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