View
302
Download
0
Category
Preview:
Citation preview
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
1/48
GENERAL
ANAESTHESIA
ASSOCIATE PROFESSOR DR ROHI GHAZALI
Father of Modern Anaesthesia, W.T.G Morton using ether
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
2/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
3/48
GENERAL ANAESTHETICS
reversible loss ofconciousness
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
4/48
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)
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
5/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
6/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
7/48
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.png8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
8/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
9/48
Pathway for General Anaesthetics
DEPTH of anaesthesia induced by an inhaled anesthetic
depends primarily on the PARTIAL PRESSURE
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
10/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
11/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
12/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
13/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
14/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
15/48
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)
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
16/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
17/48
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).
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
18/48
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.jpg8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
19/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
20/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
21/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
22/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
23/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
24/48
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)
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
25/48
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,
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
26/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
27/48
SUMMARY
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
28/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
29/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
30/48
LOCAL
ANAESTHETICS
1885 Advertisement
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
31/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
32/48
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).
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
33/48
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:
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
34/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
35/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
36/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
37/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
38/48
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:
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
39/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
40/48
LAs are weak bases (lipid soluble) + 3 amines.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
41/48
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
1/2
- amide-linked LA (e.g. lignocaine, prilocaine)metabolised mainly by N-dealkylation in liver(metabolites often active) longer activity
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
42/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
43/48
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.
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
44/48
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.jpg8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
45/48
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
8/3/2019 1307750086 General Local Anaesthetics - Fsk 2011
46/48
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
Recommended