General Anesthetic Agents
ANESTHESIA: loss of sensationGeneral Anesthesia : Renders the patient 1.amnesic 2.unconscious while causing muscle relaxation 3.suppression of undesirable reflexes
Anesthesia
In the “old days” the following were used for anesthesia.
– Alcohol– Ice for numbing– Blow to the head– Strangulation
ADJUNCT AGENTS
• Benzodiazepines• Barbiturates• Anticholinergics• Antihistamines• Antiemetics• Muscle relaxants =
atracurium,vecorunium,succinylcholine
INTRAVENOUS
• BARBITURATES• thiopental,thiamylal,methohexital• BENZODIAZEPINES• Diazepam,lorazepam,midazolam,• ETOMIDATE• OPIODS – fentanyl,morphine
INTRAVENOUS
• NEUROLEPTIC – droperidol + fentanyl• KETAMINE• PROPOFOL
Theories of anesthesia
• Anesthetic potency is closely correlated with lipid solubility
• Postulated interaction with the lipid membrane bilayer.
• Interaction with ligand-gated membrane ion channels.
• Most anesthetics enhance the activity of inhibitory GABA A-receptors
• Many inhibit activation of excitatory receptors, such as glutamate and nicotinic acetylcholine receptors.
Stages of Anesthetic Activity• Stage I - Analgesia
– conscious but drowsy. – responses to painful stimuli reduced
• Stage II - Excitement – lose consciousness– no longer responds to non-painful stimuli – responds in a reflex fashion to painful stimuli
• Stage III - Surgical anesthesia – movement ceases and respiration becomes regular
• Stage IV - Medullary paralysis – respiration and vasomotor control cease – death occurs
Properties of Ideal Inhalational Anesthetics
• Rapid & pleasant anesthetic induction & recovery
• Rapid changes in anesthetic depth• Adequate relaxation of skeletal muscles• Wide margin of safety• Absence of toxic effects or other adverse
properties in normal doses
MOA
• Increase neuronal threshold for firing leading to a decrease in neuronal activity
• Hyperpolarization of neurons via activation of K+ currents
POTENCY
–Clinical potency can’t be predicted by chemical structure
–Potency correlates w/ lipid solubility
• Defined by MAC
• MAC: • -concentration of
anesthetic gas needed to eliminate movement among 50% of patients challenged by standardized skin incision
• INVERSE of MAC is an index of potency
• *the more lipid soluble, the LOWER the concentration needed to produce anesthesia
• The lower the MAC, the more potent is the anesthetic
Highest to lowest MAC
• NO• Ether• Enflurane• Isoflurane• halothane
Solubility to blood
• Based on blood/gas partition coefficient• Lowest to highest• NO• Isoflurane• Enflurane• halothane
Types of Anesthesia
•General• Local
Individual Inhalation Anesthetics
Nitrous oxide: – low potency, therefore must be combined with
other agents – rapid induction and recovery – good analgesic, WEAK anesthetic properties – risk of bone marrow depression with prolonged
administration. – Laughing gas– Can retard O2 uptake during recovery,thus 20% of
O2 is always needed
NO
• can cause diffusion hypoxia• Least hepatotoxic• safest
HALOTHANE
• Prototype• Weak analgesic; POTENT anesthetic• Usually co-administered w/ N2O, opioids, or
local anesthetics• Metabolized to tissue-toxic hydrocarbons
(trifluroethanol) & bromide ion
HALOTHANE• Disadvantages:• Reduced myocardial contractility & causes
hypotension• Arrhythmias
Individual Inhalation Anesthetics
• Enflurane: – halogenated anesthetic similar to halothane – less metabolism than halothane; therefore, there is less
risk of toxicity – faster induction and recovery than halothane (less
accumulation in fat) – some risk of epilepsy-like seizures. Cns excitation– Metabolized to flouride ion,excreted in the kidney
ISOFLURANE
• Does NOT induce cardiac arrhythmias and does NOT sensitize the heart to cathecolamines
• Stable molecule
ISOFLURANE
• Disadvantages:– More pungent odor than halothane– Progressive respiratory depression & hypotension
Individual Inhalation Anesthetics
• Desflurane and sevoflurane – similar to isoflurane – have faster onset and recovery – lack of respiratory irritation – commonly used clinically
METHOXYFLURANE
• potent, high lipid solubility• Used in child birth• Disadvantages: Metabolized to flouride;
Respiratory and circulatory depression
HALOTHANE ENFLURANE ISOFLURANE NITROUS OXIDE
ARRHYTHMIA INCREASED
SENSITIVITY TO CATHECHOLAMINES
INCREASED SLIGHT INC.
CARDIAC OUTPUT
DECREASED DEC BUT RECOVERS
DECREASED
BP DECREASED DEC BUT RECOVERS
DECREASED
RESPI REFLEX INHIBITED INHIBITED
HEPATOTOXICITY HIGH RISK SOME RISK
Intravenous Anesthetics
• Thiopental– barbiturate with very high lipid solubility – GABA- mimetic– rapid action because of rapid transfer across blood-brain
barrier– short duration (about 5 minutes) because of
redistribution, mainly to muscle – Potent anesthetic, weak analgesic effect – Little muscle relaxation– Laryngospasm,not for asthma pt,not w/ porphyria
• Onset: 40 sec• Recovery:30min• Dose: 50mg• Use: induction anesthesia• Toxicity: respi and circulatory depression
Intravenous Anesthetics
• Etomidate - potent non barbiturate , hypnotic,
no analgesic
– similar to thiopental but more quickly metabolized
– less risk of cardiovascular depression
may cause involuntary movements during induction
possible risk of adrenocortical suppression.
Hypnotic, lacks analgesic
Intravenous Anesthetic Agents
• Ketamine – analogue of phencyclidine, w/ similar properties
(psychotic reactions)– effect on NMDA-type glutamate receptors – onset of effect is relatively slow (2-5 minutes) – produces “dissociative” anesthesia, in which patient may
remain conscious and insensitive to pain – can increase intracranial pressure– Causes cardiovascular stimulation but not respiratory
depression
Intravenous Anesthetics
• Propofol– rapidly metabolized – very rapid recovery; no cumulative effect – useful for day-case surgery – causes more respiratory and cardiovascular
depression than barbiturates– Lowers intracranial pressure
propofol (Diprivan)
• Used for maintenance of anesthesia, sedation, or treatment of agitation
• Has antiemetic properties– Drowsiness– Respiratory depression– Motor restlessness– Increased blood pressure
fentanyl
• Dosage Forms– IV (Sublimaze)– patch (Duragesic)– lozenge (Actiq) for children
• Used extensively for open-heart surgery due to lack of cardiac depression
Summary of Intravenous Anesthetics DrugDrug Speed of induction and Speed of induction and
recoveryrecovery Main unwanted effectsMain unwanted effects NotesNotes
ThiopentalThiopental Fast (cumulation Fast (cumulation occurs, giving slow occurs, giving slow recovery)recovery)
Cardiovascular and Cardiovascular and respiratory depressionrespiratory depression
Widely used as Widely used as induction agent for induction agent for routine purposesroutine purposes
HangoverHangover
etomidateetomidate Fast onset, fairly fast Fast onset, fairly fast recoveryrecovery
Excitatory effects Excitatory effects during induction and during induction and recoveryrecovery
Less cardiovascular and Less cardiovascular and respiratory depression respiratory depression than with thiopentalthan with thiopental
Adrenocortical Adrenocortical suppressionsuppression
Causes pain at injection Causes pain at injection sitesite
propofolpropofol Fast onset, very fast Fast onset, very fast recoveryrecovery
Cardiovascular and Cardiovascular and respiratory depressionrespiratory depression
Rapidly metabolizedRapidly metabolized
Possible to use as Possible to use as continuous infusioncontinuous infusion
Causes pain at injection Causes pain at injection sitesite
KetamineKetamine Slow onset, after-Slow onset, after-effects common during effects common during recoveryrecovery
Psychotomimetic Psychotomimetic effects following effects following recoveryrecovery
Produces good Produces good analgesia and amnesiaanalgesia and amnesia
Postoperative nausea, Postoperative nausea, vomiting and salivationvomiting and salivation
MidazolamMidazolam Slower than other Slower than other agentsagents
Little respiratory or Little respiratory or cardiovascular cardiovascular depressiondepression
Local Anesthesia
Relieves pain without altering alertness or mental function.
• . Local anesthesia• - MOA: blocks sodium channels in nerves• - provides analgesia without loss of
consciousness
Local Anesthesia
Variety of Dosage Forms– Topical– Superficial injection (infiltration)– Nerve block– IV– Epidural– Spinal
• Administration:• Topical, injected into nerves, epidural or
subarachnoid space (spinal)• Notes:• Reduced pH, as in inflamed tissues reduces
effectiveness (cationic form predominates)• Co-administered with vasoconstrictor epinephrine
(1:100,000)
esters
• - hydrolyzed by blood esterases; short half-life
esters
• Benzoic acid derivatives• P-aminobenzoic acid derivatives
Benzoic Acid Derivatives
• Cocaine• Cyclomethicaine• Hexylcaine • Isobucaine • Meprylcaine • Piperocaine
P-aminobenzoic acid Derivatives
• Benzocaine • Butacaine • Benoxinate • Propoxycaine • Procaine• Proparacaine • Chlorprocaine• Tetracaine
• 2. Amides• - lidocaine (Xylocaine), mepivacaine (Carbocaine,
Mepivastesin), bupivacaine (Marcaine, Sensorcaine, Senpivac), prilocaine (Citanest, Emla), Etidocaine (Duranest), Ropivacaine (Naropin), Levobupivacaine (Sensibloq), Articaine (Ubistesin)
• - metabolized in the liver; long half-life• More stable to hydrolysis than esters
• Adverse effects• Cardiovascular depression hypotension• Hepatotoxicity- halothane• Nephrotoxicity- enflurane, methoxyflurane • Malignant hyperthemia (esp. with succinylcholine)-
hyperthermia, muscle rigidity (Antidote: dantrolene)• Arrhythmia due to sensitization of heart to
cathecholamines