Pharm Ii - Local Anesthetics

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Local Anesthetics

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Reversibly to block conduction of the nerve impulse.

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Local Anesthetics:
Indication

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These drugs are used primarily to provide localized analgesia for surgical procedures, to relieve chronic pain and to treat cardiac arrhythmias

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Local Anesthetics:
Structure

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Typical local anesthetics contain a hydrophilic group, usually a tertiary or secondary amine, linked by an alkyl chain to a hydrophobic aromatic group.

The linkage to the aromatic group is by an ester or amide link. Ester link is usually shorter acting compound, amide is longer acting

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Local Anesthetics:
Mechanism of action

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The local anesthetics modify sensation and motor function by blocking conduction of the nerve impulse through an action on the cell membrane.

The local anesthetic molecules decrease the extent to which depolarization activates the fast sodium channel. As a result, the threshold potential is shifted toward zero (excitability is decreased) and the transmembrane action potential is diminished in amplitude and rate of rise. These changes in electrophysiological properties first slow, and then block conduction and thus prevent transmission of signals in afferent and efferent fibers. In the concentrations needed to block conduction, the resting potential usually is not decreased. Local anesthetics also modify the potassium conductance of the resting nerve membrane but this action is not important in relation to therapeutic actions.

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Local Anesthetics:
Chemical properties

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Commonly used local anesthetics are weak bases with pKas varying from 7.6 to 8.9. At a normal blood pH local anesthetics exist as both free base (non-ionized) and protonated cation (ionized). It is the free base which diffuses more readily across barriers (neural sheaths and nerve membrane).

Most experimental evidence indicates that it is largely the charged form of the molecule, acting from the inner surface of the membrane, that causes the changes in electrical activity responsible for blockade of impulse propagation. Raising the external pH increases the rate of development and intensity of nerve block. This is because at high pH, most of the external local anesthetic molecules will exist in their unprotonated, neutral form in which they can readily diffuse across membranes and enter the axon. Lowering the internal pH will also increase the extent of nerve block. This is because at low internal pH, the protonated (charged) active form of local anesthetics will build up to a high concentration inside the axon.

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Local Anesthetics

Use-dependence

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The intensity of action of most local anesthetics varies with the rate of firing of a nerve. Typically, local anesthetics produce much less nerve block at low firing frequencies than they do at high firing frequencies. This property is referred to as use-dependent or frequency-dependent block.

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Local Anesthetics

Modulated-receptor theory

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The modulated-receptor theory attempts to explain use-dependent block in terms of the preferential binding of local anesthetic to the inactive form of the channel (I) relative to the resting form of the channel (R).

Channels in the inactive state at the resting potential are not available to open in response to a subsequent large depolarization. There is an allosteric conformational change at the local anesthetic binding site so that the inactive channel exhibits a higher affinity for local anesthetic compared to the affinity of the resting state

Normally KR >> KI. Binding of local anesthetic will stabilize the channel in the inactive state (ID). This slows the rate at which channels recover from inactivation and shifts the relationship between steady-state inactivation and resting potential to more negative voltages

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Local Anesthetics

Use-dependence and modulated-receptor theory

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According to this theory, at low stimulus rates there will be relatively little block with local anesthetics because most of the channels will be in the resting state, where they exhibit a low affinity for local anesthetics. At higher stimulus rates, channels will spend a greater proportion of time in the inactivated state where they exhibit a high affinity for local anesthetics. Thus, at high stimulus rates a much greater proportion of channels will bind local anesthetics and there will be a greater extent of channel block.

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Local Anesthetics

CNS effects

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All nitrogenous local anesthetics cause apparent stimulation (restlessness, convulsions) of the CNS, probably by blocking or depressing inhibitory neurons. At higher drug concentrations, all CNS activity is depressed.

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Local Anesthetics

CV effects

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Local anesthetics slow or block impulse propagation in the heart and decrease contractility. Also by direct and indirect action, most local anesthetics cause arteriolar dilation.

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Local Anesthetics

Effect on nerves

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Somatic sensory fibers and postganglionic autonomic nerve (visceral motor) fibers are small in diameter and are not covered with myelin sheath. These fibers are easily blocked with lower concentrations of local anesthetic.

Somatic motor and visceral sensory fibers are larger in diameter and myelinated. Higher concentrations of the anesthetic are required to block conduction.

The onset of block of motor nerves, if it occurs, is even slower. Therefore, one can produce analgesia and block of autonomic nervous function without complete loss of motor function.

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Local anesthetics

Neurotoxicty

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Local anesthetics can inhibit axoplasmic transport by disrupting the orderly structure of microtubules in a dose-dependent manner. With clinically used concentrations this action of local anesthetic is reversible. However, one should use the lowest concentration of local anesthetic solutions compatible with clinical effectiveness to avoid possible neurotoxicity.

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Local anesthetics and epinephrine

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Addition of epinephrine to the anesthetic solution (l:200,000) causes local vasoconstriction, delays absorption and prolongs the duration of analgesia. It also reduces the total amount of anesthetic needed.

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Local anesthetics

Metabolism

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Procaine, chloroprocaine and tetracaine (esters) for the most part are hydrolyzed in the plasma by pseudocholinesterase and to a small extent by the hepatic esterase.

Local anesthetics with the amide bond are biotransformed by hepatic microsomal enzymes.

The liver extracts 70% of lidocaine from blood passing through it.

Dealkylation of the amine radical, hydroxylation of the benzene ring and cleavage of the amide bond are known pathways of degradation. Metabolites of anesthetic esters and amides are excreted by the kidney.

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Local anesthetics

Toxicity

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Toxic reactions are almost always the result of overdose or accidental intravascular injection.

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Local anesthetics

Hypersensitivity

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True allergic reactions, manifested as dermatitis, bronchospasm and anaphylactic shock, are rare and can be attributed to the metabolite of anesthetic esters -- para-aminobenzoic acid. Since the anesthetic amides do not have this moiety, hypersensitivity to amide derivatives is extremely rare.

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Local anesthetics

CNS toxicity

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Central nervous system toxicity of local anesthetics is manifested primarily as convulsion, preceded by various symptoms and signs.

Convulsions induced by local anesthetics can be and should be terminated promptly using a fast-acting barbiturate such as thiopental or thiamylal intravenously. Diazepam also is effective. Supportive treatment (oxygen, artificial ventilation) is mandatory.

Because the anesthetic esters are hydrolyzed relatively rapidly, CNS toxicity caused by them usually is short in duration. With the amide derivatives, drug concentration in the blood (and therefore the brain) may remain high for some time because of their relatively slow rate of degradation. Consequently, convulsion may persist and require repeated treatment with the anticonvulsants.

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Local anesthetics

CV toxicity

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Local anesthetics depress the heart (negative chronotropic and inotropic actions) and dilate blood vessels. Hypotension and cardiovascular collapse may occur as a result of an overdose with or without CNS toxic symptoms and signs. Treat with fast-acting barbiturate (or diazepam) and vasopressors.

These toxic reactions are especially associated with bupivacaine, possibly due to a direct effect on cardiac contraction. Toxic reactions to bupivacaine are often fatal as there is not effective treatment for an overdose with this drug. Ropivicaine, a newer drug, has less cardiac toxicity.

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Bupivacaine

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Local anesthetic. Fatal CV toxic effects are associated with use, possibly due to a direct effect on cardiac contraction. Toxic reactions to bupivacaine are often fatal as there is not effective treatment for an overdose with this drug.

(BuPiVacation) risk heart attack and cv collapse -your blood pressure may take a vacation

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Procaine (Novocaine)

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Local anesthetic
Duration of action: 0.5-1.5 hrs
Ester linkage

Procaine might be Pro-inflammatory because of its PABA metabolite (hypersensitivity a concern)

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lidocaine (Xylocaine)

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Local anesthetic
Duration of action: 1-3 hrs
Amide linkage

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mepivacaine (Carbocaine)

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Local anesthetic
Duration of action: 1-3 hrs
Amide linkage