and thiopental are the commonly used barbiturates used for induction. As more titratable induction agents have come into use, barbiturates have fallen out of favor. Barbiturates have no analgesic properties and cause dose-related depression of the respiratory, cardiac, and central nervous systems. Thiopen- tal has a short duration of action secondary to a high rate of redistribution from the brain to inactive tissues, which secondary to a high lipid solubility.

Barbiturates are contraindicated in patients with intermittent porphyria.

Side effects include venous irritation, myoclonus, and hiccupping.

Dosing: Thiopental 3–6 mg/kg IV; methohexital 1–2 mg/kg IV ◆

Inhaled Anesthetics

In the OR, general anesthesia is commonly maintained with inhaled anesthetics. These agents also provide some analgesia, amnesia, and muscle relaxation. In pediatric patients in whom there is no IV access, anesthesia may be induced by inhalation. All of the inhaled anesthetics, with the exception of nitrous oxide, are bronchodilators and may be useful in those with reactive airways. Most inhaled agents reduce blood pressure.

The onset of anesthetic induction as well as emergence from anesthesia is based on the lipid solubility characteristics of the inhaled anesthetic:

the more insoluble the anesthetic agent, the faster the induction of anesthesia. The agents with high lipid solubility prolong the emergence from anesthesia.

Minimum alveolar concentration (MAC) is defined as the alveolar concentration at which 50% of test subjects will not respond to a surgical stimulus.

Dosing of inhaled agents is based on the MAC of each particular agent. The MAC of inhaled agents depends on the individual gas properties of each agent. MAC is additive such that ½ MAC isoflurane combined with ½ MAC nitrous oxide is equivalent to one MAC of sevoflurane.

Isoflurane

Compared with other inhaled anesthetics (sevoflurane, desflurane), isoflurane has a relatively high lipid solubility, leading to increased induction and emergence time. Isoflurane causes minimal cardiac depression and decreased blood pressure secondary to decreased systemic vascular resistance.

Like other volatile anesthetics, isoflurane causes respiratory depression with a decrease in minute ventilation ( Table 1.17 ). Despite its ability to cause airway irritation, isoflurane induces bronchodilation.

Desflurane

Other than the substitution of a fluoride atom for a chloride atom, the structure of desflurane is very similar to that of isoflurane. This composi- tion makes desflurane highly insoluble. Because of its low lipid solubility,

induction and emergence from anesthesia are rapid. The time required for patients to awaken is approximately half as long as that observed follow- ing isoflurane administration. Desflurane has cardiovascular and cerebral effects similar to those of isoflurane. Like isoflurane this agent is irritating to the airway making gas induction difficult.

Sevoflurane

Sevoflurane is the primary inhaled anesthetic agent used in anesthesia induction when an IV induction cannot be performed, such as in pediatric patients. Nonpungency and a rapid increase in alveolar anesthetic concentration make it an excellent choice where inhalational induction is necessary. The blood solubility of sevoflurane is slightly greater than that of desflurane. Sevoflurane mildly depresses myocardial contractility and systemic vascular resistance. Arterial blood pressure declines slightly less than with isoflurane or desflurane. Like isoflurane and desflurane, sevoflurane causes slight increases in cerebral blood flow and intracranial pressure.

Nitrous Oxide

The uptake and elimination of nitrous oxide are relatively rapid compared with other inhaled anesthetics. This is the result of its low blood–gas parti- tion coefficient. Nitrous oxide produces analgesia, amnesia, mild myocardial depression, and mild sympathetic nervous system stimulation. It does not significantly affect heart rate or blood pressure. Nitrous oxide is a mild respiratory depressant, although less so than the volatile anesthetics. The elimination of nitrous oxide is via exhalation.

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Muscle Relaxation

Neuromuscular blocking agents are used most commonly for facilitation of endotracheal intubation and when patient movement is detrimental to Table 1.17 Physiologic Effects of Isoflurane

Organ System Physiologic Response

Cardiovascular Decreased systemic vascular resistance leads to lower arterial blood pressure.

Respiratory Can cause airway irritation and cause bronchodilation Respiratory depression

Neurologic At high concentrations, increased cerebral blood flow and intracranial pressure can develop.

Decreased cerebral metabolic oxygen requirements may provide cerebral protection.

Neuromuscular Skeletal muscle blood flow is increased.

Renal Decreases renal blood flow, glomerular filtration rate, and urinary output.

the surgical procedure. Prior to administration, ventilation must be ensured by the anesthesiologist. Ventilation can be achieved with a mask until the endotracheal tube is placed in the trachea. Neuromuscular blockers have no intrinsic sedative or analgesic properties and must be used in concert with anesthetic agents. Inadequate sedation and hypnosis while using neuromuscular blockers can produce recall by patients causing long-term side effects. There are two classifications of neuromuscular blocking agents:

depolarizing and nondepolarizing.

Depolarizing Muscle Relaxants

Depolarizing agents have a similar chemical structure to acetylcholine. They induce paralysis by binding to acetylcholine receptors at the skeletal muscle neuromuscular junction causing depolarization. Paralysis ensues because these agents have a higher affinity for the postsynaptic receptor preventing the reestablishment of its ionic gradient. Clinically, fasciculations are seen prior to relaxation after dosing. The only medication in this class that is still in use today is succinylcholine ( Table 1.18 ).

Nondepolarizing Muscle Relaxants

Nondepolarizing muscle relaxants induce paralysis by binding to the postsynaptic receptor at the skeletal muscle neuromuscular junction. Es- sentially, these medications compete with acetylcholine for binding sites Table 1.18 Depolarizing Muscle Relaxant

Agent Intubating Dose,

Onset, Duration Clinical Considerations Succinylcholine Dose: 1–1.5 mg/kg

Onset: 30–60 s Duration: ⬍10 min Maximum: 150 mg total dose

Succinylcholine is contraindicated for routine intubation in pediatric patients because of the risk of cardiac arrest with hyperkalemia in those with undiagnosed myopathies.

Agent of choice for rapid sequence induction.

Bradycardia can follow dosing, particularly in pediatric patients.

Fasciculations with receptor activation typically occur and can result in myalgias postop.

Potassium release with succinylcholine-induced depolarization can increase by 0.5 mEq/dL. Avoid in hyperkalemic patients.

Transient increases in intracranial and intraocular pressure Avoid in patients with a history of malignant hyperthermia

Metabolized by pseudocholinesterase

at the receptor. Unlike depolarizing blockade, the postsynaptic receptors are not activated and fasciculations do not occur. Nondepolarizing blockade can be reversed by increasing the acetylcholine concentration at the neuromuscular junction. This is achieved by administration of medications such as neostigmine, which prevent the breakdown of acetylcholine. The commonly used nondepolarizing agents are summarized in Table 1.19 .

Further Reading

1.4 Anesthesia

1.4.3 Anesthesia Drugs

Further Reading

Reversal of Opioids

Benzodiazepines

Benzodiazepine Reversal

Alpha-2 Agonists

Anesthesia Induction Medications

Inhaled Anesthetics

Muscle Relaxation

Further Reading