Anesthesia, Types of anesthesia, with Pharmacology

Anesthesia, Types of anesthesia, with Pharmacology

1. ANAESTHESIA

2. 2/15/2008 2

3. 2/15/2008 3 What is anaesthesia? The term anaesthesia means which produces reversible loss of all sensation and consciousness . Anesthesia controls pain during surgery or other medical procedures. It includes using medicines, and sometimes close monitoring, to keep patient comfortable It can also help control breathing, blood pressure, blood flow, heart rate and rhythm, when needed

4. ► An anesthesiologist or a nurse anesthetist takes charge of patient comfort and safety during surgery. This topic focuses on anesthesia care that you get from these specialists ► Anesthesia may be used to: Relax patient Block pain Make you sleepy or forgetful Make you unconscious for patient surgery Other drugs also may be used to relax patient muscles during surgery

5. 2/15/2008 5 Types of anesthesia 1) Local anesthesia : Numbs a small part of the body. Patient get a shot of local anesthetic directly into the surgical area to block pain. It is used only for minor procedures Patient may stay awake during the procedure, or you may get medicine to help you relax or sleep Abolish the pain sensation in localized areas without affecting the degree of consciousness

6. 3) General anesthesia : ► Affects the brain as well as the entire body. Patient may get it through a vein (intravenously) or may breathe it in. ► With general anesthesia, patient are completely unaware and do not feel pain during the surgery (loss of all modalities of sensation) ► General anesthesia also often causes to forget the surgery and the time right after it (reversible loss of consciousness)

7. 2/15/2008 7 Types of General anaesthetics 1) Inhalation general anaesthetics: Volatile liquids: Chloroform, Diethyl ether, ethyl chloride, Trichloroethylene, Halothane, Enflurane, Isoflurane Gases: Cyclopropane, Nitrous oxide

8. 2/15/2008 8 2) Nonvolatile general anaesthetics (Intravenous anaesthetics): Ultra short acting barbiturates: Thiopental sodium, Methohexital Non-barbiturates: Benzodiazepine: Midazolam Phencyclidine derivative: Ketamine Steroid: Althesin Etomidate: Propofol

9. Requirement of an ideal anaesthetic agent For Patient: ► It is pleasant to inhale without any irritation. The induction should be fast and pleasant and the recovery should be smooth and rapid ► It should not produce any toxicity or post-operative complications For Surgeon: ► It should produce good analgesia and adequate muscular relaxation. Capillary bleeding should be negligible and the drug should not be explosive

10. For anaesthetist: 2/15/2008 10 It should be stable at room temperature and be easily controllable with a wide margin of safety It should not cause respiratory or circulatory depression and should be readily eliminated from the body It should not attack the material used for anaesthesia e.g. rubber tubing and metal A complicated apparatus should not be required for its adminisration

11. For manufacturers: 2/15/2008 11 Cost of production should be cheap and should have no storage problems

12. Site & Mechanism of action of General Anaesthetics: 2/15/2008 12 The general anesthetic agents are capable of depressing all the functional elements of the CNS including the spinal cord Also it inhibit the ascending reticular activating system , which normally maintains a state of wakefulness Thalamus appears to be an important site for the sedative effect of the inhalational general anaesthetics Amnesia is due to inhibition of neurotransmitters in the hippocampus

13. 2/15/2008 13 The structural diversity of the various compounds suggests that anaesthetics do not act at a single specific receptor As pointed out by Overton and Meyer, there is a close correlation between the potency of compound and its lipid solubility Such correlation suggest that anaesthesia results when a specific number of anaesthetic molecules occupy a crucial hydrophobic site in the CNS

14. 2/15/2008 14 The hydrophobic site is probably localized to synaptic regions or the nerve terminal of axons with a small diameter Anaesthetics probably act by blocking excitatory synaptic transmission , but a few agents may act by prolonging synaptic inhibition Until recently, it was believed that the general anaesthetics act by interfering with lipid interactions in the cell membrane, thus acting indiscriminately and in a “physiochemical manner”

15. 2/15/2008 15 The hypothesis postulated that the anaesthetic molecules dissolve in the membrane lipids, changing their physical properties, which in turn was thought to modulate the activity of the integral membrane proteins such as receptors and ion channels Recent evidence, however, indicates that membrane proteins and not lipids are the primary targets of an anaesthetic These agents may also release endogenous opiate like substances which are known to produce analgesia

16. 2/15/2008 16 Most I.V. anaesthetics act predominantly on the GABA A receptors The halogenated inhalation anaesthetics have a wider molecular target Nitrous oxide and ketamine are believed to produce unconsciousness by inhibition of NMDA (N-methyl-D-aspartate) receptors

17. Stages of anaesthesia: 2/15/2008 17 Guedel , in 1920, referring mainly to the anaesthetic activity of ether, outlined the four stages of general anaesthesia The third stage of surgical anaesthesia categorized in to four planes . These stages can be distinctly discerned with the majority of the volatile general anaesthetics However, in modern anaesthetic practice, the stages are never discerned separately. Every effort is made to achieve a smooth induction, avoiding the stage of delirium with the help of IV inducing agents such as thiopentone

18. 2/15/2008 18 The stages are: Stage I: Stage of analgesia Stage II: Stage of delirium Stage III: Stage of surgical anaesthesia Stage IV: Stage of respiratory paralysis

19. Stage I: Stage of analgesia 2/15/2008 19 This stage stretches from the beginning of inhalation of anaesthetic to loss of consciousness The gradual depression of the cortical centers which develops during this phase is manifested as a sensation of remoteness, failing, suffocation or as visual or auditory aberrations A feeling of warmth is experienced by some individuals, even though minor surgical procedures such as incision of an abscess, dental extraction and obstetrical manoeuvres have been carried out during this stage, but not recommended for longer time

20. 2/15/2008 20 With continued administration of the anaesthetic agent the patient passes into the second stage of delirium Analgesia is produced before consciousness is lost

21. Stage II: Stage of delirium 2/15/2008 21 This stage extends from the loss of consciousness to the beginning of surgical anaesthesia It may be associated with excitement, shouting, increased muscular activity, breath holding, tachypnoea and hyperventilation Some of these manifestations are due to release of the lower centers from the inhibitory control of higher centers as a result of cortical depression

22. 2/15/2008 22 The pupils may dilate and marked hypertension and tachycardia may develop, due to release of adrenaline Struggling increased tone of the skeletal muscles, retching and vomiting are the undesirable features of this stage and necessitate careful vigilance However these can be minimised by proper pre-anaesthetic medication

23. Stage III: Stage of surgical anaesthesia 2/15/2008 23 As more drug gets in, deep breathing starts and patient passes in to the third stage It is characterized by a gradual loss of reflexes, regular respiration and relaxation of the skeletal muscles Reflex activity is lost, this stage is usually employed for surgical intervention & is divided in 4 planes:

24. Plane i: 2/15/2008 24 The pupils are normal in size and the eyeballs are roving If the pupils are dilated before commencing the anaesthesia or reflexly during the second stage, they assume normal size and then dilate progressively with the depth of anaesthesia The respiration is full, regular, deep and thoracoabdominal character. The blood pressure and the pulse rate are normal The skeletal muscles are incompletely relaxed

25. 2/15/2008 25 The lid reflex, swallowing, retching and vomiting get abolished The corneal reflex is present but the conjunctival reflex is lost, the loss of pharyngeal reflex in the middle of this plane enables the anaesthesiologist to pass a pharyngeal airway

26. Plane ii: 2/15/2008 26 In the second plane, the eyeballs are fixed. The respiratory excursions are still regular but the amplitude is diminished Muscular relaxation is adequate and the increase in respiratory rate or breath holding in response to skin incision is abolished Reflexes arising from the larynx are also abolished and endotracheal intubation can be performed

27. Plane iii: 2/15/2008 27 This is characterized by the beginning of asynchrony between the thoracic and the abdominal respiratory movements The blood pressure begins to fall, the intercostal muscles are gradually paralysed and the respiration assumes an increasingly abdominal character Thus the costal margins retract with the descent of diaphragm in the latter part of the third plane The pupillary light reflex and the corneal reflex are lost, the muscular relaxation is essentially complete

28. Plane iv: 2/15/2008 28 The paralysis of the intercostal muscles is complete, the pupils are dilated, do not respond to light, the muscles are flaccid and the blood pressure is low The secretions are progressively reduced from plane I onwards and are completely abolished in plane iv

29. Stage IV: Stage of respiratory paralysis 2/15/2008 29 This stage is characterized by severe depression of the vital medullary centers Initially, as the diaphragmatic contractions become irregular, the accessory muscles of respiration may be brought into use but eventually complete respiratory arrest with the paralysis of accessory muscles and diaphragm supervenes The respiratory arrest is accompanied by vasomotor collapse and cardiac arrest

30. 2/15/2008 30 The stages of anaesthesia may differ considerably with different anaesthetic agents Halothane produces hypotension much more readily than ether Pupillary dilatation is a progressive and reliable sign with ether while it is insignificant with halothane With ether the skin becomes pale, cold and wet in preparalytic stage while with halothane, it is warm and dry until the development of marked hypotension

31. 2/15/2008 31 Preanaesthetic medication with the opioid analgesics, atropine and the use of skeletal muscle relaxants also modifies the signs of the anaesthesia and may interfere with the proper assessment of the depth of anaesthesia

32. Inadequate Anaesthesia 2/15/2008 32 Signs of ANS activity, Such as tachycardia, rise of blood pressure, sweating & lacrimination Grimacing; or Other muscle activity Surgical anaesthesia Loss of eyelash (lid) reflex; and Development of rhythmic respiration

33. Methods of administration of general anaesthetics 2/15/2008 33 Open method This is a simple method of administering a volatile anaesthetic, also called an “open drop” procedure A simple mask like Schimmelbusch mask covered with six to ten layers of gauze, which does not fit the contour of the face is held on the face and an anaesthetic like ether or ethyl chloride is poured in drops The anaesthetic vapour, diluted with air, is inhaled through gap between the mask and the face, there is no rebreathing (no need any anaesthesia apparatus)

34. Deep Anaesthesia 2/15/2008 34 Depression of respiration Marked hypotension Asystole Associated blood loss and hypoxia can aggravate the stimulation. They must be avoided

35. Semi open method 2/15/2008 35 This method is similar to open method but the dilution with air is prevented by using either a well-fitting mask like ogston’s mask or layers of gauze between face and the mask A small carbon dioxide build-up occurs with this method

36. Semi-closed method 2/15/2008 36 This method allows some rebreathing of the anaesthetic drug with the help of a reservoir But in addition, part of the volume of each succeeding inspiration is a new portion from an anaesthetic mixture This method involves accumulation and rebreathing of carbondioxide

37. Close method 2/15/2008 37 This method essentially employs chemical agent (soda lime) to reabsorb the carbon dioxide present in the expired air It requires the use of a complicated apparatus but is particularly useful when the anaesthetic agent is potentially explosive

38. Volatile Liquid Anaesthetic 2/15/2008 38 The volatile general anaesthetics which are liquid at room temperature are all extremely potent but relatively soluble in blood, cell water and fat Hence, both induction and recovery with these agents are slower than that with the gaseous general anaesthetics

39. Diethyl Ether 2/15/2008 39 Ether is colourless volatile liquid with a pungent odour and with the boiling point 35 c Anaesthetic ether contains 96-98% diethyl ether Ether vapour is irritating & when exposed to air, moisture or light may form ether peroxides or acetic aldehyde , which are irritant To avoid this conversion, ether is marketed in sealed containers or amber coloured bottles covered with black paper

40. 2/15/2008 40 The containers are sometimes coated with copper as it ratrads the oxidation of ether A concentration of 10-15% of ether in the inspired air is usually required for induction while a concentration of to 5% ensures a satisfactory maintenance of anaesthesia in plane iii Ether rubbed into the skin produces local vasodilatation with a sense of warmth and pain (rubefacient action) It dissolves the sebaceous secretion and in the form of etheral soap is used as a cleansing agent

41. Absorption, fate & excretion 2/15/2008 41 Only a minor portion of ether is oxidized within the body; 85-90% is eliminated through lungs & the remainder through the skin, urine, milk & sweat Ether crosses the placental barrier and reaches comparable concentrations in the foetal blood

42. Advantage of ether 2/15/2008 42 It can induce surgical anaesthesia without any pre-anaesthetic medication. Ether is probably the safest anaesthetic, even in the hands of an inexperienced anaesthetist It is an excellent analgesic and minor surgical operations can be performed even with subanaesthetic concentrations It has a cuararimimetic effect on skeletal muscles and produces satisfactory muscular relaxation. It synergises with the muscle relaxant d-tubocurarine

43. 2/15/2008 43 The rate and volume of respiration are usually increased during ether inhalation This has been explained as a reflex stimulant effect of ether on respiration, probably by stimulation of the sensory receptors in the tracheobronchial tree It does not modify blood pressure, during planes i & iii and does not sensitize the myocardium to adrenaline. Hence it is less likely to precipitate cardiac arrhythmias

44. 2/15/2008 44 Light ether anaesthesia does not interfere with the uterine contractility significantly and intermittent ether inhalation may be employed during delivery to reduce labour pains It is devoid of significant hepatotoxicity and nephrotoxicity It can be administered without a complicated apparatus It allows the use of air as a diluents and as a source of oxygen because the concentration of ether required for anaesthesia is low

45. Disadvantages of ether 45 Induction is slow and is sometimes stormy, associated with marked excitement and thrashing Irritant nature of the ether vapour may increase the salivary and bronchial secretions and induce cough & laryngeal spasm during induction

46. 46 During induction, sensitization of the baroreceptors by ether may produce reflex inhibition of the heart. However, the heart rate usually increases during ether anaesthesia Nausea and vomiting appear especially during recovery from ether anaesthesia but may also occur during induction The recovery is slow Alcoholics are tolerant to ether and induction of anaesthesia with ether in alcoholics may be difficult Ether convulsions are uncommon but may occur in children

47. HALOTHANE 47 (Fluothane) It is a fluorinated volatile anaesthetic It is a heavy, colourless liquid with a characteristic sweet, fruity odour and is supplied for anaesthesia in amber-coloured bottles, it boils at 50 o c Halothane readily attacks most of the metals including stainless steel, brass, copper and may also affect the rubber elements of the anaesthetic equipment

48. 48 Halothane produces loss of consciousness in a concentration of 2-3% in oxygen vapour and the anaesthesia can be maintained by using 1-2% of halothane vapour with oxygen and nitrous oxide A special apparatus is usually necessary to achieve a precise control of concentration ADME: About 60-80% of halothane is eliminated unchanged through lungs in the first 24 hours About 15% appears to be retained in the body & is probably metabolised

49. Advantages of Halothane 49 Halothane is non-inflammable and does not irritate the respiratory passage. It has a fruity odour and is not unpleasant for induction Halothane is a potent anaesthetic. Induction of anaesthesia and recovery are reasonably quick, the incidence of post-operative vomiting is low Halothane may be employed to induce controlled hypotension to provide a “bloodless” field during plastic surgery but is safe for this procedure only in expert hands

50. Disadvantages of Halothane 50 Muscular relaxation with halothane alone is inadequate to permit intra-abdominal operations; however, it potentiates the actions of d-tubocurarine Halothane depresses respiration of its concentration in the anaesthetic vapour is allowed to exceed 2% Recovery of mental function after halothane takes several hours. Shivering during recovery is common

51. 51 Hepatic damage including extensive hepatocellular necrosis, due to allergy or idiosyncrasy, following the use of halothane has been reported to occur after a period of 5-20 days after anaesthesia Halothane is poor analgesic and must be supplemented with nitrous oxide or opiates to provide satisfactory conditions for operation It causes rise in intracranial pressure due to cerebral vasodilation. Hence it is contraindicated in patients with intracranial lesions Expensive & need special apparatus

52. Other volatile liquid anaesthetic 52 Enflurane Isoflurane Ethyl chloride Trichloroethylene

53. 2/15/2008 53

54. Gaseous Anaesthetics 54 NITROUS OXIDE Nitrous oxide is a colourless, inorganic, non-irritating gas with a sweet taste It is non-inflammable & is marketed in steel cylinders at a pressure of 650 to 800 lbs per square inch If administered along with air, produces a stage of excitement and delirium and also produces amnesia, hence the name amnesia

55. 55 Nitrous oxide produces analgesia when inhaled in the concentration of 35-40% with air Loss of consciousness occurs with the concentration of 65-70% and plane i of surgical anaesthesia can be reached with an 80:20 mixture of nitrous oxide and oxygen A further increase in the concentration of the anaesthetic agent produces hypoxia

56. ADME: 56 Nitrous oxide is not altered within the body and is carried in the form of a physical solution in the blood It is rapidly eliminated through lungs within 2-5 minutes after its withdrawal

57. Advantages of nitrous Oxide 2/15/2008 57 It is non-inflammable and non-irritating , it provides rapid induction and recovery Because of its analgesic action in subanaesthetic concentration, nitrous oxide is employed for tooth extraction, for obstetrical analgesia And also for painful procedures such as changing dressing of burns, cleaning and debridement of wounds and cauterisation

58. 2/15/2008 58 Nitrous oxide is commonly used with oxygen and ether to maintain anaesthesia. The technique is termed “Gas-Oxygen-Ether (G-O-E) technique”. Nitrous oxide is probably the safest of the anaesthetic agents, having no remarkable deleterious effects on circulation, respiration, liver & kidney Unpleasant sequelae like nausea and vomiting are uncommon

59. Disadvantages of nitrous oxide 2/15/2008 59 Nitrous oxide is not a potent anaesthetic by itself and has to be supplemented with either pre-anaesthetic medication or with other potent anaesthetic agents or muscle relaxants to achieve surgical anaesthesia and muscle relaxation Excitement may be violent Carbon dioxide accumulation and hypoxia may develop during prolonged nitrous oxide anaesthesia, especially when supplemented with skeletal muscle relaxants

60. Pre-Anaesthetics Medication 60 Pre-Anaesthetic medication is the term applied to the use of drugs prior to the administration of an anaesthetic agent, with the important object of making anaesthesia safer and more agreeable to the patient The reasons for such medication are: For sedation, to reduce anxiety and apprehension without producing much drowsiness To relieve pre-and post-operative pain

61. 61 To obtain an additive or synergistic effect so that induction could be smooth and rapid and the dose of the general anaesthetic could be reduced To counteract certain adverse effects of the anaesthetic drug used such as salivation, bradycardia and vomiting To suppress respiratory secretions and to reduce reflex excitability There is no single drug which can achieve all these objectives and hence usually a combination of drugs is used

62. Drugs commonly used for preanaesthetic medication 62 I) Opioid analgesics: e.g. morphine (10-15 mg. I.M.), pethidine (50-100 mg. I.M.), buprenorphine (300 mcg. I.M.) are commonly employed for their sedative and analgesic properties Buprenorphine has longer duration of action than morphine and pethidine. They also reduce the amount of general anaesthetic required

63. 63 However, they have certain disadvantages: They may depress respiration and may produce respiratory arrest even before surgical anaesthesia is induced Further, drugs like morphine increase the tone of smooth muscle such as bronchial muscles In emphysema where the pulmonary reserve is already low, use of opioids may precipitate pulmonary insufficiency

64. 64 By causing vasomotor depression, they decrease the ability of circulation to respond to stress. They often delay the awakening as their clinical effect lasts for 4-6 hours Morphine may induce vomiting; besides it has an antidiuretic effect Morphine can interfere with pupillary actions Pethidine may produce tachycardia by its vagolytic actions Both these drugs are histamine liberators

65. II) Sedatives and tranquillizers 65 Benzodiazepines (diazepam, nitrazepam) are now preffered to barbiturates because of their safety, muscle relaxant property and less respiratory depression They also provide amnesia, diazepam in doses of 5 to 20 mg. has been most widely used. It is active orally and can also be given parenterally, though its action is less predictable by this route Other tranquillizer compounds used belong to phenothiazine and butyrophenone groups

66. III) Antiemetics 66 The commonly used phenothiazines such as promethazine and trimeprazine have antiemetic properties and thus may help to prevent the post-operative nausea and vomiting This advantage should, however, be weighed against the possible hypotension following these drugs Other drugs used are cyclizine, 50 mg., trimethobenzamide 200 mg and benzquinamide 25-50 mg

67. IV) Other drugs 67 In addition to above mentioned drugs, proper pre-evaluation and specific premedication is needed in patients with special problems such as chronic lung disease, emphysema, IHD, diabetes mellitus, hypertension, undernutrition and in debilitated and old people The risk of stopping long-term medication before surgery is often greater than the risk of continuing it during surgery This applies particularly to glucocorticoids, analgesics, antiparkinsonian drugs, anti-glaucoma drugs and thyroid or antithyroid drug

68. 68 On the other hand, it is advisable to discontinue combined oral contraceptive pills 4 weeks before major surgery; MAOI’s 2 weeks before surgery and lithium 2 days before surgery

69. History of Anaesthetics ► Priestley discovered the first inhalation anaesthetic , nitrous oxide , in 1776 and accurately described the sensations following its inhalation ► It was used for the first time in 1884 by Horace Wells, a dentist in Hartford, USA, for painless extraction of a tooth ► Morton , in 1846 , successfully showed the use of ether as a general anaesthetic in the first classic demonstration held in the operating room of the Massachusetts General Hospital, Boston, USA

70. 2/15/2008 70 What is anaesthesia? The term anaesthesia means which produces reversible loss of all sensation and consciousness . Anesthesia controls pain during surgery or other medical procedures. It includes using medicines, and sometimes close monitoring, to keep patient comfortable It can also help control breathing, blood pressure, blood flow, heart rate and rhythm, when needed

71. 2/15/2008 71 Types of anesthesia 1) Local anesthesia : Numbs a small part of the body. Patient get a shot of local anesthetic directly into the surgical area to block pain. It is used only for minor procedures Patient may stay awake during the procedure, or you may get medicine to help you relax or sleep Abolish the pain sensation in localized areas without affecting the degree of consciousness

72. 3) General anesthesia : ► Affects the brain as well as the entire body. Patient may get it through a vein (intravenously) or may breathe it in. ► With general anesthesia, patient are completely unaware and do not feel pain during the surgery (loss of all modalities of sensation) ► General anesthesia also often causes to forget the surgery and the time right after it (reversible loss of consciousness)

73. 2) Regional anesthesia : ► Blocks pain to a larger part of patient body. Anesthetic is injected around major nerves or the spinal cord. Patient may get medicine to help relax or sleep. Major types of regional anesthesia include: Peripheral nerve blocks: ► A nerve block is a shot of anesthetic near a specific nerve or group of nerves. It blocks pain in the part of the body supplied by the nerve. Nerve blocks are most often used for procedures on the hands, arms, feet, legs or face Epidural and spinal anesthesia: ► This is a shot of anesthetic near the spinal cord and the nerves that connect to it. It blocks pain from an entire region of the body, such as the belly, hips or legs 2/15/2008 73

74. Local Anaesthetics 18/03/2019 74 Local aesthetics (LAs) are drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain, in a restricted area of the body. They block generation and conduction of nerve impulse at all parts of the neurone where they come in contact without causing any structural damage. Thus not only sensory but also motor impulses are interrupted when a LA is applied to a mixed nerve, resulting in muscular paralysis and loss of autotonomic control as well.

75. 2/15/2008 75 General Anaesthetic Local Anaesthetic Site of action CNS Peripheral nerves Area of body involve Whole body Restricted area Consciousness Lost Restricted Care of vital function Essential Usually not needed Physiological trespass. High Low Poor health patient Risky Safer Use in Non-cooperative patient Possible Not Possible Major surgery Preferred Cannot be used Minor surgery Not preferred Preferred

76. Chemistry of LA 2/15/2008 76 The clinically useful LAs are weak bases with amphiphilic property. A hydrophilic secondary or tertiary amine on one side and a lipophilic aromatic residue on the other are joined by an alkyl chain through an ester or amide linkage . Produce more intense and longer lasting anaesthesia •Features of amide over esters Bind to α1 acid glycoprotein in plasma • Not hydrolysed by plasma esterases • Rarely cause hypersensitivity reactions; No cross sensitivity with ester LAs

77. Classification of LA 77 Injectable anaesthetics: Low potency, short duration: Procaine, Chloroprocaine Intermediate potency and duration: Lidocaine ( Lignocaine ) Prilocaine . High potency, long duration: Tetracaine , ( Amethocaine ) , Bupivacaine , Ropivacaine , Dibucaine ( Cinchocaine )

78. 2/15/2008 78 Surface Anaesthetics: Soluble: Cocaine, Lidocaine , Tetracaine , Benoxinate . Insoluble: Benzocaine , Butylaminobenzoate ( Butamben ), Oxethazaine Ester- linked LAs Cocaine , procaine , chloroprocaine , tetracaine , benzocaine . Amide-linked LAs Lidocaine , bupivacaine, dibucaine , prilocaine , ropivacaine .

79. MECHANISM OF ACTION 2/15/2008 79 The LAs block nerve conduction by decreasing the entry of Na+ ions during upstroke of action potential (AP). As the concentration of the LA is increased, the rate of rise of AP and maximum depolarization decrease, causing slowing of conduction. Finally, local depolarization fails to reach the threshold potential and conduction block ensues The LAs interact with a receptor situated within the voltage sensitive Na+ channel and raised the threshold of channel opening. Na + permeability fails to increase in response to an impulse or stimulus.

80. 2/15/2008 80 The predominant active species (Cationic form of LA) is able to approach to its receptor only when the channel is open at the inner surface and its bind more avidly to the inactive stat of the channel prolonging the inactive state. The channel take longer time to recover  refractory period of the fibre increased

81. 2/15/2008 81 Resting nerve is rather resistance to blockade and blockade developed rapidly when nerve is stimulating. The onset of blockade is related primarily to pKa of LA. Those with lower pKa (7.6-7.8) e.g. Lidocaine , Mapivacaine are fast acting Procaine , Tetracaine , bupivacaine hav pKa ( 8.1-8.9) are slow acting.

82. LOCAL ACTIONS 25/2008 82 The clinically used LAs have no/minimal local irritant action and block sensory nerve endings, nerve trunks, neuromuscular junction, ganglionic synapse and receptors (non-selectively),i.e. structures which function through increased Na+ permeability. They also reduce release of acetylcholine from motor nerve endings. Injected around a mixed nerve they cause anaesthesia of skin and paralysis of the voluntary muscle supplied by that nerve. Autonomic fibres are generally more susceptible than somatic fibres. Among the somatic afferents order of blockade is: pain-temperature sense-touch-deep pressure sense

83. 2/15/2008 83 In general, fibres that are more susceptible to LA are the first to be blocked and the last to recover. The differential arrangement of various types of sensory and motor fibres in a mixed nerve may partly account for the differential blockade. Motor fibres are usually present circumferentially; may be blocked earlier than sensory fiber in the core of nerve.

84. SYSTEMIC ACTIONS 84 C.N.S.: All LAs are capable of producing a sequence of stimulation followed by depression. Cocaine is powerful CNS stimulant causing in sequence euphoria- excitement-mental confusion- restlessness- tremor –twitching of muscles – convulsion –unconsciousness- respiratory depression and death. Procaine are much less potent in this regard. At safe clinical doses, they produce little apparent CNS effects. Lidocaine on contrary can initially cause drowsiness and lethargy, but on higher doses produce excitation followed by depression. The basic action of all LAs is neuronal inhibition, the apparent stimulation seen initially due to inhibition of inhibitory neurones

85. 2/15/2008 85 CVS:  LAs are cardiac depressants, but no significant effect are observed at conventional doses. At high doses or on inadvertent i.v injection they decrease automaticity, excitability, contractility and conductivity, and increase in ERP. They have quinidine like antiarrhythemic action. Procaine is not used in arrhythmia because of short duration of action. Amide derivative of procaine i.e. Procainamide is a potent antiarrhythemic. Bupivacaine is more cardiotoxic as it produces ventricular tachycardia and fibrillation.

86. 2/15/2008 86 Blood Vessels: LAs tend to produce fall in BP. This is primarily due to sympathetic blockade. But high dose due cause direct relaxation of arterial smooth muscle. Bupivacaine is more vasodilatory than lidocaine. Toxic dose of LA may cause cardiovascular collapse.

87. PHARMACOKINETICS 2 5/2008 87 Soluble surface anaesthetics ( Lidocaine , tetracaine ) are rapidly absorbed from mucous membranes and abraded areas, but absorption from intact skin is poor. Procaine does not significantly penetrate mucous membranes. Rate of absorption depends on the blood flow to the area of application or injection. The absorbed LA being lipophilic is widely distributed; rapidly enters highly perfused brain, heart, liver, and kidney, followed by muscle and other viscera. Procaine is negligibly bound to plasma proteins, but amide LAs are bound to plasma α 1 acid glycoprotein.

88. 2/15/2008 88 Ester-linked LAs (procaine, etc.) are rapidly hydrolysed by plasma pseudocholinesterase and the remaining by esterases in the liver. Amide-linked LAs ( Iidocaine , etc.) are degraded only in the liver microsomes by dealkylation and hydrolysis. The maximal safe dose of LAs is lower in patients with hepatic disease and in the elderly who have decreased liver function. After oral ingestion both procaine and lidocaine have high first pass metabolism in the liver. Thus, they are not active orally for antiarrhythmic purposes

89. ADVERSE EFFECTS 2/15/2008 89 Systemic toxicity on rapid i.v . injection is related to the intrinsic anaesthetic potency of the LA. CNS effects are light-headedness, dizziness, auditory and visual disturbances, mental confusion, disorientation, shivering, twitchings , involuntary movements, finally convulsions and respiratory arrest. This can be prevented and treated by diazepam. Cardiovascular toxicity of LAs is manifested as bradycardia , hypotension, cardiac arrhythmias and vascular collapse. Inlection of LAs may be painful, but local tissue toxicity of LAs is low. Bupivacaine has the highest local tissue irritancy. Hypersensitivity reactions like rashes, angioedema , dermatitis, contact sensitization, asthma and rarely anaphylaxis occur. These are more common with ester-linked LAs, but rare with lidocaine or its congener