General anesthetics / Medicinal Chemistry III

General Anesthetics
Medicinal Chemistry III/ 4th stage / 1St semester
Lecture 6
Dr.Narmin Hamaamin Hussen
University of Sulaimani
College of Pharmacy

Anesthesia
▪ Anesthesia is a way to used to (control pain) blocks the transmission of pain.
▪ General anesthetics are a group of drugs commonly used in major surgery to
produce unconsciousness, analgesia, and depression of reflexes.
▪ General anesthesia: affects your brain and the rest of your body.
▪ Local anesthetics are used to block nerve transmission, to reduce or
eliminate sensation of pain in small area of the body without affecting
consciousness.
▪ Epidural and Spinal Anesthesia
▪ Epidural and spinal blocks are types of anesthesia in which a local
anesthetic is injected near the spinal cord and nerve roots. It blocks pain
from an entire region of the body, such as the belly, the hips, the legs, or
the pelvis. Epidural anesthesia is often used in childbirth

Stages of anesthesia produced by general anesthetics:
Stage I - analgesia results from an increase in circulating endorphins.
Stage II - loss of consciousness (secretions are managed by anticholinergic agents)
Stages I and II together are referred to as induction.
Stage III – anesthesia (surgical anesthesia) loss of spinal reflexes and muscle tone
(suitable for surgical procedures).
Stage IV - undesirable stage (characterized by respiratory depression) and ends in death
.

Mechanisms of anesthesia
1- Blocking the NMDA and glutamate controlled channels.
▪ Glutamate or NMDA (N-methyl-D-aspartate) receptors in the CNS are activated by the excitatory AA
neurotransmitter glutamic acid.
➢ Agonists: This activation opens the channel, allowing K+ to flow to the extra cellular fluid and Na and
Ca++ to flow into the nerve cell. The increased intracellular [Ca++] activates the liberation of the
(NO), which causes alertness (consciousness).
➢ Antagonists: Ketamine blocks NMDA receptors, causes CNS depression (anesthesia)
2- Activation of the inhibitory GABA receptor controlled channel.
▪ Binding of GABA (inhibitory transmitter) to their receptors will open the Cl- channel, leading to the
influx of Cl- and hyper- polarization of the neuron.
o Halothane and isoflurane inhibit the synaptic destruction of GABA, thereby increasing the GABA-ergic
neurotransmission.
o Benzodiazepines and barbiturates: Enhance GABA opening Cl channels γ-aminobutyric acid (GABA)
o Benzodiazepines and barbiturates produce anesthesia, by enhancing of GABA opening of the chloride
channel
3- Inhaled anesthetics are also known to enhance the major inhibitory receptors in the spinal cord, the
glycine receptors.

Classification Of General Anesthetics
Methohexital
Xenon
morphine
Isoflurane
desflurane
sevoflurane
Remimazolam

The Ideal Inhaled Anesthetic Drugs:
The ideal inhaled anesthetic will be:
➢ Inexpensive
➢ Potent
➢ Minimally soluble in the blood and tissues
➢ Pleasant to inhale
➢ Stable on the shelf and during administration
➢ Lack undesirable side effects such as:
▪ Cardiotoxicity
▪ Hepatotoxicity
▪ Renal toxicity
▪ Neurotoxicity.

Potency (MAC):
▪ The most common way to measure inhaled anesthetic potency is by recording the minimum alveolar
concentration (MAC) needed to prevent movement to a painful stimulus. The MAC concentrations
are recorded at 1 atmosphere and reported as the mean concentration needed to abolish movement
in 50% of subjects.
▪ MAC expressed as the percentage of gas in a mixture required to achieve the effect. Numerically,
MAC is small for potent anesthetics such as methoxyflurane and large for less potent agents such as
nitrous oxide.
▪ Potency α
Properties of the Inhaled Anesthetics
Most potent
Least potent

Solubility:
➢ Blood: gas partition coefficient:
▪ Blood : gas partition co-efficient It is a measure of solubility in the blood.
▪ The blood:gas partition coefficient is defined as the ratio of the concentration of the drug in the
blood to the concentration of the drug in the gas phase (in the lung), at equilibrium.
▪ It determines the rate of induction and recovery of Inhalational anesthetics.
▪ Lower the blood : gas co-efficient – faster the induction and recovery (Nitrous oxide)
▪ Higher the blood : gas co-efficient – slower induction and recovery (methoxyflurane )
Rock

Properties of the Inhaled Anesthetics
➢ Oil : gas partition coefficient
▪ Oil: gas partition co-efficient It is a measure of lipid solubility.
▪ Lipid solubility correlates strongly with the potency of the anesthetic.
▪ Higher the lipid solubility, more potent anesthetic (e.g., methoxyflurane )

➢ Arteriovenous concentration gradient (ACG)
▪ Difference between concentration of anesthetic drug in artery and veins.
▪ Smaller the ACG value faster will be the onset of action and vice versa.
Example:
Drug A Drug B
Artery = 100mg Artery = 100mg
Vein = 20mg Vein = 80mg
ACG= 80 mg ACG= 20 mg
Blood saturation
Slow onset of action
Blood saturation
Fast onset of action

Stability:
▪ The early inhaled anesthetics suffered from stability problems, leading to explosions
and operating room fires.
Example:
▪ Ether (Diethyl ether) is not used now in developed countries because of its
unpleasant and inflammable properties.
▪ By halogenating the ether and hydrocarbon anesthetics, the explosiveness and
flammability of the drugs were diminished, and the number of operating room fires
decreased.
▪ Halogenation clearly stabilizes the inhaled agent and all inhaled anesthetics used
today contain halogens
Diethyl ether

Structure–Activity Relationships of the Volatile General Anesthetics
▪ The inhalation anesthetics in use today are nitrous oxide, halothane, isoflurane, desflurane, and
sevoflurane.
1- 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.
▪ The cycloalkanes are more potent anesthetics than the straight chain analog with the same number of
carbons. For example, the MAC of cyclopropane in rats is about one fifth of the MAC of n-propane.

2- 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 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.
▪ 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.

3- Alkanol Series:
▪ 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.
4- Effect of Saturation:
▪ The addition of double and/or triple bonds to small anesthetic molecules having 6 carbon atoms or
less increases potency.

Inhaled anesthetic Products
Gas:
1-Nitrous oxide (laughing gas):
▪ 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.
▪ The low potency of nitrous oxide (MAC= 104%) precludes it from being used alone for surgical
anesthesia.
▪ It is a potent analgesic but a weak general anesthetic. Rapid onset and recovery, does not
depress respiration, and no muscle relaxation.
▪ To use it as the sole anesthetic agent the patient would have to breathe in pure N2O to the
exclusion of oxygen. This situation would obviously cause hypoxia and potentially lead to
death.
➢ Nitrous oxide can inactivate methionine synthase, a B12-dependent enzyme necessary for the
synthesis of DNA and therefore should be used with caution in pregnant and B12-deficient
patients.

2-Xenon(Xe):
▪ Xenon is an interesting anesthetic as it appears to lack negative inotropicy and vasodilatation,
giving great advantages to both patients with limited cardiovascular reserve or those who
require hemodynamic stability.
▪ Xenon is an inert gas that is nonflammable and nonexplosive.
▪ It has low toxicity and is not teratogenic.
▪ Xenon gives rapid induction and recovery, due to its low blood/gas partition coefficient
(0.15), and has a MAC of 63%.
▪ Several vitro studies showed that Xenon may protect neural cells against ischaemic injury

Volatile liquids:
1-Halothane:
▪ Halothane is a nonflammable, nonpungent, volatile, liquid, halogenated (F, Cl, and Br) ethane
(bp =50°C). Halothane may increase heart rate, cause cardiac arrhythmias, increase cerebral
blood flow, and increase intracranial pressure.
▪ It 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.
▪ The drug has a high potency (MAC= 0.75%), a blood:gas partition coefficient of 2.4, and high
adipose solubility.

Synthesis of halothane
1. Hydrogen fluoride is added to trichloroethylene and on
simultaneous substitution of chloride atoms in presence of
antimony(III) chloride at 130oC produces 2-chloro-1,1,1-
trifluoroethane.
2. The above formed compound undergoes bromination at 450oC
to produce halothane.

Halothane metabolism
▪ Halothane undergoes both reductive and
oxidative processes with up to 20% of the
dose undergoing metabolism.
▪ The trifluoroacetyl chloride metabolite is
electrophilic and can form covalent bonds
with proteins leading to immune
responses and halothane hepatitis upon
subsequent halothane exposure.
Halothane hepatitis is rare with 1 case
reported for every 6,000 to 35,000
patients exposed.

Malignant hyperthermia (MH)
▪ 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 rhabdomylolysis. MH is a result of the excessive release of
calcium from the sarcoplasmic reticulum (SR).
▪ Dantrolene is used for the prevention and treatment of malignant
hyperthermia during anesthesia. It achieves this by inhibiting Ca2+ ions
release from sarcoplasmic reticulum stores.

2- Methoxyflurane:
▪ Methoxyflurane is a volatile liquid (bp = 105°C) with a high blood:gas partition coefficient
and thus a slow induction and prolonged recovery. Approximately 75% of the drug
undergoes metabolism yielding dichloroacetate, difluoromethoxy acetate, oxalate, and
fluoride ions.
▪ The intrarenal inorganic fluoride concentration, as a result of renal defluorination, may be
responsible for the nephrotoxicity seen with methoxyflurane.

3-Enflurane:
▪ Enflurane is a volatile liquid (bp =56.5°C) with a blood: gas partition coefficient of 1.8 and an MAC of 1.68%.
▪ Enflurane may increase heart rate, cause cardiac arrhythmias, increase cerebral blood flow, and increase
intracranial pressure but all to a smaller degree than halothane.
▪ Enflurane also causes electroencephalographic (EEG) patterns consistent with electrical seizure activity. It
has caused tonic–clonic convulsive activity in patients when used at high concentrations or during profound
hypocarbic periods. Enflurane is therefore not recommended in patients with seizure disorders.
▪ Approximately 2% to 8% of the drug is metabolized primarily at the chlorofluoromethyl carbon. Little
chlorofluoroacetic acid is produced suggesting minor metabolism at the difluoromethyl carbon.
Difluoromethoxydifluoroacetate and fluoride ion have been reported as metabolites.

4-Isoflurane:
▪ Isoflurane is a volatile liquid (bp = 48.5°C) with an MAC of 1.15, a blood:gas partition coefficient of 1.43
and high solubility in fat.
▪ Isoflurane is a structural isomer of enflurane. It is a known respiratory irritant, but less so than
desflurane. Approximately 0.2% of the administered drug undergoes metabolism, the rest is exhaled
unchanged.
▪ The metabolism of isoflurane yields low levels of the nephrotoxic fluoride ion as well as a potentially
hepatotoxic trifluoroacetylating compound. The relatively low concentrations of these compounds
have resulted in very low risks of hepatotoxicity and nephrotoxicity.

5-Desflurane:
▪ Desflurane is a nonflammable, colorless, very volatile liquid packaged in amber-colored vials. The
boiling point is 22.8°C, and it requires a vaporizer specifically designed for desflurane.
▪ Desflurane has a blood:gas partition coefficient of 0.42, an MAC of 7.3% and an oil:gas partition
coefficient of 18.7. The low blood:gas partition coefficient leads to fast induction times and short
recovery times.
▪ Desflurane is not recommended for induction anesthesia in children because of the high incidence
of laryngospasms (50%), coughing (72%), breath holding (68%), and increase in secretions (21%).
▪ Desflurane can react with desiccated carbon dioxide absorbents to produce carbon monoxide that
may result in elevated levels of carboxyhemoglobin.
▪ Desflurane is metabolized minimally with less than 0.02% of the administered dose recovered as
urinary metabolites.
▪ Desflurane produces minimal free fluoride ion and very little trifluoroacetic acid and has not been
reported to cause either kidney or liver damage.

6-Sevoflurane:
▪ Sevoflurane is a volatile, nonpungent, nonflammable, and nonexplosive liquid with a boiling
point of 58.6°C. The blood:gas partition coefficient is 0.65, the oil:gas partition coefficient is
50, and the MAC is 2.1%.
▪ Sevoflurane reacts with desiccated carbon dioxide adsorbents, to produce compounds (A and
B) with known toxicity.
▪ The major breakdown product, compound A, pentafluoroisopropenyl fluoromethyl ether,
(PIFE, C4H2F6O) has been studied extensively. Compound A is nephrotoxic in rats and
nonhuman primates and remains a theoretical risk to humans.
▪ Approximately 5% to 8% of the administered dose of sevoflurane is metabolized in man by
CYP2E1 to hexafluo roisopropanol, CO2 and the potentially nephrotoxic fluoride ion

▪ Diethyl ether is a potent anesthetic whose actions are accompanied by analgesic and
muscle relaxant activity. It is highly flammable and explosive.
▪ The MAC of ether in humans is around 3.2%.
▪ Ether is sweet smelling and mildly pungent; although it can be used for inhalational
induction, an ether induction is very slow and risks laryngospasm.
▪ Ether is still used as an anesthetic in some developing countries because of its low
cost and high therapeutic index with minimal cardiac and respiratory depression.
▪ Chloroform is a halogenated hydrocarbon that, unlike ether, is not flammable but has
significant toxicity, including carcinogenicity, hepato-, and nephrotoxicity.
▪ chloroform soon emerged as the more widely used, as it took action faster and was
non-flammable.
▪ On the other hand, there were higher risks associated with chloroform than with
ether, and its administration required greater physician skill.
▪ Usage of ether and chloroform later declined after the development of safer, more
effective inhalation anesthetics, and they are no longer used in surgery today.
Ether and Chloroform
Diethyl ether
Chloroform

The Injectable General Anesthetics:
1-Propofol:
• Propofol is an injectable sedative–hypnotic used for the induction and
maintenance of anesthesia or sedation.
• The pKa of the propanol hydroxyl is 11 and the injectable emulsion has a pH of 7 to 8.5.
• Formulations contain either disodium ethylenediaminetetraacetic acid (EDTA) (0.005%) or
sodium metabisulfite to retard the growth of microorganisms. EDTA is a metal chelator and
patients on propofol containing EDTA for extended periods of time excrete more zinc and
iron in their urine
• Propofol is quickly and extensively metabolized with 88% of a 14C-labelled intravenous
administered dose appearing in the urine as conjugates. Less than 2% of the dose is found
unchanged in the feces and less than 0.3% found unchanged in the urine. Thirty minutes
after the 14C-labelled dose was administered, 81% of the radioactivity was in the form of
metabolites Propofol has a quick onset of action (arm-to-brain circulation time) and a quick
recovery time.

2- Fospropofol:
▪ Fospropofol is a water soluble prodrug and is converted to propofol in the liver.
▪ Breakdown by phosphatase to release propofol
▪ Fospropofol is a short acting hypnotic/sedative/anesthetic agent.
▪ Unlike propofol, does not cause injection-site pain as it is unable to activate TRPA1.FDA approved in
December 2008.
▪ It is currently approved for use in sedation of adult patients undergoing diagnostic or therapeutic
procedures such as endoscopy.
▪ Fospropofol is administered in conjunction with an opioid such as fentanyl

3-Etomidate:
▪ Etomidate is a carboxylated imidazole intended for the induction of general
anesthesia.
▪ Etomidate is rapidly metabolized in the plasma and liver via esterases. About
75% of the drug is eliminated in the urine as the inactive ester hydrolyzed
carboxylic acid.
▪ It is only used for patients with coronary artery disease or cardiovascular
dysfunction. No effect on heart and circulation. lacks analgesic activity.
Esterases
Carboxylic acid
Ester

4-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.
▪ Unlike the proposed mechanism of action for most anesthetics, ketamine does not act at the
GABAA receptor. Ketamine acts as a noncompetitive antagonist at the glutamate, NMDA receptor,
a nonspecific ion channel receptor. The NMDA receptor is located throughout the brain and
contains four well-studied binding sites. The primary binding site binds L-glutamate, NMDA, and
aspartate.
▪ Ketamine is metabolized via N-demethylation to form the main metabolite norketamine.
▪ Norketamine has about one third the potency of the parent compound. Minor metabolic pathways
include hydroxylation of the cyclohexanone ring; hydroxylation followed by glucuronide
conjugation, and hydroxylation followed by dehydration to the cyclohexenone derivative.

5- Fentanyl:
▪ Fentanil, is an opioid used as a pain medication and together with other medications for
anesthesia.
▪ Often used in cardiac surgery because not cause CV toxicity
▪ To maintain anesthesia, inhaled anesthetics and additional fentanyl may be used. These are
often given in 15-30 minute intervals throughout procedures such as endoscopy, surgeries, and
in emergency rooms.

6- Thiopental (pentothal):
▪ It is a rapid-onset short-acting barbiturate general anesthetic. , has a very low analgesic
properties (used by IV as sodium salt).
▪ Induction of the sulfur enhanced lipophilicity.
▪ Onset- 30-60 sec : Peak- 10-30 min : Half-life- 12 min : Duration- 20-30 min
▪ Adverse effects: Can produce severe respiratory depression (Respiratory), apnea, airway
obstruction, depress the myocardium and causes dysrhythmias (Cardiovascular),
hypotension.
▪ Contraindication in liver disease, severe heart disease, severe hypotension and severe
breathing disorder.

7- Midazolam:
▪ Midazolam is used before surgery or a procedure. It helps to cause drowsiness,
decrease anxiety, and to decrease your memory of the surgery or procedure.
▪ This medication may also be used to help with anesthesia or to sedate people who
need a tube or machine to help with breathing. Midazolam works by calming the brain
and nerves. It belongs to a class of drugs known as benzodiazepines.
▪ Advantage: Causes little cardiovascular and respiratory problem compare to other IV
anesthetic drugs.

▪ It acts on GABA receptors, as does midazolam, and exhibits
pharmacokinetic properties common to the ester-based opioid
remifentanil.
▪ In animal studies, remimazolam produced a more rapid onset and
faster recovery than did midazolam.
▪ Remimazolam significantly potentiated the analgesic effect of
remifentanil, without lung irritation, bronchospasm, or other adverse
pulmonary event
▪ Remimazolam was approved for medical use in the United States in
July 2020.
▪ The U.S. Food and Drug Administration (FDA) approved remimazolam
based on evidence from three clinical trials .
▪ remimazolam metabolism: the parent drug remimazolam is hydrolyzed
by carboxylesterase 1 to the inactive metabolite
Remimazolam:
remimazolam
midazolam

General anesthetics / Medicinal Chemistry III

General anesthetics / Medicinal Chemistry III

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