Anesthesia is defined as the lack of sensation. The ideal general anesthetic agent would produce unconsciousness, analgesia, amnesia, and muscle relaxation, with no untoward side effects or toxicities (Fig. 8.1). Anesthetics developed to date are not ideal and are administered in combination with numerous other preoperative and postoperative medications in order to achieve the desired effects listed above (see Table 8.1).
Table 8.1 |
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Desired Effect |
Drugs Used (Intravenously) |
Example(s) |
Induction of anesthesia |
Ultra short-acting barbiturate |
Thiopental, thiamylal, and methohexital |
Muscle relaxation |
Depolarizing and nondepolarizing neuromuscular blocking agents |
Succinylcholine, pancuronium |
Analgesia |
Short-acting, intravenous opiates |
Fentanyl |
Amnesia |
Short-acting benzodiazepines (doses given are higher than anxiolytic doses) |
Diazepam, midazolam, and lorazepam |
Autonomic stabilization |
Anticholinergic drugs Antiadrenergic drugs |
Atropine and glycopyrrolate Esmolol |
8.1 Inhalation Agents
The major anesthetic gases include several halogenated hydrocarbons (halothane, isoflurane, enflurane, desflurane, and sevoflurane) and nitrous oxide. These agents act in the brain to produce surgical anesthesia, but the precise mechanism of action for these agents and specific receptors with which these agents interact are not known. The pharmacokinetics of these agents is unique because they are administered as gases and exert their pharmacologic effects when in gaseous form. Thus, the important factor for determining the level of anesthetic effect is the partial pressure or tension of the anesthetic gas. The standard for anesthetic dosing is the minimal alveolar concentration (MAC), which is the alveolar concentration, expressed as a percentage of inspired gas, at which 50% of the patients fail to respond to a noxious stimulus.
Fig. 8.1 Goals of surgical anesthesia.
Commonly used agents as adjuncts to the general anesthetics include drugs that more selectively produce muscle relaxation, analgesia, loss of consciousness, amnesia, and autonomic stabilization.
Factors influencing the rate of induction of inhalation anesthesia
Table 8.2 discusses the factors influencing the rate of induction of inhalation anesthesia.
Table 8.2 |
|
Factor |
Explanation |
Concentration of gas in inspired air |
The higher the concentration of anesthetic in inspired air, the more rapid the increase in tension of anesthetic in the blood and therefore the brain. |
Ventilation rate and depth |
Increased ventilation rate and depth lead to an increased rate of induction of anesthesia. |
Blood solubility |
The solubility of an anesthetic agent in the blood is a very important factor in determining the rate of induction of inhalation anesthesia. The blood:gas partition coefficient is the ratio of the concentration of anesthetic in the blood to the concentration of anesthetic gas at equilibrium. Note that anesthetic molecules that are dissolved in the blood are not exerting a partial pressure and therefore not contributing to anesthesia. Thus, an agent that has high blood solubility will show a slower increase in anesthetic tension and therefore a slower induction rate. Agents that are not soluble in the blood will have a rapid rate of induction. |
Blood flow |
Uptake of anesthetic into tissues is dependent on blood flow to those tissues, so highly perfused organs will see a more rapid rise in anesthetic tension. |
Tissue solubility |
In general, anesthetic gases are soluble in fatty tissues; therefore, the rate of rise of anesthetic tension in adipose tissue is slower than in lean tissues, such as the brain.* |
* The brain is a lean, well-perfused organ; therefore, the rate of rise of anesthetic tension in the brain is rapid. |
Effects
– All of the inhalation agents produce unconsciousness, amnesia, and analgesia. They also decrease blood pressure, depress respiration, and increase intracranial pressure (with the exception of nitrous oxide). The relative analgesic and muscle relaxant effects and side effects are summarized in Table 8.3.
– The use of halogenated agents has been associated with rare cases of hyperkalemia and malignant hyperthermia, both of which require aggressive treatment.
Malignant hyperthermia
Malignant hyperthermia is a rare complication of anesthesia with any volatile anesthetic but most commonly with halothane. The anesthetic produces a substantial increase in skeletal muscle oxidative metabolism, which consumes oxygen and causes a buildup of carbon dioxide. The body also loses its capacity to regulate temperature which rises rapidly (e.g., 1°C/5 min). This can lead to circulatory collapse and death. Signs include muscular rigidity with accompanying acidosis, increased oxygen consumption, hypercapnia (increased carbon dioxide), tachycardia, and hyperthermia. Malignant hyperthermia may be treatable if dantrolene, a drug that reduces muscular contraction and the hypermetabolic state, is given promptly. Susceptibility to malignant hyperpyrexia is an autosomal dominant trait.
Table 8.3 |
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Agent |
Analgesia |
Muscle Relaxation |
Agent-specific Side Effects |
Halothane |
++ |
+ |
Sensitizes myocardium to catecholamines increasing possibility of arrhythmias Hepatotoxicity |
Enflurane |
++ |
++ |
May increase seizure activity |
Isoflurane |
++ |
++ |
Decreased blood pressure Respiratory depression |
Desflurane |
++ |
++ |
May cause cough and laryngospasm, as it is an irritant to the upper respiratory tract |
Sevoflurane |
++ |
++ |
None of note |
Nitrous oxide |
++++ |
No effect |
Contraindicated in cases of occluded middle ear and pneumothorax, as air pockets in the body may expand as larger amounts of nitrous oxide replace nitrogen |
Nitrous Oxide
Uses
– Nitrous oxide is a good analgesic (produces superior analgesia than halogenated agents without decreases in blood pressure or depressed respiration).
– It does not produce surgical levels of anesthesia except with very high doses when oxygenation is inadequate. It is therefore not used alone as an anesthetic agent but can be used as the sole agent for analgesia. It is frequently combined with one of the other anesthetic agents.
Side effects
– It is always administered with 30 to 35% oxygen, as it can cause diffusion hypoxia.
– Long-term exposure to trace concentrations may cause pernicious anemia and an increased incidence of spontaneous abortions.
Diffusion hypoxia with nitrous oxide
When nitrous oxide administration is terminated at the end of anesthesia, the concentration of nitrous oxide in the alveoli is lower than the blood. Consequently, it diffuses along this concentration gradient and floods into the lungs, displacing oxygen and nitrogen in the process. This causes a temporary diffusion hypoxia (lack of oxygen). To counteract this, patients are given 100% oxygen until the nitrous oxide is removed from the lungs by expiration.
8.2 Intravenous Anesthetic Agents
Propofol
Mechanism of action. The mechanism of action of propofol is not completely understood, but it enhances gamma-aminobutyric acid (GABA)–mediated neuronal inhibition (via GABAA receptors), and it also blocks Na+ channels (Fig. 8.2).
Pharmacokinetics
– Given intravenously (IV)
– Metabolized rapidly by the liver
– Rapid induction of anesthesia and recovery
Uses
– General anesthesia
Note: Propofol is a poor analgesic, so it must be supplemented with an opiate.
Side effects
– Hypotension (due to decreased vascular resistance)
Ketamine
This is a “dissociative anesthetic” similar to the street drug phencyclidine (angel dust). Dissociative anesthetics make the patient feel dissociated from the environment.
Uses
– Induction and maintenance of general anesthesia; it is not widely used due to side effects
Effects. At anesthetic doses, it produces catatonia, analgesia, and amnesia.
Side effects
– Disorientation and hallucinations
Barbiturates
Thiopental, Thiamylal, and Methohexital
Pharmacokinetics
– Unconsciousness occurs within the circulation time from arm to brain and is then maintained with an inhalation agent.
– Termination of CNS action of the barbiturate is by redistribution of drug from the brain to other tissues (Fig. 8.3).
Fig. 8.2 Termination of IV anesthetic agent effects by redistribution.
After an IV anesthetic is given, a high concentration accumulates rapidly in the brain because the brain has a high blood flow compared with other tissues in the body. The drug then redistributes to other tissues, and the concentration in the brain falls. Thus, the effects of the drug (anesthesia) subside before the drug has been eliminated. (CNS, central nervous system.)
Uses
– Induction of anesthesia
Side effects
– Respiratory and cardiovascular depression
Benzodiazepines
These drugs are discussed in detail in Chapter 9.
Diazepam, Midazolam, and Lorazepam
Pharmacokinetics
– Given IV.
Uses. These agents are used as anesthetic premedications to produce sedation and amnesia.
8.3 Local Anesthetics
Local anesthetics act directly on nerve axons to reversibly block nerve conduction. They produce a lack of sensation in the area innervated by those nerve fibers. The methods by which local anesthetics can be administered are outlined in Table 8.4.
Table 8.4 |
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Methods of Local Anesthetic Administration |
Technique |
Clinical Situation |
Topical |
Applied to skin or mucous membranes |
Typically used prior to injection of anesthetics to make the procedure less painful Also used prior to eye surgery and endoscopy |
Infiltration |
Inject dilute solution and let diffuse (e.g., subcutaneous or submucosal) |
Very common in dentistry to anesthetize most teeth |
Nerve block |
Inject close to the nerve trunk, proximal to the intended area of anesthesia |
Very common in dentistry to anesthetize mandibular teeth Can be useful in cases where pain sensation to a limb needs to be blocked (e.g., following femur fracture) |
Spinal |
Inject anesthetic in the subarachnoid space |
Chronic pain or surgery |
Epidural |
Inject within the vertebral canal but outside the dura |
Very commonly used in labor and delivery |
Lidocaine, Articaine, and Bupivacaine (Amides); Benzocaine, Procaine, and Tetracaine (Esters)
Mechanism of action. Local anesthetics exist in two forms in the body: as an uncharged base and as a charged acid. Only the uncharged base can cross nerve membranes. However, once inside the axon, the charged form is active. Local anesthetics interfere with the propagation of action potentials in nerve axons by blocking Na+ channels from the cytoplasmic side of the channel (Fig. 8.4).
Fig. 8.3 Effects of local anesthetics.
Local anesthetics block the inner gate of the Na+ channels in nerve cells, preventing Na+ influx and action potential initiation and propagation. Charged (cationic) local anesthetic is thought to block the sodium channel by becoming incorporated into the phospholipid membrane or channel protein. Uncharged local anesthetic may also become incorporated into the apolar region of the channel protein. (CNS, central nervous system.)
Pharmacokinetics
– Local anesthetics differ mainly in their rate of onset and duration of action (Table 8.5).
– Termination of action at the site of injection is by diffusion of the active drug into the systemic circulation followed by metabolism. Ester local anesthetics are inactivated primarily by hydrolysis via esterases in plasma and the liver. Amide local anesthetics are metabolized primarily by the liver.
Sensitivity of different nerve fibers to block
There are variations in sensitivity of different types of nerve fibers to block by local anesthetics. Smaller diameter, unmyelinated nerve fibers are more sensitive than larger diameter, myelinated fibers. Thus, there is a definite order in which sensation is blocked. Pain fibers are smallest and blocked first, followed by sensations of cold, warmth, touch, and deep pressure. Proprioceptive and motor fibers are blocked last.
Table 8.5 |
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Local Anesthetic Agent |
Rate of Onset |
Duration of Action* |
Lidocaine |
Rapid |
Short |
Articaine |
Rapid |
Intermediate |
Bupivacaine |
Slow |
Long |
Procaine |
Rapid |
Short |
Tetracaine |
Slow |
Long |
* The duration of action is prolonged when combined with epinephrine. |
Side effects
The toxic effects of local anesthetics are dependent on the amount of drug that gains entry into the systemic circulation.
– CNS effects: These include stimulation, restlessness, and tremor that may lead to clonic convulsions. This is followed by depression and death due to respiratory failure. Direct systemic injection may lead directly to death.
– Cardiac effects: Direct effects on the myocardium include decreased electrical excitability, decreased conduction rate, and a negative inotropic effect. Sudden cardiac death may occur.
– Hypersensitivity: This is rare, but it can cause dermatitis, asthma attacks, or fatal anaphylactic reactions. Allergy is more frequent with esters.
Vasoconstrictors in local anesthetics
Epinephrine is added to local anesthetic solutions to produce vasoconstriction at the site of injection. This decreases systemic absorption and prolongs the duration of action. Epinephrine should be used with caution in patients with cardiac disease, high blood pressure, hyperthyroidism, and other vascular diseases. Epinephrine is absolutely contraindicated in digital or penile blocks and around the nose or ears, as the ischemia produced may lead to gangrene.
Facial palsy with dental injections
The parotid salivary gland lies laterally to the ramus of the mandible and encloses the five branches of the facial nerve (cranial nerve VII). It is a wedge-shaped structure that wraps around the posterior border of the ramus. If a dentist is inaccurate when giving an inferior alveolar nerve block, some of the local anesthetic may penetrate the capsule of the parotid gland, causing anesthesia of the facial nerve. Symptoms include a drooping mouth and inability to blink on the affected side. The patient's affected eye should be taped closed to prevent drying and contamination with airborne debris until anesthesia subsides and the symptoms resolve.