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Local Anaesthetics Slides Dec25th 2006

Local Anaesthetics Slides Dec25th 2006

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LOCAL ANAESTHETICS

Pharmacology & Toxicology Department Dr. Mariam Yousif December 25th, 2006

Objectives
2. What is the basis for the classification of local anaesthetics (LAs) into the two classes of esters and amides? Identify individual drug examples from each class. 2. What is the mechanism of action of LAs? 3. Identify pharmacokinetic properties of LAs. 4. Why vasoconstrictors are used as adjuncts in local anaesthesia. 5. What are the main adverse effects of LAs?

Local Anaesthetics (LAs) Defined as drugs used clinically to produce reversible loss of sensation in a specific area of the body

Used to block pain conduction by nerves, mainly used to produce local nerve block.

First LA was cocaine, largely replaced by synthetic agents. Lidocaine and procaine are the prototype local anaesthetics.

Classification
LAs have a basic chemical structure of a lipophilic aromatic ring and a hydrophilic tertiary amine separated by a hydrocarbon chain.

The hydrocarbon chain is linked to the lipophilic component by either an amide or an ester bond, providing a chemical basis for local anaesthetic classification into amides or esters.

CH3 NH CH3

O C CH2 N

C2H5 C2H5

Amide bond

Lidocaine
O H2N C OCH2CH2 N

C2H5 C2H5

Procaine

Ester bond

All LAs are composed of a hydrophilic domain connected to a hydrophobic domain by an alkyl chain. The drugs are classified as amides or esters according to the bond between the hydrophobic domain and the alkyl chain.

The ester agents include cocaine, procaine, tetracaine, benzocaine,

The amides include lidocaine (lignocaine), mepivacaine, prilocaine.

Esters
O C O O H2 N C

CH3 O C O N

Amides
CH3

CH3 NH CH3 CH3 NH CH3

O C O C N O C N O C CH C2H5 N CH2 N

C2H5 C2H5

Lidocaine

Cocaine
C2H5 O CH2 CH2 N C 2H 5 CH3 O CH2 CH2 N CH3

Mepivacaine CH3
NH

CH3 CH3

Procaine
O HN C4H9 C

Dopivacaine C4H9
C2H5 C3H7 NH

CH3 CH3

Tetracaine
O C O CH2 CH3

Etidocaine
O C

H2 N

NH CH3

CH CH3

NHC3H7

Benzocaine

Prilocaine

Differences between the two classes

Esters are rapidly hydrolysed in the body by plasma cholinesterase.

Of the main breakdown products is para-amino benzoic acid (PABA) which is associated with allergic phenomena and hypersensitivity reactions.

Differences between the two classes

Amides are relatively stable, slowly metabolized in the liver and hypersensitivity reactions to amide local anaesthetics are extremely rare.

Mechanism of Action of LAs

LAs block the initiation and propagation of action potentials by preventing the voltage-dependent increase in Na+ conductance.

Mechanism of Action of LAs

Their main action is to block sodium channels.

Inhibit nerve conduction by reducing the permeability of the neuronal membrane to sodium. This prevents sodium influx which is required for propagation of action potentials.

Preferential blockade of small nerve fibers In general, LAs block conduction in smalldiameter nerve fibres more readily than in large fibres.

The smaller nerve fibers involved in pain and temperature conduction (Aδ and C fibres), are more sensitive to blockade than the larger fibers responsible for touch or motor control.

Pharmacokinetics LAs are either esters or amides.

Esters are rapidly hydrolysed by plasma cholinesterase, and amides are metabolized in the liver.

Plasma half-lives are generally short, about 1-2 hours.

Pharmacokinetics Most LAs are amine bases. In tissue fluid, the local anaesthetic present in both ionized and non-ionized form; their relative proportions depend on the pH of the solution and the PKa of the individual drug.

The non-ionized base then diffuses through the nerve sheath, peri-neuronal tissues and the neuronal membranes. Thus LAs are relatively inactive when injected into tissues with an acid pH.

Pharmacokinetics LAs whose PKa is close to pH 7.4 will have the fastest onset time, because only the uncharged lipid soluble form diffuses through tissues and crosses nerve membranes.

The PKa, protein binding and lipid solubility characteristics of LAs influence their onset time, duration of action and potency.

LAs with high protein binding attach strongly to the protein component of the nerve membrane lipid bilayer, having longer durations of action.

Epinephrine as an adjunct in local anaesthesia

Vasoconstrictors are frequently added, to enhance their potency and prolong their duration of action by localizing them in tissues.

Vasoconstrictor response to epinephrine inhibits distribution of local anaesthetic away from the site of injection, decreasing systemic absorption and prolonging duration of action. Minimizes systemic toxicity.

Unwanted effects of LAs

Relatively free from side effects if they are administered in an appropriate dosage and in the correct anatomical location.

Adverse effects result from systemic absorption of toxic amounts of the locally applied anaesthetic. Seizures are the most significant of these systemic affects.

Main unwanted effects
CNS effects: agitation, confusion, tremors progressing to convulsions and respiratory depression.

Cardiovascular effects: myocardial depression and vasodilatation, leading to fall in blood pressure.

Cocaine causes vasoconstriction consistently because of its ability to inhibit the re-uptake of noradrenaline by storage granules at the synapse.

Drug List Cocaine Procaine Tetracaine Benzocaine Lidocaine (lignocaine) Mepivacaine Prilocaine

THANK YOU & GOOD LUCK IN THE EXAM

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