INRODUCTION:

A drug is subjected to many complex processes from the time it is administered to the time the
biologic response is effected.
The action of drug mostly depends upon:
1)Nature of physicochemical properties of the compound
2)Nature of functional group attached ti the molecule
So,in order to determine the nature of compounds,the study of these functional groups is essential.
PHARMACOPHORE:
The part of drug molecule which is responsible the special type of activity to compound is called
Pharmacophore.
The biological activity of a compound may be due to:
1)a specific functional group (–OH,-COOH etc) or
2)a part of molecule
*SAR studies have shown that pharmacologically similar compouds have similar functional
group,which is responsible for the activity.
*The molecular modifications of the parent compound is a major line of approach to the
development of new drug.
The STRUTURE ACTIVITY RELATIONSHIP (SAR) is the relationship between the chemical
structure of a molecule and its biological activity.

It has been observed that chemical structure and biological activity are closely co-ordinated with
each other so, if there is any change in chemical structure then ultimately biological activity
changes.

The biological activity of a compound depends upon the different functional groups which are as
follows:

1. Effect of alkylgroup.
2. Effect of hydroxyl group.
3. Effect of acidic group.
4. Effect of amide group.
5. Effect of halogens group.
6. Effect of nitro group.
7. Effect of unsaturation.

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8. Effect of molecular weight.

9. Effect of isomerism .
1 Effect of Alkyl group:

The effect of alkyl group on different compound can be better explain with the help of following
examples:

1.1 Effect on benzene ring:

Introduction of methyl group(alkyl group) on the benzene ring increases the activity of the
compound.

1.2 Effect on antipyrine:

If we introduce methyl group in replacement of hydrogen atom in the antipyrine structure then it
show analgesic activity.

1.3 Effect on sulfanol:

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Sulfanol has hypnotic effect and it also show and it also show anticonvulsant activity up to some
extend. So if we change the position of alkyl group as in the structures given below then the
biological activity of the compound is totally changed.

In above example:
i. Structure I and II have same hypnotic activity because the number of alkyl groups is
similar.
ii. But the structure III did not show the hypnotic acticity. It means the hypnotic activity is
totally depends upon ethyl group.
iii. The structure IV show maximum hypnotic activity because it possed 4 ethyl group.
So, it has been concluded that the activity of the given compound is totally dependent upon the
given structure.
2 Effect of hydroxyl group:
There is a general rulee regarding the precence of hydroxyl group in the given compound,
i. Introduction of hydroxyl group in aliphatic ring decreases the toxicity as well as activity.
ii. Introduction of hydroxyl group in aromatic ring increases the toxicity as well as activity.
2.1 Effect on aliphatic compound:
When hydroxyl group is introduced in aliphatic compound then their activity and toxicity is
decreased and it is seen that it is roughly proportional to the hydroxyl group on the molecule.

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2.2 Effect on aromatic ring:
2.2.1 Effect on benzene ring:
When hydroxyl group is introduced in benzene ring then it becomes phenol and benzene is less
toxic than phenol.

2.2.2 Effect on benzoic acid:

If we introduce hydroxyl group on benzoic acid then the toxicity as well as activity is increased.
Benzoic Acid:Non -Toxic,Antiseptic
Salicylic Acid:Toxic,Analgesic and Anti-Rheumatic

3 Effect of acidic group:

The introduction of carboxyl group and sulphonic acid group in the molecule of the drug generally
decreases its toxicity as well as biological activity.
3.1 Effect on benzene ring:
The introduction of carboxyl group or sulphonic acid group in the benzene molecule makes the
compound non-toxic.

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3.2 Effect on phenols:

Phenol (anti-septic) Salicylic acid (analgesic)

3.3 Effect on aniline:
Aniline C6H5NH2is a blood poison but if we add carboxyl group in it then it becomes harmless and
is well tolerated.

4 Effect of amino group:

According to the general rule the introduction of amino group to aromatic compound usually
results in the increase in toxicity of compound.
4.1 Effect on benzene:

4.2 Effect on phenol:

Phenol Nitro phenol Aminophenol.

(Toxic)

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5 Effect of halogens:
If we add halogens in the compound then the activity and toxicity both increases but not at the
same rate. So, when increase in toxicity is negligible whereas halogenation increases the activity
very rapidly and also increases the safety margin.
5.1 Effect on uracil:
+halogen
Uracil 5-flurouracil(cytotoxic)
5.2 Effect on tetracycline:
+Cl
Tetracycline chlorotetracycline(CTC)
So, in this case activity is increased at a higher rate as compared to toxicity.
6 Effect of nitro group:
Here we discuss two categories:

6.1 Effect on aromatic ring:

Introduction of the nitro group to the aromatic ring increases the toxicity of compound.

Benzene Nitro benzene

However, the presences of other groups can modify the activity of compound i-e nitro-toulene
which is less toxic than nitrobenzene.

Nitro benzene Meta- nitobenzene

6.2 Effect on aliphatic compound:
Introduction of nitro group to aliphatic compound may increase their biological activity.
CH2-OH CH2 –ONO2
nitration.
CH-OH CH- ONO2
CH2-OH CH2 –ONO2

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 Glycerin Trinitroglycerine
(Inert) (Vasodilator) Use in Angina Pectoris
7 Effect of unsaturation:
In general unsaturated compounds are more reactive than the saturated compounds and
approximately same is the case with pharmacological activity.
CH3-CH2-CH2-OH CH2=CH-CH2-OH
Propanol Allyl alcohol
Mild narcotic Potent narcotic
Less toxic More toxic
8 Effect of molecular weight:
Basically there is no general rule about the molecular weight on the activity of compound.
However, it is seen that polymers show different effects than the original one.
So, we can say in some cases as molecular weight increases the toxicity will be decreases and for
this purpose we will discuss the example of oxalic acid.
COOH CH2-COOH CH2-CH2-COOH
COOH CH2-COOH CH2-CH2-COOH
Oxalic acid Succinic acid Butyric acid
(Toxic) (Very less toxic) (Non-toxic)
9 Effect of isomerism:
In case of organic compound (weather the aliphatic or aromatic) isomers usually differ in their
biological action and also in physical and chemical activities.
9.1 Effect of position isomerism:
Effect of position isomerism is better explained by the example of cocaine.
Cocaine is a local anesthetic but if the position of –COOCH3 group is changed we will obtain
alpha-cocaine and alpha cocaine is inactive and have no anesthetic activity at all.

IN Alpha cocaine,–COOCH3 Group is attached at the same position with –COOC6H5.Means

both are at the same position.

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9.2 Effect of optical isomerism:
Difference in the biological activity is expressed greater in case of optical isomerism, as in case of
optical isomerism we discuss dextro compound, levo compound and racemic mixture.
Sometimes, it is seen that levo form is basically more active than dextro form. E.g.: Atropine. In
case of atropine levo form is much more active than dextro form and dl-form.

Receptor Relevant Example

SAR of Acetylcholine:(ParaSymPathomimetic)

Modification with Oniumgroup:(Quaternary Amine Group)

i. Primary, secondary and tertiary amines are less active than quaternary amines.
ii. If methyl group is replaced by ethyl group or any other larger alkyl group then it will
produce inactive compound.
iii. The replacement of nitrogen by arsenic, antimony, phosphorus or sulphur atom then it will
produce very less active compound.
Modification in Ethylene Bridge:
i. Replacement of hydrogen in methylene group with methyl group leads to equal or greater
cholinergic activity.(But larger group then methyl leads to decrease in activity)
ii. Substitution of methyl group at beta-carbon actsselectivity on muscarinic receptors.
iii. Substitution of methyl group at alpha carbon then it will act selectively on nicotinic
receptors.
Modification of Acyl group:
i. When methyl group of acyl group is substituted with primary amine it will result into the
more potent compound.
ii. If ester functional group is substituted with ether or ketone then again more potent
compound is produced.
iii. Substitution of acyl group with aromatic or any other high molecular weight ester then it
will produce antagonist activity intead of agonist activity.

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 Metabolism Relevant Example:
SAR of cephalosporin:

1. Beta-lactam ring:
Beta Lactam ring is responsible for antibacterial activity if there is minor change in it then the
reactivity is reduced as compared to penicillins
2. Carboxyl group:
As it is acidic in nature so it results in the formulation of salt and due to this group the elimination
profile is renal in nature

3. Substitution at C-3(R1)
*)If we place hydrogen, methyl and chloride, the cephalosporin show metabolically stable
behavior and also acid stable and they have:
a- Minimal effect on spectrum of activity
b- Metabolically stable
c- Low plasma protein binding
d- Short half-life
e- Orally active

*)Cephalosporin position 3 if substituted with acetate group then it will show acidic instability and
metabolically instability.

a- Minimal effect on spectrum of activity

b- Metabolically unstable
c- Low plasma protein binding

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d- Short half-life
*)Substitution of alcohol at carbon number 3 blocks the metabolism and prolong the activity.
*)Substitution of Thiothiadiazole at carbon 3 results in metabolically stable compound that have
longer half life.

4. Substitution at C-7:

Substitution of carbon number 7 with NH2,OH or CH2O group result in a compound that
have minimal resistance to beta lactamase and have higher activity against gram positive
bacteria.

General Anesthetics
“Anesthetic are the drugs which depress the vital functions of all type of cells but especially those
of nervous tissues & produce temporary insensibility to pain in whole body or a particular organ
which has to undergo the surgical operation.”
10 Properties of ideal anesthetic agent:
An ideal anesthetic agent should have following properties:
i. It should be inert.
ii. It should be potent and non-inflammable.
iii. It should produce rapid and smooth induction without irritation.
iv. It should be non-irritating to mucous membrane.
v. It should produce the analgesia and muscle relaxation.
vi. It should be nontoxic to brain, liver,heart and kidney tissues.
vii. It should not produce nausea and vomiting.
viii. It should be economical.
ix. It should be stable to light and heat.
x. It should have a quick/short recovery period without discomfort.
xi. It should not produce severe hypotension.

11 General Anesthesia:
General anesthesia is the controlled, reversible depression of the functional activities of CNS. The
state of general anesthesia includes:
• Analgesia
• Amnesia
• Loss of consciousness
• Inhibition of sensory & autonomic reflexes
• Skeletal muscle relaxation

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12 General anesthetics:
“General anesthetics are the drugs that depress the central nervous system to such an extent that
all sensitivity to pain is lost and the individual suffers loss of consciousness.”

Mechanism of Action of General Anesthesia

• In contrast to the local anesthesia, general anesthesia alters the physical properties of nerve
membranes through non-specific interactions with lipid bilayer or the receptor/ ionic
channel proteins. Therefore, reduce membrane excitability through a number of possible
mechanisms including:
i. Changes in membrane fluidity
ii. Changes in membrane permeability
iii. Changes in receptor/channel functions
• Two main mechanisms involved are:
a. General anesthesia can hyperpolarize neurons, thereby inhibiting generation,
propagation and conduction of impulses.
b. Both inhalation and IV anesthetic have substantial effects on synaptic function.
• Inhalation anesthesia has been shown to inhibit excitatory synapses and enhance inhibitory
synapse.
• Most of IV agents act predominantly by enhancing inhibitory neurotransmission.

13 Signs and stages of general anethesia:

Generally the anesthetic effects are divided into four stages of increasing depth of central nervous
system depression.
13.1 Stage I (stage of analgesia):
It begins with administration of anesthetics and lasts till consciousness is lost.
• Initially there is analgesia without amnesia.
• Later both analgesia and amnesia ensures.
13.2 Stage II (stages of excitement):
It starts after loss of consciousness and proceeds to the beginning of surgical anesthesia.
i. Patient appears to be delirious and excited but is amnesic.
ii. Respiration is irregular both in volume and rate.
iii. Nausea and vomiting may occur.
iv. Incontinence and struggling may occur.
v. Pulse becomes rapid.
vi. B.P is increased due to increase in level of circulating catecholamine.

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13.3 Stage III (stage of surgical anesthesia):
It begins with the recurrence of regular respiration and normal B.P and extends to complete
cessation of spontaneous respiration.
Stage III is subdivided into four planes in terms of changes in ocular movements, eye reflexes
pupil size which under specified conditions may represent signs of increasing depth of anesthesia.
13.4 Stage IV (stage of medullary depression):
When spontaneous respiration ceases, stage IV is present. This stage of anesthesia includes severe
depression of the vasomotor centre (the vasomotor center is the portion of medulla oblongata
together with the cardiac centre and respiratory center that regulates blood pressure and other
homeostatic processes) in the medulla as well as the respiratory center. Without full circulatory
and respiratory support, death rapidly ensures.
14 Classification:
General anesthesia are classified as:
1. Inhalational agents:
A-Volatile liquids:
a) Ethers:
i. Diethyl ether
ii. Divinyl ether
b) Halogenated agents:
i. Halothane
ii. Chloroform
iii. Enflurane
iv. Tricholoroethylene
v. Ethyl chloride
B- Gases:
i. Nitrous oxide
ii. Cyclopropane
2- Intravenous agents:
A-Thiobarbiturates:
i. Thiopental
ii. Methohexital
B-Benzodiazepines:
i. Diazepam
ii. Midazolam
iii. Lorazepam
C-Neuroleptics and opioid analgesics:
i. Droperidol

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 ii. Fentanyl citrate
D-Arylcyclohexylamine:
i. Ketamine

E-Micellaneous:
i. Etomidate
ii. Disopropofol
3- Basal anesthetics:
i. Paraldehyde
ii. Tribromoethanol
iii. Trichloroethylene

1- Inhalational Anesthetics:
14.1 Method of synthesis:
14.2 1)Diethylether: (C2H5 -O-C2 H5 )
i- from alcohol:
C2 H5 OH + H2SO4→ C2 H5 HSO4 + H2O
C2 H5 HSO4 + C2 H5 OH → C2 H5 –O- C2 H5 + H2 SO4
( diethyl ether)
ii- from ethylene:
H2 C = C H2 + H2 SO4→C2 H5 HSO4
C2 H5 HSO4 + C2 H5 OH → (C2H5 )2 O + H2 SO4
( Diethyl ether)
14.3 2)Ethyl chloride:
C2 H5 OH + NaCl + H2 SO4→ C2 H5 Cl + NaHSO4 + H2 O
(ethyl chloride)

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14.4 3)Halothane:

14.5 4)Nitrous oxide:

NH4 NO3 (2000C)→ N2 O + 2H2 O

14.6 5)Chloroform:
It may be prepared from bleaching powder and ethanol after a series of chemical reaction.
CaOCl2 + H2 O →Ca(OH)2 + Cl2
(Bleaching powder) (slaked lime)
C2 H5OH +Cl2→ CH3 CHO + 2HCl
CH3 CHO + 3Cl2→ Cl3C . CHO + 3HCL
(trichloroethanal)
2Cl3C . CHO + Ca (OH)2→ 2CHCl3 + (HCOO)2 Ca
(chloroform)
14.7 6)Cyclopropane:

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14.8 7)Trichloroethylene:

15
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17 Pharmacological Actions:
A- Effect on CVS:
• Decreased arterial blood pressure.
Increased cutaneous blood flow.
• Depressed mayocardial contractility.
• Decreased cardiac sympathetic activity i-e, bradycardia.
• Interference with norepinephrine action, thus antagonises the sympathetic response to
hypotension.
• Increased cardiac automaticity especially in presence of adrenergic agonists, cardiac
diseases, hypoxia and electrolyte abnormalities.
B- Effect on central nervous system:
• Dilation of cereberal blood vessels, thus increasing cerebral blood flow and CSF pressure.
• Shiveringoccur during recovery.
C- Effect on respiratory system:
• Respiration becomes rapid and shallow.
• Minute volume is reduced
• Ventilatory response to CO2 is decreased
• Bronchodilation occurs
• Depressed airway mucociliary functions
D- Effect on kidney:
• Decreased glomerular filtrationrate (GFR) and effective renal plasma flow and increased
filtration fraction.
E- Effect on liver:
• Decreased hepatic blood flow ranging from 15-45% of the preanesthetic flow.
F- Effect on uterine smooth muscle:
• Relaxation of uterine muscle

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18 Uses:
• Inhaled anesthetics are rarely used alone. They are usually combined with IV agents and
the combination called “Balanced Anesthesia”
• Halothane is not used in adults but still used in pediatric anesthesia.
• Chloroform is not used now because of hepatoxicity.
• Cyclopropane and diethyl ether were previously most commonly used but now no longer
used because of their flammable and explosive characteristics.

19 Toxicity:
1) Acute toxicity:
• Hepatoxicity
• Nephrotoxicity
• Malignant hyperthermia ( it is an autosomal dominant genetic disorder of skeletal muscle
includes tachycardia and severe hypertension, severe muscle rigidity, hyperthermia,
hyperkalemia, acid-base imbalance)
2) Chronic toxicity:
• Mutagenicity (that damage DNA)
• Carcinogenicity (causing cancer)
• Hematotoxicity ( destruction of RBCs)

2- Basal Anesthetics:
It represents a degree of anesthesia short of surgical stage i.e, the patient is unconscious but yet
not sufficiently depressed for surgical operations.
19.1 1)Tribromoethanol:

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19.2 2)Paraldehyde or 2,4,6 trimethyl-s-trioxame:

It is cyclic acetal of acetaldehyde.

20 Uses:
+Basal anesthesia
+For preanesthetic medication to produce hypnosis.

20.1 3)Trichloroethylene:

LOCAL ANESTHETICS
(Drugs that eliminatepain locally)
21 Anesthetics:
Anesthetics are the agents which causes a loss of sensation with or without producing the loss of
consciousness.
22 Local Anesthetics:
Local anesthetics are the agents which when applied topically or parenterally to a localized area,
produce a condition of local anesthesia by reversibly blocking the nerve conductance that transmit
the feeling of pain from this locus (affected area) to brain.

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23 Mechanism of action of local Anesthetics:
Local anesthetics bind to receptor near intracellular ends of Na-channels. This results in the
blockade of sodium current, resulting in:
1. Increase threshold for excitation
2. Slow impulse conduction
3. Decline of rate of rise of action potential
4. Decrease action potential amplitude
5. Blockade of ability to generate action potential
All these effects results in the loss of pain sensation as well as impairment of motor functions.
24 Characteristics for ideal local Anesthetics:
An ideal local anesthetic should possess following characteristics:
1. It should produce reversible blockade of sensory nerve fibers with minimal effect on the
motor fibers
2. It should have rapid onset of action and prolonged sufficient duration of action for the
completion of major surgical procedures without any systemic toxicities.
25 Classification of local Anesthetics:
Chemically local anesthetics are classified into two main classes:
I. Esters:
• Cocaine
• Procaine
• Tetracaine
• Benzocaine
II. Amides:
• Lidocaine
• Mepivacaine
• Ropivacaine
• Bupivacaine
• Etidocaine
• Prilocaine
26 Pharmacological Actions of Local Anesthetics:
I. Effect on nerves:
• Local anesthetics preferentially block the small fibers because the distance over which such
fibers can previously propagate an electrical impulse is shorter. E.g, Type B (preganglionic
fibers) are blocked before Type C (dorsal,pain fibers and sympathetic post ganglionic
fibers).
• Myelinated nerves are blocked before unmyelinated nerves.
• In large nerve trunks ,motor nreves are blocked first because they are located
circumferentially.
• In extremities, proximal sensory fibers are blocked before the distal sensory fibers.

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 II. Effect on other excitable membranes:
• Local anesthetics have weak neuromuscular blocking effects
• They have antiarrhythmic activity.
27 Adverse effects of local Anesthetics:
I. CNS:
• Euphoria
• Sleepiness
• Headache
• Visual disturbance
• Auditory disturbance
• Restlessness
• Shivering
• Convulsions
• Depression
II. CVS:
• Hypotension
• CV collapse
III. Respiratory system:
• Respiratory depression
IV. Blood:
• Methemoglobinemia
V. Allergic reactions: are present
28 SAR of local anaesthetics:
1) Lipophilic portion of the molecule is essential for local anaesthetic activity.
2) In case of Amino esters (e.g., benzocaine, procaine) an electron donating substituent in
ortho- and para- or both positions increase local anaesthetic potency whereas in Meta
position only decrease the lipophilicity of molecule.

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 3) Electron withdrawing groups (such as –NO2, -C=O-, -C≡ 𝑁 ) decreases local anaesthetics
activity.
4) Insertion of methylene group (-CH2-) between aromatic moiety and carbonyl function in
procaine, decrease the local anaesthetics activity.
5) Lengthening alkylene chain in lidocaine decreases the local anaesthetics activity.
6) In amides, the O, O-dimethyl group (e.g., in lidocaine) resist amide hydrolysis, thus,
increases the duration of action
7) Tertiary amine series (hydrophilic portion) is needed only for formation of water soluble
salts.
8) Local anaesthetics with higher lipid solubility and lower pKa values show more rapid onset
and lower toxicity.

Details of some local anesthetics:

I. Benzocaine: (synthesis)

28.1.1 Clinical uses:

It is used for topical anesthesia.
28.2 Procaine hydrochloride:
28.2.1 Synthesis:
It can be prepared by two methods.But method 2 is more preferable.

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 28.2.2 ( I )

( II )

28.2.3 Clinical uses:

• Topical anesthesia
• Infilteration anesthesia
• Nerve block anesthesia
• Spinal anesthesia

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 I. Lidocaine or Xylocaine or Lignocaine Hydrochloride:
28.2.4 Synthesis:

28.2.5 Clinical uses:

It is used for
• Topical anesthesia
• Infiltration anesthesia
• Nerve block anesthesia
• Spinal anesthesia
• Arrhythmia

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