General anesthetics

General anesthetics

General anesthetics are drugs that produce unconsciousness and a lack of responsiveness to all painful stimuli. In contrast, local anesthetics do not reduce consciousness, and they blunt sensation only in a limited area (see Chapter 26).

General anesthetics can be divided into two groups: (1) inhalation anesthetics and (2) intravenous anesthetics. The inhalation anesthetics are the main focus of this chapter.

When considering the anesthetics, we need to distinguish between the terms analgesia and anesthesia. Analgesia refers specifically to loss of sensibility to pain. In contrast, anesthesia refers not only to loss of pain but to loss of all other sensations (eg, touch, temperature, taste), and to loss of consciousness as well. Hence, while analgesics (eg, aspirin, morphine) can selectively reduce pain without affecting other sensory modalities and without reducing consciousness, the general anesthetics have no such selectivity: During general anesthesia, all sensation is lost, and consciousness is lost too.

The development of general anesthetics has had an incalculable impact on the surgeon’s art. The first general anesthetic—ether—was introduced by Dr. William T. Morton in 1846. Prior to this, surgery was a brutal and exquisitely painful ordeal, undertaken only in the most desperate circumstances. Immobilization of the surgical field was accomplished with the aid of strong men and straps. Survival of the patient was determined by the surgeon’s speed—not his finesse. With the advent of general anesthesia, all of this changed. General anesthesia produced a patient who slept through surgery and experienced no pain. These changes allowed surgeons to develop the lengthy and intricate procedures that are routine today. Such procedures were unthinkable before general anesthetics became available.

In addition to their use in surgery, general anesthetics are used to facilitate other procedures, including endoscopy, urologic procedures, radiation therapy, electroconvulsive therapy, transbronchial biopsy, and various cardiologic procedures.

Inhalation anesthetics

Basic pharmacology

In this section, we consider the inhalation anesthetics as a group. Our focus is on properties of an ideal anesthetic, pharmacokinetics of inhalation anesthetics, adverse effects of the inhalation anesthetics, and drugs employed as adjuncts to anesthesia.

Properties of an ideal inhalation anesthetic

An ideal inhalation anesthetic would produce unconsciousness, analgesia, muscle relaxation, and amnesia. Furthermore, induction of anesthesia would be brief and pleasant, as would the process of emergence. Depth of anesthesia could be raised or lowered with ease. Adverse effects would be minimal, and the margin of safety would be large. As you might guess, the ideal inhalation anesthetic does not exist: No single agent has all of these qualities.

Balanced anesthesia

The term balanced anesthesia refers to the use of a combination of drugs to accomplish what we cannot achieve with an inhalation anesthetic alone. Put another way, balanced anesthesia is a technique employed to compensate for the lack of an ideal anesthetic. Drugs are combined in balanced anesthesia to ensure that induction is smooth and rapid, and that analgesia and muscle relaxation are adequate. The agents used most commonly to achieve these goals are (1) propofol and short-acting barbiturates (for induction of anesthesia), (2) neuromuscular blocking agents (for muscle relaxation), and (3) opioids and nitrous oxide (for analgesia). The primary benefit of combining drugs to achieve surgical anesthesia is that doing so permits full general anesthesia at doses of the inhalation anesthetic that are lower (safer) than those that would be required if surgical anesthesia were attempted using an inhalation anesthetic alone.

Molecular mechanism of action

Our understanding of how inhalation anesthetics act has changed dramatically. In the past, we believed that anesthetics worked through nonspecific effects on neuronal membranes. Today, we believe they work through selective alteration of synaptic transmission. However, despite recent advances, we still don’t know with certainty just how these drugs work.

More than 100 years ago, scientists postulated that inhalation anesthetics produced their effects through nonspecific interactions with lipid components of the neuronal cell membrane. This long-standing theory was based on the observation that there was a direct correlation between the potency of an anesthetic and its lipid solubility. That is, the more readily an anesthetic could dissolve in the lipid matrix of the neuronal membrane, the more readily that agent could produce anesthesia. Hence the theory that anesthetics dissolve into neuronal membranes, disrupt their structure, and thereby suppress axonal conduction and possibly synaptic transmission. However, this theory was called into question by an important observation: Enantiomers of the same anesthetic have different actions. Recall that enantiomers are simply mirror-image molecules that have identical atomic components, and hence have identical physical properties, including lipid solubility. Therefore, since enantiomers have the same ability to penetrate the axonal membrane, but do not have the same ability to produce anesthesia, a property other than lipid solubility must underlie anesthetic actions.

Current data indicate that inhalation anesthetics work by enhancing transmission at inhibitory synapses and by depressing transmission at excitatory synapses. Except for nitrous oxide, all of the agents used today enhance activation of receptors for gamma-aminobutyric acid (GABA), the principal inhibitory transmitter in the central nervous system (CNS). As a result, these drugs promote generalized inhibition of CNS function. It should be noted that anesthetics do not activate GABA receptors directly. Rather, by binding with the GABA receptor, they increase receptor sensitivity to activation by GABA itself. How does nitrous oxide work? Probably by blocking the actions of N-methyl-d-aspartate (NMDA), an excitatory neurotransmitter. Nitrous oxide appears to bind with the NMDA receptor and thereby prevent receptor activation by NMDA itself.

Minimum alveolar concentration

The minimum alveolar concentration (MAC), also known as the median alveolar concentration, is an index of inhalation anesthetic potency. The MAC is defined as the minimum concentration of drug in the alveolar air that will produce immobility in 50% of patients exposed to a painful stimulus. Note that, by this definition, a low MAC indicates high anesthetic potency.

From a clinical perspective, knowledge of the MAC of an anesthetic is of great practical value: The MAC tells us approximately how much anesthetic the inspired air must contain to produce anesthesia. A low MAC indicates that the inspired air need contain only low concentrations of the anesthetic to produce surgical anesthesia. The opposite is true for drugs with a high MAC. Fortunately, most inhalation anesthetics have low MACs (Table 27–1). However, one important agent—nitrous oxide—has a very high MAC. The MAC is so high, in fact, that surgical anesthesia cannot be achieved using nitrous oxide alone.

TABLE 27–1

Properties of the Major Inhalation Anesthetics

Drug	MAC* (%)	Analgesic Effect	Effect on Blood Pressure	Effect on Respiration	Muscle Relaxant Effect	Extent of Metabolism	Compatible with Epinephrine
Nitrous oxide	105	+ + + +	→	→	0	0	Yes
Halothane^†	0.75	+ +	↓	↓ ↓	+	20%	No
Desflurane	4.58	+ +	↓	↓ ↓	+ +	0.02%	Yes
Enflurane	1.68	+ +	↓	↓ ↓	+ +	2.4%	Yes^‡
Isoflurane	1.15	+ +	↓	↓ ↓	+ +	0.2%	Yes
Sevoflurane	1.71	+ +	↓	↓ ↓	+ +	3%	Yes

^*Minimum alveolar concentration.

^†No longer used in the United States and Canada.

^‡Enflurane sensitizes the myocardium to catecholamines, but less so than halothane.

Please note that, to produce general anesthesia in all patients, the inspired anesthetic concentration should be 1.2 to 1.5 times the MAC. Why? Because if the concentration were simply equal to the MAC, 50% of patients would receive less than they need.

Pharmacokinetics

Uptake and distribution

To produce therapeutic effects, an inhalation anesthetic must reach a CNS concentration sufficient to suppress neuronal excitability. The principal determinants of anesthetic concentration are (1) uptake from the lungs and (2) distribution to the CNS and other tissues. The kinetics of anesthetic uptake and distribution are complex, and we will not try to cover them in depth.

Uptake.

A major determinant of anesthetic uptake is the concentration of anesthetic in the inspired air: The greater the anesthetic concentration, the more rapid uptake will be. Other factors that influence uptake are pulmonary ventilation, solubility of the anesthetic in blood, and blood flow through the lungs. An increase in any of these will increase the speed of uptake.

Distribution.

Distribution to specific tissues is determined largely by regional blood flow. Anesthetic levels rise rapidly in the brain, kidney, heart, and liver—tissues that receive the largest fraction of the cardiac output. Anesthetic levels in these tissues equilibrate with those in blood 5 to 15 minutes after inhalation starts. In skin and skeletal muscle—tissues with an intermediate blood flow—equilibration occurs more slowly. The most poorly perfused tissues—fat, bone, ligaments, and cartilage—are the last to equilibrate with anesthetic levels in the blood.

Elimination

Export in the expired breath.

Inhalation anesthetics are eliminated almost entirely via the lungs; hepatic metabolism is minimal. The same factors that determine anesthetic uptake (pulmonary ventilation, blood flow to the lungs, anesthetic solubility in blood and tissues) also determine the rate of elimination. Since blood flow to the brain is high, anesthetic levels in the brain drop rapidly when administration is stopped. Anesthetic levels in tissues that have a lower blood flow decline more slowly. Because anesthetic levels in the CNS decline more rapidly than levels in other tissues, patients can awaken from anesthesia long before all anesthetic has left the body.

Metabolism.

Most inhalation anesthetics undergo very little metabolism. Hence, metabolism does not influence the time course of anesthesia. However, since some metabolites can be toxic, metabolism is nonetheless clinically relevant.

Adverse effects

The adverse effects discussed here apply to the inhalation anesthetics as a group. Not all of these effects are seen with every anesthetic.

Respiratory and cardiac depression.

Depression of respiratory and cardiac function is a concern with virtually all inhalation anesthetics. Doses only 2 to 4 times greater than those needed for surgical anesthesia are sufficient to cause potentially lethal depression of pulmonary and cardiac function. To compensate for respiratory depression, and to maintain a steady rate of administration, almost all patients require mechanical support of ventilation.

Sensitization of the heart to catecholamines.

Some anesthetics—most notably halothane—can increase the sensitivity of the heart to stimulation by catecholamines (eg, norepinephrine, epinephrine). While in this sensitized state, the heart may develop dysrhythmias in response to catecholamines. Exposure to catecholamines may result from two causes: (1) release of endogenous catecholamines (in response to pain or other stimuli of the sympathetic nervous system), and (2) topical application of catecholamines to control bleeding in the surgical field.

Malignant hyperthermia.

Malignant hyperthermia is a rare but potentially fatal reaction that can be triggered by all inhalation anesthetics (except nitrous oxide). Predisposition to the reaction is genetic. Malignant hyperthermia is characterized by muscle rigidity and a profound elevation of temperature—sometimes to as high as 43°C (109°F). Left untreated, the reaction can rapidly prove fatal. The risk of malignant hyperthermia is greatest when an inhalation anesthetic is combined with succinylcholine, a neuromuscular blocker that also can trigger the reaction. Diagnosis and management of malignant hyperthermia are discussed in Chapter 16.

Aspiration of gastric contents.

During the state of anesthesia, reflexes that normally prevent aspiration of gastric contents into the lungs are abolished. Aspiration of gastric fluids can cause bronchospasm and pneumonia. Use of an endotracheal tube isolates the trachea and can thereby help prevent these complications.

Hepatotoxicity.

Rarely, patients receiving inhalation anesthesia develop serious liver dysfunction. The risk is about equal with all anesthetics.

Toxicity to operating room personnel.

Chronic exposure to low levels of anesthetics may harm operating room personnel. Suspected reactions include headache, reduced alertness, and spontaneous abortion. Risk can be reduced by venting anesthetic gases from the operating room.

Drug interactions

Several classes of drugs—analgesics, CNS depressants, CNS stimulants—can influence the amount of anesthetic required to produce anesthesia. Opioid analgesics allow a reduction in anesthetic dosage. Why? Because, when opioids are present, analgesia needn’t be produced by the anesthetic alone. Similarly, because CNS depressants (barbiturates, benzodiazepines, alcohol) add to the depressant effects of anesthetics, concurrent use of CNS depressants lowers the required dose of anesthetic. Conversely, concurrent use of CNS stimulants (amphetamines, cocaine) increases the required dose of anesthetic.

Adjuncts to inhalation anesthesia

Adjunctive drugs are employed to complement the beneficial effects of inhalation anesthetics and to counteract their adverse effects. Some adjunctive agents are administered before surgery, some during, and some after.

Preanesthetic medications

Preanesthetic medications are administered for three main purposes: (1) reducing anxiety, (2) producing perioperative amnesia, and (3) relieving preoperative and postoperative pain. In addition, preanesthetic medications may be used to suppress certain adverse responses: excessive salivation, excessive bronchial secretion, coughing, bradycardia, and vomiting.

Benzodiazepines.

Benzodiazepines are given preoperatively to reduce anxiety and promote amnesia. When administered properly, these drugs produce sedation with little or no respiratory depression. Intravenous midazolam [Versed] is used most often.

Opioids.

Opioids (eg, morphine, fentanyl) are administered to relieve preoperative and postoperative pain. These drugs may also help by suppressing cough.

Opioids can have adverse effects. Because they depress the CNS, opioids can delay awakening after surgery. Effects on the bowel and urinary tract may result in postoperative constipation and urinary retention. Stimulation of the chemoreceptor trigger zone promotes vomiting. Opioid-induced respiratory depression adds with anesthetic-induced respiratory depression, thereby increasing the risk of postoperative respiratory distress.

Alpha₂-adrenergic agonists.

Two alpha₂ agonists—clonidine and dexmedetomidine—are employed as adjuncts to anesthesia. Both produce their effects through actions in the CNS.

Clonidine is used for hypertension and pain reduction. When administered prior to surgery, the drug reduces anxiety and causes sedation. In addition, it permits a reduction in anesthetic and analgesic dosages. Analgesic properties of clonidine are discussed further in Chapter 28; antihypertensive properties are discussed in Chapters 19 and 47. The formulation used for analgesia is marketed under the trade name Duraclon; the formulation for hypertension is marketed as Catapres.

Dexmedetomidine [Precedex] is a highly selective alpha₂-adrenergic agonist currently approved only for short-term sedation in critically ill patients. However, the drug is also used for other purposes, including enhancement of sedation and analgesia in patients undergoing anesthesia. The pharmacology of dexmedetomidine is discussed further in Chapter 28.

Anticholinergic drugs.

Anticholinergic drugs (eg, atropine) may be given to decrease the risk of bradycardia during surgery. Surgical manipulations can trigger parasympathetic reflexes, which in turn can produce profound vagal slowing of the heart. Pretreatment with a cholinergic antagonist prevents bradycardia from this cause.

At one time, anticholinergic drugs were needed to prevent excessive bronchial secretions associated with anesthesia. Older anesthetic agents (eg, ether) irritate the respiratory tract, and thereby cause profuse bronchial secretions. Cholinergic blockers were given to suppress this response. Since the inhalation anesthetics used today are much less irritating, bronchial secretions are minimal. Consequently, although anticholinergic agents are still employed as adjuncts to anesthesia, their purpose is no longer to suppress bronchial secretions (although they may still help by suppressing salivation).

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Tags: Pharmacology for Nursing Care

Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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