Cardiovascular Pharmacology

By:

1. Zenaw T. (B.Pharm, MSc. In Pharmacology)

2. Wubetu Y. (B.Pharm, MSc. In Pharmacology)

➢ CONTENTS:
❖ Drugs for treatment of Hypertension
❖ Management of Angina Pectoris
❖ Drugs for treatment of Heart Failure
❖ Antiarrhythmics

DRUGS USED IN THE TREATMENT OF HYPERTENSION

✓ Hypertension (HTN)
➢ Hypertension refers to persistently elevated arterial blood pressure (BP≥140/90 mmHg)
➢ Etiology of hypertension
– Essential /primary hypertension (>90% of the cases).
• No specific cause/etiology can be identified or may be genetic
– Secondary hypertension (<10% of the cases)
• Has got specific etiology → there are many potential secondary causes (co-
morbid/ concurrent diseases or drugs)
➢ Table: Classification of HTN on the basis of BP
Category Systolic Diastolic

Normal < 120 < 80

High Normal 120 – 139 80 - 89

Hypertension - Stage 1 140 – 159 90 - 99

Stage 2  160  100

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➢ Normal Regulation of Blood Pressure
• Arterial blood pressure is due to combination of:
– Cardiac output (CO) and
– Peripheral vascular resistance (PVR)
Blood Pressure (BP) = Cardiac output (CO) x Peripheral vascular resistance (PVR)

➢ Cardiac output (CO) is the product of the heart rate (HR), i.e. the number of heart beats
per minute (bpm), and the stroke volume (SV), which is the volume of blood pumped
from the ventricle per beat; thus:
CO = HR × SV

• Values for cardiac output are usually denoted as L/min.

• The normal range for cardiac output is about 4 to 8 L/min, but it can vary depending
on the body's metabolic needs
➢ Goal of therapy:

• The overall goal of treating hypertension is to reduce hypertension-associated morbidity and

mortality

– These morbidity and mortality are related to target-organ damage: cardiovascular

events, cerebrovascular accidents, heart failure, and kidney disease

➢ General Approach to Treatment

✓ Treatment involves:
– Nonpharmacologic therapy: Lifestyle modifications
– Pharmacologic therapy: Drug therapy
✓ After a definitive diagnosis of hypertension is made, patients should be placed on both
lifestyle modifications and drug therapy concurrently
– Lifestyle modification alone is considered appropriate therapy for patients with
prehypertension.
– However, lifestyle modifications alone are not considered adequate for patients with
hypertension.

I. Nonpharmacologic therapy: Lifestyle modifications

• Prescribed for all patients with prehypertension and hypertension

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 • Life style modification
– If overweight, lose weight
– Limit alcohol intake
– Reduce sodium to more than 2.4 g sodium per day
– Exercise
– Stop smoking
– Reduce intake of dietary fat and cholesterol.
– Dietary Approaches to Stop Hypertension (DASH)
II. Antihypertensive drugs
– Any one of the following classes of drugs could be used as first step agents:
• Diuretics
• Beta blockers
• Calcium antagonists
• Angiotensin converting enzyme inhibitors
• Angiotensin II receptor blockers
– Alternative Agents
• Alpha blockers
• Centrally acting antihypertensive E.g. Methyl dopa
• Arterial vasodilators e.g. hydralazine, minoxidil
1. Diuretics
– Diuretics are drugs that promote excretion of Na+ and water in urine
– Are ion transport inhibitors that decrease reabsorption of Na+ and Cl- at different sites in
the nephron; which creates an osmotic pressure within the nephron to prevent passive
diffusion of water.
– Increase volume of the urine and change its PH as the ionic composition of the urine &
blood change
– The nephron is the smallest structural and functional unit of the kidney.

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 –
• Fig- the Segments of nephron and its sites drug action

a. High ceiling diuretics (Loop diuretics)

• Eg -Bumetanide, Furosemide, Torsemide & ethacrynic acid

• Major action on the thick ascending limb of loop of Henle
• They are the most efficacious.
✓ MOA: Inhibit Na+/K+/2Cl- transport system; so inhibit reabsorption of these electrolyte

• Increase Ca++ content of the urine and induces the secretion of prostaglandin; leads to
decrease renal vascular resistance & increase blood flow (Useful for patients with poor
renal function)

✓ Therapeutic use:-

• Because of their rapid onset of action useful in emergency – acute pulmonary edema of
congestive heart failure

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 • Hypercalcemia and Hyperkalemia treatment
• Treatment of hypertension which has been unresponsive to other diuretics
• Edema related to cardiac, hepatic or renal problem.
✓ Adverse effects:-
• Ototoxicity – when used in conjunction with amino glycosides.
• Hyperuricemia – compete with uric acid tubular secretion – exacerbate gout attack
• Acute hypovolemia – hypotension, shock & cardiac arrhythmia
• Hypokalemia – At CD, high Na+ reach leads to increase exchange of Na+ for K+

b. Thiziade & related drugs

• Eg- Chlorothiazide , Hydrochlorothiazide (prototype), chlorthalidone
• The most widely used – inexpensive and well tolerated
• Greater diuretic activity than acetazolamide
✓ Mechanism of Actions:-
▪ Decreased the reabsorption of Na+ & Cl- by inhibiting the Na+ /Cl- Co- transport system
on the distal tubule
▪ Cause loss of k+ in the collecting duct (CD)
▪ KCl supplement or k+ sparing diuretics, (spironolactone) is used in conjunction
▪ Cause decrease urinary calcium excretion (opposite to loop diuretics)-reduce incidence of
kidney stones.
▪ Cause hyperglycemia due to a decrease in insulin secretion and of glucose intolerance.
✓ Therapeutic Uses:-
• Hypertension
• Congestive heart failure
• Hypercalciuria useful patients
• cardiac edema
✓ Adverse effects:-
▪ Potassium depletion:-
▪ Hyperuricemia – exacerbate gouty attack
▪ Hypercalcemia
▪ Hypersensitivity
✓ Caution in the case of diabetic and gouty patients

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c. Potassium sparing diuretics

➢ Spironolactone

✓ MOA : - prevent K+ secretion by antagonizing aldosterone action at aldosterone receptor in

collecting duct

✓ Therapeutic use:-

▪ Given with thiazide or loop diuretics to prevent hypokalemia

▪ Adverse effect:
▪ Hyperkalemia
▪ Gynaecomastia, androgen like effect and minor GIT disturbance
▪ Drug interaction:-avoid potassium containing drugs and of ACE inhibitors.

Note: Other diuretics

Type of Site of action Mechanism of drugs use Side effect
diuretics action
Carbonic Proximal Inhibition of Acetazolamide Glaucoma Hypokalemia
anhydrase convoluted carbonic Dorzolamide Acute Metabolic
inhibitors tubule (PCT) anhydrase mountain acidosis
sickness Headache
Renal stone
Osmotic PCT draw water Mannitol to reduce the pulmonary
diuretics Loop of Henle from tissues by elevated oedema (high
osmotic action intracranial dose & too
resulting in tension rapid infusion
increased to reduce the of mannitol)
excretion of elevated IOP in Headache
water and acute Nausea
electrolytes congestive Vomiting
glaucoma
Other Potasium Late DCT & Inhibition of Eplerenone As Less likely to
sparing Collecting duct aldosterone spironolactone cause
diuretics receptors Gynecomastia

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 block ‘renal Amiloride AS Eplerenone
epithelial’ or Triamterene
‘amiloride
sensitive’ Na+
channel

2. Sympatholyics (adrenergic antagonists)

• Different categories of sympatholytic drugs
I. Beta adrenergic blockers
✓ E.g. Propranolol, Metoprolol, atenolol, labetalol etc
– have at least three useful actions in hypertension
• Blockade of cardiac beta 1 receptors → decreases heart rate and contractility
• Suppress reflex tachycardia caused by vasodilators
• Blockade of beta 1 receptors on juxtaglomerualr cells of the kidney → no
releases of rennin→ reducing angiotensin II mediated vasoconstriction and
aldosterone volume expansion
✓ Two groups of β -blockers
– Non selective β1 and β2 adrenergic -blockers: Propranolol, Timolol
– Selective β1 adrenergic blockers: Atenolol, metoprolol-
• preferred in case of asthma.
• Do not disturb blood glucose level
✓ Therapeutic uses
– Hypertension- lowers B.P. by decreasing cardiac output.
– Angina pectoris -decreases oxygen requirement of heart muscle.
– Cardiac arrhythmias (tachyarrhythmias).
✓ Adverse effects of beta blockers:
– Bradycardia, decreased AV conduction, and reduction of contractility.
– Blockade of beta 2 receptors on the lung promote bronco constriction
– Mask signs of hypoglycemia; must be used with caution in patients with diabetes
– Action on the CNS cause insomnia , depression , bizarre dreams and sexual dysfunction

II. Centrally acting agents ( α-2 agonists)

o Drugs: Clonidine , Methyldopa (Aldomet)
• Acts within the brainstem to suppress sympathetic out flow to the heart and blood vessels.

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 ✓ Mechanism of action of methyl dopa

• Methyl dopa is an α - agonist which is converted to methyl norepinephrine/false

neurotransmitter/ centrally to diminish the adrenergic output from the CNS
• decrease of peripheral resistance or cardiac output
✓ Uses: Mild to moderate hypertension in pregnancy.
✓ Side effects:
• CNS - Sedation, headache, dizziness
• GIT - dry mouth, nausea, vomiting
• Others - Postural hypotension, impotence, allergic reactions
III. Alpha 1 adrenergic blockers
e.g. prazocin, terazocin
– Prevent stimulation of α1 receptors on arteries and veins → vasodilation→ reduces PR
– Orthostatic hypotension is the major adverse effect.
– Agent of choice if BPH is underlying condition along with hypertension
✓ Use: treatment of hypertension and heart failure.
✓ Adverse effect: - postural hypotension, nasal stuffiness, failure of ejaculation in males.
3. Calcium channel blockers
✓ Mechanism of action:
• Inhibit Voltage-sensitive Ca2+ channels (L-type or slow channels) in smooth muscle and
cardiac myocytes
• In vascular smooth muscle, this leads to relaxation, especially in arterial beds.
• These drugs also may produce negative inotropic and chronotropic effects in the heart
• All the Ca2+ channel blockers approved for clinical use decrease coronary vascular resistance
and increase coronary blood flow.
➢ Two subclasses
– Dihydropyridines
– Non-dihydropyridines
✓ Dihydropyridines (Vessel selective CCBs)
➢ Amlodipine, Felodipine, Isradipine
➢ Nicardipine, Nifedipine
➢ Nisoldipine

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 ✓ Non-dihydropyridines (Cardioselective CCBs)
➢ Verapamil
➢ Deltiazem

➢ Verapamil & diltiazem have direct negative effect on the heart while the dihydropyridines
don’t
• So concurrent use of β-blockers with verapamil or diltiazem can magnify the negative
chronotropic effect of these drugs & cause heart block
• Dihydropyridines cause reflex tachycardia
• But verapamil & diltiazem don’t cause reflex tachycardia due to their negative
chronotropic effect
✓ Clinical uses:
• Hypertention, Angina pectoris
• Dysrhythmia (Verapamil - to slow ventricular rate)
✓ Side effects
– Varies among the drugs in this class
– Nifedipine (immediate release capsules): cause headache, flushing, dizziness &
peripheral edema
– Verapamil: constipation, exacerbation of GERD, urinary retention
– Both verapamil & diltiazem can lead to bradycardia but not the dihydropyridines
✓ Drug-drug interactions
– Verapamil blocks P-glycoprotein drug transporter w/h is necessary for excretion of
digoxin
– So, verapamil increases toxicity of digoxin

➢ Angiotensin converting enzyme inhibitors

• Drugs:
– Captopril, Enalapril, Lisinopril, Quinapril
✓ Mechanism of Action of ACE inhibitors
Inhibition of Angiotensin converting enzyme No production of Angiotensin II
No vasoconstriction and aldosterone section
vasoconstriction Aldosterone secretion

Blood pressure

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 • ACE is in many tissues, but primarily in endothelial cells (epithelial cells of blood vessels).
• Increase bradykinin adds to vasodilation, but also to dry cough and angio edema

✓ ACE inhibitors Side effects:

o rash,
o dry cough,
o angioedema, Hyperkalemia , hypotensio

✓ C/I: Pregnancy: Pregnancy Category D

✓ Drug interaction:
o potassium supplements
o Potassium sparing diuretics
o NSAIDS- retention of fluid and decrease synthesis of PGI2

5. Angiotensin Receptor Blockers (ARBs)

✓ Angiotensin II receptor antagonists
▪ E.g. Valsartan, losartan, candesartan
✓ Are alternative to ACE inhibitors
✓ MOA:- inhibit
✓ the vasoconstrictor effect of angiotensin II by blocking their receptors.
✓ Aldosterone release
✓ Donot affect bradykinin metabolism
• avoid dry cough and Angioedemia
✓ Used in treatment of hypertension and heart failure
✓ Side Effects
✓ are not safe for pregnant women, dizziness
✓ Lowest incidence of side effects
✓ Hyperkalemia
✓ Hypotension
✓ Decrease in GFR

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 ✓ Direct acting vasodilators

o Include:
a) Arterial vasodilators eg. hydralazine, minoxidil, diazoxide
b) Arterial and venous dilators eg. Nitroprusside
✓ Vasodilators:
✓ Produce relaxation of the vascular smooth muscle-decrease peripheral resistance-
Decrease BP.
✓ But, they cause reflex tachycardia and rennin secretion which increases water and salt
retention.
✓ Therefore, the vasodilators are given with β-blockers and/or diuretics
✓ Used for treatment of emergency hypertension.
a) Hydralazine
▪ Cause a selective decrease in vascular resistance in the coronary, cerebral, and renal circulations,
with a smaller effect in skin and muscle.
▪ It is the first line drug for Hypertensive Emergencies
▪ It is also the second line drug for hypertensive pregnant women.
▪ 5 -10mg intravenous every 20 minutes whenever the diastolic BP> 110 mmHg.
b) Minoxidil
✓ By opening K+ channels in smooth muscle and thereby permitting K+ efflux, it causes
hyperpolarization and relaxation of smooth muscle
✓ Side effects
• Fluid & water retention
• Hypertrichosis: refers to excessive hair growth on face, back, arms & legs
• Topical minoxidil is marketed for treatment of male pattern baldness

➢ Sodium Nitroprusside
• It dilates both arterial and venous vessels,
– resulting in reduced peripheral vascular resistance and venous return.
• It rapidly reduces venous return and may result in excessive hypotension.

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 • Used in the treatment of hypertension and heart failure by reducing both preload and the
afterload.
✓ Adverse effect:- overdose hypotension, cyanide related metabolic acidosis which can be treated by
sodium thiosulfate.

Antianginal drugs
➢ Angina pectoris

– Refers to CVS disorder characterized by severe pain of the heart

– Often starts as crushing pain of chest which usually radiates to Left arm, shoulder, jaw
and neck
➢ Angina occurs as result of an imbalance b/n myocardial O2 demand and supply
– Increased myocardial oxygen demand
• Determined by Ventricular wall tension, HR, contractility
– Decreased myocardial oxygen supply
• Determined by coronary blood flow (CBF), oxygen-carrying capacity of the
blood
• There are three types of angina
➢ Stable angina(angina of effort)
– Also called angina of effort, typical angina
– Is the most common type
– Usually triggered by physical activity
– Also emotional excitement, large meal, cold exposure can precipitate this type of angina
– Caused by atherosclerosis blockade of blood vessels
➢ Variant angina
– Also called Prinzmetal’s or vasospastic angina
– Occurs due to spasm of coronary arteries
– Associated with pain at rest
– May occur with stable angina
– Unstable angina
– It is a medical emergency
– Associated with pain at rest
– Occurs as result of high degree of atherosclerosis in the coronary arteries
– It is the worst of all types of angina
– It has high risk for Myocardial infarction and Death

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 ➢ Therapeutic Objectives of angina treatment
– Increase blood flow to ischemic heart muscle and/or decrease myocardial oxygen demand
➢ The causes of angina includes:
– atherosclerotic heart disease, and almost invariably associated with a significant
obstruction of coronary artery.
– Vasospasm of the coronary artery due to the effect of sympathetic neurotransmitters
– An increase in workload on the heart due to an increase in heart rate , contractility and of
ventricular blood volume
– Emboli, etc
➢ Goals of angina treatment
– Terminate acute angina pain
– Reduce the frequency (recurrence) of angina attacks
– Reducing myocardial oxygen demand
– Increasing oxygen supply to the myocardium
– Prevention of myocardial infarction & death
➢ This can be achieved by:
– Slowing heart-rate
– Reducing the preload by dilating veins
– Causing heart to contract with less force
– Lowering blood pressure – less resistance in heart to pushing blood from chambers
(reduce after-load)
– Preventing (reducing) lipid & platelet accumulation in the blood vessels
➢ Classes of Drugs available for angina treatment
– Nitrates
– Calcium channel blockers
– Beta blockers
– Antiplatelet agents
➢ Organic nitrates
– Includes: nitroglycerin, isosorbide mononitrate, isosorbide dinitrate
– Except nitroglycerin which volatile liquid, these drugs are solid at room temperature
➢ MOA: nitrates are thought to work by interacting with nitrate receptors found on vascular
smooth muscles
– Nitrate receptors contain sulfohydryl (SH) groups which reduces nitrates to nitric oxide
(NO)

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 – NO (Nitric Oxide) stimulates guanylyl cyclase which synthesizes cGMP
– cGMP causes smooth muscle relaxation which leads to vasodilation
– Nitrates produce more pronounced dilation on the veins than the arteries
➢ Nitrates relieve the symptoms of angina by restoring the balance b/n myocardial O2 demand
& supply
➢ O2 demand is lowered as result of:
– Reduction in cardiac preload (as result of venous pooling of blood)
– Reduction in cardiac afterload (as result of arteriolar dilation)
➢ O2 supply is increased as result of:
– Increased blood flow to ischemic areas as result of direct vasodilatory effects of nitrates
on coronary arteries
– Nitrates were also found to prevent platelet aggregation
✓ Tolerance & dependence
➢ Repeated & frequent exposure to organic nitrates is accompanied by dev’t of tissue tolerance to
the drugs vasodilatory effects
➢ The mechanism for tolerance to nitrates is not well understood but could be due to:
– Depletion of SH group
– Decrease in sensitivity of guanylyl cyclase to NO
– Activation of RAAS
➢ To reduce/prevent nitrate tolerance, clinicians should employ the smallest effective dose &
administer the drugs infrequently
➢ A daily nitrate free period is also recommended
✓ Side effects
– Headache
– Postural hypotension
– Flushing
– Reflex tachycardia are common side effects
➢ β-blockers
– Since an increase in SNS activity is a common feature of anginal attacks, the use of β-
antagonists is rational
– β-antagonists approved for secondary angina in USA includes:
– Propranolol & nadolol (non selective β1 &2 antagonists)
– Metoprolol & atenolol (β1 selective antagonists)

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 ➢ MOA:
– Antagonize the actions of catecholamines on the heart & reduce HR, FC
➢ Mechanism not well known but expected to be due to:
– Reduced HR & FC produces reduced cardiac output
– Reduce plasma renin activity
– An action on the central nervous system
➢ So, β-antagonists reduce myocardial O2 demand by reducing 3 of the major determinants of
myocardial O2 demand
– HR, FC, Systolic wall tension
– Generally, β-antagonists produce their antianginal effects by:
– Decreasing O2 demand (by decreasing HR, FC)
➢ β-antagonists are particularly indicated in the management of patients whose anginal attack are
frequent & unpredictable
➢ They can be combined with nitroglycerin
✓ Side effects
– Abrupt interruption of β-antagonists can lead to
– Reappearance of angina
– Acute myocardial infarction
– Death
– The dose should gradually be tapered off
✓ They are contraindicated to
– bronchospastic conditions
– Bradycardia
– diabetic cases
– left ventricular failure.
➢ Calcium channel blockers (CCBs)
✓ Are orally active group of drugs approved for treatment of vasospastic & effort
angina
✓ Are particularly effective in the prophylaxis of coronary vasospasm or variant
angina
– MOA: block L-type calcium channels in vascular smooth muscles & heart
producing:
➢ Decreased HR & FC (decrease demand)
➢ Decrease PVR (decrease demand)

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 ➢ Dilate coronary arteries (increase supply)
– Different classes of CCBs are available
➢ Phenyalkylamines: verapamil, with T1/2 3-6 hours
➢ Benzothiazepines: Diltiazem; T1/2 3-6 hours
▪ Both verapamil & diltiazem are cardioselective CCBs
– Dihydropyridines:
✓ Nimodipine-: T1/2 1-2 hours
✓ Nifedipine- T1/2 2-6 hours
✓ Nifedipine sustained-release, Isradipine - T1/2 8-12 hours
✓ Amlodipine – very long acting – T1/230-50 hours
➢ Side effects
– Serious side effects
➢ Cardiac depression (non-DHPs)
➢ Cardiac arrest
➢ Bradycardia
➢ Atrio-ventricular block
➢ Heart failure
– Minor side effects
➢ Headache, flushing, dizziness, nausea, constipation, coughing, wheezing
➢ Peripheral edema due to greater arteriolar than venous dilation
➢
CONGESTIVE HEART FAILURE

➢ Congestive heart failure (CHF) is a condition in which the heart is unable to pump sufficient
blood to meet the needs of the body due to
– impaired ability of cardiac muscle to contract or increased work load imposed on the
heart
✓ Causes of heart failure
– Ischaemic heart disease
– Hypertention
– Heart muscle disorders-decrease in contractility.
– Valvular heart disease
– Drugs that has negative inotropic effects.
– Pressure and volume overload (an increase in afterload and preload).

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 ✓ Therapeutic strategies in heart failure includes:
– Reduction in physical activity
– Low dietary intake of sodium
– Avoid agents that exacerbate heart failure.
– Treatment with drugs (positive inotropic and diuretics).
✓ The current approach to therapy for CHF involves preload reduction, after load reduction,
and enhancement of inotropic state.
– Pathophysiology of HF
• Reduced tissue perfusion as result of reduced CO initiates the d/f compensatory
mechanisms
• Increased SNS activity
• Activation of the RAAS
• Activation of the SNS causes:
• Increased arterial & venous constriction which increases the afterload & preload
respectively
• Increased HR & FC which increases the CO
✓ Activation of the RAAS causes:
– Vasoconstriction
– Increased salt & water retention
✓ Unfortunately, each of these compensatory responses will also promote disease progression
✓ Elevations of both the preload & afterload leads to increased diastolic & systolic wall stress
✓ Impairs myocardial energetics & will induce hypertrophic remodeling of ventricles

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 ✓
Drugs used in the management of HF

POSSITIVE INOTROPIC AGENTS

i) Cardiac glycosides: eg Digoxin

• Cardiac glycosides come from fox gloves (Digitalis spp.) and related plants.
• Digoxin is by far the most important of these compounds.
➢ Mechanism of action
• Glycosides inhibit Na+/K+ ATPase transport system.
• Inhibition of Na+/K+ ATPase inhibits out flux of Na+ and increase intracellular Na+
concentration.
• Increased Na+ concentration slows extrusion of Ca++ via the Na+/Ca++ exchange transporter.
• The overall effect is increased intracellular calcium level.→ increase the force of
myocardial contraction→increase in the cardiac output.
• Relationship of k+ to inotropic action

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 • K+ compete with C.glycosides for binding to Na/K ATPase
• when k+ levels are low , binding of C.glycosides to Na+/K ATPase will increase
excessive inhibition  toxicity
• when K+ levels are high, inhibition is decreased reduction in therapeutic response
• Hence, it is imperative that K+ levels be kept within physiologic range(3.5-5meq/l)
➢ Therapeutic uses
• Congestive heart failure emergencies as it has fast onset of action
• Cardiac arrhythmias (supraventricular tachycardia)
– Atrial fibrillation
– Atrial flutter
– Paroxysmal tachycardia (has vagotonic action)
➢ Adverse effects
• Digitalis glycosides have a low therapeutic index.
• Digitalis toxicity includes, anorexia, nausea, vomiting, visual disturbance and ventricular
fibrillation at high dose
➢ Drug interaction:
• Diuretics that deplete potassium in the blood increase digitalis toxicity.
• Enzyme inducer (rifampicin) decrease the level of digoxin in the blood
• Antacid and kaolin decrease the bioavailability of digoxin
• Potassium increase in the blood decrease the effect of digoxin
• An increase in the blood calcium increases the action of digoxin
Note: Digoxin toxicity is also worsened by hypokalemia. Because digoxin binds to the K+ site of the Na+/K+-
ATPase pump, low serum potassium levels increase the risk of digoxin toxicity. Conversely, hyperkalemia
diminishes digoxin's effectiveness.

ii) Beta- adrenergic agonists

➢ Mechanism of action
• Increase the force of myocardial contractility and then increase cardiac output.
• Improve cardiac performance by positive inotropic effects.
• Dobutamine IV infusion is used in treatment of acute heart failure.
• NOTE: Other positive inotropic agents include bipyridines (eg-inamrinone, milrinone)

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 ✓ DRUGS WITHOUT POSITIVE INOTROPIC EFFECTS
Are the first line drugs for chronic heart failure management.
i) Vasodilators:
• The vasodilators are effective in acute heart failure because they provide a reduction in preload or
after load.
• Dilation of venules decrease cardiac preload.
• Dilation of arteries decreases cardiac afterload.
• Hydralazine has a direct vasodilator effect on arteries→ decrease vascular resistance (afterload)
→ improves in cardiac output.
• Sodium nitroprusside dilates both the arteries and veins→decrease both the afterload and the
preload.
• In general, nitroprusside initiation in patients with severe heart failure results in increased cardiac
output and a parallel increase in renal blood flow, improving both glomerular filtration and
diuretic effectiveness.
• Nitrates are the common Venus dilators (decrease the preload) used in the treatment of congestive
heart failure.
• Most vasodilators, cause hypotension .
• Calcium channel blockers should be avoided.
ii) Angiotensin converting enzyme inhibitors:
✓ mechanism of mechanism
• ACEIs, by blocking the formation of angiotensinII, reduce the vascular resistance →improve
tissue perfusion and reduce cardiac after load.
• They also cause natriuresis and diuresis by inhibiting secretion of aldosterone.
• Angiotensin II receptor blockers (like losartan) can substitute ACEI in those patients who cannot
tolerate the latter.
iii) Diuretics
• Diuretics are important in increasing salt and water excretion, especially if there is
edema.
• They decrease preload and blood pressure→results in a decrease in workload and oxygen
demand.
• Loop diuretics are used for patients who require extensive diuresis (like with edema) and
in those with renal insufficiency, but avoid over dose to prevent hypovolemia.
• Thiazides are mild diuretics (effective in normal kidney functions)

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 ANTIARRHYTHMICS
➢ A-RHYTHM –IA
✓ Defn- Arrhythmia is deviation of heart from normal RHYTHM.
✓ The heart may beat
• too slowly (bradycardia),
• too quickly (tachycardia)
• or in an irregular way.
➢ RHYTHM:
1) HR- 60-100
2) Should origin from SAN
3) Cardiac impulse should propagate through normal conduction pathway with normal velocity.
NORMAL CONDUCTION OF THE HEART

• The arrhythmias are conceptually simple dysfunctions cause abnormalities in

– impulse formation (abnormal automaticity)
– conduction in the myocardium (reentry),
– or combination of both.

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Cardiac Action Potential

Cardiac Action Potential

✓ Divided into five phases (0,1,2,3,4)

➢ Phase 4 - Diastole depolarization
o the resting membrane potential is maintained by K+ efflux and slow Na+ & Ca2+
influx
• Except for the SA node, the heart rests.
• Addition of current into cardiac muscle (stimulation) causes
➢ Phase 0 – rapid depolarization- opening of fast Na+ channels
• Drives Na+ into cell (inward current), changing membrane potential
• Transient outward current due to movement of Cl- and K+

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 ➢ Phase 1 – initial rapid repolarization
• Closure of the fast Na+ channels
• it is followed by a brief and incomplete period of repolarization.
• K + efflux: This period is mediated by a temporary movement of K+ from the
intracellular to the extracellular space.
• Cl- influx.
➢ Phase 2 - plateau phase
– sustained by the balance between Ca+ influx and K + efflux

– Unique to the cardiac action potential

– This initiates a slow repolarization, and creates a plateau in the action potential.

✓ Cardiac contraction is mediated by phase 2.

➢ Phase 3 – rapid repolarization

– The calcium channels close. The process of repolarization is accelerated.

– K + channels remain open,

– Allows K+ to build up outside the cell, causing the cell to repolarize
– K + channels finally close when membrane potential reaches certain level

Types of Arrhythmias
BRADYARRHYTHMIAS – Sinus arrest (slow junctional rhythm)
(<60bpm) TACHYARRYTHMIAS
– Sinus bradycardia (>100bpm)
– Sinoatrial (SA) block  Supraventricular Arrhythmias
– Sinus pause  Ventricular Arrhythmias

➢ Pathogenesis
• 3 basic mechanisms:
– enhanced or suppressed automaticity
• Due to
– Ischemia, scarring, electrolyte disturbances, medications,
advancing age, excess catecholamine activity

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 – triggered activity
• Attempt to depolarize before or after the cell is fully repolarized
– torsades de pointes- initiated by early after-depolarization
– ventricular arrhythmias caused by digitalis toxicity- delayed after-
depolarization
– re-entry
• Most common
• Supraventricular and monomorphic ventricular tachycardia
Antiarrhythmic Medications
CLASS ACTIONS (EXAMPLES)
I Sodium Channel blockers
IA Depress phase 0 of action potential; delay conduction, prolong
repolarization—phase III or IV (quinidine, procainamide, disopyramide)
IB Little effect on phase 0 of action potential in normal tissues; depress phase
0 in abnormal tissues; shorten repolarization or little effect (lidocaine,
tocainide, mexiletine, diphenyl-hydantoin)
IC Depress phase 0 of action potential; markedly slow conduction in normal
tissues (flecainide, propafenone, moricizine)
II β-Adrenergic blocking agents (acebutolol, atenolol, bisoprolol, carvedilol,
metoprolol, nadolol, pindolol, propranolol)
III Prolong action potential duration by increasing repolarization and
refractoriness (amiodarone, sotalol, bretylium, dofetilide, azimilide,
ibutilide)
IV Calcium channel blockers (diltiazem, verapamil)
Others Digoxin, adenosine

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 CLASS I ANTIARRHYTHMIC AGENTS

Class IA Side effects

Quinidine sulfate Diarrhea, hypotension, N/V, cinchonism, fever, thrombocytopenia,
proarrhythmia
Procainamide Hypotension, fever, agranulocytosis, systemic lupus erythematosus,
headache, proarrhythmia
Disopyramide Anticholinergic, heart failure, proarrhythmia
Class IB Side effects
Lidocaine ,Mexiletine ,Tocainide, Drowsiness, agitation, muscle twitching, seizures, proarrhythmia
Phenytoin
Class IC Side effects
Flecainide, Propafenone Dizziness, proarrhythmia
,moricizine
CLASS II Side effects
Beta blockers Hypotension, heart block, bradycardia, dyspnea, whhezing
Acebutolol
Esmolol
Propranolol
CLASS III Side effects
Amiodarone Blurred vision, corneal microdeposits, photophobia, skin
discoloration, constipation, pulmonary fibrosis,
hypo/hyperthyroidism
Sotalol Fatigue, dizziness, dyspnea, bradycardica, proarrhythmic
Dofetilide Chest pain, dizziness, headache, proarrhythmia
Bretylium Hypotension, lightheadedness, tachycardia, transitory HTN
Ibutilide Headache, nausea, proarrhythmia
CLASS IV Side effects
Calcium channel blockers Hypotension, heart block, flushing, rashes, headache, gingival
Verapamil hyperplasia
Diltiazem

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Classification of antiarrhythmic drugs summary

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