LOCAL ANESTHETICS

MODERATOR : Dr. CHANDRASHEKAR GUIDE : Dr.PRADEEP Presentation : Dr. SREELAKSHMI

Pharmacology of Local Anesthetics

History
Chemistry and Structure-Activity Relationships Mechanism of Action Pharmacological effects and toxicities

Pharmacology of Local Anesthetics - History

1860 Albert Niemann isolated crystals from the coca shrub and called it cocaine he found that it reversibly numbed his tongue! Sigmund Freud became aware of the mood altering properties of cocaine, and thought it might be useful in curing morphine addiction. Freud obtained a supply of cocaine (from Merck) and shared it with his friend Carl Koller, a junior intern in ophthalmology at the University of Vienna

1884 Following preliminary experiments using conjunctival sacs of various animals species, Koller did first eye surgery in humans using cocaine as local anesthetic 1905 German chemist Alfred Einhorn produced the first synthetic ester- type local anesthetic - novocaine (procaine) - retained the nerve locking properties, but lacked the powerful CNS actions of cocaine 1943 Swedish chemist Nils Lfgren synthesized the first amide-type local anesthetic - marketed under the name of xylocaine (lidocaine)

Chronology of local anesthetics

Cocaine Benzocaine Procaine Tetracaine Lidocaine Chloroprocaine Mepivacaine Bupivacaine Ropivacaine Niemann Salkowski Einhorn Eisler Lofgren Marks, Rubin Ekenstam Ekenstam Sandberg 1860 1895 1904 1928 1943 1949 1956 1957 1989 Ester Ester Ester Ester Amide Ester Amide Amide Amide

Amides and Esters

Lidocaine (Xylocaine) Bupivacaine (Marcaine) Etidocaine (Duranest) Mepivacaine (Carbocaine) Prilocaine (Citanest) Ropivacaine Chloroprocaine (Nesacaine) Cocaine (crack) Procaine Tetracaine (Pontocaine)

Pharmacology of Local Anesthetics - Chemistry

Structure-Activity Relationships:

All local anesthetics contain 3 structural components:

an aromatic ring (usually substituted) a connecting group which is either an ester (e.g., novocaine) or an amide (e.g. lidocaine) an ionizable amino group

Structure-Activity Relationships
Potency correlates with lipid solubility, that is, the ability of the local anesthetic molecule to penetrate membranes, a hydrophobic environment. Potency and lipid solubility increase with 1. an increase in the total number of carbon atoms in the molecule (molecular size) 2. increased by adding a halide to the aromatic ring (2chloroprocaine as opposed to procaine), 3. an ester linkage (procaine versus procainamide), 4. large alkyl groups on the tertiary amide nitrogen.

Onset of action
Onset of action depends on many factors, including lipid solubility and the relative concentration of the nonionized lipid-soluble form (B) and the ionized water-soluble form (BH+), expressed by the pKa. Local anesthetics with a pKa closest to physiological pH will have a higher concentration of nonionized base that can pass through the nerve cell membrane, and generally a more rapid onset. Exception is the relatively rapid onset of chloroprocaine, which has a high pKa. Moreover, not all local anesthetics exist in a charged form (eg, benzocaine); these anesthetics probably act by alternate mechanisms (eg, expanding the lipid membrane).

Local anesthetics are weak bases proportion of free base (R-NH2) and salt (R-NH3+) forms depends on pH and pK of amino group pH = pK + log [base]/[salt] (Henderson-Hasselbalch equation)

Example: Calculate the proportions of free base and salt forms of tetracaine (pK = 8.4) at pH (7.4). 7.4 = 8.4 + log [base]/[salt] log [base]/[salt] = -1

[base]/[salt] = 10-1 = 1/10

there is 10x more drug in the ionized than in the nonionized form at physiological pH

Duration of action
Duration of action is generally correlated with lipid solubility. 1. They are less likely to be cleared by blood flow. 2. Local anesthetics that are highly lipid soluble also exhibit a high degree of plasma protein binding, mostly to 1-acid glycoprotein and to a lesser extent to albumin; as a direct consequence, their elimination is prolonged. Sustained-release systems using liposomal encapsulation or microspheres for delivery of local anesthetics can significantly prolong their duration of action.

Mechanism of Action
Conduction of nerve impulses is mediated by action potential (AP) generation along axon Cationic form of anesthetic binds at inner surface of Na+ channel preventing Na+ influx (rising phase of membrane potential) which initiates AP blockade of nerve impulses (e.g., those mediating pain) LA slows impulse conduction ,the rate of rise and the magnitude of the action potential decrease, and the threshold for excitation is raised progressively until an action potential can no longer be generated and impulse propagation is abolished.

 Local anesthetics may also block calcium and potassium channels and N-methyl-D-aspartate (NMDA) receptors to varying degrees. Differences in these additional actions may be responsible for clinically observed differences between agents.

Conversely, other classes of drugs, most notably tricyclic antidepressants (amitriptyline), meperidine, volatile anesthetics, and ketamine also have sodium channel-blocking properties.

Mechanism of Action Local anesthetics bind to the open form of the Na+ channel from the cytoplasmic side of the neuronal membrane In contrast, a number of highly polar toxins (e.g., tetrodotoxin and saxitoxin) block the Na+ channel from the outer surface of the neuronal membrane

 1 larger subunit (260 kD) (has ion conducting path) 1 or 2 smaller subunits (30 kD) All subunits heavily glycosylated

Structural characteristics of Nav channels

Structural characteristics of Nav channels

4 domains have 6 membranespanning -helical segments (S1-S6) S5-S6 P-loop part of ion-conducting pore

Cytoplasm

Latest model for voltage-gating of ion channels

S1-S4 segments form voltage sensor Conventional models assume S4 moves in and out of lipid membrane Xray diffraction: S4-S3 hairpin loop, supports paddle

Pharmacological effects and toxicities

nerves: decrease or abolition of conduction vascular smooth muscle: vasodilatation

heart: decreased excitability (reduced pacemaker activity, prolongation of effective refractory period)
central nervous system: increased excitability, followed by generalized depression

Pharmacological effects and toxicities

Effects of local anesthetics on nerve conduction Na+ channels are present in all nerves and local anesthetics, at sufficient concentrations, can completely block action potential generation and conduction differential nerve blockade nerve fibres differ markedly in their susceptiblity to conduction blockage by local anesthetics (this is the basis of their clinical use) e.g., small, non-myelinated neurons mediating pain are much more susceptible that large, myelinated fibres mediating motor functions

Pharmacological effects and toxicities

Relative size and myelination and susceptibility to blockage by local anesthetics

Fibre type Type A alpha function proprioception, motor diameter (m) 12-20 myelination heavy susceptiblity to LA block +

beta
gamma delta Type B

touch, pressure
muscle spindles pain, temperature preganglionic

5-12
3-6 2-5 <3

heavy
heavy heavy light

++
++ +++ ++++

Type C dorsal root

pain

0.4-1.2

none

++++

Pharmacological effects and toxicities

Differential susceptibility of nerves to local anesthetics 1. In neuronal conduction, depolarizing current moves along nodes of Ranvier 2-3 successive nodes must be blocked to completely impair neuronal conduction

small fibres have smaller internodal distances - a shorter length of nerve fibre needs to be blocked to impair conduction as compared to larger nerve fibres

Pharmacological effects and toxicities

Differential susceptibility of nerves to local anesthetics (contd)
2. Anesthetic blockade of Na+ channels

exhibits use-dependence increased frequency of stimulation increased level of blockade

high stimulation frequency increases # of Na+ channels in the open form that preferentially binds anesthetic
neurons with high rates of firing

(e.g., pain fibres) or ectopic pacemakers in the myocardium will be highly susceptible to blockade by local anesthetics

Illustration of use-dependent local anesthetic neuronal blockade as stimulation frequency increases from 1 to 25, the downward Na+ current spike is progressively reduced.

Pharmacological effects and toxicities

Differential susceptibility of nerves to local anesthetics (contd)

3. In excitable tissues with long action potentials, probability of Na+ channels being in (susceptible) open form is increased enhanced susceptibility to blockade by local anesthetics e.g., pain fibres have long action potentials (3 millisec) versus motor fibres (0.5 millisec)
cardiac muscle has prolonged action potentials relative to other excitable tissues - myocardium highly susceptible to local anesthetics

Determinants of nerve fibre susceptibility

Nerve fibre size Degree of myelinisation and distance b/w the nodes of Ranvier Functional characteristics single axon with high frequency of impulse traffic are more sensitive to local anaesthetic blockade

Pharmacological effects and toxicities

Effects of local anesthetics on vascular smooth muscle Blockade of Na+ channels in vascular smooth muscle by local anesthetics vasodilatation consequences of vasodilatation:
enhanced rate of removal of anesthetic from site of administration (decreased duration of anesthetic action and increased risk of toxicity) hypotension (may be intensified by anesthetic-induced cardiodepression)

Pharmacological effects and toxicities

Effects of local anesthetics on vascular smooth muscle Anesthetic-induced vasodilatation can be counteracted by the concomitant administration of a vasoconstrictor Consequences of including vasoconstrictor: prolongation of anesthetic action decreased risk of toxicity decrease in bleeding from surgical manipulations

Pharmacological effects and toxicities

Effects of local anesthetics on heart
Local anesthetics can reduce myocardial excitability and pacemaker activity and also prolong the refractory period of myocardial tissue this is the basis of the antiarrhythmic effects of local anesthetics

Local anesthetic-induced myocardial depression (compounded by anestheticinduced hypotension) can also be a manifestation of toxicity and can lead to cardiovascular collapse and even death!

Pharmacological effects and toxicities

Effects of local anesthetics on CNS
As is the case with CNS depressants generally (e.g., alcohol) local anesthetics (at toxic doses) produce a biphasic pattern of excitation followed by depression The excitatory phase likely reflects the preferential blockade of inhibitory neurons and effects can range from mild hyperactivity to convulsions) The subsequent depressive phase can progress to cardiovascular collapse and even death if unmanaged.

Systemic Toxicity
Neurological
Symptoms include cicumoral numbness, tongue paresthesia, dizziness, tinnitus, blurred vision, restlessness, agitation, nervousness, paranoia, slurred speech, drowsiness, unconsciousness. Muscle twitching heralds the onset of tonic-clonic seizures with respiratory arrest to follow.

 Respiratory or metabolic acidosis increases the risks for CNS toxicity from local anesthetics. Elevated PaCO2 enhances cerebral blood flow and thus the anesthetic is delivered more rapidly to the brain. In addition, diffusion of carbon dioxide into neuronal cells decreases intracellular pH, which facilitates conversion of the base form of the drugs to the cationic form. The cationic form does not diffuse well across the nerve membrane, so ion trapping will occur, which will increase the apparent CNS toxicity of local anesthetics

Dose dependent toxicity

Plasma concentration (mic/ml) Effects 1-5 5-10 Analgesia Lightheadedness , tinnitus,numbness of the tounge Seizures ,unconsciousness Coma , respiratory arrest

10-15 15-25

>25

Cardiovascular depression

Cardiovascular System Toxicity

Direct Cardiac Effects Direct Peripheral Vascular Effects Indirect Cardiovascular Effects Effects of Acidosis and Hypoxia

Direct Cardiac Effects

The primary cardiac electrophysiologic effect of local anesthetics is a decrease in the rate of depolarization in the fast conducting tissues of Purkinje fibers and ventricular muscle. This reduction in rate is believed to be due to a decrease in the availability of fast sodium channels in cardiac membranes. Action potential duration and the effective refractory period are also decreased by local anesthetics.

 The electrophysiologic effects of various agents differ qualitatively. Bupivacaine depresses the rapid phase of depolarization (Vmax) in Purkinje fibers and ventricular muscle to a greater extent than lidocaine does. In addition, the rate of recovery from a use-dependent block is slower in bupivacaine-treated papillary muscles than in lidocaine-treated muscles. This slow rate of recovery results in incomplete restoration of Na+ channel availability between action potentials, particularly at high heart rates. These differential effects of lidocaine and bupivacaine have been advanced as explanations of the antiarrhythmic properties of lidocaine and the arrhythmogenic potential of bupivacaine.

 ECG - increase in the PR interval and duration of the QRS complex. Extremely high concentrations of local anesthetics depress spontaneous pacemaker activity in the sinus node, thereby resulting in sinus bradycardia and sinus arrest

Direct Peripheral Vascular Effects

Local anesthetics exert biphasic effects on peripheral vascular smooth muscle. Low concentrations of lidocaine and bupivacaine produced vasoconstriction in the cremaster muscle of rats, whereas high concentrations produced vasodilation in both isolated tissue models and in vivo. 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 to potentiate neurogenic vasoconstriction.

Comparative Cardiovascular Toxicity

The cardiotoxicity of bupivacaine appears to differ from that of lidocaine in the following manner: 1. The ratio of the dosage required for irreversible cardiovascular collapse (CC) and the dosage that will produce CNS toxicity (convulsions) (i.e., the CC/CNS ratio) is lower for bupivacaine and etidocaine than for lidocaine. 2. Ventricular arrhythmias and fatal ventricular fibrillation may occur more often after the rapid intravenous administration of a large dose of bupivacaine but far less frequently with lidocaine. 3. A pregnant animal or patient may be more sensitive to the cardiotoxic effects of bupivacaine than a nonpregnant animal or patients. 4. Cardiac resuscitation is more difficult after bupivacaineinduced cardiovascular collapse, and acidosis and hypoxia markedly potentiate the cardiotoxicity of bupivacaine.

Chiral Local Anesthetics: Ropivacaine and Levobupivacaine

Commercial bupivacaine is a racemic mixture of (R)- and (S)stereoisomers. In response to the problem of cardiovascular toxicity as a result of accidental intravenous injection of bupivacaine, single enantiomers were developed in the hope that they would be potentially safer local anesthetics. Ropivacaine and levo-(S)-bupivacaine were formulated to exploit this stereoselectivity. Ropivacaine is a single (S)-stereoisomer that differs from levobupivacaine in the substitution of a propyl for the butyl group on the piperidine ring . With these designed changes in molecular structure, it was hoped that ropivacaine and levobupivacaine would be less intrinsically cardiotoxic.

Treatment of Local Anesthetic Toxicity

LA-induced seizures should be managed by maintaining a patent airway and by providing oxygen. Seizures may be terminated with intravenous thiopental (12 mg/kg), midazolam (0.050.10 mg/kg), propofol (0.51.5 mg/kg), or a paralytic dose of succinylcholine (0.51 mg/kg) followed by mask ventilation or tracheal intubation.

 If LA CV depression is manifested by moderate hypotension, it may be treated by infusion of intravenous fluids and vasopressors (phenylephrine 0.55 mcg/kg/min, norepinephrine 0.020.2 mcg/kg/min, or vasopressin 40 mcg IV). If myocardial failure is present, epinephrine (115 mcg/kg IV bolus) may be required. When toxicity progresses to cardiac arrest, the guidelines for advanced cardiac life support are reasonable. With unresponsive bupivacaine cardiac toxicity, intravenous lipid or cardiopulmonary bypass should be considered.

Methemoglobinemia
Specific local anesthetic toxicity methemoglobinemia after the administration of large doses of prilocaine. In general, 600-mg doses are required for the development of clinically significant levels of methemoglobinemia in adults. Hepatic metabolism of prilocaine generates O-toluidine, which oxidizes hemoglobin to methemoglobin. Methemoglobinemia, if severe, may be treated by the intravenous administration of methylene blue. Standard dosing of the topical local anesthetic EMLA (a mixture of lidocaine and prilocaine) in term newborns produced minimal amounts of methemoglobin, and EMLA should be regarded as very safe in the great majority of newborns. Risk may be increased in newborns with rare metabolic disorders or after the concomitant administration of other drugs that impair reduction of methemoglobin.

True Allergic Reactions to LAs

Very uncommon Esters more likely because of p-aminobenzoic acid (allergen) Methylparaben preservative present in amides is also a known allergen

Local Anesthetic Musculoskeletal

Cause myonecrosis when injected directly into the muscle When steroid or epi added the myonecrosis is worsened Regeneration usually takes 3-4 weeks Ropivacaine produces less sereve muscle injury than bupivacaine

 Thank you

Mechanism of Action

Structures of two naturally occurring highly polar substances with powerful local anesthetic activity causing fatal paralysis tetrodotoxin (puffer fish) and saxitoxin (shell fish)

tetrodotoxin

saxitoxin

 The American surgeon William Halsted at Roosevelt Hospital in New York reported using cocaine to produce mandibular nerve block in 1884 and to produce brachial plexus block less than a year later. Leonard Corning injected cocaine near the spine of dogs, producing what was likely the first epidural in 1885. Spinal anesthesia was first accomplished in 1898 by August Bier.

Caudal epidural anesthesia was introduced in 1902 by Sicard and Cathelin.

Cocaine spinal anesthesia was used to treat cancer pain in 1898. Bier described intravenous regional anesthesia in 1909. Fidel Pages reported using epidural anesthesia for abdominal surgery in 1921.

Both free base and ionized forms of local anesthetic are necessary for activity: local anesthetic enters nerve fibre as neutral free base and the cationic form blocks conduction by interacting at inner surface of the Na+ channel