By Dr. Vishal Pawar MD Pharmacology A comprehensive up to date review

1. PHARMACOLOGY OF LOCAL ANAESTHETICS (LA)
BY: DR. VISHAL PAWAR
JR II
DEPT. OF PHARMACOLOGY 1

2. INTRODUCTION
 LA bind reversibly to specific receptor sites in sodium
channels in nerves, thus blocking ion movement
through them  blocking nerve conduction
 When applied in appropriate conc. can act on any part
of nervous system and any fibre
 Leading to sensory and motor paralysis in the area
innervated by the nerve trunk
 These effects are reversible with recovery of nerve
function and no damage to nerve cells
2

3.  First LA  Cocaine
 First isolated by Albert Niemann in 1860
 Carl Koller  introduced it in clinical practice in 1884
 Used as a topical anaesthetic for ophthalmic surgery
 Halsted  popularised its use in conduction block anaesthesia
 Alfred Einhorn produced the first synthetic ester-type local
anaesthetic -novocaine (procaine)
 Nils Löfgren synthesizedthe first amide-type local anaesthetic -
marketed under the name of xylocaine(lidocaine) 3
HISTORY

4.  Cocaine  ester of benzoic acid and complex alcohol
 Because of its addictive and toxicity properties, search
for synthetic substitutes began in 1892
 Resulting in Procaine which became the prototype
 Most widely used today are Lidocaine, Bupivacaine,
Tetracaine
4
CHEMISTRY and STRUCTURE

5.  Typical LA contain hydrophilic and hydrophobic
moieties
 Separated by intermediate ester or amide linkage
 Hydrophobic group  usually a tertiary amine
 Hydrophilic group  aromatic
5

6.  Lipid solubility correlates with potency of LA
 Protein binding correlates with duration of action
 Dissociation constant correlates with time of onset
 Some LA possess intrinsic vasoactive properties
 Lidocaine produces vasodilation in low conc.,
reducing its potency in vivo by increasing vascular
uptake
 Ropivacaine has dose-dependent vasoconstrictive
activity, which increases its duration of action,
especially after local infiltration
6

7.  First reviewed by Courtney and Strichartz in 1987
 Hydrophobicity :
 increases potency and duration of action
 enhances partitioning of drug at its site of action
 decreases rate of metabolism by plasma
esterases
 increases toxicity and decreases therapeutic
index 7
STRUCTURE ACTIVITY
RELATIONSHIP

8.  Molecular size : influences rate of dissociation of LA
from receptor sites
 Smaller : escape more rapidly
 This property is important in rapidly firing cells
 In which LA bind during action potential and dissociate
during membrane depolarisation
 This causes frequency and voltage dependence of their
action
8

9.  Act on all cell membranes to prevent generation and
conduction of nerve impulses
 LA block conduction by decreasing or preventing
transient increase in permeability of excitable
membrane to sodium ions
 This is due to their direct action in voltage gated
sodium channels
9
MECHANISM of ACTION

10.  They can also bind to other proteins membranes
 In particular, they can block potassium channels, but
requires higher conc.
 When applied externally, LA must first cross the
membrane before they can exert blocking action
10

11.  Degree of block depends on when the nerve is
stimulated
 Resting membrane potential of the nerve also plays a
role
 Thus resting nerve is much less sensitive than the one
repeatedly stimulated
 Increased frequency and more positive stimulation
results in increased degree of block
11
FREQUENCY and VOLTAGE
DEPENDENCE

12.  LA molecule in its charged form gains access to its
binding site
 The site is within the pore of the sodium channel
 But only happens when sodium channel is in open
state
 LA stabilize and bind more tightly to the inactivated
state of sodium channels
12

13.  Treatment with LA causes pain to disappear first
 Its followed by loss of temperature, deep pressure and
finally motor function
 In general, autonomic fibres, small unmyelinated C
fibres (pain) , small myelinated A delta (pain and
temperature) are blocked first
 Then larger Aɤ , Aβ , Aα fibres (posture, touch, pressure,
motor) are blocked
 Effect of pH  LA are marketed as water soluble salts
 After adm. pH of LA solution rapidly equilibrates to that
of extracellular fluids
13
DIFFERENTIAL SENSITIVITY
of NERVE FIBRES

14.  Duration of action of LA is directly proportional to time
of contact with nerve
 Thus manoeuvres that keep drug at nerve site prolongs
anaesthesia
 Eg. Cocaine inhibits the neuronal membrane
transporters for catecholamines, there by potentiating
the effect of Norepinephrine at alpha adrenergic
receptors in vasculature
 Results in vasoconstriction and reduced absorption of
cocaine in vascular beds where alpha adrenergic effects
predominates
14
PROLONGATION of ACTION by
VASOCONSTRICTORS

15.  In clinical practice, a vasoconstrictor usually Epinephrine
is often added to LA
 By decreasing rate of absorption, it localizes the
anaesthetic at desired site but also allows rate of
metabolism to keep pace with its absorption into
circulation
 This reduces systemic toxicity
 Some LA absorbed systemically, in enough conc. cause
untoward reactions, delayed wound healing, tissue
edema, necrosis
 These effects are partly produced because LA cause
increased consumption of oxygen, and therefore
contraindicated in regions with limited collateral
circulation 15

16.  Danger of adverse reaction is directly proportional to
conc. and potency of LA
 CNS  restlessness and tremors
 clonic convulsions
 Central stimulation followed by depression, death
occurs due to respiratory failure
 Drowsiness is often the most frequent complaint
16
UNDESIRED EFFECTS

17.  CVS : primary site of action  myocardium
 Decreases electrical excitability, decreased conduction
rate, decreased force of contraction
 Most LA  arteriolar dilation
 Usually seen after high conc. after CNS effects
 Smooth muscle :
 decreased contraction in bowel
 relaxes vascular, bronchial muscles
 NMJ and ganglionic synapse : blocking of nicotinic
Ach receptor  blocking the response of skeletal
muscles
17

18.  Its of great importance because their toxicity depends
largely on balance between absorption and elimination
 Rate of absorption  decreased on administration of
vasoconstrictor
 Rate of degradation  greatly varies
 Ester LA (eg. Tetracaine) are hydrolysed by plasma
esterases
 Since spinal fluid has very little or no esterases, LA
persist there till it is absorbed into circulation
 Amide linkage LA are degraded by hepatic
cytochromes
 Binding of LA with plasma proteins  decreases toxicity
18
METABOLISM

19.  An ester of Benzoic acid and methyl ecgonine
 Occurs in abundance in leaves of Coca shrub
 Has fundamental structure as other synthetic LA
 Clinically desired property : nerve blockage and
vasoconstriction
 Toxicity and potential abuse lead to decrease in its
usage
19
COCAINE

20.  Its due to decrease in catecholamine uptake in both
central and peripheral nervous system
 Its euphoric property : due to inhibition of
catecholamine uptake, particularly dopamine in CNS
 Currently used primarily as topical anaesthetic of upper
respiratory tract
 Cocaine hydrochloride : 1%, 4%, 10% solution
20

21.  Prototype amide LA
 Produces faster, more intense, longer acting
anaesthesia than procaine
 Absorbed rapidly from GIT and RS after parenteral adm.
 With Epinephrine  decreased absorption, increased
duration of action, decreased toxicity
21
LIDOCAINE

22.  Formulations: Injection, topical, ophthalmic, mucosal,
transdermal
 Transdermal patch  pain relief after post herpetic
neuralgia
 Oral patch  mucous membrane of mouth prior to
superficial dental procedures
 Lidocaine (2.5%) + Prilocaine (2.5%)  anaesthetic prior
to venepuncture , skin graft harvesting
22

23.  Lidocaine + Tetracaine  topical anaesthesia prior to
superficial dermatological procedures
 It is dealkylated in liver by hepatic cytochromes and
excreted in urine
 Toxicity  drowsiness, tinnitus, twitching, seizure, coma,
death on increasing dosage
 Clinically severe CVS depression also occurs at high
conc.
 Also used as anti arrhythmic agent
23

24.  Widely used amide LA
 Structurally similar to lidocaine
 Potent, capable of producing prolonged anaesthesia
 Has long duration of action
 Has more sensory than motor blockage
24
BUPIVACAINE

25.  Chloroprocaine
 rapid onset, short duration, rapid metabolism
 prolonged block after epidural adm.
 high incidence of muscular back pain reported
 Mepivacaine
 intermediate acting amino amide
 onset similar and longer acting than
lidocaine
 more toxic to neonate
25
OTHER SYNTHETIC AGENTS

26.  Prilocaine
 intermediate acting amino amide
 causes little vasodilation, thus can be use
without vasoconstrictor
 increased volume of distribution
 decreased toxicity
 S/E : Methhemoglobinemia, hence usage is
mainly restricted in dentistry
 Ropivacaine
 slightly less potent than bupivacaine
 but less cardio toxic
 suitable for epidural and regional anaesthesia
26

27.  Procaine
 first synthetic LA (1905)
 now replaced by other agents
 Tetracaine
 long acting amino ester
 slowly metabolised, thus increasing its toxicity
 more potent than other LA
 widely used for spinal anaesthesia when long
duration is required
 also incorporated in several topical
anaesthetics
 Levobupivacaine : recently emerged as better
alternative to Bupivacaine 27

28.  Dibucaine
 over the counter skin ointment
 Dyclonine hydrochloride
 rapid onset
 0.5% solution used for topical anaesthesia during
endoscopy,
 for oral mucositis pain following chemotherapy
 for anogenital procedures
 ingredient in various lozenges
28
LA for MUCOUS MEMBRANES

29.  Poorly soluble in water, too slowly absorbed to be toxic
 Applied directly to wounds or ulcers
 Remains localised providing sustained anaesthesia
 Most important agent  Bupivacaine
 Its incorporated in large number of topical
preparations
 It can cause Methhemoglobinemia
29
LA of LOW SOLUBILITY

30.  Most frequently used  Proparacaine and Tetracaine
 Less irritating
 Little antigenic sensitivity
 For anaesthesia  instilled single drop at a time
 Long term anaesthesia  associated with retarded
healing, pitting, sloughing of corneal epithelium
30
LA for OPHTHALMIC USE

31.  Tetradotoxin  found in fish,
salamander, frog antelopus
 Saxitoxin  found in dino flagellates
 Shell fish feeding on them become extremely toxic
 Leading to outbreaks of paralytic shell fish poisoning
31
BIOLOGICAL TOXINS

32.  Both have similar action
 Known as two of the most lethal toxins
 Minimal dose being 8 micro gm / kg
 Death occurs due to respiratory paralysis
 Hypotension is characteristic of tetradotoxin
poisoning
32

33.  Local anaesthesia defined as
Loss of sensation of body part without loss of
consciousness or impairment of central control of vital
functions
 Advantages : neuro-physiological altercations of
general anaesthesia are avoided
 Peak plasma levels achieved are highest with
intrapleural block and lowest with subcutaneous
block
33
CLINICAL USE

34.  Anaesthesia of mucous membranes of nose, mouth,
throat, tracheobronchial tree, esophagus and
genitourinary tract can be produced
 By direct application of aqueous solution of salts of LA
or by suspension of poorly soluble LA
 Tetracaine, lidocaine, cocaine are typically used
 Cocaine is only used in nose, throat, eat where it
uniquely produces vasoconstriction as well as
anaesthesia
34
TOPICAL ANAESTHESIA

35.  Shrinking of mucous membrane decreases operative
bleeding while increasing surgical visualisation
 Maximum safe dose in adults :
 lidocaine : 300 mg
 cocaine : 150 mg
 tetracaine : 50 mg
 Peak levels of anaesthetic effects achieved within 5-10
mins with lidocaine and 3-8 mins with tetracaine
 Anaesthesia is absolutely superficial
35

36.  Topical LA absorbed rapidly from mucosal surfaces or
denuded skin, hence carry risk of systemic toxicity
 Use of eutectic mixtures of LA
Lidocaine (2.5%) / prilocaine (2.5%) and lidocaine (7%) /
tetracaine (7%) bridges the gap between topical and
infiltration anaesthesia
 Mixture has melting point less than that of either
compound alone, existing as an oil at room
temperature that can penetrate the skin
 These are effective for procedures involving skin and
superficial subcutaneous structures eg. venepuncture,
skin graft harvesting
 They should not be used in mucous membranes or
abraded skin as rapid absorption may result in systemic
toxicity 36

37.  Injecting LA directly into the tissue without taking into
consideration the course of cutaneous nerves
 It can be so superficial as to only include skin; and can
also include deeper structure
 Duration of action can be almost doubled by adding
epinephrine (5 microgm/kg) which also decreases peak
plasma levels of LA
 Epinephrine containing solution should not be injected
into tissues supplied by end arteries eg. Fingers, toes,
ear and penis 37
INFILTRATION ANAESTHESIA

38.  LA most frequently used are
 lidocaine (0.5 – 1%)
 procaine (0.5 – 1%)
 bupivacaine (0.125 – 0.25%)
 Advantages : provides satisfactory anaesthesia without
disrupting normal body functions
 Disadvantage : relatively large amount of drug must be
used for relatively small regions
 Becomes a problem especially in major surgeries, and
also systemically toxic
 Amount of LA required can be decreased and its
duration of action increased significantly, by blocking
nerves that innervate that area of interest 38

39.  Produced by s.c. injection of solution of LA in order to
anaesthetize a region distal to the site of injection
 Eg. s.c. inj. at proximal forearm, produces cutaneous
anaesthesia 2-3 cm distally
 Same technique can be used in scalp, anterior
abdominal wall, lower extremity
 Drugs, doses recommended are same as infiltration
anaesthesia
 It does provide a greater area of anaesthesia than
infiltration anaesthesia 39
FIELD BLOCK ANAESTHESIA

40.  Inj. of LA solution about individual nerves or plexuses
produces even greater area of anaesthesia
 It also anesthetizes somatic nerves, producing skeletal
muscle relaxation
 The areas of sensory and motor block usually start
several cms distal to the site of inj.
40
NERVE BLOCK ANAESTHESIA

41.  Brachial plexus block  useful in upper extremity
procedures
 Intercostal block  effective for anterior abdominal
wall
 Cervical plexus block  appropriate for surgery of
neck
 Sciatic and femoral nerve block  useful for surgeries
distal to the knee
 Other useful nerve blocks are given at wrist, ankle,
individual nerves
41

42.  LA is never injected into nerve as it would be painful
and damage the nerve
 Instead they are deposited as close as possible
 Thus, LA must diffuse from site of inj. to nerve
 Rate of diffusion is determined by drug conc., it’s
degree of ionization, hydrophobicity, and physical
characteristics of tissue surrounding nerve
42

43.  LA can be divided into three categories on basis of
duration of action
Short acting (20-40 mins)  Procaine
Intermediate acting (60-120 mins)  Lidocaine,
Mepivacaine
Long acting (400-450 mins)  bupivacaine,
ropivacaine, tetracaine
 Block duration can be increased by giving epinephrine
 Types of nerve fibres that are blocked depends on the
conc. of the drug , nerve fibre size, internodal distance,
frequency and voltage dependence
43

44.  This technique relies on vasculature to bring LA
solution to the nerve trunk and endings
 An extremity is exsanguinated with an elastic bandage
 Proximally located tourniquet is inflated to 100-150
mmHg above systolic blood pressure
 Bandage is removed and LA is injected into previously
cannulated vein
44
INTRAVENOUS REGIONAL
ANAESTHESIA (BIER’S BLOCK)

45.  Typically, complete anaesthesia of the limb occurs in
5-10 mins
 Lidocaine (0.5%) is the drug of choice
 Disadvantage : can be used only for limited no. of
regions and premature release of tourniquet may
lead to systemic toxicity
 Most often used for surgeries of arm and forearm
45

46.  Follows the inj. of LA into CSF in the lumbar space
 Ability to produce anaesthesia for considerable part
of the body
 With a dose that produces negligible plasma levels,
have made it one of the most popular techniques
 Clinically most important effect of sympathetic
blockage of spinal anaesthesia is on CVS
46
SPINAL ANAESTHESIA

47.  Vasodialation (venous > arterial)  venous pooling
 Venous return can be increased by modest 10-15
degrees by head down tilt or by elevating the legs
 Patients are also adm. bolus fluids before spinal
anaesthesia in order to compensate for hypotension
 Drugs with preferential veno constrictive and
chronotropic properties are used
47

48.  Drugs most commonly used are lidocaine,
bupivacaine
 Choice of drug depends chiefly upon desired
duration of action
 For short procedures  Lidocaine
 Intermediate to long  Bupivacaine
 Long  Tetracaine
 Most important pharmacological characters include
the amount, volume of drug injected
48

49.  Epinephrine is added to increase the duration of
intensity of block
 Baricity of LA will determine the direction of its
migration
 Hyperbaric solution  settle in dependent part of the
sac
 Hypobaric solution  goes in the opposite direction
 Isobaric solution  stays in the vicinity
49

50.  Complications:
 Neurological sequalae can result from introduction of
foreign substances into subarachnoid space
 Infection, hematoma, mechanical trauma
 High conc. Of LA can cause irreversible block
 Several reports of transit or longer lasting neurological
deficit following lidocaine (5%) are reported
50

51.  Most common feature following spinal anaesthesia is
postural headache
 It should be thoroughly investigated to exclude
serious complications like meningitis
 Spinal anaesthesia is safe and effective anaesthesia
for lower abdomen, extremity and perineum
51

52.  Injecting LA into epidural space
 Can be performed in sacral hiatus (caudal anaesthesia),
lumbar, thoracic, cervical region of spine
 Its popularity is because of catheters that can be
placed into epidural space allowing either continuous
or bolus administration of LA
 Choice of drug is determined by duration of its action
required
52
EPIDURAL ANAESTHESIA

53.  Used in labor and post –op anaesthesia
 Lidocaine (2%) is most frequently used intermediate
acting
 Bupivacaine is used for long duration anaesthesia
 Chloroprocaine (2/3 %) provides rapid onset and
very short duration of action
 Duration of action prolonged and systemic toxicity is
decreased by addition of Epinephrine
53

54.  For each LA injected, relationship exists between the
volume and level of anaesthesia achieved
 A significant difference between epidural and spinal
anaesthesia is that dose of LA used can produce
high conc. in blood following absorption from
epidural space
 Another major difference is that there is no zone
differential sympathetic blockage with epidural
anaesthesia
54

55.  Spinally administered opioids by themselves do not
produce sufficient anaesthesia
 Hence have found greater use in treatment of post op
and chronic pain
 For post op anaesthesia  spinally morphine
(0.2-0.5 mg) usually provides 8-16 hrs of anaesthesia
 Epidurally, morphine (2-6 mg) is used
 For cancer pain  repeated doses of epidural LA can
provide anaesthesia for several months duration
 But, after regular usage tolerance does develop
55
OPIATE ANAESTHESIA

56.  Opioids (most frequently used) : Morphine, Fentanyl
 Epinephrine
 Alpha 2 adrenoreceptor antagonists :
Clonidine, Dexmedetomidine
 Steroids : Dexamethasone
56
ADJUVANTS

57. 57
RECENT ADVANCES

58.  Bupivacaine HCL liposome injectable suspension
 Approved November 2011
 long-acting, sustained-release formulation using
DepoFoam lipid-based delivery system
 It encapsulates the drug in multivesicular liposomal
particles which then release the drug over a desired
period of time without altering the drug molecule
 Specifically indicated for administration into the surgical
site to produce postsurgical analgesia
 Side Effects: nausea, constipation, vomiting 58
EXPAREL

59.  Lidocaine hydrochloride
 Approved October 2008
 Gel formulation (3.5%)
 Anaesthesia generally occurs between 20 seconds to
1 minute and persists for 5 to 30 minutes
 Specifically indicated for ocular surface anaesthesia
during ophthalmologic procedures
 Side Effects: Conjunctival hyperaemia, burning upon
instillation
59
AKTEN

60.  Lidocaine hydrochloride monohydrate
 Approved August 2007
 Powder intradermal injection system
 Specifically indicated for use on intact skin to
provide local analgesia prior to venipuncture or
peripheral intravenous cannulation
 Side Effects: Erythema, Edema, Pruritus Pain,
Hemorrhage
60
ZINGO

61.  Intermediate potency, short-acting amide LA with
fast metabolism
 Used as spinal, epidural, ocular, or regional nerve
block, or when injected intravenously for regional
anaesthesia
 Suitable for procedures requiring a short duration of
action in which a fast onset of anaesthesia is desired
eg. ambulatory spinal anaesthesia
61
ARTICAINE

62.  Liposome-based LA formulations
 First proposed by Gesztes & Mezei
 They are microscopic mono or multi layer phospholipid
vesicles that are biocompatible, biodegradable and non
immunogenic
 Distinct advantage is their structural versatility
combined with their ability to encapsulate different
compounds, like LA
 Advantages of encapsulating LA in liposomes are slow
drug release, prolonged anaesthetic effect and reduced
toxicity towards CVS and CNS
62
NEW DRUG DELIVERY SYSTEMS

63.  Intranasal drug delivery
 In addition to being convenient and painless, there is no
reduction in bioavailability of drugs administered nasally
 Direct deliveries to the cerebrospinal fluid due to
nose-brain pathway reduce the onset time
 Highly lipophilic drugs of low molecular weight easily
cross the nasal mucosa
 To avoid runoff, 0.25–0.3 ml of concentrated drug per
nostril is used
 Limitations: patients with bloody nose or increased
mucus production  decreased absorption
63

64.  Transdermal drug delivery system
 Advantage: it avoids first pass metabolism and
large variations in plasma drug concentrations
 Although transdermal delivery of drug is the most
patient compliant mode of delivery only lipophilic,
low molecular weight drugs can be delivered by
this route
64

65.  Pulmonary drug delivery system
 Metered dose inhalers, nebulizers, and dry powder
inhalers are used for pulmonary drug delivery
 Advantage: larger surface area and closer proximity to
blood flow, lower doses can be used thus avoiding
systemic toxicity
 Disadvantage: shorter duration and only 10–40% of
drugs delivered become available for systemic
absorption
 To overcome this limitation, nanoparticles have been
developed
65

66.  Are non biological entities and do not generate any
harmful activities, there shall be no side effects
 Being highly specific and target oriented, they reduce
anaesthesia-associated mortality and morbidity
 Since they reach specific receptors, lesser drug dosage is
required, limiting the side effects
 As they bind the terminal receptors, there shall be no
peaks and troughs in effect.
66
NANOPARTICLES

67.  Bio adhesive Plaster and Gels
 Lidocaine : Controlled-Release Local Anaesthetic
Matrix
 Encapsulation Matrices
 Injectable Liquid Polymers
 Bupivacaine : Using Lipid Nanoparticles
 Ultrasound-guided truncal blocks in regional
anaesthesia
 Computer controlled la delivery systems
67

68.  Pitfalls of drug delivery system
 Final drug product could turn out to be costly when
high-end technology is being used
 Toxicity of the various carriers
 Lack of knowledge about the degradation products
 Trained staff to administer personalized treatment
and to use various DDS
 Patient compliance may be affected due to complex
devices
68

69.  LA are widely used to manage acute, chronic, and
cancer pain, for anaesthesia
 Have similar chemical structures, but differing
pharmacokinetic and pharmacodynamic effects
 New innovations pertaining to LA formulations lead to
prolonged action and novel delivery approaches
 Development of new effective delivery systems should
suitably modulate release rate, extend their anaesthetic
effect, and enhance their localisation; this should
reduce problems of systemic toxicity 69
CONCLUSION

70. REFRENCES
 Goodman and Gilman’s, Local anaesthetics, the
pharmacological basis of therapeutics, 12th edition,
chapter 20, 565.
 Katzung, trevor, Local anaesthetics, basic and clinical
pharmacology, 13th edition, chapter 26, 596.
 Becker D, Reed K. Local Anesthetics: Review of
Pharmacological Considerations. Anesthesia Progress.
2012;59(2):90-102.
 Heesen M, Weibel S, Klimek M, Rossaint R, Arends L,
Kranke P. Effects of epidural volume extension by saline
injection on the efficacy and safety of intrathecal local
anaesthetics: systematic review with meta-analysis,
meta-regression and trial sequential analysis.
Anaesthesia. 2017;72(11):1398-1411. 70

71.  Uskova A, O’Connor J. Liposomal bupivacaine for
regional anesthesia. Current Opinion in
Anaesthesiology. 2015;28(5):593-597.
 Swain A, Nag D, Sahu S, Samaddar D. Adjuvants to
local anesthetics: Current understanding and future
trends. World Journal of Clinical Cases. 2017;5(8):307.
 Shipton E. New Formulations of Local Anaesthetics—
Part I. Anesthesiology Research and Practice.
2012;2012:1-11.
 Sharma D. Newer Local Anaesthetic Drugs and
Delivery Systems– An Update. IOSR Journal of
Medical Sciences. 2012;1(4):10-16.
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