LOCAL ANAESTHETICS These are the drugs upon topical

LOCAL ANAESTHETICS

These are the drugs upon topical application or local injection, cause reversible loss of sensory perception, especially pain in a restricted area of body. Used for temporary and reversible elimination of painful feelings These drugs are applied locally and block nerve conduction of sensory impulses from periphery to the CNS. Unlike general anaesthetics, cause loss of feelings without inducing unconsciousness

HISTORICAL DEVOLOPMENT Before the use of local anesthetics, to alleviate a patient’s pain, surgeons must perform the operation very fast Modern development of the use of drugs to induce local anesthesia probably started in the mid-19 th century. The earliest recorded use of hypothermia as a local anesthetic is believed to be by Larrey, Nepoleon’e chief surgeon during the retreat from Moscow. He reported that amputations carried out at subzero temperatures has a higher survival rate than those in warmer conditions. In 1848, Arnott reported that he had used a pig’s bladder filled with ice to alleviate pain.

Discovery of Cocaine In 1884, when studying the effects of cocaine on fatigue, a colleague of Koller reported that the drug numbed his tongue. Koller then investigated this claim and found that cocaine hydrochloride caused local anesthesia.

In 1884, cocaine was widely used as a local anesthetics. Cocaine is addictive, and has many other side effects. People modified its structures and discovered procaine in 1904.

As the undesirable effects of cocaine (toxicity, addiction, and others) gradually became known, new anesthetic drugs were sought to replace it. November 27, 1904, German chemist Alfred Einhorn (1856 -1917) patented 18 para-aminobenzoic derivatives that had been developed in the Meister Lucius and Brüning plants at Höchst, in Hesse, Germany.

Its name, novocaine, appeared for the first time in 1905 in an article published by Professor Heinrich Braun Novocaine was found to be safe and quickly became the standard local anesthetic In 1943 -1946, Nils Löfgren and Bengt Lundquist developed a xylidine derivative they called lidocaine Discovery of Lidocaine is based on the investigation of the chemical structure of Gramine, an alkaloid Procaine was prepared in 1943.

In 1957, Boaf Ekenstam et al. synthesized mepivacaine and bupivacaine; in 1969, prilocaine was synthesized by Nils Löfgren and Cläes Tegner ; and in 1972, Adams et al. developed etidocaine Currently, the pharmaceutical industry continues to explore the development of safer and more effective local anesthetics in a pursuit that has come a long way since the earliest experiments with cocaine

MECHANISM OF ACTION These agents are believed to act by inhibiting sodium channels of the nerve membrane They block nerve conduction by decreasing entry of sodium ion during upstroke of action potential It interacts with a receptor situated in voltage sensitive sodium channel and raise threshold of channel opening So the sodium permeability fails to increase in response to an impulse or stimulus. Hence they inhibits generation and conduction of nerve impulse.

SAR Both ester or amide based local anaesthetics has the general formula LIPOPHILIC CENTRE ESTER OR AMIDE GROUP BRIDGE HYDROPHILIC CENTRE

Lipophilic centre – a carboxylic or heterocylic ring system Hydrophilic centre – tert or sec amine that may or may not be cyclic. Tert amines are less irritant to tissues so it is more useful. Linkage between the aromatic ring and the amino group is either ester or amide. They may be a short hydrocarbon chain. , oxygen, nitrogen or sulphur.

Lipophilic centre is responsible for lipid solubility Hydrophylic centre for transporting drug to membrane , to cell & to receptor. The best local anaesthetic action is obtained when lipophilic and hydrophilic centre are in balance.

p. Ka value – 7. 5 – 9. 5 Those with p. Ka value below 7. 5 are not sufficiently ionised at physiologic p. H , more effective. Those with p. Ka value above 9. 5 are fully ionised at physiologic p. H , less effective. as it cannot penetrate the cell membrane.

The presence of piperidino or pyrrolidino group as hydrophylic give rise to almost identical activity. The partition coefficient of local anaesthetics having identical structure increases the activity to a maximum. Once the peak is reached the activity starts decreasing though the partition coefficient enhances.

Substitution of aryl ring of local anaesthetic by alkyl, alkoxy or alkyl amino group showed that the partition coefficient of member of series increases with increase in no. of methylene groups in the substituent. Maximum activity is achieved for C 4 to C 6 analogue Substitution of hydrophilic centre showed that as the no. of C atoms increase the partition coefficient and activity increase

The local anaesthetic activity of benzoic acid derivatives increase if the aryl lipophilic centre has electron donating group and decrease with electron withdrawing substituents. This is because the electron donor substituent increases the binding to the receptor. Those with amide functional group bind more strongly to receptor site. 95 % of bupivacaine bound to plasma and tissue proteins compared with 55% of prilocaine.

Esters local anesthetics have common basic structure, that is, the aromatic acid and amino alkane. Procaine Hydrochloride is the representative drug. Procaine was obtained by the structural modification of natural alkaloid Cocaine.

n From Cocaine to Procaine Ø Benzoate moiety is very important Ø Methoxycarbonyl is not needed for maintaining of activity Ø Tropane bicycles moiety is not necessary Ø Methyl amino benzoate have local anesthetic effect Ø The aminoalkyl side chain is very important

u. Benzoate moiety is very important

Methoxycarbonyl is not needed for maintaining activity

Lidocaine Hydrochloride Amide bond is stable than ester bond Two vicinal methyl groups introduce steric hindrance ØNot easier to be hydrolyzed either in acidic or basic atmosphere ØThe hydrolysis rate by enzyme inside body is relatively slow

CLASSIFICATION Natural agents: Cocaine Synthetic nitrogenous compounds: 1. Benzoic acid derivatives : Piperocaine, Hexylcaine 2. Aminobenzoic acid derivatives : Benzocaine , Procaine , Procainamide, Amethocaine, Orthocaine 3. Acetanilide derivatives : Lidocaine, Prilocaine , Mepivacaine , Bupivacaine 4. Quinoline derivatives: Dimethisoquine, Cinchocaine Miscellaneous : Dibucaine, Benzyl alcohol, Eugenol