Section 2: Local Anesthetics (LAs)

A. Review of neuronal physiology B. Physicochemical properties of LAs C. Side effects

Local Anesthetics (LAs) LAs are used by a wide range of practitioners (prior to suturing a laceration, for example) as well as in more specific situations such as regional anesthesia practiced mainly by anesthesiologists (interscalene block prior to shoulder surgery). An understanding of pain physiology as well as the pharmacology of local anesthetics is needed by anyone using these drugs. Regional anesthesia involves the use of LAs at specific sites along the neuraxis not only for surgical anesthesia, but also for postoperative pain management. LAs can be used alone or in conjunction with other drugs such as epinephrine or clonidine when adjustment of speed of onset, duration of action, or depth of anesthesia is desired.

Section 2A: Neuronal Physiology

How is pain transmitted and where do local anesthetics work? When a surgeon makes a cut, for example, nerves sensing a noxious stimuli in that area are stimulated, resulting in an impulse that is transmitted from that peripheral site via nociceptive afferents to the central nervous system where perception of pain occurs (link to slide with pain pathway). Nerve impulses are electrical and are the result of a propagated ionic current. Local anesthetics work by blocking this current. How? First, a review of physiology of nerve conduction:

Like other cells, neurons maintain a resting potential through the active and passive diffusion of ions of about -70mV. The ionic concentration of sodium (Na+) is large outside the cell and low inside the cell whereas with potassium (K+) the opposite is true leading to a tendency of Na+ to flow in and K+ to flow out. This ionic gradient is maintained by the Na-K ATPase pump imbedded in the neural membrane. The membrane potential is due to the relative impermeability of Na+ across the membrane compared to K+ which is selectively permeable leading to a relatively greater concentration of anions within the cell due to this passive and active diffusion. Unlike many other tissues, however, neuronal membranes contain voltage-gated sodium and potassium ion channels. According to voltage-clamp studies using the Hodgkin-Huxley model, an action potential associated with a nerve impulse results initially in an upward swing due to the transient increased permeability of the membrane to Na+ resulting in an inward flux of Na+ ions and a transient increase in the resting potential from -90mV to +60mV. It is thought that the action potential causes a change in the conformation of the nerve membrane resulting in the opening of the Na+ channel within the membrane causing the inward flux. The action potential ends with the closure of the Na+ channel and the inactivation of the transient Na+ conductance. The action potential is propagated to adjacent nerve membranes that reach threshold voltage and depolarize. Potassium ion outflow is permitted by the almost simultaneous opening of K+ channels by a similar mechanism as that resulting in the inward flow of Na+.
http://hyperphysics.phy-astr.gsu.edu/hbase/biology/imgbio/actpot4

The resting membrane potential is restored by movement of the ions back to their initial intra- and extracellular concentrations by the Na-K ATPase pump.

How and where do local anesthetics exert their effect? The Sodium Channel
LAs block conduction in all neurons by impairing the function of the sodium channels involved in action potential generation. The voltage-gated sodium channel embedded in the neuronal membrane is a membrane-bound protein composed of one large -subunit and one or two smaller -subunits. Most local anesthetics bind the -subunit and block the channel from inside the cell. This prevents subsequent channel activation and influx of sodium ions resulting in membrane depolarization. The membrane is therefore stabilized and unaffected by further nerve stimulation. In other words, a noxious stimuli is no longer propagated as an impulse to the central nervous system and perceived as pain.

Image from Catterall WA, Golden AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev. 2005 Dec;57(4):397409.

The Sodium Channel, continued . . .

Local anesthetics bind with greatest affinity when the Na+ channel is in the activated or inactivated state rather than in the resting state. The resting membrane potential is not altered but as the concentration of drug increases, the rate of firing declines as conduction slows and the rate of rise and the amplitude of the action potential diminishes. Local anesthetics have their greatest effect when nerves are firing rapidly. The above blockade mechanism is true for ester and amide local anesthetics. However, benzocaine is believed to exert its effect via membrane expansion and Na+ channel distortion. Interestingly, biotoxins like tetrodotoxin alter the Na+ channel extracellularly.

How do LAs reach the intracellular binding site? LAs are weak bases and exist in the body outside the neuronal membrane as a mixture of the uncharged base and charged cationic form (more on our friends Henderson and Hasselbach later). The form that penetrates the hydrophobic cell membrane is the lipid-soluble, uncharged base form. Once inside the cell, there is reequilibration in accord with the pKa of the drug and the cationic form is the one which actually binds to an anionic site within the Na+ channel. In addition to the increased binding of LA to rapidly-firing neurons, nerve fiber (link back to prior slide) type determines LA sensitivity. Most simply, smaller diameter, unmyelinated fibers are most sensitive to LAs.

Section 2B: Physicochemical Properties of LAs Chemical Structure

The chemistry of the most commonly used LAs is most easily described by dividing them into two categories: ester- and amide-linked amines.

Structure
1) An aromatic group (benzene ring) at one end contributes to the lipophilic nature of the drug, allowing it to pass through nerve membranes to site of action at Na+ channel. The hydrophilic group at the other end is a tertiary amine which becomes ionized in the presence of H+. The bond between the lipophilic and amine ends of the molecule is either an ester- or amide-linkage. (Here lidocaine contains an amide-linkage while procaine has an ester-linkage).

2)

3)

Chemical Structures of Common LAs

http://www.med-ed.virginia.edu/courseSites/display.cfm?keyID=181&click=0

Drug Amides Bupivacaine (Marcaine) Etidocaine (Duranest) Lidocaine (Xylocaine) Mepivacaine (Carbocaine) Prilocaine (Citanest) Ropivacaine Esters Chloroprocaine Coccaine Procaine Tetracaine

Potency and Lipid pKa Solubility ++++ ++++ ++ ++ ++ ++++ + ++ + ++++ 8.1 7.7 7.8 7.6 7.8 8.1 9.0 8.7 8.9 8.2

Duration and protein binding ++++ ++++ ++ ++ ++ ++++ + ++ + +++

Section 2B: Physicochemical Properties of LAs - Chemical and Structural Relationships

Chemical structure, lipid solubility, protein binding, ionization, and chiral forms contribute and correlate to the potency, onset, duration of action, and toxicity of LAs.

Structure and Potency

The structural differences between LAs is determined by substitutions to the aromatic ring, the type of linkage of the intermediate chain, and the alkyl groups attached to the amine nitrogen. (Link to slide with structures.) The degree to which a LA is hydrophilic or lipophilic is determined by the size of the alkyl groups on or near the ends of the molecule. Increasing the size of these groups increases the hydrophobicity, or lipid solubility, of the molecule. Lipid solubility correlates with potency in that, generally, both potency and lipid solubility increase with the total number of carbon atoms in the molecule. For example, etidocaine has three more carbon atoms than lidocaine at the amine end and is more potent and longer-acting as a result. (Link to table) The measure of relative potency is affected by many factors including nerve fiber characteristics (size, degree of myelination), frequency of nerve stimulation, and environmental factors like pH and electrolyte concentrations (hypokalemia and hypercalcemia antagonize blockade).

Structure and Duration of Action

Lipophilicity is also associated with longer duration of action. All LAs exist in large part bound to plasma and tissue proteins and the bound form is generally inactive but does serve as a reservoir. Albumin and alpha1-acid glycoprotein (AAGP) are the two major proteins that bind LAs in the body. Albumin shows low-affinity high-capacity binding while AAGP shows high-affinity low-capacity binding. The fraction of drug bound to plasma proteins correlates with duration of LA activity presumably because the drug is cleared more slowly by blood flow. Highly lipophilic drugs tend to bind more strongly to AAGP and albumin and therefore have a longer duration of action. It has been thought that the bond between the LA the the Na+ channel may be similar to that between the LA and plasma proteins such that greater protein binding in the plasma and tissues correlates to longer duration of binding to the Na+ channel and longer duration of anesthesia. Duration of action is also affected by the use of epinephrine as a chemical tourniquet causing local vasoconstriction and decreasing the elimination of the drug.

Ionization and Speed of Onset

Ionization of the hydrophilic amino group is determined by the pKa of the LA and the pH of the medium. This then determines the amount of uncharged base form (that can pass through the nerve membrane) and cation form (that binds the Na+ channel) of drug present in solution by the Henderson-Hasselbach equation:

pH = pKa + log (base / cation)

Because LAs have a pKa greater than 7.6 (link to table) (greater than physiologic pH of 7.4), they will exist in equilibrium at in the body with a greater fraction present in the cationic form; this fraction decreases as the pKa gets closer to physiologic pH. By increasing the fraction present in the uncharged, base form, the onset-time will decrease as more drug is able to cross neuronal membranes. In other words, drugs with a lower pKa will generally have a shorter onset time. However, in vivo, the pKa is not always directly correlated with speed of onset as it is with isolated fibers in vitro. For example, chloroprocaine has a pKa of 9.0 and a very rapid speed of onset (see table) which is thought to be due to the high percentage of chloroprocaine used (3%). Other factors such as speed of diffusion through tissues also plays a role. Other clinical implications of ionization characteristics exist. The tendency to be protonated is affected when the pH of the environment changes. For example, in inflammed or infected tissues, the pH tends to be lower due to lactic acidosis. This then causes more of the LA to exist in the protonated form slowing the speed of onset. Commercially available preparations of LAs are water-soluble hydrochloride salts with pH 6.0-7.0. If the solution contains epinephrine, however, the pH must be lowered as epinephrine is not stable at higher pHs. This slows the speed of onset as more of the LA is protonated. Repeated dosing of LAs also decreases effectiveness as salt forms of the drug exhausts the local buffering capacity of the tissue leading to refractoriness. Clinical Pearl: Some practitioners add sodium bicarbonate to lidocaine and mepivacaine (not to bupivacaine or ropivacaine) to increase the amount of LA in the base form and increase speed of onset.

Chiral Forms
Back in the days of biochemistry we learned that stereoisomers of molecules exist when there is an asymmetric carbon present within the molecule. An asymmetric carbon is one that has four distinctly different substitution groups. In the image shown here, the asymmetric carbons of the two enantiomers of bupivacaine are shown with an asterix. The R and S isomers are labeled Dextroand Levobupivacaine, respectively. The importance of stereoisomers of local anesthetics lies in differences in potency and toxicity that exists between different forms. Many commercial drug preparations of LAs are a mixture of the R- and S-isomers, also called racemic mixtures. As a general rule, when differences exist between isomers, the S form is less toxic and has a longer duration of action. For example, infiltration anesthesia with levobupivacaine shows longer duration of action and lower systemic toxicity when compared with dextrobupivacaine.

Structure of Ropivacaine
Ropivacaine was developed solely as an Senantiomer due to the evidence that levobupivacaine (the S-enantiomer of bupivicaine) was less toxic.

Sidebotham DA. Schug SA. Stereochemistry in anaesthesia. [Review] [42 refs] [Journal Article. Review] Clinical & Experimental Pharmacology & Physiology. 24(2):126-30, 1997 Feb.

Differential Motor and Sensory Blockade

Since local anesthetics are capable of blocking all nerves, their actions are not limited to the desired loss of sensation from sites of noxious (painful) stimuli. Nerve fibers differ significantly in their susceptibility to local anesthetic blockade on the basis of differences in size and degree of myelination (link to slide). Upon direct application of a local anesthetic to a nerve root, the smaller B and C fibers are blocked first, followed by those associated with other functions, and motor function is the last to be blocked. This is known as differential blockade. Depending on the concentration of LA around a nerve, it has been shown that some LAs can provide sensory blockade without impairing motor response as well. This is especially true for ropivacaine and bupivacaine, but not for etidocaine. The inablity of etidocaine to produce differential motor-sensory impairment has been attributed to its high lipophilicity and ease of blocking both myelinated and unmyelinated nerve fibers. Clinical Pearl: Sensory blockade without motor impairment is desired in such fields as obstetrics and postoperative analgesia in which low concentrations of bupivacaine and ropivacaine provide analgesia without impairing motor strength needed in labor or ambulation.

Absorption, Distribution, and Metabolism

Absorption Systemic absorption following local injection or application depends on blood flow and is determined by the following factors: 1) Site of injection-The rate of absorption is related to the vascularity at the injection site. intravenous > tracheal > intercostal > caudal > paracervical > epidural > brachial plexus > sciatic > subcutaneous 2) Presence of vasoconstrictor-The addition of epinephrine, and occasionally phenylephrine, decreases vascular absorption leading to increased neuronal uptake. This enhances the quality of analgesia, increases duration of action, and limits toxic side effects. The effect is more pronounced with shorter-acting LAs like lidocaine. Epinephrine also prolongs and augments analgesia through activation of 2-adrenergic receptors. 3) Local Anesthetic Agent-LAs that bind avidly to local tissues are more slowly absorbed. They also differ in intrinsic vasodilator properties. Distribution Organ uptake depends on the degree of tissue profusion, the tissue/blood partition coefficient, and organ mass. -Highly perfused organs such as brain, lungs, liver, kidney, and heart have more rapid uptake than less-highly perfused organs like muscle and fat. -Strong plasma protein binding retains LAs in the blood whereas high lipid solubility facilitates tissue uptake. -Massive organs like muscle provide a large reservoir of drug.

Metabolism An ester or amide-linkage between the lipophilic and hydrophilic ends of the LA molecule determines metabolism. Esters: Ester LAs are metabolized predominantly by plasma pseudocholinesterase. Hydrolysis is rapid and the water-soluble metabolites are excreted in the urine. The rate of hydrolysis depends on the type and location of the substitutions present on the aromatic ring. Clinical Pearls: Procaine and benzocaine are metabolized to p-aminobenzoic acid (PABA) which has been associated with allergic reactions. Patients with genetically abnormal pseudocholinesterase are at increased risk for toxic side effects as metabolism is slower. Amides: These LAs are transported in the circulation from the neural site of injection to the liver prior to metabolism by dealkalization or hydroxylation. Therefore, clearance is determined by hepatic blood flow and hepatic function. Drugs such as general anesthetics, norepinephrine, cimetidine, and propranolol, among others, decrease hepatic blood flow and increase the half-life of these LAs. Decreased hepatic function can be caused by hypothermia, immature hepatic enzyme system, or liver damage.

Section 2C: Side Effects of LAs

LAs block voltage-gated Na+ channels affecting propagation of action potentials throughout the body, not just in nerve cells. Toxicity is often directly proportional to potency and mixtures should be considered to have additive effects. (link to next slide with chart of drugs). Systemic toxicity primarily involves the central nervous system (CNS) and cardiovascular system. CNS symptoms are usually seen before cardiovascular due to higher susceptibility to LAs. Central Nervous System Early symptoms: circumoral numbness, tongue paresthesia, dizziness, tinnitus, blurred vision Excitatory symptoms: restlessness, agitation, nervousness, paranoia, muscle twitches Depressive symptoms: slurred speech, drowsiness, loss of consciousness, respiratory depression Seizures: Ultimately, generalized tonic-clonic seizures will result Clinical Pearl: Seizures produce hypoventilation resulting in combined metabolic and respiratory acidosis enhancing CNS toxicity. Respiratory or metabolic acidosis and elevated PaCO2 enhances cerebral bloodflow delivering more LA to the brain. It also increases the amount of CO2 in neurons thus raising intracellular pH trapping cations within the cell. By decreasing cerebral blood flow and drug exposure, benzodiazepines and hyperventilation raise the threshold for LA-induced seizures. Thiopental quickly and reliably ends seizures but adequate ventilation and oxygenation must be maintained.

Cardiovascular: Local anesthetics affect the heart and peripheral blood vessels directly and indirectly via inhibition of Na+ channels and the autonomic nervous system. Direct Cardiac Effects
Cardiac muscle Na+ channel blockade and autonomic nervous system inhibition-->depressed myocardial automaticity and reduced refractory period duration At higher concentrations contractility and conduction velocity are also reduced.

Direct Peripheral Vascular Effects

LAs have a biphasic effect on vascular smooth muscle producing vasoconstriction at lower doses and vasodilation at higher doses leading to hypotension. **Cocaine is the only local anesthetic that consistently causes vasoconstriction at all concentrations because of its ability to inhibit the uptake of norepinephrine by premotor neurons and thus potentiate neurogenic vasoconstriction. More potent drugs such as bupivacaine and etidocaine produce profound cardiovascular (CV) depression in the following manner: The ratio of the dosage causing irreversible CV collapse and that producing CNS toxicity is lower Ventricular arrhythmias and fatal ventricular fibrillation may occur more often Pregnant patients may be more sensitive to cardiotoxic effects Resuscitation is more difficult after bupivacaine-induced CV collapse (the R-isomer avidly blocks Na+ channels, dissociates slowly, and has a high degree of protein binding) Acidosis and hypoxia potentiate cardiotoxicity of bupivacaine

Agent Esters Benzocaine Chloroprocaine

Uses

Available Concentration

Max dose (mg/kg)

Duration (min)

Max dose with epi (mg)

Duration with epi (min)

Topical Epidural, infiltration, PNB Topical Spinal, infiltration, PNB Spinal, topical

20% 1%, 2%, 3% 12

30-60 30-60 1000 30

Cocaine Procaine

4%, 10% 1%, 2%, 10%

3 12

30-60 20-60 600 30

Tetracaine Amides Bupivacaine

0.2%, 0.3%, 0.5%, 1%, 2%

90-400

Epidural, spinal, infiltration, PNB PNB Epidural, spinal, PNB, IV regional, topical Epidural, infiltration, PNB PNB Epidural, spinal, infiltration, PNB

0.25, 0.5, 0.75%

90-240

225

180

Etidocaine Lidocaine

0.5, 1.0% 0.5, 1, 1.5, 2, 4, 5%

4.5 4.5

120-180 30-120

400 500

180 120

Mepivacaine

1, 1.5, 2, 3%

4.5

45-90

500

120

Prilocaine Ropivacaine

4% 0.2, 0.5, 0.75, 1%

8 3

30-90 90-500

600

120

PNB = Peripheral nerve block Adapted from Morgan, Mikael, and Murrays Clinical Anesthesia and Millers Anesthesia

Respiratory: Lidocaine depresses hypoxic drive. Apnea can result from phrenic and intercostal nerve paralysis or depression of the medullary respiratory center due to direct exposure to LA agents. Local anesthetics relax bronchial smooth but can cause bronchospasm in patients with reactive airway disease. Hypersensitivity Reactions: These reactions are uncommon but are more likely to be caused by esters as they are derivatives of PABA. Many commercial preparations contain the preservative methylparaben which has a structure similar to PABA and may cause the rare reactions to amide agents.. Musculoskeletal: Direct muscle injection of LAs (bupivacaine>lidocaine>procaine) causes myofibril hypercontraction, then lytic degeneration, edema, and necrosis. Hematological: Methemoglobulinemia - This can result after large doses of prilocaine and benzocaine. The metabolism of prilocaine in the liver results in the formation of O-toluidine, which is responsible for the oxidation of hemoglobin to methemoglobin. It is reversible with methylene blue. It has also been demonstrated that lidocaine decreases coagulation and enhances fibrinolysis.

Dermatomes and peripheral nerves-anterior view

http://www.regionalabc.org/images/med-illustartion/ant-dermatome.jpg

Dermatomes and peripheral nerves-posterior view

http://www.regionalabc.org/images/med-illustartion/post-dermatome.jpg