Local AnestheticsLocal Anesthetics

Liming zhou ( 周黎明）

Department of pharmacology

2010,3

Introduction and history Mechanisms of action PharmacokineticsPharmacological effectsClinic useAdverse effectsCommon drugs

INTRODUCTION AND HISTORYINTRODUCTION AND HISTORY Cocaine is a naturally occurring compound indigenous to

the Andes Mountains, West Indies, and Java.

It was the first anesthetic to be discovered and is the only naturally occurring local anesthetic

INTRODUCTION AND HISTORYINTRODUCTION AND HISTORY many of cocaine's pharmacologic actions and

adverse effects were elucidated in the latter half of the 1800s.

Koller introduced cocaine to the field of ophthalmology

Hall introduced it to dentistry.

Halsted was the first to report the use of cocaine for nerve blocks in the United States in 1885 and also became addicted to the drug.

INTRODUCTION AND HISTORYINTRODUCTION AND HISTORY

Procaine, the first derivative of cocaine, was developed in 1898.

Lofgren developed lidocaine, the most widely used cocaine derivative, during World War II.

What is local anesthetics?What is local anesthetics? block transmission of impulses along

nerves

short to medium duration of action (1-6 hrs)

useful for pain control

overdoses may cause convulsions

What is local anesthetics?What is local anesthetics? Applied in the vicinity of peripheral nerve ending or major

nerve trunks

inhibits action potential generation and propagation

Prevent conduction of electrical impulses from the periphery to the CNS

Produce transient loss of sensory, motor, and autonomic function in a discrete portion of the body without producing unconsciousness

The structure of local The structure of local anestheticsanesthetics

The classification of local The classification of local anestheticsanesthetics

Ester Cocaine Procaine Tetracaine

Amides Lidocaine Bupivicaine

All local anesthetics have an intermediate chain linking an amine on one end to an aromatic ring on the other

. The amine end is hydrophilic, and

the aromatic end is lipophilic.

Variation of the amine or aromatic ends changes the chemical activity of the drug.

Two basic classes of local anesthetics

The amino amides and the amino esters.

Amino amides have an amide link between the intermediate chain and the aromatic end

amino esters have an ester link between the intermediate chain and the aromatic end.

Amino esters and amino amides differ in several respects.

Amino esters are metabolized in the plasma via pseudocholinesterases,

Amino amides are metabolized in the liver.

Amino esters are unstable in solution, but amino amides are very stable in solution.

Amino esters are much more likely than amino amides to cause true allergic reactions

Pharmalogical effectPharmalogical effect

1 Local effect:

temporary loss of sensation in a confined region

reversible

adverse effectsadverse effects

Systemic Toxicity(CNS Toxicity )

Cause: excessively high plasma local anesthetic concentration

Manifestation: seizures

Treatment: diazepam

Effect of absorptionCNS system exciting seizure

Cardiovascular system decrease the action of the

heart

Mechanisms of action Mechanisms of action

Fig.

Mechanisms of action Mechanisms of action Inhibiting excitation of nerve

endings or blocking conduction in peripheral nerves.

Binding to and inactivating sodium channels.

Mechanisms of action Mechanisms of action

Sodium influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the course of the nerve.

when a nerve loses depolarization and capacity to propagate an impulse, the individual loses sensation in the area supplied by the nerve

block nerve fiber conduction by acting on nerve membranes

inhibit sodium ion activity

blocks depolarization--> blocks nerve conduction

PharmacokineticsPharmacokineticsAbsorption & Distribution: Factors:

    Vascularity: Highly vascular area (e.g. tracheal

mucosa): promotes rapid absorption resulting in higher blood levels

Poorly vascular area (tendon) is associated with relatively poor absorption

  Presence of vasoconstrictors (e.g. epinephrine)

Reduced systemic absorption due to local vasoconstriction

-- Increased neuronal uptake (higher local concentration)

--Blood levels: reduced as much as 1/3

distribution factors Rate of tissue distribution     Initial high uptake into lungs

and redistribution to highly perfusion tissues (heart, kidney, brain)

Following distribution to brain, kidney, heart-- redistribution to other tissues (less perfused)-- e.g. muscle, fat

The PH of local site       Local anesthetics is weak bases (pKa8-9) 

the fluid pH is higher, rapid onset of action

the fluid pH is lower, decrease onset of action

(question is why?)

Clinical UsesClinical Uses

Clinical Uses: --Most frequent use: regional

anesthesia

--Less common use:  Prevention & treatment of cardiac

arrhythmias

Clinical UsesClinical UsesSurface/topical anesthesia

Local infiltration

Peripheral nerve block

 Epidural anesthesia

Spinal anesthesia (subarachnoid)

Epidural anesthesiaEpidural anesthesia

Spinal anesthesiaSpinal anesthesia

Surface/topical anesthesia Surface/topical anesthesia application to mucous membranesLocation:  Nose  Mouth  Esophagus  Tracheobronchial tree  Genitourinary tract Commonly used drugs: Cocaine (4%-10%)

Local infiltrationLocal infiltration Definition: Extravascular placement of

the local anesthetic in the region to be anesthetized

 Most common: lidocaine

Peripheral Nerve BlockPeripheral Nerve Block

Procedure: local anesthetic injection into tissues around individual nerves or nerve

plexuses (e.g. brachial plexus)

Most common drug: 0.5% bupivacaine

Epidural AnesthesiaEpidural Anesthesia

Definition

Anesthesia caused by local anesthetic solutions injected into epidural

Mechanisms

 Direct action on nerve roots and spinal cord following local anesthetic diffusion across the dura

Spinal AnesthesiaSpinal Anesthesia

Definition Anesthesia following local anesthetic

injection into lumbar subarachnoid space

Site of action:  Primary: preganglionic fibers leading

the spinal cord in the anterior rami  Secondary: superficial spinal cord layers

adverse effectsadverse effects

Systemic Toxicity(CNS Toxicity )

Cause: excessively high plasma local anesthetic concentration

Manifestation: seizures

Treatment: diazepam

adverse effectsadverse effects

Allergic Reactions: Rare occurrence -- < 1% of local

anesthetic adverse reactions due to allergic mechanism

Higher-risk: ester-type local anesthetics (those which are metabolized to p-aminobenzoic acid-related compounds)

Cross Sensitivity May be due to common metabolite

profile (p-aminobenzoic acid)

No cross sensitivity between ester vs. amide local anesthetic classes