CONGESTIVE HEART FAILURE

DR. MA. LENY ALDA G. JUSAYAN

INTERNAL MEDICINE, FPSECP, RN, RMT

Department of Pharmacology

COURSE OBJECTIVES:

• Explain the pathophysiology of heart failure

• Discuss the different drugs used in the treatment of heart failure as to its pharmacokinetics, pharmacodynamics, drug interactions, adverse effects

• Clinical application of the use of drugs in acute and chronic types of heart failure

HEART FAILURE

• Inability of the heart to pump an adequate amount of blood to the body’s needs

• CONGESTIVE HEART FAILURE – refers to the state in which abnormal circulatory congestion exists a result of heart failure

4

Heart Failure (Pump Failure)• A disorder in which the heart

loses its ability to pump blood efficiently throughout the body

• Affects Cardiac Output– SV X HR

• End result:↓Cardiac Output

PATHOPHYSIOLOGY:

– Heart failure results in DEPRESSION of the ventricular function curve

– COMPENSATION in the form of stretching of myocardial fibers

– Stretching leads to cardiac dilatation which occurs when the left ventricle fails to eject its normal end diastolic volume

6

Heart Failure Pathophysiology: Impaired Cardiac Function

• Failure to pump: Failure to empty ventricles

& reduced delivery of blood into circulation (↓ CO)

• Increased ventricular pressures

• Elevated pulmonary and systemic pressures

• further ↓ CO• Series of compensatory

mechanisms

7

Heart Failure Compensatory mechanisms of low CO…

1. SNS stimulation… ↑ HR and

cardiac contractility… ↑ CO

3. Ventricular hypertrophy … cardiac contractility… ↑ CO

2. Starling’s Law/…

Ventricular dilation: ↑ CO

44. Decreased renal blood flow…. Decreased renal blood flow…increasing Na & H20 retention…increasing Na & H20 retention…increases blood volume, ↑ HR & CO.increases blood volume, ↑ HR & CO.

8

Heart Failure Compensatory mechanisms of low CO…

1. SNS stimulation… ↑ HR and

cardiac contractility… ↑ CO

3. Ventricular hypertrophy … cardiac contractility… ↑ CO

2. Starling’s Law/…

Ventricular dilation: ↑ CO

44. Decreased renal blood flow…. Decreased renal blood flow…increasing Na & H20 retention…increasing Na & H20 retention…increases blood volume, ↑ HR & CO.increases blood volume, ↑ HR & CO.

Compensatory Mechanisms in Heart Failure

• Mechanisms designed for acute loss in cardiac output

• Chronic activation of these mechanisms worsens heart failure

PATHOPHYSIOLOGY:

• STARLING’S LAW“Within limits, the force of ventricular contraction is a function of the end-diastolic length of the cardiac muscle, which in turn is closely related to the ventricular end-diastolic volume.”

CARDIAC FAILURE VENOUS PRESSURE

CARDIAC OUTPUT

BLOOD PRESSURE

SYMPATHETIC ACTIVITY

RENAL BLOOD FLOW

RENIN ANGIOTENSIN II

ALDOSTERONE

SODIUM RETENTION CAPILLARY FILTRATION

EDEMA

NEUROHUMORAL ACTIVATION DURING MYOCARDIAL FAILURE

MYOCARDIAL FAILURE

CARDIAC OUTPUT

BLOOD PRESSURE/TISSUE PERFUSION

ACTIVATION OF ADRENERGIC SYSTEM

ARTERIOLAR CONSTRICTION

INCREASED SYSTEMIC VASCULAR RESISTANCE

INCREASED RESISTANCE TO EJECTION

Pathophysiology of Cardiac Performance

Factor Mechanism Therapeutic Strategy

1. PRELOAD (work or stress the heart faces at the end of diastole)

increased blood volume and increased venous tone--->atrial filling pressure

-salt restriction-diuretic therapy-venodilator drugs

2. AFTERLOAD (resistance against which the heart must pump)

increased sympathetic stimulation & activation of renin-angiotensin system ---> vascular resistance ---> increased BP

- arteriolar vasodilators-decreased angiotensin II(ACE inhibitors)

3. CONTRACTILITY decreased myocardial contractility ---> decreased CO

-inotropic drugs (cardiac glycosides)

4. HEART RATE decreased contractility and decreased stroke volume ---> increased HR (via activation of adrenoceptors)

EFFECTS:

• DOWN-REGULATORY CHANGES IN THE β1-ADRENOCEPTOR-G PROTEIN EFFECTOR SYSTEM

• BETA 2 RECEPTORS ARE NOT DOWN REGULATED – COUPLING WITH IP3-DAG CASCADE

• BETA 3 RECEPTORS ARE NOT DOWN REGULATED – MEDIATE NEGATIVE INOTROPHIC EFFECTS

• EXCESSIVE BETA ACTIVATION:– LEAKAGE OF CALCIUM FROM THE SR

VIA RyR2 CHANNELS – VENTRICULAR STIFFENING & ARRYHTHMIAS

• INCREASED ANGIOTENSIN II PRODUCTION LEADS – INCREASED ALDOSTERONE SECRETION – INCREASED AFTERLOAD– REMODELLING

INTRINSIC COMPENSATORY RESPONSE:

• MYOCARDIAL HYPERTROPHY– Increase in muscle mass to help maintain cardiac

performance– Ischemic changes, impairment of diastolic filling,

alterations in ventricular geometry

• REMODELLING– Dilatation & other slow structural changes that occur in

the stressed myocardium– Proliferation of connective tissue cells & myocardial

cells– Accelerated apoptosis

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Causes of Heart Failure

Acute/Chronic ♥ Problems

• HTN -#1

• CAD

• MI

• Valvular ♥ Disease

CAUSES OF HEART FAILURE:

• Final common pathway of many kinds of heart diseases– Ischemic, alcoholic, restrictive, hypertrophic

– Optimal treatment requires identification of primary & secondary factors leading to CHF

– HELPFUL RESULT of dilatation: increases cardiac output

– HARMFUL RESULT of dilation: more wall tension, more oxygen is needed to produce any given stroke volume

CLASSIFICATION:

• SYSTOLIC DYSFUNCTION:– Inadequate force is generated to eject blood

normally – Reduce cardiac output, ejection fraction

(< 45%)– Typical of acute heart failure– Secondary to AMI– Responsive to inotropics

CLASSIFICATION:

• DIASTOLIC DYSFUNCTION– Inadequate relaxation to permit normal

filling – Hypertrophy and stiffening of myocardium– Cardiac output may be reduced – Ejection fraction may be normal– Do not respond optimally to inotropic agents

CLASSIFICATION:

• HIGH OUTPUT FAILURE– Increase demand of the body with insufficient

cardiac output– Hyperthyroidism, beri-beri, anemia, AV shunts– Treatment is correction of underlying cause

CLASSIFICATION:

• ACUTE HEART FAILURE– Sudden development of a large myocardial

infarction or rupture of a cardiac valve in a patient who previously was entirely well, usually predominant systolic dysfunction

CLASSIFICATION:

• CHRONIC HEART FAILURE– Typically observed in patients with dilated

cardiomyopathy or multivalvular heart diseases that develops or progresses slowly

PRECIPITATING CAUSES OF HEART FAILURE:• Infection• Anemia• Thyrotoxicosis & pregnancy• Arrythmias• Rheumatic, viral & other forms of myocarditis• Infective endocarditis• Systemic hypertension• Myocardial infarction• Physical, dietary, fluid, environmental & emotional

excesses• Pulmonary embolism

CLINICAL MANIFESTATIONS:

LEFT HEART FAILURE

Pulmonary EdemaThe most severe manifestation of The most severe manifestation of Left Heart Failure Left Heart Failure

Fluid leak into the pulmonary Fluid leak into the pulmonary interstitial spaces (Pulmonary interstitial spaces (Pulmonary congestion/edema)congestion/edema)

Hypoxia and poor 02 exchangeHypoxia and poor 02 exchange

PULMONARY CONGESTION & RESPIRATORY SYMPTOMS:

• Result of dilatation & increasing left ventricular end diastolic pressure, left atrial pressure & capillary pressures– Results to pulmonary vascular congestion &

symptoms associated with cough with blood tinged sputum

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Clinical picture…Left Heart Failure• Dyspnea/Dyspnea on

exertion (most sensitive: absence indicates Tx effective)

• Cough orthopnea• Paroxysmal nocturnal

dyspnea (PND)• Productive cough with pink

frothy sputum• Tachypnea • Pale, possible cyanotic• Clammy and cold skin• Crackles/Wheezes• Extra heart sounds – S3, S4• Heart murmur

Cont.

• EDEMA OF THE BRONCHIAL MUCOSA– Increases resistance to airflow producing

respiratory distress similar to asthma (cardiac asthma)

Cont:

• DYSPNEA– Results from reflexes initiated by vascular

distention– Increased rigidity of lungs & impaired gas

exchange resulting from interstitial edema– Accumulation of fluid in ALVEOLARS

SACS (pulmonary edema)

Cont.

TACHYCARDIAAn early compensatory response mediated by

increased sympathetic tone

EDEMA compensatory response mediated by the renin

angiotensin aldosterone system & by increased sympathetic outflow

CARDIOMEGALYa compensatory structural response

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Right Heart Failure

• Clinical picture…(Congestion)– JVD,

hepatomegaly and dependent edema (LEs, thighs, abdomen-ascites)

42

Heart Failure Clinical manifestations : Pulmonary Congestion (L)

and Systemic Congestion (R)

Right Heart Failure Left Heart Failure

Pulmonary fluid overloadPeripheral fluid overload

PHYSICAL EXAM:

• Jugular venous distention

• S3• Rales• Pleural effusion• Edema• Hepatomegaly• Ascites

45

Review: Subjective Data

Pt. may c/o• anxiety• DOE• PND• orthopnea• productive cough

with pink frothy sputum

• Fatigue and weakness

46

Review: Objective DataPA may reveal:

Left heart Failure• Tachypnea/SOB• Use of accessory

muscles• Wheezes/Crackles• skin

– Clammy/cold– pale/cyanotic

Right Heart Failure• peripheral edema• JVD• Ascites, enlarged

spleen/liver

FRAMINGHAM CRITERIA FOR DIAGNOSIS OF CHF:

• MAJOR CRITERIA– PND– NECK VEIN

ENGORGEMENT– RALES– CARDIOMEGALY– ACUTE PULMONARY

EDEMA– S3 GALLOP VENOUS PRESSURE

(>16 cmH2O)– (+) HEPATOJUGULAR

REFLUX

• MINOR CRITERIA– EXTREMITY EDEMA– NIGHT COUGH– DYSPNEA ON

EXERTION– HEPATOMEGALY– PLEURAL EFFUSION– VITAL CAPACITY

REDUCED BY 1/3 – TACHYCARDIA

• ONE MAJOR + 2 MINOR

NEW YORK HEART ASSOCIATION

FUNCTIONAL CLASSSIFICATION:

• CLASS I : no limitations on ordinary physical activities and symptoms that occur only with greater than ordinary exercise

• CLASS II: slight limitation of ordinary activities, which result in fatigue & palpitations with ordinary physical activity

• CLASS III: results in no symptoms at rest, but fatigue with less than ordinary physical activity

• CLASS IV: associated with symptoms even when the patient is at rest

“All the signs of CHF are the consequences of inadequate force of contraction"

Potential Therapeutic Targets in Heart Failure

• Preload

• Afterload

• Contractility

CLINICAL MANAGEMENT OF CONGESTIVE HEART FAILURE

• OBJECTIVES:Increase cardiac contractilityDecrease preload ( left ventricular

pressure)Decrease afterload (systemic vascular

resistance)Normalize heart rate and rhythm

Approaches:Reduce workload of heart1.Limit activity level reduce weight control hypertension

2. Restrict sodium (low salt diet)

3. Give diuretics (removal of retained salt and water)

• 4. Give angiotensin-converting enzyme inhibitors(decreases afterload and retained salt and water)

5. Give digitalis (positive inotropic effect on depressed heart)

6. Give vasodilators (decreases preload & afterload)

DRUGS COMMONLY USED IN HEART FAILURE

Positive Inotropic Agents

• Cardiac Glycosides

• Phosphodiesterase inhibitors

• -adrenoceptor agonists and dopamine receptor agonists

Cardiac Glycosides

• digoxin • digitoxin • deslanoside • ouabain

DIGITALIS

• Derived from foxglove plant Digitalis lanata

• Prototype – DIGOXIN

• Steroid nucleus linked to a lactone ring at the 17 position and series of sugars at carbon 3 of the nucleus

BASIC PHARMACOLOGY OF DRUGS USED IN CONGESIVE HEART

FAILURE:DIGITALIS

PHARMACOKINETICS:

DIGOXINDIGITOXIN

LIPID SOLUBILITY MEDIUM HIGH ORAL AVAILABILITY 75% >90% HALF-LIFE 40 HRS 168 HRS PLASMA PROTEIN BINDING 20-40 HRS >90 HRS PERCENTAGE METABOLIZED <20 >80 VOLUME OF DISTRIBUTION 6.3 L/KG 0.6 L/KG

PHARMACOKINETICS:

• T1/2 = (40 hrs)• Therapeutic plasma concentration:

– 0.5-2 ng/ml

• Toxic plasma concentration: >2 ng/ml• *digitalis must be present in the body in certain

"saturating" amount before any effect on congestive failure is noted

• this is achieved by giving a large initial dose in a process called "digitalization"

after intial dosages, digitalis is given in "maintenance" amounts sufficient to replace that which is excreted to avoid exceeding therapeutic range during digitalization:

- the loading dose should be adjusted according to the health of the patient

- slow digitalization (over 1 week) is the safest techniqueplasma digoxin levels should be monitored

METABOLISM & EXCRETION:• Digoxin – not extensively metabolized,

2/3 excreted unchanged in the kidneys

• Digitoxin – metabolized in the liver and excreted into the gut via the bile

PROPERTIES OF CARDIAC GLYCOSIDES:

OUABAIN DIGOXIN DIGITOXIN

Lipid solubility (oil/water coefficient)

Low Medium High

Oral availability (% absorbed)

0 75 > 90

Half-life in the body (hrs)

21 40 168

Plasma protein binding (% bound)

0 <20 >80

Volume of distribution

18 6.3 0.6

MECHANICAL EFFECTS:

• Inhibit the monovalent cation transport enzyme coupled Na+- K+ ATPase & increased intracellular Na+ content increases intracellular Ca2+ through a Na+ - Ca2+ exchange carrier mechanism

• Increases myocardial uptake of Ca2+ augments Ca2+ release to the myofilaments during excitation invokes a positive inotropic response

Mechanism of Digitalis Action: Molecular

• Inhibition of Na/K ATPase

• blunting of Ca2+ extrusion

• Ca2+i

• sarcomere shortening

ELECTRICAL EFFECTS:

• Produces alterations in the electrical properties of both contractile cells and the specialized automatic cells increased automaticity & ectopic impulse activity

• Prolongs the effective refractory period of the AV node slow ventricular rate in atrial flutter & fibrillation

Direct Electrophysiological Effects:Cellular Action Potential

Afterdepolarizations

TISSUE OR VARIABLE

EFFECTS AT THERAPEUTIC DOSAGE

EFFECTS AT TOXIC DOSAGE

Sinus node rate rate

Atrial muscle Refractory period Refractory period, arrhythmias

Atrioventricular node Conduction velocity, refractory period

Refractory period, arrhythmias

Purkinje system, ventricular muscle

Slight refractory period

Extrasystoles, tachycardia, fibrillation

Electrocardiogram PR interval, QT interval

Tachycardia, fibrillation, arrest at extremely high dosage

EFFECTS IN HEART FAILURE:• Stimulates myocardial contractility• Improves ventricular emptying• Increase cardiac output• Augments ejection fraction• Promotes diuresis• Reduces elevated diastolic pressure & volume &

end –systolic volume• Reduces symptoms resulting from pulmonary

vascular congestion & elevated systemic venous pressure

Summary Direct Electrophysiological Effects

• Less negative membrane potential: decreased conduction velocity

• Decreased action potential duration: decreased refractory period in ventricles

• Enhanced automaticity due to– Steeper phase 4– Afterdepolarizations

Parasympathomimetic Effects

• Decreased conduction velocity in the AV node

• increased effective refractory period in the AV

• Heart block (toxic concentrations)

EKG Effects of Digitalis

• decrease in R-T interval

• inversion of T wave • Uncoupled P waves

(Toxic concentrations) • Bigeminy (toxic

concentrations)

Therapeutic Uses of Digitalis

• Congestive Heart Failure

• Atrial fibrillation

Overall Benefit of Digitalis to Myocardial Function

• cardiac output

• cardiac efficiency

• heart rate

• cardiac size

NO survival benefit

Other Beneficial Effects

• Restoration of baroreceptor sensitivity

• Reduction in sympathetic activity

• increased renal perfusion, with edema formation

Adverse Effects

• Cardiac – AV block – Bradycardia – Ventricular extrasystole – Arrhythmias

• CNS

• GI

Therapeutic index is ~ 2!

INTERACTIONS:

• POTASSIUM– HYPERKALEMIA: reduces enzyme inhibiting actions

of digitalis, abnormal cardiac automaticity is inhibited– HYPOKALEMIA: facilitates enzyme inhibiting actions

• CALCIUM – Facilitates the toxic actions digitalis by accelerating the

overloading of intracellular calcium stores that appears to be responsible for abnormal automaticity

– HYPERCALCEMIA: increases the risk of digitalis induced arryhythmia

• MAGNESIUM– Opposite to those of calcium

Serum Electrolytes Affect Toxicity

• K+

– Digitalis competes for K binding at Na/K ATPase

– Hypokalemia: increase toxicity

– Hyperkalemia: decrease toxicity

• Mg2+

– Hypomagnesemia: increases toxicity

• Ca2+

– Hypercalcemia: increases toxicity

DIGITALIS INTOXICATION:

• Serious & potentially fatal complication• Anorexia, nausea & vomiting = earliest signs of

digitalis intoxication• Arrythmias: ventricular premature beats,

bigeminy, ventricular & atrial tachycardia w/ variable AV block

• Chronic digitalis intoxication = exacerbations of heart failure, weight loss, cachexia, neuralgias, gynecomastia, yellow vision, delirium

TREATMENT OF DIGITALIS INTOXICATION:

Tachyarrythmias: withdrawal of the drug, treatment with beta blocker or lidocaine

Hypokalemia: potassium administration by the oral route

Digitoxin Ab (Fab fragments)

Treatment of Digitalis Toxicity

• reduce dose: 1st degree heart block, ectopic beats• Atropine: advanced heart block• KCl: increased automaticity• Antiarrythmics: ventricular arrhythmias• Fab antibodies: toxic serum concentration; acute

toxicity

PHOSPHODIESTERASE INHIBITORS

• BIPYRIDINES– Inamrinone & Milrinone– Levosimendan– Parenteral forms only– Half-life: 2-3 hrs– 10-40% excreted in the urine– MOA: increase inward calcium influx in the heart

during action potential & inhibits phosphodiesterase– ADVERSE EFFECTS: nausea, vomiting,

thrombocytopenia, liver enzyme changes

Phosphodiesterase Inhibitors: Therapeutic Use

• short term support in advanced cardiac failure

• long term use not possible

Adverse Effects of Phosphodiesterase Inhibitors

• Cardiac arrhythmias

• GI: Nausea and vomiting

• Sudden death

-Adrenoceptor and Dopamine Receptor Agonists

• Dobutamine • Dopamine

BETA ADRENOCEPTOR STIMULANTS:• DOBUTAMINE

– Increases cardiac output – Decrease in ventricular filling pressure– Given parenterally– CONTRAINDICATIONS: pheochromocytoma,

tachyarrythmias– ADVERSE EFFECTS: precipitation or exacerbation

of arrythmia

• DOPAMINE– Raise blood pressure

Mechanism of Action: Dobutamine

• Stimulation of cardiac adrenoceptors: inotropy > chronotropy

• peripheral vasodilatation

• myocardial oxygen demand

Mechanism of Action: Dopamine

• Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors

• Splanchnic and renal vasodilatation

Therapeutic Use

• Dobutamine: management of acute failure only

• Dopamine: restore renal blood in acute failure

Adverse Effects

• Dobutamine – Tolerance – Tachycardia

• Dopamine – tachycardia – arrhythmias – peripheral vasoconstriction

DRUGS WITHOUT POSITIVE INOTROPIC EFFECTS USED IN HEART FAILURE:

• DIURETICS– Reduce salt & water retention reduce

ventricular preload– Reduction in venous pressure reduction of

edema & its symptoms, reduction of cardiac size improved efficiency of pump function

Diuretics: Mechanism of Action in Heart Failure

• Preload reduction: reduction of excess plasma volume and edema fluid

• Afterload reduction: lowered blood pressure

• Reduction of facilitation of sympathetic nervous system

ACE Inhibitors in Heart Failure

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS:• Reduce peripheral resistance reduce

afterload• Reduce salt & water retention ( by reducing

aldosterone secretion) reduce preload• Reduce the long term remodelling of the

heart vessels ( maybe responsible for the observed reduction in the mortality & morbidity)

Mechanism of Action

• Afterload reduction

• Preload reduction

• Reduction of facilitation of sympathetic nervous system

• Reduction of cardiac hypertrophy

ACE Inhibitors: Therapeutic Uses

• Drugs of choice in heart failure (with diuretics)

• Current investigational use: Acute myocardial infarction

• ATII antagonists

VASODILATORS

– Reduce the preload (through venodilatation), or reduction in afterload (through arteriolar dilatation) or both

– Decrease the load of the myocardium

VASODILATORS:

• HYDRALAZINE, ISDN

– Reduction in preload through venodilatation

– Reduction in afterload through arteriolar dilation

VASODILATORS

• NESIRITIDE– Brain natriuretic peptide (BNP)– Approved for acute heart failure– Increases cGMP in smooth muscle cells &

reduces venous & arteriolar tone – Causes diuresis– T ½ = 18 minutes– Intrvenous dose

VASODILATORS

• BOSENTAN– Competitive inhibitor of endothelin– Oral– Approved for use in pulmonary hypertension– Teratogenic & hepatotoxic effects

-Blockers in Heart Failure: Mechanism of Action

• Standard -blockers: – Reduction in damaging sympathetic influences

in the heart (tachycardia, arrhythmias, remodeling)

– inhibition of renin release

• Carvedilol: – Beta blockade effects– peripheral vasodilatation via 1-adrenoceptor

blockade (carvedilol)

BETA-ADRENOCEPTOR BLOCKERS:

• BISOPROLOL, CARVEDILOL, METOPROLOL– Reduction in mortality in patients with stable

Class II & Class III heart failure– Attenuation of the adverse effects of

cathecolamines (apoptosis)– Up regulation of Beta receptors– Decreased HR, & remodelling

DIURETICS

Principles important for understanding effects of diuretics

• Interference with Na+ reabsorption at one nephron site interferes with other renal functions linked to it

• It also leads to increased Na+ reabsorption at other sites

• Increased flow and Na+ delivery to distal nephron stimulates K + (and H +) secretion

• Diuretics act only if Na+ reaches their site of action. The magnitude of the diuretic effect depends on the amount of Na+ reaching that site

• Diuretic actions at different nephron sites can produce synergism

• All, except spironolactone, act from the lumenal side of the tubular cellular membrane

Principles important for understanding effects of diuretics

From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250

70%

20%

5%

4.5%

0.5%Volume 1.5 L/dayUrine Na 100 mEq/LNa Excretion 155 mEq/day

100%GFR 180 L/day Plasma Na 145 mEq/LFiltered Load 26,100 mEq/day

CA InhibitorsProximal tubule

Loop DiureticsLoop of Henle

ThiazidesDistal tubule

Antikaliuretics

Collecting duct

Thick Ascending Limb

RENAL TRANSPORT MECHANISM:

• PROXIMAL CONVOLUTED TUBULE:

– Carries out isosmotic reabsorption of amino acids, glucose and cations

– Bicarbonate reabsorption

– 40-50% Na reabsorption

– Via specific transport systems:• NaHCO3 – Na/H exchanger (NHE3)

LOOP OF HENLE:

• Pumps Na, K & Cl out of the lumen into the interstitium

• Provides the concentration gradient for the countercurrent concentrating mechanism

• Diluting segment – thick ascending limb of the loop of henle

• Ca & Mg reabsorption

• Na/K/2Cl cotransporter (NKCC2)

DISTAL CONVOLUTED TUBULE:

• Actively pumps Na & Cl out of the lumen nephron

• 10 % Na reabsorbed

• Impermeable to water

• Ca & Mg reabsorption

• Na/Ca exchanger (NCC)

COLLECTING TUBULE:• Final site of NaCl reabsorption• Tight regulation of body fluid volume• Determines the final Na concentration of the urine• Influenced by mineralocorticoids• Important site of K secretion by the kidney• Principal cells are the major sites of Na, K and H20

transport• Intercalated cells are the primary sites of H secretion• Do not contain cotransport system for Na

• Reabsorption of Na via the epithelial Na channel (ENaC) and its coupled K secretion is regulated by aldosterone

• ADH/AVP controls the permeability of the segment to water

DIURETICS

• Drugs that increase the rate of urine flow

• Increase the rate of Na & Cl excretion

• Decrease reabsorption of K, Ca & Mg

DIURETICS

CLASSIFICATION:1. CARBONIC ANHYDRASE

INHIBITORS

2. OSMOTIC DIURETICS

3. LOOP DIURETICS

4. THIAZIDE DIURETICS

5. POTASSIUM SPARING DIURETICS

SITE OF ACTION: Proximal tubule

Proimal tubule, Loop of Henle, Collecting tubule

Ascending limb of the loop of Henle

Distal convoluted tubule

Collecting tubule

CARBONIC ANHYDRASE INHIBITORS:

• CLASSIFICATION & PROTOTYPES: ACETAZOLAMIDE (Diamox) – a sulfonamide derivative

• MECHANISM OF ACTION:– Inhibit carbonic anhydrase w/c slows the ff. rxn:

H + HCO3 H2O + CO2

– Inhibit the dehydration of H2C03Drug effect occurs throughout the bodyBlock NaHCO3 reabsorptionHCO3 diuresis

PHARMACOKINETICS:

• Well absorbed after oral administration

• Onset of action: 30 minutes

• Duration: 12 hrs

• Excretion: proximal tubule

PHARMACODYNAMICS:

• Depresses the HC03 reabsorption in the PCT

• Significant HC03 losses – hyperchloremic metabolic acidosis

CLINICAL USES:

• Treatment of glaucoma – major application

• Urinary alkalinization

• Epilepsy

• Acute mountain sickness

• Correction of metabolic alkalosis

TOXICITY:

• Hyperchloremic metabolic acidosis

• Renal stones

• Renal potassium wasting

• Drowsiness & paresthesias – large doses

CONTRAINDICATIONS:

• HYPERAMMONEMIA– Decrease urinary excretion of NH4 due to

alkalinization of the urine

• HEPATIC ENCEPHALOPATHY

LOOP DIURETICS

CLASSIFICATION & PROTOTYPES: Furosemide – prototype & sulfonamide derivative

Bumetanide- sulfonamide

Ethacrynic Acid – phenoxyacetic acid

PHARMACOKINETICS:

• Rapidly absorbed

• Diuretic response is extremely rapid following IV injection

• Duration of effect: 2-3 hrs

• Half life: dependent on renal function

• Excreted in the kidney

PHARMACOKINETICS:

TORSEMIDE• Absorption: 1 hr• Duration: 4-6 hrs

FUROSEMIDE• Absorption: 2-3 hrs• Duration: 2-3 hrs

MECHANISM OF ACTION:

• Inhibits the coupled Na+/K+/2Cl transport system (NKCC2) in the luminal membrane of the thick ascending limb of the loop of henle reduce NaCl reabsorption

• Increases Mg & Ca+ excretion• Induces synthesis of renal prostaglandins• Increases renal blood flow• Reduces pulmonary congestion & left

ventricular filling pressures

CLINICAL USES:

• Treatment of edematous states (CHF & ascites)• Acute pulmonary edema in w/c a separate pulmonary

vasodilating action may play a useful additive role• Sometimes used in hypertension if response to

thiazide is inadequate but their short duration of action is a disadvantage

• Treatment of severe hypercalcemia induced by a carcinoma – less common

• Acute renal failure• Hyperkalemia

TOXICITY:

• Hypokalemic metabolic alkalosis

• Hyperuricemia

• Hypovolemia & cardiovascular complications

• Ototoxicity – important toxic effect of the loop agents

• hypomagnesemia

THIAZIDE DIURETICS

• CLASSIFICATION & PROTOTYPE:– HYDROCHLOROTHIAZIDE – sulfonamide derivative

– INDAPAMIDE – new thiazide like agent with a significant vasodilating effect than Na diuretic effect

MECHANISM OF ACTION:

• Inhibit NaCl transporter (NCC) in the early segment of the distal convoluted tubule

REDUCE THE DILUTING CAPACITY OF THE NEPHRON

EFFECTS:

• Urinary excretion– Full doses – produce a moderate Na & Cl diuresis

hypokalemic metabolic alkalosis– Reduced the blood pressure by reduction of the

blood volume but with continued use these agents appear to reduce vascular resistance

CLINICAL USE:

• Hypertension – major application, for w/c their long duration of action & moderate intensity of action are useful

• Chronic therapy for edematous conditions (CHF) another common application

• Recurrent renal calcium stone formation can sometimes be controlled with thiazides

• Nephrogenic diabetes insipidus

TOXICITY:

• Hypokalemic metabolic alkalosis & hyperuricemia

• Chronic therapy is often associated with potassium wasting

• Hyperlipidemia

• Hyponatremia

• Allergic reactions

CONRAINDICATIONS:

• HEPATIC CIRRHOSIS

• BORDERLINE RENAL FAILURE

POTASSIUM SPARING DIURETICS:

• CLASSIFICATION & PROTOTYPESo SPIRINOLACTONE, EPLERENONE–

antagonist of aldosterone in the collecting tubules

• Has a slow onset & offset of action (24-72 hrs)

o TRIAMTERENE & AMILORIDE – inhibitors of Na flux in the collecting tubule

CLINICAL USE:

• Hyperaldosteronism – important indication

• Potassium wasting caused by chronic therapy with loop diuretic or thiazide if not controlled by dietary K supplements

• Most common use is in the form of products that combine a thiazide with a K sparing agent

ADVERSE EFFECTS:

• Decrease K & H ion excretion and may cause hyperchloremic metabolic acidosis

• Interfere with steroid biosynthesis

TOXICITY:

• Hyperkalemia – most important toxic effect

• Metabolic acidosis in cirrhotic patients

• Gynecomastia & antiandrogenic effects

• Hyperchloremic metabolic acidosis

• Acute renal failure

• Kidney stones - triamterene

CONTRAINDICATIONS:

• Oral K administration

• Concomittant use of other agents that blunt the RAS (Beta blockers, ACE inhibitors) – HYPERKALEMIA

• Liver disease

• CYP3A4 inhibitors (ketoconazole, itraconazole) – increase blood levels of EPLERENONE

OSMOTIC DIURETICS

• CLASSIFICATION & PROTOTYPE:– MANNITOL – prototype osmotic diuretic given

intravenously

MECHANISM OF ACTION:

• Holds water in the lumen by virtue of its osmotic effect

• Major location for this action is the proximal convoluted tubule, where the bulk of isosmotic reabsorption takes place

• Reabsorption of H2O is also reduced in the descending limb of the loop of henle & the collecting tubule

EFFECTS:

• Volume or urine is increased

• Most filtered solutes will be excreted in larger amounts unless they are actively reabsorbed

CLINICAL USES:

• Maintain high urine flow (when renal blood flow is reduced & in conditions of solute overload from severe hemolysis or rhabdomyolysis)

• Useful in reducing intraocular pressure in acute glaucoma & increase intracranial pressure in neurologic conditions

• Removal of renal toxins

ANTIDIURETIC HORMONE AGONISTS

• VASOPRESSIN

• DESMOPRESSIN

• Treatment of central diabetes insipidus

TOXICITY:

• Nephrogenic Diabetes Insipidus

• Renal failure

ANTIDIURETIC HORMONE ANTAGONISTS

• CONIVAPTAN – Receptor antagonist

• LITHIUM

• DEMECLOCYLINE

• Oral administration

• T ½ = 5-10 hrs

PHARMACODYNAMICS

• Inhibits the effects of ADH in the collecting tubule

• Conivaptan – pharmacologic antagonist at V1a & V2 receptors

• Lithium & Demeclocyline – reduce the formation of cAMP in response to ADH, interfere with the actions of cAMP in the collecting tubule cells

CLINICAL INDICATIONS:

• Syndrome of Inappropriate ADH Secretion (SIADH)– When water restriction is not effective

• Other elevations of ADH

TOXICITY:

• Extracellular volume expansion

• Dehydration

• Hyperkalemia

• Hypernatremia

Asymptomatic LV Dysfunction

Mild to moderate CHF

Moderate to severe CHF

ACE inhibitor Digoxin Digoxin

Beta blocker Diuretics Diuretics

  ACE inhibitor ACE inhibitor

  Beta blocker Beta blocker

  Spironolactone  

POST TEST1. Site of action of loop diuretics:

A. loop of henle B. distal convoluted tubule2. Site of action of thiazide diuretics:

A. Loop of henle B. distal convoluted tubule3. Site of action of K sparing diuretics:

A. Collecting tubule B. loop of henle4. Toxic level of digitalis:

A. .2 ng/ml B. 2.0 ng/ml5. Prevents early remodelling of the heart:

A. ACE inhibitors B. diuretics6. A vasodilator:

A. Nitrates B. furosemide7. Decreases intracranial pressure:

A. Digitalis B. Mannitol8. Decreases intraocular pressure:

A. acetazolamide B. furosemide9. Potent vasoconstrictor:

A. bradykinin B. angiotensin II10. Early compensatory response of the heart to a decrease cardiac output:

A. tacchycardia B. cardiomegaly