Local Anesthetics

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Local Anesthetics: 

18 October 2011 Local Anesthetics

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Local Anesthetics (LAs)

Common exposure to LAs: 

Common exposure to LAs For pain and itching associated with sunburn, poison , etc. For sore throat For pain of toothache, sores on gums, etc.

DEFINITION - Local Anesthetics : 

DEFINITION - Local Anesthetics Drugs which produce a REVERSIBLE loss of sensation … in a localized part of the body….. when applied directly onto nerve tissues or mucous membranes Local anesthetics are ‘local’ ONLY because of how they are administered! ( Selectivity )

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DEFINITION… Local anaesthetics are drugs which when applied directly to peripheral nervous tissue, block nerve conduction and abolish all sensations in the part supplied by the nerve. They are generally applied to somatic nerves and are capable of acting on axons, cell body, dendrites & synapses.


History Cocaine – First local anaesthetic – Niemann in 1860, Koller in 1884 as an ophthalmic anesthetic Procaine – Einhorn in 1905. Lidocaine – (Prototype) Lofgren in 1943.

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Aim of all these efforts was to decrease in local irritation and tissue damage, minimization of systemic toxicity, faster onset of action & longer DOA


Local Anesthetics DESIRABLE CHARACTERISTICS Rapid onset of action Brief, reversible block of nerve conduction Low degree of systemic toxicity*** Soluble in water and stable in solution Effective on all parts of the nervous system, all types of nerve fibers and muscle fibers NONE totally meets these optimally yet!!


Classification According to source According to Duration of action According to chemistry Therapeutic classification


Classification 1. According to source Natural Synthetic Nitrogenous Compounds Synthetic Non-nitrogenous Compounds Miscellaneous

2. According to Duration of action: 

2. According to Duration of action Short Duration of Action Procaine Medium Duration of Action Cocaine, Lidocaine, Mepivacaine, Prilocaine Long Duration of Action Tetracaine, Bupivacaine, Etidocaine, Ropivacaine

3. According to chemistry : 

3. According to chemistry A. Esters Cocaine Procaine (Novocaine) Tetracaine (Pentocaine) Benzocaine B. Amides Lidocaine (Xycocaine etc) Mepivacaine (Carbocaine, Isocaine) Bupivacaine (Marcaine) Etidocaine (Duranest) Prilocaine (Citanest) Ropivacaine (Naropin)

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Classification - According to chemistry… C. Ethers Pramoxine D. Ketones Dyclonine E. Phenetidin Derivatives Phenacaine

Therapeutic classification: 

Therapeutic classification Drugs for Surface anesthesia Drugs for Infiltration anesthesia Drugs used for Nerve block or conduction block Drugs used for Spinal anesthesia Drugs used for Epidural anesthesia Drugs for Systemic uses R x of cardiac arrhythmias (Lidocaine) As IV analgesic in the R x of severe pruritis and pain due to malignancy.

Two types of linkages give rise to 2 chemical classes of local anesthetics. : 

Two types of linkages give rise to 2 chemical classes of local anesthetics. ESTER LINKAGE AMIDE LINKAGE (2 EYES!!) PROCAINE procaine (Novocaine) tetracaine (Pontocaine) benzocaine cocaine LIDOCAINE lidocaine (Xylocaine) mepivacaine (Carbocaine) bupivacaine (Marcaine) etidocaine (Duranest) ropivacaine (Naropin)

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Classification - According to Chemistry & Duration of Action 1. Esters: Short Duration of Action: Procaine , Chloroprocaine Medium Duration of Action: Cocaine Long Duration of Action: Tetracaine Benzocaine (for surface use only) 2. Amides: Short Duration of Action: Articaine Medium Duration of Action Lidocaine , Prilocaine , Mepivacaine Long Duration of Action Bupivacaine , Levobupivacaine , Ropivacaine


Chemistry Most local anesthetics are weak bases Consist of 3 parts:- Lipophilic Aromatic group. Intermediate chain----- Ester or Amide. Ionizable Amino group. pKa of most LA----8.0 & 9.0 Physiological pH---7.4 , low in infected tissue--- 6.4

LAs are Weak Bases: 

C LAs are Weak Bases C O O R N R R NH O R N R R Aromatic portion Amine portion Intermediate chain ESTER AMIDE LIPOPHILIC HYDROPHILIC

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Optimal activity requires delicate balance b/w the lipophilic and hydrophilic strengths of these groups Lipoidal solubility  for migration of the drug into the neuronal fiber Water solubility  site of action from the site of injection/application local anaesthetic with high lipid solubility but low water solubility …………not be much useful difficulty in transportation thru the aqueous phase surrounding the neuronal fiber.

Local Anesthetics Clinical Significance of chemical classification: 

Local Anesthetics Clinical Significance of chemical classification Cross sensitivity ( allergy ) Occurs with drugs in the same chemical class Esters are metabolized to common metabolite PABA Allergy rarely occurs with amide linkage class Biotransformation/duration of action ESTERS are rapidly metabolized in the plasma by a cholinesterase AMIDES are more slowly destroyed by liver microsomal P450 enzymes.


~ PHARMACOKINETICS ~ Usually adm by injection into the area of N-fibers to the blocked - absorption & distribution are not so imp Rate of offset of anaesthesia and the likelihood of CNS & cardiac toxicity


~ PHARMACOKINETICS ~ ABSORPTION LA generally have good absorption from mucous membranes and intradermal injection sites. ( into tissues ) Systemic absorption terminates local action ( out of tissues ). (Not local metabolism!!!)


~ PHARMACOKINETICS ~ ABSORPTION Factors influencing peak PLASMA concentration: Site of injection ( vascularity ) Total dose Specific drug characteristics tendency to produce vasodilation Presence of vasoconstrictor ( e.g., epinephrine, phenylephrine )


~ PHARMACOKINETICS ~ ABSORPTION Effects of vasoconstrictors Decrease rate of systemic absorption and decrease systemic toxicity Increase local drug concentration and increase neuronal uptake of LA Increase local duration of action ( e.g. lidocaine’s duration may increase two fold with epinephrine ) Epinephrine or alpha 2 agonists may enhance and prolong spinal anesthesia by acting on alpha 2 receptors to reduce substance P release & reduce sensory neuron firing


~ PHARMACOKINETICS ~ ABSORPTION Potential adverse effects of vasoconstrictors DON’T use in areas of toes, fingers, ear lobes, penis (ischemia) May produce tissue necrosis May produce systemic toxicity (cardiovascular)


~ PHARMACOKINETICS ~ DISTRIBUTION The Amide LA are widely distributed to all parts of the body including CNS after I/V bolus adm. Sequestration occurs in storage sites (fat tissue) Ester type have extremely short plasma half lives – not imp Distribution is a means of terminating local drug action ........ not metabolism!!


~ PHARMACOKINETICS ~ METABOLISM Ester type LA Hydrolysis by cholinesterase in plasma to PABA derivatives pseudo cholinesterase or butrylcholinesterase Generally, short acting and low systemic toxicity** short plasma half lives (< 1 min). Prolonged effects seen with genetically determined deficiency or altered esterase ( cholinesterase inhibitors)


~ PHARMACOKINETICS ~ METABOLISM Amide type LA Hydrolyzed by liver microsomal enzymes (P450) Longer acting & more systemic toxicity than esters Caution with severely compromised hepatic function Prilocaine (fastest) & levobupivacaine (slowest) Excreted in urine, ↑↑ by acidification

Comparison of LA characteristics: 

Comparison of LA characteristics Relative lipid solubility Relative potency onset pKa Local duration vasodilation Plasma protein binding procaine 1 1 slow 8.9 short +++ 5% lidocaine 4 4 rapid 7.9 moderate +++ 55% tetracaine 80 16 slow 8.5 long + 75% bupivacaine 130 16 slow 8.1 long + 90% Plasma protein binding may be used as an indirect measure of tissue binding tendencies

Mechanism of Action : 

Mechanism of Action

Mechanism of Action… : 

Mechanism of Action… Membrane Stabilizing Effect Bind the receptor site on Sodium channel from inner / cytoplasmic side in charged form Block voltage- gated sodium channels, in a time & voltage dependent fashion Block primarily active and inactive sodium channels, at specific sites within the channel Reduce the influx of Sodium ions. Prevent depolarization of the membrane Block both the generation and conduction of action potential

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Mechanism of Action… For action of LA both the non-ionized & ionized forms are important:--- non ionized---- reaches high I/C conc. more rapidly after crossing the membrane. Ionized--- binds receptor more effectively. Elevated extra cellular K + may enhance the action of LA& Ca ++ may antagonize it.

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+ + - - + + -- - - + + + + - - Na + + + + + - - - - Resting (Closed**) Open (brief) inactivated Very slow repolarization in presence of LA LA receptor LA have highest affinity for the inactivated form Refractory period **Closed state may exist in various forms as it moves from resting to open. LA have a high affinity for the different closed forms and may prevent them from opening.

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Mechanism of Action… As progressively increasing concentration of LA are applied to a nerve fiber: The threshold for excitation increases Impulse conduction slows The rate of rise of Action Potential declines The Action Potential amplitude decreases Finally the ability to generate an Action Potential is completely abolished & nerve conduction eventually fails

Pharmacologic Effects : 

Pharmacologic Effects Nerves Other tissues

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Differential Nerve block voltage & time dependent Susceptibility to block by LA depends upon Nerve fiber diameter Smaller diameter greater susceptibility Degree of myelination Myelinated blocked earlier ….2-3 nodes to be blocked Firing frequency Rapidly firing fiber (Sensory , Pain) are blocked earlier Effect of fiber position in nerve bundle fiber in outer portion of the nerve trunk blocked earlier than the central fibers

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Fiber Type Function Diameter ( μ m) Myelination Conduction (m/s) Sensitivity to block Type A Alpha Beta Gamma Delta Proprioception, motor Touch, pressure Muscle spindles Pain, temp. 12-20 5-12 3-6 2-5 Heavy Heavy Heavy Heavy 70-120 30-70 15-30 12-30 + ++ ++ +++ Type B Preganglionic autonomic <3 Light 3-15 ++++ Type C Dorsal root Sympathetic Pain Postganglionic 0.4-1.2 0.3-1.3 None None 0.5-2.3 0.7-2.3 ++++ ++++

Order of Loss of sensations : 

Order of Loss of sensations Autonomic sensation  pain  touch  vibration  deep pressure  motor sensations. Recovery in reverse order

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Effects on other excitable membranes / tissues Cardiac effects Lidocaine --- anti-arrhythmic effect due to Na + channel blockade Bupivacaine, Ropivacaine --- Lethal arrhythmias in high concentration Weak neuromuscular blocking effects Mood elevating effects of cocaine due to action on dopamine & other synaptic transmission in CNS

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Therapeutic Uses For minor surgical procedures --- surface / nerve block / infiltration For spinal anesthesia & to produce autonomic blockade in ischemic conditions Post operative analgesia as slow epidural infusion I/V analgesia for severe pruritis and pain due to malignancy Epidural infusion for painless child birth Treatment of cardiac arrhythmias In resistant neuropathic pain syndromes as adjuvant to TCA & Carbamazepine

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Routes / Types of local Anesthesia i. Surface anaesthesia Eye, ear, larynx – drops & spray Lidocaine , Tetracaine , Benzocaine , Dibucaine , Dicyclonine & Pramoxine hydrochloride Only for Eye: Proparacaine ii. Infiltration anaesthesia Infiltrated s/c & nerve is anaesthetized directly. Lidocaine , Tetracaine , Procaine iii. Nerve block or conduction block Drug in injected very close to nerve e.g brachial plexus. Bupivacaine

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Routes / Types of local Anesthesia.. iv. Spinal anaesthesia Drug is injected into the sub-arachnoid space. Lidocaine , Bupivacaine v. Epidural anaesthesia for pain less child birth. Lidocaine , Bupivacaine vi. I/V Regional Anaesthesia: Lidocaine , Prilocaine vii. Systemic uses: Lidocaine I/V Treatment of cardiac arrhythmias I/V analgesia in the Rx of severe pruritis and pain due to malignancy

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Toxicities Extensions of pharmacological action Primarily related to blocking sodium channels Intensity is dependent on blood levels Toxic levels of LA in blood will not occur if absorption ( into systemic blood ) is slow or metabolism is rapid Therefore, to avoid a systemic toxic reaction to a local anesthetic, the smallest amount of the most dilute solution that effectively blocks pain should be administered.

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Toxicities Direct Neurotoxicity from local effects At high conc – all neurotoxic. Chloroprocaine & Lidocaine more toxic when given for spinal anesthesia --- transient radicular irritation / neuropathic symptoms pooling of high conc of LA in cauda equina of SC Interfere with the axonal transport & disruption of Ca homeostasis

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Toxicities… CNS Sleepiness, light-headedness, visual & auditory disturbances & restlessness after rapid absorption or inadvertent adm Circumoral & tongue numbness & a metallic taste – 1 st sign of LA toxicity High Conc Nystagmus & muscular twitching Tonic-clonic convulsions due to depression of cortical inhibitory pathways CNS depression, Death Can be prevented by Diazepam / midazolam Cocaine – drug of abuse

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Toxicities CVS All are myocardial depressants & arteriolar dilators systemic hypotension Cocaine - vasoconstrictor & hypertension & arrhythmias Local ischemia, ulceration of MM and damage of nasal septum (ch users) Bupivacaine - More cardiotoxic than other LA. Severe hypotension & Cardiac arrhythmias (Idioventricular rhythm with broad QRS complexes & eventually, electromechanical dissociation) Direct effects on cardiac & sm muscle membranes Indirect effects by ANS

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Treatment of CNS & Cardiac Toxicity Symptomatic No antidotes Convulsions can be treated by I/V Diazepam, Midazolam , Thiopentone or Propofol I/V Succinylcholine– NMB---- for violent convulsions Hyperventilation - oxygen Cardiovascular toxicity of Bupivacaine --- difficult to treat may be fatal

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Toxicities Hematologic Effects Prilocaine Large doses -10mg/kg during regional anesthesia Formation of methemoglobin due to metabolite O -toluidine. Methemoglobin ---- may produce cyanosis (Decompensation in patients with preexisting cardiac or pulmonary disease). I/V administration (Methylene blue or ascorbic acid)

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Toxicities Allergic Reactions Rare with amide LA ,Common with Ester LA Metabolite p -aminobenzoic acid derivatives which can cause antibody formation Mild allergic dermatitis Asthmatic attack Severe / fatal anaphylactic reaction

Prevention of Toxicity: 

Prevention of Toxicity Enquire about history of allergy. Caution in presence of liver/myocardial damage Proper site (correct knowledge of nerve course) Minimal effective dose usage (avoid I/V adm) Wait after injection. Observe the face for any twitching, excitement, and pulse for tachycardia. Observe post – op for allergic reactions. Avoid food intake at least 04 hrs prior to anaesthesia to prevent vomiting.

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Other drugs that affect sodium channels Tetrodotoxin & Saxitoxin: Marine toxins Block sodium channels. Batrochotoxin, Aconite ,veratridine & some scorpion venoms: Biological toxins, Prevent inactivation--- prolonged activation.


THINGS TO REMEMBER Give smallest volume and dose Make injections slowly to avoid inadvertent IV Have drugs available to manage adverse effects Don’t take food or liquids < 60 minutes after oral topical application .... gag, swallow, cough reflexes may be not working


THINGS TO REMEMBER… LA effect can be prolonged by addition of vasoconstrictors (epinephrine or phenylephrine) - useful for short acting LAs Never used for topical LA LA effect can be accelerated by addition of sodium bicarbonate ---- ↑ lipid soluble form Repeated injection of LA ---- loss of effectiveness (tachyphylaxis) due to extra cellular acidosis Pregnancy ↑ susceptibility to LA toxicity --- less dose