INTRODUCTION TO

THE CARDIOVASCULAR
SYSTEM
&
DIURETICS
Pharmacology & Toxicology Dept
Dr. Mariam Yousif
October 14th and 15th, 2006
Main Topics in Pharmacology of the CVS
1. Diuretics
2. Polypeptides
3. Vasodilators & Treatment of Angina
4. Congestive Heart Failure
5. Hypertension
7. Antiarrhythmics
8. Drugs in Disorders of Coagulation
9. Drugs in Hyperlipidaemia
Case 1
A 70-year-old man who develops dyspnoea and
oedema and is found to have mild congestive
.cardiac failure

?What drug or drugs might he be started on

If he does not respond adequately to your first
choice of treatment for his heart failure, what
?drug or drugs might be added in later
If he develops acute pulmonary oedema, how
?should this be treated
Case 2
A 60-year-old man who smokes and who has a
history of chronic obstructive airways disease
(COAD) is diagnosed as having angina on
.exertion

?What drug therapy might be given

?What advice might be given
?What is the mechanism of action of nitroglycerin
What is nitrate tolerance and how can it be
?avoided
The cardiovascular system consists of
:three anatomical components

,Autonomic nervous system

,Heart
.Vasculature
The heart consists of four chambers and is located in the chest cavity.
The direction of blood flow through the heart chambers is shown.
Blood Vessels Controlling Blood Pressure
Resistance vessels. Arterioles are the
primary resistance vessels and control mean
arterial blood pressure and blood flow to
specific tissues.

Capacitance vessels. Systemic venules and

veins serve as a volume reservoir for the
circulatory system (approx. 50% of total blood
volume is contained in these vessels).
# The output of the heart per unit time is called the
cardiac output (CO).
CO = Stroke volume X Heart rate

# Blood pressure is a product of cardiac output and

systemic vascular resistance.
The kidneys receive about 25% of the
cardiac output.

99% of the filtrate is reabsorbed and

about 1.5 litres of the filtered fluid are
voided as urine.
Structure of the kidney
-The functional unit of the kidney is the
nephron, there are about 1.3x106 nephrons
in each kidney.

Each nephron has two major components

# The glomerulus, through which large
amounts of fluids are filtered from the blood;
# A long tubule in which the filtered fluid is
converted into urine.
The nephron and collecting ducts showing sites of action of
diuretic drugs.
 DIURETICS
OBJECTIVES
2. What are Diuretics?
3. What is the Goal of Diuretic Therapy?
3. How diuretics modify renal function?
4. What are the different classes of diuretics?
5. Identify the site of action, mechanism of action,
therapeutic uses and side effects for each class.
6. What are the main drug examples in each
category?
 Definition

# Drugs that induce a state of increased urine flow.

# Diuretics are drugs that the excretion of Na+ and H2O
from the body by an action on the kidney. The primary
effect is to the reabsorption of Na+ and Cl- from the
filtrate, H2O loss secondary to increased excretion of
NaCl.
Diuresis means an increase in urine volume. Also called
natriuretics.
 Goal of Diuretic Therapy

Adjust the volume and/or composition of

body fluids in clinical situations
(hypertension, heart failure & renal failure)

For this to occur, NaCl output MUST exceed

NaCl intake
 Diuretics act either
(1) Directly on the cells of the nephron (where most of the
active & selective reabsorption occurs; ascending loop of
Henle, early distal & collecting tubule).

(2) Indirectly by modifying content of the filtrate (by

either osmolarity or Na+ load).
How diuretics modify renal function?

Reabsorption mainly achieved by active transport of

electrolytes.
Diuretics selectively block active transport mechanisms.
Classification of Diuretics
1. Osmotic Diuretics.
2. Carbonic Anhydrase Diuretics.
3. Thiazide Diuretics.
4. Loop Diuretics.
5. Potassium-Sparing Diuretics.
 Osmotic Diuretics .1
e.g. Mannitol (given iv)
& Isosorbide (given orally)

Site of action
Parts of the nephron freely permeable to water.

Mechanism of action
Freely filtered at the glomerulus and undergo
little, if any, reabsorption.
 Actions
-Produce diuresis due to their ability to carry
water with them into the tubular fluid.

-The filtered substance undergoes little or no

reabsorption, it will cause an in the osmotic
pressure of tubular fluid, reducing the
reabsorption of water, urinary output.
 Passive water reabsorption reduced in presence

of osmotic diuretic (non-reabsorbable solute)

within the proximal tubule. This has secondary
effect of reducing sodium reabsorption.

The main effect is to increase amount of water

excreted with a smaller increase in the excretion
of Na+.
Uses of Osmotic Diuretics
As a result of increasing the osmotic pressure of plasma,

 Cerebral oedema (to reduce intracranial pressure).

 In glaucoma (to lower intraocular pressure).

The useful effects disappear following filtration in kidney.

 Prevention of acute renal failure.

Main Side Effects

Hyponatremia
 Carbonic Anhydrase Inhibitors .2
x i mal
Pr voluted
o
Conule
tub

e.g. Acetazolamide Glomerular

filtrate

Site of action
Inhibit the enzyme carbonic anhydrase (C.A.) in
the proximal tubular epithelial cells.
 Mechanism of action

 C.A. catalyzes the reaction of CO2 and H2O

leading to H+ and HCO3- (bicarbonate)

formation.
In proximal tubule cells
.C.A
H2O + CO2 H2CO3 H+ + HCO3-

HCO3- diffuses into the plasma while the H+ passes into

the tubular lumen in exchange for Na+.

In the lumen
.C.A
H+ + HCO3- H2CO3 H2O + CO2

The CO2 is returned into the cell.

 Lumen Blood

H2O + CO2 H2O + CO2 CO2

Carbonic
anhydrase
H2CO3 H2CO3

HCO-3 H+ H+ HCO-3

Na+ Na+ Na+

Epithelial cell of renal tubule
Role of carbonic anhydrase in sodium retention by epithelial cells
of renal tubule
 The net effect of these processes is that much of
the filtered bicarbonate is reabsorbed by the
proximal tubule.

 Drugs which inhibit carbonic anhydrase

increase the volume of urine flow by

preventing bicarbonate reabsorption.

 Lumen Acetazolamide Blood

H2O + CO2 H2O + CO2 CO2

Carbonic
H2CO3 anhydrase H2CO3

HCO-3 H+ H+ HCO-3

Na+ Na+ Na+

Epithelial cell of renal tubule

Effects of carbonic anhydrase inhibition in the proximal tubular cell

# Increased urinary excretion of bicarbonate ions is
accompanied by Na+, K+ and H2O

⇑ flow of alkaline urine & a mild metabolic acidosis

# The action results in depletion of extracellular

bicarbonate, self-limiting diuretic effect as the
blood bicarbonate falls.
Therapeutic Uses
Mainly used for non renal actions:

 Treatment of glaucoma: reduce the formation

of aqueous humor.

Adverse Effects

 Metabolic acidosis

 K+ depletion (hypokalemia)
Thiazide Diuretics .3
t a l uted
Di onvol
s
C bule
tu

e.g. Chlorothiazide &

Hydrochlorothiazide
Thiazide-like diuretics:
Chlorthalidone & Indapamide

Site of action: Early part of the distal tubule

Site of action: Early part of the distal tubule.
Most widely used, have a moderately powerful
diuretic action.

All are effective orally, well absorbed from the GIT

Mechanism of action

Decrease active reabsorption of Na+ and Cl- by

binding to the Cl- site of the Na+ / Cl- cotransport
system

⇑ concentration of Na+ and Cl- in the tubular

fluid
Actions

(1) Increased excretion of Na+ & Cl-

(2) Decreased calcium excretion
⇓ excretion of Ca++ by promoting the reabsorption
of Ca++ (in contrast to loop diuretics)
(3) Reduce peripheral vascular resistance

In treatment of hypertension, initial fall in BP

results from the decreased blood volume caused
by diuresis, later phase results from direct
vasodilator action on blood vessels.

(4) Hyperglycaemia
Inhibit insulin secretion and increase blood sugar.
Therapeutic uses
 Hypertension: either alone or in combination with other
antihypertensive drugs.

 Edema associated with congestive heart failure and hepatic

cirrhosis.

 Renal stone disease (nephrolithiasis): To prevent recurrent stone

formation because they inhibit urinary Ca++ excretion.

Nephrogenic (renal) diabetes insipidus.

Side Effects
Hypokalemia (Loss of K+ )

Thiazides ⇑ Na+ in the filtrate arriving at the

distal tubule  more K+ is also exchanged for Na+.
Prolonged use results in continual loss of K+ from

the body. ⇓ plasma K+, can predispose

patients on digitalis to ventricular arrhythmias.

 K+ can be supplemented by diet or K+ salt
supplementation.
Side Effects

 Hyperuricaemia: ⇑ plasma uric acid by ⇓ amount

of acid excreted. Uric acid deposits in the joints

resulting in gout.

 Hyperglycaemia.
Loop Diuretics .4

Ascending
e.g.. Furosemide, Loop of
Henle

Bumetanide, Ethacrynic Acid

Site of action
 The thick segment of ascending loop of Henle

(segment of the loop impermeable to H2O)

  Most powerful of all diuretics, cause 15-25% of

Na+ in the filtrate to be excreted; “high ceiling”

diuretics

 Absorbed from the GIT and can also be given

by injection.
Mechanism of action

 Inhibit NaCl reabsorption by inhibiting the

Na+ / K+ / 2Cl- carrier in the luminal membrane.

The high NaCl concentration in the tubular fluid
reaching distal tubules and collecting ducts
results in reduced H2O reabsorption in distal

nephron.
Actions
 Cause hypokalemia. Increased Na+ reaching the
distal tubule, enhances loss of K+ and H+ (metabolic
alkalosis).
 ⇑ Excretion of Ca2+ and Mg2+ and ⇓ excretion of
uric acid (may precipitate gout, similar to effect
to thiazides).
 Have a venodilator action, useful in patients

with acute heart failure.

Therapeutic Uses

# Acute pulmonary oedema.

# Renal failure.
# Hypertension.
Side Effects
 Hypokalemia
K+ depletion can be treated by K+-sparing diuretics or
K-supplement.
 Hyperuricemia.

 Metabolic alkalosis.

 Ototoxicity (hearing loss).

 Potassium-Sparing Diuretics .5

A. Spironolactone Collecting
duct

Site of action
Late distal tubule and collecting
duct.

Mechanism of action
A Synthetic aldosterone antagonist.
 K
+

Aldosterone
P

Na
+

R
Nucleus
R

mRNA

Na K
+ + Cl
- +
K
Induced
protein CO
Lumen
Cellular Action of Aldosterone K
+
Cl
- +
K
Spironolactone-receptor complex is inactive. It
causes:
 ⇓ Na+ reabsorption

 Decrease in potassium-secretion (K+- sparing

effect) and decreased H+ secretion.

 Decrease uric acid excretion

Therapeutic Uses
Used in combination with K+-losing diuretics
(thiazides and loop diuretics) to preserve K+
balance.

 In primary aldosteronism (Conn’s syndrome)

and secondary aldosteronism complicated by

ascites.
Side Effects

 Hyperkalemia and metabolic acidosis

 Gynaecomastia
 Testicular atrophy
 B. Triamterene & Amiloride

Collecting
duct
 Have a limited diuretic efficacy.

Site of action
 Act on the collecting tubules and collecting

ducts.
Mechanism of action
 
 Act by blocking Na+ channels. Net effect is to
inhibit Na+ reabsorption & decrease K+ excretion.
 By preventing Na+ entry, they also reduce Na+/H+

exchange  inhibit H+ excretion  metabolic

acidosis.

 Both drugs are uricosuric, i.e. they promote the

excretion of uric acid.
 Both amiloride and triamterene are effective
 
when given orally.

 Amiloride excreted mostly unchanged in the

urine.
 Therapeutic uses
 With K+-losing diuretics, to preserve K+
balance.
In combination with thiazide and loop diuretics
to treat edema associated with congestive heart
failure and liver disease.
Side Effects
 Hyperkalemia.
Recommended reading from your text book (Integrated
Pharmacology by Page et al)

Table of notable interactions between diuretics and

other drugs (Fig. 17.9 page: 349).

THIS MATERIAL IS INCLUDED IN THE EXAM

DRUG LIST
Mannitol
Acetazolamide
Chlorthalidone
Hydrochlorothiazide
Furosemide
Ethacrynic acid
Spironolactone
Amiloride
Triamterene
Diuretic Site of Mechanis Pharmacological Therapeutic Side
action m action Uses Effects
Osmotic of action
Diuretics
e. g.
Carbonic
Anhydrase
Inhibitors
e. g.
Thiazide
Diuretics
e. g.
Loop
Diuretics
e. g.
K+-sparing
A.Spironolactone
B. Amiloride &
Triamterene