General & Local Anesthesia PDF

General Anesthesia  General anesthesia  History  Alcohol and opium  Strong men to hold the patient down and a fast surgeon( surgeon were noted for their speed). Most surgeries were amputations  March 30th,1842: Crawford Long of Jefferson used Ether for a surgical procedure...

General Anesthesia  General anesthesia  History  Alcohol and opium  Strong men to hold the patient down and a fast surgeon( surgeon were noted for their speed). Most surgeries were amputations  March 30th,1842: Crawford Long of Jefferson used Ether for a surgical procedure on James Venable.  1846: William Morton performs a public demonstration of ether at Mass. General Hospital  General anesthesia  History  1845: Horace Wells demonstrates Nitrous Oxide in Boston. The patient cried out and it was deemed a failure.  1847: James Simpson in Scotland used chloroform in child birth. Chloroform is less irritating than Ether, has a sweet smell and non-flammable,however it causes hepatotoxicity and causes cardiovascular depression.  1863 Gardner Colton reintroduces Nitrous oxide to dental and surgical practice  1868 Nitrous oxide and oxygen used together  General anesthesia  History  1929 Cyclopropane( found as a contaminate in Propylene) was introduced, used for 30 years but as more electrical equipment was used in surgery and electrocautery became common something else was needed that was not flammable  1956 Halothane was synthesized, a Fluorinated hydrocarbon.  General anesthesia  Mechanism of action for the volatile anesthetics  Meyer-Overton theory Suggested in the 1900’s  The potency of the anesthetics was directly related to its lipid solubility or oil/gas partition coefficient  Compounds with higher lipid solubility required low concentrations to produce anesthesia  Later it was postulated that the compounds dissolved in the lipid portion of the membrane which caused the membrane to swell and this caused distortion of the ion channels which reduced firing  However not all lipid soluble compounds can produce anesthesia  General anesthesia  Mechanism of action for the volatile anesthetics  Another strike against the Meyer-Overton theory is the finding that in volatile anesthetics with a chiral center, one isomer is more potent than the other.  This means that the mechanism is more complex than just lipid solubility  More recently it has been demonstrated that volatile anesthetics interact with protein receptors. It appears that these compounds are allosteric modulators of ion channels such as chloride and potassium channels and may interact directly with sodium channels General anesthesia Compound MAC MACawake Blood/gas Blood/ PC Brain PC Halothane 0.75 0.41 2.3 2.9 Isoflurane 1.2 0.4 1.4 2.6 Enflurane 1.6 0.4 1.8 1.4 Sevofluran 2 0.6 0.65 1.7 e Desflurane 6 2.4 0.45 1.3  General anesthesia  Halothane B.P. 50.2  Not chemical stable to Soda Lime which is used to remove Carbon dioxide in re-breathers  Sweet Odor  Rapid Onset and recovery  About 20% metabolized Increased hepatotoxicity compared to newer agents  Can cause arrhythmias  General anesthesia  Enflurane B.P. 56.5  Chemically stable to soda lime  Mild sweet odor  Less Nausea and vomiting, arrhythmias and post-operative shivering than halothane  2% metabolized  Relaxation of uterus seen ( not used in labor)  General anesthesia  Isoflurane B.P. 48.5  Chemically stable to soda lime  Positional Isomer of Enflurane  Less cardiovascular problem than enflurane  More pungent odor, irritating to throat and respiratory tract  Generally used to maintain rather than induce  0.2 % metabolized  General anesthesia  Desflurane B.P. 23.5  Chemically stable to soda lime  Pungent odor, pre-induction with short acting agent  Induction and recovery rapid due to low blood solubility  0.02% metabolized  Good for outpatient surgery, Patient is “street ready” faster  General anesthesia  Sevoflurane ( 7 fluorine atoms)  B.P. 58.5  Unstable to soda lime. Exothermic reaction can occur causing burns to the patients airway  Similar to desflurane, but sweet odor and it is not irritating to airways  Low blood solubility gives rapid induction and recovery  Good for outpatient surgery  General anesthesia  Barbiturates Thiopental, Thiamyal, Methohexital  pKa is at or higher that pH of blood. 50% or greater in unionized form rapid entry into the Brain  Recovery from anesthesia is due to redistribution not metabolism  Side effect: decreased cerebral oxygen consumption( used in cerebral ischemia) Decreased blood pressure, respiratory depressant decreased rate and decreased response to CO2 levels used with opiates apnea can occur  General anesthesia  Barbiturates Thiopental, Thiamyal, Methohexital  Mechanism is by modulation of GABA receptor barbiturates bind to the beta subunit and make GABA work better.  Solution are fairly basic cause a warming sensation was they flow in.  General anesthesia  Propofol  Mostly commonly used IV anesthetic  Formulated as an emulsion( very low water solubility)  Bacterial contamination has been a problem with opened containers. Once opened it should be used or discarded after 6 hours.  Mechanism involves interaction with GABA receptors increasing their sensitive to GABA.  General anesthesia  Propofol  Fast induction 40 second which the time it takes to go from the arm to the brain  Recovery is through redistribution like barbiturates. Less hangover than barbiturates due to faster blood tissue distribution and elimination  Dose dependent decrease in blood pressure  Slightly greater respiratory depression compared to barbiturates  General anesthesia  Etomidate ( D-isomer)  Poorly water soluble  Formulate as 2 mg/mL (0.2%) solution in 35% propylene glycol  Used 1° in patients at risk for hypotension  Little change on blood pressure  Associated with pain on injection ( Lidocaine topical help)  Less respiratory depression than barbiturates and propofol  General anesthesia  Etomidate ( D-isomer)  Major drawbacks  Associated with nausea and vomiting  Inhibits adrenal enzymes needed to produce cortisol, which inhibits the adrenalcorticoid stress response. Not generally a problem on short term use.  General anesthesia  Ketamine  Structurally similar to phencyclidine (PCP)  Inhibits NMDA receptor by binding to the PCP binding site  The S-isomer is the most potent, used as the racemic mixture  Useful for patient at risk for hypotension and bronchospasms  Use in pediatric patients most often  Dependent on redistribution for recovery  General anesthesia  Ketamine  Special properties in that it produces profound analgesia, patient is unresponsive to commands and it produces amnesia. The patient may have their eyes open, move their limbs involuntarily and breathe spontaneously. This is termed dissociative anesthesia  The cataleptic state is accompanied by nystagmus, dilation of the pupils, salivation, lacrimation and spontaneous limb movements with an increased overall muscle tone  General anesthesia  Ketamine  Increases cerebral blood flow, increased intracranial pressure and increased intraocular pressure.  Increases blood pressure and heart rate by inhibition of catecholamine reuptake  Potent bronchodilator good for patients at risk for bronchospasms  Less respiratory depression than other agents  Emergence is associated with delirium, hallucinations vivid dreams, illusions. Generally in the first hour after emergence. Less frequent in children Local anesthetics Local Anesthetics  Local anesthesia is by definition , the loss of sensation or motor function in a local or circumscribed area. Compounds that produce local anesthesia are used for the temporary relief of localized pain in dentistry and minor surgical procedures as well as a state of non resistance in the case of spinal anesthesia.  Topical local anesthetic are use for the relief of pain and itching caused by minor burns, bites, allergic responses , hemorrhoids, and for procedures such as endoscopy,sigmoidoscopy, intubation, etc. Local Anesthetics  Local anesthetics block conduction by decreasing or preventing the influx of sodium during the propagation of an action potential. Their action is due to a direct interaction with the voltage gated Na+ channels  It has been found that the site of interaction is on the inside side surface of the membrane  Lipophilicity, that is the ability of these compounds to cross the membrane is an important factor in the potency and duration of action of these compounds Local Anesthetics  The first local anesthetic and the lead compound for all ester type compounds that are in current use is cocaine, a natural product derived for the coca bush. Local Anesthetics:Benzoic acid type SAR  The Aryl Group  Direct attachment to the sp2 carbon is the best ( most active)  electron donating group(such as RO, NH2, RNH) at the ortho and para position increase activity by decreasing the + on the sp2 carbon. Local Anesthetics:Benzoic acid type SAR  Decreasing the + on the carbonyl decreases the ease of hydrolysis and increases duration of action  Increasing the + on the carbonyl increases the ease of hydrolysis and decreases the duration of action Local Anesthetics:Benzoic acid type SAR  X Bridge  May be C, O, N, S  the order of Activity is S > O > C > N  S, sulfur analogues are the most potent but they tend to cause dermatitis and are not used.  C and N analogues have the longest duration of action due to resistance to hydrolysis but are less potent. Local Anesthetics:Benzoic acid type SAR  Amino alkyl chain  the amino group is not really necessary for activity but it aids in the formation of water soluble salts for injection  3˚ amines more potent  2˚ amines are longer acting but tend to be more irritating  1˚ amines not very active and are very irritating Local Anesthetics:Benzoic acid ester type  Cocaine  Used by topical application only, 1-4% concentration dependent on the area to be anesthetized.  Due to its abuse potential and chance for diversion. Its use has decreased, however it still is used in surgical procedures of the head and neck.  It was once extensively used in ophthalmology but due to problem with corneal sloughing it has fallen out of favor. Local Anesthetics:Benzoic acid ester type  Cocaine has an advantage over other newer local anesthetic in that it cause vasoconstriction in the area thus prolonging its duration of action.  This property is due to 2 blockade which increases NE concentration in the synapse and increases the vascular tone.  This 2 blockade is the mechanism by which cocaine cause the CNS stimulation which is focus of cocaine abuse. Local Anesthetics:Benzoic acid ester type  Other local anesthetic are sometimes used with epinephrine to mimic this vasoconstrictive property of cocaine.  Cocaine should never be used with epinephrine due the possibility of additive increases in blood pressure and heart rate which could lead to the death of the patient. Local Anesthetics:Benzoic acid ester type  Hexylcaine  Topical use on the skin but tends to be irritating to mucus membranes such as the eye.  Note: Secondary amines See SAR  May also be used for nerve block and spinal anesthesia Local Anesthetics:PABA ester type  Benzocaine  Used topically only, not effective on intact skin but effective on mucous membranes and injured skin. For minor burns, hemorrhoids, severe sunburn, psoriasis, pruritus.  Cannot be used by injection because of insolubility in water.  the NH2 is a weak base therefore strongly acidic solution would be required for salt formation.  Possible allergic response due to p-aminobenzoic acid (PABA) some individuals become sensitive and this sensitivity carries over to other local anesthetic which contain the PABA functionality. Local Anesthetics:PABA ester type  Procaine, Novocain®  Used by injection only not effective topically due to high polarity  1˚ in dental practice  Onset: slow, Duration of action : short  Can be co-administered with epinephrine to increase duration by causing vasoconstriction which decreases blood flow in area and decreases the diffusion of the compound from the site of injection. Local Anesthetics:PABA ester type  Choroprocaine, Nesacaine®  Ortho chloro analogue of procaine  more lipophilic not as water soluble  Onset: fast ( due to lipophilic character) duration : short (rapid hydrolysis due to EWG, Cl)  Ester hydrolysis is 4X faster than procaine  Safest for systemic use due to this rapid hydrolysis Local Anesthetics:PABA ester type  Tetracaine, Pontocaine®  More lipophilic than Chlorprocaine due to n- butyl group on aromatic amine  Onset : fast Duration : long 8-10X more potent, 2-3X longer duration of action than procaine  nBuNH in para position donates electrons to carbonyl decreasing the rate of hydrolysis and increasing duration of action.  Injection and topical some systemic toxicity due to slow rate of hydrolysis Local Anesthetics:PABA ester type  Proparacaine Alcaine®, Ophthaine®  Used topically only 1˚ for eye  m-NH2 makes it too toxic for systemic use Local Anesthetics: non-PABA  Dibucaine Nupercainal®, Nupercaine®  Topical: 15-20X more potent than procaine  Injection: most potent of all long acting locals  Amide is resistant to hydrolysis  Can cause transient liver abnormalities  This compound can be considered a member of the ester type or it may also be considered a member of the Lidocaine type of compounds Local Anesthetics: Lidocaine type  History  A compound called isogramine was the lead compound for this series of analogues  Found in a reed that Camels would not eat. Local Anesthetics: Lidocaine type SAR 6 2  The Aryl Group  Aryl group attached to the sp 2 must be though a NH bridge  2 and 2,6 methyl groups increase activity. Local Anesthetics: Lidocaine type SAR 6 2  The X Substitution  X may be O or C Local Anesthetics: Lidocaine type SAR 6 2  The Amino alkyl Chain  Attached directly to sp2 carbon  the amino group is not really necessary for activity but it aids in the formation of water soluble salts for injection  3˚ amines more potent  2˚ amines are longer acting but tend to be more irritating  1˚ amines not very active and are very irritating Local Anesthetics: Lidocaine type  Lidocaine, Xylocaine®  Free base: topical use skin only  Salt: topical ( ear, nose throat) and Injection  2X more potent than procaine  Longer duration of action due to decreased rate of hydrolysis a little more toxic than procaine  can be used in those who are sensitive to PABA  Little metabolism in plasma 1˚ in liver Local Anesthetics: Lidocaine type  Individual who are genetically deficient in choline esterase or who have been exposed to cholinesterase inhibitors may have toxic reaction to the ester type local anesthetics. Amide type may be used Local Anesthetics: Lidocaine type  Patients with liver disease should not receive amide type, ester type is preferred  Lidocaine is also used in the treatment of arrhythmias the mechanism of action is basically the same as for local anesthesia in the the compound decreases conduction of the nerve but in this cases in the heart. Local Anesthetics: Lidocaine type  Etidocaine Duranest®  Similar to Lidocaine, greater potency and duration of action due to increased lipophilic nature  Uses same as for Lidocaine as local anesthetic Local Anesthetics: Lidocaine type  Mepivacaine, Carboacaine®, Arestocaine®  Injection  Potency same as Lidocaine  Slightly longer duration  Primarily used for Epidural Local Anesthetics: Lidocaine type  Bupivacaine, Duocaine®, Marcaine®  Long duration of action 2-3X that of Lidocaine  potency 6X that of Procaine  Produces a motor nerve blockade which is useful in some cases.  Good for Epidurals preferred for abdominal surgery Local Anesthetics: Lidocaine type  Prilocaine, Citanest®  Duration of action intermediate between Lidocaine and mepivacaine  Injection use primarily for infiltration tends to be irritating  Also topically dentistry Local Anesthetics: Lidocaine type  Can cause methemoglobinemia due to the oxidation of 2 methyl aniline produce from metabolism to 2-methyl nitroso benzene which oxidizes the Fe++ in hemoglobin to Fe+++ this form can not carry O2.  The 2,6 dimethyl aniline of compounds such as Lidocaine are resistant to such oxidations Local Anesthetics: miscellaneous  Pramoxine: an ether type  Topical for throat, hemorrhoids, skin  Too irritating for nose, eye, or injection  Used in sigmoidoscopy, endotracheal intubation, does not abolish the gag reflex. Local Anesthetics: miscellaneous  Dyclonine a ketone type  Too irritating for injection  used topically for throat, rectum and skin as pramoxine was.  Sore Throat Lozenges Local Anesthetics:  Toxic Side Effects  The toxic side effect of all compounds are CNS and Cardiovascular  CNS reaction include excitatory and/or depressant and may be characterized by nervousness, dizziness, blurred vision, tremors, followed by drowsiness, merging into unconsciousness and respiratory depression.  Cardiovascular reactions are depressant , characterized by hypotension myocardial depression bradycardia and possibly cardiac arrest.