Anesthetics Anesthesia- drug-induced absence of sensations 2Types: 1)Local anesthetic 2) General anesthetic Local anesthetics- loss of sensation in a localized

area of the body Classification: derivatives of PABA Ester & Amide Structure: Ester

Amide

Conclusion: ALL local anesthetics consist: a.hydrophilic amino group b.connecting group (ester or amide) c.lipophilic aromatic group Relationship: the greater the length of the connecting group & amino groups= greater potency= greater toxicity!!! Local anesthetics are weak bases water-insoluble, liposoluble, uncharged/unionized Local anesth is usually prepared as an acidic salt solution highly water soluble, hydrophilic. Charged/ionized exerts anesthetic effect Site of action: nerve membrane MOA: decrease the influx of Na+ into the nerve membrane slow the propagation of nerve impulses reduce rate of depolarization (causes pain) reduce the rate of rise of the action potential reduce rate of repolarization =blocking of conduction Theories of MOA: 1)Specific receptor theory local anesthetic displaces Ca++ from a site near the Na+ channel & then blocks the adjacent Na+ channel 2)Membrane expansion theory local anesth are liposoluble so they incorporate into the cell membrane, preventing the opening of pores, interfering with the passage of electrolytes Pain activates action potential increase inward flow of Na+ OUCH!!!

Local Anesthetics bind to Ca++ receptors & decrease the influx of Na+

Actions: abolish sensation (& in higher conc, motor activity) in a limited area without loss of consciousness : loss of nerve function occurs in the ff order 1)autonomic 2)cold 3)warmth 4)pain 5)touch 6)pressure 7)vibration 8)proprioception 9)motor response :nerve function returns in reverse order (1) Ester Local anesthetics- more likely to produce hypersensitivity reactions -metabolized by: Plasma ChE/pseudoChE/butyrylChE a.cocaine g.Procaine b.hexylcaine h.Benzocaine c.meprylcaine i.propoxycaine d.isobucaine j.Chlorprocaine e.piperocaine k.tetracaine f.cyclomethicaine l.benoxinate Cocaine CNS effects: euphoria CV effects: blocks re-uptake of NEtachycardia, v.constriction & HPN Produces tolerance, abuse & poisoning Causes hyperpyrexia & anorexia Also used as analgesic in terminal CA Procaine 1st synthetic anesthesia STANDARD DRUG FOR ESTER LOCAL ANESTHETICS Well absorbed after parenteral administration Slow onset of action Short duration of action Metabolic product: PABA inhibits action of sulfonamides Lacks topical activity Marked v.dilation Tetracaine 10x more potent (more toxic) than Procaine Usually combined with 10% dextrose Onset of action: 5 minutes Duration of action: 2-3hrs

(2) Amides Local anesthetics- lower incidence of hypersensitivity rxns -longer shelf life -greater degree of anesthesia -increase the duration of action -metabolized by: liver a.Lidocaine

b.Etidocaine c.Mepivacaine d.Bupivacaine e.Prilocaine Lidocaine Rapidly absorbed after parenteral administration Most widely used local anesth Rapid onset of action, longer duration of action, greater potency than Procaine Has anti-arrhythmic property Mepivacaine Onset of action is more rapid than Lidocaine Duration is 20% longer than Lidocaine EPI is rarely used with this drug Etidocaine Greater potency and longer duration of action than Lidocaine & Mepivacaine Bupivacaine More potent and has a longer duration of action than mepivacaine Duration: <24hrs Onset of action is slower than mepivacaine May cause cardiac arrest at a conc of 0.75% solution (as obstetric epidural anesthetic) Ideal for procedures (dental) requiring more than 90 minutes of anesthesia Prilocaine Onset and duration of actions slightly longer than Lidocaine Major disadvantage: methemoglobinemia Dibucaine Potent anesthetic Long duration of action High systemic toxicity only used as a topical anesthetic Procedures requiring: 30-60 minutes of anesthesia 30-60 minutes 30-90 minutes More than 90minutes Or when postoperative pain is anticipated 30-90 minutes More than 90 minutes Or when postoperative pain is anticipated Up to 90 minutes

Anesthetic Agent Procaine (+propoxycaine) Propoxycaine Lidocaine Etidocaine Mepivacaine (w/ vasoconstrictor) Bupivacaine Prilocaine

Pharmacokinetics: Absorption Rate of absorption depends on tissue blood supply & route of administration Increase in amount of blood supply is affected by: a.degree of inflammation b.vasodilating properties of the anesthetic

c.warmth & massage Vasodilationincrease blood flow increase systemic absorption decrease duration of action Distribution Distributed throughout the body Protein binding longer duration of actionmore potent anesthesia Metabolism Ester anesthetics metabolized in the plasma(pseudocholinesterase) Amides in the liver (hepatic microsomal mixed-function oxidases) except Prilocaine- metabolized in the lungs CI: ptx with liver disease Excretion Kidneys Caution: use in ptx with renal disease & elderly ptx Adverse Reactions: due to systemic absorption >remedy: add vasoconstrictor Why? 1)decrease rate of absorption 2)decrease systemic toxicity 3)remain intact locally 4)extend duration of action of the local anesth Adverse Effects: 1.CNS- convulsions/seizures, tremors, depression 2.CV- depression hypotension 3.Respiratory failure 4.Allergic reactions 5.Methemoglobinemia- Prilocaine Most common adverse effect: Seizure Additives in anesth: Local anesth solutions- local anesthetic Methylparaben Na metabisulfite/bisulfate Carbon dioxide salt Dextran Vasoconstrictor Vasoconstrictors = EPI & levonordefrin Topical Local Anesthetics -absorption: through mucous membrane of oral cavity Drugs: a)benzocaine b)Lidocaine c)Tetracaine **Dont swallow. Dont drink/eat hot/cold beverages/food. Concerns: Lower the dose of the drug- if ptx is feeling anxious, nervous, or having heart palpitations. Lidocaine may cause sedation- ptx should have someone to drive them home. Use of an opioid analgesic or antianxiety agent with anesthetics = increased sedation & drowsiness ptx should be advised not to drive, operate machines or do anything which requires concentration.

 Local anesthetics will make it difficult for ptx to detect temperature changes. Ptx should refrain from eating or drinking very hot or cold foods or drinks. Vasoconstrictors (added to local anesth) & Patients with cardiovascular disease check blood pressure of ptx before administration Local anesthetics with vasoconstrictors are: o Caution to patients with Uncontrolled hypertension Hyperthyroidism Unstable angina Controlled arrhythmias Myocardial infarction or cerebrovascular accident within the past 6 months o Contraindicated in patients with Uncontrolled arrhythmias Pheochromocytoma Uncontrolled hyperthyroidism General Anesthetics General Anesthesia- combination of reversible unconsciousness, absence of response to painful stimuli, CNS depressant-action, immobility, amnesia upon recovery Adm: hospital operating rooms Important: attain BALANCED ANESTHESIA Use of adjuncts to anesthesia, consisting of: o Preanesthetic medication o Skeletal muscle relaxant o Co-administration of local anesthetics Preanesthetic medication- calm the ptx, relieve pain, & protect against undesirable effects of anesthetic or surgical procedure o Anticholinergics o Antiemetics o Antihistamines o Barbiturates o BZDs o Opioids Skeletal Muscle Relaxant- facilitate intubation & suppress muscle movement to permit surgery o Atracurium o Succinylcholine o Vecuronium I. Patient Factors that Affect Selection of Anesthetic Agents Safety & effectiveness of anesthetic to ptx condition & procedure a.nature of surgical procedure b.ptx physiological & pharmacological state Patient status: A.Liver & Kidney o Main metabolic & excretion sites good target organ for toxicity o Fluoride, bromide, & other metabolites of halogenated HC may affect organs B.Respiratory system

o Important consideration especially for inhalational anesthetics o Asthma, obstructive respiratory disorders C. CV System o Anesthetics have hypotensive effect that may lead to ischemic injury due to reduced perfusion o Important to have a vasoactive agent at hand D.Nervous System o Neurologic disorders affect choice of anesthetics o Ex: epilepsy, MG E.Concomittant use of adjunct agents like: o BZDs (Diazepam)- to relieve anxiety & facilitate amnesia o Barbs (Phenobarbital)- for sedation o Antihistamines: (diphenhydramine)- for prevention of allergic reactions (cimetidine)- to reduce gastric acidity o Amtiemetics (droperidol) o Opioids (fentanyl)- for analgesia o Anticholinergics (scopolamine)- prevent bradycardia & decrease secretion of fluids into respiratory tract o Skeletal muscle relaxants- to facilitate induction of anesthesia ALL these agents LOWER the dose of anesthetic required to maintain anesthesia F.Concomittant use of additional nonanesthetic drugs o Alcohol elevates the hepatic enzymes & affects metabolism of Barbs o Drug abusers tolerant to effects of anesthetics ALTERATION of RESPONSE to anesthetics II.Stages of Anesthesia : depth A.Stage 1- Analgesia Ptx is conscious and conversational Reduced awareness of pain occurs when near Stage II B.Stage II- Delirium/ Excitement Ptx has delirium, violent & combative behavior Rise & irregularity of blood pressure Increased respiratory rate THIS STAGE MUST BE AVOIDED. How? An USA Barb should be given IV before inhalation anesthesia is administered. C.Stage III- Surgical Anesthesia Regular respiration and relaxation of muscles Eye reflexes are decreased Surgery may proceed D.Stage IV- Respiratory & Medullary Paralysis Severe depression of respiratory center death **Goal: Go into Stage I then Stage III. III. Anesthesia & Related Terms A.Induction- period of time from onset of administration of the anesthetic to the development of effective surgical anesthesia Depends on how fast effective conc reach the brain Very essential to avoid dangerous Stage II Normally, induction is done with an IV anesth, ex: thiopental or skeletal muscle relaxant Additional anesth is then given to achieve desired depth

B.Maintenance- provides a sustained surgical anesthesia Monitoring of ptx vital signs & response to stimuli Achieved by adm of gas or volatile liquid anesth C.Recovery- the time from discontinuation of the adm of the drug until consciousness is regained Depends how fast the drug is removed from the brain Redistribution of drug from the site of action Continued monitoring of ptx for possible delayed toxic reactions General Anesthetic Agents Inhalation Anesthetics Potency: MAC (Minimum Alveolar Concentration) 1.quantitative parameter to indicate potency of inhaled GAS 2.is the conc of anesthesic gas needed to eliminate movement among 50% of ptx challenged by a standardized skin incision 3.expressed as the percent of gas in a mixture required to achieve the effect Higher MAC = more potent drugs T or F? ______ Lower MAC = more potent drugs T or F? ______ Conclusion: _________________________________________________________________ Uptake and Distribution of Inhalation Anesthetics Alveolar space bloodbrain & other parts >movement of gas to achieve steady state: partial pressure gradient Partial pressure of gas- driving force that moves anesth Steady state- when partial pressure in the different body compartments is equal

Factors Affecting Steady State: (1) Alveolar wash-in Refers to the replacement of the normal lung gases with the anesthetic mixture Depends on the lung function Uptake of anesth from lungs depends on the partial pressure (2) Concentration of an inhalation anesthetic in blood or tissue Determined by: a)solubility in blood b)partial pressure Solubility in blood is determined by: a)Blood:gas partition coefficient b)Tissue:gas partition coefficient Blood:Gas Partition Coefficient = low blood solubility (nitrous oxide) equilibrium between the inhaled anesth & arterial blood occurs rapidly few additional anesth required SS is rapidly achieved induction is immediate =high blood solubility (halothane) dissolves more completely in blood so greater amount is requiredtakes longer time to achieve SS increase in induction time Tissue:Blood Partition Coefficient

-tissue uptake -arterial circulation distributes free anesth to other tissues Time for SS ---- blood flow to that tissue Longer time = lesser blood supply Shorter time = greater blood supply Time for SS ---- capacity to store anesth Longer time = greater amount stored Capacity to store ---- tissue volume Larger capacity = large tissue volume Tissues a.brain, heart, liver, kidney, endocrine highly perfused b.skeletal muscles- poorly perfused; large tissue volume c.fat- poorly perfused; however, anesth are LIPOSOLUBLE; & large capacity to store d.bone, ligaments, cartilage- poorly perfused; low capacity to store (3) Return of gas-depleted blood to the lung -venous circulation (4) Uptake curves -depends on solubility of blood (5) Washout -opposite of uptake (FIFO) A.Inhalational Anesthetics MOA: alter function of GABA & glutamate receptors Drugs: Volatile Anesthetics -are liquids that evaporate easily upon exposure to room temperature -halogenated HC 1)Halothane -MAC = 0.75% -potent anesthetic; weak analgesic -hepatotoxic/ hepatic necrosis (death) -drops the renal function to 50% 2)Enflurane -MAC = 1.68% -less potent than halothane but more rapid induction & recovery -colorless, nonflammable liquid, sweet odor -curare-like effects CI; labor -80% eliminated unchanged as expired gas -causes bronchodilation, seizures -CI: epileptic ptx 3)Isoflurane -MAC = 1.15% -potent agent; pungent smell difficult to use -most commonly used GA -produces respiratory depression, hypotension, smooth muscle relaxation, respiratory acidosis

-better SMR than enflurane 4)Desflurane -newly approved agent; pungent smell -lowest blood:gas PC most rapid induction -causes myocardial & respiratory depression 5)Diethyl ether -highly flammable & explosive -produces bronchodilation -curare -like action -sympathetic activation: increased hepatic glycogenolysis ***curare-like actions of GA increased with aminoglycoside antibiotics Gas Anesthetic 6)Nitrous oxide (Laughing Gas) -inorganic inert & colorless gas that supports combustion -MAC = 105.2% -eliminated as expired gas -powerful analgesic -given in combination with oxygen (20% - 40%) -adm: 100% oxygen given first for 2-3minutes then add nitrous oxide in 5-10% increments -termination of adm: give 100% oxygen for 5 minutes to prevent hypoxia -develops headache tx: 100% oxygen -ptx may experience euphoria -color-coded cylinders: blue- nitrous oxide ; green oxygen -CI: ptx w/ obstructive respiratory disorders, pregnancy B. Intravenous Anesthetics/ C. Preanesthetic Medications Intravenous General Anesthetics -conscious sedation Drugs: 1) USA Barbitals- effect: induction of anesthesia Thiopental Thiomylal Methohexital o Rapid & pleasant induction o Given before strong GA (inhalation GA) o ALL Barbs cause: apnea, coughing, chest wall spasm, laryngospasm, bronchospasm, Acute intermittent porphyria o CI: asthmatic & COPD Ptx with porphyria 2) BZDs- effect: induction of anesthesia Midazolam Lorazepam Diazepam 3) Propofol- effect: induce & maintain anesthesia -onset: 1 minute ; duration: 3-5minutes -milky white emulsion -adm: infusion pump -disadv: Phlebitis interaction of the blood and catheter

4) Etomidate- effect: hypnotic for 5 minutes without analgesic effect -potent -cause pain on injection -produces myoclonic movements (uncontrollable) -has embryocidal activity 5) Ketamine- effect: dissociative anesthesia -substance of abuse -related to PCP (Angel Dust) -Ptx is not asleep but will fail to respond to environment and doesnt remember the proceduresedated, analgesic, amnestic, immobile 6) Opioid Analgesics- effect: Neuroleptanesthesia -Neuroleptanesthesia = neuroleptanalgesia + 65% N2O in O2 -Neuroleptanalgesia = Droperidol + Fentanyl => Innovar -Droperidol = respiratory depression = -adrenergic blockade sedation = antiemetic =anticonvulsant =EPS Parkinsons disease -Fentanyl = bradycardia, hypotension =respiratory muscle spasm -Other adverse effects = confusion =mental depression Opioid analgesics: -provide analgesia during surgery & post-surgery -as preanesthetic medication -ex: Fentanyl, Alfentanil, Sulfentanil -disadv: respiratory depression