PHA051 LAS#10

RATIONALE
A. Structure–Activity Relationships of the
Volatile General Anesthetics
ALKANE/ CYCLOALKANE
The potency of alkanes, cycloalkanes, and aromatic hydrocarbons increases
in direct proportion to the number of carbon atoms in the structure up to a
cutoff point.
Within the n-alkane series, the cutoff number is 10, with n-decane showing
minimal anesthetic potency.
In the cycloalkane series, the cutoff number in most studies is eight with
cyclooctane showing no anesthetic activity in the rat.
The reduced activity of the compounds beyond their cutoff number could be
a result of problems getting to the site of action (reduced vapor pressure or
high blood solubility) or inability to bind to the site of action and induce the
conformational change required for anesthetic action.
ALKANOL
A similar increase in potency with increase in carbon length was
seen in the n-alkanol series. In addition, the n-alkanol with a given
number of carbons is more potent than the n- alkane with the
same chain length.
EFFECT OF HALOGENATION/ETHER HALOGENATION
The first inhaled anesthetics used in the late 1800s, diethyl
ether and cyclopropane caused laryngospasms. These compounds
were also explosive and flammable requiring careful handling. Early
studies found that halogenating the ethers decreased the
flammability of the compounds, enhanced their stability and
increased their potency. Higher atomic mass halogens increased
potency compared to lower atomic mass halogens
• For example, replacing the fluorine in desflurane (CF2HOCFHCF3)
with a chlorine to form isoflurane (CF2HOCClHCF3) increased
potency more than fourfold. Replacing the chlorine with bromine
in the investigational agent I-537 (CF2HOCBrHCF3) increased
potency threefold further.
• In general, halogenated ether compounds also caused less
laryngospasms than unhalogenated compounds.
• Unfortunately, halogenation also increased the propensity of the
drugs to cause cardiac arrhythmias and/or convulsions.
• Halogenated methyl ethyl ethers were found to be more stable
and potent than halogenated diethyl ethers.
• The commonly used inhaled anesthetics are ethers or aliphatic
hydrocarbons with 2 to 5 carbon atoms.
EFFECT OF SATURATION
Molecular flexibility of the inhaled anesthetics
is not required. The addition of double and/or
triple bonds to small anesthetic molecules
having 6 carbon atoms or less increases
potency
B. SAR of the injectable general
anesthetics
2. Describe the structure of each of
the ff. injectable general
anesthetics:
a. Propofol
Propofol is an injectable
sedative–hypnotic used for the induction
and maintenance of anesthesia or
sedation. Propofol is only slightly soluble
in water with an octanol/water partition
coefficient of 6,761:1; thus, it is
formulated as an oil-in water emulsion.
b. Etomidate
Etomidate is a
carboxylated imidazole
intended for the
induction of general
anesthesia. It is
marketed as the more
potent R (+) isomer.
c. Ketamine
• Ketamine is formulated as an acidic
solution, pH 3.5 to 5.5, available with or
without 0.1 mg/mL benzethonium
chloride preservative.
• Ketamine is marketed as the racemic
mixture and some properties of the
individual isomers have been elucidated.
• Ketamine is a rapid-acting agent that can
be used for induction, used as the sole
agent for general anesthesia or combined
with other agents
 3. Explain the mechanism of Action of General
Anesthetics:
• The general anesthetics inhibit CNS neuronal activity. But their
precise mechanism of neuronal inhibition is not clear. Several
mechanisms were proposed to explain general anesthesia. They are:
(i) Lipid Theory. According to this theory the more lipid soluble
general anesthetics concentrate in hydrophobic regions of neuronal
cell membrane and causes swelling of these membranes.
Due to this swelling of structure of membrane alters, thereby blocks
the Na+ channels. Thus the generation of action potential is inhibited
and produces anesthesia. In 1901, Meyer and Overton correlated the
potency of general anesthetics with their lipid solubility. The higher
the value of partition coefficient of the compound, more will be its
general anesthetic potency
(ii) Protein Theory. According to this theory
the anesthetic bind to the hydrophobic sites of
protein molecules of neuronal cell membrane,
thus the membrane function is altered and
produces anesthesia.
4. Explain the mechanism of action of
Local anesthetics
• The mechanism of action of the local anesthetics is
believed to be via their sodium channel blocking effects.
• The local anesthetic drug binds to the channel in an
area just beyond the selectivity filter or P region
• When the local anesthetic binds, it blocks sodium ion
passage into the cell and thus blocks the formation and
propagation of the action potential.
• This blocks the transmittance of the message of “pain”
or even “touch” from getting to the brain.
5. Discuss the SAR of local
anesthetics:
A. The Aromatic Ring
The aromatic ring adds lipophilicity to the
anesthetic and helps the molecule penetrate
through biological membranes. It is also
thought to have direct contact with the local
anesthetic binding site on the sodium channel.
• Substituents on the aromatic ring may increase the
lipophilic nature of the aromatic ring.
• SAR study of para substituted ester type local
anesthetics showed that lipophilic substituents and
electron-donating substituents in the para position
increased anesthetic activity.
• The lipophilic substituents are thought to both
increase the ability of the molecule to penetrate the
nerve membrane and increase their affinity at the
receptor site
B. The Linker
• The linker is usually an ester or an amide group along
with a hydrophobic chain of various lengths. In general,
when the number of carbon atoms in the linker is
increased, the lipid solubility, protein binding, duration of
action, and toxicity increases
• Esters and amides are bioisosteres having similar sizes,
shapes, and electronic structures. The similarity in their
structures means that esters and amides have similar
binding properties and usually differ only in their stability
in vivo and in vitro.
C. The Nitrogen

•Most local anesthetics contain a tertiary

nitrogen with a pKa between 7.5 and 9.5.
•Therefore, at physiological pH, both the
cationic and neutral form of the
molecule exists
6. What are the vasoconstrictors which may
be used in combination with local
anesthetics?
• Many anesthetic preparations are commercially
available combined with the vasoconstrictor
epinephrine. Some anesthetics are also
combined with other agents such as
norepinephrine, phenylephrine, oxymetolazone,
or clonidine to achieve a desired formulation
7. What are the advantages of epinephrine
given in combination with local anesthetics?
The epinephrine in the anesthetic solution has multiple purposes:
• As a vasoconstrictor, the injected epinephrine will constrict
capillaries at the injection site and thus limit blood flow to the
area. The local anesthetic will thus stay in the immediate area of
injection longer and not be carried away to the general
circulation.
• This will help keep the drug where it is needed and allow minimal
drug to be absorbed systemically.This will reduce the systemic
toxicity from the anesthetic and increase the duration of
anesthetic activity at the site of injection.
8. Enumerate the Ester local anesthetics and
describe their chemical structures.
• Ester anesthetics are metabolized in the plasma by the
enzyme pseudocholinesterase. Procaine undergoes
hydrolysis to para-aminobenzoic acid (PABA), which is
excreted unchanged in the urine, and diethylamino
alcohol, which undergoes further transformation prior to
excretion.
• Approximately 1 in 3000 persons has an a typical form of
pseudocholinesterase, resulting in the inability to
hydrolyze the ester-type local anesthetics. This in turn
may cause a prolongation of high blood levels of the
agent and increased toxicity.
9. Enumerate the Amino amide local
anesthetics and describe their chemical
structures.
• Amide anesthetics are metabolized in a more complex fashion
in the liver.
• The status of the liver function is therefore significant. In a
patient with a healthy liver, about 70% of the drug undergoes
biotransformation.
• Patients with compromised liver function are unable to break
down amide-type anesthetics at a normal rate, which leads to
slower biotransformation and increased levels of local
anesthetic in the blood as well as increased potential for
toxicity.
10. What causes the allergic reactions to local
anesthetics?

• Allergic reactions that occur in response to

ester anesthetics are usually not in response
to the parent compound but rather to the
para aminobenzoic acid (PABA), which is a
major metabolic product of all ester-type
local anesthetics.
• True allergy to an amide local anesthetic is exceedingly
rare, whereas the ester procaine is somewhat more
allergenic.
• Allergy to one ester rules out use of another ester,
because the allergenic component is the metabolite
para-aminobenzoic acid, produced by all esters. In
contrast, allergy to one amide does not rule out the use
of another amide.
• A patient may be allergic to other compounds in the
local anesthetic, such as preservatives in multidose vials.