Far

Eastern University – Nicanor Reyes Medical Foundation - Reflex Tachycardia distention

PHARMA: DRUGS FOR HEART FAILURE AND DIURETICS - Increased BUN - Hepatomegaly
Dra. Co, MD (poor renal - Hepatojugular
HEART FAILURE perfusion) reflux
- Occurs when cardiac output is inadequate to provide the
oxygen needed by the body. CLASSIFICATION AND ETIOLOGY OF LEFT VENTRICULAR
- 2 major types: DYSFUNCTION
o Systolic: with reduced mechanical pumping action TYPES OF HEART CHARACTERISTI CONTRIBUTIN ETIOLOGY
(contractility) and reduced ejection fraction FAILURE CS G FACTORS
o Diastolic: with stiffening and loss of adequate relaxation LOW OUTPUT, Hypofunctionin Decreased Coronary
SYSTOLIC g left ventricle, contractility, ischemia, MI,
playing a major role in reducing filling and cardiac
DYSFUNCTION enlarged heart mitral valve
output. (DILATED (dilated increased stenosis or
§ Ejection Fraction may be normal (preserved) in CARDIOMYOPAT ventricle), afterload regurgitation,
diastolic failure even though stroke volume is HY) increased left (elevated SVR) alcoholism,
significantly reduced. ventricular end- viral
diastolic syndromes,
volume, EF nutritional
<40%, deficiency,
decreased calcium and
stroke volume, potassium
decreased CO, depletion,
S3 heart sound drug-induced
present idiopathic

Hypertension,
aortic
stenosis,
volume
overload
DIASTOLIC Normal left Thickened left Coronary
DYSFUNCTION ventricular ventricle ischemia, MI,
contractility, (hypertrophic hypertension,
normal size cardiomyopat aortic stenosis
heart, stiff hy) and
ventricular, regurgitation,
impaired left Stiff left pericarditis,
ventricular ventricle enlarged
relaxation, (restrictive ventricular
- Progressive lethal disease, usually a complication of impaired left cardiomyopat septum
uncontrolled hypertension, myocardial infarction, valve ventricular hy) (hypertrophic
dysfunction, viral myocarditis, and other conditions filling, normal cardiomyopat
- Primary Manifestations: REDUCED cardiac output and EF, S4 heart Increased hy)
sound Preload
unfavorable compensatory responses EXCESSIVE sympathetic
Amyloidosis,
discharge and salt and water RETENTION sarcoidosis
- Long-term changes: remodeling, cardiac hypertrophy, cardiac
cell apoptosis Sodium and
water
SIGNS AND SYMPTOMS OF HEART FAILURE retention
LEFT VENTRICULAR RIGHT VENTRICULAR HIGH OUTPUT Normal or Metabolic and Anemia and
FAILURE FAILURE FAILURE increased oxygen hyperthyroidis
(UNCOMMON) contractility, demand m
SUBJECTIVE - Difficulty of - Peripheral normal size
Breathing Edema heart, normal
- SOB left ventricular
- Orthopnea (2-3 end-diastolic
pillows) volume, normal
- PND or increased EF,
normal or
- Cough
Increased SV,
- Weakness increased CO
- Fatigue
- Confusion DRUGS THAT MAY INDUCE HEART FAILURE
OBJECTIVE - LVH, - Weight gain Negative Inotropic Agents
- decreased BP, EF, (fluid - Beta Blockers:
- < 40% Rales retention) o most evident with PROPRANOLOL OR OTHER NON-
- S1 gallop rhythm - Neck vein SELECTIVE AGENTS

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 o Less with agents with intrinsic sympathomimetic activity
(ACETBUTOLOL, CARTEOLOL, PINDOLOL)
o Can also be caused by TIMOLOL eye drops
- Calcium Channel Blockers:
o VERAPAMIL has most negative inotropic and AV-
blocking effect
o AMLODIPINE has less
- Antiarrhythmic: Most with DISOPYRAMIDE AND ALSO
QUINIDINE
o Least with AMIODARONE

Direct Cardiotoxins
- COCAINE, AMPHETAMINES: overdoses and long-term
myopathy
- ANTHRACYCLINE cancer chemotherapeutic drugs:
DAUNORUBICIN AND DOXORUBICIN (Adriamycin)
o Dose-related


Proarrhythmytic Effects
- Class IA. Class III
o QT interval widening
o Probable TORSADES DE POINTES
o HF develops if distributed rhythm compromises cardiac
functioning
- Nonantiarrhythmytic drugs
o Same mechanism as above
o Often associated with drug interactions that inhibits
metabolism of the offending drug leading to higher than
desired plasma levels

Expansion of Plasma Volume
- Antidiabetics
o High dose of metformin may increase risk of lactic
acidosis
o Na Retention with PIOGLITAZONE AND ROSIGLITAZONE
- NSAIDs
o Prostaglandin inhibition
o Na Retention
- Glucocorticoids, Androgens and Estrogens
o Mineralocorticoid effect
o Na Retention
- Licorice
o Aldosterone-like effect
o Na Retention
- Antihypertensive vasodilators (HYDRALAZINE, METHYLDOPA,
PRAZOSIN, MINOXIDIL)
o Decreased renal blood flow
o Activation of RAS
- Drugs high in sodium
o Selected IV CEPHALOSPORINS AND PENICILLINS
o Effervescent or bicarbonate-containing antacids and
analgesic
o Liquid nutrition supplements

Unknown Mechanism
- Tumor Necrosis Factor Antagonists
o Multiple case reports of new-oust HF or exacerbation of
prior HF with ETANERCEPT and INFLIXIMAB in patients

with Crohn’s Disease or RA
GOALS IN THE TREATMENT OF HEART FAILURE

- Alleviation of Symptoms

o Improve the quality of life

- Arrest ventricular remodeling

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 - Avoid complications (e.g. arrhythmias)
- Prolong survival
o Prevent sudden death
CO = HR x SV
Normal: 5 L/min
- Common Cause of RSHF Left sided Heart Failure
3 Compensatory Physiologic Response
- Fluid Retention, Increased Sympathetic Drive, Hypertrophy
of Cardiac Muscle

THERAPIES USED IN HEART FAILURE

Stage A: High Risk With NO Symptoms
- Control Risk Factors
o Eliminate Alcohol, smoking cessation, regular exercise
- Treat HTN, DM, HLD, CAD
o à ACEI or ARBs
Stage B: Structural Heart disease, NO symptoms
- LVH, LVEF <40
o No Signs and symptoms of HF
§ à All measures under Stage A
§ àACEI or ARB and BB titrated to target maximum
tolerated doses
Stage C: Structured Heart disease, previous or current symptoms
- Volume Overload
o à Diuretics
- Salt and Water Restriction
- ACEI or ARB and BB titrated to target/maximum tolerated
doses
o à Consider (aldosterone blockers, hydralazine nitrate,
digoxin**)
o àIn selected patients ICD and for cardiac
resynchronization
Stage D: Refractory Symptoms requiring special intervention
- Refractory HF
o Cardiac Transplant
o Permanent/Destination mechanical circulatory support.

ACC.AHA NYHA DESCRIPTION MANAGEMENT TREATMENT PRINCIPLES
STAGE CLASS - Most patients with HF should be treated routinely with a
combination of the following drug classes:
A Prefailure No Symptoms but Treat obesity,
o ACEI or ARB and β-adrenergic blocker
with risk factors hypertension,
§ DIGOXIN can be added anytime to reduce
diabetes,
hyperlipidemia, symptoms and prevent hospitalization
etc. o Diuretics
§ Recommended for patients with signs of
B I Symptoms with ACEI/ARB, Beta-
congestion
severe exercise blocker, diuretic
o Aldosterone Antagonist
C II/III Symptoms with Add aldosterone
§ Recommended for patients with advanced HF or
marked (class I) or antagonist,
after MI in the presence of symptoms or DM with
mild (class III) digoxin, CRT,
a low EF or patients with NYHA II
exercise hydralazine/nitrate
o Non-specific medical management of systolic HF
D IV Severe symptoms Transplant, L VAD
§ Addressing CV risk factors
at rest
§ Correcting underlying disease states

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 • HTN DRUG GROUP DRUGS BENEFICIAL EFFECTS
• IHD CHRONIC FAILURE (ORAL)
• Arrhythmias Diuretics Thiazides Reduced preload,
• Lipid disorders Furosemide afterload;
• Anemia Spironolactone Spironolactone
• Hyperthyroidism reduces aldosterone
§ Moderate physical activity as tolerated effects
§ Vaccination Cardiac Digoxin Positive inotropic
• Influenza Glycosides effect
• Pneumococcal Vasodilators Hydralazine Reduced afterload,
§ Discontinuing possible drug-induced causes Isosorbide Dinitrate preload
o Investigational drugs Angiotensin Captopril Reduced remodeling,
§ Natriuretic peptides Antagonists Losartan preload, afterload,
§ Endothelin inhibitors apoptosis
§ Vasopressin receptor antagonists Beta-blockers Carvedilol Reduced afterload,
§ Calcium sensitizers Metoprolol reduced remodeling,
o Non-digitalis inotropic agents and TNF-α inhibitors apoptosis
§ Theoretically valuable but recent studies have
shown disappointing results and significant DRUG GROUP DRUGS BENEFICIAL EFFECTS
complications (arrhythmias), and increased ACUTE FAILURE (PARENTERAL)
mortality rates Diuretics Furosemide Reduced pulmonary
o Treatment of HF with preserved LVEF (HFPEF) pressures, preload
§ Less well-defined β1-agonists Dobutamine Increased cardiac
§ Sodium-restricted diet and diuretics for force, output
symptomatic relief of SOB or edema Vasodilators Nitroprusside Reduced preload,
§ Treatment for comorbidities (AF, HTN, DM, CAD) Nitroglycerine afterload
to decrease cardiovascular events and improve
survival. DIURETICS
- Loop Diuretics (FUROSEMIDE)
PHYSICAL ACTIVITY o Are particularly effective in acute pulmonary edema and
- Exercise training is recommended as adjunctive therapy to severe chronic HF
improve clinical status in ambulatory patients with current or - Thiazides (HYDROCHLOROTHIAZIDE)
prior symptoms of heart failure and reduced ejection fraction o May be adequate in mild chronic failure
- ACUTE EXACERBATIONS: bed rest and restricted physical - SPIRONOLACTONE
activity o Can reduce morbidity and mortality (see separate
- Reduces metabolic demands of the failing heart section on diuretics)
- Minimizes gravitational forces contributing to edema - Indicated in HF patients with congestion or cardiac dilation
formation - Produce symptomatic relief more rapidly than other HF drugs
- Prone position, increases renal perfusion, diuresis and - Should be combined with ACEIs and a β-blocker (unless
eventual mobilization of edema fluid. contraindicated)
- RATIONALE: RAAS and sympathetic nervous system activation
SODIUM-RESTRICTED DIET contributes to HF progression
- < 1 g is required to meet physiologic needs - Initial GOAL in HF: symptomatic relief by DECREASING EXCESS
o average US diet = 10 g VOLUME without causing intravascular volume depletion
- Dietary indiscretion (high salt intake) o GOAL AFTER REMOVAL OF EXCESS VOLUME: maintain
o Common cause of HF exacerbation and hospital sodium balance and prevent accumulation of new fluid,
admission while avoiding dehydration
- Reduction of dietary salt is prudent in patients with o Rate of edema fluid removal: limited by mobilization
hypertension or evidence fluid retention rate from interstitium to the intravascular compartment
- In patients with clinically evident HF, moderate sodium o Too Vigorous diuresis à intravascular volume depletion
restriction (<3g/day) may allow patients to use lower doses of à paradoxical decrease in cardiac output (compromised
diuretics by decreasing blood volume and offsetting abnormal venous return and inadequate ventricular filling)
retention of sodium by the kidneys o Typical weight loss: not > 1 kg/day
- If the kidney’s ability to excrete sodium is not severely - Effectiveness of Diuretics depends on:
compromised, it is possible to approach normal balance by o Amount of sodium delivered to their site of action in the
restricting intake to match excretion kidney
- Dietary sodium can be reduce to 2-4g by eliminating cooking o Patient’s renal function
salt more palatable, leads to better adherence (compared to a - THEREFORE, THIAZIDE AND POTASSIUM SPARING DIURETICS
severely salt-restricted diet) (act primarily in DCT) are minimally effective in patients with
severe HF because PCT reabsorption of sodium is increased
when renal blood flow is compromised.

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 - THIAZIDES VASODILATORS
o Increase fractional Na excretion by only ~5% - Vasodilators: one of the primary treatment modalities in HF
o Lose effectiveness with CreaCl < 30 to 40 mL/minute o Arterial dilation: decreases arterial impedance
(except METOLAZONE) (afterload) to LV outflow
- Loop Diuretics (FUROSEMIDE, BUMETANIDE, AND o Venous dilation: decreases LV congestion (preload)
TORSEMIDE): preferred in most patients with HF o Combination additive benefits (alleviate symptoms and
o Act on ascending limb of the loop of Henle increase exercise tolerance)
o More potent in inducing natriuresis than thiazides - Historical Note:
o With retained effectiveness in renal failure o HYDRALAZINE (pure arterial dilator) + NITRATES
o FUROSEMIDE: (predominantly vasodilators) = reduced HF symptoms
§ additional MOA: vasodilation, DECREASE RENAL and mortality rates
vascular resistance § Secondary role today because above effects are
o DO NOT MODIFY underlying cause of HF or mortality achieved by ACE inhibitors and ARBs
rates
- Ceiling doses and Loop Diuretics ACE INHIBITORS
o Effectiveness depends on delivery (active secretion) - Block angiotensin II-mediated vasoconstriction, reduced
drug into the PCT afterload and preload
o Slow absorption (even if bioavailability is high) or - Inhibit aldosterone activation potentially volume-reducing
protein binding impairs tubular delivery compromised - Advantages
diuretic response o Produce similar hemodynamic effects of hydralazine-
o Once in the tubule and the diuretic threshold is met nitrate combination as a single agent
increased drug delivery DOES NOT increase diuresis o Favorably modify cardiac remodeling independent of
§ THEREFORE, increasing single doses beyond in the vasodilation
ceiling dose produces no additional diuretic o More tolerable side effect
response - Recommendation: DOC for initial therapy, even in relatively
o ALTERNATIVE: give loop diuretics MORE FREQUENTLY mild LV systolic dysfunction
instead to increase diuretic response
- Combination diuretics with different MOA (LOOP +
METOLAZONE)
o Used if refractory to high dose loop diuretics
- Also indicated in HFPEF but its use is challenging
o Highly volume dependent à becomes worse during
fluid overload, but responds well after acute diuresis
(reduced filling pressure, dyspnea resolution)
o HOWEVER, with chronic diuresis à reduced end-
diastolic volume à reduced CO à High filling pressure
may be controlled at the expense of a greatly reduced
SV
§ Dyspnea resolves but patient experiences fatigue

and loss of exercise tolerance
- RECOMMENDATION: prescribe to all patients with HF caused
ALDOSTERONE ANTAGONISTS by LV systolic dysfunction unless contraindicated or patient is
- EPLERENONE AND SPIRONOLACTONE: mild diuretic effect unable to tolerate adverse effects
o MOA: competitive binding of the aldosterone receptor - Generally used together with β-blockers
site in the DCT - Initiated at low doses, followed by incremental increase if
o SPIRONOLACTONE: can substantially reduce both well-tolerated
morbidity and mortality in a select group of patients - Fluid retention in HF blunt therapeutic effects
with severe HF (NYHA Class III and IV) - Fluid depletion potentiate adverse effects
o Protective effect is related to reduction in aldosterone- - Use evidenced-based dosing to reduce CV events
induced vascular damage and myocardial or vascular
- DO NOT DELAY initiation of β-blockers because of a failure to
fibrosis
reach target ACE inhibitor doses.
o EPLERENONE reduces mortality in patients with LV
dysfunction after a recent MI.
ARBs

- Theoretical advantages compared with ACE inhibitors
ANGIOTENSIN-COVERTING ENZYME ANTAGONISTS
o MORE SPECIFIC for angiotensin II blockade
- First-line agents (along with diuretics) in HF à USED ORALLY
(preferentially bind to AT1 receptors)
o Angiotensin II-receptor antagonists (LOSARTAN) are
o Lower risk of drug-induced cough
used if ACEIs are not tolerated
- However, indirect block of bradykinin, NE or prostaglandins by
- Reduced remodeling and sympathetic excess in chronic HF
some or all of the ACE inhibitors advantage over ARBs
o Little or no effect on cardiac contractility or
- Recent trials show that ARBs are as effective as ACE inhibitors
manifestations of acute decompensation in reducing morbidity and mortality in patients with HF
o TOXICITIES: ACEIs cause cough and renal damage in the fetus
- FDA APPROVED: CANDESARTAN AND VALSARTAN
(CI in pregnancy and lactation à affect renal of fetus )

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 β-ADRENORECEPTOR BLOCKERS INOTROPINES
- CARVEDILOL AND METOPROLOL can prolong life in chronic HF
o Usually ORALLY
- MOA in heart failure is unclear
o May involve reduced renin and angiotensin production
and decreased cardiac cell apoptosis
- TOXICITIES
o May cause worsening of HF, AV blockade, hypotension
and sedation
- Contraindicated in patients with systolic HF until the mid-
1990s,
- Former belief
o Sympathomimetic agonists and other positive inotropes
were the logical choices
o Negative inotropes would exacerbate HF
- Better understanding HF pathophysiology à new
recommendations
- Now considered first-line agents in combination with ACE
inhibitors in patients with HF and LVSD
- β-blockers should be prescribed to all patients with stable HF
unless contraindicated or patient is unable to tolerate
treatment β-ADRENOCEPTOR AGONIST AND DOPAMINE
- Intolerance or resistance to other HF therapies, should not - DOBUTAMINE
preclude nor delay β-blocker use in HF patients o β1-selective agonist given parenterally for severe acute
- Some patients can experience initial temporary worsening HF (acutely decompensated)
symptoms § LIMITATION: short duration of action (minutes)
o Continued use improves quality of life, fewer administered by IV Infusion
hospitalizations, and reduces mortality by ~34% - DOPAMINE
- Approved preparations for HF o NOT β1-selective agonist
o Extended release METOPROLOL SUCCINATE, o Has similar benefits, toxicities and limitations in HF as
CARVEDILOL, AND BISOPROL above
- Both increase cardiac force and reduce afterload, increases
INOTROPES cardiac output
- DIGOXIN: does not prolong survival - TOXICITIES:
o Can be given chronically o Tachycardia
o Improves quality but not duration of life o Arrhythmias
- DOPAMINE, DOBUTAMINE, PHOSPHODIESTERASE o Angina
INHIBITORS
o Generally given for acutely decompensated heart failure CARDIAC GLYCOSIDES: DIGOXIN
o Used chronically in some cases of Stage D patients - Steroidal Molecules from digitalis and other plants
o Initial positive hemodynamic effects during the FIRST o The only most important cardiac glycoside in the US
+ +
WEEKS TO MONTHS are followed by increased mortality - Blocks Na , K -ATPase and increases intracellular sodium
§ RATIONALE: overall enhancement of sympathetic o Decreased outside/inside sodium gradient results in less
tone, overstimulation of an already fatigued expulsion of calcium from the cell (via NA-CA exchanger)
heart, Proarrhythmic effect and increased calcium stores in the sarcoplasmic
reticulum
o Increased release of calcium occurs increased
contractility à increased EF and CO
- Has Cardiac parasympathomimetic effect reduces AV
conduction à used in atrial fibrillation
- Available in oral and IV preparation, half-life – 36 hours
o TOXICITIES:
§ Cardiac arrhythmias
§ GI Upset
§ Neuroendocrine effects (rare)
§ Cardiac arrest (severe overdose)
§ ANTIDOTE: DIGOXIN ANTIBODIES (DIGIBIND)
HOW TO RECOGNIZE DIGOXIN TOXICITY: (COMMON SIGNS AND
SYMPTOMS)
DIGESTIVE Vomiting, Nausea, Anorexia, Diarrhea
NEUROLOGIC Fatigue, Headache, disorientation, delirium,
confusion

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 VISUAL Blurred or double vision, altered color DIGOXIN DRUG INTERACTION
perception, greenish yellow halos around DRUG EFFECT
images or lights DRUGS LOWERING SERUM DIGOXIN CONCENTRATION
CARDIAC Paroxysmal atrial tachycardia with AV Block, RIFAMPIN Probable induction of intestinal P-
ARRHYTHMIA PVCs, regularized atrial fibrillation (regular R-R (AKA: glycoprotein causing:
intervals). Bidirectional VT (QRS complexes from RIFAMPICIN) - ↓bioavailability
2 different ectopic foci), bradycardia (due to
markedly enhanced vagal effect) - ↓serum concentration after oral, but
not IV digoxin. No change in digoxin
EFFECTS OF DIGOXIN ELECTRICAL PROPERTIES OF CARDIAC TISSUES renal clearance or half-life
TISSUE OR EFFECTS AT EFFECTS AT TOXIC ST. JOHN’S WORT Possible induction of P-glycoprotein (33%
VARIABLE THERAPEUTIC DOSAGE reduction in digoxin through
DOSAGE concentrations)
Sinus Node Decrease Rate Decrease Rate SULFASALAZINE Malabsorption of digoxin (decrease AUC of
Atrial Muscle Decrease refractory Decrease Refractory doses > 2g/d digoxin by 24%)
period Period, arrhythmias
Atrioventricular Decrease conduction Decrease refractory DRUG EFFECT
Node velocity, increase period, arrhythmias DRUGS RAISING SERUM DIGOXIN CONCENTRATION
refractory period AMIODARONE ↑Serum digoxin levels by inhibiting
Purkinje Slight decrease Extrasystole, intestinal P-glycoprotein (70% in one day)
System, refractory period tachycardia, ATORVASTATIN 20% increase in serum digoxin
Ventricular fibrillation concentration with 80-mg dose, minimal
Muscle effect with 20-mg dose. Speculated to
ECG Increase PR interval, Tachycardia, inhibit intestinal P-glycoprotein but not
decrease QT interval fibrillation, arrest at proven.
extremely high CALCIUM- Inhibition of P-glycoprotein.
dosage CHANNEL Best documented with VERAPAMIL (70%-
BLOCKERS 80%).
CARDIAC GLYCOSIDE: DIGOXIN DILTIAZEM increases digoxin
- Beneficial neurohormonal and autonomic effects occur at concentrations by some 50% in some
serum concentrations below those associated with positive patients.
inotropism ERYTHROMYCIN ↑Bioavailability in persons who normally
+ +
- Inhibition of Na /K ATPase in: metabolize digoxin in intestinal tract.
o Vagal Afferent Fibers sensitization of cardiac May also inhibit P-glycoprotein in the gut.
baroreceptors reduced sympathetic outflow from CNS DIGOXIN concentrations may increase
+
o Renal Cells reduction, renal tubular reabsorption of Na , 100% in some patients
indirect suppression of renin secretion CLARITHROMYCIN Inhibition of P-glycoprotein, decreased
- Benefits of digoxin can be obtained with a lower risk of side renal clearance.
effects by using small doses DIGOXIN clearance may be reduce 60%,
o Optimal serum DIGOXIN concentration for systolic HF = and plasma concentrations may increase by
0.5 to 1ng/mL twofold.
- Other Effects: CYCLOSPORINE Inhibition of P-glycoprotein, decreased
o Decreases conduction velocity and prolongs the renal clearance
refractory period of the AV node, AV node-blockade
prolongs PR interval DRUG EFFECT
o Basis for its use in slowing the ventricular response rate
DRUGS RAISING SERUM DIGOXIN CONCENTRATION
in patients with AF and other supraventricular
ITRACONAZOLE ↑ serum digoxin levels by unknown
arrhythmias.
- Can reduce HF symptoms, but does not slow benefit on mechanism.
In one study the AUC (area under the
survival; unlikely to benefit stage A or stage B HF patient.
curve) for digoxin was increased by 50%
o DIGOXIN can be used for symptom management but
must be treated with drugs shown to prolong survival and renal elimination was decreased by
20%
(ACE inhibitors and β-blockers) or if they have not
responded adequately to appropriate therapy. PROPAFENONE Inhibition of P-glycoprotein, increases
digoxin concentration by 30-60%
- Symptomatic patients with Stage C or Stage D HF: DIGOXIN
can reduce HF-related hospitalizations QUINIDINE Inhibition of P-glycoprotein
- NOT RECOMMENDED: Monotherapy or in combination with (usually doses Decreased digoxin renal clearance and
only a diuretic above 50 mg/day increased bioavailability
- Consider also in HF patient with AF (but β-blockers may be may increase Increases 25-100% digoxin concentrations
serum digoxin
more effective in controlling the ventricular response,
especially in exercise) concentrations)

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 WOLFF-PARKINSON-WHITE SYNDROME NEW DRUGS FOR HEART FAILURE
- caused by presence of an abnormal accessory electrical - LCZ696: Angiotensin Receptor-Neprilysin Inhibitor
conduction pathway between the atria and the ventricles o VALSARTAN + SACUBITRIL (AHU377)
- Electrical signals traveling down this abnormal pathway o NEPRILYSIN: breaks down natriuretic and other
(bundle of Kent) may stimulate the ventricles to contract vasoactive peptides
prematurely result in a unique type of supraventricular § Inhibition results in lowering of BP and promotes
tachycardia atrioventricular reciprocating tachycardia sodium excretion.
- USE: IA or III antiarrhythmics - Compared to ACE inhibition alone, there is a greater
- DO NOT USE: drugs that slow AV conduction digoxin, β- reduction in:
blocker, Calcium channel blocker, ADENOSINE o CV death as hospitalization for HF
o Overall mortality
PHOSPODIESTERASE INHIBITORS (BIPYRIDINES) o Symptoms improved function
- AMRINONE, MILIRINONE, AMINOPHYLLINE, THEOPHYLLINE - Possible risks from long term therapy (still under study - all
- Occasionally, used parenterally for acute decompensation of in vitro)
HF; o Alzheimer’s Disease
o duration of action varies from 2 to 8 hours o Prostate and Breast Cancer
- Increased inward calcium influx in the heart during the action
potential INVESTIGATIONAL POSITIVE INOTROPIC DRUGS
- Inhibit phosphodiesterase, increase cAMP in cardiac tissue - ISTAROXAMINE
and vessels o Act like glycosides but also facilitates sequestration of
- Associated with an increased risk of mortality with chronic calcium ions by the sarcoplasmic reticulum less
use. arrhythmogenic than digitalis
- TOXICITIES - Calcium Sensitizers
o Primary: cardiac arrhythmias o LEVISOMENDAN
o AMINOPHYLLINE AND THEOPHYLLINE: seizures § Sensitizes the troponin system to calcium
o Reason PDE inhibitors are used infrequently § Also inhibits phosphodiesterase à may also cause
vasodilation
VASODILATORS o OMECAMTIV, MECARBIL
- NITROPRUSSIDE AND NITROGLYCERIN § Activates cardiac myosin and prolongs systole
o Administered IV for acute decompensation without increasing oxygen consumption of the
- NESIRITIDE: synthetic form of the endogenous brain heart.
natriuretic peptide
o Used IV for acute HF DEVICES
o Vasodilator with diuretic properties - Implantable Cardioverter-defibrillator (ICD)
- ISOSORBIDE DINITRATE AND HYDRALAZINE o For ventricular arrhythmias (symptomatic ventricular
o Used occasionally for chronic HF premature beats, sustained ventricular tachycardia,
o May be more beneficial in African American HF patients ventricular fibrillation)
- Vasodilators reduced afterload (increasing ejection fraction), § which are common in patients with HF and
and preload (reduction in myocardial oxygen requirement) cardiomyopathy à sudden cardiac death
- TOXICITIES: - Cardiac Resynchronization Therapy (CRT)
o NITROVASODILATORS: orthostatic hypotension o For patients with ventricular dyssynchrony (QRS
o ALL: tachycardia duration of at least 120 milliseconds)
o NESIRITIDE: renal damage - Left Ventricular Assist Device (LVAD)
o Battery-operated, mechanical pump implanted
CALCIUM CHANNEL BLOCKERS surgically maintains pumping ability of the heart
- DIHYROPYRIDINES: with arterial vasodilating effects o Clinical Trials show increased survival and quality of life
o AMLODIPINE FELODIPINE, ISRADIPINE, NIFEDIPINE, o End-stage HF: bridge to transplant or destination
AND NICARDIPINE therapy
o Have minimal negative inotropic properties
o Only AMLODIPINE and FELODIPINE have been HERBAL AND DIETARY SUPPLEMENTS
documented to be safe in HF (i.e. do not make HF - Hawthorn (leaf and flower extracts of Crataegusmonogyna
worse) and Crataegusoxyacantha) and coenzyme Q
o Some patients with non-ischemic dilated - Both are SAFE in treatment of HF
cardiomyopathy may have improved survival with - Might provide symptomatic improvement, especially in
AMLODIPINE patients with mild HF (NYHA Class II)
o NOT ENOUGH DATA therefore, CCBs other than - Conflicting data on hawthorn
AMLODIPINE AND FELODIPINE are CONTRAINDICATED - ONLY COENZYME Q has been shown to be of benefit as an
in patients with systolic dysfunction. adjunct to conventional therapies
- NON-DIHYDROPYRIDINES (VERAPIMIL AND DILTIAZEM) - Unknown whether using both will provide addictive effect
o Safe to use in HFPEF - Effects on mortality rates – inconclusive
o May improve symptoms by reducing HR and increases
duration of ventricular filling

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 DIURETICS - Methychlorothiazide
- Act by reduction of blood volume and direct vascular effects - Polythiazide
- Deplete body sodium stores - Quinethazone
- Often provide adequate treatment for mild to moderate - Thrichlormethiazide
hypertension POTASSIUM SPARING - Spironolactone
- In more severe hypertension COMBINED with sympathoplegic DIURETICS - Triamterene
and vasodilators. - Amiloride
SODIUM GLUCOSE - Dapagliflozin
COTRANSPORTER 2 - Canagliflozin
(SGLT2) INHIBITORS

ELECTROLYTE CHANGES PRODUCED BY DIURETIC DRUGS
GROUP URINARY ELECTROLYTES BODY pH
NaCl NaHCO3 K
CARBONIC + +++ + Acidosis
ANHYDRASE
INHIBITORS
LOOP ++++ 0 + Alkalosis
AGENTS
THIAZIDE ++ + + Alkalosis
LOOP +++++ + ++ Alkalosis
AGENTS +
THIAZIDES
POTASSIUM- + (+) - Acidosis
SPARING
DIURETICS

OSMOTIC DIURETICS
- MANNITOL
o For acute glaucoma
o Increased ICP
o Protects kidney from solute overload due to crush injury
or chemotherapy
- Small, non-absorbable molecule
- Osmotically inhibits resorption of water in water-permeable
portions of the nephron
- Given IV
- Duration of action: 1-2 hours
- TOXICITIES:
o Headache
o GI upset
OSMOTIC DIURETICS - Mannitol o Hypotension
- Isosorbide o Mild hyponatremia followed by hypernatremia
- Glycerin - REMEMBER: In HF, the increased hydrostatic pressure
CARBONIC ANHYDRASE - Acetazolamide proximal to the left atrium causes transudation in the lungs
INHIBITORS - Dorzolamide o Prior to diuresis, MANNITOL initially increases plasma
- Dichlorphenamide volume due to its effects on elevating plasma oncotic
- Brinzolamide pressure
ADH AGONISTS - Vasopressin o Increased plasma volume, increased left atrial preload in
- Desmopressin the face of decompensation (even at a lower preload)
LOOP DIURETICS - Furosemide à increased left atrial preload and PCWP à
- Torasemide exacerbation of fluid transudation in the lungs
- Bumetamide o MANNITOL is confined to the extracellular
- Ethacrynic Acid compartment exclusively raises osmolarity of the ECF à
THIAZIDES - Bendroflumethazide draws water out of intracellular compartment à higher
- Chlorothiazide overall extracellular volume à volume overload and
- Chlorthalidone edema.
- Hydrochlorothiazide
- Hydroflumethiazide
- Indapamide
- Metolazone

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 CARBONIC ANHYDRASE INHIBITORS o Clinical Applications: SIADH, hyponatremia
- ACETAZOLAMIDE o PK: administered parenterally
o Used for glaucoma o TOXICITIES:
o Altitude sickness § Infusion site reactions
o To reduce metabolic alkalosis
- Block carbonic anhydrase in the brush border and cytoplasm - TOLVAPTAN
of proximal tubule cells and other tissues (eye and brain) o Like conivaptan but more selective for V2 receptors
- Orally active
o Some members of the group (DORZOLAMIDE) are LOOP DIURETICS
available in topical form for glaucoma - FUROSEMIDE, ETHACRYNIC ACID (PROTOTYPE: EA)
o Duration of action: 8-12 hours o Used for conditions associated with moderate or severe
- TOXICITIES: hypertension or fluid retention (heart failure, cirrhosis,
o Oral: nephrotic syndrome)
§ GI upset - Most efficacious diuretics currently available
+ + -
§ Paresthesia - BLOCK Na /K /2Cl symporter in the ascending limb of the
§ Hepatic encephalopathy (if with sever hepatic loop of Henle
impairment) o Indirect Effect: increase calcium and magnesium
o Cross-allergenicity with sulfonamides excretion
- MOA: carbonic anhydrase inhibition results in: § Useful in the management of severe
+
o ↓ H formation inside the PCT cell hypercalcemia
+ +
o ↓ Na /H antiport § Must be given with saline infusion to prevent
+ 3-
o ↑Na and HCO in lumen hemoconcentration
o ↑Diuresis - Orally active but can also be used IV
o Duration of action: 2-4 hours
ANTIDIURETIC HORMONE AGONISTS - TOXICITIES: ELECTROLYTE IMBALANCE
- VASOPRESSIN, DESMOPRESSIN (analogue of vasopressin) o Hypokalemia
o For pituitary deficiency diabetes insipidus o Hyperuricemia
§ Collecting ducts are responsive to vasopressin and o Hypomagnesemia
insert additional water channels (aquaporins) into o Ototoxicity
the luminal membrane facilitate water resorption o Renal impairment
à restores urine concentrating power to normal § Effects are diminished by NSAIDS
- NOT USEFUL for nephrogenic diabetes insipidus § All Are sulfonamides EXCEPT ETHACRYNIC ACID
+ + -
o Does not respond to pituitary peptides - MOA: Na /K /2Cl transporter inhibition results in:
+
o Treated INDIRECTLY with THIAZIDES, urine osmolality is o ↓ intracellular K in TAL
+
increased but not to normal maximal levels o ↓ back diffusion of K
o THIAZIDES decrease blood volume à lead to o ↓ positive potential
2+ 2+
compensatory water reabsorption from proximal tubule o ↓ reabsorption of Ca and Mg
à reduces urine volume o ↑Diuresis
- Duration of Action
o VASOPRESSIN AND DESMOPRESSIN: 4-8 hours THIAZIDES
o THIAZIDES: up to 12 hours - PROTOTYPE: HYDROCHLOROTHIAZIDE
- TOXICITIES - one of the first-line agents for hypertension
o VASOPRESSIN AND DESMOPRESSIN – rarely cause - inhibit Na/Cl transporter predominantly in the distal
vasoconstriction with hypertension or coronary spasm convoluted tubule
o THIAZIDES – hyponatremia, hyperlipidemia, - Reduces blood/extracellular volume and cardiac output
hyperuricemia initially
- Eventually, normal cardiac output, ↓PVR (due to depleted
ANTIDIURETIC HORMONE ANTAGONISTS sodium stores)
+ -
- DEMECLOCYCLINE: prevents hyponatremia in SIADH - MOA: Na /Cl transporter inhibition results in:
+ -
o MOA: unclear o ↑luminal Na and Cl in DCT
- Can cause iatrogenic diabetes insipidus (like lithium) by o ↑Diuresis
blocking ADH-like peptides
- Used orally - CHLOROTHIAZIDE
- Duration of Action: 10-16 hours o less lipid soluble and given in large doses
- TOXICITIES: - CHLORTHALIDONE
o Like other Tetracycline: o slowly absorbed
§ Disorder of developing bones and teeth in o longer duration of action
children
§ Rashes, GI upset, hepatic dysfunction - BENDROFLUAZIDE, HYDROCHLOROTHIAZIDE,
CYCLOPENTHIAZIDE AND CHLOROTHIAZIDE
- CONIVAPTAN o onset of action: 12 hours; maximum: 4-6 hours,
o Antagonist at V1a V2 receptors o duration: 8-12 hours

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 - INDAPAMIDE
o excreted primarily by the biliary system

THIAZIDES: all secreted by organic secretory system and compete
with secretion of UA by that system

CLINICAL USES
- hypertension
- congestive heart failure
- Neprholithiasis secondary to idiopathic hypercalciuria
- Nephrogenic diabetes insipidus
- Severe resistant edema

TOXICITIES:
- Hypokalemic metabolic alkalosis
- Hyperuricemia
- Impaired carbohydrate tolerance SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITORS
- Hyperlipidemia (5-15% increase in serum cholesterol and LDL) - CANAGLIFLOZIN, DAPAGLIFLOZIN
- Hyponatremia o Inhibitor of subtype 2 sodium-glucose transport protein
- Hypercalcemia (SGLT2)
- Allergic reactions § Responsible for 90% reabsorption in the kidney
- Weakness (SGLT1 for the remaining 10%)
- Fatigability o Causes about 100g of blood glucose per day to be
- Parethesias eliminated through the urine (450kcal)
- Impotence has been reported probably related to volume - Additional water is eliminated by osmotic diuresis, lowers BP
depletion - Can cause weight loss as the body metabolizes adipose tissue
to replace the lost glucose.

US FDA SAFETY ANNOUNCEMENT
- December 4, 2015: FDA revises labels of SGLT2 inhibitors for
diabetes to include warnings about too much acid in the blood
and serous urinary tract infections
- Factors identified in some reports as having potentially
triggered the ketoacidosis included:
o major illness
o reduced food and fluid intake
o reduced insulin dose

SUMMARY OF THE MODES OF ACTION AND EFFECTS OF THE
VARIOUS CLASSES OF DIURETICS
DRUG MECHANISM URINARY BLOOD
OF ACTION ELECTROLYTES pH
ACETAZOLAMIDE Inhibition of ↑Na Acidosis
carbonic ↑K

anhydrase in 3
↑↑HCO
POTASSIUM-SPARING (ALDOSTERONE ANTAGONIST) DIURETICS PCT
- Used to prevent potassium wasting by other diuretics ETHACRYNIC ACID, Inhibition of ↑↑Na Alkalosis
- SPIRONOLACTONE AND EPLERENONE FUROSEMIDE Na/K/2Cl ↑K
o Particularly effective in treating heart failure and other TORSEMIDE cotransporter ↑Ca
high-aldosterone conditions in TAL ↑Mg
o Block cytoplasmic aldosterone receptor ↑Cl
o Weak antagonism of androgen receptors HYDROCHLOROTHIAZIDE Inhibition of ↑Na Alkalosis
o EPLERENONE: more selective for mineralocorticoid INDAPAMIDE Na/Cl ↑K
receptor METOLAZONE cotransporter ↑Cl
- AMILORIDE AND TRIAMTERENE in DCT ↓Ca
- Block sodium channels in the collecting tubule AMILORIDE Block Na ↑Na (Small) Acidosis
TRIAMTERENE channels,
- Orally active ↓K
SPIRONOLACTONE block
- Duration of action is 12-72 hours EPLERENONE aldosterone
- TOXICITIES
receptors in
o Hyperkalemia (MAJOR) collecting
o GI upset tubule
§ SPIRONOLACTONE: antiandrogen effects.

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 SUMMARY:

HEART FAILURE DIURETICS
DIURETICS Loop Diuretics OSMOTIC DIURETICS - Mannitol
- Furosemide - Isosorbide
Thiazides - Glycerin
- Hydrochlorothiazide CARBONIC - Acetazolamide
ALDOSTERONE - Spironolactone ANHYDRASE - Dorzolamide
ANTAGONISTS - Eplerenone INHIBITORS - Dichlorphenamide
ANGIOTENSIN ACE Inhibitors - Brinzolamide
ANTAGONISTS - Captopril ADH AGONISTS - Vasopressin
ARBs - Desmopressin
- Losartan LOOP DIURETICS - Furosemide
BETA BLOCKERS - Carvedilol - Torasemide
- Metoprolol - Bumetamide
CARDIAC GLYCOSIDE - Digoxin - Ethacrynic Acid
VASODILATORS Venodilators THIAZIDES - Bendroflumethazide
- Isosorbide dinitrate - Chlorothiazide
Arteriolar Dilators - Chlorthalidone
- Hydralazine - Hydrochlorothiazide
Combined - Hydroflumethiazide
- Nitroprusside - Indapamide
BETA-ADRENOCEPTOR - Dobutamine - Metolazone
AGONISTS - Dopamine - Methychlorothiazide
BYPRIDINES - Milirinone - Polythiazide
NATRIURETIC PEPTIDE - Nesiritide - Quinethazone
- Thrichlormethiazide
POTASSIUM SPARING - Spironolactone
DIURETICS - Triamterene
- Amiloride
SODIUM GLUCOSE - Dapagliflozin
COTRANSPORTER 2 - Canagliflozin
(SGLT2) INHIBITORS




























Notes from MANUAL and LECTURE only

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