DRUGS ACTING ON CARDIOVASCULAR SYSTEM

Melese Z. ( B. Pharm, MSc in Pharmacology)

School of Pharmacy
College of Health Sciences & Medicine
Wolaita Sodo University
1
 The most commonly encountered cardiovascular disorders include:

q Heart failure

q Hypertension

q angina pectoris ,and

q cardiac arrhythmias.

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 Drugs used for the treatment of Heart Failure

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Learning Objectives
Ø Know the class of drugs that are used in HF.

Ø Explain the mechanism of action of drugs that are used in HF.

Ø Compare the various classes of drugs.

Ø Describe common adverse effects and

Ø contraindications of these drugs

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  Heart failure (HF) is a complex, progressive disorder in which the

heart is unable to pump sufficient blood to meet the needs of the body.

 HF occurs when cardiac output is inadequate to provide the oxygen

needed by the body.

 Two major types of failure may be distinguished.

 Systolic failure,

 with reduced mechanical pumping action (contractility)

 reduced ejection fraction (HFrEF).

 Accounts 50% of younger patients

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  Diastolic failure,

- Stiffening and loss of adequate relaxation

- Ejection fraction may be normal (preserved, HFpEF)

ü however stroke volume is significantly reduced.

- Account 50% of patients

ü Proportion increases with age

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Compensatory physiological responses in HF

 The failing heart evokes three major compensatory mechanisms to enhance

cardiac output

 Increased sympathetic activity

 Activation of the renin–angiotensin–aldosterone system

 Myocardial hypertrophy

 Although initially beneficial, these alterations ultimately result in further

deterioration of cardiac function.

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 Drugs Used in Heart Failure

 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

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9
 Angiotensin-converting enzyme inhibitors(ACEIs)
(Captopril, Enalapril, Lisinopril, Ramipril & Trandolapril)

 HF leads to activation of the renin–angiotensin–aldosterone system via

two mechanisms:

 1) increased renin release by juxtaglomerular cells in renal afferent arterioles

due to diminished renal perfusion pressure produced by the failing heart and

 2) renin release by juxtaglomerular cells promoted by sympathetic stimulation

and activation of β receptors.

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ACEIs…

 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.

 In addition, high levels of angiotensin II and aldosterone have direct detrimental

effects on the cardiac muscle, favoring remodeling,

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ACEIs…

 ACEIs drugs block the enzyme that cleaves angiotensin I to form angiotensin II.

 They also diminish the inactivation of bradykinin

 Vasodilation occurs as a result of decreased levels of the vasoconstrictor

angiotensin II and increased levels of bradykinin (a potent vasodilator).

 By reducing angiotensin II levels, ACEIs also decrease the secretion of aldosterone.

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ACEIs…

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Mechanism of Action of ACEIs…

 The ACEIs lower the circulating level of AngII & thereby reduce its deleterious

effects.

ü ACEIs not only act as vasodilators but also reduce aldosterone levels and

thereby act as an indirect diuretic,

ü have direct antiremodeling effects on the heart, and produce sympatholytic

effects

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 The effects of ACEIs on renal

 When renal perfusion pressure is reduced, AngII constricts renal efferent arterioles, and

this serves to maintain glomerular filtration pressure and GFR.

 Thus, under conditions in which renal perfusion pressure is compromised, inhibition of

the RAAS may induce a sudden and marked decrease in GFR.

ü For this reason, ACEIs are contraindicated in bilateral renal artery stenosis.

 because patients with heart failure often have low renal perfusion pressures, aggressive

treatment with ACEIs may induce acute renal failure.

ü To avoid this, for patients with HF, ACEIs should be initiated at very low doses
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 The ACEI-induced lowering of aldosterone levels

 causes reduced expression of the aldosterone-dependent epithelial Na+ channel

(ENaC) in the distal tubule.

ü Lower levels of ENaC lead to less absorption of Na+ and less excretion of K+.

 ACE has other actions, including the inactivation of bradykinin and substance P.

 ACEIs increase bradykinin and substance P levels, with two prominent consequences:

cough and angioedema

 Experimental evidence suggests that increases in bradykinin contribute to the

therapeutic efficacy of ACEIs and

ü may explain why ARBs, which do not increase bradykinin, have not been consistently

associated with improved survival in patients with HFrEF .

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 Pharmacokinetics

 ACEIs are adequately absorbed following oral administration.

 Food may decrease the absorption of captopril,

ü so it should be taken on an empty stomach.

 Except for captopril, ACEIs are prodrugs that require activation by hepatic

enzymes.

 Renal elimination of the active moiety is important for most ACE inhibitors

 Plasma half-lives of active compounds vary from 2 to 12 hours.

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 Adverse effects

 The ACEIs are generally well tolerated in the majority of patients.

Ø Important ADRs are the following:

ü dry cough, necessitating a change to ARBs;

ü hyperkalemia

ü angioedema

ü allergic skin reactions

Ø ACEIs are teratogenic and should not be used in pregnant women.

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Angiotensin receptor blockers (ARBs)
(Candesartan, Losartan & Valsartan)

 The ARBs are highly selective, competitive receptor antagonists at the AT1 receptor,

which mediates the major effects of AngII.

 are alternatives to ACEIs and second choice in all stages of HF in patients who do

not tolerate ACEIs.

 The unopposed activity of AT2 receptor pathways in the presence of AT1 blockade

by an ARB seems to confer no therapeutic advantage to ARBs over ACEIs.


19 Further, ARBs do not affect bradykinin levels.
 Pharmacokinetics

 All the drugs are orally active

 except for candesartan, have large volumes of distribution.

 Losartan, the prototype of the class, differs in that it undergoes extensive first-

pass hepatic metabolism, including conversion to its active metabolite.

ü The other drugs have inactive metabolites.

 Elimination of metabolites and parent compounds occurs in urine and feces.

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 ARBs have an adverse effect and drug interaction profile similar to that of ACEIs.

 However, the ARBs have a lower incidence of cough and angioedema.

 Like ACE inhibitors, ARBs are contraindicated in pregnancy.

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 Aldosterone antagonists

 Patients with advanced heart disease have elevated levels of aldosterone due to

AngII stimulation and reduced hepatic clearance of the hormone.

 Aldosterone promotes

 Na+ and fluid retention,

 loss of K+ and Mg2+,

 sympathetic activation,

 parasympathetic inhibition,

 myocardial and vascular fibrosis, and vascular damage,

Ø all adverse effects in the setting of heart failure.

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 Spironolactone is a direct antagonist of aldosterone, thereby preventing salt

retention, myocardial hypertrophy, and hypokalemia.

 Spironolactone is a nonspecific steroid hormone receptor antagonist with

similar affinity for progesterone and androgen receptors;

 it causes gynecomastia (painful breast swelling) in men and dysmenorrhea in women.

 Eplerenone is selective for the mineralocorticoid receptor

 therefore does not cause gynecomastia.

 The most important ADR of both drugs is hyperkalemia.

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β-blockers
 Major Effects of β Adrenergic Antagonists

 Most patients with chronic heart failure respond favorably to certain β blockers .

 Studies with bisoprolol, carvedilol, metoprolol, and nebivolol showed a

reduction in mortality in patients with stable severe HF,

o but this effect was not observed with another β blocker.

 β-blockers prevent the deleterious effects of NE on the cardiac muscle fibers,

decreasing remodeling, hypertrophy, and cell death

 In addition, β blockers improve perfusion of the myocardium by prolonging diastole,

thereby reducing ischemia.

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 Pharmacokinetic Considerations

 Metoprolol has a too short t1/2 (3–5 h)

ü metabolized by the CYP2D6 isoenzyme

 Bisoprolol has a sufficiently long plasma t1/2 (10–12 h) for once-daily dosing

ü is not metabolized by CYP2D6.

 Carvedilol has a shorter t1/2 (6–10 h) and requires twice-daily dosing.

 Carvedilol metabolism depends on CYP2D6, but less so than metoprolol.

 Nebivolol plasma concentrations are 10- to 15-fold higher in CYP2D6 poor

metabolizers,
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 Diuretics

 Diuretics increase Na+ and water excretion by inhibiting transporters in the

kidney and thereby improve symptoms of CHF.

 They have no direct effect on cardiac contractility;

 their major mechanism of action in HF is to reduce venous pressure and ventricular

preload.

 Diuretics are an integral part of the combination therapy of symptomatic forms of

heart failure.

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 As diuretics have not been shown to improve survival in HF, they should only be

used to treat signs and symptoms of volume excess.

 Loop diuretics are the most commonly used diuretics in HF.

 especially furosemide, are drugs of choice in heart failure

 These agents are used for patients who require extensive diuresis and those with renal

insufficiency.

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Vasodilators

 Vasodilator drugs can be divided into selective arteriolar dilators, venous dilators,

and drugs with nonselective vasodilating effects.

 The choice of agent should be based on the patient’s signs and symptoms and

hemodynamic measurements.

 In patients with high filling pressures in whom the principal symptom is dyspnea,

 venous dilators such as long-acting nitrates will be most helpful in reducing

filling pressures and the symptoms of pulmonary congestion.

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 In patients in whom fatigue due to low left ventricular output is a primary
symptom,
 arteriolar dilator such as hydralazine may be helpful in increasing
forward cardiac output.
 In most patients with severe chronic failure that responds poorly to other therapy,
the problem usually involves both elevated filling pressures and reduced cardiac
output.
 In these circumstances, dilation of both arterioles and veins is required.

 A combination of hydralazine and isosorbide dinitrate is recommended

ü Headache, hypotension, and tachycardia are common adverse effects with this
combination.
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Inotropic Agents

 Most currently employed positive inotropes act by increasing the concentration of

free intracellular Ca2+ ([Ca2+]i).

 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 Ca2+ concentration

 that enhances the contractility of cardiac muscle.

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  Digitalis glycosides

 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.

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  Mechanism of action

ü Regulation of cytosolic calcium concentration

Ø at therapeutic concentrations mildly inhibit the cardiac Na+/K+ ATPase, causing

an increase in intracellular [Na+].

Ø Increased [Na+] inhibits Ca2+ extrusion via the NCX resulting in higher

intracellular [Ca2+] and enhanced contractility

Ø The increased contractility and hence cardiac output provides symptomatic relief

in patients with HF.

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33
  Digoxin therapy is indicated in patients with severe HFrEF after initiation of

ACE inhibitor, β-blocker, and diuretic therapy.

 Patients with mild to moderate HF often respond to treatment with ACE

inhibitors, β-blockers, aldosterone antagonists, direct vaso- and venodilators,

and diuretics and

ü may not require digoxin.

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  Pharmacokinetics

ü It has a large volume of distribution,

Ø because it accumulates in muscle.

ü Digoxin has a long half-life of 30 to 40 hours.

ü It is mainly eliminated intact by the kidney,

Ø requiring dose adjustment in renal dysfunction.

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  Adverse Effects.

ü At low serum drug concentrations, digoxin is fairly well tolerated.

ü The most frequent and most serious adverse effects are arrhythmias

ü In CG overdosing, patients exhibit arrhythmias (90%), GI symptoms (~55%),

and neurotoxic symptoms (~12%).

ü The most frequent causes of toxicity are renal insufficiency and overdosing.

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 β-Adrenergic agonists

 β-Adrenergic agonists, such as dobutamine and dopamine , improve cardiac

performance by causing positive inotropic effects and vasodilation.

 Dobutamine is the most commonly used inotropic agent other than digoxin

 β-Adrenergic agonists lead to an increase in intracellular cAMP, which results in the

activation of protein kinase.

ü Protein kinase then phosphorylates slow calcium channels, thereby increasing entry of

calcium ions into the myocardial cells and enhancing contraction

 Both drugs must be given by IV infusion and are primarily used in the short-term

treatment of acute HF in the hospital setting.

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38
 Phosphodiesterase inhibitors (PDEIs)

 Milrinone is a PDEIs that increases the intracellular concentration of cAMP

 Like β-adrenergic agonists, this results in an increase of intracellular calcium and,

therefore, cardiac contractility.

 Long-term, milrinone therapy may be associated with a substantial increased risk of

mortality.

 However, short-term use of IV milrinone is not associated with increased mortality in

patients without a history of coronary artery disease, and some symptomatic benefit may

be obtained in patients with refractory HF.

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 ???

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 Anti hypertensive drugs

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  Learning Objectives

ü Able to explain drugs, general PK properties, MoA and their ADE of drugs

that used in HTN

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 Hypertension

 Hypertension (HTN) is defined as either a sustained systolic blood pressure of >140

mmHg or a sustained diastolic blood pressure of > 90 mmHg.

 The most common cardiovascular disease.

 Prevalence ↑ with advancing age

ü E.g. ~50% of people between the ages of 60 and 69 years old have hypertension

 Most patients are asymptomatic

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 Hypertension…
Classification of HTN on the basis of blood pressure

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 Hypertension…

 Classification of HTN based on etiology

ü Primary (or essential) hypertension (90-95% pts)

- a single reversible cause cannot be identified

ü Secondary hypertension (5-10% pts)

- cause can be identified

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 Hypertension…
Hypertensive crisis
- severely elevated blood pressure (BP >180/110 mm Hg).

- can present as hypertensive urgency or emergency.

 Hypertensive urgency

ü severely elevated BP (≥180/ ≥110 mm Hg ) with out associated organ damage.

 Hypertensive emergency

ü occur at BP exceeding 180/120 mmHg

ü with organ damage (stroke, myocardial infarction, renal failure, and loss of

consciousness).

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 Mechanisms for BP regulation
§ Arterial blood pressure is directly proportional to cardiac output and peripheral

vascular resistance.

§ Cardiac output and peripheral resistance, in turn, are controlled mainly by two

overlapping control mechanisms: the baroreflexes and the RAAS

1) Baroreflexes adjust moment-to-moment blood pressure

ü Carotid baroreceptors respond to stretch, and their activation modulate

sympathetic discharge.
2) The RAAS provides tonic, longer term regulation of blood pressure.
ü Decreased renal pressure stimulates renin production and leads to enhanced

levels of angiotensin II (constriction & aldosterone release).

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 Mechanisms for BP regulation…

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 Classification of Antihypertensive Drugs

ü Diuretics ü Ca2+ Channel Blockers

ü Sympatholytic Drugs ü Angiotensin-converting Enzyme

 β−receptor antagonists Inhibitors (ACEIs)

 Selective α1 Blockers ü Angiotensin Ii Receptor Blockers

 Mixed , β − receptor antagonists (ARB)

 Centrally acting adrenergic agents
ü Vasodilators

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 Diuretics
Thiazide diuretics

Ø Hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, methylclothiazide,

metolazone

Ø Most frequently used class of antihypertensive agents for mild to moderate

hypertension;

ü considered as first-line therapy for most patients

Ø Can be used either alone or in combination with other antihypertensive drugs

Ø lower blood pressure initially by increasing sodium and water excretion.

ü This causes a decrease in extracellular volume, resulting in a decrease

in cardiac output and renal blood flow

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 Diuretics…

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 Diuretics…

Loop diuretics
 The loop diuretics (furosemide, torsemide, bumetanide, and ethacrynic acid)

ü act promptly by blocking sodium and chloride reabsorption in the kidneys

 are necessary

ü in severe hypertension, when multiple drugs with sodium-retaining properties

are used;
ü in renal insufficiency, when glomerular filtration rate is less than 30–40

mL/min;
ü in cardiac failure or cirrhosis, in which sodium retention is marked.

ü for patients who have not responded to thiazide diuretics

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 Diuretics…
Potassium-sparing diuretics

 Amiloride, triamterene, eplerenone, spironolactone

 are useful both to avoid excessive potassium depletion and to enhance the natriuretic

effects of other diuretics.

 Low efficacious diuretics, generally used in combination with thiazide/loop diuretics

to minimize hypokalemia.

 Aldosterone antagonists have the additional benefit of diminishing the cardiac

remodeling that occurs in heart failure

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 Diuretics…

 Diuretics should be administered

ü in the morning if given once daily and

ü in the morning and late afternoon when dosed twice daily to ↓risk of nocturnal

diuresis

 The sites of action within the kidney and the pharmacokinetics of various diuretic

drugs were discussed in the chapter of “ Diuretics”.

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 Diuretics…

Adverse effects
ü Hypokalemia (barring K+ sparing---hyperkalemia)

ü Hypercalcemia (with thiazide; loop --- hypocalcemia), hypomagnesemia, hyperuricemia

ü Hyperglycemia, dyslipidemia (dose-related, particularly thiazide; less significant with loop)

Less common AEs

ü Gynecomastia in up to 10% of patients (with spironolactone)

ü Hypersensitivity (e.g. skin rash)—sulphonamide derivatives (thiazide, loop)

ü Nephrotoxicity

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  - adrenergic antagonists

Cardioselectiv Nonselective Mixed (1, ) blockers

e/ 1 selective

Atenolol Nadolol Labetalol, carvedilol

Betaxolol Propranolol
Bisoprolol Timolol
Metoprolol
Esmolol

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  - adrenergic antagonists…
Effects of β‐ blockers on the cardiovascular
system

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  - adrenergic antagonists…
Mechanism of actions
 The β-blockers reduce blood pressure primarily by decreasing cardiac output.

 inhibit the release of renin from the kidneys,

ü thus decreasing the formation of angiotensin II and the secretion of aldosterone.

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  - adrenergic antagonists…

 Thiazide diuretics, ACEIs, ARBs, and CCBs should be used as the initial first-line

agent before  -blockers.

 Cardioselective agents…advantages over non-selective; they are safer for patients

with asthma or diabetes; cardioselectivity is dose dependent

 Pharmacokinetics

ü The β-blockers are orally active for the treatment of hypertension.

ü Propranolol undergoes extensive and highly variable first-pass metabolism.

ü Oral β-blockers may take several weeks to develop their full effects.

ü Esmolol, metoprolol, and propranolol are available in intravenous formulations.

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  - adrenergic antagonists…

Adverse effects
 Common effects

ü The β-blockers may cause bradycardia, hypotension, and CNS side effects such as fatigue,
lethargy, and insomnia
ü The β-blockers may decrease libido and cause erectile dysfunction, which can severely
reduce patient compliance.
 Alterations in serum lipid patterns

ü Non-cardioselective β-blockers may disturb lipid metabolism, Decreasing high-density

lipoprotein cholesterol and increasing triglycerides.
 Drug withdrawal

ü Abrupt withdrawal may induce angina, myocardial infarction, and even sudden death in
patients with ischemic heart disease.
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 Centrally Acting Sympatholytic Drugs

 Methyldopa, clonidine, guanabenz, guanfacine

 Act centrally to reduce sympathetic outflow

ü Lower BP primarily by stimulating 2-AR in the brainstem⇒ ↓sympathetic

outflow from the vasomotor center

 Also there could be peripheral stimulation of presynaptic 2-AR to

↓sympathetic tone (↓NE release)

Ø ↓sympathetic activity + ↑ parasympathetic activity⇒ ↓ HR, CO, TPR, plasma

renin activity,

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 Centrally Acting Sympatholytic Drugs…
Clonidine
 Clonidine acts centrally as an α2 agonist to produce inhibition of sympathetic vasomotor

centers, decreasing sympathetic outflow to the periphery.

ü This leads to reduced TPR and decreased BP.

 Clonidine is used primarily for the treatment of hypertension that has not responded

adequately to treatment with two or more drugs (i.e. used in resistant hypertension).

 Clonidine does not decrease renal blood flow or glomerular filtration,

ü therefore, is useful in the treatment of hypertension complicated by renal disease.

Adverse effects

 sedation and dry mouth… most frequent; sexual dysfunction, marked bradycardia,

rebound hypertension following abrupt withdrawal of clonidine therapy

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 Centrally Acting Sympatholytic Drugs…
Methyldopa
 Methyldopa is an α2 agonist that is converted to α-methylnorepinephrine and α-

methyldopamine centrally to diminish adrenergic outflow from the CNS.

 Methyldopa is first-line agent for hypertension in pregnant women, where it has a

record of safety.

 The most common side effects of methyldopa are sedation and drowsiness.

ü Its use is limited due to adverse effects and the need for multiple daily doses.

Guanabenz and guanfacine

 are centrally active antihypertensive drugs that share the central α-AR-stimulating

effects of clonidine.

63 They do not appear to offer any advantages over clonidine and are rarely used.
 Calcium channel blockers(CCBs)

 Voltage-gated Ca2+ channels (L-type or slow channels) mediate the entry of

extracellular Ca2+ into;

ü Smooth muscle and cardiac myocytes

ü SA and AV nodal cells in response to electrical depolarization.

 CCBs “block” the entry of calcium through the calcium channel in both smooth

muscle and myocardium, so that less calcium is available to the contractile

apparatus.

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 CCBs…

 In addition to their antianginal and antiarrhythmic effects, CCBs also reduce

peripheral resistance and blood pressure.

 CCBs are a recommended treatment option in hypertensive patients with diabetes

or angina.

 Hemodynamic differences among calcium channel blockers may influence the

choice of a particular agent.

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 CCBs…
Classes of CCBs
 Non-dihydropyridines

 Verapamil
ü is a diphenylalkylamines

ü is the least selective of any CCB and has significant effects on both cardiac and vascular

smooth muscle cells.

 Diltiazem

ü is the benzothiazepines

ü Like verapamil, diltiazem affects both cardiac and vascular smooth muscle cells,

Ø but it has a less pronounced negative inotropic effect on the heart compared to that
of verapamil.
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 CCBs…
 Dihydropyridines
ü This class of CCBs includes nifedipine, nicardipine, nimodipine amlodipine, felodipine,
isradipine, clevidipine.
Ø These agents differ in pharmacokinetics, approved uses, and drug interactions.

ü All dihydropyridines have a much greater affinity for vascular calcium channels than for
calcium channels in the heart.
Ø They are, therefore, particularly beneficial in treating hypertension.

ü The dihydropyridines have the advantage in that they show little interaction with other
cardiovascular drugs,
Ø such as digoxin or warfarin, which are often used concomitantly with calcium channel

blockers

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 CCBs…

Mechanism of actions of CCBs

 CCBs 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.

ü This causes vascular smooth muscle to relax, dilating mainly arterioles.

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 CCBs…
Pharmacological Actions
ü Vascular Tissue
- All Ca2+ channel antagonists relax arterial smooth muscle and thereby decrease
arterial resistance, blood pressure, and cardiac afterload.
- Ca2+ channel blockers do not affect cardiac preload significantly when given at
normal doses in patients.
ü Heart
- decreased activity of the heart (decrease heart rate, AV conduction and
contractility).
- DHP group has little direct cardiac activity and acts mainly on blood vessels.
- Verapamil and diltiazem have strong direct cardio-depressant (verapamil >
diltiazem) activity.
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 CCBs…
Cardiac vs vascular selectivity

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 CCBs…
Therapeutic uses
 They are useful in the treatment of hypertensive patients who also have asthma,
diabetes, and/or peripheral vascular disease,
ü because unlike β-blockers, they do not have the potential to adversely affect these
conditions.

 Other uses

ü Angina (variant Angina, exertional angina, unstable angina)

ü Myocardial infarction…diltiazem and verapamil may reduce the incidence of

reinfarction
ü Arrhythmia

 Supraventricular tachyarrhythmias: cardioselective preferable

ü Effective in migraine prophylaxis (esp. verapamil)

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 CCBs…

Pharmacokinetics

 Most of these agents have short half-lives (3 to 8 hours) following an oral dose.

 Sustained-release preparations are available and permit once-daily dosing.

 Amlodipine has a very long half-life and does not require a sustained-release

formulation.

 are characterized by high first-pass effect, high plasma protein binding, and

extensive metabolism.

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 CCBs…
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
ü due to their negative inotropic (force of cardiac muscle contraction) and dromotropic

(velocity of conduction) effects.

 Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure

are more frequent with dihydropyridines

 Peripheral edema is another commonly reported side effect of this class

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 Inhibitors of the renin-angiotensin system

üACE Inhibitors

üAT Receptor Blockers

üDirect Renin Inhibitors

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 Inhibitors of the Renin–Angiotensin System…

75 of action of drugs that interfere with the renin-angiotensin-aldosterone system

Sites
 Angiotensin-converting Enzyme Inhibitors (ACEIs)

 Captopril, enalapril, lisinopril, benazepril, quinapril, moexipril, ramipril,

trandolapril, perindopril, fosinopril

 The ACE inhibitors are recommended as first-line treatment of hypertension in

patients with a variety of compelling indications,

Ø including high coronary disease risk or history of diabetes, stroke, heart

failure, myocardial infarction, or chronic kidney disease.

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 ACEIs…
 Mechanism of action

üACEIs decrease angiotensin II and increase bradykinin levels by blocking the enzyme

ACE
Ø Vasodilation of both arterioles and veins occurs as a result of decreased vasoconstriction

(from diminished levels of angiotensin II) and

Ø enhanced vasodilation (from increased bradykinin).

üBy reducing circulating angiotensin II levels, ACEIs also decrease the secretion of

aldosterone,
Ø resulting in decreased sodium and water retention.

üACE inhibitors reduce both cardiac preload and afterload, thereby decreasing cardiac

work.

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 ACEIs…

Pharmacological Effect

 Arterial and venous blood vessel dilation causing a reduction of arterial pressure,

preload and after-load on the heart

 ↓Stimulation of production and release of aldosterone and ADH release⇒↓blood

volume and hence BP

 Down regulates sympathetic adrenergic activity

 Obviate effects of Ang-ІІ on cardiac and vascular remodeling

 Inhibits inactivation of bradykinnin

78
 ACEIs…

Therapeutic uses
 Hypertension

ü First line agents in most hypertensive patients.

ü Normalize BP in ~50% of patients with mild to moderate hypertension

ü 90% of patients are controlled by the combination of an ACEIs and either a

Ca2+ channel blocker/or a diuretic

 ACE inhibitors slow the progression of diabetic nephropathy

ü Beneficial effects on renal function may result from decreasing intraglomerular

pressures, due to efferent arteriolar vasodilation.

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 ACEIs…

 ACEIs have a useful role in treating patients with CKD(with diabetic and non-

diabetic)
ü because they diminish proteinuria and stabilize renal function

 There is evidence that ACEIs reduce the incidence of diabetes in patients with high

cardiovascular risk.

 ACE inhibitors are a standard in the care of a patient following a myocardial

infarction and first-line agents in the treatment of patients with systolic dysfunction.

 ACE inhibitors are first-line drugs for treating heart failure, hypertensive patients
with CKD, and patients at increased risk of coronary artery disease.

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 ACEIs…

Pharmacokinetics
 All of the ACE inhibitors are orally bioavailable as a drug or prodrug.

 All but captopril and lisinopril undergo hepatic conversion to active metabolites, so

these agents may be preferred in patients with severe hepatic impairment.

 All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily

by the kidneys;
ü doses of these drugs should be reduced in patients with renal insufficiency.

 Enalaprilat is the only drug in this class available intravenously

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 ACEIs…

Adverse effects

ü Hypotension following the first dose of an ACEI

ü Mild hyperkalemia

ü Dry cough i

ü Angioedema

ü Skin Rash

 CIs: absolute CIs during pregnancy

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 Angiotensin II Receptor Blockers (ARBs)

 Losartan, valsartan, Azilsartan, candesartan, eprosartan, irbesartan,

olmesartan, and telmisarta
ü are blockers of the angiotensin II type 1 (AT1) receptor.

 They have no effect on bradykinin metabolism and are therefore more selective
blockers of angiotensin effects than ACEIs.
 They also have the potential for more complete inhibition of angiotensin action
compared with ACE inhibitors
ü because there are enzymes other than ACE that are capable of generating Ang-ІІ.

 The rank-order affinity of the AT1 receptor

ü Candesartan = olmesartan > irbesartan = eprosartan > telmisartan = valsartan >

losartan
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 ARBs…
 Their pharmacologic effects are similar to those of ACEIs in that

ü they produce arteriolar and venous dilation and block aldosterone secretion,

thus lowering blood pressure and decreasing salt and water retention

 They may be used as first-line agents for the treatment of hypertension,

ü especially in patients with a compelling indication of diabetes, heart failure, or

chronic kidney disease

 Associated with low incidence of some of the ADEs with ACEIs

 Similar to ACEIs with regard to

ü Pharmacological effect, therapeutic use

ü Adverse effects and contraindications

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 Direct Renin Inhibitors (DRI)

 A selective renin inhibitor, aliskiren, is available for the treatment of hypertension.

 Aliskiren directly inhibits renin and,

ü thus, acts earlier in the renin–angiotensin–aldosterone system than ACEIs or

ARBs
 It lowers blood pressure about as effectively as ARBs, ACEIs, and thiazides.

 Aliskiren should not be routinely combined with an ACEIs or ARB.

 Aliskiren can cause diarrhea, especially at higher doses, and can also cause cough and

angioedema, but probably less often than ACE inhibitors.

 As with ACE inhibitors and ARBs, aliskiren is contraindicated during pregnancy.

 Aliskiren is metabolized by CYP 3A4 and is subject to many drug interactions.

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 Direct acting Vasodilators

 Arterial vasodilators: hydralazine, minoxidil

 Arterial and venous vasodilators: nitroprusside

 Oral vasodilators: hydralazine and minoxidil

ü for long-term management of hypertension

 Parenteral vasodilators: nitroprusside

ü for hypertensive emergencies

 Direct-acting vasodilators are associated with sodium and water retention and

must be used with a diuretic and beta-blocker.

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 Vasodilators…
Hydralazine
 It dilates arterioles but not veins, causing ↓BP accompanied by reflex tachycardia

and ↑CO and ↑plasma renin activity as a result of hypotension

 Used in the treatment of severe hypertension, hypertensive emergencies in pregnant

women

Mechanism of action
1. Causes smooth muscle hyperpolarization through the opening of K+ channels;
2. May inhibit IP3-induced calcium release from the smooth muscle sarcoplasmic reticulum
3. Stimulates the formation of NO by the vascular endothelium, leading to cGMP-mediated
vasodilation
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 Vasodilators…

 Pharmacokinetics of Hydralazine

- Well absorbed via the GI tract.

- rapidly metabolized by the liver during the first pass

- bioavailability is low (averaging 25%) and variable among individuals.

- N-acetylated in the bowel and the liver

- elimination is principally a function of hepatic blood flow than the rate of

acetylation.
- Although its t1/2 in plasma is about 1 h, the hypotensive effect of hydralazine can

last as long as 12 h, no clear explanation.

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 Vasodilators…

 Clinical uses of Hydralazine

- Hydralazine is an accepted medication for controlling blood pressure in

pregnancy induced hypertension.

- Hydralazine elicits the baroreceptor reflex,

Ø necessitating coadministration with a diuretic to counteract sodium

and water retention and a β-blocker to prevent tachycardia.

- The combination of hydralazine with nitrates is effective in heart failure and

should be considered in patients with both hypertension and heart failure,

especially in African-American patients.

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 Vasodilators…

 Adverse effects of Hyralazine

- The most common adverse effects of hydralazine are headache, nausea,

anorexia, palpitations, sweating, and flushing.

- In patients with ischemic heart disease, reflex tachycardia and sympathetic

stimulation may provoke angina or ischemic arrhythmias.

- A lupus-like syndrome can occur with high dosages,

- The syndrome is not associated with renal damage and is reversed by

discontinuance of hydralazine.
- Peripheral neuropathy and drug fever are other serious but uncommon adverse

effects.

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 Vasodilators…

Minoxidil
 Mechanism
- Prodrug and converted to minoxidil sulfate
- The effect results from the opening of potassium channels in smooth muscle
membranes by minoxidil sulfate, the active metabolite.
Ø Increased potassium permeability stabilizes the membrane at its resting
potential and makes contraction less likely.
- Like hydralazine, minoxidil dilates arterioles but not veins.
- extremely efficacious, and systemic administration is reserved for severe
hypertension.

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 Vasodilators…

 PK

- is readily absorbed from the gut.

- About 90% metabolized by glucuronidation

- excreted principally in the urine

- The elimination half‐ life is approximately 4h.

 Use

- particularly useful in patients with chronic renal failure

- use in combination with loop diuretic, β blocker & RAS inhibitor

- produces hirsutism, used to reduce hair loss(Alopecia).

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 Vasodilators…

ü Adverse effects

- fluid and salt retention (increase renin release)

- Tachycardia & angina (reflex)

- hypertrichosis (growing of body hair)

 Minoxidil is contraindicated in pheochromocytoma,

ü because it may stimulate secretion of catecholamines from the tumor through

its antihypertensive action.

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 Vasodilators…

Sodium Nitroprusside
 is a powerful parenterally administered vasodilator

 is used in treating hypertensive emergencies as well as severe heart failure.

 Nitroprusside dilates both arterial and venous vessels,

ü resulting in reduced peripheral vascular resistance and venous return.

 The action occurs as a result of activation of guanylyl cyclase, either via release of

nitric oxide or by direct stimulation of the enzyme.

ü The result is increased intracellular cGMP, which relaxes vascular smooth muscle

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 Vasodilators…

 Pharmacokinetics

- onset of action:30 sec; peak effect:2 min, DOA:3 min.

- very short acting drug; has to be given by constant i.v. infusion.

- Its metabolism is initiated by its reduction, which is followed by the release of

cyanide and then NO.

- Cyanide is further metabolized by hepatic rhodanase to form thiocyanate,

which is eliminated in the urine.

- Should be freshly prepared (unstable & light sensitive).

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 Vasodilators…

 Toxicity and precautions

- Cyanide toxicity with prolonged use can result in irreversible neurologic

changes and cardiac arrest

Ø The concomitant administration of sodium thiosulfate or hydroxocobalamin can

prevent accumulation of cyanide

- It can also result in hypothyroidism due to the accumulation of thiocyanate

(antithyroid compound).
- It is contra-indicated in pregnancy.

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 Selective α1 Blockers

ü Prazosin, Terazosin, Doxazosin

- These drugs are the treatment of choice for patient with hypertension and
benign prostate hyperplasia (BPH).
- not recommended as monotherapy for hypertensive patients
- Monotherapy for hypertension increases the risk for developing CHF.
- These drugs do not impair the metabolism, thus can be safely used in patients
with diabetes (no change in blood glucose), coronary artery disease (improves
lipid levels) and gout (do not affect uric acid).
- Cause retention of fluid and reflex tachycardia (used in combination with

diuretics, β blockers)
- Major adverse effect of alpha blockers is first dose hypotension (postural
hypotension occurring at the start of treatment or on dose escalation).
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 HTN & compelling indications

Concomitant condition Drugs preferred Drugs to be

avoided
Angina (CAD) β blocker, CCB Vasodilators
Diabetes & Hyperlipidemia ACEI, ARB, CCB, α blocker β blocker, Diuretics
Elderly & Isolated systolic HTN Diuretics, CCB
Low renin hypertension Diuretics, CCB
High renin hypertension ACEI, ARB, β blocker
Asthma CCB, Diuretics, ACEI, ARB β blocker
CHF ACEI, Diuretics CCB
CKD ACEI, ARB
Post MI β blocker, ACEI
BPH α blocker
Peripheral vascular disease CCB, α blocker β blocker
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 THANK YOU

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