pharmacology 3 - management of heart failure

7/31/2019 Pharmacology 3 - Management of Heart Failure

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Drugs Used for Management of

Heart Failure


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1. Compensatory mechanisms in CHF

2. Different classes of drugs used for management of CHF

3. Pharmacology of angiotensin-converting enzyme inhibitors,-blockers and calcium channel blochers regarding:

a) Mode of action

b) Pharmacokineticsc) Clinical Uses

d) Adverse Effects

e) Drug Interactions

Learning Objectives

At the end of this class, students are supposed to befamiliar with:


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Compensatory physiological responses in CHF


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If these mechanisms adequately restore cardiac output, the

heart failure is said to be compensated.

However, these compensations increase the work of the

heart and contribute to further decline in cardiac

performance.

If the adaptive mechanisms fail to maintain cardiac output,

the heart failure is termed decompensated.

Decompensated heart failure


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Drugs commonly used in management of HF

1. Angiotensin-Converting Enzyme (ACE) Inhibitors: Captopril

3. Diuretics: Thiazides (eg, hydrochlorothiazide) and furosemide

4. Inotropic-cardiotonic drugs: Digoxin, Inamrinone and Nesiritide

5. Aldosterone Antagonist: Spironolactone

6. Vasodialators: Nitrates, hzdralayine and isosorbide dinitrate

7. Beta adrenergic blocking agents: Propranolol, atenolol, metoprolol

2. Angiotensin II receptor blockers: Losartan, candesartan, irbesartan

8. Adrenergics : Dopamine or dobutamine


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Drugs used for management of CHF

In CHF, compensatory mechaqnisms increase both

preload and afterload.Preload is the volume of blood that fills the

ventricle during diastole.

Elevated preload causes overfilling of the heart,

which increases the workload.

Afterload is the pressure that must be overcome

for the heart to pump blood into the arterial system.

Elevated afterload causes the heart to work harderto pump blood into the arterial system.

Vasodilators are useful in reducing excessive

preload and afterload.

1. Vasodilators: Dilation of venous blood vesselsincreases venous capacitance

leading to a decrease in cardiac

preload

Arterial dilatation reduces systemicarteriolar resistance and decrease

afterload.

2. Diuretics : Decrease blood volume thus

decreasing pre- and afterload and

decreasing oedema


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Angiotensin- Converting Enzyme

(ACE) Inhibitors


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Introduction

Treatment of hypertension and heart failure

Captopril and enalapril the fore-runners, followed by several

others such as perindopril, lisinopril, cilazapril, quinapril,

fosinopril, ramipril, trandolapril and zofenopril

Angiotensin Converting Enzyme Inhibitors (ACE-I)


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Mechanism of action of ACE -I
http://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.png


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ACE inhibitors inhibit the conversion of Angiotensin I to

Angiotensin II, which results in vasodilation and less sodium

and water retention via the kidneys .

Angiotensin converting enzyme inhibitors work best when the

renin-angiotensin system is activated

Mechanism of action of ACE -I


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IndividualMembers

1. Captopril

- Was the first ACE-inhibitor to become available

- Characterized by a much shorter half-life than other ACE inhibitors (2 hs)

2. Enalapril

- Differs from captopril in that it is a prodrug, converted to the

active enalaprilic acid during its first passage through the liver .

- enalaprilic acid has a half life of approximately 10 hours compared with two

hours for captopril .

More recently released ACE-inhibitors

longer elimination half-lives .

Otherwise, similar in terms of their clinical properties and side effects .



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Pharmacokinetics

Poor relationship between plasma concentration of ACE inhibitor and its

action action dependent to large extent on the state of activation of the

renin-angiotensin system (RAS)

Bioavailability varies between 25 and 80%

All excreted via the kidneys but some also undergo hepatic metabolism,

such as fosinopril, perindopril, ramipril, spirapril and trandolapril

Captopril has a short half-life, therefore dosing 2-3 times daily is required.

Most others have half-lives in excess of 10 hours .

Captopril bioavailability is reduced by 30-40% if co-administered with food .



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Clinical Uses

Hypertension

Cardiac Failure

Diabetes

Myocardial infarction

1. Cardiac Failure

Prolong survival as well as improve exercise tolerance and quality of life

Reduce the mortality of moderate to severe cardiac failure by 20-30%

Delay progression of heart failure in those with asymptomatic left

ventricular dysfunction

Introduce with caution to avoid hypotension, test dose and monitor BP,

increase dose slowly if tolerated .



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Clinical Uses

2. Hypertension

Relatively weak anti-hypertensive effect when administered alone .

Synergistic when administered with diuretics or vasodilators.

First-line agents in those with concomitant heart failure or type I diabetes

3. DiabetesReduce proteinuria and slow the progression of nephropathy in diabetes

Used as first-line therapy in diabetics with hypertension

Increasingly as first-line therapy in diabetics with early renal disease

who are normotensive

4. Myocardial Infarction

ACE inhibitors improve survival after MI in those with left ventricular failure

(even if transient) - Study - 26% reduction in mortality



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Adverse Effects

First dose hypotension -more likely if RAS activated i.e. elderly, sodiumand water depletion, diuretic use, renal artery stenosis.

Initiate therapy with a test dose .

Exacerbation of hypotension

Renal failure - 0.5-1%

Cough -20%

Rash, taste disturbance, neutropenia

Angioedema - rare but life-threatening

Reproductive effects -oligohydramnios, delayed fetal growth and decreased

fetal survival



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DRUG INTERACTIONS

Potassium-sparing diuretics - Severe hyperkalaemia may result if these

drugs are used in combination with potassium sparing diuretics

(eg amiloride) especially if the patient has some pre-existing degree of

renal insufficiency.

Beta-blockers : because beta blockers suppress renin release, they

reduce sensitivity to the effect of ACE-inhibitors.

Diuretics : potentiate the hypotensive activity of ACE inhibitors.



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Mode of Action

Competitively block binding of Angiotensin II (AT II) to ATII receptors

Blocks the vasoconstrictor and growth-promoting effects of AT II

Reduce sodium reabsorption and aldosterone release.

Available agents

Losartan, candesartan, irbesartan

Pharmacokinetics

Oral bioavailability of losartan 33%, therefore considerable FPM

Undergoes hepatic metabolism so reduce dose in hepatic dysfunction

Once daily dosing with all agents

Angiotesin II Receptor Blockers


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2. Diuretics

Diuretics are used in treating both acute and chronic HF.

Thiazides (eg, hydrochlorothiazide) can be used for mild

diuresis in clients with normal renal function;

loop diuretics (eg, furosemide) should be used in clients who

need strong diuresis or who have impaired renal function.


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3. Cadiotonic-inotropic drugs


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inotropic drugs?-What are cadiotonic

Inotropics and cardiotonics are medications that increase the strength

of the muscle contractions that pump blood from the heart.

They are mainly used for treatment for heart failure .

What are the different classes of inotropics?1. Digitalis glycosides (Mainly Digoxine)

2. Phosphodiestrase inhibitors e.g Inamrinone (Inocor), and milrinone IV

(Primacor)

3. Human Natriuretic Peptide B-type e.g Nesiritide (Natrecor)

4. Endothelin Receptor Antagonists

A Di i (L i )


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Pharmacology of digoxin on CVS:

Positive inotropic action - inhibits Na+/K+ATPase

Suppression of sympathetic nervous system activity

Increase of parasympathetic activity .

Negative chronotropic effect

Actions in Heart Failure

In HF, digoxin exerts a cardiotonic or positive inotropic effect that improves

the pumping ability of the heart.

Increased myocardial contractility allows the ventricles to empty more

completely with each heartbeat.

Improved cardiac output leads to decrease in all the following:

heart size, heart rate, end-systolic and end-diastolic

pressures, vasoconstriction, sympathetic nerve

stimulation, and venous congestion.

A. Digoxin (Lanoxin)


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Digoxin indirectly increases intracellular calcium levels by binding

to the Na-K-ATPase

Mechanism of action of digoxin

(Na-K-ATPase), an enzyme in cardiac cellmembranes that stimulates the movementof sodium out of myocardial cells aftercontraction.

Cardiac cellmembrane

Na-K-ATPase


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Mechanism of action of digoxin in arrhythmia

In atrial dysrhythmias, digoxin slows the rate of ventricular contraction

(negative chronotropic effect). This effect is caused by several factors:

1. First, digoxin has a direct depressant effect on cardiac conduction

tissues, especially the atrioventricular node. This action decreases

the number of electrical impulses allowed to reach the ventricles from

supraventricular sources.

2. Second, digoxin indirectly stimulates the vagus nerve.

3. Third, increased efficiency of myocardial contraction and vagal stimulation

decrease compensatory tachycardia that results from the sympathetic

nervous system in response to inadequate circulation.


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Medium lipid solubility and is relatively water soluble

Oral availability 70%

Protein-binding 20-40%

Large volume of distribution and high concentrations are found in the

myocardium, brain, liver, and skeletal muscle

It also crosses the placenta, and serum levels in neonates are similar to

those in the mother.

20% metabolized - renal excretion 60%, largely unchanged

Dosage must be reduced in the presence of renal failure to prevent drug

accumulation and toxicity.

Half-life 36-40 hours with normal renal function

Narrow therapeutic range 0.8-2.0 ng/ml

Therapeutic serum levels of digoxin are 0.5 to 2 ng/mL; toxic serum levels

are above 2 ng/mL. However, toxicity may occur at virtually any serum level.

Pharmacokinetics of digoxin


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Digoxin Dosages

Oral or intravenous

Loading dose for rapid "digitalization" only if patient can be monitored

closely for toxicity .

Steady-state plasma levels take about 7 days to achieve due to slow

elimination, longer if renal impairment .

Usual maintenance dose 0.125-0.25 mg/day

Trough plasma levels to monitor for toxicity

Therapeutic Uses of Digoxin

Management of HF,

Atrial fibrillation, and atrial flutter.


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Contraindications to Digoxin use

Digoxin is contraindicated in:

Severe myocarditis, ventricular tachycardia, or ventricular fibrillation and

must be used cautiously in clients with acute myocardial infarction, heart

block, Wolff-Parkinson-White syndrome (risk of fatal dysrhythmias),

electrolyte imbalances

(hypokalemia, hypomagnesemia, hypercalcemia), and renal impairment


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Administration and Digitalization

Digoxin is given orally or intravenously (IV).

I.M route is not recommended because pain and muscle necrosis may occur

at injection sites.

When given orally, onset of action occurs in 30 minutes to 2 hrs, and peak

effects occur in approximately 6 hrs.

When given IV, the onset of action occurs within 10 to 30 minutes, and peak

effects occur in 1 to 5 hours.

In the heart, maximum drug effect occurs when a steady-state tissue

concentration has been achieved. This occurs in approximately 1 week

unless loading doses are given for more rapid effects.

Traditionally, a loading dose is called a digitalizing dose.


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Administration and Digitalization

Traditionally, a loading dose is called a digitalizing dose.

Digitalization (administration of an amount sufficient to produce therapeutic

effects) may be accomplished rapidly by giving a total dose of 0.75 to 1.5 mg

of digoxin in divided doses, 6 to 8 hours apart, over a 24-hour period.

When digoxin is discontinued, the drug is eliminated from the body in

approximately 1 week.

Di i T i i


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Digoxin Toxicity

Narrow therapeutic range 0.8-2.0 ng/ml

Risk of toxic effects at levels above 2.0 ng/ml

Severe toxicity at levels above 3.5 ng/ml

GIT and CNS S/E are commonest and include anorexia, nausea, vomiting,

diarrhoea, abdominal cramps, visual disturbance, disorientation,

hallucinations and convulsions

Cardiac toxicity includes bradycardia, heart block and ventricular

tachyarrhythmias

Others - gynaecomastia, allergic skin reactions

M t f T i it


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Management of Toxicity

Mild to moderate toxicity without serious arrhythmia

Withdrawal of digoxin

Correction of electrolyte disturbance

Moderate to severe toxicity with arrhythmia

Withdrawal of digoxin

Correction of electrolyte disturbance (K+, Ca++ and Mg++)

Cardiac pacing for bradyarrhythmias

Antiarrthymic drugs, lidocaine, phenytoin and propranolol

Digoxin antibodies (Digibind)


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Inamrinone (Inocor), and milrinone IV (Primacor)

Cardiotonic-inotropic agents used in short-term management of acute, severe

HF that is not controlled by digoxin, diuretics, and vasodilators.

Mechanism of action

- The drugs increase levels of cyclic adenosine monophosphate (cAMP) in

myocardial cells by inhibiting phosphodiesterase, the enzyme thatnormally metabolizes cAMP.

- They also relax vascular smooth muscle to produce vasodilation and

decrease preload and afterload.

B. Phosphodiesterase Inhibitors

cAMP & cGMP Positive inotropic effectVasodialation

cyclic nucleotide

phosphodiesterasesDegradation

Inamrinonemilrinone


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Inamrinone (Inocor), and milrinone IV (Primacor)

Kinetics and Toxicity

- There is a time delay before the drugs reach therapeutic serum levels as

well as inter-individual variability in therapeutic doses.

- Both drugs are given IV by bolus injection followed by continuous infusion.

- Dose-limiting adverse effects of the drugs include tachycardia, atrial or

ventricular dysrhythmias, and hypotension.

B. Phosphodiesterase Inhibitors

C Human Natriuretic Peptide B type


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Nesiritide (Natrecor)

The first in this class of drugs to be used in the management of acute HF.

Nesiritide is identical to endogenous human B-type natriuretic peptide,

which is secreted primarily by the ventricles in response to fluid and

pressure overload.

Mechanism of actionThis drug acts to compensate for deteriorating cardiac function by:

1. Reducing preload and afterload,

2. Increasing diuresis and secretion of sodium,

3. Suppressing the reninangiotensinaldosterone system, and

4. Decreasing secretion of the neurohormones endothelin and

norepinephrine.

Onset of action is immediate with peak effects attained in 15 minutes with a

bolus dose followed by continuous IV infusion.

C. Human Natriuretic Peptide B-type

D E d h li R A i


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This new class of drugs relaxes blood vessels and improves blood flow by

targeting endothelin-1 (a neurohormone) that is produced in excess in HF.

Endothelin-1 causes blood vessels to constrict, forcing the ailing heart to work

harder to pump blood through the narrowed vessels.

Studies indicate that endothelin antagonist drugs improve heart function,

as measured by cardiac index; animal studies indicate that structural

changes of heart failure (eg, hypertrophy) may be reversed by the drugs.

Currently, one endothelin receptor antagonist, bosentan

(Tracleer), is Food and Drug Administration (FDA) approvedbut only for treatment of pulmonary hypertension.

Additional data are being collected to support specific indications for these

drugs in the management of heart failure

D. Endothelin Receptor Antagonists


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4. Beta AdrenergicBlockers


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Beta Adrenergic Blockers

Decrease heart rate, force of myocardial contraction,

cardiac output, and renin release from the kidneys

Drugs of choice for patients with tachycardia, angina, MI,

left ventricular hypertrophy and high renin hypertension

Most are pregnancy category C and D ?????

B t Ad i Bl k


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Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the firsttrimester of pregnancy (and there is no evidence of risk in later trimesters).

Pregnancy Category A

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are noadequate and well-controlled studies in pregnant women OR Animal studies have shown anadverse effect, but adequate and well-controlled studies in pregnant women have failed to

demonstrate a risk to the fetus in any trimester.

Pregnancy Category B

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequateand well-controlled studies in humans, but potential benefits may warrant use of the drug inpregnant women despite potential risks.

Pregnancy Category C

There is positive evidence of human fetal risk based on adverse reaction data from investigationalor marketing experience or studies in humans, but potential benefits may warrant use of the drugin pregnant women despite potential risks.

Pregnancy Category D

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positiveevidence of human fetal risk based on adverse reaction data from investigational or marketingexperience, and the risks involved in use of the drug in pregnant women clearly outweigh potentialbenefits.

Pregnancy Category X


The pregnancy categoryof a pharmaceuticalagent is an assessment of the risk offetal injury due to the pharmaceutical, if it is used as directed by the mother during

pregnancy


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B t Bl k


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Beta Blockers

Propranolol (Inderal): Non-selective -blocker

Nadolol (Corgard): Non-selective -blocker

Timolol (Timolol): Non-selective -blocker

Metoprolol (Lopressor)

Atenolol (Tenormin)

Betaxolol (Betoptic) for glaucoma and ocular and malignant hypertension

Eff t f B t Ad i Bl k


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Effects of Beta Adrenergic BlockersIn HF

Decreasemyocardialworkload

ADRENERGIC BLOCKING AGENTS


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Clinical applications

a. Hypertension: lower b.p by decreasing cardiac output .

b. CHF: decrease myocardial workload

C. Glaucoma: Propranolol and other blockers (timolol) are effective

in diminishing IOP in glaucoma by decreasing the secretion of

aqueous humor by the ciliary body.

d. Migraine prophylaxis: blockade of catecholamine-induced

vasodilation in the brain vasculature.

e. Hyperthyroidism: -blockers are effective in blunting the

widespread sympathetic stimulation that occurs in hyperthyroidism

-ADRENERGIC BLOCKING AGENTS

ADRENERGIC BLOCKING AGENTS


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Clinical applicationsf. Angina pectoris: -blockers decrease the oxygen requirement of

heart muscle (not for acute treatment).

g. Myocardial infarction: -blockers have a protective effect on themyocardium.

-ADRENERGIC BLOCKING AGENTS



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Adverse Effects

1. Bronchospasm -may aggravate asthma, impair responsiveness to 2

agonists or precipitate an acute attack (avoid all -blockers in asthma as 1selective agents are only relatively selective.)

2. Heart failure -may precipitate or worsen heart failure, therefore introduce

cautiously, in those who might benefit

3. Bradycardia, heart block -beta-blockers devoid of ISA (pindolol, acebutolol)

produce bradycardia, which may be well tolerated. Avoid in second or

third-degree heart block .4. Hypotension

5. Sleep disturbance, depression, sexual dysfunction

6. Tiredness, reduced work capacity -20%

7. Peripheral circulation -unopposed alpha-receptor mediated vasoconstriction.


B t Ad i Bl k


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Adverse Effects

8. Hypoglycaemia -use only cardioselective beta-blockers in diabetics prone to

hypoglycaemia

9. Withdrawal symptoms -chronic beta-blockade causes upregulation of

beta-receptor numbers. Withdrawal of beta-blocker may be associated with

exaggerated tachycardia on mild exertion. Therefore, withdraw slowly over

1-2 weeks .

10. Hypertension -may worsen hypertension in patients with

phaeochromocytoma, so combine with vasodilator (alpha-blocker)




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Clinically relevant drug interactions

Reduce liver blood flow, therefore, reduced clearance of highly-extracted

drugs, such as, lignocaine, morphine and pethidine

Combined with verapamil or diltiazem, may depress SA and AV nodes

Cimetidine (hepatic enzyme inhibition) may increase plasma level of

hepatically metabolised -blockers

Rifampicin and phenobarbital (enzyme induction) have the opposite effect

Combined with reserpine, may cause bradycardia and syncope

Combined with sympathomimetic agents, such as pseudoephedrine and

ephedrine, may cause elevated BP due to unopposed alpha-receptor

induced vasoconstriction



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5. Calcium Channel BlockingAgents


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Calcium Channel Blocking Agents

Useful in hypertension as they dilate peripheral arteries and decrease

peripheral vascular resistance by relaxing vascular smooth muscle

Monotherapy or in combination

Tolerated well in renal failure

Amlodipine (Norvasc)

Diltiazem (Cardizem)

Felodipine (Plendil)

Nifedipine (Procardia)

Verapamil (Calan)may cause gingival hyperplasia

Commonly used agents



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Chemical classes of organic Ca2+ channel blockers:

1. Dihydropyridines (DHPs; prototype nifedipine)

2. Phenylalkylamines (prototype verapamil)

3. Benzothiazepines (prototype diltiazem). Despite their different

structure they all bind within a single drug binding region

close to the pore of the channel.

1. DHPs: nifedipine, amlodipine, nitrendipine, nisoldipine,

nicardipine and isradipine.

They directly bind to and stabilize the inactivated state of thechannel

DHPs block the channels in arterial smooth muscle at lower

concentrations than cardiac muscle.

Ca c u C a e oc g ge ts



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2. Phenylalkylamines: Verapamil is the most widely used

phenylalkylamine.The more active methoxyverapamil (gallopamil) is also licensed

for clinical use in some countries.

Verapamil block of Ca2+ channels becomes more pronounced

during tachyarrhythmias. Therefore, it has antiarrhythmic,

vasodilating and cardiodepressive actions.

3. Benzothiazepines: Diltiazem is the only benzothiazepine in

clinical use.

Its molecular mechanism of action as well as its pharmacological

effects closely resemble those of phenylalkylamines.




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Mode of Action

In cardiac and vascular smooth muscle, calcium entry into the cell triggers

muscle contraction this is inhibited by CCBs, resulting invasodilation

Skeletal muscle relies on intracellular calcium to initiate contraction and is

therefore little affected by CCBs


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Simplified view of the pharmacological action of L-type Ca2+ channel blockers in

cardiac myocytes:

In cardiac myocytes L-type Ca2+ channels open when the plasma membrane is

depolarised by an action potential carried along the muscle cells by the opening ofvoltage-gated sodium-channels (Na-Ch). The action potential is terminated (an its

duration is determined) by the opening of potassium channels (K-Ch). Ca2+ influx

triggers massive release of Ca2+ from intracellular stores by opening ryanodine-

sensitive Ca2+ channels (ryanodine receptors, RyR) in the sarcoplasmic reticulum,

resulting in an intracellular Ca2+ transient. Ca2+ influx and released Ca2+ directly

initiate contraction. Contraction is terminated by the rapid uptake into the SR by SR

Ca2+ ATPases (SERCA). b-adrenergic receptor stimulation increases inotropy by

hosphorylation (P) of phospholamban (PLN) and L-type channels through cAMP-

dependent protein kinase (cAMP-PK). The resulting stimulation of Ca2+ influx and

Ca2+ - pump activity increases the load of Ca2+ in the SR stores. This leads to

enhanced Ca2+ transients upon depolarization. Inhibition of Ca2+ influx through L-type Ca2+ channels by Ca2+ channel blockers causes decreased Ca2+ entry and SR

load. Less Ca2+ influx and release result in smaller Ca2+ transients and a decrease

in contractile force.



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Site of Action and Clinical Effects

The CCB subgroups exert their major effects at different sites

Verapamil (phenylalkylamine) affects all calcium receptors. It vasodilates,

slows A-V conduction and reduces the force of contraction of cardiac smooth

muscle (-ve inotropic).

Uses : hypertension, angina, some SVTs

Dihydropyridines (nifedipine, amlodipine and felodipine) act on smooth

muscle only, resulting in peripheral and coronary vasodilation. This is

associated with reflex tachycardia and increased cardiac output.

Uses : hypertension

Diltiazem has intermediate properties, resulting in vasodilation, mild A-V

node conduction depression and mild negative inotropic effect.

Uses: angina, some arrhythmias



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Adverse effects

Constipation Common with verapamil, also occurs with diltiazem .

Results from the relaxing effect of these drugs on smooth muscle .

Prevalence of constipation is reduced by avoiding the upper dose levels

Cardiac failure

Verapamil and diltiazem suppress myocardial contractility and may

precipitate or worsen cardiac failure. more likely if high doses are used or if

they are used along with other cardiac depressant drugs especially beta

blocking agents .




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Adverse effects

Disturbed cardiac conduction (verapamil, diltiazem)

A-V node suppression can manifest as A-V block - may result in sinus arrest,

sino-atrial block, sinus bradycardia or AV block .

Exacerbation of ischaemic chest pain

DHP - worsening of angina due to a reflex tachycardia .

DHP - increase mortality in patients after myocardial infarction and should

be avoided in this setting .

Vascular headaches

precipitation of migraine in predisposed persons

most common with nifedipine and other dihydropyridines .

Flushing and postural hypotension may also occur .




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Drug Interactions with Calcium Antagonists

Beta blockers Nifedipine and other DHPs ok in hypertension but may produce excessive

hypotension in a normotensive patient with angina .

Avoid the combination of a beta blocker and verapamil.

Oral verapamil and an oral beta blocker can be tolerated only if the patient

has normal cardiac function it may precipitate cardiac failure if myocardial

function is borderline .

Intravenous verapamil should never be administered to a patient receiving

beta blockers because of the danger of producing severe hypotension and

cardiac failure. Similar care should be taken with diltiazem .




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Drug Interactions with Calcium Antagonists

Digoxin

Verapamil transiently raises plasma digoxin levels by 30 to 50% overa few weeks. This may result in additive AV blockade.

Other CCB may also increase digoxin levels but to a lesser degree .

Grapefruit juice

Concomitant intake of nifedipine with grapefruit juice (and possibly orange

juice) increased bioavailability of nifedipine and may cause hypotension.

Cytochrome P450 inhibitors

Calcium antagonists (particularly dihydropyridines) are metabolised

by oxidation in the liver and may compete with other drugs for this

pathway. This may explain increased levels of drugs such astheophylline, cyclosporine and terfenadine.

Nifedipine levels may also be increased by these drugs.

Lithium

Nifedipine increases lithium plasma levels.




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Adrenergics : Dopamine or dobutamine may be used in acute, severe

heart failure (HF) when circulatory support is required, usually in a criticalcare unit.

Aldosterone Antagonist

Increasingly, spironolactone is also being added for clients with moderate tosevere HF.

Spironolactone is an aldosterone antagonist that reduces the aldosterone-

induced retention of sodium and water and impaired vascular function.

Although ACE inhibitors also decrease aldosterone initially, this effect is

transient.

Spironolactone is given in a daily dose of 12.5 to 25 mg, along with standard

doses of an ACE inhibitor, a loop diuretic, and usually digoxin.



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Vasodilators

Vasodilators are essential components of treatment regimens

for HF, and the beneficial effects of ACE inhibitors and angiotensin

receptor antagonists stem significantly from their vasodilating effects .

Other vasodilators may also be used.

Venous dilators (eg, nitrates) decrease preloadArterial dilators (eg, hydralazine) decrease afterload.

Isosorbide dinitrate and hydralazine may be combined to decrease both

preload and afterload. The combination has similar effects to those of an ACE

inhibitor or an ARB, but may not be as well tolerated by clients.

Oral vasodilators usually are used in clients with chronic HF and parenteral

agents are reserved for those who have severe HF or are unable to take oral

g y g

pharmacology 3 - management of heart failure

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