This document provides an overview of anaesthesia. It begins with definitions of anaesthesia and a brief history highlighting key developments. It then outlines the major steps of anaesthesia including induction, maintenance and recovery. The document discusses the pharmacology of various anaesthetic agents including intravenous and inhalation anaesthetics. It explains their mechanisms of action, focusing on interactions with ion channels and receptors in the brain and spinal cord. Minimum alveolar concentration is introduced as a measure of comparing agent potency. Specific intravenous agents are then summarized, including properties of propofol and thiopental such as their rapid induction times and effects on physiological parameters.

1. Anaesthesia
Ms. K.D.S.V. Karunanayaka (B.Pharm)
Department of Pharmacy
Faculty of Health Sciences
The Open University Sri Lanka

2. Out Line
• Introduction to Anaesthesia
• General Anaesthetics
• Pharmacology of Anaesthetics
• Intravenous Anaesthetics
• Inhalation Anaesthetics

3. Introduction to Anaesthesia
• Anaesthesia is a condition of having sensation blocked or temporarily
taken away.
• It is a pharmacologically induced and reversible state
of amnesia, analgesia, loss of responsiveness, loss of skeletal
muscle reflexes or decreased stress response
• Until the mid 19th century surgery as was possible had to be undertaken
at tremendous speed. Surgeons did their best to terrified patients by
using alcohols, opium, cannabis, hemlock or hyoscine.
• With the introduction of general anaesthesia surgeons could operate
for the first time with careful deliberation.
• In the 1984s solved the problem of long term unconsciousness using
nitrous oxide, ether and chloroform.

4. Three Principals of Anaesthesia
Katzung
12th edition

5. History of Anaesthesia
The key events around 1840s were,
• 1842 – W.E. Clarke of Rochester, New York administered ether for dental
extraction
• 1844 – Horace Wells, Hartford introduced nitrous oxide to produce
anaesthesia during dental extraction.
• 1846 (October) – William Mortan, Boston successfully demonstrated the
anaesthetic properties of ether.
• 1846 (December) – Robert Liston, England performed the first surgical
operation using ether.
• 1847 – James Y Simpson, Prof. of Midwifery at University of Edinburgh
introduced chloroform for the relief of labour pain.

6. Major Steps of Anaesthesia
• Induction
• Period of time from onset of administration of the anesthetics
to the development of effective surgical anesthesia.
• Usually effective with IV agents.
• Maintenance
• Sustain surgical anesthesia.
• Usually with inhalation agents.
• Recovery
• Time from discontinuation of anesthesia to recovery.

7. Stages of Anaesthesia
1. Stage of analgesia
• Initially only analgesia & later stages analgesia and amnesia.
• Patient is still conscious.
2. Stage of excitement
• Patient still in amnestic stage but produce delirious effects/produce violent behaviour
• Respiration and BP-usually irregular.
3. Stage of surgical anesthesia
• Recurrence of regular respiration and ends in complete cessation of respiration
(apnea), relaxation of skeletal muscles, eye movement cease, pupil is fixed.
4. Stage of medullary depression
• Complete depression of vasomotor center in medulla and respiratory center.
• Without the circulatory and respiratory support death might occur rapidly.

8. Phases of General Anaesthesia
• Balanced surgical anaesthesia (Hypnosis, analgesia and muscle
relaxation) with a single drug would require high doses.
• It might cause adverse effects such as slow and unpleasant
recovery and depression of cardiovascular and respiratory
function.
• In modern practice, different drugs are used to minimize adverse
effects.
• Perioperative phase will divide into three phases.
• Before Surgery
• During Surgery
• After Surgery

9. Before Surgery
An assessment is made of,
• the patient’s physical and psychological condition
• any current illness
• the relevance of any existing drug therapy
• All of above conditions depend of the choice of anaesthetics.
• Principles aims are to provide,
• Anxiolysis and amnesia
• Analgesia
• Timing
• Gastric contents
PhasesofGeneralAnaesthesia

10. Before Surgery
Drugs used in,
• Anxiolysis and amnesia
• Benzodiazepines (Tamazepam 10-30mg for an adult)
• Provide anxiolysis and amnesia for the immediate presurgical period.
• Analgesia
• Parenteral Opioid (Morphine)
• Non-steroidal anti-inflammatory drugs – NSAIDs
• Paracetamol
• For moderate and major surgeries to prevent pain before surgery and postoperative pain.
• Timing
• Given about one (01) hour before surgery.
• Gastric contents
• Antacid (Sodium citrate)
• H2 receptor blocker (Ranitidine)
• Proton pump inhibitor (Omeprazole)
• Antiemetic (Metoclopromide)
• Pulmonary aspiration of gastric contents may cause severe pneumonitis.
PhasesofGeneralAnaesthesia

11. During Surgery
Drugs require to provide,
• unconsiousness
• analgesia
• muscular relaxation
• control of blood pressure, heart rate & respiration.
• Total muscular relaxation (Paralysis) is required for some surgical
procedures.
• Ex:- intra abdominal surgery
• Main functions of anaesthetics during surgery are,
• Induction
• Maintenance
PhasesofGeneralAnaesthesia

12. During Surgery
Induction
1. Intravenous anaesthetics
2. Inhalation anaesthetics
Maintenance
1. Oxygen + Air / Nitrous Oxide + Inhalation anaesthetics
2. Continuous infusion of Intravenous anaesthetics
PhasesofGeneralAnaesthesia

13. After Surgery
Drugs will play a part in,
• reversal neuromuscular block (if required)
• relief of pain
• relief of postoperative nausea & vomiting
• The anaesthetist ensures that the effects of neuromuscular blocking
drugs and opioid –induced respiratory depression have been reversed
by an antagonist.
• The important is that patient will not left alone until conscious with
protective reflexes restored and with stable circulation.
PhasesofGeneralAnaesthesia

14. After Surgery
• Relief of pain
• Mixture of local anaesthetic & opoid (Ex:- Laparatomy)
• Parenteral morphine
• Paracetamol and NSAIDs
• Postoperative nausea & vomiting (PONV)
• Propofol
• Antiemetics (Cyclizine, Metaclopramide, Ondansetron)
• Dexamethasone
PhasesofGeneralAnaesthesia

15. Functions of adjuncts to
anesthesia
Adjuncts to
anesthesia
Relieve
anxiety
Relax
muscles
Prevent
secretion
of fluids in
to the RT
Rapid
induction
of
anesthesia
Prevent
postsurgic
al nausea
and
vomiting

16. Type of Anaesthetics
• General Anaesthetics
• Local Anaesthetics

17. Mode of Action of General Anaesthetics
• General anaesthetics act on the brain, primarily on the mid brain reticular
activating system, and the spinal cord.
• Many anaesthetics are lipid soluble and there is good correlation between this
and effectiveness. (Overton-Meyer hypothesis)
• More lipid soluble drug tend to be the more potent anaesthetic.
• But some agents are not lipid soluble and many lipid soluble agents are not
anaesthetics.
• Until recently it was thought that the principal site of action of general
anaesthetics were relatively non specific action in the neuronal lipid bilayer
membrane.
• Current view is that these interact with protein to alter the activity of specific
neuronal ion channels, particularly the fast neurotransmitter receptors such as
nicotinic acetylcholine, GABA (Gamma Amino Butyric Acid) and glutamate
receptors.

18. Mode of Action of General Anaesthetics
Katzung 12th edition

19. Mode of Action of General Anaesthetics
• They stimulate GABA receptor-chloride channel and depress the action potential
(most of the anesthetics)
• Direct activation of GABA receptors by binding to specific subunits
• Ketamine block the excitatory neurotransmission by glutamic acid on the N-
methyl-D-aspartate (NMDA) receptors
• Some of the anesthetics stimulate potassium channels in addition to stimulating
GABA to cause membrane hyperpolarization
• Some other cation channels may also be blocked
• Some blocks in nicotine receptors
• The strychnine sensitive glycine receptor might also be effected
• The neuropharmacologic basis for the effects that characterize the stages of
anesthesia appear to be differential sensitivity of specific neurons or neuronal
pathways to anesthetic drugs

20. Mode of Action of General Anaesthetics
• The suppression of motor response to painful stimuli by
anaesthetics is mediated mainly by the spinal cord, where as
hypnosis and amnesia are mediated within the brain.
• Efficacy can be compared using minimum alveolar concentration
(MAC), the oxygen required to prevent movement in response to a
standard surgical skin incision in 50% of subjects.
• The MAC of the volatile/inhalational anaesthetics are reduced by
the co-administration of nitrous oxide.

21. Minimum alveolar concentration
• Minimum alveolar concentration or MAC is a concept
used to compare the strengths, or potency of
anaesthetic vapours
• It is defined as the concentration of the vapour in the
lungs that is needed to prevent movement (motor
response) in 50% of subjects in response to surgical (pain)
stimulus
• Smaller the MAC high potent are the anesthetics
(halothane)
• Less potent(nitrous oxide)

22. Oxygen in Anaesthesia
• To prevent hypoxia
• To prevent hypoxemia
• At least 30% concentration of oxygen
• Concentration more than 80% has toxic effect ( Mild substernal
irritation, pulmonary exudation, atelectasis)
• Use of unnecessary high concentrations cause retrolental
fibroplasia and permanent blindness

23. Type of General Anaesthetics
• Intravenous Anaesthetics
• Inhalation Anaesthetics
• Balanced Anaesthetics

24. Intravenous Anaesthetics
• Usually given alone or in combination with other drugs
• Fully trained staff should be there to handle IV anaeshetics
• Drugs include
• Barbiturates (thiopental, methohexital, Thiamylal)
• Benzodiazepines (midazolam, diazepam, lorazepam)
• Propofol
• Ketamine (dissociative)
• Opioid analgesics (morphine, fentanyl, sufentanil,
alfentanil, remifentanil)
• Other drugs (etomidate, dexmedetomide)

25. Pharmacokinetic – Intravenous
Anaesthetics
• Extremely rapid induction
• Steep concentration gradient of blood and expediting diffusion
into the brain
• Rate of transfer depends on lipid solubility and arterial
concentration of unbound, non-ionized drugs
• Considerable accumulation and prolong recovery
• Main function is induction of anaesthesia

26. Propofol
• Induction fo anaesthesia with 1.5-2.5 mg/kg occurs within 30 s
• Smooth and pleasant low incidence of excitatory movements.
• Pain of injection can be eliminated using lidocaine 20 mg.
• Recovery is rapid.
• Used as sole anaesthetic.
• Nausea & vomiting is low.
• Causes dose-dependant cortical depression.
• Act as anticonvulsant.
• Depress laryngeal reflexes.
• Reduce vascular tone and heart rate remains unchanged.
• Cause transient apnea.

27. Thiopental
• Very short acting barbiturate
• Induce smoothly – one arm to brain circulation
• Typical induction dose – 3-5 mg/kg
• Rapid distribution, initial t ½ = 4 minutes
• Swift recovery after a single dose
• Terminal t ½ = 11 hours
• Continuous infusion lead accumulation in fat and very prolonged recovery
• Metabolized in liver
• Nausea & vomiting higher than propofol
• pH = 11

28. Thiopental
• Antaanalgesic
• Potent anticonvulsant
• Cerebral metabolic rate for oxygen (CMRO2) consumption is
reduced, causing cerebral vasoconstriction.
• Reduction in cerebral blood flow and intracranial pressure.
• Reduces vascular tone, causing hypotension.
• Antihypertensive or diuretics may augment the hypotensive effect.
• Slight increase in heart rate.
• Reduces respiratory rate and tidal volume.

29. Metohexitone
• Barbiturate
• Terminal t ½ is shorter
• Inducing anaesthesia for electroconvulsive therapy (ECT)

30. Etomidate
• Carboxylated imidazole
• Cause pain in injection and excitatory muscle movements
• 20-50% incidence of nausea & vomiting
• Cause adrenocortical suppression after a single dose that can lasts
for as long as 72 hours.
• Not to be used in patients with sepsis as it increases incidence of
organ failure.
• Therefore this is useful in emergency anaesthesia, as it causes less
cardiovascular depression and hypotension than thiopental or
propofol.

31. Ketamine
• Phencyclidine / hallucinogen derivative
• Antagonist of N- methyl D aspartate
• Produce dissociative anaesthesia (sedation, amnesia, dissociation,
analgesia)
• Persists for 15 minutes after a single intravenous injection
• Sole analgesic for diagnostic and minor surgical interventions
• Causes tachycardia and increase in blood pressure and cardiac
output.
• Popular choice of inducing anaesthesia in shocked patients.
• Potent bronchodilator – treatment choice in severe bronchospasm

32. Ketamine
• Produces no muscle relaxation
• Hallucinations and delirium can occur during recovery.
• Used to provide analgesia for painful procedures. (Dressing of
burns, minor orthopedic procedures)
• Both induction and maintenance of anaesthesia for short lasting
diagnostic and surgical interventions that do not require skeletal
muscle relaxation.
• Contraindicated in patients with,
• Moderate to severe hypertension
• Cerebral trauma
• Eye injury
• Psychiatric disorders (Schizophrenia)

33. Ketamine
• Induction dose = 2 mg/kg IV (60 s infusion produce 5-10 min)
or 5 mg/kg IM (last for 25 min)
• Maintenance dose = 50% IV dose or 25% IM dose
• Recovery of consciousness is gradual and lessened by benzodiazepine
premedication.
• Ketamine is contraindicate in pregnancy before term, as it has oxytoxic
activity.
• Also contraindicated patients with eclampsia and pre-eclampsia.
• It may be used for assisted vaginal delivery by an experienced
anaesthetist.
• Better for use during caesarian section, it causes less fetal and neonatal
depression than others.

34. Context-Sensitive Half Time
Katzung 12th edition

35. Diazepam
• Benzodiazepine with sedative and amnesic properties
• Depresses the CNS at the limbic and subcortical levels of the
brain
• Depresses the ventilatory response to PaCO2
• Mild muscle relaxation mediated at the spinal cord level; not
at the neuromuscular junction
• No analgesic properties
• Used for,
• Basal sedation
• Induction agent
• Pre-anesthetic
• Drug of choice for seizures

36. Midazolam
• Benzodiazepine that has a rapid onset with sedative and amnesic
properties
• Depresses the CNS at the limbic and subcortical levels of the brain
• Depresses the ventilatory response to PaCO2
• No analgesic properties
• Mild muscle relaxation mediated at the spinal cord; not at the
neuromuscular junction
• Water soluble--which allows for better absorption following IM
injection

37. Flumazenil
• Selective, competitive antagonist of benzodiazepines
• Relatively short duration of action between one and two hours
• Acts through competitive inhibition of GABA (benzodiazepine receptor
in the CNS)
• Uses: Reversal of benzodiazepine sedation or overdose
• Reversal of conscious sedation 0.2-1.0 mg IV q 20 min @ 0.2 mg/min
• Overdose 1.0 mg IV at 0.5 mg/min
• Maximum total safe total dose 3mg in an hour

38. Morphine
• Most common opioid analgesic used in anesthesia
• Both depressive and stimulatory effects
• Binds with opiate receptor sites in the CNS, altering both perception of
and emotional response to pain
• Has little CV effect, but produces peripheral dilation
• Used for the relief of moderate to severe pain
• May be given IM, SC or IV
• 1- 3 mg IV prn
• 10 -15 mg IM or SC q4h
• 2 - 20 mcg/kg/hr infusion rate

39. Nalbuphine
• Synthetic opioid agonist-antagonist that binds with opiate receptor
sites in the CNS, altering both perception of and emotional response
to pain
• Relative potency of Nalbuphine as compared to Morphine is 0.5 to 0.9
• Inactivated in the liver and eliminated primarily by secretion in the
bile with fecal excretion
• Relief of moderate to severe pain
• Not a useful component in balanced anesthesia because of its ceiling
analgesia action
• May be used as a pre-operative sedative-analgesic
• There is a ceiling for analgesia that is not increased beyond doses
greater than 0.4 mg/kg IV
• 10 mg q 3-6 hr prn SC, IV, IM

40. Naloxone
• Narcotic antagonist
• Use in the management and reversal of overdoses caused
by narcotics or synthetic narcotics
• For the complete and partial reversal of depression
caused by the following drugs:
• Narcotics: Morphine, Heroin, Percodan, Methadone,
Demerol, Paregoric, Codeine, and Fentanyl
• Synthetic Narcotics: Nubain, Stadol, Talwin, Darvon
• 1-2 MG IV q5min up to 3 times
• Continuous infusion may be started at 400 mcg/hr.

41. Inhalation Anaesthetics
• Minimally irritant and nonflammable.
• All of these are volatile agents,
• Nitric oxide gas is used as an important adjuvant to volatile
agents
• Drugs include
• Halothane
• Enflurane
• Methoxyflurane
• Isoflurane
• Desflurane
• Sevoflurane

42. Pharmacokinetic – Inhalation
Anaesthetics
• Efficacy of general anesthetics and its rapid action depends on how quickly
its therapeutic level is achieved in the brain/CNS.
• Uptake and distribution of inhaled anesthetics
• The rate at which anesthetic therapeutic drug concentration achieved in
the brain depends on
• Solubility properties of anesthetics
• Concentration of anesthetics in the inspired air
• The volume of pulmonary ventilation
• The pulmonary blood flow
• The partial pressure gradient between arterial and mixed venous
blood anesthetic concentrations

43. Pharmacokinetic – Inhalation
Anaesthetics
• The elimination of anesthetics
• Time to recovery from anesthetics depends on speed, quickly
anesthetics are eliminated.
• The factors that determine the eliminations are
• Blood: gas partition coefficient of the anesthetics
• Pulmonary blood flow
• Magnitude of ventilation
• Tissue solubility

44. Pharmacokinetic – Inhalation
Anaesthetics
• Depth of anaesthesia is correlated with partial pressure or tension
of anaesthetic drugs in brain tissue.
• High solubility in blood, high blood/gas partition coefficient will
provide a slow induction and adjustment of depth of anaesthesia.
• Blood act as a reservoir, so that drug will not enter the brain
readily until the blood reservoir is filled.
• Low solubility in blood, low blood/gas partition coefficient will
provide a rapid induction of anaesthesia because blood reservoir
is small and drug available to pass into the brain sooner.

45. Pharmacokinetic – Inhalation
Anaesthetics
• During induction of anaesthesia the blood is taking up
anaesthetic selectively and rapidly, and the resulting loss
of volume in the alveoli leads to a flow of anaesthetic into
the lungs that is independent of respiratory activity.
• Mild hypoxia can be occurred. And lasts for as long as 10
minutes.

46. Pharmacodynamics - Inhalation
Anaesthetics
Effects on the CVS
• All inhaled anesthetics decrease the mean arterial pressure in direct
proportion to their mean alveolar concentration
• Bradycardia (halothane), increase heart rate (desflurane , isofleurane),
no effect on heart rate (other drugs)
• Cardiac depression activity
• Net cardiac effect of inhaled anesthetics depends on
• Surgical stimulation, intravascular volume status, ventilatory status,
duration of anesthesia

47. Pharmacodynamics -
Inhalation Anaesthetics
Effects on the respiratory system
• Dose dependent decrease in tidal volume, increase RR
(exception NO)
• All volatile anesthetics are respiratory depressants
• They increase the apneic threshold and decrease the
ventilatory response to hypoxia
• The respiratory depression can be overcome by assisting
ventilation mechanically
• Prolong use of anesthetics causes pooling of mucous
• They also produce some broncho-dilatory effects

48. Pharmacodynamics -
Inhalation Anaesthetics
Effects on the brain
• They decrease the metabolic rate of the brain.
• All soluble volatile anesthetics can cause cerebral vascular
dilation which is not a favorable condition in patient with
increased intracranial pressure.
• Least effect on cerebral flow is caused by nitrous oxide.
• Depressant effect on EEG activity at doses of 1-1.5 MAC.

49. Pharmacodynamics -
Inhalation Anaesthetics
Effect on the kidney
• Decrease the glomerular filtration rate and renal blood flow.
Effects on the liver
• Decrease the hepatic blood flow.
Effects on uterine smooth muscles
• Uterine muscle relaxants (except Nitrous oxide)

50. Nitrous Oxide
• Slightly sweetish smell, neither flammable nor explosive.
• Produce slight anaesthesia without demonstrably depressing
respiratory or vasomotor center.
Advantages
• Reduces the requirement for other more potent/ toxic anaesthetics.
• Strong analgesic action.
• Entonox (50% NO) has similar effects of morphine.
• Induction is rapid.
• Recovery time rarely exceeds 4 minutes.

51. Nitrous Oxide
Disadvantages
• Expensive to buy and transport.
• Used with conjunction to has full surgical anaesthesia.
Uses
• To maintain surgical anaesthesia with combination of other
anaesthetic agents. (Isoflurane, Propofol)
• Muscle relaxant
• Analgesic (Entonox)

52. Nitrous Oxide
Dose & Administration
• Maintenance of anaesthsia = 70% NO + 30% O2
• Analgesia = 50% NO + 50% O2
Contraindications
• Air filled space expands during administration. Therefore Contraindicated in
patients with,
• Collections of air in the pleural
• Pericardial & peritoneal spaces
• Intestinal obstructions
• Arterial air embolism
• Decompression sickness
• Severe chronic obstructive airway disease
• Emphysema

53. Nitrous Oxide
Precautions
Continued administration of oxygen is required during recovery.
(Especially in elderly patients)
Adverse effects
• Nausea & vomiting
• Megaloblastic changes in the bone marrow for more than 4 hours
exposure
• Bone marrow depression
• Tetratogenic effects

54. Halogenated Anaesthetics
• Halothane – MAC 0.74 % (1st halogenated anaesthetic)
• Isoflurane – MAC 1.2 %
• Enflurane - MAC 1.7 % Largely superseded in the
• Sevoflurane - MAC 2.0 % developed world
• Desflurane - MAC 6.0 %

55. Halothane
• Highest blood/gas partition coefficient
• Recovery comparatively slow
• Pleasant to breath
• Reduces cardiac output more than other volatile anaesthetics
• Sensities the heart for arrhythmic effects
• Trigger malignant hyperthermia
• 20% metabolized and induces hepatic enzymes
• Fever develops 2-3 days after anaesthesia
• Adverse effects are anorexia, nausea & vomiting
• More serious – transient jaundice
• Very rarely – fatal hepatic necrosis
• Repeatedly administration - hepatitis
HalogenatedAnaesthetics

56. Isoflurane
• Volatile colourless liquid, Nonflammable at normal concentrations
• Lower blood/gas partition coefficient than halothane
• Pungent odour
• Can cause bronchial irritation
• Unpleasant inhalational induction
• Metabolised 0.2%
• Although it is a bronchodilator, occur respiratory depression
• Slight impairment of myocardial contractility
• Cause peripheral vasodilatation and reduce blood pressure
• Relaxes voluntary muscles
• Depress cortical EEG activity
• Cause “coronary steal”
HalogenatedAnaesthetics

57. Sevoflurane
• Metabolised 2.5%
• Degraded with contact of carbon dioxide, soda lime
• Less chemically stable
• Nephrotoxic
• Less soluble than isoflurane
• Very pleasant to breath
• Excellent choice for children
• Does not cause “coronary steal”
HalogenatedAnaesthetics

58. Desflurane
• Lowest blood/gas partition coefficient
• Negligible metabolism – 0.03%
• Extremely volatile
• Very pungent odour
• Very rapid recovery
HalogenatedAnaesthetics

59. Effect of blood/gas partition
coefficient
Katzung 12th edition

60. Alveolar Anaesthetic Concentration
Katzung 12th edition

61. Effect of ventilation
Katzung 12th edition

62. Balanced Anaesthetics
• Combination of both intravenous (to induce
anesthesia) and inhaled (to maintain the anesthesia)
• Muscle relaxants are commonly given to facilitate ET
tube insertion

63. References
• Bennet p.n., Brown M.J & Sharma P., Clinical Pharmacology; 11th
edition; Chapter 19; Page 295-310.
• Katzung B.G., Masters S.B & Trevor A.J., Basic & Clinical
Pharmacology; 12th edition; Chapter 25 & 26; Page 429-463.

64. THANK YOU!