Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

system effects and induce a plateau of central depression less than that required for a true anesthetic state. Large doses of benzodiazepines can prolong the postanesthetic recovery period (an undesirable effect), but they can produce a high incidence of anterograde amnesia which is clinically useful. Because it causes a high incidence of amnesia (> 50%), midazolam is frequently given intravenously before induction of general anesthesia. Midazolam has a more rapid onset, a shorter elimination half-life (2–4 hours), and a steeper dose-response curve than do the other benzodiazepines used in anesthesia.

The benzodiazepine antagonist flumazenil is sometimes used to accelerate recovery from excessive sedative actions of intravenous benzodiazepines, but reversal of respiratory depression by flumazenil is less predictable. Its short duration of action (< 90 minutes) may necessitate multiple doses to prevent recurrence of central nervous system depressant effects of longer-acting benzodiazepines.

Opioid Analgesics

Large doses of opioid analgesics have been used to achieve general anesthesia, particularly in patients undergoing cardiac surgery or other major surgery when their circulatory reserve is minimal. Intravenous morphine, 1–3 mg/kg, or the high-potency opioid fentanyl, 100–150 g/kg, have been used in such situations with minimal evidence of cardiovascular deterioration. More recently, several congeners of fentanyl, namely sufentanil, alfentanil, and remifentanil, have also been used. Despite the use of high doses of these potent opioids (see Table 31–2 for conventional analgesic doses), awareness during anesthesia and unpleasant postoperative recall have occurred.

Furthermore, high intravenous doses of opioids can cause chest wall rigidity, thereby acutely impairing ventilation, as well as postoperative respiratory depression requiring prolonged assisted ventilation and the administration of opioid antagonists (eg, naloxone). Low doses of fentanyl have been used as premedication and as an adjunct to both intravenous and inhaled anesthetics. Alfentanil and remifentanil have been used as induction agents since they both have a rapid onset of action. Remifentanil has an extremely short duration of action because it is rapidly metabolized by esterases in the blood (not plasma cholinesterase) and muscle tissues. The metabolism of remifentanil is not subject to genetic variability, and the drug does not interfere with the clearance of compounds metabolized by plasma cholinesterase (eg, esmolol, mivacurium, or succinylcholine. Rapid recovery following remifentanil is important regarding its potential utility in anesthesia regimens for ambulatory surgery. Fentanyl and droperidol (a butyrophenone related to haloperidol) together produce analgesia and amnesia and are sometimes used with nitrous oxide to provide a state of neuroleptanesthesia.

Opioid analgesics can also be used at low doses by the epidural and spinal routes of administration to produce excellent postoperative analgesia.

Propofol

Propofol (2,6-diisopropylphenol) is an extremely popular intravenous anesthetic. Its rate of onset of action is similar to that of the intravenous barbiturates; recovery is more rapid; and patients are able to ambulate sooner after propofol. Furthermore, patients subjectively "feel better" in the immediate postoperative period after propofol as compared with other intravenous anesthetics. Postoperative nausea and vomiting is less common because propofol has antiemetic actions. Propofol is used for both induction and maintenance of anesthesia; however, cumulative effects can delay arousal following prolonged infusion. These favorable properties are responsible for the extensive use of propofol as a component of balanced anesthesia and for its great popularity as an anesthetic for use

in day surgery outpatient procedures. The drug is also effective in producing prolonged sedation in patients in critical care settings (see Conscious Sedation and Deep Sedation). However, use of propofol for the sedation of children under intensive care has led to severe acidosis in the presence of respiratory infections and possible neurological sequelae on withdrawal.

After intravenous administration of propofol, the distribution half-life is 2–8 minutes; the elimination half-life is approximately 30–60 minutes. The drug is rapidly metabolized in the liver (ten times faster than thiopental) and excreted in the urine as glucuronide and sulfate conjugates. Less than 1% of the drug is excreted unchanged. Total body clearance of the anesthetic is greater than hepatic blood flow, suggesting that its elimination includes extrahepatic mechanisms in addition to metabolism by liver enzymes. This property is useful in patients with impaired ability to metabolize other sedative-anesthetic drugs.

Effects on respiration are similar to those of thiopental at usual anesthetic doses. However, propofol causes a marked decrease in systemic blood pressure during induction of anesthesia, primarily through decreased peripheral resistance. In addition, propofol has greater negative inotropic effects on the heart than etomidate and thiopental. Apnea and pain at the site of injection are common adverse effects of bolus administration. Muscle movements, hypotonus, and (rarely) tremors have also been reported following its use. Clinical infections due to bacterial contamination of the propofol emulsion have led to the addition of antimicrobial adjuvants (eg, ethylenediaminetetraacetic acid and metabisulfite).

Etomidate

Etomidate is a carboxylated imidazole that can be used for induction of anesthesia in patients with limited cardiovascular reserve. Its major advantage over other intravenous agents is that it causes minimal cardiovascular and respiratory depression. Etomidate produces a rapid loss of consciousness, with minimal hypotension. The heart rate is usually unchanged, and the incidence of apnea is low. The drug has no analgesic effects, and coadministration of opioids may be required to decrease cardiac responses during tracheal intubation and to lessen spontaneous muscle movements. Following an induction dose, recovery is rapid (< 5 minutes).

Distribution of etomidate is rapid, with a biphasic plasma concentration curve showing distribution half-lives of 3 and 29 minutes. Redistribution of the drug from brain to highly perfused tissues appears to be responsible for the short duration of its anesthetic effects. Etomidate is extensively metabolized in the liver and plasma to inactive metabolites with only 2% of the drug excreted unchanged in the urine.

Etomidate causes a high incidence of pain on injection, myoclonus, and postoperative nausea and vomiting. The involuntary muscle movements are not associated with electroencephalographic epileptiform activity. Etomidate may also cause adrenocortical suppression via inhibitory effects on steroidogenesis, with decreased plasma levels of hydrocortisone after a single dose. Prolonged infusion of etomidate in critically ill patients may result in hypotension, electrolyte imbalance, and oliguria due to its adrenal suppressive effects.

Ketamine

Ketamine (Figure 25–2) produces dissociative anesthesia, which is characterized by catatonia, amnesia, and analgesia, with or without actual loss of consciousness. The drug is an arylcyclohexylamine chemically related to phencyclidine (PCP), a drug frequently abused because of its psychoactive properties. The mechanism of action of ketamine may involve blockade of the

membrane effects of the excitatory neurotransmitter glutamic acid at the NMDA (N-methyl-D- aspartate) receptor subtype (see Chapter 21: Introduction to the Pharmacology of CNS Drugs).

Ketamine is a highly lipophilic drug and is rapidly distributed into highly vascular organs, including the brain, and subsequently redistributed to less well perfused tissues with concurrent hepatic metabolism and both urinary and biliary excretion.

Ketamine is the only intravenous anesthetic that possesses analgesic properties and produces cardiovascular stimulation. Heart rate, arterial blood pressure, and cardiac output are usually significantly increased. The peak increases in these variables occur 2–4 minutes after intravenous injection and then slowly decline to normal over the next 10–20 minutes. Ketamine produces its cardiovascular stimulation by excitation of the central sympathetic nervous system and possibly by inhibition of the reuptake of norepinephrine at sympathetic nerve terminals. Increases in plasma epinephrine and norepinephrine levels occur as early as 2 minutes after intravenous ketamine and return to baseline levels 15 minutes later.

Ketamine markedly increases cerebral blood flow, oxygen consumption, and intracranial pressure. In this regard ketamine resembles the volatile anesthetics as a potentially dangerous drug when intracranial pressure is elevated. In most patients, ketamine decreases the respiratory rate. However, upper airway muscle tone is well maintained, and airway reflexes are usually preserved.

Although it is a desirable anesthetic in many respects, ketamine has been associated with postoperative disorientation, sensory and perceptual illusions, and vivid dreams (so-called emergence phenomena). Diazepam, 0.2–0.3 mg/kg, or midazolam, 0.025–0.05 mg intravenously, given prior to the administration of ketamine reduces the incidence of these adverse effects. Because of the high incidence of postoperative psychic phenomena associated with its use, ketamine is not commonly used in general surgery in the USA. It is considered useful for poor-risk geriatric patients and in unstable patients (eg, cardiogenic or septic shock) because of its cardiostimulatory properties. It is also used in low doses for outpatient anesthesia in combination with propofol and in children undergoing painful procedures (eg, dressing changes for burns). Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous

System > Chapter 25. General Anesthetics >

Conscious Sedation & Deep Sedation

Many diagnostic, therapeutic, and minor surgical procedures require neither general anesthesia nor the availability of specialized equipment and facilities necessary for inhaled anesthesia. In this setting, regional or local anesthesia supplemented with midazolam or propofol and opioid analgesics may be a more appropriate and safer approach than general anesthesia.

Another approach has been the development of protocols to provide a state of conscious sedation or drug-induced alleviation of anxiety and pain in combination with an altered level of consciousness, but with retention of the ability of the patient to maintain a patent airway and to respond to verbal commands. A wide variety of intravenous anesthetic agents have proved to be useful drugs in conscious sedation techniques. For example, intravenous benzodiazepines, propofol, and opioid analgesics can provide amnestic, sedative, and analgesic effects without loss of consciousness. Use of benzodiazepines and opioid analgesics in conscious sedation protocols has the advantage of being reversible by the specific receptor antagonist drugs (eg, flumazenil and naloxone, respectively).

A special form of conscious sedation is sometimes needed in the ICU, when patients are under

severe stress and often require mechanical ventilation for long periods (days) with an endotracheal tube in place. In this situation, sedative drugs or intravenous anesthetics in low dosage, neuromuscular blockers, and dexmedetomidine may be combined. Dexmedetomidine is an 2 agonist with strong sedative properties. It has a half-life of 2–3 hours and is metabolized in the liver and excreted, mainly as metabolites, in the urine.

Deep sedation is a controlled state of anesthesia involving decreased consciousness from which the patient is not easily aroused. Since deep sedation is often accompanied by a loss of protective reflexes, an inability to maintain a patent airway, and lack of response to surgical stimuli, the state may be indistinguishable from that of general anesthesia. Intravenous agents used in deep sedation protocols include thiopental, ketamine, propofol, and certain intravenous opioid analgesics. Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous

System > Chapter 25. General Anesthetics >

Preparations Available1

Desflurane (Suprane)

Liquid: 240 mL for inhalation

Dexmedetomidine (Precedex)

Parenteral: 100 g/mL for IV infusion

Diazepam (generic, Valium)

Oral: 2, 5, 10 mg tablets; 5 mg/5 mL and 5 mg/mL solution

Oral sustained-release: 15 mg capsules

Parenteral: 5 mg/mL for injection

Droperidol (generic, Inapsine)

Parenteral: 2.5 mg/mL for IV or IM injection

Enflurane (Enflurane, Ethrane)

Liquid: 125, 250 mL for inhalation

Etomidate (Amidate)

Parenteral: 2 mg/mL for injection

Halothane (generic, Fluothane)

Liquid: 125, 250 mL for inhalation

Isoflurane (Isoflurane, Forane)

Local anesthetics reversibly block impulse conduction along nerve axons and other excitable membranes that utilize sodium channels as the primary means of action potential generation. This action can be used clinically to block pain sensation from—or sympathetic vasoconstrictor impulses to—specific areas of the body. Cocaine, the first such agent, was isolated by Niemann in 1860. It was introduced into clinical use by Koller in 1884 as an ophthalmic anesthetic. Cocaine was soon found to be strongly addicting but was widely used, nevertheless, for 30 years, since it was the only local anesthetic drug available. In an attempt to improve the properties of cocaine, Einhorn in 1905 synthesized procaine, which became the dominant local anesthetic for the next 50 years. Since 1905, many local anesthetic agents have been synthesized. The goals of these efforts were reduction of local irritation and tissue damage, minimization of systemic toxicity, faster onset of action, and longer duration of action. Lidocaine, still a popular agent, was synthesized in 1943 by Löfgren and may be considered the prototype local anesthetic agent.

None of the currently available local anesthetics are ideal, and development of newer agents continues. However, while it is relatively easy to synthesize a chemical with local anesthetic effects, it is very difficult to reduce the toxicity significantly below that of the current agents. The major reason for this difficulty is the fact that the much of the serious toxicity of local anesthetics represents extensions of the therapeutic effect on the brain and the circulatory system. However, new research into the mechanisms of cardiac and spinal toxicity and alternative drug targets for spinal analgesia (eg, 2 receptors) suggest that it may be possible to find better drugs, at least for spinal anesthesia. In an attempt to extend the duration of the local anesthetic action, a variety of novel delivery systems are in development (eg, polymers). Transdermal local anesthetic delivery systems are also being investigated.

Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 26. Local Anesthetics >

Basic Pharmacology of Local Anesthetics

Chemistry

Most local anesthetic agents consist of a lipophilic group (frequently an aromatic ring) connected by an intermediate chain (commonly including an ester or amide) to an ionizable group (usually a tertiary amine; Table 26–1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers for a few compounds, eg, bupivacaine, ropivacaine. Since ester links (as in procaine) are more prone to hydrolysis than amide links, esters usually have a shorter duration of action.

Table 26–1. Structure and Properties of Some Ester and Amide Local Anesthetics.1

Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 26. Local Anesthetics >

Clinical Pharmacology of Local Anesthetics

Local anesthetics can provide highly effective analgesia in well-defined regions of the body. The usual routes of administration include topical application (eg, nasal mucosa, wound margins), injection in the vicinity of peripheral nerve endings and major nerve trunks (infiltration), and injection into the epidural or subarachnoid spaces surrounding the spinal cord (Figure 26–2). Intravenous regional anesthesia of the arm or leg (Bier block) is used for short surgical procedures (< 45 minutes). This is accomplished by intravenous injection of the anesthetic agent into a distal vein while the circulation of the limb is isolated with a proximally placed tourniquet. Finally, an infiltration block of autonomic sympathetic fibers can be used to evaluate the role of sympathetic tone in patients with peripheral vasospasm.

Figure 26–2.

Schematic diagram of sites of injection of local anesthetics in and near the spinal canal.

The choice of local anesthetic for a specific procedure is usually based on the duration of action

an intermediate duration of action; and tetracaine, bupivacaine, levobupivacaine, etidocaine, and ropivacaine are long-acting drugs (Table 26–1).

The anesthetic effect of the agents with short and intermediate durations of action can be prolonged by increasing the dose or by adding a vasoconstrictor agent (eg, epinephrine or phenylephrine). The vasoconstrictor retards the removal of drug from the injection site. In addition, it decreases the blood level and hence the probability of central nervous system toxicity.

The onset of local anesthesia can be accelerated by the use of solutions saturated with carbon dioxide ("carbonated"). The high tissue level of CO2 results in intracellular acidosis (CO2 crosses membranes readily), which in turn results in intracellular accumulation of the cationic form of the local anesthetic.

Repeated injection of local anesthetics can result in loss of effectiveness (ie, tachyphylaxis) due to extracellular acidosis. Local anesthetics are commonly marketed as hydrochloride salts (pH 4.0– 6.0). After injection, the salts are buffered in the tissue to physiologic pH, thereby providing sufficient free base for diffusion through axonal membranes. However, repeated injections deplete the buffering capacity of the local tissues. The ensuing acidosis increases the extracellular cationic form, which diffuses poorly into axons. The clinical result is apparent tachyphylaxis, especially in areas of limited buffer reserve, such as the cerebrospinal fluid.

Pregnancy appears to increase susceptibility to local anesthetic toxicity in that median doses required for nerve block or to induce toxicity are reduced. Cardiac arrest leading to death following the epidural administration of 0.75% bupivacaine to women in labor resulted in the temporary withdrawal from the market of the high concentration of this long-acting local anesthetic and subsequent introduction of potentially less cardiotoxic alternatives (ie, ropivacaine and levobupivacaine) for this high-risk population. It is not clear whether the increased sensitivity during pregnancy is due to elevated estrogen, elevated progesterone, or some other factor.

Topical local anesthesia is often used for eye, ear, nose, and throat procedures and for cosmetic surgery. Satisfactory local anesthesia requires an agent capable of rapid penetration of the skin or mucosa and with limited tendency to diffuse away from the site of application. Cocaine, because of its excellent penetration and vasoconstrictor effects, has been used extensively for nose and throat procedures. It is somewhat irritating, however, and is thus much less popular for ophthalmic procedures. Recent concerns about its potential cardiotoxicity when combined with epinephrine has led most otolaryngologists and plastic surgeons to switch to a combination containing lidocaine and epinephrine. Other drugs used for topical anesthesia include lidocaine, tetracaine, pramoxine, dibucaine, benzocaine, and dyclonine.

Since local anesthetics are membrane-stabilizing drugs, both parenteral (eg, intravenous lidocaine) and oral (eg, mexiletine, tocainide) formulations of these drugs have been used to treat patients with neuropathic pain syndromes. Systemic local anesthetic drugs are commonly used as adjuvants to the combination of a tricyclic antidepressant (eg, amitriptyline) and an anticonvulsant (eg, carbamazepine) in patients who fail to respond to the standard tricyclic plus anticonvulsant combination. One to 3 weeks are required to observe a therapeutic effect after introduction of the local anesthetic in patients with neuropathic pain.

Toxicity

Two major forms of local anesthetic toxicity are recognized: direct neurotoxicity from the local effects of certain agents administered around the cord or other major nerve trunks, and systemic