Cardiovascular drugs

FOR DEGREE PHARMACY STUDENTS
By Tasisa Ketema (B.Pharm)
January 2017

INTRODUCTION TO KIDNEYS
• The primary function of the kidneys is to
regulate ECF environment
• Control of blood volume and hence arterial
blood pressure
• Control of concentration of waste products of
blood
• Control of electrolyte, nutrient composition of
the ECF
• Control of pH plasma

• Excretion (excess water, excess electrolytes,
urea, uric acid, sulphates, creatinine, toxins,
drugs, etc.)
• Retention (glucose, amino acids,
bicarbonates, electrolytes, etc.)
• Synthesis (ammonia, bicarbonate,
prostaglandins)
• Regulation of calcium/phosphate balance/
(vitamin D3 metabolism)

Urine Formation
• Processes of urine formation involves
–Filtration
–Reabsorption
–Secretion

Glomerular filtration
• The glomerulus is a ball of capillaries situated in
Bowman’s capsule, which is the first part of the
nephron.
• Water, ions and substances of low MW can pass
through the filtration membrane into the
nephron, leaving proteins and cells behind in the
blood.
• In inflammatory conditions and infection, the
filtration membrane becomes leaky and large
amounts of protein, particularly albumin, may
escape into the nephron and appear in the
urine.

• Glomeruli can be damaged as a result of an
apparently minor streptococcal throat infection.
• Alterations in renal function and return to normal
function can be estimated by renal function tests
such as concentration/ dilution tests and
estimation of GFR.

8
Physiology of proximal Convoluted Tubule
Reabsorption
– 100 % for Glucose, amino acids, vitamins,
–65-80 % of Na + and 98% K+(active)
–Cl, HCO3 follow Na + and K + reabsorption
(passive)
–80 % of water (obligatory water reabsorption)
–50 % urea (solvent drag)
–90% of bicarbonate
–60-65% Ca2+ in PCT driven by water & NaCl

9
Descending segment
• Highly permeable to water (10 % obligatory
water reabsorption)
• Impermeable to solutes
• Concentrating segment
Thick ascending segment
• Active Na transport (Na+ -K+- 2Cl- co-transport)
Active reabsorption of 25% Na+, K+, CL-, 2nd
reabsorption of Ca2+,
• Impermeable to water
• Diluting segment

10
Thin ascending segment
–Moderate permeability to Na, Cl, urea and
water
Distal Convoluted Tubule (DCT)
• ADH-dependent water reabsorption
• Aldosterone dependent Na+ reabsorption by
– Na+-H+ antiport or
– Na+-K+ countertransport at apical surface
• K+ -secretion
• H+ secretion
• Poor passive permeability to urea and NaCl

IMPORTANT PRINCIPLES
Approximate Percentage of Sodium Reabsorption
in Renal Tubular Segments
• Proximal convoluted tubule (PCT >60%).
• Thick ascending limb of the loop of Henle (TAL
<25%).
• Distal convoluted tubule (DCT < 10%).
• The collecting tubules and ducts (CT <4%).

 are drugs that increase the out put of urine.
 have two major applications:
1. Treatment of hypertension and
2. Mobilization of edematous fluid caused by:
-Heart failure, cirrhosis or kidney disease
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 water.

Classification of Diuretics
1. high-ceiling or loop diuretics,
2. thiazide,
3. osmotic,
4. potassium-sparing (aldosterone antagonists
and nonaldosterone antagonists), and
5. unique drugs to lower intraocular pressure
called carbonic anhydrase inhibitors
High-Ceiling (Loop) Diuretics
 Drugs: Furosemide, Torsemide, Ethacrynic acid
 All are orally effective and are highly protein
bound
Furosemide
 MOA—Acts in thick segment of ascending
limb of Henle’s loop and inhibit Na+-K+-2Cl-
symport to provide profound diuresis

 Pharmacokinetics— PO, IV, and IM; PO action in
60 minutes; with IV it begins within 5 minutes and
lasts for 2 hours; hepatic metabolism, eliminated
by the kidney
eliminated in the urine by both glomerular
filtration and tubular secretion (organic acid
secretory system in proximal tubule)
 Therapeutic uses:- When rapid and massive fluid
removal is needed:
Acute pulmonary edema;
Chronic CHF
edema of hepatic, cardiac, or renal origin
unresponsive to other drugs;

Hypertension -The loop diuretics act promptly,
even among patients who have poor renal
function or have not responded to thiazides or
other diuretics
 Adverse effects—
Hyponatremia, hypochloremia, hypokalemia ,
dehydration, hypotension, ototoxicity,
hyperglycemia, hyperuricemia (2o gout)
 Drug interactions
a. Digoxin—Risk of toxicity if low K from diuretic
b. Ototoxic drugs—Increased chance of hearing
loss if combined
c. Potassium-sparing diuretics—counterbalance
K wasting effects to decrease risk of
hypokalemia

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
 Pharmacokinetics—Diuresis 2 hours after oral
with peak 4–6 hours, lasting 12 hours.
 Therapeutic uses—Primary hypertension(mild
to moderate), edema (mild to moderate heart
failure), hypercalciuria and diabetes insipidus
 Adverse effects—similar to loop diuretics but
lack ototoxicity
• Other Thiazide-Type Diuretics;-chlorthalidone,
flumethazide, etc.

Potassium-Sparing Diuretics
spironolactone
• MOA—Blocks actions of aldosterone in distal
nephron (collecting duct system) to increase
retention of K and excretion of Na but may take up
to 48 hours to work
• inhibit the binding of aldosterone to
Mineralocorticoid Receptors.
• Therapeutic Uses—For hypertension and edema in
combination with loop or thiazide most often and
for primary hyperaldosteronism
• Partially absorbed from GIT
• Extensive hepatic 1st pass: short half life

• Adverse Effects—Hyperkalemia, endocrine
effects of gynecomastia, menstrual
irregularities, impotence, hirsutism, and
deepening voice.
Other potassium sparing diuretics include
Triamterene and Amiloride.

Osmotic Diuretics
 Water soluble and are hence freely filtered
 Insoluble in lipids and hence are poorly
reabsorbed
 Pharmacologically inert
 Hence increase the osmolarity of tubular
fluid
 Site of action -Nephron segments which are
freely permeable to water
 Drugs: Mannitol, Urea, Glycerin, Isosorbide
Glycerin & Isosorbide: orally effective
Mannitol & urea: orally ineffective
(hence IV.)

mannitol
–MOA—Osmotic force in lumen of nephron
–Pharmacokinetics—IV works in 30–60
minutes, lasts up to 8 hour
Therapeutic uses—
»prophylaxis of renal failure,
»reduction of intracranial pressure
(ICP), and
»reduction of intraocular pressure
Adverse effects—Can leave vascular system at
capillary beds except in brain; caution with
heart disease, headache, nausea, vomiting,
and fluid and electrolyte imbalance

 Preparation, dosage, and administration—IV
rate to get urine flow of at least 30–50 ml/hour;
keep warm or may crystallize; stop if no urine
other osmotic diuretics- Urea, Glycerin, and
Isosorbide
»Only for decreasing intraocular and
intracranial pressure.

Carbonic Anhydrase Inhibitors
acetazolamide
 MOA- inhibits the enzyme carbonic anhydrase
in the proximal tubular epithelial cells.
»are less efficacius diuretic drugs than the
others
–Inhibition of carbonic anhydrase in the eye
reduces intraocular pressure
 Therapeutic uses.
–Treatment of glaucoma: The most
common use
–Mountain sickness: Less commonly

 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

 Hypertension is defined as a sustained blood
pressure of greater than 140/90 mm Hg on
repeated BP measurement
 Sustained arterial hypertension damages
blood vessels in kidney, heart and brain and
leads to an increased incidence of renal
failure, cardiac failure, and stroke.

Classification of Blood Pressure for Adults Age
18 years and older
Category Systolic
(mmHg)
Diastolic
(mmHg)
Normal <130 <85
Pre-hypertension 130-139 85-89
Hypertension
Stage 1 (mild)
Stage 2 (moderate)
Stage 3 (Severe)
Stage 4 (very severe)
140-159
160-179
180-209
>210
90-99
100-109
110-119
>120

 Types of Hypertension
A.Primary (essential) hypertension—
Most common(85-90% of all cases), no
identifiable cause.
B. Secondary hypertension—10-15% of
cases, has identified primary cause
chronic renal disease, renovascular
disease, primary aldosteronism, etc

• 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 baroreflexes
 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

Eg. Decreased BP leads to reflex response of
increased sympathetic and decreased
parasympathetic output to the heart and
vasculature causing vasoconstriction and
increased cardiac output (rise in BP)
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
baroreceptors 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)
 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

Hypertension management
Non-pharmacologic
Pharmacologic
 Non-Pharmacological therapy of hypertension
1.Reduction of weight
2.Salt restriction
3.Alcohol restriction
4.Physical exercise
5.Relaxation
6.Stop smoking

Classification of Antihypertensive agents
1.Diuretics
• Mechanism: reducing blood volume
 Loop diuretics eg. Furosemide
 Thiazide diuretics eg. Chlorthiazide
 K+ sparing diuretics eg. Triamterene
2. Sympatholytic agents
I. Centrally acting α2 agonists
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

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

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

Treatment Strategies
–goal of therapy is to reduce cardiovascular and
renal morbidity and mortality
–Using non-pharmacologic as well as
pharmacologic approaches
• Mild hypertension can often be controlled with a
single drug; but most patients require more than
one drug
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 receptor blockers, and calcium-
channel blockers can also be used to initiate
therapy.

diuretics
–antihypertensives alone and enhance the
efficacy of other antihypertensive drugs
–used as first-line drug therapy for hypertension
unless there are compelling reasons to choose
another agent
–thiazides have found the most widespread use
among diuretics
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
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

Sympatholytic agents
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) resulting in a decrease in total
peripheral resistance and blood volume

 are orally active
 Propranolol undergoes extensive and highly
variable first-pass metabolism
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

Figure :Actions of ß-adrenoceptor blocking agents.

-Adrenoceptor Blocking Agents
• Prazosin, doxazosin, and terazosin
 MOA
–Competitivly 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
–is prescribed in combination with
propranolol or a diuretic for additive
effects
Given PO
Cause postural hypotension, headache, sexual
dysfunction

 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

centrally acting 2 adrenergic
Clonidine
 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
 can produce sedation and dry mouth,
ejaculation problem, rebound hypertension
occurs following abrupt withdrawal of clonidine

-Methyldopa
 blood flow to vital organs including the kidney is
not diminished
• so it is especially valuable in treating
hypertensive patients with renal
insufficiency
 Given PO or IV
 most common side effects are sedation and
drowsiness.
 dry mouth, nausea, vomiting, diarrhea, postural
hypotension, impotence, haemolytic anemia,
hepatotoxicity, weight gain may also occur
 It has been used in hypertensive pregnant
patients.

Adrenergic neuron – blocking agents,
 guanethidine
–Depletes NE storage
–lowers blood pressure by reducing both
cardiac out put and total peripheral resistance
–recommended for treatment of severe forms
of hypertension when others fail but it is
rarely used
–Poor CNS penetration
–Has significant adverse effects

reserpine
Depletes NE storage
leads to reduction of cardiac out put and
peripheral vascular resistance
Seldom used for treatment of mild to moderate
hypertension.
Has significant adverse effects

Ganglion blockers, e.g. trimethaphan
–is reserved for use in hypertensive
emergencies only and is now rarely used
Vasodilators
–Eg. hydralazine and minoxidil
direct-acting smooth muscle relaxants
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 and a ß-blocker.

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

minoxidil
–Metabolized by hepatic sulfotransferase to the
active molecule
–causes dilation of resistance vessels
(arterioles) but not of capacitance vessels
(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.

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)
 used for treatment of hypertensive
emergencies (continuous IV infusion)

Adverse effects are secondary to
 Excessive lowering of BP causing
hypotension and
 Accumulation of thiocyanate
Metabolic acidosis, arrhythmias etc
Hypothyroidism (thiocyanate inhibits
uptake of iodine)

ACE Inhibitors: eg captopril, enalapril
 MOA
–block the ACE that cleaves angiotensin I to
form the potent vasoconstrictor angiotensin II
–ACE is also responsible for the breakdown
of bradykinin
 Vasodilation 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
 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

–Given PO
–Common side effects include dry cough, rash,
fever, altered taste, hypotension (in
hypovolemic states), and hyperkalemia
dry cough 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

angiotensin II receptor antagonists
–Eg. losartan
 MOA
block the effect of angiotensin II at
AT1receptors
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
decrease the nephrotoxicity of diabetes,
making them an attractive therapy in
hypertensive diabetics
Given PO
Adverse effects
similar to those of ACE inhibitors, although
the risks of cough and angioedema are
significantly decreased

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
Calcium channels are divided into three chemical
classes, each with different pharmacokinetic
properties and clinical indications
Diphenylalkylamines
Benzothiazepines
Dihydropyridines

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

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

Hypertensive Emergency
 is a rare but life-threatening situation with BP in
the very severe stage
a. Sodium nitroprusside
administered IV
capable of reducing blood pressure in all
patients regardless of the cause of
hypertension
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
c. Nicardipine
– can be given as an IV infusion
– major limitation is long half-time
(approximately 8 hours), which precludes rapid
titration

d. 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.

• 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; Avoid β
blockers
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

 angina pectoris is a characteristic sudden,
severe, pressing chest pain
 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.
• Types of Angina
–Angina pectoris has three overlapping
patterns:
I. stable or typical angina,
II. unstable angina, and
III.Prinzmetal's or variant angina.

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

2. Unstable angina /preinfarction
–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
–chest pains occur with increased frequency
and are precipitated by progressively less
effort
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.
– generally responds promptly to coronary
vasodilators, such as nitroglycerin and calcium-
channel blockers.

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
 Some; decrease HR, decrease contractility.
3. ß-adrenergic antagonists
 Decrease HR, contractility and afterload
4. Miscellaneous drugs e.g. aspirin, heparin,
dipyridamole.

Organic Nitrates/nitrites:
»nitroglycerin/glyceryl trinitrate,
isosorbide mononitrate
–are potent vasodilators
–They differ in their volatility
–cause a rapid reduction in myocardial
oxygen demand
effective in all forms of angina
 Mechanism of action
Relax coronary arteries
–increase perfusion of the myocardium
In addition, they relax veins,
–decreasing preload and myocardial
oxygen consumption
–Inhibit platelet aggregation

intracellular conversion to nitrite ions and then to
nitric oxide—activation of guanylate cyclase---
increased cellular cGMP-----ultimately leads to
vascular smooth muscle relaxation
–All are effective but differ in their onset of action
and rate of elimination
–For prompt relief of attack of angina precipitated
by exercise or emotional stress, sublingual (or
spray form) nitroglycerin is the drug of choice.
 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.

–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(usually at night) to
restore sensitivity to the drug

 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 chronic obstructive
pulmonary disease
–The dose should be gradually tapered off over
5 to 10 days to avoid rebound angina or
hypertension.

 Calcium-Channel Blockers
–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
–At clinical doses, these agents affect
primarily the resistance of vascular smooth
muscle and the myocardium
–Verapamil mainly affects the
myocardium, whereas nifedipine exerts
a greater effect on smooth muscle in
the peripheral vasculature.
–Diltiazem is intermediate in its actions

Therapeutics of Angina
 Acute management: Nitrovasodilators.
 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 )

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 in some
patients

 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
»dyspnea, fatigue, and fluid retention are its
cardinal symptoms
 Etiology - Almost all forms of cardiac diseases can lead
to heart failure
 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
• 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.

Pathophysiology of cardiac performance
 Is a function of four primary variables
Increased preload
• Treatment: reducing preload (salt restriction,
diuretic therapy and venodilator drugs)
Increased Afterload
• Treatment: reducing arterial tone (arteriolar
vasodilators)
Depressed intrinsic contractility of
myocardium
• Treatment: increasing contractility using
inotropic agents
Increased HR due to sympathetic over
activity
• Treatment: reducing the HR (β blockers)

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 the
myocardium, decreased extracellular fluid
volume, improved cardiac contractility, and
slowing of the rate of cardiac remodeling
 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,
Bipyridine derivatives,
Sympathomimetics, and
Methylxanthines
 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

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

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)
• 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

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.

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
methylxanthines, e.g. theophylline in the form of
aminophylline
–has a positive inotropic effect, bronchodilating
effect and a modest effect on renal blood flow.
–used for management of acute left ventricular
failure or pulmonary edema.

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.
–reduction in venous pressure causes
reduction of edema and reduction of cardiac
size which leads to improved efficiency of
pump function.

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
• are the agents of choice in HF
• All ACE inhibitors are adequately absorbed
following oral administration
• food may decrease absorption, so they should
be taken on an empty stomach

Angiotensin-receptor blockers
–have the advantage of more complete
blockade of angiotensin action because they
act on the receptor
–are a substitute for ACE inhibitors in patients
who can not tolerate the ACE inhibitors (b/c
of severe cough or angioedema)
–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

 long-term management of chronic heart
failure:
–Modify cardiovascular risk factor profile,
e.g. cigarette smoking, obesity, salt intake
–Underlying causes should be treated, e.g.
anemia, hypertension, valvular disease
• If this proves inadequate
–diuretic should be given
–Give ACE inhibitor and digitalis (ACE
inhibitors may be used before digitalis).
• In patients with persisting symptoms give
vasodilators besides increasing the dose of
diuretic and ACE inhibitors.

 Order of CHF Therapy
– as the disease progresses, polytherapy is initiated
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.
– Gradually titrate the dosage to that which is
maximally tolerated and/or produces optimal cardiac
output.
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

Abnormal rhythms of the heart that cause the heart
to pump less effectively
Arrhythmia occurs:
–when the heart’s natural pacemaker develops
an abnormal rate or rhythm
–when the normal conduction path is
interrupted
–when another part of the heart takes over as
pacemaker

Types of arrhythmia:
Tachycardia: unusually fast heartbeat
Bradycardia: unusually slow heartbeat
Atrial fibrillation: the atria quiver (rapid shaking
movement) rather than contract normally because of
rapid and irregular electrical signals in the heart.
Beside the abnormal heart beat, there is also a risk
that blood will pool in the atria, possibly causing the
formation of blood clots.
Ventricular fibrillation: life threatening condition in
which the heart ceases to beat regularly and instead
“quivers” or fibrillates very rapidly – sometimes at 350
beats per minute or more (causes 350,000 death/year
in the US - “sudden cardiac arrest”)

• Pharmacotherapy of cardiac arrhthmias:
–Drugs used in the treatment of cardiac
arrhthmias are traditionally classified into:
1. Class I: Na+ channel blockers [quinidine,
lidocaine, phenytoin, flcainide,]
2. class II: beta-adrenergic blockers
[propranolol,atenolol, etc]
3. class III: K+ channel blockers [amiodarone,
bretylium, sotalol, etc]
4. class IV: Ca2+ channel blockers [verapamil, etc]
5. class V: digitalis [digoxin]

Class I drugs
Quinidine
- Blocks Na+ channel so that it increase in
threshold for excitability
- It is well absorbed
- Adverse effect: SA block, cinchonism, severe
headache, diplopia and photophobia
Lidocaine
- Used commonly as local anesthetic
- Block both open and inactivated sodium channel
- Decrease automaticity
- Adverse effect: excessive dose cause cardiac
arrest, dizziness, drowsiness, seizures, etc

Flecainide
-Procainamide analogue and well absorbed orally
-Used in ventricular ectopic beats in pateints with
normal left ventricular function
Class II drugs
Propranolol:
Myocaridial sympathetic beta-receptor
stimulation increases automaticity, enhances AV
conduction velocity and shortens the refractory
period. Propranolol can reverse these effects.

Therapeutic uses:
–useful in tachyarrhythmias,
pheochromocytoma and in thyrotoxicosis
–Useful in patients with atrial fibrillation and
flutter refractory to digitalis
Class III drugs
Amiodarone:
• Used in Rx of refractory supraventricular
tachyarrhythmia and ventricular
tachyarrhythmia
• It depresses sinus, atrial and AV nodal function
• Adverse effect: anorexia, nausea, abdominal
pain, tremor, hallucination, peripheral
neuropathy, AV block

Class IV drugs
Verapamil:
• It is drug of choice in case of paroxysmal
supraventricular tachycardia (rapid but regular
beat) for rapid conversion to sinus rhythm
Class V drugs
Digoxin:
• Prolongs the effective refractory period of AV
node
• This action is important in slowing rapid
ventricular rate in patients with atrial
fibrillation

Others
1. Adenosine
– Acts at A1 receptors to slow AV conduction
– Used acutely (i.v.) to reverse supraventricular
tachycardia
– Adverse effects:
• Flushing (vasodilator effect)
• Bronchospasm
• Chest pain (due to bronchospasm)
2. Atropine
– Blocks parasympathetic activity to the heart
– Used to treat sinus bradycardia (< 60/min)

Summary of Drugs for arrhythmia
1. Atrial Fibrillation
First line:
Propranolol 10-40mg p.o..3-4 times daily.
OR
Verapamil, 40-80 mg P.O 2-3 times daily.
Alternative
Digoxin, 0.25 - 0.375 mg
2. Paroxysmal supra-ventricular tachycardia
First line:
Verapamil, 5mg IV can be repeated once or twice 10 min apart.
Alternative:
Digoxin, 0.5 to 1 mg IV over a period of 10 to 15 min followed by
0.25 mg every 2-4 hours with a total dose less than 1.5mg with in 24-
hour period.
Prevention of recurrence
Propranolol 10-40mg p.o..3-4 times daily.

3. VENTRICULAR TACHYCARDIAS
•originate below the bifurcation of the bundle of His.
•accompany some form of structural heart disease,
commonly, ischemic HD.
For Acute termination
First line:
Lidocaine, 1-1.5 mg/kg i.v. can be repeated with
in 3 min to a
maximum of 3mg/kg
Alternative
Procainamide, 25-50 mg i.v. over one-min period
then repeated
every 5 min until the arrhythmia is controlled.

Prevention of recurrence
First line:
1. Propranolol, p.o 20-160 mg in divided doses.
OR
2. Amiodarone, initially 200 mg three times daily, to
be reduced
gradually to 100-200 mg daily for maintenance.

What are lipids?
Lipids are the fats that are present in the body.
The major lipids in the bloodstream are
cholesterol and it’s esters, triglycerides and
phospholipids.

 It is necessary for new cells to form and for older
cells to repair themselves after injury.
 Is important precursor molecule for the
biosynthesis of bile acids, steroid hormones,
and several fat-soluble vitamins
 Cholesterol is also used by the adrenal glands to
form hormones such as cortisol, by the testicles
to form testosterone, and by the ovaries to form
estrogen and progesterone.
FUNCTIONS OF CHOLESTEROL IN THE BODY

MAJOR DIETARY SOURCES OF CHOLESTEROL
cheese, egg yolks, beef, pork, poultry, and
shrimp
Synthesized in the body
‐ 20–25% of total daily cholesterol production
occurs in the liver other sites of high synthesis
rates: intestines, adrenal glands, and
reproductive organs
* Total fat intake, especially saturated fat and
trans fat, plays a larger role in blood
cholesterol than intake of cholesterol itself

FUNCTIONS OF TRIGLYCERIDES AND PHOSPHOLIPIDS
Triglycerides supply energy for the body.
Triglycerides either meet immediate energy
needs in muscles or stored as fat for future energy
requirements.
Phospholipids are compounds that are used to
make cell membranes, generate second
messengers, and store fatty acids for the use in
generation of prostaglandins

How do Cholesterol & Triglycerides transport?
Since blood and other body fluids are watery
(polar), fats need a special transport system to
travel around the body.
They are carried from one place to another by
mixing with protein particles, called lipoproteins

What is Lipoproteins and its role?
• Spherical macromolecular complexes of lipids
and specific proteins (apoproteins or
apolipoproteins)
• Differ in lipid and protein composition, size,
and density.
• lipoproteins are:
–composed of a neutral lipid core containing
triacylglycerol or cholesteryl esters or both,
–surrounded by a shell of apolipoproteins
(apoproteins), phospholipid and non-
esterified cholesterol ( less hydrophobic
than esterified–cholesterol)

 The apolipoproteins associated with lipoprotein
particles have a number of diverse functions
including:
1. Serving as structural components of the
particles.
2. Providing recognition sites for cell – surface
receptors.
3. Serving as activators or coenzymes involved in
lipoprotein metabolism.

The lipoprotein particles include:
- chylomicrons
- very-low density lipoproteins (VLDL)
- low-density lipoproteins (LDL), and
- high-density lipoproteins (HDL)

Types of Lipoproteins
Lipid
Content lipoprotein classification Protein conten
Most chylomicron Least
 very-low density lipoprotein 
(VLDL)
 Intermediate-density lipoprotein
(IDL) 
Least High-density lipoprotein
(HDL) Most

B.VLDL (very low density lipoproteins)
These are synthesized in the liver
Transport triacylglycerols from the liver to
extrahepatic tissues.
A. Chylomicrons
These are derived from intestinal absorption of
triacylglycerols and other lipids
Have a very short life span
They have the least density and richly consist
TAG.
Transport dietary triacylglycerols and cholesterol
from the intestine to the liver for metabolism.

C. LDL (Low density lipoproteins):
• Produced from the final stage in the
catabolism of VLDL.
• Transport cholesterol synthesized in the liver
to peripheral tissues.
• LDL is metabolized via the LDL receptor
• Approximately 30% of the LDL is degraded in
extra hepatic tissues, the rest is degraded in
liver.

D. HDL (High Density Lipoproteins)
• Has the highest density since it contains more
protein and cholesterol than triacylglycerols.
• Transports excess cholesterol from peripheral
tissues to the liver for degradation and removal.
• Therefore, HDL cholesterol is good cholesterol
but LDL cholesterol is called bad cholesterol.
• High concentration of circulating VLDL,LDL are
indicative of possible atherosclerosis.

Classification Composition Primary function
Chylomicrons Triglyceride TGs Transport dietray TGs to
adepose tissue & muscle
VLDL newly synthesized
TGs
Transport endogenous TGs to
adepose tissue & muscle
IDL intermediate
between VLDL and
LDL
They are not usually detectable
in the blood.
LDL Mainly cholesterol
((bad cholesterol
lipoprotein))
Transport endogenous
cholesterol towards body's
tissues
HDL Mainly cholesterol
((good cholesterol
lipoprotein))
Collect cholesterol from the
body's tissues, and take it back
to the liver

Hyperlipidemia is defined as elevated
concentration of Lipids (mainly Cholesterol/
Triglyceride) and it is caused by disorder of lipid
and/or lipoprotein synthesis and/ metabolism.
The elevated serum concentrations of the above
Lipoproteins except HDL indicates
hyperlipedimia
( Cholesterol and  TG) and lead to Atherosclerosis
  Coronary heart diseases (CHD)
NB: Atherosclerosis is narrowing blood vessel
due to deposition of cholesterol and apo B-100

CAUSES OF HYPERLIPIDEMIA/ risk factors
Mostly hyperlipidemia is caused by
 lifestyle habits or treatable medical conditions.
Obesity, not exercising, and smoking
Diabetes, kidney disease, pregnancy, and an
under active thyroid gland.
Inherited/ (Genetic)
In the next few slides metabolisms of
lipoproteins and commonly genetic
hyperlipidemia will be discussed.

Fig *
Metabolism of
plasma lipoproteins
and related genetic
diseases.
Roman numerals refer
to specific genetic types
of hyperlipidemias
‐CM = chylomicron;
‐TG = triglyceride;
‐VLDL = very–low-
density lipoprotein;
‐LDL = low-density
lipoprotein;
‐IDL = intermediate
density lipoprotein;
‐apo CII =
apolipoprotein CII found
in chylomicrons and
VLDL.

Type I (FAMILIAL HYPERCHYLOMICRONEMIA)
Massive fasting hyperchylomicronemia, even
following normal dietary fat intake, resulting in
greatly elevated serum TG levels.
Type I is not associated with an increase in
coronary heart disease.
Deciency of lipoprotein lipase or deciency of
normal apolipoprotein CII (rare).
Treatment: Low-fat diet. No drug therapy is
effective for Type I hyperlipidemia.

Type IIA (FAMILIAL HYPERCHOLESTEROLEMIA)
Elevated LDL with normal VLDL levels due to a
block in LDL degradation.
This results in increased serum cholesterol but
normal TG levels.
Caused by defects in the synthesis or
processing of LDL receptors.
Ischemic heart disease is greatly accelerated.
Treatment: Diet, Heterozygotes: Cholestyramine
and niacin, or a statin.

Type IIB (FAMILIAL COMBINED
[MIXED] HYPERLIPIDEMIA)
Similar to Type IIA except that VLDL is also
increased, resulting in elevated serum TG as well
as cholesterol levels.
Relatively common.
Caused by overproduction of VLDL by the liver.
Treatment: Diet. Drug therapy is similar to that
for Type IIA

Type III (FAMILIAL DYSBETALIPOPROTEINEMIA)
Serum concentrations of IDL are increased,
resulting in increased TG and cholesterol levels.
Cause is either overproduction or
underutilization of IDL due to mutant
apolipoprotein E.
Xanthomas and accelerated vascular disease
develop in patients by middle age.
Treatment: Diet. Drug therapy includes niacin
and fenobrate, or a statin

Type IV (FAMILIAL HYPERTRIGLYCERIDEMIA)
VLDL levels are increased, whereas LDL
levels are normal or decreased, resulting in
normal to elevated cholesterol, and greatly
elevated circulating TG levels.
Cause is overproduction and/or decreased
removal of VLDL and TG in serum.
This is a relatively common disease. It has few
clinical manifestations other than accelerated
ischemic heart disease. Patients with this
disorder are frequently
obese, diabetic, and hyperuricemic.
Treatment: Diet. If necessary, drug
therapy includes niacin and/or fenobrate.

Type V(FAMILIAL MIXED
HYPERTRIGLYCERIDEMIA)
Serum VLDL and chylomicrons are elevated.
LDL is normal or decreased.
This results in elevated cholesterol and greatly
elevated TG levels.
Cause is either increased production or
decreased clearance of VLDL and chylomicrons.
Usually, it is a genetic defect.
Occurs most commonly in adults who are
obese and/or diabetic.
Treatment: Diet. If necessary, drug therapy
includes niacin, and/or fenobrate, or statin.

WHY WE FEAR CHOLESTEROL
Risk of coronary artery disease linked to LDL levels
• Plaque cap can rupture
• Collagen exposed
• Clotting cascade activated
• Platelet adhesion
• Thrombus formation
• Embolus formation possible
• Occlusion causes ischemia

CLASSIFICATIONS OF LIPID
LOWERING DRUGS
1. HMG-CoA reductase Inhibitors
(Statins): Fluvastatin, lovastatin,
pravastatin, simvastatin, atorvastatin,
rosuvastatin
2. SPECIFIC CHOLESTEROLABSORPTION
INHIBITORS: ezetimibe
3. BILE ACID BINDING (RESINS):
Cholestyramine and Colestipol,
colesevelam
4. FIBRATES: Clofibrate,
Gemifbrozil, Bezafibrate,and
Fenofibrate, ciprofibrate
5. Nicotinic Acid (NIACIN)

I. Bile Acid Sequestrants
• Cholestyramine
• colestipol hydrochloride
Also called bile acid-binding resins and ion
exchange resins
Mechanism of Action
• Prevent resorption of bile acids from small
intestine
• Bile acids are necessary for absorption
of cholesterol

Therapeutic Uses
• Type II hyperlipoproteinemia
• Relief of pruritus associated with partial biliary
obstruction (cholestyramine)
Side Effects
Constipation
Heartburn, nausea, belching, bloating
These adverse effects tend to disappear
over time

II. HMG-CoA Reductase Inhibitors (statins)
• lovastatin
• simvastatin
• atorvastatin
Most potent LDL reducers
Mechanism of Action
• Inhibit HMG-CoA reductase, which is used by
the liver to produce cholesterol
• Lower the rate of cholesterol production
• cerivastatin
• fluvastatin
• pravastatin

Therapeutic Uses
• Treatment of type IIa and IIb hyperlipidemias
–Reduce LDL levels by 30 to 40%
–Increase HDL levels by 2 to 15%
–Reduce triglycerides by 10 to 30%
Side Effects
• Mild, transient GI disturbances
• Rash
• Headache
• Myopathy (muscle pain)
• Elevations in liver enzymes

III.Fibric Acid Derivatives
• Clofibrate
• gemfibrozil
• fenofibrate
Mechanism of Action
• Believed to work by activating lipase, which
breaks down cholesterol
• Also suppress release of free fatty acid from
the adipose tissue, inhibit synthesis of
triglycerides in the liver, and increase the
secretion of cholesterol in the bile

Therapeutic Uses
• Treatment of type IV and V hyperlipemias
• Treatment of type III, IV, and V
hyperlipidemias
• Decrease the triglyceride levels and increase
HDL by as much as 25%
Side Effects
• Abdominal discomfort
• Diarrhea
• Nausea
• Blurred vision
• Increased risk of gallstones
• Prolonged prothrombin time
• Liver studies may show increased function

IV. Niacin (Nicotinic Acid)
Vitamin B3
• Lipid-lowering properties require much higher
doses than when used as a vitamin
• Effective, inexpensive, often used in
combination with other lipid-lowering agents
Mechanism of Action
• Thought to increase activity of lipase, which
breaks down lipids
• Reduces the metabolism or catabolism of
cholesterol and triglycerides

Therapeutic Uses
• Effective in lowering triglyceride, total serum
cholesterol, and LDL levels
• Increases HDL levels
Side Effects
• Flushing (due to histamine release)
• Pruritus
• GI distress

Functions of Blood
• Blood performs a number of functions dealing with:
– Substance distribution
– Regulation of blood levels of particular substances
– Protection
• Blood transports:
– Oxygen from the lungs and nutrients from the
digestive tract
– Metabolic wastes from cells to the lungs and to
kidneys for elimination
– Hormones from endocrine glands to target organs
• Blood maintains:
– Appropriate body temperature by absorbing and
distributing heat
– Normal pH in body tissues using buffer systems
– Adequate fluid volume in the circulatory system

• Blood prevents blood loss by:
–Activating plasma proteins and platelets
–Initiating clot formation when a vessel is
broken
• Blood prevents infection by:
–Synthesizing and utilizing antibodies
–Activating WBCs to defend the body against
foreign invaders
Physical characteristics and volume
• Blood is a sticky, opaque fluid with a metallic taste
• It is a viscus fluid connective tissue.
• Color varies from scarlet (oxygen-rich) to dark red
(oxygen-poor)

• The pH of blood is 7.35–7.45 and its salt
content is 0.9%
• Temperature is 38C.
• Blood accounts for approximately 8% of body
weight
• Average volume of blood is 5–6 L for males,
and 4–5 L for females.
Composition of Blood
• Blood is the body’s only fluid connective
tissue
• It is composed of -liquid plasma (55%) and
-formed elements (45%)

• Formed elements include:
– Erythrocytes, or red blood cells (RBCs)
– Leukocytes, or white blood cells (WBCs)
– Thrombocytes, or Platelets
• Hematocrit – the percentage or proportion of
blood volume that is RBCs.
Plasma
• It is the liquid portion of blood
• It makes up 55% of the blood volume

Composition of plasma
Blood plasma composed of
1. Water (90%)
2. Organic constituents (9%)
– Plasma proteins: albumin, globulins, clotting
proteins and others (7%)
– Lipids, lipoproteins, phospholipids
– Hormones and enzymes
– Nutrients: CHO, vitamines, amino acids, fats
– Metabolic waste products: urea, creatinine
3. Inorganic constituents: electrolytes (1%)
4. Respiratory gases – oxygen and carbon dioxide

Principal plasma proteins
• There are 3 principal plasma proteins
Albumin: 4 g/dl
Globulin: 2.7 g/dl
Fibrinogen: 0.3 g/dl
• Plasma proteins are synthesized by hepatocytes,
lymphocytes, platelets and endothelial cells.
Function of plasma proteins
1. Immunologic function: γ-globulins are
immunoglobulin's (antibodies)
2. Nutritional function in starvation
3. Haemostasis: fibrinogen, prothrombin and most
other clotting factors are plasma proteins

4. Transport of hormones, electrolytes and drugs.
5. pH regulation (buffering function)
6. Maintenance of plasma osmotic pressure
7. Enzymatic and hormonal function
Erythrocytes (Red blood cells)
Function
• Transport of O2 and CO2
• Regulation of acid-base balance
• Major content of RBCs is Hb (97% )
• Size: Diameter 7.5 µm
Thickness 1 and 2 µm
• Hematocrit: The percentage of blood cells
M = 42-48%
F = 38-43%

 Hematopoiesis- is the production of circulating
erythrocytes, platelets and leukocytes from
undifferentiated stem cells
– The hemopoietic machinery resides primarily
in the bone marrow in adults, and requires
constant supply of three essential nutrients –
iron, vitamin B12 and folic acid
 Anemia:- is defined as a below-normal plasma
hemoglobin concentration (12-20g/dl)
– arise from a decreased number of circulating
red blood cells or an abnormally low total
hemoglobin content per unit of blood volume.
– Anemia may occur due to deficiency of iron,
vit B12 or a folic acid
155

 Generally the different types of anemia include:-
– Aplastic anemia:-due to bonemarrow abnormality
– Hemolytic anemias:- RBC loss> RBC production
– anemias caused by inherited abnormalities of RBCs
(for example, sickle cell anemia and thalassemia)
– Iron deficiency anemia
– Vitamin deficiency anemia(vitaminB12 or folic acid)
– Anemia caused by chronic (ongoing) disease
– Anemia also occur due to blood loss as in injuries
 Most cases of anemia are either iron deficient or
vitamin deficient
156

 Generally the different types of anemia include:-
– Aplastic anemia:-due to bonemarrow abnormality
– Hemolytic anemias:- RBC loss> RBC production
– anemias caused by inherited abnormalities of RBCs
(for example, sickle cell anemia and thalassemia)
– Iron deficiency anemia
– Vitamin deficiency anemia(vitaminB12 or folic acid)
– Anemia caused by chronic (ongoing) disease
– Anemia also occur due to blood loss as in injuries
 Most cases of anemia are either iron deficient or
vitamin deficient
157

 Signs and Symptoms:
 Symptoms of anemia can be mild at first. They
include:
»tiredness, weakness, shortness of
breath, pale skin, lightheadedness,
headache, feeling cold, rapid heartbeat
and chest pain
158

 Treatment may include:-
– treatment of the causative disease
– change in diet
– vitamin and mineral supplements
– medication
– blood transfusion
–transfusions -- may help treat certain
types of anemia, including anemia of
chronic disease, sickle cell anemia, and
aplastic anemia
– bone marrow or stem cell transplant -- may
be used in severe cases of aplastic anemia or
some cases of sickle cell anemia
159

Agents used in Anemias
Iron
– is part of hemoglobin that carries oxygen to tissues
– when there is deficiency of iron, small erythrocytes
with insufficient hemoglobin are formed resulting in
microcytic hypochromic anemia.
– the most common type of anemia
 Causes of iron deficiency anemia
nutritional deficiency
reduced absorption after gastrectomy, as a result of
mucosal damage, coadministration of drugs that
chelate iron e.g. antacids
Chronic blood loss:-chronic nose bleeding,
menorrhagia, occult GI bleeding, worm infestation
and ulers (e.g. PUD)
–blood loss- the most common cause of iron
deficiency in adults 160

 Pharmacokinetics of Iron
 Daily requirement of Iron
iron requirement increases in growing children,
pregnant and lactating women
 Sources
dietary - mostly in the organic form from meat,
cereals, etc.
 Iron distribution in normal adults
hemoglobin, storage ( ferritin and other form),
myoglobin, enzymes, transport (transferin) in
decreasing order of amounts
161

 Absorption
– absorbed in duodenum and proximal jejunum
– a normal individual with out iron deficiency
absorbs 5-10 % of daily intakes.
– absorption is increased in states with increased
requirements , deficiencies and/or dietary factors
such as heme-iron (from meat, etc), HCl and
vitamin C
– absorption is decreased from non heme iron
(Fe3+), in the presence of antacids and other
chelators, and following gastric resection.
– Iron crosses the intestinal mucosal cell by active
transport
 Storage
– Iron is stored primarily as ferritin (an iron-protein
complex) in intestinal mucosal cells and in
macrophages in the liver, spleen and bone. 162

 Elimination:
– Very small amount is execrated in stool by
exfoliation of intestinal mucosal cells and
trace amounts are execrated in bile, urine and
sweat with total daily excretion not more than
1mg/day.
163

 Treatment of iron deficiency anemia
– The cause should always be identified and treated
whenever possible.
– Treatment of iron deficiency anemia consists of
administration of oral or parenteral iron preparation
– they should be used only when dietary measures
have failed
1. Oral Iron Therapy:
– only ferrous salts should be used because of most
efficient absorption
– Drugs: Ferrous sulfate, ferrous gluconate, ferrous
fumarate are most commonly used
– 200-400mg elemental irons should be given daily to
correct iron deficiency most rapidly 164

–For best absorption, iron should be taken
between meals.
» Iron may cause stomach and intestinal
disturbances.
» Low doses of ferrous sulfate can be
taken with food and are still absorbed
but with fewer side effects.
–Taking orange juice with an iron pill can help
increase iron absorption.
» Some prescribers also recommend
taking a vitamin C supplement with the
iron pill
–Treatment should be continued for 3-6
months to replenish iron stores
165

– Side effects: Oral iron therapy can cause nausea,
vomiting, epigastric discomfort, abdominal
cramps, constipation and diarrhea.
– Some patients have less severe
gastrointestinal adverse effects with one iron
salt than another and benefit from changing
preparations
– Certain medications, including antacids, can
reduce iron absorption.
– Iron tablets may also reduce the effectiveness of
other drugs, including the antibiotics tetracycline,
penicillamine, and ciprofloxacin and the
Parkinson's disease drugs methyldopa, levodopa,
and carbidopa.
– At least 2 hours should elapse between
doses of these drugs and iron supplements.
166

2. Parenteral iron therapy:
 Drug: iron dextran , sodium ferric
gluconate complex in sucrose, iron sucrose
 may be given by deep IM or occasionally IV
 Should be reserved for patient unable to
tolerate or absorb oral iron
 Iron dextran may cause allergic reaction
» The other two are at least equally
effective and safer than iron dextran
 Side effect: - include local pain, tissue staining,
headache, light headedness, fever, arthralgia,
nausea, vomiting, urticaria, back pain,
bronchospasm, and rarely anaphylaxis and death
167

 Acute iron Toxicity
Is exclusively seen in children b/c of over
ingestion and rarely seen in adults
 Signs and symptoms
Necrotizing gastroenteritis with vomiting,
abdominal pain and bloody diarrhea, shock,
metabolic acidosis, coma
 Treatment
Whole bowel irrigation
Deferoxamine- A potent iron chealating
compound should be given systemically to bind
iron and promote excretion through urine
Given parentally (i.m., s.c. or i.v.)
Recently, an oral iron chelator deferasirox
has been approved for treatment of iron
overload. 168

 Chronic iron toxicity
– excess iron is deposited in the heart, liver,
pancreas, and other organs.
– It can lead to organ failure and death
– most commonly occurs in patients with
inherited hemochromatosis (a disorder
characterized by excessive iron absorption,
and in patients who receive many red cell
transfusions over a long period of time)
169

 Iron dextran
– It can be given by deep intramuscular injection or by
intravenous infusion, although the intravenous route
is used most commonly.
– IV administration eliminates the local pain and
tissue staining that often occur with the IM route
and allows delivery of the entire dose of iron
necessary to correct the iron deficiency at one time
– Anaphylactic reactions to iron dextran, including
fatal reactions, have been clearly documented
– Owing to the risk of a hypersensitivity reaction, a
small test dose of iron dextran should always be
given before full intramuscular or intravenous doses
are given
– The favored route of administration is i.v. infusion in
several hundred mls of normal saline over 1-2 hrs.
170

 iron-sucrose complex and iron
sodium gluconate complex
– are alternative preparations. these agents
can be given only by the iv route
– these preparations appear to be much less
likely than iron dextran to cause
hypersensitivity reactions.
171

 Blood Transfusions
– Transfusions are used to replace blood loss
due to injuries and during certain surgeries.
– They are also commonly used to treat
severely anemic patients who have
thalassemia, sickle cell disease,
myelodysplastic syndromes, or other types of
anemia.
– Some patients require frequent blood
transfusions.
– Iron overload can be a side effect of these
frequent blood transfusions.
–If left untreated, iron overload can lead
to liver and heart damage.
172

– Iron chelation therapy is used to remove the
excess iron caused by blood transfusions
– For many years, deferoxamine was the only
drug used in chelation therapy
–This drug is usually injected
intravenously, using an infusion pump.
– A new drug, deferasirox , is approved as a
once-daily treatment for iron overload due
to blood transfusions.
–It does not require injections.
–Patients mix the deferasirox tablets in
liquid and drink the medicine.
173

Vitamin B12
– Daily requirement is 2-5 mg
– Source:-mainly obtained from animal products
–Ultimate source of vit B12 is from microbial
synthesis
– Importance:-serves as a co factor for essential
biochemical reaction in humans including DNA synthesis
 Pharmacokinetics
– Absorbed in distal ileum after combined with intrinsic
factor secreted by stomach
– Absorbed through a highly specific receptor mediated
transport system
– Transported/distributed to various cells of the body
bound to plasma glycoprotein, transcobalamin II
– Excess vitamin B12 is transported to the liver for storage
and excreted in the urine. 174

 Deficiency of Vit B 12- it results in:-
– Megaloblastic anemia
– Neurological syndrome involving spinal cord and
peripheral nerves
–The neurologic syndrome usually begins with
paresthesias and weakness in peripheral
nerves and progresses to spasticity and other
central nervous system dysfunctions
 Causes of deficiency:
– defective secretion of intrinsic factor necessary for
absorption of vitB 12, partial or total gastrectomy,
diseases that affect distal ileum, malabsoption
syndrome e.g inflammatory bowel disease, small
bowel resection etc.
– Almost all cases of vit B12 deficiencies are caused
by malabsorption
175

 Treatment of Vit B 12 deficiency
»Drugs: cyanocoblamin and
hydroxycobalamin
– Hydroxocobalamin is preferred because it is
more highly protein-bound and therefore
remains longer in the circulation
– may be administered orally (for dietary
deficiencies) and intramuscularly, or deep
subcutaneously (for pernicious anemia)
– patients with pernicious anemia will need life-
long therapy.
176

Folic acid
– Daily requirement is 50 -100μg
– Folic acid deficiency is not uncommon
 Sources
– include yeast, liver, kidney and green vegetables
 Physiologic functions
– required for essential biochemical reactions that
provide precursors for the synthesis of amino
acids, purines and DNA
 Deficiency
– Common among elderly patients, poor patients,
pregnant ladies.
– It results in megaloblasiic anemia.
– The causes are dietary deficiency, alcoholics with
liver disease, hemolytic anemia, malabsorption
syndrome, drugs such as methotrexate 177

 Phamacokinetics
– folic acid is readily and completely absorbed
in the proximal jejunum.
– 5 -20 mg of folates are stored in the liver and
other tissues
– Body stores of folates are relatively low and
daily requirement is high
– hence folic acid deficiency and magaloblasitc
anemia can develop within 1 -6 months after
the in take of folic acid stops
178

 Treatment
– Folic acid 1mg orally per day
 N.B
– Folic acid supplementation to prevent folic acid
deficiency should be considered in high-risk
individuals including pregnant women, alcoholics and
patients with hemolytic anemia, liver disease, certain
skin disease, and patients on renal dialysis.
– The administration of folic acid in the setting of vitB12
deficiency will not prevent neurological manifestation
even though it will largely correct the anemia caused
by the vitamin B 12 deficiency.
179

 Erythropoietin (Epoetin alpha)
– Erythropoietin is a glycoprotein normally made by
the kidney, that regulates red blood cell
proliferation and differentiation in bone marrow
– Erythropoietin deficiency results in a normocytic
anemia
– Epoetin alfa is a glycoprotein manufactured by
recombinant DNA technology, and has the same
biological effects as endogenous erythropoietin
– is effective in the treatment of anemia caused by
end-stage renal disease, anemia associated with
HIV, and anemia in some cancer patients
– erythropoietin has had a significant positive
impact for patients with anemia of chronic renal
failure
180

 Pharmacokinetics:
– given IV or SC Half life of 4-13 hrs in patients
with chronic renal failure.
 Side Effects:
– a rapid increase in hematocrit & hemoglobin may
cause hypertension & thrombotic complications.
These can be minimized by raising the hematocrit
slowly and treating the hypertension.
 Contraindications:
– Uncontrolled hypertension
 Novel erythropoiesis stimulating protein (NESP), also
called darbepoetin alfa , lasts longer in the blood
than epoetin alfa and requires fewer injections.
181

Thrombogenesis
Hemostasis is the spontaneous arrest of
bleeding from damaged blood vessel
The immediate haemostatic response of a
damaged vessel is vasospasm

MECHANISMS OF BLOOD COAGULATION
A clot that adheres to a vessel wall is called a
thrombus, whereas an intravascular clot that floats
in the blood is termed an embolus, a detached
thrombus becomes an embolus.
Both thrombi and emboli are dangerous, because
they may occlude blood vessels and deprive tissues
of oxygen and nutrients
Physical trauma to the vascular system, such as a
puncture or a cut, initiates a complex series of
interactions between platelets, endothelial cells, and
the coagulation cascade.
This results in the formation of a platelet-fibrin
plug (clot) at the site of the puncture.

The creation of an unwanted thrombus involves
many of the same steps as normal clot formation,
except that the triggering stimulus is a pathologic
condition in the vascular system rather than an
external physical trauma.
At resting condition
Platelets circulate freely since chemical signal
indicate that there is no vascular system damage.
Prostacycline bind membrane receptor [GP
IIb/IIIa] stablizing and inactivating release of
mediators of platelet aggregation [cAMP and Ca++,
thromboxane A2, adenosine, serotonin, platelet
activating factor ].
When endothelium injured, platelets activated and
trigger series of chemical reaction

Ⅻ Ⅻa
Ⅺa
Ⅸa
Ⅹa
Ⅲa,Ⅶa
Ⅺ
Ⅸ
Ⅹ
Ⅲ, Ⅶ
Ⅹ
+
+
+ +
+
Prothrombin(Ⅱ) Thrombin(Ⅱa)
Fibrin
( Insoluble)
Fibrin
(soluble)fibrinogen
++
ⅩIII
ⅩIIIa
+
Fibrin clot
process of normal blood coagulation
extrinsic pathway
intrinsic pathway

Factor Common Name
Number
I Fibrinogen
II Prothrombin
III Tissue Factor
IV Ca2+
Va Proaccelerin
VII Proconvertin
VIII Antihemophilic Factor
IX Christmas Factor
X Stuart Factor
XI Plasma thromboplastin antecedent
XII Hageman factor
XIII Fibrin Stabilizing Factor

Clotting
Disorders
Anti clotting
Drugs
Antiplatelets
Anticoagulants
Thrombolytic
drugs
Clotting drugs
(Coagulants)
Clotting Disorders /Coagulation Disorder
The Drugs used in clotting and bleeding
(Clotting disorders/Coagulation disorder) fall
into two as shown blow:

2.1. Anti clotting Drugs
A) Antiplatelet Drugs
Platelet aggregation
Is facilitated by thromboxane, ADP, fibrin, 5-HT, and
other substances.
Inhibited Prostacyclin and increased cAMP
Antiplatetes includes
NSAID (aspirin)
ADP receptor antagonist (Ticlopidine and
Clopidogrel)
Glycoprotein IIb/IIIa receptor antagonist (abciximab)

Aspirin
NSAID inhibits thromboxane synthesis by
blocking the enzyme cyclo-oxygenase
Inhibition by aspirin persists until new
platelets are formed (several days)
Aspirin prevent further infarcts myocardial
infarction ,transient ischemic attacks (TIAs),
ischemic strokes and other thrombic events.
Low dose aspirin used

Ticlopidine and Clopidogrel
Ticlopidine:
Inhibit platelet aggregation by inhibiting ADP
pathway
involved in binding of platelets to fibrinogen.
Used orally. Can cause bleeding and neutropenia
so reserved for patients who cannot tolerate
aspirin.
Clopidogrel:
Analog of ticlopidine and prevents ADP-mediated
activation of the glycoprotein complex GPIIb/IIIa,
thereby inhibiting platelet aggregation.

Abciximab
Glycoprotein IIb/IIIa receptor antagonist. It is a
monoclonal antibody that inhibits the receptors that
form the final common pathway for platelet
aggregation. It can reduce platelet aggregation by more
than 90%. It is given IV as an adjunct to percutaneous
coronary intervention for prevention of cardiac
ischemic complications. It is given with heparin and
aspirin
Dipyridamole
Coronary vasodilator, used prophylactically with
aspirin to treat angina. It increases intracellular levels
of cAMP by inhibiting phosphdiesterase. It is combined
with warfarin

Antiplatelet Drugs: Eptifibatide and Tirofiban
Act similarly to Abciximab, blocking the
GPIIb/IIIa receptor.
They mimic the arginine-glycine-aspartic acid
sequence of fibrinogen, which accounts for
their specific antagonism at this receptor.
They decrease the incidence of thrombotic
complications associated with acute coronary
syndromes.
Used IV

Toxicity of antiplatelates
Aspirin: gastrointestinal
disturbances
GP IIb/IIIa inhibitors: bleeding
and throbocytopenia
Ticlopidine: bleeding and
neutropenia
Dipyridamole: headache and
palpitation

B) THROMBOLYTICS
Rapidly lyse thrombi by catalyzing the formation
plasmin from its precursor plasminogen
Create a generalized lytic state when
administered intravenously. Thus, both protective
haemostatic thrombi and target thromboemboli
are broken down. Thrombolytic drugs reduce the
mortality of acute myocardial infarction
Can be either endogenous tissue plasminogen
activators(t-PA): alteplase, teneplatase, reteplase
or protein synthesized by streptococi
(Streptokinase)

The process of dissolution of clot is called
fibrinolysis
Plasminogen
t-PA
Endothelial
cells
Plasmin
fibrin Fibrin degraded
products

Plasminogen
Plasmin
Streptokinase
Urokinase
Alteplase
+ EACA
Tranexamic acid
Aprotinin
-
Fibrinolytics Antifibrinolytics

Streptokinase
Streptokinase is a non-enzyme protein isolated
from streptococci; it binds to plasminogen to
catalyze the conversion of plasminogen to active
plasmin.
It acts on both circulating plasminogen and fibrin-
bound plasminogen.
It is used in AMI and stroke, acute pulmonary
embolism, DVT, and reperfusion of occluded
peripheral arteries. It is also used to clear occluded
venous catheters.
Adverse effects: systemic bleeding allergic
reactions in patients having streptococcal
antibodies

Urokinase
A protease originally isolated from urine;
the drug isnow prepared in recombinant form
from cultured kidney cells.
Urokinase activates circulating and fibrin-
bound plasminogen
Urokinase is approved for the treatment of
pulmonary embolism. It is less antigenic than
streptokinase and is indicated in patients
sensitive to streptokinase

Clinical Use of Thrombolytics
Acute Myocardial Infarction
Pulmonary Embolism
Deep Vein Thrombosis [DVT]
Arterial Thrombosis or Embolism

C) ANTICOAGULANTS
•These are drugs which interfere with the
coagulation of blood either in vivo or in vitro
•They are used clinically to prevent the
extension of an existing thrombus and stop
formation of new thrombi in the vascular bed
Classification of anticoagulants
A. Parenteral anticoagulants
B. Oral anticoagulants

I. Parenteral anticoagulants
Substances which inhibit conversion of
prothrombin to thrombin and interfere with the
action of thrombin on fibrinogen
Indirect thrombin inhibitors
Heparin and Low molecular weight heparin
Direct thrombin inhibitors
lipirudin and Danaparoid
II. Oral anticoagulants:
Substances which interfere with synthesis of
prothrombin and factor VII, IX and X.
These agents comprises:
Coumarins, e.g. Warfarin, Dicoumarol,
Tromexan, Cyclocoumar

Indirect thrombin inhibitors
- Include unfractionated heparin (UFH = heparin)
& low molecular weight heparin (LMWH)
Mechanism of action of Heparin
A. It acts indirectly by markedly increasing the
activity of antithrombin-III (heparin-
antithrombin-III complex) that inhibits several
activated clotting cofactors, namely; IIa, IXa,
Xa, XIa & XIIa); most importantly thrombin &
factor Xa
B. Antithrombin III then inhibits the conversion of
prothrombin to th

Low Molecular Weight Heparin (LMWH)
Low molecular weight heparin is synthesized by
depolymerization of heparin
unlike heparin which has equivalent activity against
factor Xa &thrombin, LMWHs have greater activity
against factor Xa
DIRECT THROMBIN INHIBITORS
Lepirudin, Danaparoid:
Directly bind to the active site of thrombin inhibiting
thrombin'sdownstream effects thus exerting their
antithrombotic activity
Anticoagulant in vivo only
Advantages over UFH:
Useful in patients with heparin – induced thrombocytopenia

Anticoagulants: Heparin
Mucopolysaccharide
Partially in the liver by heparinase to uroheparin,
which has only slight antithrombin activity.
20-50 % is excreted unchanged.
The heparin polysaccharide chain is degraded in
the gastric acid administered IV or SC.
Heparin should not be given IM }danger of
hematoma formation{.

Anticoagulants: Heparin
Unfractionated heparin (UFH)
Mol weight: 3000-30000
Also inhibits the effects of factor Xa on the
coagulation cascade & limits platelet
aggregation.
Heparin-induced thrombocytopenia
is systemic hypercoagulable state
platelet count falls below the lower limits of
normal
or by 50% but remains in the normal range.
Platelets are activated by Immunoglobulin G
causing platelet aggregation

ORAL ANTICOAGULANTS ( VIT. K antagonists)
Coumarin anticoagulants include warfarin and
dicumarol
Mechanism of action:
It inhibits vitamin K reductase & vitamin K epoxide
reductase enzymes, so blocking the activation of vitamin
K
This leads to inhibition of the synthesis of factors II,
VII, IX & X
Adverse drug reaction
Hemorrhage
Teratogenicity
Hair loss (alopecia)
Hypersensitivity
Cutaneous necrosis

Warfarin: indication
Warfarin is given orally.
After absorption from intestine, it is largely bound
99% to plasma albumin
It is eliminated by liver metabolism, and its t½ is
about 36 h .
To adjust the dose, Lab. control of anti-coagulation is
done using INR
Therapeutic uses of Warfarin :
DVT: Treatment is started with Heparin for 5-7 days
(either LMW heparin SC OR IV UFH ( in case PE is also
present ) , and then continue anti-coagulation with
warfarin (INR 2.5- 3) for about 6 weeks in case of DVT
alone, OR 3 months in cases complicated by PE ; the
aimis to maintain anti-coagulation in order to prevent
recur

2. Long-term use of Warfarin : for about 12
months
a. Recurrent DVT or recurrent PE ( INR 3-4)
b. Prosthetic cardiac valves (INR 3-4)
c. Atrial fibrillation esp. if chronic or recurrent
or complicating mitral valve disease (INR 2.5-
d. Myocardial infarction in young men (< 50 yea

Adverse effects of Warfarin
1. Overdose bleeding : stop drug for few days;
the specific antidote is vitamin K given in dose
of 5 mg IV for serious bleeding OR 0.5-2 mg for
mild bleeding ; it takes about 3-5 h to induce
synthesis of effective clotting factors by liver.
In urgency : transfusion of blood or fresh
plasma or prothrombin complex concentrate (
contains factors II, IX, and X) is needed to stop
the bleeding
Note : Vitamin K IV may render patient resistant
to warfarin anti-coagulation for about 1-2
weeks , but heparin remains effective during
this period

2. Teratogenicity : warfarin passes across the
placental barrier to reach the fetus during
pregnancy; its use may be associated skeletal
malformations; CNS malformations, probably due
to intra cerebral bleeds. The anticoagulant action
render fetus susceptible to bleeding. It should be
stopped before labor and heparin substituted.
3. Skin necrosis : may occur early with its use &
esp. in those patients with hereditary deficiency of
protein C or S
4. Allergy : include skin rashes; these are rare

Warfarin: disease-drug-interaction
Decreased absorption due to diarrhea or
binding to cholestyramine
Hepatic microsomal enzyme induction : e.g.
use of phenobarbital, phenytoin, Rifampin
Hereditary resistance : due to reduced
sensitivity of epoxide reductase to warfarin
Hypothyroidism
Pregnancy or use of combined estrogen
cont

Increased anti-coagulant effect (with
increased risk of bleeding) occurs with :
Vitamin K deficiency due to malabsorption
resulting from biliary obstruction or intestinal
disease, or from prolonged use of broad
spectrum antimicrobials e.g. tetracyclines
Displacement of warfarin from binding to
plasma albumin by salicylates and other
NSAIDs, anti-microbials such as sulfonamides
Liver disease

2.2. Drugs used to treat bleeding/ Coagulants
Bleeding problems may have their origin in naturally
occurring pathologic conditions, such as hemophilia, or
as a result of fibrinolytic states that may arise after
gastrointestinal surgery or prostatectomy.
The use of anticoagulants may also give rise to
hemorrhage.
Certain natural proteins and vitamin K, as well as
synthetic antagonists, are effective in controlling this
bleeding.
For example, hemophilia is a consequence of a
deficiency in plasma coagulation factors, most
frequently Factors VIII and IX. Concentrated
preparations of these factors are available from human
donors.

Hepatic microsomal enzyme inhibitors e.g.
cimetidine, ciprofloxacin, imidazole
antifungals, protease inhibitors for HIV, OR
competitive inhibition of warfarin
metabolism by other drugs e.g. cotrimoxazole
, metronidazole
Hyperthyroidism : due to increased
turnover of plasma clotting factors
NOTE : NSAIDs may cause gastric irritation
and erosions and also inhibit platelet
aggregation so increase the risk of bleeding
from warfarin; thus NSAIDs should be avoided

A. Aminocaproic acid: inhibit plasminogen
activation, are orally active, and excreted in the
urine. A potential side effect of treatment is
intravascular thrombosis.
B. Protamine sulfate: antagonizes the anticoagulant
effects of heparin and is derived from fish sperm
or testes and is high in arginine content, which
explains its basicity. The positively charged
protamine interacts with the negatively charged
heparin, forming a stable complex without
anticoagulant activity.
C. Vitamin K: Important for clotting factor synthesis
D. Aprotinin: Stop bleeding by blocking plasmin

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