This presentation is about the pharmacology of LA

1. Pharmacology Of
Local anesthesia
By,
Gauri Bargoti

2. Contents
• Introduction
• Definition
• Ideal properties
• Classification of LA
• Esters
• Amides
• Pharmokinetics of LA
• Uptake
• Distribution
• Metabolism
• Excretion
• Systemic action of LA in different systems

3. Introduction
• Local anesthesia is used for management of pain. All other
drugs regardless of the route need to ultimately enter
circulation while LA can exert pain control when absorbed
from site of administration into circulation.

4. Definition
• Local anesthesia is defined as loss of sensation in a
circumscribed area of body caused by depression of excitation
in nerve endings and loss of conduction process in peripheral
nerves.

5. Ideal properties
• Should not be irritating to the tissue to which it is applied.
• It should not cause any permanent alteration to the nerve
structure
• Its systemic toxicity should be low
• It must be effective whether it is applied topically or is
injected into the nerve
• The time of onset should be as short as possible
• The duration of action should be long enough to permit
completion of procedure

6. Bennet later on added few more
properties
• It should have potency sufficient to give complete anesthesia
without the use of harmful concentration.
• It should be relatively free from producing allergic reaction
• It should be stable in solution and should readily go
biotransformation in body.
• It should be sterile or capable of undergoing sterilization by
heat without deterioration.

7. Classification of LA
• Local anesthetics are classified according to following criteria:
• A) Duration of action
• B) Chemical structure
• C) Occurrence in nature
• On basis of site and mode of action
• D)

8. Classification Of Local Anesthesia
• Local anesthesia are divided according to their chemical structures:
• Only CENTBRUCIDINE is QUINOLONE type.
Local
anesthesia
Ester
Amides
Quinolone

9. Esters
Esters
Ester of benzoic acid
Butacaine
Cocaine
Ethyl aminobenzoate
Hexylcaine
Piperocaine
Tetracaine
Ester of para-benzoic
acid
Chlorprocaine
Procaine
Propoxycaine

10. Amides
• Articaine
• Bupivacian
• Dibucaine
• Etidocaine
• Lidocaine
• Mepivacaine
• Prilocaine
• Ropivacaine

11. A) Ester type
B) Amide type

12. According to duration of action
• 1) Ultra short acting: Where the duration of action is less than
30minutes: Procaine without vasoconstriction, 2-
chlorprocaine, 2% lidocaine without vasoconstrictor, 4%
prilocaine without vasoconstriction for infiltration
• 2) Short acting: Where duration is between 45 to 90 minutes :
2% lidocaine with 1:100,000 epinephrine, 2% mepivacaine
with 1:200,000 levonordefrine, 4% prilocaine when used for
nerve block, 2% procaine
• 3) Intermediately acting: Where duration of action is between
90 to 150 minutes : 4% prilocaine with 1:200,000
epinephrine,2% lidocaine and 2% mepivacaine with a
vasoconstictor for pulpal anesthesia
• 4) Long acting : 0.5% bupivacaine with 1:200,000 epinephrine,
0.5% or 1.5% etidocaine with 1:2,00,000 epinephrine

13. According to occurrence in
nature
• 1) Naturally occurring eg : cocaine
• 2) Synthetic compounds : these are further divided into:
• A) Nitrogenous compound: i) Derivatives of PABA : Freely
soluble eg is prilocaine and poorly soluble eg is benzocaine
• ii) Derivatives of acetanilide: eg lignocaine
• iii) Derivatives of quinolone, cinchocaine
• iv) Derivatives of acridine eg is bucricaine
• B) Non-nitrogenous compound: eg is benzyl alcohol and
propanediol
• 3) Miscellaneous compounds: Drugs with local anesthetic
actions, eg clove oil, phenol, chlorpromazine, certin
antihistaminic such as diphehydramine.

14. According to site and mode of
action
Class Definition Chemical substance
A Local anesthetic agents
acting on receptor site
on external surface of
nerve membrane
Biotoxins like tetrodoxin
and saxitoxin
B Local anesthetic agents
acting on receptor sites
on internal surface of
nerve membrane
Quaternary ammonium
analogue of lidocaine
and benzocaine
C Local anesthetic agents
acting on receptor-
independent mechanism
Benzocaine
D Local anesthetic agents
acting by combination of
receptor-dependent and
receptor-independent
mechanism
lidocaine., mepivacaine
and prilocaine

15. Vasoconstrictors and medical
condition of patient
• Vasoconstrictors are chemical agents or adjuncts added to local
anesthesia to a) oppose the vasodilation caused by agent b) to
achieve hemostasis
• In cases of significant CVS disease or non-cardiovascular disease, It is
essential to determine the degree of severity of disease, determine
whether vasoconstrictor can be safely given to patient or not, obtain
a medical consultation and necessary information from the treating
physician.
• The group where vasoconstrictors are contraindicated:
• Patient with significant CVS disease such as ischemic heart disease,
hypertension and cerebral strokes
• Patient with uncontrolled diabetes mellitus and hyperthyroid
• Patient having tricyclic antidepressant, MAOs, phenothiazine
• Patient undergoing GA under halogenated agents.
• Pregnancy

16. Vasoconstriction and medical
status of patient
• Epinephrine and other vasoconstrictors can be used in mild
and moderate amount in patient with mild to moderate CVS
after negative aspiration.
• Felypressin has minimal cardiothoracic stimulatory action and
nondysrhythmogenic; it is recommended in patient with CVS.
It can also be given when patient is under GA by halogenated
agents
• In pregnancy felypressin is contraindicated due to oytocic
action

17. Pharmokinetics Of LA
• LA causes vasoactivity : Mostly exert vasodilation based on the
concentration. Some may cause vasoconstriction
• Tetracaine, chlorprocaine, propoxycaine and procaine all cause
vasodilation.
• Most effective VASODILATION is caused by PROCAINE.
• Cocaine after initial vasodilation cause vasoconstriction
• Vasodilation cause increase rate of absorption of local
anesthesia and thus decreasing the duration and quality of
pain control.

18. Different routes of uptake
Method
of
uptake
Oral route
Topical route
Injection

19. Oral route
• Except cocaine, all are poorly absorbed orally.
• All LA undergo significant hepatic first pass metabolism.

20. Topical route
• Depends on site of application
• Action is not seen on intact skin
• In sunburn or damaged skin as in burns, action is rapid and
hence lidocaine and benzocaine can be given for relief
• Action is faster in trachea, slower in pharyngeal mucosa and
even slower in esophageal and bladder mucosa.

21. Injection
• Rate of uptake after Intravenous, intramuscular or
subcutaneous route is related to vascularity of site
or vasoactivity of drug
• Intravenous can be used for primary management
of ventricular dysrhythmias but can cause serious
toxic reaction. So, the positive and negative
implication should be weighed before giving LA.

22. Time to achieve peak blood
levels
Route Time to achieve level(in
min)
Intravenous 1 minute
Topical 5 minute(approximately)
Intramuscular 5 to 10 minutes
Subcutaneous 30 to 90 minutes

23. Distribution
• Once absorbed into blood, local anesthetics are distributed
throughout the body to all tissues.
• The blood level of local anesthesia is influenced by following
factors:
1. Rate at which drug is absorbed in CVS.
2. Rate of distribution of drug from vascular compartment to
tissues
3. Elimination of drug through metabolic and excretory
pathway.

24. Metabolism
Site of injection
Blood
Fat
Muscles
Brain
Myocardium
Lungs
liver
Slow
equilibrium
space
Rapid
equilibrium
space

25. Factors influencing
metabolism
• Depends on way they(esters, amides) are biologically
transformed from active to inactive form
• Overall toxicity depends on the balance between rate of
absorption into blood stream at site of injection and its
elimination from body through tissue uptake and metabolism.

26. Metabolism of ester type
• Local anesthetics are inactivated by hydrolysis
• A water molecule is added to at ester linkage, thus splitting the
molecule into 2 entity.
• The bulk of hydrolysis occurs in plasma followed by liver with help of
plasma cholinesterase.
• The variation in structural formula of ester type of compound effects
the hydrolysis
• More the hydrolysis, less the toxicity.
• For example: The addition of chlorine atom in aromatic chain
produces an agent called 2 chlorprocaine that is hydrolyzed 4 times
faster than parent compound and hence is the least toxic of all
agents .
• People with atypical pesudocholinesterase do not hydrolyze ester LA
and hence increased toxicity and it is relative contraindication of
ester type LA

27. Metabolism of amide type
• Primary metabolism in liver by microsomal enzymes
• Lidocaine, etidocaine, mepivacaine and bupivacaine are
hydrolyzed in liver.
• Prilocaine undergoes metabolism in liver and to some extent
in lungs
• Subsequent degradation of the compound leads to hydrolysis
or splitting of amide and the presumed hydroxylation of
aromatic ring
• Articaine a hybrid is metabolised in both liver and blood.
• Hepatic and renal failure are relative containdication of amide
type LA

28. Metabolism of amides
• Biotransformation of amide type LA results in product that can
cause significant clinical activity when accumulated in blood.
• For instance:
Prilocaine orthotoluidine
methemoglobin Methemogloni
nemia

29. Excretion
• Primary organ: Kidney
• Esters appear only in small concentration in unchanged form
• Esters when compared to amides are excreted in greater
concentration as parent compound.
• In case of renal failure the blood level of LA are increased and
hence increased toxicity.

30. Systemic actions of LA
• LA are chemicals that reversibly block action potential in all
excitable membranes.
• CNS and CVS are most susceptible.
• Higher the level of LA, greater the clinical action
• Local anesthesia after being absorbed goes to circulatory
system and from there gets diluted and goes to different parts
of body,

31. Factors influencing Blood levels of
LA
1. Uptake from site of administration to site of action
(increased blood levels)
2. Rates of distribution in tissue and biotransformation (in liver)
3. Process that remove drug from blood (decreasing blood
level).

32. Effect of pH on LA
• Local anesthetics are alkaloid bases that are combined with
acid , usually hydrochloric to form water-soluble salts.
• In solution the salts of local anesthetic compounds exist as
both uncharged molecule called free base and positively
charged molecules called cation in equilibrium
• RNH+ RN + H+
• This relative proportion depends on pH and pKa of the
solution.
• When pH and pKa are same the solution have equal number
of free base and cation.
• Since pKa of any solution is constant so relative proportion
depends on the pH.
• When pH is down the equilibrium shift towards cation and
when pH is increased the equilibrium is towards free base

33. Effect of pH on LA
• So it is the alkalinity of the tissue (7.3 or 7.4) that is
responsible for liberation of free base and more the number
of free base more effective is LA.
• One solution with high pKa will have less number of free base
and will be ineffective but a solution with low pKa will also be
ineffective as their will be few base molecule to dissociate
cationic form that is responsible for binding with specific
receptors
• Since the action of LA also depends on the pH at which the LA
reaction is taking place so in an INFECTED TISSUE with low pH
the anesthesia will not be effective as deprotonization (that is
conversion of RHN+ to RN) and liberation of free base will be
prevented

34. Effects on CNS
• LA can cross blood brain barrier
• Cause depression of CNS.
• At low levels cause no symptoms
• At high levels cause generalized tonic-clonic convulsion.

35. Anticonvulsive levels of LA
Levels Concentration of LA( mu gm/mL)
Anticonvulsive level 0.5 to 4
Preseizure sign and symptoms 4.5 to 7
Tonic- clonic seizure >7.5

36. Anticonvulsive properties
• Lidocaine, procaine, prilocaine, mepivacaine even cocaine
demonstrated anticonvulsive properties
• It occurs at level below the level at which seizure occurs
• Procaine, mepivacaine and lidocaine are used IV to reduce
duration of grand mal and petit seizure
• Lidocaine at therapeutic dose of 2 to 3mg/kg is given at rate of
40 to 50mg/min for interrupting status epileptics.

37. Mechanism of anticonvulsant
property
• Epileptic patients have hyper excitable cortical neurons at site
within brain where convulsive property occurs
• LA raise the seizure threshold and decrease excitability od
neurons thereby preventing and terminating seizures.

38. Pre- convulsive phase
• It is the second phase observed at level of 4.5 and 7 mu
gm/mL.
• Since CNS is most susceptible to overdose and hence effects
are first seen on CNS

39. Signs Symptoms
Slurred speech Numbness of tongue and
circumoral region
Shivering
Muscular twitching Warm, flushed feeling of skin
Tremor of muscle of face and
distal extremities
Generalized lightheadedness Pleasant dreamlike state
Dizziness
Visual disturbance
Auditory disturbance
Drowsiness
Disorientation

40. Convulsive phase
• Further increase leads to phase of generalized tonic- clonic
seizures.
• This is directly proportional to level of LA and inversely to
partial pressure of carbon-di-oxide.
• This phase is seen at levels between 7.5 to 10 mu gm/mL.
• When pCO2 level in more the level of LA decreases but seizure
duration is increased.

41. Effect of CO2 on convulsive
threshold of LA
Agent PCO2 (25 to 40
torr)
PCO2 (6581 torr) % change
Procaine 35 17 51
Mepivacaine 18 10 44
Prilocaine 22 12 45
Lidocaine 15 7 53
Bupivacaine 5 2.5 30
Both cerebral blood flow and metabolism is increased during LA
induced convulsion. This cause increase in volume of LA being
delivered to brain and hence increased duration of seizures
If LA levels are further increased CNS depression occurs.

42. Mechanism of pre-convulsive and
convulsive phase
• De Jong stated that “ Inhibition of inhibition thus is a
presynaptic event that follows local anesthetics blockade of
impulses travelling along inhibitory pathway”
• Neuron has both inhibitory and facilitatory neurons that are in
balance
• Although specific site of action on CNS is not known but its
effect is largely seen on inhibitory neurons.
• Different phases act differently on brain neurons.

43. Inhibitory
Facilitatory Inhibitory Facilitatory
Inhibitory Facilitatory
Inhibitory
Facilitatory
Normal Pre- convulsive
phase
Convulsive phase State of complete
depression

44. Analgesia
• Administering LA through IV route increases pain threshold
and analgesia is produced.
• Earlier procaine in 4 mg/kg of body weight concentration was
infused for 20 minutes.
• Technique of procaine infusion was discontinued after narrow
safety margin

45. Mood elevation
• Used for mood elevation and rejuvenation.
• Cocaine has long been used for euphoria-inducing and fatigue-
lessening actions, but due to habituation and sudden deaths
of many professionals demonstrated dangers involved in
cocaine.
• In some clinic of central Europe and Mexico procaine is used
for “restoring youthful vigor” or rejuvenation.

46. Effect on Cardiovascular
system
• LA acts on myocardium and peripheral vasculature.

47. Action on myocardium
• As LA increases phase of myocardial depression also increases.
• LA decreases the excitability of myocardium, conduction rate
of myocardium and force of contraction.
• LA can be used in management of ventricular dysrhythmia
management.
• Many LA show anti- dysrhythmic activity in animals but only
lidocaine and procaine are useful in humans.

48. Action on myocardium
• Tocanamide is oral analog of lidocaine and is used as lidocaine
is not effective orally but this produces toxic effects.
• Lidocaine is administered IV in bolus of 50 to 100mg at rate of
25 to 50 mg/min.
• This dose is 1 to 1.5 mg/kg of body weight at every 3 to 5
minutes.

49. Signs and symptoms of minimal to
moderate level
Signs Symptoms
Talkativeness Lightheadedness and dizziness
Apprehension Restlessness
Excitability Nervousness
Slurred speech Sensation of twitching
Euphoria Metallic taste
Dysarthia Tinnitus
Nystagmus Visual disturbance
Sweating Loss of consiousness
Vomiting

50. Moderate to high overdose
• Tonic – clonic seizures
• Generalized CNS depression
• Depressed blood pressure, heart rate and respiratory rates.

51. Direct action on peripheral
vasculature
• Cocaine is the only drug that cause vasoconstriction.
• Ropivacaine cause vasoconstriction but its congener
bupivacaine causes vasodilation.
• All other drugs causes vasodilation due to relaxation of
smooth muscles in wall of blood vessels.
• Primary action of LA on BP is hypotension
• Negative effects are seen only at high levels of LA

52. The usual sequence of action on
CVS
Non-overdose
• At non overdose levels there is slight increase or no change in BP as
cardiac output and heart rate are increased due to increased
sympathetic activity
Slight increase
and overdose
• With slight increase in level but less than overdose level there is
slight degree of hypotension. It is due to direct relaxation on vascular
smooth muscles.
• At high levels profound hypotension occurs
Lethal dose
• At lethal levels, CVS collapse. This is due to massive peripheral
vasodilation and decreased myocardial contractility and heart rate

53. Local Tissue Toxicity
• Skeletal muscles are most susceptible.
• IV and intraoral injection of articaine, lidocaine, mepivacine,
prilocaine, bupivacaine and etidocaine can produce skeletal
muscle alteration.
• Longer acting LA cause more skeletal alteration than shorter
acting LA
• Changes in skeletal muscles are reversible with muscle
regeneration complete within 2 weeks.

54. Respiratory system
• At non overdose level they have direct relaxation action on
bronchial smooth muscles.
• At overdose levels, they produce respiratory depression due
to depression of CNS

55. Drug interaction
• CNS depressant such as opioid, antianxiety drugs,
phenothiazine, barbiturates when interact with LA leads to
potentiation of CNS depressant action of LA.
• Ester LA with muscle relaxant like succinylcholine cause
prolonged apnea.
• Hepatic microsomal enzymes like barbiturates induce rate of
metabolism of LA

56. Neuromuscular blockade
• Caused due to sodium diffusion inhibition through sodium
channels in cell membrane
• This is slightly normal and clinically insignificant
• It can cause additive effect to depolarizing and non-
depolarizing muscle relaxants
• This produce increased duration of muscle paralysis.

57. Malignant hyperthermia
• It is a pharmacogenic disorder.
• Manifestation include: tachycardia, tachypnea, unstable BP,
cyanosis, respiratory and metabolic acidosis, fever, muscle
rigidity and death
• LA can induce malignant hyperthermia
• Until recently amide LA was absolutely contraindicated in MH
susceptible patients but MHAUS concluded that there is no
documented case of amide causing MH

58. References
• Handbook of local anesthesia by Stanley F. Malamed
• Monheim’s local anesthesia and pain control in dental practice
• Manual of local anesthesia in dentistry: AP Chitre