Historically used Agents

6.15.5.1.1 Diethyl ether

Diethyl ether (Figure 1) is a potent anesthetic whose actions are accompanied by analgesic and muscle relaxant activity. It has a long induction period and is highly flammable and explosive.

6.15.5.1.2 Chloroform

Chloroform (Figure 1) is a halogenated hydrocarbon that, unlike ether, is not flammable but has significant toxicity, including carcinogenicity, hepato-, and nephrotoxicity.

6.15.5.1.3 Barbiturate anesthetics

Barbiturate anesthetics include sodium thiopental, thiamylal, and methohexital (Figure 1). While these agents have demonstrated enantioselective effects, they are typically used as racemates. Thiopental (3-5mgkg— 1) induces anesthesia within 30 s, with a duration of 5-8 min. Barbiturates reduce cerebral metabolism leading to decreases in cerebral blood flow and intracranial pressure. They also produce respiratory depression and can elicit dose-dependent decreases in blood pressure.

6.15.5.1.4 Cyclopropane

Cyclopropane (Figure 1) was discovered as a contaminant of propylene that was being investigated for its anesthetic potential in 1928. Like ether, it is an explosive gas and has been largely replaced by newer generations of inhaled anesthetic.

6.15.5.2 Currently used Anesthetics

6.15.5.2.1 Inhalation anesthetics

6.15.5.2.1.1 Nitrous oxide

Nitrous oxide (Figure 1) is an inorganic, nonflammable gas. It boils at — 88 °C with low solubility and results in rapid induction or awakening. It is a weak anesthetic, producing reliable surgical anesthesia only in hyperbaric conditions, and is used to supplement other inhalation agents. High concentrations of nitrous oxide increase the alveolar concentration of simultaneously administered gases - the second-gas effect. At 70% nitrous oxide, the MAC for other inhalation anesthetics can be reduced by 60%. Nitrous oxide does not inhibit the hypoxic pulmonary vasoconstriction response in the lungs nor produce skeletal muscle relaxation. It is a sympathomimetic and increases systemic vascular resistance. Nitrous oxide diffuses into air-containing cavities more than 30 times faster than nitrogen leaves, causing dangerous accumulation of volume and increase in pressure in closed spaces, e.g., bowel, middle ear, and pneumothorax. In patients with ileus, the volume of air in the bowel can double within 4h of nitrous oxide administration. The maximum dose of nitrous oxide should not exceed 70%, to avoid the occurrence of hypoxemia. It may produce its effects via interactions with the NMDA receptor.9 Nitrous oxide has significant analgesic properties at subanaesthetic concentrations, hence its application in the treatment of dental and labor pain while the patients remain conscious.

6.15.5.2.1.2 Halothane

Halothane (Figure 1) is a nonflammable halogenated alkene with a blood/gas coefficient of 2.3 and an MAC in 100% oxygen of 0.74 and 0.29 in 70% nitrous oxide. Halothane has superior hypnotic activity but lacks analgesic properties. Induction of anesthesia is rapid and can be achieved by using 1-3% halothane in air or oxygen, or by using 0.8% halothane in 65% nitrous oxide. Halothane produces a dose-dependent reduction (20-25%) in arterial blood pressure at its MAC and increases cerebral blood flow, raising intracranial pressure. It has no effect on systemic vascular resistance but causes myocardial depression and has negative inotropic actions. It sensitizes the myocardium to the arrhythmogenic effects of epinephrine. Halothane can elicit malignant hyperthermia, a hypermetabolic, condition that is potentially lethal. It does not cause coronary artery vasodilatation and therefore does not lead to coronary artery steal syndrome. Halothane hepatitis and hepatic necrosis are complications of halothane anesthesia that occur in 1 in 6,000-35,000 cases and can be fatal.

6.15.5.2.1.3 Isoflurane

Isoflurane (Figure 1) is a nonflammable halogenated methyl ethyl ether with a blood/gas coefficient of 1.4 and the MAC in 100% oxygen of 1.15 and in 70% nitrous oxide of 0.50. Induction of anesthesia is achieved with 3-4% isoflurane in air or in oxygen, or 1.5-3% in 65% nitrous oxide. It is administered following induction due to its pungent odor. The use of isoflurane alone can lead to coughing and apneic periods and it is therefore used in combination with intravenous anesthetics. Emergence from anesthesia with isoflurane is faster than with halothane or enflurane. Isoflurane produces a dose-dependent reduction in arterial blood pressure due to peripheral vasodilatation but has no effect on cardiac output. It increases cerebral blood flow, and may raise intracranial pressure, but this effect is much less potent than with halothane. Isoflurane does not sensitize the myocardium to produce arrhythmias. Coronary artery vasodilatation can lead to coronary artery steal; however, this does not appear to be a significant clinical problem. Like halothane, isoflurane can trigger malignant hyperthermia.

6.15.5.2.1.4 Enflurane

Enflurane (Figure 1) is a nonflammable fluorinated ethyl methyl ether with a blood/gas coefficient of 1.8. The MAC in 100% oxygen is 1.68 and that in 70% nitrous oxide is 0.57. Induction of anesthesia is achieved by using 3-4% enflurane in air or in oxygen or 1.5-3% in 65% nitrous oxide. It is used as a maintenance, rather than an induction, agent. Enflurane enhances the action of paralyzing agents more than other inhalation anesthetics and produces a dose-dependent reduction in arterial blood pressure due to its negative inotropic effects. Enflurane does not sensitize the heart and does not elicit coronary artery steal. Enflurane can increase intracranial pressure and, especially in combination with hyperventilation, increases the risk of seizure activity. Like other inhalation anesthetics, it can also trigger malignant hyperthermia. Emergence from anesthesia with enflurane is somewhat slower than with isoflurane.

6.15.5.2.1.5 Sevoflurane

Sevoflurane (Figure 1) is a nonflammable fluorinated isopropyl ether with a blood/gas coefficient of 0.59. The MAC in 100% oxygen is 1.71 and that in 63% nitrous oxide is 0.66. Sevoflurane reacts with carbon dioxide absorbents to form the haloalkene, compound A, that has been linked to renal injury in some studies, but not in others. Sevoflurane dose-dependently decreases arterial blood pressure due to peripheral vasodilatation. It is considered superior to isoflurane and halothane for inhalant anesthetic induction as its low blood solubility results in rapid induction of anesthesia without intravenous anesthetic use, with a concomitant rapid recovery that favors its use in the outpatient situation. Sevoflurane causes less airway irritation, resulting in less coughing and excitation during induction. It can be used without intravenous anesthetics.

6.15.5.2.1.6 Desflurane

Desflurane (Figure 1) is a nonflammable fluorinated ether derivative with a blood/gas coefficient of 0.42. The MAC in 100% oxygen is 6.0 and in 60% nitrous oxide is 2.8. Unlike other inhalation anesthetics, desflurane requires the use of electrically heated rather than standard vaporizers. Its low tissue solubility results in rapid elimination and awakening. Desflurane evokes a dose-dependent reduction in arterial blood pressure due to peripheral vasodilatation. Desflurane can cause coughing and is not used without intravenous anesthetics.

Xenon is an inert gas that produces rapid induction and recovery due to its insolubility in blood and tissues and has minimal side effects.47'48 Its status as an inert gas limits its availability and it is expensive. It is not approved for use in the US.

6.15.5.2.2 Parenteral anesthetics

6.15.5.2.2.1 Propofol

Propofol (Figure 2) has a similar anesthetic profile to that of thiopental; however, it is distinguished by having a much larger clearance (propofol clearance is greater than liver blood flow, while thiopental clearance is much smaller than liver blood flow), and is therefore much shorter-acting when given in repetitive boluses or by constant infusion. It is the most commonly used parenteral anesthetic in the US. Propofol infusion (25-300 mgkg_ 1 min _ 1) is commonly used for procedural sedation and for the maintenance of general anesthesia. Propofol acts at least in part by blocking Nav channels.

6.15.5.2.2.2 Ketamine

Ketamine (Figure 2) is an arylcyclohexylamine congener of phencyclidine. While used as a racemate, its S-isomer is a more potent anesthetic with fewer side effects. Ketamine is a dissociative anesthetic, producing a hypnotic state distinct from that of other parenteral anesthetics that is reminiscent of cataplexy, in addition to being an efficacious analgesic. It also increases blood pressure, cerebral blood flow, and intracranial pressure, effects that can be attenuated by coadministration of BZs or thiopental. Individuals treated with ketamine do not respond to verbal commands and have amnesia. At the same time they are able to breathe spontaneously and keep their eyes open, a situation that is accompanied by nystagmus, salivation, and lacrimation. Ketamine can be given via the oral, rectal, and intramuscular as well as intravenous routes. Emergence from ketamine anestheia is frequently accompanied by hallucinations and symptoms of delirium. Mechanistically, ketamine acts as a modulator of the NMDA receptor and can also block monoamine uptake, leading to indirect sympathomimetic activity.

6.15.5.2.2.3 Etomidate

Etomidate (Figure 2) is a substituted imidazole that is used in the form of its active D-isomer. Etomidate has the fewest cardiovascular side effects of any of the intravenous anesthetics, producing no cardiac depression and having little or no direct effect on peripheral vascular resistance. It is frequently considered the intravenous induction agent of choice for patients with hypovolemia, myocardial depression, and other forms of cardiovascular instability. Myoclonic jerking may be seen following administration, more commonly than with thiopental or propofol. A single induction dose of etomidate inhibits the biosynthesis of cortisol, thereby preventing the adrenocortical stress response. Cortisol plasma levels remain normal, but do not rise in response to surgery as would ordinarily occur. Inhibition of cortisol biosynthesis by etomidate has not been shown to be harmful, except when etomidate was infused (e.g., for sedation in the intensive care unit) continuously for days, resulting in Addisonian crisis in some patients.

6.15.5.2.2.4 Alphaxalone

Alphaxalone (Figure 2) is a steroid anesthetic, a neurosteroid, used for short-term anesthesia that is similar in its effects to barbiturates but has a wider margin of safety than barbiturates and produces less apnea on induction. It produces its anesthetic effects via interactions with a neurosteroid binding site on the GABAa receptor. It is primarily used in for veterinary surgery being given together with alphadolone (Figure 2). The latter was initially used to improve the solubility of alphaxalone in the excipient, Cremophor, but was subsequently found to have anesthetic activity on its own. The alphaxalone/alphadolone was withdrawn from human use in the 1980s because of major anaphylactic reactions to Cremophor.

6.15.5.2.3 Local anesthetics

Local anesthetics (Figure 3) produce their effects by blocking Nav channels in the neuronal membrane, thus preventing nerve impulse generation and conduction.13

6.15.5.2.3.1 Cocaine

Cocaine is an effective blocker of nerve impulse conduction and, as such, an efficacious local anesthetic. However, it is a potent and highly addictive stimulant due to its ability both to stimulate dopamine release and block its reuptake.

6.15.5.2.3.2 Procaine

Procaine is the first synthetic local anesthetic and was introduced into use in 1905. It has been replaced by newer generations of local anesthetics, its use being reserved for infiltration anesthesia and diagnostic nerve blocks.

6.15.5.2.3.3 Lidocaine

Lidocaine is an aminoethylamide that is superior to procaine in its speed to onset, intensity, extensiveness, and duration of effect. It is used in a patch formulation for the treatment of the pain associated with postherpetic neuralgia and is also used as an antiarrhythmic agent. Lidocaine has been extensively used for spinal anesthesia when relatively short duration is required. However, spinal administration of lidocaine has been associated with nerve root irritation (transient radicular irritation), the mechanism of which is not well understood, resulting in the reluctance of many anesthesiologists to continue using lidocaine for spinal anesthesia. Lidocaine continues to be widely used for peripheral nerve block, infiltration, and epidural block.

6.15.5.2.3.4 Bupivacaine

Bupivacaine is a butyl piperidine amide anesthetic that has a long duration of action that is widely used during labor and postoperative pain. It is much more cardiotoxic than lidocaine. Overdosage of bupivacaine can produce intractable cardiac arrest from ventricular tachycardia or fibrillation due to tight binding to cardiac sodium channels. Ropivacaine and levobupivacaine (Figure 3) were developed in an attempt to find a local anesthetic with long duration similar to bupivacaine but with less cardiotoxicity. All of the amide local anesthetics except for lidocaine contain an asymmetric carbon, and the (S)-enantiomer of the cardiotoxic amide local anesthetics, such as bupivacaine, appears to be somewhat less cardiotoxic than the R-enantiomer. Bupivacaine is typically used as the racemate. The (S)-enantiomer of bupivacaine (levobupivacaine; Figure 3) and the (S)-enantiomer of propivacaine (ropivacaine) appear to be somewhat less cardiotoxic than bupivacaine.

6.15.5.2.3.5 Other local anesthetics

Other local anesthetics include articaine, chloroprocaine, etidocaine, mepivacaine, prilocaine, and ropivicaine (Figure 3). Their use is mainly dictated by differences in their pharmacokinetic profiles, potency of motor blockade, and cardiac toxicity.

6.15.5.3 Anesthetic Adjuvants

Anesthetic adjuvants or adjuncts are given together with general anesthetics to reduce the doses of the latter and result in reduced side effects.

6.15.5.3.1 Benzodiazepines

BZs (e.g., midazolam, diazepam, lorazepam; Figure 4) produce anesthesia similar to the barbiturates but are limited in this use due to the potential for prolonged sedation and amnesia, unless this is desired. They are used as adjuncts prior to induction with their anxiolytic, amnestic, and sedative effects providing patient benefit. Midazolam has a pharmacokinetic advantage over other BZs with sedative doses (0.10-0.07mgkg_ 1 intravenously) that have a peak effect in 2 min that is sustained for approximately 30 min. The incidence of thrombophlebitis following intravenous administration of midazolam is much lower compared to diazepam because of the pH-dependent ring opening of the diazepine ring of midazolam. At low pH, the diazepine ring is in the open form, resulting in greater water solubility and suitable for formulation in an aqueous vehicle. By contrast, highly lipid-soluble diazepam is commonly formulated in propylene glycol, an irritating vehicle that results in a high rate of thrombophlebitis. Once midazolam is injected, physiologic pH results in predominance of the closed form of the diazepine ring, and greatly increased lipid solubility, suitable for crossing the blood-brain barrier.

6.15.5.3.2 Analgesics

Ketamine (Figure 2) and nitrous oxide (Figure 1) are the only general anesthetics with significant analgesic activity. As a result, analgesics are typically coadministered with anesthetic agents to reduce anesthetic dose and to minimize hemodynamic and nociceptive responses to painful stimuli. The latter is termed preemptive analgesia. In surgical procedures, pain often persists long after the procedure. The introduction of an analgesic regimen, e.g., opioid or nonsteroidal anti-inflammatory drug (NSAID: ketoprofen; Figure 4), before the surgical procedure has been shown in some instances to prevent the sensitization or 'wind-up' of the nervous system to noxious stimuli, reducing the pain cascade. Intravenous opioids, novel analgesics like adenosine, H1 antagonists like doxepine (Figure 4), local anesthetic infiltration, NSAIDs and nerve, subarachnoid, and epidural block can reduce the pain following surgery, thus decreasing the recovery period. Parenteral opioids used as anesthetic adjuncts include the m-opioid agonists fentanyl, sufentanil, alfentanil, remifentanil, meperidine, and morphine (Figure 3), with sufentanil being the most potent. The choice between these opiods is generally based on their duration of action. The duration of action of remifentanil is ultrashort, being approximately 10 min, and rapid clearance takes place by ester hydrolysis. Remifentanil is an example of successful rational drug design. Modeled after several other ester drugs with extremely rapid clearance due to ester hydrolysis (e.g., succinylcholine, esmolol), a series of fentanyl ester analogs were synthesized with the intent of discovering a fentanyl ester analog with potent opioid activity that would be rapidly cleared to an inactive metabolite. Remifentanil was chosen for development from the series, and has proven to be an extremely valuable opioid in anesthetic practice.

6.15.5.3.3 a2-Adrenoceptor agonists

Dexmedetomidine (Figure 4) is an imidazole-based, short-acting a2-adrenoceptor agonist modestly selective for the a2A adrenoceptor that is used in the intensive care setting to sedate critically ill adults. It has associated analgesic and anxiolytic effects.49'50 Dexmedetomidine does not produce respiratory depression; its main side effects are hypotension, bradycardia, and nausea.49

6.15.5.3.4 Neuromuscular blockers

Muscle relaxants, e.g., succinylcholine (Figure 4), are used during anesthetic induction to relax the muscles of the jaw, neck, and airways to facilitate laryngoscopy and endotracheal intubation, or for relaxation of thoracic, abdominal, hip, or shoulder muscles to facilitate surgical exposure. Mivacurium and rocuronium (Figure 4) are newer myorelaxants in development; the former has a short half-life due to its esterase susceptibility.51

6.15.6 Unmet Medical Needs

While major strides have been made in understanding the mechanisms through which general, parenteral, and local anesthetics produce their beneficial effects, there still remains an unmet medical need in terms of the differing side effects of the various agents in current use which have been outlined above. The therapeutic index of general or

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