pharmacology of local anesthetics
TRANSCRIPT
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
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