ß- Adreno blockers

INTRODUCTION

The adrenergic receptors (adrenoceptors) are a class of G-protein coupled

receptors, which are the targets of catecholamines. Adrenergic receptors
specifically bind their endogenous ligands, the catecholamines, epinephrine, and
norepinephrine (also called adrenaline and noradrenaline), and are activated by
these. The term adrenoblocker refers to drugs that are capable of competing with
catecholamines and other adrenomimetics for binding with adrenergic receptors,
thus blocking effects of sympathetic nerves caused by either stimulation by
endogenic sympathomimetics or generated by adrenergic drugs of exogenic origin.
True adrenoblockers do not affect the process of norepinephrine (noradrenaline)
synthesis in the organism.
Adrenoblocking drugs are classified as α-adrenoblockers, β-adrenoblockers,
and adrenergic neuron blockers depending on the response brought about in the
organism. α-Adrenoreceptors cause dilation of peripheral blood vessels, and a few
of them relax smooth muscles. On the other hand, β-adrenoblockers have a minor
effect on vascular tonicity. In addition, β-adrenoblockers prevent the vasodilatory
effect of epinephrine. In organs such as the heart, which are regulated mainly by β-
adrenoreceptors, β-adrenoblockers counteract the excitatory effect of
norepinephrine.
In turn, α- and β-adrenoblockers are subdivided into selective and nonselective
groups. Nonselective β-adrenoblockers exhibit affinity for both β1- and β2-
adrenoreceptors. Included in this category are propranolol, nadolol, timolol, and
labetalol (a combined α- and β-adrenoblocker). Selective β1-blockers are acebutol,
atenolol, esmolol, and metoprolol, which in therapeutic doses predominantly binds
to β1-adrenoreceptor regions. Currently, there are no therapeutically useful

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ß- Adreno blockers
selective β2- adrenoblockers, although a number of experimental compounds with
expressed β2-adrenoblocking activity already exist.
Drugs that exhibit reversible competitive blocking action on β-adrenoreceptive
receptor system and that counteract effects of catecholamines are called β-
adrenoblockers. These drugs selectively reduce cardiostimulatory, vasodilating,
broncholytic, and metabolic (glycogenolytic and lipolytic) action of
catecholamines released from adrenergic nerve endings and adrenal glands.
β1-Receptors are present in heart tissues, and cause an increased heart rate by
acting on the cardiac pacemaker cells. Many β-blockers used for treatment of
angina will mainly affect these receptors and the β2-receptors to a lesser extent.
These are referred to as ‘cardio-selective’ β-blockers.
β2-Receptors are in the vessels of skeletal muscle, and cause vasodilation,
which allows more blood to flow to the muscles, and reduces total peripheral
resistance. These tend to work with epinephrine (adrenaline), but not
norepinephrine (noradrenaline). β2-Receptors are also in bronchial smooth muscle,
and cause bronchodilation when activated. Some antiasthma drugs, such as the
bronchodilator salbutamol work by binding to and stimulating the β2-receptors.
Nonselective β-blocking drugs, such as propranolol, can represent a risk to people
with asthma by blocking the β2-receptors, causing bronchoconstriction.
Introduction of β-adrenoblockers into medicine was one of the main
advancements of pharmacology of the cardiovascular system. Initially these drugs
were used only in treating essential hypertension. Currently, they are used in
treating angina, arrhythmia, migraines, myocardial infarctions, and glaucoma.
Their efficacy in many illnesses is explained by the competitive binding of β-
adrenoreceptors in the autonomic nervous system by basically any of the employed
drugs of the 1-aryloxy-3-aminopropanol-2 class, which result in reduction of heart
rate and strength of cardiac beats, slowing of atrioventricular conductivity,

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ß- Adreno blockers
reduction of the level of renin in the plasma, and reduction of blood pressure. The
main effects of β-adrenoblockers are expressed at the level of the vasomotor center
in the hypothalamus, which result in a slowing of the release of sympathetic, tonic
impulses.
Practically, all of them are derivatives of 1-aryloxy-3-aminopropanol-2, the C1
position of which always possesses a substituted or nonsubstituted aromatic or
heteroaromatic group connected by an ether bond to a three-carbon chain. An R
group at the nitrogen atom of the propanoic region must be represented as either a
tertiary butyl group (nadolol, timolol), or an isopropyl group (the remainder of the
drugs).
Levorotatory isomers of these drugs are much more powerful adrenoblockers
than dextrorotatory isomers; however, all of these drugs are made and used as
racemic mixtures. The examined drugs reversibly bind with β-adrenergic receptive
regions and competitively prevent activation of these receptors by catecholamines
released by the sympathetic nervous system, or externally introduced
sympathomimetics. It is important to note that selectivity is not absolute, and it
depends on the administered dose. In large doses, selectivity is even and both
subtypes of β-adrenoreceptors are inhibited equally. In addition to blocking β-
adrenoreceptors, these drugs affect the cardiovascular system in a different
manner. In addition, β-blockers prevent the release of renin, which is a hormone
produced by the kidneys which leads to constriction of blood vessels. Drugs that
block β2-receptors generally have a calming effect and are prescribed for anxiety,
migraine, esophageal varices, and alcohol withdrawal syndrome, among others. β-
Adrenoblockers are most widely used in treating angina, hypertonic diseases,
tachycardia, and arrhythmia.

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ß- Adreno blockers

CLASSIFICATION

β-adrenoblockers can be classified in the following ways:

A. Based on their structures:

1.Arylethanolamines:

E.g: Dichloroisoproterenol.

2.Aryloxypropanolamines:

E.g:Propranolol,
Nadolol,
Practolol,
Metoprolol.
B.Classification of β-Blockers based on receptor selectivity :

1.Non-selective β-Blockers:

E.g:Propranolol ,
Nadolol,
Timolol,
Pindolol.
2.Selective β-Blockers:
a.Selective β1-Blockers:
E.g: Atenolol,
Acebutolol,
Metoprolol.
b.Selective β1-Blockers:

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ß- Adreno blockers
E.g:Butoxamine.

STRUCTURES
Structures of β-adrenoblockers are discussed in the following table 1.
Table 1: Structures
GENER
C IUPAC NAME STRUCTURE
NAME

Propr 1-(iso
anol propylamino)-3-(1-
naphthyloxy)-2-propanol

5-[3-(tert-butylamino)-2-
hydroxypropoxy]naphthalene
Nadolol -2,3-diol

1-(tert-butylamino)-3-[(4-
Timolol morpholin-4-yl-1,2,5-
thiadiazol-3-yl)oxy]
propan-2-ol

1-(tert-butylamino)-3-(2,3-
Pindolol dihydro-1H-indol-4-
yloxy)propan-2-ol

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ß- Adreno blockers

5-[3-(tert-butylamino)-2-
Carteolol hydroxypropoxy]-3,4-
dihydroquinolin-2(1H)-one

2-{4-[3-(tert-butylamino)-
Atenolol 2hydroxypropoxy]phenyl}
acetamide

N-{3-acetyl-4-[2-hydroxy-
Acebutolol 3(methylamino)propoxy]
phenyl}butanamide

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ß- Adreno blockers

1-[4-(2-
Metoprol methoxyethyl)phenoxy]-3-
ol [(1methylethyl)amino]propan
-2-ol

4-(4-{2-hydroxy-3-[(1-
Esmolol methylethyl)amino]
propoxy}phenyl)
butan-2-one

Bisop 1-{4-[(2-
rolol methoxyethoxy)methyl]phe
noxy}-3-[(1-
methylethyl)amino]
propan-2-ol

B 2-(tert-butylamino)-1-(2,5-
utoxamine dimethoxyphenyl)
propan-1-ol

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ß- Adreno blockers

STRUCTURE-ACTIVITY RELATIONSHIP OF β- BLOCKERS

β-Blockers are structurally similar to β-agonsits. The catechol ring can be replaced
by a variety of ring systems without loss of antagonistic activity.

Ar O CH2 CH CH2 NH R
OH
Basic structure to explain β-blockers .

1.Substitution on the ring system

 Replacement of catechol hydroxyl (—OH) groups with chlorine (Cl) or
phenyl ring system retains β-blocking activity.
E.g : Dichloroisoproterenol,
Pronethalol.

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ß- Adreno blockers

 Unfortunately dichloroisoproterenol could not be used clinically, because it

was found to exhibit partial agonist activity,which proved that it was not a
pure antagonist.Pronethalol was also withdrawn from the market, because of
its thymic tumours in mice.
 Substituents on aromatic ring in the para position and no substituents on
meta positon is responsible for cardioselective antagonist activity.

E.g : Practolol.

Practolol

 The catechol ring system of adrenergic agonists when replaced by various

substituted phenyl rings in aryloxypropanolamines, gives rise to different
antagonists.
E.g : Pindolol.

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ß- Adreno blockers
OH

O CH2 CH CH2
(H3C)2 CH2 CH2

N
H
Pindolol

Labetalol

2.Introduction of the oxymethylene bridge

 The failure of pronethalol urged the scientists to discover clinically useful β
antagonists, thus propranolol was discovered.
 Incorporation of —OCH2—group into the molecule between the aromatic
ring and the ethylamine side chain provides β-blocking agents. Propranolol
differs from pronethalol , that it contains an oxymethylene bridge in the
arylethanolamine chain of pronethalol.
E.g:Propranolol

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ß- Adreno blockers

Propranolol
 Introduction of oxymethylene bridge is responsible for the compounds with
greater potency.
3.Substitution on the side chain
 Presence of two carbon side chain is necessary.
 Hydroxyl (OH) group present on the β carbon atom is essential for the
activity.
 Any modification in the side chain can reduce the activity of the beta
blockers.
3.Substitution on the amino nitrogen
 Nitrogen atom should be secondary for specific β-blocking activity. N, N-
Disubstitution decreases β-blocking activity.
 Activity is maintained when phenylethyl, hydroxyphenyl ethyl or
methoxyphenylethyl groups are added to amine part of the molecule.
 As carbon chain becomes larger than butyl, affinity for β receptors increases,
but not intrinsic activity, which means large lipophilic groups can afford
compounds with β-blocking activity.
E.g : labetalol

Labetalol

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ß- Adreno blockers
 In addition, the N-substitution can also provide selectivity for different β-
receptors.
4. Stereoisomerism
 β-Blockers exhibits a high degree of stereoselectivity in the production of
their β-blocking effects.
 The carbon of side chain bearing hydroxyl group must be (s)-configuration
for optimal affinity to the β-receptor.
 Levo isomer of propranolol is 100 times more active than dextro isomer.
 First pass effect is substantial and 4-OH metabolite is active.
 Propranolol is a mixed β-blocker. S-isomer is most active.
E.g : Propranolol

Propranolol
 4-Hydroxypropranolol is a short acting β-antagonist. It also posess some
intrinsic sympathomimetic activity.

E.g : 4-Hydroxypropranolol

4-Hydroxypropranolol

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ß- Adreno blockers
 Timolol is a selective β-blocker, acts on β1-adrenergic receptors.
E.g : Timolol

Timolol

 Metoprolol is moderately lipid soluble. Metoprolol is β1-selective

antagonist.
E.g : Metoprolol

Metoprolol

 Atenolol has significantly fewer CNS side effects compared to propranolol.

Atenolol is hydrophilic β1-selective antagonist.
E.g : Atenolol

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ß- Adreno blockers

Atenolol

MECHANISM OF ACTION

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ß- Adreno blockers
The beta blockers have the similar structure to that of the of the agonist.the
agonist generally bind to the receptor and then activates the G-protien receptor
present in the cell membrane.the activation is done by the conversion of the GDP
to GTP.These activated receptors exhibit the strong or moderate action.The
blocking agents competitively bind to the receptor and thus block the receptor for
the agonists.The mechanism of the beta blockers can be explained by the following
figures.

Figure-1

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ß- Adreno blockers
Figure-2

β-Blocker acts by inhibiting the adenylate cyclase enzyme

Causes decreased levels of CAMP

Cause decrease in intracellular calcium ions

Decreasing plasma calcium levels

Leading to negative chronotropic and ionotropic effects.

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ß- Adreno blockers

PHARMACOKINETICS
The pharmacokinetics of some of the drugs are discussed in the following table 2.

Table No:2 - Pharmacokinetics

DRUGS ABSORPTION FATE ELIMINATION

Highly lipophilic,
Under goes high first Extensively
completely absorbed
Propranolol pass metabolism, only metabolized, with
after oral
about 25% reaches the most metabolites
administration.
systemic circulation. appearing in the
urine.

Metabolized
Well absorbed from Only a small
Timolol extensively by
the gastrointestinal amount of
CYP2D6 in the
tract. unchanged drug
liver and
appears in the
undergoes first-
urine.
pass metabolism.
Almost Approximately unchanged
Pindolol completely 50% of pindolol drug appears
absorbed after ultimately is in the urine.
oral metabolized in
administration. the liver.

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ß- Adreno blockers

Completely Metabolized Only 10% of the

absorbed after extensively by administered drug
Metoprolol oral CYP2D6 in the is recovered
administration, liver and unchanged in the
but undergoes urine.
bioavailability first-pass
is relatively metabolism.
low
Most of the The drug is
absorbed dose excreted largely
Incompletely
Atenolol absorbed reaches systemic unchanged in the
(about 50%)
circulation. urine.

undergoes unchanged drug is

well absorbed significant
excreted through
Acebutolol after oral first-pass
administration metabolism to urine.
an active
metabolite,
diacetolol.

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ß- Adreno blockers

PHYSICAL PROPERTIES
Table – 3: Physical properties

Drug Mol.Wt Appearance M.P(°C) Solubility

(g/mole)

Solid,
Propranolol cold water
295.81 Colourless 162

Solid,
Timolol cold water
432.49 Colourless 199

Solid,
Nadolol
309.4 Colourless 124 cold water

Solid,
Pindolol
248.33 Colourless 172 hot water

Solid,
Metoprolol
684.81 Colourless 685 cold water

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 ß- Adreno blockers

Solid, slightly
Atenolol
266.38 Colourless 147 soluble in
water.

Acebutolol Solid,
336.426 Colourless 121 cold water

THERAPEUTIC USES AND ADVERSE EFFECTS

Therapeutic uses and adverse effects of some β- blockers.

Table No: 4 – Therapeutic uses and adverse effects

Drug Therapeutic uses Adverse effects

name

.Angina pectoris .Bradycardia

Propranol
.Hypertension .Bradyarrhythmias
.Cardiac arrhythmias .Bronchoconstriction
ol .CHF
.Glaucoma

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ß- Adreno blockers

Timolol
.Glaucoma .Reduces the production of
.Angina pectoris aqueous humour in the eye.

.Hypertension .Insomnia.
.Myocardial infarction .Bronchoconstriction

. Angina pectoris .Bradycardia

.Hypertension
Pindolol .Cardiac .Bradyarrhythmias
.Hyperthyroidism .Bronchoconstriction
.Migraine .Fatigue

.Blood pressure .Contraindicated for the

treatment of acute myocardial
Metoprolol .Myocardial infarction infarction
.chronic heart failure .Fatigue
.Bradyarrhythmias
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ß- Adreno blockers

.Angina pectoris .Bradycardia

Atenolol .Hypertension .Bradyarrhythmia
.Cardiac arrhythmias .Fatigue

.Angina pectoris .Shows partial agonist activity

Acebutolol .Hypertension .Myocardial infarction
.Cardiac arrhythmias .Fatigue
.Bradyarrhythmias

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ß- Adreno blockers

.Angina pectoris .Bradycardia

.Hypertension
Nadolol
.Cardiac arrhythmias .Bronchoconstriction
.CHF .Fatigue

SYNTHESIS
Synthesis of some β-adrenoblockers are shown below
1.Propranolol

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ß- Adreno blockers

2. Timolol
O
O
S CH2 Cl S
H2N C C N + S2Cl2 N N
piperidine
HN NH
OH
CYANOFORMAMIDE
Cl OH Cl O
Cl
H2NC(CH3)2

O
H
N
N
CH2CHOHCH2NHC(CH3)3
CH2CHOHCH2NHC(CH3)3 Cl
O

N NH
N NH
S
S
Timolol

3. Nadolol

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ß- Adreno blockers
OH
OH OH
HO
N a A g O 3C O C H
l i q 3 N H
HO
1 - Napthol
O
CH2
Cl

O CH2 CH2 OH O CH2 CH OH

HO H 2C Cl H 2C Cl
H 2N C 3 )( 3 C H

HO
Nadolol

4. Pindolol
OH

O C H2 C H C H2
OH
O O C H2 (H3C )2
C H2 Cl C H2 C H2
N aO H

N N
(C H2)C H N H2
H H N
4 - H ydroxy indole H
P indolol

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ß- Adreno blockers

5. Metaprolol

H3CO(H2C)2 H3CO(H2C)2
(CH3)2CHCH2Cl
O

OH O CH2
P - (2 - Methoxy ethyl)-Phenol
( C 3 ) 2HC H 2 N H

H2CO CHOH
CH2
NH
CH(CH3)2

H3C O (CH2)2

Metaprolol

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ß- Adreno blockers

6.Atenelol
OH OH
OH

N a C l / N a O H H 2O

D M F / H e a t

HC COOH H2 C C N O
H2 C CONH2
NH2
1. Cl CH2
D,L - 4 hydroxy Phenyl glycine
2. (CH3)2CHNH2

O CH2 CH(OH)
CH2
HN CH(CH3)2

CH2CONH2

Atenolol

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ß- Adreno blockers

7. Acebutolol

OH OCOCH3 OH
COCH3
CH3COCl AlCl3

HCl fries
-
NHCO(CH2)2CH3 NHCO(CH2)2 CH3
NHCO(CH2)2CH3
-
4 Butyramidophenol O
(CH3) 2CHNH2
Cl CH2 H2C CH2

CH3OCH2CH(OH)CH2NHCH(CH3)2

COCH3

NHCO(CH2)CH3

Acebutolol

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ß- Adreno blockers
ESTIMATIONS
Estimations of some of the β-adrenoblockers are shown below

Propranolol hydrochloride

Weigh accurately about 0.25gm

Dissolve in 25 ml of ethanol(95%)

Titrate with 0.1M sodium hydroxide

Determine end point potentiometrically

Carry out a blank titration

1 ml of 0.1M sodiumhydroxide is equivalent to 0.02958g of C16H21N02.HCl

Timolol maleate

Weigh accurately about 0.25g

Dissolve in 25ml of ethanol (95%)

Titrate with 0.1M sodium hydroxide

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ß- Adreno blockers
Determine end point potentiometrically

Carry out a blank titration

1ml of 0.1M perchloric acid is equivalent to 0.04325gm of C13H24N4O3S.C4H4O4

Metaprolol tartarate

Weigh accurately about 0.3gm

Dissolve in 30ml of glacial acetic acid

Titrate with 0.1M perchloric acid

Determine end point potentiometrically

Carry out a blank titration

Atenolol

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ß- Adreno blockers

Weigh accurately about 0.2gm

Dissolve in 80 ml of anhydrous glacial acetic acid

Titrate with 0.1M perchloric acid

Determine end point potentiometrically

Carry out a blank titration

1ml of 0.1M perchloric acid is equivalent to 0.02663 gms of C14H22N2O3

1ml of 0.1M perchloric acid is equivalent to0.03424gms of (C15H25NO3)2.C4H6O6

Acebutolol hydrochloride

Weigh and powder 20 tablets.

Weigh accurately a quantity of the powder containing about 0.1gm of acetobutolol
hydrochloride

Shake with 40ml ofHCl and add sufficient water to produce 100 ml.

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ß- Adreno blockers
Filter and dilute 10ml of the filtrate to 100ml with water

Measure the absorbance of resulting solution at the maximum at about 233nm

Labetalol hydrochloride

Weigh accurately about 0.2gm

Dissolve in 10 ml of anhydrous formic acid and 40 ml of acetic anhydride

Titrate with 0.1M perchloric acid

Determine end point potentiometrically

Carry out a blank titration

1ml of 0.1M perchloric acid is equivalent to 0.03649gms of C19H24N2O3.HCl

Note: Mix thouroughly throughout the titration and stop the titration immediately
after the end point is reached.

Calculate the content of C18H28N2O4.HCl, taking 580nm as the specific absorbance

at 233nm.

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ß- Adreno blockers
CONCLUSION
So far we have gone through β-adrenoblockers. In this we have discussed
about the classification of β-adrenoblockers. It is classified as selective and non
selective. Secondiy we have discussed about the SAR of β-adrenoblockers.In the
basic structure of the β-adrenoblockers, the substitution on aromatic ring in the
para position is responsible for cardio selective activity. The presence of
oxymethylene bridge is responsible for β-blocking activity. The presence of
hydroxyl group on the β-carbon is essential for the activity. β-Blockers exhibits a
high degree of stereoselectivity in the production of their β-blocking effects. E.g :
Levo isomer of propranolol is 100 times more active than dextro isomer. Thirdly
we discussed the MOA of the β-Blockers, where the β-Blockers competetively
binds with the receptor and inactivates the G-protein coupled receptor which
results in the inhibition of Ca2+ inflow. This results in negative ionotropic and
chronotropic effects. Fourthly we discussed about the pharmacokinetics, physical
properties, uses and adverse effects of some β-Blockers. Fifthly we have seen the
synthesis of some of the β-Blockers such as Propranolol,Nadolol,Timolol ,
Pindolol, Atenolol, Acebutolol and Metoprolol. Lastly we have seen the estimation
of some the above discussed β-Blockers.

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ß- Adreno blockers
REFERENCES
1. Modern Pharmacology with clinical Applications.Charles R. Craig. Fifth
Edition.

2. Pharmacokinetics.Milo Gibaldi.Second edition revised and Expanded.

3. An Introduction to Medicinal Chemistry.Graham L. Pattrick.

4. The Pharmacological basis of Therapeutics.Goodman and Gillman.11th

Edition.

5. Pharmacology.Rang and Dale. Sixth edition.

Appendix-1

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ß- Adreno blockers
Full form of the abbreviation

1. Ar. – Aromatic ring system

2. E.g – Example

3. S.A.R – Structure Activity Relationship

4. Mol.Wt – Molecular weight

5. M.P – Melting Point

6. G.T.P – Guanine Tri Phosphate

7. G.D.P – Guanine Di Phosphate

8. CAMP – Cyclic Adenosine Mono Phosphate

9. Ca2+ - Calcium Ion

10. β – Beta

11. α - Alpha

12. M – Molar Concentration

13. ml – Millilitre

14. gm – Gram

15. nm - Nanometer

16. CHF-Cardiac heart failure

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