LOCAL ANESTHETICS GUIDES: DR VINAY JOSHI DR MANOJ KAMAL

PRESENTED BY : DR SHIKHA SONI

General Structure

A lipophilic groupusually a benzene ring y A Hydrophilic groupusually a tertiary amine y These are connected by an intermediate chain that includes an ester or amide linkage y LAs are weak bases
y

Amides and Esters

y y y y y y

Lidocaine (Xylocaine) Bupivacaine (Marcaine) Etidocaine (Duranest) Mepivacaine (Carbocaine) Prilocaine (Citanest) Ropivacaine

y y y y

Chloroprocaine (Nesacaine) Cocaine (crack) Procaine Tetracaine (Pontocaine)

PROPERTIES

AMINOESTERS
rapid by plasma cholinesterase less likely possible - PABA derivatives form breaks down in ampules (heat,sun) slow as a general rule higher than PH = 7.4 (8.58.9)

AMINOAMIDES

Metabolism Systemic toxicity Allergic reaction Stability in solution Onset of action

slow, hepatic

more likely

very rare

very stable chemically

moderate to fast close to PH = 7.4 (7.6-8.1)

pKa's

Local Anesthetics
y

Used at multiple sites throughout the body:

Epidural Spinal Peripheral nerve blocks IV (Bier Block) Skin sites locally

MECHANISM OF ACTION
Local anesthetics work in general by binding to sodium channel receptors inside the cell and thereby inhibiting action potentials in a given axon. They work the best when the axon is firing. y The Cell membrane consists of ion pumps, most notably the Na/K pump that create a negative 70mV resting potential by pumping 2 K+ intracellular for every 3 Na+ it pumps extracellular.
y

MECHANISM (contd)
If the resting potential encounters the proper chemical, mechanical or electrical stimuli to reduce the membrane potential to less than -55 mV then an action potential is produced that allows the influx of sodium ions. LA act here to block the Na influx. y The influx allows the membrane potential to further increase to +35mV temporarily. y Sodium and potassium channels along with the sodium/potassium pump eventually returning a given axon back to its resting membrane potential after an action potential.
y

Activity of local anesthetics is a function of their lipid solubility, diffusibility, affinity diffusibility, for protein binding, percent ionization at physiologic pH, and vasodilating properties

Lipid solubility
y

Most lipid soluble:

Tetracaine Bupivicaine Ropivacaine Etidocaine

Increased lipid solubility also equals greater potency and longer duration of action.
Why? Because it has less of a chance of being cleared by blood flow

Decreased lipid solubility means a faster onset of action. y What else effects onset of action???
y

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. y The charged cation form more avidly binds to the Na+ channel receptors inside the cell membrane. y pKa > 7.4 more cations, pKa < 7.4 more anions
y

y y y

The potency of Local Anesthetics, their onset and duration of action are primary determined by physicochemical properties of various agents and their inherent vasodilator activity of same local anesthetics. Lipid solubility is the primary determinant of anesthetic potency and it is expressed as lipid: water Partition Coefficient Protein binding influences the duration of action pKa of Local anesthetics determines the onset of action The addition of vasoconstrictors, such as epinephrine or phenylephrine can prolong duration of action of local anesthetics, decrease their absorption (and the peak plasma level) and enhance the blockade.

Infiltration plain sol'n With Epinephrine Chloroprocain e

Spinal plain With Epinephrine

Epidural plain sol'n With Epinephrine

30-45 45-60 Hyperbaric 60 60-90

Lidocaine

60-120 90-180

80-120 120-180

Mepivacaine

90-140 140-200 Hyperbaric 120-180 180-400 140-200 160-220 Hyperbaric 120-360 120-360

Tetracaine

Ropivacaine

Bupivacaine

180-360 300-480

180-360 120-240

Absorption
Intravenous > tracheal > intercostal > caudal > paracervical > epidural> brachial plexus > sciatic > subcutaneous y Mucous membranes easily absorb LA as compared to skin. y Presence of vasoconstrictors & high tissue binding decrease absorption.
y

Metabolism
y

Amides
N-dealkylation and hydroxylation P-450 enzymes, liver, slower process than esterase activity Prilocaine>lidocaine>mepivacaine>ropivacaine>bupiv acaine

Esters
Pseudocholinesterase Procaine and benzocaine are metabolized to PABA (p-aminobenzoic acid) allergy risk
Tetracaine intrathecal no esterase activity intrathecally therefore absorption into bloodstream terminates its action

TOXICITY
SYSTEMIC:

of voltaged-gated Na channel affects action potential propagation throughout the bodytherefore the potential is present for systemic toxicity. Mixtures of LA have additive affects i.e. a 50% toxic dose of lidocaine and a 50% toxic dose of bupivicaine have 100% the toxic affect of either drug TYPES - CNS(usually preceed cvs) CVS ALLERGIC METABOLIC(methemoglobinemia)
LOCALISED

Blockage

NERVE DAMAGE

AGENT Procaine 0.5-1% (Novocain) Chloroprocaine 2-3% (Nesacain) Tetracaine 0.1-0.5% (Pontocain) Lidocaine 1-5% (Xylocaine) Mepivacaine 1.5% (Carbocaine) Bupivacaine 0.25-0.75% (Marcainesensorcaine) Etidocaine 0.5-1.5% (Duranest)

Potency
1 4 16 1 1 4 4

onset
Rapid Rapid Slow Rapid Mod Slow Rapid

pKa 8.9 8.7 8.5 7.9 7.6 8.1 7.7

%P B 5.8 ? 75.6 64.3 77.5 95.6 94

P. coef 0.02 0.14 4.1 2.9 0.8 27.5 141

Prilocaine

7.9

55

0.9

Ropivacaine 0.75% (Naropin)

Mod

8.1

94

2.9

CNS TOXICITY
y y y y y y

LIGHTHEADEDNESS f/b DIZZINESS VISUAL TROUBLES & TINNITUS DISORIENTATION & DROWSINESS TWITCHING & TREMORS f/b GTCS CNS EXITATION f/b DEPRESSION RESPIRATORY DEPRESSION & APNEOA:

-Respiratory center may be depressed (medullary)postretrobulbar apnea syndrome -Lidocaine depresses hypoxic respiratory drive (PaO2) -Direct paralysis of phrenic or intercostal nerves

EXACERBATING FACTORS:
Respiratory acidosis y Metabolic acidosis
y
PaCO2 or pH

CBF

portion of free drug available for diffusion into brain

TREATMENT
Identify the problem clinically y Seizure treatment:
y

Thiopental 1-2mg/kg abruptly terminates seizure activity Midazolam is also equally effective BZDs and hyperventilationdecrease CBF and therefore drug exposure. These raise the threshold of local anesthetic-induced seizures Severe cases need intubation & ventilatory & circulatory support

CVS TOXICITY
y

Alteration in the excitatory mechanism

slower depolarization decreased HR prolonged PR interval widened QRS

Arrythmias
bradycardia ectopic beats ventricular fibrillation

Decreased cardiac output on the basis of

HR contractility

-ve ionotropicity is directly proportional to the potency of drug used

Na conductance

APD &

ERP

rate of depolarisation in fast conducting fibres of heart ie. Purkinje fibres & ventricular muscles

Bupivacaine v/s Lignocaine

More reduction in rapid depolarisation of fast muscles of heart y Rate of recovery of the muscle from the block is slower so Na+ channels are less restored in b/w two APs y This accounts for the carditoxic arrythmogenic action of bupivacine while xylocaine being less pronounced is used as antiarrythemic
y

Treatment
Basic Life Support y Cardiac support should be continued as ACLS dictates y intubation, vasopressors, appropriate defibrillation, fluids, stop injection of LA, y Epinephrine and vasopresin should likely both be used in the resusitation efforts
y y

Lipid rescue: Intralipid Bolus 1.5cc/kg of 20% intralipid (100 ml in adults) 0.25cc/kg/min of 20% intralipid for 10 minutes Bolus can be repeated every 5 minutes up to a maximum of 8cc/kg of 20% intralipid

Possible mechanisms
lipid infusion may create plasma lipid droplets capable of segregating uncharged bupivacaine molecules from plasma, which makes them unavailable for interaction at their target sites y bupivacaine molecules preferentially segregated from plasma to their lipid infusion in a 1:12 ratio y greater segregation of bupivacaine into lipid may occur with large reductions in particle size to the dimension of the nanometer. y lipid or its component fatty acids either interact in a clinically significant way with tissue bupivacaine molecules or directly overcome bupivacaines inhibitory effect on cellular metabolism by supplying substrate for cellular energy production
y

S-enatiomersenatiomerslevobupivacaine& levobupivacaine& ropivacaine

y

Cardiac toxicity
Na+ channel blockade recovery is fast Less ve ionotropic effect

Response of toxicity to lipids is better y Dose for similar degree of block is y Metabolism by liver is slower so chances of accumulaion are higher. Cautious use in prolonged infusions.
y

CHIRALITY

ROPIVACAINE
y

y y

y y

Ropivacaine is 2-3 times less lipid soluble and has a smaller volume of distribution, greater clearance, and shorter elimination half-life than bupivacaine in humans. The two drugs have a similar pKa and plasma protein binding Ropivacaine is slightly less potent than bupivacaine.When used for spinal anesthesia, 0.75% ropivacaine produces less intense sensory and motor block than 0.5% bupivacaine. Epinephrine does not prolong the duration of ropivacaine block. block. Ropivacaine is indistinguishable from bupivacaine when used in obstetric anesthesia.

Allergic S/E
Esters more likely because of paminobenzoic acid (allergen) y Methylparaben preservative present in amides is also a known allergen y Agents contaminated with latex antigen y Certain Pt allergic to both esters and amides can be give meperidine as LA
y

Methemoglobinemia
Prilocaine is sole LA causing it y Dosage higher than 600 mg are required to produce clinically significant MetHb y Routinely used EMLA does causes such high systemic levels y prilocaine o-toluidine +Hb MetHb Methylene blue is used in cases of methemoglobinemia
y

Local Toxicity
y

Transient Neurological Symptoms This is associated with dysethesia, burning pain and aching in lower ext, buttocks. Follows spinal anesthesia with variety of agents (lido), attributed to radicular irritation and resolves in 1 week usually Risk factors include
Lidocaine intrathecally Lithotomy position Obesity Outpatient status

Repeated doses of 5% lidocaine and .5% tetracaine may be responsible for cauda equina syndrome following infusion through small bore catheters in spinal anesthetics. y Pooling of drug around the cauda equina resulted in permanent neurological damage y Animal studies suggest that neurological damage is: Lido=tetracaine>bupivacaine>ropivacaine. Also perservative free chloroprocaine may be neurotoxic
y

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

Drug Interactions
y y y y y

Chloroprocaine epidurally may interfere with the analgesic effects of intrathecal morphine Opioids and E2 agonists potentiate LAs Propranolol and cimetidine decrease hepatic blood flow and decrease lidocaine clearance Pseudocholinesterase inhibitors decrease Ester LA metabolism Dibucaine (amide LA) inhibits pseudocholinesterase used to detect abnormal enzyme Succinylcholine and ester LA need pseudocholinesterase for metabolism therefore adminstering both may potentiate their activity LA potentiate nondepolarizing muscle relaxant blockade

Special preparations
y

EMLA

lidocaine 2.5% +prilocaine 2.5%

requires 45-60 min application on intact skin
y

TAC

tetracaine 0.5%+epi 1 in 2000+cocaine 10%

application into wound maximum dose for kids 0.05ml/Kg toxicity due to cocaine
y

Tumescent Anesthesia

lidocaine +dilute epinepherine

liposuction dose 35-55mg/Kg Peak levels 8-12h later

EMLA
Eutectic Mixture of Local Anesthetics
 Most

pure anesthetic agents exist as solids. Eutectic mixtures are liquids and melt at lower temperatures than any of their components, permitting higher concentrations of anesthetics.  Eutectic mixture of local anesthetics (EMLA) represents the first major breakthrough for dermal anesthesia on intact skin.  It consists of 25 mg per mL of lidocaine, 25 mg per mL of prilocaine, a thickener, an emulsifier, and distilled water adjusted to a pH level of 9.4.3

TAC
y

Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percent tetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percent cocaine, was the first topical anesthetic mixture found to be effective for nonmucosal skin lacerations to the face and scalp.2 From 2 to 5 mL of solution is applied directly to the wound using a cotton-tipped applicator with firm pressure that is maintained for 20 to 40 minutes.2,3

Iontophoresis
Iontophoresis is a method of delivering a topical anesthetic with a mild electric current. Lidocainesoaked sponges are applied to intact skin, and electrodes are placed on top of the anesthetic. A DC current is then applied to the skin (Figure 2). The anesthetic effect occurs within 10 minutes and lasts approximately 15 minutes. The depth of anesthesia can reach up to 1 to 2 cm.12 y Although the effectiveness of iontophoresis has been compared favorably to that of EMLA, it remains underused. Some patients find the mild electrical sensation uncomfortable. The apparatus is expensive and bulky, and cannot be used over large surface areas of the body.8 Other applications using iontophoresis are still being developed.
y

Liposomes
Liposomes are comprised of lipid layers surrounded by aqueous layers. They are able to penetrate the stratum corneum because they resemble the lipid bilayers of the cell membrane. A liposomal delivery system product called ELA-Max. It contains 4 percent lidocaine cream in a liposomal matrix and is FDA-approved for the temporary relief of pain resulting from minor cuts and abrasions. ELA-Max is applied to intact skin for 15 to 40 minutes without occlusion. ELA-Max has also proved effective in providing dermal analgesia before chemical peeling & other dermatologic procedures.

Other liposomal formulations

Liposomes are effective drug delivery systems to improve the therapeutic efficacy of drugs by increasing drug circulation times, facilitating targeting of drugs, and enhancing stability without compromising safety or tolerability. y Extended-release MVL preparation has proved to be an effective drug delivery vehicle for morphine sulfate pain relief for up to 48 hours postoperatively. y liposomal bupivacaine formulation had a favorable drugto-phospholipid ratio and prolonged the duration of bupivacaine ana lgesia in a dose-dependent manner. y The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively .
y

Other agents with LA properties

Meperidine y TCAs (amitriptyline) y Volatile anesthetics y Ketamine y Tetrodotoxin (blocks Na channels from the outside of the cell membrane) Animal studies suggest that when used in low doses with vasoconstrictors it will significantly prolong duration of action of LA
y

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