MBBS Sem IV theory lecture

1. Local Anaesthetics-1
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College
29 July 2018 (13 Shrawan 2075),
Sunday

2. At the end of the class, MBBS
Sem IV students will be able
to:
Review relevant physiology of pain (definition,
conducting pathways, fibres, channels and ions
involved)
Classify local anaesthetics (LA)
Explain the mechanism of action of LA
List the actions of LAs
Discuss the salient features of different LAs

3. A case scenario
18 years male
Presented to ER
with:
Laceration of pinna
Decided to suture the
pinna
How to address pain
during suturing?

4. Preliminaries
Pain:
An unpleasant sensory and emotional
experience associated with actual or
potential tissue damage, or described in
terms of such damage
Tissue conducting pain sensation:
Nervous tissues forming lateral
spinothalamic tract

5. Preliminaries

6. Transmission of nerve impulse:
Unmyelinated fibres:
• Depolarization of successive areas
• Slower
Myelinated fibres:
• Impulse jumps from one node to another:
– saltatory conduction
• Faster
Preliminaries

7. Preliminaries
Conduction in
unmyelinated fibres
Conduction in
myelinated fibres

8. Preliminaries
• Ion responsible for
depolarization:
• Na+ ions
• Channel
responsible:
• Voltage gated Na+
channels

9. Preliminaries
Voltage gated Na+ channels

10. Local Anaesthetics:
Introduction
Reversible loss of sensation at the area
applied
Pain sensation
Block generation and conduction of nerve
impulse
No structural damage
Motor and autonomic control is also lost
Amphiphilic molecules

11. Local Anaesthetics:
Classification
Injectables
Low potency, short duration
• Procaine, Chloroprocaine
Intermediate potency and duration
• Lidocaine, Prilocaine
High potency, long duration
• Tetracaine, Bupivacaine, Ropivacaine,

12. Local Anaesthetics:
Classification
Surface anaesthetics
Soluble
• Cocaine, Lidocaine, Tetracaine,
Benoxinate
Insoluble
• Benzocaine, Butylaminobenzoate,
Oxethazaine

13. Local Anaesthetics: Amides vs
Esters
Esters Amide

14. Local Anaesthetics: Amides vs
Esters
Esters Amides
Short acting Longer acting
Less intense action More intense action
High risk of
hypersensitivity
Low risk of
hypersensitivity
Cross sensitivity seen No cross sensitivity
Only used topically Versatile uses
E.g.: Cocaine,
procaine, tetracaine,
E.g. Lidocaine,
bupivacaine, dibucaine

15. Local Anaesthetics:
Mechanism of Action
Unionised form penetrates the axon
Gets ionised inside the neuron
Binds to the inner face of the voltage gated
Na+ channels
Local depolarization fails to reach threshold
potential
Impulse generation as well as conduction
blocked

16. Local Anaesthetics:
Mechanism of Action
H+ + B BH+
H+ + B BH+
Resting
Activated Inactivated
Na
+
Na
+
Na
+
Na
+
Na
+
++++
++++
Blocked
Axon of a nerve

17. Local Anaesthetics: Nature of
blockade
Activated and inactivated states preferred
Use dependent blockade seen
Inactive state prolonged
Channel takes longer to recover
Refractory period prolonged
Onset of blockade depends on pKa of the drug
LAs are weak basic drug

18. Local Anaesthetics: Local
actions
Blocks all structures that functions through
increased Na+ permeability
Sensory nerve endings, Nerve trunks
• Mixed nerve: sensation as well as motor
tone supply lost
Neuromuscular junctions
Ganglionic synapse
Decreased Acetylcholine release

19. Factors determining sensitivity
of LA
Sensory vs motor:
Equally sensitive
Bupivacaine – sensory block seen at lower
concentration
Fibre size (length):
Smaller fibres more sensitive
• Shorter critical length

20. Factors determining sensitivity
of LA
Myelinated vs unmyelinated fibres:
Myelinated fibres more sensitive
Fibre diameter:
Slender fibres more sensitive
• Shorter internodal distance
• Smaller sensory fibres carry high
frequency longer lasting action potentials

21. Factors determining sensitivity
of LA
Autonomic vs somatic fibres:
Autonomic fibres
Among somatic afferents:
Pain(maximum sensitivity)
Temperature
Touch
Deep pressure (minimal sensitivity)

22. Factors determining sensitivity
of LA
Nerve sheath: restricts diffusion of LA
Peripheral nerves of nerve trunk affected
initially
• Supplies proximal areas
• Motor fibres present in outer layers

23. Factors determining sensitivity
of LA
Analgesia in inflamed tissue: not achieved
Lower pH greater fraction ionised (pH vs
pKa) thus ion trapping
Increased blood flow  drug removed more
rapidly
Effectiveness of adrenaline injected with LA
reduced at inflamed site
Inflammatory products may oppose LA
action

24. Adding adrenaline to LA
Used concentration: 1:50,000 to 1:2,00,000
Prolongs duration of action
Enhances intensity of nerve block
Reduces systemic toxicity
Bloodless field for surgery
Chances of subsequent tissue edema and
necrosis, delayed wound healing
May raise BP and promote arrhythmia in

25. Systemic Actions of LA
Central Nervous System:
Stimulation followed by depression
Cocaine:
• Euphoria  excitement  mental
confusion restlessness  tremor and
twitching of muscles  convulsions 
unconsciousness respiratory depression
 death

26. Systemic Actions of LA
Central Nervous System:
Other LAs:
• No CNS effect at clinically used doses
• High dose or inadvertent i.v. injection 
CNS effects seen

27. Systemic Actions of LA
Central Nervous System:
Overdose:
• Circumoral numbness, abnormal
sensation in tongue, dizziness, blurred
vision, tinnitus, drowsiness, dysphoria,
lethargy
• Excitation, restlessness, agitation, muscle
twitching, seizures, unconsciousness

28. Systemic Actions of LA
Cardio-Vascular System:
Cardiac depressants
• At doses 2-3 times that producing CNS
effects
• Inadvertent i.v. injection
Decreased automaticity, excitability,
contractility, conductivity, prolonged effective
refractory period

29. Systemic Actions of LA
Cardio-Vascular System:
High dose:
• Prolonged QTc interval  arrhythmia
• Bupivacaine: more cardiotoxic
• Lidocaine: minimal cardiotoxicity

30. Systemic Actions of LA
Blood vessels:
Fall in BP
• Sympathetic blockade
• Direct vasodilatation at the site of injection
►Bupivacaine: more vasodilatory
►Procaine: least vasodilatory
Cocaine: Rise in BP, tachycardia
(sympathomimetic)

31. Pharmacokinetics
Soluble surface anaesthetics:
Rapidly absorbed from mucosal surface and
abraded skin
Rate of absorption
• Depends on local blood flow
Not active orally
Widely distributed- rapid distribution to high
blood flow organs

32. Pharmacokinetics
Soluble surface anaesthetics:
Amide LA: bound to plasma proteins
Metabolism:
• Ester LA: plasma esterase and liver
esterase
• Amide LA: liver microsomes
• Lignocaine: depends on hepatic blood flow
►Decrease dose with lower hepatic
functions

33. Adverse effects
CNS effects:
Light headedness, mental confusion,
auditory and visual disturbances,
convulsions, respiratory arrest
• Treatment: Diazepam
Cardiovascular effects:
Bradycardia, hypotension
Arrhythmia, vascular collapse

34. Adverse effects
Local irritation:
Pain
Delayed wound healing, increased chances
of necrosis when combined with
vasoconstrictors
• Do not combine with vasoconstrictors for
areas supplied by end arteries
Hypersensitivity
Commonly seen with ester LA
Methyl paraben added to LA: leads to
hypersensitivity reaction

35. That’s all for today!
We will continue with individual compounds in
next class
Question???
Thank you!