PHARMACOLOGY OF LOCAL ANESTHETICS

WHAT ARE LOCAL ANESTHETICS?

Local anesthetic: produce loss of sensation to pain in a specific area of the body without the loss of consciousness

MANY CLASSES OF COMPOUNDS BIND AND INHIBIT NA CHANNELS

Local anesthetics General anesthetics Ca channel blockers 2 agonists Tricyclic

antidipressants Substance P

antagonists Many nerve toxins

BatrachotoxinGrayanotoxinTetrodotoxin (TTX)

HISTORY

Alkaloid has natural nitrogen bases found in the coca leaves, also known as cocaine

discovered in South America, Venezuela, Bolivia, and Peru since pre-Columbian periods

Earliest cultivation and use of the coca leaf went back to about 700 BC in Bolivia and Andes regions

Cocaine HCl isolated by Albert Niemann (1860)

Merck produces 100 g cocaine (1862)

Koller and Gartner report local anesthesia (1884)

Merck produces 1450 kg (1884); 72,000 kg (1886)

Coca-Cola (1886) and many other products contain cocaine

Cocaine HCl powder

Cocaine Niemann 1860Benzocaine Salkowski 1895Procaine Einhorn 1904Dibucaine Meischer 1925Tetracaine Eisler 1928Lidocaine Lofgren 1943Chloroprocaine Marks, Rubin 1949Mepivacaine Ekenstam 1956Bupivacaine Ekenstam 1957Ropivacaine Sandberg 1989

CHRONOLOGY OF LOCAL ANESTHETICS

After: Cartwright & Fyhr. Reg Anesth 1988;13:1-12

Niemann discovered the effect of numbness of the tongues caused by alkaloid in 1860

Based on Niemann’s discovery, Russian physician Basil Von Anrep did experiments on animals, such as rats, dogs, and cats.

He injected small quantity of 1% solution to his tongue; tongue became insensitive

He concluded cocaine is a good drug for surgical anesthetic

William Steward Halsted and Richard John Hall developed the inferior dental nerve block techniques for dentistry

COCAINE

Cocaine is the only anesthetics producing vasoconstriction acts by inhibiting the uptake of catecholamines, leading to prolonged vasoconstriction

CHEMISTRY

Local anesthetics are weak bases the pKa of most local anesthetics is in the

range of 8.0–9.0 Cationic form is the most active form The uncharged form is important for rapid

penetration of biologic membranes

CHARACTERISTICS OF LAS

Physical and chemicalIncreasing lipid solubilityIncreased protein binding

Pharmacological & toxicologicalIncreasing potencyProlonged onset timeProlonged duration of actionIncreasing tendency to produce

severe cardiovascular toxicity In general, all tend to sort together

Local anesthetics most commonly exert dilation of vascular bed, vasodilation .

• Some local anesthetics produce vasoconstriction.

• Procaine is the most potent vasodilator clinically given for treating arteriospasm caused by arterial injection of thiopental

PHARMACOLOGY OF LOCAL ANESTHETICS: THECLINICIAN’S PERSPECTIVE

LA potency LA speed of onset LA duration of action Tendency to produce cardiac toxicity Tendency to produce differential block

ADDITIVES AND MODIFIERSVasoconstrictors: ↑duration, ↑block success, ↓[LA]

LAs bind and inhibit Na channels

Potency, lipid solubility, protein binding, onset time, duration, CV toxicity tend to sort together

PHARMACODYNAMICS

With increasing concentrations of a local anesthetic The threshold for excitation increases Impulse conduction slows The rate of rise of the action potential declines The action potential amplitude decreases The ability to generate an action potential is

completely abolished These effects result from binding of the local

anesthetic to more and more sodium channels

CLASSIFICATION OF LOCAL ANESTHETICS Esters” Esters of benzoic acid1. Butacaine2. Cocaine3. Benzocaine4. Hexylcaine5. Piperocaine6. Tetracaine

7. Esters of paraaminobenzoic acid Chloroprocaine Procaine propoxycaine

Amides1. Articaine2. Bupivacaine3. Dibucaine4. Etidocaine5. Lidocaine6. Mepivacaine7. Prilocaine8. Ropivacaine9. Quilonine10. centbucridine

LOCAL ANESTHETICS:AMIDES VS. ESTERS

Common structure Aromatic ring Tertiary amine Alkyl chain

Linking bond Amide bond (see

lidocaine) Ester bond (see

procaine)

Lidocaine

Procaine

METABOLISM

Esters: esters are hydrolysed in the plasma by the enzyme pseudo cholinesterase

Procaine undergoes hyrolysis to paraamino benzoic acid the major metabolic product. Which can cause allergy

Xxxxxx----- persons with atypical form of psedocholinesterase which causes inability to hydrolyse ester local anesthetics and other drugs succinylcholine

Persons who are given general anesthesia should be checked for this to prevent respiratory arest.

AMIDE LOCAL ANESTHETICS

Primary biotransformation in the liver Toxicity can be seen in patients with

hypotension, congestive heart failure, and liver cirrhosis

large doses of prilocaine can cause methemoglobinemia

Lidocaine metabolite monoethylglycinexylidide and glycine xylidide can cause sedation

SYSTEMIC ACTIONS OF LOCAL ANESTHETICS

CNS: Local anesthetics readily crosses the blood

brain barrier At low therapeutic, non toxic levels no cns

effects Anti convulsive levels______0.5 – 4 ug/ml presizure signs and symptoms---- 4.5- 7

ug/ml Tonic clonic seizure---------------- greater than

7.5ug/ml

LIDOCAINE In 1940, the first modern local

anesthetic agent was lidocaine, trade name Xylocaine®

It developed as a derivative of xylidine

Lidocaine relieves pain during the dental surgeries

Belongs to the amide class, cause little allergenic reaction; it’s hypoallergenic

Sets on quickly and produces a desired anesthesia effect for several hours

LIDOCAINE HYDROCLORIDE

Amide 2 diethylamino 2’, 6’ acetoxylidide Lofgren Metabolism in liver by microsomal fixed

function oxidases Ph- 6.5 Half life- 90 minutes We use 2% lignacaine Maximum recommended dose 7mg/kg body

weight with epinephrine not to exceed 500mg Mrd without epinephrine 4.4mg/kg not to

exceed 300mg

TIME TO ACHIEVE PEAK BLOOD LEVELS

Intravenous----- 1 min Topical========5 min Intramuscular------5-10 min Subcutaneous------ 30-90 min Skin---- solarcaine is used EMLA- FOR SKIN a eutectic mixture of oil

in water emulsion of lidocaine and prilocaine 5% cream 25mg lido and 25mg prilocaine

INJECTION OF LA AND DISTRIBUTION Absorption into the blood , LA undergoes

distribution kidney------- cardiac output 22 Gi T--------------------------------21 Skeletal muscle-----------15 Brain-----------14 Skin--------6 Liver--------6 Bone-------5 Heart muscle-------3 Others--------8 Highest is the kidney so elimination is an

important part Elimination half life is time needed for 50%

reduction in blood levels

PRECONVULSIVE SIGNS AND SYMPTOMS OF CNS TOXICITY

Slurred speech Shivering Muscular twitching Tremor of muscles of face and extremities Generalized light headedness Dizziness Visual disturbance Auditory disturbance Drowsiness disorientation

CARDIOVASCULAR SYSTEM

Local anesthetics produce myocardial depression, decrease electrical excitability of the myocardium decrease the conduction rate, force of contraction.

Blood levels normally noted of injection of 1 or 2 dental cartridgres -- 0.5- 2ug/ml

Therapeutic levels of lidocaine for antidysrhytmic activity--- 1.8- 6ug/ml

Overdose beyond 6ug/ml

MINIMAL TO MODERATE OVERDOSE LEVEL

Signs; Talkativeness Apprehension Excitability Slurred speech Generalized slutter Euphoria Dysarthria Nystagamus Sweating Vomiting Elevated blood pressure Elevated heart rate Elevated respiratory rate

MODERATE TO HIGH OVERDOSE LEVELS

Tonic clonic seizure Generalized cns depression Depressed blood pressure, heart rate,

respiratory ratew

OTHER DRUGS

Bupivicaine (Marcaine® 1 Butyl 2,6 pipecoloxylidide HCL--Produce very long acting anesthetic

effect to delay the post operative pain from the surgery for as long as possible

--0.5% solution with vasoconstrictor--Onset time is longer than other

drugs b/c most of the radicals (about 80%) bind to sodium channel proteins effectively

--most toxic local anesthetic drug

Prilocaine (Citanest)--Identical pKa and same conc. with

lidocaine--Almost same duration as lidocaine--Less toxic in higher doses than lidocaine

b/c small vasodilatory activity

Articaine (Septocaine) --newest local anesthetic drug approved by

FDA in 2000--Same pKa and toxicity as lidocaine, but its

half life is less than about ¼ of lidocaine--Used with vasoconstrictor.--Enters blood barrier smoothly--The drug is widely used in most nations

today

CONCLUSION

Anesthetic pKa Onset Duration (with Epinephrine) in minutes

Max Dose (with Epinephrine)

Procaine 9.1 Slow 45 - 90 8mg/kg – 10mg/kg

Lidocaine 7.9 Rapid 120 - 240 4.5mg/kg – 7mg/kg

Bupivacaine

8.1 Slow6-10 min

4 hours – 8 hours

2.5mg/kg – 3mg/kg

Prilocaine 7.9 Medium

90 - 360 5mg/kg – 7.5mg/kg

Articaine 7.8 Rapid 140 - 270 4.0mg/kg – 7mg/kg

TOPICAL ANAESTHETIC

Lidocaine 2-5% Mepivicaine 12-15% Procaine 10-20%

Effective upto 2-3 mm Benzocaine in 140mg per ml Dyclonine HCL 0.5% solution Tetracaine HCL 0.7mg metered spray

EMLA

Lidocaine 2.5% Prilocaine 2.5% Eutectic mixture

THANK YOU