These are the drugs upon topical application or local injection, cause reversible loss of sensory perception, especially pain in a restricted area of body.

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• 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

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HISTORICAL DEVOLOPMENT

• Before the use of local anesthetics, to alleviate
  a patients pain, surgeons must perform the
  operation very fast
• Modern development of the use of drugs to induce
  local anesthesia probably started in the mid-19th
  century. The earliest recorded use of hypothermia
  as a local anesthetic is believed to be by
  Larrey, Nepoleone 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 pigs
  bladder filled with ice to alleviate pain.

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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.

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• 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.

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• 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.

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• 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.

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• 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

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• 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.

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SAR
Both ester or amide based local anaesthetics has
the general formula
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• 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.

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• 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.

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• pKa value 7.5 9.5
• Those with pKa value below 7.5 are not
  sufficiently ionised at physiologic pH ,more
  effective.
• Those with pKa value above 9.5 are fully ionised
  at physiologic pH ,less effective.as it cannot
  penetrate the cell membrane.

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• 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.

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• 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 C4 to C6
  analogue
• Substitution of hydrophilic centre showed that as
  the no. of C atoms increase the partition
  coefficient and activity increase

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• 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.

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• 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.

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

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• Benzoate moiety is very important

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• Methoxycarbonyl is not needed for maintaining
  activity

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• Lidocaine Hydrochloride
• Amide bond is stable than ester bond
• Two vicinal methyl groups introduce steric
  hindrance
• Not easier to be hydrolyzed either in acidic or
  basic atmosphere
• The hydrolysis rate by enzyme inside body is
  relatively slow

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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

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