Drugs which produce anesthesia are called as anaesthetics

Anaesthesia : Reversible loss of sensation

General Anaesthetics
Controlled reversible depression of the functional activity of the CNS

Stages of action
Cortical Stage
Analgesia and sleep are produced and consciousness remains.

Excitement Stage
Consciousness is lost. Depression of motor centres cause excitement and delerium.

Stages of action
Surgical stage
Spinal cord reflexes are depressed and skeletal muscles are relaxed.

Medullary Paralysis
Respiratory failure and Vasomotor collapse occur.

Mode of Uptake of anaesthetics

1. Inhalation. 2. Intravenous.

Transport
1. Carried to the brain by circulating blood tissue liver kidney lungs

Classification
Anaesthetics

General Anaesthetics

Local Anaesthetics

General Anaesthetics Eg: Ether, Chloroform, Halothane. Local Anaesthetics Eg: Cocaine, Procaine.

General Anaesthetics
They are classified as 1. Ethers 2. Halogenated Hydrocarbons 3. Gaseous Anaesthetics 4. Intra-venal Anaesthetics

1. Ethers
Ethers used as anaesthetics
Diethyl ether Divinyl ether Methoxyflurane

Diethyl ether
Preparation Williamsons ether synthesis
H3CCH2ONa + BrCH2CH3 NaBr + C2H5OC2H5

Commercial Preparation
C2H5OH + H2SO4 C2H5OSO3H
C2H5OSO3H +C2H5OH H2SO4(l) + C2H5OC2H5(g) + H2O(g)

 Properties
Colourless mobile liquid with characteristic odour Mixes freely with alcohol Insoluble in H2O Specific gravity 0.72 & b. pt. 35o C Highly Flammable liquid and chemically inert.

Anaesthetic grade Ether

Anaesthetic grade Ether Purified ether containing a stabilizer (<0.002 % w/v) Stabilizers Reducing agents added to ether to prevent the formation of peroxides. Commonly used stabilizer are di or polyhydric phenols, propyl gallate

Test for Purity

Tested for
Distillatio Range Wt/ml Acetone and aldehyde Foreign odour MeOH Acidity & non volatile matte peroxides

 Since ether is highly volatile 4% EtOH is added to

Raise its boiling pt. Prevent from frosting

Advantages
First General Anaesthetic, safe About 8% in air is used in surgical purposes Causes muscular relaxation without depressing CNS Stops respiration before it stops heart. Hence it is possible to revive a patient by artificial respiration

Adverse Effects
Irritates respiratory track & causes secretion of saliva (atropin is administered) Produces post anaesthetic N & V. Induction is slow Flammable

Divinyl ether or vinesthene

Preparation
2 Cl-CH2-CH2OH ClCH2-CH2-O-CH2-CH2Cl ClCH2-CH2-O-CH2-CH2Cl

CH2=CH-O-CH=CH2 + HCl

4% EtOH is added to raise b.pt. Stabilizer: 0.001% w/v of N-phenyl - naphthyl amine

 Uses
Short Anaesthetics. Minor surgery.

Properties
Unstable in air.

Methoxy Flourane or penthrane

Cl F O Cl
Preparation Liquid with fruity odour b. pt 101o C Pharmacologial action Produces muscular relaxation & analgesia Uses Obsterics Depressed respiration

 Mechanism
Vapours produce anaesthesia with slow onset & long duration of action

Disadvantages
Its long stay in body & bioconversion to fluoride which causes venal failure

Halogenated hydrocarbons
CHCl3, C2H5Cl, Cl2C=CHCl and Halothane
As the no. of halogen atoms increases, the toxicity is increases and hence cannot be used

Tests for purity

Acidity litmus paper (in CO2 free water extract) Free Cl2 CdI2 & starch blue colour. Aldehyde detection Nesslers reduction Phosgene test impregnating a paper in dimethylamino phenyl benzaldehyde & diphenyl amine yellow colouration.

Chloroform CHCl3
Preparation Bleaching powder H2C-CH2-OH CH3CHO CCl3CHO + NaOH Uses
Used as a obstetric anaesthetic

CCl3CHO

CHCl3 +HCOONa

 Undesirable properties
Toxic to liver and kidney Sudden cardiac arrest may occur during induction phase of anaesthesia Non-flammable Decomposes to poisonous phosgene on heating 2 CHCl3 + O2 2 COCl2 Adding EtOH converts phosgene to harmless diethyl carbonate COCl2 + 2C2H5OH 2 HCl + (C2H5)2CO3

Ethyl chloride (C2H5Cl)

Preparation
Methyl chloride
C hlo rinatio n

Ethyl Chloride + methyl chloride + harmless impurity

Volatile anaesthetic Liq. under pressure (b. pt 12o C)

Mechanism
Causes rapid induction

Uses
Used in minor surgeries of short duration Local anaesthetic (sprayed on skin)

Trichloroethylene (Cl2C=CHCl)
Preparation
Cl H Cl H Cl Cl

dry Ca(OH) 2 - HCl

Cl

Cl

H Cl

Properties
Non flammable Less toxic than CHCl3

 Use
Administered through inhalation for minor surgery & obstetrics In fabric covered sealed glass tubes To get relief from intense pain of trigeminal nueralgia To supplement N2O anasthesia

Stabilizer
Thymol (2 isopropyl 5- methyl phenol) Dyed blue (Distinguish from CHCl3) For thymol TiO2 + H2SO4 test.

Halothane
C l H B r , -trif l

ro

o -

-c h lo ro -

o ro e th a n e

Cl C=CHCl + HCl Cl3C=CH -Cl + HF F3C-CH -Cl + Br

Cl3C=CH -Cl + HF F3C-CH -Cl F3C-CHBrCl

Fl othane Colatile heavy liq id with odo r rese ling CHCl3

 Metabolic Products
High electronegativity of fluorine atom stabilizes the C-F bonds & weakenn adjacent C-C & C-X bonds. Metabolic products are chloride, bromide & CF3COOH

 Halothane is a better anaesthetic

Its potency is 4 times than that of ether Its anaesthetic potency is close to that of CHCl3 but very much les toxic than CHCl3. Induction period is rapid. Recovery following removal of anaesthetic is also rapid. Non-irritant of respiratory tracks Produces bronchiolar dilation as a result of direct action on smooth muscles. So can be used for anaesthesia on asthma patients Non-flammable Post anaesthetic N & V are rare.

Cl

Cl

Adverse effect
F

(2 Z )-2 ,3 -d ic h lo ro -1 ,1 ,1 ,4 ,4 ,4 -h e x a f lu o ro b u t-2 -e n e

Formed in the presence of O2

2 Fluothane

2,3-dichloro-1,1,1,4,4,4hexafluorobut-2-ene + HBr

Hypertension, liver necrosis Post-operative shivering (due to heat loss during operation)

Assay Fluothane + Na

NaF extract

NaF extract + PbCl2 Pb chloro fluoride It is filtered, dried and washed and gravimetrically estimated. Test NaF extract + gla. CH3COOH Soln. + mix of Na alizarin sulphonate + Zirconyl nitrate Red colour changes to yellow

Gaseous Anaesthetics
Cyclopropane
Manufacture Br-CH2-CH2-CH2-Br
Zn

 Adverse effect
Potent Analgesia without loss in consciousness Premedication with morphine or barbiturate use surgical aids Rapid induction Rapid elimination through lungs For elderly patients For poor risk patients Controls respiration use in chest surgery Support the circulation of O2 in blood so used for haemorrage

 Disadvantages
Sensitizes the heart to epinephrine & ventricular arrhythyria occur Produces branchiospasm, asthmatic patients should not be given with Flammable Expensive Explosive

N2O Laughing gas

Manufacture NH4NO3 N2O + H2O Properties
Colourless gas with sweet odour Soluble in H2O

Purity tests
For halides AgNO3 solution Formation of opalascence Sulphide AgNO3 dark solution. CO 5CO + I2O5 I2 + CO2 I2 KI absorption NO2 Spectrophotometric method CO2 Absorbed in KOH H2O vapour absorbed in P2O5. Official dosage Mix of 85% N2O & 15% O2 in surgical area

 Advantages
Rapid & pleasant induction Recovery is quick Non-flammable No iritation No combination with Hb Used in dental surgery and in obsetrics Cardiovascular depressant

Properties of halothane and methoxy flurane are decreased by mixing with N2O in therapuetic administration

 Disadvantages
Always administered with other agents such as narcotic analgesics, halothane or methoxy flurane.

Assay
50 ml of N2O (in evacuated vessel) immersed in liq. O2.. The uncondensed gas is drawn into eudiometer and the final volume is measured. The difference in vol. gives a measure of vol. of N2 as impurity. 3% of uncondensed gas is permissible for anaesthetic purposes

Intra-venal anaesthetics
a. Barbiturates b. Miscellaneous

Ultra short-acting barbiturates

Advantages
1. 2. 3. 4. 5. 6. 7. 8. Intra-venal administration Anaesthetic effect begins with 1 minutes Lasts for a short duration Smooth induction Produces muscular relaxation Non-explosive Rapid elimination or recovery It can be used in combination with other general anaesthetics 9. No salivary secretions

 Disadvantages
Produces respiratory depression Fall in blood pressure Irritates tissues Aggravates poor circulatory condition Should not be used for patients in shock

Rapid onset & brief duration of anaesthesia is attributed to lipid solubility

O R5 R5 O N R1 R5 R5

O N R1

N O N O O H Methohexital sodium R5 = allyl R5 = 1-methyl-2-pentynyl R1 = CH3 C 2 O Na+ C2 O C2 = or HN

Thioamylal sodium R5 = allyl R5 = 1-methyl butyl R1 = H or C2 C2 =

3

C2

 Thiopental sodium R5 = ethyl R5 = 1-methyl butyl R1 = H C C2 = or

2

C2

Methohexital sodium
Brevital sodium or Methohexitone. Sodium -(1)-1-methyl-5-allyl-5(-1-methyl-2pentynyl) barbiturate It does not produce muscular relaxation. Hence it requires supplementation with a gasous anaesthetic and a muscle relaxant. It is supplies in crystalline form with anhydrous sodium carbonate and is administered only intravenally.

Thioamylal sodium
Surital; sodium 5-allyl-5-(1-methylbutyl)-2thio barbiturate It is available as a sterile powder mixed with anhydrous sodium carbonate as a buffer. Onset of anaesthetics is with 20 to 60 seconds and lasts for 10 to 30 minutes. A non-sterile form of thioamylal sodium contains a dreen dye and characterised by this colour. Applies rectally.

Thiopental sodium
Sodium-5-(1-mthylbutyl)-5-ethyl-2-thio barbiturate: white or yellow white sterile powder containing sodium carbonate as a buffer.

Preparation
t a r t t t

Na

Urea

aq. Na
l

 Using methyl urea CH3-NH-CO-NH2 in place of urea in the above synthesis barbiturates with 1-methyl group can be prepared. Using thiourea thio barbiturates are prepared

 Eg. Sodium thiopentone is prepared as follows

H2N C H2N S H3CH2C COOEt C EtOOC CH(Me)CH2CH2CH3

H N S=C N H

CO C CO

CH2 CH CH3

CH3 CH2 CH2 H3C

SAR in barbituric acid

1. Replacement of both C5 hydrogen by alkyl group gives maximum activity. Acidic hydrogen is susceptible to metabolic action 2. Increasing the alkyl chain length to 5 or 6 carbon atoms increase the anaesthetic potency. When the no. of carbon atoms are >6, CNS depressive action decreases and convulsive action increases. This is duw to excess lipophilic character.

3. Alkyl groups at position 1 or 3 decreases the induction period and duration of action. 4. Replacement of oxygen by sulphur at position 2 shortens the onset and duration of action. 5. Compared to normal saturated chains with same number of carbon atoms, branched cyclic and unsaturated chainsin position 5 decreases the duration of action.