Intravenous anaesthetic-hypnotic drugs Propofol Pentothal ...

25/11/2010
Intravenous anaesthetic-hypnotic drugs
Propofol
Pentothal
Etomidate
Midazolam
Diazepam
Ketamine
DHBP
Considerations For Anaesthetic Drug
Selection
• Predictable pharmacokinetic profile
– linear kinetics
– short t 1/2 k eO
– short context-sensitive half-time
– high clearance through non-organ
dependent metabolism
– inactive metabolites
• Predictable pharmacodynamic profile
– rapid onset
– predictable duration
– rapid recovery
– no drug interactions
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Intravenous drug delivery
• manual infusion techniques :
– bolus ( single or repeated)
– constant rate infusion.
– bolus + constant rate infusion.
• PK/PD based infusion techniques :
– open loop target controlled infusion
techniques
plasma target controlled delivery.
effect side target controlled delivery.
– closed loop infusion techniques
Titration of anaesthetic depth
(actual clinical practice)
Inhaled anaesthetics :
VAPOR (vol%) ---- Inspired conc. ----- Endtidal conc. ----- drug
effect
Intravenous anaesthetics :
( “MAC” on line)
Dose (mg/kg) --------????????? --------?????????? ------- drug
effect
(Cp50 and Cp95 not on line)
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Titration of anaesthetic depth
(actual clinical practice)
Inhaled anaesthetics :
VAPOR (vol%) ---- Inspired conc. ----- Endtidal conc. ----- drug
effect
Intravenous anaesthetics :
( “MAC” on line)
Dose (mg/kg) --------????????? --------?????????? ------- drug
effect
Need for calculated (estimated) concentrations
t 1/2 k e0 and time to peak effect
Drug t 1/2 k e0 (min) Time to peak effect
(min)
Propofol 2.4 1.6 - 2.2
Thiopental 1.5 1.7
Midazolam 4.0 2.8
Etomidate 1.5 2.0
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Pharmacology of iv. anaesthetic-hypnotics
CVS
Drug MAP HR CO SVR Venodilation
Thiopental - + - 0/+ +
Diazepam 0/- -/+ 0 -/+ +
Midazolam 0/- -/+ 0/- 0/- +
Etomidate 0 0 0 0 0
Ketamine ++ ++ + + 0
Propofol - + 0 - +
Drug depression of ventilation Airway resistance
Thiopental ++ 0
Diazepam + 0
Midazolam + 0
Etomidate + 0
Ketamine 0 --
Propofol ++ 0
CNS : all : CBF , ICP , CMRO 2
ketamine : CBF , ICP , CMRO 2
γ-aminobutyric acid
• a.k.a GABA
• Most widespread inhibitory neurotransmitter in
the CNS
• Three classes of receptors
• GABA A
» Ligand gated ion channel
» Cl - channel
» Site of action of benzodiazepines, barbiturates, and
propofol
» Not the site of action of inhaled anesthetics
• GABA B
» Slow inhibitory post-synaptic potentials, regulates K +
and Ca ++ conductance
» Not a binding site of anesthetic drugs
• GABA C
» Also a Cl - channel
» Not a binding site of anesthetic drugs
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GABA A Receptor
• Transmembrane
pentamer composed of 2
α, 2 β, and 1 γ or δ
subunits
• Each has a binding site for
GABA
• Benzodiazepines
• Bind a cleft of α and γ
subunits
• Increases frequency of
channel opening
• Barbiturates, (propofol)
• Bind α subunit
• Increase duration of
channel opening
• Agonist: muscimol
• Antagonist: bicuculine
Propofol / Characteristics (1)
1. 2,6-diisopropylphenol is used for induction and
maintenance of general anaesthesia.
2. It is prepared as a 1% or 2% isotonic oil-in-water
emulsion, which contains egg lecithin, glycerol,
and soybean oil.
3. Bacterial growth is inhibited by either ethylenediaminetetraacetic
acid or sulfite.
4. Mode of action: Increases activity at inhibitory
γ-aminobutyric acid (GABA) synapses.
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Propofol / Pharmacokinetics (1)
a. Elimination occurs primarily through hepatic metabolism
to inactive metabolites.
b. Context sensitive half-time (CSHT) of propofol is important.
CSHT is defined as the time for a 50% decrease in the
central compartment drug concentration after an infusion
of specified duration.
c. Induction doses rapidly produce unconsciousness
(app. 30 to 45 sec), followed by rapid reawakening due
to redistribution.
Propofol / Pharmacodynamics (1)
a. Central nervous system (CNS)
1. Induction doses produce unconsciousness,
whereas low doses produce
conscious sedation.
2. No analgesic properties.
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Propofol / Pharmacodynamics (2)
b. Cardiovascular system
1. A cardiovascular depressant.
2. Produces dose-dependent decreases in
arterial blood pressure and cardiac output.
3. Heart rate is minimally affected, and
barostatic reflex is blunted.
c. Respiratory system
1. Produces a dose-dependent decrease in
respiratory rate and tidal volume.
2. Ventilatory response to hypercarbia
is diminished.
Propofol / Administration (1)
a. Induction: 2.0 to 2.5 mg/kg g IV.
b. Sedation: 25 to 75 µg/kg/min by IV infusion is
often sufficient (titrate to effect).
c. Maintenance of general anesthesia:
100 to 150 µg/kg/min IV (titrate to effect).
d. Reduce dosages in elderly or hemodynamically
compromised patients or if
administered with other anesthetics.
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Propofol / Administration (2)
e. May be diluted, if necessary, only in 5%
dextrose in water to a minimum
concentration of 0.2%.
f. Propofol emulsion supports bacterial growth;
prepare drug under sterile conditions and
discard unused opened propofol after six
hours to prevent inadvertent bacterial
contamination.
Propofol / Other effects (1)
a. Venous irritation
1. May cause pain during IV administration
in as many as 50 to 75% of patients.
2. Pain may be reduced by prior
administration of opioids or the addition
of lidocaine to the solution; alternatively,
lidocaine (0.5 mg/kg) g) may be given IV
1 to 2 minutes before the propofol with a
tourniquet proximal to the IV site.
3. If possible, administer intravenously in
a large vein.
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Propofol / Other effects (2)
b. Postoperative nausea and vomiting occurs
less frequently after a propofol-based
anesthetic compared with other methods.
c. Lipid disorders
Propofol is a lipid emulsion and should be
used cautiously in patients with disorders of
lipid metabolism (e.g. hyperlipidemia, pancreatitis).
Benzodiazepines / Characteristics
1. For anesthetic use: midazolam, diazepam, lorazepam.
2. They are often used for sedation and amnesia
or as adjuncts to general anesthesia.
3. Mode of action: Bind at specific receptors in the CNS
and enhance the inhibitory tone of GABA receptors.
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Benzodiazepines / Pharmacokinetics
a. Metabolized in the liver.
b. Peak CNS effect occur 4 to 8 minutes after
an IV dose of diazepam, and its terminal halflife
is app. 20 hours. Repeated doses result
in accumulation and a prolonged effect.
Active metabolites of diazepam are longer
lasting than the parent drug.
c. Both midazolam and diazepam redistribute
rapidly and similarly after bolus injections.
d. Metabolism may be significantly slower in elderly
patients or those with hepatic disease.
Benzodiazepines / Pharmacodynamics (1)
a. Central nervous system (CNS)
1. Produce amnestic, anticonvulsant,
hypnotic, musclerelaxant, and sedative
effects in a dose-dependent manner.
2. Do not produce significant analgesia.
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Benzodiazepines / Pharmacodynamics (2)
b. Cardiovascular system
1. Produce a mild systemic vasodilation and
reduction in cardiac output. Heart rate is
usually unchanged.
2. Hemodynamic changes may be pronounced
in hypovolemic patients or in those with
little cardiovascular reserve, if rapidly
administered in a large dose, or if
administered with an opioid.
Benzodiazepines / Pharmacodynamics (3)
c. Respiratory system
1. Produce a mild dose-dependent decrease
in respiratory rate and tidal volume.
2. Respiratory depression may be
pronounced if administered with an
opioid, in patients with pulmonary disease,
or in debilitated patients.
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Benzodiazepines / Administration
a. Sedation (incremental doses)
1. Midazolam: 0.5 to 1.0 mg IV or
0.07-0.1mg/kg IM. Midazolam is the only
benzodiazepine that can be given reliably
by the intramuscular route.
2. Diazepam: 2.5 to 5.0 mg IV or orally.
3. Lorazepam: 0.5 to 2.0 mg IV or orally
4. Preoperative benzodiazepine
administration may lead to prolonged
sedation postoperatively.
Benzodiazepines / Adverse effects
a. Drug interactions
Administration of a benzodiazepine to a patient
receiving the anticonvulsant valproate may
precipitate a psychotic episode.
b. Pregnancy and labor
1. May be associated with birth defects
(cleft lip and palate) when administered
during the first trimester
2. Cross the placenta and may lead to a
depressed neonate.
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Flumazenil (1)
Flumazenil is a competitive antagonist t for
benzodiazepine receptors in the CNS.
a. Reversal of benzodiazepine-induced sedative
effects occurs within 2 minutes; peak effects at
app. 10 minutes.
b. Flumazenil is shorter acting than the
benzodiazepines it is used to antagonize.
Repeated administration may be necessary due to
its short duration of action.
Flumazenil (2)
c. Metabolized to inactive metabolites in the liver.
d. Dose: 0.3 mg IV every 30 to 60 seconds
(to a max. dose of 5 mg).
e. Flumazenil is contraindicated in patients with
tricyclic antidepressant overdose and patients
receiving benzodiazepines for control of seizures or
elevated intracranial pressure. Use cautiously in
patients who have had long-term treatment with
benzodiazepines because acute withdrawal may
be precipitated.
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Ketamine / Characteristics
1. An arylcyclohexylamine and a congener
of phencyclidine (PCP).
2. Ketamine is usually employed as an induction agent.
3. Mode of action: Not well defined but may include
antagonism at the N-methyl-D-aspartate receptor.
Ketamine / Pharmacokinetics
a. Metabolized in the liver to multiple metabolites,
some of which are active.
b. Produces unconsciousness in 30 to 60 sec after an
IV induction dose; unconsciousness may last 15 to
20 minutes. After IM administration, the onset of CNS
effects is delayed for app. 5 minutes, with peak effect
at app. 15 minutes.
c. Repeated bolus doses or an infusion results in
accumulation.
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Ketamine / Pharmacodynamics (1)
a. Central nervous system (CNS)
1. Produces a “dissociative” state
accompanied by amnesia and profound
analgesia.
2. Increases cerebral blood flow, metabolic
rate, and intracranial pressure.
Ketamine / Pharmacodynamics (2)
b. Cardiovascular system
1. Increases heart rate and systemic and pulmonary
artery blood pressure by causing release of
endogenous catecholamines.
2. Often used for induction of general anesthesia in
hemodynamically compromised patients.
3. May act as a myocardial depressant if
administered in the presence of hypovolemia,
autonomic nervous system blockade, or maximal
sympathetic nervous system stimulation.
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Ketamine / Pharmacodynamics (3)
c. Respiratory system
1. Mildly depresses respiratory rate and tidal volume.
2. Minimal effect on responsiveness to hypercarbia.
3. Laryngeal protective reflexes tend to be
maintained longer than with other intravenous
anesthetics.
4. Alleviates bronchospasm by a sympathomimetic
effect.
Ketamine / Administration
a. It may be especially useful for IM induction in
patients in whom IV access is not available
(e.g. children). Ketamine is water soluble and may be
administered either IV or IM.
b. Induction dosages are 1 to 2 mg/kg IV or 5 to
10 mg/kg IM (a concentrated 10% solution is available
for IM use only).
c. IV sedative doses may be significantly lower
(e.g. 0.2 mg/kg) and should be titrated to the desired
effect.
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Ketamine / Side effects (1)
a. Oral secretions are markedly stimulated by ketamine.
Coadministration of an antisialogogue
(e.g. glycopyrrolate) may be helpful.
b. Muscle tone. May lead to random myoclonic
movements, especially in response to stimulation.
Muscle tone is often increased.
c. Increases intracranial pressure and is relatively
contraindicated in patients with head trauma or
intracranial hypertension.
Ketamine / Side effects (2)
d. Eye movements. May lead to nystagmus, diplopia,
i
blepharospasm, and increased intraocular pressure:
alternatives should be considered during
ophthalmologic surgery.
e. Anesthetic depth may be difficult to assess.
Common signs of anesthetic depth
(e.g. respiratory rate, blood pressure, heart rate,
eye signs) are less reliable when ketamine is used.
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Ketamine / Side effects (3)
Emotional disturbance
1. Administration of ketamine may occasionally result
in restlessness and agitation during emergence;
hallucinations and unpleasant dreams may occur
postoperatively.
2. Patient characteristics associated with adverse effects
include increased age, female gender, and dosages
greater than 2 mg/kg.
Ketamine / Side effects (4)
3. The incidence (up to 30%) of these untoward
sequelae may be greatly reduced with
coadministration of a benzodiazepine (e.g. midazolam)
or propofol.
4. Children seem to be less troubled by the
hallucinations than adults. Alternatives to ketamine
should be considered in patients with psychiatric
disorders.
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Etomidate / Characteristics
1. It is an imidazole-containing hypnotic unrelated to
other anesthetics.
2. It is most commonly used as an IV induction agent
for general anesthesia.
3. Mode of action: Augments the inhibitory tone of
GABA in the CNS.
Etomidate / Pharmacokinetics
a. Metabolized in the liver and by circulating
esterases to inactive metabolites.
b. Times to loss of consciousness and
awakening after a sleep dose are similar to
those of propofol.
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Etomidate / Pharmacodynamics (1)
a. Central nervous system (CNS)
1. Does not possess analgesic properties.
2. Cerebral blood flow and metabolism decrease
in a dose-dependent manner.
b. Cardiovascular system
Produces minimal changes in heart rate, blood
pressure, and cardiac output; accordingly,
etomidate may be a preferred agent for induction
of general anesthesia in a hemodynamically
compromised patient.
Etomidate / Pharmacodynamics (2)
c. Respiratory system
Produces a dose-dependent decrease in
respiratory rate and tidal volume; transient apnea
may occur. The respiratory depressant effects of
etomidate appear to be less than those of propofol
or the barbiturates.
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Etomidate / Administration
Available as a solution in propylene glycol.
l
An IV induction dose is 0.3 mg/kg.
Etomidate / Side effects
a. Myoclonus may occur after administration,
particularly in response to stimulation.
b. Nausea and vomiting occur more frequently in the
postoperative period than with other anesthetic agents.
c. Venous irritation may be minimized by administration
into a free-flowing IV carrier infusion.
d. Adrenal suppression
Suppresses adrenal steroid synthesis for up to 24
hours (probably an effect of little clinical significance).
Repeated doses or infusions are not recommended
because of the risk of significant adrenal suppression.
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Barbiturates / Characteristics
1. For anesthetic use: thiopental, methohexital.
2. These medications, like propofol, rapidly
produce unconsciousness (app. 30 to 45 sec)
followed by rapid reawakening due to
redistribution.
3. Barbiturates are very alkaline (pH>10) and
are usually prepared as dilute solutions
(1.0 to 2.5%) for IV administration.
i ti
4. Mode of action
Barbiturates occupy receptors adjacent to
GABA receptors in the CNS and augment the
inhibitory tone of GABA.
Barbiturates / Pharmacokinetics
a. Metabolism to inactive metabolites occurs in the liver.
b. Produce unconsciousness in one arm-tobrain
circulation time (app. 30 sec).
c. Recovery from an induction dose occurs
quickly (app. 5 to 10 minutes) as a result of
high lipid solubility and rapid redistribution
into muscle and organs with high blood flow.
d. Multiple doses or a prolonged infusion may
produce prolonged sedation or unconsciousness.
The CSHT of these drugs are long,
even after short infusions.
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Barbiturates / Pharmacodynamics (1)
a. Central nervous system (CNS)
1. Produce unconsciousness but cause
hyperalgesia in subhypnotic doses.
2. Produce a dose-dependent decrease in
cerebral metabolism and blood flow and,
at high doses, may produce an isoelectric
electroencephalogram.
Barbiturates / Pharmacodynamics (2)
b. Cardiovascular system
1. Decrease arterial blood pressure and
cardiac output in a dose-dependent
manner.
2. May increase heart rate via baroceptor
reflexes.
c. Respiratory system
Produce a dose-dependent decrease
in respiratory rate and tidal volume.
Apnea may result for 30 to 90 sec after
a sleep dose.
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Barbiturates / Administration
a. Thiopental and thiamylal: 3 to 5 mg/kg IV.
b. Methohexital: 1 to 2 mg/kg IV or
25 to 30 mg/kg per rectum
c. Reduce doses in sick, elderly, or
hypovolemic patients.
Barbiturates / Side effects (1)
a. Allergy
Do not administer to patients with history of
allergy to any barbiturate. bit t Anaphylactic and
anaphylactoid reactions occur rarely.
b. Porphyria
1. Absolutely contraindicated in patients with
acute intermittent porphyria, variegate
porphyria, and hereditary coproporphyria.
2. Barbiturates induce the enzyme δ-aminolevulinic
acid synthetase, the rate-limiting
step in porphyrin synthesis, and may
precipitate an acute attack.
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Barbiturates / Side effects (2)
c. Venous irritation and tissue damage
1. May cause pain at the site of administration
because of venous irritation.
2. Infiltration of intraarterial administration of a
barbiturate may cause severe pain, tissue
damage, and necrosis due to its high alkalinity.
If intraarterial administration occurs,
heparinization and regional sympathetic blockade
may be helpful in treatment.
d. Myoclonus and hiccoughing are often associated
with the administration of methohexital.
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