Prof Dr Riffat Butt

PREANAESTHETIC
MEDICATION & GENERAL
ANAESTHETIC AGENTS

Prof. Riffat M Butt

Dept. Of Pharmacology
AIMC
 Pre-anaesthetic medication

 “It is the term applied to the

administration of drugs prior to general
anaesthesia so as to make anaesthesia
safer for the patient”

 Ensures comfort to the patient & to

minimize adverse effects of anaesthesia
 Aims
 Relief of anxiety & apprehension
preoperatively & facilitate smooth
induction

 Amnesia for pre- & post-operative events

 Potentiate action of anaesthetics, so less

dose is needed
 Aims(contd.)
 Antiemetic effect extending to post-
operative period

 Decrease secretions & vagal stimulation

caused by anaesthetics

 Decrease acidity & volume of gastric

juice to prevent reflux & aspiration
pneumonia
 DRUGS USED FOR
PREANESTHETIC MEDICATION
 Anti-anxiety drugs-

- Provide relief from apprehension &

anxiety

-Pre and Post-operative amnesia

e.g. Diazepam (5-10mg oral), Lorazepam (2mg
i.m.) (avoided co-administration with
morphine, pethidine)
 Sedatives-hypnotics-

- e.g. Promethazine (25mg i.m.) has

sedative, antiemetic & anticholinergic
action

- Causes negligible respiratory

depression & suitable for children
 Opioid analgesics-

- Morphine (8-12mg i.m.) or Pethidine

(50-100mg i.m.) used one hour before
surgery

- Provide sedation, pre-& post-operative

analgesia, reduction in anaesthetic dose

- Fentanyl (50-100μg i.m. or i.v.)

preferred nowadays (just before induction
of anaesthesia)
 Anticholinergics-

- Atropine (0.5mg i.m.) or Hyoscine (0.5mg

i.m.) or Glycopyrrolate (0.1-0.3mg i.m.) one hour
before surgery.

- Reduces salivary & bronchial secretions,

vagal or sinus bradycardia, hypotension

- Glycopyrrolate(selective peripheral action)

acts rapidly, longer acting, potent anti-secretory
agent, prevents vagal bradycardia effectively
 Antiemetics-

- Metoclopramide (10mg i.m.) used as

antiemetic & as prokinetic gastric emptying
agent prior to emergency surgery

- Domperidone (10mg oral) more preferred

(does not produce extrapyramidal side effects)

- Ondansetron (4-8mg i.v.), a 5HT 3 receptor

antagonist, found effective in preventing post-
anaesthetic nausea & vomiting
 Drugs reducing acid secretion -

- Ranitidine (150-300mg oral) or

Famotidine (20-40mg oral) given night
before & in morning along with
Metoclopramide reduces risk of gastric
regurgitation & aspiration pneumonia

- Proton pump inhibitors like

Omeprazole (20mg) with Domperidone
(10mg) is preferred nowadays
GENERAL ANESTHETICS
 In early 1800, surgeons were using Alcohol, Opium,
Hyoscine, Cannabis, or a Brutal Remark, Concussion
produced by a Wooden Bowl or a Partial Suffocation for
making the patient unconscious, e.g.,

Do you think I should give him 50 or 100 ?

 For
Surgical
Procedures

patient must be
Skeletal Muscles Minimal
unaware of &
be adequately Vital Centers
unresponsive to
relaxed depression
Painful Stimuli
 ANESTHESIA

a “Reversible State” in which one is insensitive

to the trauma of surgery
or

“drug induced state” in which the patient

neither perceives nor recalls noxious
stimulation
The state of general anesthesia therefore
usually includes

A nalgesia
mnesia
 A________

consciousness
 Loss of _____________.
 Inhibition of sensory and autonomic
reflexes
 Skeletal muscle ___________
relaxation
Minimum cardiac and respiratory depression .
Types of General Anesthesia

 Inhalational anesthetics

 Intravenous anesthetics
Ideal Anesthetic

 Induces anesthesia smoothly and rapidly

 Permits rapid smooth recovery
 Possess a wide range of safety
 is devoid of adverse effects
 Level of anesthesia must be adjustable as-
required during operation

But
No single anesthetic is capable of achieving all these goals
BALANCED ANESTHESIA

 PREANESTHETIC MEDICATION with

Benzodiazepines, Anticholinergics, Opioids
 ENDOTRACHEAL INTUBATION: with
Suxamethonium
 INDUCTION (onset) OF ANESTHESIA with I/v
Thiopental, Propofol
 MAINTENANCE with Inhaled anesthetic, Enflurane
 PERIOPERATIVE MUSCLE RELAXATION with Cis
Atracurium
 PERIOPERATIVE ANALGESIA
Local anesthetic + Fentanyl by epidural inj
 CARDIOVASCULAR DRUGS
To control autonomic responses to painful stimuli: β
Blocker, Ca2+ channel blocker Opioids alone or as
adjuncts in c.v.s surgery
Inhalation Anesthetics
Inhalational Anesthetic are
small lipid soluble molecules,
which cross the alveolar membrane
with great ease.
Nitrous oxide (Gas)
Halothane
Enflurane
Isoflurane Volatile liquids
Desflurane
Sevoflurane
Methoxyflurane

Older renowned agents

Ether, Cyclopropane, Chloroform
 Anesthesiologists observe different signs &
symptoms during general anesthesia

 To observe: good operating conditions,

 To avoid: vital centers depression.

These signs and symptoms are grouped into

different stages.
These stages are well marked by the slowly
acting agents like Ether or Chloroform
 Signs and Stages of Anesthesia
( Guedel’s Signs )

I. Stage of analgesia or altered consciousness.

II. Stage of Excitement.

III. Stage of Surgical Anesthesia: 4 planes

( according to Eye Movements, Reflexes, & Pupil
Size, etc.)

IV. Stage of Medullary Depression or Paralysis,

Signs of First Stage

Analgesia, sense of smell is lost, Warm body,

Sounds in the Head, Flashes of light before eyes,
Confusion, Questions not answered, No
response to pain.

Respiration : may or may not be changed,

Pulse, BP : slightly increased ( anxiety ),
All reflexes : present;

This stage lasts until consciousness is lost.

Stage I ( of Analgesia )
 Cells of substantia gelatinosa in the dorsal horn
of spinal cord are very sensitive to relatively low
anesthetic concentration in the CNS.

 A decrease in the activity of neuron in this region

interrupts sensory transmission in the
spinothalamic tract, including transmission of
nociceptive stimuli.

 These effects contribute to the analgesia seen in

stage I
Signs of 2nd Stage

Signs more marked in otherwise healthy patients;

(usually increased autonomic activity)

Patients may move, vocalize, salivate, cough, retch or

vomit ( aspiration pneumonia ); hearing & sight lost;
Respiration: irregular & increased in depth,
Skeletal Muscles Tone: increased,
Reflexes exaggerated, (only eyelid & eyelash reflexes are
lost.)
Pupil dilated, vigorous eye movement & eyes become
divergent later
Pulse & BP much raised ( IHD ? )
Stage II ( of Excitement )

 Disinhibitory effect of General Anesthetic at

higher brain concentrations results from
blockage of many small inhibitory neurons such
as Golgi II cells,

 with the paradoxical facilitation of excitatory

neurotransmitters.
Indications to go to stage III anesthesia

 Loss of eye lash reflex.

Maintained BP , relaxed muscles
Establishment of a regular rate and
depth of respiration
 Pt unconscious, loss of pain reflexes
Stage III The stage of Surgical Anesthesia

 A progressive depression of ascending pathways

in the reticular activating system.

 with suppression of spinal reflex activity which

leads to muscle relaxation
Four Planes: depending upon Eye Movements, Reflexes &
Pupil Size.
Plane – I : begins with Plane – II : begins with
rhythmic regular respiration & ends with cessation of eye movement & ends with
cessation of eye movements. relaxation of respiration;
Pupil constricted, corneal reflex present, Respiration : shallow but regular,
eye ball centrally fixed; Pupil : half dilated, No corneal reflex,
Pulse & BP : normal Skeletal Muscles : moderately relaxed,
Superficial Skeletal Muscles relaxed; Pulse & BP : Normal
Suitable for: Thoracic surgery, Neurosurgery, Suitable for: orthopedic, abdominal surgery.

Thyroid / bladder / hernia operations.

Plane – III : begins with paralysis of Plane – IV : begins with

intercostal respiratory muscles & ends with paralysis of all respiratory muscles
paralysis of all respiratory skeletal muscles & ends with diaphragmatic paralysis.
Respiration : shallow, regular with pause; Respiration: jerky, irregular, quick inspiration
Pupils : 3/4th dilated but prolonged expiration; like “see-saw”.
Skeletal Muscles : complete relaxation, Respiration may stop at any time.
Pulse: increased ( reflex ) Skeletal Muscles : markedly relaxed,
BP : decreased Light Reflex : lost,
Suitable for: upper & lower abdominal BP : markedly decreased
surgery; breech extraction
FOUR PLANES OF SURGICAL STAGE

Plane – I : begins with

rhythmic regular respiration & ends with
cessation of eye movements.

Pupil constricted, corneal reflex present,

eye ball centrally fixed;

Pulse & BP : normal

Superficial Skeletal Muscles relaxed;

Suitable for: Thoracic surgery, Neurosurgery,

Thyroid / bladder / hernia operations.
Plane – II : begins with
cessation of eye movement & ends with
relaxation of respiration;

Respiration : shallow but regular,

Pupil : half dilated, No corneal reflex,

Skeletal Muscles : moderately relaxed,

Pulse & BP : Normal

Suitable for: orthopedic, abdominal surgery.

 Plane – III : begins with paralysis of
intercostal respiratory muscles & ends with
paralysis of all respiratory skeletal muscles

Respiration : small, regular with pause;

Pupils : 3/4th dilated

Skeletal Muscles : complete relaxation,

Pulse: increased ( reflex ) BP : decreased

Suitable for: upper & lower abdominal

surgery; breech extraction
Plane – IV : begins with
paralysis of all respiratory muscles
& ends with diaphragmatic paralysis.

Respiration: jerky, irregular, quick inspiration

but prolonged expiration; like “see-saw”.
Respiration may stop at any time.

Skeletal Muscles : markedly relaxed,

Light Reflex : lost,

BP : markedly decreased
Signs of 4th Stage:

 Respiration : stops,
 Circulation : fails,
 Skeletal Muscle Tone : completely lost,
 Urine / stool : passed,
 Skin : cold, clammy & grey,
 Eyes : fixed dry & starring,
 Pulse : imperceptible,
 Cardiac arrest may occur.
This stage is NEVER allowed to appear.
Stage IV

 Neurons in the respiratory and vasomotor

centers of the medulla are relatively insensitive
to the effects of general anesthetics,

 but at higher concentrations their activity is

depressed ---- cardio respiratory collapse
During the induction phase of anesthesia

The tissues that exert greatest influence on the

arterio–venous anesthetic concentration gradient
are those which are highly perfused.

including
brain, liver, Kidney and splanchnic bed.
 Inhaled Anesthetic

Pharmacokinetics
Depth of anesthesia :

Determined by:
concentration of anesthetics in the CNS.

Achievement of a brain concentration of an anesthetic

adequate to cause anesthesia requires:
transfer of that anesthetic from alveolar air to blood
and then to brain.
 At Equilibrium
the tension of the gas are equal in the :

Inspired air,
Alveolar air,
Arterial blood,
Body tissue,
Venous blood.
 Ideally due to uptake of the anesthetic
the concentration in blood should follow
as quickly as possible so that
depth of anesthesia can be controlled rapidly.

Similarly the blood concentration should fall

to a sub anesthetic level rapidly,
in particular when
administration of anesthetic is stopped.
 PHARMACOKINETICS
The rate at which a given concentration of
anesthetic in the brain is reached, depends on:

• the solubility properties of anesthetic

• concentration in the inspired air,
• pulmonary ventilation rate,
• pulmonary blood flow,
• arterio-venous concentration gradient.
 1. Solubility

 After transfer of anesthetic from the

lungs to the arterial blood
 Relative affinity of an anesthetic for the
blood as compared to air
i.e. Blood : Gas Partition Coefficient:
 Is a useful index of solubility.
 Anesthetic Partition
Coefficient Low
Nitrous Oxide 0.47 ( i.e.
not very soluble
Desflurane 0.42
in blood )

Sevoflurane 0.69

Isoflurane 1.40
Enflurane 1.80 High
( >10 )
Halothane 2.30
( very soluble in
Methoxyflurane 12 blood )
When an anesthetic with low blood
solubility diffuses from the lung into
the arterial blood,
relatively few molecules are required
to raise its partial pressure,
and the arterial tension rises quickly.
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 onset of action / induction of anesthesia
 Airway Alveoli Blood Brain

It will take much longer time for partial pressure in the

blood 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
 Anesthetic Concentration
2. in the Inspired Air

Increases in the inspired anesthetic

concentration will increase the speed of
induction of anesthesia
by
increasing the rate of transfer into the
blood.
 Advantage:
for anesthetics with moderate blood solubility
( Enflurane, Isoflurane, Halothane ).
with a relatively slow onset of action
3-4 % concentration of anesthetic is administered
initially to increase the speed of induction.
This is reduced to 1- 2 % for maintenance when
adequate anesthesia is achieved
3. Pulmonary Ventilation Rate

rate of rise of
anesthetic gas tension in arterial blood is
directly dependent on both
the rate and depth of ventilation i.e.
minute ventilation.
 Hyperventilation
( by mechanical control of respiration )
increases the speed of induction of
anesthesia with
inhaled anesthetic with high blood
solubility that would normally have
a slow onset
 SO Increased ventilation has a much greater effect on
equilibration of Halothane than Nitrous oxide
4. Pulmonary Blood Flow

an increase in pulmonary blood flow

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

Decrease in pulmonary flow has opposite effect

 In a patient with circulatory shock
This is because increased
the combined effects of
pulmonary blood flow
 decreased exposes
cardiac output
a (larger volume
decreased of bloodflow
pulmonary to ) &
the anesthetic
 increased ;
ventilation
thus blood capacity increases
may tension
and accelerate theslowly.
rises induction of
anesthesia with some anesthetics
5. Arterio-Venous Concentration Gradient

depends mainly on uptake of anesthetic by the tissues.

Depending on the rate and extent of tissue uptake;

venous blood returning from the tissues to the lungs
may contain significantly less anesthetic than that
present in the blood going from the lungs to the
tissues.

Anesthetic entry into tissues is influenced by

 Tissue : Blood Partition Coefficient
 Rate of blood flow to tissues
 Concentration gradients
 ALVEOLAR
CONCENTRATION
 Minimum Alveolar Concentration
( MAC )

1.0 MAC or the minimum alveolar

concentration is defined as the minimum
concentration of inhalational anesthetic that
result in immobility in 50% of pts when
exposed to a noxious stimulus (skin incision)
The potency of a given anesthetic is measured
as Minimum Alveolar Concentration (MAC).

Technically, MAC is the alveolar partial

pressure of a gas at which 50%of humans will
not respond to a skin incision

Injected liquid anesthetics have a "MAC

equivalent" which is the blood concentration of
the liquid anesthetic at which 50% of humans
will not respond to a surgical stimulus
 Anesthetic MAC Comment
Nitrous Oxide > 100
Desflurane 6-7
Sevoflurane 2.0
Isoflurane 1.40 Smaller the MAC
Enflurane 1.7 more potent the
anesthetic
Halothane 0.75
Methoxyflurane 0.16
 Elimination

Time to recover from inhalation

anesthetics depends upon the

rate of elimination of anesthetic from brain

after the inspired concentration of anesthetic
has been decreased.
 Factors Affecting Rate of Recovery

1. Blood : Gas Partition Coefficient

2. Solubility of anesthetic in the tissues
3. Magnitude of ventilation
4. Pulmonary blood flow
5. Duration of exposure
Inhaled anesthetics that are relatively insoluble

in blood and brain ( possess a low blood gas

partition coeffecient) e.g., Nitrous oxide,
Desflurane, Sevoflurane are eliminated at faster
rates and lead to rapid recovery from anesthetic
effects than more soluble anesthetics like
isoflurane and halothane

Halothane is twice soluble in brain

and five times more soluble in blood than
nitrous oxide, its elimination is more slow and
recovery from anesthesia is less rapid
 Duration of Exposure
Has marked Effect on recovery e.g.,
Methoxyflurane ( more soluble )

Accumulation of anesthetic in tissues like

skin, muscles, and fat increases with
continuous inhalation and blood tension
may decline slowly during recovery as the
anesthetic gradually leaves such tissues
 Major Route of Elimination

Liver
Lungs
( metabolism by enzymes also contribute )

Washout of halothane is more rapid than that

of enflurane which would not be predicted by
their respective solubilites. i.e. 2.30 and 1.80
 90% of inhaled anesthetics excreted
unchanged in the expired air

Most inhalational anesthetics are marginally

metabolized by the liver
e.g. Enflurane 10%

however, Halothane is 40%

metabolized by the liver
&
Methoxyflurane 70%
Chloroform ( Obsolete )
forms free radicals in the liver cells
and causes hepatic-toxicity

Methoxyflurane ( halogenated ether )

70% is metabolized in liver, generating
fluoride and oxalate, which cause
renal toxicity. SO NOT USED
 Halothane
is the only volatile anesthetic in current
use that undergoes substantial metabolism.
40% converted to trifluoroacetic acid
with release of bromide & chloride

A free radical chloro-trifluoro-ethyl is

formed in low oxygen tension which can react
with hepatic membrane components
&
CAUSE HEPATITIS
 Sevoflurane & Enflurane metabolism also
generates low fluoride levels

Sevoflurane is also degraded by contact

with CO2 absorbent in anesthesia
machines, yielding a
vinyl ether called “compound A”,
that can cause “renal damage”.

Isoflurane and Desflurane are least

metabolized fluorinated anesthetics with only
traces of trifluoroacetic acid in urine
Extent of metabolism of inhaled
anesthetics

Methoxyflurane > Halothane > Enflurane

> Sevoflurane > Isoflurane > Desflurane
> Nitrous Oxide
Pharmacodynamics
 Depress spontaneous and
evoked activity of neurons in
many regions of brain.
Anesthetics
produce
“ descending paralysis ” of CNS
in the following order:

cerebral cortex,
basal ganglia,
cerebellum,
spinal cord,
cranial nerves &
medulla oblongata.

( recovery occurs in reverse order )

 Anesthetics interact with functional
membrane proteins particularly ion channels

 Many anesthetics
 inhibit the excitatory function of ionotropic
receptors for GLUTAMATE, ACETYLCHOLINE or
5 – HT

As well as
 enhance the function of inhibitory receptors
for GABAA AND GLYCINE
Primary molecular targets of many general
anesthetics i.e.
i.e
benzodiazepine, barbiturate, propofol, etomidate
IS GABAA receptor-chloride synaptic
channel

Inhaled & I/V anesthetics ( except N2O & ketamine)

e.g., Barbiturates Propofol etc

facilitate the action of GABA at low
concentration to increase chloride ion flux,
but can also directly activate GABAA
receptors
Anesthetics e.g. Ketamine, N2O also

a). inhibit or block the excitatory amino acids :

block release of Glutamate,
block NMDA receptors
( subtype of glutamate )

( NMDA= N-Methyl-D-Aspartate)
Inhaled anesthetics may activate
Ligand gated K+ channels.
and cause inhibitory action through
membrane hyperpolarization
via their link to several
neurotransmitters including:
acetylcholine, dopamine, nor epinephrine
and serotonin.
 Systemic Effects
of
Inhaled Anesthetic
On CVS
Changes in Blood pressure
Halothane and Enflurane:
reduce blood pressure by decrease in
cardiac output

Desflurane, Isoflurane and

Sevoflurane:
reduce blood pressure as a result of
endothelial mediated decrease in
systemic vascular resistance.
ALL INHALED ANESTHETICS DECREASE MYOCARDIAL
OXYGEN CONSUMPTION
 Changes In Heart Rate

Halothane: Bradycardia ( Vagal stimulation ? ) also

sensitizes myocardium to circulating catecholamines–
ventricular arrhythmias

Enflurane, Methoxyflurane and Sevoflurane:

Sevoflurane have little
effect.

Desflurane and Isoflurane: (high levels)

BY sympathetic activation increase heart rate & BP

Halogenated anesthetics, specially cause

cardiac dysrhythmias:
 Effect on Respiratory System

All inhaled anesthetics except NO2

depress respiration & increase arterial partial
pressure of CO2.
They decrease the tidal volume and increase
the respiratory rate
but
Increase in rate is insufficient to compensate
the decrease in tidal volume ----
so there is decrease in minute ventilation.
They Increase the apneic threshold & decrease
the ventilatory response to hypoxia
 Inhaled anesthetics depress
mucociliary function in the airway.
Prolonged anesthesia may lead to
pooling of mucus and may result in
Respiratory Infections

Bronchodilator Action of inhaled

Anesthetic
Halothane & savoflurane
Produce bronchodilation
so are agent of choice for induction in
Patient with airway problems
 Desflurane causes Airway Irritation
Enflurane & Isoflurane are pungent so
breath holding and coughing are relatively
common

[ breath holding ---- limit speed of induction ]

 Effects on Brain
•INHALED ANESTHETICS
•Decrease cerebral metabolic rate & produce
vasodilation depending on the concentration
•The more soluble volatile anesthetics lead to
Decrease cerebral vascular resistance
•Increased blood flow leads to Increase in
Undesirable
cerebral blood volume and further increase
in intracranial pressure
?????????
•Undesirable in patients with brain tumor or
head injury
• hyperventilation produces vasoconstriction
• Of the inhaled anesthetic
Nitrous oxide causes increase cerebral blood
• flow by sympathetic stimulation
• It has analgesic and amnesic properties

• Enflurane & sevoflurane

• Cause cerebral irritation
• at higher doses and auditory stimuli can
• precipitate generalized muscle twitching
 Effects on Kidney

All inhaled anesthetics

 decrease the renal blood flow
Impaired effective renal autoregulation
Decrease glomerular filtration rate
Filtration fraction is maintained
Effects on Liver

All inhaled anesthetic:

Produce transient changes in LFT’s

intraoperatively
Decrease portal venous blood flow
Total hepatic blood flow maintained
due to increased hepatic arterial flow
 MUSCLE RELAXATION
 All halogenated inhalational anesthetics
produce some degree of muscle relaxation
and potentiate actions of muscle relaxants
 Enflurane > > Desflurane, isoflurane,
sevoflurane > > Halothane
 N2O does not produce muscle relaxation
 Effects on Uterine Smooth Muscles

Halogenated hydrocarbon anesthetics are

potent uterine smooth muscle relaxants

Advantage when profound uterine relaxation is

required for intrauterine manipulation during
delivery
Removal of placenta
Disadvantage: Uterine bleeding can occur
 Toxicity
with

inhaled anesthetics
Nitrous Oxide

Diffusional Hypoxia
During recovery from nitrous oxide anesthesia,
transfer of gas from the blood into the alveoli,
can be sufficient to reduce, by dilution,
Second Gas Effect ???
the alveolar partial pressure of oxygen,
producing a
transient hypoxia
important in patients with
respiratory disease
 SECOND GAS EFFECT
Nitrous oxide is insoluble in blood

rapid uptake of nitrous oxide from alveolar gas &

rapid induction takes place with it

this leads to rapid rise in concentration of co-

administered halogenated anaesthetic agent &
increases speed of induction of volatile
anaesthetic agent also
Hepatotoxicity
Potentially severe and life threatening
hepatitis (Halothane)
{ Probability: 1:20,000-35,000 }

Mechanism underlying is unclear but

formation of chloro-tri-fluoroethyl , a free
radical
that either causes
 Direct hepatocellular damage or
 Initiate immune mediated responses ( auto
antibodies against hepatic proteins in a
trifluoroetylated form )
Nephrotoxicity

Methoxyflurane use limited clinically in

anesthesia Because of nephrotoxicity
It is caused by inorganic fluoride released
during metabolism of anesthetic.

Enflurane & Sevoflurane metabolism generate

less fluoride ions so less nephrotoxicity ??
Sevoflurane: is degraded by carbon dioxide
absorbent & Generates Compound A a venyl
Ether, metabolized by renal β-lyase & forms
thioacylhalide →proximal tubular necrosis.
 MALIGNANT HYPERTHERMIA

• Rare hyper-catabolic reaction due to a genetic defect

• 70 % lethal if untreated
• Seen with Succinylcholine, Halothane, Desflurane,
Isoflurane
• Characterized by
• Increased core body temp, muscle rigidity, due to ↑ed
mobilization of intracellular Ca2+ from SR in sk
muscle & ↑ in metabolic activity
• Cardiac dysrhythmias electrolyte imbalance
• Treat with Dantroline to inhibit Ca2+ transport
 Chronic toxicity

 Mutagenicity
 Carcinogenicity
 Reproduction
 Hematotoxicity
 Clinical Use of inhaled anesthetics
Never used alone
Used in combination with intravenous anesthetics
“BALANCED ANAESTHESIA”
ANAESTHESIA
Halothane: not often used in adults,but is still used in pediatric
anesthesia, sevoflurane is replacing it.
Nitrous Oxide: lacks sufficient potency to produce surgical
anesthesia by itself and is commonly used with another inhaled or
intravenous anesthetic. E.g. desflurane, sevoflurane and isoflurane
they afford short stay, rapid recovery and fewer adverse effects
Methoxyflurane: occasionally used especially in obstetric
anesthesia but not for long procedure (Nephrotoxic)
 HALOTHANE
 ADVANTAGES
 Potent with moderate onset & recovery
 Blood gas partition coeffecient = 2.3 MAC 0.75%
 Sweet smell , lack of irritation good for mask induction


 DISADVANTAGES
 Poor analgesic, add N2O or opioid
 Incomplete muscle relaxation
 Hepatotoxicity, significant metabolism by liver
 Malignant hyperthermia
 PHARMACOLOGICAL ACTIVITIES
CARDIOVASCULAR
Sensitizes myocardium to catecholamines
Depresses sino-atrial node and slows the heart
Depresses baroreceptor reflex
Hypotension (BP ↓ by 20-25 % at 1 MAC )

MUSCLE
Marked relaxation of smooth muscle
Incomplete relaxation of skeletal muscle
Enhance action of non depolarizing muscle relaxants
 LIVER
 Extensive biotransformation in liver generates a
hepatotoxic reactive Trifluoroacetic Acid
metabolite
 20% exhibit elevated liver enzymes

 HALOTHANE HEPATITIS
 Repeated exposure
 1: 10,000 to 35,000 risk of massive hepatic failure
with high mortality
 Attributed to reactive Trifluoroacetic Acid
metabolite
 NITROUS OXIDE
THE ONLY GASEOUS ANESTHETIC
 ADVANTAGES
 Weak anesthetic with rapid onset & recovery
 Blood gas partition coefficient = 0.47, MAC= 105
 Never used alone for surgical anesthesia but as a
component of balanced anesthesia
 Decreases amount of other anesthetics needed
 Great analgesic at 20% MAC
 Sedative at 30 to 70% MAC
 No hepato or nephro toxicity 99.9% eliminated by
lungs
 ENFLURANE
 ADVANTAGES
 Potent with slow onset and recovery
 Blood gas partition coefficient =1.9, MAC = 1.7
 Significant muscle relaxation
 No hepato or nephrotoxicity,
 2-10% metabolized by liver
 DISADVANTAGE
 contraindicated in patients with seizure disorders
 Pharmacological actions
 CVS
 Hypotension,but minimal effects on heart rate

 CNS
 Produce seizure like EEG activity and can produce
frank seizures

 Muscle
 Significant muscle relaxation & Enhances actions of
non depolarizing muscle relaxants
Intravenous Anesthetics
 Ultra short acting barbiturate, Thiopental

 Benzodiazepines, midazolam

 Opioid analgesic anesthesia, fentanyl

 Propofol

 Etomidate

 Ketamine


Barbiturates for induction of anesthesia

Thiopental, Thiamylal, Methohexital

 Benzodiazepines: preoperative as sedatives &

perioperative as adjunct with other anesthetics
Midazolam, Diazepam, Lorazepam

 Opioid Analgesics (balanced anesthesia, peri &

post op analgesia Morphine,
Fentanyl + Droperidol, Alfentanil,
Remifentanil
Propofol (for induction, no analgesia,
emulsion, allergy, hypnotic,,
anti-emetic, inj is painful)
Fospropofol (water soluble pro-drug)
 Ketamine (dissociative anesthesia,
emergence reaction)
 Etomidate rapid induction, no analgesia
hypnotic, post op nausea
vomiting
Dexmedetomidine
( 2 agonist, sedation,
analgesia)
 Ultra Short Acting Barbiturates
Thiopental / Thiamylal, Methohexital
largely being replaced by Propofol

Thiopental
 Very High lipid solubility
Most common use is for induction of anesthesia
Following administration

Rapid onset of action

 Rapidly crosses the blood brain barrier
 Plasma : Brain equilibrium occurs rapidly (in < 1min)
 Duration of action is 5-10 min
 Effect terminates due to redistribution
 Metabolism

 Slower than its redistribution

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

Action terminated by redistribution, not by metabolism

Actions

On intravenous injection
 Causes unconsciousness within about 20 seconds
 This lasts for 5-10 minutes. Analgesia is not produced

 Dose dependent ( myocardial depressant effect )

 Respiratory depression
 ( lowers the sensitivity of respiratory center to CO2 )
Actions

 METHOHEXITAL
T less than thiopentone, fast recovery
1/2

 SHORT AMBULATORY PROCEDURE

 preferred over thiopental for short surgical procedures

 ACTIVATES EPILEPTIC FOCI

 Useful in identifying epileptic foci for ablation during surgery
 Cerebral metabolism and oxygen utilization
are decreased;
Produce cerebral vasoconstriction
decrease cerebral blood flow.

because blood volume & intracranial pressure

are decreased This makes thiopental a much more
desirable drug for use in patients with
cerebral swelling and space occupying lesions
than the inhaled anesthetics,
.
 Adverse effects

 Acute intermittent porphyria:-- by inducing

hepatic δ aminolevulinic acid (ALA) synthase
 Respiratory depression
 laryngospasm due to inadequate depression of
cough & laryngeal reflexes Vs propofol
 Accidental injection around rather than
into a vein or artery can cause local tissue
necrosis and ulceration → gangrene.
 Benzodiazepines

 Diazepam
 Lorazepam
 Midazolam
 Have 1.sedative
 2.anxiolytic
 3.amnesic effects
 4. ability to control acute agitation
 Slower onset of CNS effect.

 Plateau of central depression appears to be

below that of a true anesthetic state.

 High doses prolong the post anesthetic recovery period

(undesirable)

 High incidence of anterograde amnesia

(amnesia for events occurring after the drug
is administered)
 Midazolam

 Water soluble salt but after inj lipid soluble at

physiologic pH, crosses the BBB
 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
Used in anesthetic procedures
Inadequate to produce surgical anesthesia
 As pre-anesthetic medication
 As adjuvant in surgery under L. anesthesia
 For Intraoperative sedation
 As part of balanced anesthesia
 FLUMAZENIL
 Accelerate recovery, but repeated doses may be required
 OPIOIDS
postoperative & intraoperative analgesics in
balanced anesthesia

 Morphine
 Fentanyl
 Sufentanil
 Alfentanil
 Remifentanil
 Even high doses cannot prevent recall unless used with
high doses of benzodiazepines
 Larger doses of opioid analgesics have
been used to achieve general Anesthesia
with large doses of Benzodiazepines

 Pt with Limited circulatory reserve

in Cardiac & other major surgery

 Post operative analgesia in

Epidural & subarachnoid space
 Fentanyl
uses:
 Pre-anesthetic
 Adjunct to anesthetics
 Peri-operative analgesia
 Post-op analgesia (low dose spinal & epidural)

 Fentanyl + Droperidol (Neuroleptanalgesia)

 Fentanyl + Droperidol + Nitrous oxide ----
Neuroleptanesthesia
 NEUROLEPT ANALGESIA / ANESTHESIA

Neuroleptanalgesia Fentanyl an opiate analgesic

combined with Droperidol a D2 antagonist related to
antipsychotic drugs can be used to produce a state of
•deep sedation,
• analgesia and
• amnesia
patient remains responsive to simple commands but
does not respond to painful stimuli or retain any memory
of the procedure.
used for minor surgical procedures such as endoscopy.
Alfentanil and Remifentanil

 Some times used for induction (rapid onset of action)

 Co - induction agent
 Remifentanil :
 Rapid recovery( esterases in blood and muscle tissues so
useful in anesthesia regimens for ambulatory surgery )
 Potant & Extremely short acting
 Adverse effects
 Awareness during anesthesia & unpleasant post-
op recall
 Nausea, vomiting and itching on recovery
 Laryngeal & chest wall rigidity → Impaired ventilation
 Acute tolerance →↑ post operative opioid requirement
HIGH DOSE TECHNIQUE Increase post operative morbidity
 Prolonged post OP ventilatory support needed
 G.I. & bladder complication
 Increased mortality after cardiac surgery

 So low doses should be used both with i/v

and with inhaled agents
 Propofol
MOST POPULAR INTRAVENOUS ANESTHETIC

Rapid induction & very fast recovery t1/2=1- 8 min inj

painful. It has No analgesic effect but has hypnotic effect

No peri & post op nausea or vomiting, early ambulation,

feeling of well being post operatively

Formulated as an emulsion→ bacterial growth, allergy,

additives added (EDTA), ↓ in lipid content more painful

Used for both induction and maintenance & As part of

total intravenous or balanced anesthesia techniques
 May produce muscle twitches on induction although it is has
anticonvulsant effects
 It decreases cerebral blood flow and cerebral metabolic rate.
 Large doses produce burst suppression in EEG . Produce
neuroprotection in neurosurgurical procedures
 The presumed mechanism is through potentiation of the chloride
current mediated through the GABAA receptor complex
 addition of metabisulfite raised concerns in patients with reactive
airway disease and with sulfite allergies
 Termination of the drug effects after a single bolus dose are mainly
the result of redistribution from highly perfused brain to les well
perfused skeletal muscle compartment
 Undergoes hepatic metabolism but 30% of a bolus dose is eliminated
through the lungs
Used as I/v sedative in operating room & for procedural
sedation & for prolonged sedation in critical care setting
Prolonged I/V emulsion → cumulation, delayed arousal,
↑ serum lipids & in young children, acidosis in ICU
Metabolized in liver, glucuronide & sulfate conjugates

 Depresses Ventilatory drive & marked decrease in BP by

dilating blood vessels and myocardial depression.,
bradycardia &asystole,Preload & after load are decreased
 Used In burn units for painful burn debridement and
dressing changes
 Popular as an anesthetic for use in day surgery
 Ketamine
Dissociative anaesthetic
( Related to Phencyclidine [PCP] )
A drug with high abuse potential
Only I/V anesthetic to possess both analgesic
and anesthetic properties and stimulate the
CVS and ↑ the HR, ABP & CO
 Ketamine
Dissociative Anesthesia
The characteristic state wherein the patients is in a trance,
eyes are open with a slow nystagmus gaze with lack of
response to external stimuli (cataleptic state)
Characterized by
• CATATONIA Muscular rigidity so that the limbs
remain in whatever positionCatalepsy
Catatonia/ they are placed.
Amnesia
• AMNESIA With or without loss of consciousness
Analgesia
• ANALGESIA Is very significant
Without actual
• DISSOCIATION Lack ofloss of consciousness
response to external stimuli
Mechanism of action

Blockage of membrane effects of

excitatory neurotransmitter
glutamic acid at NMDA receptor
subtype
 KETAMINE
 Mostly used for pediatric procedures
 Useful In adult patients who are at risk of
bronchospasm or hypotension
 Highly lipid soluble, little plasma protein binding
 Rapid onset of action < than 1min after I/V
 Central sympathetic stimulation in 2 minutes
increases catechol-amines → increase in CO, BP
and HR in 3-4 mins and back in 20 minutes.
 Decreases respiratory rate but maintains airway
muscle tone, Preserves ventilatory reflex responses
 I/V, I/M, rectal and oral formulations available
 Increases cerebral blood flow & I/C pressure
 Like volatile anesthetics dangerous in conditions
with elevated intracranial pressure.
 EMERGENCE PHENOMENON
 Post operative disorientation ē sensory & perceptual
illusions, vivid dreams, hallucinations & delirium
 Seen in 30% adults with high doses for induction
 Prior administration of 0.2-0.3mg/kg diazepam or
0.5-1 mg/kg of I/V propofol reduces its incidence.
 In low doses ( 0.1-0.25mg/kg) with inhaled or I/V
anesthetics it is a Popular alternative to opioids to
minimize ventilatory depression
 Uses
In outpatient, low dose ketamine anesthesia ē I/V
propofol or midazolam for superficial surgical
procedures
Procedures of ear nose eye and mouth, dental extraction.
In children undergoing painful procedures such as
dressing changes, skin grafting in burn.
Used in obstetrics to help dilation of cervix and D&C
 Very useful In poor risk geriatric patients
 useful in high risk pts ē cardiogenic or septic shock
because of its cardio-stimulant action
Topical use for arthritic pain
 Etomidate
Used for
 Induction of anesthesia in patients with limited
cardiovascular reserve

 rapid loss of consciousness with minimal

hypotension even in elderly with poor
cardiovascular reserve

 Heart rate unchanged & low incidence of apnea

• Co administration of opioid needed to produce analgesia
and to Decrease cardiac responses and spontaneous
muscle movements during tracheal intubation

• Recovery less rapid than propofol, Short duration is

Because of Redistribution but less rapid than propofol

• Rapid distribution with Biphasic plasma concentration

Showing initial & intermediate distribution half lives

• Used In balanced anesthesia

• Metabolized in liver

• Major advantage:
•
 Disadvantages
 No analgesic effect so opioids co-administered
 Premedication with analgesic is required
 post-op Nausea and vomiting
 Pain on injection site
 Myoclonus, involuntary muscle movements
 Adrenocortical supprssion on prolonged use
 Decrease steroidogenesis -↓ cortisol level
 On prolonged use may cause hypotension,
electrolyte imbalance and oliguria