seminar on induction agents (oral and maxillofacial surgery)

1. INDUCTION AGENTS
DR. JEFF K. ZACHARIA
POST GRADUATE STUDENT
ORAL & MAXILLOFACIAL SURGERY
A.J. INSTITUTE OF DENTAL SCIENCES

2. CONTENTS
• Introduction
• General principles of pharmacology
• Properties of ideal iv anesthetic agent
• Classification of iv anesthetics
• Thiopental sodium
• Propofol
• Etomidate
• Ketamine hydrochloride
• Midazolam
• Fentanyl
• Dexmedetomidine
• References

3. INTRODUCTION

4. GENERAL ANESTHESIA
General anesthesia is a reversible state of unconsciousness from which a person cannot be
aroused by an external stimulus. There is a complete or partial loss of protective reflexes
including the ability to maintain airway independently.
General Anesthetics are drugs which produce reversible loss of all sensation and consciousness.

5. CARDINAL FEATURES OF GENERAL ANESTHESIA
• Loss of all sensation (analgesia)
• Sleep (unconsciousness) & amnesia
• Immobility & muscle relaxation
• Abolition of somatic & autonomic reflexes

6. GENERAL PRINCIPLES OF PHARMACOLOGY

7. ACTION ON RECEPTORS
• A receptor is a complex structure on the cell membrane which can bind selectively with endogenous
compounds or drugs resulting in changes within the cell which can modify its function.
These include changes in GABA receptors, cGMP receptors, NMDA receptors.
PLASMA PROTEIN BINDING
• Many drugs are bound to plasma and only unbound drug is free to cross the BBB.
• Protein binding may be reduced by low plasma protein concentration or displacement by drugs
resulting in higher concentration of free drug leading to exaggerated anesthetic effect.
• Protein binding is also affected by changes in blood pH.

8. THE BLOOD BRAIN BARRIER
• The brain is protected from most potentially toxic agents by tightly overlapping endothelial cells
which surround the capillaries & interfere with passive diffusion.
Many drugs used in the anesthetic procedure must cross the BBB to reach their site of action
• Highly ionized drugs (e.g., muscle relaxants, glycopyronium) do not cross the BBB
• Reduced cerebral blood flow results in reduced delivery of drug to the brain. E.g., carotid artery
stenosis
If the CBF is low because low cardiac output, the initial blood concentrations are higher than normal
after IV anesthetic administration, therefore, the anesthetic effect is delayed but enhanced.

9. SOLUBILITY OF DRUG IN LIPIDS
• Highly lipid soluble drug enhances transfer into the brain.
SPEED OF INJECTION
Rapid IV administration results in high initial concentration of the drug
Decreased protein binding
There is increased intensity of side effects (cardiovascular & respiratory side effects)

10. DISTRIBUTION TO OTHER TISSUES
• Anesthetic effect of all IV anesthetics is terminated by distribution to other tissues.
• A large proportion of the drug is distributed initially into well perfused organs (brain, liver,
kidneys).
• Distribution into muscle is slower because of low lipid content but important because of its
good blood supply & large mass.
• Distribution to fat is slower because of its poor blood supply but contains large proportions of
injected dose. It could remain in the body for up to 24 hours.

11. PROPERTIES OF IDEAL IV ANESTHETIC AGENT
• Rapid onset: achieved by an agent which is mainly unionized at blood pH & which is highly
soluble in lipids
• Rapid recovery: early recovery of consciousness is usually produced by rapid redistribution of
the drug into other tissues. The quality of late recovery is related to the rate of metabolism of
the drug. Decreased recovery = prolonged “hangover” effect
• Analgesia at subanesthetic concentrations.
• Minimal cardiovascular & respiratory depression.
• No emetic effects

12. PROPERTIES OF IDEAL IV ANESTHETIC AGENT
• No excitatory phenomena on induction (e.g., coughing, hiccup, involuntary movements)
• No emergence phenomena (e.g., nightmares)
• No interaction with neuromuscular blocking drugs.
• No venous sequalae
• Safe if inadvertently injected into an artery.
• No toxic effect on other drugs
• No release of histamine
• Water soluble formulation
• No stimulation of porphyria

13. CLASSIFICATION OF IV ANESTHETICS
RAPIDLY ACTING AGENTS [PRIMARY INDUCTION]
 Barbiturates
methohextal
thiobarbiturates: thiopental, thiamylal
 Imidazole compounds
etomidate
 Sterically hindered alkyl phenol
propofol
 Steroids (none currently available)
eltomolone, althesin, minaxolone
 Eugenols (none currently available)
propanidid

14. SLOWER ACTING AGENTS [BASAL NARCOTIC]
 Ketamine
 Benzodiazepines
diazepam, midazolam
 Large dose opiods
fentanyl, alfentanil, sulfentanil
 Neuroleptic combination
opiod + narcoleptic

15. THIOPENTAL SODIUM

16. THIOPENTAL SODIUM
• It is an ultra short acting barbiturate
• Pale yellow colour.
• Stored in Nitrogen to prevent chemical reaction with atmospheric CO2
• Onset of action: One arm brain circulation 15 – 20 seconds
• Duration of action : α Half life - 10 minutes
β Half life - 45 minutes
γ Half life - 6-20 hours
Dosage: 1-2mL of 2.5% solution for adults
4mg/Kg for adults
6mg/Kg for children
• Clearance : 3.4 ml/Kg/min

17. Metabolism
• It follows zero order kinetics i.e. constant amount
of drug is eliminated per unit time irrespective of
plasma concentration.
Mechanism of action
• Activation of GABAA which increases transmembrane Chloride channels
• This results in Hyperpolarization of post synaptic neurons
• causing “FUNCTIONAL INHIBITION OF POST-SYNAPTIC NEURONS”

18. Central Nervous System
 Produces anesthesia within 30 minutes
 Potent hypnotic action
 Analgesic effect is poor
At subanesthetic doses (i.e. low dose or during recovery), it can decrease pain threshold
resulting in restlessness during post op period.
 Surgical anesthesia is difficult to achieve unless large doses are used
 Sympathetic nervous system is depressed resulting in bradycardia
followed by tachycardia (due to baroreceptor inhibition caused by modest hypotension
& partly because of loss of vagal tone)

19. Cardiovascular System
 Myocardial contractility is depressed & peripheral vasodilatation occurs when large doses are
administered or injected rapidly.
 Arterial pressure decreases & hypotension may occur
 Heart rate may decrease, but there is often reflex tachycardia
Respiratory System
 Ventilatory drive [product of TV x RR i.e. 6L/min, rate and strength of contraction of
respiratory muscles] is decreased
 When spontaneous ventilation is resumed, ventilatory rate & TV are usually lower than
normal but they increase in response to surgical stimulation.
Skeletal Muscle
 There is poor muscle relaxation & movement in response to surgical stimulation

20. Eye
 Intraocular pressure is reduced by approximately 40 %
 Corneal, conjunctival, eyelash & eyelid reflexes are abolished.
Hepatorenal Function
 Hepatic microsomal enzymes are induced and this may increase the metabolism &
elimination of other drugs.

21. ADVERSE EFFECTS
• Contraindicated in porphyrias
• Abdominal pain
• Psychiatric symptoms like hysteria
• CNS symptoms like seizures, cortical blindness & coma
• Local tissue necrosis
• Inadvertent intra – arterial injection causes intense pain
Management
a) Stop further injection
b) Inject saline into canula & flush
c) Inject preservative free lignocaine Papaverine 40 – 80 mg (vasodilation) Heparin
d) Stellate ganglion nerve block or brachial plexus nerve block to achieve sympatholysis if pain is intense & tissue
perfusion is in jeopardy.

22. PROPOFOL

23. PROPOFOL
• 2,6 Di isopropyl phenol
• Highly lipid soluble
• Contains 10% Soybean oil,
1.2% Egg Lecithin and
2.25% Glycerol (osmotic agent)
• Propofol causes pain on injection
PROPOFOL LIPURO – preparation of propofol containing both long & medium chain triglycerides
in 1:1 ratio. It reduces pain on injection
FOSPROPOFOL- A water soluble methylphopshorylated prodrug of propofol, no Pain on injection
but slow onset of action.

24. PHARMACOKINETICS
• Volume of distribution – 4.6 L/Kg
• Clearance – 25 ml/Kg/min
• Protein binding - 98%
• Water solubility – No
• pH: 7.0 – 8.5
• Onset of action – One arm brain circulation time ( 15 -20 seconds)
• Duration of action – 3 to 5 minutes when given I.V.
• Half life: α half life – 3-5 min
β half life – 20-50 min
γ half life – 200-500 min

25. MECAHNISM OF ACTION
• Activates chloride channels of GABA receptors inhibitory synaptic transmission.
• It also inhibits NMDA subtype of glutamate receptors
DOSES
• Induction: 2 – 2.5 mg/Kg in adults ; 2.5 – 3 mg/Kg in children
• Maintenance: At a dose of 50-150 μg/Kg/min
• Conscious sedation: @ 50-75 μg/Kg/min
ELIMINATION
• Propofol is metabolized by conjugation to glucuronide & sulfate by liver.
• Propofol also undergoes extrahepatic metabolism in kidney and lungs (30%)

26. Central Nervous System
• Reduces Cerebral metabolic rate
• Reduces Cerebral blood flow through auto-regulation Reduces Intracranial pressure
• Can cause some involuntary movements during induction
• Dose dependent depression of CNS
Loss of response to verbal commands end point of induction
Cardiovascular System
• Causes hypotension due to peripheral vasodilatation which can be minimized by slow injection.
Respiratory system
• Causes transient apnea
• Obtunds airway reflexes.
GIT
Propofol has low anti emetic properties

27. USES
• Useful in day care anaesthesia and surgery
• Useful in patients susceptible to Malignant hyperthermia
• Can be used as an anticonvulsant
• Can be used as anti-puritic & anti emetic
• Safe in patients with porphyria

28. PROPOFOL VERSUS THIOPENTONE
• Residual impairment is less & short lasting, hence, patient is ambulatory early.
• Incidence of post operative nausea & vomiting is low.
• Patient acceptability is very good
• Does not cause bronchospasm, hence can be used in asthamatics.

29. ADVERSE EFFECTS
• Hypotension
• Allergic reactions to egg protein
• Pain on injection ( can be reduced with lignocaine 20 mg)
• Susceptible to growth of microorganisms (emulsions must be discarded after 12 hours)
• Can cause involuntary epileptiform movements.

30. PROPOFOL INFUSION SYNDROME
• Occurs in children & infants
• Due to prolonged infusion
• Occurs when used in excess of 4mg/kg/hour for more than 48 hours.
Causes:
Metabolic acidosis, hyperkalemia, rhabdomyolysis, renal failure, hepatomegaly, cardiac failure,
hyperlipidemia
Management:
Cardiorespiratory support
Hemodialysis

32. ETOMIDATE

33. ETOMIDATE
• Carboxylated Imidazole ester.
• Weak Base & poorly water soluble
• Available as lipid emulsion at a concentration of 2mg/mL
• MECAHNISM OF ACTION
Activates chloride channels of GABA Inhibitory synaptic transmission
• Onset of action: One arm-brain circulation time 15-20 seconds
• Duration: 3-5 minutes when given I.V.
Dosage: 0.3mg/Kg IV

34. Central Nervous System
• Dose dependent depression of CNS
• Can produce involuntary movements during induction.
• Recovery is rapid due to redistribution.
Cardiovascular System
• Least cardiovascular depression
• Used in shock and cardiovascularly compromised patients.
Respiratory system
• Can cause cough or hiccups.
• Transient apnea occurs with induction doses
GIT
• Increased incidence of Nausea & Vomiting

35. ADVERSE EFFECTS
• Pain on injection & Thrombophlebitis
• Recovery is frequently unpleasant and accompanied by nausea and vomiting
• Continuous infusion of etomidate for sedation in critically ill patients has been shown to increase mortality.
• Adreno-cortical suppression:
It inhibits 11-β-hydroxylase, an enzyme important in adrenal steroid production.
A single induction dose: blocks the normal stress induced increase in adrenal cortisol production for 4-8 hours,
and up to 24 hours in elderly and debilitated patients.

36. KETAMINE HYDROCHLORIDE

37. KETAMINE HYDROCHLORIDE
• Phencyclidine derivative
• Produces DISSOCIATIVE ANAESTHESIA
• Dissociative anaesthesia resembles a cataleptic state in which the eyes remain open with a
slow nystagmic gaze.
• Exists in two optical isomers

38. S(+) ketamine produces:
• More intense analgesia
• More rapid metabolism & thus recovery
• Less salivation
• Lower incidence of emergence reactions

39. Mechanism of action:
• Inhibits NMDA receptors
• Inhibits serotonin & muscarinic receptors
• Onset of action: 30-60 seconds I.V,
5 minutes I.M
25-45 minutes orally
• Duration of action : 10-15 min when given I.V
α half life – 10-15 minutes
γ half life – 2-3 hours
• Dosage: Induction: 2 mg/Kg
• Maintenance: 1-1.5 mg/Kg

40. Central Nervous System
• Produces “ Dissociative anaesthesia”
• Causes Functional & Electrophysiological dissociation of Thalamocortical system (depressed) from Limbic
system (stimulated).
• This produces intense analgesia & amnesia as the sensory impulses from the body do not reach the cortex.
• Increases CBF which increases the Intracranial pressure.
• Also increases the intraocular pressure.
Cardiovascular System
• Causes hypertension & tachycardia: by indirect stimulation of sympathetic system causing release of
catecholamines.
• In larger doses or patients with depressed sympathetic system, can cause hypotension due to direct
myocardial depression

41. Respiratory system
• Good bronchodilator
• But does not obtund airway reflexes well.
GIT:
• Increases secretions salivary & bronchial secretions

42. Doses
• As a sole anesthetic for short procedures .
• Can be given as infusion:
@ 15-45 μg/Kg/min with 50% Nitrous oxide
@ 30-90 μg/Kg/minutes without Nitrous oxide

43. ADVERSE EFFECTS
• EMERGENCE REACTIONS: occurs due to ketamine induced depression of
auditory & visual relay nuclei, leading to misperception or misinterpretation
of auditory & visual stimuli.
• Muscle rigidity due to increased muscle tone.
• Hypertension & Tachycardia

44. PROPOFOL VERSUS KETAMINE
• Propofol causes transient decrease in arterial blood pressure
• Propofol causes less respiratory depression.
• Time for recovery is less for propofol is less than ketamine
• Recovery agitation is less in propofol

45. MIDAZOLAM

46. MIDAZOLAM
• Water soluble Benzodiazepine with an IMIDAZOLE ring in its structure
• The solubility of midazolam is pH dependent
@ pH: 3.5, Imidazole ring is open: Water soluble
@ body pH, Imidazole ring is closed: Lipid soluble
MECHANISM OF ACTION
Activates chloride channels of GABA inhibitory synaptic transmission
Duration of action: 1 hour when given IV

47. Central Nervous System
Dose dependent depression of the CNS
Cardiovascular System
Doesn’t affect Heart rate and Blood pressure
Respiratory System
Does not produce change in respiration at usual doses

48. Doses
• Induction: 0.1 – 0.2 mg/kg IV
• Premedication: Given 0.5 mg/kg orally up to maximum dose of 10 mg
Uses
• Used to supplement regional anesthesia for sedation
• Used as anticonvulsant
• Used for sedating critically ill patients as it is cardio-stable
Adverse Effects
• In patients with hypovolemia, it may aggravate hypotension

49. FENTANYL

50. FENTANYL
• It is a highly lipophilic, short acting potent opiod analgesic.
• Frequently used to supplement anesthetics in balanced anesthesia.
• It is combined with Benzodiazepines
• Induction: 2-4 µg/kg

51. Cardiovascular system
• Heart rate decreases because fentanyl stimulates the vagus nerve.
• Fall of blood pressure.
Respiratory System
• Respiratory depression is marked.
Muscles
• Masseter & chest muscles become rigid. ( a muscle relaxant is needed)

52. ADVERSE EFFECTS
• Cerebral flow and Oxygen consumption decreases.
• Nausea, vomiting and itching
• Respiratory depression

53. DEXMEDETOMIDINE

54. DEXMEDETOMIDINE
• Developed in the 1980s
• Acts on alpha 2 adrenergic receptors.
• Dose: 0.2 to 0.7ug/kg/hr
• Duration of action: 6 minutes
• Elimination: 2 hours
• Protein binding capacity: 94%

55. Central Nervous System
• It reduces the CBF
• Its effect on the ICP is not yet clear
Cardiovascular System
• Biphasic BP response: Hypertensive phase & subsequent Hypotension
Respiratory effects
• Does not depress respiration even at high doses

56. USES
• Locoregional analgesia
• Sedation in intensive care units
• Can be used for treatment of withdrawal from benzodiazipines, opiods,
alcohol, drugs, etc.
• Management of Tetanus
• Anti shivering agent
• Prevents alcohol induced neurodegeneration.

57. ADVERSE EFFECTS
• Hypotension
• Vomiting
• Bradycardia
• pleural effusion
• Atelectasis
• Hypocalcaemia
• Acidosis
• Long term use can result in sensitization

59. THANK YOU

60. REFERENCES
• Essentials of medical Pharmacology, 7th Edition, KD Tripathi
• Miller’s Anesthesia, 8th Edition, Ronald D. Miller