Download Part 4: Drugs affecting the cardiovascular system. I

ACE inhibitors:
Part 4: Drugs affecting the
cardiovascular system.
I: Antihypertensives
If the pressure becomes too high, the person is said to be
hypertensive. If the pressure becomes too low and blood cannot
be delivered effectively, the person is said to be hypotensive.
Helping the patient to maintain the blood pressure within normal
limits is the goal of drug therapy.
Hypertension:
When a person’s blood pressure is above normal limits for a
sustained period, a diagnosis of hypertension is made.
Untreated hypertension increases a person’s risk for the
following conditions: coronary artery disease, and cardiac death,
stroke, heart failure, renal failure and peripheral vascular
disease. The classification scheme used to categorize
individual cases of hypertension has been simplified to the
following four stages based on blood pressure
measurements: normal, prehypertension, stage 1 hypertension,
and stage 2 hypertension.
Hypertension can also be defined by its cause. When the
specific cause of hypertension is unknown, it may be called
essential, idiopathic, or primary hypertension. About 90% of
cases of hypertension are of this type. Secondary hypertension
accounts for the other 10%. Secondary hypertension is most
commonly the result of another disease such as
pheochromocytoma (adrenal tumor), preeclampsia of
pregnancy, or renal artery disease. It also may result from the
use of certain medications. If the cause of secondary
hypertension can be eliminated, blood pressure usually returns
to normal.
Hypotension:
If blood pressure becomes too low, the vital centers in the brain,
as well as the rest of the tissues of the body, may not receive
enough oxygenated blood to continue functioning. Hypotension
can progress to shock, in which the body is in serious jeopardy
as waste products accumulate and cells die from lack of oxygen.
Hypotensive states can occur in the following situations:
• When the heart muscle is damaged and unable to pump
effectively.
• With severe blood loss, when volume drops dramatically.
• When there is extreme stress and the body’s levels of
norepinephrine are depleted, leaving the body unable to
respond to stimuli to raise blood pressure.




Captopril.
Enalapril.
Lisinopril.
Ramipril.
Angiotensin-receptor blockers:



Candesartan.
Valsartan.
Losartan.
Beta-blockers:






Atenolol.
Betaxolol.
Propranolol.
Carvedilol.
Metoprolol.
Bisoprolol
Diuretics:






Bumetanide.
Furosemide.
Amiloride.
Indapamide.
Hydrochlorothiaze.
Spirnolactone.
Calcium channel blockers:





Amlodipine.
Felodipine.
Nicardipine.
Dilitiazem.
Verapamil.
Alpha-blockers:



Doxazosin.
Terazosin
Prazosin.
Others:





Methyldopa.
Hydralazine.
Nitroprusside.
Minoxidil.
Clonidine.
Antihypertensive agents:
Because an underlying cause of hypertension is usually unknown, altering the body’s regulatory
mechanisms is the best treatment currently available. Drugs used to treat hypertension work to
alter the normal reflexes that control blood pressure. See Figure below for a review of the sites
of action of drugs used to treat hypertension.
Treatment for essential hypertension does not cure the disease but is aimed at maintaining the
blood pressure within normal limits to prevent the damage that hypertension can cause.
Not all patients respond in the same way to antihypertensive drugs because different factors
may contribute to each person’s hypertension. Patients may have complicating conditions, such
as diabetes, that make it unwise to use certain drugs. Several different types of drugs that affect
different areas of blood pressure control may need to be used in combination to maintain a
patient’s blood pressure within normal limits.
There are essentially seven main categories of pharmacologic drugs:
1.
2.
3.
4.
5.
6.
7.
8.
Angiotensin-converting enzyme inhibitors (ACEIs).
Angiotensin II–receptor blockers (ARBs).
Calcium channel blockers (CCBs).
Direct vasodilators.
Diuretic agents.
Beta-blockers.
Alpha-blockers.
others
1-
Diuretics:
The diuretics are a highly effective class of antihypertensive drugs. They may used as a
monotherapy or in combination with other drugs. Their primary therapeutic effect is decreasing
the plasma and extracellular fluid volumes, which results in decreased preload. This leads to
decrease in cardiac output and total peripheral resistance, all of which decrease the workload of
the heart. The thiazide diuretics are the most commonly used for treatment of hypertension.
2- Beta blockers:
A. The beta-blocker (atenolol (Tenormin), betaxolol (Kerlone),
bisoprolol, metoprolol ,and propranolol (Inderal).:
These drugs are discussed in more detail before. Their antihypertensive effects are related to
their reduction of the heart rate through beta1- receptor blockade. Furthermore, they also cause
a reduction in the secretion of renin, which in turn reduces vasoconstriction. Long term use of
beta-blockers also reduces peripheral vascular resistance.
B.
Two dual-action alpha1 and beta receptor
blockers (labetalol and carvedilol.):
Which act in the periphery at the heart and blood vessels. They have dual
antihypertensive effects of reduction in heart rate (beta1 receptor blockade) and
vasodilation (alpha1 receptor blockade). Patients often complain of fatigue, loss of libido,
inability to sleep, and GI and genitourinary disturbances.
3-
Alpha blockers:
A. Periphery the alpha1-blockers (doxazosin (Cardura),
prazosin,and terazosin):
They are able to block the postsynaptic alpha1-receptor sites. This decreases vascular tone and
promotes vasodilation, which reduces peripheral vascular resistance and subsequently
decreases blood pressure. These drugs do not block the presynaptic alpha2-receptor sites, and
therefore the reflex tachycardia that accompanies a fall in blood pressure does not occur.
B. The centrally acting alpha2-adrenergic drugs (clonidine, and
methyldopa):
Acts centrally, stimulate the alpha2-receptors in the CNS and inhibit the cardiovascular
centers, leading to a decrease in sympathetic outflow from the CNS and a resultant drop in
blood pressure. These drugs are associated with many adverse CNS and GI effects, as well
as cardiac dysrhythmias.

Indications:
All of the drugs mentioned are used primarily for the treatment of hypertension, either alone or
in combination with other antihypertensive drugs. Methyldopa is indicated to treat
hypertension in pregnant women. The alpha1-blockers have been used to relieve the
symptoms associated with BPH.
4-
Angiotensin-Converting enzyme
inhibitors (captopril, enalapril, lisinopril and ramipril):
These drugs are very safe and efficacious and are often used as first line drugs in the treatment
of both heart failure and hypertension. ACE inhibitors as a class are very similar and differ in
only a few of their chemical properties, but there are significant differences among them in their
clinical properties.
All of the ACE inhibitors or administered orally. Enalapril also has the advantage of parenteral
use. Captopril has the shortest half-life. It may be best to start with a drug that has a short halflife in a patient who is still very critically ill and may not tolerate medications well. Both captopril
and enalapril can be dosed multiple times a day.
Captopril and lisinopril is an important advantage in treating a patient with liver dysfunction;
because all of the other ACE inhibitors are prodrugs. All ACE are classified as pregnancy
category C in first trimester and as pregnancy D drugs in their second or third trimester.

Mechanism of action:
They inhibit angiotensin—converting enzyme, which is responsible for converting angiotensin I
to angiotensin II. Angiotensin II is a potent vasoconstrictor and induces aldosterone secretion by
adrenal glands. The primary effects of the ACE inhibitors are cardiovascular and renal. Their
cardiovascular effects are due to their ability to reduce blood pressure by decreasing SVR. They
do this by preventing the breakdown of vasodilating substance bradykinin and also of substance
P, and preventing the formation of angiotensin II. These combined effects decrease afterload, or
the resistance against which the left ventricle must pump to eject its volume of blood during
contraction.
The ACE inhibitors they also prevent sodium and water resorption by inhibiting aldosterone
secretion. This causes diuresis, which decreases blood volume and return to the heart. This in
turn decreases preload and the work required of the heart, so this class can beneficial in
treatment of heart failure.

Indications:

Hypertension and HF (either alone or in combination with
diuretics or other drugs)

Slow progression of left ventricular hypertrophy after MI
(cardioprotective)

Renal protective effects in patients with diabetes (Drugs of
choice)

Drugs of choice in hypertensive patients with HF

Adverse effects:

Fatigue, Dizziness, Headache, postural hypotension and
Mood changes


Impaired taste and possible hyperkalemia
Persistence dry, nonproductive cough, which reverses when
therapy is stopped


Interactions:

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

5-
Angioedema: rare but potentially fatal.
are teratogenic and should not be used in pregnant women
Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce
the antihypertensive effect of ACE inhibitors.
The use of NAIDs and ACE inhibitors may also predispose
patients to the development of acute renal failure.
Potassium supplements and potassium-sparing diuretics
when administered with ACE inhibitors may result in hyperkalemmia.
Angiotensin II receptor blockers:
Valsartan, Candesartan,Losartan.
The ARBs selectively bind with the angiotensin II receptors in vascular smooth muscle and in
the adrenal cortex to block vasoconstriction and the release of aldosterone. These actions block
the blood pressure–raising effects of the renin–angiotensin system and lower blood pressure..
Both are well tolerated but ARBs do not cause cough. Both can’t be used in pregnant women.




Indications:
They may be used alone or in combination with diuretics to
treat hypertension and heart failure.
Their use in HF is mainly as a substitute for ACEIs in those patients with severe cough
or angioedema
they also were found to slow the progression of renal
disease in patients with hypertension and type 2 diabetes

Adverse effects:

Symptoms of upper respiratory infections




May cause occasional dizziness, inability to sleep, diarrhea,
dyspnea, heartburn, nasal congestion, back pain, fatigue, and headache.
Hyperkalemia much less likely to occur
have a lower incidence of cough and angioedema than
ACEIs
should not be used in pregnant women
6-
Calcium Channel Blockers:
Calcium channel blockers inhibit the movement of calcium ions across the membranes of
myocardial and arterial muscle cells, altering the action potential and blocking muscle cell
contraction. This effect depresses myocardial contractility, slows cardiac impulse formation in
the conductive tissues, and relaxes and dilates arteries, causing a fall in blood pressure and a
decrease in venous return.
Their primary use is for the treatment of hypertension and angina. Amlodipine is the CCB most
commonly used for hypertension. Calcium channel blockers are given orally and are generally
well absorbed, metabolized in the liver, and excreted in the urine. These drugs cross the
placenta and enter breast milk. Nicardipine is also available in an intravenous form.


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Benzothiazepines: Diltiazem.
Phenylalkamines: Verapamil.
Dihydropyridines: Amlodipine, Nicardipine, Nifedipine,
Nimodipine.
Indications:


Angina, Hypertension, and Dysrhythmias
Migraine headaches
Adverse effects:

Cardiovascular: Hypotension, palpitations, tachycardia

Gastrointestinal: Constipation, nausea

Other: Rash, flushing, peripheral edema, dermatitis
7- Vasodilators (hydralazine, minoxidil, and nitroprusside):
Vasodilators act directly on arteriolar and/or venous smooth muscle to cause relaxation. They
do not work through adrenergic receptors.

Mechanism of action:
Direct-acting vasodilators are useful as antihypertensive drugs because of their ability to directly
elicit peripheral vasodialtion. This results in a reduction in SVR. In general, the most notable
effect of vasodilators is their hypotensive effect. Diazoxide, Hydralazine, and Minoxidil work
through arteriolar vasodilation, whereas nitroprusside has both arteriolar and venous effects.

Indications:
All of the vasodilators can be used to treat hypertension, either alone or in combination with
other antihypertensives. Sodium nitroprusside and intravenous diazoxide are reserved for the
management of hypertensive emergencies, in which blood pressure is severely elevated.
Minoxidil in its topical form is used to restore hair growth.

Adverse effects:

o

o
hydralazine
Dizziness, headache, anxiety, tachycardia, nausea and
vomiting, diarrhea, anemia, dyspnea, edema, nasal congestion, others
sodium nitroprusside
Bradycardia, hypotension, possible cyanide toxicity (rare)
Hypertensive emergency:
Hypertensive emergency is a rare but life-threatening situation characterized by severe
elevations in blood pressure (systolic greater than 180 mm Hg or diastolic greater than 120 mm
Hg) with evidence of impending or progressive target organ damage (for example, stroke,
myocardial infarction). [Note: A severe elevation in blood pressure without evidence of target
organ damage is considered a hypertensive urgency.]
Hypertensive emergencies require timely blood pressure reduction with treatment administered
intravenously to prevent or limit target organ damage.
A variety of medications are used, including:
1- calcium channel blockers (nicardipine and clevidipine).
2- Nitric oxide vasodilators (nitroprusside and nitroglycerin).
3- Adrenergic receptor antagonists (phentolamine, esmolol, and labetalol).
4- The vasodilator hydralazine.
5- The dopamine agonist fenoldopam.
Treatment is directed by the type of target organ damage present and/or comorbidities present.
Nursing implication:
 Before beginning therapy, obtain a thorough health history and head-to-toe physical
examination, assess for contraindications to specific antihypertensive drugs and for
conditions that require cautious use of these drugs
 Educate patients about the importance of not missing a dose and taking the medications
exactly as prescribed, and instruct patients to check with their physician for instructions
on what to do if a dose is missed; patients should never double up on doses if a dose is
missed
 Monitor BP during therapy; instruct patients to keep a journal of regular BP checks
 Instruct patients that these drugs should not be stopped abruptly because this may
cause a rebound hypertensive crisis, and perhaps lead to stroke
 Oral forms should be given with meals so that absorption is more gradual and effective
 Administer IV forms with extreme caution, and use an IV pump
 Remind patients that medication is only part of therapy. Encourage patients to watch
their diet, stress level, weight, and alcohol intake and instruct patients to avoid smoking
and eating foods high in sodium. Encourage supervised exercise
 Teach patients to change positions slowly to avoid syncope from postural hypotension
 Instruct patients to report unusual shortness of breath; difficulty breathing; swelling of the
feet, ankles, face, or around the eyes; weight gain or loss; chest pain; palpitations; or
excessive fatigue
 Male patients who take these drugs may not be aware that impotence is an expected
effect, and this may influence compliance with drug therapy
 If patients are experiencing serious adverse effects, or if they believe the dose or
medication needs to be changed, they should contact their physician immediately
 Hot tubs, showers, or baths; hot weather; prolonged sitting or standing; physical
exercise; and alcohol ingestion may aggravate low blood pressure, leading to fainting
and injury; patients should sit or lie down until symptoms subside
 Patients should not take any other medications, including over-the-counter drugs,
without first getting the approval of their physician
 Monitor for adverse effects (dizziness, orthostatic hypotension, fatigue) and for toxic
effects
 Monitor for therapeutic effects
 Blood pressure should be maintained at less than 130/90 mm Hg
 If a patient with hypertension also has diabetes or renal disease, the BP goal is
less than 130/80 mm Hg (JNC-7)
 Carbonic anhydrase
inhibitors.
 Acetazolamide.




II. Diuretics:
Overview:
Diuretics are drugs that accelerate the rate of urine
formation via a variety of mechanisms. The result is the
removal of sodium and water from the body.
Before we discuss the classes of diuretic drugs, it is
important to quickly review kidney function, because all
diuretics work primarily in the kidneys.
Loop diuretics.
Bumetanide.
Furosemide.
Ethacrynic acid
 Osmotic diuretics.
 Mannitol.
 Urea.
 Potassium-sparing diuretics.
 Amiloride.
 Spirnolactone.
 Eplerenone
 Triamterene
 Thiazide and Thiazide-like
diuretics.
 Chlorthalidone.
 Chlorothiazide.
 Hydrochlorothiazide.
 Indapamide.
 Metolazone.
The kidney plays a very important role in the day-today functioning of the body. It filters out toxic waste
products from the blood while simultaneously
conserving essential substances. This delicate balance
between elimination of toxins and retention of essential
chemicals is maintained by the nephron. The nephron is the main structural unit of the kidney.
Diuretics exert their effect in the nephron.
The initial filtering of the blood takes place in the glomerulus. The rate at which this filtering
occurs is referred to as the glomerular filteration rate (GFR). The GFR can be estimated
mathematically by calculating creatinine clearance. GFR is regulated by afferent arteriols and
efferent arterioles. The proximal tubule returns (60-70) % of the sodium and water from the
filtered fluid back into the bloodstream. Another (20-25) % is reabsorbed back into the
bloodstream in the ascending loop of henle. The remaining (5-10) % of sodium resorption
takes place in the distal tubule. In the distal tubule, sodium is actively filtered in exchange for
potassium or hydrogen ions, a process regulated by the hormone aldostrone. The collecting
duct is the final common pathway for the filtrate that started in the glomerulus. It is here that
antidiuretic hormone ADH acts to increase the absorption of water back into bloodstream.
The hypotensive activity of diuretics is due to many different mechanisms:.

They cause arteriolar dilation, which decreases peripheral
vascular resistance PVR.

Reduce extracellular fluid volume, plasma volume, and
cardiac output.
Advantages:

Their relatively low cost and their favorable safety profile.
Main problem:

The metabolic adverse effects that can result from excessive
fluid and electrolyte loss
Pharmacology overview:
1-
Carbonic
Anhydrase Inhibitors CAIs:
The site of action of the CAIs is the location of
carbonic anhydrase enzyme system along the
nephron, primarily in the proximal tubule.
Acetazolamide is the most commonly used.
Mechanism of action:
In the proximal tubules, an active transport
system operates that exchanges sodium for
hydrogen ions. For sodium and thus water to
be reabsorbed back into the blood, hydrogen
must be exchanged for it. Without hydrogen,
this cannot occur, and the sodium and water
will be eliminated with the urine. Carbonic
anhydrase helps to make hydrogen ions
available for this exchange. When its actions
are inhibited by CAIs, little sodium and water can be resorbed into the blood and they are
eliminated with the urine.
The CAIs reduce the formation of hydrogen and bicarbonate ions from the carbon dioxide
and water by the noncompetitive, reversible inhibition of carbonic anhydrase activity.

Indications:
The therapeutic applications of CAIs include the treatment of glaucoma, edema, and high
altitude sickness (Mountain sickness) and rare as an antiepileptic.

Adjunct drugs in the long-term management of open-angle
glaucoma.

Used with miotics to lower intraocular pressure before ocular
surgery in certain cases.

Acetazolamide is used in the management of edema
secondary to HF when other diuretics are not effective

Adverse effects:


Metabolic acidosis and Hypokalemia
Drowsiness, renal stone formation, and paresthesia may
occur.

The drug should be avoided in patients with hepatic
cirrhosis, because it could lead to a decreased excretion of NH4
Acetazolamide is available in both oral and parenteral forms. Pregnancy category C.
2-
Osmotic Diuretics (mannitol, urea):
The osmotic diuretics include mannitol, urea, organic acids, and glucose. Mannitol, a
nonabsorbable solute, is the most commonly used of these drugs.






Mechanism of action:
Mannitol works along the entire nephron.
Its major site of action, however, is the proximal tubule and
descending limb of the loop of henle.
Because it is nonabsorbable, it produces osmotic pressure
in the glomerular filtrate, which in turn pulls fluid, primarily water, into the renal tubules
from the surrounding tissues. This process also inhibits the tubular resorption of water
and solutes, which produces a rapid diuresis. Ultimately this reduces cellular edema and
increases urine production, causing diuresis.
However, it produces only a slight loss of electrolytes,
especially sodium.
Mannitol may induce vasodilation and in doing so increase
both glomerular filtration and renal plasma flow.

Indications:



To reduce intracranial pressure
Treatment of cerebral edema
Treatment of patients in the early, oliguric phase of acute
renal failure ARF


To promote excretion of toxic substances
NOT indicated for peripheral edema

Adverse effects:



Convulsions
Pulmonary congestion
Also headaches, chest pains, tachycardia, blurred vision,
chills, and fever
Mannitol is available only in parenteral form as 5%, 10%, 15%, 20% and 25% solutions for
intravenous injection. Mannitol may crystallize when exposed to low temperatures. Because of
this, mannitol should always be administered intravenously through a filter, and vials of drug are
often stored in a warmer in the pharmacy.
3-
Loop Diuretics (furosemide,
bumetanide):

Mechanism of action:

These drugs act primarily along the thick ascending limb of
the loop of Henle.



Act by blocking chloride and, secondarily, sodium resorption.
They are also believed to activate renal prostaglandins,
which results in dilation of the blood vessels of the kidneys, the lungs, and the rest of the
body.
The beneficial hemodynamic effects of loop diuretics are a
reduction in both the preload and central venous pressure.
Indications:

Loop diuretics are used to:
 The loop diuretics are the drugs of choice for reducing acute pulmonary edema and
acute/chronic peripheral edema caused from heart failure or renal impairment.

Control hypertension.

Increase the renal excretion of calcium in patients with
hypercalcemia.




Side effects:
Metabolic
Hypokalemia.
Hypomagnesemia,hyperuricemia,acute hypovolemia
Ototoxicity
.
Interactions:
Loop diuretics exhibit both neurotoxic and nephrotoxic properties, and they produce additive
effects when given in combination with drugs that have similar toxicities.
They also affect certain laboratory results, they cause increases in the serum levels of uric acid,
glucose, alanine aminotransferase ALT , and aspartate aminotransferase AST
Furosemide (Lasix):




4-
Most commonly used loop diuretic.
It is available in oral and injectable forms.
IV: duration of action 2 hr/ onset: 5 min.
Oral: duration of action 6-8 hr/ onset: 30-60 min.
Potassium-Sparing Diuretics
(spironolactone, amiloride):




Mechanism of action:
These drugs work in collecting ducts and distal tubules,
where they interfere with sodium-potassium exchange.
Spironolactone competitively binds to aldosterone receptors
and therefore blocks the resorption of sodium and water that is induced by aldosterone
secretion. These receptors are found primarily in the distal tubule.
Amiloride do not bind to aldosterone receptors, however
they inhibit both aldosterone-induced and basal sodium resorption, working in both the
distal tubule and collecting ducts.

Drug profile:

Spironolactone
Block aldosteron receptors.
Available only in oral form.
It also available as combination with hydrochlorothiazide.
Reversing potassium loss caused by potassium-losing
o
o
o
o
drugs.
o
o
o

o
o
o
o
o
Has antihypertensive therapy.
Used in certain cases of HF
The serum potassium level should be monitored in patients
who have impaired renal function.
Amiloride:
Is available only in oral form.
Used in combinartion with a thiazide or loop diuretic in the
treatment of heart failure.
Hyperkalemia may occur in as many as 10% of the patients
who take amiloride alone.
Used with caution in patients who have renal impairment,
DM, and in elderly patients.
It has only weak antihypertensive properties.

Adverse effects:
Spironolactone: Gynecomastia, Amenorrhea, Irregular menses, gastric upset
Potassium-sparing diuretics should be used with caution with other medications that can induce
hyperkalemia, such as angiotensin-converting enzyme inhibitors and potassium supplements.
5-
Thiazides And Thiazide-Like Diuretics:
The thiazide diuretics include chlorothiazide, and hydrochlorothiazide.
The thiazide-like diuretics are very similar to the thiazides and include chlorthalidone,
indapamide, and metolazone.

-
-
-
Mechanism of action:
The primary site of action of this group is the distal tubule,
where they inhibit the secretion of sodium, potassium, and chloride. This results in
osmotic water loss.
Thiazides also cause direct relaxation of arterioles, which
reduces peripheral vascular resistance. Decreased preload and decreased afterload are
the beneficial hemodynamic effects.
This makes them very effective for the treatment of both
heart failure and hypertension.
Thiazides should not be used if creatinine clearance is less
than 30 to 50 mL/min (normal is 125 mL/min)
Metolazone remains effective to a creatinine clearance of 10
mL/min

Indications:

Hypertension (one of the most prescribed group of drugs for
this)





Edematous states
Idiopathic hypercalciuria
Diabetes insipidus
Heart failure due to diastolic dysfunction
Adverse effects:
Body System





Adverse Effects
CNS
Dizziness, headache, blurred vision.
GI
Anorexia, nausea, vomiting, diarrhea
GU
Impotence
Integumentary Photosensitivity
Metabolic
Hypokalemia, Hyponatremia, Hyperuricemia,
Hypercalcemia
Hydrochlorothiazide:

Is a very commonly prescribed and inexpensive thiazide
diuretic.



It's very safe and effective.
Available only in oral form
Pregnancy category B.
Nursing Implications:
 Instruct patients to take the medication in the morning if possible to avoid interference
with sleep patterns
 Monitor serum potassium levels during therapy
 Potassium supplements are usually not recommended when potassium levels exceed 3
mEq/L
 Teach patients to maintain proper nutritional and fluid volume status
 Patients taking diuretics along with a digitalis preparation should be taught to monitor for
digitalis toxicity
 Diabetic patients who are taking thiazide and/or loop diuretics should be told to monitor
blood glucose and watch for elevated levels
 Teach patients to change positions slowly and to rise slowly after sitting or lying to
prevent dizziness and fainting related to orthostatic hypotension
 Patients who have been ill with nausea, vomiting, and/or diarrhea should notify their
physician because fluid loss may be dangerous. Instruct patients to notify their physician
immediately if they experience rapid heart rates or syncope (reflects hypotension or fluid
loss)
 Signs and symptoms of hypokalemia include muscle weakness, constipation, irregular
pulse rate, and overall feeling of lethargy.Excessive consumption of licorice can lead to
additive hypokalemia in patients taking thiazides
 Monitor for adverse effects:
 Metabolic alkalosis, drowsiness, lethargy, hypokalemia, tachycardia, hypotension, leg
cramps, restlessness, decreased mental alertness. Monitor for hyperkalemia with
potassium-sparing diuretics
 Monitor for therapeutic effects



Reduction of edema, fluid volume overload, HF
Reduction of hypertension
Return to normal intraocular pressures
ACE inhibitors:




Captopril.
Enalapril.
Lisinopril.
Ramipril.
Angiotensin-receptor blockers:



Candesartan.
Valsartan.
Losartan.
Aldosterone antagonist


Eplerenone
Spironolactone
Beta-blockers:



Carvedilol.
Metoprolol.
Bisoprolol
Diuretics:


Bumetanide.
Furosemide.
Inotropic agents:
III. Heart failure drugs.
Heart failure is a pathologic state in which the heart is
unable to pump blood in sufficient amount from the
ventricles to meet the body’s metabolic needs. The signs
and symptoms typically associated with this insufficiency
constitute the syndrome of heart failure.



Digoxin.
Dobutamin.
Milrinone.
Direct Vaso and vasodilators
 Hydralazine
 Isosorbide dinitrate
This syndrome can affect primarily the left ventricle, primarily the right ventricle, or both
ventricles simultaneously. Left ventricular heart failure often leads to pulmonary edema,
coughing, shortness of breath, and dyspnea. Right ventricular heart failure typically involves
systemic venous congestion, ascite and hepatic congestion.
The physical defec
ts producing heart failure are of two types: (1) myocardial defect such as myocardial
infarction or valve insufficiency, which leads to inadequate cardiac contractility and ventricular
filling; and (2) a defect outside the myocardium (e.g.; coronary artery disease, pulmonary
hypertension, or diabetes).
Pharmacology overview:
Drugs used in HF:

Positive inotropic drugs (cardiotonic): Increase the force
of myocardial contraction



Beta-blockers.
Angiotensine-converting enzyme inhibitiors.
Diuretics.
Digoxin used to be mainstay in heart failure treatment, but because of adverse effects and drug
interactions, it has been widely replaced by other drugs. Therefore, the drugs of choice
(standard treatment for H) at the start of therapy are the ACE inhibitors or the angiotensin II
receptor blockers and certain beta-blockers.
Loop diuretics are used to reduce symptoms of heart failure secondary to fluid overload, and
the aldosterone inhibitors are added as the heart failure progresses. Only after these drugs
are used is digoxin added. Dobutamine, a positive inotropic drug, has also been used to treat
acute heart failure.
If the patient is intolerant of ACE inhibitors or β-blockers, or if additional vasodilator response is
required, a combination of hydralazine and isosorbide dinitrate may be used.
A.
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS (captopril, Enalapril, Lisinopril, Ramiplril):

Mechanism of action:
They inhibit angiotensin—converting enzyme, which is responsible for converting angiotensin I
to angiotensin II. Angiotensin II is a potent vasoconstrictor and induces aldosterone secretion by
adrenal glands. The primary effects of the ACE inhibitors are cardiovascular and renal. Their
cardiovascular effects are due to their ability to reduce blood pressure by decreasing systemic
vascular resistance. They do this by preventing the breakdown of vasodilating substance
bradykinin and also of substance P, and preventing the formation of angiotensin II. These
combined effects decrease afterload, or the resistance against which the left ventricle must
pump to eject its volume of blood during contraction. The ACE inhibitors they also prevent
sodium and water resorption by inhibiting aldosterone secretion. This causes diuresis, which
decreases blood volume and return to the heart. This in turn decreases preload and the work
required of the heart, so this class can beneficial in treatment of heart failure.
B.

Angiotensin II (AII) Receptor Blockers
ARBs (Losartan, Candesartan, Valsartan).
Mechanism of action:
The ARBs selectively bind with the angiotensin II receptors in vascular smooth muscle and in
the adrenal cortex to block vasoconstriction and the release of aldosterone. These actions block
the blood pressure–raising effects of the renin–angiotensin system and lower blood pressure
Both are well tolerated but ARBs do not cause cough. Both can’t be used in pregnant women.




Indications:
They may be used alone or in combination with diuretics to
treat hypertension and heart failure.
Their use in HF is mainly as a substitute for ACEIs in those patients with severe cough
or angioedema
they also were found to slow the progression of renal
disease in patients with hypertension and type 2 diabetes






Adverse effects:
Symptoms of upper respiratory infections
May cause occasional dizziness, inability to sleep, diarrhea,
dyspnea, heartburn, nasal congestion, back pain, fatigue, and headache.
Hyperkalemia much less likely to occur
have a lower incidence of cough and angioedema than
ACEIs
should not be used in pregnant women
C.
BETA-BLOCKERS
Although it may seem counterintuitive to administer drugs with negative inotropic activity in HF,
evidence clearly demonstrates improved systolic functioning and reverses cardiac remodeling in
patients receiving β-blockers. These benefits arise in spite of an occasional, initial exacerbation
of symptoms.
The benefit of β-blockers is attributed by reducing or blocking sympathetic nervous system
stimulation to the heart and heart’s conduction system. By doing this, beta-blockers prevent
catecholamine-mediated actions on the heart. This is known as a cardioprotective quality of
beta-blockers.
The resulting cardiovascular effects include reduced heart rate, delayed AV node conduction,
and reduced myocardial contractility.
β-Blockade is recommended for all patients with chronic, stable HF. Treatment should be
started at low doses and gradually titrated to target doses based on patient tolerance and vital
signs
Three β-blockers have shown benefit in HF: bisoprolol, carvedilol and metoprolol succinate
D.
Cardiotonic (inotropic)drugs:
Cardiotonic (inotropic) drugs affect the intracellular calcium levels in the heart muscle,
leading to increased contractility. This increase in contraction strength leads to increased
cardiac output.
1.

PHOSPHODIESTERASE INHIBITORS
(Inamrinone, Milrinone):
Mechanism of action:
This type of drugs inhibits the action of phosphodiesterase, which results in an increase in
intracellular adenosine monophosphate (cAMP). This result in two beneficial effects in an
individual with HF: a positive inotropic response and vasodilation. Finally, inhibition of PDE
results in the availability of more calcium for myocardial muscle contraction this leads to an
increase in the force of contraction.

Adverse effects:
Although inamrinone and milrinone are both PDIs, they have very different adverse effect
profiles. The adverse effect that is most worrisome with inamrinone is thrombocytopenia. The
primary adverse effect seen with milrinone therapy is dysrhythmia.
2.


CARDIAC GLYCOSIDES (digoxin, digitoxin)
Mechanism of action:
Positive inotropic effect: Increased force and velocity of
myocardial contraction (without an increase in oxygen consumption)
Negative chronotropic effect: Reduced heart rate
Decreased automaticity at SA node, decreased AV nodal
conduction, and other effects
Increased stroke volume.
Reduction in heart size during diastole
Decrease in venous BP and vein engorgement
Increase in coronary circulation.
Promotion of diuresis because of improved blood circulation








Indications:
 Digoxin therapy is indicated in patients with severe HF after initiation of ACE inhibitor, βblocker, and diuretic therapy.
 Supraventricular dysrhythmias

Pharmacokinetics:
Digoxin is available for oral and parenteral administration. The drug has a rapid onset of action
and rapid absorption (30 to 120 minutes when taken orally, 5 to 30 minutes when given I.V). It is
widely distributed throughout the body.
Digoxin is primarily excreted unchanged in the urine. Because of this, caution should be used in
the presence of renal impairment because the drug may not be excreted and could accumulate,
causing toxicity.

Adverse effects:
 it has a very narrow therapeutic index, and digoxin toxicity is one of the most common
adverse drug reactions leading to hospitalization, and levels of digoxin are monitored when
the patient first starts taking the drug.

Normal therapeutic levels for digoxin are 0.5-2 ng/ml.
If patient experience toxicity, the following may happen:




Anorexia, nausea, and vomiting may be initial indicators of toxicity.
Patients may also experience blurred vision, yellowish vision (xanthopsia), Colored
vision (seeing green, yellow, purple), halo vision, flickering lights
CNS: Headaches, fatigue, malaise, confusion, convulsions
various cardiac arrhythmias (including bradycardia or tachycardia)

Conditions That Predispose to Digoxin
Toxicity:

Hypokalemia and Hypercalcemia, so electrolytes levels must
be monitored

Dysrhythmias and renal disease

Advanced age

Treatment of toxicity:

The treatment strategies of toxicity depend on the severity of
the symptoms.

Toxicity can often be managed by discontinuing digoxin, determining serum potassium
levels, and, if indicated, replenishing potassium

When significant toxicity develops, administration of antidote
(digoxin immune fab) is indicated.

The following are the clinical settings in which digoxin
immune Fab (Digibind) therapy usage may be indicated:

Life-threatening cardiac dysrhythmias.

Life-threatening digoxin overdose: more than 10mg in adult
and more than 4mg in children.
The amount of digoxin immune Fab that is infused intravenously is determined by the amount of
digoxin ingested or by the serum digoxin level if the ingested amount is unknown. The patient’s
cardiac status should be monitored continually while the drug is given and for several hours
after the infusion is finished.

Digibind available only in parenteral form.

After given digibind the clinical signs of digoxin toxicity, rather than the digoxin
serum levels should be the primary focus.
E. BETA adrenergic agonists:
β-Adrenergic agonists, such as dobutamine and dopamine improve cardiac performance by
causing positive inotropic effects and vasodilation.
Both drugs must be given by intravenous infusion and are primarily used in the short-term
treatment of acute HF in the hospital setting. Diuretics relieve pulmonary congestion and
peripheral edema. These agents are also useful in reducing the symptoms of volume overload,
including orthopnea and paroxysmal nocturnal dyspnea.
Diuretics decrease plasma volume and, subsequently, decrease venous return to the heart
(preload). This decreases cardiac workload and oxygen demand. Diuretics may also decrease
afterload by reducing plasma volume, thereby decreasing blood pressure. These agents are
used for patients who require extensive diuresis and those with renal insufficiency
As diuretics have not been shown to improve survival in HF, they should only be used to treat
signs and symptoms of volume excess.
Nursing Implications:
 Assess clinical parameters, including:
 BP
 Apical pulse for 1 full minute
 Heart sounds, breath sounds
 Weight, Intake &Output (I & O) measures
 ECG
 Serum labs: potassium, sodium, magnesium, calcium, renal, and liver function
studies
 For digoxin:
 Before giving any dose, count apical pulse for 1 full minute. For apical pulse less than 60
or greater than 100 beats/minute: Hold dose and Notify prescriber
 Hold dose and notify prescriber if patient experiences signs/symptoms of toxicity:
Anorexia, nausea, vomiting, diarrhea, and Visual disturbances (blurred vision, seeing
green or yellow halos around objects)
 Check dosage forms carefully, and follow instructions for giving
 IV inamrinone


Do not mix with dextrose
Solution color is true yellow
 Monitor for therapeutic effects


Increased urinary output
Decreased edema, shortness of breath, dyspnea, crackles,
fatigue


Resolution of paroxysmal nocturnal dyspnea
Improved peripheral pulses, skin color, temperature
 Monitor for adverse effects
Class I (Na+ channel blockers):



Class Ia: quinidine,
disopyramide, procainamide.
Class Ib: lidocaine,
phenytoin.
Class Ic: flecainide,
propafenone.
Class II (Beta-blockers):

E
smolol.

M
etoprolol.

P
ropranolol.
Class III (K+ channel blockers):

A
miodarone.

S
otalol.
Class IV (Ca+2 channel blockers):

V
erapamil.

D
iltiazem.
Other:
IV.
Antiarrhythmic drugs:
DYSRHYTHMIAS AND NORMAL CARDIAC
ELECTROPHYSIOLOGY
D
igoxin.
A
denosine.
Dysrhythmias involve changes to the automaticity or conductivity of the heart cells. These
changes can result from several factors, including electrolyte imbalances that alter the action
potential, decreased oxygen delivery to cells that changes their action potential, structural
damage that changes the conduction pathway, or acidosis or waste product accumulation that
alters the action potential. In some cases, changes to the heart’s automaticity or conductivity
may result from drugs that alter the action potential or cardiac conduction.
Cardiac cell:
Inside a resting cardiac cell there exists a net negative charge relative to the outside of the cell.
This difference in the electronegative charge exists in all types of cardiac cells and is refers to
as the resting membrane potential (RMP). The RMP results from an uneven distribution of
ions (e.g., sodium, potassium, and calcium) across the cell membrane. This is known as
polarization. Each ion moves primarily through its own specific channel. At RMP, potassium ions
are more highly concentrated intracellularly, whereas sodium and calcium ions are both more
highly concentrated extracellularly. This polarized distribution of ions is maintained by the
sodium-potassium adenosine triphosphatase (ATPase) pump.
Conductivity:
With normal heart function, each cycle of cardiac contraction and relaxation is controlled by
impulses arising spontaneously in the sinoatrial (SA) node and transmitted via a specialized
conducting system to activate all parts of the heart muscle almost simultaneously. These
continuous, rhythmic contractions are controlled by the heart itself. This property allows the
heart to beat as long as it has enough nutrients and oxygen to survive, regardless of the status
of the rest of the body.
Automaticity:
All cardiac cells possess some degree of automaticity in which the cells undergo a spontaneous
depolarization during diastole or rest because they decrease the flow of potassium ions out of
the cell and probably leak sodium into the cell, causing an action potential. The action potential
of the cardiac muscle cell consists of five phases:
• Phase 0 occurs when the cell reaches a point of stimulation. The sodium gates open along the
cell membrane, and sodium rushes into the cell; this positive flow of electrons into the cell
results in an electrical potential. This is called depolarization.
• Phase 1 is a very short period during which the sodium ion concentration equalizes inside and
outside of the cell.
• Phase 2, or the plateau stage, occurs as the cell membrane becomes less permeable to
sodium, calcium slowly enters the cell, and potassium begins to leave the cell. The cell
membrane is trying to return to its resting state, a process called repolarization.
• Phase 3 is a time of rapid repolarization as the sodium gates are closed and potassium flows
out of the cell.
• Phase 4 occurs when the cell comes to rest; the sodium–potassium pump returns the
membrane to its resting membrane potential, and spontaneous depolarization begins again.
Each area of the heart has a slightly different-appearing action potential that reflects the
complexity of the cells in that area. Because of these differences in the action potential, each
area of the heart has a slightly different rate of rhythmicity. The SA node generates an impulse
about 60 to 100 times per minute, the atrioventricular (AV) node about 40 to 50 times per
minute and the complex ventricular muscle cells about 10 to 20 times per minute.
Electocardiography (ECG or EKG):
The P wave corresponds to spontaneous impulse generation in the SA node. The QRS
complex (or QRS interval) corresponds to depolarization and contraction of ventricular fibers.
The J point marks the start of the ST segment, which corresponds to the beginning of
ventricular repolarization. The T wave corresponds to completion of repolarizationof these
ventricular fibers. The U wave is not always present, and when U wave occurs it is generally
correlated with electrophysiologic events may be a source of dysrythmias caused by a triggered
automaticity.
Types of Dysrhythmias:
Dysrhythmias can be caused by changes in rate (tachycardia, which is a faster-than-normal
heart rate, or bradycardia, which is a slower-than-normal heart rate); by stimulation from an
ectopic focus, such as premature atrial contractions (PACs) or premature ventricular
contractions (PVCs), atrial flutter, atrial fibrillation, or ventricular fibrillation; or by alterations in
conduction through the muscle, such as heart blocks and bundle-branch blocks.
Pharmacology overview:
Antidysrhythmic drugs:
Numerous drugs are available to treat dyshythmias. These drugs are categorized according to
where and how they affect cardiac cells. The most commonly used system for this purpose is
still the Vaughan Williams classification. This system is based on the electrophysiology effect of
particular drugs on the action potential. This approach identifies four major classes of drugs.

o
Class I
Class Ia: quinidine, disopyramide, procainamide.
o
o
Class Ib: lidocaine, phenytoin.
Class Ic: flecainide, propafenone.
Class II: beta-blockers.
Class III: amiodarone, sotalol.
Class IV: verapamil, diltiazem.
Other: digoxin, adenosine.




Antidysrhythmic drugs work by correcting, to varying degrees and various mechanisms,
abnormal cardiac electrophysiologic function.
Class I:
As membrane-stabilizing drugs, class I drugs exert their actions on the sodium fast channels.
However there are some slight differences in the actions of the drugs in this class, so they are
divided into three subclasses. These subclasses are class Ia, Ib, and Ic drugs, and they are
based on the magnitude of the effects of each drug on phase 0, the action potential duration,
and the effective refractory period.
 Class Ia: quinidine, procainamide, disopyramide
 Class Ib: phenytoin, lidocaine
 Class Ic: flecainide, propafenone
Class II: beta-blockers: atenolol, esmolol, metaprolol, propranolol

Reduce or block sympathetic nervous system stimulation,
thus reducing transmission of impulses in the heart’s conduction system

Depress phase 4 depolarization

General myocardial depressants for both supraventricular
and ventricular dysrhythmias

Also used as antianginal and antihypertensive drugs
Class III: amiodarone, sotalol*, ibutilide, others
o
o
o


Increase APD (action potential duaration).
Prolong repolarization in phase 3
Used for dysrhythmias that are difficult to treat
Life-threatening ventricular tachycardia or fibrillation, atrial
fibrillation or flutter—resistant to other drugs
Sustained ventricular tachycardia
Class IV: verapamil, diltiazem
o

o
o
Digoxin, adenosine
Calcium channel blockers
Inhibit slow-channel (calcium-dependent) pathways
Depress phase 4 depolarization
Reduce AV node conduction
 Have properties of several classes and are not placed into one particular class
 adenosine (Adenocard)


Slows conduction through the AV node
Used to convert paroxysmal supraventricular tachycardia to
sinus rhythm





Very short half-life—less than 10 seconds
Only administered as fast IV push
May cause asystole for a few seconds
Other adverse effects minimal
Drug profile:
Amiodarone:


Marketed as both oral and injectable forms.
Has two significant drug interactions, namely with digoxin
and warfarin. Increase concentration of digoxin and INR.

Has long half-life (15-100 days)

Adverse effects:

Can cause hyperthyroidism and hypothyroidism.

Photosensitivity.

Pulmonary toxicity.
Lidocaine:



Administered parenterally.
Onset of action:2-15 min. and half-life: 8 min.
Has CNS toxic effects: twitching, convulsions.
Nursing Implications:
 Measure serum potassium levels before initiating therapy
 During therapy, monitor cardiac rhythm, heart rate, BP, general well-being, skin color,
temperature, heart and lung sounds.
 Instruct patients to take medications as scheduled and not to skip doses or double up for
missed doses
 Instruct patients to contact their physician for instructions if a dose is missed
 For class I drugs, monitor ECG for QT intervals prolonged more than 50%
 Solutions of lidocaine that contain epinephrine should not be given IV—they are to be
used ONLY as local anesthetics
 Ensure that the patient knows to notify health care provider of any worsening of
dysrhythmia: Shortness of breath, Edema, Dizziness, Chest pain, GI distress.
V.
Antiangi
nal Drugs:
Heart requires a large supply of oxygen to meet the
incredible demands placed on it. Pumping blood to all
the tissues and organs of the body is a difficult job. The
heart’s much needed oxygen supply is delivered to the
heart muscle by means of the coronary arteries. When
the heart’s supply of blood carrying oxygen and energyrich nutrients is insufficient to meet the demands of the
heart, the myocardium aches. This is called angina
pectoris, or chest pain. Poor blood supply to an organ
is referred to ischemia. When the organ involved is the
heart, the condition is called ischemic heart disease.
Nitrates:
 Isosorbide dinitrate.
 Isosorbide mononitrate.
 Nitroglycerin.
Beta-blockers:
 Atenolol.
 Metoprolol.
 Propranolol.
Calcium-Channel blockers:






Amlodipine.
Diltiazem.
Felodipine.
Nicardipine.
Nifedipine.
Verapamil.
The primary cause of ischemic heart disease is a
disease of the coronary arteries known as
atherosclerosis (fatty plaque deposits in the arterial
walls). When atherosclerotic plaques project from the
walls into the lumens of these vessels, the vessels become narrow. The supply of oxygen and
energy-rich nutrients needed for the heart to meet the demands placed on it is then decreased.
This disorder is called coronary artery disease (CAD). An acute result of CAD and of ischemic
heart disease is myocardial infarction (MI), or heart attack. It occurs when blood flow through
the coronary arteries to the myocardium is completely blocked so that part of the heart muscle
cannot receive any of the blood borne nutrients (especially oxygen) necessary for normal
function. If this process is not reversed immediately, the area of the heart will be dying and
become necrotic.
There are three classic types of chest pain, or angina pectoris. Chronic stable angina has
atherosclerosis as its primary cause. Classic angina or effort angina is other names for it.
Chronic stable angina can be triggered by exertion or other stress. The pain of chronic stable
angina is commonly intense but subsides within 15 minutes of either rest are appropriate
antianginal therapy. Unstable angina is usually the early stage of progressive CAD. It often
culminates in MI in subsequent years. For this reason, unstable angina is also called
preinfarction angina. Vasospastic angina results from spasms in the layer of smooth muscle
that surrounds atherosclerotic coronary arteries. This type of pain often occurs at rest and
without any precipitating cause. This type of angina is also called prinzmetal angina or variant
angina.
Pharmacology overview:
The three main classes of drugs used to treat angina pectoris are the nitrates and nitrites, the
beta-blockers, and the CCBs. There are three main therapeutic objectives of antianginal drug
therapy. It must (1) minimize the frequency of attacks and decrease the duration and intensity of
the angina pain; (2) improve the patient’s functional capacity with as few adverse effects as
possible; and (3) prevent or delay the worst possible outcome, MI. the overall goal antianginal
drug therapy is to increase blood flow to ischemic myocardium, decrease myocardial
oxygen demand, or both. The figure below illustrates how drug therapy works to alleviate
angina.
1-
NITRATES AND NITRITES:
Nitrates have long been the mainstay of both the prophylaxis and treatment for angina and
other cardiac problems. They are available in a wide variety of preparations, including
sublingual, chewable, and oral tablets; capsules; ointments; patches; a translingual spray; and
intravenous solutions. The following are rapid- and long-acting nitrates available for clinical use:





Amyl nitrite (rapid acing).
Nitroglycerin (both rapid and long acting).
Isosorbid dinitrate (both rapid and long acting).
Isosorbid mononitrate (primarily long acting).
Mechanism of action:
Nitrates and nitrites, more commonly referred to simply as nitrates, dilate all blood vessels. They
predominantly affect venous vascular beds; these vasodilatory effects are the result of
relaxation of the smooth muscle cells that are part of the wall structure of veins and arteries.
This causes redistribution of blood and therefore of oxygen to previously ischemic myocardial
tissue and reduction of angina symptoms.
By causing venous dilation, the nitrates reduce venous return and, in turn, reduce the left
ventricular end-diastolic volume (or preload), which results in a lower left ventricular pressure.
Left ventricular systolic wall tension is thus reduced, as is myocardial oxygen demand.
Coronary arteries that have been narrowed by atherosclerosis can still be dilated as long as
there remains smooth muscle surrounding the coronary artery and the atherosclerostic plaque
does not completely obstruct the arterial lumen.

Indications:
The nitrates are used to treat stable, unstable, and vasospastic (prinzmetal) angina. Long-acting
dosage forms are used more for prevention of angina episodes. Rapid-acting dosage forms,
most often sublingual nitroglycerin tablets, or an intravenous drip in the hospital setting, are
used to treat acute angina attacks.

Adverse effects

Headaches. (Usually diminish in intensity and frequency with
continued use).



Tachycardia, postural hypotension
Tolerance may develop
Phosphodiesterase type 5 inhibitors such as sildenafil
potentiate the action of the nitrates. To preclude the dangerous hypotension that may
occur, this combination is contraindicated
Tolerance:

Occurs in patients taking nitrates around the clock or with
long-acting forms




Tolerance can be overcome by providing a daily “nitrate-free
interval” to restore sensitivity to the drug.
This interval of 10 to 12 hours is usually taken at night
because demand on the heart is decreased at that time.
Nitroglycerin patches are worn for 12 hours and then
removed for 12 hours.
However, variant angina worsens early in the morning.
Therefore, the nitrate-free interval in these patients should occur in the late afternoon.
2-
BETA-BLOCKERS:
β-Blockers are recommended as initial antianginal therapy in all patients unless
contraindicated.
The exception to this rule is vasospastic angina, in which β-blockers are ineffective and may
actually worsen symptoms.
Most available bata-blockers demonstrate antianginal efficacy, although not all have been
approved for this use. Those beta-blockers approved as antianginal drugs are atenolol,
metoprolol, and propranolol.

Mechanism of action:



Block beta1-receptors on the heart.
Decrease HR, resulting in decreased myocardial oxygen
demand and increased oxygen delivery to the heart.
Decrease myocardial contractility, helping to conserve
energy or decrease demand.

After an MI a high level of circulating catecholamines irritate
the heart, causing an imbalance in supply and demand ratio and even leading to lifethreatening dysrhythmias. Beta-blockers block the harmful effects of catecholamines,
thus improving survival after an MI.

Adverse effects:
Body System
Adverse Effects



Cardiovascular Bradycardia, hypotension.
Other
Impotence, wheezing, dyspnea
CNS
Dizziness, fatigue, mental depression, lethargy,
drowsiness.
3-
CALCIUM CHANNEL BLOCKERS:
The three chemical classes of CCBs are phenylalkylamines, benzothiazepines, and
dihydropyridines, commonly represented by verapamil, diltiazem, and amlodipine, respectively.

Mechanism of action:
These drugs prevent calcium from entering into excitation-coupling process that occurs in the
heart and vascular smooth muscle cells and promotes muscle relaxation. Relaxations of the
smooth muscles that surround the coronary arteries cause them to dilate. This increases blood
flow to the ischemic heart, which in turn increases the oxygen supply and helps shift the
supply/demand ratio back to normal. This dilation also occurs in the arteries throughout the
body, which results in a decrease in the force against which the heart must exert itself when
delivering blood to the body (afterload). Decreasing the afterload reduces the workload of the
heart and therefore reduces myocardial oxygen demand. Another cardiovascular effect of the
CCBs is depression of the automaticity of and conduction through the SA and AV nodes. For
this reason, they are useful in treating cardiac dysrhythmias.
 Dihydropyridine calcium channel blockers
Amlodipine an oral dihydropyridine, functions mainly as an arteriolar vasodilator. This drug has
minimal effect on cardiac conduction. The vasodilatory effect of amlodipine is useful in the
treatment of variant angina caused by spontaneous coronary spasm. Nifedipine is another
agent in this class
 Nondihydropyridine calcium channel blockers
Verapamil slows atrioventricular (AV) conduction directly and decreases heart rate, contractility,
blood pressure, and oxygen demand. Verapamil has greater negative inotropic effects than
amlodipine, but it is a weaker vasodilator. Diltiazem can relieve coronary artery spasm and is
particularly useful in patients with variant angina. Nondihydropyridine calcium channel blockers
can worsen heart failure due to their negative inotropic effect, and their use should be avoided
in this population.

Indications




First-line drugs for treatment of angina, hypertension, and
supraventricular tachycardia
Coronary artery spasms (Prinzmetal’s angina)
Short-term management of atrial fibrillation and flutter
Migraine headaches.

Adverse effects

Very acceptable adverse effect and safety profile
May cause hypotension, palpitations, tachycardia or bradycardia, constipation, nausea,
dyspnea, other adverse effects
4-
SODIUM CHANNEL BLOCKERS:
Ranolazine improves the oxygen supply and demand equation. Ranolazine has
antianginal as well as antiarrhythmic properties.
It is indicated for the treatment of chronic angina and may be used alone or in
combination with other traditional therapies. It is most often used in patients who have
failed other antianginal therapies. Ranolazine is subject to numerous drug interactions.
ranolazine can prolong the QT interval, cause constipation, headache and edema.
Nursing Implications:
 Patients should report blurred vision, persistent headache, dry mouth, dizziness, edema,
fainting episodes, weight gain of 2 pounds in 1 day or 5 pounds in 1 week, pulse rates
less than 60, and dyspnea.
 Alcohol consumption and spending time in hot baths or whirlpools, hot tubs, or saunas
will result in vasodilation, hypotension, and the possibility of fainting
 Teach patients to change positions slowly to avoid postural BP changes
 Encourage patients to keep a record of their anginal attacks, including precipitating
factors, number of pills taken, and therapeutic effects.
 Monitor vital signs frequently during acute exacerbations of angina and during IV
administration
 Nitroglycerin

Instruct patients in proper technique and guidelines for
taking sublingual nitroglycerin for anginal pain

Instruct patients never to chew or swallow the sublingual
form

Instruct patients to keep a fresh supply of sublingual
medication on hand; potency is lost in about 3 months after the bottle has been
opened. To preserve potency, medications should be stored in an airtight, dark glass
bottle with a metal cap and no cotton filler

Instruct patients in the proper application of nitrate topical
ointments and transdermal forms, including site rotation and removal of old
medication

To reduce tolerance, the patient may be instructed to
remove topical forms at bedtime and apply new doses in the morning, allowing for a
nitrate-free period

Instruct patients to take prn nitrates at the first hint of anginal
pain

If experiencing chest pain, the patient taking sublingual
nitroglycerin should lie down to prevent or decrease dizziness and fainting that may
occur because of hypotension
 If anginal pain occurs:





Stop activity and sit or lie down
Take a sublingual tablet, and call Emergency Services immediately!
If no relief in 5 minutes, take a second sublingual tablet
If no relief in 5 minutes, take a third sublingual tablet
Do not try to drive to the hospital
 Discard parenteral solution that is blue, green, or dark red
 Follow specific manufacturer’s instructions for IV administration
 Calcium channel blockers : Constipation is a common problem; instruct patients to
take in adequate fluids and eat high-fiber foods
 Beta-blockers
 Patients taking beta-blockers should monitor pulse rate daily and report any rate lower
than 60 beats per minute
 Instruct patients to report dizziness or fainting
 Inform patients that these medications should never be abruptly discontinued because of
risk of rebound hypertensive crisis
 Inform patients that these medications are for long-term prevention of angina, not for
immediate relief
 Antianginal drugs:
 Monitor for adverse reactions
 Allergic reactions, headache, lightheadedness, hypotension, dizziness
 Monitor for therapeutic effects
 Relief of angina, decreased BP, or both
Anticoagulants:








Heparin.
Enoxaparin.
Tinzaparin.
Lepirudin.
Warfarin.
Dabigatran etexilate
Rivaroxaban
apixaban
Antiplatelets:
VI. Coagulation Modifier
Drugs:
Overview:








Aspirin.
Clopidogrel.
Ticlopidine
Dipyridamole
Abciximab.
Tirofiban.
Eptifibatide.
Cilostazol
Thrombolytic agents:
The vascular system must maintain an intricate balance
between the tendency to clot or form a solid state, called
 Alteplase.
coagulation, and the need to “unclot,” or reverse
coagulation, to keep the vessels open and the blood
 Streptokinase.
flowing.
If a great deal of vascular damage occurs, such as with
Treatment of bleeding:
a major cut or incision, the balance in the area shifts to a
procoagulation mode and a large clot is formed. At the
 Aminocaproic acid.
same time, the enzymes in the plasma work to dissolve
 Tranexamic acid.
this clot before blood flow to tissues is lost, which
otherwise would lead to hypoxia and potential cell death.
Drugs that affect blood coagulation work at various steps in the blood clotting and clotdissolving processes to restore the balance that is needed to maintain the cardiovascular
system.
Blood coagulation is a complex process that involves vasoconstriction, platelet clumping or
aggregation, and a cascade of clotting factors produced in the liver that eventually react to
break down fibrinogen (a protein also produced in the liver) into insoluble fibrin threads. When a
clot is formed, plasmin (another blood protein) acts to break it down.
Substances that promote coagulation include platelets, von Willbrand factor, activated
clotting factors, and tissue thromboplastin. Substances that inhibit coagulation include
prostacyclin, antithrombin III, and protein C and S. in addition, tissue plasminogen activator is
a natural
When blood vessels are damaged by penetration from the outside, thrmboplastin, a substance
contained in the walls of blood vessels, is released. This initiates the extrinsic pathway by
activating factors VII and X. All of the components of the intrinsic pathway are present in the
blood in their inactive forms. This pathway is activated when factor XII comes in contract with
exposed collagen on the inside of damaged blood vessels. Figures below illustrate the steps
that occur in the extrinsic and intrinsic pathways, respectively, and the coagulation factors
involved, they also illustrate the site of action of two commonly used anticoagulant drugs:
warfarine and heparin.
Once a clot is formed and fibrin is present, the fibrinolytic system is activated. This is the
system that initiates the breakdown of clots and serves to balance the clotting process.
Fibrinolysis is the reverse to balance the clotting process. It is the mechanism by which formed
thrombi are lysed to prevent excessive clot formation and blood vessel blockage. It is the fibrin
in the clot that binds to a circulating protein known as plasminogen. This converts plasminogen
to plasmin. Plasmin is the enzymatic protein that eventually breaks down the fibrin thrombus
into fibrin degradation products. This keeps the thrombus localized to prevent it from becoming
an embolus that can travel to obstruct a major blood vessel in the lung, heart, or brain.
Pharmacology overview:
Drugs discussed here aid the body in reversing or achieving hemostasis, and they are divided
into several main categories based on their actions:
Anticoagulants inhibit the action or formation of clotting factors and therefore prevent clots
from forming.
Antiplatelet drugs prevent platelet plugs from forming by inhibiting platelet aggregation, which
can be beneficial in preventing heart attacks and strokes.
Thrombolytic drugs lyse clots, or thrombi, that have already formed.
Antifibrinolytic drugs (prevent lysis of fibrin, promote clot formation), also known as
hemostatic drugs, have the opposite effect of these other classes of drugs; they actually
promote blood coagulation and are helpful in the management of conditions in which excessive
bleeding would be harmful.
1-
Anticoagulants:





Heparin
Low–molecular-weight heparins
Direct thrombin inhibitors (antithrombin): Lepirudin.
warfarin (Coumadin)
Selective factor Xa inhibitor: fondaparinux.
Drugs that prevent the formation of a clot by inhibiting certain clotting factors are called
anticoagulants. These drugs are only given prophylactically because they have no direct effect
on a blood clot that has already formed. By decreasing blood coagulability, anticoagulants
prevent intravascular thrombosis.
Once a clot forms on the wall of a blood vessel, it may dislodge and travel through the blood
stream. This is referred to as an embolus. If it lodges in a coronary artery, it causes a
myocardial infarction, if it obstructs a brain vessel, it causes a stroke; if it goes to the lungs, it
is a pulmonary embolism; and if it goes to a vein in the leg, it is a deep vein thrombosis.
Collectively, these complications are called thromboembolic events. Anticoagulants can
prevent all of these from occurring if used in the correct manner.
Both orally and parentarally administered anticoagulants are available, and each drug has a
slightly different mechanism of action and indications. All of them have their own risks, mainly
the risk for causing bleeding. The mechanisms of action of the anticoagulants vary depending
on the drug. Drug classes of anticoagulants include older drugs such as unfractionated heparin
and warfarin. There are also several newer drug classes, including low molecular weight
heparins LMWHs, direct thrombin inhibitors, and a selective factor Xa inhibitor.

Mechanism of action:
Heparin works by binding to a substance called antithrombin III, which turns off three main
activating factors: activated factor II (also called thrombin), activated factor X, and activated
factor IX. Of these, the thrombin is the most sensitive to the actions of heparin. Antithrombin
III is the major natural inhibitor of thrombin in the blood. The overall effect of heparin is that
turns off the coagulation pathway and prevents clots from forming.
The drug name heparin usually refers to unfractionated heparin, which is a relatively large
molecule and is derived from various animal sources. In contrast, LMWHs are synthetic and
have a smaller molecular structure.
Heparin and LMWHs drugs are the anticoagulants of choice for treating pregnant women,
because they do not cross the placenta, due to their large size and negative charge
Advantages of LMWHs:
These include enoxaparin, and tinzaparin. All work similarly to heparin.


LMWHs have a much more predictable anticoagulant
response. As a result, frequent laboratory monitoring of bleeding times using test such
as activated partial thromboplastin time (aPPT), which is imperative with unfractionated
heparin, is not required with LMWHs.
LMWHs given S.C. While heparin is given IV or deep S.C
Warfarin works by inhibiting vitamin K synthesis by bacteria in the gastrointestinal tract. This,
in turn inhibits production of clotting factors II, VII, IX and X. These four factors are normally
synthesized in the liver and are known as vitamin K-dependent clotting factors. The final
effect is the prevention of clot formation.
Fondaparinux, rivaroxaban and apixaban inhibits thrombosis by its specific action against
factor Xa alone.
Drugs that inhibit the thrombin molecules directly, one is natural and other are synthetic.
The natural drug is human antithrombin III (Thrombate), which is isolated from the plasma of
human donors. The synthetic drugs are Dabigatran etexilate, lepirudin, argatroban, and
bivalirudin. All of these drugs work similarly to inhibit thrombus formation by inhibiting thrombin.

Indications:
Prevention of clot formation also prevents Stroke, Myocardial infarction (MI), Deep vein
thrombosis (DVT), pulmonary embolism (PE), and unstable angina. Warfarin is indicated for
prevention of any of these events, where as both UFHs and LMWHs are used for prevention
and treatment.
Patients at risk for clots (e.g. hip replacement surgery) are given prophylaxis while in hospital
and after major surgery. LMWHs are used routinely as anticoagulant therapy bridge.

Contraindications:
LMWHs are contraindicated in patients with an indwelling epidural catheter; they can be given 2
hours after the epidural is removed. This is very important for nurses to remember, because
giving an LMWH with an epidural has been associated with epidural hematoma.
Anticoagulants are contraindicating in any acute bleeding process or high risk for such an
occurrence. warfarin is contraindicated in pregnancy.
Dabigatran is contraindicated in patients with mechanical prosthetic heart valves. Rivaroxaban
and apixaban should be used in severe renal dysfunction

Adverse effects:
Heparin and LMWHs:

Bleeding. Careful monitoring of the patient and laboratory parameters is required to
minimize bleeding.
 Risk increases with increased dosages
 May be localized or systemic
 Management of excessive bleeding may be managed by discontinuing the drug
or by treating with protamine sulfate.


Heparin-induced thrombocytopenia (HIT) is a serious condition
 Heparin therapy should be discontinued when patients develop HIT or show
severe thrombocytopenia.
 In cases of HIT, heparin can be replaced by another anticoagulant, such as
argatroban. [Note: LMWHs can have cross-sensitivity and are not recommended
in HIT]
May also cause: Nausea, vomiting, abdominal cramps,
osteoporosis with prolonged use
Drug profiles:









Warfarin:
Warfarin is available only for oral use.
Use of this drug requires careful monitoring of the
prothrombin time/international normalized ratio (PT/INR), which is a standardized
measure of degree to which a patient’s blood coagulability has been reduced by the
drug. A normal INR without warfarin is 1.0, whereas a therapeutic INR with warfarin
ranges from 2-3.5, depending on the indication for use of the drug.
Warfarin has significant interactions with many drugs,
including amiodarone, fluconazole, erythromycin, and metronidazole.
The patient's age and state of health should be considered
before given warfarin.
Poor nutrition and heart failure may increase patient's
sensitivity to warfarin.
Heparin
o
Monitored by activated partial thromboplastin times (aPTTs)
o
Parenteral
o
Short half-life (1 to 2 hours)
o
Effects reversed by protamine sulfate
Low–molecular-weight heparins
o
enoxaparin (Lovenox) and tizaparin (innohip)
o
More predictable anticoagulant response
o
Do not require laboratory monitoring
o
Given subcutaneously.
o
Long half-life.
Rivaroxaban and apixaban:
o
given orally
o
o
Compared to warfarin, they have fewer drug interactions.
There are no laboratory monitoring requirements for either
agent
o
There is no antidote available to reverse bleeding

Dabigatran:
Given orally
capsules should be stored in the original container and
o
o
swallowed whole
o
o
o
There is no approved antidote for reversing bleeding
associated with dabigatran.
Dabigatran does not require routine monitoring of the
international normalized ratio
has fewer drug interactions as compared to warfarin
2-
Antiplatelet Drugs:
a.
b.
c.
i.
d.
(ReoPro)
i.
Aspirin
Dipyridamole (Persantine)
Clopidogrel (Plavix) and ticlopidine (Ticlid)
ADP inhibitors
Tirofiban (Aggrastat), eptifibatide (Integrilin), abciximab
New class, GP IIb/IIIa inhibitors
Antiplatelet drugs work to prevent platelet adhesion to the site of blood injury, which actually
occurs before the clotting cascade. Knowledge of the role of platelets in the clotting process is
essential to understanding how antiplatelet drugs work.
Platelets normally flow through blood vessels without adhering to their surfaces; blood vessels
can be injured by a disruption of blood flow, trauma, or the rapture of plaque from a vessel wall.
When such events occur, collagen which is present in the walls of blood vessels, become
exposed.


Collagen is a potent stimulator of platelet adhesion.
Once platelet adhesion occurs, stimulators are released
from the activated platelets.


These cause the platelets to aggregate at the site of injury.
Once at the site of vessel injury, the platelets change shape
and release their contents, which include ADP, secrotonin, and platelet factor 4.

The hemostatin function of these substances is twofold:

First, they act as platelet recruiters, attracting additional
platelets to the site of injury.

Second, they are potent vasoconstrictiors. Vasoconstriction
limits blood flow to the damaged blood vessel to reduce blood loss.

A platelet plug that has formed at a site of vessel injury is not
stable and can be dislodged.

The clotting cascade is therefore stimulated to form a more
permanent fibrin plug (blood clot).

Mechanism of action:
Many of the antiplatelet drugs affect the cyclogenase pathway, which is one of the common final
enzymatic pathways in the complex arachidonic acid pathway that operates within platelets and
on blood vessel walls.
Aspirin is also widely used for its analgesic, anti-inflammatory, and antipyretic properties.
In terms of its antiplatelet effects, aspirin acetylates and inhibits cyclooxygenase in the
platelet irreversibly so that the platelet cannot regenerate this enzyme. Therefore, the effects
of aspirin last the life span of a platelet, or 7 days. This irreversible inhibition of cyclooxygenase
in the platelet prevents the formation of TXA2, a substance that causes blood vessels to
constrict and platelets to aggregate.
Dipyridamole, also works to inhibit platelet aggregation by preventing the release of ADP,
platelet factor4, and TXA2, all substances that stimulate platelets to aggregate or form a clot.
Dipyridamole may also directly stimulate the release of prostacyclin and inhibit the formation of
TXA2.
Clopidogrel is an ADP inhibitor, it inhibits platelet aggregation by altering the platelet
membrane so that it can no longer receive the signal to aggregate and form a clot. This signal is
the form of fibrinogen molecules, which attach to glycoprotein receptors (GP IIb/IIIa) on the
surface of the platelet. Clopidogrel inhibits the activation of this receptor. Clopidogrel has been
shown to be somewhat better than aspirin at reducing the number of heart attacks, strokes, and
vascular deaths in patients at risk.
The newest available antiplatelet class of drugs is the GP IIb/IIIa inhibitors. They work blocking
the receptor protein by the same name that occurs in the platelet wall membranes. This protein
plays a role in promoting the aggregation of platelets in preparation for fibrin clot formation.
There are currently three available drugs in this class: tirofiban, eptifibatide, and abciximab.
The GP IIb/IIIa inhibitors are available only for IV infusion.

Indications:
The therapeutic effects of the antiplatelet drugs depend on the particular drug. Aspirin (oral)
has multiple therapeutic effects, but many of them vary depending on the dosage. Aspirin is
officially recommended for stroke prevention in daily doses of 50-325 mg. clopidogrel (oral) is
also given to reduce the risk for fatal and nonfatal thrombotic stroke, and is used for prophylaxis
against transient ischemic attacks well for post-MI prevention of thrombosis. Dipyridamole
(oral) is used as an adjunct to warfarin in the prevention of postoperative thromboembolic
complications. The GP IIb/IIIa inhibitors are used to treat acute unstable angina and MI, and are
given during percutaneous coronary intervention procedures, such as angioplasty.

Contraindications: Contraindications to the use of
antiplatelet include known drug allergy, active bleeding and GI ulcer.

Adverse effects: They all pose a risk for inducing a serious
bleeding episode.
Drug- drug interaction

Nonsteroidal anti-inflammatory drugs, such as ibuprofen,
inhibit COX-1 by transiently competing at the catalytic site. Ibuprofen, if taken within
the 2 hours prior to aspirin, can obstruct the access of aspirin to this enzyme and,
thereby, antagonize platelet inhibition by aspirin. Therefore, immediate release
aspirin should be taken at least 60 minutes before or at least 8 hours after ibuprofen
3-
Thrombolytic drugs:
Streptokinase, urokinase and alteplase:
The natural fibrinolytic system within the blood takes several days to break down a clot
(thrombus). This is of little value in the case of a clotted blood vessel that supplies blood to the
heart muscle. Necrosis of the myocardium could be prevented by these natural means, but
thrombolytic drug therapy activates the fibrinolytic system to break down the thrombus in the
blood vessel quickly so that the delivery of blood to the heart muscle via the coronary arteries is
quickly reestablished. Thrombolytics accomplish this by activating the conversion of
plasminogen to plasmin, which lyses the thrombus.

Indications:






Acute MI
Arterial thrombolysis
DVT
Occlusion of shunts or catheters
Pulmonary embolus
Acute ischemic stroke

Adverse effects:

bleeding and allergies

These drugs are contraindicated in pregnancy, and in patients with healing wounds, a
history of cerebrovascular accident, brain tumor, head trauma, intracranial bleeding, and
metastatic cancer.
 Patients develop streptokinase antibodies after about 4 days of treatment, and it
should not be used again for at least 12 months to allow this antibody titer to fall,
since the antibodies will neutralize the streptokinase and render it useless. Alteplase
can be used if needed in this case because these antibodies cannot neutralize
alteplase. However alteplase is more expensive than atreptokinase. These drugs
administer by I.V.
4-
Treatment of bleeding:
Antifibrinolytic Drugs:




aminocaproic acid.
tranexamic acid
protamine sulfate
vitamine K
Fibrin is the substance that helps make a platelet plug insoluble and anchors the clot to
the damaged blood vessel. The term antifibrinolytic refers to what these drugs do, which
is to prevent the lyses of fibrin; in doing so, they actually promote clot formation.
Indications:
 Prevention and treatment of excessive bleeding
Adverse effects:


Uncommon and mild
Rare reports of thrombotic events
Nursing implications:
Assess:
 History of abnormal bleeding conditions
 Intravenous doses are usually double-checked with another nurse
 Ensure that SC doses are given SC, not IM
 SC doses should be given in areas of deep subcutaneous fat, and sites rotated
 Heparin:

Anticoagulant effects seen immediately

Laboratory values done daily to monitor coagulation effects
(aPTT)

Protamine sulfate can be given as an antidote in case of
excessive anticoagulation
 LMWH:
 Given subcutaneously in the abdomen
 Rotate injection sites
 Protamine sulfate can be given as an antidote in case of excessive
anticoagulation
 Warfarin:
 May be started while the patient is still on heparin until PT-INR levels indicate adequate
anticoagulation
 Full therapeutic effect takes several days
 Monitor PT-INR regularly—keep follow-up appointments
 Antidote is vitamin K
 Many herbal products have potential interactions—increased bleeding may occur
 Capsicum pepper, Garlic, Ginger, Gingko, Ginseng, Feverfew
Patient education:
Education should include:
Importance of regular lab testing
Signs of abnormal bleeding
Measures to prevent bruising, bleeding, or tissue injury
Wearing a medical alert bracelet
Avoiding foods high in vitamin K (tomatoes, dark leafy green vegetables)
Consulting physician before taking other meds or over-the-counter products, including herbals
 Antiplatelet drugs:
 Concerns and teaching tips same as for anticoagulants
 Dipyridamole should be taken on an empty stomach
 Monitoring for abnormal bleeding
 Thrombolytic drugs:
 Follow strict manufacturer’s guidelines for
preparation and administration
 Monitor IV sites for bleeding, redness,
pain
 Monitor for bleeding from gums, mucous
membranes, nose, injection sites
 Observe for signs of internal bleeding
(decreased BP, restlessness, increased
pulse)
 Coagulation modifier drugs:
 Monitor for therapeutic effects
 Monitor for signs of excessive bleeding
 Bleeding of gums while brushing teeth,
unexplained nosebleeds, heavier
menstrual bleeding, bloody or tarry stools,
bloody urine or sputum, abdominal pain,
vomiting blood
 Monitor for adverse effects: Increased
BP, headache, hematoma formation,
hemorrhage, shortness of breath, chills,
fever
STATINS:







Atorvastatin
Fluvastatin
Lovastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin.
Bile acid sequestrants:
 Cholystyramine.
 Colesevelam
 Colestipol
Niacin.
Fibric acid derivatives:
 Gemfibrozil.
 Fenofibrate.
Cholesterol absorption inhibitor:
 Ezetimibe.
Omega -3 fatty acids
 Docosahexaenoic and
eicosapentaenoic
acids
 Icosapent ethyl
VII. Antilipemic Drugs:
Overview:
Lipids and lipid abnormalities:
Primary forms of lipids:
Triglycerides and cholesterol are the two primary forms of lipids in the blood. Triglycerides
function as an energy source and are stored in adipose tissue. Cholesterol is primarily used to
make steroid hormones, cell membranes and bile acids. Triglycerides and cholesterol are both
water-insoluble fats and that must be bound to specialized lipid-carrying proteins called
apolipoproteins. This combination of triglycerides and cholesterol with an apolipoprotein is
referred to as a lipoprotein. Lipoproteins transport lipids via the blood. There are various types of
lipoproteins, and they are classified according to their density and the type of apolipoproteins
they contain.
Lipoprotein classification:





Chylomicron.
Very low density lipoprotein (VLDL).
Low density lipoprotein (LDL).
Intermediate density lipoprotein (IDL).
High density lipoprotein (HDL).
Coronary heart disease CHD:
 The risk of CHD in patients with cholesterol levels of 300 mg/dL is three to four times
greater than that in patients with levels less than 200 mg/dL
 Positive risk factors for CHD:
 Age
 Male 45 years or older
 Female 55 years or older
 Family history of premature CHD
 Current cigarette smoker
 Hypertension (BP 140/90 or higher, or on antihypertensive medication)
 Low HDL levels: less than 40 mg/dL
 Diabetes mellitus
Atherosclerotic plaque formation:
When the serum cholesterol levels are elevated, circulating monocytes adhere to the smooth
endothelial surfaces of the coronary vasculature. These monocytes burrow into the next layer of
the blood vessel and change into macrographage cells, which then take up cholesterol from
circulating lipoproteins until they become filled with fat. Soon they become what are known as
foam cells, the characteristic precursor lesion of atherosclerosis, also known as a fatty streak.
Once this process is established, it is usually present throughout the coronay and systemic
circulation.
Treatment guidelines:
 Antilipemic drugs
 Drugs used to lower lipid levels
 Used as an adjunct to diet therapy
 Drug choice based on the specific lipid profile of the patient
 All reasonable non-drug means of controlling blood cholesterol levels (e.g., diet,
exercise) should be tried for at least 6 months and found to fail before drug therapy is
considered.
Pharmacology overview:
There are currently four established classes of drugs used to treat dyslipidemia;
123456-
Hydroxymethylglutaryl-coenzyme A(HMG-CoA)
reductase inhibitors (statins).
Fibric acid derivatives (fibrates).
Bile acid sequesters.
The new drug ezetimibe is now available that is a
cholesterol absorption inhibitor.
Vitamin niacin (vitamin B3, also known as nicotinic acid)
Omega -3 fatty acids.
1





Hydroxymethylglutaryl-Coenzyme A HMGCoA Reductase Inhibitors (statins)
Levostatin.
Pravastatin.
Simvastatin.
Atorvastatin.
Fluvastatin.
Rosuvastatin.
The rate-limiting enzyme in cholesterol synthesis is known as HMG-CoA reductase. The
class of medication that competitively inhibit this enzyme, called the hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, are the most potent of the drugs available for
reducing plasma concentrations of LDL cholesterol.
When these drugs are taken, lipid levels may not be lowered to their maximum extent until 6 to
8 weeks after the start of therapy. The following doses of drugs are considered to be
therapeutically equivalent, meaning they produce the same therapeutic effect: simvastatin
10mg; pravastatin 20mg; atorvastatin 10mg; fluvastatin 40mg; rosuvastatin 5mg.
Mechanism of action:
Statins lower the blood cholesterol level by decreasing the rate of cholesterol production. The
liver requires HMG-CoA reductase to produce cholesterol. It is the rate-limiting enzyme in the
reactions needed to make cholesterol. The statins inhibit this enzyme, thereby decreasing
cholesterol production. When less cholesterol is produced, the liver increases the number of LDL
receptors to augment the recycling of LDL from the circulation back into the liver, where it is
needed for the synthesis of other required substances such as steroids, bile acids, and cell
membranes.
Adverse effects:




Mild, transient GI disturbances
Rash
Headache
Myopathy (muscle pain), possibly leading to the serious
condition rhabdomyolysis
 Elevations in liver enzymes or liver disease (Therefore, liver function should be
evaluated prior to starting therapy and if a patient has symptoms consistent with liver
dysfunction
 The HMG CoA reductase inhibitors may also increase the effect of warfarin. Thus, it
is important to evaluate INR frequently.
 These drugs are contraindicated during pregnancy and lactation
2 cholestyramine (Questran)
Bile acid sequesterants:
 Also called bile acid–binding resins and ion-exchange resins
Mechanism of action:
Bile acid sequesterants bind bile, preventing the resorption of the bile acids from the small
intestine. Instead, an insoluble bile acid and resin (drug) complex is excreted in the bowel
movement.
Bile acids are necessary for the absorption of cholesterol from the small intestine and are also
synthesized from cholesterol by the liver. This is one natural way that the liver excretes
cholesterol from the body. The more bile acids are excreted in the feces, the more the liver
converts cholesterol to bile acids. This reduces the level of cholesterol in the liver and thus in
the circulation as well. The liver then attempts to compensate for the loss of cholesterol by
increasing the number of LDL receptors on its surface. Circulating LDL molecules bind to these
receptors to be taken up into the liver, which also has the benefit of reducing circulating LDL in
the bloodstream.
Adverse effects:
 These agents may impair the absorption of the fat-soluble vitamins (A, D, E, and K)
 They interfere with the absorption of many drugs (for example, digoxin, warfarin, and
thyroid hormone).
 Therefore, other drugs should be taken at least 1 to 2 hours before, or 4
to 6 hours after, the bile acid–binding resins.
 These agents may raise triglyceride levels and are contraindicated in patients with
significant hypertriglyceridemia (≥400 mg/dL).
 The most common side effects are GI disturbances,constipation, heartburn, nausea,
belching, bloating

These adverse effects tend to disappear over time
3-
Niacin:


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 drugs
Mechanism of action:
Although the exact mechanism of action of niacin is unknown, the beneficial effects are believed
to be related to its ability to inhibit lipolysis in adipose tissue, decrease esterification of
triglycerides in the liver, and increase the activity of lipoprotein lipase. The drug effects of niacin
are primarily limited to reduction of the metabolism or catabolism of cholesterol and triglycerides.
Adverse effects:
 The most common side effects of niacin are an intense cutaneous flush (accompanied
by an uncomfortable feeling of warmth) and pruritus.
 Some patients also experience nausea and abdominal pain
 The drug should be avoided in hepatic disease
4-
Fibric acid derivatives :


Gemfibrozil
Fenofibrate.
These drugs primarily affect the triglyceride levels but may also lower the total cholesterol and
LDL cholesterol levels and raise the HDL cholesterol level. They are often collectively referred
to as fibrates.
Mechanism of action:
 Believed to work by activating lipase, which breaks down cholesterol. Also suppress the
release of free fatty acid from adipose tissue, inhibit synthesis of triglycerides in the liver,
and increase secretion of cholesterol in the bile
Adverse effects:

Abdominal discomfort, diarrhea, nausea (most common)

Blurred vision, headache

Increased risk of gallstones
 The use of gemfibrozil is contraindicated with simvastatin.
 Both fibrates may increase the effects of warfarin
 Fibrates should not be used in patients with severe hepatic or renal dysfunction or in
patients with preexisting gallbladder disease
5-
Cholesterol Absorption Inhibitor:
 Ezetimibe (Zetia)
 Inhibits absorption of cholesterol and related sterols from the small intestine
 Results in reduced total cholesterol, LDL, and triglyceride levels
 Also increases HDL levels
 Often combined with a statin drug
 Clinical usefulness has been questioned; new trials underway
Ezetimibe is often used as an adjunct to statin therapy or in statin-intolerant
patients
6- Omega 3 fatty acids
Omega-3 PUFAs can be considered as an adjunct to other lipid-lowering therapies for
individuals with significantly elevated triglycerides (≥500 mg/dL).
 Nursing implication:
 Obtain baseline liver function studies
 Patients on long-term therapy may need supplemental fat-soluble vitamins (A, D, K)
 Take with meals to decrease GI upset
 Counsel patient concerning diet and nutrition on an ongoing basis
 Bile acid sequestrants often come in Powder forms and must be taken with a liquid,
mixed thoroughly but not stirred, and NEVER taken dry, and other medications should
be taken 1 hour before or 4 to 6 hours after meals to avoid interference with absorption
 To minimize adverse effects of niacin, start on low initial dose and gradually increase it,
and take with meals. Small doses of aspirin or NSAIDs may be taken 30 minutes before
niacin to minimize cutaneous flushing
 HMG-CoA reductasebinhibitors should be taken at bed time.
 Monitor for therapeutic effects: Reduced cholesterol and triglyceride levels