Pharmacology of
Local Anesthetics
Isaac NSHIMYUMUREMYI,MD, MMed
Pediatric Anesthesia Fellow/UON
Objectives
• Introduction/definitions/usages
• LA-chemical Structures
• LA-Mechanism of Action
• LA –Factors affecting LA activity
• LA: Chemical properties
• Pharmacokinetics: LA-Absorption- Distribution-
Mtb & excretion
• LA-TOXICITY
• Management of LA Toxicity
Anesthesia: Definition?
• Greek word / anaïsthêsis:
# an : privation
# aïsthêsis : sensibility
Usages?
1/ Local Anesthesia (terminal nerves ). eg.:Local
Infiltration, Topical Block.
2/ Regional Anesthesia ( blockade of a nerve /
group of nerves ) eg: Spinal Anesthesia
Introduction
• LA : interrupt pain impulses in a specific region of
the body without affecting consciousness and the
process is completely reversible;
• LA are weak bases
• LA end in “…..caine”
Two groupes: LA structures
Lipid soluble
hydrophobic Hydrophilic
aromatic amine
group group
LA: Examples
Esters:
• Cocaine, procaine, tetracaine, chloroprocaine…….
Amides:
• Lidocaine, mepivicaine, prilocaine, bupivacaine,
etidocaine…….
Mechanism of Action
• Unionized LA (neutral form) enters cell→ becomes
ionized→ binds to a specific site(internal site of the
Na+ channels)→ blocks channel function.
Mechanism of Action
Mechanism of Action (3)
• A second mechanism is also thought to operate,
involving the disruption of ion channel function by
the incorporation of LA molecules into the cell
membrane = the membrane expansion theory.
• This is thought to be mediated mainly by the
unionised form acting from outside the neuron.
LA activity
• What determines time to onset of action?
pKa ↓ (= ionization ↓) = time to onset ↓
• What determines potency?
Lipid solubility ↑ = potency ↑
• Duration of action?
Protein binding ↑ and lipid solubility ↑ =
duration of action↑
LA: Chemical properties
Agent link pKa Prot/ lipo onse Dur. Pot.
Bind t
.
Lido Ami 7.7 65% 3 Shor 1h30/ 2
d t 2h
Mepi Ami 7.6 75% 2 Shor idem 2
d t
Ropi Ami 8.1 95% 9 Long 2h30/ 8
d 3h
Bupi Ami 8.1 95% 27 Long 2h30 8
d 3h
proc este 8.9 5% 1 Long 1h/ 1
Order of sensory function block
• 1. pain
• 2. temperature
• 3. touch
• 4. deep pressure
• 5. skeletal muscle tone
This is why people may still feel touch but not pain
when using local anesthesia.
! ! ! Recovery in reverse order
Pharmacokinetics: LA Absorption
• LA Systemic absorption↔ blood flow↔TOXICITY
- Vascularity of the site of injection: IV > tracheal >
intercostal > caudal > paracervical > epidural>
brachial plexus > sciatic > subcutaneous
- Association with VC: duration of action
(lido>bupi)
-Mode of administration - eg. topical vs. injection
Pharmacokinetics: LA Distribution
• LA distribution: highest level at site of application
• LA distribute to all tissues
• Cross BBB and placenta
• More protein bound the agent, the longer the
duration of action
Pharmacokinetics: LA Mtb & excretion
• In general:
- Esters : by plasma cholinesterases to inactive
compounds. One of the by-products of metabolism
is PABA, the common cause of allergic reactions
seen with these agents
- Amides : by liver to inactive agents.
- Excretion is renal
Doses of LA ( mg/kg - max)
Drug Without ADR with ADR
Lidocaine 4 (4.5 - 5) 7
Bupivacaine 2 3
Local Anesthetics-TOXICITY
• Result of over-dosage BUT MOSTLY an accidental
intravascular injection leading to rapid high blood levels
of the agent given.
• Systemic reactions: CNS & CVS effects
• To avoid a systemic toxic reaction to LA, the smallest
amount of the most dilute solution that effectively
blocks pain should be administered.
• Lipid soluble agents: more potent& toxic
LA toxicity : CNS effects
• Excitatory symptoms:
- low levels: tremors and oral numbness, with
possible dizziness, agitation
- moderate levels: confusions, convulsions,
immediately preceded by muscle twitching
• CNS Depression↔ High levels-Na channel bloc
centrally: respiratory depression →→ respiratory
arrest as well
LA toxicity: CVS effects
• LA absorbed systematically can cause depression of the
cardiovascular system.
• Peripheral vascular action is arteriolar dilation
(except cocaine )
• Hypotension , myocardial depression
• Result in both cardiac and respiratory arrest.
• Bupivacaine effects >>> lidocaine
Manifestation of Lidocaine Toxicity
Treatment of Toxicity
• Preparations: IV line, Monitors
• Get assistance,ABC
• A/W:Oxygen, Ventilation, airway equipments
• Drugs to stop seizures
BZP, barbiturates, other drugs/interventions
• Post seizures management/ICU
References
• Lange-Clinical anesthesia,5th edition
• Stoelting RK.(eds) clinical anesthesia 1997.J.B.Lippncott
• Barash PG,Cullen BF
THANK YOU !
