1. IV induction drugs cause rapid loss of consciousness within one arm-brain circulation time by depressing the reticular activating system when given in appropriate doses. 2. An ideal IV induction drug would have rapid onset, short duration, and few side effects. It would be water soluble, stable, and inexpensive. 3. Common IV induction drugs include barbiturates like thiopental and methohexital, non-barbiturates like propofol and etomidate, benzodiazepines, and dissociatives like ketamine. Each drug has unique properties affecting absorption, distribution, metabolism, and excretion.

1. Dr. Upasana Gupta

2. IV induction drugs
drugs when given intravenously in an appropriate dose, cause a rapid loss of consciousness.
described as occurring within “one arm-brain circulation time”: the time taken for the drug
to travel from the site of injection (usually the arm) to the brain, where they have their
effect.
They are used:
• To induce anaesthesia prior to other drugs being given to maintain anaesthesia.
• As the sole drug for short procedures.
• To maintain anaesthesia for longer procedures by intravenous infusion.
• To provide sedation.
concept of intravenous anaesthesia -1932
when Wesse and Schrapff published their report into the use of hexobarbitone: the
first rapidly acting intravenous drug.

3. Properties of an ideal IV induction drug:
 Physical properties
 • Water soluble & stable in solution
 • Stable on exposure to light
 • Long shelf life
 • No pain on intravenous injection
 • Painful when injected into an artery
 • Non-irritant when injected subcutaneously
 • Low incidence of thrombophlebitis
 • Cheap
Pharmacodynamic properties
• High therapeutic ratio ( ratio of toxic dose :
minimally effective dose )
• Minimal cardiovascular and respiratory effects
• No histamine release/hypersensitivity
reactions
• No emetic effects
• No involuntary movements
• No emergence nightmares
• No hang over effect
• No adrenocortical suppression
• Safe to use in porphyria
Pharmacokinetic properties
• Rapid onset in one arm-brain circulation time
• Rapid redistribution to vessel rich tissue
• Rapid clearance and metabolism
• No active metabolites

4.  Barbiturates
▼ Oxybarbiturate - pentobarbital and methohexital
▼ Thiobarbiturates - thiopental and thiamylal
 Non-barbiturates:
▼ Propofol
▼ Etomidate
Benzodiazepines
 Dissociatives:
▼ Ketamine

5. derived from barbituric acid.
Substitution at carbon C 5 - hypnotic potency and anticonvulsant
activity.
A long branched chain- more potency than does a short straight
chain.
Replacing the oxygen at C 2 ( oxy barbiturates) with a sulfur
atom ( thiobarbiturates) increases lipid solubility.
thiopental and thiamylal have a greater potency, more rapid
onset of action, shorter durations of action (after a single “sleep
dose”) than pentobarbital

7. Mechanism of Action
depress the reticular activating system in the brainstem, which
controls multiple vital functions, including consciousness.
affect the function of nerve synapses than axons.
 Binds to the beta subunit of γ-aminobutyric acid type A (GABA A
)receptor
potentiate the action of GABA in increasing the duration of openings
of a chloride ion channel.

8. A. Absorption
rapid onset & rapid awakening after a single IV dose
due to rapid uptake & rapid redistribution out of the brain into inactive
tissues.
drug is sequestered in fat & skeletal muscle  reenters the circulation
prevents plasma concentration from dropping rapidly.
 metabolized hepatocytes and small extent, kidneys & CNS.
Metabolites ( hydroxythiopental & 5-carboxylic acid) –
inactive, more water soluble than parent compound facilitates renal
excretion.
 thiopental (small fraction) metabolized  active long-acting oxybarbiturate pentobarbital.

9.  After rapid i.v. injection, thiopental in the blood decreases ( drug
moves from the blood  tissues.)
 Time taken to achievement of peak levels is direct function of
tissue Capacity
for barbiturate relative to blood flow.
 Initially- taken up by the vessel-rich group tissues due to high
blood flow.
 redistributed to skeletal muscles to a lesser extent, to fat.
 Loss of consciousness- 30 s
 awaken within 20 min duration - determined by redistribution.
 thiopental is highly protein bound (80%)
 its great lipid solubility and high nonionized fraction (60%) account
for rapid brain uptake (within 30 s).

10. Barbiturates
pediatric patients- elimination t1/2 of thiopental shorter than in adults
due to more rapid hepatic clearance of thiopental by pediatric patients.
 recovery after large or repeated doses of thiopental- infants and children >
adults.
Elimination half-time is prolonged in pregnancy- due to inc. protein binding
of thiopental.
less lipid-soluble barbiturates have much longer distribution half-lives and
durations of action after a sleep dose.
Repetitive administration of barbiturates saturates the peripheral
compartments(eg, infusion of thiopental for “barbiturate coma” and brain
protection)

11. C. Biotransformation
biotransformed via hepatic oxidation to inactive water-soluble metabolites.
D. Excretion
Increased protein binding decreases barbiturate glomerular filtration,
whereas increased lipid solubility increases renal tubular reabsorption.
less protein-bound and less lipid-soluble agents (phenobarbital)- renal
excretion is limited to water-soluble end products of hepatic
biotransformation.
Methohexital is excreted in the feces.

12. Effects on Organ System
A. Cardiovascular
Depends on rate of administration, dose, volume status, baseline
autonomic tone, and preexisting cardiovascular disease.
Intravenous bolus induction doses of barbiturates  decrease in B.P.
& increase HR .
 Depression of the medullary vasomotor center  vasodilation of
peripheral capacitance vessels  increases peripheral pooling of
blood, mimicking a reduced blood volume.

13. Tachycardia following administration  due to a central vagolytic effect
and reflex responses to hypotension.
Cardiac output is maintained by an increased HR & increased myocardial
contractility from compensatory baroreceptor reflexes.
Conditions where the baroreceptor response is blunted or absent (eg,
hypovolemia, congestive heart failure, β-adrenergic blockade) cardiac
output and arterial bp fall due to uncompensated peripheral pooling of
blood & direct myocardial depression.
slow rate of injection and adequate preoperative hydration attenuates or
eliminates these changes.

14.  B. Respiratory
depress the medullary ventilatory center decreasing the
ventilatory response to hypercapnia & hypoxia.
Deep barbiturate sedation leads to upper airway obstruction;
apnea after an induction dose.
During awakening, tidal volume and respiratory rate are decreased
following barbiturate induction.
 incompletely depress airway reflex responses to laryngoscopy,
intubation & airway instrumentation  bronchospasm (in asthmatic
patients) or laryngospasm in lightly anesthetized patients.

15. C. Cerebral
 constrict the cerebral vasculature  decrease in cerebral blood flow, cerebral blood volume, ICP.
Intracranial pressure decreases more than arterial blood pressure cerebral perfusion pressure (CPP)
increases.
CPP = cerebral artery pressure - jugular venous pressure or intracranial pressure
decline in cerebral oxygen consumption (up to 50% of normal) than in cerebral blood flow.
degree of cns depression ranges from mild sedation to unconsciousness- depends on dose
administered.
do not impair the perception of pain, lower the pain threshold.
Small doses cause a state of excitement and disorientation.
do not produce muscle relaxation and some induce involuntary skeletal muscle contractions (eg,
methohexital).
small doses of thiopental (50–100 mg iv) rapidly (but temporarily) control most grand mal seizures.
acute tolerance & physiological dependence on the sedative effect of barbiturates develop quickly.

16. D. Renal
 reduce renal blood flow & glomerular filtration rate.
E. Hepatic
Hepatic blood flow is decreased.
binding of barbiturates to the cytochrome P-450 enzyme system interferes with
the biotransformation of drugs (e.g. tricyclic antidepressants).
promote amino-levulinic acid synthetase stimulates formation of porphyrin
may precipitate acute intermittent porphyria or variegate porphyria in
susceptible individuals.
F. Immunological
Anaphylactic or anaphylactoid allergic reactions - rare.
Sulfur-containing thiobarbiturates evoke mast cell histamine release in vitro.

17. Uses and dosages of common barbiturates
Thiopental: Induction, cerebral
protection (e.g. status epilepticus)
Methohexital: Induction, especially for
ECT
Phenobarbital: Seizure suppression.
Adverse effects:
Garlic or onion tastes, Allergic
reactions
Local tissue irritation or rarely
necrosis
Bronchoconstriction in
asthmatics.

18.  Thiopental (aka thiopentone and Pentothal)
 Barbiturate which comes as pale yellow powder.
 Ampoules commonly contain 500mg of sodium thiopental with 6% sodium
carbonate.
 The alkaline solution is bacteriostatic and safe to keep for 48 hours.
 The molecular structure of thiopental is based upon the barbiturate ring - A
sulphur atom at the carbon R2 position confers the short duration of action
 A dose of 4-5mg/kg of thiopental - smooth onset of hypnosis.
 Recovery after a single dose is rapid - due to redistribution and there is a
low incidence of restlessness and nausea and vomiting.
Sodium Thiopental

19. Thiopental reduces cerebral blood flow, cerebral metabolic
rate and oxygen demand.
 It has potent anticonvulsant properties.
Following traumatic brain injury, infusion of thiopental to
produce a “barbiturate coma” lowers intracranial pressure
and may improve neurological outcome.
Thiopental may precipitate porphyria due to hepatic enzyme
induction in susceptible patients.

20. Midazolam (short acting)
Lorazepam and Temazepam (intermediate)
Diazepam (long acting)
Flumazenil (antidote, shorter half life than most of the
benzos

21. BENZODIAZEPINES
Mechanisms of Action
Benzodiazepines bind the same set of receptors in the CNS as
barbiturates but bind to a different site on the receptors.
binding to the GABA- A receptor- increases frequency of openings of
associated cl ion channel.
benzodiazepine-receptor binding facilitates binding of GABA to its
receptor.
 Flumazenil (an imidazobenzodiazepine) - specific benzodiazepine–
receptor antagonist.
 Competitive antagonist
 Short half-life. Rapid onset, 1-3 min, lasts 3-30 min.

22.  Benzodiazepines (benzo) attach
selectively to a subunits and are
presumed to facilitate the action of the
inhibitory neurotransmitter GABA on a
subunits.
Model of the g-aminobutyric acid (GABA) receptor
forming a chloride channel.

23. Structure–Activity Relationships
 chemical structure of benzodiazepines includes a
benzene ring and a seven-member diazepine ring
 Substitutions at various positions on these rings
affect potency and biotransformation.
 imidazole ring of midazolam contributes to its
water solubility at low pH.
Diazepam and lorazepam are insoluble in water so
parenteral preparations contain propylene glycol,
which can produce venous irritation.

24.  Pharmacokinetics
A. Absorption
 Diazepam and lorazepam - well absorbed from the git
peak plasma levels usually achieved in 1 and 2 h, respectively.
B. Distribution
relatively lipid soluble, readily penetrates the blood–brain barrier.
Although midazolam is water soluble at reduced pH, its imidazole ring closes at physiological
pH, increasing its lipid solubility.
Lorazepam- moderate lipid solubility- slower brain uptake and onset of action.
Redistribution - rapid.
 initial distribution half-life - 3–10 min
All three benzodiazepines are highly protein bound (90–98%).

25. C. Biotransformation
Uses liver for biotransformation into water-soluble glucuronidated
end products.
 Slow hepatic extraction & a large volume of distribution ( V d ) 
long elimination half-life for diazepam (30 h).
 lorazepam - low hepatic extraction ratio, its lower lipid solubility
limits its Vd
shorter elimination half-life (15 h).
 the clinical duration of lorazepam - prolonged due to increased
receptor affinity
Midazolam elimination half-life (2 h) is the shortest.

26. D. Excretion
 metabolites  urine.
Enterohepatic circulation  secondary peak in diazepam plasma
concentration 6–12 h following administration.
Kidney failure  prolonged sedation in patients receiving larger
doses of midazolam (accumulation of a conjugated metabolite α-
hydroxymidazolam).

27.  Midazolam
 Rapid onset <1min, peak 2-3 min
 Distribution half life 6-15 min
 Hepatically metabolized by CYP system including active metabolite 1-hydroxymidazolam
 Not an issue with normal renal function but in renal impairment can build up.
 Lorazepam
 Conjugated in liver (not by CYP) to inactive compounds
 so renal impairment doesn’t prolong action but liver failure can
 Infusion can cause propylene glycol toxicity
 Remimazolam
 New, cleared by non-specific tissue esterase

28. intranasal (0.2–0.3 mg/kg), buccal (0.07 mg/kg), and sublingual (0.1mg/kg)
midazolam provide effective preoperative sedation.

29.  Effects on Organ Systems
A. Cardiovascular
 minimal cardiovascular depressant effects even at general anesthetic
doses,
except when they are coadministered with opioids (these agents interact to
produce myocardial depression and arterial hypotension).
decrease arterial blood pressure, cardiac output, and peripheral vascular
resistance slightly, & sometimes increase heart rate.
Intravenous midazolam reduce bp and peripheral vascular resistance.
decreased vagal tone (ie, drug-induced vagolysis).

30. B. Respiratory
depress the ventilatory response to CO 2 .
significant if the drugs are administered intravenously or in
association with other respiratory depressants.
careful titration of drug to avoid overdosage & apnea bcz of
steep dose–response curve, slightly prolonged onset.
Ventilation - monitored in all patients receiving intravenous
benzodiazepine
Resuscitation equipment must be immediately available.

31. C. Cerebral
 reduce cerebral oxygen consumption, cerebral blood flow, and
icp
effective in preventing and controlling grand mal seizures.
Oral sedative doses - produce antegrade amnesia
(premedication)
mild muscle-relaxing property of these drugs is mediated at the
spinal cord level
at lower doses - antianxiety, amnestic, and sedative effects.
Induction with benzodiazepines is associated with a slower rate
of loss of consciousness and a longer recovery.
 no direct analgesic properties.

32.  Midazolam is a water-soluble benzodiazepine with imidazole ring
 its structure that accounts for stability in aqueous solutions and rapid metabolism.
 exhibits a form of isomerism known as tautomerism.
 In the ampoule, as an acidic solution, the molecule exists in an ionized form.
 At physiological pH ; molecule changes to becomes a highly lipid soluble unionized ring,
accounting for its rapid onset of action.

33.  MIDAZOLAM
does not cause pain on injection.
Like other benzodiazepines- acts at specific receptors closely allied to the
GABA-A receptor.
Activation of the benzodiazepine receptor increases chloride influx to
neuronal cells via the GABA-A receptor  neuronal hyperpolarisation 
clinical effects.
used for sedation at a dose range of 0.05-0.1mg/kg (IV) due to short
duration of action and amnesic properties.
In children - useful as premedication.
It can be used as a sole iv induction drug, at a dose of 0.3mg/kg, but its
duration of onset is slow, limiting its use.
 Duration of action ~ 30 min (longer than that of the other induction drugs)

34. undergoes hepatic metabolism and renal elimination.
 In the elderly, the lower hepatic blood flow and metabolic activity -
prolonged half life.
 mild cardiovascular and respiratory depressant effects- monitoring is
important during sedation.
When used as a sole induction drug, midazolam causes apnoea - 70%
of patients.
.

35. PROPOFOL
Substituted isopropyl phenol(2,6-diisopropylphenol)
Administered i.v. as
1% solution in an aqueous solution of
10% soybean oil
2.25% glycerol
& 1.2% purified egg phosphatide.

36. COMMERCIAL PREPARATIONS:
Requires a lipid vehicle for emulsification.
Uses soybean oil as oil phase & egg lecithin as emulsifying agent.
This formulations supports bacterial growth & causes raised plasma triglycerides, on
prolonged iv infusion.
low lipid emulsion- Ampofol, contains 5% soybean oil. 0.6% egg lecithin. ( associated with
higher incidence of pain on injection)
aquavan : non lipid formulation.
Absence of lipid emulsion- inc pain on injection, the release of formaldehyde byproduct
causes burning sensation in genital areas.
Another non lipid formulations uses cyclodextrins as solubilizing agent. still in clinical trial.
pain during injection - decreased by prior injection of lidocaine or by mixing lidocaine with
propofol prior to injection (2 mL of 1% lidocaine in 18 mL propofol)

37. Propofol formulations can support the growth of bacteria
sterile technique must be observed in preparation and handling.
Propofol should be administered within 6 h of opening the ampule.
Sepsis and death - contaminated propofol preparations.
Current formulations of propofol - 0.005% disodium edetate or 0.025% sodium metabisulfite
to retard the rate of growth of microorganisms

38. A. Absorption
available only for i.v. administration - induction of general anesthesia &
for moderate to deep sedation
B. Distribution
 rapid onset of action.
Awakening from a single bolus dose - rapid due to very short initial
distribution t1/2 (2–8 min).
good agent for outpatient anesthesia.
A smaller induction dose is recommended in elderly patients because of
their smaller V d .

39. C. Biotransformation
 clearance of propofol exceeds hepatic blood flow, implying the existence of extrahepatic
metabolism.
exceptionally high clearance rate contributes to rapid recovery after continuous infusions.
Conjugation in the liver results in inactive metabolites - eliminated by renal clearance.
pharmacokinetics of propofol – not affected by obesity, cirrhosis, or kidney failure.
Use of propofol infusion for long-term sedation of children who are critically ill or young adult
neurosurgical patients- associated with sporadic cases of lipemia, metabolic acidosis, and death-
propofol infusion syndrome.
D. Excretion
 metabolites of propofol - primarily excreted in the urine,
But chronic kidney failure does not affect clearance of the parent drug

40.  facilitation of inhibitory neurotransmission mediated by
GABA-a receptor binding.
It increases binding affinity of GABA for GABA-a receptor.
Activation of receptor increase in transmembrane
chloride conductance  hyperpolarisation of the nerve
membrane functional inhibition of postsynaptic nerve .

41.  Effects on Organ Systems
A. Cardiovascular
major cardiovascular effect of propofol : decrease in arterial bp due to a
drop in systemic vascular resistance (inhibition of sympathetic
vasoconstrictor activity), preload, and cardiac contractility.
Factors associated with propofol-induced hypotension include
large doses, rapid injection, and old age.
 impairs the normal arterial baroreflex response to hypotension.
Changes in heart rate and cardiac output - transient.
myocardial oxygen consumption and coronary blood flow - decreases
coronary sinus lactate production increases in some patients, indicating
mismatch between myocardial oxygen supply and demand.

42. B. Respiratory
profound respiratory depressant- usually causes apnea following
an induction dose.
Even when used for conscious sedation in subanesthetic doses-
inhibits hypoxic ventilatory drive & depresses normal response to
hypercarbia.
Propofol-induced depression of upper airway reflexes >>
thiopental allowing intubation, endoscopy, or laryngeal mask
placement in the absence of neuromuscular blockade.

43.  C. Cerebral
 Propofol decreases cerebral blood flow and intracranial pressure.
In patients with elevated icp  cause a critical reduction in CPP (<50 mm Hg) .
antipruritic properties.
antiemetic effects - Subhypnotic doses of propofol (10 to 15 mg IV) may be used in the
postanesthesia unit.
Induction is occasionally accompanied by excitatory phenomenon- muscle twitching,
spontaneous movement, opisthotonos, or hiccupping.
Anticonvulsant properties- used successfully to terminate status epilepticus.
Propofol in doses >1 mg/kg IV decreases seizure duration 35% to 45% in patients undergoing
ECT.
safely administered to epileptic patients.
decreases IOP.
Tolerance does not develop after long-term propofol infusions.

44.  Uses:
 Induction:
 1-2.5mg/kg based on lean body mass, adjusted for age, reduced with premed.
 Maintenance:
 50-150mcg/kg/min based on total body weight, adjusted to individual (older and sicker
 patients require much less)
 Sedation:
 25-75mcg/kg/min
 Anti-emetic
 10-20mg IV intermittently or infusion of 10mcg/kg/min
 Infusions>30mcg/kg/min usually cause amnesia

45. Advantages:
Does not prolong neuromuscular blockade but large doses may
provide good
intubating conditions without paralysis.
No adrenal suppression
Pleasant dreams
Anti-emetic even at low doses (10mcg/kg/min)
Also relieves pruritis from opiates and from cholestasis.

46. Adverse effects
Anaphylactoid reactions, especially in people with multiple
allergies
Pancreatitis-likely from hypertriglyceridemia-older, longer
duration, higher dose
Pain on injection-rare thrombophlebitis of vein
Propofol infusion syndrome
Usually doses >70mcg/kg/min for >48h
Acute bradycardia leading to asystole with metabolic
acidosis, rhabdo, hyperlipidemia, fatty liver, hyperkalemia

47. FOSPROPOFOL
Fospropofol - water-soluble prodrug
metabolized in vivo to propofol, phosphate, and formaldehyde.
It has been released in the United States and other countries
it produces more complete amnesia and better conscious sedation
for endoscopy than midazolam plus fentanyl.
slower onset and slower recovery than propofol.

48. 
synthesized in 1962
first used in humans in 1965
released for clinical use 1970
Racemic mixture of S and R ketamine.
S isomer is more potent and has fewer psychomimetic effects
phencyclidine derivative
 produces “dissociative anesthesia: Produced “dissociative anesthesia” because patients may
not appear asleep (eyes open, reflexes intact)
“dissociates” the thalamus (which relays sensory impulses from the reticular activating
system to the cerebral cortex) from the limbic cortex
resembles a cataleptic state - which the eyes remain open with a slow nystagmic gaze.

49.  Mechanism of Action
mechanism of action of ketamine-induced analgesia and
dissociative anesthesia – unknown
known to interact with multiple CNS receptors
binds noncompetitively to the phencyclidine recognition site on
N-methyl-d-aspartate (NMDA) receptors.
 exerts effects at other sites including opioid receptors,
monoaminergic receptors, muscarinic receptors, & voltage-
sensitive sodium and L-type calcium channels and neuronal
nicotinic acetylcholine receptors.
ketamine has only weak actions at GABA-A receptors

50.  Pharmacokinetics
 A. Absorption
Can be administered orally, nasally, rectally, subcutaneously, and epidurally.
 Peak plasma levels - within 1 minute after IV administration & within 5 minutes after IM
injection.
B. Distribution
 not significantly bound to plasma proteins
leaves the blood rapidly to be distributed into tissues.
Initially- distributed to highly perfused tissues (brain,where the peak concentration may 4x
plasma.)
extreme lipid solubility- rapid transfer across the blood–brain barrier.
 ketamine-induced increase in cerebral blood flow facilitate delivery of drug - enhance rapid
achievement of high brain concentrations.
 Redistributed from the high perfused  less well-perfused tissues.
high hepatic clearance rate (1 L per minute) & large Vd (3 L/kg)  elimination half-time of 2 to 3
hrs.
C. Biotransformation in liver & Excreted through Renal

51.  Effects on Organ Systems
A. Cardiovascular
increases arterial bp, HR and cardiac output after rapid bolus injections
due to central stimulation of sympathetic nervous system
Inhibition of the reuptake of norepinephrine after release at nerve terminals.
increases pulmonary artery pressure and myocardial work.
large bolus injections of ketamine should be administered cautiously in patients with
coronary artery disease,uncontrolled hypertension, congestive heart failure, arterial aneurysms.

52.  KETAMINE
B. Respiratory
Ventilatory drive - minimally affected by induction doses.
rapid intravenous bolus administration or combinations of ketamine with
opioids - apnea.
Racemic ketamine - potent bronchodilator – good induction agent for
asthmatic patients
Upper airway reflexes remain intact, but partial airway obstruction may
occur
Patients with “full stomachs” - intubated during ketamine induction-
increased risk for aspiration pneumonia
increased salivation.

53.  C. Cerebral
increases cerebral oxygen consumption, cerebral blood flow, and
intracranial pressure.
use in patients with space-occupying intracranial lesions such
as occur with head trauma.
Myoclonic activity due to increased subcortical electrical activity.
Undesirable psychotomimetic side effects (eg, disturbing dreams
and delirium) during emergence and recovery-
less common in children and in patients premedicated with
benzodiazepines

54. Adverse effects:
Increased ICP and IOP
Increased myocardial O2 consumption
Repeated abuse can cause liver and renal toxicity

55. ETOMIDATE
contains carboxylated imidazole
structurally unrelated to other anesthetic agents.
imidazole ring provides water solubility in acidic solutions and lipid solubility at physiological
pH.
etomidate is dissolved in propylene glycol for injection.  causes pain on injection(lessened
by prior iv injection of lidocaine)
Mechanisms of Action
 depresses the reticular activating system & mimics the inhibitory effects of GABA.
 R(+) isomer—bind to a subunit of the GABA A receptor, increasing the receptor’s affinity for
GABA.
etomidate may have disinhibitory effects on areas which control extrapyramidal motor
activity.

56. Pharmacokinetics
Absorption
 available only for i.v. administration
 used primarily for induction of GA
 sometimes used for brief production of deep (unconscious) sedation
e.g.prior to placement of retrobulbar blocks.
B. Distribution
 highly protein bound & great lipid solubility
 rapid onset of action - due to large nonionized fraction at physiological pH.
 Redistribution - responsible for decreasing the plasma concentration to awakening levels.
 C. Biotransformation
Hepatic microsomal enzymes and plasma esterases rapidly hydrolyze etomidate  inactive
metabolite.
D. Excretion
 end products excreted - urine.

57.  Effects on Organ Systems
 A. Cardiovascular
minimal effects on the cardiovascular system.
mild reduction in peripheral vascular resistance  slight decline in arterial blood pressure.
 Myocardial contractility and cardiac output are usually unchanged.
even in large doses, produces relatively light anesthesia for laryngoscopy,
marked increases in heart rate and blood pressure may be recorded when etomidate
provides the only anesthetic depth for intubation.
B. Respiratory
Ventilation is affected less with etomidate than with barbiturates or benzodiazepine.

58.  C. Cerebral
 decreases cerebral metabolic rate, cerebral blood flow, and intracranial
pressure.
etomidate increases the amplitude of somatosensory evoked potentials.
Postoperative nausea and vomiting - common
lacks analgesic properties.
 D. Endocrine
Transiently inhibit enzymes involved in cortisol and aldosterone synthesis.
 Long term infusion and adrenocortical suppression - increased mortality
rate in critically ill (particularly septic) patients.

59. Dextromethorphan
 D-isomer of the opioid agonist,levomethorphan- low-affinity NMDA
antagonist
activity at multiple other ligands including neuronal nicotinic receptors
equal in potency to codeine as an antitussive but lacks analgesic or
physical dependence properties.
rarely produces sedation or gastrointestinal disturbances.
psychoactive effects - abuse potential.
Signs and symptoms of intentional excessive intake of
dextromethorphan
systemic hypertension
Tachycardia, Somnolence, Agitation
slurred speech, Ataxia diaphoresis,
skeletal muscle rigidity, seizures, coma, and decreased core body temperature.
Hepatotoxicity- when dextromethorphan with acetaminophen
ingested in excessive amounts.

60.  Dexmedetomidine
 potent alpha2 adrenergic agonist
shorter acting than clonidine , much more selective for a2 vs. a1 receptors.
sedative effects- due to inhibition of alpha-2 receptors in pontine locus ceruleus
nucleus mediating sympathetic nervous system function, vigilance, memory, analgesia,
and arousal nucleus.
dextro isomer- active component of medetomidine.
Atipamezole - specific and selective investigational a2 receptor antagonist.
rapidly and effectively reverses the sedative and cardiovascular effects of IV
dexmedetomidine.
 produces sedation - decreasing sympathetic nervous system activity and the level of arousal.
result is a calm patient who can be easily aroused to full consciousness.
Amnesia is not assured.
Drugs that activate GABA receptors - clouding of consciousness and can cause paradoxical
agitation,tolerance and dependence.

61.  Pharmacokinetics
elimination half-time dexmedetomidine - 2 - 3 hrs (6 to 10 hours clonidine).
highly protein bound (.90%)
undergoes extensive hepatic metabolism.
excreted by kidneys.
weak inhibiting effects on cytochrome P450 enzyme systems
manifest as increased plasma concentrations of opioids as administered
during anaesthesia.

62.  Clinical Uses
pretreatment with dexmedetomidine attenuates hemodynamic responses to
tracheal intubation.
decreases plasma catecholamine concentrations during anesthesia
decreases perioperative requirements for inhaled anesthetics and opioids
 decreases MAC for volatile anesthetics
In patients isoflurane MAC was decreased 35% and 48% by plasma conc.
of 0.3 ng/mL & 0.6 ng/mL, respectively.
produces total IV anesthesia without associated depression of ventilation.
potential anesthetic technique for patients with a difficult upper
airway.

63.  Clinical Uses(contd.)
 Addition of 0.5 mg/kg dexmedetomidine to lidocaine in IV regional
anesthesia- postoperative analgesia.
an effective treatment for nonthermally induced shivering.
 Severe bradycardia may occur- administration of dexmedetomidine
 cardiac arrest has been reported in a patient receiving a
dexmedetomidine infusion
 as a supplement to general anaesthesia.

65. THANK YOU