seminar on intravenous anaesthetic agents incudes benzodiazipenes, opiods,TIVA ,neurolept analgesia &anaesthesia

2.  Diazepam (Valium) was synthesized by Sternbach
in 1959
 Lorazepam a 2′ chloro-substitution product of
oxazepam , was synthesized in 1971
 Fryer and Walser's in 1976 synthesized
midazolam
 Midazolam was the first benzodiazepine that was
produced primarily for use in anesthesia

4.  Three benzodiazepine receptor agonists are
commonly used in anesthesia are :-
 short-lasting (midazolam),
 intermediate-lasting (lorazepam),
 long-lasting (diazepam)
 relatively small and are lipid soluble at
physiologic pH
 Midazolam is the most lipid soluble of the three
drugs

7. Binding of drug facilitates the actions of GABA
ie principal inhibitory neurotransmitter in the
CNS
Enhance the affinity of the receptors for GABA
enhanced opening of chloride gating channels
leading to increased chloride conductance
hyperpolarization of the postsynaptic cell
membrane, rendering postsynaptic neurons
more resistant to excitation

8.  Results into anxiolysis,sedation, anterograde
amnesia, alcohol potentiation and
anticonvulsant and skeletal muscle relaxant
effects
 Alpha-1 containing GABAA receptors are the
most abundant receptor subtypes
 Sedative effects of benzodiazepines reflect
activation of alpha-1 subunits of GABAA
receptors
 Anxiolytic activity is due to alpha-2 subunit
activity

10.  Midazolam is a water-soluble benzodiazepine
with an imidazole ring in its structure that
accounts for stability in aqueous solutions
 Compared with diazepam, midazolam is two to
three times more potent
 has an affinity for the benzodiazepine receptor
that is approximately twice that of diazepam
 Compared with other benzodiazepines, the
amnestic effects of midazolam are more potent
than its sedative effects

12.  Midazolam undergoes rapid absorption from the
gastrointestinal tract and prompt passage across
the blood-brain barrier
 Only about 50% of an orally administered dose of
midazolam reaches the systemic circulation,
reflecting a substantial first-p ass hepatic effect
 extensively bound to plasma proteins
 elimination half-time of midazolam is 1 to 4 hours,
 Short duration of action of a single dose of
midazolam is due to its lipid solubility, leading to
rapid redistribution from the brain to inactive
tissue sites as well as rapid hepatic clearance

13.  Midazolam is rapidly metabolized by hepatic and
small intestine cytochrome P-450 (CYP3A4) enzymes
 principal metabolite of midazolam, 1-hydroxym
idazolam,has approximately half the activity of the
parent compound
 metabolite is rapidly conjugated to glucuronide and
subsequently cleared by the kidneys
 Metabolism of is slowed in the presence of drugs
(cimetidine, erythromycin, calcium channel
blockers,antifungal drugs) that inhibit cytochrome P-
450 enzymes resulting in unexpected CNS depression
 hepatic clearance rate of midazolam is five times
greater than that of lorazepam and ten times greater
than that of diazepam

14. Central Nervous System
 Produces decreases in cerebral metabolic
oxygen requirements(CMR0 2 ) and cerebral
blood flow
 Cerebral vasomotor responsiveness to carbon
dioxide is preserved during midazolam
anesthesia
 show little or no change in intracranial
pressure (ICP)
 Midazolam is a potent anticonvulsant
effective in the treatment of status epilepticus

15.  produces dose-dependent decreases in venti
lation
 Transient apnea may occur after rapid
injection of large doses of midazolam
 depress the swallowing reflex and decrease
upper airway activity
Cardiovascular System:-
 decrease in systemic blood pressure and
increase in heart rate
 Cardiac output is not altered by midazolam

16.  Induction
0.05-0.15 mg/kg
 Maintenance
0.05 mg/kg
 Sedation 0.5-1 mg
repeated
0.07 mg/kg IM

17. 1)Preoperative Medication:-
 most commonly used oral preoperative
 Midazolam 0.5 mg/kg administered orally 30
minutes before induction of anesthesia,
provides reliable sedation and anxiolysis in
children without producing delayed
awakening
2) Intravenous Sedation:- Midazolam in doses
of 1.0 to 2.5 mg i/v(onset within 30 to
60 seconds) is effective for sedation during
regional anesthesia as well as for brief
therapeutic procedures

18.  Anesthesia can be induced by administration of
midazolam,0.1 to 0.2 mg/kg N, over 30 to 60
seconds
 Elderly patients require less midazolam for the
i/v induction
4) Maintenance of Anesthesia:-
 may be administered to supplement opioids,
propofol, and/or inhaled anesthetics during
maintenance of anesthesia
5)Postoperative Sedation:-
 loading dose 0.5 to 4 mg i/v and maintenance
dose 1 to 7 mg/hr IV) to produce sedation in
intubated patients

19. 6)Paradoxical Vocal Cord Motion:-
Paradoxical vocal cord motion is a cause of
non organic upper airway obstruction and
stridor that may manifest postoperatively.
Midazoalm 0.5 to 1 mg IV may be an effective
treatment for paradoxical vocal cord motion
7) Midazolam is a potent anticonvulsant
effective in the treatment of status
epilepticus
8) Nausea and Vomiting Prophylaxis:-
midazolam, may play in the prevention of
PONV

20.  highly lipid-soluble benzodiazepine with a
more prolonged duration of action compared
with midazolam
 dissolved in organic solvents (propylene
glycol,sodium benzoate) because it is insoluble
in water
 Dilution with water or saline causes cloudiness
but does not alter the potency of the drug
 Injection by either the iM or IV route may be
painful

21.  Diazepam is well absorbed from the
gastrointestinal tract, with peak plasma levels
usually achieved in 1hr
 relatively lipid soluble and readily penetrates
the blood–brain barrier
 highly protein binding limits the efficacy of
hemodialysis in the treatment of diazepam
overdose.
 Diazepam rapidly crosses the placenta,
achieving fetal concentrations equal to and
sometimes greater than those present in the
maternal circulation

22.  metabolized by hepatic microsomal enzymes
using an oxidative pathway of
N demethylation
 metabolites of diazepam are
desmethyldiazepam and oxazepam, with a
lesser amount metabolized to temazepam
 removed as a conjugate of glucuronic acid
 Cimetidine inhibits P-450 hepatic microsomal
enzymes and thus prolongs the elimination
half-time of both diazepam and
desmethyldiazepam
 elimination half-time of diazepam is
prolonged, ranging from 21 to 37 hours in
healthy volunteers

23.  Central Nervous System - reduce the CMRO2
and CBF similar to midazolam
 CNS intoxication can be expected at
diazepam plasma concentrations of > 1,000
ng/mL.
 Respiratory system-
Diazepam produces minimal depressant
effects on ventilation
 Combination of diazepam with other CNS
depressants (opioids, alcohol) or in patients
with COPD may result in exaggerated or
prolonged depression of ventilation

24.  produces minimal decreases in systemic
blood pressure, cardiac output, and systemic
vascular resistance
 transient depression of baroreceptor-
mediated heart rate
 Skeletal Muscle:-
diminishes the tonic facilitatory influence on
spinal gamma neurons, and, thus, skeletal
muscle tone is decreased

25. -Induction:-
0.3-0.5 mg/kg
-Maintenance:-
0.1 mg/kg
-Sedation:-
2 mg repeated until
sedated

26.  Preoperative medication of adults
 management of delirium tremens
 treatment of local anesthetic-induced
seizures
 Production of skeletal muscle relaxation by
diazepam is often used in the management of
lumbar disc disease and may be in the rare
patient who develops tetany

28.  Lorazepam is a more potent sedative and
amnesic than midazolam and diazepam
 Pharmacokinetics:-
 conjugated with glucuronic acid in the liver to
form pharmacologically inactive metabolites
that are excreted by the kidneys

29.  The elimination halftime is 10 to 20 hours
 Lorazepam has a slower onset of action than
midazolam or diazepam because of its lower
lipid solubility and slower entrance into the
CNS
 metabolism of lorazepam is less likely than
that of diazepam to be influenced by
alterations in hepatic function, increasing
age, or drugs that inhibit P-450 enzymes
such as cimetidine

30. Induction-0.1 mg/kg
Maintenance-0.02 mg/kg
Sedation-0.25 mg repeated until sedated
Clinical use:-
 (a)IV induction of anesthesia,
 (b) IV sedation during regional anesthesia
 (c) use as an anticonvulsant
 (d) effective in limiting the incidence of
emergence reactions after administration of
ketamine

31.  Fatigue and drowsiness are the most common
side effects in patients treated chronically with
benzodiazepines.
 Decreased motor coordination and impairment of
cognitive function may occur, especially when
benzodiazepines are used in combination with
other CNS depressant drugs
 Acute administration of benzodiazepines
may produce transient anterograde amnesia
 Benzodiazepines may inhibit platelet-activating
factor induced aggregation resulting in drug-
induced inhibition of platelet aggregation

32.  Respiratory depression:-most commonly
assosiated with midazolam
 venous irritation and thrombophlebitis:-
-lorazepam and diazepam mainly
 Dependence:- Even therapeutic doses of
benzodiazepines may produce dependence as
evidenced by the onset of physical or
psychologic symptoms after the dosage is
decreased or the drug is discontinued
 Withdrawal symptoms (irritability,insomnia,
tremulousness)

33.  first benzodiazepine antagonist approved for
clinical use
 it is a competitive antagonist at the
benzodiazepine receptor
 Antagonism is reversible and surmountable
 Uses and Doses of Flumazenil
 Reversal of benzodiazepines 0.2 mg
repeated up to 3 mg
 Diagnosis in coma 0.5 mg repeated up to
1 mg

34.  term opioid refers broadly to all compounds
related to opium(Papaver somniferum )
 In 1806, Sertürner reported the isolation of a
pure substance in opium that he named
morphine after Morpheus, the Greek god of
dreams
 i/v used opioids are mainly –
 fentanyl,
 alfentanil,
 sufentanil,
 remifentanil

35. Receptor Clinical Effect
μ Supraspinal analgesia (μ 1 )
Respiratory depression (μ 2 )
Physical dependence
Muscle rigidity
κ Sedation
Spinal analgesia
δ Analgesia
Behavioral
Epileptogenic
σ Dysphoria
Hallucinations
Respiratory
stimulation

36.  All opioid receptors couple to G proteins;
binding of an agonist to an opioid receptor
causes membrane hyperpolarization
 Acute effects are mediated by inhibition of
adenyl cyclase (reductions in intracellular
cyclic adenosine monophosphate
concentrations) and activation of
phospholipase C
 Opioid receptor activation inhibits the
presynaptic release and postsynaptic
response to excitatory neurotransmitters (eg,
acetylcholine, substance P) from nociceptive
neurons

37.  Rapid and complete absorption
 After intravenous administration, the
distribution half-lives of all of the opioids are
fairly rapid (5–20 min).
 low molecular weight and high lipid solubility
of fentanyl also favor transdermal absorption
the transdermal fentanyl “patch”
 increased lipid solubility of fentanyl and
sufentanil, are associated with a faster onset
and shorter duration of action when
administered iv

38.  alfentanil has a more rapid onset of action
and shorter duration of action than fentanyl
(Sufentanyl-most potent)
 After smaller doses of the lipid- soluble
drugs (eg, fentanyl or sufentanil),
redistribution alone is the driver for reducing
blood concentrations, whereas after larger
doses biotransformation becomes an
important driver in reducing plasma levels
below those that have clinical effects.
 time required for fentanyl or sufentanil
concentrations to decrease by half is context
sensitive

39.  all opioids depend primarily on the liver for
biotransformation and are metabolized by the
cytochrome P (CYP) system
 Small V d of alfentanil contributes to a short
elimination half-life (1.5 h)
 End products of fentanyl, sufentanil, and
alfentanil are inactive
 Norfentanyl, the metabolite of fentanyl has
greatest importance in diagnosing fentanyl
abuse.
 ester structure of remifentanil makes it
susceptible to hydrolysis (in a manner similar
to esmolol) by nonspecific esterases in red
blood cells and tissue

40.  A. Cardiovascular:-
 Larger doses of fentanyl, sufentanil,
remifentanil,and alfentanil are associated with
a vagus nerve–mediated bradycardia
 sufentanil and fentanyl can be associated
with reduced cardiac output
 mild myocardial depression

41.  Opioids depress ventilation, particularly
respiratory rate
 Sequestration by stomach and reabsorbed opoids
may produce Biphasic resp. depression(Fentanyl
Most commonly)
 The apneic threshold—rises, and hypoxic drive is
decreased
 Rapid administration of larger doses of opioids
(particularly fentanyl, sufentanil,remifentanil, and
alfentanil) can induce chest wall rigidity(Wooden
chest syndrome) severe enough to prevent
adequate bag-and-mask ventilation effectively -
-treated with neuromuscular blocking agents
B. Respiratory:-

42.  High dose
 Sleep
 Old age
 Central nervous system depressant
 Inhaled anesthetics
 alcohol, barbiturates, benzodiazepines
 Renal insufficiency
 Hyperventilation,
 Respiratory acidosis

43.  opioids reduce cerebral oxygen consumption,
cerebral blood flow,cerebral blood volume,
 Stimulation of the medullary chemoreceptor
trigger zone is responsible for opioid-
induced nausea and vomiting
 Repeated dosing of opioids will reliably
produce tolerance, a phenomenon in which
larger doses are required to produce the
same response
 Prolonged dosing of opioids can also produce
“opioid-induced hyperalgesia”

44.  slow gastrointestinal motility by binding to
opioid receptors in the gut and reducing
peristalsis
 Biliary colic may result from opioid-induced
contraction of the sphincter of Oddi
 Patients receiving long-term opioid therapy
(eg, for cancer pain)doesn’t become tolerant
to constipation,so it lead to recent
development of the peripheral opioid
antagonists like methylnaltrexone and
alvimopan

45.  neuroendocrine stress response to surgical
stimulation is measured in terms of the
secretion of specific hormones, including
catecholamines, antidiuretic hormone, and
cortisol
 Large doses of opioids (typically fentanyl or
sufentanil) block the release of these
hormones in response to surgery
 F.Dependence-both physical &psychological
 G.Tolerance-mainly pharmacodynamic ,seen
with all actions except constipation & miosis

46.  Sufentanil- Intraoperative anesthesia
- 0.25–20 mcg/kg iv
 Alfentanil- Intraoperative anesthesia
Loading dose- 8–100 mcg/kg iv
Maintenance infusion- 0.5–3 mcg/kg/min iv
 Remifentanil- Intraoperative anesthesia
 Loading dose- 1.0 mcg/kg iv
 Maintenance infusion- 0.5–20 mcg/kg/min iv
 Postoperative analgesia/sedation- 0.05–0.3
mcg/kg/min i/v

47.  Fentanil-100 times more potent than
morphine
 Can be given
iv,i/m,transmucosal,epidural,intrathecally
 Cardiac stable
 Maximum biphasic respiratory depression
 Alfentanil-compared to fantanil quick onset
and short acting & assosiated with highest
incidence of muscle rigidity
 Sufentanil-most potent & opoid of choice for
inhibiting cardiovascular response to
laryngoscopy and intubations

48.  Metabolized by non specific esterase(pseudo
cholinesterase)
 Shortest acting so agent of choice for day
care surgery
 Opoid of choice for renal patients
 Causes significant hypotension
 Contains glycine so cann’t be used through
spinal/epidural because it can cause motor
weakness

49.  Most commonly, an opioid is combined with
another drug more likely to provide hypnosis
and amnesia
 combination of alfentanil and propofol produces
excellent TIVA, Alfentanil provides analgesia and
hemodynamic stability while blunting responses
to noxious stimuli, On the other hand, propofol
provides hypnosis and amnesia and is antiemetic
 Profound synergism also exists when more than
two agents, such as propofol-alfentanil-
midazolam, are combined
 TIVA techniques are especially useful when
delivery of inhaled agents is compromised

50. Loading Dose
(µg/kg)
Maintenance
Infusion Rate
Additional
Boluses
Alfentanil 25-100 0.5-
2 µg/kg/min
5-10 µg/kg
Sufentanil 0.25-2 0.5-
1.5 µg/kg/hr
2.5-10 µg
Fentanyl 4-20 2-10 µg/kg/hr 25-100 µg
Remifentanil 1-2 0.1-
1.0 µg/kg/min
0.1-1.0 µg/kg

51.  Premedication before alfentanil-propofol
anesthesia can prolong postoperative recovery
and should be avoided
 Induction of anesthesia with alfentanil (25 to
50 µg/kg) and propofol (0.5 to 1.5 mg/kg),
followed by infusions of alfentanil at 0.5 to
1.5 µg/kg/min and propofol at 80 to
120 µg/kg/min, will produce anesthesia in
patients ventilated with air and O2 with or
without N2O for a variety of procedures
 Maintenance infusions vary according to
patient condition and surgical stimuli
 optimal propofol concentration decreases in
the order of fentanyl > alfentanil > sufentanil
≫ remifentanil

52.  Drug infusions should be terminated 10 to 20
minutes before the end of anesthesia if N2O
is used,Otherwise, propofol infusions should
be terminated 5 to 10 minutes before
anticipated patient awakening. Alfentanil
infusion rates do not need to be less than
0.25 to 0.5 µg/kg/min until surgery is
terminated

53.  In patients undergoing ear-nose-throat
surgery
 children at risk for malignant hyperthermia
(in whom volatile agents are to be avoided)
 Patients undergoing brief radiologic or
painful procedures when rapid recovery is
needed (e.g., mri, bone marrow aspiration)
 Neurosurgical procedures to assist with
control of intracranial pressure and for
cerebral metabolic protection
 Other minor surgical procedures

54.  1959 De Castro and Mundeleer derived the
concept of Neuroleptanalgesia, which involved
the combination of a major tranquilizer (usually
the butyrophenone droperidol) and a potent
opioid analgesic (fentanyl) to produce a
detached, pain-free state of immobilization and
insensitivity to pain
 characterized by analgesia, absence of clinically
apparent motor activity, suppression of
autonomic reflexes, maintenance of
cardiovascular stability, and amnesia
 addition of an inhaled agent, usually N2O,
improves amnesia and has been called
Neuroleptanesthesia

55.  Butyrophenones cause sedation, tranquility,
immobility, antiemesis, an extrapyramidal
syndrome with face and neck dyskinesia,
oculogyric crises, torticollis, agitation, and
hallucinations so now a days it is rare used
 Neuroleptanalgesia or neuroleptanesthesia is
absolutely contraindicated in patients
receiving monoamine oxidase inhibitors
(MAOIs), in those who abuse drugs or
alchohol, or in patients with Parkinson's
disease.