Diuretics

PHRM 306: Drugs affecting CVS

 Diuretics
• Diuretics are drugs that act on the kidney to
increase the excretion of water and sodium
chloride.
• Most diuretics work by reducing the
reabsorption of electrolytes by the kidney
tubules.
• The increased electrolyte excretion is
accompanied by an increase in water
excretion, necessary to maintain an osmotic
balance.
 Diuretics
• Can be used as first-line drug therapy for
hypertension unless there are compelling
reasons to choose another agent.
• Low-dose diuretic therapy is safe, inexpensive.
• Diuretics are effective in lowering blood
pressure by 10-15 mm Hg in most patients.
• Prevents stroke, myocardial infarction, and
congestive heart failure, all of which can cause
mortality.
 Thiazides
• Mechanism of Action
• Thiazides increase urine output by
inhibiting the NaCl cotransporter on the
luminal membrane of the earliest
portion of the distal convoluted tubule.
• Inhibition of the NaCl cotransporter
increases luminal concentrations of
Na+ and Cl– ions in the late distal tubule;
 Thiazides
• Mechanism of Action
• the large Na+ load downstream promotes
K+ excretion in the late distal tubule and the
collecting duct.
• Thiazides also lead to increased reabsorption of
Ca++ into the blood and may lead
to hypercalcemia.
• Thus thiazides increase urinary levels of Na+, K+,
and Cl– and decrease levels of Ca++ in the urine.
• https://www.youtube.com/watch?v=_v7-PGBTqPk
 Thiazide diuretics

• All oral diuretic drugs are effective in the

treatment of hypertension, but the thiazides
have found the most widespread use.
 Actions
• Thiazide diuretics, such as
hydrochlorothiazide, lower blood pressure
initially by increasing sodium and water
excretion.
• This causes a decrease in extracellular volume,
resulting in a decrease in cardiac output.
• Peripheral vascular resistance may increase
(due to calcium reabsorption in the tubules)
 Actions
• They control hypertension in part by inhibiting
reabsorption of sodium (Na+) and chloride
(Cl−) ions from the proximal part of distal
convoluted tubules in the kidneys by blocking
the thiazide-sensitive Na+-Cl− symporter/
co-transpoter.
 Therapeutic uses
• Thiazide diuretics are appropriate for most
patients with mild or moderate hypertension
and normal renal and cardiac function.
 Therapeutic uses
• Thiazide diuretics decrease blood pressure in
both the supine (seating) and standing
positions
• Postural hypotension is rarely observed
except in elderly, volume-depleted patients.
 Therapeutic uses
• Thiazides are therefore useful in combination
therapy with a variety of other
antihypertensive agents, including β-blockers,
ACE inhibitors, angiotensin-receptor blockers,
and potassium-sparing diuretics.
 Pharmacokinetics
• Thiazide diuretics are orally active.
• Absorption and elimination rates vary
considerably, although no clear advantage is
present for one agent over another.
• All thiazides are ligands for the organic acid
secretory system of the nephron, and as such,
they may compete with uric acid for
elimination.
 Adverse effects
• Thiazide diuretics induce
– Hypokalemia (most common adverse effect) and
hyperuricemia in 70% of patients and
– Hyperglycemia in 10% of patients.
– Hypomagnesemia may also occur. ▪
 Adverse effects
• In the treatment of hypertension, the most
common adverse effect of diuretics (except for
potassium-sparing diuretics) is potassium
depletion (Hypokalemia)
▪ Hyperglycemia
▪ Hyperlipidemia
▪ Hyperuricemia
▪ Hypercalcemia
▪ Hyponatremia
Diuretics

LOOP DIURETICS
 Loop diuretics
• Loop diuretics are diuretics that act on the
ascending loop of Henle in the nephron.
• Loop diuretics act on the Na+-K+-2Cl-
symporter (cotransporter) in the thick
ascending limb of the loop of Henle to inhibit
sodium and chloride reabsorption.
• Example: Furosemide (most common),
Bumetanide, Ethacrynic acid, Torsemide.
• https://www.youtube.com/watch?v=22DTm-J
VdWo
Diuretics

POTASSIUM-SPARING DIURETICS
 Potassium-Sparing Diuretics
• Potassium-sparing diuretics act in the
collecting tubule to inhibit Na+ reabsorption
and K+ excretion.
 Aldosterone antagonists
• Spironolactone:
• Spironolactone is a synthetic steroid that
antagonizes aldosterone at intracellular
cytoplasmic receptor sites.
• The spironolactone-receptor complex is
inactive.
 Spironolactone
• It is a weak diuretic, because only 2% of the
total Na+ reabsorption is under aldosterone
control.
 Heart failure

PHRM 306: Drugs affecting CVS

 Overview
• Heart failure (HF) is a complex, progressive
disorder in which the heart is unable to pump
sufficient blood to meet the needs of the
body.
• HF is due to an impaired ability of the heart to
adequately fill with and/or eject blood.
 Overview
• Underlying causes of HF include
arteriosclerotic heart disease, myocardial
infarction, hypertensive heart disease,
valvular heart disease, dilated
cardiomyopathy, and congenital heart
disease.
 Overview
• Left systolic dysfunction secondary to
coronary artery disease is the most common
cause of HF, accounting for nearly 70 percent
of all cases.
• The number of newly diagnosed patients with
HF is increasing, because more individuals
now survive acute myocardial infarction.
 a) Increased sympathetic activity
• Baroreceptors sense a decrease in blood
pressure and activate the sympathetic
nervous system, which stimulates
β1-adrenergic receptors in the heart.
• This results in an increased heart rate and a
greater force of contraction of the heart
muscle.
 a) Increased sympathetic activity
• In addition, vasoconstriction (α1-mediated)
enhances venous return and increases cardiac
preload.
• These compensatory responses increase the
work of the heart and, therefore, can
contribute to further decline in cardiac
function.
 b) Activation of the
renin-angiotensin system
• A fall in cardiac output decreases blood flow
to the kidney, prompting the release of renin,
with a resulting increase in the formation of
angiotensin II and release of aldosterone.
• This results in increased peripheral resistance
and retention of sodium and water.
 b) Activation of the
renin-angiotensin system
• Blood volume increases, and more blood is
returned to the heart. If the heart is unable to
pump this extra volume, venous pressure
increases and peripheral edema and
pulmonary edema occur.
• These compensatory responses increase the
work of the heart and, therefore, can
contribute to further decline in cardiac
function.
 c) Myocardial hypertrophy
• The heart increases in size, and the chambers
dilate and become more globular.
• Initially, stretching of the heart muscle leads
to a stronger contraction of the heart.
• However, excessive elongation of the fibers
results in weaker contractions, and the
geometry diminishes the ability to eject blood.
 c) Myocardial hypertrophy
• This type of failure is termed systolic failure
and is the result of a ventricle being unable to
pump effectively.
• Less commonly, patients with HF may have
diastolic dysfunction- a term applied when the
ability of the ventricles to relax and accept
blood is impaired by structural changes, such
as hypertrophy.
 Goals of treatment
• The goals are to alleviate symptoms, slow
disease progression, and improve survival.
• Accordingly, six classes of drugs have been
shown to be effective:
1) Inhibitors of the renin-angiotensin system
2) β-adrenoreceptor blockers
3) Diuretics
4) Inotropic agents
5) Direct vasodilators
6) Aldosterone antagonists
 5. Inotropic Drugs
• Positive inotropic agents enhance cardiac
muscle contractility and, thus, increase cardiac
output.
• Although these drugs act by different
mechanisms, in each case the inotropic action
is the result of an increased cytoplasmic
calcium concentration that enhances the
contractility of cardiac muscle.
 A. Digitalis
• The cardiac glycosides are often called digitalis
or digitalis glycosides, because most of the
drugs come from the digitalis (foxglove) plant.
• They are a group of chemically similar
compounds that can increase the contractility
of the heart muscle and, therefore, are widely
used in treating HF.
 Digitalis
• The cardiac glycosides influence the sodium
and calcium ion flows in the cardiac muscle,
thereby increasing contraction of the atrial
and ventricular myocardium (positive
inotropic action).
• https://www.youtube.com/watch?v=T4Nujey
PTAo