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DRUGS USED FOR ANESTHESIA, MUSCLE RELAXATION A. Local anesthesia • As the name implies, local anesthetics are applied locally and function to block nerve conduction. 1. General information • The mechanism by which local anesthetics work is well known • Recall that the concentration of sodium ions is normally higher on the outside of neurons than on the inside. • A rapid flood of sodium ions into cells is necessary for neurons to fire and conduct an action potential. • Local anesthetics act by blocking sodium channels. • This blocking is nonselective, which means that both sensory and motor impulses are affected. • This blocking is brought about by the anesthetic reversibly binding to and inactivating sodium channels. • Sodium influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the course of the nerve. • When a nerve loses depolarization and capacity to propagate an impulse, the individual loses sensation in the area supplied by the nerve. • Example: An injectable local anesthetic which combines capsaicin with QX-314, a variation of lidocaine • All local anesthetics have an amine functional group, an aromatic ring, and either an ester or amide group linking them. • amine • aromatic ring • ester • amide • Therefore, all local anesthetics are classified as esters or amides. • This is important because the amides are chemically stable in vivo, whereas the esters are subject to hydrolysis. • In addition, the hydrolysis of an ester local anesthetic leads to the formation of PABA, which causes an allergic response in some individuals. • Local anesthetics may be administered topically (i.e. nasal mucosa); • through infiltration (injection into the dermis and soft tissues located near peripheral nerve endings); • and in/near the spinal cord (includes caudal block, epidural block, and spinal nerve block). • Which local anesthetic should be used generally depends on the duration of action of the procedure. • For short procedures, procaine would be recommended. • An intermediate duration of action is found with cocaine, lidocaine, and mepivacaine. • Long- acting local anesthetics include bupivacaine (and levobupivacaine), ropivacaine, and tetracaine. 2. Ester local anesthetics • Commonly used local anesthetics containing the ester functional group are benzocaine, cocaine, procaine, and tetracaine. a. procaine(Novocain) • Procaine is the prototype drug of the local anesthetics. It has the lowest potency (except for Benzocaine). • It is used for nerve block, epidural and spinal anesthesia. Novocaine is generally not used in dentistry anymore. b. benzocaine • Topical use only • benzocaine (Solarcaine, Orajel, Lanacaine etc) • It is used for minor mouth conditions (i.e teething, canker sores) sore throat, sunburn, and other minor skin conditions c. cocaine • Cocaine is 2 times as potent as procaine. It is used for ear, nose and throat procedures. d. tetracaine(Pontocaine) • Used for: • spinal anesthesia requiring 2 to 3 hours of anesthesia • surface anesthesia of the eye, nose and throat. • It is 16 times as potent as procaine. 3. Amide local anesthetics • Commonly used local anesthetics containing the amide functional group are bupivacaine, lidocaine, mepivacaine, and ropivacaine. a. bupivacaine(Marcaine) and levobupivacaine (Chirocaine) • These are used in infiltration and epidural anesthesia. They are 16 times more potent than procaine. • Generally, they are more cardiotoxic than the other long acting local anesthetics. b. lidocaine • Used topically for minor dermatological procedures (i.e skin tag removal) • It is 4 times more potent than procaine and has replaced procaine in the area of dental anesthesia. c. mepivacaine (Carbocaine) • This local anesthetic is used for dental procedures, surgical procedures and during labor and delivery. d. ropivacaine (Naropin) • This is used for surgical procedures, including caesarian sections. Although it is similar pharmacologically to bupivacaine, it is less cardiotoxic. • 4. Adverse effects • • • • a. Low concentration dosages: dizziness sleepiness restlessness • b. Higher concentration dosages: • muscular twitching • seizures • and hypotension (except for cocaine, which can result in vasoconstriction and hypertension, as well as cardiac arrhythmias). B. General anesthesia 1. general information • General anesthesia provides rapid and complete loss of sensation. • • • • • It is characterized by: total analgesia (no pain) unconsciousness deeper than sleep loss of memory complete muscle relaxation. • Although similar to sleep there are profound differences: • There is the loss of the “fight or flight response”, which is not lost during sleep. • General anesthetics stop most nervous activity in the brain, sleep only stops activity in very specific areas, and increases activity in other areas. • It is the ultimate “altered state”, like flipping a switch to temporarily turn off the nervous system. • In the past decade it has become apparent that the GABA receptor-chloride channel is the target of many general anesthetics (inhaled anesthetics, BZ’s, barbiturates, propofol). • The GABA receptor complex consists of alpha, beta, and gamma subunits surrounding and controlling a central chloride ion channel. • All anesthetics bind at sites in the α and β subunits, which are removed from the GABA binding site. • The binding of GABA (gamma aminobutyric acid) to its receptor causes an opening of the chloride ion channel. • The increase of chloride ion leads to a hyperpolarization of the cell. • For IV benzodiazepine anesthetics and the inhalation anesthetics, binding to the GABA receptor complex, concurrent with GABA binding, results in a greater duration of chloride channel opening. • This increases the entry of chloride ion into the cell. The increased hyperpolarization reduces neural excitability by making it more difficult for the cell to depolarize. • This means that a much larger than normal stimulus is required to reach the threshhold potential and generate an action potential. • IV barbiturate binding to the GABA receptor complex also increases the duration of GABA-activated chloride channel opening. • In addition, higher concentrations of barbiturates may directly activate chloride channel opening even in the absence of GABA, leading to "barbiturate anesthesia”. • In addition to their actions on these chloride channels, general anesthetics also decrease the duration of opening of various cation channels (K1+, Ca2+). • This enhances the hyperpolarization of the membrane. • General anesthesia usually requires more than one drug. Multiple medications are used to rapidly cause unconsciousness and muscle relaxation and to maintain deep anesthesia. • IV agents are usually administered first because they act within a few seconds. • After the patient loses consciousness, inhaled agents are used to maintain the anesthesia. • This approach allows the dose of inhalation anesthetic to be lower so that the procedure is safer for the patient • General anesthesia occurs in distinct steps or stages: Stage 1 • Loss of pain, loss of general sensation, but the patient may be awake Stage 2 • Excitement and hyperactivity • The patient may try to resist, their heartbeat and breathing may become irregular and blood pressure can increase. • The anesthesiologist will try to quickly move through stage 2. Often an IV agent will be given to calm the patient during this stage. Stage 3 • Called surgical anesthesia • Skeletal muscles become relaxed, cardiovascular and breathing activities stabilize • Eye movements slow down and the patient becomes very still. This is the stage when surgery begins and remains until the procedure ends. Stage 4, or overdose • This is marked by hypotension or circulatory failure. Death may result if the patient cannot be revived quickly. 2. Inhaled general anesthetics These agents are nonflammable, nonexplosive gases or volatile liquids. • One of their major advantages is that the depth of anesthesia may be very quickly changed by altering the concentration of the agent. • The median alveolar concentration (MAC) is a term used to determine the potency of various inhalation anesthetics. • It is the median effective dose (ED50) of the anesthetic, and is expressed as the % of the gas in the mixture necessary to achieve an anesthetic effect. • The smaller the MAC, the more lipid soluble is the anesthetic, and the lower the concentration of the anesthetic needed to produce anesthesia. Therefore, the more potent is the anesthetic. • • • • • Anesthetic MAC value, in % Isoflurane 1.2 Sevoflurane 2.0 Desflurane 6.0 Nitrous oxide 100 • All of the inhalation anesthetics (except nitrous oxide) are respiratory depressants. • Isoflurane is more depressant than desflurane and sevoflurane • All 3 increase the resting partial pressure of CO2 in arterial blood (PaCO2), increase the apneic threshold, and decrease the ventilator response to hypoxia. • These effects can be mitigated by mechanically assisting ventilation. a. Nitrous oxide (laughing gas) • This is the only gas used routinely for anesthesia. • It is not very soluble in blood and tissues, which enables it to move in and out of the body very rapidly • Used for dental procedures and brief obstetrical and surgical procedures • See Youtube video from the Pink Panther Strikes again (Google video Peter Sellers; Clouseau, Dentist) • It may also be used together with other general anesthetics. • Nitrous oxide in higher doses has been found to depress the heart. 3. Volatile anesthetics • These are liquid at room temperature, converted into a vapor and inhaled • The most commonly administered liquid volatile agents in the U.S. are: • desflurane (Suprane) • Sevoflurane (Ultane) • Isoflurane (Forane) a. desflurane • Advantages: • rapid onset and recovery of anesthesia (useful for outpatient procedures) • one of least metabolized to toxic byproducts • Disadvantages: • low volatility, so requires a special vaporizer • pungent and irritating to the airway (leading to more coughing, laryngospasm, so it is not as useful for extended surgical procedures) • In addition, when high inspired gas concentrations are administered, there is a significant increase in the patient’s blood pressure and heart rate. sevoflurane: • Advantages: • rapid onset and very rapid recovery of anesthesia (useful with children) • Not as pungent as desflurane (also useful with children) • Has good bronchodilating properties and is the agent of choice in patients with asthma, bronchitis, and COPD. It has little effect on the heart rate. • Disadvantages: • Its metabolism results in F1- which may reach toxic levels in kidneys • In addition, carbon dioxide absorbents in anesthesia machines degrade sevoflurane to a fluorinated hydrocarbon, which is degraded by renal lyase enzymes to a thioacylhalide. • This compound has been observed to cause necrosis of the proximal tubule in rats. isoflurane: • Advantages: • It causes peripheral vasodilation and increased coronary blood flow (useful in patients with ischemic heart disease) • one of least metabolized to F1- • Disadvantages: • moderate solubility, so recovery from anesthesia may be delayed • Isoflurane can make the heart “more sensitive” to circulating catecholamines (like epinephrine). • This could lead to a ventricular arrhythmia in patients with heart disease who are given epinephrine in combination with an anesthetic, or in chronically anxious, “Type A” patients (they have higher circulating levels of endogenous epinephrine). C. Intravenous anesthesia • Intravenous anesthesia is used for the rapid induction of, but not the maintenance of anesthesia. • The maintenance of anesthesia is with an inhalation anesthetic. • There are 5 categories of drugs used as intravenous anesthetics: 1. Benzodiazepines (BZ) • The 3 main drugs used in this category are diazepam, lorazepam and midazolam. • They sedate, relieve anxiety, and control acute agitation, therefore their primary indication is for premedication. • They are inadequate for use in surgical anesthesia “on their own”, and must therefore be used with another anesthetic agent (i.e. an inhalation anesthetic). a. diazepam (Valium) • This is the prototype drug of the BZ’s • It is water-insoluble, so IV use requires a nonaqueous vehicle which can cause local irritation/pain b. midazolam (Versed) • Midazolam is water soluble, so drug of choice for IV administration • It has a more rapid onset and more rapid elimination than the other BZ’s. • In addition, midazolam is the most potent amnestic c. lorazepam (Ativan) • It is water-insoluble, so IV use requires a nonaqueous vehicle which can cause local irritation/pain • It is a less potent amnestic than midazolam, but a more potent amnestic than diazepam. 2. Barbiturates • The 3 main drugs used in this category are thiopental, thiamylal, and methohexital. • Their hypnotic activity is due to side chains at position 5 (especially if one of them is branched). • There is a more rapid onset and shorter duration of action if there is a sulfur instead of oxygen atom at position 2 (so, thiamylal and thiopental have more rapid onset and shorter duration of action than methohexital). • None of these drugs provides analgesia or significant muscle relaxation. • Like most of the “older” drugs, barbiturates have a worse toxicological profile than the benzodiazepines • They all may cause coughing, laryngospasm, bronchospasm, or apnea. a. Thiopental • Thiopental, the flagship of the barbiturate anesthetic group, has been a standard anesthetic induction agent for more than 60 years and is the drug in this category, to which all others are compared. b. Thiamylal c. Methohexitol • Thiamylal is not significantly different from thiopental in potency, incidence of laryngospasm, respiratory depression, cardiotoxicity or recovery time. 3. Opioids • The terms opioid and opiate are often used interchangeably, but have different meanings. • An opiate is derived from the juice of the opium poppy, Papaver Somniferum, which is commonly called ‘White Poppy’ and ‘Herb of Joy’. • An opioid is a compound, either synthetic, or a natural product which has morphinelike effects. • Opioids produce moderate sedation and profound analgesia. They exert their effects by binding with opioid receptors in the central nervous system. • There are 3 major opioid receptors classified, functionally, as μ (mu), κ (kappa), and δ (delta). • There is pharmacological evidence for subtypes of each receptor in addition to other, less well-known opioid receptors, epsilon (ε ), zeta (ζ ), iota (ι ) and lambda (λ). • There is a common general structure found in all opioid receptors embedded in plasma membranes. They are, usually, linked to a G protein. • Once the receptors are bound, a portion of the G protein is activated, allowing it to diffuse within the plasma membrane. • The G protein moves laterally within the membrane until it reaches its target, an ion channel. • The ion channels are involved with either a reduction of Ca2+ influx or an increase in K1+ efflux. • Either of these results in hyperpolarization (becoming more negative) which impairs the firing of neurons and neurotransmitter release. • Opioids may be used to supplement anesthesia when other anesthetic drugs don’t adequately control pain reactions. • They may be used as induction agents or as the primary drug for the maintenance of anesthesia when hemodynamic stability is essential • The high doses required to produce unconsciousness do not depress the myocardium, nor do they cause a significant reduction in blood pressure. • Doses must be at least 10 times the dose used for control of pain in ambulatory patients, thus this is referred to as high dose opioid. • Opioids depress respiration by inhibiting the responsiveness of the medullary respiratory center to PCO2 and alter the rhythm of breathing. • Consequently, it is necessary to assist ventilation. • Since respiratory depression may extend into the post-operative period as a result of drug accumulation in the tissues, the use of opioids whose clearances are slow remain most appropriate for patients who are expected to require p.o. ventilatory care. • • • • • The opioids most commonly used are fentanyl (Sublimaze) sufentanil citrate (Sufenta) alfentanil (Alfenta) remifentanil (Ultiva) a. fentanyl (Sublimaze) • One of the most frequently used because of how quickly it produces analgesia • Fentanyl is a potent synthetic opioid agonist with between 50-100 times the analgesic potency of morphine. • Fentanyl is used to aid induction and maintenance of general anesthesia and to supplement regional and spinal anesthesia. • Fentanyl is preferred to morphine in anesthesia due to its ability to maintain cardiac stability. • Fentanyl may be administered alone or in combination with inhalation anesthetics, local anesthetics, or benzodiazepines. b. sufentanil citrate (Sufenta) • Rapid induction of analgesia (similar to Fentanyl) c. alfentanil (Alfenta) • Compared to fentanyl and sufentanil, alfentanil has a shorter duration of action because its high protein binding and relatively low lipid solubility favor its sequestration in plasma d. remifentanil (Ultiva) • Remifentanil is ultra short acting and rapidly cleared because it’s ester linkages are susceptible to hydrolysis by esterases in tissues and RBC’s. • This converts the ester functional group into an inactive carboxylic acid metabolite. • This particular opioid is useful when dealing with patients with liver or kidney failure. • Less potent opioids such as morphine and demerol have fallen into disfavor because of their adverse effects when given in high doses. • Demerol may cause V-tach • Morphine may produce hypotension and bronchoconstriction as a consequence of its histamine-releasing action. • One of the most serious drawbacks of the opioid anesthetics overall, is the possibility of inadequate anesthetic depth. • Signs of this include sweating, wrinkling of the forehead, and opening of the eyes. • To prevent this, the high dose opioid techniques may be supplemented with inhalation anesthetics or hypnotics such as benzodiazepines (midazolam for shorter cases, lorazepam for cases longer than 4 hours), or more recently, propofol. • However, the use of these may result in some loss of cardiovascular stability. 4. Dissociative anesthetics • This relates to a type of general anesthesia that is characterized by amnesia, sedation, and analgesia, although the patient appears to be awake. • One of the dissociative anesthetics commonly used is ketamine (Vetalar, Ketaset). • Ketamine, is an N-methyl-D-aspartate (NMDA) receptor antagonist. • Ketamine blocks the ion channel in the following diagram • It increases blood pressure and increases cardiac output (useful in patients experiencing shock) • Ketamine has both very poor muscle relaxation and analgesic activity. • Ketamine may be used, along with diazepam for cosmetic/reconstructive surgery anesthesia. • It is not widely used for anesthesia as it tends to induce postoperative hallucinations. • It is sometimes used as a recreational drug, but it has a number of adverse effects: • loss of coordination • exaggerated sense of strength • blank stare • slurred speech • A BBC report in May 2000 claimed that medical research had shown that controlled tests on ketamine users had revealed impaired memory and mild schizophrenia several days after taking the drug. • Ketamine was classified as a Class C drug in 2005. • Other class C drugs include cannabis and anabolic steroids • Ketamine plays an extensive role in the season 2 finale of House, M.D, titled “No reason” 5. Propofol (Diprivan) • From DI-isoPRopyl IV ANesthetic • chemical name: 2,6-diisopropylphenol • Propofol is a sedative/hypnotic that can be used for induction or maintenance of general anesthesia. • It is also used for sedating intubated, mechanically ventilated patients. • Analgesic effect is poor and addition of an analgesic to the anesthetic regimen is necessary for surgery. • Advantages: • Rapid induction and recovery times • It can be given for prolonged periods without resulting in prolonged recovery • Disadvantages: • apnea • bradycardia and hypotension. • Propofol’s abuse as a recreational drug (it produces euphoria) has been seen, in some anesthesiologists who have access to the drug. • In addition, Michael Jackson’s death in June 2009 has been attributed to a “cocktail” of propofol and other drugs • Jackson’s cardiologist, Dr. Conrad Murray had been administering to Jackson 50 mg of propofol IV, nightly for 6 weeks for his insomnia. • Fearing that Jackson was forming an addiction to the anesthetic, he attempted to wean him by lowering the dose to 25 milligrams and adding the sedatives lorazepam and midazolam. • According to the MSNBC news service, the sequence of drugs given, on the day of his death were: • 1:30 a.m. 10 mg tablet of diazepam • 2 a.m. 2 mg, IV of lorazepam • 3 a.m. 2 mg, IV of midazolam • 5 a.m. 2 mg, IV of lorazepam • 7:30 a.m. 2 mg, IV of midazolam • 10:40 a.m. 25 mg, IV of propofol diluted with lidocaine • 10:50 a.m. — Dr leaves Jackson’s room; returns minutes later to him not breathing. Administers 0.2 mg of flumazenil (a BZ antagonist) D. Neuromuscular blocking drugs • These drugs are used during surgery (especially intra-abdominal and intrathoracic), and to aid intubation for surgical and diagnostic procedures (endoscopy). • Previously, adequate muscle relaxation was only possible with deep anesthesia (which leads to CNS depressant effects). • Contraction of skeletal muscles is voluntarily controlled by impulses that originate in the CNS. • Impulses from the brain are conducted through the spinal cord to the somatic motor neutrons. • Somatic motor neurons eventually connect with skeletal muscle fibers forming a neuromuscular junction (NMJ). • The neuronal endings of the somatic motor fibers contain the neurotransmitter acetylcholine (ACH). • When ACH is released into the neuromuscular synapses, it binds to receptors known as nicotinic-II (NII) receptors. • Neuromuscular blockers inhibit skeletal muscle contraction by interfering with the NII receptors. • There are 2 types of neuromuscular blockers: • nondepolarizing • depolarizing 1. Nondepolarizing blockers • These bind to the receptors but do not stimulate the receptors. They are structurally similar to ACH and function as a competitive inhibitor. • By binding to the nicotinic receptor, they prevent ACH from binding and inhibit muscular contraction. • They do not cause the sodium channels in the membrane to open, therefore no depolarization of the receptor occurs. • Remember, the resting membrane potential (on the inside of the cell membrane) is typically –70mV, with closed sodium channels. Any shift from the resting potential toward 0mV is called a depolarization. • After I.V. injection, there is generally, a rapid onset of effects: 1st: Fine muscles affected (those of eyes & fingers) • 2nd: limbs, neck & trunk • 3rd: intercostal muscles • 4th: diaphragm • Recovery is in the reverse order a. Tubocurarine • This is the prototype of the nondepolarizing neuromuscular blockers. It is found in curare, which derives from the South American plant genus Strychnos. • It has a slow onset (>5 min) and a long duration of action (1-2 hours), and it is not commonly used any more. b. Pancuronium bromide (Pavulon) • Full muscle paralysis for major surgery is achieved in about 2–4 minutes, recovery is about 2-3 hours • It is also found as one of the components in lethal injections. Amnesty International has objected to this use stating that it "may mask the condemned prisoner's suffering during the execution”. • Pancuronium bromide was one of the compounds used by Efren Saldivar, the "Angel of Death”. • He was a serial killer who murdered patients while working as a respiratory therapist. • He was employed by the Glendale Adventist Medical Center, working the night shift, when there were fewer staff on duty. • The police, in searching for evidence strong enough to obtain a court conviction, exhumed the remains of 20 patients who had died during the time Saldivar was on duty. • They were specifically looking for unusually high levels of Pavulon in the cadaver, as this drug remains identifiable for many months. • 6 of the 20 cadavers had evidence of a lethal concentration of Pancuronium bromide. • In 2002, Saldivar pleaded guilty to six counts of murder and received six consecutive life sentences without the possibility of parole. c. Atracurium besylate (Tracrium) • and its isomer cisatricurium besylate (Nimbex) • They are widely used and have an intermediate duration (recovery is 95% complete one hour after injection). • However, a breakdown product of atracurium, laudanosine may accumulate due to very slow hepatic metabolism and upon crossing into the brain may cause seizures • Cisatracurium has less laudanosine formed and less histamine released than atracurium. • Federal regulators have cited St. Margaret Mercy Healthcare Centers in Indiana for dispensing Tracrium to Hammond Fire Department Capt. Michael Magdziarz in January 2002. • Magdziarz had underwent a successful bypass surgery and was recovering. His surgeon had ordered a penicillin to fight infection. Instead, the nurse administered Tracrium. • He became restless, complained of shortness of breath, stopped breathing and suffered cardiac arrest. d. Vecuronium bromide(Norcuron) • This has a shorter duration of action than pancuronium (recovery is 95% complete 45 minutes to one hour after injection). • Its lack of significant cardiovascular effects and lack of dependence on good kidney function for elimination provide advantages over other neuromuscular blocking agents. • Overall, the extent of adverse effects on the nondepolarizing neuromuscular blockers depends on the specific agent. • The older drugs (i.e. tubocurarine, pancuronium) tend to have more cardiovascular actions (blood pressure and heart rate changes) as well as histamine release, and more difficulty with their controlled reversal. • The newer drugs (i.e. vercuronium) tend to have minimal to no cardiac effects, slight to no histamine release, and an easier reversal. 2. Depolarizing • Depolarizing agents are also structurally similar to acetylcholine and function as competitive inhibitors. • However, when they bind to the nicotinic receptor, they cause the sodium channels in the membrane to open, leading to depolarization of the receptor. • These sodium channels only open briefly and cannot be opened again until the membrane is repolarized. • Depolarizing neuromuscular blockers act as persistent agonists at nicotine receptors, but unlike acetylcholine, their relatively slower degradation rate results in paralysis. • Generation of an action potential requires a rapid change (increase) of membrane potential from a negative state. • As these drugs are eventually cleared and receptors become unoccupied, they revert to the original active state. • Succinycholine is the only drug in this class that is used by anesthesia providers today. • The duration of action of succinylcholine is very short, because it is metabolized in the body very quickly by an enzyme called plasma cholinesterase. • This short duration of action makes succinylcholine a useful drug in situations where muscle relaxation is needed for only a short time such as to facilitate intubation. • Side effects of succinycholine include: • fasciculations (small muscle movements caused when the drug binds to receptors) • • myalgias (muscle soreness which may be the result of the fasciculations) • cardiac rhythm disturbances • increases in ocular and gastric pressure, • hyperkalemia in at-risk patients • malignant hyperthermia: a dramatic increase in body temperature, acidosis, electrolyte imbalance and shock • The syndrome is though to be due to a reduction in the reuptake of calcium, which is necessary for termination of muscle contraction. Consequently, muscle contraction is sustained.