Local and General Anesthetics



Local and General Anesthetics



Classification of Local and General Anesthetics




aAlso tetracaine (PONTOCAINE) and proparacaine (OPHTHAINE). The first ester local anesthetic, procaine (NOVOCAIN) is no longer available.


bAlso levobupivacaine (CHIROCAINE), mepivacaine (CARBOCAINE), and dibucaine (NUPERCAINAL).


cAlso enflurane (ETHRANE).


dAlso sufentanil (SUFENTA), alfentanil (ALFENTA), and remifentanil (ULTIVA).


eDantrolene is not an anesthetic but rather is used to treat malignant hyperthermia.




Overview


Anesthesia is the loss of all sensation, whereas analgesia is the selective loss of pain sensation. Local anesthetics block the conduction of nerve impulses in the peripheral nerves or spinal cord. General anesthetics block cortical neuronal activity underlying consciousness and all sensation.


Local anesthetics, which are used to anesthetize a particular part or region of the body, are given to patients undergoing surgery on the skin and subcutaneous tissues, ears, eyes, joints, or pelvis. They are also used for anesthesia during labor and delivery and for diagnostic procedures such as gastrointestinal endoscopy. Occasionally, local anesthetics are used to relieve pain associated with pathologic conditions.


General anesthetics are used to prevent consciousness during major surgical procedures. Unlike local anesthetics, general anesthetics produce loss of consciousness and amnesia and thereby prevent the anesthetized patient from recalling the surgical procedure.



Local Anesthetics



Drug Properties


Chemistry and Pharmacokinetics


Based on their chemical structure, local anesthetics can be divided into ester-type drugs and amide-type drugs. Each local anesthetic has a lipophilic (hydrophobic) portion and a hydrophilic portion (Fig. 21-1). The hydrophilic portion, an amine that is a weak base, exists in both ionized and nonionized forms. The ionized, protonated form predominates at lower pH levels, and the nonionized, unprotonated form predominates at higher pH levels. Only the nonionized form can penetrate neuronal membranes to reach binding sites on the internal surface of sodium channels. Inflammation and acidosis decrease the pH of tissues, thereby increasing the ionization of local anesthetics. For this reason, local anesthetics are less effective in the presence of these conditions, necessitating larger doses.


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FIGURE 21-1 Structures of selected local anesthetics.

Local anesthetics are formulated as hydrochloride salts with a pH less than 7, as the ionized molecule is more soluble and stable than the free base. Once injected, the local anesthetic solution is quickly buffered to the pH of the tissue.


The duration of action of local anesthetics can be short, medium, or long (Table 21-1). Because local anesthetics act directly at the site of administration, their duration of action is determined primarily by the rate of diffusion and absorption away from the site of administration. Diffusion and absorption, in turn, depend on the chemical properties of the anesthetics and on such factors as local pH and blood flow. In some formulations, epinephrine is added to prolong a local anesthetic’s duration of action by producing vasoconstriction and slowing its rate of absorption. Because of the risk of ischemia and necrosis, however, local anesthetics with epinephrine are not used to anesthetize tissues with end arteries, such as tissues of the fingers, toes, ears, nose, and penis.



After systemic absorption, ester-type local anesthetics are metabolized in the plasma by butyrylcholinesterases to p-aminobenzoic acid (PABA) derivatives. Amide-type local anesthetics undergo metabolism by hepatic P450 enzymes to yield polar metabolites. In both cases, the metabolites are excreted in the urine.



Mechanism of Action


Local anesthetics cause a reversible inhibition of action potential conduction by binding to the sodium channel and decreasing the nerve membrane permeability to sodium. The nonpolar, lipophilic form of the anesthetic molecule passes through the neuronal membrane and switches to the polar, hydrophilic form in the cytoplasm of the neuron. This cationic form of the anesthetic binds to the cytoplasmic side of the sodium channel protein and prolongs the inactivation state of the sodium channel (Fig. 21-2). With sodium channels blocked, action potentials cannot propagate along the neuronal fiber, and sensory input is lost.


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FIGURE 21-2 Mechanisms of action of local anesthetics. A, The local anesthetic binds to sodium channels and blocks the generation and conduction of action potentials in peripheral neurons. B, The sodium channel includes four large transmembrane domains, each with six transmembrane spanning regions. The inactivation gate is a short, intracellular loop between domains 3 and 4. The local anesthetic binds to amino acid residues located on domain 4. C, The nonionized form of the local anesthetic (R—NH2) penetrates the axonal membrane and is then converted to the ionized form (R—NH3+). The ionized form binds to the sodium channel in the open state, and this prolongs the sodium channel inactivation state. Sodium entry is blocked during the inactivation state.


Pharmacologic Effects


Local anesthetics have a greater affinity for sodium channels that are in the depolarized (open) configuration than for channels that are closed. Nerve fibers that are firing, therefore, are more susceptible to sodium channel blockade. This use-dependent blockade causes a selective inhibition of nerve fibers that are stimulated by the surgical procedure, such as pain fibers during suturing. Size-dependent blockade refers to the finding that small diameter fibers are blocked more easily than are larger fibers. Small unmyelinated C and lightly myelinated Aδ pain fibers, therefore, are more easily anesthetized than are large myelinated touch fibers. Autonomic and sensory nerves are blocked more easily than are motor nerves. Nerves recover from blockade in the reverse order.



Adverse Effects and Interactions


The adverse effects of local anesthetics are primarily caused by their absorption into the systemic circulation and subsequent alteration of central nervous system (CNS), cardiovascular, and other organ system functions.


Local anesthetics often produce CNS stimulation (restlessness, tremor, and euphoria) followed by inhibition (drowsiness and sedation). Other symptoms of local anesthetic toxicity include headache, paresthesias, and nausea. Higher concentrations can cause seizures followed by coma. Death is usually caused by respiratory failure.


Adverse cardiovascular effects include hypotension and cardiac depression. Most local anesthetics are vasodilators, and they also block vasoconstriction induced by the sympathetic nervous system. Most local anesthetics have antiarrhythmic activity, but toxic levels of local anesthetics suppress cardiac conduction and can cause tachyarrhythmia characterized by a wide QRS complex.


Local anesthetic blockade of autonomic ganglia and neuromuscular transmission can lead to loss of visceral and skeletal muscle tone. For this reason, local anesthetics potentiate the effect of neuromuscular blocking drugs (e.g., atracurium) and must be used with great caution in patients with myasthenia gravis.


Allergic reactions to local anesthetics are fairly common. Patients who have repeated applications of topical anesthetics are particularly susceptible to sensitization. The ester-type anesthetics cause hypersensitivity reactions more frequently than do the amide-type anesthetics. This is because ester-type anesthetics (e.g., chloroprocaine) are metabolized to PABA. PABA causes allergic reactions in a small percentage of individuals. Patients who are allergic to an ester-type anesthetic will usually tolerate an amide-type anesthetic.


Recently, a greater appreciation of the dangers of even the apparently benign administration of topical local anesthetics has caught the attention of the U.S. Food and Drug Administration (FDA). They issued a new warning to highlight the risk of systemic absorption and cardiac abnormalities when topical anesthetics are used on large body surfaces or when subsequently covered. This may apply to women undergoing mammography or a number of other medical procedures.



Indications


Local anesthetics are usually administered parenterally but are sometimes applied topically. The route of administration depends on factors such as the site of anesthesia.



Topical Anesthesia

The topical application of local anesthetics is used to anesthetize the skin, mucous membranes, or cornea. A local anesthetic can be applied to the skin to treat pruritus (itching) caused by poison ivy, insect bites, eczema, or cutaneous manifestations of systemic diseases such as chickenpox (varicella). A eutectic mixture of local anesthetics (EMLA) consisting of two or more solid compounds that form a liquid when they are combined is sometimes used to anesthetize the skin before venipuncture or minor surgery. The topical application of a local anesthetic to mucous membranes can relieve pain caused by oral, nasal, laryngeal, or rectal disorders or surgery. For example, an anesthetic ointment is used to relieve the discomfort of hemorrhoids. The topical ocular administration of local anesthetics is used to anesthetize the cornea before diagnostic or surgical procedures (e.g., radial keratotomy), the removal of foreign bodies, and cataract surgery.






Spinal Intrathecal Anesthesia

Spinal anesthesia is used to block somatosensory and motor fibers during procedures such as surgery on the lower limb or pelvic structures. A local anesthetic is injected into the subarachnoid, intrathecal space below the level at which the spinal cord terminates. The spread of the anesthetic along the neuraxis is controlled by the horizontal tilt of the patient and by the specific gravity (baricity) of the local anesthetic solution. Hyperbaric solutions of local anesthetics are available for this purpose, and these spread along the neuraxis for about 15 minutes. By this time, they have mixed with cerebrospinal fluid to become isobaric and are said to be “fixed” at a certain level of the spinal cord. Spinal anesthesia can cause headaches associated with cerebrospinal fluid leakage from the lumbar puncture, and respiratory depression can occur if the anesthetic ascends too high up the spinal cord. Entry into the CNS by spinal injection also carries a small risk of infection or meningitis.




Specific Agents


Ester-Type Local Anesthetics


Cocaine, a naturally occurring plant alkaloid, was the first local anesthetic to be discovered. It has both local anesthetic and CNS stimulant properties, and it is the only local anesthetic that causes significant vasoconstriction as a result of its sympathomimetic effect. Because of its CNS effects and potential for abuse (see Chapter 25), cocaine is seldom used as a local anesthetic. It is occasionally used, however, to anesthetize the internal structures of the nose, where its vasoconstrictive action helps prevent bleeding after nasal surgery. A cocaine solution is applied to gauze and inserted into the nose for this purpose.


Procaine, the first synthetic local anesthetic drug to be prepared after the discovery of cocaine, became the standard of comparison for many years. It is no longer available but is included here because of its significance and the popularity of its trade name (NOVOCAIN). Procaine and chloroprocaine have a low potency and a relatively short duration of action. They are not effective after topical administration and must be administered parenterally. Both drugs are metabolized to PABA. For this reason, they are more likely to cause allergic reactions than are the amide-type local anesthetics. Tetracaine is another ester-type local anesthetic with a longer duration of action than procaine. It is used for infiltration anesthesia. It is also available in a topical spray and gel formulation in combination with butamben (butyl aminobenzoate) and benzocaine in a preparation called CETACAINE.


Benzocaine, a frequently used topical anesthetic, is available in a number of nonprescription products for the treatment of sunburn, pruritus, and other skin conditions. In some patients the drug causes hypersensitivity reactions, which can exacerbate preexisting dermatitis. Benzocaine is also used to anesthetize mucous membranes and is available in cough lozenges and sprays to relieve coughing.


Proparacaine is available in a 0.5% solution for instillation during eye surgery and other ophthalmic procedures.



Amide-Type Local Anesthetics


Lidocaine produces local anesthesia after topical or parenteral administration. The most widely used local anesthetic, it is available in a number of formulations. These include topical solutions and ointments, oral sprays, viscous gels for oral and laryngeal application, and various parenteral formulations. EMLA, a eutectic mixture of the local anesthetics lidocaine and prilocaine, is available as a cream to anesthetize intact skin to a depth of 5 mm. In pediatric patients, EMLA cream has been used for local anesthesia before venipuncture, intravenous cannulation, or circumcision. Lidocaine is also used for infiltration, nerve block, epidural, and spinal anesthesia. Lidocaine is also available as a transdermal patch (LIDODERM) approved for postherpetic neuralgia and widely used off label for conditions such as vertebral fractures.


Etidocaine has properties similar to those of lidocaine, but its duration of action is considerably longer. It is primarily used for infiltration and nerve block anesthesia.


Bupivacaine, mepivacaine, and ropivacaine have similar clinical uses but differ in their duration of action, as shown in Table 21-1. Bupivacaine has been the most widely used local anesthetic for obstetric anesthesia, but it causes cardiac depression more frequently than do many other local anesthetics. Bupivacaine is also available in a liposome-encapsulated formulation (EXPAREL) for long-acting analgesia in the treatment of postsurgical pain. Ropivacaine is a newer drug that may cause fewer cases of cardiac toxicity. Levobupivacaine is the isolated S(−)-stereoisomer of racemic bupivacaine, which is the active form of the chiral drug mixture. It is used in epidural anesthesia for labor and delivery.


Prilocaine is a congener of lidocaine. It is converted to O-toluidine, a toxic metabolite that can cause methemoglobinemia if it is allowed to accumulate. For this reason, prilocaine use is limited to topical and infiltration anesthesia.


Dibucaine is formulated in an ointment used to relieve the pain and itching of hemorrhoids (piles) and other problems in the rectal area.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Local and General Anesthetics

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