GENERAL ANESTHETICS

Dr Saba Razzak
M.Phil. Pharmaceutical Chemistry
 INTRODUCTION
• General anesthetics are group of drugs that Goals of General
produce loss of consciousness, and therefore, loss of Anesthetics
all sensations.
• The absolute loss of sensation is termed as To produce analgesia
anesthesia.
• General anesthetics bring about the descending Skeletal muscle
relaxation
depression of the central nervous system (CNS),
starting with the cerebral cortex, the basal ganglia,
Loss of reflex
the cerebellum, and finally the spinal cord.
• These drugs are used in surgical operations to induce Loss of consciousness
unconsciousness and, therefore, abolish the
sensation of pain.
 INTRODUCTION
• Horace Wills, a dentist, in 1844 successfully used N2O as an anesthetic for tooth
extraction.
• Mortan, a dentist, demonstrated ether as an anesthetic agent and it became popular.
• In 1847, chloroform was used by Simpson in Britain for obstetrical purposes.
• The first intravenous anesthetic, thiopentone, was introduced in 1935.
• In 1901, Mayer and Overton pointed out a direct parallelism between the lipid/water
partition coefficient of general anesthetics and their anesthetic property known as
minimal alveolar concentration (MAC).
• MAC is the lowest concentration of an inhalational anesthetic in pulmonary alveoli that is
needed to produce immobility in response to a painful stimulus in 50% of the individuals.
➤MAC is the ED 50 of the anesthetic.
➤the inverse of MAC is an index of the potency of the anesthetic(The lower the MAC
value, the more potent the anesthetic.).
• MAC of several general anesthetics shows excellent correlation with their oil/gas partition
coefficients. However, this only reflects the capacity of anesthetics to enter the CNS and
attain sufficient concentration in the neuronal membrane.
 STAGES OF ANAESTHESIA
• Stage I (analgesia): The patient is conscious and experiences sensations of warmth,
remoteness, drifting, falling, and giddiness.
• There is a marked reduction in the perception of painful stimuli.
• This stage is often used in minor surgery.
• Stage II (delirium): This stage begins with the loss of consciousness.
• Depression of higher centres produces variety of effects including excitement,
involuntary activity, and increased skeletal muscle tone, and respiration is typically
irregular.
• Stage III (surgical anesthesia): This is the stage of unconsciousness and paralysis of
reflexes, respiration is regular and blood pressure is maintained.
• All surgical procedures are carried out in this stage.
• Stage IV (medullary paralysis): Respiratory and circulatory failures take place as a
result of the depression of the vital centers of the medulla, and brain stem.
 TARGET FOR ANESTHETIC DRUGS
• The basic molecular targets show that the ligand-gated ion channels are the
major target of anesthetic action.
• Many inhalation anesthetics, such as barbiturates, benzodiazepines, and
propofol potentiate the action of inhibitory transmitter GABA to open
chloride channels.
• The action of glycine transmitter, which also activates chloride channels in
the spinal cord and medulla, is augmented by barbiturates, propofol, and
many other inhalation anesthetics.
• N2O and ketamine do not act on GABA or glycine, but they selectively
inhibit the excitatory N-methyl D-aspartate(NMDA) type of glutamate
receptor, which belongs to calcium-gated channels in the neurons and
leads to neuronal hyper-polarization.
 TYPES OF GENERAL ANESTHETICS
• Usually given through inhalation or by intravenous injection.

Inhalation anesthetics: Intravenous anesthetics:

Nitrous oxide, a gas at ambient
temperature and pressure, continues to
be an important compound of many
anesthesia regimens.
Halothane, enflurane, isoflurone,
desflurane, sevaflurane, and
methoxyflurane are volatile liquids.
Several drugs are used intravenously, alone, or in
combination with other drugs to achieve an
anesthetic state for minute surgery of the patients
in the intensive care unit.
These drugs include the following:
Barbiturates (thiopental, methohexital)
Benzodiazepines (midazolam, diazepam)
Opioid analgesics (morphine, fentanyl, sulfentanyl,
alfentanil, remifentanil)
Miscellaneous:
Propofol
Ketamine
droperidol, etomidate, dexmedetomide
 SAR OF GENERAL ANESTHETICS
✓ Volatile General Anesthetics
The inhalation anesthetics in use today are nitrous oxide, halothane, isoflurane,
desflurane, and sevoflurane.
While it is true that there is no single pharmacophore for inhaled anesthetics, the
chemical structure is related to the activity of the drug molecule.
Meyer and Overton conducted the first SAR studies in the 1880s, showing a positive
correlation between anesthetic potency and solubility in olive oil.
• They proposed that the potency of an anesthetic is directly linked to its lipid
solubility, specifically its oil: gas partition coefficient.
• They conducted experiments using substances like olive oil and octanol to measure
the lipid solubility of various anesthetic agents available at the time.
• Their findings suggested that compounds with higher lipid solubility required lower
concentrations to produce anesthesia, as indicated by a lower minimum alveolar
concentration (MAC). They hypothesized that these anesthetic molecules
interacted with a hydrophobic portion of the cell membrane, distorting sodium ion
channels responsible for neuronal firing.
 CONT.
✓ ALKANE/CYCLOALKANE
• Compounds like alkanes, cycloalkanes, and aromatic hydrocarbons demonstrate
increased potency with the number of carbon atoms, up to a certain cutoff point.
• For n-alkanes, the cutoff number is around 10, beyond which minimal anesthetic
potency is observed.
• In cycloalkanes, this cutoff is usually around eight, with cyclooctane showing no
activity.
• Compounds beyond their cutoff number may have difficulty reaching the site of
action due to reduced vapor pressure or high blood solubility. They may also
struggle to bind to the site of action and induce the necessary conformational
changes.
• Cycloalkanes tend to be more potent anesthetics compared to straight-chain
analogs with the same number of carbons. For example, the MAC of cyclopropane
in rats is about one-fifth of the MAC of n-propane.
 CONT.
✓ALKANOL SERIES
• A similar increase in potency with an 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 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.
 CONT.
✓ 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.
• 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.
 VOLATILE/INHALATION
ANESTHETICS
• 1. Ether (Diethyl ether)
Properties and uses:
It is a clear, colorless liquid, volatile, highly flammable, soluble in
water, miscible with alcohol, methylene chloride, and fatty oils.
Low molecular weight ethers display anesthetic activity that increases
along with toxicity as the chain length increases.
The introduction of unsaturation into the aliphatic ether increases
potency and also shortens induction and emergence.
Ether is an absolute anesthetic with a pungent, irritant odor.
It is flammable and explosive at concentrations necessary for
anesthesia.
Storage: It should be stored in well-closed airtight containers and
protected from light, stored at a temperature of 8°C–15°C.
 CONT.
• 2. Trichloro Ethylene
Properties and uses:
It may be used sporadically as a weak volatile anesthetic,
administered through inhalation.
It possesses an excellent analgesic property.
It is frequently employed in short surgical operations, where
mild anesthesia having potent analgesia is desired.
• 3. Halothane CONT.
•
Halothane, a halogenated volatile liquid introduced
in 1956, is primarily used as an inhalational anesthetic
in clinical settings.
Its metabolism yields three major metabolites:
1. trifluoroacetic acid,
2. N-trifluoro acetyl ethanolamine, and
3. N-acetyl-s-(2-bromo,2 chloro-1,1-difluoro ethyl)-1-
cysteine.
• One significant metabolite is trifluoroacetyl chloride,
an electrophilic compound capable of forming
covalent bonds with proteins.
• This reaction can trigger immune responses and
contribute to the development of halothane
hepatitis upon subsequent exposure to halothane.
• Properties and uses:
✓ Nonflammable,
✓ nonpungent, and volatile, with a boiling point of
approximately 50°C.
• Halothane may increase heart rate, cause cardiac
arrhythmias, increase cerebral blood flow, and
increase intracranial pressure
 CONT.
• Halothane can undergo spontaneous oxidation when exposed to ultraviolet light to yield
HCl, HBr, Cl_, Br_, and phosgene (COCl2).
• To prevent oxidation, it is packaged in amber bottles with a low concentration of thymol
(0.01%) as a stabilizer.
• Being a nonirritant, its inherent hypotensive effect retards capillary bleeding and renders
a comparatively bloodless field.
• It is a potent, relatively safe general inhalation anesthetic used in conjunction with N2O.
• For skeletal muscle relaxation, it is used with succinylcholine or tubocurarine.
• The use of inhaled anesthetics and halothane in particular can produce malignant
hyperthermia (MH) in genetically susceptible individuals.
• This results in an increase in body temperature, tachycardia, tachypnea, acidosis, and
rhabdomyolysis.
• Storage: It should be stored in well-closed airtight containers, protected from light, at a
temperature not exceeding 25°C in a nonreactive metal container.
4. Nitrous oxide (N2O)
CONT.
Properties and uses:
• Nitrous oxide is a gas at room temperature
and is supplied as a liquid under pressure in
metal cylinders.
• Nitrous oxide is a “dissociative anesthetic” and
causes slight euphoria and hallucinations.
• It is a colorless gas, without appreciable odor
to taste, soluble in water, freely soluble in
alcohol, soluble in ether, or oils.
• This is the least toxic and least potent
anesthetic.
• It is a noninflammable, nonirritating, and
powerful analgesic agent.
• Nitrous oxide is a weak anesthetic with good
analgesic properties and relatively no skeletal
muscle relaxant properties.
• Nitrous oxide is a popular anesthetic in
dentistry where it is commonly referred to as
“laughing gas.
• 5. KETAMINE
CONT.
• Ketamine is available as an acidic solution with a pH
ranging from 3.5 to 5.5, and it may contain a
preservative called benzethonium chloride.
Mechanism of Action:
• It acts as a noncompetitive antagonist at the
glutamate NMDA receptor, a type of ion channel
receptor found throughout the brain.
• It binds to the PCP site on the receptor, blocking ion
flow and preventing calcium synaptic transmissions.
• The primary binding site binds L-glutamate, NMDA,
and aspartate.
• The allosteric site binds glycine, which facilitates
primary ligand binding.
• There is also a magnesium binding site that blocks ion
flow through the channel and a phencyclidine (PCP)
binding site that blocks the ion channel when
occupied.
 CONT.
• Ketamine is a rapid-acting agent used for induction and maintenance of
anesthesia.
• It can be used alone or in combination with other agents.
• Ketamine also binds to opioid receptors, including mu, delta, and kappa receptors,
as well as sigma receptors.
• It has different effects at different doses on the opioid receptors and the use of
ketamine as a postoperative analgesic or for chronic pain requires more study.
• The S(+) ketamine is 2-3times more potent than the R(-) ketamine as an analgesic.
• Ketamine may cause a transient increase in blood pressure after administration,
making it unsuitable for patients for whom elevated blood pressure poses a serious
risk.
• Ketamine is classified as a "dissociative anesthetic," and approximately 12% of
patients may experience psychological manifestations during emergence from
anesthesia.