Medicinal chemistry 1

Code: CPM2201
Lecture 9

Pharm D Clinical Pharmacy

Faculty of Pharmacy
Nahda University

Pharmaceutical Chemistry Department

A. Diuretics 4

1.Site of action
Renal Nephron

2. Mechanism of action 1
urinary Na+ excretion

urinary water excretion

3
5
Extracellular fluid and /or
plasma volume 2

3. Effect on CV system
acute decrease in CO

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 Classification of Diuretic Drugs
Class Drug Tubular segment
Carbonic anhydrase Acetazolamide Proximal convoluted (1)
Inhibitors
High - Ceiling Furosemide, Loop (3)
Bumetanide,
Ethacrinic acid
Thiazides Hydrochlorothaiazide, Distal convoluted (4)
Bendroflumethiazide,
Chlorthalidone

Potassium sparing Spironolactone; Collecting duct (5)

Triamtrine;
Amiloride
Osmotic agents Mannitol 1, 2, 3, 5

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carbonic anhydrase inhibitors
1. Acetazolamide
Prototype; Developed from sulfanilamide, after
it was noticed that sulfanilamide caused
metabolic acidosis and alkaline urine.

MOA:
Inhibit carbonic anhydrase in
proximal tubule; blocks reabsorption
of bicarbonate ion, preventing Na+/H exchange.

Therapeutic Uses
Urinary alkalinization; Metabolic alkalosis
Glaucoma: acetazolamide, dorzalamide
Acute mountain sickness
 2. Diclofenamide
4, 5-Dichloro-m-benzenedisulphonamide
• Diclofenamide is employed to lower intraocular
pressure by reducing the rate of secretion of
aqueous humor.
• It is recommended for the treatment of both primary and
secondary glaucoma.

3. Dorzolamide (Trusopt®)
It is an anti-glaucoma agent and topically
applied in the form of eye drops; market
introduction 1995
Dorzolamide hydrochloride is used to lower
increased intraocular pressure in open-angle
glaucoma and ocular hypertension.
 High – Ceiling (Loop diuretics)
Members of this class
• Furosemide
• Bumetanide
• Ethacrinic acid
First line treatment of hypertension
• The diuretics that belong to this class are of extremely diverse
chemical structure, such as:

• The 5-Sulfamoyl-2- and -3-aminobenzoic acid

derivatives. Examples, furosemide and bumetanide

• 6 Phenoxyacetic acid derivatives as ethacrynic acid

 Loop diuretics
• Act by inhibition of Na+, K+, and Cl- reabsorption from the
ascending limb of the loop of Henle in the renal tubule.

• They also tend to reduce renal Ca+ reabsorption, thus they

are used in treatment of hypercalcemia.
• High efficiency diuretics.
• High ceiling diuretics.( what is mean? )

Furosemide (lasix)
O O O
S
H2N OH
O
Cl N
H
 Mechanism of Action:
They inhibit the 1Na+/1K+/2Cl- cotransport system located on the
luminal membrane of cells of the thick ascending limb of Henle’s
loop

Adverse Effects: Luminal membrane

Basolateral membrane

1. Hypokalemic alkalosis. Na Na

2. Fluid and electrolyte losses 2Cl ATP

K K
3. Reduction in plasma volume
may result from long-term use Na K
of these diuretics. H Cl
4.Hypersensitivity reactions such
as urticaria, fever, and
interstitial nephritis. K Cl

Na

Urine Blood
 Bumetanide
HN Bu
3- Butylamino-4-phenoxy-5-
sulfamoylbenzoic acid O 3
4
5 1

H2NO2S COOH

The framed groups are the important structural requirements

in furosemide and in bumetanide :
5- sulfamoylbenzoic acid
Substituted basic aminogroup at position 2 or 3
Activating e-withdrawing group at position 4
pKa = 5.2; 10.0
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 Ethacrinic acid
Cl
H3C Cl O COOH

H2C
O

It is a phenoxy acetic acid derivative containing 2-

ethylpropenoyl group
Ethacrynic acid is prescribed for individual who has a
known hypersensitivity to Sulfamoyl containing drugs
pKa = 3.5

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 The methylene group in ethacrinic acid forms
an adduct with the free sulfhydryl (SH)
containing compounds as glutathione (GSH).
The adduct appears to be an active form of
ethacrinic acid.
Cl Cl
H3C Cl O COOH H3C Cl O COOH

GSH CH
H2C H2C
O O
SG

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 Thiazides
Members of this class
Hydrochlorothiazide,
Bendroflumethiazide ,
Chlorthalidone.
Compete for the chloride binding site of the
Na+Cl- and inhibit the reabsorption of sodium and
chloride ions in the distal convoluted tubules.
Used for patients with mild or moderate
hypertension and normal renal and cardiac
functions

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Class 3: Thiazide and Thiazide-like diuretics
O O O O

H2NS SNH2

Cl NH2
Chloraminophenamide

Aldehydes
Acylating Agents (or Ketones)

O O O O O O O O

H2NS S H2NS S
NH NH

Cl N R Cl N R
H

Thiazides Hydrothiazides
(Hydrochlorothiazide)
 K+ sparing diuretics
Members of this class
Spironolactone , Triamterene and Amiloride
The members of this group antagonize by different mechanisms the
effects of aldosterone (antidiuretic hormone) at the collecting system
and late distal tubule.

Potassium-sparing diuretics

Competitive
Blockers of the amiloride-sensitive
aldosterone
Na+ channels:
antagonists:
•Amiloride
•Spironolactone
14 •Triamterene
 OH OH
O HO O
O
CH O CH

Spironolactone HO

(Steroid nucleus)

Direct pharmacologic O O
aldosterone
antagonism of O
aldosterone receptors
O

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3 7 CH3
4
O S C
O

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 Potassium- Amiloride
Triamterene
sparing diuretics Spironolactone
3%

Often they are used

They have weak
in combination with
diuretic action
diuretics, causing
and save K+.
hypokalemia.
 O NH
H2N N N NH2
8 1
Cl N
1 N NH2
5 4 N 6 2 H
Ph N
4
H2N N NH2
NH2

Triamterene Amiloride
(pteridine nucleus) (pyrazine nucleus )
pKa = 6.2 pKa = 8.7
By inhibition of luminal Na+ ion channels in the distal
tubule the reabsorption of Na+ ion is blocked, and
block the secretion of K+ ions.
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 Osmotic Diuretics OH
OH
OH
Mannitol HO
OH
OH
* The prototypic osmotic diuretic,
• D-Mannitol is a water-soluble, lipid-insoluble hexahydroxy
alcohol.
• Mannitol enters renal luminal fluid only by glomerular filtration.

* Its high luminal fluid concentration creates an osmotic effect that

may prevent the reabsorption of up to 28% of the filtered load of
water.
• Taken only by IV injection because if taken orally can cause
diarrhea
 Cardiovascular Drugs
They are drugs that used for treatment of cardiovascular
diseases (heart diseases).

• Cardiovascular Diseases
Congestive Heart Failure
Angina pectoris
Arrhythmia
Hypertension
Blood Clotting
Atherosclerosis
Hyperlipidemia
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 Antihypertensive Drugs

Diuretics
Sympathetic (adrenergic) drugs:
- β-blockers; α1-antagonists (azocin group);
centrally acting α2-agonists (Clonidine); methyldopa.
Vasodilators: - Hydralazine; - Sodium nitroprusside
Calcium channel blockers nifedipine, diltiazem, verapamil
Drugs affecting the renin angiotensin system (RAS):
- Angiotensin converting enzyme inhibitors (ACEIs)
-Angiotensin II-antagonists.
 1) Sympathetic depressants
a- Centrally acting
1- α-Methyldopa (Aldomet)
2-Amino-3-(3,4-dihydroxyphenyl)-2-
methylpropionic acid
MOA: COOH
HO HO
L-aminoacid decarboxylase
NH2 NH2
1) - CO2
CH3 CH3
HO in the CNS HO
Methyldopa a-Methyldopamine
OH

HO
2) dopamine-hydroxylase NH2

CH3
HO
Methyl noeepinephrine

1- Decarboxylation in CNS. 2- Hydroxylation.

** Lead to the formation of a-methyl norepinephrine (active metabolite).
It interacts with central a2 adrenergic receptors decreasing sympathetic 21
 ** a-Methyl norepinephrine displaces NE in nerve terminal and
acts as a false transmitter.

** Methyldopa is suitable for oral use, it is a zwitter ion and is not

soluble enough for parental use. This problem was solved by
making the ester leaving the amino free to form water soluble
hydrochloride salt.

2- Clonidine hydrochloride (Catapress) Cl H

N
2-(2,6-Dichloroanilino)-2-imidazoline
NH
N
Cl

Clonidine is used to treat all degrees of hypertension, to

reduce intraocular pressure, to relieve migraine headache
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and some symptoms of menopause.
 2) Direct vasodilators
A- Arterial vasodilators
1- Diazoxide N CH3

NH
7-Chloro-3-methyl-2H- Cl S
O O
1,2,4-benzthiadiazine-1,1-dioxide

It is taken by I.V injection in emergency

(sodium salt).

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2- Minoxidil O

The N→O is essential for activity in human. H2N

3
4 N 2 NH2

The reduced form is inactive in

5 N1
human but active in cats and dogs. 6
N

Direct acting vasodilator prodrug activated by

metabolic sulfate conjugation to minoxidil sulfatein the liver.

• Another use:
- It is used locally in alopecia (stimulate hair growth).
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 B- Arterial and venous vasodilators
Sodium nitroprusside: (sodium nitroferricyanide)
-2
CN
CN
Na2(Fe(CN)5NO) [[ Na+ ]2 NC-Fe-CN
ON CN
Uses n

** In hypertensive crises, since it is the most potent given by

I.V injection used during surgery.
** It is vasodilator on both arterial and venous blood vessels
due to the release of NO.
** Also, it is used in congestive heart failure.
Toxicity is due to accumulation of thiocyanate (final metabolite).
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 Calcium channel blockers (CCB)
• Calcium plays a major role in the regulation of many cellular processes,
mainly in muscle contraction.
• The entry of extracellular Ca++ into the smooth muscle cytosol and their
release from the intracellular storage sites is very important for the
initiation of muscle contraction…..vasoconstriction…high blood pressure.
• Calcium channel blockers will interfere with the entrance of calcium in to
the cytosol…vasodilatation…reduce blood pressure.
• They act mainly on the L-type calcium channel (L for long lasting effect)
• After binding they cause conformational changes that affect Ca++
movement .
• The majority of calcium channel blockers are 1,4-dihydropyridine
derivatives.
 Calcium channel blockers
heart loads : nifedipine
heart rate and contractility : verapamil and diltiazem

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