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local anesthetics pharmacology
1. JJM MEDICAL COLLEGE DAVANGERE DEPARTMENT OF ANAESTHESIOLOGY SEMINAR ON PHARMACOLOGY OF LOCAL ANAESTHETICS CHAIRPERSON PRESENTED BY DR.RAVI.R DR.RAVIVARMA.D PROFFESSOR PG IN ANAESTHESIA DEPT OF ANAESTHESIA
19. Common framework of local anaesthetics 1. The aromatic ring gives the lipophillic character. 2. The tertiary amine is relatively hydrophilic. 3. The intermediate bond may Estericor Aminoamide.
34. Ionic currents in action potential genesis 1.what is resting membrane potential? 2. which ion maintains the RMP ? 3. what is the RMP of the nerve ? 4. what is all or none law ?
40. Electrophysiological effects 1. what do these terms mean ? 2. what is frequency dependent block ? 3. what is the reason for it ? Tonic inhibition Phasic inhibition
41. Understanding the sodium gates resting activated inactivated the upper gate is voltage dependent the lower gate is time dependent
42. Binding of local anaesthetics is increased by membrane depolarization for two reasons: 1 . More binding site becomes accessible during activation – The guarded receptor model 2. drug dissociation from the inactivated channels is slower than from the resting channel – The modulated receptor model
54. Other targets Inhibition of cardiac calcium channels: The inhibition of calcium channels in the cardiomyocytes has been proposed as an additional reason for the negative ionotropiceffect of local anaesthetics.
61. “Different fiber types are also differentially sensitive to local anesthetic blockade. In vivo experiments in which continuous superperfusion of peripheral nerve analogous to clinical peripheral nerve block, show unequivocally that small myelinated axons (Aγmotor and Aδ sensory fibers) are the most susceptible to impulse annihilation. Next in order of block are the large myelinated (Aα and Aβ) fibers, and the least susceptible are the small, nonmyelinated C fibers”
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63. summary 1. Solutions of local anesthetic are deposited near the nerve. Removal of free drug molecules away from this locus is a function of tissue binding, removal by the circulation, and local hydrolysis of aminoester anesthetics. 2. Local anesthetic molecules then permeate the nerve's axon membranes and reside there and in the axoplasm. The speed and extent of these processes depend on a particular drug's pKaand on the lipophilicity of its base and cation species.
64. 3. Binding of local anesthetic to sites on voltage-gated Na+ channels prevents opening of the channels by inhibiting the conformational changes that underlie channel activation. Local anesthetics bind in the channel's pore and also occlude the path of Na+ ions. 4. The clinically observed rates of onset and recovery from blockade are governed by the relatively slow diffusion of local anesthetic molecules into and out of the whole nerve, not by their much faster binding and dissociation from ion channels.
66. difference The ester and amide local anesthetics differ in their chemical stability, locus of biotransformation, and allergic potential.
67. Two exceptions to this trend include cocaine, an ester that is metabolized predominantly by hepatic carboxylesterase articaine, an amide local anesthetic widely used in dentistry that is inactivated by plasma carboxylesterase-induced cleavage of a methyl ester on the aromatic ring.
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69. Chloroprocaine has a rapid onset of action in humans despite the fact that its Pka is approximately 9 and its proportion of chargedmolecules is high (97 % ) why is that so ?
70. It is because chloroprocaine is used in large concentration ( 3 % ) due to its low toxicity.
78. Eg : Etidocaine is more potent than Bupivacainein isolated nerve but the same does not holds good in vivo, where Bupivacaine is slightly more potent.
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80. Bupivacaine is more popular than etidocaine(which is also long acting) because of the differential blockade property.
81. The older concept of fiber diameter based susceptibility to local anaesthetics is no longer valid for explaining the differential blockade. Why ?
82. Newer concepts: 1. The length of drug exposed nerve in the intrathecal space. 2. Selective ability to inhibit Na channels over K channels.
101. The use of catheter techniques for regional blocks has alleviated the need for anaesthetic mixtures. CAUTION: do not use the maximum doses of two local anaesthetics in combination in the mistaken belief that their toxicities are independent.
104. Hormonal alterations are probably the more important of these two factors because greater spread of epidural anesthesia occurs during the first trimester of pregnancy, before any gross change in vascular dimensions within the epidural or subarachnoid spaces.
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107. When large surface areas have to be anesthetized, large volumes of dilute anesthetic solutions should be used.
108. As an example, consider a 4-kg infant receiving infiltration anesthesia with the maximum safe dose of lidocaine, 5 mg/kg. Dosing to 5 mg/kg × 4 kg permits 20 mg, which is 1 mL of a 2% solution or 4 mL of a 0.5% solution.
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111. One might suppose a safety advantage with the aminoester-linked compounds because of their hydrolysis in blood; however, thrombophlebitis has been reported in several patients with chloroprocaine.
112. Cardiovascular collapse has occurred after the use of bupivacaine for intravenous regional anesthesia, and this use of bupivacaine is discouraged.
119. It is a eutectic mixture of 2.5% lidocaine base and 2.5%prilocaine base
120. It is widely used for venipuncture, intravenous cannulation, skin grafting, and a range of other uses, including circumcision.
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123. The ester, or procaine-like, drugs undergo hydrolysis in plasma by the pseudocholinesterase enzymes; clearance of chloroprocaineis especially rapid.
124. The aminoamide drugs undergo enzymatic degradation primarily in the liver. Lidocaine is metabolized somewhat more rapidly than mepivacaine, which in turn is more rapidly metabolized than bupivacaine.
129. In general CNS is more susceptible to actions of systemic local anaesthetics compared to that of CVS
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131. Objective signs are usually excitatory in nature like shivering, twitching particularly in face and distal parts of the extremities.
132. These can lead to development of generalized tonic clonicseizures.
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134. La dose and blood concentrations producing convulsion in sheep Rutten. AnesthAnalg 1989;69:291-9
135. The influence of acidosis Respiratory and metabolic acidosis increases the risk of CNS toxicity of LA by : 1. Enhancing the cerebral blood flow 2. Causing intracellular acidosis 3. Ion trapping 4. Decreased protein binding What is the clinical implication ?
136. Cardiovascular systemic toxicity Direct cardiac effects : 1. The primary effect is the decrease in the rate of depolarization in the fast conducting tissues of purkingefibres and ventricular muscle. 2. Bupivacaine depresses the rapid phase of depolarization to a greater extent than lidocaine 3. ECG shows an increase in PR interval and the duration of QRS complex 4. All LA exert a dose dependent negative ionotropicaction on cardiac muscle.
152. Usually occurs in high dermatomal levels of blockade, liberal use of sedatives, delays in recognition of the problem, delays in administration of direct acting combined alpha and beta agonists such as epinephrine
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154. More than 600 mg is required for the development of clinically significant levels of methemoglobinemia in adults
155. Hepatic metabolism of prilocaine generates O-toluidine , which oxidizes hemoglobin to methemoglobin
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157. Aminoesters may produce allergic reaction more commonly than amides but even with esters, vast majority of reactions are not allergic
160. A meta-analysis concluded that the pooled relative risk for transient neurologic symptoms after spinal anesthesia with lidocaine was 6.7-fold higher than with bupivacaine and 5.5-fold higher than with prilocaine
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162. In response to the problem of cardiovascular toxicity as a result of accidental intravenous injection of bupivacaine, single enantiomers were developed in the hope that they would be potentially safer local anesthetics.
164. Ropivacaine is a single (S)-stereoisomer that differs from levobupivacaine in the substitution of a propyl for the butyl group on the piperidine ring .
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166. The very slow reversal of Na+ channel blockade after a cardiac action potential, which is a hallmark of bupivacaine, is considerably faster with ropivacaine.
167. Overall, it appears that ropivacaine is slightly less potent than (1 : 1.3 to 1 : 1.5) bupivacaine for regional anesthesia.
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169. Liposomal encapsulation can prolong nerve blockade, depending on the dose and the physical properties of the liposome (surface charge, size, lamellar structure).
170. Local anesthetics can be incorporated into biodegradable polymer microspheres for sustained release. These preparations produce peripheral nerve blockade in animal models and human volunteers ranging from 2 to 8 days, depending on the dose, site, and species.
