1. Medicinal Chemistry II 4th year Pharm Students 1435-2014
Prepared by;
Dr. Munjed Ibrahim
Tel: Ext.; 4268

2. General Anaesthetics - Introduction
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).
General anaesthesia involves administration of different drugs:
Premedication
Inducing agent(s)
Maintenance agent(s)
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3. General Anaesthetics - Introduction
Premedication
Prevention of bradycardia, bronchial secretion, muscle spasm
Benzodiazepines (Diazepam)
Narcotic analgesics
Anticholinergic drugs (Scopolamine)
Skeletal muscle relaxants (CNS)
Inducing agent
Normally an intravenous anaesthetic
Barbituate (thiopentone, methohexitone)
Non-barbituate (propofol, ketamine)
Maintaining anaesthesia
Normally an inhaled gas
halogenated hydrocarbons and ethers
nitrous oxide (and….)
Anti-emetic agents may be required post-anaesthesia
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4. 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.
Halothane and isoflurane inhibit the synaptic destruction of GABA, thereby increasing the GABA-ergic neurotransmission.
Benzodiazepines and barbiturates: Inhance GABA opening Cl channels
γ-aminobutyric acid (GABA)
Benzodiazepines and barbiturates produce anesthesia, by enhancing of GABA opening of the chloride channel

5. Depending on route of administration, general anesthetics are classified
1- Inhalation (pulmonary) Anesthetics: - Gases or vapors of volatile liquids that inhaled in a mixture with air or O2.
2- Intravenous Anesthetics: Agents are psychologically well tolerated. They are quite useful as induction agents for inhalation anesthesia.
3- Combination Anesthesia: Combinations of medications is preferred to broaden the therapeutic range. Moreover, minimal doses of several substances are administered for particular goals of anesthesia.
Classification of General Anesthetics
The general anesthetics are classified according to their nature (volatile or non-volatile) at room temperature. They are:
A. Volatile Inhalation general anesthetics. They are administered by inhalation
and are further subdivided as;
_ Gases: Ex: Cyclopropane: Ethyl chloride, Nitrous oxide
_ Liquids: Diethyl ether, Halothane, Chloroform, Trichloroethylene
B. Non-Volatile or Intravenous anesthetics. They are non-volatile at room temperature
and are administered by intravenous route. They are;
_ Barbiturates : Thiopental sodium, Methohexital sodium.
_ Non-barbiturates : Propanidid, Propofol

6. Inhaled anesthetics Nitrous oxide: N2O, laughing gas
- 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 m. 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.
2. Non-halogenated Hydrocarbons:
They have a tendency to produce cardiovascular toxicity.
The longer chain of the hydrocarbon, the higher the potency.
Cyclopropane is
colorless, explosive and flammable, may cause laryngospasms.
the only hydrocarbon still in use.
mixed with oxygen (15 – 30% Cyclopropane) for medical purposes.
In contrast to nitrous oxide, its concentration of 20% can produce anesthesia.

7. SAR of the Volatile General Anesthetics
ALKANE / CYCLOALKANE
1. 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.
In the n-alkanes, the cutoff number is 10. While in cycloalkanes, 8
2. There is a positive correlation between anesthetic potency and solubility in olive oil.
3. 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.
The common way to measure the potency ; MAC concentrations are recorded at 1 atmosphere and reported as the mean concentration needed to abolish movement in 50% of subjects.
Solubility
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
quick onset, the solubility in the blood should be low.
Recovery is faster for those drugs with a low blood: gas partition coefficient.

8. 3. Halogenated hydrocarbons
Effect of halogenation / ether halogenation:
Addition of a halogen reduce or eliminate flammability, and increase potency.
Higher atomic mass halogens increased potency compared to lower atomic mass halogens.
For the n-alkane series, fully saturating the alkane with fluorine abolished activity except when n equaled one.
When n was 2 – 4 Cs the highest potency was seen when the terminal carbon contained one H (CHF2(CF2)nCHF2). When n was greater than 5 carbons the potency decreased in this series.
2. Ex; replacing the fluorine in desflurane (CF2HOCFHCF3) with a chlorine to form isoflurane (CF2HOCClHCF3) increased potency more than fourfold.
Rate of metabolic defluorination:
methoxyF > enF = sevoF >isoF > desF > halothane

9. Halothane Chemical Name; 2-bromo-2-chlorol-1,1,1-trifluoroethane
It is noninflammable liquid with a characteristic sweet odor.
The presence of three fluorine atoms, increases potency, volatility and chemical stability.
The induction of and recovery from anesthesia are rapid.
Halothane reduces peripheral vascular resistance. 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.
Halothane MAC= 0.75%
B:G coefficient= 2.4
It erodes rubber and plastic tubing, no effect on polyethylene tubing
It corrodes all metals except nickel, chromium and titanium
The trifluoromethyl group is quite stable; the C—H bond, however, is destabilized and is the probable site of metabolic entry

10. Name: 2-chloro- I,I ,2-trifluoroethyl difluoromethyl ether
4. Halogenated ethers.
Polyfluorinated ethers have analgesic and muscle-relaxing properties but are more difficult to control. In addition, some are inflammable.
Enflurane :
Name: 2-chloro- I,I ,2-trifluoroethyl difluoromethyl ether
Noninflammable liquid, mixed with various amounts of O2 &N2O
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)
F2HCOCF2CClFOH →F2HCOCF2COOH + F-
Properties Resemble Halothane Except
Better Muscle Relaxant
Tachypnoea is uncommon
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.

11. Resemble Halothane Except:
Isoflurane:1 -chloro-2,2,2-trifluoethyl difluoromethyl ether.
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.
3. blood:gas partition coefficient of 1.43
MAC of 1.15
Resemble Halothane Except:
Less incidence of hypotension
Less sensitization of heart to Catecholamines
Less toxic
Powerful Coronary vasodilator
No pro-convulsive properties
Not cost effective

12. 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 (Deprivan)
2,6-Di-isopropylphenol
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. It achieves hypnosis in one minute & lasts for 5 minutes.
Maintenance of anesthesia is achieved with volatile anesthetics or additional doses of it.
It is formulated as 1 or 2% emulsion in soybean oil or glycerol.
It is more, effective than thiopental. Rarely associated with vomiting.
Metabolism proceeds rapidly via glucuronide and sulfate conjugation in liver.
Pharmacokinetics
After IV adm distribution ½ life: 2-8 min,
redistribution ½ life is approximately min.
Rapidly metabolised in the liver and excreted in the urine as glucuronide and sulphate conjugates (less than 1% excreted unchanged)
Uses Propofol…
For rapid induction
For maintenance of G.A in day surgery
For short operations
For prolonged sedation in ICU
Useful antiemetic action

13. Ketamine 2-(2-Chlorophenyl)-2-methylaminocyclohexanone
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 during emergence, that may last for 24 hours and so it is only indicated for children less than 16 years old.
Related to Phencyclidine; arylcyclohexylamine
The drug exerts its effect by entering and blocking the open channels .
Produces ‘dissociative’ anaesthesia, in which patient may remain conscious, though amnesic and insensitive to pain.

14. 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.
[O]

15. Ultrashort-acting barbiturates:
- Used to produce rapid unconsciousness for surgical and basal anesthesia (induce anesthesia).
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
a- 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

16. b- Methohexital sodium
It is N-methylated barbiturate that has pKa of 8.4, versus 7.6 for the non-methylated compound.
This pKa value increases the concentration of the lipid-soluble free acid form at the physiological pH.
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.
Finally, it has an accessible site of metabolic inactivation, the CH2 α to the triple bond.

17. Benzodiazepines Adjuvant to general anesthesia
-Benzodiazepines alone can not produce surgical anesthesia. However, some benzodiazepines are used to induce anesthesia. e.g: Medazolam maleate
Adjuvant to general anesthesia
1.Narcotic analgesics: such as morphine and meperidine to reduce anxiety .
2.Sedatives: such as benzodiazepines, to produce sedation and reduce anxiety.
3.Anticholinergics: such as scopolamine, to inhibit excessive respiratory secretion.
4.Skeletal muscle relaxants: such as succinylcholine and vencuronium to relax the muscles for optimum surgical working conditions.