1. PHARMACOLOGY OF LOCAL
ANESTHETICS

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

7. Cocaine Niemann 1860
Benzocaine Salkowski 1895
Procaine Einhorn 1904
Dibucaine Meischer 1925
Tetracaine Eisler 1928
Lidocaine Lofgren 1943
Chloroprocaine Marks, Rubin 1949
Mepivacaine Ekenstam 1956
Bupivacaine Ekenstam 1957
Ropivacaine Sandberg 1989
CHRONOLOGY OF LOCAL ANESTHETICS
After: Cartwright & Fyhr. Reg Anesth 1988;13:1-12

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

17.  Amides
1. Articaine
2. Bupivacaine
3. Dibucaine
4. Etidocaine
5. Lidocaine
6. Mepivacaine
7. Prilocaine
8. Ropivacaine
9. Quilonine
10. centbucridine

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

28. 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

29. MODERATE TO HIGH OVERDOSE LEVELS
 Tonic clonic seizure
 Generalized cns depression
 Depressed blood pressure, heart rate, respiratory
ratew

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

32. 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 Slow
6-10
min
4 hours – 8
hours
2.5mg/kg – 3mg/kg
Prilocaine 7.9 Mediu
m
90 - 360 5mg/kg – 7.5mg/kg
Articaine 7.8 Rapid 140 - 270 4.0mg/kg – 7mg/kg

33. 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

34. EMLA
 Lidocaine 2.5%
 Prilocaine 2.5%
 Eutectic mixture

35. THANK
YOU