1307750086 general local anaesthetics - fsk 2011

8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011

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GENERAL

ANAESTHESIA

ASSOCIATE PROFESSOR DR ROHI GHAZALI

Father of Modern Anaesthesia, W.T.G Morton using ether


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OUTLINE

Anaesthesia

["without "sensation]

General Anaesthetics:puts person to sleep

Background & Concept

Inhaled, I.V. & BalancedGA

Indications & Sideeffects

Local Anaesthetics:causes loss of feeling in a

part of body withoutaffecting consciousness

Background & Concept Amide & Ester-Linked LA Indications & Side effects


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GENERAL ANAESTHETICS

reversible loss ofconciousness


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Stages of Anaesthesia: Arthur Guedel (1883-1956)

I. Stage of Analgesia:

analgesia without amnesia.

II. Stage of Excitement:delirium, excited, irregular respiration+amnesic.

III. Stage of Surgical Anaesthesia:

recurrence of regular respiration + apnea.ocular signs ( anaesthesia).

IV. Stage of Medullary Depression:

stoppage of respiration till DEATH.

Diethyl Ether

( solubility in blood, slow onset of central action)


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Types of General Anaesthesia

A. Inhaled Agents

volatile liquids or gases.

B. Intravenous Agents

drugs administered intravenouslyeither alone or in combination.

C. Balanced Agents

combination of IV and inhaleddrugs including muscle relaxants,LAs, opioid analgesics, CVSdrugs.


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Mechanism of Action

UNKNOWN!!

acts on CNSby modifying electrical

activity of neuronsat a molecular level

by modifying functions ofION CHANNELS.

AnaestheticSuppression ofPhysiological

Response to Surgery


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Inhalational Agents

1. Halogenated HydroCarbon (HHC)

- Halothane- Enflurane- Isoflurane- Methoxyflurane- Desflurane- Sevoflurane

2. Nitrous oxide

3. Older agents- Diethyl ether- Chloroform- Cyclopropane(obsolete: slow onset + recovery + highly explosive)

Nitrous oxide

Ether
http://upload.wikimedia.org/wikipedia/commons/8/87/Diethylether_chemical_structure.png


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Pharmacokinetics ofInhaled Anaesthetics

1. Amount that reaches brain

Indicated by oil:gas ratio (lipid solubility).

2. Partial Pressure of anaesthetics

5% anaesthetics = 38 mmHg.

3. Solubility of gas into blood

blood:gas ratio,

anaesthetics will arrive at brain.

4. Cardiac Output

CO= greater induction time


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Pathway for General Anaesthetics

DEPTH of anaesthesia induced by an inhaled anesthetic

depends primarily on the PARTIAL PRESSURE


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Increase in Anaesthetic Partial Pressure inBlood is Related to its Solubility

Agents of low solubility in blood (nitrous oxide),

the partial pressure in blood rises quickly.


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Rate of Entry into the Brain:Influence of Blood and Lipid Solubility

LOW solubility in blood= fast induction and recoveryHIGH solubility in blood= slower induction and recovery.


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MAC

Minimum Alveolar Concentration (%) :A measure of potency. 1MAC is the concentration

necessary to prevent respondingin 50% of population.

Values of MAC are additive: AVOID cardiovascular depressive concentration

of potent agents.


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Anaesthetic Blood: Gaspartition coeff

Minimum AlveolarConcentration (MAC) %

Nitrous oxide 0.47 > 100

Desflurane 0.42 6-7

Sevoflurane 0.69 2.0

Isoflurane 1.40 1.4

Enflurane 1.80 1.7

Halothane 2.30 0.75

Methoxyflurane 12.00 0.16

MAC = a measure of potencyA close correlation with lipid solubilityie. Overton-Meyer correlation.


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Correlation of anaesthetic potency with lipid:gas partition coefficient.Anaesthetic potency in humans is expressed as minimum alveolar partialpressure (MAC) required to produce surgical anaesthesia. There is a close

correlation with lipid solubility, expressed as the oil:gas partition coefficient.


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ELIMINATION

Mainly via lungs

Low blood solubilityLow brain solubility

Faster elimination

Liver metabolism:

Methoxyflurane > Halothane > Isoflurane > Nitrous oxide

TOXICITY PARTLY RELATED TO METABOLISM:Halothane Trifluoroacetic acid + Br - + Cl

(normal pathway)Halothane Chlorotrifluoroethyl free radical

(low O2 tension) (HEPATOTOXIC)

Methoxyflurane Fl ions (NEPHROTOXIC)


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used in surgery and dentistry

for its anaesthetic + analgesic effects.

Anaesthesia:together with other inhalationalor i.v. agents.concentration: 50-70% in oxygen

Note: NOT suitableas sole anaesthetic

Analgesiaconcentration 50% in oxygen (ENTONOX ) analgesia without loss of consciousness

NITROUS OXIDE

sweet smelling + taste + irritant.


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NITROUS OXIDE

Onset of action:

rapid, beginning within 15 - 30 s.

Duration of action:last around 1 - 3 m.unless more of the gas is administered,

it will be out of the system within 5 - 10 m.

Side effects:risk of bone marrow depression

(accumulates in gaseous cavities).megaloblastic anaemia.

Contraindication:pregnancy (teratogenic + foetotoxic).


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OTHER INHALATIONAL AGENTS

Ether:

analgesic + muscle relaxant properties.

obsolete except where modern facilities are not available.

slow onset + recovery, with postoperative nausea + vomiting. highly explosive.

irritant to respiratory tract.
http://wiki.chemprime.chemeddl.org/images/9/93/Various_ethers.jpg


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Enflurane:faster induction + recoverythan halothane

(less accumulation in fat)less metabolism thanhalothane, less risk oftoxicity.some risk of epilepsy-like

seizures.

Isoflurane:similar to enfluranebut lacks

epileptogenicity.may precipitate myocardialischaemia in patients withcoronary disease.irritant to respiratory tract.

Desflurane:similar to isoflurane but with

faster onset and recovery.respiratory irritant, so liable tocause coughing andlaryngospasmuseful for day case surgery.

Sevoflurane:

similar to desflurane, with

lack of respiratoryirritation.


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TOXICITY OF HHC ANAESTHESIA

Hepatotoxicity (esp. halothane- hepatitis)

Nephrotoxicity(esp. methoxyflurane)

Malignant hyperthermia:all HHC anaesthetics - potentially lethal. genetic disorder of skeletal muscle

in susceptible individuals under HHC.

symptoms include: tachycardia, hypertension,muscle rigidity, hypoterthermia due to excessive release of Ca2+

from the sarcoplasmic reticulum of skeletal muscle.


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Intravenous anaesthetics act much more rapidly,

producing unconsciousness in about 20 seconds

as soon as the drug reaches the brain

from its site of injection.

Example:

thiopentone

etomidate

propofol are normally used for induction of

anaesthesia.

Intravenous Agents


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Intravenous Agents

1. Barbiturates

thiopentone methohexital secobarbital

2. Propofol

3. Ketamine

4. Benzodiazepines

midazolam diazepam

5. Opioid analgesics fentanyl sufentanil remifentanil

6. Misc. sedative-hypnotics etomidate

dexmedetomidine


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KETAMINE

Ketamine is used for veterinary medicine.

slow onset BUT rapid-acting GA& causes profound analgesia+ has a wide margin of safety.MOA: on multiple receptors(the nightmare of the pharmacologist).

a dissociative anaesthetic (1963) to replacephencyclidine (PCP) ie. psychomimetic.

misused & abused drug ie. Super K" or "K. pleasant feeling of being floating + dreamy

states + hallucinations + amnesia, BP + respiratory depression.

bladder dysfunction.


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PROPOFOL

milk of amnesia ~ barbiturates (i.v.)

fast onset, very fast recoverywith NO hangover.very rapidly liver metabolism+ excreted in urine.

patients feel better,in immediate post-op periodbecause nausea + vomiting.

causes PAIN at injection site(with pain killers eg. opioid)


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PROPOFOL

MOA:GABAA receptor as a potential target of

anesthetics acton.

Uses:

induction and maintenance ofanaesthesia as part of total i.v. orbalanced anaesthesia. prolonged sedation in ICU patients

(continuous infusion).

Adverse effects:BP.

cardiovascular & respiratory depression,


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CONCLUDING REMARKS:Ideal Properties of Anaesthetic Drugs

1. Smooth + rapid inductionof anaesthesia

2. Rapid recovery

after cessation3. Minimum adverse effects

4. Wide margin of safety

5. Adequate

skeletal muscle relaxation

Combination of drugs anaesthetic protocols


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SUMMARY


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Drug type and name Mechanism of action

Inhalational

HalothaneEnfluraneIsofluraneMethoxyfluraneDesfluraneSevoflurane

Nitrous oxide

Non-specific interactions of these agents with thelipid matrix of the nerve membrane which leads tosecondary changes in ion flux?Directly act at the GABAA receptor-chloridechannel?

Intravenous

BarbituratesBDZ

Facilitate inhibitory action of GABA at the GABAAreceptor by altering Cl- channel opening

Opioids Agonists at opioid receptors

Propofol Unclear

Ketamine Antagonist at the NMDA subtype of the excitatoryglutamic acid receptor


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Drug Speed ofinduction and

recovery

Main unwanted effect(s) Notes

Thiopental Fast

(cumulationoccurs, givingslow recovery)'Hangover'

Cardiovascular and

respiratory depression

Widely used as induction agent for

routine purposes

Etomidate Fast onset,fairly fastrecovery

Excitatory effects duringinduction and recoveryAdrenocortical suppression

Less cardiovascular and respiratorydepression than with thiopentalCauses pain at injection site

Propofol Fast onset,very fastrecovery

Cardiovascular andrespiratory depression

Rapidly metabolised Possible to useas continuous infusion Causes painat injection site

Ketamine Slow onset,after-effects

common duringrecovery

Psychotomimetic effectsfollowing recovery

Postoperative nausea,vomiting and salivationRaised intracranialpressure

Produces good analgesia andamnesia

Midazolam Slower thanother agents

- Little respiratory or cardiovasculardepression


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LOCAL

ANAESTHETICS

1885 Advertisement


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LOCAL ANAESTHETICS

a transient loss of sensation in a defined region

without producing a loss of consciousness. reversibly depress excitation of nerve endings; blockade of impulse conduction

along nerve axons from site of pain stimulus to CNS.

-100

-50

0

50

0 5 10 15

Milliseconds

Transmemb

ranepotential

(m

V)

Resting RestingUndershoot

D

epo

larizati

on

Re

polarizatio

n

Action Potential

ChannelOpens

ChannelCloses

Cocaineblocks


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History

Cocaine is found in the leaves of

Erythroxylon coca, a South American shrub(high altitude in the Andes).Cocaine was introduced into clinical use bychemist Albert Niemann as a local anaestheticin Germany in 1884.

Physician Sigmund Freud used the stimulanteffect of cocaine to treat morphine addiction inpatients.

In 1884, an ophthalmologist Carl Koller used it

as the first local anaesthetic on a patient withglaucoma.1886: John S. Pemberton invented Coca Cola,combining cocaine with Cola nitidaextract(kola nut).


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Sodium ChannelsA small machine with:Ion selector

(very specific for Na+) Voltage sensor

Gate connected tovoltage sensor

opens when voltagerises, Na+ enters cell.

Inactivation gatecloses when voltagegets to +30 mV, endingNa+ flux.

SelectivityFilter

Gate

Inactivationgate

Voltagesensor

Outside

+++++

- - - - -

Inside

70-90mV atrest

LocalAnaesthetic

Mechanism of Action:


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Local anesthetics blocks Na+ channel

from intracellular side:must enter neuron to work lipophilicity, potency [unionized], potency

adding bicarbonate,unionized fraction

Tetrodotoxin (TTX) binds Na+ channel from outside.

Mechanism of Action:

Zombie powder


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Factors Affecting Reaction of Local Anaesthetics

Lipid solubilitylipid solubility nerve penetration,

block sodium channels + faster onset of action.more tightly local anaesthetics bind to protein,

duration of onset action.

All local anesthetics are weak bases.So, [unionized], faster onset action.

pH influence

usually at range 7.6 8.9.adding bicarbonate, rate of onset.in pH shifts equilibrium

towards [ionized] form,delaying onset action.


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Potency, pKa, Lipophilicity

Drug pKa Octanol/H2OLow Potency

Procaine 8.9 100

Intermediate potency

Mepivacaine 7.7 130Prilocaine 8.0 129

Chloroprocaine 9.1 810

Lidocaine 7.8 366

High potency

Tetracaine 8.4 5822Bupivacaine 8.1 3420

Etidocaine 7.9 7320

Ropivacaine 8.1

Levobupivacaine 8.1 3420


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VasodilationVasoconstrictor keeps anaesthetic at a longer period +prolongs action. delays absorption into bloodstream rate at which drug washes away

eg. adrenaline (epinephrine) decreases vasodilator.

Side effects of adrenalineadrenaline heart beat stronger & faster

+ makes people feel nervous.

Factors Affecting Reaction of Local Anaesthetics


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Small diameter nerves are more easily blocked

than large diameter nervesMyelinated nerves will be blocked beforeunmyelinated nerves.Nerves that fire frequently are preferentially blocked

over nerves that fire infrequently.

Nerves Action:


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LOCAL ANAESTHETICS

ESTER GROUPProcaine (prototype)Tetracaine

BenzocaineCocaine

AMIDE GROUPLidocaine (prototype)

MepivacaineBupivacainePrilocaineRopivacaine

1. Short-acting :Procaine

2. Intermediate-acting:

LidocaineMepivacaineCocainePrilocaine

3. Long-acting:TetracaineBupivacaineRopivacaine

Administration: injection or topical


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LAs are weak bases (lipid soluble) + 3 amines.


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Pharmacokinetics

Systemic absorption is determined by:

dose & physicochemical properties of drug use of vasoconstrictor agent tissue perfusion, site of injection +drug-tissue binding

Metabolism:- ester-linked LA (e.g. procaine)

rapidly hydrolyzed by plasma cholinesteraseto produce p-aminobenzoic acid derivatives short t

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- amide-linked LA (e.g. lignocaine, prilocaine)metabolised mainly by N-dealkylation in liver(metabolites often active) longer activity


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METHODS OF ADMINISTRATION

1. Surface anaesthesia

topical application to external or mucous surface.

LA must penetrate tissues.

2. Infiltration anaesthesia

Injected directly into tissues

to act on local nerve endings,

usually with a vasoconstrictor(adrenaline).

Effects of vasoconstrictors: in effect of LA and duration of effect of LA in toxicity of LA


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METHODS OF ADMINISTRATION

3. Nerve block

i. In spinal anaesthesia- intrathecal block.

ii. In epidural anaesthesia- injected outside dura.

iii. infiltration of anaesthetic- around a single nerve

or nerve trunks.

4. IV regional anaesthesiai.v. into an exsanguinated limb(Biers block).A tourniquet prevents agent

reaching systemic circulation.


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Toxicity

LAs depress other excitable tissues:

BRAIN (CNS) HEART

smooth muscle

neuromuscular junction

TWO major forms of LA toxicity:

Systemic toxicity ???????

Direct neurotoxicity from local effects of drugs when

administered close to spinal cord and other majornerve trunks

>> lidocaine transient neuropathic symptoms

e.g for spinal anaesthesia
http://www.fi.edu/learn/heart/enrichment/images/heart.jpg


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ESTER-LINKED LA

PROCAINE: Novocaine

Indications:infiltration and nerve block localanaesthesia (NOT effective for surface anaesthesia).

rapidly metabolized by esterase enzymes and used inpatients with liver dysfunction.

is not sufficiently effective without a vasoconstrictor.

one of the least toxic of currently available localanaesthetics.incidence of allergy is greater than amide-type agents.should not be used in patients taking sulfonamide. Adverse effects:

acute toxicityallergy

vasodilation


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AMIDE-LINKED LA

LIDOCAINE (lignocaine) : prototype local anaesthetic.

Indications:

all types of LA ( infiltration, nerve block, topically)

also as antiarrhythmic agent

anaesthesia of only short duration when used without avasoconstrictor.

Pharmacokinetic:quickly absorbed + dealkylated in liver.

Toxicity:-ventricular fibrilation or cardiac arrest (massive OD).-CNS effects.-Intermediate in toxicity: twice as toxic as procaine but

1307750086 general local anaesthetics - fsk 2011

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