GENERAL

ANESTHETICS
 Anesthesia
• A better way to explain in three Stages…

• INDUCTION…the period of time from the onset of

administration to the development of anesthesia.

• MAINTENANCE… Sustained surgical anesthesia.

• RECOVERY…The time from discontinuation of

administration of anesthesia until consciousness and
physiological reflexes are regained.
HISTORY OF ANESTHESIA • • • • • • • • •
 General anesthesia was absent until the mid-1800s.
Ether synthesized in 1540 by cordus

 Ether used as anesthetic in 1842 by dr. Crawford W.Long

Ether publicized as anesthetic in 1846 by dr. William morton.

 Ether is no longer used in modern practice, yet considered to

be the first “ideal” anesthetic

 Chloroform used as anesthetic in 1853 by dr. John snow

Thiopental first used in 1934

Curare first used in 1942 - opened the “Age of anesthesia”

 Anesthetics

Local General
anesthetics anaesthetics
What is General Anesthesia?

Do you think I should give him 50 or 100?

 General Anaesthetics
The neurophysiologic state produced by general
anaesthetic is characterized by five primary
effects
O Unconsciousness
O Amnesia
O Analgesia
O Inhibition of autonomic reflexes
O Skeletal muscle relaxation
 Classification of General
Anesthetics
Inhalation anesthetics

Intravenous anesthetics
 INHALATION ANESTHETICS
Nitrous oxide (Gas)

Halothane
Enflurane
Volatile liquids
Isoflurane
Desflurane
Sevoflurane
Methoxyflurane

Ether, Cyclopropane, Chloroform

 INTRAVENOUS ANESTHETICS

 Barbiturates (Thiopental, Methohexital)

 Benzodiazepines (Midazolam, Diazepam)
 Opioid Analgesics (Morphine, Fentanyl,
Alfentanil, Remifentanil)
 Propofol
 Ketamine
 Etomidate
 IDEAL ANESTHETIC
 Induce anesthesia smoothly and rapidly
 Permit rapid recovery (rapidly reversible on
discontinuation)
 Possess a wide range of safety
 Devoid of adverse effects

But
No single anesthetic is capable of achieving all these goals
 SIGNS AND STAGES OF ANESTHESIA
(GUEDEL’S SIGNS)

Stage I -Analgesia
Stage II-Excitement
Stage III-Surgical Anesthesia(4 planes).
Stage IV-Medullary Depression
 Stages of General Anesthesia
Stage I: Disorientation, altered consciousness

Stage II: Excitatory stage, delirium, uncontrolled movement, irregular breathing. Goal
is to move through this stage as rapidly as possible.

Stage III: Surgical anesthesia; return of regular respiration.

Plane 1: “light” anesthesia

Plane 2: Loss of blink reflex, regular respiration . Surgical procedures can be

performed at this stage.

Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation needed. Level

of anesthesia for painful surgeries

Plane 4: Diaphragmatic respiration only, assisted ventilation is required.

Cardiovascular impairment.

Stage IV: Too deep; essentially an overdose and represents anesthetic crisis. This is the
stage between respiratory arrest and death due to circulatory collapse.
 INHALED
ANAESTHETICS
* INHALED ANESTHETIC
Pharmacokinetics
Taken up by gaseous exchange in alveoli
Alveoli Blood Compartments

An ideal anesthetic should have rapid

onset(induction) and effects should be readily
terminated
*PATHWAY FOR GENERAL ANESTHETICS
The rate at which a given concentration
of anesthetic in the brain is reached
depends on the;
Anesthetic concentration in the inspired air.
Solubility properties of anesthetic
Cardiac output
Pulmonary ventilation rate
Pulmonary blood flow
Alveolar venous partial pressure difference
UPTAKE AND DISTRIBUTION
A.Inspired concentration & alveolar ventilation
Uptake driving force alveolar conc

Two parameters controlled by anesthesiologist

1.Partial pressure(inspired conc)
2. alveolar ventilation
Alveolar conc FA approaches 1
Inspired airFI Faster
anesthesia
induction
The magnitude of effect varies according to blood-gas partition
co-effcient
Anesthetic concentration in the inspired air
Increases in the inspired anesthetic concentration
will increase the rate of induction of anesthesia

Advantage: for anesthetics with moderate blood solubility

(Enflurane, Isoflurane, Halothane). With a relatively slow
onset of action e.g. 3-4 % concentration of halothane
administered initially to increase the rate of induction.
This is reduced to 1-2 % for maintenance when adequate
anesthesia is achieved
 * SOLUBILITY
Transfer of anesthetic from the lungs to the arterial blood
Blood:Gas partition coefficient:
Relative affinity of an anesthetic for the blood compared to air.
Useful index of solubility.
Anesthetic Partition Coefficient
Low (i.e. not very
Nitrous Oxide 0.47 soluble in blood)
Desflurane 0.42
Sevoflurane 0.69
Isoflurane 1.40 High (>10) (very
Enflurane 1.80 soluble in blood)
Halothane 2.30
Methoxyflurane 12
 Airway Alveoli Blood Brain

Nitrous oxide with low solubility in blood reaches

high arterial tensions rapidly, which in turn results
in more rapid equilibrium with the brain and faster
induction of anesthesia
 Airway Alveoli Blood Brain

It will take much longer time for blood partial pressure

of more soluble gas (halothane) to rise to the same
partial pressure as in the alveoli. Onset of anesthesia will be
slower with halothane than with nitrous oxide
 Pulmonary blood flow

An increase in pulmonary blood flow

(increased cardiac output) slows the rate the
rise in arterial tension, particularly for those
anesthetics with moderate to high blood
solubility

Decrease in pulmonary flow has opposite effect

 ARTERIOVENOUS CONCENTRATION
GRADIENT

Depends mainly on uptake of anesthetic by the tissues.

Depending on the rate and extent of tissue uptake

Venous blood returning to the lungs may contain significantly
less anesthetic than that present in blood.

Anesthetic entry into tissues is influenced by

Tissue : Blood partition coefficient
Rates of blood flow to tissues
Concentration gradients
 During the induction phase of anesthesia

The tissues that exert greatest influence on the arterial –

venous anesthetic concentration gradient

are those which are highly perfused.

Include: brain, liver, Kidney and splanchnic bed.

 ELIMINATION

Time to recovery from inhalation anesthetics depends on

Rate of elimination of anesthetic from brain

after the inspired concentration of anesthetic has been

decreased.
 Factors affecting rate of recovery

Blood:gas partition coefficient

Pulmonary blood flow
Magnitude of ventilation
Solubility of anesthetic in the tissues
Duration of exposure
Inhaled anesthetics that are relatively insoluble in blood and brain
are eliminated at faster rates than more soluble anesthetics
e.g.Nitrous oxide, Desflurane, Sevoflurane leads to rapid recovery
from anesthetic effects

Halothane is twice soluble in brain

and five times more soluble in blood than
nitrous oxide, its elimination is more slowly and
recovery from anesthesia is less
rapid
 Major Route of Elimination

Lungs
Liver
(metabolism by enzymes also contibute)

e.g. washout of halothane is more rapid than that of enflurane

Which would not be predicted by their respective solubilites.
However >40% of Halothane is metabolized while <10% of enflurane
Is metabolized during an average anesthetic procedure
Chloroform (Obsolete) causes hepatoxicity associates with
free radical formation in liver cells.

Methoxyflurane (halogenated ether) is now very rarely used

because about 50% is metabolized,
generating fluoride and oxalate, which
causes renal toxicity.

Enflurane and sevoflurane also generate fluoride

Isoflurane and Desflurane are least metabolized of

fluorinated anesthetics

Halothane is only volatile anesthetic in current use that

undergoes substantial metabolism. 30% converted
to bromide, chloride and trifluoroacetic acid and
other metabolites which may rarely cause liver
toxicity.
Extent of metabolism of inhaled anesthetics

Methoxyflurane > Halothane > Enflurane >

Sevoflurane > Isoflurane > Desflurane
> Nitrous Oxide
PHARMACODY
NAMICS
 How general anesthetic work
It is not completely clear exactly how general anesthetics
work at a cellular level, but it is speculated that general
anesthetics affect:
the spinal cord (resulting in immobility),
the brain-stem reticular activating system
(resulting in unconsciousness) and
the cerebral cortex (seen as changes in electrical
activity on an electroencephalogram).
 Inhaled anesthetics (and most of the
intravenous anesthetics) depress
spontaneous and evoked activity of neurons
in many regions of the brain.

 TheMeyer-Overton correlation (or

principle) = There is a good correlation
between anesthetic potency and lipid
solubility.
 Anesthetics interact with functional
membrane proteins particularly ion channels

 Many anesthetics inhibit the function of

excitatory receptors such as: ionotropic
glutamate, acetylcholine or 5 HT receptors
As well as
 enhance the function of inhibitory receptors such
as GABAA
NMDA= N-Methyl-D-Aspartate
 Another type of channel that appears to be
specifically anesthetic sensitive is
Potassium channel (TREK)
 When activated
reduces membrane excitability
Inhaled anesthetics have been reported to cause
membrane hyperpolarization (inhibitory action)
Via their activation of Ligand gated potassium
channels

Such channels are linked to several

neurotransmitters including
acetylcholine, dopamine, nor epinephrine and serotonin.
ORGAN SYSTEM
EFFECTS OF
INHALED
1.EFFECT ON CVS
Changes in Blood pressure

 Nitrous oxide: causes an increased sympathetic

discharge and increase plasma
nor
adrenaline concentration ----
increase blood pressure

 Halothane and other halogenated anesthetics

have opposite effect
Halothane and enflurane: reduces blood
pressure by a reduction in cardiac output.

Isoflurane, Desflurane,and Sevoflurane:

reduces blood pressure as a result of
endothelium mediated decrease in systemic
vascular resistance.
changes in heart rate:
Halothane ------- Bradycardia (Vagal stimulation )

Enflurane, Methoxyflurane and Sevoflurane --- little

effect.
Desflurane and Isoflurane: increases heart rate
(sympathetic activation)

Many anesthetics specially halogenated causes

cardiac dysrthymias --- ventricular extra systoles.
(Mechanism is not clear but may involve sensitization to adrenaline).
 2. EFFECT ON RESPIRATORY
SYSTEM

With the exception of nitrous oxide

All inhaled anesthetic depress respiration

markedly and increase arterial partial pressure of
PaCO2
Bronchodilator action of inhaled anesthetic

Inhaled anesthetic tend to be

bronchodilators

Halothane: agent of choice in patients with

airway problems

(because of its bronchodilating action)

 3.EFFECTS ON KIDNEY

All inhaled anesthetics

 Decrease glomerular filtration rate
 Increase renal vascular resistance and
 Decrease effective renal plasma flow
 4 EFFECTS ON LIVER
All inhaled anesthetic:

Decrease hepatic blood flow

Transient changes in LFT’s intraoperatively
 TOXICITY
WITH
INHALED
ANESTHETICS
 HEPATOTOXICITY
Potentially severe and life threatening hepatitis
(Halothane)
{Probability: 1:20,000-35,000}

Mechanism underlying is unclear but formation of

reactive metabolites (free radicals) ---- that either cause
Direct hepatocellular damage or
Initiate immune mediated responses (auto antibodies
against hepatic proteins in a trifluoroacetylated form)
 NEPHROTOXICITY

Methoxyflurane --- limits its clinical use in

anesthesia.
Mechanism: caused by inorganic fluoride released
during metabolism of anesthetic.
Enflurane & Sevoflurane metabolism ----- formation of fluoride
ions ----- nephrotoxicity

Enflurane: changes in renal concentrating ability (prolonged use)

Sevoflurane: Compound A (Haloalkene) --- proximal tubular
necrosis (in test animals but not in humans)
 MALIGNANT
HYPERTHERMIA
• It is a rare life-threatening condition that is
genetic in origin.
• The defect is typically located on the 19 th
chromosome.
• Malignant hyperpyrexia is a rare life-threatening
condition that is usually triggered by exposure to
certain drugs used for general anesthesia —
specifically the volatile anesthetic agents and
succinylcholine, a neuromuscular blocking agent.
SIGNS AND SYMPTOMS OF MALIGNANT
HYPERTHERMIA

• A very high temperature with more than 2C 0

rise in Temperature/ hour
• Tachycardia
• Acidosis
• Hypercapnia
• Rigid muscles
TREATMENT OF MALIGNANT HYPERTHERMIA
INTRAVENOUS
ANESTHETIC
• INTRAVENOUS
ANESTHETIC
• Ultra short acting barbiturates
• Benzodiazepines
• Opioid analgesic
• Propofol
• Etomidate
• Ketamine
 ULTRA SHORT ACTING BARBITURATES
Thiopental/ Methohexital

Thiopental
• Very High lipid solubility
• Most commonly used for induction of anesthesia
Onset of action
• Rapidly crosses the blood brain barrier
• Plasma:Brain equilibrium occurs rapidly (in approx 1 min)
 METABOLISM

• Slower than its redistribution

• Takes place primarily in liver
• Metabolized at a rate of 12-16% per hour
following a single dose.

Action is not terminated by metabolism

 ACTIONS
On intravenous injection
 Causes unconsciousness within about 20 seconds
 This lasts for 5-10 minutes.
 Dose dependent decrease in arterial blood
pressure, stroke volume, cardiac output.
(myocardial depressant effect)
 Respiratory depression
(lowers the sensitivity of medullary respiratory center to CO2)
 Cerebral metabolism and oxygen
utilization are decreased

Cerebral blood flow is also decreased.

This makes thiopental a much more

desirable
drug for use in patients with cerebral swelling
than the inhaled anesthetics,
since intracranial pressure and blood volume
are not increased.
 BENZODIAZEPINES

• Diazepam
• Lorazepam
• Midazolam

• Used in anesthetic procedures

• Slower onset of CNS effect.

• Plateau of central depression appears to be below that of a true anesthetic state.

• Prolong the post anesthetic recovery period (undesirable)

• High incidence of anterograde amnesia

(amnesia for events occurring after the drug is administered)
 MIDAZOLAM
• is frequently given I/V 15-60 min before induction of GA
(high incidence of amnesia >50%)

• Rapid onset
• Shorter elimination half life (2-4 hours)
• Steeper dose response curve
 Uses of Benzodiazepines

Useful in anesthesia

 As premedication
 For Intraoperative sedation
 As part of balanced anesthesia
 Opioid analgesics
 Morphine
 Fentanyl
 Sufentanil
 Alfentanil
 Remifentanil

Larger doses of opioid analgesics have

been used to achieve general anesthesia
 FENTANYL
uses:
 Preanesthetic
 Adjunct to anesthetics

 Fentanyl + Droperidol (Neuroleptanalgesia)

 Fentanyl + Droperidol + Nitrous oxide ----
Neuroleptanesthesia
 ALFENTANIL AND
REMIFENTANIL
 Some times used for induction (rapid onset of action)

 Rapid recovery
 (useful in anesthesia regimens for ambulatory surgery )
 PROPOFOL
 Rapid induction
 Rapid recovery
 Patient feel better in immediate post
operative period
 Anti-emetic effects
 Used for both induction and maintenance
 Component of balanced anesthesia
 Popular as an anesthetic for use in day
surgery
 Ketamine
(Related to Phencyclidine [PCP])
 KETAMINE

Dissociative anesthesia
Characterized by

A condition characterized by
Catatonia/ Catalepsy
Lack of response to Amnesia
external stimuli
and by Muscular rigidity,
Analgesia
so that the limbsactual
Without remain
loss in
of consciousness
whatever position they are placed.
 MECHANISM OF ACTION

Blockage of membrane effects of

excitatory neurotransmitter glutamic
acid at NMDA receptor subtype
 Peak increase in these variables occur 2-4 min after I/V Inj
and then slowly decline to normal over the next 10-20 minutes

Increase in plasma epinephrine & Nor epinephrine occurs as

early as 2 min after i.v Ketamine & return to control levels
15 min later
 Diazepam 0.2-0.3 mg/kg i.v. 5 min
Emergence Before admin of Ketamine
reduces the incidence
phenomena
Markedly increases cerebral blood flow,
oxygen consumption and intracranial pressure
 USES

In outpatient anesthesia
In children undergoing painful procedures such as
dressing changes on burn.
In poor risk geriatric patients in shock because of
its cardio stimulant action
Etomidate
 Etomidate
Used for
• Rapid Induction (with in seconds)
• Recovery with in 3-5 min (Rapid Redistribution)
• In balanced anesthesia
• Useful in patients with limited cardiovascular reserves,
e.g., elderly patients

Major advantage:
• Minimal cardiovascular and respiratory depressant
effect (Slight hypotension, low frequency of
apnea).
 DISADVANTAGES:

• No analgesic effect
• Premedication with analgesic is required
• Nausea and vomiting
• Pain on injection
PRACTICAL APPROACH-
PROTOCOL
• Preoperative assesment
• preanaesthetic medication
• induction by thiopentone or propofol
• muscle relaxants
• intubation
• nitrous oxide +halogenated hydrocarbons
• withdraw & recovery