Presenter-Dr Surabhi Gupta Moderator- Dr Bharti Taneja

History of LAy Cocaine isolated 1856 y 1884 cocaine used in occular surgery y 1880 s Regional anesthesia plexus y 1898 cocaine used in spinal anesthesia y 1905 1st synthetic LA (procaine) introduced y 1943 lidocaine synthesized y Mepivacaine (1957), Bupiv ( 63), Ropiv ( 96)

Why the need for newer LA: shortcomings in the conventionally used LAy Slower onset y Lesser safety index y CNS and CVS Toxicity y Need for differential block in certain situations y Special situations; cardiac patient

Newer LAy Ropivacaine y Levo bupivacaine y Proparacaine y EMLA (lignocaine and prilocaine)

Let us compare ..y Between older drug

Bupivacaine and the newer drugs

y Ropivacaine and Levobupivacaine

STRUCTURE Family of N-alkylsubstituted pipecoloxylidide BUPIVACAINE has a butyl grp at amino terminal

more lipophillic and more potent..Same is the case with levobupivacaine ROPIVACAINE has a propyl grp less lipophillic and less potenty highly lipid soluble, chiral centre

piperidine grp y Lipophilicity accounts for potency of the drugs..

contd ..y Potency ropivacaine< bupivacaine and levobupivacaine .

Physiochemical & PharmacokineticActivity of local anesthetics is a function of their Lipid solubility, Diffusibility, Affinity for protein binding, Percent ionization at physiologic pH Vasodilating properties

Physiochemical & PharmacokineticBupivacaine Molecular wt Pka Protein binding Lipid Solubility Vol of Distribution (lt) Clearance (lt/min) Elimination T1/2 (min) 288 8.1 95% 30 Levobupivacaine 274 8.1 >97% 30 55 0.32 156 Ropivacaine 288 8.1 94% 2.8 59 0.72 108

730.58 210

All have slow onset with duration of 4-8 hours

pH & pKay pH of the tissue determines the ratio of ionized to non-ionized drug. y This ratio depends on the pKa of the drug. y Ionization determines onset, duration and pharmacodynamics of LA y Henderson Hasselbalch equation: pKa - pH= log_ionized

non-ionizedy pKa equals the pH where the ionized and non-ionized forms are at equilibrium. In other words, 50% of each form is present. y Local anesthetics are weak bases y At physiological pH, more in ionized form y Explains the action of bicarbonisation for increasing the onset of action

Contd pH acidic in conditions of infection or inflammation. Results in a greater proportion of the ionized (charged) form of the

anaesthetic, Delayed onset or inadequate action. For example, if lidocaine (pKa 7.9) is administered into an area of infection (pH 4.9) emanating from a dental abscess, then: 7.9 - 4.9 = log [ionized/non-ionized] 103 = ionized/non-ionized The resulting ratio of 1,000:1 ionized to non-ionized indicates a poorer penetration into the nerve tissue and therefore a less effective nerve block

Lipid solubilityy Lipid solubility is an important characteristic. Potency is related

to lipid solubility, because 90% of the nerve cell membrane is composed of lipid. This improve transit into the cell membrane y Consequent to a low lipid solubility (2.8), Ropivacaine has a slow onset of action

Protein bindingy Protein binding implies the duration of action of the drug. The .

site of action (the Na channel) is primarily protein in a lipid environment. environment. Binding affinity will thus affect duration of action. action. y Higher protein binding less free fraction thus reduced metabolism and longer duration of action y Protein binding also plays a part in the availability of the drug as LA binds to lipoproteins in the blood stream y More free fraction greater toxicity y levobupivacaine (>97%) has the longest duration of action of the three drugs

Contdy Highly plasma protein bound drug will stay in plasma and less

will go to tissues thereby less volume of distribution hence larger dose will be required to attain the adequate plasma concentration- as in the case with levobupivacaine among the three drugs. y Plasma protein binding will then decrease the toxicity of drug as less will go to the tissues.. y Higher clearance and lower elimination T1/2 implies to earlier removal of the drug from the circulation as seen with ropivacaine .hence less of the systemic toxicity..

Metabolism

Amino amide microsomal degradation (Liver) More complex & slower than amino ester group - systemic toxicity & cumulative effectBUPIVACAINE Ropivacaine only 1 % excreted unchanged in urine 2,6 propylcoloxylidide & 3 hydroxy ropivacaine

> 40 % excreted via kidney N- desbutylbupivacaine

HENCE clearance is higher and elimination half life shorter for ropivacaine as compared to bupivacaine, therefore it has lesser systemic toxicity.

So, what do these tables mean?y Ropivacaine is less potent of the three y Bupivacaine requires lesser dose for the adequate effect y Levobupivacaine has longest duration of action y Ropivacaine has the least systemic toxicity

CLINICAL APPLICATION

Surgical anaesthesia Epidural blocks for surgery,including caesarian section Intrathecal(spinal)block Major nerve blocks Field blocks Acute pain anage ent Labor analgesia audal analgesia Topical Local infiltration

Clinical Application (comparison)Infiltration AnesthesiaBupivacaine oncentration (%) Max dos (mg) ( lai / it adr) Duration ( r) ( lain/ it adr) 0.25 0.5 175/200 2-4/3-4 Levobupivacaine 0.25 150/200 2-4/3-4 Ropivacaine 0.2 - 0.5 200/250 2-4/3-4

Doses- bupivacaine 3 mg /kg levobupivacaine 3 mg/kg ropivacaine 4 mg/kg

Contd..Minor BlockBupivacaine oncentration (%) Volu e ( l) Dosage ( g) Duration (plain/with adr) 0.25 0.5 5-20 12.5 100 3-6/4-7 Levobupivacaine 0.25 0.5 5-20 10 100 3-6/4-7 Ropivacaine 0.2 0.5 5-20 12.5 100 3-6/4-7

Major Nerve Blocks Similar Volume 30 -50 ml Similar Onset 20-30 mins Similar Duration 6-9 hrs except fpr max dose which is ropivacaine (250mg) & other (225 mg)

Contd..Epidural Anesthesia Similar Volume (15-30 ml) Similar Onset (15-20 mins) Similar Duration (3-6 hours) Similar total dose (40-225 mg) Spinal Anesthesia Similar Volume (0.5 % 3-4ml) & (0.75% 2-3ml) Similar Dose (15-20 mg) Similar Duration (90-200 min)

Special considerationsy 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 bindingy Epinephrine does not prolong the duration of ropivacaine block. The addition of epinephrine does not prolong the duration of ropivacaine in subclavian brachial plexus or epidural block. Low concentrations of ropivaciane may produce clinically significant vasoconstriction, which is not increased further by the addition of epinephrine

Contdy 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. However, multiple clinical trials comparing the two local anesthetics in epidural and axillary block demonstrate similar potency of bupivacaine and ropivacaine with respect to the intensity of sensory anesthesia

CONTRAINDICATIONy Not recommended for emergency situations where a fast onset

of surgical anesthesia is necessary y IVRA y Avoid injections in inflamed areas y Hypovolemia,hypotension y Intravenous use

SYSTEMIC TOXICITY

Central Nervous System Sign & Symptoms Light Headedness Dizziness Visual & auditory disturbance (difficulity focusing & tinitus) Shivering Muscular twitching & tremors

GTCS Respiratory depression ( terminated by small doses of i.v benzodiazepines or small dose of i.v thiopentone)

Bupivacaine

> Levobupivacaine & Ropivacaine

(race ic

ixture)

( left iso ers)

Contd.. CARDIOVASCULAR TOXICITY Depress myocardium but stimulate sympathetic system often can be overlooked PR interval & QRS duration & QTc Prolongation Negative ionotropic effect Myocardial Contractility proptional to lipid solubility & nerve blocking potency of LA Bupivacaine > Levobupivacaine > Ropivacaine

MYOTOXICITYy The long term myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blocks

IMPLICATIONS: In a period of 4 wk after peripheral nerve block, both long-acting local anesthetics, bupivacaine and ropivacaine, produced calcific myonecrosis suggestive of irreversible skeletal muscle damage. In comparison with ropivacaine, however, the extent of bupivacaineinduced muscle lesions was significantly larger.y

Anesth Analg. 2005 Aug;101(2):548-54

Treatment of toxicityy Identify the problem y signs and symptoms y temporal relationship y IV injection y 40-60 min post for peak plasmalevels y CNSy treatment with benzodiazepines

Contdy With CVS toxicity

The agent is an important considerationy bretyllium and y lipid rescue- intralipids , lipid infusion may create plasma lipid droplets capable ofsegregating uncharged bupivacaine molecules from plasma, which makes them unavailable for interaction at their target sites.

y act on nitric oxide pathways and reverse bupivacaine s inhibitory effects. y Rapid bolus of 20% intra lipid y Dose 1.5 ml/kg or 100 ml in adults y f/b infusion of 0.25 ml/kg/min for the next 10 min.

Contd .y When there is CVS collapse

ABCs defibrillation Epinephrine Vasopressin Lidocaine Bretylium Amiodarone Intra lipids

New and not-so new Developments in Local Anestheticsy Liposomal encapsulated local anesthetics y Ionotophoresis y Tumescent Anesthesia y TAC patch y EMLA y Proparacaine

TAC ( topical L.A. )y Tetracaine, Adrenaline (Epinephrine), and ocaine y Tetracaine, adrenaline, and cocaine (TAC), a compound of 0.5 percent tetracaine (Pontocaine), 0.05 percent epinephrine, and 11.8 percent cocaine y first topical anesthetic mixture found to be effective for nonmucosal skin lacerations to the face and scalp. y 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. However, the use of TAC is no longer supported by the literature because of general concern about toxicity and expense, and federal regulatory issues involving medications containing cocaine.

COMMERCIALLY available asy TAC y constitute of-tetracaine 0.5% epi 1 in 2000

cocaine 10% y Application into wound y Max Dose for kids 0.05ml/Kg y Toxicity due to cocaine

Technique of iontophoresisy charged ions of drug are driven across the epidermis by

applying a direct electric current y When an electrical potential difference is established, ions of the drug migrate across the skin, and the dose delivered is therefore a product of the magnitude and duration of current y allows us to deliver drugs to the skin without the trauma associated with intradermal injection y Therapeutic iontophoresis devices typically use a current of 24 mA

Mechanism of actiony Repulsive electromotive force cause transdermal migration of

medication using a small electrical charge y An iontophoretic chamber contains a similarly charged active agent and its vehicle. y One or two chambers are filled with a solution containing an active ingredient and its solvent, also called the vehicle. y The anode will repel a positively charged chemical, whereas the cathode will repel a negatively charged chemical into the skin.

LA IONTOPHORESISy Lidocaine-soaked sponges are applied to intact skin, and electrodes are placed on top of the anesthetic. y A DC current is then applied to the skin.The anesthetic effect occurs within 10 minutes and lasts approximately 15 minutes. y The depth of anesthesia can reach up to 1 to 2 cm.

Iontophoresis vs EMLAy Although the effectiveness of iontophoresis has been compared favorably to that of EMLA, it remains underused. y Some patients find the mild electrical sensation uncomfortable. y The apparatus is expensive and bulky, and cannot be used over large surface areas of the body. y Other applications using iontophoresis are still being developed

LIPOSOMAL DRUGSy 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.y y y y

vary in size from 0.3-10microns Drug can be incorporated either in the aqueous or lipid layer Often act as barrier to drug diffusion Act as a slow release preparation with prolonged action

MECHANISM - gradual erosion or reorganization of the lipid membranes

Contd .....y The liposome-encapsulated formulation protects the anaesthetic

from being metabolized too quickly y Thus, prolonged action y Increased lipophilicity y Thus, It has short onset of action y Minimal vasoactive properties that minimize any potential interference with cannulation success y Not associated with methemoglobinemia.

ELA-MAXy 4 percent lidocaine cream in a liposomal matrix y FDA-approved for the temporary relief of pain resulting from minor cuts and abrasions. y ELA-Max is applied to intact skin for 15 to 40 minutes without occlusion. y ELA-Max has also proved effective in providing dermal analgesia before chemical peeling. y The safety of its application to mucous membranes has not been evaluated.

Liposomal Bupivacainey A Novel For ulation to Produce Ultralong-Acting Analgesia ( a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia 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.

EMLAEutectic mixture of 2.5%lignocaine and 2.5%prilocaine along with carboxy polymethylene (thickening agent)and sodium hydroxide ( to adjust pH )(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. )

Mechanis of action-when applied to intact skin under occlusive dressing it provides dermal analgesia by acting on dermal pain receptors and nerve endings thereby inhibiting the ionic fluxes required for initiation and conduction of impulse

Pharmacokinetics Volume of distribution more woth lignocaine Plasma protien binding more with lignocaine Crosses blood brain barrier and placental barrier Metabolized in liver and kidney Elimination half life-1.5 hrs(adult) 2.5hrs(elderly) Absorption 1 to 3 hrs through intact skin

5 to 10 min. through mucosa dose 2.5 gm over 20 to 25 sq.cm. to 2 gm per 10 sq cm.

CLINICAL APPLICATION Prior to i.v. cannulation Prior to skin graft harvesting In laser treatment of facial port wine stain in children Genital mucosa membranes for minor superficial

surgical procedure

LIMITING FACTORS IN CLINICAL USEy Ineffective in presence of pus; thus, cannot be used for I & D. y Vasoconstriction: can make cannulation difficult. y Not suitable for use in infants less than 6 months.

INTERACTION Local reaction Allergic phenomenon Carcinogenicity Meth-hemoglobinemia: specially in G6PD deficiency

antimalarials,sulfonamide.

PROPARACAINEy Topical anaesthetic y Available as proparacaine hydrochloride y Sterile aqueous ophthalmic solution y Each ml = proparacaine hydrochloride 0.5%

benzalkonium chloride 0.01% y Stored at 2 -8 degree celsius y To be discarded if darker than pale yellow

MECHANISM OF ACTIONy Acts on nerve cell membrane y Interferes with transient increase in membrane permeability to

sodium ions y Hence prevents fundamental change necessary for generation of action potential y Onset -30 sec. y Duration of action- few minutes

INDICATIONS Tonometry Removal of foreign bodies in cornea Removal of corneal sutures Gonioscopy Conjunctival scraping for diagnosis Cataract extraction

SIDE EFFECTS Pupillary dilatation Hyperallergic corneal reaction Iritis Epithelial keratitis Allergic contact dermatitis Erosion of corneal epithelium Conjunctival congestion and heamorrhage

Tu escent anesthesiay Jeffery Klein, 1987 y anesthesia in liposuction y use of dilute solutions of lidocaine (0.05-0.1%) in large volumes to provide superior anesthesia. y Epinephrine (1:1,000,000) is added for hemostasis, and the solution is buffered with sodium bicarbonate to decrease injection discomfort. y Concentrations as high as 55 mg/kg have been used safely with the tumescent technique. y Subcutaneous injection of large volumes of dilute L.A. y Total dose- 35

55 mg/kg y May peak more than 8 to 12 hrs after infusion

Contd high total doses of anesthetic without systemic

toxicity ??? y The absorption kinetics of lidocaine change with high-volume, low-concentration solutions. y Decreased concentrations of lidocaine result in slower plasma absorption with decreased peak plasma levels. y The development of this anesthetic delivery system has revolutionized the surgical technique of liposuction.

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