B Pharmacy subject - Medicinal Chemistry

1. general anaesthetics

2. General anaesthesia: loss of sensation with reversible loss of conciousness &
Depression of defense and muscle reflexes.
Anesthetics are depressant drugs that produce a partial or total loss of the
sensation.
Stages of anaesthesia produced by general anaesthetics
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).
characteristics of the Ideal Inhaled Anesthetic
• potency
• solubility
• stability

3. Mechanism of Action of general anaesthetics
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)

4. 2) Activation of the inhibitory GABA receptor controlled channel.
• γ-aminobutyric acid (GABA): inhibitory neurotransmitter
• Binding of GABA to their receptors will open the Cl- channel, leading to the
influx of Cl- and hyper- polarization of the neuron.
• Halothane and isoflurane inhibit the synaptic destruction of GABA, thereby
increasing the GABA-ergic neurotransmission.
• Benzodiazepines and barbiturates: produce anesthesia, by enhancing of
GABA opening of the chloride channel

5. Other receptors involved
volatile anaesthetics enhance the major inhibitory receptors in the spinal cord, the
glycine receptors.
Inhaled anesthetics are also proposed to inhibit the activity of neuronal nicotinic
acetylcholine receptors, amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
[AMPA]), sodium channels, potassium channels, calcium channels (voltage-gated
cardiac and neuronal), and ryanodine receptors.
The multitude of receptor channels that are affected to various degrees by specific
inhaled anesthetics leads to the current theory that multiple receptors are targets
of the volatile anesthetics and no single receptor–drug interaction can fully explain
their mechanism of action.

6. Classification of General Anesthetics
• The general anesthetics are classified according to their nature (volatile or
non-volatile) at room temperature.
Inhalation anesthetics:
Nitrous oxide, Halothane*, Methoxyflurane, Enflurane,
Sevoflurane, Isoflurane, Desflurane.Chloroform
Intravenous anaesthetics
Propofol, Ultra short acting barbitutrates: Methohexital sodium*, Thiamylal
sodium, Thiopental sodium.
Dissociative anesthetics: Ketamine hydrochloride.*

7. Nitrous oxide (N2O)
• A colorless gas, exerts low anesthetic effect.
• It is mixed with oxygen and ether or halothane, as deep anesthesia cannot be
achieved with it alone.
• Has good analgesia & minimal toxicity, it has poor muscle relaxant effect.
Dosage:
• For induction, 70% nitrous oxide with 30% oxygen for 2 to 3 minutes.
• For maintenance, 30 to 70% nitrous oxide with oxygen.

9. Halothane
• The induction of and recovery from anesthesia are rapid.
• It is a poor muscle relaxant.
• Mostly halothane is eliminated as intact. However, about 20% is
metabolized to trifluroacetic acid.
• The trifluoroacetyl chloride metabolite is electrophilic and can form
covalent bonds with proteins leading to immune responses and
halothane hepatitis upon repeated use.
• It erodes rubber and plastic tubing, no effect on polyethylene tubing
• It corrodes all metals except nickel, chromium and titanium

11. Halogenated ethers.
• Polyfluorinated ethers have analgesic and muscle-relaxing properties but are more
difficult to control. In addition, some are inflammable.
Enflurane :
• Non inflammable liquid,
• Its advantage over halothane is the more rapid induction & recovery.
• Arrhythmias are observed less frequently.
• It has a low frequency of nephrotoxicity due to low [F-] released from metabolism. (Only
2% is metabolized to fluoride ions and fluoromethoxy difluoroacetic acid)
Properties
• Produces convulsions and involuntary movements during induction or recovery
• Liver damage is rare, Recovery is faster
• Drug interaction:
• INH which facilitate its deflourination, renal damage occurs
• Drug toxicity:
• ↑ doses it produces convulsions; not used in patients with epilepsy.
• Enflurane relaxes the uterus; not used as anesthetic during labor

12. Isoflurane:
• It is noninflammable liquid with a faint odor.
• It has a low blood/gas distribution coefficient, which leads to rapid recovery
from the anesthesia.
• Only 0.2% of the drug is metabolized to F- and trifluoroacetic acid, therefore
kidney, liver and myocardial functions remain intact.
• The (+) isomer was found to be 53% > potent than the(-) isomer.
• It is the best general anesthetic so far.
• Isoflurane is a structural isomer of enflurane.
• Not cost effective

14. Methoxyflurane
• volatile liquid 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
• Methoxyflurane was removed from the U.S. market in 2000
because of safer alternatives. Both isoflurane and enflurane
produce less fluoride ion upon metabolism than methoxyflurane

15. DESFLURANE
• Desflurane is a nonflammable, colorless, very volatile liquid
• 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
, coughing, breath holding, and increase in secretions .
• Desflurane produces minimal free fluoride ion and very
little trifluoroacetic acid and has not been reported to cause
either kidney or liver damage

16. SEVOFLURANE
• Sevoflurane reacts with desiccated carbon dioxide adsorbents, to produce
compounds (A and B) with toxicity .
• The type of CO2 absorbent used, the temperature of the absorbent, and the
duration of exposure can influence the degree to which sevoflurane breaks
down
• sevoflurane breakdown by CO2 absorbents generates heat and has resulted
in sporadic operating room fires.
• Approximately 5% to 8% of the administered dose of sevoflurane is
metabolized in man by CYP2E1 to hexafluoroisopropanol, CO2 and the
potentially nephrotoxic fluoride ion
• Sevoflurane has been shown to cause epileptic changes case reports of
seizures during surgery, especially in children, have been reported

18. Intravenous Anesthetics
• Intravenous anesthetics are nonexplosive solids. They produce rapid loss of
consciousness but insufficient anesthesia. So, they are seldom used alone.
Administration of oxygen is recommended, particularly with barbiturates and
thiobarbiturates.
Propofol
• Propofol is a short acting anesthetic that act via enhancing the GABA-ergic
neurotransmission in the CNS. It binds allosterically to GABA receptor at a site
different from that of benzodiazepines.
• Maintenance of anesthesia is achieved with volatile anesthetics or additional
doses of it.
• It is more effective than thiopental. Rarely associated with vomiting.
• Metabolism proceeds rapidly via glucuronide and sulfate conjugation in liver.

20. Ultrashort-acting barbiturates:
• The induction is very rapid. The long side chain substitution at position-5 is an
essential feature for increasing lipid solubility and hence the rate of passing
through the BBB.
• There is an inverse correlation between the total number of carbon atoms
substituted on the 5 position and the duration of action
Thiopental sodium
• It is the most widely used ultrashort-acting barbiturate.
• The presence of sulfur in thiopental increases lipid solubility and
facilitates its entry to the brain.
• Its short duration of action is due to partitioning from the brain into
body fat.
• It is metabolized by oxidative desulphurization

21. Methohexital sodium
• It is N-methylated barbiturate
• N-methylation decreases duration of action.
• The compound also has extensive hydrophobic character because the long
unsaturated side chains (9-Cs).
• Overall, it can rapidly penetrate the CNS after IV injection and then redistribute
rapidly to other body sites and undergo rapid
metabolic inactivation.

22. Ketamine :Dissociative anaesthetic agent
• Ketamine hydrochloride is a very potent, rapidly acting anesthetic
agent.
• The S (+) ketamine is two to three times more potent than the
R (-) ketamine as an analgesic.
• Its duration of action is relatively short (10-25 minutes).
• It produces anesthesia by blocking the NMDA controlled channels.
• ketamine is suitable for diagnostic purposes and for surgical procedures that do not
require muscle relaxation.
• Patients older than 16 will often (27%) have wild dreams and hallucinations, that
may last for 24 hours and so it is only indicated for children less than 16 years old.
• Produces ‘dissociative’ anaesthesia, in which patient may remain conscious, though
amnesic and insensitive to pain.
• The termination of action is due to redistribution from the brain into other tissues.
• In the liver ketamine is metabolized into norketamine (active metabolite), which account
for the longer effect of this anesthetic. It is also conjugated with glucuronic acid.

24. Which of the following is an example of an inhalation anesthetic?
Enflurane
Thiopental
Ketamine
Methohexital
Norketamine, which is an active metabolite of Ketamine is formed via ____
N-demethylation
O-demethylation
Glucoronidation
Acetylation

25. Isoflurane is an isomer of ____
Enflurane
Halothane
Sevoflurane
Ketamine
Ketamine is a ________ anesthetic
Dissociative
Local
Reversible
Inhalation

26. Which of the following is an example of an ultra short acting barbiturate anesthetic?
Methohexital
Enflurane
Sevoflurane
Benzocaine
Identify the drug given below
Ketamine
Thiopental
Meperidine
Methadone