General and Local Aesthetics

General and Local Anesthetics Abdu Tuha (B.Pharm., MSc in Medicinal Chemistry.) Local anesthetics Local anesthetics Block the nerve that carries the pain sensation and automatic impulses in local areas of the body Prevent conduction and formation of an action potential by either full or partial blockage of sodium ion channel Used in dentistry, ophthalmology and minor surgical operations 2 7/27/2020 Local … Ester and amide type Cocaine,an alkaloid from the leaves of Erythroxylon coca, was the first local anesthetic The development of local anesthetics began after the discovery of local anesthetic properties of cocaine CH N 3 CO2CH3 O C O H Because of its addictive properties the search for non-habit 3 forming local anesthetics began 7/27/2020 CH3 N H3C H H Local … O C O H3C C O H3C O -eucaine H Tropacocaine The carbomethoxy group is not required for local action as seen in tropacocaine which lack this group The synthesis and testing of -eucaine showed a tropane ring is not a prerequisite for local anesthetic activity Based on the above findings many other simple analogs like procaine and benzocaine were synthesized H2N COOC2H5 H2N COOCH2CH2N(C2H5)2 4 Benzocaine Procaine 7/27/2020 Local … General structural features Lipophilic center Ester or Amide Bridge Hydrophilic center CH CH3 N O 3 O Aryl C X Aminoalkyl CO2CH3 NH C R2 Benzoic acid derivatives O R1 C O Anilides derivatives Cocaine H 5 7/27/2020 Local … SAR of local anesthetics The lipophilic center is usually either a cyclic or heterocyclic system The hydrophilic center is normally a secondary or tertiary amine, which may or may not be cyclic Tertiary amines are more useful since they are less irritating to tissue The hydrophilic center may be attached to ester or amide by a short hydrocarbon chain The lipophilic center is responsible for lipid solubility as it 6 7/27/2020 affects cell penetration and their action Local … The hydrophilic center provides water solubility and is believed to be involved in binding to the receptor For best action a balance between lipophilic and hydrophilic center is essential Ester type require a carbonyl group in conjugation with an aromatic ring or related system C H H N X C OCH CH N 2 5 2 2 2 C H O 2 5 When X= CH2, there is no activity; carbonyl is not conjugated C CH When X = H , there is activity as the aromatic ring is conjugated with carbonyl group 7 7/27/2020 Local … O R1 C O R2 Benzoic acid derivatives Generic name R1 R2 Hexylcaine H H2CHN HC CH3 Dyclonine CH CH CH CH O 3 2 2 2 H2CH2C N Piperocaine H H3C H2CH2CH2C N 8 7/27/2020 In the lidocaine (the amino amide) series the ortho dimethyl groups are required for protection from amide hydrolysis ensuring desirable duration of action Generic name R1 R2 CH Etidocaine CH3 3 CH2 CH2CH3 NHCH2OCH N CHC3H2CH2CH3 O Mepivacaine CH3 N NH C R2 H3C CH2CH2CH2CH3 Bupivacaine CH3 R1 C H lidocaine CH3 2 5 NHCH2OCH2N C2H5 CH prilocaine CH3 3 NHCOCHNHCH2CH2CH3 9 7/27/2020 General Anaesthetics General anaesthesia is a controlled reversible depression of the functional activity of the CNS The neurophysiologic state produced by general anesthetics is characterized by five primary effects: Unconsciousness, Amnesia, Analgesia, Inhibition of autonomic reflexes, and Skeletal muscle relaxation. Early agents were ether, chloroform & nitrous oxide 10 7/27/2020 Nowadays, multiple drug regimes are used including; Pre-anaesthesia + skeletal muscle relaxants + drugs to control side effects + actual anaesthetic agent are used in combination General anaesthetics are given either by inhalation or i.v. 11 7/27/2020 General… Inhalation anaesthetics (gases and liquids) Current inhalation drugs include halothane & several other F&Cl- containing molecules, and nitrous oxide. Gas inhalation anaesthetics H2 C N2O CF3 CHClBr CHCl2 CF2 O CH3 H2C CH2 Halothane Methoxyflurane Cyclopropane Nitrous oxide CF3 CHCl O CHF2 CHF2 O CHF CF3 CHClF CF2 O CHF2 Isoflurane Enflurane Desflurane 12 7/27/2020 General … Intravenous anaesthetic They produce unconsciousness but not sufficient depth to permit surgical procedures The intravenous anaesthetics is given prior to inhalation anaesthetics Classification Ultrashort acting barbiturates Benzodiazepines Ketamine hydrochloride Propofol 14 Etomidate 7/27/2020 Cl NHCH3 HCl O Ketamine •The presumed mechanism of action of propofol is through potentiation of the chloride current mediated through the GABAA receptor complex. •Etomidate appears to have GABA-like effects and seems to act primarily through potentiation of GABAA-mediated chloride currents, •Ketamine’s major effect is probably produced through inhibition of the NMDA 15 receptor complex. 7/27/2020 Non-Streoidial Anti-Inflammatory Drugs (NSAIDs) NSAIDs… These drugs are of different chemical structures and are used for treatment of inflammatory and painful conditions Cell injury Phospholipase A2 C ell membrane Arachidonic acid Lipoxygenase Cyclooxygenase Leukotrienes NSAIDS Inhibit Cyclooxygenase Prostaglandins The COX enzyme exists in at least two isoforms. COX-1 is constitutive isoform that is responsible for the basal production of prostaglandins, prostacyclins, and thromboxanes. COX-2 is inducible by cytokines and other inflammatory stimuli and 17 is believed to predominate during chronic inflammation. 7/27/2020 NSAIDs… Prostaglandins contribute to sign and symptoms of inflammatory processes including pain and edema COOH Arachidonic acid COOH Prostaglandins 18 7/27/2020 19 7/27/2020 NSAIDs… Non-steroidal ant-inflammatory drugs can be divided: 1. Saliclyates 2. Para-aminophenol derivatives 3. pyrazolone and pyrazolidinediones derivatives 4. Arylacetic acids 5. Arylpropionic acids 6. Anthranilates 7. Arylsulfonamides 8. COX-2 Selective Inhibitors (diaryl pyrazole derivatives) 20 7/27/2020 NSAIDs… O 6 1 C Salicyates 5 OH 4 2 OH 3 Are derivatives of salicylic acid and are two types (I and II) O O O C C C OH OR OH O C R OH OR O Type I Type IIa Type IIb Type I represents those that are formed by modifying the carboxyl group. Type II (a and b) represents those that are substitution on the hydroxyl group of salicylic acid The derivatives were introduced to prevent gastric symptom and undesirable tests of some common salt of salicylate 21 7/27/2020 NSAIDs… Structure activity relationship The active moiety appears to be the salicylate anion Reduction of the acidity of the carboxylic group of the salicylate retain analgesic effect eliminating anti-inflammatory (Salicylamide) Shift of phenolic OH group to meta or Para to carboxyl abolish activity Halogen atom substitution on the aromatic ring enhances potency & toxicity Hydrophobic substituent at 5 position of salicylic acid improved activity O O C O OH C F C NH2 OH O C CH3 F O OH OH Aspirin Salicylamide Diflunisal 22 7/27/2020 NSAIDs… NH 2. Para- aminophenol derivatives 2 Are para aminophenol derivatives OH They possess analgesic and antipyretic but not anti- inflammatory activity Paracetamol is a prototype Based on the discovery that aniline and acetanilide have powerful antipyretic property 23 7/27/2020 NSAIDs… Both are converted to paracetamol and are more toxic O O O NHCCH3 NHCCH3 NHCCH3 OH OC2H5 Acetanilid Paracetamol Phenacetin 24 7/27/2020 NSAIDs… Structure activity relationship Amino phenols are less toxic than corresponding aniline derivatives Esterification of phenolic group with methyl or propyl group produce more toxic derivative than ethyl Nitrogen substituents that reduce its basicity reduce activity unless it is metabolically removed Paracetamol overdose causes sever hepatotoxicity with necrosis and liver failure Due to the formation of hepatotoxic metabolite 25 7/27/2020 NSAIDs… Glucuronide Major O HO NCOCH NHCCH3 3 NCH2OCH3 NCH2OCH3 Sulfate minor glutathione * Major glutathione OH OH O O Paracetamol *N- acetylimidoquinone "toxic metabolite" 26 7/27/2020 NSAIDs… 4 3 O 3. 3, 5-pyrazolidinediones 5 2 1 NH O N The most important once are phenylbutazoneH and oxyphenylbutazone (its metabolite) Both of them inhibit prostaglandin synthesis and stabilize lysosomal membranes Have analgesic, antipyretic and anti-inflammatory effects H3CH2CH2CH2C O H3CH2CH2CH2C O O N N N O N OH 27 Phenylbutazone Oxyphenylbutazone 7/27/2020 NSAIDs… Structure activity relationship Hydrogen atom at C4 is acidic & this is enhanced by the two-ketone groups Decreasing /eliminating acidity abolishes activity If acidity increases too much uricosuric activity increases while ant inflammatory decreases Single alkyl substituent at C4 enhances anti-inflammatory activity n- butyl is the most active The presence two phenyl groups in the ring nitrogen is not important for anti-inflammatory & analgesic activity H N O 2 N Pyrrole (5 1 )and isoxazole ( ) analogue of phenylbutazone retain activity 4 3 28 7/27/2020 NSAIDs… 4. Arylalkanoic acids CH3 O H O AR C C OH AR C C OH H H Aryl or Hetero-aryl propionic acid analogs Aryl or Hetero-aryl acetic acid analogs Arylalkanoic acid represents the largest numbers of NSAIDs Have analgesic, antipyretic and anti-inflammatory property 29 7/27/2020 NSAIDs… Structure activity relationship All agents have an acidic and aromatic center Derivatives of aryl or heteroaryl acetic/propionic acid correlates with carboxylic acid and double bond at position C5 and C8 of arachidonic acid The activity of ester& amide derivatives carboxylic acid is due to its metabolic hydrolysis The center of acidity is located one carbon atom from the aromatic ring This distance is critical Increase distance to two or three carbons

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