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Medicinal chemistry of local anaesthetics

Local anaesthetics work by blocking sodium channels in nerves, preventing the generation of action potentials and nerve impulses that mediate pain sensation. They are classified into natural agents like cocaine, synthetic nitrogenous compounds derived from benzoic acid, p-aminobenzoic acid, and acetanilides. Important examples include lidocaine, bupivacaine, and procaine. The mechanism of action, structure-activity relationships, and factors affecting duration are discussed. Substitutions that increase lipid solubility and stabilize the molecule result in longer-lasting local anaesthetics with greater potency.

Science◦
Suresh Bairi MS.(Pharm.), (Ph. D) Asst. Professor UCPS, Palamuru University, MBNR Medicinal Chemistry of Local Anaesthetics 1
Local anaesthetics  Local anaesthetics are the drugs that when applied directly to the peripheral nervous tissue blocks nerve conduction and abolish all the sensation in that part supplied by the nerve.  These are used in dentistry, in ophthalmology in minor surgical operations, including endoscopy, and relieving pain in certain medical conditions such as tumours growing on spine.  These are also used for temporary relief of pain from insect bites, burns, and other surface wounds 2
Mechanism ofAction  Conduction of nerve impulses is mediated by action potential (AP) generation along axon.  Cationic form of local anesthetic binds at inner surface of Na+ channel – preventing Na+ influx (rising phase of membrane potential) which initiates AP → blockade ofnerve impulses (e.g., those mediating pain). 3
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General classification of local anaesthetics 1. Natural agents : Cocain 2. Synthetic nitrogenous compounds i)Derivatives of benzoic acid: Hexylocaine, cyclomethacain, meprylcain ii)P-amino benzoic acid derivatives: benzocain, procain, butacain, propoxycain iii) Derivatives of acetanilides: lignocain, mepivacain, bupivacain iv) Derivatives of quinolines: cinchocain, dimethisoquin 3. Synthetic non-nitrogenous agents: benzyl alcohol, propane diol 4. Miscellaneous drugs: Phenacaine, Diperodon, Dibucaine, clove oil, phenol, chlorpromazine, antihistamines. 6
Natural agents  Cocaine: it is an alkoloid obtained from erythroxylon coccoa (first local anaesthetic)  Employed topically 1-2% solution (earlier days) for anaesthesia of ear, nose, throat, rectum and vagina. 7
Benzoic acid derivatives Name R R1 Hexylocain -H Meprylocain -H Cyclomethycain piperocain -H 8
P-Aminobenzoic acid derivatives: Name R1 R2 R3 R4 R5 Benzocain -H -H -H - Butamben -H -H -H - Procain -H -H -H Butacaine -H -H -H Propoxycai n -H -H -PrO Tetracain -Bu -H -H Bunoxynat e -H -BuO -H 9
Synthesis of Benzocain  It is used to get rid of pain caused by wounds, ulcers and in mucus surfaces 10
Synthesis of Procain  It is used in infiltration anaethesia and spinal anaesthesia (5-20%)  It is not effective topically 11
Anilides (amide) derivatives Name R1 R2 Description Lidocaine (Lignocain) -CH3 -CH2N(C2H5) 2 Vasodilatory action, used with vasoconstrictors Ointments, jelly & Topical solutions Duration 60-75min prolonged to 2hrs Mepivacain (carbocaine ) -CH3 Topically not active, longer duration of action 120-150min Mostly used infiltration Prilocaine -H Used for ephineprine intolerance patients Causes methemoglobanemia Etidocaine -CH3 More potent than lidocaine and longer duration of action can be used by infiltration, epidural and regional anaesthesia 12
Miscellaneous LAs  Diperodon: potent surface anaesthetic  Used primarily for anus  Highly toxic upon IV administration causes hypersensitivity reactions • Phenacaine: mainly used for local anaesthesia of Eye • Dibucaine 13
Synthesis of Dibucaine 14
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Dibucaine  Generally used for surface anaesthesia  When administered by IV Inhibits plasma cholinesterase causes toxic effect.  Neuromuscular blockers generally administered in anaesthesia to prevent respiratory paralysis 16
SAR of Local Anaesthetics 1. General SAR LA s are broadly belongs to two main basic chemical structures 1. Esters (Procaine) 17
Cont..  Amide 2. Amide ( Lidocaine) 18
Cont..  LA’s activity and duration of action is very much dependent upon the stability of those structures  The main factor the stability of these two derivatives is the hydrolysis of esters and amides  Xylidine ion is a poor leaving group than the diethyl amino ethyloxide group, which is responsible for slower hydrolysis of the lidocaine amide bond, resulting more stable and longer duration of action 19
Cont..  By the introduction of electron withdrawing group (O- Chloro) in procaine (chloroprocaine) makes the ester linkage more susceptible to hydrolysis therefore chlorprocaine having shorter duration of action.  Introduction of electron-releasing group O-Propoxy group (propoxycain) makes the ester hydrolysis difficult as compared to procaine hence proxycain having longer duration of action 20
2. SAR of Ester Derivatives i) Aryl group (substitution on aryl group) :  Chloroprocaine: Chloro substitution in the 2- position. the electron withdrawing chlorine destabilises the ester link to hydrolysis  Chlorine is hydrolysed by plasma more than four times faster than procaine and having rapid onset of action21
Cont..  The presence of non-polar n-butyl group on the aromatic ring probably accounts for the grater lipid solubility of tetracaine, which is one of most easily absorbed drugs  Presence of 3-BuO group appears to stabilize the molecular hydrolysis as in bunoxinate  The aryl group is attached directly to the carbonyl group conjugation of the aromatic moiety with carbonyl group enhances the LAs activity  Substitution of the aryl moiety with substituents that increase the electron density of the carbonyl oxygen enhances the activity22
Cont..  The favourable substituents include alkoxy, amino and alkyl amino in para and ortho positions and these alter the lipophilic activity ii) Bridge X : X may be carbon, oxygen, nitrogen or sulphur  In an isosteric procaine series anaesthetic potency decreases in the order, these modifications affects duration of action and toxicity  Amides X=N most resistant to metabolic hydrolysis than (X=O); thio esters (X=S) may cause demerits 23
Cont.. iii) Aminoalkyl group:  This is considered to be hydrophilic part of local anaesthetic molecule  Territory amines appear to produce longer duration of action but they are more irritating  Primary amines are not very active and causes irritating.  Alkyl groups including the intermediate chain linked to X, primarily influence the relative lipid solubility 24
3.SAR of Amide derivatives Aryl group at 2 or 6 with methyl group enhances the activity And the methyl substituents provides more steric hindrance to the hydrolysis of amide bonds 25
Cont.. X may be carbon(Isogramine), oxygen (Lidocaine) or nitrogen (phenacain) Lidociane (X=O) has provided useful product Aminoalkyl group: it is hydrophilic portion of the molecule and undergoes salt formation Tertiary amines are more useful clinically and 1o, 2o are more irritating. 26
4. Coefficient Distribution:  Nerve membrane consists primary lipids, increasing the lipid solubility a series of compounds facilitated penetration of nerve membrane.  The potency of local anaesthetic is directly proportional to distribution coefficients in vitro.  Substitution of aryl group by alkyl, alkoxy, alkylamino groups leads to homologous series in which partition coefficient with increasing CH3 groups at C4, C5 or C6 27
Cont..  Branching of N-alkyl groups in often accompanied by an intensification of activity  Territory amino group may be diethyl amino, piperidino or pyrrolidino with the same degree of activity.  Clinically useful agents exhibits Pka values in the range of 8.0 – 9.5 because of the compounds with higher Pka values ionised 100% at Physiological PH and so have difficulty in reaching the bio-phase. 28
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