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"First Operation Under Ether“ In 1846 On October 16 William T. G. Morton 1819-1868-First in the world to publicly and successfully demonstrate the use of ether anesthesia for surgery.

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In the practice of medicine especially surgery and dentistry anesthesia or anaesthesia is a temporary induced state with one or more of analgesia relief from or prevention of pain paralysis muscle relaxation amnesia loss of memory and unconsciousness.

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Surgical Procedures Prior to Anesthesia

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History of Anesthesia • Joseph Priestly – discovers N2O in 1773 • Sir Humphrey Davy – experimented with N2O reported loss of pain euphoria • 1842 Crawford Long – First used ether. Did not publicize. Tried to claim credit after Morton’s demonstration but… • Important lesson learned – if you don’t publish it it didn’t happen. • 1846 William Morton dentist – Diethyl Ether – First demonstration of successful surgical anesthesia • 1847 James Simpson – Chloroform • 1930s Intravenous Barbiturates • 1940s d-Tubocurarine to induce skeletal muscle relaxation • 1956 Halothane halogenated hydrocarbon • 1981 Isoflurane currently most popular

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Classification Of Anesthetics

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GENERAL ANESTHETICS General anesthetics depress the central nervous system to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures. Not surprisingly general anesthetics have low therapeutic indices and thus require great care in administration. An ideal anesthetic drug would induce loss of consciousness smoothly and rapidly while allowing for prompt recovery of cognitive function after its administration is discontinued. The drug would also possess a wide margin of safety and be devoid of adverse effects.

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No single anesthetic agent is capable of achieving all of these desirable effects without some disadvantages when used alone. The modern practice of anesthesiology most commonly involves the use of combinations of intravenous and inhaled drugs taking advantage of their individual favorable properties while minimizing their adverse reactions

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STAGES OF ANESTHESIA The traditional description of the stages of anesthesia the so- called Guedels signs were derived from observations of the effects of diethyl ether which has a slow onset of central action owing to its high solubility in blood. Using these signs anesthetic drug effects can be divided into four stages of increasing depth of central nervous system depression: I. Stage of analgesia: The patient initially experiences analgesia without amnesia. Later in Stage I both analgesia and amnesia are produced. II. Stage of excitement: During this stage the patient often appears to be delirious and may vocalize but is definitely amnesic.

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Respiration is irregular both in volume and rate and retching and vomiting may occur if the patient is stimulated. For these reasons efforts are made to limit the duration and severity of this stage which ends with the reestablishment of regular breathing. III. Stage of surgical anesthesia: This stage begins with the recurrence of regular respiration and extends to complete cessation of spontaneous respiration apnea. Four planes of stage III have been described in terms of changes in ocular movements eye reflexes and pupil size which under specified conditions may represent signs of increasing depth of anesthesia. IV. Stage of medullary depression: This deep stage of anesthesia includes severe depression of the vasomotor center in the medulla as well as the respiratory center. Without circulatory and respiratory support death rapidly ensues.

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TYPES OF GENERAL ANESTHESIA  Intravenous Anesthetics Several drugs are administered intravenously alone or in combination with other anesthetic drugs to achieve an anesthetic state or to sedate patients in intensive care units ICUs who must be mechanically ventilated. These drugs include the following: 1 barbiturates eg thiopental methohexital 2 benzodiazepines eg midazolam diazepam 3 propofol

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1. ketamine 2. opioid analgesics morphine fentanyl sufentanil alfentanil remifentanil and 3. miscellaneous sedative-hypnotics eg etomidate dexmedetomidine. Inhaled Anesthetics The most commonly used inhaled anesthetics are halothane isoflurane desflurane and sevoflurane. These compounds are volatile liquids. Nitrous oxide a gas at ambient temperature and pressure continues to be an important adjuvant to the volatile agents.

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Few Terms BalancedAnesthesia Although general anesthesia can be produced using only intravenous or only inhaled anesthetic drugs modern anesthesia typically involves a combination of intravenous eg for induction of anesthesia and inhaled eg for maintenance of anesthesia drugs. Muscle relaxants are commonly used to facilitate tracheal intubation and optimize surgical conditions. Local anesthetics are often administered by tissue infiltration and peripheral nerve blocks to provide perioperative analgesia. In addition potent opioid analgesics and cardiovascular drugs eg b blockers a 2 agonists calcium channel blockers are used to control autonomic responses to noxious painful surgical stimuli. Basal anesthesia may mean simple induction anesthesia with prompt recourse to inhalation or regional anesthesia as soon as the patient has become unconscious.

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Minimum Alveolar Concentration MAC  Concentration i.e the of an alveolar gas mixture that results in immobility in 50 of patients when exposed to a noxious stimulus such as a surgical incision Analogous to ED50  A measure of relative potency and standard for experimental studies  Anesthetic dosage is expressed in multiples of MAC  MAC values for different agents are additive 0.7 MAC N2 + 0.6 MAC halothane 1.3 MAC total  MAC can exceed 100 for weak anesthetics like N2O

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Some functions of adjuncts to anesthesia Components of balanced anesthesia.

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INHALATION ANESTHETICS Pharmacokinetics · Absorption: - Mechanism: diffusion across the alveolar membrane driven by the concentration gradient - Speed: rapid due to large alveolar surface short diffusion distance and large blood flow · Distribution from the blood to tissues including the brain: Mechanism: diffusion an equilibrative process Speed: depends on the degree of lipid solubility of the anesthetic: - Less lipophilic drugs e.g. desflurane are less dissolved in blood lipids ® less retained in the blood ® equilibrate rapidly between the blood and tissues including the brain ® the anesthetic concentration in the brain is rapidly reached ® rapid induction of anesthesia at 1.3 MAC More lipophilic drugs e.g. halothane are more dissolved in blood lipids ® more retained in the blood

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® equilibrate slowly between the blood and tissues including the brain ® the anesthetic concentration in the brain is slowly reached ® slow induction of anesthesia at 1.3 MAC However one may facilitate induction by: - transiently increasing the inhaled conc. of the anesthetic - increasing the minute ventilation by hyperventilation · Elimination: - Mechanism: largely by exhalation halothane is also eliminated by biotransformation 20-40 forms a reactive metabolite - Speed of elimination determines the speed of recovery from anesthesia after GA inhalation is stopped: slow for highly lipophilic anesthetics as they are retained the brain and adipose tissue rapid for less lipophilic anesthetics as they are less retained the brain and adipose tissue

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Pharmacodynamic Theories About the Mechanisms of Anesthesia Lipid Theory: based on the fact that anesthetic action is correlated with the oil/gas coefficients. • The higher the solubility of anesthetics is in oil the greater is the anesthetic potency. • Meyer and Overton Correlations Protein Receptor Theory: based on the fact that anesthetic potency is correlated with the ability of anesthetics to inhibit enzymes activity of a pure soluble protein. Also attempts to explain the GABA A receptor is a potential target of anesthetics acton. 3. Binding theory: – Anesthetics bind to hydrophobic portion of the ion channel

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• All anesthetics appear to shut off the brain from external stimuli. One way they can do this is by altering the chemistry of the synapes. Which are the gaps between nerve cells. • Chemicals called neurotransmitters normally act as MESSAGERS crossing the synapse to relay a nerve signal. Other brain chemicals in particular once called GABA tend to shut off the signal. Many anesthetics appear to block the excitatory neurotransmitters or enhance the natural effect of GABA. • Yet precisely how they do this remains unclear

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Mechanism of Action of General Anesthetics katzung  Primary molecular target of general anesthetics is the GABA A receptor-chloride channel a major mediator of inhibitory synaptic transmission. Inhaled anesthetics barbiturates benzodiazepines etomidate and propofol facilitate GABA- mediated inhibition at GABA A receptor sites.  Both inhaled and intravenous anesthetics with sedative- hypnotic properties directly activate GABA A receptors but at low concentrations they can also facilitate the action of GABA to increase chloride ion flux.  Ketamine does not produce its effects via facilitation of GABA A receptor functions but it may function via antagonism of the action of the excitatory neurotransmitter glutamic acid on the N- methyl-D-aspartate NMDA receptor. This receptor may also be a target for nitrous oxide.

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In addition to their action on GABA A chloride channels certain general anesthetics have been reported to cause membrane hyperpolarization ie an inhibitory action via their activation of potassium channels. These channels are ubiquitous in the central nervous system and some are linked to neurotransmitters including acetylcholine dopamine norepinephrine and serotonin. Electrophysiologic analyses of membrane ion flux in cultured cells have shown that inhaled anesthetics decrease the duration of opening of nicotinic receptor-activated cation channels¾an action that decreases the excitatory effects of acetylcholine at cholinergic synapses.

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Most inhaled anesthetics inhibit nicotinic acetylcholine receptor isoforms particularly those containing the a 4 subunit though such actions do not appear to be involved in their immobilizing actions. The strychnine-sensitive glycine receptor is another ligand-gated ion channel that may function as a target for inhaled anesthetics which can elicit channel opening directly and independently of their facilitatory effects on neurotransmitter binding.

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Clinical Use of Inhaled Anesthetics V olatile anesthetics are rarely used as the sole agents for both induction and maintenance of anesthesia. Most commonly they are combined with intravenous agents as part of a balanced anesthesia technique. Of the inhaled anesthetics nitrous oxide desflurane sevoflurane and isoflurane are the most commonly used in the USA. Use of less soluble volatile anesthetics especially desflurane and sevoflurane has increased during the last decade as more surgical procedures are performed on an ambulatory "short-stay" basis. The low blood:gas coefficients of desflurane and sevoflurane afford a more rapid recovery and fewer postoperative adverse effects than halothane enflurane and isoflurane.

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Although halothane is still used in pediatric anesthesia sevoflurane is rapidly replacing halothane in this setting. As indicated previously nitrous oxide lacks sufficient potency to produce surgical anesthesia by itself and therefore is used with volatile or intravenous anesthetics to produce a state of balanced general anesthesia. Despite the obvious advantages of the less soluble inhaled anesthetics there is reason to believe that better ones might be developed

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Toxicity Of Inhaled anesthetics A. HEPATOTOXICITY HALOTHANE The mechanisms underlying hepatotoxicity from halothane remain unclear but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage eg free radicals or initiate immune- mediated responses. B. NEPHROTOXICITY Metabolism of methoxyflurane enflurane and sevoflurane leads to the formation of fluoride ions and this has raised questions concerning the nephrotoxicity of these three volatile anesthetics.

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C.MALIGNANT HYPERTHERMIA Malignant hyperthermia is an autosomal dominant genetic disorder of skeletal muscle that occurs in susceptible individuals undergoing general anesthesia with volatile agents and muscle relaxants eg succinylcholine. The malignant hyperthermia syndrome consists of the rapid onset of tachycardia and hypertension severe muscle rigidity hyperthermia hyperkalemia and acid-base imbalance with acidosis that follows exposure to a triggering agent see Loading . Malignant hyperthermia is a rare but important cause of anesthetic morbidity and mortality. The specific biochemical abnormality is an increase in free calcium concentration in skeletal muscle cells. Treatment includes administration of dantrolene to reduce calcium release from the sarcoplasmic reticulum and appropriate measures to reduce body temperature and restore electrolyte and acid-base balance.

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INTRAVENOUS ANESTHETICS BARBITURATES After an intravenous bolus injection thiopental rapidly crosses the blood-brain barrier and if given in sufficient dosage produces loss of consciousness hypnosis in one circulation time. Similar effects occur with the shorter-acting barbiturate methohexital. With both of these barbiturates plasma:brain equilibrium occurs rapidly 1 minute because of their high lipid solubility. Thiopental rapidly diffuses out of the brain and other highly vascular tissues and is redistributed to muscle and fat . Because of this rapid removal from brain tissue a single dose of thiopental produces only a brief period of unconsciousness. Thiopental is metabolized at the rate of only 12-16 per hour in humans following a single dose and less than 1 of the administered dose of thiopental is excreted unchanged by the kidney.

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BENZODIAZEPINES Diazepam lorazepam and midazolam are used in anesthetic procedures. The primary indication is for premedication because of their sedative anxiolytic and amnestic properties and to control acute agitation. Diazepam and lorazepam are not water- soluble and their intravenous use necessitates nonaqueous vehicles which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. It is important that the drug becomes lipid- soluble at physiologic pH and can readily cross the blood-brain barrier to produce its central effects. Compared with the intravenous barbiturates benzodiazepines produce a slower onset of central nervous system depressant effects which reach a plateau at a depth of sedation that is inadequate for surgical anesthesia.

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Using large doses of benzodiazepines to achieve deep sedation prolongs the postanesthetic recovery period and can produce a high incidence of anterograde amnesia. Because it possesses sedative-anxiolytic properties and causes a high incidence of amnesia 50 midazolam is frequently administered intravenously before patients enter the operating room. Midazolam has a more rapid onset a shorter elimination half-life 2-4 hours and a steeper dose-response curve than do the other available benzodiazepines. The benzodiazepine antagonist flumazenil can be used to accelerate recovery when excessive doses of intravenous benzodiazepines are administered especially in elderly patients

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OPIOID ANALGESICS Large doses of opioid analgesics have been used in combination with large doses of benzodiazepines to achieve a general anesthetic state particularly in patients undergoing cardiac surgery or other major surgery when the patients circulatory reserve is limited. Although intravenous morphine 1-3 mg/kg was used many years ago the high- potency opioids fentanyl 100-150 mcg/kg and sufentanil 0.25-0.5 mcg/kg IV have been used more recently in such patients. More recently also remifentanil a potent and extremely short-acting opioid has been used to minimize residual ventilatory depression.

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PROPOFOL Propofol 26-diisopropylphenol has become the most popular intravenous anesthetic. Its rate of onset of action is similar to that of the intravenous barbiturates but recovery is more rapid and patients are able to ambulate earlier after general anesthesia. Propofol is used for both induction and maintenance of anesthesia as part of total intravenous or balanced anesthesia techniques and is the agent of choice for ambulatory surgery. The drug is also effective in producing prolonged sedation in patients in critical care settings Pain at the site of injection is the most common adverse effect of bolus administration. Muscle movements hypotonus and rarely tremors have also been reported after prolonged use

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. Use of propofol for the sedation of critically ill young children has led to severe acidosis in the presence of respiratory infections and to possible neurologic sequelae upon withdrawal. After intravenous administration of propofol the distribution half-life is 2-8 minutes and the redistribution half-life is approximately 30-60 minutes. The drug is rapidly metabolized in the liver at a rate ten times faster than thiopental. Propofol is excreted in the urine as glucuronide and sulfate conjugates with less than 1 of the parent drug excreted unchanged.

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KETAMINE • Ketamine is a racemic mixture of two optical isomers S+ and R- ketamine. The drug produces a dissociative anesthetic state characterized by catatonia amnesia and analgesia with or without loss of consciousness hypnosis • The drug is an arylcyclohexylamine chemically related to phencyclidine PCP a drug with a high abuse potential owing to its psychoactive properties. The mechanism of action of ketamine may involve blockade of the membrane effects of the excitatory neurotransmitter glutamic acid at the NMDA receptor subtype

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• use of low doses of ketamine in combination with other intravenous and inhaled anesthetics has become an increasingly popular alternative to opioid analgesics to minimize ventilatory depressiona • It is also used in low doses for outpatient anesthesia in combination with propofol and in children undergoing painful procedures eg dressing changes for burns  ENTONOX Mixture of nitrous oxide 50 oxygen 50 used to relieve pain during child birth.

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LOCAL ANESTHETICS Local anesthetic agents are drugs that when given either topically or administered directly into a localized area produce a state of local anesthesia by reversibly blocking nerve conductances that transmit the sensations of pain from this localized area to the brain. Unlike the anesthesia produced by general anesthetics the anesthesia produced by local anesthetics is without loss of consciousness or impairment of vital central cardiorespiratory functions.

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History Coca leaves have been chewed for their psychotropic effects for thousands of years by South American Indians who knew about the numbing effect they produced on the mouth and tongue. Cocaine was isolated in 1860 and proposed as a local anaesthetic for surgical procedures. Sigmund Freud who tried unsuccessfully to make use of its psychic energising power gave some cocaine to his ophthalmologist friend in Vienna Carl Köller who reported in 1884 that reversible corneal anaesthesia could be produced by dropping cocaine into the eye. The idea was rapidly taken up and within a few years cocaine anaesthesia was introduced into dentistry and general surgery. A synthetic substitute procaine was discovered in 1905 and many other useful compounds were later developed.

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Structure –Activity Relationships The smaller and more lipophilic the local anesthetic the faster the rate of interaction with the sodium channel receptor. Potency is also positively correlated with lipid solubility as long as the agent retains sufficient water solubility to diffuse to the site of action on the neuronal membrane. Lidocaine procaine and mepivacaine are more water-soluble than tetracaine bupivacaine and ropivacaine. The latter agents are more potent and have longer durations of local anesthetic action. These long-acting local anesthetics also bind more extensively to proteins and can be displaced from these binding sites by other protein-bound drugs. In the case of optically active agents eg bupivacaine the S+isomer can usually be shown to be moderately more potent than the R- isomer.

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Mechanism of Action Local anesthetics act at the cell membrane to prevent the generation and the conduction of nerve impulses. Conduction block can be demonstrated in squid giant axons from which the axoplasm has been removed. Local anesthetics block conduction by decreasing or preventing the large transient increase in the permeability of excitable membranes to Na + that normally is produced by a slight depolarization of the membrane. This action of local anesthetics is due to their direct interaction with voltage-gated Na + channels.

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As the anesthetic action progressively develops in a nerve the threshold for electrical excitability gradually increases the rate of rise of the action potential declines impulse conduction slows and the safety factor for conduction decreases. These factors decrease the probability of propagation of the action potential and nerve conduction eventually fails. Local anesthetics can bind to other membrane proteins. In particular they can block K + channels. However since the interaction of local anesthetics with K + channels requires higher concentrations of drug blockade of conduction is not accompanied by any large or consistent change in resting membrane potential.

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COCAINE Pharmacological Actions and Preparations. The clinically desired actions of cocaine are the blockade of nerve impulses as a consequence of its local anesthetic properties and local vasoconstriction secondary to inhibition of local norepinephrine reuptake. Toxicity and its potential for abuse have steadily decreased the clinical uses of cocaine. Its high toxicity is due to reduced catecholamine uptake in both the central and peripheral nervous systems. Its euphoric properties are due primarily to inhibition of catecholamine uptake particularly dopamine in the CNS. Currently cocaine is used primarily for topical anesthesia of the upper respiratory tract where its combination of both vasoconstrictor and local anesthetic properties provide anesthesia and shrinking of the mucosa. Cocaine hydrochloride is provided as a 1 4 or 10 solution for topical application. For most applications the 1 or 4 preparation is preferred to reduce toxicity.

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LIDOCAINE Pharmacological Actions. Lidocaine produces faster more intense longer lasting and more extensive anesthesia than does an equal concentration of procaine. Lidocaine is an alternative choice for individuals sensitive to ester-type local anesthetics. Absorption Fate and Excretion. Lidocaine is absorbed rapidly after parenteral administration and from the gastrointestinal and respiratory tracts. Although it is effective when used without any vasoconstrictor epinephrine decreases the rate of absorption such that the toxicity is decreased and the duration of action usually is prolonged.

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A lidocaine transdermal patch LIDODERM is used for relief of pain associated with postherpetic neuralgia. The combination of lidocaine 2.59 and prilocaine 2.5 in an occlusive dressing EMLA ANESTHETIC DISC is used as an anesthetic prior to venipuncture skin graft harvesting and infiltration of anesthetics into genitalia. Lidocaine is dealkylated in the liver by CYPs to monoethylglycine xylidide and glycine xylidide which can be metabolized further to monoethylglycine and xylidide. Both monoethylglycine xylidide and glycine xylidide retain local anesthetic activity. In humans about 75 of the xylidide is excreted in the urine as the further metabolite 4- hydroxy-2 6-dimethylaniline

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Toxicity The side effects of lidocaine seen with increasing dose include drowsiness tinnitus dysgeusia dizziness and twitching. As the dose increases seizures coma and respiratory depression and arrest will occur. Clinically significant cardiovascular depression usually occurs at serum lidocaine levels that produce marked CNS effects. The metabolites monoethylglycine xylidide and glycine xylidide may contribute to some of these side effects. Clinical Uses Lidocaine has a wide range of clinical uses as a local anesthetic it has utility in almost any application where a local anesthetic of intermediate duration is needed. Lidocaine also is used as an antiarrhythmic agent

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BUPIV ACAINE Pharmacological Actions. Bupivacaine is a widely used amide local anesthetic its structure is similar to that of lidocaine except that the amine-containing group is a butyl piperidine. Levobupivacaine CHIROCAINE the S- enantiomer of bupivacaine also is available. Bupivacaine is a potent agent capable of producing prolonged anesthesia. Its long duration of action plus its tendency to provide more sensory than motor block has made it a popular drug for providing prolonged analgesia during labor or the postoperative period. By taking advantage of indwelling catheters and continuous infusions bupivacaine can be used to provide several days of effective analgesia. Toxicity. Bupivacaine and etidocaine below are more cardiotoxic than equi-effective doses of lidocaine. Clinically this is manifested by severe ventricular arrhythmias and myocardial depression after inadvertent intravascular administration of large doses of bupivacaine.

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Benzocaine Benzocaine is an unusual local anaesthetic of very low solubility which is used as a dry powder to dress painful skin ulcers or as throat lozenges. The drug is slowly released and produces long-lasting surface anaesthesia. Most local anaesthetics have a direct vasodilator action which increases the rate at which they are absorbed into the systemic circulation thus increasing their potential toxicity and reducing their local anaesthetic action. Adrenaline epinephrine is often added to local anaesthetic solutions injected locally in order to cause vasoconstriction although care is needed to avoid adrenaline-induced cardiovascular changes.

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Assignment:  Differences between LA GA Enlist some marketed products of LA GA from QUIM

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References 1. Gilman A.G. Rall T.W. Nies A.S. and Taylor P. 1990. Goodman and Gilmans The pharmacological basis of therapeutics pp. 1-2. New York etc.: Pergamon press. 2. Rang H.P. Ritter J.M. Flower R.J. and Henderson G. 2014. Rang Dales Pharmacology: With student consult online access. Elsevier Health Sciences. 3. Katzung B.G. Masters S.B. and Trevor A.J. eds. 2004. Basic clinical pharmacology V ol. 8. New York NY USA:: Lange Medical Books/McGraw-Hill. 4. Howland R.D. Mycek M.J. Harvey R.A. and Champe P.C. 2006. Lippincotts illustrated reviews: Pharmacology pp. 159-171. Philadelphia: Lippincott Williams Wilkins.

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