UNIT III - CARDIOVASCULAR

& RENAL PHARMACOLOGY

1
Review of Renal Physiology
Diuretics
Drugs for hypertension
Drugs for congestive heart failure
Drugs for angina pectoris
Drugs for arrhythmia

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Review of Renal Physiology
The kidneys are organs specialized to filter the blood, make an
important contribution to the removal of metabolic waste products
as well as to maintenance of fluid and electrolyte balance.
Specific functions of the kidneys include:
• Regulation of extracellular fluid volume
• Regulation of electrolyte & extracellular fluid concentration
• Removal of metabolic waste products
• Excretion of foreign compounds
• Maintenance of acid-base balance
• Hormone and enzyme production
 NEPHRON is the functional unit of the kidney , basic urine
forming unit

3
Cont…
The nephron has two components:
 Vascular component ( Afferent & Efferent arteriole)
Tubular component
The tubular component of the nephron includes
 Bowman’s capsule, which receives the filtrate
 proximal convulted tubule(PCT)
 Loop of Henle
 Distal tubule.

The tubule processes the filtrate, excreting waste products and

reabsorbing nutrient molecules, electrolytes, and water.

4
Cont……
The nephron performs three basic renal processes.
 Filtration, Reabsorption, Secretion
Filtration: is the movement of fluid and solutes from the
glomerular capillaries into Bowman’s capsule.
Reabsorption: is the movement of filtered substances from the
renal tubule into the peritubular capillaries for return to the
vascular compartment.
Secretion: is the movement of selected unfiltered substances
from the peritubular capillaries into the renal tubule for excretion.
 Any substance that is filtered or secreted, but not reabsorbed, is
excreted in the urine.
5
 RENAL TUBULE TRANSPORT MECHANISMS
PROXIMAL TUBULE
the water permeability of the PCT is very high.

Proximal convoluted tubule (PCT)

Reabsorption of 65% of filtered Na+/ K+/ Ca2+, & Mg2+; 85% of

NaHCO3, & nearly 100% of glucose & amino acids

 Carbonic anhydrase inhibitors
Proximal tubule, straight segments

 Secretion & reabsorption of organic acids & bases, including

uric acid & most diuretics Alemseged,2011 E.C
6
Cont…..
 NaHCO3 reabsorption by the PCT is initiated by the action of

a Na+/H+exchanger (NHE3)located in the luminal membrane

of the proximal tubule epithelial cell.
Bicarbonate reabsorption by the proximal tubule is thus

dependent on carbonic anhydrase activity

Alemseged,2011 E.C 7
Cont……
 Loop of Henle
Thin descending limb
 Passive reabsorption of H2O
The thick ascending limb (TAL)
 Activereabsorption of 15–25% of filtered Na+/ K+/ 2Cl–;
secondary reabsorption of Ca2+ & Mg2+
The thin ascending limb is relatively water impermeable but is
permeable to some solutes.
It actively reabsorbs NaCl from the lumen
Salt reabsorption in the TAL, dilutes the tubular fluid, and it is
called a diluting segment.
The NaCl transport system in the luminal membrane of the TAL is a
Na+/K+/2Cl− cotransporter Alemseged,2011 E.C 8
Major segments of the nephron and their functions

Alemseged,2011 E.C 9
 DIURETICS
Diuretics are drugs, which increase renal excretion of salt and
water: are principally used to remove excessive extracellular
fluid from the body.
are drugs that increase the out put of urine by acting on the
kidney.
- have two major applications:
1. Treatment of hypertension and
2. Mobilization of edematous fluid caused by eg heart failure
 How Diuretics Work?
 Most diuretics share the same basic mechanism of action that is
blockade of sodium (and chloride) reabsorption.
 Create an osmotic pressure within the nephron that prevents the
passive reabsorption of H2 O

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Classification of the diuretics
High ceiling (loop) diuretics Potassium – sparing diuretics
Bumetanide, Ethacrynic Spironolactone
acid =Aldosterone antagonist
Furosemide, Torsemide Amiloride Non aldosterone
Thiazide diuretics Trimteren
Hydrochlorthiazide, Osmotic diuretics
Chlorthalidone, mannitol
Chlorthiazide urea
Hydroflumethiazide isosorbide
Carbonic anyhdrase inhibitors glycerol
acetazolamide
methazolamide
 High-Ceiling (Loop) Diuretics
Drugs: Furosemide, Torsemide, Ethacrynic acid
» All are orally effective and are highly protein bound
Furosemide( Lassix)
MOA: inhibit the Na+/K+/2Cl- contransport of the luminal
membrane in the thick ascending loop of henle   reabsorption
of Na+, K+, & cl-
 the amount of Na+ reaching the collecting duct & there
by increased K+ - secretion.
Ca2+ & Mg2+ reabsorption is also inhibited
Pharmacokinetics : PO, IV, and IM; hepatic metabolism,
eliminated by the kidney
eliminated in the urine by both glomerular filtration and
tubular secretion.
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Cont….
 Absorption of oral torsemide is more rapid (1 hour) than
that of furosemide (2–3 hours) and is nearly as complete
as with IV administration.
The duration of effect for furosemide is usually 2–3
hours. The effect of torsemide lasts 4–6 hours.
Half-life depends on renal function
Reduction in the secretion of loop diuretics may result
from simultaneous administration of agents
such as NSAIDs or probenecid, which compete for weak
acid secretion in the proximal tubule

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Pharmacodynamic
 Loop diuretics inhibit NKCC2, the luminal
Na+/K+/2Cl−transporter in the TAL of Henle’s loop.
By inhibiting this transporter, the loop diuretics reduce the
reabsorption of NaCl and also diminish the lumen-positive
potential that comes from K+ recycling.
positive potential normally drives divalent cation (Ca & Mg)
reabsorption in the TAL.
Loop diuretics induce expression of the COX-2, which
participates in the synthesis of prostaglandins from arachidonic
acid.
They increase renal blood flow

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Pharmacological effects.
 ed urinary excretion of Na+
& Cl- (25% of filtered)
 ed excretion of Ca++ and
Mg++
 Some carbonic anhydrase
inhibition activity
 ed excretion of HCO3- &
Phosphate – Furosemide
 ed excretion of K+
Therapeutic use
Acute pulmonary edema
(emergency situation)
Edema due to CHF, liver
disease or nephritic
syndrome (if not responsive
to thiazide).
Oliguria due to renal failure
Hypertension (not
responding to other
diuretics)
Hyperkalemia or hyper
calcaemia
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Adverse effects
 Hyponatremia, hypokalemia
hypochloremia, ,
dehydration, hypotension,
hyperglycemia,
 Ototoxicity (electrolyte
imbalance in the inner ear)
 Hyperuricemia (2o gout)
 Abnormalities in serum
lipids: LDL & TGs;
HDL
Drug interactions
 Digoxin—Risk of toxicity if
low K from diuretic
 Ototoxic drugs—Increased
chance of hearing loss if
combined
 Potassium-sparing diuretics
—counterbalance K wasting
effects to decrease risk of
hypokalemia
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Thiazides and Related Diuretics
Drugs: Chlorothiazide, Hydrochlorothiazide
 All are well absorbed from GIT except chlorothiazide
Hydrochlorothiazide
MOA—inhibits Na+-Cl- symporter in early segment of distal
convoluted tubule ,  secretion of K+ & H+,  Ca2+ excretion
Pharmacokinetics: Diuresis within 2 hours after oral with peak
4–6 hours, lasting 12 hours.
Pharmacological effects
  Na+ & Cl- excretion /only 5% filtered Na+ load/
 Also possess carbonic anhydrase inhibition
  HCO3- & Phosphate excretion
  excretion of K+
 Reduce uric acid excretion (Hyper uricemia)
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Therapeutic uses
Edema associated with
CHF, Nephrotic syndrome
 HTN
 Nephrolithiasis due to
idiopathic hypercalciuria
 Nephrogenic diabetes
inspidus
Adverse Effect
 Vertigo, headache, NVD,
blood dyscrasias
 Photosensitivity,skin
rashes
 hyponatremia,
 hyperglycemia.
 hyperuricemia
 se plasma levels of
LDL, total cholesterol &
total TGs

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Potassium-Sparing Diuretics
Include: Spironolactone ,Amiloride ,Triamterene
Spironolactone : aldosterone antagonist
 The effect of aldosterone is to decrease Na+ excretion
and increase K+ and H+ secretion in urine.
MOA: Blocks actions of aldosterone by inhibiting the binding of
aldosterone to mineralocorticoid receptors in distal nephron
(collecting duct system) to increase retention of K and excretion
of Na
 take up to 48 hours to work.

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PharmacoKinetics
 Orally effective with bioavailability of 10-60%

 Moderately protein bound: enter the lumen via filtration &

secretion in the PT.

 Elimination metabolism: bile & urine (intact & metabolite)

Pharmacological effect:
 Mild  in Na+ & Cl- excretion (2% of filtered Na+ load)

 ed excretion of H+ & K+

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Adverse effects
 Nausea, Vomiting, headache, photosensitivity, cramps,
hyperkalemia, hyperglycemia. gynecomastia, menstrual
irregularities, impotence, hirsutism, and deepening voice

Therapeutic use
 Combination with other diuretics

 Decrease the Kaluretic effect of other diuretics.

Osmotic Diuretics
Drugs: Mannitol, Urea, Glycerin, Isosorbide
- Water soluble and are hence freely filtered
- Insoluble in lipids and hence are poorly reabsorbed
- Hence increase the osmolarity of tubular fluid
 Site of action - Nephron segments which are freely
permeable to water

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Mannitol
MOA: Osmotic force in lumen of nephron
Pharmacokinetics—IV works in 30–60 min, lasts up to 8 hour
Therapeutic uses—
» prophylaxis of renal failure,
» reduction of intracranial pressure (ICP), and
» reduction of intraocular pressure
Adverse effects—headache, nausea, vomiting, and fluid and
electrolyte imbalance

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Carbonic Anhydrase Inhibitors
acetazolamide
 MOA- inhibits the enzyme carbonic anhydrase in the
proximal tubular epithelial cells.
» are less efficacious diuretic drugs than the others
Inhibition of carbonic anhydrase in the eye reduces
intraocular pressure
Therapeutic uses.
 Treatment of glaucoma: most common use
 preventing or treating acute mountain sickness: Less
commonly 25
  Pharmacokinetics- Acetazolamide is given orally once to
four times daily. It is secreted by the proximal tubule
 Adverse effects- Metabolic acidosis (mild), potassium
depletion, renal stone formation
other carbonic anhydrase inhibitors:- dorzolamide,
methazolamide

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27
PHARMACOLOGY OF
HYPERTENSION

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- Hypertension is defined as a sustained blood pressure of
greater than 140/90 mm Hg on repeated BP measurement
- is an extremely common disorder

- Sustained arterial hypertension damages blood vessels in

kidney, heart and brain and leads to an increased incidence
of renal failure, cardiac failure, myocardial infarction, and
stroke.

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 Classification of Blood Pressure

Category Systolic Diastolic

(mmHg) (mmHg)
Normal <130 <85

High Normal 130-139 85-89

Hypertension
Stage 1 (mild) 140-159 90-99
Stage 2 (moderate) 160-179 100-109
Stage 3 (Severe) 180-209 110-119
Stage 4 (very severe) >210 >120

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 Mechanisms for Controlling Blood Pressure

- Arterial BP is directly proportional to the product of the

cardiac output(CO) and the peripheral vascular
resistance(PVR)
- CO and PVR are controlled mainly by two overlapping
control mechanisms
I. The baro reflexes

- responsible for the rapid, moment-to-moment regulation of

blood pressure
- Mediated by autonomic nerves
 Sensory input: receptors on carotid sinus and aortic arc

 Stimulus: stretch
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

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33
 II.the renin-angiotensin-aldosterone system

-Humoral mechanism
-kidney provides for the long-term control of blood pressure
by altering the blood volume
 kidney releases the enzyme renin when its baro
receptors are stimulated by reduced arterial pressure
(and to sympathetic stimulation of ß-adrenoceptors)
 Low sodium intake and greater sodium loss also
increase renin release
- Renin converts angiotensinogen to angiotensin I which inturn
changed to angiotensin II in the presence of angiotensin-converting
enzyme (ACE)
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- Effects of angiotensin II: on angiotensin II AT1 receptors

i. Is potent vasoconstrictor (both arterioles and veins)

causing an increase in BP

ii. stimulates aldosterone secretion, leading to increased

renal sodium reabsorption and increased blood volume
which contribute to a further increase in blood pressure

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 Types of Hypertension

A. Primary (essential) hypertension—Most common (85-

90% of all cases), no identifiable cause or origin.

B. Secondary hypertension—10-15% of cases, has identified

primary cause chronic renal disease, renovascular disease,
primary aldosteronism, etc

 Hypertension management

 Non-pharmacologic

 Pharmacologic

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37
 Non-Pharmacological therapy of hypertension
1. Reduction of weight
2. Salt restriction
3. Alcohol restriction
4. Physical exercise
5. Relaxation
6. Stop smoking
 NB:- Lack of patient compliance is the most common reason
for failure of antihypertensive therapy.
» The adverse effects associated with the hypertensive
therapy may influence the patient more than the
future benefits.

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Classification of Antihypertensive agents
1. Diuretics
Mechanism: reducing blood volume
- Loop diuretics eg. Furosemide
- Thiazide diuretics eg. Chlorthiazide
- K+ sparing diuretics eg. Triamterene
2. Antiadrenergic agents
I. Centrally acting α2 agonists- eg clonidine
II. Ganglionic Nicotinic receptor blocking agents
III. Adrenergic neuron blocking agents
IV. Adrenergic receptor blocking agents
 α-AR blockers
 β-AR blockers
 mixed α-, β-AR blockers
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3. Vasodilators
 Arteriolar dilators
 Mixed artery & venous dilators
4. Blockers of production or action of Angiotensin II
 Angiotensin converting enzyme inhibitors
 Angiotensin II receptor blockers

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 Vasodilators

1. Oral vasodilators
 Hydralazine, Minoxidil (aretriolar vasodilator)
 Used for long term treatment of HTN

2. Parenteral vasodilators
 Nitroprusside, Diazoxide (Arteriovenous vasodilators )
 For treatment of hypertensive emergencies

3. Ca++ channel blockers

 Verapamil, Diltiazem
 For long term treatment of HTN & treatment of hypertensive
emergencies
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42
 Treatment Strategies
 Goal of therapy : is to reduce cardiovascular and renal
morbidity and mortality
i. initiate therapy with a thiazide diuretic unless there are
compelling reasons to employ other drug classes
ii. A second drug is added, with the selection based on
minimizing the adverse effects of the combined regimen.
 A ß-blocker is usually added if the initial drug was a diuretic, or a
diuretic is usually added if the first drug was a ß-blocker.

iii. A vasodilator can be added as a third step

 NB: angiotensin II converting enzyme inhibitors, angiotensin

II AT1 receptor blockers, and calcium-channel blockers can
also be used to initiate therapy. 43
1. diuretics

antihypertensive alone and enhance the efficacy of other

antihypertensive drugs

 Thiazide diuretics eg. hydrochlorothiazide

 initially the BP is lowered by increasing Na and water

excretion which causes a decrease in extracellular volume,
resulting in a decrease in cardiac output

 with long-term treatment, plasma volume approaches a

normal value and so does CO, but peripheral resistance
decreases

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 - Used in mild to moderate HTN for patients with proper
renal and cardiac function
- Potassium-sparing diuretics are often used combined with
thiazides
- are orally active

 Loop diuretics: eg furosemide

act promptly, even in patients with poor renal function or
who have not responded to thiazides (severe HTN) or other
diuretics
 Potassium-sparing diuretics
Amiloride:- inhibitors of epithelial sodium transport at the
late distal and collecting ducts
Spironolactone:- aldosterone-receptor antagonist

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 2. Sympathoplegic agents (Depressants of sympathetic
activity)
A. ß-adrenoceptor blocking agents
 non- selective ß-blocker-Propranolol
 Selective ß-blockers-metoprolol and atenolol
 How BP is reduced?

 primarily by decreasing cardiac output (through reducing rate and

force of myocardium contraction)
 may also decrease sympathetic outflow from CNS and inhibit the
release of renin from the kidneys (blockade of ß receptors on the
kidney)
 resultingin a decrease in total peripheral resistance
and blood volume
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 are orally active
 are useful in treating conditions that may coexist with
hypertension:
 such as myocardial infarction, tachyarrhythmia,
angina pectoris, chronic heart failure, and
migraine headache
 Abrupt withdrawal may induce angina, myocardial
infarction, or even sudden death in patients with ischemic
heart disease
 the dose of these drugs must be tapered over 2 to 3

weeks in patients with hypertension and ischemic

heart disease

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A. -Adrenoceptor Blocking Agents
 Prazosin, doxazosin, and terazosin
 MOA
Competitively block 1-adrenoceptors and cause
relaxation of both arterial and venous smooth muscle
 Therapeutic use
Prazosin is used to treat mild to moderate hypertension
and HTN with congestive heart failure
 isprescribed in combination with propranolol or a
diuretic for additive effects
 Given PO
 Cause postural hypotension, head ache, sexual dysfunction

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C.  and ß adrenoceptor blocking agents
 Labetalol and carvedilol
block both  1- as well as ß 1- and ß 2- receptors

Reduce BP without reflex tachcardia

Given PO/IM/IV

Fatigue, impotence, orthostatic hypotension may occur

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D. centrally acting 2 adrenergic
 Clonidine:
 reduced total peripheral resistance and Cardiac output is
not decreased
 Used for mild to moderate hypertension
 used primarily for the treatment of hypertension
unresponsive to treatment with two or more drugs
- absorbed well after oral administration
 Because it may cause sodium and water retention,
clonidine may be administered in combination with a
diuretic

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Cont….
 useful in the treatment of hypertension complicated by renal
disease b/c it doesn’t decrease renal blood flow
- can produce sedation and dry mouth, ejaculation problem,
rebound hypertension occurs following abrupt withdrawal of
clonidine.
most common side effects are sedation and drowsiness.
dry mouth, NVD, postural hypotension, impotence,
haemolytic anemia, hepatotoxicity, weight gain may also
occur

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 -Methyldopa

- Methyldopa is a prodrug and must be converted in the

CNS to active α – methylnorepinephrine to exert the
effect on blood pressure.

- blood flow to vital organs including the kidney is not

diminished
 soit is especially valuable in treating hypertensive
patients with renal insufficiency

52
Cont…
- Given PO or IV

- It has been used in hypertensive pregnant patients.

Cause sedation, vertigo, dry mouth, nausea, vomiting,
diarrhea, postural hypotension, impotence, haemolytic
anemia, weight gain and hypersensitivety reactions (fever,
liver damage, thrombocytopenia).

53
E. Adrenergic neuron – blocking agents
 guanethidine, reserpine
Depletes NE storage

lowers blood pressure by reducing both cardiac out put and

total peripheral resistance
guanethidine is recommended for treatment of severe
forms of hypertension when others fail but it is rarely used,
Poor CNS penetration
reserpine is seldom used for treatment of mild to
moderate hypertension, partially depletes NE
Both have significant adverse effects

F. Ganglion blockers, e.g. trimethaphan

is reserved for use in hypertensive emergencies only and is
now rarely used 54
3. Vasodilators
 Eg. hydralazine and minoxidil
 direct-acting smooth muscle relaxants

 This effect is called direct because it does not depend on the

innervation of vascular smooth muscle and is not mediated by
receptors, such as adrenoceptors, cholinoreceptors, or receptors
for histamine, that are acted on by classical transmitters and
mediators.
 produce reflex stimulation of the heart
 Also increase plasma renin concentration, resulting
in sodium and water retention
 can be blocked by concomitant use of a diuretic
55
 Cont…..
 Unlike many other antihypertensive agents, the vasodilators
do not inhibit the activity of the sympathetic nervous system;
therefore, orthostatic hypotension and impotence are not
problems.
Additionally, most vasodilators relax arterial smooth muscle to
a greater extent than venous smooth muscle, thereby further
minimizing postural hypotension.
the lack of sympathetic nervous system inhibition produced by
the vasodilators, which is advantageous in some ways, can also
be a disadvantage in that reflex increases in sympathetic nerve
activity will lead to hemodynamic changes that reduce the
effectiveness of the drugs.
Therefore, the vasodilators are generally inadequate as the sole
therapy for hypertension 56
 hydralazine
relax arteriolar smooth muscle but does not relax venous
smooth muscle
Therapeutic use
used to treat moderately severe hypertension
Hydralazine monotherapy is an accepted method of controlling

blood pressure in pregnancy-induced hypertension

almost always administered in combination with a ß-
blocker, such as propranolol (to balance the reflex
tachycardia), and a diuretic (to decrease sodium retention)
Given PO/IM/IV

headache, tachycardia, nausea, sweating, arrhythmia, and

precipitation of angina
Postural hypotension is not a common problem 57
Minoxidil
 metabolized by hepatic sulfotransferase to the active
molecule
 causes dilation of arterioles but not venules
Reflex tachycardia and fluid retention may be severe and
require the concomitant use of a loop diuretic and a ß-
blocker
 administered orally for treatment of severe to malignant
hypertension that is refractory to other drugs
causes hypertrichosis (the growth of body hair)
 is now used topically to treat male pattern baldness.

58
sodium nitroprusside
 Activates guanylyl cyclase via release of NO
 Dilates both arteriolar & venular vessels with reflex
tachycardia.
- Has rapid onset (30 s) & brief duration of effect (3 min)

- Potent vasodilator and is administered parentally

- poisonous if given orally because of its hydrolysis to

cyanide
- Metabolically degraded by the liver to thiocyanate, which
are excreted by the kidney (patients with impaired renal
function likely to develop toxicities)

59
 used for treatment of hypertensive emergencies
(continuous IV infusion)
 Adverse effects :are secondary to
- Excessive lowering of BP causing hypotension
- Accumulation of thiocyanate
 Metabolic acidosis, arrhythmias etc
 Hypothyroidism (thiocyanate inhibits uptake of
iodine)

60
4. Drugs acting on the renin angiotensin system
 ACE Inhibitors: eg captopril, enalapril

 MOA

 block the ACE that cleaves angiotensin I to form the potent

vasoconstrictor angiotensin II
 NB: ACE is also responsible for the breakdown of
bradykinin
- arteriolar and venous dilation occurs as a result of the
combined effects of lower vasoconstriction caused by
diminished levels of angiotensin II and the potent
vasodilating effect of increased bradykinin

61
 also decrease the secretion of aldosterone by reducing the
angiotensin II level
 Therapeutic use
 are recommended when the preferred first-line agents
(diuretics or ß-blockers) are contraindicated or
ineffective
 are also effective in the management of HTN patients
with chronic heart failure or diabetic nephropathy

62
Given PO

Common side effects include dry cough, rash, fever, altered

taste, hypotension (in hypovolumic states), and
hyperkalemia
® drycough is thought to be due to increased levels of
bradykinin in the pulmonary tree
® Angioedema is a rare but potentially life-threatening
reaction and may also be due to increased levels of
bradykinin
should not be used by pregnant women

63
 angiotensin II receptor antagonists
 Eg. losartan
 MOA
® block the effect of angiotensin II at AT1 receptors
® Produce arteriolar and venous dilation and block
aldosterone secretion
pharmacologic effects are similar to those of ACE
inhibitors but do not increase bradykinin levels
 Therapeutic use
are alternatives to the ACE inhibitors
 Given PO
Adverse effects
similar to those of ACE inhibitors, although the risks of
cough and angioedema are significantly decreased
64
5. Calcium-Channel Blockers
MOA: Calcium-channel antagonists block the inward
movement of calcium by binding to L-type calcium channels
in the heart and in smooth muscle of the coronary and
peripheral vasculature.
This causes vascular smooth muscle to relax, dilating
mainly arterioles.
 Calcium-channel blockers have an intrinsic natriuretic
effect and, therefore, do not usually require the addition of
a diuretic.
Therapeutic use
antihypertensive when the preferred first-line agents are
contraindicated or ineffective
 useful in the treatment of hypertensive patients who
also have asthma, diabetes, angina 65
 are divided into three chemical classes, each with
different pharmacokinetic properties and clinical
indications
i. Diphenylalkylamines: eg. verapamil
- has significant effects on both cardiac and vascular
smooth muscle cells
- Used to treat angina, arrhythmia, and migraine
headache
 Adverse effects:- dizziness, edema, bradycardia,
constipation and headache
 should be avoided in patients with congestive heart
failure or with AV block due to its negative inotropic
(force of cardiac muscle contraction) and dromotropic
(velocity of conduction) effects

66
ii. Benzothiazepines: eg. diltiazem
- affects both cardiac and vascular smooth muscle cells;

- has a less pronounced negative inotropic effect on the heart

compared to that of verapamil
iii. Dihydropyridines: eg. amlodipine, nifedipine
- have a much greater affinity for vascular calcium channels
than for calcium channels in the heart
- are therefore particularly attractive in treating hypertension

- Adverse effects:-Tachycardia, headache, flushing,

peripheral edema
- Dizziness, headache, and a feeling of fatigue caused by a
decrease in BP are more frequent with dihydropyridines

67
 Hypertensive Emergency
- is a rare but life-threatening situation with BP in the very severe
stage
a. Sodium nitroprusside
- administered IV

- Metabolized rapidly (half-life of minutes) and requires

continuous infusion to maintain its hypotensive action
b. Labetalol
is given as an IV bolus or infusion
does not cause reflex tachycardia
major limitation is a longer half-life, which precludes rapid
titration

68
c. Fenoldopam
is a peripheral dopamine-1 receptor agonist that is given
as an IV infusion
Unlike other parenteral antihypertensive agents,
fenoldopam maintains or increases renal perfusion
while it lowers blood pressure.
can be safely used in all hypertensive emergencies and
may be particularly beneficial in patients with renal
insufficiency.
contraindicated in patients with glaucoma.

d. Nicardipine
 can be given as an IV infusion
 major limitation is long half-time (approximately 8
hours), which precludes rapid titration

69
 Conditions warranting special emphasis
 Pregnancy: Drugs used to be taken prior to pregnancy can
be continued
 Except ACEIs & AT1 receptor antagonists

 Methyldopa is commonly used;

 Elderly: use smaller doses; simpler regimens
 Monitor for adverse drug effects
 Diabetic patient: use drugs with fewer adverse effect on
carbohydrate metabolism
 ACEIs, AT1 receptor blockers, CCB, and α1-AR blockers

 Asthma: avoid β- blockers

70
 Congestive heart failure(CHF)
 Definition: Inability of the heart to maintain a CO which is
adequate to meet the metabolic demands of the body.
- often accompanied by abnormal increases in blood volume and
interstitial fluid, hence the term congestive HF
Etiology - Almost all forms of cardiac diseases can lead to heart
failure. Heart failure can result from any disorder that reduces
ventricular filling (diastolic dysfunction) and/or myocardial
contractility (systolic dysfunction).
The leading causes of heart failure are coronary artery disease and
hypertension.
Heart failure is usually caused by one of the following: Ischaemic
heart disease, Hypertension, Heart muscle disorders, and Valvular
heart disease.
71
The primary manifestations of the syndrome are
dyspnea, fatigue, and fluid retention
Classification
 Right ventricular Vs Left ventricular failure
 Acute Vs Chronic Heart failure
 Diastolic Vs Systolic heart failure
Pathogenesis of CHF
 Lack or loss of contractile force  ed ventricular
function  reduced CO
 As a result a variety of adaptive mechanisms are
activated

72
 Compensatory physiological responses in HF
the failing heart evokes three major compensatory
mechanisms to enhance cardiac output
i. increased sympathetic activity (increased preload
by  mediated vasoconstriction, ß mediated heart
work load)
ii. activation of the renin-angiotensin system (Blood
volume increases, and more blood is returned to
the heart)
iii. myocardial hypertrophy(diminishes the ability to
eject blood)
although initially beneficial, these alterations ultimately
result in further deterioration of cardiac function.

73
 Pathophysiology of
cardiac performance
 Is a function
primary of four
variables
 Increased
• Treatment: preload
reducing
preload (saltdiuretic
restriction,
therapy and
venodilator drugs)
 Increased Afterload
• Treatment: reducing
arterial tone
(arteriolar
vasodilators)
 Depressed intrinsic
contractility
myocardium
• Treatment:
of
increasing
contractility using
inotropic agents
 Increased HR due to
sympathetic
activity over
• Treatment: reducing
the HR (β blockers)
74
 Drug groups commonly used in Heart Failure
 ACE inhibitors

 β blockers

 Angiotensin receptor blockers

 Diuretics

 Cardiac glycosides

 β agonists

 Vasodilators

- These cause reduction of the load on myocardium, decreased

extracellular fluid volume, improved cardiac contractility, and
slowing of the rate of cardiac remodeling

75
76
77
Pharmacologic Therapy
Algorithm for Rx of CHF
Diagnosis of CHF confirmed

Assess for fluid retention

Fluid retention No fluid retention

Diuretics ACE inhibitors

B blockers

ARB
*ARB if ACEI intolerant Aldosterone Antagonist
Hydralazine/ Isosorbide
Fig 2 Digoxin

78
 Drugs used to treat heart failure can be broadly divided into:
1. Drugs with positive inotropic effect.
2. Drugs without positive inotropic effect.

 Drugs with positive inotropic effect:-

Drugs with positive inotropic effect increase the force of
contraction of the heart muscle. These include:
 Cardiac glycosides, eg digoxin
 Bipyridine derivatives,
 Sympathomimetics, and
 Methylxanthines

79
 Drugs without positive inotropic effect. These
include:
 Diuretics, e.g. hydrochlorothiazide, furosemide
 Vasodilators, e.g. hydralazine, sodium nitroprusside
 Angiotensin converting enzyme inhibitors e.g. captopril,
enalapril

80
 Cardiac glycosides
a group of steroid compounds that can increase cardiac
out put and alter the electrical functions
Commonly used cardiac glycosides are digoxin and
digitoxin.
 MOA
inhibition of the membrane-bound Na+/K+ ATPase
resulting in an increased intracellular Na+
Finally leading to an increase in the intracellular calcium
that acts on contractile proteins.
digitoxin is more lipid soluble and has long half-life than
digoxin.

81
 Therapeutic uses
Congestive heart failure
 Toxicity of cardiac glycosides
Gastrointestinal effects such as anorexia, nausea,
vomiting, diarrhoea
Cardiac effects such as bradycardia, heart block,
arrhythmias
CNS effects such as headache, malaise,
hallucinations, delirium, visual disturbances
(yellow vision)

82
 Mild toxicities such as gastrointestinal and visual disturbance
can be managed by reducing the dose of the drug.

 For the management of arrhythmias or serious toxicity,

potassium supplementation, administration of anti-
arrhythmic drugs (e.g. lidocaine), and use of digoxin
antibodies can be helpful.

83
 Bipyridine derivatives, e.g. amrinone, milrinone

possess both positive inotropic effect and vasodilator

effects.

 MOA

is inhibition of an enzyme known as phophodiesterase,

which is responsible for the inactivation of cyclic AMP.

 Therpaeutic use

are used in cases of heart failure resistant to treatment with

cardiac glycosides and vasodilators.

84
 Beta - adrenergic stimulants e.g. dobutamine, dopamine
increase in myocardial contractility and hence cardiac
out put by beta adrenoceptor stimulation
- However, positive chronotropic effect of these agents
minimizes the benefit particularly in patients with
ischaemic heart disease.
- The positive inotropic effect of dobutamine is
proportionally greater than its effect on heart rate.
- It is reserved for management of acute failure or failure
refractory to other agents

85
 methylxanthines, e.g. theophylline in the form of
aminophylline
has a positive inotropic effect, bronchodilating effect
and a modest effect on renal blood flow.
 Diuretics
For mild heart failure, a thiazide may be sufficient but
are ineffective at low glomerular filtration rates
Moderate or severe failure requires a loop diuretic.
In acute failure, diuretics play important role by reducing
ventricular preload.

86
 angiotensin converting enzyme (ACE) inhibitors
HF leads to activation of the renin-angiotensin system via
two mechanisms:
a. Increased renin release by the kidney due to
decreased renal perfusion
b. renin release is promoted by sympathetic
stimulation
 The consequence is increase in both preload and
afterload
 ACE inhibitors reduce angiotensin II formation and
hence both the preload and the after load
All ACE inhibitors are adequately absorbed following oral
administration

87
 Angiotensin-receptor blockers
have the advantage of more complete blockade of
angiotensin action because they act on the receptor
are orally active and require only once-a-day dosing
all are highly plasma protein bound (>90%)
losartan, differs from the others in that it undergoes
extensive first-pass hepatic metabolism

88
 Order of CHF Therapy
I. In patients with overt heart failure, loop diuretics are often
introduced first for relief of signs or symptoms of volume
overload, such as dyspnea and peripheral edema.
II. ACE inhibitors, or if not tolerated, ARBs are added after the
optimization of diuretic therapy.
III. ß blockers are initiated after the patient is stable on ACE
inhibitors
 begin at low doses
IV. Digoxin is initiated in patients who continue to have
symptoms of heart failure despite the multiple drug therapy

89
Rx Contd…
1. IDEAL TREATMENT
Drugs Initiating Dose Maximal Dose
Furosemide 20–40 mg qd or bid 400 mg/d
Hydrochlorothiazide 25 mg qd 100 mg/d
Captopril 6.25 mg tid 50 mg tid
Enalapril 2.5 mg bid 10 mg bid
Lisinopril 2.5–5.0 mg qd 20–35 mg qd
Losartan 12.5 mg qd 50 mg qd

Carvedilol 3.125 mg bid 25–50 mg bid

Metoprolol 12.5–25 mg qd 200 mg qd

Spiranolactone 12.5–25 mg qd 25–50 mg qd
Digoxin 0.125 mg qd 0.375 mg/d

90
Thank U!!!
91
 Antianginal Drugs
- angina pectoris is a characteristic sudden, severe, pressing chest
pain, radiating to neck, jaw, back and arms
- chest pain is due to myocardial ischemia due to imbalance b/n O2
demand (higher) & myocardial b/d supply (lower)
- caused by coronary blood flow that is insufficient to meet the
oxygen demands of the myocardium , & leading to ischemia.
» Such imbalance may arise during exertion, from a spasm of
the vascular smooth muscle, or from obstruction of blood
vessels caused by atherosclerotic lesions.
Factor affecting O2 demand
 Heart rate
 Myocardial inotropic state
 Myocardial wall tension (after load & preload) 92
Factor affecting myocardial blood supply
atheriosclerosis (decrease in vessel radius) & xoronary artery
stenosis( chronic spasm)
Abnormal ventricular capacity of coronary microcirculation
Decreased O2 carrying capacity of blood (Anemia)

Types of Angina
Angina pectoris has three overlapping patterns:

I. stable or typical angina

II. unstable angina, and
III. Prinzmetal's or variant angina.
93
1. Stable /exertional, typical, classic.../ Angina
the most common form and hence called typical

caused by the reduction of coronary perfusion due to

coronary atherosclerosis
 Theheart becomes vulnerable to ischemia whenever
there is increased demand, such as that produced by
physical activity, emotional excitement, or any other
cause of increased cardiac workload
 Characterized by a burning, heavy, or squeezing feeling in
the chest
Episodes precipitated by exercise, cold, stress, emotion

94
Cont…..
 Treatment principles: Decrease cardiac load (pre &
after load), increase myocardial blood flow
 It is promptly relieved by rest or nitroglycerin (a
vasodilator).

95
2. Unstable angina /pre-infarction
 Cause: recurrent episodes of small platelet clots.

 Treatment principles: inhibit platelet aggregation & thrombus

formation, decrease cardiac load, Vasodilate coronary arteries.
 lies between stable angina on the one hand and myocardial infarction
on the other
 The symptoms are not relieved by rest or nitroglycerin

 Increases in myocardial oxygen supply are more difficult to achieve,

especially when coronary blood vessels are partially or totally
obstructed
 requires hospital admission and more aggressive therapy to prevent
death and progression to myocardial infarction.

96
3. Prinzmetal's or variant or vasospastic angina
is an uncommon pattern of episodic angina that occurs at rest
and is due to coronary artery spasm.
» individuals with this form of angina may have significant
coronary atherosclerosis
» But the angina attacks are unrelated to physical activity,
heart rate, or blood pressure
generally responds promptly to coronary vasodilators, such as
nitroglycerin and calcium-channel blockers.

97
 Antianginal Agents
1. Organic nitrates
 Reduce preloads & after load, dilate coronary
arteries. Inhibits platelet aggregation.
2. Ca++ channel blockers
 Vasodilate coronary arteries. Reduce after load,
inhibit platelet aggregation
3. ß-adrenergic antagonists
 Decrease HR, contractility and afterload

4. Miscellaneous drugs e.g. aspirin, heparin,

dipyridamole.
 at the doses of 75 mg per day aspirin can produce antiplatelet
activity and reduce the risk of myocardial infarction in anginal
patients.
98
 Organic Nitrates/nitrites:
» nitroglycerin/glyceryl trinitrate, isosorbide
mononitrate
are potent vasodilators
cause a rapid reduction in myocardial oxygen demand
 effective in all forms of angina
 Mechanism of action
Nitrates are believed to act by mimicking the vasodilator
action of endothelium derived relaxing factor (EDRF)
identified as nitric oxide
 intracellular conversion to nitrite ions and then to nitric
oxide—activation of guanylate cyclase---increased cellular
cGMP-----ultimately leads to vascular smooth muscle
relaxation

99
Cont….
 Relax coronary arteries
 increase perfusion of the myocardium
 In addition, they relax veins,
 decreasing preload and myocardial oxygen
consumption
Inhibit platelet aggregation
For prompt relief of attack of angina precipitated by
exercise or emotional stress, sublingual (or spray form)
nitroglycerin is the drug of choice.

100
 Nitroglycerin:- has two major effects at therapeutic
doses
 First, dilation of the large veins resulting in pooling
of blood in the veins. This diminishes preload
(venous return to the heart) and reduces the work of
the heart.
 Second, nitroglycerin dilates the coronary
vasculature, providing an increased blood supply to
the heart muscle.

101
 significant first-pass metabolism of nitroglycerin occurs in
the liver
 common to take the drug either sublingually or via a
transdermal patch
isosorbide dinitrate can be given orally
most common adverse effect of nitrates is headache
high doses of organic nitrates can also cause postural
hypotension, facial flushing, and tachycardia
 Tolerance to the actions of nitrates develops rapidly(blood
vessels become desensitized to vasodilation)
 can be overcome by providing a daily nitrate-free interval to
restore sensitivity to the drug

102
 ß-Adrenergic Blockers
reduce the work of the heart by decreasing heart rate,
contractility, cardiac output, and blood pressure
Reduce demand for oxygen by the myocardium both during
exertion and at rest
The selective ß blockers such as metoprolol or atenolol are
preferred
ß blockers can be used with nitrates to increase exercise
duration and tolerance
contraindicated in patients with asthma, diabetes, severe
bradycardia, peripheral vascular disease, or COPD
The dose should be gradually tapered off over 5 to 10 days to
avoid rebound angina or hypertension.
103
 Calcium-Channel Blockers eg Verapamil, diltiazem
Calcium is essential for muscular contraction
Influx of calcium is increased in ischemia
Calcium channel blockers protect the tissue by inhibiting
the entrance of calcium into cardiac and smooth muscle cells
of the coronary and systemic arterial beds
» All calcium-channel blockers are arteriolar vasodilators
 Therapeutics of Angina
major therapeutic objectives :
 terminating or preventing an acute attack and
increasing the patient’s exercise capacity.
 Acute management: Nitrovasodilators.

104
 Chronic /maintenance/ management.

i. Non specific pharmacological risk factor

modification
 Hyperlipidemia (Lipid lowering agents), HTN
(Antihypertensive), DM (insulin, oral hypoglycemic
agents), Obesity (Diet control), Smoking (cessation),
Antiplatelet agents (Aspirin)
ii. Specific pharmacological treatments
 Decrease oxygen demand (Nitrates, CCB and ß-AR
blockers)
 Increase oxygen supply (Nitrates, CCB )

105
 Stable Angina
 Maintenance treatment includes
 Long acting Nitrates, CCB and ß-AR blockers individual
or in combination
 Vasospastic Angina
 Nitrates & CCBs are effective
 -blockers may worsen the angina
 Unstable Angina
 vasodilators
 Aspirin, IV Heparin or thrombolytic Agents

106
Cont….
 Normotensive: Monotherapy with long acting Nitrates
 Hypertensive: Monotherapy: CCBs or ß-AR blockers.
 Persistent HTN, Sinus bradycardia, AV node dysfunction
 Long acting Dihydropyridines
 Combination therapy: if monotherapy is ineffective
 ß-blockers + long acting dihydropyridine CCB.
 Two CCBs with different selectivity, etc .
 Refractory: Surgical revascularization (Coronary by pass,
Angioplasty)

107
Reading Assignment on Anti Arrhythmic &
Anti hypotensive state

108
Antiarrhythmics

 arrhythmias -abnormalities in impulse formation and

conduction in the myocardium
 arrhythmias can be grouped according to the anatomic site
of the abnormality : the atria, the AV node, or the
ventricles.

109
 Class – I drugs
quinidine
It blocks sodium channel so that there is an increase in
threshold for excitability.
well absorbed orally
has low therapeutic ratio
Main adverse effects are SA block, cinchonism, severe
headache, diplopia and photophobia.
lidocaine
used commonly as a local anaesthetic
Blocks sodium channel and decreases automaticity.
given parenterally
excessive dose cause massive cardiac arrest, dizziness,
drowsiness, seizures, etc.

110
 Class –II drugs: Beta-adrenergic receptor blockers
propranolol
decreases automaticity
slows A.V. conduction velocity and prolongs the refractory
period
 Class – III: Potassium channel blockers
amiodarone
Effect includes depressing atrial and A.V nodal function.
used in the treatment of supraventricular tachyarrhythmias
and ventricular tachyarrhythmias
main adverse effects of this drug are anorexia, nausea,
abdominal pain, tremor, hallucinations, peripheral
neuropathy, A.V. block

111
 Class IV drugs: Calcium channel blockers
Verapamil
drug of choice in case of certain type of supraventricular
tachycardia
 Class - V drugs/others
digoxin
- prolongs the effective refractory period of A.V node
directly and through the vagus
 with small doses causes shortening of the atrial refractory
period (vagal action)
 with the larger doses prolongation of the atrial refractory
period (direct action).
important in slowing the rapid ventricular rate in
patients with atrial fibrillation

112
Drugs used in hypotensive states and shock
Antihypotensive drugs or agents are used to elevate a low
blood pressure and may be classified as follows:
Agents intended to increase the volume of blood in
active circulation
 These include intravenous fluids such as whole
blood, plasma, plasma components, plasma
substitutes and solution of crystalloids
Vasoconstrictor drugs
 theseinclude Peripherally acting vasoconstrictors
which are further divided into sympathomimetic
drugs and direct vasoconstrictors.

113
  Sympathomimetics used to elevate the blood
pressure include adrenaline, noradrenaline,
methoxamine, phenylephrine, mephentermine and
ephedrine.
 Direct
vasoconstrictors include vasopressin and
angiotensin.
Treatment of shock
Shock is a clinical syndrome characterized by decreased
blood supply to tissues.
Common signs and symptoms include oliguria, heart
failure, disorientation, mental confusion, seizures, cold
extremities, and comma.

114
Most, but not all people in shock are hypotensive. The
treatment varies with type of shock.
The choice of drug depends primarily on the patho-
physiology involved.
I. For cardiogenic shock and decreased cardiac out put,
dopamine or other cardiotonic drug is indicated.
 With severe CHF characterized by decreased CO and high
PVR, vasodilator drugs (nitropruside, nitroglycerine) may
be given along with the cardiotonic drug.
 Diuretics may also be indicated to treat pulmonary
congestion if it occurs
II. For anaphylactic shock or neurogenic shock
characterized by severe vasodilation and decreased PVR,
a vasoconstrictor drug (e.g. levarterenol) is the first drug
of choice

115
II. For hypovolemic shock, intravenous fluids that replace
the type of fluid lost should be given
III. For septic shock, appropriate antibiotic therapy in
addition to other treatment measures.

116