2. WHAT ARE LOCAL ANESTHETICS?
Local anesthetic: produce loss of sensation to pain in a
specific area of the body without the loss of
consciousness
3. 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
Batrachotoxin
Grayanotoxin
Tetrodotoxin (TTX)
4. 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
5. 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
8. 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
9. COCAINE
Cocaine is the only anesthetics producing
vasoconstriction acts by inhibiting the uptake of
catecholamines, leading to prolonged
vasoconstriction
10. 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
11. CHARACTERISTICS OF LAS
Physical and chemical
Increasing lipid solubility
Increased protein binding
Pharmacological & toxicological
Increasing potency
Prolonged onset time
Prolonged duration of action
Increasing tendency to produce severe
cardiovascular toxicity
In general, all tend to sort together
12. 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
13. PHARMACOLOGY OF LOCAL ANESTHETICS: THE
CLINICIAN’S PERSPECTIVE
LA potency
LA speed of onset
LA duration of action
Tendency to produce cardiac toxicity
Tendency to produce differential block
14. ADDITIVES AND MODIFIERS
Vasoconstrictors: ↑duration,
↑block success, ↓[LA]
LAs bind and inhibit Na
channels
Potency, lipid solubility, protein
binding, onset time, duration,
CV toxicity tend to sort together
15. 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
16. CLASSIFICATION OF LOCAL ANESTHETICS
Esters”
Esters of benzoic acid
1. Butacaine
2. Cocaine
3. Benzocaine
4. Hexylcaine
5. Piperocaine
6. Tetracaine
7. Esters of paraaminobenzoic acid
Chloroprocaine
Procaine
propoxycaine
18. 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
19. 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.
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
30. 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
31. 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
Effect of repetitive activity on the block of sodium current produced by a local anesthetic in a myelinated axon. A series of 25 pulses was applied, and the resulting sodium currents (downward deflections) are superimposed. Note that the current produced by the pulses rapidly decreased from the first to the 25th pulse. A long rest period after the train resulted in recovery from block, but the block could be reinstated by a subsequent train. nA, nanoamperes. (Modified and reproduced, with permission, from Courtney KR: Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J PharmacolExpTher 1975;195:225.)