brief review of inhalational agents

1. INHALATIONAL
ANAESTHETIC
AGENTS-II
Presenter: Pawan Kumar Ray

2. Flow of content
History
Ideal anesthetic agents
 -property-physical
 -pharmacokinatical
 -pharmacodynamical.
Classification of anesthetic agents.
Stages of anesthesia.
Individual drugs and properties.`

3. History
 During the Middle Ages, attempts were made to use
alcohol fumes as an analgesic during surgery.
 Another inhaled technique, the soporific sponge, is
mentioned in numerous manuscripts written in the Middle
Ages.

4. History
 The first public demonstration of inhalation
anaesthetic was nitrous oxide used by Professor
Gardner Q. Colton and dentist Horace Wells on 11
December 1844.
 On Oct 16th 1846 William Morton successfully
demonstrated Ether anaesthesia at Massachusetts
general hospital.

5. John collin
warren
W.T.G.MORTON
Gilbert Abott

6. Ideal inhalational anaesthetic
 Physical properties
 (1) Stable over a range of temperatures
 (2) Not be degraded by light
 (3) Does not require the presence of a preservative
 (4) Non-explosive and does not support combustion
 (5) Odourless or has a pleasant smell
 (6) Environmentally safe
 (7) Does not react with other compounds (e.g. Soda
lime, plastic and metals etc.)
 (8) Has a boiling point well above room temperature

7. Pharmacodynamic properties
 (1) Predictable dose-related CNS depression
 (2) Analgesic, anti-emetic and muscle relaxation properties
 (3) Minimal respiratory depression, does not cause
coughing or bronchospasm
 (4) Minimal cardiovascular effects.
 (5) No increase in cerebral blood flow (and therefore
intracranial pressure).
 (6) Not epileptogenic
 (7) Does not impair renal or hepatic function
 (8) No effect on uterine smooth muscle
 (9) Does not trigger of malignant hyperthermia

8. Pharmacokinetic properties
 (1) Low blood: gas solubility co-efficient
 (2) Low oil: gas solubility co-efficient
 (3) Not metabolised or no active metabolites
 (4) Is excreted completely by the respiratory system

9. Classification of
inhalational anesthetics
Historical Gases Volatile agents
 Ether
 trilene
Methoxyflurane
Cyclopropane
 chloroform
 Nitrous oxide
 Xenon
 Halothane
 Enflurane
 Isoflurane
 Sevoflurane
 Desflurane

10. In administering an anesthesia
Signpost
Guides in determination of depth of anesthesia
 Guedel describe depth of anaesthesia by dividing it
into stages and planes.
Stages of Anesthesia

11.  Guedel’s criteria based on :
 Respiration
 Eyeball movement
 Presence or absence of various reflexes
 Gillespie added other criteria
 Secretion of tears
 Response to skin incision
 Evaluation of pharyngeal &
laryngeal reflexes

12.  Stages were first described for ether anesthesia
 Can be used with modification for all agents
 Can be recognized during both induction & recovery

13.  Starts from beginning of anaesthetic inhalation and
lasts up to the loss of consciousness.
 Pain is progressively abolished.
 Patient remains conscious, can hear and see, and feels
a dream like state
Stage I- Stage of Analgesia

14.  Reflexes and respiration remain normal.
 Some minor operations can be carried out during this
stage
 But it is difficult to maintain
 Therefore use is limited to short procedures

15.  Stage starts from loss of consciousness upto gain of
rhythmical respiration
 Respiration – Irregular and large in volume
 Heart rate and BP raises
 Pupils – Large and divergent
 Muscle tone increased – jaw may be tight
 Patient may shout or struggle
 Involuntary micturation , or defecation
Stage II – Stage of Excitement

17.  Extends from onset of regular respiration to cessation of
spontaneous breathing.
 This has been divided into 4 planes:
o Plane 1- Roving eyeballs.
o This plane ends when eyes become fixed.
o Plane 2- Loss of corneal and laryngeal reflexes.
o Plane 3- Pupil starts dilating and light reflex is lost.
o Plane 4- Intercostal paralysis
Shallow abdominal respiration
Dilated pupil.
Stage III- Surgical Anaesthesia

18.  As anaesthesia passes to deeper planes
 Progressively-muscle tone decreases
 BP falls
 Heart Rate increases with weak pulse
 Respiration decreases in depth and later in frequency

19.  There is cessation of breathing leading to failure of
circulation and death.
 Pupil is widely dilated
 Muscles are totally flabby
 Pulse is thready or imperceptible
 BP is very low.
Stage IV- Stage of Medullary
Paralysis

20. Ether
 MAC 1.92
 ,B:G partition coefficient 12
 Guedel’s 4 stages of anaesthesia based on ether
 Good Analgesic
 Good Muscle Relaxant

21.  Pungent smell
 Inflammable and explosive
 Irritant
 Slow Induction and Recovery
 High incidence of Nausea and Vomitting

22. ether
 High CVS stability ; no myocardial depression.
 sympathetic stimulation and preservation of
baroreceptor reflex.
 No respiratory depression and no blunting of Hypoxic
drive.
 Bronchodilatation and Preserves cilliary activity

23. Nitrous oxide
Physical Property
• Not flammable but support combustion.
• Odorless
• Colorless
• Tasteless
• Prepared by heating NH4NO3 at 245-270°C

24. NH4NO3 --> N2O + 2H2O
Small amounts of NH3 and HNO3 produced recombine to
NH4NO3 on cooling.
Small amounts of NO and NO2 are also produced-
- Can cause methaemoglobinaemia, pulmonary edema
if inspired.
- N2O must be purified to remove these contaminants

25. Nitrous oxide
Colour of cylinder = blue.
MAC - 104%
Blood gas partition coefficient -0.46.
Pin index - 3;5

26. Nitrous oxide
 Unlike the potent volatile agents, nitrous oxide is a gas at
room temperature and ambient pressure.
 It can be kept as a liquid under pressure because its critical
temperature lies above room temperature
 With a MAC value of 104%, nitrous oxide, by itself is not
suitable as a sole anaesthetic agent.
 Nitrous oxide is an effective analgesic but poor muscle relaxant
 It undergoes minimal metabolism.

27. Nitrous Oxide
C.V.S EFFECTS-
 The circulatory effects of nitrous oxide are explained
by its tendency to stimulate the sympathetic nervous
system.
 Even though nitrous oxide directly depresses
myocardial contractility in vitro, arterial blood
pressure, cardiac output, and heart rate are essentially
unchanged or slightly elevated in vivo because of its
stimulation of catecholamine

28. Nitrous oxide
CEREBRAL
 By increasing CBF and cerebral blood volume, nitrous
oxide produces a mild elevation of intracranial
pressure.
 Nitrous oxide also increases cerebral oxygen
consumption (CMRO2).

29. The second gas effect
 The second gas effect usually refers to nitrous oxide
combined with an inhalational agent. Because nitrous
oxide is not soluble in blood, its' rapid absorption from
alveoli causes an abrupt rise in the alveolar
concentration of the other inhalational anaesthetic
agent.

30. Diffusion Hypoxia
•At the end of anesthesia after discontinuation of N2O,
N2O diffuses from blood into the alveoli much faster
than N2 diffuses from alveoli into the blood.
• Total volume of gas in the alveolus → fractional
concentration of gases in the alveoli is diluted by N2O
→ ↓ PaO2 & PaCO2 → hypoxia.
•This occurs in the first 5-10 mins of recovery. Therefore
it is advised to use 100% O2 after discontinuation of
N2O.

33. Toxicities – Nitrous Oxide
 Hematologic:
 N2O antagonizes B12 metabolism
 inhibition of methionine-synthetase
 Decreased DNA production
 RBC production depressed (megaloblastic anaemia)
 Neurologic
 Long term exposure to N2O is hypothesized to result in
neurologic disease similar to B12 deficiency

34. 35 times more soluble in blood than nitrogen, N2 so fills and expands
any air-containing cavities:
air embolism
pneumothorax
intracranial air
lung cysts
intraocular air bubbles
tympanoplasty
may exacerbate pulmonary hypertension

35. Entonox
50% N2O + 50% O2
Colour coding = blue body with blue &white quarters.
Pin index = 7
Poyinting effect: normally N2O is liquid at 2400 psig.
But If N2O is mixed with O2 it remains in gaseous
state called poyinting efect.
 Use: 1)labour analgesia.
2)field analgesia(wars)

36. Halothane
2-chloro,bromo 1-trifluro ethane.
Halogenated alkane compound chemically
Amber colored bottled – red colour coding
• Thymol preservative-to prevent spontaneous oxidative
decomposition.
• MAC- 0.75% So potent anesthetic.
• low blood/gas solubility coeffient - 2.5 thus induction -
relatively rapid.

37. HALOTHANE
 Volatile- kept in sealed bottles
 Colorless,
 Pleasant odor-suitable in pediatrics for inhalation
induction (although sevoflurane is now the agent
of choice )
 Non-irritant
 Non-explosive, Non-inflammable
 Light-sensitive
 Corrosive-Interaction – rubber and plastic tubing

38. metabolism
 20% metabolized in liver by oxidative pathways.
 Major metabolites : bromin, chlorine, Trifloroacetic
acid, Trifloroacetylethanl amide

39. Systemic effects of Halothane
 CNS:
 Generalized CNS depression
 cerebrovascular dilation causes increased ICP
 Autoregulation is blunted
 Cardiovascular:
• A dose-dependent reduction of arterial blood pressure is due to direct
myocardial depression
• blunts baroreceptor reflex

40. •Although halothane is a coronary artery vasodilator,
coronary blood flow decreases, due to the drop in systemic
arterial pressure.
• Adequate myocardial perfusion is usually maintained, as
oxygen demand also drops- maybe advantages In pts with
CAD
•Halothane sensitizes the heart to the arrhythmogenic
effects of catecholamine
◦To minimize effects :
Avoid hypoxemia and hypercapnia
Avoid conc. Of adrenaline higher than 1 in 10000

41. Pulmonary:
 best bronchodilator among the currently available volatile
anesthetics.
 attenuates airway reflexes and relaxes bronchial smooth muscle
by inhibiting intracellular calcium mobilization.
 depresses clearance of mucus from the respiratory tract
(mucociliary function), promoting postoperative hypoxia and
atelectasis.

42.  Renal:
-Both GFR and renal blood flow is decreased-because of
decrease cardiac output.
- associated with reversible reduction in GFR.
Gastro intestinal tract:-
Inhibition of gastrointestinal motility.
Cause sever post. Operative nausea & vomiting.
Uterus:
 Halothane relaxes uterine muscle, may cause postpartum
hemorrhage .
 Concentration of less than 0.5 % associated with increase
blood loss during therapeutic abortion.

43. Skeletal muscle:
 Its cause skeletal muscle relaxation .
 Postoperatively, shivering is common , this increase
oxygen requirement>>> which cause hypoxemia.
Post operative shivering (halothane shakes) and
hypothermia is maximum with halothane among
inhalational agents.

44. Halothane - Hepatic Toxicity
 All inhaled AA can cause hepatic injury in animal
studies
 All inhaled AA have immunohistochemical
evidence of binding to hepatocytes
 Thought that Trifluoroacetic acid metabolites are
root cause
 Another theory is due to Hypoxia as halothane causes
Hepatic arterial constriction

45. Halothane Hepatitis
 The incidence of fulminant hepatic necrosis terminating
in death associated with halothane was found to be 1 per
35,000.
 Demographic factors ; It’s a idiosyncratic reaction,
susceptible population include Mexican Americans,Obese
women, , Age >50 yrs, , Familial predisposition, Severe
hepatic dysfunction while Children are resistant.
Prior exposure to halothane is a important risk factor &
multiple exposure increases the chance of hepatitis.

46. Mechanism of Toxicity
 There are various proposed mechanisms:
• Metabolite-mediated direct toxicity
• Immunologically-mediated damage to liver cells
 a proportion is biotransformed by hepatic microsomal enzyme CYP 2E1
to a trifluoroacetic acid which can be detected in the urine, but which
also can trifluoroacetylate hepatic proteins, some of which may be
immunogenic and induce cytotoxic reactions.
• Hypoxia alone

48. Hepatic dysfunction:
 Two type of dysfunction:
 1- Type I hepatotoxicity:-mild, associated with
derangement in liver function test , this result from
metabolic of Halothane in liver. results from reductive
(anaerobic) biotransformation of halothane rather than the
normal oxidative pathway.
 2- Type II hepatotoxicity: fulminate (uncommon); sever
jaundice ,fever, progressing to fulminating hepatic
necrosis,
Its increased by repeated exposure of the drugs.
high mortality 30-70%

49.  1- A careful anesthetic history .
 2- repeated exposure of halothane within 3 months should be
avoided.
 3- History of unexplained jaundice or pyrexia after previous
exposure of halothane.
Recommendation for Halothane anesthesia:

50. Drug Interactions
 1. Beta blockers and calcium channel blockers can
produce severe depression of cardiac function with
halothane
 2. Aminophylline can produce serious ventricular
arrhythmias with halothane.
 3 .Halothane sensitizes the heart to the
arrhythmogenic effects of epinephrine, so that doses
of epinephrine above 1.5 g/kg should be avoided.

51. Contraindication
 Malignant hyperthermia.
 susceptibility unexplained liver dysfunction after
previous halothane exposure
 intracranial mass lesion
 hypovolemia
 aortic stenosis
 pheochromocytoma
 with aminophylline has been associated with severe
ventricular dysrhythmias

52. Isoflurane
2-chloro 1-trifluro methyl-
ethyl ether.
MAC is 1.17 % B:G p co-ef is 1.17.
Isoflurane is characterized by extreme physical
stability, undergoing no detectable deterioration during 5 years of
storage or on exposure to carbondioxide absorbents or sunlight.
The stability of isoflurane obviates the need to add preservatives such
as thymol to the commercial preparation.

53.  RESPIRATORY SYSTEM
 Initially, until deeper levels of anesthesia are reached,
isoflurane stimulates airway reflexes with:
 increases in secretions
 coughing
 laryngospasm.

54. Isoflurane
 CNS:
 low concentration Vs High concentration.
 Low : no change on the flow.
 High : increase blood flow by vasodilatation of the cerebral
arteries.
Generalized CNS depression; Rapid emergence
 Increased ICP reversed by Hyperventilation
 Agent of choice for neuro-anaesthesia.

55.  Cardiovascular:
 myocardial depression, decreased vascular assistance &
decreased MAP
 Preserves baroreceptor reflex . So that reflex tachycardia
occurs in response to decrease B.P maintaining cardiac
output.
 Agent of choice for cardiac anaesthesia.

56. Coronary steal phenomenon
 Isoflurane induced coronary artery vasodilatation can lead to
redistribution of coronary blood flow away from diseased areas
where arterioles are maximally dilated to areas with normal
responsive coronary arteries. This phenomenon is called
the coronary steal syndrome

57. Sevoflurane
Florinated Methyl –
isopropyl ether.
MAC -1.80.
Low blood:gas partition coefficient -0.69 (Rapid induction and
recovery.
Compared with isoflurane, recovery from sevoflurane anesthesia
is 3 to 4 minutes faster and the difference is magnified in longer
duration surgical procedures (>3 hours)

58.  Pleasant smell , non irritant,bronchodilatation and least airway irritation
among current volatile agents makes it acceptable for inhalation induction
of anesthesia.
• agent of choice for paediatric anesthesia.
• 2nd agent of choice for
• Neuro anesthesia.
• Cardiac anesthesia .
• Asthmatics
Does not sensitize the myocardium to catecholamines as much as
halothane.
Does not result in carbon monoxide production with dry soda lime.
Sevoflurane

59.  Sevoflurane may be 100-fold more vulnerable to metabolism
than desflurane -estimated 3% to 5% of the dose undergoing
biodegradation.
 metabolites - inorganic fluoride
 hexafluoroisopropanol.
 cannot undergo metabolism to an acyl halide.
 does not result in the formation of trifluoroacetylated liver
proteins.
 Therefore cannot stimulate the formation of
antitrifluoroacetylated protein antibodies.
 So devoid of the potential to produce hepatotoxicity as well
as cross-sensitivity between drugs.

60. Sevoflurane and Compound A
 Sevoflurane forms a degradation product, compound
A [fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl
ether] on contact with the soda lime in a rebreathing
apparatus.
 Compound A is a dose-dependent nephrotoxin in rats.
 A proposed mechanism for nephrotoxicity is the metabolism of
compound A to a reactive thiol via the β-lyase pathway.
 Because humans have less than one-tenth of the enzymatic
activity for this pathway compared to rats, it is possible that
humans should be less vulnerable to injury by this mechanism.

61.  Sevoflurane can also be degraded into hydrogen fluoride by
metal and environmental impurities present in manufacturing
equipment, glass bottle packaging, and anesthesia equipment.
 Hydrogen fluoride can produce an acid burn on contact with
respiratory mucosa.
 The risk of patient injury has been substantially reduced by
inhibition of the degradation process by adding water to
sevoflurane during the manufacturing process and packaging it
in a special plastic container.
 Postoperative agitation may be more common in children then
seen with halothane.

62. Desflurane
2-fluro,1-trifluro methyl ethyl ether.
 MAC =6.6 %
differs from isoflurane only by substitution of a fluorine atom for
the chlorine atom found on the alpha-ethyl component of
isoflurane.
Fluorination rather than chlorination increases vapor pressure
(decreases intermolecular attraction), enhances
molecular stability, and decreases potency.

63.  desflurane would boil at normal operating room temperatures
 A new vaporizer technology addressed this property, producing
a regulated concentration by converting desflurane to a gas
(heated and pressurized vaporizer that requires electrical
power),which is then blended with diluent fresh gas flow
 Solubility characteristics (blood:gas partition coefficient 0.45)
and potency (MAC 6.6%) permit rapid achievement of an
alveolar partial pressure necessary for anesthesia followed by
prompt awakening when desflurane is discontinued.

64. Desflurane
 Pungent odor --desflurane less likely to be used for
inhalation induction compared to halothane or
sevoflurane.
 Airway irritation, breath-holding, coughing,
laryngospasm,significant salivation, when >6%
desflurane administered to an awake patient.
 Produces the highest carbon monoxide
concentrations, followed by enflurane and isoflurane

65. Desflurane
 CNS:
 Generalized depression
 Extremely rapid emergence
 Increased ICP
 Cardiovascular:
 Vascular resistance decreased
 Heart rate (deep anesthesia); tachycardia with rapid concentration
change
 Pulmonary:
 decrease tidal volume
 increase respiratory rate
 irritant

66. Dual-circuit gas–vapour blender
 It was created specifically for the agent desflurane.
 Desflurane boils at 23.5 ºC, which is very close to room
temperature.
 This means that at normal operating temperatures, the saturated
vapour pressure of desflurane changes greatly with only small
fluctuations in temperature.
 A desflurane vaporiser (e.g. the TEC 6 produced by Datex-
Ohmeda) is heated to 39C and pressurised to 200kPa
.

68.  Agent of choice for day care (fastest induction)
 Agent of choice for geriatric (old) patients.
 Agent of choice for hepatic failure
 Agent of choice for renal failure

69. Anesthetic B:G PC MAC Features Notes
Halothane 2.3 0.74% PLEASANT Arrhythmia
Hepatitis
Hyperthermia
Enflurane 1.9 1.69% PUNGENT Seizures
Hyperthermia
Isoflurane 1.4 1.17% PUNGENT Widely used
Sevoflurane 0.62 1.92% PLEASANT Ideal
Desflurane 0.42 6.1% IRRITANT Cough
Nitrous 0.47 104% PLEASANT Anemia

70. XENON
 Most ideal inhalational agent.
 Blood gas partition co-efficient is 0.14. least of all .least
soluble. so fastest induction and fastest recovery.
 MAC is 70% so can be given with 30%O2.
 Most cardiostable.
 No metabolism in body –least side effects non terratogenic.
 Non inflamble,does not deplete ozone layer.
 Disadvantages = costly, needs special equipment for
delivary, bronchospasm.
 Acts on NMDA receptor

71. Enflurane
1-chloro ,fluro 2-difluro
methyl-ethyl ether.
•Halogenated, methyl ethyl ether
•Pungent odour
•MAC 1.68%
•B:G- 1.8
•Inflammable at> 5 %concentration

72.  : CNS-
• increased ICP secondary to increased cerebral blood flow (CBF)
• produce fast frequency and high voltage on the EEG.
• Decrease the threshold for seizure-Epileptogenic inhalational
agent.
• It is primarily used for procedure in which a low threshold for
seizure generation is required like ECT.
 Cardiovascular:
• myocardial depressant
• decreased vascular resistance; decreased mean arterial pressure
(MAP), tachycardia

73. ENFLURANE
 Contraindications/Precautions
 malignant hyperthermia susceptibility
 preexisting kidney disease
 seizure disorder
 intracranial hypertension
 isoniazide enhances enflurane defluorination

74. Trichloroethylene (trilene)
 Most potent analgesic agent - trielene
 Reaction with sodalime :-
dichloroacetylene – neurotoxic- V, VII.
phosgene - pulmonary toxicity(ARDS)
CHLOROFORM
 1st agent used for labour analgesia.
 Cardiotoxic- death due to ventricular fibrillation.
 Hepatotoxic.
 Profound hyperglycemia.

75. Methoxy-flurane
 Most potent inhalational agent (mac-0.16%).
 Slowest induction and recovery(b:g – 15).
 Most nephro-toxic agent –high output renal failure
 Reacts with rubber tubing of closed circuit

76. Cyclopropane
Most inflamable & explosive agent
Liquid gas-Orange cylinder.
Increases sympathetic tone and B.P.
Agent Of Choice in Shock
Cyclopropane shock.