Intravenous anaesthetics have been used since the 1600s when wine and beer were injected into dogs. Early intravenous anaesthetics caused adverse effects. Thiopental was the first widely accepted intravenous anaesthetic due to its rapid onset and lack of excitatory effects. Other intravenous anaesthetics developed include ketamine, methohexital, and propofol. Propofol is now one of the most commonly used intravenous anaesthetics due to its rapid onset, short duration of action, and minimal side effects. Intravenous anaesthetics work primarily by enhancing the effects of the inhibitory neurotransmitter GABA at GABA-A receptors in the brain, causing sedation and loss of consciousness. They must have properties allowing for rapid onset,

1. INTRAVENOUS
ANAESTHETICS
DR. MUHAMMED ALIF

2. History
• In 1656, Percival Christopher Wren and Daniel Johann Major
tried injecting wine and beer into a dog’s vein.
• Early 1900s Hedonal, ether, chloroform into veins—syncope,
cyanosis, pulmonary edema.
• HEXOBARBITAL : The first ultra short acting barbiturate
The first successful i.v. anaesthetic Introduced by Weese in
Germany in 1932.
• THIOPENTAL : Introduced in 1935 by Lundy in Minnesota &
Waters in Wisconsin.
• Thiopental – widely accepted because of lack of excitatory
myoclonic movements seen with hexobarbitone.

3. History…
• KETAMINE – was first synthesized in 1962 by Calvin Stevens
First human use was in 1969.
• METHOHEXITAL - a shorter-acting barbiturate with central
nervous system stimulating properties, was introduced in
1956 for electroconvulsive therapy (ECT).
• PROPOFOL – launched in 1986 under the brand name
DIPRIVAN.

4. What are IV anaesthetic drugs
• When given intravenously in appropriate dose, cause rapid
LOC
• Rapid onset – described as “one arm brain circulation time”.
• i.e., the time taken for the drug to travel from the site of
injection (usually arm) to brain where they have the effect.

5. IdealIVanaestheticagent–describedbyHemmings
Pharmacodynamics/Pharmacokinetic properties:
• Produces hypnosis and amnesia
• Rapid onset (one arm brain circulation time)
• Rapid metabolism to inactive metabolites
• Minimal cardiovascular and respiratory depression
• No histamine release or hypersensitivity reaction
• Non-toxic, non-mutagenic, non-carcinogenic
• No untoward neurological effects such as seizures, myoclonus,
antanelgesia, neurotoxicity
• Other beneficial effects – analgesia, antiemetic,
neuroprotection, cardioprotection
• Pharmacokinetic based models to guide accurate dosing
• Ability to continuously monitor delivery

6. Physio-chemical properties:
• Water soluble
• Stable formulation, non-pyrogenic
• Non irritating, painless on IV injection
• Small volume needed for IV induction
• Inexpensive to prepare and formulate
• Antimicrobial preparation
* No single IV anaesthetic is perfect

7. Uses:
• Induction and maintenance of anaesthesia
• For amnesia
• As a sole anaesthetic for short procedures
• To blunt the cardiovascular response to intubation
• Intravenous infusion- to maintain anaesthesia for longer
procedures e.g. TIVA ( Total intravenous anaesthesia)
• To provide sedation in places like ICU

8. Classification
A. Isopropyl phenols: propofol, fospropofol
B. Barbutrates: thiopentone, methohexital
C. Benzodiazepines: diazepam, midazolam, lorazepam,
remimazolam
D. Phencyclidine: ketamine
E. Carboxylated imidazole: etomidate
F. Alpha 2 adrenergic agonists: dexmedetomidine

9. Barbiturates:
Barbiturates- broadly classified as
a) Thiobarbiturates : Sulphur at C2 e.g. Thiopental,
thiamylal
b) Oxybarbiturates : Oxygen at C2 e.g. Methohexital
Thiopentone:
• 1st IV anesthetic used in clinical practice
• By Water and Lundy
• Ultra short acting barbiturate
• Chemically: sodium ethyl thiobarbiturate

10. Physical and chemical properties
• Available as yellow amorphous powder of 0.5g and 1g vial
• 20 mL sterile water added - make concentration of 2.5% and 5%.
• 5% solution is further diluted to 2.5%.
• Solution is not stable and should be used with within 48 hours
• But can be used for 1 week if refrigerated or till precipitates appear.
• Should not be mixed with RL
• Sulphur analogue of phenobarbitone – sulphur added to increase
lipid solubility.
• Ultrashort action – due to methyl group added to it.
• Available as sodium salt to make it water soluble which makes it
alkaline
• pH of 2.5% thiopentone solution is 10.5
• 6% sodium carbonate added - prevent formation of free acid from
atmospheric CO2.

11. Anesthetic propertiesand pharmacokinetics
• Unconsciousness produced within one arm brain circulation
time i.e. 15 secs.
• Induction is largely smooth (it may be associated with initial
excitatory response)
• Elimination t1/2 – 12 hours, consciousness regained after 15 -
20 mins.
• Means – drug is redistributed from brain to tissues with less
vascularity like muscles and fat.
• Repeated dosing saturate this tissues and regaining of
consciousness depends on metabolism and elimination.
• At induction it may cause mild hypokalemia

13. • Repeated doses or infusions of thiopental – zero order kinetics
i.e., a constant amount of drug is being eliminated per unit
time, irrespective of the plasma concentration.
• Some drugs are metabolized by first order kinetics; a constant
fraction of drug is eliminated per unit time, i.e. dependent on
plasma concentration.
• Zero order kinetics – metabolic pathways become saturated.
• Leads to an accumulation of the active drug and delayed
recovery.

14. Metabolism
• Metabolised hepatically
• The metabolites are almost all inactive, water soluble, and
excreted in the urine.
• Barbiturates are biotransformed by four processes:
• Oxidation of the aryl, alkyl, or phenyl moiety at C5
• N-dealkylation
• desulfuration of the thiobarbiturates at C2
• destruction of the barbituric acid ring.

15. • Relatively long elimination half-life (12 hours).
• Clearance rate (3 mL/kg/min) is 10-fold longer than that of propofol.
• Methohexital elimination half-life (4 hours) is also shorter than
thiopental, due to a more efficient hepatic extraction of the drug
(clearance rate 11 mL/kg/min).
• A negligible percentage of barbiturates is eliminated without
metabolism in the urine.
• In paediatric patients, the elimination half-time of thiopental is
shorter than in adults – rapid hepatic clearance.
• Recovery after large or repeated doses – rapid for infants and
children than for adults.
• Protein binding and Vd – not different in paediatric and adult
patients.
• Elimination half-time is prolonged during pregnancy because of the
increased protein binding of thiopental.

16. Mechanism of action:
• Inhibits the function of synapses
• Mediates action through GABA receptor GABA –A subtype
• Increased membrane conductance to chloride ion causes
hyperpolarisation of the membrane.
• At larger concentrations, the barbiturates activate the chloride
channels directly, without the binding of GABA, and act as
agonists.
• The GABA-mimetic effect at slightly higher concentrations
termed as “barbiturate anesthesia’’.
• The second mechanism of action – involves the inhibition of
the synaptic transmission of excitatory neurotransmitters,
such as glutamate and acetylcholine.

17. Systemic effects
Central nervous system:
• Unconsciousness produced in 15seconds
• End point of induction- Loss of “EYELASH REFLEX”
• Sleep cycle – increase stage 2 sleep, decrease stage 3, 4, REM sleep.
• Decreases ICP, CMR, CMO2.
• Can be used for cerebral protection in focal ischemia.
• Does not offer any protection in global ischemia as in cardiac arrest.
• Anticonvulsant action – because of phenyl group – potent
anticonvulsant
• Convulsions not controlled by other AED’s.
• At subanaesthetic doses  Antanalgesic action
• If initial doses are high  Acute tolerance
• Low concentration: used for narcoanalysis

18. Cardiovascular system:
• Hypotension – not only because of central mechanism, but
also direct depression of vasomotor centre
• At high doses can cause direct myocardial depression
• Increase in heart rate ( 10-30%) occurs as compensation to
hypotension
• Mechanisms for the decrease in cardiac output include:
• Direct negative inotropic action resulting from a decrease of
calcium influx into the cells.
• Decreased ventricular filing caused by increased capacitance.
• Transiently decreased sympathetic outflow from the CNS.

19. Respiratory system:
• Cause respiratory depression in a dose-dependent manner, leading
to central apnoea at deeper stages of anesthesia.
• After a typical induction dose, apnoea is commonly noted after 1 to
1.5 minutes.
• Returns to baseline in approximately 6 minutes with ventilatory
response to carbon dioxide.
• The time course to recovery from respiratory depression is shorter
with thiopental than with propofol.
• If painful stimulus given at inadequate depth  severe
laryngospasm/bronchospasm.
• Transient apnoea  common after thiopentone  requires no rx
• If prolonged >25 secs  gentle IPPV with BMV
• At higher doses, depresses the respiration after brief recovery from
transient apnoea
• Termed as “double apnoea”

20. Eye:
• Decreases IOP.
Pregnancy:
• Crosses placenta readily
• Equilibrium with maternal circulation is achieved within 3 – 5
minutes
Thyroid:
• Has antithyroid activity

21. Dosage
• Males > females
• Obese > thin
• Young > adults

22. CONTRAINDICATIONS
The following conditions should be considered contraindications
to the use of IV barbiturates:
• When the patient has respiratory obstruction or an
inadequate airway, thiopental may worsen respiratory
depression.
• Severe cardiovascular instability or shock contraindicates
barbiturate use.
• Status asthmaticus is a condition in which airway control and
ventilation may be worsened by thiopental.
• Porphyria may be precipitated or acute attacks may be
accentuated by the administration of thiopental.
• Without proper equipment (IV instrumentation) and airway
equipment (means of artificial ventilation), thiopental should
not be administered.

23. Complications
General complications:
• Respiratory depression
• Cardiovascular depression
• Laryngospasm, bronchospasm
• Hiccups and coughing
• Allergic manifestations varying from cutaneous rash, pruritus
to severe anaphylaxis
• Post operative disorientation, vertigo, euphoria (delirium).

24. Local complications:
• High alkallinity responsible for local complications.
A. Perivenous and i.m. injections:
• Commonly seen if injected with hypodermic/SV set.
• High alkalinity lead to tissue necrosis and ulceration
• Treatment:
• Preventive:
• Always use 2.5% solution
• Inject slowly in incremental dose
• If patient c/o pain, stop immediately.
• Curative: 10mL 1% lignocaine with 100 units of hyaluronidase to
be injected to the local area.

25. B. Intra arterial injection:
• Dreaded complication
• May cause gangrene and limb loss if not managed timely
• Commonly occur if injected in antecubital vein.
• 10% cases, the brachial artery divides above the elbow giving a very
superficial ulnar artery which lies deep to antecubital vein.
Symptoms:
c/o burning pain down the injection site followed by pallor,
cyanosis, edema and gangrane of the limb.
Pathophysiology:
Because of its high alkalinity – get precipitated in the acidic
pH of blood forming crystals – cause endothelial damage
precipitating vasospasm and thrombus formation blocking
microcirculation

26. Management:
Preventive:
• Always use 2.5% solution
• Inject very slow and in incremental dose
• Avoid thiopentone injection in the antecubital fossa (best site;
dorsum of the hand).
Curative:
• Leave the needle at the site – all the therapeutic injections to be
given trough this needle.
• Start dilution with NS.
• Inject heparin to prevent thrombus formation.
• Inject local vasodilators like papaverine, α-blockers, 1% lignocaine.
• Stellate ganglion block – relieve the vasospasm by blocking the
sympathetic supply.
• Continue oral anticoagulants for 1-2 weeks
• Defer the elective surgery.

27. Propofol
• Since introduction in 1970s, most widely used IV hypnotic.
• Initial solution was released in 1977, withdrawn due to
anaphylaxis.
• Reintroduced in its more current form consisting of 1%
propofol, 10% soybean oil, 2.25% glycerol, and 1.2% egg
phospholipid emulsifier.
• 1990s – ethylenee-diamine-tetraacetic acid (EDTA) was added
- to deter microbial growth within the emulsion.
• Lipid emulsion comes in a milky white consistency.
• Can be stored at room temperature without any significant
degradation.
• Used for induction and maintenance of anaesthesia and for
sedation in and outside operating room.

28. Physical and chemical properties:
• Consists of phenol ring with isopropyl group attached.
• Chemical name – 2,6 di isopropyl phenol.
• Available as 1% and 2% milky white solution prepared in soybean oil
making it painful while injecting.
• Highly lipid soluble
• pKa – 11
• Volume of distribution – 4.6 L/Kg
• Clearance – 25 ml/Kg/min
• Protein binding - 98%
• Water solubility – No
• pH 7.0 – 8.5
• PROPOFOL LIPURO – preparation of propofol containing both long &
medium chain triglycerides in 1:1 ratio. Reduces pain on injection
• FOSPROPOFOL- A water soluble methylphopshorylated prodrug of
propofol, No Pain on injection, But slow onset of action.

29. Mechanism of action
• Not fully understood
• Selective modulator of g-aminobutyric acid (GABA) receptors.
• It also has activity at glycine receptors.
• Presumed to exert its sedative-hypnotic effects through a
GABA-A receptor interaction (beta sub unit).
• Alpha and gamma sub units also contributes.
• It also has action on α adrenergic receptor and NMDA
receptors.
• Alteration of the central cholinergic transmission may also
play a role in achieving a state of unconsciousness.

30. • Initial low doses of propofol produce sedation.
• At increased doses - state of paradoxical excitation may occur,
where a patient is disinhibited, has unpredictable movement,
broken speech, and is not readily arousable.
• Further increase in dose of propofol leads to loss of
consciousness, apnea, relative relaxation of muscles, loss of
brainstem reflexes, and subsequently necessitates airway
support.
• Increases dopamine in nucleus accumbens (sense of well-
being)
• Decreases serotonin in area postrema (anti-emetic)

31. Pharmacokinetics
• Induction is achieved in one arm brain circulation time.
• Consciousness is regained after 2 – 8 minutes due to rapid
redistribution.
• Elimination half life is 2-4 hours.
• Less hang over than thiopentone.
• Metabolized in liver and excreted through kidneys.
• Propofol is oxidized to 1,4-diisopropyl quinol in the liver.
• Propofol and 1,4-diisopropyl quinol are conjugated with
glucuronic acid to propofol-1 glucuronide and quinol-1-
glucuronide and quinol-4-glucuronide.
• Excreted by the kidneys.

32. • After a 2.5- hour anesthetic regimen with propofol, patients
excrete propofol and propofol metabolites for more than 60
hours.
• Less than 1% propofol – excreted unchanged in urine.
• 2% is excreted in feces.
• The metabolites of propofol are thought to be inactive.
• Because clearance of propofol (>1.5 L/minute) exceeds
hepatic blood flow, extrahepatic metabolism or extrarenal
elimination may occur.

33. • The most important extrahepatic site of propofol metabolism
is the kidney.
• Renal metabolism - accounts for up to 30% of propofol
clearance, and this explains the rapid clearance of propofol,
which exceeds liver blood flow.
• The lungs also may play a role in extrahepatic propofol
metabolism.

34. • Propofol – generally known for its hemodynamic depressant
effects and may reduce hepatic blood flow.
• It may reduce the clearance of other drugs metabolized by the
liver, in particular those with a high extraction ratio.
• Propofol is known as a CYP3A4 inhibitor.
• Short-term exposure to propofol at a blood concentration of 3
μg/mL already reduces CYP3A4 activity by approximately 37%.
• The pharmacokinetics of propofol has been described
by two-compartment and three-compartment models.
• After a single bolus dose, whole blood propofol levels
decrease rapidly as a result of redistribution and elimination.
• The initial distribution half life of propofol is 2 to 8 minutes.

36. Uses & Dose:

37. Systemic effects

38. Cardiovascular system
• Hemodynamic effects – dose dependant
• More significant after an induction dose than a continuos infusion.
• Characteristic drop in SBP and DBP without expected increase in HR.
• Decreases sympathetic activity  leads to indirect
arterial vasodilation and venodilation.
• This effect is enhanced by direct effects on smooth muscle and
depressant effects on the myocardium, affecting intracellular
calcium balance and influx.
• The decreased sympathetic tone is also coupled with direct
inhibition of the baroreceptor response, leading to a diminished
reflex increase in heart rate and a more pronounced hemodynamic
effect.
• Suppression of supraventricular tachycardia has also been reported,
and may be a direct result of propofol effects on the heart
conduction system.

39. Respiratory system:
• Incidence of apnoea is higher than thiopentone
• Respiratory depression is more severe and prolonged than
thiopentone.
• Induces bronchodilatation in COPD patients
• Depression of airway reflexes are more than thiopentone –
preferred for surgeries done under LMA wthout muscle
relaxants.

40. Central nervoussystem
• The hypnotic action of propofol is mostly mediated by
enhancing γ-aminobutyric acid (GABA)-induced chloride
current through its binding to the β subunit of the GABA-A
receptor.
• Sites on the β1, β2, and β3 subunits of the transmembrane
domains are crucial for the hypnotic action of propofol.
• The α subunit and γ2 subunit subtypes also seem to
contribute to modulating the effects of propofol on the GABA
receptor.
• At higher propofol concentrations, propofol is also thought to
activate GABA-A receptor channels directly.

41. • The exact mechanism and location of changes that are
associated with the change from consciousness to the
unconscious state – not fully understood.
• Action on GABA-A receptors in the hippocampus – inhibits
acetylcholine release in the hippocampus and prefrontal
cortex.
• The α2-adrenoreceptor system also seems to play an indirect
role in the sedative effects of propofol.
• By using positron emission tomography, propofol hypnosis has
been found to be related to reduced activity in the thalamic
and precuneus regions.
• These regions likely play an important role in propofol induced
unconsciousness.

42. • Results in widespread inhibition of the N-methyl-d-aspartate
(NMDA) subtype of glutamate receptor through modulation of
sodium channel gating may also contribute to the drug’s
CNS effects.
• Propofol has a direct depressant effect on neurons of the
spinal cord.
• In spinal dorsal horn neurons, propofol acts on GABAA and
glycine receptors.
• The sense of well-being in patients – increase in dopamine
concentrations in the nucleus accumbens.
• Antiemetic action – the decrease in serotonin levels it in the
area postrema, through its action on GABA receptors.

43. • The onset of hypnosis after a dose of 2.5 mg/kg is rapid (one arm–
brain circulation), with a peak effect seen at 90 to 100 seconds.
• The median effective dose (ED50) of propofol for loss of
consciousness is 1 to 1.5 mg/kg after a bolus.
• The duration of hypnosis is dose dependent and is 5 to 10 minutes
after 2 to 2.5 mg/kg.
• Age markedly affects the induction dose, which is highest at younger
than 2 years (95% effective dose [ED95], 2.88 mg/kg) and decreases
with increasing age.
• This is a direct result of the altered pharmacokinetics in children and
in older adults.
• Children exhibit a relatively larger central compartment and thus
need a higher dose to ensure a similar blood drug concentration.

44. • The rapid clearance of propofol in children requires a larger
maintenance dose.
• Increasing age decreases the propofol concentration required
for loss of consciousness.
• At subhypnotic doses - provides sedation and amnesia.
• During surgical procedures, extremely high infusion rates
producing blood concentrations in excess of 10 μg/mL may be
necessary to prevent awareness, if propofol is used as the sole
anesthetic.
• Propofol may suppress seizure activity through GABA agonism,
inhibition of NMDA receptors (NMDARs), and modulation of
slow calcium ion channels.

45. • Decreases intracranial pressure (ICP) in patients with either
normal or increased ICP.
• Many anesthetic-related drugs decrease the required dose or
blood concentrations of propofol’s pharmacologic action.
• End point for induction – Loss of response to verbal
commands.
Cp50
• Blood concentration needed for 50% of subjects to not
respond to a defied stimulus.

46. Cp50
• Loss of response to verbal command in the absence of any
other drug is 2.3 to 3.5 μg/ mL.
• To prevent movement on skin incision is 16 μg/mL; this is
markedly reduced by increasing concentrations (i.e., doses) of
fentanyl or alfentanil.
• For skin incision when combined with benzodiazepine
premedication (lorazepam, 1 to 2 mg) and 66% nitrous oxide is
2.5 μg/mL.
• This concentration is reduced to 1.7 μg/mL when morphine
(0.15 mg/kg) rather than lorazepam is used for premedication.

47. • The concentration (when combined with 66% nitrous oxide)
required during minor surgical procedures is 1.5 to 4.5 μg/mL.
• And for major operations is 2.5 to 6 μg/mL.
• Awakening usually occurs at concentrations less than
1.6μg/mL and orientation occurs at concentrations less than
1.2 μg/mL.
• Awakening is postponed in the presence of high blood
concentrations of opioids.

48. • Eye: reduces the IOP significantly (30-40%).
• GIT: potent antiemetic action by inhibiting central serotonin
release. Even more effective than ondansetron in PONV.
• Immunologic: antipruritic, can be used for the treatment of
cholestatic pruritus.

49. Uses:
• Because of its shorter action half life it is the agent of choice
for induction
• Because of its early and smooth recovery, inactive metabolites
and antiemetic effects – agent of choice for day care surgery
• Along with opioids – agent of choice for TIVA
• Infusion can be used in ICU for sedation
• Agent of choice for in susceptible individuals for malignant
hyperthermia

50. Advantages over thiopentone:
• Rapid and smooth recovery
• Completely eliminated from body in 4 hours, therefore patient is
ambulatory early
• Antiemetic
• Antipruritic
• Bronchodilator

51. Disadvantages:
• Apnoea is more profound and longer
• Hypotension is more severe
• Injection is more painful
• Solution is less stable
• Chances of sepsis with contaminated solution are high.
• Myoclonic activity may occur.
• Sexual fantasies and hallucinations are additional side effects.
• Expensive than thiopentone.
• Because of maximum inhibition of airway reflexes – aspiration
risk is high.
• As propofol increases the dopamine concentration in brain,
addiction has been reported.

52. Propofol infusion syndrome:
• Rare but lethal complication
• Seen usually if infusion continued for >48 hours.
• More common in children
• Occurs because of failure of free fatty acid metabolism caused
by propofol.
• Associated with severe metabolic acidosis (lactic acidosis),
acute cardiac failure, cardiomyopathy, skeletal myopathy,
hyperkalemia, lipemia and hepatomegaly.

53. Etomidate
• In 1972, etomidate was introduced into anesthetic practice as
an induction agent.
• Gained much popularity because of its safe hemodynamic
profile.
• It lost some proponents with increased reports of adrenal
suppression, pain on injection, thrombophlebitis, PONV,
myoclonus, and hiccups.
• If hemodynamic stability is of paramount importance, one
may choose to induce with etomidate and prepare to manage
these unwanted side effects.

54. Pharmacokinetics:
• An imidazole derivative (the D(+ ) enantiomer).
• Not stable in neutral pH solutions.
• Solvents in its formulation  propylene glycol, contribute to veno-
irritation and phlebitis that occur frequently.
• Has a quick onset of action (“vein to brain”), fast resolution of effect
secondary to redistribution, and follows the three-compartment
kinetic model.
• Use as a continuous infusion is limited by its association with
adrenal suppression.
• metabolized in the liver and excreted predominantly by the kidney
(approximately 80%) and in bile (approximately 20%).
• It is largely protein bound (approximately 75%) and thus affected by
pathologic conditions and/or drugs that alter serum proteins.

55. Initial distribution half life 2.7 minutes
Redistribution half life 29 minutes
Elimination half life 2.9 – 5.3 hours
Volume of distribution 2.5 – 4.5 L/kg
Induction dose 0.2 – 0.3 mg/kg

56. Pharmacodynamics and clinical uses:
• Binds as an agonist to the GABA-A receptor.
• Potent vasoconstrictor that reduces CBF, ICP, and CMRO2.
• Because of etomidate’s minimal effect on the mean
arterial pressure (MAP), CPP is either maintained or increased.
• Unlike benzodiazepines, etomidate can achieve burst
suppression with a concomitant decrease in ICP.
• Despite its neurodepressant properties at high doses,
etomidate is often associated with epileptogenic activity
(excitatory spikes) on EEG.
• Has a minimal or nonexistent effect on MAP, pulmonary artery
(PA) pressure, pulmonary artery wedge pressure, central
venous pressure (CVP), stroke volume, cardiac index, SVR, and
pulmonary vascular resistance (PVR).

57. • Frequently used for induction of anesthesia in cardiac
operating rooms.
• Also used for trauma patients who are hemodynamically
unstable and are often hypovolemic.
• Widely believed that etomidate depresses airway reflexes less
than propofol.
• Reasonable choice for MAC sedation because of the
preservation of airway reflexes.
• Special place in the treatment of endogenous
hypercortisolemia.
• Proven to be effective parenteral treatment for this indication.

58. Side effects:
• Adrenocortical suppression – most significant adverse effect.
• Inhibits the activity of the enzyme 11β-hydroxylase and
prevents the conversion of cholesterol to cortisol.
• It has been postulated that one dose is sufficient to transiently
suppress the adrenocortical axis.
• Some suggest pretreatment with dexamethasone to curtail
this effect.
• Although many studies conclude that there are no direct
adverse outcomes following a bolus of etomidate, even in the
septic population, other studies are opposite.
• In an effort to limit this possibility, will not administer repeat
doses or continuous infusions.

59. Ketamine hydrochloride
• Phencyclidine derivative.
• Synthesized in 1962 by Stevens and was first used in humans
in 1965 by Corssen and Domino.
• Ketamine was released for clinical use in 1970 and is still used
in various clinical settings.
• Produces DISSOCIATIVE ANAESTHESIA – dissociation between
thalamocortical & limbic systems
• Dissociative anaesthesia resembles a cataleptic state in which
the eyes remain open with a slow nystagmic gaze.
• AVAILABILTY : vials containing 10 mg/ml & 50 mg/ml
• Preservative free ketamine is available for use for Central
neuraxial blockade.

60. Structure activity relationships
• Presence of asymmetric carbon atom results in the existence
of two OPTICAL ISOMERS of ketamine: S(+) & R(-) forms
• Most frequently used preparation of ketamine – Racemic
mixture.
• S(+) ketamine produces ( when compared to R(-) form):
a) More intense analgesia
b) More rapid metabolism & thus recovery
c) Less salivation
d) Lower incidence of emergence reactions
• Preservative used – BENZETHENIUM CHLORIDE

61. Stereoisomers of ketamine
Anaesthetic Hallucinogen

62. • Mechanism of action :
• Inhibits N-methyl-D-aspartate (NMDA) receptors which have been
activated by Glutamate, an excitatory neurotransmitter.
• Also inhibits SEROTONIN & MUSCARINIC receptors
• It is an agonist of μ type of opioid receptors
• Onset of action :
• 30-60 sec when given i.v
• 5 min when given i.m
• 25-45 min when given orally
• Duration of action : 10-15 min when given i.v
( α half life – 10-15 min , γ half life – 2-3 hours)

63. Ketamine : Uses, Dose & Route
• Induction of anaesthesia : 1-2 mg/Kg .
Particularly useful in
• Bronchial asthma – Bronchodilatory effect
• Tetralogy of fallot – Maintains SVR
• Hypovolemic patients.
• Analgesia : 0.5 mg/Kg bolus followed by infusion @
3μg/Kg/min
• Premedication :
• I.M. – 3-5 mg/Kg ( onset time – 5 min)
• Nasal – 3-6 mg/Kg ( onset time- 5 min)
• Orally – 3-10 mg/Kg ( onset – 20-45 min)

64. • As a Bronchodilator : for treatment of Status asthmaticus @
30-40 μg/Kg/min
• 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/min without Nitrous oxide
• POINTS TO REMEMBER WITH USE OF KETAMINE :
• Ketamine can produce “ Hallucinations & Increase in secretions”
• Hence ketamine administration should be preceded by a
benzodiazepine like midazolam & an anti-sialogogue like
Glycopyrrolate

65. Ketamine : Effects on the body
Central Nervous system:
• Produces “ Dissociative anaesthesia” resembling a cataleptic
state.
• 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 CMRO2, CBF and thereby increases Intracranial
pressure.
• Also increases the intraocular pressure.

66. Cardiovascular system :
• DUAL EFFECT
• 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
Respiratory system :
• Very good BRONCHODILATOR,
• But does not obtund airway reflexes well.
GIT :
• Increases secretions especially Salivary & bronchial

67. Ketamine : Adverse effects
• Hallucinations :
• also called “ Emergence reactions”
• Occur due to ketamine induced depression of auditory and
visual relay nuclei, leading to misperception/misinterpretation
of auditory and visual stimuli.
• Muscle rigidity due to increased muscle tone
• Hypertension and tachycardia.
• liver and renal toxicity occurs in the recreational abuse of
ketamine.

68. Benzodiazepines
• Commonly used in the perioperative period
• includes:
• diazepam, midazolam, and lorazepam, as well as the selective
benzodiazepine antagonist flumazenil
• Benzodiazepines are unique among intravenous anesthetics –
action can readily be terminated by administration of their
selective antagonist flumazenil.
• Most desired effects – anxiolysis and anterograde amnesia,
which are extremely useful for premedication.

69. Physicochemical Characteristics
• The chemical structure – contains a benzene ring fused to a
seven-member diazepine ring, hence their name.
• The three benzodiazepines commonly used in the perioperative
setting are all highly lipophilic, with midazolam having the
highest lipid solubility.
• All three drugs are highly protein bound, mainly to serum
albumin.
• Although they are used as parenteral formulations, all three
drugs are absorbed after oral administration.
• Other possible routes of administration include intramuscular,
intranasal, and sublingual.

70. Pharmacokinetics
• Water soluble Benzodiazepine with an IMIDAZOLE ring in its
structure  accounts for stability in aqueous solutions & rapid
metabolism
• The solubility of midazolam is pH dependent.
• At pH 3.5, imidazole ring is open  water soluble
• At body pH imidazole ring closes  lipid soluble  rapid action.
• The highly lipid-soluble benzodiazepines rapidly enter the CNS,
• accounts for their rapid onset of action.
• Redistribution to inactive tissue sites  termination of the drug
effect.
• Metabolism of benzodiazepines occurs in the liver through
microsomal oxidation (N-dealkylation and aliphatic hydroxylation)
and glucuronide conjugation.

71. • Microsomal oxidation:
• The primary pathway for metabolism of midazolam and
diazepam.
• Is more susceptible to external factors such as age, diseases
(hepatic cirrhosis), and the administration of other drugs that
modulate the efficiency of the enzyme systems.
• Lorazepam is one of few benzodiazepines that does not
undergo oxidative metabolism and is excreted after a single-
step conjugation to glucuronic acid.
• Diazepam undergoes hepatic metabolism to active
metabolites (desmethyldiazepam and oxazepam) that may
contribute to the prolonged effects of this drug.

72. • Midazolam is selectively metabolized by hepatic cytochrome P450
3A4 to a single dominant metabolite, 1-hydroxymidazolam.
• 1-hydroxymidazolam has sedative effects similar to the parent
compound, it undergoes rapid glucuronidation and clearance.
• This metabolite does not cause significant sedation in patients with
normal hepatic and renal function unless midazolam is given as a
prolonged infusion.
• Despite its prompt passage into the brain, midazolam is considered
to have a slower effect-site equilibration time than propofol and
thiopental.
• In this regard, intravenous doses of midazolam should be sufficiently
spaced to permit the peak clinical effect to be recognized before a
repeat dose is considered.

73. • The elimination half-time of diazepam greatly exceeds that of
midazolam, thus explaining why the CNS effects of diazepam
are prolonged, especially in elderly patients.
• Of the three commonly used intravenous benzodiazepines,
midazolam has the shortest context-sensitive halftime, making
it the most suitable for continuous infusion.
• Recently, a new ultrashort-acting benzodiazepine named
remimazolam has entered clinical trials.
• Contains a carboxylic ester group that is rapidly hydrolyzed by
tissue esterases, analogous to remifentanil.

74. • As compared to midazolam, remimazolam has a smaller
volume of distribution, faster clearance, and clearance
independent of body weight.
• The metabolite of remimazolam has extremely low GABAA
affinity and is unlikely to yield clinically relevant sedation.
• The kinetic properties of remimazolam make it a promising
intravenous anesthetic drug that may yield less prolonged
sedation compared with midazolam, particularly in patients
with liver disease or those taking cytochrome P450–inhibiting
drugs.

75. • Benzodiazepines work through activation of the GABAA
receptor complex.
• There are specific binding sites for benzodiazepines on GABAA
receptors, thus explaining why they were initially termed
“benzodiazepine receptors.”
• Midazolam has an affinity for GABAA receptors
approximately twice that of diazepam.
• GABAA receptors that are responsive to benzodiazepines
occur almost exclusively on postsynaptic nerve endings in the
CNS, with the greatest density found in the cerebral cortex.

76. • The anatomic distribution of GABAA receptors (restricted to
the CNS) is consistent with the minimal effects of
benzodiazepines outside the CNS.
• The magnitude of depression of ventilation and the
development of hypotension after the administration of
benzodiazepines are lower than that observed when
barbiturates are used for induction of anesthesia

77. Spectrum of Effects
• The wide spectrum of effects of benzodiazepines is similar for
all drugs in this class, although potencies for individual effects
may vary between drugs.
• The most important effects of benzodiazepines are their
sedative-hypnotic action and their amnestic properties
(anterograde, but not retrograde, amnesia).
• Function as anticonvulsants and are used to treat seizures.
• These effects are mediated through the α-subunits of the
GABA receptor, whereas anxiolysis and muscle relaxation are
mediated through the γ-subunits.
• The site of action for muscle relaxation is in the spinal cord,
• This effect requires much larger doses.

78. Safety Profile
• Benzodiazepines have a very favorable side effect profile.
• When administered alone  cause only minimal depression
of ventilation & cardiovascular system  makes them
relatively safe even in larger doses.
• Furthermore, the CNS effects can be reversed by the selective
benzodiazepine antagonist – flumazenil.

79. Systemic effects
Central Nervous System
• Like propofol and barbiturates, benzodiazepines decrease
CMRO2 and CBF, but to a lesser extent.
• In contrast to propofol and thiopental, midazolam is unable to
produce an isoelectric EEG, thus emphasizing that there is a
ceiling effect on reduction of CMRO2.
• Patients with decreased intracranial compliance demonstrate
little or no change in ICP after the administration of
midazolam.
• Benzodiazepines have not been shown to possess
neuroprotective properties.
• They are potent anticonvulsants for the treatment of status
epilepticus, alcohol withdrawal, and local anesthetic-induced
seizures.

80. Cardiovascular System
• When used for induction of anesthesia – produces a larger
decrease in arterial blood pressure than diazepam.
• These changes are most likely due to peripheral vasodilation –
cardiac output is not changed.
• Midazolam-induced hypotension is more likely in hypovolemic
patients.

81. Respiratory System
• Produce minimal depression of ventilation.
• Transient apnea may follow rapid intravenous administration of
midazolam for induction, especially in the presence of opioid
premedication.
• Decrease the ventilatory response to carbon dioxide, but this
effect is not usually significant if they are administered alone.
• More severe respiratory depression can occur when
benzodiazepines are administered together with opioids.

82. Side effects
• Allergic reactions to BZDs – extremely rare to nonexistent.
• Pain during intravenous injection and subsequent
thrombophlebitis – most pronounced with diazepam.
• Organic solvent - propylene glycol, required to dissolve
diazepam
• Most likely responsible for pain during intramuscular or
intravenous administration,
• For the unpredictable absorption after intramuscular injection.
• Midazolam is more water soluble (but only at low pH).
• Decreases the likelihood of exaggerated pain or erratic absorption
after intramuscular injection or pain during intravenous
administration

83. Clinical uses
Preoperative Medication and Sedation
• The amnestic, anxiolytic, and sedative effects – basis for the use of
these drug for preoperative medication.
• Midazolam (1 to 2 mg IV) is effective for premedication, sedation
during regional anesthesia, and brief therapeutic procedures.
• Addition of midazolam to propofol sedation for colonoscopy may
improve operating conditions without slowing recovery time or
worsening cognitive impairment at discharge.
• When compared with diazepam, midazolam produces a more rapid
onset, with more intense amnesia and less postoperative sedation.
• Although awareness during anesthesia is rare , benzodiazepines
seem to be superior to ketamine and barbiturates for prevention of
recall.

84. • Midazolam is commonly used for oral premedication of
children.
• 0.5 mg/kg administered orally 30 minutes before induction of
anesthesia provides reliable sedation and anxiolysis in children
without producing delayed awakening.
• Midazolam also lowers the incidence of PONV.
• Despite these possible benefits, the routine use of
premedication with benzodiazepines for elective surgery may
not improve patient experience.
• The synergistic effects between benzodiazepines and other
drugs, especially opioids and propofol, facilitate better
sedation and analgesia.
• The combination of these drugs also exacerbates respiratory
depression and may lead to airway obstruction or apnea.

85. • Increase the risk for aspiration of gastric contents by impairing
pharyngeal function and the coordination between breathing
and swallowing.
• Benzodiazepine effects, as well as synergy with other
respiratory depressants, are more pronounced in the elderly ,
so smaller doses and careful titration may be necessary.
• Caution is advised when using benzodiazepines for sedation of
critically ill, mechanically ventilated patients,
• Linked to longer duration of ICU stay and increased delirium
compared with alternative regimens (propofol or
dexmedetomidine).

86. Induction of Anesthesia
• Although rarely used for this purpose, general anesthesia can
be induced by the administration of midazolam (0.1 to 0.3
mg/kg IV).
• The onset of unconsciousness, is slower than after the
administration of thiopental, propofol, or etomidate.
• Onset of unconsciousness is facilitated when a small dose of
opioid (fentanyl, 50 to 100 μg IV) is injected 1 to 3 minutes
before midazolam is administered.
• Despite the possible production of lesser circulatory effects,
use of midazolam or diazepam for induction of anesthesia
does not offer any advantages over barbiturates or propofol.
• Delayed awakening is a potential disadvantage after an
induction dose of a benzodiazepine.

87. Suppression of Seizure Activity
• The efficacy of benzodiazepines as anticonvulsants owes to
their ability to enhance the inhibitory effects of GABA,
particularly in the limbic system.
• Diazepam (0.1 mg/kg IV) is often effective in abolishing seizure
activity produced by local anesthetics or alcohol withdrawal.
• Lorazepam (0.1 mg/kg IV) is the intravenous benzodiazepine
of choice for status epilepticus.
• Diazepam (0.2 mg/kg IV) may also be used.
• For prehospital treatment of status epilepticus, intramuscular
(IM) administration of midazolam (10 mg IM for patients > 40
kg; 5 mg IM for patients 13 to 40 kg) is effective, can be
performed more rapidly than intravenous therapy, and may
decrease the need for hospitalization.

88. DEXMEDETOMIDINE
• Dexmedetomidine is a highly selective α2-adrenergic agonist.
• Recognition of the usefulness of α2-agonists was
based on the observation that patients receiving chronic
clonidine therapy have decreased anesthetic requirements.
• The effects of dexmedetomidine can be reversed
with α 2-antagonist drugs.

89. Physicochemical Characteristics
• Dexmedetomidine is the active S-enantiomer of medetomidine, a highly
selective α2-adrenergic agonist and imidazole derivative that is used in
veterinary medicine.
• Dexmedetomidine is water soluble and available as a parenteral
formulation.
Pharmacokinetics
• Undergoes rapid hepatic metabolism involving conjugation, N-
methylation, and hydroxylation.
• Metabolites are excreted through urine and bile.
Clearance is high, and the elimination half-time is short.
• There is a signifiant increase in the context-sensitive half-time from 4
minutes after a 10-minute infusion to 250 minutes after an 8-hour
infusion.
Pharmacodynamics
• Dexmedetomidine produces its effects through activation of CNS α 2
receptors.

90. Central Nervous System
• Hypnosis results from stimulation of α2- receptors in the locus
ceruleus, and the analgesic effect originates at the level of the spinal
cord.
• The sedative effect produced by dexmedetomidine has a different
quality than that of other intravenous anesthetics.
• it more resembles a physiologic sleep state through activation of
endogenous sleep pathways.
• Dexmedetomidine decreases CBF without significant changes in ICP
and CMRO2.
• Tolerance and dependence can develop.
• Although changes in the EEG do occur, spikes from seizure foci are
not suppressed making dexmedetomidine a useful drug for epilepsy
surgery.
• Evoked potentials monitored during spine surgery are not
suppressed at usual infusion doses.

91. Cardiovascular System
• Dexmedetomidine infusion produces moderate decreases in
heart rate and systemic vascular resistance and, consequently,
decreases in systemic arterial blood pressure.
• A bolus injection may produce transient increases in systemic
arterial blood pressure and pronounced decreases in heart
rate, an effect that is probably due to vasoconstriction
mediated by peripheral α2-adrenergic receptors.
• Clinically useful initial doses (0.5 to 1 μg/kg IV over 10
minutes) increase systemic vascular resistance and mean
arterial pressure, but probably do not signifiantly increase
pulmonary vascular resistance.

92. • Increasing age and decreased baseline arterial blood pressure
(mean arterial pressure < 70 mm Hg) are risk factors for
hemodynamic instability during dexmedetomidine infusion.
• Heart block, severe bradycardia, or asystole may result from
unopposed vagal stimulation.
• The response to anticholinergic drugs is unchanged.
• When used as an adjunct to general anesthesia,
dexmedetomidine reduces plasma catecholamine levels and
may attenuate heart rate increases during emergence.

93. Respiratory System
• Produces a small to moderate decrease in tidal volume and
minimal change in the respiratory rate.
• The ventilatory response to carbon dioxide is minimally
impaired, but the response to hypoxia seems reduced to a
similar degree as propofol.
• Although the respiratory effects are mild, upper airway
obstruction as a result of sedation is possible.
• Also has a synergistic sedative effect when combined with
other sedative-hypnotics.

94. ClinicalUses
• Principally used for the short term sedation of tracheally intubated
and mechanically ventilated patients in an intensive care setting.
• Although there is no evidence of benefit to mortality risk,
dexmedetomidine may reduce the duration of mechanical
ventilation, shorten length of ICU stay and improve sleep quality.
• In the operating room,
• may be used as an adjunct to general anesthesia or to provide
sedation during regional anesthesia or awake fiberoptic tracheal
intubation.
• When administered during general anesthesia, dexmedetomidine
(0.5- to 1 μg/kg IV initial dose over a period of 10 to 15 minutes,
followed by an infusion of 0.2 to 0.7 μg/ kg/h) decreases the dose
requirements for inhaled and intravenous anesthetics.
• Awakening and the transition to the postoperative setting may
benefit from dexmedetomidine-produced sedative and analgesic
effects without respiratory depression.

95. • Seems to decrease perioperative opioid consumption and
improve pain scores, but analgesic benefit has not been
shown in all settings.
• Has been used extensively in children and has demonstrated
effiacy in this population.
• Specifially, it may be beneficial for prevention of emergence
delirium after pediatric anesthesia.
• At the other extreme of age, dexmedetomidine may be
superior to propofol for reducing delirium in elderly patients
requiring sedation after cardiac or noncardiac surgery.

96. DROPERIDOL
• Droperidol is a butyrophenone, a flourinated derivative of
phenothiazines.
• Butyrophenones produce CNS depression, characterized by
marked apparent tranquility and cataleptic immobility, and are
potent antiemetics.
• Droperidol is a potent butyrophenone, and, similar to the
others, it produces its action centrally at sites where
dopamine, norepinephrine, and serotonin act.
• Droperidol and fentanyl in the ratio 50:1 produces
neuroleptanalgesia.
• Addition of nitrous oxide to this combination produces
neuroleptanaesthesia.

97. • This neuroleptanesthesia combination produce more rapid
onset of analgesia, less respiratory depression, and fewer
extrapyramidal side effects.
• The use of neuroleptanesthesia has largely disappeared in
modern anesthetic practice.
• The primary use of droperidol in anesthesia has been as an
antiemetic and, to a lesser extent, as a sedative and
antipruritic.
• In 2001, the FDA issued a black box warning regarding the use
of droperidol and its potential for QT prolongation and fatal
arrhythmias
• Recommended that it be administered only during continuous
electrocardiogram monitoring.

98. • Droperidol results in submaximal inhibition of the
GABAA α1-, β1-, and γ2-acetylcholine receptors and full
inhibition of α2-acetylcholine receptors.
• This submaximal inhibition of GABA receptors by droperidol
may explain the anxiety, dysphoria, and restlessness that may
occur with its administration.
• Droperidol is biotransformed in the liver into two primary
metabolites.
• Plasma decay can be described by a two-compartment model.

99. Systemic effects
Central nervous system:
• The effects of neurolept anesthetics on human CBF and
CMRO2 have not been studied.
• The EEG in conscious patients shows some reduction in
frequency, with occasional slowing.
• Droperidol may produce extrapyramidal signs and worsens the
symptoms of Parkinson disease.
• the drug should be used with great caution in patients with
this degenerative disorder.
• It also rarely may precipitate malignant neuroleptic syndrome.

100. Respiratory System
• When used alone, droperidol has little effect on the
respiratory system.
• Droperidol (0.044 mg/kg) given to surgical patients produced a
slight reduction in respiratory rate, and IV droperidol (3 mg)
had no signifiant effect on tidal volume in volunteers.
• More detailed respiratory studies are unavailable.

101. Cardiovascular System
• Similar to most antipsychotics, droperidol may prolong the QT
interval by delaying myocardial repolarization and
precipitating torsades de pointes.
• This effect seems to be dose dependent and may be of clinical
signifiance when other causes of QT prolongation also are
present.
• Droperidol also may have some antiarrhythmic effects that are
similar to those of quinidine.
• Droperidol produces vasodilation, with a decrease in blood
pressure.
• This effect is considered to be a result of moderate α
adrenergic blockade.
• Droperidol has little effect on myocardial contractility.

102. • The use of droperidol today in the perioperative period is largely
restricted to its antiemetic and sedative effects.
• It is an effective antiemetic; the dose for this use ranges from 10 to
20 μg/kg IV (typically 0.6 to 1.25 mg for a 70-kg individual).
• Because droperidol in doses lower than 1 mg produce antiemetic
effects and because the cardiac side effects may be dose dependent,
an IV dose lower than 1 mg for prevention of PONV is advisable.
• These doses of droperidol, given at the start of anesthesia for
operations lasting 1 hour, reduce the incidence of nausea and
vomiting by approximately 30%.
• These doses given at induction have little effect on wake-up time,
but given at the end of the surgical procedure, they could have some
residual hypnotic effect.

103. • Overall, the antiemetic effiacy of droperidol alone is equal to that of
ondansetron and results in an equal number of side effects, but
droperidol is more cost effective.
• The effiacy of droperidol as an antiemetic is enhanced when it is
used in combination with serotonin antagonists or dexamethasone,
or both.
• Droperidol also has been shown to be effective in the treatment and
prevention of pruritus secondary to opioid administration.
• It has been given by the IV route and into the epidural space for this
purpose. When used in this fashion, droperidol also effectively
reduces nausea, but it increases sedation.
• The safety of droperidol administration into the epidural space has
not been fully evaluated, however, and it is not approved for
administration by this route.

104. 0.5-1 μg/kg

105. References:
• Miller’s Anesthesia,
• Clinical Anesthesia, Paul G. Barash, MD
• Morgan and Mikhail’s Clinical Anesthesiology
• Stoelting’s pharmacology and physiology in anesthetic practice

106. THANK YOU