• Hypertension is defined as either a sustained systolic blood
pressure of greater than 140 mm Hg or a sustained diastolic
blood pressure of greater than 90 mm Hg.
• Hypertension results from increased peripheral vascular
arteriolar smooth muscle tone, which leads to increased
arteriolar resistance and reduced capacitance of the venous
system. In most cases, the cause of the increased vascular
tone is unknown.
• Hypertension is also an important risk factor in the development
of chronic kidney disease and heart failure.
• The incidence of morbidity and mortality significantly decreases
when hypertension is diagnosed early and is properly treated.
• In recognition of the progressive nature of hypertension,
hypertension is classified into four categories for the purpose of
ETIOLOGY OF HYPERTENSION
• Although hypertension may occur secondary to other disease
processes, more than 90% of patients have essential
hypertension (hypertension with no identifiable cause).
• A family history of hypertension increases the likelihood that
an individual will develop hypertension.
• The prevalence of hypertension increases with age, but
decreases with education and income level.
• Non-Hispanic blacks have a higher incidence of hypertension
than do both non-Hispanic whites and Hispanic whites.
• Persons with diabetes, obesity, or disability status are all more
likely to have hypertension than those without.
• In addition, environmental factors, such as a stressful lifestyle,
high dietary intake of sodium, and smoking, may further
predispose an individual to hypertension.
Blood Pressure Regulating Mechanisms
1.Short Term (Nervous System works within few
Chemoreceptors CNS Ischemic Response
2.Long Term (Renal Control works within few
3.Intermediate (Within few hours) Stress
relaxation Capillary fluid shift
• For most patients, the blood pressure goal when treating hypertension is a
systolic blood pressure of less than 140 mm Hg and a diastolic blood
pressure of less than 90 mmHg.
• Mild hypertension can sometimes be controlled with monotherapy, but
most patients require more than one drug to achieve blood pressure
control. Current recommendations are to initiate therapy with a thiazide
diuretic, ACE inhibitor, angiotensin receptor blocker (ARB), or calcium
• If blood pressure is inadequately controlled, a second drug should be
added, with the selection based on minimizing the adverse effects of the
combined regimen and achieving goal blood pressure.
• Patients with systolic blood pressure greater than 160 mm Hg or diastolic
• Thiazide diuretics: Thiazide diuretics, such as hydrochlorothiazide and
chlorthalidone, lower blood pressure initially by increasing sodium and water
excretion. This causes a decrease in extracellular volume, resulting in a
decrease in cardiac output and renal blood flow. With long-term treatment,
plasma volume approaches a normal value, but a hypotensive effect persists
that is related to a decrease in peripheral resistance.
• Loop diuretics: The loop diuretics (furosemide, torsemide, bumetanide, and
ethacrynic acid) act promptly by blocking sodium and chloride reabsorption
in the kidneys, even in patients with poor renal function or those who have
not responded to thiazide diuretics. Loop diuretics cause decreased renal
vascular resistance and increased renal blood flow.
• Potassium-sparing diuretics: Amiloride, triamterene ,spironolactone and
eplerenone reduce potassium loss in the urine. Potassium-sparing diuretics
• β-Blockers are a treatment option for hypertensive patients with concomitant
heart disease or heart failure. M/A:
• Selective: metoprolol, atenolol and nebivolol,esmolol
• Nonselective β-blockers: propranolol, nadolol.
• The selective β-blockers may be administered cautiously to hypertensive
patients who also have asthma. The nonselective β-blockers, such as
propranolol and nadolol, are contraindicated in patients with asthma due to
• Therapeutic uses:The primary therapeutic benefits of β-blockers are
seen in hypertensive patients with concomitant heart disease, such as
supraventricular tachyarrhythmia (for example, atrial fibrillation), previous
myocardial infarction, angina pectoris, and chronic heart failure.
• Contraindication: Conditions that discourage the use of β-blockers
include reversible bronchospastic disease such as asthma, second- and
third-degree heart block, and severe peripheral vascular disease.
• Adverse effects
• 1. Common effects: The β-blockers may cause bradycardia,
• and CNS side effects such as fatigue, lethargy, and insomnia. The β-
blockers may decrease libido and cause erectile dysfunction, which can
severely reduce patient compliance.
• 2. Alterations in serum lipid patterns: Noncardioselective
• β-blockers may disturb lipid metabolism, decreasing high-density
lipoprotein cholesterol and increasing triglycerides.
• 3. Drug withdrawal: Abrupt withdrawal may induce angina, myocardial
infarction, and even sudden death in patients with ischemic heart
• The ACE inhibitors, such as enalapril and lisinopril, are
recommended as first-line treatment of hypertension in patients with
a variety of compelling indications, including high coronary disease
risk or history of diabetes, stroke, heart failure, myocardial infarction,
or chronic kidney disease.
The ACE inhibitors lower blood pressure by reducing peripheral
vascular resistance without reflexively increasing cardiac output,
heart rate, or contractility.
These drugs block the enzyme ACE that cleaves angiotensin I to
form the potent vasoconstrictor angiotensin II.
ACE inhibitors decrease angiotensin II and increase bradykinin
levels which interm increase the production of nitric oxide and
prostacyclin both of which are potent vasodilators.
Vasodilation of both arterioles and veins occurs as a result of
decreased vasoconstriction (from diminished levels of angiotensin II)
and enhanced vasodilation (from increased bradykinin).
• Therapeutic uses: ACE inhibitors are first-line drugs for treating
heart failure, hypertensive patients with chronic kidney disease, and
patients at increased risk of coronary artery disease.
• ACE inhibitors slow the progression of diabetic nephropathy and
decrease albuminuria and, thus, have a compelling indication for use
in patients with diabetic nephropathy.
• Adverse effects : Common side effects include dry cough, rash,
fever, altered taste, hypotension (in hypovolemic states), and
hyperkalemia. Angioedema, ACE inhibitors can induce fetal
malformations and should not be used by pregnant women.
• ***The dry cough, which occurs in up to 10% of patients, is thought to
be due to increased levels of bradykinin and substance P in the
ANGIOTENSINII RECEPTOR BLOCKERS
• The ARBs, such as losartan and irbesartan, are alternatives to the ACE
• These drugs block the AT1 receptors, decreasing the activation of AT1
receptors by angiotensin II.
• Their pharmacologic effects are similar to those of ACE inhibitors in that they
produce arteriolar and venous dilation and block aldosterone secretion,thus
lowering blood pressure and decreasing salt and water retention. ARBs do
not increase bradykinin levels.
• They may be used as first-line agents for the treatment of hypertension,
especially in patients with a compelling indication of diabetes, heart failure,
or chronic kidney disease.
• Adverse effects are similar to those of ACE inhibitors, although the risks of
• A selective renin inhibitor, aliskiren, is available for the
treatment of hypertension.
• Aliskiren directly inhibits renin and, thus, acts earlier in the
renin–angiotensin–aldosterone system than ACE inhibitors or
• It lowers blood pressure about as effectively as ARBs, ACE
inhibitors, and thiazides.
• Aliskiren should not be routinely combined with an ACE
inhibitor or ARB.
• Aliskiren can cause diarrhea, especially at higher doses, and
Calcium Channel Blockers
• Calcium channel blockers are a recommended treatment option in
hypertensive patients with diabetes or angina.
• High doses of short-acting calcium channel blockers should be avoided
because of increased risk of myocardial infarction due to excessive
vasodilation and marked reflex cardiac stimulation.
• Classes of calcium channel blockers
• 1. Diphenylalkylamines: Verapamil is the least selective of any calcium
channel blocker and has significant effects on both cardiac and vascular
smooth muscle cells. It is also used to treat angina and supraventricular
tachyarrhythmias and to prevent migraine and cluster headaches.
• 2. Benzothiazepines: Diltiazem;Like verapamil, diltiazem affects both
cardiac and vascular smooth muscle cells, but it has a less pronounced
negative inotropic effect on the heart compared to that of verapamil.
Diltiazem has a favorable side effect profile.
• 3. Dihydropyridines:Nifedipine ,amlodipine , felodipine, isradipine,
nicardipine, and nisoldipine. All have a much greater affinity for vascular
calcium channels than for calcium channels in the heart. They are, therefore,
particularly beneficial in treating hypertension.
• Have the advantage in that they show little interaction with
CALCIUM CHANNEL BLOCKERS
• Actions: Calcium channel antagonists block the inward movement of
calcium by binding to L-type calcium channels in the heart and in smooth
muscle of the coronary and peripheral arteriolar vasculature. This causes
vascular smooth muscle to relax, dilating mainly arterioles. Calcium channel
blockers do not dilate veins.
• Therapeutic uses: In the management of hypertension, as an initial therapy
or as add-on therapy. They are useful in the treatment of hypertensive
patients who also have asthma, diabetes, and/or peripheral vascular
disease, because unlike β-blockers, they do not have the potential to
adversely affect these conditions. All CCBs are useful in the treatment of
angina. In addition, diltiazem and verapamil are used in the treatment of
• Adverse effects
• First-degree atrioventricular block and constipation are common dose
dependent side effects of verapamil.
• Verapamil and diltiazem should be avoided in patients with heart failure or
with atrioventricular block due to their negative inotropic and dromotropic
• Dizziness, headache, and a feeling of fatigue caused by a decrease in blood
pressure are more frequent with dihydropyridines.
α -& α-/β- ADRENOCEPTOR–BLOCKINGAGENTS
• α-ADRENOCEPTOR–BLOCKING AGENTS
• Prazosin, doxazosin, and terazosin produce a competitive block of
• They decrease peripheral vascular resistance and lower arterial
blood pressure by causing relaxation of both arterial and venous
• These drugs cause only minimal changes in cardiac output, renal
blood flow, and glomerular filtration rate. Therefore, long-term
tachycardia does not occur, but salt and water retention does.
• Reflex tachycardia and postural hypotension often occur at the onset
of treatment and with dose increases, requiring slow titration of the
drug in divided doses.
• α-/β-ADRENOCEPTOR–BLOCKING AGENTS
• Labetalol and carvedilol block α1, β1, and β2 receptors.
• Carvedilol, although an effective antihypertensive, is mainly used in
the treatment of heart failure.
CENTRALLY ACTINGADRENERGIC DRUGS
• A. Clonidine
• Clonidine acts centrally as an α2 agonist to produce inhibition
of sympathetic vasomotor centers, decreasing sympathetic
outflow to the periphery. This leads to reduced total peripheral
resistance and decreased blood pressure.
• Clonidine is used primarily for the treatment of hypertension
that has not responded adequately to treatment with two or
• Adverse effects include sedation, dry mouth, and constipation.
• Rebound hypertension occurs following abrupt withdrawal of
clonidine. The drug should, therefore, be withdrawn slowly if
discontinuation is required.
• Methyldopa is an α2 agonist that is converted to
methylnorepinephrine centrally to diminish adrenergic outflow
from the CNS.
• The direct-acting smooth muscle relaxants, such as hydralazine and
minoxidil, are not used as primary drugs to treat hypertension. These
vasodilators act by producing relaxation of vascular smooth muscle,
primarily in arteries and arterioles. This results in decreased
peripheral resistance and, therefore, blood pressure.
• Hydralazine is an accepted medication for controlling blood pressure
in pregnancy induced hypertension.
• Adverse effects of hydralazine include headache, tachycardia,
nausea, sweating, arrhythmia, and precipitation of angina. A lupus-
like syndrome can occur with high dosages, but it is reversible upon
discontinuation of the drug.
• Minoxidil treatment causes hypertrichosis. This drug is used topically
• Hypertensive emergency is a rare but life-
threatening situation characterized by severe
elevations in blood pressure 120/180 with
evidence of impending or progressive target
organ damage (for example, stroke, myocardial
• Hypertensive emergencies require timely blood
pressure reduction with treatment administered
intravenously to prevent or limit target organ
• A variety of medications are used, including
calcium channel blockers, nitric oxide
vasodilators, adrenergic receptor antagonists, the
RESISTANTHYPERTENSION& COMBINATION THERAPY
• RESISTANT HYPERTENSION
• Resistant hypertension is defined as blood pressure that remains elevated
(above goal) despite administration of an optimal three-drug regimen that
includes a diuretic.
• The most common causes of resistant hypertension are:
• poor compliance,
• excessive ethanol intake,
• concomitant conditions (diabetes, obesity, sleep apnea, hyperaldosteronism,
high salt intake, and/or metabolic syndrome),
• concomitant medications (sympathomimetics, nonsteroidal anti-inflammatory
drugs, or antidepressant medications),
• Insufficient dose and/or drugs, and use of drugs with similar mechanisms of
• COMBINATION THERAPY
• Combination therapy with separate agents or a fixed-dose combination pill
may lower blood pressure more quickly with minimal adverse effects.
• Initiating therapy with two antihypertensive drugs should be considered in
patients with blood pressures that are more than 20/10 mm Hg above the
• Diuretics are most commonly used for management of abnormal fluid
retention or treatment of hypertension.
• A. Thiazides: Chlorothiazide, hydrochlorothiazide
• Mechanism of action: The thiazide and thiazide-like diuretics act
mainly in the cortical region of the ascending loop of Henle and the
distal convoluted tubule to decrease the reabsorption of Na+,
apparently by inhibition of a Na+/Cl− cotransporter on the luminal
membrane of the tubules thus increase excretion of Na+ and Cl- .
• a. Increased excretion of Na+ and Cl−,
• b. Loss of K+
• c. Loss of Mg2+
• d. Decreased urinary calcium excretion,
• e. Reduced peripheral vascular resistance
• Therapeutic uses:
• Hypertension: The antihypertensive actions of angiotensin-converting enzyme
inhibitors are enhanced when given in combination with the thiazides.
• Heart failure: Along with loop diuretics if needed. When given in
combination, thiazides should be administered 30 minutes prior to loop diuretics
in order to allow the thiazide time to reach the site of action and produce effect.
• Hypercalciuria: Particularly beneficial for patients with calcium oxalate stones
in the urinary tract.
• Diabetes insipidus: Thiazides can substitute for ADH in the treatment of
nephrogenic diabetes insipidus.
• Potassium depletion: Hypokalemia is the most frequent problem with the
thiazide diuretics, and it can predispose patients who are taking digoxin to
ventricular arrhythmias . Often, K+ can be supplemented by dietary measures
such as increasing the consumption of citrus fruits, bananas, and prunes.
• Hyponatremia: Hyponatremia may develop due to elevation of ADH as a result
• Volume depletion
• Hyperglycemia: Therapy with thiazides can lead to glucose intolerance,
Loop Or High-ceiling Diuretics
• Bumetanide, furosemide , torsemide and ethacrynic acid have
their major diuretic action on the ascending limb of the loop of
• Mechanism of action:
• Loop diuretics inhibit the cotransport of Na+/K+/2Cl− in the
luminal membrane in the ascending limb of the loop of Henle.
Therefore, reabsorption of these ions is decreased.
• Therapeutic uses:
• 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. Loop diuretics (along
with hydration) are also useful in treating hypercalcemia, and
• Adverse effects:Ototoxicity, Hyperuricemia, Acute
hypovolemia, Potassium depletion, Hypomagnesemia
• Potassium-sparing diuretics act in the collecting tubule to inhibit Na+
reabsorption and K+ excretion. The major use of potassium sparing agents is in
the treatment of hypertension (most often in combination with a thiazide) and in
• A. Aldosterone antagonists: spironolactone and eplerenone:
• Mechanism of action: Spironolactone decreases mediator proteins production
thus prevents Na+ reabsorption and, therefore,K+ and H+ secretion. Eplerenone
is another aldosterone receptor antagonist, which has actions comparable to
those of spironolactone, although it may have less endocrine effects than
• Therapeutic uses: Diuretic, Secondary hyperaldosteronism, Heart failure,
Resistant hypertension, Ascites, Polycystic ovary syndrome.
• Adverse effects: Spironolactone can cause gastric upset.
• May induce gynecomastia in male patients and menstrual irregularities in female
• Hyperkalemia, nausea, lethargy, and mental confusion can occur.
• B.Triamterene and amiloride
CARBONIC ANHYDRASE INHIBITOR
Acetazolamide:Acetazolamide inhibits carbonic
anhydrase thus decreases ability to exchange Na+
for H+ results in a mild diuresis.
• Therapeutic uses:
• a. Glaucoma: Acetazolamide decreases the
production of aqueous humor and reduces
intraocular pressure in patients with chronic open-
• b. Mountain sickness: Acetazolamide can be
used in the prophylaxis of acute mountain
• Adverse effects: Metabolic acidosis (mild),
• A number of simple, hydrophilic chemical substances that are
filtered through the glomerulus.Filtered substances that
undergo little or no reabsorption will cause an increase in
• The presence of these substances results in a higher
osmolarity of the tubular fluid and prevents further water
reabsorption, resulting in osmotic diuresis.
• They are used to maintain urine flow following acute toxic
ingestion of substances capable of producing acute renal
failure. Osmotic diuretics are a mainstay of treatment for
patients with increased intracranial pressure or acute renal
• Heart failure (HF) is a complex, progressive disorder in which the
heart is unable to pump sufficient blood to meet the needs of the
• Its cardinal symptoms are dyspnea, fatigue, and fluid retention.
• Underlying causes of HF include arteriosclerotic heart disease,
myocardial infarction,hypertensive heart disease, valvular heart
disease, dilated cardiomyopathy, and congenital heart disease.
• Role of physiologic compensatory mechanisms in the progression
• Chronic activation of the sympathetic nervous system and the
renin–angiotensin–aldosterone system is associated with
remodeling of cardiac tissue, loss of myocytes, hypertrophy, and
Goals of pharmacologicintervention in HF
• Goals of treatment are to alleviate symptoms, slow disease progression,and improve
• Accordingly, seven classes of drugs have been shown to be effective:
• 1) angiotensin-converting enzyme inhibitors,
• 2) angiotensin-receptor blockers,
• 3) aldosterone antagonists,
• 4) β-blockers,
• 5) diuretics,
• 6) direct vaso- and venodilators, and
• 7) inotropic agents .
• Depending on the severity of HF and individual patient factors, one or more of these
classes of drugs are administered.
• Pharmacologic intervention provides the following benefits in HF:
reduced myocardial work load, decreased extracellular fluid volume,
improved cardiac contractility, and a reduced rate of cardiac remodeling.
• Therapeutic strategies in HF
Chronic HF is typically managed by fluid limitations (less than 1.5 to 2 L daily);
low dietary intake of sodium (less than 2000 mg/d); treatment of comorbid conditions;
and judicious use of diuretics, inhibitors of the renin–angiotensin–aldosterone system,
and inhibitors of the sympathetic nervous system.
Inotropic agents are reserved for acute HF signs and symptoms in mostly the inpatient
Inhibitors Of The Renin–angiotensin–aldosterone System
• HF leads to activation of the renin–angiotensin–aldosterone system via two
• 1) increased renin release by juxtaglomerular cells in renal afferent
arterioles due to diminished renal perfusion pressure produced by the failing
• 2) renin release by juxtaglomerular cells promoted by sympathetic
stimulation and activation of β receptors.
• The production of angiotensin II, a potent vasoconstrictor, and the
subsequent stimulation of aldosterone release that causes salt and water
retention lead to increases in both preload and afterload that are
characteristic of the failing heart.
• A. Angiotensin-converting enzyme inhibitors: See previous slide.
• B. Angiotensin receptor blockers : See previous slide.
• Aldosterone antagonists
• Patients with advanced heart disease have elevated levels of aldosterone
due to angiotensin II stimulation and reduced hepatic clearance of the
hormone. Spironolactone is a direct antagonist of aldosterone, thereby
preventing salt retention, myocardial hypertrophy, and hypokalemia.
• Eplerenone is a competitive antagonist of aldosterone at mineralocorticoid
• Improved systolic functioning and reverse cardiac remodeling in
HF patients have been observed for 𝝱-blockers. These agents
decrease heart rate and inhibit release of renin in the kidneys.
In addition, β-blockers prevent the deleterious effects of
norepinephrine on the cardiac muscle fibers, decreasing
remodeling, hypertrophy, and cell death.
• Three β-blockers have shown benefit in HF: bisoprolol,
carvedilol and long-acting metoprolol succinate. They reduce
morbidity and mortality associated with HFrEF. Treatment
should be started at low doses and gradually titrated totarget
doses based on patient tolerance and vital signs.
• Diuretics relieve pulmonary congestion
and peripheral edema.This decreases
cardiac workload and oxygen demand.
• Diuretics may also decrease afterload by
reducing plasma volume, thereby
decreasing blood pressure.
• Loop diuretics are the most commonly
used diuretics in HF. These agents are
used for patients who require extensive
diuresis and those with renal insufficiency.
VASO- AND VENODILATORS
• Dilation of venous blood vessels leads to a decrease in cardiac
preload by increasing venous capacitance.
• Nitrates are commonly used venous dilators to reduce preload
for patients with chronic HF.
• Arterial dilators, such as hydralazine reduce systemic arteriolar
resistance and decrease afterload.
• 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 fixed-dose combination of these agents has been shown to
improve symptoms and survival in black patients with HFrEF on
standard HF treatment (β-blocker plus ACE inhibitor or ARB).
• Headache, hypotension, and tachycardia are common adverse
effects with this combination.
• Rarely, hydralazine has been associated with drug-induced
Positive inotropic agents enhance cardiac contractility and, thus, increase
cardiac output. Although these drugs act by different mechanisms, the
inotropic action is the result of an increased cytoplasmic calcium
concentration that enhances the contractility of cardiac muscle.
The cardiac glycosides are often called digitalis or digitalis glycosides, because
most of the drugs come from the digitalis (foxglove) plant. They are a group
of chemically similar compounds that can increase the contractility of the
heart muscle and, therefore, are used in treating HF.
The digitalis glycosides have a low therapeutic index, with only a small
difference between a therapeutic dose and doses that are toxic or even fatal.
The most widely used agent is digoxin . Digitoxin is seldom used due to its
considerable duration of action.
Therapeutic uses: Digoxin therapy is indicated in patients with severe HFrEF
after initiation of ACE inhibitor, β-blocker, and diuretic therapy. A low serum
drug concentration of digoxin (0.5 to 0.8 ng/mL) is beneficial in HFrEF.
• Toxicity:Cardiac effects:
– Severe bradycardia
– Paroxysmal or non-paroxysmal atrial tachycardia
– A-V block due to vagal over-activity.
– Ventricular ectopic—premature beat.
– Ventricular tachycardia or fibrillation.
• Non-cardiac effects:
– Anorexia, nausea, vomiting (CNS effects)
– Visual disturbance
– Very rarely delirium or convulsion
• Features of digitalis poisoning:
• GIT problem—anorexia, nausea, vomiting
• CVS problem—arrhythmia, bradycardia
• CNS problem—visual haloes, hallucination
• Management of digitalis poisoning / Toxicity:
• Stop or correct the dose
• Correct the electrolyte abnormality, that is hypokalemia (K+ therapy can be given)
• Use drug like atropine to ↑ the HR if Bradycardia is present
• Administer digitalis antibody
• To prevent arrhythmia Lidocaine or Phenytoin can be given
• To insert temporary pacemaker
• * Now a days Digitalis antibody (Digibine) is used IV.
At low serum drug concentrations, digoxin is fairly well tolerated.
However, it has a very narrow therapeutic index, and digoxin toxicity
is one of the most common adverse drug reactions leading to
hospitalization. Anorexia, nausea, and vomiting may be initial
indicators of toxicity. Patients may also experience blurred vision,
yellowish vision (xanthopsia), and various cardiac arrhythmias.
Toxicity can often be managed by discontinuing digoxin, determining
serum potassium levels, and, if indicated, replenishing potassium.
Severe toxicity resulting in ventricular tachycardia may require
administration of antiarrhythmic drugs and the use of antibodies to
digoxin (digoxin immune Fab), which bind and inactivate the drug.
Digoxin should also be used with caution with other drugs that slow AV
conduction, such as β-blockers, verapamil, and diltiazem.
B. β-Adrenergic agonists: β-Adrenergic agonists, such as dobutamine
and improve cardiac performance by causing positive inotropic
effects and vasodilation.
C. Phosphodiesterase inhibitors: Milrinone is a phosphodiesterase
ORDER OF THERAPY
• Experts have classified HF into four
stages, from least severe to most severe.
• Dysfunction of impulse generation or conduction at any of a
number of sites in the heart can cause an abnormality in
• Dysfunctions cause abnormalities in impulse formation and
conduction in the myocardium.
• However, in the clinical setting, arrhythmias present as a
complex family of disorders with a variety of symptoms. To
make sense of this large group of disorders, it is useful to
organize the arrhythmias into groups according to the
anatomic site of the abnormality: the atria, the AV node, or
• Causes of arrhythmias
• Most arrhythmias arise either from aberrations in impulse
generation (abnormal automaticity) or from a defect in
• 1. Abnormal automaticity: The SA node normally sets the
pace of contraction for the myocardium. If cardiac sites other
than the SA node show enhanced automaticity, they may
generate competing stimuli,
• and arrhythmias may arise.
• CLASS I (Na+-channel blockers) :
• Disopyramide (IA),Flecainide(IC), Lidocaine (IB),
Mexiletine(IB), Procainamide (IA), Propafenone(IC)
• CLASS II (ß-adrenoreceptor blockers)
• Atenolol, Metoprolol
• CLASS III (K+ channel blockers)
• Amiodarone, Dofetilide , Dronedarone, Ibutilide
• CLASS IV (Ca2+ channel blockers)
• Diltiazem, Verapamil
• OTHER ANTIARRHYTHMIC DRUGS
• Adenosine, Digoxin, Esmolol, Sotalol, Magnesium sulfate
CLASS I ANTIARRHYTHMIC DRUGS
• Class I antiarrhythmic drugs act by blocking voltage-sensitive
Na+channels. The use of Na+channel blockers has declined
due to their proarrhythmic effects, particularly in patients with
reduced left ventricular function and ischemic heart disease.
• Class IA antiarrhythmic drugs Quinidine, procainamide,
and disopyramide:Quinidine binds to open and inactivated
sodium channels and prevents sodium influx, thus slowing the
rapid upstroke during phase 0. It decreases the slope of phase
4 spontaneous depolarization, inhibits potassium channels, and
• Therapeutic uses: Quinidine is used in the treatment of a wide
variety of arrhythmias, including atrial, AV junctional, and
• Adverse effects: Large doses of quinidine may induce the
symptoms of cinchonism (for example, blurred vision, tinnitus,
headache, disorientation, and psychosis). Drug interactions are
common, dry mouth, urinary retention, blurred vision, and
CLASS I ANTIARRHYTHMIC DRUGS
• Class IB antiarrhythmic drugs: Lidocaine and mexiletine are useful
in treating ventricular arrhythmias.
• Mechanism of action: In addition to sodium channel
blockade,lidocaine and mexiletine shorten phase 3 repolarization
anddecrease the duration of the action potential
• Therapeutic uses: lidocaine is used in ventricular fibrillation or
pulseless ventricular tachycardia. Mexiletine is used for chronic
treatment of ventricular arrhythmias, often in combination with
• Adverse effects: Lidocaine causes CNS effects include nystagmus
(early indicator of toxicity), drowsiness, slurred speech, paresthesia,
agitation, confusion, and convulsions, which often limit the duration
of continuous infusions. Mexiletine creates Nausea, vomiting, and
dyspepsia are the most common adverse effects.
• Class IC antiarrhythmic drugs: Flecainide and propafenone:
Propafenone, and flecainide, slow conduction in all cardiac tissues
but does not block potassium channels.
• Adverse effects: Flecainide is generally well tolerated, with
CLASS II ANTIARRHYTHMICDRUGS
• Class II agents are β-adrenergic antagonists, or β-blockers. These drugs
diminish phase 4 depolarization and, thus, depress automaticity, prolong
AV conduction and decrease heart rate and contractility.
• They are useful in treating tachyarrhythmias caused by increased
sympathetic activity. They are also used for atrial flutter and fibrillation
and for AV nodal reentrant tachycardia. In addition, β-blockers prevent
life-threatening ventricular arrhythmias following a myocardial infarction
• Metoprolol is the β-blocker most widely used in the treatment of cardiac
arrhythmias. Compared to nonselective β-blockers, such as propranolol ,
it reduces the risk of bronchospasm.
• Esmolol is a very-short-acting β-blocker used for intravenous
administration in acute arrhythmias that occur during surgery or
emergency situations. It has a fast onset of action and a short half-life,
CLASS III ANTIARRHYTHMIC DRUGS
• Class III agents block potassium channels and, thus, diminish
the outward potassium current during repolarization of
cardiac cells. These agents prolong the duration of the action
potential without altering phase 0 of depolarization or the
resting membrane potential. Instead, they prolong the
effective refractory period, increasing refractoriness. All class
III drugs have the potential to induce arrhythmias.
• A. Amiodarone
• Mechanism of action: Amiodarone has complex effects,
showing class I, II, III, and IV actions, as well as α-blocking
activity. Its dominant effect is prolongation of the action
potential duration and the refractory period by blocking K+
• 2. Therapeutic uses: Amiodarone is effective in the
treatment of severe refractory supraventricular and
ventricular tachyarrhythmias. It has been a mainstay of
therapy for the rhythm management of atrial fibrillation or
CLASS III ANTIARRHYTHMIC DRUGS
• B. Dronedarone: It is less lipophilic, has lower tissue accumulation, and has a
shorter serum half-life than amiodarone. Like amiodarone, it has class I, II, III,
and IV actions. It has a better adverse effect profile than amiodarone but may
still cause liver failure. The drug is contraindicated in those with symptomatic
heart failure or permanent atrial fibrillation due to an increased risk of death.
• C. Sotalol : Sotalol, although a class III antiarrhythmic agent, also has potent
nonselective β-blocker activity. Sotalol blocks a rapid outward potassium
current, known as the delayed rectifier. This blockade prolongs both
repolarization and duration of the action potential, thus lengthening the
effective refractory period. It is used for maintenance of normal sinus rhythm in
patients with atrial fibrillation, atrial flutter, or refractory paroxysmal
supraventricular tachycardia and in the treatment of ventricular arrhythmias.
• D. Dofetilide:Dofetilide is a pure potassium channel blocker. It can be used as
a first-line antiarrhythmic agent in patients with persistent atrial fibrillation and
CLASS IV ANTIARRHYTHMIC DRUGS
• Class IV drugs are the nondihydropyridine calcium channel blockers
Verapamil and diltiazem .
• In the heart, verapamil and diltiazem bind only to open depolarized
voltage-sensitive channels, thus decreasing the inward current
carried by calcium. They prevent repolarization until the drug
dissociates from the channel, resulting in a decreased rate of phase 4
• These drugs are therefore use-dependent. They also slow conduction
in tissues that are dependent on calcium currents, such as the AV and
• These agents are more effective against atrial than against ventricular
• They are useful in treating reentrant supraventricular tachycardia and
in reducing the ventricular rate in atrial flutter and fibrillation.
OTHER ANTIARRHYTHMIC DRUGS
• A. Digoxin
• Digoxin inhibits the Na+/K+-ATPase pump,ultimately shortening
the refractory period in atrial and ventricular myocardial cells while
prolonging the effective refractory period and diminishing
conduction velocity in the AV node.
• Digoxin is used to control ventricular response rate in atrial
fibrillation and flutter; however, sympathetic stimulation easily
overcomes the inhibitory effects of digoxin.
• B. Adenosine
• Adenosine is a naturally occurring nucleoside, but at high doses,
the drug decreases conduction velocity, prolongs the refractory
period, and decreases automaticity in the AV node. Intravenous
adenosine is the drug of choice for abolishing acute
• C. Magnesium sulfate
• Magnesium is necessary for the transport of sodium, calcium, and
• Atherosclerotic disease of the coronary arteries, also known as coronary
artery disease (CAD) or ischemic heart disease (IHD), is the most common
cause of mortality worldwide.
• Typical angina pectoris is a characteristic sudden, severe, crushing chest
pain that may radiate to the neck, jaw, back, and arms. Patients may also
present with dyspnea or atypical symptoms such as indigestion, nausea,
vomiting, or diaphoresis.
• Transient, self-limited episodes of myocardial ischemia (stable angina) do
not result in cellular death; however, acute coronary syndromes and chronic
ischemia can lead to deterioration of cardiac function, heart failure,
arrhythmias, and sudden death.
• All patients with IHD and angina should receive guideline-directed medical
Types Of Angina
• Angina pectoris has three patterns:
• 1) stable, effort-induced, classic, or typical
• 2) unstable angina; and
• 3) Prinzmetal, variant, vasospastic, rest
• They are caused by varying combinations of
increased myocardial demand and
decreased myocardial perfusion.
A. Stableangina, effort-induced angina, classicor typical angina
• Classic angina is the most common form of angina and, therefore, is also called
typical angina pectoris.
• It is usually characterized by a short-lasting burning, heavy, or squeezing feeling
in the chest.
• Some ischemic episodes may present “atypically”—with extreme fatigue,
nausea, or diaphoresis—while others may not be associated with any symptoms
• Atypical presentations are more common in women, diabetic patients, and the
• Classic angina is caused by the reduction of coronary perfusion due to a fixed
obstruction of a coronary artery produced by atherosclerosis.
• Due to the fixed obstruction, the blood supply cannot increase, and the heart
becomes vulnerable to ischemia whenever there is increased demand, such as
B. Unstableangina & C. Prinzmetal, variant,vasospastic, or rest angina
• B. Unstable angina
Unstable angina is classified between stable angina and MI.
• In unstable angina, chest pain occurs with increased frequency,
duration, and intensity and can be precipitated by progressively less
• Any episode of rest angina longer than 20 minutes, any new-onset
angina, any increasing (crescendo) angina, or even sudden development
of shortness of breath is suggestive of unstable angina.
• The symptoms are not relieved by rest or nitroglycerin. Unstable angina
is a form of acute coronary syndrome and requires hospital admission
and more aggressive therapy to prevent progression to MI and death.
• C. Prinzmetal, variant, vasospastic, or rest angina
• Prinzmetal angina is an uncommon pattern of episodic angina that
occurs at rest and is due to coronary artery spasm.
• Symptoms are caused by decreased blood flow to the heart muscle from
the spasm of the coronary artery.
• Although individuals with this form of angina may have significant
coronary atherosclerosis, the angina attacks are unrelated to physical
activity, heart rate, or blood pressure.
• Prinzmetal angina generally responds promptly to coronary vasodilators,
Acute coronary syndrome
• Acute coronary syndrome is an emergency that commonly results from rupture of
an atherosclerotic plaque and partial or complete thrombosis of a coronary artery.
• Most cases occur from disruption of an atherosclerotic lesion, followed by platelet
activation of the coagulation cascade and vasoconstriction.
• This process culminates in intraluminal thrombosis and vascular occlusion.
• If the thrombus occludes most of the blood vessel, and, if the occlusion is
untreated, necrosis of the cardiac muscle may ensue.
• MI (necrosis) is typified by increases in the serum levels of biomarkers such as
troponins and creatine kinase.
• The acute coronary syndrome may present as ST-segment elevation
• myocardial infarction, non–ST-segment elevation myocardial infarction, or as
• Four types of drugs, used either alone or in combination, are commonly
used to manage patients with stable angina: β-blockers, calcium channel
blockers, organic nitrates, and the sodium channel–blocking drug,
• These agents help to balance the cardiac oxygen supply and demand
equation by affecting blood pressure, venous return, heart rate, and
• Figure 21.3 summarizes the treatment of angina in patients with
• They decrease the oxygen demands of the myocardium by blocking β1
receptors, resulting in decreased heart rate, contractility, cardiac output, and
• These agents reduce myocardial oxygen demand during exertion and at
rest. As such, they can reduce both the frequency and severity of angina
• They can be used to increase exercise duration and tolerance in patients
with effort-induced angina.
• These are recommended as initial antianginal therapy in all patients unless
contraindicated. ***[Note: The exception to this rule is vasospastic
angina, in which β-blockers are ineffective and may actually worsen
• They reduce the risk of death and MI in patients who have had a prior MI
• Agents with intrinsic sympathomimetic activity (ISA) such as
pindolol should be avoided in patients with angina and those who
have had a MI.
• Propranolol is the prototype for this class of compounds, but it is
not cardioselective.Thus, other β-blockers, such as metoprolol and
atenolol, are preferred. ***[Note: All β-blockers are nonselective
at high doses and can inhibit β2 receptors.]
• They should be avoided in patients with severe bradycardia;
however, they can be used in patients with diabetes, peripheral
vascular disease, and chronic obstructive pulmonary disease,as
long as they are monitored closely.
• Nonselective β-blockers should be avoided in patients with
• The calcium channel blockers protect the tissue by inhibiting the entrance
of calcium into cardiac and smooth muscle cells of the coronary and
systemic arterial beds.
• All calcium channel blockers are, therefore, arteriolar vasodilators that
cause a decrease in smooth muscle tone and vascular resistance.
• These agents primarily affect the resistance of peripheral and coronary
arteriolar smooth muscle.
• In the treatment of effort-induced angina, calcium channel blockers reduce
myocardial oxygen consumption by decreasing vascular resistance,
thereby decreasing afterload.
• Their efficacy in vasospastic angina is due to relaxation of the coronary
• ***[Note: Verapamil mainly affects the myocardium, whereas
• A. 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; it is usually administered as an
extended-release oral formulation.
• ***Short-acting dihydropyridines should be avoided in CAD because of
evidence of increased mortality after an MI and an increase in acute MI
in hypertensive patients.
• B. 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. Verapamil is contraindicated in patients with preexisting
depressed cardiac function or AV conduction abnormalities.
• Diltiazem also slows AV conduction, decreases the rate of firing of the sinus
node pacemaker, and is also a coronary artery vasodilator. Diltiazem can
• These compounds cause a reduction in myocardial oxygen demand,
followed by relief of symptoms. They are effective in stable, unstable,
and variant angina.
• Mechanism of action
• Adverse effects
• Headache is the most common adverse effect of nitrates.
• High doses of nitrates can also cause postural hypotension, facial
flushing, and tachycardia.
• Tolerance to the actions of nitrates develops rapidly as the blood
Sodium Channel Blocker
• Ranolazine inhibits the late phase of the sodium current (late INa),
improving the oxygen supply and demand equation.
• Inhibition of late INa reduces intracellular sodium and calcium
overload, thereby improving diastolic function.
• 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
• It is also a substrate of P-glycoprotein. As such, ranolazine is subject
to numerous drug interactions.
• In addition, ranolazine can prolong the QT interval and should be