Download General Anesthetics

General Anesthetics
• Agents are used to produce unconsciousness
and loss of perception to painful surgical
procedures.
• Physiologic state induced by general anesthetics
include: analgesia, amnesia, loss of
consciousness, inhibition of sensory and
autonomic reflexes, skeletal muscle relaxation.
• An ideal anesthetic would induce a smooth and
rapid loss of consciousness while allowing for
prompt recovery after discontinuation of
administration.
General Anesthetics
• An ideal anesthetic would
– induce a smooth and rapid loss of
consciousness while allowing for prompt
recovery after discontinuation of
administration.
– Possess a wide margin of safety and be free
of adverse effects
General Anesthetics
• No agent alone has the ideal properties
• Most commonly the drugs are used in
combination of i.v. and inhalation
General Anesthetics
Intravenous Anesthetics
used alone or in combination with other
anesthetic and analgesics
General Anesthetics
• I.V. anesthetics
– Barbiturates
– The sodium salts of the ultra-short-acting barbiturates
may be administered in aqueous solutions to induce
anesthesia
– Unconsciousness is produced within seconds of
injection
– Duration of action is about 30 minutes
General Anesthetics
• I.V. anesthetics
– Barbiturates
Ultra-Short-Acting Barbiturates Used to Produce General Anesthesia
O
R5
6
5
4
R'5
O
3
1N
General Structure
2
N
Generic Name
Proprietary Name
R1
R2 Na
R5
R'5
R1
R2
CH3
O
H
S
H
S
CH3
Methohexital Sodium H2C
Brevital Sodium
C
H
CH2 -
CH3CH2C
C
CHCH3
Thiamylal Sodium
Surital Sodium
H2C
C
H
CH2 -
CH3CH2CH2 -CHCH3
Thiopental Sodium
Pentothal Sodium
CH3CH2-
CH3CH2CH2 -CH-
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….Intravenous Anesthetics
This intravenous group include the Na salts of ultra-short acting
barbiturates (~30 min duration); administered IV in aqueous solution
Administered with maintaining inhalation anesthesia
Methohexital Sodium (Brevital Sodium)
N-methyl barbiturate: 1-Methyl-5-allyl-5-(1-methyl-2-pentynyl)
barbiturate
pKa of 8.4 compared to pKa of ~7.6 for non-N-methylated cpds.
Therefore higher amounts of lipid-soluble free acid form that easily
penetrates the BBB. It has an accessible site for metabolic
inactivation: hydroxylation at the CH2 a to the triple bond.
Thiopental Sodium (Pentothal Sodium): 5-Ethyl-5-(1-methylbutyl)-2thiobarbiturate
Most widely used ultra-short acting anesthetic barbiturate.
A prototype for ultra-short acting barbiturates; a standard for
studying effects of structure on duration of action. Fast onset of
action, the time it takes to reach the CNS. Consciousness is gained in
about 30 minutes.
…General Anesthetics (Benzodiazepines)
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Benzodiazepines: Tend to bind to benzodiazepine recognition site that modulate the GABA binding to
GABAA (a receptor which is a ligand- gated chloride ion channel)
SAR: An electroneg. atom at position 7 is required for activity. No sub. in positions 6, 8 and 9. A
phenyl at position 5 promotes activity. If the phenyl has ortho (2’) or diortho (2’,6’) electron attracting
sub., activity is increased, para sub. decreases activity. Saturation of the 4,5 double bond or a shift of
it to the 3,4 position decreases actvity. Alkyl subs. At the 3-position decrease actiity. The 3-OH are
much more polar and are converted to the excreted glucoronide. Those without 3-OH, have longer half
lives and undergo hepatic oxidation.
Diazepam: Non polar and is rapidly absorbed (has high lipid/water partition coefficient; therefore very
long acting). Known metabolism to oxazepam as shown below. Used for anxiety states,
anticonvulsant and pre-medication in anesthesia.
CH3
O
9
N
1
8
8
2
O
H
N
1
9
3
Cl
4
N
5
7
6
8
2
O
H
N
1
9
2
3
Cl
4
N
5
7
6
1'
3
Cl
4
N
5
7
6
1'
1'
6'
2'
6'
2'
6'
2'
5'
3'
5'
3'
5'
3'
4'
Diazepam
(Valium)
4'
Nordazepam
4'
Oxazepam
(Serax)
OH
…General Anesthetics (Benzodiazepines)
Midazolam (Versed) a benzodiazepine that is CNS depressant; used IV to induce
anesthesia. Midazolam has lower lipid/water partition coefficient and an improved
pharmacokinetic properties.
Lorazepam (generic, Ativan) – almost insoluble in water. Is also a CNS depressant,
highly addictive
H3C
9
N
N
1
8
2
3
Cl
4
N
5
7
6
1'
F
6'
5'
3'
4'
Midazolam
(Versed)
Lorazepam
…General Anesthetics (Phenols, Ketones)
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Ketamine. HCl, USP (Ketalar): It is a 2-(o-chlorophenyl)-2-methylaminocyclohexanone, a structural
relative of phencylidine (PCP); different mechanism than other anesthetics; blocks glutamic acid Nmethyl-D-aspartate (NMDA) receptors. Causes dissociation from events being experienced followed
by anesthesia, analgesia and sometimes amnesia. Incidence of hallucinations is lower than PCP.
Cl
Ketamine HCl
NHCH3 . HCl
O
H
N Cl
Phencyclidine HCl
…General Anesthetics (Phenols)
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Fosprofofol (Lusedra) – sedative/analgesic. Metabolized to Propofol in the liver by phosphatases.
Water soluble.
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Propofol (Diprivan): Phenols are generally toxic (tissue destruction) but the 2,6-isopropyl groups of
propofol mitigate the effect.
Insoluble in water. Thus, given IV as an emulsion.
Rapid BBB penetration and distribution as a product with high lipid-water partition coefficient. Used
for induction and maintenance of anesthesia.
Binds allosterically to GABAA receptors at non-benzodiazepine sites.
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OH
Propofol (Diprivan)
Fospropofol (Lusedra)
…General Anesthetics
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Etomidate (Amidate) Etomidate is a base. Thus, water-soluble salts are used for IV
administration. A 4-carboxylic acid ester-substituted imidazole moiety and is related to
the imidazolo benzodiazepines. It is a positive allosteric modulator of GABAA
receptors. Has a depression of steroidogenesis as a side effect.
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Dexmedetomidine - is the S-enantiomer of medetomidine
and has a pKa of 7.1
Both drugs are also sedative-hypnotics
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N
N
H
.
It is freely soluble in water
O
C OC2H5
Etomidate (Amidate)
H3C
Dexmedetomidine (Precedex)
General Anesthetics
• Droperidol (Inapsine)
– Reducing nausea and vomiting during surgeries and diagnostic procedures.
– Inapsine is a tranquilizer. It is unknown exactly how Inapsine works.
– Infrequent but possibly fatal heart problems have occurred with Inapsine when
used at or even below recommended doses
Inhaled Anesthetics
• Volatile liquids
• Nitrous oxide is an important adjuvant
• Most commonly used agents are:
isoflurane, desflurane and sevoflurane
• Other agents are also used
…Inhalation Anesthetics
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Nitrous oxide: N2O, Nitrogen Monoxide,
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Is a gas at room temperature, but a liquid under pressure when supplied. Good analgesic at lower
conc. from depressant effect on synaptic transmission of pain messages (possible effect on opioid
receptors). Required to be 80% in inspired air to achieve anesthesia; (care for dangers of possible
hypoxia).
Given with other anesthetics.
It is a positive modulator of GABA on GABAA receptors for its anesthetic action.
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N
N
O
General Anesthetic Agents
• Inhalation Anesthetics:
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Halothane: CH(Br)Cl-CF3
Volatile (B.P. of 500 C), Nonflammable, Highly potent with low blood/gas partitioning,
Mostly is excreted unmetabolized
High electronegativity of F makes –CF3 group stable.
Methoxyflurane (Penthrane): CHCl2CF2-O-CH3
Volatile liquid (B.P. 1050 C), it does not have a high vapor pressure, so conc. Of the
inspired air is low. The compound is very soluble in lipids; thus, recovery is slow.
Large blood/gas partition coefficient (slow induction of anesthesia). Produces
excellent anesthesia and good muscle relaxation.
70% metabolized to form: Dichloroacetic acid, Difluoromethoxyacetic acid, Oxalic acid
and Fluoride
Fluoride and oxalic acid cause renal damage due to prolonged use.
Cl
Br
F
C
C
F
H
F
Halothane
(2-Bromo -2-chloro -1,1,1-trifluroethane)
H
Cl
F
C
C
Cl
F
H
O
C
H
H
Methoxyflurane
(2,2-Dichloro -1,1-difluoro
ethyl methyl ether)
…Inhalation Anesthetics
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Enflurane (Ethrane): HF2COCF2CHFCl, Volatile liquid;
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Depresses respiration, therefore mechanical ventilation and O2 supplementation.Tonic-clonic
convulsive side effect (not recommended for patients with epileptic foci).
5% of drug metabolized to F- & difluoromethoxydifluoroacetic acid.
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Isoflurane (Forane): F3CC(H)ClOCF3
Structurally and functionally related to enflurane except:
Lack of electroencephalogram and tonic-clonic activity.
Only 0.2% is metabolized to F- and trifluoroacetic acid.
Desflurane (Suprane): FC(H2)-O-C(H)F-C(H)F2
Sevoflurane: FC(H2)-O-CH(CH3)2: Rapidly taken up and rapidly eliminated
F
F
Cl
C
C
F
O
C
F
H
Isoflurane
F
H
(1-chloro -2,2,2-trifluoro
ethyl difluoromethyl ether)
H
Cl
F
C
C
F
O
C
F
F
Enflurane
F
H
(2-chloro -1,1,2-trifluoro
ethyl difluoromethyl ether)
F
F
F
H
C
C
F
F
F
O
Desflurane
C
F
H
F
C
F
F
H
C
O
C
F
C
F
H
H
F Sevoflurane