Local Anesthetics

Question 1

Local anesthetics

Answer 1

are drugs that produce reversible conduction blockade of impulses along central and peripheral nerve pathways following regional anesthesia. With progressive increases in concentrations of local anesthetics, the transmission of autonomic, somatic sensory, and somatic motor impulses is interrupted, producing autonomic nervous system blockade, sensory anesthesia, and skeletal muscle paralysis in the area innervated by the affected nerve. Removal of the local anesthetic is followed by spontaneous and complete return of nerve conduction with no evidence of structural damage to nerve fibers as a result of the drug effects.

Question 2

first local anesthetic

Answer 2

cocaine- was serendipitously discovered to have anesthetic properties in the late 19th century.
Cocaine was first isolated in 1806 by Albert Niemann. He like many chemist of that era, tasted this newly isolated compound and noted that it caused a numbing of the tongue.
Carl Koller introduced cocaine into clinical practice in 1884 as a topical anesthetic for ophthalmological surgery.
Halstead popularized its use in infiltration and conduction block anesthesia

Question 3

The basic components in the structure of local anesthetics are

Answer 3

(1) lipophilic aromatic portion
(2) intermediate chain- either an ester linkage or amide linkage
(3) hydrophilic amine portion

Question 4

The commonly used local anesthetics are classified as

Answer 4

ESTERS or AMIDES based upon the intermediate chain.
Changes in the amine or ring chemical structure result in marked alterations in lipid or aqueous solubility, potency and protein binding. The major differences between the esters and amides are metabolism (plasma cholinesterase versus liver) and allergic potential (ester greater than amide).

Question 5

These molecules are

Answer 5

tertiary amines (weak bases). The pKa of these molecules ranges between 7.5 and 9.5; thus at a pH of 7.4 most of the drug is in the charged (ionized) form. This is important because the uncharged ( conjugated ) base form of most agents is more lipid soluble and can therefore more rapidly reach the site of action ( the cell membrane ) where it can become ionized and interfere with Na+ channels. Also, a high lipid solubility is thought to increase the potency and duration of the drug effect because it ensures the drug remains on or at the site of action for a longer period.

Question 6

moa

Answer 6

When the nerve is active, Na+ channels in the membrane are triggered to open and the Na+ permeability increases so the membrane potential becomes less negative. If the membrane potential increases enough, additional Na+ channels open and a wave of depolarization is propagated along the length of the axon.
Local anesthetics block conduction by decreasing or preventing the large transient increases in the permeability of excitable membranes to Na+ that normally is produced by a slight depolarization of the membrane
This action of anesthetics is due to their direct interaction with voltage-gated Na+ channels. As the anesthetic action progressively develops in a nerve, the threshold for electrical excitability increases, the rate of rise of the action potential declines, impulse conduction slows, and the safety factor for conduction decreases; these factors decrease the probability of propagation of the action potential and nerve conduction fails

Question 7

SPECIFIC RECEPTOR THEORY

Answer 7

• all locals can exist as either the uncharged base or as an ionized cation
• the uncharged base is important for adequate penetration to the site of action, and the charged for of the molecule is required at the site of action.
• the cation appears to be required for binding to specific sites in the Na+ channels.
• thereby blocking the channel and interferes with the normal passage of Na+ through the cell membrane

Question 8

The degree of block produced by given concentration of local anesthetic depends on

Answer 8

how the nerve has been stimulated and on its resting membrane potential.

• –therefore a resting nerve is much less sensitive to a local anesthetic than is one that is repetitively stimulated—higher frequency of stimulation cause a greater degree of anesthetic block.
• –these effects occur because the local anesthetic molecule in its charged form gains access to its binding site within the pore only when the Na+ channel is in an open state and because the local anesthetic binds more tightly to and stabilizes the inactive state of the Na+ channel
• —In general the frequency and voltage dependence of local anesthetic depends critically on the rate of dissociation from the receptor site in the pore of the Na+ channel. A high frequency of stimulation is required for rapidly dissociating drugs so that drug binding during the action potential exceeds dissociation between action potentials

Question 9

DIFFERENTIAL SENSITIVITY OF NERVE FIBERS TO LOCAL ANESTHETICS

Answer 9

• as a general rule, small nerve fibers are more susceptible to the action of local anesthetics than are large fibers
• in general autonomic fibers, small unmyelinated C fibers (mediating pain sensations) and small myelinated A-DELTA fibers (mediating pain and temperature sensations) are blocked before larger A types (carrying postural, touch, pressure, and motor information)

Question 10

The differential rate of block exhibited by fibers of varying sizes and firing rates is

Answer 10

of considerable practical importance and appears to explain why local anesthetics affect the sensory functions of most nerves in a predictable order. Fortunately for the patient, the sensation of pain usually is the first modality to disappear; it is followed in turn by the sensations of cold, warmth, touch, deep pressure, and finally by motor function, although variation among individuals is great.

Question 11

VASOCONSTRICTOR ADDITION

Answer 11

The duration of action of a local anesthetic is proportional to the time during which it is in contact with the nerve. So procedures that keep the drug at the nerve prolonging the period of anesthesia. Cocaine itself constricts blood vessels by potentiating the action of norepinephrine—prevents its own absorption.
–in clinical practice, local anesthetics often contain a vasoconstrictor, usually epinephrine.

Question 12

vasoconstriction performs a dural service

Answer 12

By decreasing the rate of absorption (1) it not only localized the anesthetic at the desired site but (2)also allows the rate at which it is destroyed in the body to keep pace with the rate at which it is absorbed into circulation

• -use of local anesthetics containing vasoconstrictors during surgery of digits, hands, or feet resulting in prolonged constriction of the major arteries in the presence of limited collateral circulation could produce irreversible hypoxic damage, tissue necrosis, and gangrene
• -use with caution in patients with type 1 diabetes

Question 13

pharmokinetics

Answer 13

Local anesthetics are weak bases that have pKa values somewhat above physiologic pH. As a result, less than 50% of the local anesthetic exists in a lipid soluble nonionized form at physiologic pH. Acidosis in the environment into which the local anesthetic is injected further increases the ionized fraction of the drug. This is consistent with the poor quality of local anesthesia that often results when a local anesthetic in injected into an acidic infected area. Local anesthetics with pKa’s nearest to physiologic pH have the most rapid onset of action, reflecting the presence of an optimal ratio of ionized drug fraction. Intrinsic vasodilator activity will also influence apparent potency and duration of action.

Question 14

Absorption

Answer 14

of a local anesthetic from its site of injection into the systemic circulation is influenced by the site of injection and dosage, use of epinephrine, and pharmacologic characteristics of the drug. The ultimate plasma concentration of a local anesthetic is determined by the rate of tissue distribution and the rate of clearance of the drug. Lipid solubility of the local anesthetic is important in this redistribution as well as being a primary determinant of intrinsic local anesthetic potency. After distribution to highly perfused tissues, the local anesthetic is redistributed to less well perfused tissues including skeletal muscles and fat. Finally, the local anesthetic is eliminated from the plasma by metabolism and excretion.

Question 15

what will inflence absorption

Answer 15

In addition to tissue blood flow and lipid solubility of the local anesthetic, patient related factors such as age, cardiovascular status and hepatic function will also influence the absorption and resultant plasma concentrations of local anesthetics. Protein binding of local anesthetics will influence their distribution and excretion. In this regard, protein binding parallels lipid solubility of the local anesthetic and is inversely related to the plasma concentration of drug. Overall, amide local anesthetics are more widely distributed in tissues than ester local anesthetics following systemic absorption.

Question 16

Clearance values and elimination half times for amide local anesthetics

Answer 16

Clearance values and elimination half times for amide local anesthetics probably represent mainly hepatic metabolism, since renal excretion of unchanged drug is minimal. Pharmacokinetic studies of ester local anesthetics are limited because of a short elimination half time due to their rapid hydrolysis in the plasma and liver.

Question 17

esters

Answer 17

Ester local anesthetics are metabolized by pseudocholinesterase (plasma cholinesterase) and partially by red cell esterases. Hydrolysis occurs at the ester linkage and yields an alcohol and para-aminobenzoic acid (or a PABA derivative). Because ester local anesthetics are metabolized by pseudocholinesterase, toxicity and duration of blockade may be prolonged in patients with liver disease, in neonates or in atypical cholinesterase carriers

Question 18

amides

Answer 18

Amide local anesthetics are metabolized by the liver. Three main routes of biotransformation have been identified: aromatic hydroxylation, N-de-alkylation, and amide hydrolysis. Clearance of these agents varies in the following in the following order: bupivacaine< mepivacaine< lidocaine< etidocaine< prilocaine.
Liver disease affects metabolism of amide local anesthetics while having minimal effects on ester-linked compounds. In severe cirrhosis, the half life and volume of distribution of lidocaine are increased, while clearance is decreased by decreased enzyme activity and shunting. Liver enzyme-inducing agents, such as barbiturates, increase the systemic clearance of amide local anesthetics.

Question 19

esters

Answer 19

benzocaine
cocaine
procaine
chloroprocaine
tetracaine

Question 20

benzocaine

Answer 20

Almost insoluble in water. Limited to topical applications as in orotracheal administration.

Question 21

cocaine

Answer 21

Topical use only, usually for anesthesia of nasal mucosa for intubation or surgery. Safe dose is 3mg/kg. Sensitizes myocardium to catecholamines. Central nervous system (CNS) toxicity is initially excitatory with euphoria, then eventual depression. Cardiovascular side effects can be life threatening.

Question 22

procaine

Answer 22

Used mainly for skin infiltration and spinal blocks because of its low potency, slow onset, and short duration of action in peripheral nerve blocks.

Question 23

chloroprocaine

Answer 23

Rapid onset, low toxicity makes it ideal for labor and delivery. Used for infiltration, axillary, and epidural blocks, but usually intrathecal injection is avoided because of the possibility of prolonged deficits.

Question 24

tetracaine

Answer 24

Tetracaine remains a popular drug for spinal anesthesia because of its rapid onset, dense block, and long duration ( 4-6 hours with epinephrine). Tetracaine can also be used topically, although toxic reactions have been reported because of rapid uptake.

Question 25

amides

Answer 25

lidocaine
mepivacaine
Bupivacaine
Etidocaine

Question 26

lidocaine

Answer 26

Lidocaine is the most commonly used local anesthetic because of its potency, rapid onset, moderate duration of action, and versatility. It can be used for infiltration as well as peripheral and central nerve blocks in concentrations ranging from 0.5% to 2.0%.

Question 27

Mepivacaine

Answer 27

Can be used in the same manner as lidocaine. Duration of action is somewhat longer in the epidural space.

Question 28

Bupivacaine

Answer 28

Valued for its long duration in peripheral nerve and epidural blockade, also popular as an intrathecal agent. While duration of intrathecal blockade is similar to tetracaine, the frequency of satisfactory anesthesia may be greater with bupivacaine.

Question 29

Etidocaine

Answer 29

Etidocaine, while having a similar duration of action to bupivacaine, has a much shorter onset of anesthesia because it has greater lipid solubility. The degree of motor block is also more profound than that seen with bupivacaine, resulting in a block more suited to prolonged surgical procedures requiring muscle relaxants.

Question 30

TOXICITY OF LOCAL ANESTHETICS

Answer 30

Most episodes of local anesthetic toxicity result from high blood levels of local anesthetic that are caused either by accidental intravascular injection or by increased uptake from perivascular areas such as the epidural space or axillary sheath.

Prevention and treatment of local anesthetic toxicity depends on the injection of an appropriate volume and concentration of local anesthetic, knowledge of the pharmacologic properties of these drugs, and also increased vigilance for the early detection of toxic reactions.

Question 31

Central Nervous System Toxicity

Answer 31

CNS toxicity is proportional to local anesthetic potency. More potent, longer-acting drugs tend to be more toxic.
Initial symptoms are excitatory, resulting from a selective blockade of the inhibitory pathways. Eventual CNS depression and collapse develop as blood levels increase. The convulsive threshold is decreased by 50% in the presence of hypercarbia. An increase inPaCO2 increases cerebral blood flow, while a decrease in pH results in decreased protein binding ( more free drug available).

Question 32

Cardiovascular Toxicity

Answer 32

All local anesthetics cause a dose-dependent depression in myocardial contractility and also exhibit vasodilating properties ( with the exception of cocaine, a vasoconstrictor).
Myocardial depression is proportional to local anesthetic potency. Bupivacaine has also been associated with ventricular arrhythmias, perhaps because unidirectional conduction blockade resulted in a re-entrant pathway.

Question 33

ALLERGY TO LOCAL ANESTHETICS

Answer 33

True allergies to amide local anesthetics are extremely rare. Metabolism of ester local anesthetics yields para-aminobenzoic acid (PABA), which is a known allergen. It should be assumed that a patient who is allergic to PABA is allergic to ester local anesthetics. Methylparaben, a preservative in both ester and amide local anesthetic solutions, is also metabolized to PABA and may cause allergic reactions.

Question 34

DIAGNOSIS, PREVENTION AND TREATMENT OF TOXIC REACTIONS

Answer 34

Most toxic reactions to local anesthetics can be prevented through safe performance of neural blockade, including careful selection of local anesthetic dose and concentration, use of a test dose, and incremental injections with intermittent aspiration to decrease the risk of systemic toxicity during epidural anesthesia.
Patients should be closely monitored for signs of intravascular injection (increased blood pressure and heart rate in the presence of epinephrine) or signs of CNS toxicity. The judicious use of a benzodiazepine will raise the seizure threshold.

Question 35

Treatment of local anesthetic toxic reactions is similar to the management of other medial emergencies

Answer 35

airway, breathing, and circulation.
Most toxic reactions are limited to the CNS. Cardiovascular collapse with refractory ventricular fibrillation may occur, especially with bupivacaine. Sustained cardiopulmonary resuscitation and repeated cardioversion may be necessary. High doses of epinephrine are often required for circulatory support. Ventricular dysrhythmias should be treated with bretylium, rather than lidocaine.

Question 36

LOCAL ANESTHETIC PRESERVATIVES

Answer 36

Multiple dose vials of commercially prepared local anesthetic solutions contain 0.1% methylparaben as an antimicrobial agent. Methylparaben is effective against gram-positive bacteria and fungi but has limited effectiveness against gram-negative bacteria. This preservative agent has a chemical structure similar to that of para-aminobenzoic acid (PABA), sulfonamide antibiotics and ester type local anesthetics. All three of these classes of drugs are well known for their potential allergenic properties. In sensitive individuals, exposure to methylparaben may result in anaphylactoid symptoms, cutaneous lesions, urticaria or edema.

Question 37

ANTIOXIDANTS AND STABILIZERS

Answer 37

Commercially prepared ester-type local anesthetic solutions and epinephrine-containing amide-type local anesthetic solutions may contain one or more antioxidant or stabilizing agents including sodium metabisulfite, acetone sodium bisulfite, ascorbic acid, citric acid, EDTA, and monothioglycerol. These compounds are added to prolong shelf life of the product as well as to enhance its ability to withstand autoclaving. Although most of these innocuous chemicals are used commonly in the food and wine industry, sodium metabisulfite has two potentially serious toxicity problems

Question 38

Sulfiting agents can cause serious allergic reactions in sensitive individuals

Answer 38

including anaphylactic symptoms and asthmatic episodes. Known asthmatic patients have an increased risk of allergic reactions to these agents, but symptoms may occur in non-asthmatic individuals as well. Because these agents are ubiquitous in many common commercially prepared foods, most individuals will have received potentially sensitizing doses before administration of any metabisulfite-containing local anesthetic solution.

Question 39

Surface & infiltration anesthesia

Answer 39

Surface anesthesia: direct application of lidocaine, tetracaine or cocaine to mucosal membranes of mouth, nasal passage, throat or genitourinary tract; substantial systemic absorption may occur with possible CNS or CV toxicity; cannot use epinephrine as vasoconstrictor because it is not effective topically, but can use phenylephrine instead.

Infiltration anesthesia: direct injection of local anesthetic into tissue to be incised; may require large amounts

Question 40

uses

Answer 40

1. Field block: subcutaneous injection of local anesthetic in order to block nerves proximal to site of surgery; requires less drug than infiltration technique; requires good knowledge of neuroanatomy.
2. Nerve block: uses direct injection into peripheral nerves or nerve plexuses, e.g., brachial plexus, intercostals nerves, cervical plexus, etc.; onset depends upon penetration of unionized drug to nerve bundle; duration of local anesthesia depends on choice of drug (short=procaine; intermediate=lidocaine; long=bupivacaine or tetracaine).

Question 41

IV regional

Answer 41

usually best for surgery on hand or arm at or below elbow; requires exsanguination of limb (Esmarch bandage) and application of tourniquet, followed by injection of lidocaine (bupivacaine is not approved for iv regional techniques); about 15-30% of drug administered enters systemic circulation when tourniquet is removed.

Question 42

spinal anesthesia

Answer 42

injection of local anesthetic (lidocaine or tetracaine) into lumbar (usually) subarachnoid space; most frequent side effect is postural headaches; can get sympathetic block 2 segments above level of sensory block; CV consequences of a “high spinal” block include arteriolar dilation (compensated) and venous dilation (uncompensated) leading to severe hypotension and decreased cardiac output; best treatment is head-down tilt (10-15) and low-dose phenylephrine or ephedrine (venous vasoconstrictor with mild inotropic action, but less likely to increase TPR)

Question 43

Epidural anesthesia

Answer 43

lidocaine or bupivacaine commonly used; may get high potentially toxic levels of local anesthetic in systemic circulation; unlike spinal anesthesia, levels of sensory and sympathetic block are similar, but motor block may be more widespread; often used in childbirth (“saddle block”), but drugs do cross placenta where neonatal metabolism of amide anesthetics is impaired.