Local Anesthetics

Local Anesthetics(LAs)

Common exposure to LAsFor pain and itching associated with sunburn, poison , etc.

For sore throat

For pain of toothache, sores on gums, etc.

DEFINITION - Local Anesthetics

Drugs whichproduce 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)

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.

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 AnestheticsDESIRABLE CHARACTERISTICSRapid onset of actionBrief, reversible block of nerve conductionLow degree of systemic toxicity***Soluble in water and stable in solutionEffective on all parts of the nervous system, all types of nerve fibers and muscle fibers

NONE totally meets these optimally yet!!

ClassificationAccording to sourceAccording to Duration of actionAccording to chemistryTherapeutic classification

Classification

1. According to sourceNaturalSynthetic Nitrogenous CompoundsSynthetic Non-nitrogenous CompoundsMiscellaneous

2. According to Duration of actionShort Duration of ActionProcaineMedium Duration of ActionCocaine, Lidocaine, Mepivacaine, PrilocaineLong Duration of ActionTetracaine, Bupivacaine, Etidocaine, Ropivacaine

3. According to chemistry

A.EstersCocaineProcaine (Novocaine)Tetracaine (Pentocaine)BenzocaineB.AmidesLidocaine (Xycocaine etc)Mepivacaine (Carbocaine, Isocaine)Bupivacaine (Marcaine)Etidocaine (Duranest)Prilocaine (Citanest)Ropivacaine (Naropin)

Classification - According to chemistry

C.EthersPramoxineD.KetonesDyclonineE.Phenetidin DerivativesPhenacaine

Therapeutic classificationDrugs for Surface anesthesia Drugs for Infiltration anesthesiaDrugs used for Nerve block or conduction blockDrugs used for Spinal anesthesia Drugs used for Epidural anesthesia Drugs for Systemic usesRx of cardiac arrhythmias (Lidocaine)As IV analgesic in the Rx of severe pruritis and pain due to malignancy.

Two types of linkages give rise to 2 chemical classes of local anesthetics. ESTER LINKAGEAMIDE LINKAGE (2 EYES!!)PROCAINEprocaine (Novocaine)tetracaine (Pontocaine)benzocainecocaineLIDOCAINElidocaine (Xylocaine)mepivacaine (Carbocaine)bupivacaine (Marcaine)etidocaine (Duranest)ropivacaine (Naropin)

Classification -According to Chemistry & Duration of Action

1. Esters:Short Duration of Action: Procaine , ChloroprocaineMedium Duration of Action: CocaineLong 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 ActionBupivacaine , Levobupivacaine , Ropivacaine

ChemistryMost 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 BasesCCOORNRRNHORNRRAromatic portionAmine portionIntermediate chainESTERAMIDELIPOPHILICHYDROPHILIC

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 fiberWater 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 AnestheticsClinical Significance of chemical classificationCross sensitivity (allergy)Occurs with drugs in the same chemical classEsters are metabolized to common metabolite PABA Allergy rarely occurs with amide linkage class

Biotransformation/duration of actionESTERS are rapidly metabolized in the plasma by a cholinesteraseAMIDES 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 doseSpecific drug characteristicstendency to produce vasodilationPresence of vasoconstrictor (e.g., epinephrine, phenylephrine)

~ PHARMACOKINETICS ~ABSORPTIONEffects of vasoconstrictorsDecrease rate of systemic absorption and decrease systemic toxicityIncrease local drug concentration and increase neuronal uptake of LAIncrease local duration of action (e.g. lidocaines 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 vasoconstrictorsDONT use in areas of toes, fingers, ear lobes, penis (ischemia)May produce tissue necrosisMay produce systemic toxicity (cardiovascular)

~ PHARMACOKINETICS ~DISTRIBUTIONThe 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 ~METABOLISMEster type LAHydrolysis 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 LAHydrolyzed by liver microsomal enzymes (P450)

Longer acting & more systemic toxicity than esters

Caution with severely compromised hepatic functionPrilocaine (fastest) & levobupivacaine (slowest)

Excreted in urine, by acidification

Comparison of LA characteristicsPlasma protein binding may be used as an indirect measure of tissue binding tendencies

Mechanism of Action

Mechanism of Action

Membrane Stabilizing EffectBind the receptor site on Sodium channel from inner / cytoplasmic side in charged formBlock voltage- gated sodium channels, in a time & voltage dependent fashionBlock primarily active and inactive sodium channels, at specific sites within the channelReduce the influx of Sodium ions.Prevent depolarization of the membrane Block both the generation and conduction of action potential

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.

+ +- -+ +--

- -+ ++ +- -Na+ + ++ +- -- -Resting (Closed**)Open(brief)inactivatedVery slow repolarization in presence of LALA receptorLA have highest affinity for the inactivated formRefractory 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.

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

Pharmacologic Effects

NervesOther tissues

Differential Nerve blockvoltage & time dependent

Susceptibility to block by LA depends upon Nerve fiber diameter Smaller diameter greater susceptibilityDegree of myelinationMyelinated blocked earlier .2-3 nodes to be blockedFiring frequency Rapidly firing fiber (Sensory , Pain) are blocked earlier Effect of fiber position in nerve bundlefiber in outer portion of the nerve trunk blocked earlier than the central fibers

Order of Loss of sensations

Autonomic sensation pain touch vibration deep pressure motor sensations.

Recovery in reverse order

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

Therapeutic Uses

For minor surgical procedures --- surface / nerve block / infiltration For spinal anesthesia & to produce autonomic blockade in ischemic conditionsPost operative analgesia as slow epidural infusionI/V analgesia for severe pruritis and pain due to malignancy Epidural infusion for painless child birthTreatment of cardiac arrhythmiasIn resistant neuropathic pain syndromes as adjuvant to TCA & Carbamazepine

Routes / Types of local Anesthesia

i. Surface anaesthesiaEye, ear, larynx drops & spray Lidocaine , Tetracaine , Benzocaine , Dibucaine , Dicyclonine & Pramoxine hydrochlorideOnly for Eye: Proparacaine

ii.Infiltration anaesthesiaInfiltrated 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

Routes / Types of local Anesthesia..

iv. Spinal anaesthesiaDrug 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/VTreatment of cardiac arrhythmias I/V analgesia in the Rx of severe pruritis and pain due to malignancy

TOXICITIES OF LOCAL ANESTHETICS

ToxicitiesExtensions of pharmacological actionPrimarily 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.

ToxicitiesDirect Neurotoxicity from local effectsAt 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 SCInterfere with the axonal transport & disruption of Ca homeostasis

ToxicitiesCNSSleepiness, light-headedness, visual & auditory disturbances & restlessness after rapid absorption or inadvertent admCircumoral & tongue numbness & a metallic taste 1st sign of LA toxicity

High ConcNystagmus & muscular twitching Tonic-clonic convulsions due to depression of cortical inhibitory pathwaysCNS depression, DeathCan be prevented by Diazepam / midazolam

Cocaine drug of abuse

Toxicities CVSAll are myocardial depressants & arteriolar dilators systemic hypotension

Cocaine - vasoconstrictor & hypertension & arrhythmiasLocal 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 membranesIndirect effects by ANS

Treatment of CNS & Cardiac Toxicity

SymptomaticNo antidotesConvulsions can be treated by I/V Diazepam, Midazolam , Thiopentone or Propofol I/V Succinylcholine NMB---- for violent convulsionsHyperventilation - oxygenCardiovascular toxicity of Bupivacaine --- difficult to treat may be fatal

Toxicities Hematologic Effects

PrilocaineLarge doses -10mg/kg during regional anesthesiaFormation 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)

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

Prevention of ToxicityEnquire about history of allergy.Caution in presence of liver/myocardial damageProper 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.

Other drugs that affect sodium channels

Tetrodotoxin & Saxitoxin: Marine toxinsBlock sodium channels.Batrochotoxin, Aconite ,veratridine & some scorpion venoms: Biological toxins,Prevent inactivation--- prolonged activation.

THINGS TO REMEMBERGive smallest volume and dose

Make injections slowly to avoid inadvertent IV

Have drugs available to manage adverse effects

Dont 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

Idioventricular relating to or affecting the cardiac ventricles alone