1

Local Anesthetic Pharmacology

Dr. Hiwa K. Saaed,

PhD Pharmacology & Toxicology

College of Pharmacy/ University of Sulaimani

2

Local anesthetics (LAs)

LAs are drugs that: used to prevent or relieve pain in specific regions of

the body without loss of consciousness block pain sensation by blocking nerve conduction

of sensory impulse from the periphery to the CNS Reversibly block impulse conduction along nerve

axons & other excitable membranes that utilize sodium channels as the primary means of action potential generation

3

History of local anesthetics • 3000 B.C.: cocaine • 1905: procaine• 1932: Tetracaine• 1943: Lidocaine• 1957: Mepivacaine• 1960: Prilocaine• 1963: Bupivacaine• 1972: Etidocaine• 1996: Ropivacaine• 1999: Levobupivacaine

• The first local anesthetic introduced into medical practice Cocaine, was isolated from coca leaves by Albert Niemann in Germany in the 1860s.

• The very first clinical use of Cocaine was in 1884 by Sigmund Freud who used it to wean a patient from morphine addiction. 

• Freud and his colleague Karl Kollar first noticed its anesthetic effect and introduced it to clinical ophthalmology as a topical ocular anesthetic. 

4

Chemistry of LAs

• The LAs consists of three parts. 1. A lipophilic ‘hydrophobic’ aromatic group.2. An intermediate chain (ester or amide).3. A hydrophilic an ionizable group (usually a tertiary amine

group).• Esters usually have a shorter duration of action because ester

links are more prone to hydrolysis than amide links

5

Classes: The rule of “i”

• AmidesLidocaineBupivacaineLevobupivacaineRopivacaineMepivacaineEtidocainePrilocaine

• Esters

ProcaineChloroprocaineTetracaineBenzocaineCocaine

6

Clinical pharmacology of LAs

Short :Short:• Procaine • chlorprocaine

Intermediate:• Lidocaine, • mepivacaine • prilocaine

Long acting :• tetracaine, • bupivacaine, • etidocaine • ropivacaine.

The choice of LA for a specific procedure is usually based on the duration of procedure required

7

Local anesthetics

• Local anesthetics are weak bases. • The pKa for most local anesthetics is in the range of 8-9

(Except benzocaine).• the larger percentage in body fluids at physiologic pH will

be the charged, cationic form.• The ratio between the cationic and uncharged forms of

these drugs is determined by the Henderson-Hasselbalch equation:

Log cation (charged)/ uncharged= pKa - pH

8

Effectiveness of Local anesthetics are affected by pH of the application site

Effect of pH: Charged (cationic) form binds to receptor site uncharged form penetrates membrane ,efficacy of drug can be changed by altering extracellular or intracellular pH

9

Local anesthetics; Effect of lipophilicity

• LAs bind to receptor near the intracellular end of the channel. It is not readily accessible from the external side of the cell membrane.

• The uncharged form is more lipophilic and thus more rapidly diffuses through the membrane. However, the charged form has higher affinity for the receptor site of the sodium channel, because it cannot readily exit from closed channels.

• Therefore, LA are much less effective when they are injected into infected tissues because a larger % of the LA is ionized in an environment with a low extracellular pH and can not diffused across the membrane

10

Systemic absorption

Local anesthetics are removed from depot site mainly by absorption into blood. Systemic absorption is determined by several factors, including:

• Dosage• Site of injection; Local blood flow: highly or poorly

perfused• Use vasoconstrictors (e.g., epinephrine)• Drug tissue binding• Physicochemical properties of the drug itself

11

Effect of epinephrine on local anesthetics

• Addition of vasoconstrictor drugs such as epinephrine reduces absorption of local anesthetics by decreasing blood flow (imp. For intermediate & short duration of action), thus prolonging anesthetic effect and reducing systemic toxicity.

• Epinephrine also reduce sensory neuron firing via α2 receptors, which inhibit release of substance-P (neurokinin-1).

• Clonidine (α2 agonist) augment LA effect

Epinephrine is included in many local anesthetic preparations. Know your patient’s health status!

12

Pharmacokinetics

Distribution• Amide are widely distributed & sequestered in fat.• Ester short plasma t1/2

; No enough time for distribution

Metabolism and excretion• Amide: in the liver by CYP450• Ester: in plasma butyrylcholinesterase

13

LAs mechanism of action

• Local anesthetics reversibly bind to the voltage-gated Na+ channel, block Na+ influx, and thus block action potential and nerve conduction.

14

Membrane Potential and neurotransmission • The excitable membrane of neuronal axons

maintains a transmembrane potential of -90 to -60 mv.

• The transmembrane ionic gradients are maintained by the Na+/K+ ATPase (Na+ pump).

• During excitation the Na+ channels open, a fast inward Na+ current quickly depolarizes the membrane toward the Na+ equilibrium potential +40mv.

15

Membrane Potential and neurotransmission • As a result of depolarization:

– the Na+ channels close (inactivate) – & K+ channels open → outward flow of K+ repolarizes

the membrane toward the K+ equilibrium potential about

-95mv• As a result of repolarization the Na+ channels returns to the

rested state.

16

17

18

The function of sodium channels can be disrupted in several ways. such as

Agonists: • Biologic toxins (batrachotoxin, aconitine,

veratridines & some scorpion venoms bind to receptors within the channels & prevent inactivation → prolonged Na+ influx

Antagonists: • The marine toxins (tetradotoxin & saxitoxin) block

these channels by binding to channel receptors near the extracellular surface

19

Effects of Ca+2 & K+ on LAs• Elevated extracellular Ca+2 [↑membrane potential

→ resting state (low affinity)] particularly antagonized the action of LA.

• Increase of extracellular K+ depolarizes the membrane potential & favors the inactivated state → enhance the effect of LA

20

Actions on Nerves• Since LAs are capable of blocking all nerves, • Their actions are not usually limited to the desired

loss of sensation.• Although motor paralysis may at times be desired,

it may also limit the ability of the patient to cooperate, e.g., during obstetric delivery.

• During spinal anesthesia, motor paralysis may impair respiratory activity & AN blockade may lead to hypotension

21

Effect of fiber diameter

• Local anesthetics preferably block small, unmylinated fibers that conduct pain, temperature, and autonomic nerves.

• for the same diameter, myelinated nerves will be blocked before unmyelinated nerves.– The smaller B preganglionic autonomic & C (pain) fiber are

blocked 1st.– The small type A delta (sensations) are blocked next.– Motor function is blocked last.

22

Relative size and susceptibility to block of types of nerve fibers

1. pain, 2. cold, 3. warmth, 4. touch, 5. deep pressure & 6. motor

Recovery in reverse order

23

Time & voltage-dependent fashion

• The effect of a drug is more marked in rapidly firing axons than in resting fibers.

Because LAs block the channel in a time & voltage-dependent fashion.

• Channels in the rested state (-ve mps) have a low affinity for LAs

• Channels in the activated (open state) and inactivated (+ve mps) have a high affinity for LAs

24

Effect of firing frequency (state dependent mechanism)

• Nerves with higher firing frequency, more positive membrane potential, & with longer depolarization (duration) are more sensitive to local anesthetic block

• Sensory fibers especially pain fibers, have a high firing rate & relatively long action potential duration (up to 5 ms)

• Motor fibers fire at a slower rate & have a shorter AP (<0.5 ms)

• In nerve bundles, fibers that are located circumferentially are affected first by local anesthetics

25

Effect on other excitable membranes

• LAs have weak NM blocking-little clinical importance.

• Cardiac cell membrane; – antiarrhythmia at concentration lower than those

required to produce nerve block – Arrhythmogenic: and all can cause arrhythmias in high

enough concentration.

26

Clinical pharmacology of LAs• The onset of LAs is sometimes accelerated by the

use of solutions saturated with CO2 (carbonated) → intracellular acidosis → intracellular accumulation of the cationic form of LA.

• Repeated injection of LAs during epidural anesthesia → tachyphylaxis because of extracellular acidosis.

• Pregnancy appears to increase susceptibility to LAs

27

Toxicity and side effects • A. CNS: at• low dose: sleepiness, light headedness, visual and

auditory disturbances, restlessness, circumoral & tongue numbness.

• high dose (stimulatory effects): nystagmus, muscular twitching, finally tonic-clonic convulsions, followed by CNS depression→ death may occur.

• Convulsion because of cortical inhibitory pathways → unopposed activity of excitatory components.

28

Convulsion preventionConvulsion prevented by:• administering smallest dose of LA • premedication with BDZ (diazepam)

↓LA toxicity by: • Prevent hypoxemia (hypercapnia) & acidosis by

hyperventilation →↑blood pH → ↓ E.C K+ → hyperpolarization → resting state → ↓LA toxicity

Seizure Rx: • thiopental 1-2mg/kg• Diazepam 0.1 mg/kg• succinylcholine for muscular manifestation.

29

Toxicity and side effects B. PNS (neurotoxicity)

C. Cardiovascular system (CVS): direct & indirect effect • Direct: all LAs are vasodilators (except cocaine) and also

decrease the strength of cardiac contraction→ both effects → hypotension

• Indirect: ANS, cocaine blockade of NE reuptake → • vasoconstriction → ischemia → ulceration of mucous

membrane & damage nasal septum .• HTN• Precipitate cardiac arrhythmia

NB. Bupivacaine is more cardiotoxic → CV collapse, after accidental I.V

30

Toxicity and side effects

D. Blood: prilocaine (large dose; 10mg/kg) → accumulation of metabolite an oxidating agent, convert Hb to metHb → cyanotic

• RX: methylene blue or ascorbic acid I.V to rapidly convert metHb → Hb.

E. Allergy: the ester type LA are metabolized to PABA derivative responsible for allergic reaction in a small % of population.

31

Examples of LA use:• Topical • Infiltration• Field block• Nerve block• Intravenous regional

block• Spinal nerve block• Epidural nerve block

32