CHAPTER FOUR

DIURETICS AND
CARDIOVASCULAR AGENTS
BY: TESFAYE.N (B.Sc,B.Pharm,M.Sc)

HARAMBEE UNIVERSITY,2022
1
 OUTLINE
1.Diuretics
Carbonic anhydrase inhibitors
High-ceiling or loopdiuretics
The thiazide and thiazide-like diuretics
Potassium-sparing and other diuretics
2.Antianginal agents
3.Anti-hypertensive agents
4.Cardiac glycosides and derivatives
5.Antiarrhythmic drugs
6.Antilipemic drugs
7.Coagulants & anticoagulants, and other cardiovascular drugs
TESFAYE. N 2
 DIURETI
CS
 Diuretics are drugs that promote the output of urine
excreted by kidney.
 Diuretics mainly promotes the excretion of the sodium
ions(Na+), chloride ions (Cl-) or bicarbonate ions(HCO3-) and
water from the body, the net result being increase the urine flow.
 These drugs act by decreasing tubular reabsorption.
• do not affect the glamerular filtration rate or the action of anti
diuretic hormone (ADH)

3
TESFAYE. N 3333
 Cont…

 Diuretics are very effective

 for the treatment of cardiac edema (CHF)

 nephrotic syndrome

 diabetes insipidus

 hyper tension

 nutritional edema

 edema of pregnancy

 cirrhosis of liver

 lower the intracellular and cerebrospinal fluid pressure.

TESFAYE. N 4433
 CLASSIFICATION OF DIURETICS
I. Carbonic anhydrase inhibitors (Site-I Diuretics)

II. High ceiling or Loop Diuretics (Site-II Diuretics)

III. Thiazide and Thiazide like Diuretics (Site-III Diuretics)

IV. Potassium sparing Diuretics (Site-IV Diuretics)

V. Xanthine Derivatives and Miscellaneous

Site-III

Site-I
Site-IV
Site-II

TESFAYE. N 5 5335
 A. Carbonic Anhydrase Inhibitors
(Site-I Diuretics)

Examples: Acetazolamide, Methazolamide, Dichlorphenamide

Disulfamide and Ethoxzolamide

Methazolamide
Acetazolamide

diclofenamide Disulfamide
TESFAYE. N 663
 Cont…

Structure Activity Relationship for CAI

 The free sulfamoyl nitrogen is important for diuretic activity.
 Substitution of the methyl group on one of the ring nitrogen
(Methazolamide) retains the activity.

 The heterocyclic sulphonamides have highest lipid/water

partition coefficient and lowest pKa values have greatest CA
inhibitory and diuretic activity.

 The benzene meta sulphonamide derivatives have activity only

when substituted with chlorine or methyl groups.

TESFAYE. N 773
 B. High ceiling or Loop Diuretics
(Site-II Diuretics)
Their major action is to reduce active Cl- reabsorption in the
ascending limb of the loop of Henle. I
Examples
 Organo mercurials – Chlormerodine mercury, Meralluride,
Mercaptomerin, Merethoxylline procaine, Mersalyl.
 5-Sulpamoyl & 2-Amino Benzoic acid derivatives- Bumetanide,
Furosemide,
 4-Amino-3-pyridine sulphonyl ureas- Torsemide, Triflocin.
 Phenoxy acetic acids- Ethacrynic acid.

Furosemide Ethacrynic acid Bumetanide

TESFAYE. N 8
 Cont…

Structure Activity Relationship for Loop diuretics

 5-sulfomoyl and 2-aminobenzoic acid group is required for
good diuretic activity.
 Substitution at 1st position must be acidic for good diuretic
activity.
 The activating group at 4th position can be Cl or CF3 group
increases the activity.
 Phenoxy, alkoxy, anilino, benzyl or benzoyl groups substituted
at 4th position decreases diuretic activity.
TESFAYE. N 9
 C. Thiazide and Thiazide like Diuretics (Site-III Diuretics)

Thiazide diuretics acts by inhibiting Na+ and Cl-

reabsorption at distal tubules

Examples
Chlorthiazide, Benzthiazide, Hydrochlorothiazide,
Hydroflumethiazide, Bendroflumethiazide,
Trichlormethiazide, Methyclothiazide, Polythiazide,
Cyclothiazide, Mefruside, Clopamide, Xipamide, Indapamide,
Quinethazone, Metolazone, Clorexolone, Chlortalidone.

TESFAYE. N 10
 Cont…

Thiazide and Thiazide like Diuretics (Site-III Diuretics)

chlorthiazide Hydrochlorthiazide Benzthiazide

Hydroflumethiazide Bendroflumethiazide Methylchlothiazide

TESFAYE. N 11
 Cont…

Structure Activity Relationship for Thiazides

 Thiazides having benzothiadiazine 1,1-dioxide with weakly
acidic character is important for good activity.

 Presence of electron withdrawing group at C-6 is necessity for

good diuretic activity. Substitution of chlorine at C-6 has good
activity.

 Substitution of CF3 group has more lipid soluble and larger

diuretic action than Chloro compound.

 Presence of electron donating groups like methyl or methoxy at

TESFAYE. NC-6 reduces the diuretic activity. 12
 Cont…

 Removal or replacement of sulphonamide at C-7 reduces

the diuretic activity.
 Saturation of double bond between 3&4 having 10 times
more diuretic activity than unsaturated analogue.

 Introduction of lipophilic groups such as aralkyl, halo alkyl,

thioether enhances the diuretic activity and increase the
duration of action.
 Alkyl substitution at N2 lowers the polarity and enhances
the duration of action.

TESFAYE. N 13
 D. Potassium sparing Diuretics
(Site-IV Diuretics)

 Aldosteron inhibitors – Spiranolactone, Metyrapone

 2,4,7-Triamino-6-aryl pteridines – Triamterene
 Pyrazinoyl Guanidines – Amiloride HCl.
Note: Both Triamtere and Amiloride are sodium channel inhibitors

Spironolactone (aldactone) Triamterene Amiloride hydrochloride

TESFAYE. N 14
 CARDIOVASCULAR AGENTS

 The American Heart Association estimates that greater than

50% of deaths are related to some form of cardiovascular
disease.
 Cardiovascular drugs can be broadly categorized as
1) anti-anginals
2) anti-arrhythmics
3) anti-hypertensives
4) anticoagulants
5) anti-hyperlipidemic agents
6) hypo-glycemic agents and
7) anti-thyroid drugs and thyroid hormones

TESFAYE. N 15
 1. ANTIANGINAL DRUGS

Anti-anginals are pharmaceutical agents used to treat angina

pectoris, a disease of the coronary arteries.
Transient coronary ischemia Ischemic Heart Disease Coronary thrombosis

Acute vasospasm
Angina pictoris Myocardial
Variant angina infraction

Atheroschelorosis
and excertion
Stable angina
Typical angina

Unstable angina
Platelate rapture and
platelate agregation
TESFAYE. N 16
 Cont..
 Angina pectoris is characterized by a severe constricting pain
in the chest.
 This usually happens when there is imbalance between the
myocardial oxygen demand and supply.
 Goal of Antianginal Drugs: to restore balance between
Myocardial O2 Demand and Supply

1.Organic nitrates 2. Calcium channel blockers

TESFAYE. N
3.Beta-blockers 4. Vasodilators 17
 1.Organic Nitrates

 Organic nitrates are also called nitrovasodilators.

O2N O
O2N NO2 O
O O
NO O O
O NO2 O NO2
Isopentyl Nitrite, Amyl Nitrite Nitroglycerin Isosorbid dinaitrate

Sodium nitroprusside
TESFAYE. N 18
 2. Calcium channel blockers

 Verapamil, Bepridil
 Diltiazem
 Nefidipine, Amlodipine & Nicardipine
NO2

O
Diltiazem
MeOOC N
O

N
H

Nicardipine
Verapamil
calcium channel blockers reduce Ca2+ influx in cardiac muscle
TESFAYE. N 19
 3. β –blockers and vasodilators

β -blockers
 Propranolol
 Atenolol
 Metoprolol
 Nadolol
Coronary Vasodilators
N
OH H
+ N NO2
N O
H O
Nicotinyl alcohol Nicorandil

Nicotinyl alcohol (pyridylcarbinol) is a niacin derivative used

TESFAYE. N
as a hypolipidemic agent and as a 20
 2. ANTI-HYPERTENSIVE AGENTS

 Hypertension, or high blood pressure, is the most common of all

cardiovascular diseases with nearly 40 million people affected in
the US alone.
 It is the number one cause of stroke and heart attack.
 Normal blood pressure is about 120/80 in a healthy adult.
 People with sustained readings of 140/90 are said to have .

 Consistent high blood pressure can damage the brain, eyes, and
kidneys.
 Hypertension is often called "the silent killer" because it rarely
exhibits symptoms even as it inflicts serious damage on the body.

TESFAYE. N 21
 Cont…

 Numerous anti-hypertensive drugs are currently available.

They can be categorized into:
1) Angiotensin – converting enzyme inhibitors
 reduce the production of angiotensin-II and -III, chemicals that
cause arterioles to constrict
2) sympathetic nervous system depressants including
vasodilators and calcium channel blockers
 each of which cause dilatation of blood vessels resulting in
reduction of peripheral vascular resistance
3) diuretics
 cause the body to excrete water and salt, producing anti-
hypertensive effects
TESFAYE. N 22
 Cont…
Blood Pressure = CO X PV Cardiac Output = SV x HR
PVR = Afterload

Key: CCB = calcium channel blockers

CA Adrenergics = central-acting adrenergics
ACEi’s = angiotensin-converting enzyme inhibitors
TESFAYE. N 23
 Cont…

TESFAYE. N 24
 Cont…

 The renin-angiotensin system is a hormonal regulatory mechanism

controlling the excretion of sodium and maintains body fluids.
 ACE increases the secretion of angiotensin-II and -III, constricting
peripheral blood vessels, thereby raising blood pressure.
Examples of ACE Inhibitors
 Captopril

 Lisinopril

 Enalapril

 Benazepril

 Quinapril and

 Ramipril

TESFAYE. N 25
 Cont…

Alpha Alpha1 Blockers

 Stimulate alpha1 receptors -> hypertension
 Block alpha1 receptors -> hypotension
Examples: doxazosin ,prazosin and terazosin

Central Acting Adrenergics

 stimulate alpha 2 receptors – inhibit alpha1 stimulation hypotension
Examples: clonidine and methyldopa

Peripheral Acting Adrenergics

 inhibits the release of NE diminishes NE stores leads to
hypotension
TESFAYE. NExample: reserpine 26
 Cont…
Calcium Channel Blockers
 decreased smooth muscle tone
 decreased PVR
Examples: Diltiazem, verapamil and nifedipine

Diuretics
Examples: Thiazides: chlorothiazide & hydrochlorothiazide
Loop Diuretics : furosemide & bumetanide
Potassium Sparing Diuretics: spironolactone (Aldactone)
Vasodilators
Directly relaxes arteriole smooth muscle
Decrease SVR = decrease afterload
Examples: diazoxide, hydralazine , minoxidil and sodium
TESFAYE. N nitroprusside 27
 3. ANTIARRHYTHMIC DRUGS

 Arrhythmia is a disease in which the rhythmic contraction of the

heart is disturbed or altered.

 Rhythmic contractions are caused by a sequence of electrical

activity propagating through the myocardial tissue that engulfs
the heart.
 These contractions are controlled by the pacemaker cells of the

heart, or by the S-A node.

 Antiarrythmic drugs (AADs) may be defined as the “drugs that

are capable of reverting any irregular cardiac rhythm or rate to

normal.
 The antiarrhythmic agents are also termed as ‘antidysrhythmic

drugs’
TESFAYE. N or ‘antifibrillatory drugs’. 28
 Cont…

TESFAYE. N 29
 Cont…

is a class 1a (voltage-gated Na+ channel

blockers) anti-arrhythmic drug.
found in Cinchona bark (Cinchona officinalis L.).
Quinidine sulphate It is the dextrorotatory diastereomer of quinine.

is the sodium salt form of phenytoin, a

hydantoin derivate.
Phenytoin sodium It is a Type Ib anti-arrhythmic drug.

is a Class 1c antiarrhythmic agent.

It is a member of acetamides
targets Voltage-gated Na+ channel blockers in
the inactivated state
Lorcainide hydrochloride
TESFAYE. N
30
 Cont…
is a class IIIa antiarrhythmic drug.
Chemically it is a benzofuran derivative.
molecular structure of amiodarone has some
similarities with iodothyronines.
Amiodarone is a nonselective K+ channel blockers

is a class IIIa antiarrhythmic drug.

has effects that are related to class II drugs.
Chemically it is a sulfonamide that is N-
phenylmethanesulfonamide
It contains a chiral centre and racemic mixture.
The levo enantiomer of satolol has both β-
blocking and potassium channel
blocking activities.
Sotalol  The dextro enantiomer has class III properties
TESFAYE. N 31
 4. ANTILIPEMIC DRUGS

 The major lipids found in the bloodstream are cholesterol,

cholesterol esters, triglycerides, and phospholipids.

 An excess plasma concentration of one or more of these

compounds is known as hyperlipidemia.
 Antihyperlipidemic agents promote reduction of lipid levels in
the blood.
 Some antihyperlipidemic agents aim to lower the levels of
low-density lipoprotein (LDL) cholesterol, some reduce
triglyceride levels, and some help raise the high-density
lipoprotein (HDL)

TESFAYE. N 32
 Classification of antihyperlipidemic agents
 Hydroxymethylglutaryl-CoA (HMGCoA) reductase inhibitors
Eg.Statins (Atrovastatin, lovastatin, Metastatin, Pravastatin,
Fluvastatin)
 Phenoxyisobutyric acid derivatives Eg. Fibrates (Clofibrates,
Gemfibrozil)

 Pyridine derivatives Eg. Nicotinic acid, Nicotinamide

 Bile acid sequestrans Eg. Cholestyramine, Colestipol

 Cholesterol absorption inhibitors Eg. Ezetimibe

 LDL oxidation inhibitors Eg. Probucol

 Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
Eg. Alirocumab 12
 Miscellaneous Antihyperlipidemic Agents Eg. β-Sitosterol,
Dextrothyroxine
33
 Figure :Mechanism of actions of antihyperlipidemic agents 34
TESFAYE. N
 Cont…

Clofibrate (CLOF)
 Clofibrate is an ester of phenoxyisobutyric acid (fibric acid).
 It is regarded as a broad spectrum lipid lowering drug.
 It is a prodrug, metabolized to chlorophenoxyisobutyric
acid (CPIB) which is the active form of the drug.
Mechanism of action
 Clofibrate increases the activity of extrahepatic lipoprotein lipase
(LL), thereby increasing lipoprotein triglyceride lipolysis.
Note: Clofibrate was discontinued in 2002 due to adverse effects.

TESFAYE. N 35
 Cont…

Lovastatin
 is a fungal polyketide derived synthetically from a fermentation
product of Aspergillus terreus.
 It is a prodrug.
 The inactive gamma-lactone closed ring form is hydrolysed in vivo
to the active βhydroxy acid open ring form.

Mechanism of action
 is a potent competitive reversible inhibitors of HMG-CoA

reductase. HMH-CoA reductase enzyme is required for

mevalonate synthesis i.e cholesterol biosynthesis.
 It inhibits hepatic synthesis of very low density lipoprotein (VLDL)
TESFAYE. N 36
 Cont…
Cholesteramine
is a bile acid sequestrant
is the chloride form a highly basic anion exchange resin.
It is a styrene copolymer with divinylbenzene with quaternary
ammonium groups.
Mechanism of action
Cholestyramine limits the reabsorption of bile acids in the
gastrointestinal tract. Forms an insoluble complex resin matrix in
the intestine which is excreted in the feces.
Cholestipol
is a bile acid sequestrant.
It is an anion exchange resin.
It is hydrophilic, but it is water-insoluble (99.75%).
Mechanism of action
It binds with bile acids to forms complex in the intestine.
TESFAYE. N 37
 5. COAGULANTS, ANTICOAGULANTS
AND OTHER CARDIOVASCULAR DRUGS

 Blood Coagulation: It is a complex process of enzymatic reactions

in which clotting factors activate other clotting factors in a fixed
sequence until a clot is formed
 The coagulation process can be activated and proceed through
one of two possible sequential pathways:
 Intrinsic system path: components present within the circulating blood,
 Extrinsic system: components present in the extravascular and
intravascular compartment.
 Coagulants :are substances which promote coagulation
indicated in hemorrhagic states like
Haemophilia.

TESFAYE. N 38
 Cont…

TESFAYE. N 39
 Cont…

Menadione
 Menadione is a synthetic naphthoquinone

 It is also called as vitamin K

 It is a prothrombin activator.

 It is used in the treatment of hypoprothrombinemia.

Acetomenadione
 Acetomenadione is a member of naphthalenes.

 It is a synthetic vitamin.

 It is also known as davitamon-K or acetomenaphthone.

 Acetomenaphthone is an extremely weak basic

 It is used for Coagulation disorders due to vitamin K deficiency

 Used for anticoagulant-induced prothrombin deficiency

TESFAYE. N 40
 ANTICOAGULAN
TS with blood coagulation are known as anticoagulants.
Drugs that interfere
Anticoagulants eliminate or reduce the risk of blood clots.
Classification
1. Used in vivo
a. Parenteral anticoagulants
i. Indirect thrombin inhibitors Eg. Heparin, Danaparoid, Fondaparinux
ii. Direct thrombin inhibitors Eg. Lepirudin, Bivalirudin, Argatroban
b. Oral anticoagulants
i. Coumarin derivatives Eg. Warfarin, Bishydroxycoumarin, Acenocoumarol
ii. Indanedione derivatives Eg. Phenindione
iii. Direct factor Xa inhibitors Eg. Rivaroxaban
iv. Oral direct thrombin inhibitors Eg Dabigatran
2. Used in vitro
Heparin (Calcium complexing )
i.Oxalate compounds Eg. Calcium oxalate
ii.Citrate compounds Eg. Sodium citrate.
TESFAYE. N 41
 Warfarin

 Warfarin is a synthetic anticoagulant.

 Warfarin exists in tautomeric form.

 Warfarin contains a stereocenter and consists

of two enantiomers. This is racemate.

 Anticoagulant activity of S –warfarin is 2–5 times more than the

R-isomer.
Mechanism of action :
 Warfarin acts by antagonizing vitamin K and so inhibits vitamin

K reductase enzyme, which results in decrease amount of

reduced form of vitamin K.
use: For venous thromboembolism and related pulmonary embolism.
For thromboembolism associated with cardiac valve replacement.
TESFAYE. N 42
 Anisindione

 Anisindione is a synthetic indanedione anticoagulant.

Mechanism of action: inhibits the vitamin K–mediated
gamma-carboxylation of precursor proteins.
Uses: treatment of pulmonary embolism.
 treatment of venous thrombosis and its extension
the treatment of atrial fibrillation with embolization
Clopidogrel
 is a prodrug of the thienopyridine family.
Mechanism of action: is a prodrug and its thiol metabolite is a
platelet inhibitor by using
P450 enzymes.
Use:
TESFAYE. N to reduce the risk of heart disease and stroke in those at 43
 Heparin

 It is a linear polysaccharide composed of alternating residues

of glucosamine and uronic acid that are linked to each other in
a 1→4 manner.
 Heparin is a strongly acidic.

MOA: through antithrombin, a glycoprotein that inhibit many

proteases enzymes.
 So,antithrombin prevents the conversion of fibrinogen to fibrin
TESFAYE. N
thereby inhibiting clotting. 44
6. CARDIAC GLYCOSIDES AND DERIVATIVES

 Cardiac glycosides constitute a group of closely related natural

products with highly specific and powerful action on cardiac
muscles (cardiotonic).
 They showed effects on the tone, excitability and contractility of
the cardiac muscle and diuretic activity.

 Cardiac glycosides are steroid derivatives, characterized by the

presence of a lactone ring attached to C-17β-position and a sugar
moiety at the 3β- position.

 The steroid aglycones or genins are of 2 types: a cardenolide or a

bufadienolide.

TESFAYE. N 45
 Cont…

 The more prevalent in nature are the cardenolides, which are

C23 steroids that have as a 17β-side chain and α/β-unsaturated
5- membered lactone ring.
 The bufadienolides are C24 homologs of the cardenolides and
carry a doubly unsaturated 6-membered lactone ring at the 17-
position.

Figure : Aglycone types of cardiac glycosides

TESFAYE. N 46
 Cont…
 In both cardenolides and bufadienolides the C/D ring junction has the
cis-configuration.
To obtain optimum cardiac activity:
 the aglycone should possess an α/β-unsaturated lactone ring that is
attached at the 17-position of the steroid nucleus and
 the A/B and C/D ring junctions should have the cis-configuration.

Characteristic Features
1. An unsaturated lactone ring attached to steroid nucleus at C 17 with
βconfiguration.
2. A tertiary β-hydroxy group at C-14.
3. An axially oriented hydroxy group at C-3 to which is attached the sugar
residue.
4. The cis fusion of the ring C/D and in most cases also of the rings A/B.
5. Methyl groups at C-10 and C-13.
6. The methyl group at C-19 may be replaced by a CHO or CH2OH group (e.g.
Strophanthus).
7. Additional hydroxy groups may be present at C-, C-2, C-5, C-11, C-12 and C-16
TESFAYE. N
47
 Structure-Activity Relationships
 The sugar moieties have no cardiac activities, but when
attached to 3-OH group of the steroid they modify the
activity and are of great importance for the pharmacokinetic
behavior. They affect the potency of the cardiac glycosides.

 Cardiac glycosides with 6-deoxy sugar are more potent than

the corresponding 6-CH2OH analogs.
 In oligosaccharides the potency decreases in the order:
Monosaccharide >disacchardide > trisaccharide >aglycone.
Aglycone Moiety
the more -OH groups the more rapid onset of action
and subsequent elimination from the body.
The activity of the cardiac glycosides is due to the aglycone
part, in lactone ring ,the cis-junction of the ring A/B
and C/D and the 3-OH group.
TESFAYE. N 48
 Cont…
Lactone ring
Saturation of the lactone ring reduces the potency 10 folds.
 It was found that the β-oriented C-17 side chain is required
for the activity and 17 αcardenolides (allo-cardenolides) are
inactive.
The A/B cis fused rings are more potent than A/B trans.

 It was found that cis-junction of the rings C/D is required for

the cardiac activity.
C-3 and C-14 hydroxyl groups
 Replacement of the C-3 and C-14 hydroxyl groups with
hydrogens reduces the potency slightly.

TESFAYE. N 49
 Drugs Containing Cardioactive Glycosides

Digoxin
 Digoxin is a cardiac glycoside extracted from foxglove leaves
(Digitalis lanata, Family : Scrophulariaceae).
 Digoxin includes a steroid nucleus and a lactone ring; most
also have one or more sugar residues.
 It differs from digitoxin in that it has an additional hydroxyl
group at C16 of the steroid skeleton.
 The 17- lactone and the steroid (A-B-C-D) ring system are
essential for cardiac glycoside.
 Digoxin inhibits Na+ /K+- ATPase enzyme

TESFAYE. N 50
 Digitoxin

 Digitoxin is a lipid soluble cardiac glycoside obtained from

cardiac glycoside obtained from Digitalis purpurea, Digitalis
lanata and other suitable species of Digitalis.

 Its side chain is comprised of three molecules of digitoxose in a

glycosidic linkage.
 It has a longer half-life than digoxin.

TESFAYE. N 51