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1. General Anesthetics
Jagir R. Patel
Asst Professor
Dept: Pharmacology

2. What are General Anesthetics ?
• General anaesthetics (GAs) are drugs which
produce reversible loss of all sensation and
consciousness.

3. Goals of General Anesthesia
• Loss of all sensation, especially pain
• Sleep (unconsciousness) and amnesia
• Immobility and muscle relaxation
• Abolition of somatic and autonomic
reflexes.

6. No single agent can produces all effects
• Hence the anesthetic protocol includes
1. Premedication
2. Induction of anesthesia e.g. propofol
3. Maintainace of anesthesia ( nitrioxide + isoflurane/ halothane)
4. Skeletal muscle relaxants
5. Analgesia during and after surgery
6. Use of other drugs
to reverse neuromuscular blocked
to reverse the residual effects of opioids and benzodiazepines

7. GA general considerations
1. Depth of anesthesia directly relates to the partial pressure of the
anesthetic in the brain.
2. Anesthetic potency is expressed as the minimum alveolar
concentration (MAC).
• 1 MAC is the concentration in inspired air at which 50% of patients
have no response to a skin incision thus surgery must be performed
above 1 MAC.
• The higher the lipid solubility
(a) The greater the potency
(b) The lower the MAC
• Inhalational anesthetics exert additive synergism
• 0.5 MAC from two anesthetics together will produce 1
MAC anesthesia

8. • Speed of induction is influenced by several factors.
• (1) Higher inspired concentration equals more rapid induction.
• (2) Lower solubility in blood equals more rapid induction.
• (3) Higher ventilation rate equals more rapid induction.
• (4) Lower pulmonary blood flow equals more rapid induction.
• The lower the blood-gas partition coefficient, the more rapid
is the onset and recovery from anesthesia

9. Measurement of anesthetic potency
• Minimal alveolar concentration (MAC): is the lowest concentration of
the anaesthetic in pulmonary alveoli needed to produce immobility in
response to a painful stimulus (surgical incision) in 50% individuals.
• It is accepted as a valid measure of potency of inhalational GAs, because
it remains fairly constant for most young adults.
• The MAC of all inhalational anaesthetics declines progressively as age
advances beyond 50 year.
• The MAC of a number of GAs shows excellent correlation with their
oil/gas partition coefficient

10. Locus for Causation of unconsciousness
• Unconsciousness = Thalamus or
reticular activating system
• Amnesia = cerebral cortex and
hippocampus
• Immobility on surgical
stimulation = spinal cord

11. Different Agents Different Actions
General anesthetics
GAs appear to act by depressing
synaptic transmission
fluorinated anaesthetics
and barbiturates
Inhibit the neuronal cation
channel gated by nicotinic
cholinergic receptor which may
mediate analgesia and amnesia
1
2
34
5
6 barbiturates,
benzodiazepines
potentiate the action of inhibitory
transmitter GABA to open Cl¯
channels
Action of glycine (another inhibitory
transmitter which also activates Cl¯
channels) in the spinal cord and
medulla
potentiate the action of inhibitory
transmitter GABA to open Cl¯ channels
Action of glycine (another inhibitory
transmitter which also activates Cl¯
channels) in the spinal cord and medulla
volatile anaesthetics/ gas
Activation of a specific type of K+
channels called ‘two-pore domain’
channels
N2O and ketamine
selectively inhibit the excitatory
NMDA type of glutamate
receptor.
Inhalational anaesthetics

12. Barbiturates and BZS
Interact with its own
specific binding site
on the GABAA
receptor but not on
GABA binding site
Potentiation of
Cl- channel
opening
fluorinated
anaesthetics and
barbiturates
Inhibit the neuronal
cation channel gated
by nicotinic
cholinergic receptor
which may mediate
analgesia and
amnesia
Barbiturates, propofol
and many inhalational
anaesthetics.
Action on glycine (another
inhibitory transmitter which
also activates Cl¯ channels) in
the spinal cord and medulla
This action may block
responsiveness to painful
stimuli resulting in
immobility of the anaesthetic
state

13. N2O
ketamine
ketamine do not affect GABA or
glycine gated Cl¯ channels. Rather
they selectively inhibit the excitatory
NMDA type of glutamate receptor
This receptor gates mainly Ca2+
selective cation channels in the
neurones, inhibition of which appears
to be the primary mechanism of
anaesthetic action of ketamine as well
as N2O
Gas
Activation of a specific type of K+
channels called ‘two-pore domain’
channels.
This may cause inhibition of
presynaptic transmitter release as well
as postsynaptic activation.
Inhibition of transmitter release from
presynaptic neurones has also been
related to interaction with certain
critical synaptic proteins.

14. STAGES OF ANAESTHESIA

15. Induction / Maintainace and Recovery
• A. Induction:
• General anesthesia in adults is normally induced with an IV agent like
propofol, producing unconsciousness in 30 to 40 seconds.
• Additional inhalation and/or IV drugs may be given to produce the desired
depth of anesthesia.
• [Note: This often includes an IV neuromuscular blocker such as rocuronium,
vecuronium, or succinylcholine to facilitate tracheal intubation and muscle
relaxation.]
• For children without IV access, nonpungent agents, such as sevoflurane, are
inhaled to induce general anesthesia.

16. • Maintenance of anesthesia
• After administering the anesthetic, vital signs and response to stimuli are
monitored continuously to balance the amount of drug inhaled and/or
infused with the depth of anesthesia.
• Maintenance is commonly provided with volatile anesthetics, which
offer good control over the depth of anesthesia.
• Opioids such as fentanyl are used for analgesia along with inhalation
agents, because the latter are not good analgesics. IV infusions of various
drugs may be used during the maintenance phase.

17. • Recovery
• Postoperatively, the anesthetic admixture is withdrawn, and the patient is
monitored for return of consciousness.
• For most anesthetic agents, recovery is the reverse of induction.
Redistribution from the site of action (rather than metabolism of the
drug) underlies recovery.
• If neuromuscular blockers have not been fully metabolized, reversal
agents may be used.
• The patient is monitored to assure full recovery, with normal physiologic
functions (spontaneous respiration, acceptable blood pressure and heart
rate, intact reflexes, and no delayed reactions such as respiratory
depression).

19. I Stage of analgesia
• Starts from beginning of anaesthetic inhalation and lasts upto the loss
of consciousness.
• Pain is progressively abolished.
• Patient remains conscious
• Can hear and see
• Feels a dream like state
• Amnesia develops by the end of this stage.
• Reflexes and respiration remain normal.
• Though some minor operations can be carried out during this stage, it is
rather difficult to maintain—use is limited to short procedures
• Minor operations and short procedures only

20. II. Stage of delirium
• From loss of consciousness to beginning of regular respiration.
• Apparent excitement is seen—patient may shout, struggle and hold his
breath; muscle tone increases, jaws are tightly closed, breathing is jerky;
vomiting, involuntary micturition or defecation may occur.
• Heart rate and BP may rise and pupils dilate due to sympathetic stimulation.
• No stimulus should be applied or operative procedure carried out during
this stage. This stage is inconspicuous in modern anaesthesia

21. III. Surgical anaesthesia
• Extends from onset of regular respiration to cessation of spontaneous
breathing.
• Plane 1 Roving eyeballs. This plane ends when eyes become fixed.
• Plane 2 Loss of corneal and laryngeal reflexes.
• Plane 3 Pupil starts dilating and light reflex is lost.
• Plane 4 Intercostal paralysis, shallow abdominal respiration, dilated
pupil.
• As anaesthesia passes to deeper planes, progressively— muscle tone
decreases, BP falls, HR increases with weak pulse, respiration decreases in
depth and later in frequency also. Thoracic respiration lags behind
abdominal respiration.

22. IV. Medullary paralysis
• Cessation of breathing to failure of circulation and
death.
• Pupil is widely dilated
• Muscles are totally flabby
• pulse is thready or imperceptible and BP is very low.

23. Can we rob indices of GAs ?
Can be robbed by the use of
1. Atropine (pupillary, heart rate)
2. Morphine (respiration, pupillary)
3. Muscle relaxants (muscle tone, respiration, eye movements, reflexes)
Modern anaesthetist has to depend on several other observations to gauge the depth of
anaesthesia. If eyelash reflex is present and patient is making swallowing movements—stage II
has not been reached. Loss of response to painful stimulus (e.g. pressure on the upper nasal
border of orbit) stage III has been reached.
Incision of the skin causes reflex increase in respiration, BP rise or other effects; insertion of
endotracheal tube is resisted and induces coughing, vomiting, laryngospasm; tears appear in eye;
passive inflation of lungs is resisted—anaesthesia is light.
Fall in BP, cardiac and respiratory depression are signs of deep anaesthesia.

24. Properties of an ideal anaesthetic
A. For the patient It should be pleasant, nonirritating, should not cause
nausea or vomiting. Induction and recovery should be fast with no
after effects.
B. For the surgeon It should provide adequate analgesia, immobility and
muscle relaxation. It should be noninflammable and nonexplosive so
that cautery may be used.
C. For the anaesthetist Its administration should be easy, controllable and
versatile. Margin of safety should be wide—no fall in BP.
• Heart, liver and other organs should not be affected.
• It should be potent so that low concentrations are needed and
oxygenation of the patient does not suffer.
• Rapid adjustments in depth of anaesthesia should be possible.
• It should be cheap, stable and easily stored.
• It should not react with rubber tubing or soda lime.

25. Classification
• Nitrous oxide EtherGas
• Halothane, Isoflurane, Desflurane,
Sevoflurane
Volatile liquids
• Thiopental sod, propofol, ethomidateFast acting drugs
• diazepam, lorazepam, midazolamSlower acting: Bzds
• ketamine
Dissociative
anesthetics
• FentanylOpioid analgesia

26. Putative targets of anesthetic action. Anesthetic drugs may
(A) enhance inhibitory synaptic activity or (B) diminish
excitatory activity. ACh, acetylcholine; GABAA, γ-
aminobutyric acid-A

27. G-anaesthetics potential targets

28. General MOA, PK/PD inhalational anesthetics
• Actions: CNS depressant. Causes unconsciousness. Only weakly analgesic.
• MOA: Potentiates GABA action on GABAA receptors and opens K+
channels (TREK type) to reduce neuronal activity, especially in cerebral
cortex, thalamus and hippocampus. Lipid solubility important for action.
• Abs / Distrib / Elim: Given by inhalation with oxygen. Rate of
equilibration with body and onset of anaesthesia depends on the ‘blood/gas
solubility’. Halothane has a medium onset of action – des•urane and
sevo•urane (with lower blood/gas solubilities) a fast onset. Mostly
eliminated unchanged by the lungs
• Clinical use: Maintenance, and less frequently induction, of general
anaesthesia..

29. Effects of Inhaled Anesthetics
CNS Effects
Inhaled anesthetics decrease brain
metabolic rate.
They reduce vascular resistance
and thus increase cerebral blood
flow.
This may lead to an increase in
intracranial pressure
Cardiovascular
Effects
Decrease arterial blood pressure moderately.
Isoflurane, descflurane, and sevoflurane cause
peripheral vasodilation. Nitrous oxide is less
likely to lower blood pressure
Enflurane and halothane are myocardial
depressants that decrease cardiac output
Inhaled anesthetics depress myocardial
function—nitrous oxide least.

30. Respiratory Effects
• Although the rate of respiration may be increased, all inhaled anesthetics
cause a dose-dependent decrease in tidal volume and minute ventilation,
leading to an increase in arterial CO2 tension.
• Inhaled anesthetics decrease ventilatory response to hypoxia even at
subanesthetic concentrations (eg, during recovery).
• Nitrous oxide has the smallest effect on respiration.
• Most inhaled anesthetics are bronchodilators, but desflurane is a pulmonary
irritant and may cause bronchospasm.
• The pungency of enflurane causing breath-holding limits its use in anesthesia
induction

31. Toxicity
• Postoperative hepatitis has occurred
• Hypovolemic shock or other severe stress.
• Renal insufficiency after prolonged anesthesia e.g: methoxyflurane
• Nitrous oxide decreases methionine synthase activity and may lead to
megaloblastic anemia.
• Malignant hyperthermia when anesthetics are used together with
neuromuscular blockers (especially succinylcholine).
The uncontrolled release of calcium by the sarcoplasmic reticulum of skeletal
muscle leads to muscle spasm, hyperthermia, and autonomic lability.
Dantrolene is indicated for the treatment of this life-threatening condition, with
supportive management

32. PK of Inhalational anaesthetics
• Inhalational anaesthetics are gases or vapours that diffuse rapidly across
pulmonary alveoli and tissue barriers.
• The depth of anaesthesia depends on the potency of the agent (MAC is
an index of potency) and its partial pressure (PP) in the brain, while
induction and recovery depend on the rate of change of PP in the brain.
• Transfer of the anaesthetic between lung and brain depends on a series of
tension gradients which may be summarized as— Alveoli Blood Brain

33. 1. PP of anaesthetic in the inspired gas
This is proportional to its concentration in the inspired gas mixture. Higher
the inspired tension more anaesthetic will be transferred to the blood
hastening induction.
1. Pulmonary ventilation
It governs delivery of the GA to the alveoli. Hyperventilation will bring in
more anaesthetic per minute and quicken induction.
1. Alveolar exchange
The GAs diffuse freely across alveoli, but if alveolar ventilation and
perfusion are mismatched (as occurs in emphysema and other lung
diseases) the attainment of equilibrium between alveoli and blood will be
delayed. Induction and recovery both are slowed.

34. 4. Solubility of anaesthetic in blood
• This is the most important property determining induction and recovery.
• Large amount of an anaesthetic that is highly soluble in blood (ether) must
dissolve before its PP is raised.
• The rise as well as fall of PP in blood and consequently induction as well as
recovery are slow.
• Drugs with low blood solubility, e.g. N2O, sevoflurane, desflurane induce
quickly.
• 5. Solubility of anaesthetic in tissues
• Relative solubility of anaesthetic in blood and tissues determines its
concentration in tissues at equilibrium.

35. • Cont.….
• Most of GAs are equally soluble in lean tissues as in blood but more
soluble in fatty tissue.
• Anaesthetics with higher lipid solubility (halothane) continue to enter
adipose tissue for hours and also leave it slowly.
6. Cerebral blood flow
• Brain is a highly perfused organ; as such GAs are quickly delivered to it.
• This can be hastened by CO2 inhalation which causes cerebral
vasodilatation—induction and recovery are accelerated.

36. Elimination
• When anaesthetic inhalation is discontinued, gradients are reversed and the
channel of absorption (pulmonary epithelium) becomes the channel of
elimination.
• All inhaled anaesthetics are eliminated mainly through lungs.
• The same factors which govern induction also govern recovery.
• Anaesthetics, in general, continue to enter and persist for long periods in
adipose tissue because of their high lipid solubility and low blood flow to
fatty tissues.
• Muscles occupy an intermediate position between brain and adipose tissue.
• Most GAs are eliminated unchanged.
• Metabolism is significant only for halothane which is >20% metabolized in
liver.
• Others are practically not metabolized.
• Recovery may be delayed after prolonged anaesthesia, especially in case of
more lipid soluble anaesthetics (halothane, isoflurane), because large
quantities of the anaesthetic have entered the muscle and fat, from which it is
released slowly into blood.

37. Second gas effect and diffusion hypoxia
• With Nitrous Oxide if second anesthetic gas is present, the rate of rise of
arterial tension of the second gas is enhanced also.
• If the first gas is nitrous oxide and the second enflurane, the concentration
effect due to NO which pull more gas from the breathing circuit into the
lung, pulls both fresh NO and fresh enflurane.
• Thus the rate of rise of arterial tension of enflurane is faster as well.
• Diffusion hypoxia
• Reverse of the concentration effect: high rate of transfer of anesthetic from
the blood and tissues to the alveoli.
• This additional gas dilutes alveolar oxygen and can result in postoperative
hypoxia.
• This process is referred to as “diffusion hypoxia”• Lessened by
administration of supplemental oxygen.

38. Adverse effects of inhalational GA
• Cardiac and respiratory depression.
• Cardiac dysrhythmias.
• Post-operative nausea and vomiting.
• Rarely malignant hyperthermia
• liver damage (due to metabolites)
• Sevo•urane may produce kidney damage

39. Nitrous oxide (N2O) “laughing Gas”
• It is a colourless, odourless, heavier than air, noninflammable gas
supplied under pressure in steel cylinders.
Characteristics
1. Cannot produce surgical anesthesia by itself
2. To produce unconsciousness, N2O must be used with other anesthetics.
3. A mixture of O2 and N2O often used as a carrier gas for halogenated
anesthetics.
4. Significantly reduces the required concentration of halogenated
anesthetics when used as an adjunct to anesthesia N2O has excellent
analgesic properties.
Pharmacokinetics
(1) Extremely fast absorption and elimination
(2) Resulting in rapid:
•(a) Induction
•(b) Recovery from anesthesia

40. Cont.…
c.Uses
1. Has good analgesic properties
2. Therefore, used to decrease pain in:
(a) Obstetrics
(b) Procedure that does not require unconsciousness Dental
procedures
d.Contraindications
1. Head injury
2. Preexisting increased intracranial pressure
3. Brain tumors.
N2O can raise intracranial pressure. N2O contraindicated with head
injuries.

41. MOA of nitrous oxide

42. Ether (Diethyl ether)
• It is a highly volatile liquid, produces irritating vapours which are
inflammable and explosive. (C2H5 — O — C2H5)
• MOA
• Ether is a potent anaesthetic, produces good analgesia and marked
muscle relaxation by reducing ACh output from motor nerve endings.
• The dose of competitive neuromuscular blockers should be reduced to
about 1/3.
• Properties
• It is highly soluble in blood.
• Induction is prolonged and unpleasant with struggling, breath holding,
salivation and marked respiratory secretions (atropine must be given as
premedication to prevent the patient from drowning in his own
secretions).
• Recovery is slow; postanaesthetic nausea, vomiting and retching are
marked.

43. • Respiration and BP are generally well maintained because of reflex
stimulation and high sympathetic tone.
• It does not sensitize the heart to Adr, and is not hepatotoxic.
• Ether is not used now in developed countries because of its unpleasant
and inflammable properties.
• However, it is still used in developing countries, particularly in
peripheral areas because it is—cheap, can be given by open drop method
(though congestion of eye, soreness of trachea and ether burns on face
can occur) without the need for any equipment, and is relatively safe
even in inexperienced hands.

44. Halothane
• Halothane is the prototype to which newer inhalation anesthetics are
compared.
• Rapid induction and quick recovery made it an anesthetic of choice.
• Therapeutic uses: Halothane is a potent anesthetic but a relatively weak
analgesic.
• It is coadministered with nitrous oxide, opioids, or local anesthetics.
• It is a potent bronchodilator.
• Relaxes both skeletal and uterine muscles and can be used in obstetrics
when uterine relaxation is indicated.
• Halothane is not hepatotoxic in children (unlike its potential effect on
adults). Combined with its pleasant odor, it is suitable in pediatrics for
inhalation induction, although sevoflurane is now the agent of choice

45. Pharmacokinetics:
• Halothane is oxidatively metabolized in the body to tissue-toxic
hydrocarbons (for example, trifluoroethanol) and bromide ion.
Toxic metabolites:
• These substances may be responsible for toxic reactions that some adults
(especially females) develop after halothane anesthesia.
• This begins as a fever, followed by anorexia, nausea, and vomiting, and
possibly signs of hepatitis. Although the incidence is low (approximately
1 in 10,000), half of affected patients may die of hepatic necrosis.
• To avoid this condition, halothane is not administered at intervals of less
than 2 to 3 weeks.
• All halogenated inhalation anesthetics have been associated with
hepatitis, but at a much lower incidence than with halothane.
• Due to adverse effects and the availability of other anesthetics with fewer
complications, halothane has been replaced in most countries.

46. • Adverse effects:
• Cardiac effects:
• Halogenated hydrocarbons are vagomimetic and may cause atropine-
sensitive bradycardia.
• Cardiac arrhythmias. [Note: Halothane can sensitize the heart to effects
• of catecholamines such as norepinephrine.]
• Concentration-dependent hypotension.
• This is best treated with a direct-acting vasoconstrictor, such as
phenylephrine.
• Malignant hyperthermia:
• Exposure to halogenated hydrocarbon anesthetics or the neuromuscular
blocker succinylcholine may induce malignant hyperthermia (MH), a rare
life-threatening condition.
• MH causes a drastic and uncontrolled increase in skeletal muscle
oxidative metabolism, overwhelming the body’s capacity to supply
oxygen, remove carbon dioxide, and regulate temperature, eventually
leading to circulatory collapse and death if not treated immediately.
Strong evidence indicates that MH is due to an excitation–contraction
coupling defect.

47. Isoflurane
• Properties
• This potent fluorinated anaesthetic has properties similar to halothane,
but is less soluble in blood—produces rapid induction and recovery.
• MOA:
• Isoflurane, a volatile halogenated anaesthetic, alters activity of neuronal
ion channels esp the fast synaptic neurotransmitter receptors (e.g.
nicotinic acetylcholine, γ-aminobutyric acid, and glutamate receptors)
thereby depressing myocardial contractility, decreasing BP through a
decrease in systemic vascular resistance, and decreasing sympathetic
nervous activity.

48. • Disadvantages / side effects
• Fall in BP is like halothane, but it tends to increase heart rate.
• Isoflurane does not sensitize the heart to adrenergic arrhythmias.
• Respiratory depression is prominent and assistance is usually needed to avoid
hypercarbia.
• Secretions are slightly increased.
• Renal and hepatic toxicity has not been encountered.
• Postanaesthetic nausea and vomiting is low.
• Though slightly irritant, isoflurane has many
• Advantages, i.e. better adjustment of depth of anaesthesia and low toxicity. It
does not provoke seizures and is preferred for neurosurgery. In many hospitals it
has become the routine anaesthetic, but cost is a constraint.

49. • Indications
• Induction and maintenance of general anaesthesia
Adult: Induction: 0.5% v/v w/ oxygen (or oxygen and nitrous oxide
mixt), increased to 1.5-3% v/v.
• Maintenance: 1-2.5% v/v w/ oxygen and nitrous oxide mixt or
alternatively, 1.5-3.5% v/v w/ oxygen.
• For maintenance of anaesthesia during caesarean section: 0.5-0.75% v/v
w/ oxygen and nitrous oxide mixt. Doses are given via calibrated
vaporiser.

50. Desflurane
• Properties
• It is a recently developed all fluorinated congener of isoflurane which has
gained popularity as an anaesthetic for outpatient surgery in western
countries.
• Its distinctive properties are high volatility, lower oil: gas partition
coefficient and very low solubility in blood as well as tissues because of
which induction and recovery are very fast.
• Depth of anaesthesia changes rapidly with change in inhaled
concentration. Postanaesthetic cognitive and motor impairment is short
lived— patient can be discharged a few hours after surgery.

51. • MOA:
• It enhances inhibitory postsynaptic activity and inhibits excitatory
synaptic activity, resulting in reversible loss of consciousness and of pain
sensations, suppression of voluntary motor activity, reduction of
autonomic reflexes, and sedation of respiratory and the cardiovascular
system.

52. • Indications:
• inhalation
Induction and maintenance of general anaesthesia
• Adult: Induction: Initially, 3% v/v inhaled via calibrated vaporiser, increased
in 0.5-1% increments every 2-3 breaths (end-tidal concentrations of 4-11%
v/v).
• Maintenance: 2-6% v/v w/ nitrous oxide or 2.5-8.5% v/v in oxygen or
oxygen-enriched air.
• Child: Maintenance (after induction w/ agents other than desflurane): 5.2-
10% v/v w/ or w/o nitrous oxide.
• Renal impairment: Chronic impairment and during renal transplantation
surgery: 1-4% v/v in oxygen and nitrous oxide.
• Hepatic impairment: Chronic impairment: 1-4% v/v in oxygen and nitrous
oxide.

53. Sevoflurane
• Properties
• It is the latest polyfluorinated anaesthetic with properties intermediate
between isoflurane and desflurane.
• Solubility in blood and tissues as well as potency are less than isoflurane but
more than desflurane.
• Induction and emergence from anaesthesia are fast and rapid changes in
depth can be achieved.
• Absence of pungency makes it pleasant and administrable through face
mask.
• Unlike desflurane, it poses no problem in induction; acceptability is good
even by pediatric patients.
• Recovery is smooth; orientation, cognitive and motor functions are regained
almost as quickly as with desflurane.
• Sevoflurane is suitable for both outpatient and inpatient surgery, but its high
cost and need for high flow open system makes it very expensive to use.

54. • MOA:
• It alters the activity of fast synaptic neurotransmitter receptors like
nicotinic acetylcholine, GABA, and glutamate. It may depress
myocardial contractility and decrease both BP and sympathetic nervous
activity. Additionally, it has muscle relaxant properties w/o analgesia.
• Indications: inhalation
• Induction and maintenance of general anaesthesia
• Adult: Induction: Premeditated patient: Up to 5% v/v w/ oxygen (or
mixture of oxygen and nitrous oxide), individualised according to age
and clinical status. Unpremeditated patient: Up to 8% v/v. Maintenance:
0.5-3% v/v w/ or w/o nitrous oxide. Doses are given via calibrated
vaporiser.
• Child: Induction: Up to 7% v/v w/ oxygen (or mixture of oxygen and
nitrous oxide) given via calibrated vaporiser.

56. Intravenous Anesthetics

57. Need of intravenous Anesthetics
• These are drugs which on i.v. injection produce loss of consciousness in
one arm-brain circulation time (~11 sec).
• They are generally used for induction because of rapidity of onset of
action.
• Anaesthesia is then usually maintained by an inhalational agent.
• They also serve to reduce the amount of maintenance anaesthetic.
• Supplemented with analgesics and muscle relaxants, they can also be
used as the sole anaesthetic

58. Propofol
• Propofol, introduced in 1983, has now largely replaced thiopental as an
induction agent.
• It has a rapid onset of action (approximately 30 s) and a rapid rate of
redistribution (t1/2 2–4 min), which makes it short acting.
• Because of its low water solubility, it is administered as an and supports
microbial growth.
• Fospropofol is a recently developed water-soluble derivative that is less
painful on injection and rapidly converted by alkaline phosphatases to
propofol in the body.
• Metabolism
• Propofol metabolism to inactive conjugates and quinols follows first-
order kinetics, in contrast to thiopental, resulting in more rapid recovery
and less hangover effect than occurs with thiopental.

59. Cont.…
• Adverse effects
• It has a cardiovascular depressant effect that may lead to hypotension
and bradycardia.
• Respiratory depression may also occur.
• It is particularly useful for day-case surgery, especially as it causes less
nausea and vomiting than do inhalation anaesthetics.

60. Propofol Infusion Syndrome
• There have been reports of a propofol infusion syndrome occurring in
approximately 1 in 300 patients when it has been given for a prolonged
period to maintain sedation, particularly to sick patients – especially
children in whom it is contraindicated in this setting – in intensive care units.
This is characterized by
• Severe metabolic acidosis
• Skeletal muscle necrosis (rhabdomyolysis)
• Hyperkalaemia
• Lipaemia
• Hepatomegaly
• Renal failure
• Arrhythmia
• Cardiovascular collapse.

61. Thiopental / Thiopentone ultra short acting
barbiturate
• Thiopental is the only remaining barbiturate in common use.
• It has very high lipid solubility, and this accounts for the speed of onset
and transience of its effect when it is injected intravenously.
• The free acid is insoluble in water, so thiopental is given as the sodium
salt.
• On intravenous injection, thiopental causes unconsciousness within about
20 s, lasting for 5–10 min.
• The anaesthetic effect closely parallels the concentration of thiopental in
the blood reaching the brain, because its high lipid solubility allows it to
cross the blood–brain barrier without noticeable delay.

62. MOA
• Binds to particular site (di.erent to benzodiazepine binding site) on GABAA
receptor to enhance opening of intrinsic Cl- channel by GABA. Higher
concentrations directly activate receptor.

63. • Pharmacokinetics:
• I.v. injection.
• Very lipid soluble allowing rapid CNS penetration.
• Rapid onset (20s) and short acting (5–10min).
• Short duration due to rapid redistribution in body, particularly to muscle.
• Thiopental is slowly metabolised (T0.5 8–10h) and may produce a
‘hangover’.
• Propofol is rapidly metabolised and lack of hangover makes it suitable
for day case surgery.
• Cardiorespiratory depression: less with etomidate.
• Use: Anaesthesia for short procedures and to induce anaesthesia for
subsequent maintenance with volatile agents.

64. Why thiopental Is used as inductive
agent
• Thiopental metabolism shows saturation kinetics, Because of this, large
doses or repeated intravenous doses cause progressively longer periods
of anaesthesia, as the plateau in blood concentration becomes
progressively more elevated as more drug accumulates in the body and
metabolism saturates.
• For this reason, thiopental is not used to maintain surgical anaesthesia
but only as an induction agent. It is also still used to terminate status
epilepticus or (in patients with a secured airway) to lower intracranial
pressure.

65. Etomidate
• Etomidate is good over thiopental sodium why?
• It has gained favour over thiopental on account of the larger margin
between the anaesthetic dose and the dose needed to produce
cardiovascular depression.
• It is more rapidly metabolised than thiopental, and thus less likely to
cause a prolonged hangover.
• It causes less hypotension than propofol or thiopental.
• In other respects, etomidate is very similar to thiopental, although
involuntary movements during induction, postoperative nausea and
vomiting, and pain at the injection site are problems with its use.
• Etomidate suppresses the production of adrenal steroids, an effect that
has been associated with an increase in mortality in severely ill patients.
It should be avoided in patients at risk of having adrenal insufficiency,
e.g. in sepsis.
• It is preferable to thiopental in patients at risk of circulatory failure.

66. Ketamine
• Actions: Dissociative anaesthesia, in which the patient may remain conscious
but have good pain relief and short-term amnesia. Analgesia at subanaesthetic
doses.
• PK
• I.v. or i.m. admin. Rapid onset and short duration of action following i.v.
dosing. Metabolised in liver; T0.5 2.5h.
• Use:
• Induction and maintenance of anaesthesia for brief surgical/diagnostic
procedures. Mainly used for minor procedures in children, who exhibit fewer
untoward psychotic side effects.
• ADV:
• Increased heart rate and blood pressure (by activation of sympathetic system).
Involuntary muscle movement. Hallucinations, delerium and dysphoria during
recovery. Respiratory depression in overdose.

67. MOA of Ketamine
• Blocks NMDA type glutamate receptor ion channel

68. “Clandestinely mixed in drinks,
ketamine has been misused as
rape drug”

69. Benzodiazepines (BZDs)
• In addition to Preanaesthetic medication, BZDs are now frequently used for
inducing, maintaining and supplementing anaesthesia as well as for ‘conscious
sedation’.
• Diazepam 0.2–0.3 mg/kg or equivalent injected i.v. produce sedation,
amnesia and then unconsciousness in 5–10 min.
• If no other anaesthetic or opioid is given, the patient becomes responsive in 1 hr
or so due to redistribution of the drug (distribution t½ of diazepam is 15 min),
but amnesia persists for 2–3 hr and sedation for 6 hr or more.
• Recovery is further delayed if larger doses are given.
• BZDs are poor analgesics : an opioid or N2O is usually added if the procedure
is painful postoperative nausea or vomiting.
• Involuntary movements are not stimulated.

70. Where BZDs are preferred ?
• BZDs are now the preferred drugs for
• Endoscopies
• Cardiac catheterization
• Angiographies
• Conscious sedation during local/regional anaesthesia
• Fracture setting, ECT, etc.
• They are a frequent component of balanced anaesthesia employing several
drugs.
• The anaesthetic action of BZDs can be rapidly reversed by flumazenil 0.5–2
mg i.v

71. Cont.…
• Diazepam 0.2–0.5 mg/kg by slow undiluted injection in a running i.v. drip:
this technique reduces the burning sensation in the vein and incidence of
thrombophlebitis.
• Lorazepam Three times more potent, slower acting and less irritating than
diazepam. It distributes more gradually—awakening may be delayed.
Amnesia is more profound.
• Dose: 2–4 mg (0.04 mg/kg)
• Midazolam This BZD is water soluble, nonirritating to veins, faster and
shorter acting (t½ 2 hours) and 3 times more potent than diazepam.
• Fall in BP is somewhat greater than with diazepam.
• It is being preferred over diazepam for anaesthetic use: 1–2.5 mg i.v. followed
by 1/4th supplemental doses.
• Also used for sedation of intubated and mechanically ventilated patients and
in other critical care anaesthesia as 0.02–0.1 mg/kg/hr continuous i.v. infusion

73. Complications of General anaesthesia
During
anaesthesia
Respiratory depression
and hypercarbia.
Salivation,
respiratory
secretions..
Cardiac
arrhythmias,
asystole.
Fall in
BP.
Aspiration of
gastric contents:
acid pneumonitis.
Laryngospasm
and asphyxia.

74. Cont.…
1. Awareness: dreadful perception and recall of events during surgery.
This may occur due to use of light anaesthesia + analgesics and muscle
relaxants.
2. Delirium, convulsions and other excitatory effects are generally
seen with i.v. anaesthetics; especially if phenothiazines or hyoscine
have been given in premedication. These are suppressed by opioids.
3. Fire and explosion. This is rare now due to use of non-inflammable
anaesthetics

75. Cont.…
• Nausea and vomiting.
• Persisting sedation: impaired psychomotor function
• Pneumonia, atelectasis.
• Organ toxicities: liver, kidney damage.
• Nerve palsies—due to faulty positioning.
• Emergence delirium.
• Cognitive defects: prolonged excess cognitive decline has
been observed in some patients, especially the elderly, who
have undergone general anaesthesia, particularly of long
duration.
After
anaesthesia

76. DRUG INTERACTIONS
1. Antihypertensives + general anaesthetics = fall in BP
2. Neuroleptics, opioids, clonidine and monoamine oxidase inhibitors +
anesthetics = potentiate anaesthetics.
3. Halothane sensitizes the heart to Adr.
4. If a patient on corticosteroids is to be anaesthetized, give 100 mg
hydrocortisone intraoperatively because anaesthesia is a stressful state—
can precipitate adrenal insufficiency and cardiovascular collapse.
5. Insulin need of a diabetic is increased during GA: switch over to plain
insulin even if the patient is on oral hypoglycaemics.

77. Preanaesthetic medication
Preanaesthetic medication refers to the use of drugs before
anaesthesia to make it more pleasant and safe. The aims are:
Relief of anxiety and
apprehension
preoperatively and to
facilitate smooth
induction.
Amnesia for pre- and
postoperative events.
Supplement analgesic
action of anaesthetics and
potentiate them so that less
anaesthetic is needed.
Decrease secretions and
vagal stimulation that may
be caused by the
anaesthetic.
Antiemetic effect
extending to the
postoperative period.
Decrease acidity and
volume of gastric juice so
that it is less damaging if
aspirated

78. • Sedative-antianxiety drugs Benzodiazepines like diazepam or
lorazepam i.m. 1 hour before have become popular drugs for
Preanaesthetic medication because they produce
• Tranquility and smoothen induction
• There is loss of recall of perioperative events (especially with
lorazepam) with little respiratory depression or accentuation of
postoperative vomiting.
• They counteract CNS toxicity of local anaesthetics and are being used
along with pethidine/fentanyl for a variety of minor surgical and
endoscopic procedures.
• Midazolam is a good amnesic with potent and shorter lasting action; it
is also better suited for i.v. injection, due to water solubility

79. • Opioids:
• Morphine (10 mg) or pethidine (50–100 mg), i.m. allay anxiety and
apprehension of the operation, produce pre- and postoperative
analgesia, smoothen induction, reduce the dose of anaesthetic required
and supplement poor analgesics (thiopentone, halothane) or weak
anaesthetics ( N2O). Postoperative restlessness is also reduced.
• Anticholinergics:
• Atropine or hyoscine (0.6 mg or 10–20 μg/kg i.m./i.v.) or glycopyrrolate
(0.2–0.3 mg or 5–10 μg/kg i.m./ i.v.) have been used, primarily to reduce
salivary and bronchial secretions.

80. • Neuroleptics
• Chlorpromazine (25 mg), triflupromazine (10 mg) or haloperidol (2–4 mg)
i.m. are infrequently used in premedication.
• They allay anxiety, smoothen induction and have antiemetic action.
• However, they potentiate respiratory depression and hypotension caused by
the anaesthetics and delay recovery.
• Involuntary movements and muscle dystonias can occur, especially in
children.
• H2 blockers/proton pump inhibitors
• Patients undergoing prolonged operations, caesarian section and obese
patients are at increased risk of gastric regurgitation and aspiration
pneumonia.
• Ranitidine (150 mg)/famotidine (20 mg) or omeprazole (20
mg)/pantoprazole (40 mg) given night before and in the morning benefit by
raising pH of gastric juice and may also reduce its volume and thus chances
of regurgitation.

81. • Antiemetics
• Metoclopramide 10–20 mg i.m. preoperatively is effective in reducing
postoperative vomiting. By enhancing gastric emptying and tone of LES,
it reduces the chances of reflux and its aspiration. Extrapyramidal effects
and motor restlessness can occur. Combined use of metoclopramide and
H2 blockers is more effective.
• Domperidone is nearly as effective and does not produce extrapyramidal
side effects.
• Ondansetron (4–8 mg i.v.) the selective 5-HT3 blocker has been found
highly effective in reducing the incidence of post-anaesthetic nausea and
vomiting. It is practically devoid of side effects and has become the
antiemetic of choice in anaesthetic practice.

82. Regimen for balanced anesthesia