Transcript diuretics - Caangay.com

CONGESTIVE HEART
FAILURE
MA. LENY ALDA G. JUSAYAN,
MD
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
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 is 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
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
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.
TACHYCARDIA
An early compensatory response
mediated by increased sympathetic tone
EDEMA
 compensatory response mediated by the
renin angiotensin aldosterone system & by
increased sympathetic outflow
CARDIOMEGALY
a compensatory structural response
SYMPTOMS:
• Due to inadequate perfusion of peripheral
tissues (fatigue, dyspnea)
• Elevated intracardiac filling pressures
(orthopnea, PND, peripheral edema)
PHYSICAL EXAM:
• Jugular venous
distention
• S3
• Rales
• Pleural effusion
• Edema
• Hepatomegaly
• Ascites
“All the signs of CHF are the
consequences of inadequate force of
contraction"
PATHOPHYSIOLOGY:
• STARLING’S LAW
“Within limits, the force of ventricular
contraction is a function of the enddiastolic length of the cardiac muscle,
which in turn is closely related to the
ventricular end-diastolic volume.”
PATHOPHYSIOLOGY:
– Heart failure results in DEPRESSION of the
ventricular function curve
– COMPENSATION in the form of stretching
of myocardial fibers results
– Stretching leads to cardiac dilatation
which occurs when the left ventricle fails
to eject its normal end diastolic volume
CARDIAC FAILURE
 VENOUS
PRESSURE
 CARDIAC
OUTPUT
 SYMPATHETIC
ACTIVITY
 BLOOD
PRESSURE
 RENAL
BLOOD FLOW
 RENIN ANGIOTENSIN II
 ALDOSTERONE
 CAPILLARY
FILTRATION
 SODIUM RETENTION
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
COMPENSATORY RESPONSES
DURING HEART FAILURE:
 CARDIAC OUTPUT
 CAROTID SINUS FIRING
 SYMPATHETIC
DISCHARGE
 RENAL BLOOD FLOW
 RENIN RELEASE
 FORCE
 RATE
 PRELOAD
CARDIAC OUTPUT
(VIA COMPENSATION)
 AFTERLOAD
REMODELING
Pathophysiology of Cardiac Performance
Factor
1. Preload (work or stress the
heart faces at the end of
diastole)
Mechanism
Therapeutic Strategy
increased blood volume and
-salt restriction
increased venous tone--->atrial -diuretic therapy
filling pressure
-venodilator drugs
2. Afterload (resistance against increased sympathetic
which the heart must pump)
stimulation & activation of
renin-angiotensin system --->
vascular resistance --->
increased BP
- arteriolar vasodilators
-decreased angiotensin II
(ACE inhibitors)
3. Contractility
decreased myocardial
-inotropic drugs (cardiac
contractility ---> decreased CO glycosides)
4. Heart Rate
decreased contractility and
decreased stroke volume --->
increased HR (via activation of
b adrenoceptors)
CLINICAL MANAGEMENT OF
CONGESTIVE HEART FAILURE
• OBJECTIVES:
Increase cardiac contractility
Decrease preload ( left ventricular
pressure)
Decrease afterload (systemic vascular
resistance)
Normalize heart rate and rhythm
Approaches:
Reduce workload of heart
1.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 USED TO TREAT
CONGESTIVE HEART DISEASE:
• VASODILATORS
– Reduce the preload (through
venodilatation), or reduction in afterload
(through arteriolar dilatation) or both
– Decrease the load of the myocardium
DIURETIC AGENTS:
• Reduce salt & water retention, thereby
reducing ventricular preload
INOTROPIC AGENTS:
oIncrease the strength of
contraction of cardiac muscles
DRUGS USED TO TREAT
CONGESTIVE HEART FAILURE
VASODILATORS
-CAPTOPRIL
-ENALAPRIL
-FOSINOPRIL
INOTROPIC AGENTS
-DIGOXIN
-DIGITOXIN
-LISINOPRIL
-QUINAPRIL
-DOBUTAMINE
-HYDRALAZINE
-ISOSORBIDE
-MINOXIDIL
-SODIUM
NIITROPRUSSIDE
DIURETICS
-BUMETANIDE
-FUROSEMIDE
-HYDROCHLOROTHIAZIDE
-METALAZONE
-AMRINONE
-MILRINONE
BASIC PHARMACOLOGY OF DRUGS
USED IN CONGESIVE HEART FAILURE:
DIGITALIS
PHARMACOKINETICS:






LIPID SOLUBILITY
ORAL AVAILABILITY
HALF-LIFE
PLASMA PROTEIN BINDING
PERCENTAGE METABOLIZED
VOLUME OF DISTRIBUTION
DIGOXIN
DIGITOXIN
MEDIUM
75%
40 HRS
20-40 HRS
<20
6.3 L/KG
HIGH
>90%
168 HRS
>90 HRS
>80
0.6 L/KG
PHARMACOKINETICS:
-T1/2 is long (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 technique
- plasma 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
MECHANISM OF ACTION:
• Inhibit the monovalent cation transport
enzyme coupled Na+, K+ ATPase &
increased intracellular Na+ content 
increases intracellular Ca2+ through a
Na+ - Ca2+ exchange carrier mechanism.
• Increased myocardial uptake of Ca2+
augments Ca2+ release to the
myofilaments during excitation  invokes
a positive inotropic response
MECHANISM OF ACTION:
• Produce alterations in the electrical
properties of both contractile cells and the
specialized automatic cells, leading to
increased automaticity & ectopic impulse
activity
• Prolong the effective refractory period of
the AV node  slow ventricular rate in
atrial flutter & fibrillation
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
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
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
OTHER POSITIVE INOTROPIC
DRUGS USED IN HEART FAILURE:
• BIPYRIDINES
– Amrinone & Milrinone
– 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
BETA ADRENOCEPTOR
STIMULANTS:
• DOBUTAMINE
– Increases cardiac output
– Decrease in ventricular filling pressure
– Given parenterally
– CONTRAINDICATIONS:
pheochromocytoma, tachyarrythmias
– ADVERSE EFFECTS: precipitation or
exacerbation of arrythmia
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
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)
VASODILATORS:
• HYDRALAZINE, ISDN
– Reduction in preload through
venodilatation or reduction in
afterload through arteriolar dilation
or both
BETA-ADRENOCEPTOR
BLOCKERS:
• BISOPROLOL, CARVEDILOL,
METOPROLOL
– Reduction in mortality in patients with
stable Class II & Class III heart failure
DIURETICS
RENAL TRANSPORT MECHANISM:
• PROXIMAL CONVOLUTED TUBULE:
– Carries out isosmotic reabsorption of
amino acids, glucose and cations
– Bicarbonate reabsorption
– 40-50% Na reabsorption
THICK PORTION OF ASCENDING LIMB
OF THE LOOP OF HENLE:
• Pumps Na, K & Cl out of the lumen into
the interstitium
• Provides the concentration gradient for the
countercurrent concentrating mechanism
• Ca & Mg reabsorption
DISTAL CONVOLUTED TUBULE:
• Actively pumps Na & Cl out of the lumen
nephron
• 10 % Na reabsorbed
• Ca & Mg reabsorption
COLLECTING TUBULE:
• Primary site of acidification of urine &
aldosterone regulated reabsorption of Na
• 2-4 % reabsorbed filtered Na
• H2O reabsorption under ADH control
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 ducts
CARBONIC ANHYDRASE
INHIBITORS:
• CLASSIFICATION & PROTOTYPES:
ACETAZOLAMIDE (Diamox) – a
sulfonamide derivative
• MECHANISM OF ACTION:
– Inhibits carbonic anhydrase w/c slows the
ff. rxn:
H + HCO3  H2O + CO2
Necessary for maximum reabsorption of
HCO3 from the glomerular filtrate
Drug effect occurs throughout the body
PHARMACOKINETICS:
•
•
•
•
Well absorbed after oral administration
Onset of action: 30 minutes
Duration: 12 hrs
Excretion: proximal tubule
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
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
MECHANISM OF ACTION:
• Inhibit the coupled Na+/K+/2Cl transport
system in the luminal membrane of the
thick asceding limb of the loop of henle
reduce NaCl reabsorption
• Increase Mg & Ca+ excretion
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 transport in the early segment
of the distal convoluted tubule ( a site w/c
significant dilution of urine takes place)
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
TOXICITY:
• Hypokalemic metabolic alkalosis &
hyperuricemia
• Chronic therapy is often associated with
potassium wasting
• hyperlipidemia
POTASSIUM SPARING DIURETICS:
• CLASSIFICATION & PROTOTYPES
o SPIRINOLACTONE – 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 this portion of the tubule
ADVERSE EFFECTS:
• Decrease K & H ion excretion and may
cause hyperchloremic metabolic
acidosis
• Interfere with steroid biosynthesis
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
TOXICITY:
• Hyperkalemia – most important toxic effect
• Metabolic acidosis in cirrhotic patients
• Gynecomastia & antiandrogenic effects
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
TOXICITY:
• Hyponatremia & pulmonary edema due to
removal of water from the intracellular
compartment
• Headache, nausea, vomiting
• dehydration
Asymptomatic
Mild to
LV Dysfubction moderate CHF
Moderate to
severe CHF
ACE inhibitor
Digoxin
Digoxin
Beta blocker
Diuretics
Diuretics
ACE inhibitor
ACE inhibitor
Beta blocker
Beta blocker
Spironolactone