5th unit local anaesthetics

Introduction.
Methods of Administration of Local Anaesthetics
Classification .
Drugs used in local anaesthetics.
Mechanism of action and SAR.
Structure and Synthesis.
Adverse Drug Reactions and Uses.
Reference

1. 5 th UNIT LOCAL ANAESTHETICS Prepared by G. Nikitha, M.Pharmacy Assistant Professor Department of Pharmaceutical Chemistry Sree Dattha Institute Of Pharmacy Hyderabad 1 Subject: Medicinal Chemistry-II Year: B.Pharmacy 3 rd Year Semister: 1 st Semister

2. Contents Introduction. Methods of Administration of Local Anaesthetics Classification . Drugs used in local anaesthetics . Mechanism of action and SAR. Structure and Synthesis. Adverse Drug Reactions and Uses. Reference 2

3. Introduction The term anesthesia which is derived from Greek word meaning insensitivity or lack of feeling is defined as the absolute loss of sensation with or without loss of consciousness to painful stimuli such as surgical procedures, painful skin abrasions, and severe burns etc. The agents which induce the state of anesthesia are called anesthetics, which are of two types i.e local anesthetics and General anesthetics. Local anesthetics are chemical agents which reversibly block the conduction of impulse in all neurons when applied locally in appropriate concentrations. They provide transient loss of sensory perceptions (pain, touch etc.) in a restricted region of the body. 3

4. Ideal Properties Local anesthetics should be potent. Should be non-irritating to the tissues. Should be non-toxic and should not cause any permanent damage. Should have less systemic toxicity. Should be rapid and long lasting in action. Should act selectively and effectively when injected. Should not interfere with the healing process. Should be sterile and stable. Should not interfere with other drugs like miotics , antibacterial, mydriatics etc. Should produce reversible action. Since nerve membranes are made up of lipids therefore, they should be adequately Lipophilic to cross these membranes. They should also be water soluble. 4

5. General Mechanism of Action Local anesthetics exert membrane stabilizing effects i.e failure in propagation of an impulse without affecting the resting potential. They block the entry of Na + channels, there by inhibiting the initiation and propagation of impulses across the nerves. 5

6. Na + channels contain an activation gate on their extracellular site and an inactivation gate on intracellular site. At the resting state, activation of Na + channels is closed. When depolarization occurs the activation gates opens allowing Na + ions to flow into the nerve. During the repolarization the inactivation gate closes thus ceasing the influx of Na + ions. The Local anesthetics are weak bases which undergo ionization at the physiological pH. The unionized form of LA is able to cross the lipophilic cell membrane. Once the LA reaches the axoplasm it reionises (BH + ) and binds to the Local anesthetics reporter located within the Na + channel in its intracellular half. Binding the Local anesthetic to its receptor decreases the permeability of Na + ions through the voltage Na + channels and thus prevents the generations and conduction of nerve impulses. 6

7. General Properties Local anesthetics contain an aromatic molecule and tertiary amine groups which are linked either by an ester or amide linkage. The tertiary amine group is hydrophilic while aromatic part of local anesthetic is Lipophilic in nature. Local anesthetics are weak bases with a pKa range of 8.0-9.0. They are usually available in their salt forms. In in vivo conditions they exist in their cationic forms. 1. The Local anesthetics are insoluble in water and unstable in amine forms, but their salt forms are usually stable. 2. The Local anesthetics action is exerted better at alkaline pH. In vivo a part of the drug is in ionized from while the rest is in unionized form are essential for exerting local anaesthetic action. The unionized form is essential for the penetration into the nerve which undergoes re-ionization to cationic form. This cationic form binds to the receptors. 7

8. If the pH is acidic the local anaesthetic remains in an ionized form which prevents its active diffusion. Hence local anaesthetics are less effective in infected and inflamed tissues as these have acidic pH. 8

9. General Pharmacokinetics Absorption Systemic absorption of local anaesthetics is affected by several factors like dosage, site of injection, drug tissue binding, local blood flow and other physic-chemical properties of the drug. Surface anaesthetics are well absorbed from broken kin ends, mucus membranes and poorly absorbed from unbroken areas. Due to their lipophilic nature they are widely distributed. They easily penetrate the brain, heart, kidneys, muscle etc . 9

10. Metabolism: The amide type local anaesthetics such as lignocaine undergo metabolism in the liver where they converted to water soluble metabolites which finally get excreted in urine 10

11. General Adverse Drug Reactions 1. CNS Manifestations 2. CVS Manifestations 3. Allergic reactions/ Hypersensitivity 4. Other effects includes blockade of neuromuscular transmission with high doses of local anaesthetics . 11

12. Methods of Administration of Local Anaesthetics 1. Topical or Surface Anaesthesia 2. Infiltration Anaesthesia 3. Conduction Block Anaesthesia a. Field Block b. Nerve block 4. Central Nerve Block Anaesthesia a. Epidural Block/ Peridural Block Anaesthesia b. Spinal Block Anaesthesia 5. Intravenous Regional Anaesthesia 12

13. Classification 1. Natural Agents: Cocaine 2. Synthetic nitrogenous agents: a. Derivatives of Para-amino benzoic acid Freely soluble- Procaine, Amethocaine Poorly soluble- Benzocaine , Orthocaine b. Derivatives of benzoic acid: Hexylcaine , Meprylcaine , Piperocaine , Cyclomethycaine , c. Derivatives of Acetanilide: Prilocaine , Lignocaine , Mepiracaine d. Derivatives of Quinoline: Cichocaine , dimethisoquin 3. Synthetic nitrogenous agents: Benzyl alcohol, propanediol 4. Miscellaneous Drugs with Local Action: Clove oil, Phenol, Chloropremazine 13

14. Classification Based on Mode of Administration 1. Injectable anaesthetics a. Low potency and short duration: Procaine, Chloroprocaine b. Intermediate potency and duration: Prilocaine , Lidocaine c. High potency and long duration: Bupivacaine , Tetracaine , Ropivacaine , Dibucaine 2. Surface anaesthetics a. Soluble: Cocaine, Lidocaine , Tetracaine b. Insoluble: Benzocaine , Oxethazaine , Butameben 14

15. Classification Based on Chemical nature 1. Benzoic acid derivatives: 15 Name R 1 R 2 Hexylcaine -H Meprylcaine -H

16. Piperocaine -H Cyclomethycaine 16 Cocaine:

17. 2. Para-amino benzoic acid derivatives:   17 Name R 1 R 2 R 3 R 4 R 5 Benzocaine H H H -CH 2- CH 3 --------- Butamben H H H -(CH 2 ) 3- CH 3 ---------- Procaine H H H -CH 2- CH 2

18. Tetracaine n-Butyl H H -CH 2- CH 2 Butacaine H H H -CH 2- CH 2 -CH 2 Benoxinate H n-Butyl H -CH 2- CH 2 propoxycaine H H n-propoxy -CH 2- CH 2 18

19. 3. Anilide derivatives:   19 Name R 1 R 2 Lidocaine CH 3 Mepiracaine CH 3

20. Prilocaine H Etidocaine CH 3 20

21. 4. Miscellaneous Drugs 21 Phenacaine Diperodon Dibucane

22. Benzoic Acid Derivatives 22

23. SAR of Benzoic Acid Derivatives: Most of these local anaesthetics are tertiary amines available as Hcl salts with pKa in the range of 7.5 to 9.0. Any structural modification of the local anaesthetics that cause change in pKa will have pronounced effect to reach hypothetical receptor or the binding site. 1. Lipophilic The clinical useful local anaesthetics of this class possess aryl radical that is attached directly to the carbonyl group and are highly Lipophilic. They appear to play an important role in the binding of the local anaesthetics to the channel receptor protein 23

24. Placement of aryl group with substituent that increases the electron density of the carbonyl oxygen enhances the activity. Structural modification leads to change in physical and chemical properties. Electron withdrawing substituent in ortho , para or at both the position leads to an increase of its local anaesthetics property. Amino (procaine, butacaine ) alkyl amino ( tetracaine ) alkoxyl ( cyclomethycaine ) group can contribute to electron density in the aromatic ring by both resonance and inductive effects. Hence the increase in local anaesthetic property. Any substitution that enhances zwitter ion formation will be more potent. Hence meta-position substitution decreases activity. 24

25. 25 Zwitter ion Tetracaine is more potent than procaine (40-50 times). Although the butyl group present in it increases lipid solubility, the potentiation is partly due to electron releasing property of the n-butyl group via inductive effect which intends to increase the formation of zwitter ion. Presence of electron withdrawing group such as Cl - ortho to carbonyl pulls electron density away from carbonyl group thus making it more susceptible for nucleophilic attack by the esterase.

26. 2. Intermediate: In procaine series anaesthetic potency decreases in the following order sulphur, oxygen, carbon and nitrogen. Modifications also affect the duration of action and toxicity. In general amides (X-N) are more resistant to metabolic hydrolysis than esters (X-O). Thoiesters (X-S) may cause dermatitis. Placement of small alkyl groups (branching) around ester group ( hexylcaine / meprylcaine ) or the amide function also hinder hydrolysis, and hence, increase in duration of action. 26

27. 3. Hydrophilic Portion The amino alkyl group is not necessary for local anaesthetic activity but it is used to form water soluble salts such as Hcl salts. Tertiary amines are more useful agents. The secondary amines appear to have longer duration of action, but they are more irritating. Primary amines are not active or cause irritation. The tertiary amines groups may be diethyl amino, piperidine, or pyrolidino leading to a product that exhibits same degree of activity, essentially. The more hydrophilic morpholino group usually leads to diminished potency. In general, the local anaesthetic drug should have increased lipid solubility and lower pKa values that leads to rapid onset and lower toxicity. 27

28. Cocaine It is a natural alkaloid obtained from coca tree Erythroxylon coca . Chemically, Cocaine is methylbenzoyl ester of ecgonine . It was the first local anaesthic to be discovered. It is too toxic to be used parenterally , but is still being employed topically to produce anaesthesia . Structure: IUPAC: methyl-3-benzoyloxy-8-methyl-8-azabicyclo octane-2-carboxylate Properties: Colorless to white crystals or white powder, Slightly soluble in water, soluble in volatile oils, ethyl ether, benzene, chloroform, toluene; very soluble in ethanol; insoluble in  glycerol, petroleum ether 28 Molecular Formula: C 17 H 21 NO 4

29. Pharmacokinetics: Topical and nasal route of administration, cocaine is metabolized to benzoylecgonine and ecgonine methyl ester, which are both excreted in the urine. In the presence of alcohol, a further active metabolite, cocaethylene is formed, and is more toxic then cocaine itself. Adverse Drug Reactions: CVS manifestations include vasoconstriction, rise in blood pressure, Tachycardia and myocardial infarction. Allergic reactions, mydriasis , hyperglycaemia and hyperthermia are other adverse effects with cocaine. At large doses, it causes sexual dysfunction and sexual disinterest etc. Anorexia (loss of appetite), emaciation, tremors, emotional disturbances etc, are seen. Drug independence is one of the serious toxic side effects of cocaine and withdrawal symptoms include CNS depression. 29

30. Therapeutic Uses: Cocaine is no longer used for producing through parental route. It is employed as a topical anaesthetic . 1-2 % solution of cocaine is required for including anaesthesia of ear, nose, throat, rectum and vigina . Dose: Formulated as 1-2 % solution, for anaesthesia of the ear, nose, throat, rectum and vagina, applied topically. 30

31. Hexylcaine Hexylcaine hydrochloride is also known as cyclaine and osmocaine . It is a short acting local anesthetic that acts through inhibition of sodium channels. Patients experience an overdose may present with headache, tinnitus, numbness and tingling around the mouth and tongue, convulsions, inability to breathe, and decreased heart function. Hexylcaine has been discontinued in the US market. Structure: IUPAC : 1-( cyclohexylamino )propan-2-yl benzoate Properties: It is a white powder, soluble in water and chloroform 31 Molecular Formula: C 16 H 23 NO 2

32. Pharmacokinetics: Topical and nasal route of administration, metabolized in liver (Hydrolyzed by plasma esterases to benzoic acid and other derivatives) Adverse Drug Reactions: Headache, Tinnitus Numbness around the mouth and tongue Tingling around the mouth and tongue Inability to breathe Decreased heart function Difficulty breathing Swelling of Lips, tongue, chest pain Dizziness, drowsiness Anxiety, convulsions Nausea, vomiting 32

33. Therapeutic Uses: Hexylcaine  is a benzoic acid ester, is a local anaesthetic that has been used for surface anaesthesia of mucous membranes. Local anesthetics produce a transient block of nerve conduction by interfering with sodium channels. Dose: For infiltration anaesthesia 1%, for nerve block anaesthesia , 1% and 2% solution, and for topical application to skin and mucus membrane 1% to 5%. 33

34. Meprylcaine Structure: IUPAC : [2-methyl-2-( propylamino ) propyl ] benzoate Properties: Oil, practically insoluble in water. Soluble in alcohol, ether, acetone, oils. 34 Molecular Formula: C 14 H 21 NO 2

35. Pharmacokinetics: I.v, subcutaneous route of administration, metabolized in liver, eliminated through kidneys. Adverse Drug Reactions: Difficulty breathing Allergic reactions Chest pain, Irregular heart rate Drowsiness Anxiety, convulsion Nausea, vomiting Therapeutic Uses: Used as local anaesthetics 35

36. Cyclomethycaine Structure: IUPAC: 3-(2-methylpiperidin-1-yl) propyl 4-cyclohexyloxybenzoate Properties: It is a white crystalline powder, soluble in water and chloroform.  36 Molecular Formula: C 22 H 33 NO 3

37. Pharmacokinetics: Oral route of administration, metabolized in liver, eliminated through kidneys. Adverse Drug Reactions: Difficulty in breathing Pain in chest, Vasoconstriction, Tachycardia Anxiety, Cardio toxicity by blocking Na + channels. Therapeutic Uses: Used to relieve pain from damaged skin mucous membrane of rectum, vigina , urinary bladder . Dose: The usual dose for topical purpose is 0.25% to 1% in suitable form. 37

38. Piperocaine Structure: IUPAC: 3-(2-methylpiperidin-1-yl) propyl benzoate Properties: White odorless crystals or a white crystalline powder, stable in air, freely soluble in water, alcohol and chloroform. 38 Molecular Formula: C 16 H 23 NO 2

39. Pharmacokinetics: Ophthalmic, Topical route of administration, metabolized in Plasma.   Adverse Drug Reactions: Blurred vision Redness of the clear part of the eye Sensitivity to light Severe stinging in the eye Tearing Throbbing eye pain Tearing of eyes Bloody eye Burning, stinging, itching, redness, or irritation of the eye Change in vision 39

40. Therapeutic Uses: Piperocaine ( Metycaine ) is a local anesthetic drug. It is an ester and primarily is a sodium channel blocker. Piperocaine can partially inhibit dopamine. It is known as a alpha-1-proteinase inhibitor. Used in the form of its hydrochloride as a local or spinal anesthetic and in dental anesthesia. 40

41. Amino benzoic acid derivatives 41

42. Benzocaine It is a synthetic nitrogenous derivative of PABA which is poorly water soluble. It generally exhibits poor penetration through skin. It is available as ointments, gels, liquids and as sprays. Structure: IUPAC: ethyl4-aminobenzoate 42 Molecular Formula: C 9 H 11 NO 2

43. Properties: White crystalline powder, or colorless crystals, sparingly soluble in water; it is more soluble in dilute acids and very soluble in ethanol, chloroform, and ethyl ether.  Mechanism of Action: Benzocaine binds to sodium channels and reversibly stabilizes the neuronal membrane which decreases its permeability to sodium ions. Depolarization of the neuronal membrane is inhibited thereby blocking the initiation and conduction of nerve impulses. 43

44. Synthesis: 44

45. Pharmacokinetics: Dental, Topical, oral route of administration, metabolized into at least three compounds by acetylation and hydrolysis.  Benzocaine  and its acetylated metabolite are rapidly eliminated across the gills while the more polar de-ethylated and de-ethylated-acetylated metabolites are excreted at slower rates primarily in the urine. 45

46. Adverse Drug Reactions: stinging, burning, or itching, skin tenderness or redness, or Dry white flakes. headache, weakness, dizziness, breathing problems, fast heart rate, and gray or bluish colored skin (rare but serious side effects of benzocaine ); severe burning, stinging, or sensitivity where the medicine is applied; swelling, warmth, or redness; or Oozing, blistering, or any signs of infection. 46

47. Therapeutic Uses: Benzocaine topical is used to reduce pain or discomfort caused by minor skin irritations, sore throat, sunburn, teething pain, vaginal or rectal irritation, ingrown toenails, hemorrhoids, and many other sources of minor pain on a surface of the body. Benzocaine is also used to numb the skin or surfaces inside the mouth, nose, throat, vagina, or rectum to lessen the pain of inserting a medical instrument such as a tube or speculum. It can be used for performing minor surgeries in the eye. Dose: Formulated as 5%, 6% creams 15-20% gels and 5-20% ointment applied topically. 47

48. Butamben Structure: IUPAC: butyl 4-aminobenzoate Properties: A white, odorless, crystalline, tasteless powder. that is mildly soluble in water (1 part in 7000) and soluble in alcohol, ether, chloroform, fixed oils, and dilute acids. It slowly hydrolyses when boiled with water.  48 Molecular Formula: C 11 H 15 NO 2

49. Pharmacokinetics: Dental, Topical route of administration. The metabolic pathway of butamben follows the same pattern of other local anesthetics and it is driven mainly by the hydrolysis via cholinesterase for the formation of inert metabolites. The metabolites found in plasma after cholinesterase processing are disposed of in the urine. Adverse Drug Reactions: A Skin Rash, Itching, Allergic reaction A Stinging Sensation On The Skin, A Type Of Allergic Reaction Called Angioedema Erythema Or Skin Redness, Hives, Irritation of mouth Skin Inflammation Due To A Topically Applied Medication Drowsiness, headache, Tremors Irregular heart rate, low blood pressure 49

50. Therapeutic Uses: Used as local anaesthetics . Butamben was indicated for the treatment of chronic pain due to its long-duration effect. It is also indicated as a surface anesthetic for skin a mucous membrane and for the relief of pain and pruritus associated with anorectal disorders. Dose: Topical gel: 14%/2%/2% Topical liquid: 14%/2%/2% Ointment: 14%/2%/2% Topical aerosol: 14%/2%/2% Topical Anesthetic: Minor dermal procedure Normal intact skin for local analgesia: Apply 2.5 g of cream over 20-25 cm of skin surface or 1 anesthetic disc (1 g over 10 cm) for at least 1 hour Major dermal procedure Apply 2 g of the cream per 10 cm of skin surface and allow to remain in contact with skin for at least 2 hours 50

51. Procaine It was the first synthetic local anaesthetic to be introduced. It is a nitrogenous derivative of PABA which is freely water soluble. It is not used as surface anaesthethic as it is ineffective when applied topically. It has a slower on set of action than lidocaine and prilocaine and its duration of action is also short. Structure: IUPAC: 2-( diethylamino )ethyl 4-aminobenzoate 51 Molecular Formula :C 13 H 20 N 2 O 2

52. Properties: A white, odorless, crystalline powder, Soluble in water, alcohol, ethyl ether, and benzene, ether, slightly soluble in chloroform, insoluble in ethanol. Mechanism of Action: Procaine acts mainly by inhibiting sodium influx through voltage gated sodium channels in the neuronal cell membrane of peripheral nerves. When the influx of sodium is interrupted, an action potential cannot arise and signal conduction is thus inhibited. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Procaine has also been shown to bind or antagonize the function of N-methyl-D- aspartate (NMDA) receptors as well as nicotinic acetylcholine receptors and the serotonin receptor-ion channel complex. 52

53. Synthesis: Method-1: Preparation from 4-amino benzoic acid 53

54. Method-2: Preparation from 2-chloroethyl P-amino benzoate 54

55. Method-3: Preparation from 4--nitro benzoic acid 55

56. Pharmacokinetics: Procaine being a vasodilator requires the addition of vasodilators like epinephrine retard its synthetic absorption. Procaine is poorly absorbed from mucus membrane. It is rapidly hydrolyzed from liver and plasma estarases to its metabolites, PABA and diethylamino ethanol where in the PABA inhibits the action of sulphonamides . The cerebrospinal fluid contains little or no esterases , hence when procaine is given through this route it remains active until it gets absorbed into the systemic circulation. 56

57. Adverse Drug Reactions: diarrhea that is watery or bloody; peeling skin , severe pain, or changes in skin color where the medicine was injected; dizziness, joint or muscle pain; fast or pounding heartbeats; numbness, tingling, pain, swelling, or redness in your arms or legs; confusion, agitation, depression, unusual thoughts or behavior; chest pain, problems with vision or speech; feeling like you might pass out; fever, chills, dizziness, muscle pain, rapid breathing or heart rate; uncontrolled muscle movements, problems with balance or walking; pale skin, easy bruising or bleeding, unusual weakness; sore throat, flu symptoms; urinating less than usual or not at all; 57

58. rash or itching with swollen glands, joint pain, or general ill feeling; or Slow heart rate, weak pulse, fainting, slow breathing. pain where the injection was given; vaginal itching or discharge; white patches in your mouth or throat; nausea, vomiting; blurred vision, ringing in your ears; headache, dizziness; or mild skin rash, Difficulty breathing; swelling of your face, lips, tongue, or throat. 58

59. Therapeutic Uses: Used for infiltration, peripheral nerve block and in spinal anaethesia . It can also be used for central nerve block anaethesia . Its amide derivative used as an antiarryhthmic drug. Procaine penicillin has antibacterial activity. Dose: Formulated as 1-2% solution and 10% injection, given parenterally . Usual infiltration 50ml of 0.5% solution Usual peripheral nerve block 25ml of 1% or 2% solution Usual epidural 25ml of 1.5% solution 59

60. Butacaine Structure: IUPAC: 3-( dibutylamino ) propyl 4-aminobenzoate Properties: It is a white crystalline ester, Soluble in Water. 60 Molecular Formula: C 18 H 30 N 2 O 2

61. Pharmacokinetics: Topical, parental route of administration, metabolized in liver, eliminated through kidneys. Adverse Drug Reactions: Sleepiness, muscle twitching,  ringing in the ears, changes in vision,  low blood pressure, and an irregular heart rate  Concerns exist that injecting it into a joint can cause problems with the cartilage.  Concentrated bupivacaine is not recommended for epidural freezing, Lower blood plasma concentrations. circumoral numbness, facial tingling,  vertigo, tinnitus, restlessness, anxiety, dizziness, seizure, coma  hypotension, arrhythmia,  bradycardia , heart block, cardiac arrest. 61

62. Therapeutic Uses: Used by dentists to minimize pain during tooth extract. Used to relieve pain in lower back, surgeries and in spinal anaesthesia , central nerve block anaesthesia . Dose: Several instillatiocs of 2% solution about 3 minutes apart allows most surgical procedure. 62

63. Tetracaine Structure: IUPAC: 2-( dimethylamino )ethyl 4-( butylamino )benzoate Properties: It is a white crystalline powder, slightly hygroscopic in nature, soluble in alcohol, freely soluble in water. 63 Molecular Formula: C 15 H 24 N 2 O 2

64. Pharmacokinetics: Ophthalmic, Topical, Subarachnoid, Intraspinal , Oral route of administration. Being an ester type local anaesthetic , tetracaine gets hydrolyzed by plasma and liver esterases to PABA which is highly allergic. The metabolism is usually slow which makes it highly toxic. Adverse Drug Reactions: Blurred vision, redness of the clear part of the eye, severe stinging in the eye, tearing sensitivity to light, throbbing eye pain, Bloody eye burning, stinging, itching, redness, or irritation of the eye change in vision nausea, vomiting, Irregular heart rate Drowsiness, Dizziness , Swelling, irritation of skin Breathing problems, Sleep disorders, Loss of hearing 64

65. Therapeutic Uses: Tetracaine is prominently used for the induction of spinal anaesthesia . It is topically applied on the nose, eye, throat and respiratory passages. Dose: Usually Subarachnoid 0.5 to 2ml as 0.5%, topically 0.1ml of 0.5% solution to conjunctiva. 65

66. Benoxinate Structure: IUPAC: 2-( diethylamino )ethyl 4-amino-3-butoxybenzoate Properties and Pharmacokinetics: White crystalline powder soluble in water. Ophthalmic route of administration, 66 Molecular Formula: C 17 H 28 N 2 O 3

67. Adverse Drug Reactions: temporary stinging and burning in the treated eye, eye irritation, conjunctival redness, contact dermatitis on fingertips, and Allergic reaction (rare). blurred vision, and punctate   keratitis Therapeutic Uses: Used as local anaesthetics , in eye surgery. Dose: Removal of foreign bodies and sutures, and for tonometry : 1 to 2 drops (in single instillations) in each eye before operating. 67

68. Propoxycaine Structure: IUPAC: 2-( diethylamino )ethyl 4-amino-2-propoxybenzoate 68 Molecular Formula: C 16 H 26 N 2 O 3

69. Pharmacokinetics: Topical route of administration. Metabolism: This drug his hydrolyzed in both the plasma and the liver by plasma esterases , excreted through kidneys. Adverse Drug Reactions: Blurred vision Sensitivity to the light Tearing Vision Problems Allergic reaction Therapeutic Uses: Used for infiltration and nerve block anaesthesia . Dose: Usually 2 to 5ml of 5% solution 69

70. Anilide derivatives 70

71. SAR of Anilide derivatives: General structure of anilide is represented as follows: 1. Aryl group The clinically useful local anaesthetics of this type possess a phenyl group attached to the sp 2 carbon atom through a nitrogen bridge. Placement of substituent on the phenyl ring with a methyl group in the 2 or 2 and 6-position enhances the activity. In addition the methyl substituent provides steric hindrance to hydrolysis the amide bound and enhances the coefficient of distribution. Any substitution on the aryl ring that enhances zwitter ion formation will be more potent. 71

72. 72 2. Substituent of X X may be carbon or nitrogen among them lidocaine series (X-O) has provided more useful products. 3. Amino alkyl group The amino function has the capacity for the salt formation and is consider as the hydrophilic portion of the molecule. Tertiary amines (diethyl amine, piperidine) are more useful because the primary and secondary amines are more irritating to tissues.

73. Lidocaine : The agents of this class are more stable to hydrolysis. They are more potent have lower frequency of side effects and induce less irritation than benzoic acid derivatives. Structure: IUPAC: 2-( diethylamino )-N-(2,6-dimethylphenyl) acetamide Properties: White crystalline powder, Characteristic odor, very soluble in water, benzene, ethyl ether, ethanol, and chloroform, freely soluble in alcohol, ether. 73 Molecular Formula: C 14 H 22 N 2 O

74. Pharmacokinetics: Infiltration, Ophthalmic, Topical, Subcutaneous, Epidural, Intra- articular , Perineural , Intravenous, Cutaneous , oral route of administration. Rapidly absorbed from GIT, and respiratory tract. It is also absorbed from mucosa and skin. It is metabolized in liver where it gets dealkylated by CYP450 to its metabolites, monethyl glycine , xylidide . The metabolites excreted in urine. Adverse Drug Reactions: Low blood pressure (hypotension), Cardiac arrest, Abnormal heartbeat Swelling (edema), Redness at injection site, Small red or purple spots on skin, Skin irritation, Severe allergic reactions (anaphylaxis) Constipation Headache, Nausea, Vomiting Confusion, Dizziness, Drowsiness, Numbness and tingling, Tremor, Seizures Irritation symptoms (topical products); i.e., redness, swelling Methemoglobinemia , Malignant hyperthermia 74

75. Therapeutic Uses: Topically on mucus membrane Used for Infiltration, nerve block and epidural anaesthesia . Used as spinal anaesthesia , 5% hyperbaric solution of lidocaine is used Used as transdermal path for post herpetic Used as surface anaesthesia Used for producing dental anaesthesia It is combine with opioid analgeics for epidural administration Uses as an antiarrhthymic agent for managing ventricular arrhythmais It is the drug of choice in individuals sensitive to procaine and ephinephrine . Dose: Infiltration or epidural up to 600 ml (or 100 ml with epinephrine) as 0.5% solution, 2% topical solution, 2% jelly, 2% ointment. 75

76. Mepivacaine :  Structure: IUPAC: N-(2,6-dimethylphenyl)-1-methylpiperidine-2-carboxamide Properties: White crystalline powder, Characteristic odor, freely soluble in water, alcohol, very slightly soluble in methylene chloride. 76 Molecular Formula: C 15 H 22 N 2 O

77. Pharmacokinetics: Epidural, Infiltration, Intracaudal , Subcutaneous route of administration. Rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. 77

78. Adverse Drug Reactions: numbness and tingling of the lips, tongue, and oral tissues; nervousness, Lightheadedness, unconsciousness, and dizziness, confusion, depression, drowsiness, tremors, convulsions, blurred vision, slurred speech possible respiratory arrest, sweating, and, Metallic taste, Ringing in ears, Head ache Therapeutic Uses: It will block the nerve impulses that send pain signals to brain, spinal block. Dose: Infiltration and nerve block 20ml of 1% or 2% solution in sterile saline caudal, peridural 15 to 3o ml of 1% solution in modified ringer’s solution. 78

79. Prilocaine : Structure: IUPAC: N-(2-methylphenyl)-2-( propylamino ) propanamide Properties: White crystalline powder or colorless crystals, freely soluble in water, alcohol, very slightly soluble in acetone. 79 Molecular Formula: C 13 H 20 N 2 O

80. Pharmacokinetics: Infiltration, Dental, Submucosal , Subcutaneous, Parentral , Intra- articular ; Intramuscular; Topical route of administration, it is metabolized in both the liver and the kidney and excreted via the kidney. Adverse Drug Reactions: slow or shallow breathing, pale or bluish skin around the mouth or lips, dizziness, fainting, fast/slow/irregular heartbeat, mental/mood changes (e.g., confusion, nervousness), seizures, or Severe drowsiness. Redness, swelling, tingling/burning, or lightening of the skin may occur. 80

81. Therapeutic Uses: Widely used as dental procedures Used for Infiltration, Epidural, nerve block anaestheia . For anaesthetizing intact skin, eutectic mixture of lignocaine and prilocaine is used Used in patients with hypertension, diabetes, thyrotoxicosis , because this drug is not combined with epinephrine. Dose: Usually therapeutic nerve block 3 to 5 ml of 1% or 2% solution, infiltration 20 to 30 ml of 1% or 2% solution, peridural , caudal, regional 15 to 20 m of a 3% solution, infiltration and nerve block, 0.5 to 5 ml of a 4% solution, formulated as 5% cream applied by topical route. 81

82. Etidocaine Structure: IUPAC: N-(2,6-dimethylphenyl)-2-[ethyl( propyl )amino] butanamide Properties: White crystalline powder, soluble in water, freely soluble in alcohol, very slightly soluble in acetone. 82 Molecular Formula: C 17 H 28 N 2 O

83. Pharmacokinetics: Parental route of administration, undergoes hepatic metabolism, eliminated through urine. It has rapid onset of action, is more potent and has a longer duration of action than lidocaine . Adverse Drug Reactions: headedness, , nervousness, , apprehension, euphoria, confusion, dizziness, drowsiness,  tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, Tremors, convulsions, unconsciousness, respiratory depression and arrest. bradycardia , and cardiovascular collapse, which may lead to cardiac arrest. Allergic reactions are characterized by  cutaneous  lesions,  urticaria , edema or anaphylactoid reactions.  83

84. Therapeutic Uses: Used for Infiltration and nerve block anaestheia . In peridural analgesia, it is used to relax abdominal muscles and to block motor nerves. Dose: Solution for injection 1% without epinephrine. Formulated as 0.5% scream applied topically. 84

85. Miscellaneous Drugs 85

86. Phenacaine Structure: IUPAC: N , N '-bis (4-ethoxyphenyl) ethanimidamide Properties: It exists as small white odorless and crystalline powder, soluble in water. 86 Molecular Formula: C 18 H 22 N 2 O 2

87. Adverse Drug Reactions: . Blurred vision Sensitivity to the light Tearing Vision Problems Allergic reaction   Therapeutic Uses: Used as local anaesthesia for eye surgery. Dose: To the conjunctiva as 1% to 2% ointment or as a 1% solution 87

88. Diperodon Structure: IUPAC: 2-[( phenylcarbamoyl )oxy]-3-(piperidin-1-yl) propyl N-phenyl carbamate Properties : It exists as fine, white crystalline, odorless power with a characteristically bitter taste followed by a sense of numbness, soluble in water, 88 Molecular Formula: C 22 H 27 N 3 O 4

89. Adverse Drug Reactions: Itching , redness, burning of skin Therapeutic Uses: Potent surface anaesthetic , used primarily for anus. Dose: Topically 0.5 to 1% solution, to the mucous membrane 89

90. Dibucane Structure: IUPAC: 2-butoxy- N -[2-( diethylamino )ethyl]quinoline-4-carboxamide Properties: It exists as white powder, slight characteristic odor, Soluble in alcohol and acetone, ether, chloroform; insoluble in water, alkaline aqueous solutions. 90 Molecular Formula: C 20 H 29 N 3 O 2

91. Synthesis: 91

92. Mechanism of Action: Local anesthetics block both the initiation and conduction of nerve impulses by decreasing the neuronal membrane's permeability to sodium ions through sodium channel inhibition. This reversibly stabilizes the membrane and inhibits depolarization, resulting in the failure of a propagated action potential and subsequent conduction blockade. Pharmacokinetics: Topical, I.v route, rectal of administration, metabolized in liver eliminated through kidneys 92

93. Adverse Drug Reactions: A Skin Rash, A Stinging Sensation On The Skin A Type Of Allergic Reaction Called Angioedema Erythema Or Skin Redness, Hives Itching, redness, Skin Inflammation Due To A Topically Applied Medication Drowsiness, headache, Tremors Low blood pressure, Decrease lung function Therapeutic Uses: It is used as surface anaesthetic in anal canal, rectum. Used topically for relieving pain and itching due to sunburn, insect bites or minor skin irritations Ointment or suppositories are used for relieving itching and pain associated with haemorrhoids (piles). Dose: Topically to the skin as 0.5% ointment or lotion 2 to 4 time/day 93

94. SAR of Local anaesthesia 94

95. Most of the widely used local anaesthics are divided into two main classes: Ester type local anaesthetics which are developed from cocaine and are considered as derivative of benzoic acid. Amide type local anaesthetics developed from isogramine and are considered as derivatives of aniline. Both these classes in general contain the basic structural formula. Lipophilic or Hydrophilic center-----Ester/ amidegroup ----X-----hydrophilic center X- Bridge or linkage between hydrophilic and hydrophobic groups. 95

96. 1. Lipophilic/ Hydrophobic centre: Presence of Lipophilic portion is necessary for a local anaesthetic in order to exhibit lipid solubility. These portion aids in the penetration of drug into the lipid bilayer of cell membrane. The Lipophilic part is either an aromatic group or an aryl group directly attached to a carbonyl group (amine ester) via -NH group. Any alternation on this portion affects the physical and chemical properties of a drug which in turn has impact on its local anaesthetic activity. As Lipophilicity increases there is an increase in potency of the compound. a. For Esters All the ester type local anaesthetics possess the basic formula 96

97. The aryl may be directly attached to the carbonyl moiety or through a vinyl group. Direct attachment of the carbonyl moiety is known to increase the local anaesthetic activity. The aryl groups can be either aryl or aryl alicyclic compounds. Presence of aryl vinyl radicals (Aryl-CH CH-) or an alkylene (methylene group) between the aryl radical and carbonyl moiety result in compounds that are clinical ineffective. Presence of electron withdrawing groups like NO 2 decreases the local anaesthetic activity. Presence of electron donating like alkoxy , amino, alkylamino groups as substituent at ortho and para position on the aryl group, increases the activity of local anaesthetic due to resonance and inductive effect. Examples: Propaxicaine (contains alkoxy substituents ), Procaine (contain amino- substituents ), Tetracaine (contains alkylamino substituent). 97

98. b. For Amides: The amide type local anaesthetics possess the general formula, Aryl moiety must be a 2,6-dimethyl phenyl group attached through a NH group to the sp 2 carbon atom of . Methyl group substitution at 2,6 position ( ortho or para positions) present on aryl moiety increases the local anaesthetic activity. Substitution by methyl group not only increases the lipid solubility but also provides resistance to hydrolysis (by providing stearic hindrance). 98

99. 2. Bridge(X) The hydrophilic portion is bridged to an ester group via short hydrocarbon chain or with the help of oxygen, sulphur, atoms. The ester or amide groups link the Lipophilic portion and the hydrophobic portion of local anaesthetics . a. For Esters The bridge (X) might be carbon, oxygen, nitrogen or sulphur moiety. The duration of action and the toxicity exerted by a local anaesthetic depends upon moiety present as –X-. Thio esters i.e X-S produce skin irritations like dermatitis hence they are rarely used as local anaesthetics . b. For Amides X might be carbon ( isogramine ), nitrogen ( Phenacaine ) or oxygen ( lidocaine ). The preferred atom is oxygen because when X-O clinically useful products have been produced. Generally compounds containing X-N (i.e amides) are more stable to hydrolysis and hence are preferred over compounds containing X-O. 99

100. 3. Hydrophobic Center The Hydrophobic portion plays a role in aiding the movement of the drug to the cell and thus facilitates the binding of the drug to the receptors. The hydrophilic centre can be tertiary amines are more preferred as they are less irritating to the tissues. Substitution of the hydrophilic will be more number of carbon atoms increases the partition coefficient and thus increases the activity of local anaesthetic . a. For esters This group does not have any role in exerting anaesthesia but is useful to prepare water soluble compounds. Generally, tertiary amines are preferred because of their rapid solubility. Secondary amines exhibits long duration of action but are highly irritating. Primary amines are not used because of lack of activity and also because they cause irritation. Molecules like benoxinate are resistant to hydrolysis because of the presence of 3-butoxy group. Tetracaine is readily absorbed because of the presence of n-butyl group (non polar group) on the aryl nitrogen which tends to increase the lipid solubility of tetracaine .   100

101. b. For Amides This group necessary for forming water soluble compounds. Generally tertiary amines are preferred as they are more useful clinically than the secondary and primary amines which are more irritating. The nerve membranes are generally lipodial in nature. As increase in the Lipophilic character enhances the penetration of local anaesthetic into the membrane, but decreases the solubility of the drug in the extracellular and intracellular fluids. An increase in the hydrophilic portion of local anaesthetic decreases the drug penetration into the membrane. Hence the local anaesthetic should possess an equal balance for both Lipophilic and hydrophilic centers. Substitution of aryl ring by alkyl, alkoxy or alkyl amino groups tends to give homologues series that shows an increases in partition coefficient upon increase in the number of methylene substituent attached to the aryl moiety. Maximum activity is exerted by the compounds belonging to C 4 to C 6 homologues series. 101

102. Binding of local anaesthetics to plasma and tissue proteins is due to the presence of van der waals force, dipole-dipole attractions and electrostatic attractions. Moreover compounds exhibiting high potency and long duration of action tend to binds strongly to the plasma and tissue proteins. 102

103. Presence of electron donating substituent on the aryl Lipophilic center increases the activity of benzoic acid derivatives, whereas presence of electron withdrawing substituent tends to decrease the activity of local anaesthetics . This is because electron withdrawing groups decreases the strength of carbonyl dipole by accepting electron from carbinol group and thus decreases dipole-dipole attraction with the receptors. Different enantiomers of local anaesthetics exhibit difference in terms of their selectivity and toxicity. Examples: Ropivacaine and (-) laevo bupivacaine are less toxic than bupivacaine . S(-) bupivacaine is less toxic than R(+) bupivacaine . The activity and duratiod of action of local anaesthetics depends upon their stability. Hydrolysis reaction explains about the stability of both ester and amide type local anaesthetics . 103

104. Reference books Text book of Medicinal chemistry volume-1-3 rd edition by V.Alagarasamy. Text book of Medicinal chemistry volume-2-3 rd edition by V.Alagarasamy. Medicinal chemistry by Rama Rao Nadendla. Principals of Medicinal chemistry volume-1 by Dr. S.S. Kadam , Dr. K.R. Mahadik , Dr.K.G . Bothara . Faye’s Principles of Medicinal Chemistry- 7 th edition by Thoms L.Lemke , Victoria F.Roche , S. Willam Zito . Medicinal Chemistry- 4 th edition by Ashutosh Kar Medicinal and Pharmaceutical Chemistry by Harkishan Singh, V.K Kapoor . Wilson and Gisvolid’s Textbook of Organic Medicinal and Pharmaceutical chemistry-12 th edition by John M. Beale, John. H. Block. 104

105. Thank YOU 105