PHARMACOLOGY OF LOCAL ANESTHEICS

1. 1
PHARMACOLOGY
OF
LOCAL ANESTHETICS

2. What is local anesthesia?
2
• Local anaesthesia has been defined as loss of sensation in a
circumscribed area of the body caused by depression of
excitation in nerve endings or inhibition of the conduction
process in peripheral nerves.

3. INTRODUCTION
3
• Ancient time – dental treatment was associated with pain
• Earliest pain relief – Coca shrub  mood elevator
• Cocoa shrub – foot hills of Andes
• Introduced by  Europeans to South America

4. INDICATIONS FOR LOCAL
ANESTHESIA
10
•Most frequent use: regional anesthesia.
•Analgesic , espescially post operative pain.
•Lidocaine (xylocaine) also reduces blood pressure response to direct
laryngoscopic tracheal intubation, an effect probably secondary to
generalized cardiovascular depression.
•Treatment of intractable cough.

5. Local Vs General Anaesthesia
5
General Local
Site of action CNS Peripheral nerves
Area Whole body Restricted areas
Consciousness Lost Unaltered
Preferential use Major surgery Minor surgery
Use in non-coperative
patients
Possible Not possible
Poor health patient Risky Safer
Care for vital functions Essential Not needed

6. CLASSIFICATION OF LOCAL
ANESTHESIA
6

7. CLASSIFICATION ACCORDING
TO ROUTE OF ADMINISTRATION
7
• Injectable :
– Low potency, short duration – Procaine and
Chlorprocaine
– Intermediate potency – Lidocaine (Lignocaine) and
Prilocaine
– High potency and long duration – Tetracaine,
Bupivacaine, Ropivacaine, Etidocaine, Mepivacaine and
Dibucaine (Cinchocaine)

8. • Surface :
– Soluble – Cocaine, Lidocaine, Tetracaine and Benoxinate
– Insoluble – Benzocaine, Butylaminobenzoate and
Oxethazine
• Miscellaneous :
– Clove oil, phenol, chlorpromazine and diphenhydramine
etc.
8

9. CLASSIFICATION ACCORDING TO
CHEMISTRY
9
1. Esters (of benzoic acid)
-Butacaine
-Cocaine
-Benzocaine
-Hexylcaine
-Piperocaine
-Tetracaine

10. 2. Esters (of paraaminobenzoic acid)
-Chloroprocaine
-Procaine
-Propoxycaine
10

11. 3. Amides
-Articaine
-Bupivacaine
-Dibocaine
-Etidocaine
-Lidocaine
-Mepivacaine
-Prilocaine 17

12. 4. Quinoline
-Centbucridine
5. Combinations
- Lidocaine/Prilocaine(emla)
18

13. 6. Natural local anesthetics
- Saxitoxin and Tetrodotoxin
-Naturally occurring local anesthetics not derived from cocaine are
usually neurotoxins, and have the suffix -toxin in their names.
-Unlike cocaine produced local anesthetics which are intracellular in
effect,
-Saxitoxin & Tetrodotoxin bind to the extracellular side of sodium
channels. 19

15. LAs are Weak Bases
N
R
N
H
O
C R N
R
R
Aromatic
portion
Amine
portion
R
Intermediate
O chain
C O R
ESTER
AMIDE
LIPOPHILIC
(quality of
dissolving in
lipids)
HYDROPHILIC
(able to absorb
water)
21

16. MECHANISM - LAs
• entry of Na+ is essential
for Action potential
• Two things happen:
– Rate and rise of AP and
depolarization decreases
–slowing of
conduction.
– Finally, local
depolarization fails to
reach threshold potential
– conduction block.
22

17. Mechanism of LAs – contd.
• LAs interact with a receptor
within the voltage sensitive
Na+ channel and raise the
threshold of opening the
channel
• Na+ permeability decreased
and ultimately stopped in
response to stimulus or
impulse
• Impulse conduction is
interrupted when a critical
length of fiber is blocked (2-
3 nodes of Ranvier). 23

18. Mechanism of LA – contd.
- Higher concentration of Ca++ reduces inactivation of Na+
channel
- Blockade is not due to hyperpolarization (RMP is unaltered as
K+ channels are not blocked)
- Blockade is related to pKa (acid dissociation constant) of
particular drug:
- 7.6 to 7.8: e.g. lidocaine - fast acting drugs (more
undissociated form)
- 8.1 to 8.9 : Bupivacine – slow acting (more dissociated
form) 24

19. 19

20. Summary of Mechanism - LAs
20
• All local anesthetics are membrane stabilizing drugs
– slows down speed of AP - ultimately stop AP generation
• Reversibly decrease the rate of depolarization and
repolarization of excitable membranes
• Act by inhibiting sodium influx through sodium-specific ion
channels in the neuronal cell - voltage-gated sodium channels
• When the influx of sodium is interrupted - action potential
cannot rise and signal conduction is inhibited

21. • Local anesthetic s bind (located at inner surface) more readily
to sodium channels in activated state – and slows its reversion
to the resting state – refractory period is increased - “state
dependent blockade” - no action on resting nerve.
• Blockade develops rapidly on stimulation of nerves repeatedly
(Greater the stimulation higher is the blockade)
• Many other drugs also have membrane stabilizing properties,
all are not used as LA, e.g. propranolol
21

22. Fundamentals Of Impulse
Generation And Transmission
22
• Concept behind action of local anaesthesia- prevent
conduction and generation of nerve impulse, set up chemical
roadblock between the source of impulse and the brain.
• NEURON is the fundamental unit of nerve cell.
• It transmits messages between CNS and all parts of the body.
• It is of 2 types:-
– Sensory (afferent)
– Motor (efferent)

23. Physiology Of Peripheral
Nerves
23
• The function of nerve is to carry messages from one part of the
body to another in the form of electrical action potential called
IMPULSES initiated by chemical, mechanical, thermal or
electrical stimuli.
• Action Potential- transient depolarization of membrane which
leads to brief increase in permeability of membrane with
delayed increase in permeability of potassium.

24. THE ELECTRICAL IMPULSE
24

25. Nerve impulses are conducted by a
wave of action potentials. When a
stimulus is great enough to reach the
threshold potential of -55mV, sodium
ions flow into the neurone. It does so
via sodium gates to produce
depolarisation.
When depolarised, the membrane
potential is reversed to +40 mV.
At the same time, there is passive
outwards diffusion of potassium ions
to bring about repolarisation and the
membrane potential is again reversed
to -70mV
** mV - milivolt 34

26. Electrophysiology Of Nerve
Conduction
26
• Nerve possesses a resting potential which is negative electrical
potential of -70mV because of differing in concentration of
ions on either side of membrane.
• Internal to the membrane is negative in respect to the outer
part.

27. STEP 1
27
• Stimulation excites the nerve cells.
• Initial phase of slow depolarization, the electrical potential in the
nerve becomes slightly less negative.
• Falling electrical potential reaches a critical level. Extremely rapid
phase of depolarisation result reaches to a threshold potential or
firing potential where reversal of electrical potential across nerve
membrane occurs.
• Internal to the membrane becomes positive in respect to the
outside (+40mV)

28. 28

29. STEP 2
29
• This is a phase of Repolarisation.
• Electrical potential gradually becomes more negative in
respect to the outside until -70mv is achieved.
• Step1- 0.3msec
• Step2- 0.7msec

30. Mechanism of action
30
- Inhibiting excitation of nerve endings or blocking conduction in
peripheral nerves. Binding to and inactivating sodium channels.
- Local Anaesthetics are alkaloid bases that are combined with
acids, usually hydrochloric, to form water soluble salts. All
anaesthetic salts are formed by a combination of weak base and a
strong acid. They are stable and soluble in water; water solubility
is necessary for their diffusion through interstitial fluids to the
nerve fibers.

31. -Sodium influx through these channels is necessary for the
depolarization of nerve cell membranes and subsequent propagation
of impulses along the course of the nerve.
31
-when a nerve loses depolarization and capacity to propagate an
impulse, the individual loses sensation in the area supplied by the
nerve

32. block nerve fiber conduction by acting on nerve membranes
inhibit sodium ion activity
blocks depolarization
blocks nerve conduction
32

33. • When the influx of sodium is interrupted, an action potential
cannot arise and signal conduction is inhibited. LA drugs bind
more readily to sodium channels in activated state, thus onset
of neuronal blockade is faster in neurons that are rapidly firing.
This is referred to as state dependent blockade.
33

34. 34

35. BINDING OF LOCAL
ANESTHETIC TO RECEPTOR
35

36. • The affinity of the receptor site within the sodium channel for the
LA is a function of the state of the channel
• drugs binds to open and inactivated channels, therefore for those
with higher activity/firing
• use dependence - rapidly firing fibers are usually blocked before
slowly firing fibers.
36

37. 37

38. INDIVIDUAL AGENTS
38

39. THE GOLD STANDARD DRUG

40. Lidocaine
Lidocaine, the first amino amide-type local anesthetic,
was first synthesized under the name Xylocaine by
Swedish chemist Nils Löfgren in 1943.
FDA Approved-November 1948

41. Pharmacology
⚫Half life: 1.6 hrs(~90 min)
⚫Distribution: Lipo-philic, widelydistributed into body
⚫pH of plain solution-6.5
⚫pH of vasoconstrictorcontaining solution-5.0-5.5
⚫Onsetof action –rapid
⚫Pregnancyclissification-B
⚫Effectivedental concentration-2%
⚫Protein binding: 60-80 %

42. MAXIMUM RECOMMENDED DOSE
⚫The max. manufactures recommended dose of
lidocainewith epinephrine is 7.0mg/kg bodyweight
foradult patient,not to exeed doseof 500mg.
⚫4.4mg/kg body weightdoseof lidocainewithouta
vasoconstrictor

43. ACTIONS
ON CNS
(i) Blocksconduction around a nerve
Anaesthesia
(ii)Initiallycausesdrowsiness &
lethargy
(iii) Higherdosescauseexcitation
followed bydepression
ON CVS
Heart Blood vessels
Vasodilatation in
the injected area
Abbreviates
Effective
Refractory
Period

44. MECHANISM OF ACTION
Alters depolarization in
neurons by blocking the fast
voltagegated sodium (Na+)
channels in the cell
membrane.
With sufficient
blockade, the membraneof
the presynaptic neuron will
notdepolarizeand so fail to
transmitan action potential,
leading to its anaesthetic
effects

45. PHARMACOKINETICS
 Absorption:
Absorbed rapidly after
parenteral administration &
from GIT & RespiratoryTract
 Metabolism:
Metabolized in the liver
 Excretion:
Metabolitesand unchanged
drug areexcreted by the
kidneys in the urine

46. ROUTES OF ADMINISTRATION
⚫ Intravenous injection
(sometimescombined with
epinephrine)
⚫ Dermal patch (sometimes
combined with prilocaine)
⚫ Nasal instillation/spray
(combined with
phenylephrine)
⚫ Topical gel

47. Itsvasodilating
effect limits
pulpal anesthesia
to only 5-10min.
This leads to
higher blood
levels& increased
risk of adverse
reaction
The inclusion of
epinephrine
produces a
decrease in blood
flow leading to
decrease in
bleeding at the
site of injection.
Increased
duration-~60min
of pulpal
anesthesia
Decreases blood
flow .
Increases
duration of
action~60minof
pulpal
anesthesia.
2% WITHOUT
VASOCONSTRICTOR
(LIDOCAIN
PLAIN)
2% WITH
EPINEPHRINE
1:50,000
2% WITH
EPINEPHRINE
1:100,000
The duration &depth obtained with both lidocaine-epinephrine
solution are equivalent although not the same level of
hemostasis.{2%lidocaine with 1:50,000 epinephrine is recommended
because it decrease bleeding by 50% as compared with 1:100,000
epinephrenedilution}
DIFFERENT FORMS OF LIDOCAINE

48. Intravenous Lidocaine for Ambulatory
Anesthesia
Christopher L. Wu, MD ,Inter Anes Research Society,Dec. 2009
Using 1.5–3 mg kg h
lidocainesignificantly reduced the incidenceof
nauseaand vomiting (32% vs 52%),
Marginally reduced pain scores .

49. ADVERSE EFFECTS

50. OVERDOSE

51. CONTRAINDICATIONS

52. Indications
⚫Rapid acting local anesthetic forprocedures ranging
from infiltration to regional nerve block
⚫Antiarrhythmic in the treatment of vent. arrhythmias
⚫Treatmentof status epilepticus (INVESTIGATIONAL)
⚫ Treatmentof pain
Operative
Neuropathic pain

53. EUTECTIC MIXTURE OF LOCAL
ANESTHETICS (EMLA)- LIDOCAINE &
PRILOCAINE
Eutectic mixture refers to lowering
of melting point of two solids when
they are mixed
Lidocaine+Prilocaine at 25oC
Oil emulsified into water to form a
cream

54. CLINICAL USES/ INDICATIONS
 Dermal anaesthesia, specifically
applied to prevent pain associated
with intravenouscatheter insertion,
blood sampling, superficial surgical
procedures on intactskin & mucous
membranes
 Topical anaesthesia for cleansing or
debridement of ulcers, to numb the
skin before tattooing as well as laser
hairremoval

55. Bupivacaine
55
Classified under amide
• 1-butyl 2,6 pipecoloxylidide
• Toxicity <4 times – Lignocaine, Mepivacaine
• Metabolism –Liver by Amidases
• Excretion by kidney (16% unchanged)
• Vasodilation- relatively significant

56. • Pka-8.1,ph(plain)- 4.5-6, ph(vc)- 3-4.5
• Onset of action –6-10 min, Anesthetic half life-2.7hrs,Dose
1.3mg/kg ,Maximum dose-not >40mg,Absolute maximum
dose-not> 90mg
56

57. N
C4H9
57
CH3
NH.CO
CH3
BUPIVACAINE

58. • Available as 0.5% soln 1:2,00,000 (vc)
• Indicaton- pulpal anesthesia.
58
•
•
•
Full mouth recontruction.
Extensive perio surgery.
management of post op pain.
• Duration –Pulpal- 90- 180 min
• Soft tissue-4-12 hrs
• Contra indication- burning sensation at site of injecton, in
children-anticipating self trauma .

59. Procaine
59
Procaine is a local anesthetic drug of the amino
ester group. It is most commonly used in dental
procedures to numb the area around a
tooth[1] and is also used to reduce the pain
of intramuscular injection of penicillin

60. • Kinetics
• Metabolised-in Plasma by plasma pseudocholine esterases
• Excretion >2%unchanged, 90% -PABA,8% diethyl
aminoethanol
in urine.
• Pka-9.1,High degree of vasodilation, 2% procaine 15-
30min soft tissue LA

61. ADRS
hypersensitive, producing restlessness and shaking,
leading to minor to severe convulsions
Studies on animals have shown the use of procaine led to
the increase of dopamine and serotonin levels in the
brain.
respiratory failure if overdosed. Procaine may also induce
weakening of the myocardium leading to cardiac arrest

62. Mepivacine
• Classified -amide type
• 1 methyl 2,6 pipecoloxylidide hcl
• Metabolism-microsomal fixed funcn oxidasea in liver.
• Maximum dose 4.4 mg/kg , absolute max dose-300mg.
• Excretion-1-10% unchanged urine.
• Pka-7.6,anesthetic half life-90min,
• Mild vasodilator, 3% mepivacaine used in patients with vc
contraindicaton. Low reported cases-allergy. Over dose CNS
stimulation followed by depression. 102

63. Articaine
63
Classified- amide
– 2 carboxymethoxy 4 methylthiophene hcl
– Metabolised- liver
– Excretion – kidney 10% - unchanged.
– Pka 7.8, anesthetic half life-1.2-2 hrs,
– Maximum dose – 1mg/kg , absolute maximum dose –
500mg

64. • First LA agent with thiophene ring,little potential to diffuse
through soft tissue.
• Adverse reaction-methymoglobinemia-rx by using
methylene blue 1mg/kg.
64

65. Etidocaine
65
Classified –amide
– Metabolism –liver
– Excretion –urine- kidney
– Pka 7.7 ,anesthetic half life-56 min.
– Maximum dose 8mg /kg, absolute max dose 400 mg
– Employed mainly in epidural or caudal regional block.