CARDIOVASCULAR DRUGS

Asst. Prof. Levent HACISÜLEYMAN

 Drugs Used in Hypertension
Essential hypertension Hypertension of unknown etiology; also called primary hypertension

Secondary hypertension Hypertension caused by a diagnosable abnormality, eg, aortic coarctation, renal artery stenosis, adrenal
tumor, etc. Compare essential hypertension.

Baroreceptor reflex Primary autonomic mechanism for blood pressure homeostasis; involves sensory input from carotid sinus
and aorta to the vasomotor center and output via the parasympathetic and sympathetic motor nerves.

Hypertensive emergency An accelerated form of severe hypertension associated with rising blood pressure and rapidly progressing
(“malignant hypertension”) damage to vessels and end organs. Often signaled by renal damage, encephalopathy, and retinal
hemorrhages or by angina, stroke, or myocardial infarction
Orthostatic hypotension Hypotension on assuming upright posture; postural hypotension

Rebound hypertension Elevated blood pressure (usually above pretreatment levels) resulting from loss of antihypertensive drug
effect

Reflex tachycardia Tachycardia resulting from lowering of blood pressure; mediated by the baroreceptor reflex

Sympatholytic, sympathoplegic Drug that reduces effects of the sympathetic nervous system
 Hypertension
• High blood pressure is a common condition that affects the body's arteries.
• The force of the blood pushing against the artery walls is consistently too high
and the heart has to work harder to pump blood.
• Blood pressure is measured in millimeters of mercury (mm Hg). In general,
hypertension is a blood pressure reading of 130/80 millimeters of mercury (mm
Hg) or higher.
• Blood pressure higher than 180/120 mm Hgis considered a hypertensive emergency
• Untreated, high blood pressure increases the risk of heart attack, stroke and
other serious health problems.
• Most people with high blood pressure have no symptoms, even if blood pressure
readings reach dangerously high levels.
• A few people with high blood pressure may have:
• Headaches
• Shortness of breath
• Nosebleeds
 Drugs Used in Hypertension
• DIURETICS :
• These drugs lower blood pressure by reduction of blood volume.

• The most important diuretics for treating hypertension are the thiazides (eg,
chlorthalidone, hydrochlorothiazide) and the loop diuretics (eg, furosemide).

• Thiazides may be adequate in mild and moderate hypertension

• loop agents are used in severe hypertension and in hypertensive emergencies

Diuretics & Other Drugs
That Act on the Kidney

• The kidney filters plasma water and

solutes at the glomerulus at a very high
rate (180 L/day) and must recover a
significant percentage of most of these
substances before excretion in the
urine.
• Because the mechanisms for
reabsorption of salt and water differ in
each of the 4 major tubular segments,
the diuretics acting in these segments
have differing mechanisms of action.
 CARBONIC ANHYDRASE INHIBITORS
• Acetazolamide is the prototypic agent.
• The mechanism of action is inhibition of carbonic anhydrase in the brush border membranes
and cytoplasm of the proximal tubule cells.
• Bicarbonate itself is poorly reabsorbed through the luminal membrane, but conversion of
bicarbonate to carbon dioxide via carbonic acid permits rapid reabsorption of the carbon
dioxide. Bicarbonate can then be regenerated from carbon dioxide within the tubular.
• The major renal effect is bicarbonate diuresis (ie, sodium bicarbonate is excreted); body
bicarbonate is depleted, and metabolic acidosis results.
• It is used for the diuretic effect only if edema is accompanied by significant metabolic
alkalosis.
• Carbonic anhydrase also plays an important role in the secretion of aqueous humor.
Secretion of bicarbonate into aqueous humor by the ciliary epithelium is also reduced by
Carbonic anhydrase inhibitors.
• Acetazolamide is used parenterally in the treatment of severe acute glaucoma.
Acetazolamide can also be administered orally, but topical analogs are available
(dorzolamide, brinzolamide) for chronic use in the eye.
LOOP DIURETICS
• Furosemide is the prototypical loop agent. Other loop diuretics include
bumetanide, torsemide and ethacrynic acid.
• Loop diuretics inhibit the cotransport of sodium, potassium, and
chloride (NKCC2) in the thick ascending limb of the loop of henle.
• A full dose of a loop diuretic produces a massive sodium chloride
diuresis. Blood volume may be significantly reduced. edema fluid is
rapidly excreted.
• The major application of loop diuretics is
• In the treatment of edematous states eg, heart failure, ascites
(the accumulation of fluid in the peritoneal cavity, causing
abdominal swelling), and acute pulmonary edema.
• They are sometimes used in hypertension if response to thiazides
is inadequate, but the short duration of action of loop diuretics is
a disadvantage in this condition.
THIAZIDE DIURETICS
• Hydrochlorothiazide, the prototypical agent.
• The major action of thiazides is to inhibit sodium chloride
transport in the early segment of the distal convoluted tubule
(NCC).
• In full doses, thiazides produce moderate but sustained sodium
and chloride diuresis.
• The major application of thiazides is in hypertension.
• Chronic therapy is often associated with potassium wasting.
• Diabetic patients may have significant hyperglycemia. Serum
uric acid and lipid levels are also increased in some persons.
POTASSIUM-SPARING DIURETICS
• Cortical collecting tubule is the last tubular site of sodium reabsorption and is controlled by aldosterone, a
steroid hormone secreted by the adrenal cortex.
• The reabsorption of sodium occurs via the epithelial sodium ion channel (ENaC) and is accompanied by loss
of potassium or hydrogen ions.
• Spironolactone and eplerenone are steroid derivatives and act as pharmacologic antagonists of aldosterone
in the collecting tubules.
• Amiloride and triamterene act by blocking the ENaC sodium channels.
• All drugs in this class cause an increase in sodium clearance and a decrease in potassium ion excretion.
• Clinical Uses:
• Potassium wasting caused by chronic therapy with loop or thiazide diuretics, if not controlled by
dietary potassium supplements.
• Aldosteronism (elevated serum aldosterone levels that occur in cirrhosis and heart failure).
• The most important toxic effect of potassium-sparing diuretics is hyperkalemia.
• Other aldosterone antagonists (eg, angiotensin [ACE] inhibitors and angiotensin receptor blockers [ARBs]), if
used at all, should be used with caution.
OSMOTIC DIURETICS
• Mannitol, the prototypical osmotic diuretic, is given intravenously.
• Because they are freely filtered at the glomerulus but poorly reabsorbed
from the tubule, they remain in the lumen and “hold” water via their
osmotic effect.
• The volume of urine is increased. Most filtered solutes ,including sodium,
are excreted in larger amounts because the rate of urine flow through the
tubule is greatly accelerated.
• Mannitol can also reduce brain volume and intracranial pressure by
osmotically extracting water from the tissue into the blood. A similar effect
occurs in the eye.
• Clinical Use:
• to maintain high urine flow (eg, when renal blood flow is reduced and in conditions
of solute overload.
• in reducing intraocular pressure in acute glaucoma.
• in reducing intracranial pressure in neurologic conditions.
ANTIDIURETIC HORMONE AGONISTS & ANTAGONISTS

• Antidiuretic hormone (ADH) and desmopressin are prototypical ADH

agonists. They are peptides and must be given parenterally.
• ADH facilitates water reabsorption from the collecting tubule by activation
of V2 receptors.
• ADH and desmopressin reduce urine volume and increase its
concentration. ADH and desmopressin are useful in pituitary diabetes
insipidus (caused by a problem with vasopressin (ADH) production in the
pituitary gland).
• Conivaptan and tolvaptan are ADH antagonists.
• ADH antagonists oppose the actions of ADH and other naturally occurring
peptides that act on the same V2 receptor. Such peptides are produced by
certain tumors (eg, small cell carcinoma of the lung) and can cause
significant water retention and dangerous hyponatremia.
• SYMPATHOPLEGICS
1. Sympathoplegics That Act in the Central Nervous System:
• Alpha2-selective agonists (eg, clonidine, methyldopa) cause a decrease in sympathetic
outflow by activation of α2 receptors in the CNS.
• These drugs readily enter the CNS when given orally.
• Methyldopa is a prodrug; it is transported into the brain and then converted to
methylnorepinephrine.
• Clonidine and methyldopa reduce blood pressure by reducing cardiac output, vascular
resistance, or both.
• Methyldopa is safe and preferred for hypertension in pregnancy.
2. Adrenoceptor Blockers:
• Alpha1-selective agents (eg, prazosin, doxazosin, terazosin)
• They reduce vascular resistance and venous return.
• They do, however, cause orthostatic hypotension, especially with the first few doses.
• Beta blockers
• Propranolol is the prototype, and atenolol, metoprolol, and carvedilol are among the most popular.
• They initially reduce cardiac output
• In chronic use their action may include a decrease in vascular resistance as a contributing effect as a
result of reduced angiotensin levels (β blockers reduce renin release from the kidney).
• Nebivolol is a newer β blocker with some direct vasodilator action caused by nitric oxide release.
• VASODILATORS:
Vasodilators act by four major mechanisms: blockade of calcium channels,
release of nitric oxide, opening of potassium channels (which leads to
hyperpolarization), and activation of D1 dopamine receptors.
A. Calcium Channel-Blocking Agents:
• Calcium channel blockers (eg, nifedipine, amlodipine, felodipine, verapamil, diltiazem) are
effective vasodilators, orally active and therefore suitable for chronic use in hypertension of
any severity.
• Verapamil and diltiazem also reduce cardiac output in most patients.
B. Hydralazine and Minoxidil:
• They are orally active and suitable for chronic therapy.
• Hydralazine apparently acts through the release of nitric oxide from endothelial cells.
• Minoxidil is a potassium channel opener that hyperpolarizes and relaxes vascular smooth
muscle.
• They cause significant baroreceptor homeostatic responses and must be combined with other
drugs, usually diuretics and β blockers.
• Because it can cause hirsutism, minoxidil is also available as a topical agent for the treatment
of baldness.
C. Nitroprusside, Diazoxide, and Fenoldopam:
• These parenteral vasodilators are used in hypertensive
emergencies.
• Nitroprusside: is a short-acting agent (duration of action is a
few minutes) that must be infused continuously. The release
of nitric oxide (from the drug molecule itself) stimulates
guanylyl cyclase and increases cyclic guanine monophosphate
(cGMP) concentration and relaxation in vascular smooth
muscle.
• Diazoxide: is given as intravenous boluses or as an infusion
and has several hours’ duration of action. Diazoxide opens
potassium channels, thus hyperpolarizing and relaxing
smooth muscle cells. This drug also reduces insulin release
and can be used to treat hypoglycemia caused by insulin-
producing tumor.
• Fenoldopam: activates dopamine D1 receptor causing
marked arteriolar vasodilation. This drug is given by
intravenous infusion. It has a short duration of action (10
min).
• ANGIOTENSIN ANTAGONISTS & A RENIN INHIBITOR
All these drugs cause fetal renal toxicity and are thus contraindicated in
pregnancy
A. ACE inhibitors (ACEIs) (eg, captopril, Enalapril, Lisinopril):
• ACEIs inhibit angiotensin-converting enzyme, causing a reduction in blood levels of
angiotensin II and aldosterone and an increase in endogenous vasodilators of the kinin
family (bradykinin).
• The toxicities of ACE inhibitors include cough (up to 30% of patients), hyperkalemia, and
renal damage in occasional patients with preexisting renal vascular disease.
B. Angiotensin II receptor blockers (ARBs) (losartan, valsartan, irbesartan,
candesartan):
• ARBs competitively inhibit angiotensin II at its AT1 receptor site.
• have the advantage of a lower incidence of cough, although they do cause hyperkalemia.
C. Aliskiren:
• inhibits renin’s action on its substrate, angiotensinogen. It thus reduces the formation of
angiotensin I and, in consequence, angiotensin II.
• Angiotensin II is a major
stimulant of aldosterone
release.
• Aldosterone release causes
sodium and water retention,
which causes increased blood
volume, and a subsequent
increase in blood pressure. It
also increases the amount of
potassium released in your
urine.
 Drugs Used in the Treatment of Angina Pectoris
• Angina pectoris refers to a strangling or pressure-like pain caused by cardiac ischemia.
• The pain is usually located substernally but is sometimes perceived in the neck, shoulder and arm, or epigastrium.
• Drugs used in angina exploit two main strategies: reduction of oxygen demand and increase of oxygen delivery to the myocardium.
 PATHOPHYSIOLOGY OF ANGINA
• Atherosclerotic angina (angina of effort or classic angina):
• It is associated with atheromatous plaques that partially occlude one or more
coronary arteries.
• When cardiac work increases (eg, in exercise), the obstruction of flow and
inadequate oxygen delivery results in the accumulation of metabolites, eg, lactic
acid, and ischemic changes that stimulate myocardial pain endings.
• Rest usually leads to complete relief of the pain within 15 min.
• Atherosclerotic angina constitutes about 90% of angina cases.
• Vasospastic angina (rest angina, variant angina, or Prinzmetal’s angina):
• It involves reversible spasm of coronaries, usually at the site of an atherosclerotic
plaque.
• Spasm may occur at any time, even during sleep.
• Unstable angina (acute coronary syndrome):
• It is characterized by increased frequency and severity of attacks that result from a
combination of atherosclerotic plaques, platelet aggregation at fractured plaques,
and vasospasm.
• Unstable angina is thought to be the immediate precursor of a myocardial infarction
and is treated as a medical emergency.
DETERMINANTS OF CARDIAC OXYGEN REQUIREMENT

• Intramyocardial fiber tension: Force exerted by

myocardial fibers, especially ventricular fibers at any
given time; a primary determinant of myocardial O2
requirement
• Preload: Filling pressure of the heart, dependent on
venous tone and blood volume; determines end-
diastolic fiber length and tension.
• Afterload: Impedance to ejection of stroke volume;
determined by vascular resistance (arterial blood
pressure) and arterial stiffness; determines systolic
fiber tension.
 THERAPEUTIC STRATEGIES
• Traditional pharmacologic therapies include the nitrates, the calcium
channel blockers, and the β blockers.
• all reduce the oxygen requirement in atherosclerotic angina.
• Nitrates and calcium channel blockers (but not β blockers) can also
increase oxygen delivery by reducing spasm in vasospastic angina.
• Myocardial revascularization corrects coronary obstruction either by
bypass grafting or by angioplasty (enlargement of the coronary lumen
by means of a special catheter).
• Therapy of unstable angina also includes platelet inhibitors.
• NITRATES (Nitroglycerin, Isosorbide dinitrate, Isosorbide
mononitrate):
• Nitroglycerin is available in forms that provide a range of durations of
action from 10–20 min (sublingual for relief of acute attacks) to 8–10 h
(transdermal for prophylaxis).
• Isosorbide dinitrate is available in sublingual and oral forms.
• Isosorbide mononitrate is available for oral use.
• Nitrates release nitric oxide (NO) within smooth muscle cells. NO
stimulates soluble (cytoplasmic) guanylyl cyclase and causes an increase
of cGMP (cyclic guanosine monophosphate); the latter results in smooth
muscle relaxation by stimulating the dephosphorylation of myosin light-
chain phosphate.
• Mechanism of Action:
• The primary mechanism of therapeutic benefit in atherosclerotic angina is
reduction of the oxygen requirement;
• By reduced preload from venodilation, which results in reduced cardiac size and cardiac
output.
• And reduced afterload, from arteriolar dilation of resistance vessels which contributes
to an increase in ejection and a further decrease in cardiac size.
• A secondary mechanism is by relaxation of arterial smooth muscle which may
increase flow through partially occluded epicardial coronary vessels.
• Toxicity of Nitrates: The most common toxic effects of nitrates are the
responses evoked by vasodilation.
• tachycardia (from the baroreceptor reflex)
• dizziness from orthostatic hypotension (a direct extension of the venodilator
effect)
• throbbing headache from meningeal artery vasodilation.
• CALCIUM CHANNEL-BLOCKING DRUGS:
• nifedipine, a dihydropyridine, several other dihydropyridines, and the
nondihydropyridines diltiazem and verapamil.
• Calcium channel blockers block voltage-gated L-type calcium channels, the
calcium channels most important in cardiac and smooth muscle and reduce
intracellular calcium concentration and muscle contractility.
• Calcium blockers are effective as prophylactic therapy in both effort and
vasospastic angina.
• Toxicity: The calcium channel blockers cause constipation, pretibial edema,
nausea, flushing, and dizziness. More serious adverse effects include heart
failure, AV blockade.
• BETA-BLOCKING DRUGS:
• Because they reduce cardiac work (and oxygen demand), all β blockers
are effective in the prophylaxis of atherosclerotic angina attack.
• Beta blockers are used only for prophylactic therapy of angina; they are
of no value in an acute attack.
• They are effective in preventing exercise-induced angina but are
ineffective against the vasospastic form.
• The combination of β blockers and nitrates is useful because the
undesirable compensatory effects evoked by the nitrates (tachycardia
and increased cardiac force) are prevented or reduced by β blockade.
 Drugs Used in Heart Failure
• Heart failure results when cardiac output is inadequate for the needs
of the body.
• the major manifestations are dyspnea (Shortness of breath) and
fatigue.
• It is frequently associated with chronic hypertension, valvular disease,
coronary artery disease, and a variety of cardiomyopathies.
• The natural history of heart failure is characterized by a slow
deterioration of cardiac function, punctuated by episodes of acute
cardiac decompensation that are often associated with pulmonary or
peripheral edema or both (congestive heart failure).
 THERAPEUTIC STRATEGIES
• Pharmacologic therapies for heart failure include:
• removal of retained salt and water with diuretics.
• reduction of afterload and salt and water retention by means of angiotensin-
converting enzyme (ACE) inhibitors.
• reduction of excessive sympathetic stimulation by means of β blockers.
• reduction of preload or afterload with vasodilators.
• and in systolic failure, direct augmentation of depressed cardiac contractility with
positive inotropic drugs such as digitalis glycosides.
• Acute heart failure should be treated with a loop diuretic; if severe, a
prompt-acting positive inotropic agent such as a β agonist or
phosphodiesterase inhibitor, and vasodilators should be used as required
to optimize filling pressures and blood pressure.
• Chronic failure is best treated with diuretics (often a loop agent plus
spironolactone) plus an ACE inhibitor and, if tolerated, a β blocker. Digitalis
may be helpful if systolic dysfunction is prominent.
• Diuretics:
• Diuretics are the first-line therapy for both systolic and diastolic failure.
• Furosemide is a very useful agent for immediate reduction of the pulmonary
congestion and severe edema associated with acute heart failure and for
moderate or severe chronic failure.
• Thiazides such as hydrochlorothiazide are sometimes sufficient for mild chronic
failure.
• Clinical studies suggest that, unlike other diuretics, spironolactone and eplerenone
(aldosterone antagonist diuretics) have significant long-term benefits and can
reduce mortality in chronic failure.
• Angiotensin Antagonists:
• angiotensin antagonists are now considered, along with diuretics, to be first-line
drugs or chronic heart failure.
• They reduce aldosterone secretion, salt and water retention, and vascular
resistance.
• The angiotensin receptor blockers (ARBs, eg, losartan) appear to have the same
benefits as ACE inhibitors (eg, captopril).
• Beta-Adrenoceptor Antagonists:
• Several β blockers (carvedilol, labetalol, metoprolol) have been shown in long-
term studies to slow progression of chronic heart failure.
• Beta blockers are of no value in acute failure and may be detrimental if
systolic dysfunction is marked.
• Beta1-Adrenoceptor Agonists:
• Dobutamine and dopamine are often useful in acute failure in which systolic
function is markedly depressed.
• Phosphodiesterase Inhibitors:
• Milrinone is the major representative of this infrequently used group.
• These drugs increase cyclic adenosine monophosphate (cAMP) by inhibiting its
breakdown by phosphodiesterase and cause an increase in cardiac intracellular
calcium similar to that produced by β-adrenoceptor agonists.
• Phosphodiesterase inhibitors also cause vasodilation, which may be responsible for a
major part of their beneficial effect.
• Vasodilators:
• Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe
failure with congestion.
• The natriuretic peptide nesiritide acts chiefly by causing vasodilation. It is given by IV
infusion for acute failure only.
• Chronic heart failure sometimes responds favorably to oral vasodilators such as
hydralazine or isosorbide dinitrate (or both).
CARDIAC GLYCOSIDES
• Mechanism of Action: Inhibition of Na+ /K+ ATPase which results in a small increase in
intracellular sodium. The increased sodium alters the driving force for sodium-calcium
exchange by the exchanger, NCX, so that less calcium is removed from the cell. The
increased intracellular calcium is stored in the sarcoplasmic reticulum and upon release
increases contractile force and cardiac output.
• Digoxin is the prototype agent
• Digoxin has vagomimetic effects on the AV node. By stimulating the parasympathetic
nervous system, it slows electrical conduction in the atrioventricular node,
therefore, decreasing the heart rate.
• Clinical Uses:
• Congestive heart failure: clinical studies indicate that while digitalis may improve
functional status (reducing symptoms), it does not prolong life like the other
agents (diuretics, ACE inhibitors, vasodilators) do.
• Atrial fibrillation: In atrial flutter and fibrillation, it is desirable to reduce the
conduction velocity of the AV node so that ventricular rate is controlled.
• Digitalis Toxicity:
• The major signs of digitalis toxicity are arrhythmias, nausea, vomiting, and
diarrhea.