Chemistry and SAR of Local Anesthetics

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LOCAL ANESTHETICS By- Gaurav Kayal Assistant Professor (Pharmaceutical Chemistry)

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By Gaurav Kayal History Cocaine, the first local anesthetic introduced into medical practice, was isolated by Niemann in 1860 Procaine was synthesized by Einhorn in 1905 Lidocaine , which is still a widely used local anesthetic, was synthesized in 1943 by Löfgren .

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1. Topical anesthetics Classification on the basis of mode of application By Gaurav Kayal

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2. Compounds that bind on the outside of the Na + ion channel with affinities of 2-8 nM . Tetrodotoxin from Fugu and Saxitoxin from dinoflagellates . By Gaurav Kayal

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3. Injectable local anesthetics. These can exist in either ionized and unionized forms. 4. Miscellaneous Local Anesthetics. By Gaurav Kayal

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All local anesthetics contain 3 structural components : an aromatic ring (usually substituted) a connecting group which is either an ester (e.g., novocaine) or an amide (e.g. lidocaine ) an ionizable amino group By Gaurav Kayal Chemistry

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Chemical structures of prototypical ester - and amide -type local anesthetics – comparison with cocaine ( note 3 structural components of procaine) procaine/novocaine lidocaine / xylocaine cocaine By Gaurav Kayal

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Two important chemical properties of local anesthetic molecule that determine activity: Lipid solubility : increases with extent of substitution on aromatic ring and/or amino group Ionization constant ( pK ) – determines proportion of ionized and non-ionized forms of anesthetic By Gaurav Kayal

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Lipid solubility : determines, potency , plasma protein binding and duration of action of local anesthetics Lipid solubility Relative potency Plasma protein binding (%) Duration (minutes) procaine 1 1 6 60-90 lidocaine 4 2 65 90-200 tetracaine 80 8 80 180-600 By Gaurav Kayal

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Local anesthetics are weak bases – proportion of free base (R-NH 2 ) and salt (R-NH 3 + ) forms depends on pH and pK of amino grou p pH = pK + log [base]/[salt] (Henderson- Hasselbalch equation) Example : Calculate the proportions of free base and salt forms of tetracaine ( pK = 8.5) at pH (7.5). 7.5 = 8.5 + log [base]/[salt] log [base]/[salt] = -1 [base]/[salt] = 10 -1 = 1/10 ∴ there is 10x more drug in the ionized than in the non-ionized form at physiological pH By Gaurav Kayal

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Both free base and ionized forms of local anesthetic are necessary for activity : Local anesthetic enters nerve fibre as neutral free base and the cationic form blocks conduction by interacting at inner surface of the Na + channel By Gaurav Kayal

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Local anesthetics with lower pK have a more rapid onset of action (more uncharged form more rapid diffusion to cytoplasmic side of Na + channel) pK % free base at pH 7.7 Onset of anesthesia (min) lidocaine 7.9 25 2-4 bupivacaine 8.1 18 5-8 procaine 9.1 2 14-18 By Gaurav Kayal

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By Gaurav Kayal Mechanism of Action

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By Gaurav Kayal Type I: Generally, local anesthetics interfere with Na + ion channel passage across the nerve cell membrane. The greatest effect is on small, unmyelinated nerves. Myelinated nerves are also susceptible due to access at the nodes of Ranvier . Fig. Regeneration of action potentials at the nodes of Ranvier . (A) the influx of Na+ ions with an action potential at one node results in the depolarization of that region of the axonal membrane. The depolarizing current moves the next Node of Ranvier because the high resistance of the myelin sheath prevents discharge of the internodal membrane capacitance. (B) The nodal region, however, depolarizes to threshold, resulting in a new action potential. By this mechanism, the action potential "jumps" down the axon .

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By Gaurav Kayal Type II: The unionized form of local anesthetics diffuses through the nerve cell membrane to a specific hydrophobic binding site on the Na + ion channel. The ability to exist in an ionized form improves water solubility and there may be polar interactions between the drug and the binding site. All the injectable anesthetics exist as a equilibrium mixture of ionized and unionized forms.

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By Gaurav Kayal Structure Activity Relationship (SAR)

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By Gaurav Kayal Lipophilic Portion is essential for local anesthetic activity Either an aromatic group directly attached to a carbonyl function (amino esters) or a 2,6-dimethylphenyl group attached to a carbonyl function through an –NH- group (amino amides) These groups plan an important role in the binding of local anesthetics to the channel receptor proteins

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By Gaurav Kayal Intermediate Chain The intermediate chain includes the ester or amide group and the bridge This chain almost always contains a chort chain of one to three carbons in length linked to the aromatic ring ( lipophilic center) Amino amides are more resistant to metabolic inactivation than the amino esters and are thus longer acting Small alkyl groups around the ester function or the amide function hinders esterase or amidase catalyzed hydrolysis prolonging the duration of action

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By Gaurav Kayal Hydrophilic Portion Most clinically useful local anesthetics have a tertiary alkylamine which readily forms water soluble salts suitable for pharmaceutical preparations The hydrophilic group can be in the form of a secondary or tertiary amine or part of a nitrogen heterocycle

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By Gaurav Kayal

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By Gaurav Kayal Lipophilic center Ester Carbon bridge Tertiary amine Amino Esters

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By Gaurav Kayal Lipophilic center Ester Carbon chain No terminal amine Benzocaine ( Americaine ) In para position of the lipophilic center there is an amino group Lacks the basic aliphatic amine function yet has potent local anesthetic activity. Used topically

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By Gaurav Kayal Lipophilic center Ester Carbon chain Tertiary amine Tetracaine ( pontocaine , Amethocaine , Prax ) In para position of the lipophilic center there is an alkylamino group

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By Gaurav Kayal Lipophilic center Ester Carbon bridge Tertiary amine Procaine (Novocain) In the ortho position there is a hydrogen and in the para position there is an amino

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By Gaurav Kayal Lipophilic center Amide Carbon bridge Tertiary amine Amino Amides Lidocaine ( Xylocaine ) The o,o -dimethyl groups are required to provide suitable protection from amide hydrolysis to ensure a desirable duration of action

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By Gaurav Kayal Dibucaine ( Nupercainal , Cinchocaine ) The lipophilic group is the bicyclic quinoline Tertiary amine Lipophilic center Amide Tertiary amine Carbon bridge

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By Gaurav Kayal Aryl group - Attached to an sp 2 carbon via a nitrogen bridge. Substituents at the 2 and 6 positions enhance activity, and also increase stability to hydrolysis. The amides are already more stable than esters X group - The “carbonyl” X, may be C, O, or N. “Can be”, but is almost always “O”. Aminoalkyl group - This is not necessary for activity, but is used to form water-soluble salts. 3° amines are best. Basically the same story as for the esters.

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By Gaurav Kayal Benzoic Acid Derivatives Aryl group - This group is either attached directly to the carbonyl or through a vinyl group. Substituents on the aryl group that are electron donating ( alkoxy , amino, alkylamino ) enhance activity if at the para or ortho positions. (alter liposolubility . X group - The bridge, X, may be C, O, N, or S. When X = N, these amides are less prone to hydrolysis. Aminoalkyl group - This is not necessary for activity, but is used to form water-soluble salts. 3° amines are best.

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THANK YOU For Doubts/ Queries- Mr. Gaurav Kayal Assistant Professor (Pharmaceutical Chemistry) (Ph-9009991186, [email protected])

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