I. INTRODUCTION.
Anesthesia is a reversible process resulting in the total loss of sensation in a body part or the whole body. Anesthesia may be induced by a drug or drug combination that depresses nervous tissue activity peripherally (local and regional anesthesia) or centrally (general anesthesia). General anesthesia implies that the animal is experiencing unconsciousness, hyporeflexia, analgesia, and has skeletal muscle relaxation.
A. Local anesthetics block nerve impulse conduction and render an area or region of the body insensitive to painful stimuli. These agents do not induce unconsciousness. Local anesthetics may be administered in the following ways:
1. Topically
2. By injection
a. Into the tissues in the vicinity of peripheral nerve endings that are to be anesthetized (i.e., infiltration)
b. Around major nerves to desensitize the tissues they innervate
c. Into the epidural or subarachnoid space to desensitize a large region of the body bilaterally
d. Into joint spaces
II. LOCAL ANESTHETICS
A. Introduction
1. Action potentials are changes in the resting membrane potential that convey information within the nervous system. The resting membrane potential (approximately −60 to −90 mV) results from the difference between the intracellular and extracellular concentration of K+ and the selective permeability of the cell membrane to Na+ and K+. This concentration difference is maintained by an ion pump within the cell membrane that is fueled by ATP. The Na+, K+-ATPase pump transports three Na+ out of the cell for every two K+ transported into the cell.
a. Phases of the action potential
(1) Threshold. The resting membrane potential must reach a specific threshold value before an action potential results.
(a) Small decreases in the membrane potential (toward zero potential) that do not reach the threshold value do not lead to the propagation of an action potential.
(b) Action potentials are an all-or-none response to a stimulus (i.e., they do not reflect the strength of the stimulus).
(2) Depolarization results from a rapid transient change in the cell’s permeability to Na+. Positively charged Na+ rapidly stream into the cell through Na+ channels, altering the membrane potential.
(3) Repolarization. The channels that allow Na+ to move into the cell close after a few milliseconds at the peak of the action potential. K+ then rapidly diffuses out of the cell, returning the membrane potential to its resting level.
(4) Return to resting potential. After repolarization, the Na+-K+-ATPase pump reestablishes the normal concentration difference of Na+ and K+ across the membrane of the cell, readying it to fire again.
b. Propagation of action potentials. Action potentials self-perpetuate along the length of the nerve fiber.
(1) Unmyelinated nerves develop a flow of current from the depolarized region into the resting segment. The current flow reduces the membrane potential of the resting segment to a value that exceeds threshold and the action potential is propagated.
(2) In myelinated nerves, action potentials are generated only at the nodes of Ranvier. Action potentials appear to “jump” from node to node. Nerve impulse conduction velocity is much faster in myelinated nerves, as compared with unmyelinated nerves.
2. Classification of nerves. Nerves are classified according to their size, myelination, and function.
a. Historically, the unmyelinated C fibers and small diameter myelinated A-δ fibers (i.e. pain fibers) have been shown to be easier to block with local anesthetics than myelinated, large fibers (i.e. sensory and motor fibers).
b. More recent studies have shown that the small unmyelinated C (pain) fibers are the last fiber type to be blocked by lidocaine. Thus, controversy exists concerning the susceptibility of the various nerve types to local anesthetics and results also vary depending on the nerve and lipid solubility of the drug studied.
B. Mechanism of action
1. Local anesthetics block the propagation of an action potential by inhibiting the flux of Na+ through voltage-gated Na+ channels.
2. The exact site of action of local anesthetics is unknown. One popular theory is that the uncharged base form of the local anesthetic molecule diffuses through the nerve cell membrane, becomes protonated (i.e. binds with H+) inside the cell, and then binds to the Na+ channel and essentially “plugs” the channel.
C. Chemistry
1. Structure. Local anesthetics have three structural components: an aromatic group, an intermediate bond, and a tertiary amine (Figure 6-1).
a. The intermediate bond is a connecting hydrocarbon chain that is either an ester or an amide.
b. The addition of carbon atoms to the aromatic region or the amine end of the molecule increases its lipid solubility and, therefore, its potency.
2. Characteristics
a. Local anesthetic drugs are weak bases; therefore, they are usually water insoluble. Commercial products are prepared as hydrochloride salt solutions, which are acidic. The acidity increases the stability and water solubility of the local anesthetic solution.
b. Local anesthetics exist in solution as uncharged and charged molecules.
B + H+ ↔ BH+, where
B is the basic uncharged form of the local anesthetic; BH+ is the positively charged cation form; and H+ is the hydrogen ion.
(1) The relative proportions of uncharged and charged molecules depend on the pH of the solution and the dissociation constant (pKa) of the drug (Table 6-1).
(a) If the local anesthetic is injected into an acidic environment, the increased [H+] produces more ionized drug (BH+), thus, decreasing the effectiveness of the local anesthetic.
(b) Conversely, if the local anesthetic is injected into an alkaline environment, which has low [H+], greater amounts of the drug will exist in the base form, increasing the effectiveness of the local anesthetic.
(2) The uncharged molecule (B) diffuses more rapidly across the nerve sheath than the ionized or charged molecule (BH+). The charged molecule, however, is thought to be the active form of the drug in the axoplasm.
FIGURE 6-1. Structures of lidocaine and procaine. Lidocaine is amidelinked and procaine is ester-linked.
TABLE 6-1. Properties of Local Anesthetics
D. Pharmacokinetics
1. Absorption and speed of onset (Table 6-1)
a. Lipid solubility is directly proportional to potency and duration of action. The higher the lipid solubility, the more potent the agent and the longer its duration of action.
b. The pKa correlates with the speed of onset.
(1) Drugs with a pKa closest to the body’s pH of 7.4 (e.g., 7.6–6.9) have a rapid onset of action.
(2) Drugs with a high pKa (e.g., 8.1–8.9) have a slower rate of onset.
2. Distribution
a. Protein binding correlates with the duration of action. The binding site for the local anesthetic within the Na+ channel is thought to be a protein (receptor).
b. Epinephrine is added to some local anesthetics (e.g., lidocaine) to prolong the duration of action. The local vasoconstriction induced by the epinephrine limits systemic absorption of the local anesthetic, maintaining the local tissue concentration. When epinephrine is combined with drugs that already have a long duration of action (e.g., bupivacaine), the effect is less dramatic.
3. Metabolism
a. Ester-linked local anesthetics undergo hydrolysis by cholinesterase in the plasma and, to a lesser extent, in the liver.
b. Amide-linked local anesthetics are metabolized in the liver which requires conjugation with glucuronic acid. Cats are more likely to develop toxicity from these drugs because they glucuronidate drugs less than other species.
E. Therapeutic uses
1. Anesthesia
a. Topical anesthesia. Local anesthetics are used to desensitize the mucous membranes of the eye, nose, and larynx.
(1) Lidocaine is commonly used to desensitize the larynx of cats prior to endotracheal intubation.
(2) Proparacaine is used to desensitize the cornea.
(3) Topical application of lidocaine (2.5%) and prilocaine (2.5%) in a eutectic mixture can be used to penetrate intact skin. After 45–60 minutes of contact time the skin is anesthetized enough for painless venipuncture.
(4) Lidocaine (5%) transdermal patches do not desensitize the skin or interfere with normal motor function but may provide local analgesia by blocking abnormally functioning Na+ channels and are used to treat dermal (e.g., incision) pain.
b. Infiltrative anesthesia. Local anesthetics are used to desensitize tissues in a limited area (e.g., in order to debride and suture a laceration).
c. Peripheral nerve blocks are used to desensitize larger areas. For example, a paravertebral nerve block would be used to desensitize the paralumbar fossa of a cow prior to a laparotomy.
d. Epidural injection of a local anesthetic desensitizes the spinal cord or cauda equine and is useful for procedures such as caudal abdominal, pelvic limb, or perineal surgery.
e. Neurolytic anesthesia. Ethyl alcohol, which is neurolytic, has been used in veterinary medicine to produce a prolonged nerve blockade in animals. Loss of nerve function can last as long as 1 year (i.e., as long as it takes the nerve to regenerate).
2. Control of arrhythmias. Lidocaine infused or injected IV is used to control premature ventricular contractions.
3. Constant rate IV infusion of lidocaine produces analgesia which facilitates general anesthesia and may be part of a multimodal approach to pain control postoperatively.
4. IV infusion of lidocaine in the horse may increase intestinal motility and be useful in treating some forms of hypomotility. The mechanism of action is unknown but thought to involve anti-inflammatory, analgesia, or altering the sympathetic inhibitory reflexes by suppressing the nerve transmission in afferent sensory pathways.
F. Adverse effects can occur if the plasma concentration of the local anesthetic reaches certain threshold values. The relative toxicity of the local anesthetics closely follows their anesthetic potency. For example, bupivacaine is toxic at a lower plasma concentration than lidocaine.
1. Central nervous system (CNS). Skeletal muscle twitches are the first sign of toxicity, but tonic-clonic seizures are imminent and often the first clinical sign.
2. Cardiovascular system. Signs of toxicity usually occur at higher plasma concentrations than those associated with CNS signs. Plasma concentration of lidocaine that produces cardiovascular toxicity may be lower for cats than in other species.
a. Prolongation of the PR and QRS intervals may result from slowed impulse conduction.
b. Hypotension and decreased myocardial strength (i.e., a negative inotropic effect) may occur.
3. Methemoglobinemia may occur following use of prilocaine or benzocaine in cats and rabbits.
4. Tissue damage from the injection of local anesthetics is rare. But, neurotoxicity and myotoxicity have been reported.
III. INHALANT ANESTHETICS.
The primary site of action of these agents is the brain and spinal cord. Analgesia and unconsciousness are produced when the concentration of the anesthetic reaches a specific level in the CNS.
A. Mechanism of action. Because the physiologic mechanism of consciousness is unknown, it is not surprising that the mechanism of action of inhalant anesthetics is also unknown. The following are two current hypotheses regarding the mechanism of action of inhalant anesthetics:
1. Single mechanism. The observation that anesthesia has been produced using the gaseous phase of a wide variety of chemically unrelated compounds has led to the unitary hypothesis, which holds that all general anesthetics act through one basic mechanism.
a. The fact that increasing the atmospheric pressure reverses the anesthetic effect of all inhalant anesthetics tested seems to support a single mechanism of action.
b. In 1908, Meyer and Overton observed that anesthetic potency is correlated with the solubility of the drug in olive oil. This observation has been cited as support for a common mechanism of action.
2. Multiple mechanisms. Each anesthetic may have a unique mechanism of action.
B. Pharmacokinetics. Through ventilation of the lungs, an anesthetic partial pressure is established within the alveoli. Increasing either the inspired concentration of anesthetic or alveolar ventilation will increase the partial pressure in the alveolus. The drug diffuses from the alveoli into the blood and is circulated to all parts of the body. Anesthetic molecules move from areas of high partial pressure to areas of low partial pressure. Removal of anesthetic from the alveolus is affected by the solubility of the anesthetic in blood (i.e., the blood:gas partition coefficient), cardiac output, and the difference in partial pressure between the alveolus and the venous blood entering the lung.
1. Minimum alveolar concentration (MAC). The MAC of an inhalant anesthetic is the alveolar concentration that prevents gross purposeful movement in 50% of patients in response to a standardized painful stimulus. The MAC is used as a measure of potency. MAC values for the most frequently used inhalant anesthetics are listed in Table 6-2.
(1) The anesthetic dose required to anesthetize 95% of animals is ~1.2–1.4 times the MAC. Surgical anesthesia levels are achieved by obtaining alveolar concentrations equal to 1.4–1.8 times the MAC.
(2) If two anesthetics are administered simultaneously, the MAC multiples are additive.
b. Factors affecting MAC values
(1) Hypothermia, severe hypotension, advanced age, pregnancy, severe hypoxemia, severe anemia, or the concurrent administration of certain drugs (e.g., opioids, tranquilizers) may decrease the MAC value for a particular patient.
(2) Hyperthermia or hyperthyroidism may increase the MAC value for a particular patient.
(3) The duration of anesthesia, patient gender, acid–base balance, and hypertension have no effect on the MAC value.
c. Relationship to lipid solubility. The Meyer–Overton Observation states that the oil:gas partition coefficient correlates inversely with anesthetic potency. The more lipid soluble the anesthetic, the lower the MAC and the higher the potency. Conversely, the lower the lipid solubility, the higher the MAC and the lower the potency (Table 6-3)
2. Blood:gas partition coefficient. The solubility of an agent is most commonly expressed in terms of a blood:gas partition coefficient. Solubility of the agent in blood correlates with the speed of induction and recovery. Table 6-3 contains the blood:gas partition coefficients for the inhalant anesthetics.
a. A high blood:gas partition coefficient indicates that the blood can hold a large amount of the anesthetic. Therefore, it will take longer to raise the alveolar partial pressure because the blood will keep absorbing the anesthetic as it is brought by ventilation to the alveolus.
b. In addition, it takes a long time before the blood is saturated with enough drug to cause diffusion of an adequate amount into the tissues. Therefore, induction and recovery are slow.
3. A plot of the ratio of concentration of anesthetic in the alveolus (FA) to the concentration inspired (FI) provides information about the various inhalant anesthetics (Figure 6-2).
TABLE 6-2. Minimum Alveolar Concentration (MAC) for Inhalant Anesthetics
TABLE 6-3. Inhalant Anesthetics in Decreasing order of Lipid Solubility
C. Administration
1. By controlling the anesthetic concentration in the alveolus, the anesthetist is controlling the anesthetic concentration in the brain. Because the inhalant anesthetics move in the body by diffusion, it is necessary to administer high concentrations to the lungs initially in order to establish the necessary partial pressure in the brain.
2. Most inhalant anesthetics are liquid at room temperature and require a vaporizer to form a safe and accurate vapor concentration to be inhaled by the patient.
a. The boiling point indicates what physical state the drug will be in at room temperature. If the boiling point is below room temperature (20°C), then the drug exists as a gas at room temperature (Table 6-4).
b. The vapor pressure of a liquid compound indicates how volatile it is and the maximum concentration that can be achieved (see Table 6-4).
(1) The higher the vapor pressure, the easier it is to vaporize the compound.
(2) The maximum concentration that can be achieved is calculated by dividing the vapor pressure by the atmospheric pressure (760 mm Hg at sea level) and multiplying by 100.
(3) To determine the volume of gaseous anesthetic that will result from the vaporization of a liquid anesthetic, the following formula can be used:
X is volume of liquid anesthetic (mL); SG is specific gravity (g/mL); GMW is gram molecular weight (g/mole); and V1 is the volume of anesthetic gas produced (mL).
The resultant volume (V1) assumes standard conditions of 1 atm of pressure (760 mm Hg) and 0°C. To convert the volume to room temperature (20°C) requires Charles’s law, which states that if pressure is held constant,
V1 is the volume of gas at 0°C (273°K); T1 is 273°K; V2 is the volume at room temperature; and T2 is the room temperature (293°K, 20°C).
Table 6-5 contains the specific gravity, gram molecular weight, and volume at room temperature for some of the common inhalant anesthetics.
FIGURE 6-2. The rise in the alveolar anesthetic concentration (FA) toward the inspired concentration (FI). The less soluble the anesthetic, the faster the rise in the ratio toward 1.0. Nitrous oxide has a more rapid rise than desflurane because of its greater inspired concentration.
TABLE 6-4. Physical–Chemical Properties of the Inhalant Anesthetics
TABLE 6-5. Physical–Chemical Properties of the Liquid Inhalant Anesthetics
FIGURE 6-3. Chemical structures of the inhalant anesthetics.
volume and temperature will vary directly.
D. Preparations. When selecting an anesthetic agent, physical examination and clinical test results, as well as the underlying condition necessitating anesthesia, are factors that must be considered when selecting an anesthetic agent.
1. Nitrous oxide
a. Chemistry (Figure 6-3). Nitrous oxide is an odorless, nonflammable, inorganic gas at room temperature. It will support combustion by dissociating into nitrogen and oxygen.
b. Pharmacokinetics
(1) Induction and recovery from anesthesia are rapid because of nitrous oxide’s extremely low solubility—the body quickly becomes saturated with the inhaled concentration.
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