CVS

PHARMACOLOGY
Prajogo Wibowo
Lecture from home, May 2020
Topics

• Diuretics
• Ischemic Heart Disease
• Hypertension
• HF
• Antiarrhytmic
• PAH, Corpulmonale
• Antiplatelet, Fibrinolytic
Diuretics

• Diuretics are drugs that increase the rate of urine flow; clinically
useful diuretics also increase the rate of Na+ excretion (natriuresis)
and of an accompanying anion, usually Cl−. Most clinical applications
of diuretics are directed toward reducing extracellular fluid volume
by decreasing total-body NaCl content.
• Although continued diuretic administration causes a sustained net
deficit in total-body Na+, the time course of natriuresis is finite
because renal compensatory mechanisms bring Na+ excretion in line
with Na+ intake, a phenomenon known as diuretic braking. These
compensatory mechanisms include activation of the sympathetic
nervous system, activation of the renin-angiotensin-aldosterone axis,
decreased arterial blood pressure (which reduces pressure
natriuresis), renal epithelial cell hypertrophy, increased renal
epithelial transporter expression, and perhaps alterations in
natriuretic hormones such as ANP.
Types

• Carbonic Anhydrase Inhibitors (Site I)

• Osmotic Diuretic (Site II)
• Loop Diuretics (Site III)- TALH
• Thiazide Diuretics (Site IV)
• Potassium Sparing Diuretics (Site V)
Inhibitors of Carbonic Anhydrase

• Acetazolamide
• Dichlorphenamide
• Methazolamide
Pharmacokinetics

• The carbonic anhydrase inhibitors are well absorbed after oral

administration. An increase in urine pH from the HCO3− diuresis is
apparent within 30 minutes, is maximal at 2 hours, and persists for 12
hours after a single dose. Excretion of the drug is by secretion in the
proximal tubule S2 segment. Therefore, dosing must be reduced in
renal insufficiency.
Pharmacodynamics

• Inhibition of carbonic anhydrase activity profoundly

depresses HCO3− reabsorption in the PCT.
• Carbonic anhydrase inhibition causes significant HCO3− losses
and hyperchloremic metabolic acidosis. Because of reduced
HCO3− in the glomerular filtrate and the fact that HCO3−
depletion leads to enhanced NaCl reabsorption by the
remainder of the nephron, the diuretic efficacy of
acetazolamide decreases significantly with use over several
days.
• At present, the major clinical applications of
acetazolamide involve carbonic anhydrase–
dependent HCO3− and fluid transport at sites other
than the kidney. The ciliary body of the eye secretes
HCO3− from the blood into the aqueous humor.
Clinical Indications & Dosage

• Glaucoma
The reduction of aqueous humor formation by
carbonic anhydrase inhibitors decreases the
intraocular pressure. The major indication for
carbonic anhydrase inhibitors is open-angle
glaucoma. 2 products developed specifically for this
use are dorzolamide and brinzolamide, which are
available only as ophthalmic drops.
• Urinary Alkalinization
Uric acid and cystine are relatively insoluble and may
form stones in acidic urine.
• Metabolic Alkalosis
Acetazolamide can be useful in correcting the
alkalosis as well as producing a small additional
diuresis for correction of volume overload.
Acetazolamide can also be used to rapidly correct the
metabolic alkalosis that may appear following the
correction of respiratory acidosis.
• Acute Mountain Sickness
Weakness, dizziness, insomnia, headache, and nausea can
occur in mountain travelers who rapidly ascend above 3000
m. The symptoms are usually mild and last for a few days. In
more serious cases, rapidly progressing pulmonary or cerebral
edema can be life-threatening. By decreasing CSF formation
and by decreasing the pH of the CSF and brain, acetazolamide
can increase ventilation and diminish symptoms of mountain
sickness.
Toxicity

•Hyperchloremic Metabolic Acidosis

•Renal Stones
• Renal excretion of solubilizing factors (eg, citrate) may also decline with
chronic use. Calcium phosphate salts are relatively insoluble at alkaline pH
• Potassium Wasting
• In addition to potassium wasting, carbonic anhydrase inhibitors can lead to
phosphorus wasting, and even symptomatic
hypophosphatemia has been reported with these agents.
• Drowsiness and paresthesias are common following large doses of
acetazolamide.
• Hypersensitivity reactions
Osmotic Diuretics (self learning)

• Such agents can be used to reduce intracranial

pressure and to promote prompt removal of renal
toxins. The prototypic osmotic diuretic is mannitol.
Pharmacokinetics

• Mannitol is poorly absorbed by the GI tract, and when

administered orally, it causes osmotic diarrhea rather than
diuresis. For systemic effect, mannitol must be given
intravenously.
• Mannitol is not metabolized and is excreted by glomerular
filtration within 30–60 minutes, without any important
tubular reabsorption or secretion. It must be used cautiously
in patients with even mild renal insufficiency.
Pharmacodynamics

• Through osmotic effects, they also oppose the action of ADH in the
collecting tubule. The presence of a non reabsorbable solute such as
mannitol prevents the normal absorption of water by interposing a
countervailing osmotic force. As a result, urine volume increases. The
increase in urine flow decreases the contact time between fluid and
the tubular epithelium, thus reducing Na+ as well as water
reabsorption. The resulting natriuresis is of lesser magnitude than
the water diuresis, leading eventually to excessive water loss and
hypernatremia.
Clinical Indication

• Osmotic diuretics alter Starling forces so that water leaves cells and
reduces intracellular volume. This effect is used to reduce
intracranial pressure in neurologic conditions and to reduce
intraocular pressure before ophthalmologic procedures. A dose of 1–
2 g/kg mannitol is administered intravenously. Intracranial pressure,
which must be monitored, should fall in 60–90 minutes.
• At times the rapid lowering of serum osmolality at initiation of
dialysis (from removal of uremic toxins) results in symptoms.
Toxicity

• Mannitol is rapidly distributed in the extracellular

compartment and extracts water from cells. Prior to
the diuresis, this leads to expansion of the
extracellular volume and hyponatremia. This effect
can complicate heart failure and may produce florid
pulmonary edema.
• Excessive use of mannitol without adequate water
replacement can ultimately lead to severe dehydration, free
water losses, and hypernatremia. As water is extracted from
cells, intracellular K+ concentration rises, leading to cellular
losses and hyperkalemia.
• When used in patients with severe renal impairment,
parenterally administered mannitol cannot be excreted and
is retained in the blood. This causes osmotic extraction of
water from cells, leading to hyponatremia without a
decrease in serum osmolality.
• Acute Renal Failure
The effect is thought to be mediated by the increase in osmolality.
LOOP DIURETICS
(self learning)
• The two prototypical drugs of this group are
furosemide and ethacrynic acid
Pharmacokinetics

• The loop diuretics are rapidly absorbed. They are eliminated

by the kidney by glomerular filtration and tubular secretion.
Absorption of oral torsemide is more rapid (1 hour) than that
of furosemide (2–3 hours) and is nearly as complete as with
intravenous administration. Bumetanide pharmacokinetics
are similar to those of torsemide, but bumetanide is a much
more potent loop diuretic.
• 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. Since loop agents act on the luminal side of
the tubule, their diuretic activity correlates with their
secretion by the proximal tubule. 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. Metabolites of ethacrynic acid and furosemide have
been identified, but it is not known whether they have any
diuretic activity. Torsemide has at least one active metabolite
with a half-life considerably longer than that of the parent
compound.
Pharmacodynamics

• Loop diuretics inhibit NKCC2, the luminal Na+/K+/2Cl− transporter in

the Thick Ascending Limb 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. This positive potential normally drives divalent cation
reabsorption in the TAL, and by reducing this potential, loop diuretics
cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can
cause significant hypomagnesemia in some patients. Since vitamin
D–induced intestinal absorption and parathyroid hormone–induced
renal reabsorption of Ca2+ can be increased, loop diuretics do not
generally cause hypocalcemia.
Clinical Indication

• The most important indications for the use of the loop diuretics
include acute pulmonary edema and other edematous conditions.
• Other indications for loop diuretics include hypercalcemia,
hyperkalemia, acute renal failure, and anion overdose.
Toxicity

By inhibiting salt reabsorption in the TAL, loop diuretics

increase Na+ delivery to the collecting duct. Increased Na+
delivery leads to increased secretion of K+ and H+ by the duct,
causing hypokalemic metabolic alkalosis
Contra Indication

• Furosemide, bumetanide, and torsemide may exhibit allergic

cross-reactivity in patients who are sensitive to other
sulfonamides, but this appears to be very rare. Overzealous
use of any diuretic is dangerous in hepatic cirrhosis,
borderline renal failure, or heart failure.
Thiazides Pharmacokinetics

• All thiazides can be administered orally, but there are differences in

their metabolism.
• Chlorothiazide, the parent of the group, is not very lipid-soluble and
must be given in relatively large doses. It is the only thiazide available
for parenteral administration. HCTz is considerably more potent and
should be used in much lower doses.
• Chlorthalidone is slowly absorbed and has a longer duration of
action. Although indapamide is excreted primarily by the biliary
system, enough of the active form is cleared by the kidney to exert its
diuretic effect in the DCT.
• Thiazides inhibit NaCl reabsorption from the
luminal side of epithelial cells in the DCT by blocking
the Na+/Cl− transporter (NCC).
• The major indications for thiazide diuretics are
(1) hypertension
(2) heart failure
(3) nephrolithiasis due to idiopathic hypercalciuria, and
(4) nephrogenic diabetes insipidus.
 Toxicity

• Hypokalemic Metabolic Alkalosis

These toxicities are similar to those observed with loop
diuretics

• Impaired Uric Acid Metabolism and Gout

Thiazides are the diuretics most associated with
development of gout.
Contraindications

• Excessive use of any diuretic is dangerous in

patients with hepatic cirrhosis, borderline renal
failure, or heart failure.
POTASSIUM-SPARING DIURETICS

• Potassium-sparing diuretics prevent K+ secretion by

antagonizing the effects of aldosterone in
collecting tubules. Inhibition may occur by direct
pharmacologic antagonism of mineralocorticoid
receptors (spironolactone, eplerenone) or by
inhibition of Na+ influx through ion channels in the
luminal membrane (amiloride, triamterene).
Pharmacokinetics

• Spironolactone is a synthetic steroid that acts as a

competitive antagonist to aldosterone. Onset and duration
of its action are determined substantially by the active
metabolites canrenone and 7-α-spirolactone, which are
produced in the liver and have long half-lives (12–20 and
approximately 14 hours, respectively). Spironolactone binds
with high affinity and potently inhibits the androgen
receptor, which is an important source of side effects in
males (notably, gynecomastia and decreased libido).
• Amiloride and triamterene are direct inhibitors of
Na influx in the CCT. Triamterene is metabolized in
the liver, but renal excretion is a major route of
elimination for the active form and the metabolites.
Because triamterene is extensively metabolized, it
has a shorter half-life and must be given more
frequently than amiloride (which is not
metabolized).
 Pharmacodynamics

• Potassium-sparing diuretics reduce Na+ absorption in

the collecting tubules and ducts. Since K+ secretion is
coupled with Na+ entry in this segment, these agents
are also effective K+-sparing diuretics.
• The actions of the aldosterone antagonists depend on
renal prostaglandin production. The actions of K+-
sparing diuretics can be inhibited by NSAIDs under
certain conditions.
Toxicity

• Hyperkalemia
Unlike most other diuretics, K+-sparing diuretics reduce
urinary excretion of K+ and can cause mild, moderate, or even
life-threatening hyperkalemia.
The risk of this complication is greatly increased by renal
disease (in which maximal K+ excretion may be reduced) or by
the use of other drugs that reduce or inhibit renin (β blockers,
NSAIDs, aliskiren) or angiotensin II activity (ACEI or ARB).
• Gynecomastia, impotence, and BPH (very rare)
have been reported with spironolactone.
Contraindications

• Patients with chronic renal insufficiency are especially vulnerable and

should rarely be treated with these diuretics.
• Oral K+ administration should be discontinued if K+-sparing diuretics are
administered.
• Concomitant use of other agents that blunt the renin-angiotensin system
(β blockers, ACEi, ARB) increases the likelihood of hyperkalemia.
• Patients with liver disease may have impaired metabolism of triamterene
and spironolactone, so dosing must be carefully adjusted.
• Strong CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, and
grapefruit juice) can markedly increase blood levels of eplerenone, but
not spironolactone.
Ischemic Heart Disease
Ischemic Heart Disease

• Increase oxygen supply or reduce oxygen demands of myocardium

Reduce heart rate
Reduce preload
Reduce afterload
Improve coronary blood flow
Ischemic Heart Disease

• Nitrate
• CCB
• Beta Blocker
• Newer
Nitrate
CCB

• Calcium channel blockers (CCBs) are agents that

inhibit several specific calcium-dependent functions
in the cardiovascular system. By decreasing vascular
smooth muscle contraction and tone they produce
peripheral and coronary vasodilation.
Pharmacodynamics

MAJOR CARDIOVASCULAR ACTIONS OF CALCIUM CHANNEL BLOCKERS

1. Vasodilation is more marked in arterial and arteriolar vessels than
on veins and includes the coronary vasculature; veins do not
appreciably dilate with CCBs.
2. Negative chronotropic and dromotropic effects are seen on the
SA and AV nodal conducting tissue (NDHP agents only).
3. Negative inotropic effects are seen on myocardial cells; in the
case of DHPs, this effect may be offset by reflex adrenergic
stimulation after peripheral vasodilation.
• The differing pharmacodynamic effects of various CCBs
accounts for their classification. All the DHPs bind to the
same sites on the α1 subunit and exert a greater Ca2+
inhibitory effect on vascular smooth muscle than on the
myocardium, which explains their common property of
vascular selectivity; thus their major hemodynamic and
therapeutic effect is peripheral and coronary vasodilation.
Pharmacokinetics

• From the point of view of drug interactions, all of the CCBs are
metabolized in the liver by an enzyme system that is inhibited by
cimetidine, azole antifungals, and hepatic dysfunction; CCBs are
increased in activity metabolized by phenytoin and phenobarbital.
• The CCBs act more specifically on the smaller coronary
resistance vessels, where the tone is higher, and the calcium
inhibitory effect is more marked. CCBs are particularly
effective in those types of angina caused by or exacerbated
by coronary spasm or constriction, such as Prinzmetal
angina or cold-induced angina.
DHPs

1st Generation
• Oral nifedipine is the prototypical DHP. It is rapidly absorbed with
peak blood levels in 20 to 45 minutes and a duration of action of 4 to
8 hours. Because of its short half-life and difficulty controlling the
degree of blood pressure lowering, it is rarely used in its short- acting
form. Slow-release forms are currently available and are preferred by
most physicians. The dose for the slow-release form is 30 to 90 mg
once a day.
• The short-acting forms are generally contraindicated because of their
rapid hypotensive effect in some patients.
Side Effects
• Because DHPs have no SA or AV effects, reflex tachycardia may occur
if excessive blood pressure lowering occurs. Headache can occur with
any of the CCBs, but they occur more frequently with the first-
generation DHPs.
Pregnancy
• Category C specifies use only if potential benefit justifies the
potential risk to the fetus; no well-controlled trials are available.
2nd Generation DHPs
• Although amlodipine is no more vascularly selective than nifedipine,
it has unusual pharmacokinetics, including slow onset and offset of
binding to the calcium channel site and a prolonged elimination half-
life. Based on these pharmacokinetic characteristics and new
extensive experience with this agent in both angina and
antihypertensive studies, amlodipine has become the DHP of choice
for most physicians in the Western Hemisphere.
Non DHPs
Verapamil

• After peripheral vasodilation induced by verapamil, the cardiac output

and LV ejection fraction do not increase as much as they do with the
DHPs, probably owing to the negative inotropic effect and depression
of contractility of verapamil.
Pharmacokinetics
• The elimination half-life of standard verapamil tablets is usually 3 to 7
hours, but it increases significantly during long-term administration
and inpatients with liver or renal insufficiency. In significant hepatic
dysfunction, the dose of verapamil should be decreased by 50% to
75%. In significant renal dysfunction, such as a creatinine clearance of
less than 30 mL/min, the dose should be reduced by 50%.
Bioavailability is only 10% to 20% (high first-pass liver metabolism).
The parent compound and the active hepatic metabolite, nor
verapamil, are excreted 75% by the kidneys and 25% by the
gastrointestinal (GI) tract. Verapamil is 87% to 93% protein bound.
Oral
• The usual dosage of the standard preparation is 80 to 120
mg three times daily. During long-term oral dosing, less
frequent daily doses are needed (norverapamil metabolites).
Slow-release preparations (240 to 480 mg/day) are available
and are the usual regimen.
IV
• For supraventricular reentry tachycardias, a bolus of 5 to 10 mg (0.1
to 0.15 mg/kg) can be administered over 2 minutes and repeated 15
to 20 minutes later if needed. After successful administration, the
dose may be stopped or continued at 0.005 mg/kg/ min for
approximately 30 to 60 minutes, decreasing thereafter. When used
for control of the ventricular rate in AF, verapamil may be
administered at 0.005 mg/kg/min, increasing as needed, or as an IV
bolus of 5 mg, followed by a second bolus of 10 mg if needed.In the
presence of myocardial disease or interacting drugs, a very low
dosage (0.0001 mg/kg/min) may be infused and titrated upward
against the ventricular response.
• Side effects include headaches, facial flushing, dizziness, and ankle
edema—all lower in frequency than with DHPs. Constipation occurs
in up to one third of patients who receive verapamil, and the
negative inotropic effect of verapamil may precipitate or exacerbate
CHF.
DILTIAZEM

• Diltiazem is used for the same spectrum of CV disease as verapamil:

hypertension, angina pectoris, prevention of AV nodal reentry,
tachycardia, and rate control in acute and chronic AF. The side-
effect profile is similar, except that constipation is much less
common.
Pharmacokinetics
• More than 90% of oral diltiazem is absorbed, with approximately 45%
bioavailability (first-pass hepatic metabolism). The onset of action is
within 15 to 30 minutes, and peak effects occur at 1 to 2 hours.The
elimination half-life is 4 to 7 hours, and protein binding is 80% to
90%. Diltiazem is acetylated in the liver to the active metabolite
desacetyl diltiazem (40% of the activity of the parent compound),
which accumulates during long-term therapy. Only 35% of diltiazem
is excreted by the kidneys; the rest is excreted by the GI tract.
• The standard oral dose of short-acting diltiazem is 120 to 360 mg
daily in three or four divided daily doses. The slow-release
preparations are administered once or twice daily. IV diltiazem
(approved for arrhythmias) is administered as 0.25 mg/kg over 2
minutes with electrocardiographic (ECG) and blood pressure
monitoring; if the response is inadequate, the dose is repeated as
0.35 mg/kg in 15 to 20 minutes. Acute loading therapy may be
followed by an infusion of 5 to 15 mg/h.
• Contraindications are similar to those of verapamil: preexisting
depression of the SA or AV node, hypotension, low ejection fraction,
heart failure, and AF associated with Wolff-Parkinson-White
syndrome. LV failure ejection fraction of less than 40% after MI is a
clear contraindication.

Pregnancy
• Category C specifies use only if potential benefit justifies the
potential risk to the fetus; no well-controlled trials are available.
βETA-Blocker

• The decrease in intraventricular pressure and volume caused by the

sympathetic-mediated enhancement of cardiac contractility tends to
reduce myocardial oxygen consumption by reducing myocardial wall
tension (LaPlace’s law)
• Reduction in myocardial consumption, heart rate, blood pressure,
and myocardial contractility
• Augmentation of coronary blood flow, increase in diastolic perfusion
time by heart rate reduction, augmentation of collateral blood flow,
and redistribution of blood flow to ischemic areas
• Prevention or attenuation of atherosclerotic plaque rupture and
subsequent coronary thrombosis
• Alterations in myocardial substrate utilization
• Decrease in microvascular damage
stabilization of cell and lysosomal membranes,
shift of oxyhemoglobin dissociation curve to the right, inhibition of
platelet aggregation,
• inhibition of myocardial apoptosis, which allows natural cell
regeneration to occur
• Therefore, because β-blockers primarily reduce myocardial oxygen
consumption but fail to exert vasodilating effects on coronary
vasculature, they may not be totally effective in patients whose
angina is caused or increased by dynamic alterations in coronary
luminal diameter.
• Despite potential dangers in rest and vasospastic angina, β-blockers
have been used successfully as monotherapy and in combination
with vasodilating anti-anginal agents in the majority of patients. In
addition, there is evidence that β-blockers can reduce C-reactive
protein levels, an inflammatory marker of increased CV morbidity
and mortality.
Combined Use of β-Blockers with Other Antianginal

+ Nitrate
• The primary effects of β-blockers are to cause a reduction in both
resting heart rate and the response of heart rate to exercise. Because
nitrates produce a reflex increase in heart rate and contractility from
a reduction in arterial pressure, concomitant β-blocker therapy is
extremely effective because it blocks this reflex increment in the
heart rate. Similarly, the preservation of diastolic coronary blood flow
with a reduced heart rate will also be beneficial. In patients with a
propensity for myocardial failure who may have a slight increase in
heart size with the β-blockers, the nitrates will counteract this
tendency by reducing heart size as a result of its peripheral
venodilator effects.
Contraindications

• Several absolute contraindications exist, which include CV

contraindications such as severe bradycardia (heart rate <40
beats/min); preexisting high-degree AV nodal block (PR interval of
>0.24 seconds without a functioning pacemaker); overt LV failure,
except when the β-blocker is administered initially at low doses and
under supervision to patients already receiving diuretics, digoxin, and
an ACE inhibitor; and active peripheral vascular disease with rest
ischemia. Severe bronchospasm is an absolute contraindication, even
to β-selective agents; severe psychological depression is an important
relative contraindication, particularly for propranolol.
Newer Drugs

• Nicorandil may improve ischemia by two proposed mechanisms of

action.The first is by activating adenosine triphosphate (ATP)-
dependent potassium channels, which directly dilates peripheral and
coronary arteries. Like nitrates, nicorandil also promotes smooth
muscle cell relaxation and vasodilation via increased cGMP activity
through a nitrate moiety.
• Ivabradine, an inhibitor of the If current in the sinoatrial cells,
reduces resting and exercise heart rate in patients in sinus rhythm
but has no significant hemodynamic effects. In several smaller studies
of patients with chronic angina, ivabradine was shown to prolong the
symptom-free interval of ST-segment depression on exercise stress
test compared with placebo and resulted in similar reductions in
anginal symptoms and nitroglycerin use compared with atenolol.
• Ranolazine is a piperazine derivative first believed to inhibit partial
fatty acid oxidation and thereby to preferentially shunt cardiac
metabolism to a more metabolically favorable glucose pathway.
Subsequent cellular and animal experimental models indicate that at
clinically relevant levels, ranolazine does not significantly inhibit
partial fatty acid oxidation, but rather it inhibits the late phase of the
sodium current (late INa).
• Trimetazidine is believed to improve myocardial metabolism during
ischemia by inhibiting partial fatty acid oxidation and enhancing
utilization of glucose-dependent oxidation, which generates ATP
more efficiently in a low-oxygen environment. In clinical trials of
patients with angina, trimetazidine has been shown to reduce weekly
symptomatic episodes and prolong the interval before ST depression
on exercise testing, even in patients on maximal amounts of
traditional antianginal agents.
ANTIPLATELET Therapy

• Currently, three classes of antiplatelet agents are approved for the

treatment and/or prevention of recurrent events in patients with
CAD.
• These include
• cyclooxygenase (COX)-1 inhibitors
• adenosine diphosphate (ADP) P2Y12 receptor antagonists
• glycoprotein (GP) IIb/IIIa inhibitors.
• Ticlopidine, clopidogrel, and prasugrel reduce platelet
aggregation by inhibiting the ADP pathway of platelets.
These drugs irreversibly block the ADP P2Y12 receptor on
platelets. Unlike aspirin, these drugs have no effect on
prostaglandin metabolism.
Ticlopidine

• Ticlopidine is approved for prevention of stroke in patients

with a history of a transient ischemic attack (TIA) or
thrombotic stroke, and in combination with aspirin for
prevention of coronary stent thrombosis.
• Adverse effects of ticlopidine include nausea, dyspepsia, and
diarrhea in up to 20% of patients, hemorrhage in 5%, and, most
seriously, leukopenia in 1%. The leukopenia is detected by regular
monitoring of the white blood cell count during the first 3 months of
treatment. Development of thrombotic thrombo- cytopenic purpura
has also been associated with the ingestion of ticlopidine. The dosage
of ticlopidine is 250 mg twice daily orally. Because of the significant
side effect profile, the use of ticlopidine for stroke prevention should
be restricted to those who are intolerant of or have failed aspirin
therapy. Dosages of ticlopidine less than 500 mg/d may be efficacious
with fewer adverse effects.
Clopidogrel

• Clopidogrel is approved for patients with unstable angina or non-ST-

elevation acute myocardial infarction (NSTEMI) in combination with
aspirin; for patients with ST-elevation myocardial infarction (STEMI);
or recent myocardial infarction, stroke, or established peripheral
arterial disease. For NSTEMI, the dosage is a 300-mg loading dose
orally followed by 75 mg daily of clopidogrel, with a daily aspirin
dosage of 75–325 mg. For patients with STEMI, the dosage is 75 mg
daily of clopidogrel orally, in association with aspirin as above; and
for recent myocardial infarction, stroke, or peripheral vascular
disease, the dosage is 75 mg/d.
• Clopidogrel has fewer adverse effects than ticlopidine and is rarely
associated with neutropenia. Thrombotic thrombocytopenic purpura
has been reported. Because of its superior adverse effect profile and
dosing requirements, clopidogrel is frequently preferred over
ticlopidine
• The antithrombotic effects of clopidogrel are dose-dependent; within
5 hours after an oral loading dose of 300 mg, 80% of platelet activity
will be inhibited. The maintenance dosage of clopidogrel is 75 mg/d,
which achieves maximum platelet inhibition. The duration of the
antiplatelet effect is 7–10 days. Clopidogrel is a prodrug that requires
activation via the cytochrome P450 enzyme isoform CYP2C19.
Depending on the single nucleotide polymorphism (SNP) inheritance
pattern in CYP2C19, individuals may be poor metabolizers of
clopidogrel, and these patients may be at increased risk of
cardiovascular events due to inadequate drug effect.
Prasugrel

• Prasugrel, similar to clopidogrel, is approved for patients with acute

coronary syndromes. The drug is given orally as a 60-mg loading dose
and then 10 mg/d in combination with aspirin as outlined for
clopidogrel.
ticagrelor

• Ticagrelor is a newer type of ADP inhibitor (cyclopentyl

triazolopyrimidine) and is also approved for oral use in
combination with aspirin in patients with acute coronary
syndromes.
• Cangrelor is a parenteral P2Y12 inhibitor approved for IV use
in coronary interventions in patients without previous ADP
P2Y12 inhibitor therapy.
GP IIb/IIIa antagonists

• Three parenteral GP IIb/IIIa antagonists are approved for clinical use:

abciximab, eptifibatide, and tirofiban.
HYPERTENSION
Classification

1. Diuretics, which lower blood pressure by depleting the body of

sodium and reducing blood volume and perhaps by other
mechanisms.
2. Sympathoplegic agents, which lower blood pressure by reducing
peripheral vascular resistance, inhibiting cardiac function, and
increasing venous pooling in capacitance vessels. (The lat- ter two
effects reduce cardiac output.) These agents are further subdivided
according to their putative sites of action in the sympathetic reflex
arc (see below).
3. Direct vasodilators, which reduce pressure by relaxing vascular
smooth muscle, thus dilating resistance vessels and—to varying
degrees—increasing capacitance as well.
4. Agents that block production or action of angiotensin and thereby
reduce peripheral vascular resistance and (potentially) blood volume.
Centrally acting sympathoplegic drugs

• Methyldopa (l-α-methyl-3,4-dihydroxyphenylalanine) is an analog of

l-dopa and is converted to α-methyldopamine and α-
methylnorepinephrine; this pathway directly parallels the synthe- sis
of norepinephrine from dopa.
• The antihypertensive action of clonidine, a 2-imidazoline derivative,
was discovered in the course of testing the drug for use as a nasal
decongestant. After intravenous injection, clonidine produces a brief
rise in blood pressure followed by more prolonged hypoten- sion.
Methyldopa

• Methyldopa was widely used in the past but is now used primarily for
hypertension during pregnancy. It lowers blood pressure chiefly by
reducing peripheral vascular resistance, with a variable reduction in
heart rate and cardiac output.
• Methyldopa enters the brain via an aromatic amino acid transporter.
The usual oral dose of methyldopa produces its maximal
antihypertensive effect in 4–6 hours, and the effect can persist for up
to 24 hours. Because the effect depends on accumulation and
storage of a metabolite (α-methylnorepinephrine) in the vesicles of
nerve endings, the action persists after the parent drug has
disappeared from the circulation.
• The most common undesirable effect of methyldopa is sedation,
particularly at the onset of treatment. With long-term therapy,
patients may complain of persistent mental lassitude and impaired
mental concentration.
• Lactation, associated with increased prolactin secretion, can occur
both in men and in women treated with methyldopa. This toxicity is
probably mediated by inhibition of dopaminergic mechanisms in the
hypothalamus.
• Other important adverse effects of methyldopa are develop- ment of
a positive Coombs test (occurring in 10–20% of patients undergoing
therapy for longer than 12 months),
Clonidine

• Reduction in arterial blood pressure by clonidine is accompanied by

decreased renal vascular resistance and maintenance of renal blood
flow.
• Clonidine is lipid-soluble and rapidly enters the brain from the
circulation. Because of its relatively short half-life and the fact that its
antihypertensive effect is directly related to blood concentration, oral
clonidine must be given twice a day (or as a patch, below) to
maintain smooth blood pressure control.
• Dry mouth and sedation are common. Both effects are centrally
mediated and dose-dependent and coincide temporally with the
drug’s antihypertensive effect.
• Clonidine should not be given to patients who are at risk for mental
depression and should be withdrawn if depression occurs during
therapy. Concomitant treatment with tricyclic antidepressants may
block the antihypertensive effect of clonidine. The interaction is
believed to be due to α-adrenoceptor-blocking actions of the
tricyclics.
• Withdrawal of clonidine after protracted use, particularly with high
dosages (more than 1 mg/d), can result in life-threatening
hypertensive crisis mediated by increased sympathetic nervous
activity. Patients exhibit nervousness, tachycardia, headache, and
sweating after omitting one or two doses of the drug. Because of the
risk of severe hypertensive crisis when clonidine is suddenly
withdrawn, all patients who take clonidine should be warned of this
possibility. If the drug must be stopped, it should be done gradually
while other antihypertensive agents are being substituted.
Ganglion blockers
GUANETHIDINE
• Guanethidine is too polar to enter the central nervous system.
• Guanethidine inhibits the release of norepinephrine from
sympathetic nerve endings.
• Because neuronal uptake is necessary for the hypotensive activity of
guanethidine, drugs that block the catecholamine uptake process or
displace amines from the nerve terminal (cocaine, amphetamine,
tricyclic antidepressants, phenothiazines, and phenoxybenzamine)
block its effects.
• Because of guanethidine’s long half-life (5 days), the onset of
sympathoplegia is gradual (maximal effect in 1–2 weeks), and
sympathoplegia persists for a comparable period after cessation of
therapy. The dose should not ordinarily be increased at intervals
shorter than 2 weeks.
• Guanethidine- induced sympathoplegia in men may be associated
with delayed or retrograde ejaculation (into the bladder).
Guanethidine commonly causes diarrhea, which results from
increased gastrointestinal motility due to parasympathetic
predominance in controlling the activity of intestinal smooth muscle.
• Similarly, guanethidine can produce hypertensive crisis by releasing
catecholamines in patients with pheo- chromocytoma. When tricyclic
antidepressants are administered to patients taking guanethidine,
the drug’s antihypertensive effect is attenuated, and severe
hypertension may follow.
reserpine

• Reserpine, an alkaloid extracted from the roots of an Indian plant,

Rauwolfia serpentina, was one of the first effective drugs used on a
large scale in the treatment of hypertension. At present, it is rarely
used owing to its adverse effects.
• Reserpine blocks the ability of aminergic transmitter vesicles to take
up and store biogenic amines, probably by interfering with the
vesicular membrane-associated transporter. This effect occurs
throughout the body, resulting in depletion of nor- epinephrine,
dopamine, and serotonin in both central and peripheral neurons.
• At lower doses used for treatment of mild hypertension, reserpine
lowers blood pressure by a combination of decreased cardiac output
and decreased peripheral vascular resistance.
• Reserpine rather often produces mild diarrhea and gastrointestinal
cramps and increases gastric acid secretion. The drug should not be
given to patients with a history of peptic ulcer.
• Much less frequently, ordinary low doses of reserpine produce
extrapyramidal effects resembling Parkinson’s disease, probably as a
result of dopamine depletion in the corpus striatum.
β blockers

• Propranolol decreases blood pressure primarily as a result of a

decrease in cardiac output.
• Propranolol inhibits the stimulation of renin production by
catecholamines (mediated by β1 receptors)
• Resting bradycardia and a reduction in the heart rate during exercise
are indicators of propranolol’s β-blocking effect, and changes in these
parameters may be used as guides for regulating dosage. Propranolol
can be administered twice daily, and slow-release once-daily
preparations are available.
• β2-blocking action occur in patients with asthma, peripheral vascular
insufficiency, and diabetes.
METOPROLOL, ATENOLOL

• Metoprolol and atenolol, which are cardioselective, are the most

widely used β blockers in the treatment of hypertension.
• Metoprolol is extensively metabolized by CYP2D6 with high first-pass
metabolism. The drug has a relatively short half-life of 4–6 hours, but
the extended-release preparation can be dosed once daily
• Atenolol is not extensively metabolized and is excreted primarily in
the urine with a half-life of 6 hours; it is usually dosed once daily.
Atenolol is reported to be less effective than metoprolol in preventing
the complications of hypertension. A possible reason for this
difference is that once-daily dosing does not maintain adequate
blood levels of atenolol. The usual dosage is 50–100 mg/d.
BISOPROLOL

• Nadolol and carteolol, nonselective β-receptor antagonists, are not

appreciably metabolized and are excreted to a considerable extent in
the urine.
• Betaxolol and bisoprolol are β1-selective blockers that are primarily
metabolized in the liver but have long half-lives. Because of these
relatively long half-lives, these drugs can be administered once daily.
• Nadolol is usually begun at a dosage of 40 mg/d, carteolol at 2.5
mg/d, betaxolol at 10 mg/d, and bisoprolol at 5 mg/d.
• Pindolol, acebutolol, and penbutolol are partial agonists, ie, β
blockers with some intrinsic sympathomimetic activity.
Labetalol

• Labetalol has a 3:1 ratio of β:α antagonism after oral dosing. Blood
pressure is lowered by reduction of systemic vascular resistance (via
α blockade) without significant alteration in heart rate or cardiac
output. Because of its combined α- and β-blocking activity, labetalol
is useful in treating the hypertension of pheochromocytoma and
hypertensive emergencies.
• Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol
is given as repeated intravenous bolus injections of 20–80 mg to treat
hypertensive emergencies.
CARVEDILOL

• Carvedilol, like labetalol, is administered as a racemic mixture. The

S(-) isomer is a nonselective β-adrenoceptor blocker, but both S(-)
and R(+) isomers have approximately equal α-blocking potency. The
isomers are stereoselectively metabolized in the liver, which means
that their elimination half-lives may differ. The average half-life is 7–
10 hours. The usual starting dosage of carvedilol for ordinary
hypertension is 6.25 mg twice daily. Carvedilol reduces mortality in
patients with heart failure and is therefore particularly useful in
patients with both heart failure and hypertension.
NEBIVOLOL

• Nebivolol is a β1-selective blocker with vasodilating properties that

are not mediated by α blockade. d-Nebivolol has highly selective β1-
blocking effects, while the l-isomer causes vasodilation; the drug is
marketed as a racemic mixture. The vasodilating effect may be due to
an increase in endothelial release of nitric oxide via induction of
endothelial nitric oxide synthase.
• Nebivolol is extensively metabolized and has active metabolites. The
half-life is 10–12 hours, but the drug can be given once daily. Dosing
is generally started at 5 mg/d, with dose escalation as high as 40
mg/d, if necessary. The efficacy of nebivolol is similar to that of other
antihypertensive agents, but several studies report fewer adverse
effects.
ESMOLOL

• Esmolol is a β1-selective blocker that is rapidly metabolized via

hydrolysis by red blood cell esterases. It has a short half-life (9–10
minutes) and is administered by intravenous infusion. Esmolol is
generally administered as a loading dose (0.5–1 mg/kg), followed by
a constant infusion. The infusion is typically started at 50–150
mcg/kg/min, and the dose increased every 5 minutes, up to 300
mcg/kg/min, as needed to achieve the desired therapeutic effect.
• Esmolol is used for management of intraoperative and post-
operative hypertension, and sometimes for hypertensive
emergencies, particularly when hypertension is associated with
tachycardia or when there is concern about toxicity such as
aggravation of severe heart failure, in which case a drug with a short
duration of action that can be discontinued quickly is advantageous.
α - blocker

• Prazosin, terazosin, and doxazosin produce most of their

antihypertensive effects by selectively blocking α1 receptors in
arterioles and venules. These agents produce less reflex tachycardia
when lowering blood pressure than do nonselective α antagonists
such as phentolamine.
• α blockers reduce arterial pressure by dilating both resistance and
capacitance vessels. As expected, blood pressure is reduced more in
the upright than in the supine position. Retention of salt and water
occurs when these drugs are administered without a diuretic. The
drugs are more effective when used in combination with other
agents, such as a β blocker and a diuretic, than when used alone.
Owing to their beneficial effects in men with prostatic hyperplasia
and bladder obstruction symptoms, these drugs are used primarily in
men with concurrent hypertension and BPH.
• Terazosin is also extensively metabolized but undergoes very little
first-pass metabolism and has a half-life of 12 hours. Doxazosin has
an intermediate bioavailability and a half-life of 22 hours.
• Terazosin can often be given once daily, with doses of 5–20 mg/d.
Doxazosin is usually given once daily starting at 1 mg/d and
progressing to 4 mg/d or more as needed. Although long-term
treatment with these α blockers causes relatively little postural
hypotension, a precipitous drop in standing blood pressure develops
in some patients shortly after the first dose is absorbed. For this
reason, the first dose should be small and should be administered at
bedtime.
• The α1 blockers do not adversely and may even beneficially affect
plasma lipid profiles, but this action has not been shown to confer
any benefit on clinical outcomes.
VASODILATORS

• This class of drugs includes the oral vasodilators, hydralazine and

minoxidil, which are used for long-term outpatient therapy of
hypertension; the parenteral vasodilators, nitroprusside and
fenoldopam, which are used to treat hypertensive emergencies; the
calcium channel blockers, which are used in both circumstances; and
the nitrates, which are used mainly in ischemic heart disease but
sometimes also in hypertensive emergencies
Hydralazine

• Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It

has been available for many years, although it was initially thought
not to be particularly effective because tachyphylaxis to its
antihypertensive effects developed rapidly. The benefits of
combination therapy are now recognized, and hydralazine may be
used more effectively, particularly in severe hypertension.
• The half-life of hydralazine ranges from 1.5 to 3 hours, but vascular
effects persist longer than do blood concentrations, possibly due to
avid binding to vascular tissue.
Minoxidil

• Minoxidil is a very efficacious orally active vasodilator. The effect

results from the opening of potassium channels in smooth muscle
membranes by minoxidil sulfate, the active metabolite. Increased
potassium permeability stabilizes the membrane at its resting
potential and makes contraction less likely. Like hydralazine, min-
oxidil dilates arterioles but not veins.
Sodium nitroprusside

• Sodium nitroprusside is a powerful parenterally administered

vasodilator that is used in treating hypertensive emergencies as well
as severe heart failure. Nitroprusside dilates both arterial and venous
vessels, resulting in reduced peripheral vascular resistance and
venous return. The action occurs as a result of activation of guanylyl
cyclase, either via release of nitric oxide or by direct stimulation of
the enzyme. The result is increased intracellular cGMP, which relaxes
vascular smooth muscle
• Diazoxide is an effective and relatively long-acting potassium channel
opener that causes hyperpolarization in smooth muscle and
pancreatic β cells. Because of its arteriolar dilating property, it was
formerly used parenterally to treat hypertensive emergencies.
Injection of diazoxide results in a rapid fall in systemic vascular
resistance and mean arterial blood pressure. At present, it is used
orally in the USA for the treatment of hypoglycemia in
hyperinsulinism. Diazoxide inhibits insulin release from the pancreas
(probably by opening potassium channels in the beta cell membrane)
and is used to treat hypoglycemia secondary to insulinoma.
• Fenoldopam is a peripheral arteriolar dilator used for hypertensive
emergencies and postoperative hypertension. It acts primarily as an
agonist of dopamine D1 receptors, resulting in dilation of periph- eral
arteries and natriuresis. The commercial product is a racemic mixture
with the (R)-isomer mediating the pharmacologic activity.
Anti arrhytHmia

• Class 1 action is sodium channel blockade. Subclasses of this action

reflect effects on the action potential duration (APD) and the kinetics
of sodium channel blockade. Drugs with class 1A action prolong the
APD and dissociate from the channel with intermediate kinetics;
drugs with class 1B action shorten the APD in some tissues of the
heart and dissociate from the channel with rapid kinetics; and drugs
with class 1C action have minimal effects on the APD and dissociate
from the channel with slow kinetics.
• Class 2 action is sympatholytic. Drugs with this action reduce β-
adrenergic activity in the heart.
• Class 3 action manifests as prolongation of the APD. Most drugs with
this action block the rapid component of the delayed rectifier
potassium current, IKr.
• Class 4 action is blockade of the cardiac calcium current. This action
slows conduction in regions where the action potential upstroke is
calcium dependent, eg, the SA and AV nodes.
COMPETITIVE INHIBITORS OF HMG-COA
REDUCTASE (STATINS)

• These compounds are structural analogs of HMG-CoA (3-hydroxy- 3-

methylglutaryl-coenzyme A):
• Lovastatin
• Atorvastatin
• Fluvastatin
• Pravastatin
• Simvastatin
• Rosuvastatin
• Pitavastatin
Pharmacokinetics

• Lovastatin and simvastatin are inactive lactone prodrugs that are

hydrolyzed in the gastrointestinal tract to the active β-hydroxyl
derivatives, whereas pravastatin has an open, active lactone ring.
• Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing
congeners that are active as given. Absorption of the ingested doses
of the reductase inhibitors varies from 40% to 75% with the
exception of fluvastatin, which is almost completely absorbed. All
have high first-pass extraction by the liver. Most of the absorbed dose
is excreted in the bile; 5–20% is excreted in the urine. Plasma half-
lives of these drugs range from 1 to 3 hours except for atorvastatin
(14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours).
• The active forms of the reductase inhibitors are structural analogs of
the HMG-CoA intermediate that is formed by HMG-CoA reductase in
the synthesis of mevalonate. These analogs cause partial inhibition of
the enzyme and thus may impair the synthesis of isoprenoids such
as ubiquinone and dolichol and the prenylation of proteins.
• the reductase inhibitors clearly induce an increase in high-affinity LDL
receptors. This effect increases both the fractional catabolic rate of
LDL and the liver’s extraction of LDL precursors (VLDL remnants) from
the blood, thus reducing LDL
• Because cholesterol synthesis occurs predominantly at night, reductase
inhibitors—except atorvastatin, rosuvastatin, and pitavastatin—should
be given in the evening.
• Absorption generally (with the exception of pravastatin and pitavastatin)
is enhanced by food.
• Daily doses of lovastatin vary from 10 to 80 mg. Pravastatin is nearly as
potent on a mass basis as lovastatin with a maximum recommended daily
dose of 80 mg. Simvastatin is twice as potent and is given in doses of 5–80
mg daily. Because of increased risk of myopathy with the 80-mg/d dose,
the U.S. Food and Drug Administration (FDA) issued labeling for scaled
dosing of simvastatin and combined ezetimibe/simvastatin in 2011.
Pitavastatin is given in doses of 1–4 mg daily. Fluvastatin appears to be
about half as potent as lovastatin on a mass basis and is given in doses of
10–80 mg daily. Atorvastatin is given in doses of 10–80 mg/d, and
rosuvastatin at 5–40 mg/d.
• Medication should be discontinued immediately in these patients
and in asymptomatic patients whose aminotransferase activity is
persistently elevated to more than three times the upper limit of
normal. These agents should be used with caution and in reduced
dosage in patients with hepatic parenchymal disease
• Myopathy may occur with monotherapy, but there is an increased
incidence in patients also receiving certain other drugs.
• The 3A4-dependent reductase inhibitors tend to accumulate in
plasma in the presence of drugs that inhibit or compete for the 3A4
cytochrome. These include the macrolide antibiotics, cyclosporine,
ketoconazole and its congeners, some HIV protease inhibitors,
tacrolimus, nefazodone, fibrates, paroxetine, venlafaxine, and others.
Concomitant use of reductase inhibitors with amiodarone or
verapamil also causes an increased risk of myopathy.
FIBRATES

• Fibrates function primarily as ligands for the nuclear transcription

receptor PPAR-α. They transcriptionally upregulate LPL, apo A-I, and
apo A-II, and they downregulate apo C-III, an inhibitor of lipolysis.
• A major effect is an increase in oxidation of fatty acids in liver and
striated muscle. They increase lipolysis of lipoprotein triglyceride via
LPL. Intracellular lipolysis in adipose tissue is decreased. Levels of
VLDL decrease, in part as a result of decreased secretion by the liver.
Only modest reductions of LDL occur in most patients. In others,
especially those with combined hyperlipidemia, LDL often increases
as triglycerides are reduced. HDL cholesterol increases moderately.
• Fibrates are useful drugs in hypertriglyceridemias in which VLDL
predominate and in dysbetalipoproteinemia. They also may be of
benefit in treating the hypertriglyceridemia that results from
treatment with antiviral protease inhibitors.
• The usual dose of gemfibrozil is 600 mg orally once or twice daily. The
dosage of fenofibrate is one to three 48-mg tablets (or a single 145-
mg tablet) daily. Dosages of other preparations vary. Absorption of
gemfibrozil is improved when the drug is taken with food.
• Rhabdomyolysis has occurred rarely. Risk of myopathy increases
when fibrates are given with reductase inhibitors. Fenofibrate is the
fibrate of choice for use in combination with a statin.
• Fibrates should be avoided in patients with hepatic or renal
dysfunction. There appears to be a modest increase in the risk of
cholesterol gallstones, reflecting an increase in the cholesterol
content of bile.
NIACIN (NICOTINIC ACID)

• Niacin decreases triglycerides and LDL levels,

• Niacin inhibits VLDL secretion, in turn decreasing production of LDL.
Increased clearance of VLDL via the LPL pathway contributes to
reduction of triglycerides.
• In combination with a resin or reductase inhibitor, niacin normalizes
LDL in most patients with heterozygous familial hypercholesterolemia
and other forms of hypercholesterolemia.
• Patients should be warned to expect the flush and under- stand that
it is a harmless side effect.
• Hyperuricemia occurs in some patients and occasionally precipitates
gout.
• Patients should be instructed to report blurring of distance vision.
BILE ACID–BINDING RESINS

• Colestipol, cholestyramine, and colesevelam are useful only for

isolated increases in LDL.
• Bile acids, metabolites of cholesterol, are normally efficiently
reabsorbed in the jejunum and ileum. Excretion is increased up to
tenfold when resins are given, resulting in enhanced conversion of
cholesterol to bile acids in liver via 7α-hydroxylation, which is
normally controlled by negative feedback by bile acids.
• Colestipol and cholestyramine are available as granular preparations.
A gradual increase of dosage of granules from 4 or 5 g/d to 20 g/d is
recommended. Total dosages of 30–32 g/d may be needed for
maximum effect. The usual dosage for a child is 10–20 g/d. Granular
resins are mixed with juice or water and allowed to hydrate for 1
minute.
• Colestipol is also available in 1-g tablets that must be swallowed
whole, with a maximum dose of 16 g daily.
• Colesevelam is available in 625-mg tablets and as a suspension
(1875-mg or 3750-mg packets). The maximum dose is six tablets or
3750 mg as suspension, daily. Resins should be taken in two or three
doses with meals.
• Common complaints are constipation and bloating, usually relieved
by increasing dietary fiber. Resins should be avoided in patients with
diverticulitis. Heartburn and diarrhea are occasionally reported.
• Absorption of certain drugs, including those with neutral or cationic
charge as well as anions, may be impaired by the resins.
INHIBITORS OF INTESTINAL STEROL
ABSORPTION
• Ezetimibe inhibits intestinal absorption of phytosterols and
cholesterol. Added to statin therapy, it provides an additional effect,
decreasing LDL levels and further reducing the dimensions of
atherosclerotic plaques.
• Ezetimibe is synergistic with reductase inhibitors, producing
decrements as great as 25% in LDL cholesterol beyond that achieved
with the reductase inhibitor alone.
TREATMENT WITH DRUG
COMBINATIONS
• Fibric Acid Derivatives & Bile Acid-binding Resins
• HMG-CoA Reductase Inhibitors & Bile Acid-binding
Resins
• Niacin & Bile Acid-binding Resins
• Niacin & Reductase Inhibitors
• Reductase Inhibitors & Ezetimibe
• Reductase Inhibitors & Fenofibrate
• Combinations Of Resins, Ezetimibe, Niacin, &
Reductase Inhibitors
TERIMA KASIH