2. Case Study …
A 67-year-old woman is scheduled for elective total
knee arthroplasty.
What LA would be most appropriate if surgical
anesthesia were to be administered using a spinal or
an epidural technique ?
What potential complications might arise from
their use?
What anesthetics would be most appropriate for
providing postoperative analgesia via an indwelling
epidural or peripheral nerve catheter?
Berhan B. 2
3. Pharmacology of LAs
Drugs that suppress pain by blocking impulse
conduction along axons.
Conduction is blocked only in neurons located
near & the blockade is reversible.
Render parts of the body insensitive to pain
without affecting consciousness
Berhan B. 3
5. Important Property of Ideal LA:
Low systemic toxicity at an effective concentration
Onset of action should be quick
Duration of action should be sufficient
Should be soluble in water and stable in solution.
Should not deteriorate by the heat of sterilization
Should be effective both when injected & topically.
Its effects should be completely reversible
Berhan B. 5
8. Weak bases – proportion of free base (R-NH2) & salt
(R-NH3
+) forms depends on pH & pK of amino group
Both free base & ionized forms are necessary for
activity
Enters nerve fibre as neutral free base & the cationic
form blocks conduction by interacting at inner surface
of the Na+ channel
Berhan B. 8
11. MoA of LAs
Act by blockade of sodium channels, so that:
1) Elevate the threshold for electrical excitation
2) The rate of rise of the AP decline
3) Slow the impulse conduction/propagation
4) The ability to generate an AP is abolished.
Completely block conduction.
Berhan B. 11
12. MoA...
Conduction of nerve impulses is mediated by AP
generation along axon.
Cationic form binds at inner surface of Na+ channel
Preventing Na+ influx (rising phase of membrane
potential) which initiates AP Blockade of nerve
impulses (e.g., those mediating pain)
Berhan B. 12
13. MoA…
When the influx of Na is interrupted, an AP
cannot arise & signal conduction is inhibited.
LA drugs bind more readily to Na+ 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.
Berhan B. 13
14. Important chemical properties of LA molecule that
determine activity:
Lipid solubility
es with extent of substitution(# carbons)
on aromatic ring &/or amino grp
shorten the onset time of a regional
block.
Enables diffusion of LA
Directly related to potency & duration
Berhan B. 14
16. Smaller & more highly lipophilic LAs have faster
rate of interaction with Na+ channel receptor.
Lidocaine, procaine, & mepivacaine are more
water soluble than tetracaine, bupivacaine &
ropivacaine.
The latter agents are more potent & have
longer durations of action.
» Duration of effect also correlates with
protein binding
16
Berhan B.
Berhan B.
17. Ionization constant (pK)
Determines proportion of ionized & non-
ionized forms of anaesthetics
LAs with lower pKa have a more rapid onset
of action (more uncharged form more rapid
diffusion to cytoplasmic side of Na+ channel)
Benzocaine: pKa ~ 3.5 exist as non-ionized
base under normal PH
Berhan B. 17
18. Drugs pKa % free base
at pH 7.7
Onset of
anaesthesia
(mins)
Lidocaine 7.9 25 2-4
Bupivacaine 8.1 18 5-8
Procaine 9.1 2 14-18
Berhan B. 18
22. LAs depress small unmyelinated fibers first &
larger myelinated fibers last.
The order of loss of function is therefore:
• Pain
• Temperature
• Touch
• Motor function
Differential Blockade
Berhan B. 22
23. Functional consequences of Na+ channel
blockade by LAs:
Nerves: se or abolition of conduction
Vascular smooth muscle: Vasodilatation
Heart: ed excitability (ed pacemaker activity,
prolongation of effective refractory period)
CNS: ed excitability, followed by generalized
depression
Berhan B. 23
24. Time Course of LA
1.Onset
Determined primarily by molecular size,
lipid solubility, concentration, degree of
ionization (pKa), nerve morphology &
tissue pH
2.Termination
Occurs as molecules diffuse out of neurons
& are carried away by the blood based on
the above properties plus regional blood
flow
Berhan B. 24
26. Applications/DeliveryTechniques/ of LA
a) Nerve block [ Lidocaine]
b) Topical /surface [ Tetracaine 2%, lidocaine 2- 4%]
c) Spinal anaesthesia [ Lidocaine, bupivacaine, tetracaine]
d) Infiltration anesthesia [ Lignocaine, bupivacaine]
e) Epidural anesthesia [ Lidocaine, bupivacaine]
f) Regional anesthesia [ Lidocaine, bupivacaine]
g) Field block [ Lidocaine1- 2% ]
Berhan B. 26
27. Pharmacokinetics
Most ester-linked LAs rapidly hydrolyzed by
plasma cholinesterase PABA
Short plasma half-life
Most LAs have a direct vasodilator action
es the rate of absorption potential toxicity
Biotransformation of amides occurs primarily in
the liver.
• Longer plasma t1/2 Longer duration of action
27
Berhan B.
Berhan B.
29. Uses
Provide anesthesia for many surgical procedure
Provide good quality post-operative analgesia
[Continuous epidural infusion]
The method of choice for pts with severe cardio-
respiratory Ds as the risks of GA & narcotic
Antiarrhythmic
Berhan B. 29
34. Properties of Individual LAs
A. Procaine —An ester-type must be administered
by injection, readily absorbed but rarely toxic as
plasma esterases rapidly convert drug to inactive
form.
Rapid onset & short duration of action
Berhan B. 34
35. Properties of Individual LAs
B. Lidocaine — Available as;
Lidocaine HCl inj.: 0.5%, 1%, 2%, 5%, spray 4%.
Rapid onset & intermediate duration of action
The reference standard
Lidocaine HCl + Adrenaline - Injection
Most widely used today, effects extended with use
of epinephrine.
If levels are too high, produce CNS & CV toxicity
[ Used also for arrhythmias ].
Berhan B. 35
36. C. Bupivacaine - Injection 0.25%, 0.5% in vial
Indicated for LA including infiltration, nerve block,
epidural, & intra-thecal anesthesia.
Often is administered by epidural injection before
total hip arthroplasty.
Epidural infusions for postoperative pain control &
for labor analgesia
Also is commonly injected to surgical wound sites to
reduce pain for up to 20 hrs after the surgery.
Sometimes, co-administered with epinephrine to
prolong duration of action; fentanyl for epidural
analgesia.
Berhan B. 36
37. D. Levobupivacaine
S(–) enantiomer of bupivacaine & less cardiotoxic
Less potent & tends to have a longer duration of
action.
E. Ropivacaine
◦ Analogue of bupivacaine
◦ Less potent than bupivacaine, with a slightly shorter
duration of action.
◦ Its advantages are that it produces less motor block
& less cardiac toxicity if inadvertently administered
Ivly.
Berhan B. 37
38. F. Prilocaine: Similar to lidocaine
◦ Onset & duration of action is longer than lidocaine
◦ But its clearance is more rapid, so it is 40% less
toxic than lidocaine
◦ In dental procedures, prilocaine is often used with
the peptide vasoconstrictor felypressin.
Berhan B. 38
39. G. Cocaine
First local anesthetic (1884)
Ester-type for topical administration with intense
vasoconstriction.
reduce bleeding
Restricted to ENT procedure
Absorbed through mucous membranes with
generalized CNS excitation followed by depression,
respiratory arrest, & death.
Berhan B. 39
40. H. Tetracaine
• Ester group.
• It is mainly used topically in ophthalmology
• Also used as an antipruritic
• Has been used in spinal anesthesia.
I. Other LAs—Differ in respect to indications,
routes of administration (topical versus
injection) & mode of elimination, duration of
action & toxicity
Berhan B. 40
