GA Types and Mechanisms

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Amnesia
sedation
Hypnosis
Coma
Death
Awake

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General anesthetics (GA)
•Depress CNS to the extent that permit
performance of surgery & other
noxious/unpleasant procedures
•Physiologic state induced by GA
– analgesia
– amnesia
– loss of consciousness
– inhibition of sensory & autonomic reflexes
– skeletal muscle relaxation

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Property of an Ideal anesthetic
1.For patient
• Pleasant, non-irritant, not cause nausea,
vomiting & with wide margin of safty
•Fast induction & recovery without after effect
2.For the surgeon
•Adequate analgesia, immobility and muscle
relaxation
3.For the anesthetist
•Easy administration, controllable and versatile
General anesthetics

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No single anesthetic has all these
Balanced anesthesia, pre and post oprative
medications are required
General anesthetics

STAGES OF GENERAL ANESTHESIA
1. Stage of analgesia: The patient initially experiences analgesia
without amnesia. Later, both analgesia and amnesia are produced.
2. Stage of excitement: During this stage, the patient often appears
to be delirious and may vocalize but is definitely amnesic.
3. Stage of surgical anesthesia: This stage begins with the
recurrence of regular respiration and extends to complete cessation
of respiration (apnea).
4. Stage of medullary depression: Includes severe depression of
the vasomotor center in the medulla, as well as the respiratory
center. Without circulatory and respiratory support, the patient dies.
7

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• Most anaesthetics enhance activity of inhibitory
GABAA receptors, and inhibit activation of
excitatory receptors such as glutamate and nAch
receptors
• However individual anaesthetics differ in their
actions and affect cellular function in several
different ways
Mechanism of action GA

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1. Inhaled anesthetics (gases or volatile liquids)
Types of GA
•Enflurane
•Halothane
•Ethoxyflurane
•Nitrous oxide
•Diethyl ether
•Xenon
• Desflurane
• Sevoflurane
• Isoflurane
(Most commonly used)

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Main factors that determine the speed of induction
and recovery of inhalational anesthetic
• Properties of the anaesthetic
–solubility in blood (blood:gas partition coefficient)
–Partial pressure of anesthetics
–lipid solubility (oil:gas partition coefficient)
• Physiological factors
–alveolar ventilation rate
–cardiac output (CO)
greater induction time
Increased CO

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• Rapid induction and recovery allowing flexible
control over the depth of anaesthesia
• low solubility in blood produce rapid induction and
recovery (e.g. nitrous oxide, desflurane)
• High solubility in blood - slow induction and
recovery (e.g.halothane)
• High lipid solubility (e.g. halothane) accumulate
gradually in body

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•Potency expressed as Minimal Alveolar Conc (MAC)
•1MAC = the lowest concentration of anaesthetics in
alveoli needed to produce immobility in response to
a painful stimulus (surgical incision) in 50%
individuals
Steady-state alveolar concentration provide relative
potencies of GA
–MAC inversely proportional to potency
–The MAC value for nitrous oxide is greater than
100% (least potent)
Measurement of anesthetic potency

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Anes
theti
c
Blood:Gas
Partition
Coefficient1
Brain:Blood
Partition
Coefficient1
Minimal Alveolar
Conc (MAC) (%)2
Meta
bolis
m
Comments
Nitrous
oxide
0.47 1.1 > 100 None Incomplete anesthetic; rapid
onset and recovery
Desflur
ane
0.42 1.3 6–7 <
0.05%
Low volatility; poor
induction agent; rapid
recovery
Sevoflu
rane
0.69 1.7 2.0 2–5%
(fluoride
)
Rapid onset and recovery;
unstable in soda-lime
Isoflura
ne
1.40 2.6 1.40 < 2% Medium rate of onset and
recovery
Enflura
ne
1.80 1.4 1.7 8% Medium rate of onset and
recovery
Halotha
ne
2.30 2.9 0.75 > 40% Medium rate of onset and
recovery
Methox
yfluran
e
12 2.0 0.16 > 70%
(fluoride
)
Very slow onset and
recovery
anesthetic potency

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• Respiration
– Depressed respiration and response to CO2
• Kidney
– Depression of renal blood flow and urine
output
• Muscle
– High concentrations will relax skeletal muscle
General actions of inhaled anesthetics

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•CVS
– Generalized reduction in arterial pressure and
peripheral vascular resistance
•CNS
– Increased cerebral blood flow and decreased
cerebral metabolism
•Liver
– Conc-dependent decrease in hepatic blood flow
– permanent changes in liver enzyme function are
rare
General actions of inhaled anesthetics

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• Hepatotoxicity (halothane)
• Nephrotoxicity
• Malignant hyperthermia
• Mutagenicity
• Carcinogenicity
• Hematotoxicity
Toxicity

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Individual inhalation anaesthetics
• Halothane (widely used)
– potent, non-explosive and non-irritant,
hypotensive
– 'hangover' likely, due to high lipid solubility
– risk of liver damage if used repeatedly

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• Nitrous oxide
– low potency, therefore must be combined with
other agents
– rapid induction and recovery
– good analgesic properties
– risk of bone marrow depression with
prolonged administration

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• Enflurane
– less metabolism than halothane , therefore
less risk of toxicity
– faster induction and recovery than halothane
(less accumulation in fat)
– some risk of epilepsy-like seizures

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• Isoflurane
– similar to enflurane but lacks epileptogenic
property
– may precipitate myocardial ischemia in
patients with coronary disease
– irritant to respiratory tract

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• Desflurane
– similar to isoflurane but with faster onset and
recovery
– respiratory irritant, so liable to cause coughing
and laryngospasm
• Sevoflurane
– similar to deslurane with lack of respiratory
irritation

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• Ether
– obsolete except where modern facilities are
not available
– easy to administer and control
– slow onset and recovery, with postoperative
nausea and vomiting
– analgesic and muscle relaxant properties
– highly explosive
– irritant to respiratory tract

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2. Intravenous anesthetics
•Barbiturates (eg, thiopental, methohexital)
•Propofol
• Ketamine
• Etomidate
•Dexmedetomidine
Types of GA

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• I.V. anaesthetics have faster onset of action than
the most rapid inhaled agents (eg. desflurane
and sevoflurane)
• Used for induction of general anesthesia
• Rapid recovery and used for short ambulatory
(outpatient) surgical procedures
Intravenous anesthetics

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Thiopental (barbiturate)
• high lipid solubility
• Rapid action due to rapid transfer across BBB
• Short duration due to redistribution
• Slowly metabolised and liable to accumulate in
body fat
• No analgesic effect
Adverse effects
– narrow margin between anaesthetic dose and
dose causing cardiovascular depression
– risk of severe vasospasm if accidentally
injected into artery

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Etomidate
• Similar to thiopental but more quickly
metabolised
• Causes minimal cardiovascular and respiratory
depression(compared to other i.v.anesthetics)
• Used for induction of anesthesia in patients with
limited cardiovascular reserve
• Minimal hypotension even in elderly patients
with poor cardiovascular reserve

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Etomidate
Adverse effects
•Pain on injection
•Postoperative nausea and vomiting
•Prolonged use may cause suppresses of adrenal
steroids production
(not to be used for patients with adrenal insufficiency)
•Prolonged infusion to critically ill patients may
result in
– hypotension and electrolyte imbalance
– oliguria b/c of its adrenal suppressive effects

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Propofol
• Rapidly metabolized / rapid recovery with out
hangover
• Patients are able to ambulate earlier after general
anesthesia
• less postoperative nausea and vomiting
• For induction and maintenance of anesthesia as
part of total intravenous or balanced anesthesia
• Effective to induce prolonged sedation for patients
in critical care settings (prolonged infusion )

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ketamine
• MoA: may involve blockage of glutamate on
NMDA receptor subtype
• The only i.v anesthetic with analgesic & dose-
related cardiovascular stimulation effects
• cardiovascular effects via
– stimulating central sympathetic nervous
system
– to some extent by inhibiting the reuptake of NE
• Slow onset of action (2-5 minutes)

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• Increases cerebral blood flow, oxygen
consumption, & intracranial pressure
• Causes dissociative anesthesia (patient may
remain conscious)
ketamine

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3. Balanced anesthesia
•Combination of i.v and inhaled anesthetics
– i.v.( induction of anesthesia)
– inhaled (maintenance of anesthesia)
•Muscle relaxants used to facilitate tracheal
intubation and optimize surgical conditions
•Local anesthetics provide perioperative analgesia
•Potent opioid analgesics and cardiovascular
drugs (eg, β-blockers, α2 agonists, Ca 2+ channel
blockers)
Types of GA

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Characteristics of Intravenous Anesthetics.
Drug Induction and Recovery Comments
Etomidate Rapid onset and moderately
fast recovery
Cardiovascular stability; decreased
steroidogenesis; involuntary muscle
movements
Ketamine Moderately rapid onset and
recovery
Cardiovascular stimulation; increased
cerebral blood flow; emergence reactions
impair recovery
Midazolam Slow onset and recovery Used in balanced anesthesia and conscious
sedation; cardiovascular stability; marked
amnesia
Propofol Rapid onset and rapid
recovery
Used in induction and for maintenance;
hypotension; useful antiemetic action
Thiopental Rapid onset and rapid
recovery (bolus dose)—
slow recovery following
infusion
Standard induction agent; cardiovascular
depression; avoid in porphyrias
Fentanyl Slow onset and recovery Used in balanced anesthesia and conscious
sedation; marked analgesia

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• Preanesthetic medications
–Anticholinergics
–Anxiolytics
–Antiemetics
–Antacids
• Post anesthetic medications
–Analgesics

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Comparing features of general & local anesthesia
GA LA
Site of action CNS PNS
Area of body involved Whole body Restricted area
Consciousness lost Maintained
Care for vital functions Essential Not needed
For poor health patient Risky Safer
Surgery For major surgery For minor surgery
Use in non cooperative
patients
Possible Difficult
MoA Enhance inhibitory &
inhibit excitatory NTs
actions
↓Na+ entry
Local anaesthetics

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•Coca leaves used to be chewed for numbing effect
they produced on mouth and tongue
•The leaves contains cocaine
•Cocaine was the 1st local anaesthetic proposed for
surgical procedures
•Sigmund Freud studied cocaine's physiological
actions
•Carl Koller introduced cocaine as ophthalmic
anesthetic
Local anaesthetics

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Chemistry of LAs
• Most local anesthetic agents consist of
• hydrophobic /lipophilic group
• Amine substituents /ionizable group
– separated by an intermediate ester or
amide linkage
Benzocaine does not have basic / ionizable
group

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Cocaine
Procaine
Tetracaine
Benzocaine
Lipophilic
group
Ester
bond
Amine
substituents
Chemistry of LAs

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Lidocaine
Mepivacaine
Bupivicaine
Prilocaine
Ropivacaine
Chemistry of LAs

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•Ester links prone to hydrolysis in plasma or
tissue by non-specific esterases & have short
duration of action
•Amide links are more stable & have longer
plasma half lives
•LAs are weak bases with pKa values mainly in
the range 8-9
Chemistry of LAs

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Pharmacokinetics (ADME)
Absorption of LA determined by
–dosage
–site of injection
–drug-tissue binding
–local blood flow
–presence of vasoconstrictors
–physicochemical property of the drug

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• Distribution
– Amides well distributed
– Initial distribution to highly perfused organs
(Brain , heart, kidney, liver)
Pharmacokinetics

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•Amide type (in liver) or ester type(in plasma)
converted to more water-soluble metabolites
•Ester-type LAs hydrolyzed very rapidly in the blood
to inactive metabolites
– Enzyme: plasma butyrylcholinesterase
(pseudocholinesterase)
•Amides metabolised in liver
– Enzyme: microsomal cytochrome P450
Metabolism
Pharmacokinetics

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•Amide metabolism depends on
• liver disease & hepatic blood flow
• competition for the same enzyme
•Toxicity from amide type LAs is more likely to
occur in patients with hepatic disease
• Reduced hepatic blood flow decreased hepatic
elimination of LAs
– volatile anesthetics reduce liver blood flow
Pharmacokinetics

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Excretion
•Acidification of urine promotes ionization of the
tertiary amine base to the more water-soluble
charged form
•more readily excreted
•Unionized form diffuse readily through lipid
membranes, little/no urinary excretion of the neutral
form occurs
Pharmacokinetics

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•LAs block voltage-gated Na+ channel
•Bind the intracellular component of the channel
•LAs block the initiation & propagation of action
potentials by preventing the voltage-dependent
increase in Na+ conductance
•Use dependent effect
– Cationic form of LA is able to interact with the
receptor only when the channel is open
– No significant affinity for resting channels
Mechanism of action Pharmacodynamics

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• LAs prolong inactive state of the channel & it
will take longer time for recovery
• Higher Ca2+ concentration reduce inactivation of
Na+ channel & lowers LA effects
• K+ increases the activity of LA
Mechanism of action

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Use and techniques of LAs
1. Topical /surface anaesthesia
– Applied to mucus membrane & abraded skin
– Only superficial layer is anaesthetized
– Onset & duration of action depends on the site,
the drug, conc.,& form
– Typically are used LAs; tetracaine (2%), lidocaine
(2% to 10%) & cocaine (1% to 4%)
– Dosage form could be
Drops, ointment, cream, spray, suspension,
suppository

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2. Infiltration anesthesia
•Dilute solution of LA is infiltrated under the skin in
the area of operation - block sensory nerve endings
•Duration of action can be approximately doubled
by adding epinephrine to the injection solution
•Epinephrine-containing solutions should not be
injected into tissues supplied by end arteries (Eg.
ears, nose, penis, fingers & toes)
– vasoconstriction may cause gangrene
•Commonly used; lidocaine (0.5% to 1%), procaine
(0.5% to 1%) & bupivacaine (0.125% to 0.25

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3. Conduction block
3.1.Field block anaesthesia
• Injecting LA subcutaneously so that all nerves
coming to a particular field are blocked
• Used in case of appendicectomy,dental
procedure, scalp stitching, operation of forearms
& legs, etc

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3. Conduction block
3.2.Nerve block anaesthesia
• Injecting LA into or about individual peripheral
nerves or nerve plexuses
• Blockade of mixed peripheral nerves & nerve
plexuses anesthetizes somatic motor nerves
– producing skeletal muscle relaxation & is
essential for some surgical procedures
• Produces greater areas of anesthesia than the
topical & infltiration anaesthesia do

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4. Spinal Anesthesia
• Injection of LA into the cerebrospinal fluid (CSF)
in the lumbar space
• Safe & effective technique, especially during
surgery involving the lower abdomen, the lower
extremities & the perineum
5. Epidural anesthesia
• Injecting into the epidural space

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CNS effects
• All LAs produce sequence of stimulation
followed by depression
• Initial stimulation is due to inhibition of inhibitory
NTs & at high dose all neurons are inhibited
• Cociane is powerful CNS stimulant causing the
following effects in sequence
– Euphoria/excitement--mental confusion--
convulsion--unconsciousness--respiratory
depression--death
– Effect is concentration dependent

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• Procaine & other synthetic LAs
– Produce little CNS effects at safe clinical dose
– Higher dose produce CNS stimulation followed
by depression
• Lidocaine
– Initially causes drowsiness & lethargy
– At higher dose it produces excitation followed by
depression

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Toxicity
Two major forms of LAs toxicity
1. Systemic effects
•CNS
•CVS
•Hematological
• Allergic reactions from p-aminobenzoic acid
derivatives (ester link LAs metabolite)
2. Direct neurotoxicity from the local effects
•At high concentration

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