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DIURETICSThiazides:Chlorthalidone (Hygroton)Hydrochlorothiazide
(Microzide, Diuril Loop:Bumetanide (Bumex)Furosemide
(Lasix)Ethacrynic acid (Edecrin)K+ sparing:Spironolactone
(Aldactone)Amiloride (Midamor)
Combos:Dyazide (Thiazide + K+ sparing)
ACE InhibitorsAngiotensin II Receptor Blockers (ARBs)CALCIUM
CHANNEL BLOCKERSCaptopril (Capoten)Enalapril (Vasotec)Lisinopril
(Prinivil, Zestril)Benazepril (Lotensin) & Lotensin HCT
(Benazepril + HCTZ)Quinapril (Accupril)Losartan (Cozaar) &
Hyzaar (Losartan + HCTZ)Valsartan (Diovan)Olmesartan
(Benicar)Cardiac selective:Diltiazem (Cardizem)Verapamil
(Calan)Vascular selective:Amlodipine (Norvasc) & Lotrel
(Amlodipine + Benazepril)Nifedipine (Procardia)Nicardipine
(Cardene)BETA BLOCKERSNon-selectivePropranolol (Inderal)
CardioselectiveMetoprolol (Lopressor, Toprol XL)Atenolol
(Tenormin)Nebivolol (Bystolic)Bisoprolol (Zebeta)ISAPindolol
(Visken)Acebutolol (Sectral)
Mixed alpha/beta blockersCarvedilol (Coreg)Labetalol
(Trandate)
Alpha-1 Adrenergic Blockers (Peripheral Adrenergic
Blockers)Alpha-2 Adrenergic Agonists (Centrally Acting Drugs)Direct
Vasodilators
Doxazosin (Cardura)Prazosin (Minipress)Clonidine (Catapres)
Methyldopa (Aldomet)Hydralazine (Apresoline)Minoxidil
(Loniten)NITRATESShort ActingIV: Nitroglycerin, Nitroprusside
(Nitropress), Nesiritide (Natrecor)Sublingual: Nitroglycerin (NTG,
Nitrostat, Nitroquick)Sublingual: Isosorbide dinitrate (ISDN,
Isodil, Nitrostat, Sorbitrate)Long Acting:Oral: Isosorbide
mononitrate (ISMN, Ismo, Monoket, Omdur)Oral: Isosorbide dinitrate
(ISDN, Isordil, Cedocard SR)Topical: Nitroglycerin (2% ointment,
Nitro-bid; transdermal patch Minitran, Nitro-dur, etc; ointment
Nitro-bid)Oral : BiDil (Hydralazine + ISDN)OTHER ANGINALPOSITIVE
INOTROPESRanolazine (Ranexa)Disopyramide (Norpace,
Rythmodan)Antiplatelet TherapyLow dose ASAClopidogrel
(Plavix)Digoxin (Lanoxin) *Cardiac (digitalis) glycosideMilrinone
(Primacor) *PDE inhibitorDobutamine (Dobutrex) *Beta agonist
BACKGROUNDAn estimated 30% of U.S. adults Almost 70 million
Americans are hypertensive, according to an analysis based on
surveys from 2003 to 2010 and included more than 20,000 individuals
aged 18 and older.Among the other findings:More than half of
hypertensive adults did not have their condition under control.Of
those with uncontrolled hypertension, nearly 40% were not aware of
their condition, 16% were aware but were not receiving medication,
and 45% were aware and were being treated.Almost 90% of those with
uncontrolled hypertension had a regular source of medical care!
ANTIHYPERTENSIVE DRUG GROUPSDiuretics (3 classes: thiazides, loops,
K+ sparing)ACE inhibitors (ACEIs)Angiotensin receptor blockers
(ARBs)Beta adrenergic blockersAlpha1 adrenergic blocker Other
adrenergic drugsCalcium channel blockersCentral alpha2 receptor
activatorsDirect vasodilators Classification of Hypertension (HTN)
Systolic BP Diastolic BP (mm Hg) (mm Hg)Normal 5mEq/L), acidosis,
hirsutism, gynecomastia, menstrual irregularities.
LOOP DIURETICS LOOP DIURETICSInhibit Na+/K+/2Cl- transporter in
thick ascending limb (TAL) of the loop of Henle.Bumetanide (Bumex)
0.5-5mg bid/tidEthacrynic acid (Edecrin) 25-100 mg bid/tid not a
sulfa!Furosemide (Lasix) 20-320 mg qdEffective if creatinine
clearance < 30mL/min, but should be avoided in anuria.While
highly potent diuretics their use in hypertension is usually
reserved for patients with chronic renal insufficiency.Adverse
Effects: More likely than thiazides to cause dehydration, and
hypokalemic alkalosis, but less likely to cause hyperglycemia and
hyperlipidemia! Similar to thiazides in causing hyperuricemia.
Renal actions can result in electrolyte disturbance including
hypocalcemia & hypomagnesemia.Ethacrynic acid is potentially
ototoxic.Relative contraindications: diabetes, gout,
hyperlipidemia
4ACE INHIBITORS & ANGIOTENSIN BLOCKERS (ARBs) BLACK BOX
WARNINGWhen used in the second half of pregnancy, ACEIs can cause
reduced amniotic fluid (oligohydramniosis), fetal growth
retardation, pulmonary hypoplasia, joint contractures, hypoplastic
cranial bones (hypocalvaria) and neonatal renal failure,
hypotension, and death. These effects result from blockade of the
conversion of angiotensin I to angiotensin II in the developing
fetal kidneys. A similar pattern of fetal anomalies has been
reported after treatment of women in the second or third trimester
of pregnancy with angiotensin IIreceptor antagonists. So the -prils
& -sartans ARE ABSOLUTELY CONTRAINDICATED IN PREGNANCYACEI, ARB
& DIURETIC COMBINATIONS When used alone, EITHER an ACE
inhibitor or ARB improves outcomes in patients with diabetes, heart
disease, or kidney disease. ACEI + ARB DOES give a little better BP
lowering BUTthe combo may cause more adverse effects, such as
hypotension, hyperkalemia, or increased serum creatinine. Consider
more frequent monitoring of serum potassium and creatinine if you
have a patient on both an ACE inhibitor and ARB.To increase
antihypertensive effect consider the addition of a low dose of a
thiazide diuretic (or calcium channel blocker, see below) to either
an ACEI or ARB, rather than increasing the dose of the ACEI or the
ARB! Angiotensin Converting Enzyme Inhibitors (ACEIs)Captopril
(Capoten) 25-100 mg bid/tidEnalapril (Vasotec) 2.5 - 40 mg
qd/bidLisinopril (Prinivil, Zestril) 10-40 mg qd .. and 7 or 8
more!
Mechanism: Block angiotensin II formation preventing stimulation
of AT-1 receptors in kidney and vasculature aldosterone ( diuresis)
& vasodilation) plus bradykinin degradation by ACE the
vasodilating action of bradykinin.Uses in HTN: 1st choice drugs in
patients with HF and compete with thiazides for initial treatment
of HTN; especially good in patients with proteinuria including type
2 diabetics (But not if bilateral renal artery
stenosis).Contraindications: Pregnancy (an absolute
contraindication, see below), renal stenosis (bilateral).
Adverse effects: Cough (10-20% incidence enhanced bradykinin),
loss of taste, rash, hyperkalemia, angioedema (? 1%),
agranulocytosis (very rare)
Angiotensin II Receptor Blockers (ARBs)Losartan (Cozaar) 25-100
mg qd/bidValsartan (Diovan) 80-320 mg qd .. & 5-6 other
sartans
Mechanism: Bind to AT-1 receptors in kidney and blood vessels
preventing their activation by angiotensin II.
Do NOT block bradykinin metabolism by ACE.
Uses in HTN: Compete with prils as 1st choice drugs in patients
with HF and in type 2 diabetics with nephropathy. Several ARBs are
available in combinations with thiazides.
Contraindications: pregnancy, renal stenosis
Adverse effects: less than prils, less cough (do not affect
bradykinin) and hyperkalemia, angioedema (very rare)
CALCIUM CHANNEL BLOCKERSBlock of membrane Ca2+ channels in the
heart decreases contractility and in the vasculature causes
relaxation in both cases the result is decreased BP. Cardiac
selective drugs include Diltiazem (Cardizem et al) 180-480 mg qd
Verapamil (Calan) 120-480 mg qdVascular selective drugs
(dihydropyridines) include Amlodipine (Norvasc) 2.5 10mg qd
Nifedipine (Procardia, Adalat) 30-60 mg qd Nicardipine (Cardene)
60-120 mg bidIn HTN CCBs are used in monotherapy, or as add-ons
with thiazides (very effective in African Americans), especially if
co-existing ischemic heart disease (IHD).Contraindications:Cardiac
selective drugs accelerate HF (but amlodipine is safer) and should
also be avoided in heart block or LV dysfunction. Short-acting
forms of dihydropyridines (eg, nifedipine) have caused problems,
including reflex cardiac stimulation, if used for hypertensive
emergencies.Toxicity: Diltiazem & verapamil cause GI upset,
constipation (verapamil), lupus-like rash, peripheral edema &
cardiac depression.Dihydropyridines cause headache, flushing,
gingival hyperplasia, reflex tachycardia & fluid retention.
BETA-ADRENERGIC BLOCKING AGENTS & ALPHA BLOCKERS
BETA-ADRENERGIC BLOCKING AGENTS (1)Primary actions in HTN are
antagonism of 1 receptors in the heart (decrease rate &
contractility) and the kidney (decrease renin release). Several
subgroups with distinctive characteristics
Nonselective - block all beta receptors including 2 receptors in
lungs & some blood vessels the prototype Propranolol (Inderal)
40-160 mg bid
2. Selective 1 receptor blockers these drugs are safer in
patients with asthma, COPD, or peripheral vascular disease
Metoprolol (Lopressor, Topral XL) 50-100 mg qd/bid Atenolol
(Tenormin) 25-100 mg qd
3. Blockers with intrinsic sympathomimetic activity minimal
effect in resting states, but block CV responses with excessive
SANS outflow (or if used at high doses) like partial agonists
Pindolol (Visken) 10- 40 mg bid Acebutolol (Sectral) 200- 600 mg
bid
4. Blockers of both alpha & beta receptors highly potent
since they block 1 receptor mediated vasoconstriction - Carvedilol
(Coreg) 12.5 50 mg bid Labetalol (Normodyne, Trandate) 200- 800 mg
bid
Some beta blockers slow progression of HF - carvedilol &
metoprolol have both been shown to decrease ventricular remodeling
and carvedilol decreases mortality rate in HF patients! More
laterIn HTN are generally considered 2nd to thiazides (or ACEIs),
mostly as add-on. However they do have some advantages in patients
with coexisting LVH, angina, or tachycardia & also in acute
MI.
AVOID ABRUPT WITHDRAWAL REBOUND HYPERTENSION
Contraindications: 1st trimester of pregnancy, HF (except
carvedilol & metoprolol), sinus bradycardia, asthma* &
COPD*; relatively contraindicated in depression, diabetes,
hyperlipidemia and peripheral vascular disease*.
Toxicity: bronchospasm, drowsiness, fatigue, NV are relatively
common; more serious effects include AV conduction abnormalities
& heart failure.
* 1 selective blockers safest
Alpha-1 Adrenergic Blockers (Peripheral Adrenergic Blockers)
Alpha-2 Adrenergic Agonists (Centrally Acting Drugs)Act
peripherally to relax vascular smooth muscle via block of NE
activation of alpha-1 receptors on arterioles & veins. May
decrease LDL-cholesterol modestly.
Also relax prostate sphincter smooth muscle to improve urine
flow used in BPH +/- HTN! otherwise usually back-up drugs.
Doxazosin (Cardura) 1-16 mg qd Prazosin (Minpress) 2-20 mg
bid/tid
Contraindications: Increase mortality in CV disease; watch the
PDE5 inhibitors, the -afils like Viagra (sildenafil) additive
hypotension.
Toxicity: First dose phenomena (syncope), postural hypotension,
palpitations, fluid retention, CNS effects.Drugs that activate
alpha-2 receptors in the CNS can decrease sympathetic outflow,
which in turn results in a decrease in cardiac output &
vascular peripheral resistance.
Clonidine (Catapres) 0.1-0.8 mg-tid or weekly transdermal
patchGuanfacine (Tenex) 0.5-2mg qdMethyldopa (Aldomet) 250-1000 mg
bid
Not for initial monotherapy they cause marked fluid retention so
must be used with a diuretic.
AVOID ABRUPT WITHDRAWAL REBOUND HYPERTENSION
Toxicity: sedation, dry mouth, bradycardia, postural
hypotension, decreased alcohol tolerance (guanfacine); in addition
methyldopa also causes autoimmune disorders, colitis, hepatitis
& hemolytic anemia ( veins.Their ability to block cardiac
calcium channels is modest at doses used in angina so they may
elicit a reflex tachycardia. Several agents are available for oral
use in angina. Most are characterized by high first-pass
metabolism. Elimination half-lives (& dosing regimens)
vary.
Short-acting forms of dihydropyridines (eg, nifedipine) have
caused problems, including reflex cardiac stimulation resulting in
heart attacks, if used for hypertensive emergencies. A rapid-onset
form of nifedipine was shown to increase the risk of MI in patients
with HTN! Short-acting CCBs should be avoided in unstable angina
they increase risk of cardiac events.
Dihydropyridines cause headache, flushing, gingival hyperplasia,
reflex tachycardia & fluid retention. Edema, especially in the
legs, may sometimes necessitate dosage reduction or discontinuance.
Overall, amlopidine seems safer than other dihydropyridines in HF
patients. Other dihydropyridine calcium channel blockers in the USA
include felodipine (Plendil), isradipine (Dynacirc) &
nisoldipine (Sular) though approved for HTN, they are also
sometimes used in angina. Another dihydropyridine CCB, nimodipine
(Nimotop, PO) improves neurological outcome in subarachnoid
hemorrhage.This class of drugs is also used in the treatment of
Raynauds disease.
CALCIUM CHANNEL
BLOCKERSDrugCharacteristicsContraindicationsToxicityDiltiazem
(Cardizem, generic): 30-80mg QID; extended release, (Cardizem CD,
Dilacor XL, Tiazac): 180-420 mg qd: an IV prep is also
available
Verapamil (immediate release (Calan, Isoptin): 80-320 mg bid;
extended release (Calan SR, Isoprin SR) 120-480 mg qd
Diltiazem and verapamil are less selective than dihydropyridines
since they block calcium channels involved in cardiac pacemaker
activity i.e. they are cardiodepressant (V > D) and there is no
reflex tachycardia. Diltiazem causes more vasodilation than
verapamil.
This pair of CCBs also have well-documented clinical use in
treatment of supraventricular tachycardias. Verapamil blocks
P-glycoprotein drug transporters (involved in drug resistance) and
has been used adjunctively in cancer chemotherapy.
These drugs are more cardiodepressant than dihydropyridine CCBs
and can cause problems in patients with LV dysfunction, conduction
abnormalities, or in heart failure. Dizziness, flushing, nausea
& constipation (esp. verapamil) may be troublesome. AV block,
bradycardia, cardiac arrest & heart failure are all possible,
but uncommon other than in overdose. Edema, especially in the legs,
may sometimes necessitate dosage reduction or discontinuance.
Diltiazem (like dihydropyridines) may cause gingival
hyperplasia.
OTHER ANGINARANOLAZINE (Ranexa)
Anti-ischemic drug approved for chronic angina - used
adjunctively with other anti-anginal drugs. Dose 500 mg PO bidMOA:
Inhibits fatty acid oxidation in cardiac tissue; blocks late Na+
current in myocardial cells, prolonging QTc interval. Does NOT
reduce blood pressure or heart rate! Modest efficacy, M >
F?Kinetics: Hepatic metabolism (CYP 3A4)Contraindications:
Pre-existing QT prolongation (or other QT-prolonging drugs);
hepatic impairment; class C pregnancy.Interactions: Cardiotoxicity
with drugs that prolong QT interval (eg, erythromycin,
antiarrhythmics). May increase toxicity of dextromethorphan,
digoxin & some statins!Toxicity: Nausea, constipation,
dizziness, headache.ANTIPLATELET DRUGSASA (80-325 mg
qd).Clopidogrel (Plavix, 75 mg qd)Antiplatelet drug treatment in
patients with acute or chronic ischemic conditions decreases the
incidence of MI. ASA is commonly used at low doses (80-325 mg qd)
in classic angina. See past lectures on NSAIDs for reminders of ASA
pharmacology such as side effects, contraindications & drug
interactions.The ADP antagonist clopidogrel (Plavix, 75 mg qd) is
an effective alternative if ASA is contraindicated and has less GI
side effectsNitrates plus CCBsFOR VASOSPASTIC (VARIANT)
ANGINANitrates plus CCBs are highly effective in abolishing attacks
in >70% of patients and almost all remaining patients have
reduced incidence and severity of attacks.Nitroglycerin or ISDN +
Nifedipine, verapamil, or diltiazem (from Wells)Disopyramide
(generic, Norpace and RythmodanThis is usually classified as an
antiarrhythmic class IA drug (see Drugs for Cardiac Arrhythmias
lecture, May 15). It has minimal effects on adrenergic receptors,
but has a negative inotropic effect on the heart . Its usually
considered to be a back-up drug in HCM, if beta blockers or
verapamil are ineffective or contraindicated. Unfortunately
disopyramide can have marked antimuscarinic effects, so it is
advisable to use the drug together with low doses of a beta
blocker. Side effects include blurred vision, constipation, dry
mouth & urinary retention. TREATMENT OF ANGINARECOMMENDED
TREATMENT OF ANGINA -1All patients diagnosed with angina should be
prescribed a short-acting nitrate (eg, nitroglycerin) for aborting
acute (or predictable) attacks. If episodes are infrequent and
nitroglycerin works this may be adequate. If not effective, then
start either a beta blocker (especially if symptoms relate to
exercise) or a CCB (if symptoms are linked to coronary vasospasm)
this may be adequate.If not try combinations, typically a beta
blocker together with a long-acting nitrate (reflex tachycardia is
neutralized) or a beta blocker + a CCB (as long as no cardiac
conduction abnormality) may be adequate.If not consider a three
drug regimen and get help eg, surgical revascularization by
coronary artery bypass grafting or percutaneous coronary
intervention (PCI, angioplasty) EFFECTS OF NITRATES ALONE & IN
COMBINATIONS Nitrates Beta Blkrs or CCAs Combined
Heart rate (reflex)
Arterial Pressure
End diastolic vol. None or
Contractility (reflex) None
Ejection time None
Reflex effects are usually undesirable.TREATMENTPOTENTIAL
VASODILATOR PROBLEMS?
Reflex sympathetic activation: With vasodilation reflex
sympathetic output may lead to unwanted cardiac effects and to an
increased release of renin from the kidney causing formation of the
angiotensins.
The Steal phenomenon: Some data show that the ability of
vasodilators to promote blood to ischemic tissue is limited because
the small blood vessels there are already significantly dilated
instead vessels in adjacent non-ischemic tissue dilate thus
stealing blood from the ischemic tissue!
Effects on non-vascular smooth muscle:In Rx of HTN associated
with toxemia in pregnancy, vasodilators may decrease the activity
of uterine smooth muscle during labor.
Stable CAD- Treatment Guidelines
Intensive medical therapy (aspirin, beta-blocker, ACE inhibitor,
or possibly ARB) Reduction of risk factors (lipid-lowering therapy,
optimization of HDL, diabetes control) Lifestyle intervention
(weight reduction, smoking cessation, exercise).
These are collectively known as optimal medical therapy. Despite
this, 30-40% of patients (over 1 million annually) will ULTIMATELY
undergo catheterization and PCI for stable CAD!
PERCUTANEOUS CORONARY INTERVENTION (PCI)The Clinical Outcomes
Utilizing Revascularization and Aggressive Drug Evaluation
(COURAGE) trial compared the use of PCI plus optimal medical
therapy with optimal medical therapy alone in patients with stable
CAD. Boden et al: Optimal medical therapy with or without PCI for
stable coronary disease. N Engl J Med 2007;356:1503-16.PCI is
proven to reduce the risk of death and myocardial infarction (MI)
in patients with acute coronary syndromes. HOWEVER these benefits
of PCI have yet to be proven in those patients with stable coronary
artery disease (CAD)!Clinical Outcomes Utilizing Revascularization
In general and according to current guidelines and studies, the
patients who will benefit from PCI include those who receive an
immediate intervention for acute MI with ST-segment elevation or
high-risk ACS without ST-segment elevation, and possibly that small
group of patients who are post-MI and receive late PCI for silent
ischemia. Those who are NOT likely to benefit from the addition of
PCI to optimal medical therapy include initial therapy of patients
with stable angina and late intervention for those who are post-MI
with occlusion of the infarct-related artery.
Post-CAD Depression Linked to Higher Heart Failure Risk From
Journal of the American College of Cardiology April
2009.Researchers prospectively followed, for roughly 6 years,
nearly 14,000 patients with CAD who had no previous diagnosis of
depression or heart failure at the time of their index
angiography.In patients who had depression after CAD diagnosis,
their incidence of heart failure was 4x higher than that of
non-depressed patients. Heart failure was about as likely to occur
among those with depression whether or not they received
antidepressant drugs!The authors speculate on biological pathways
between heart failure and depression: Both are associated with
increased inflammatory levels and endothelial dysfunction, and both
share such risk factors as smoking and being overweight. They
conclude: "Although this association needs further investigation,
its consequences and future interventions could have a significant
public health impact.TREATMENT HYPERTROPHIC CARDIOMYOPATHY (HCM)
-1
A genetic CV disorder with incidence about 1 in 500. Many
patients are asymptomatic, but others may have severe limitations
including dyspnea on exertion, chest pain (sometimes with normal
arteriogram) and at worst sudden death after strenuous physical
exercise the latter is more likely in children & young adults.
In addition to the symptoms, diagnosis may be established via 2D
echocardiography.HCM pathology involves impaired ventricular
filling due to abnormal relaxation which can ultimately lead to
diastolic heart failure. Drug therapy includes the use of beta
blockers, verapamil & disopyramide.HYPERTROPHIC CARDIOMYOPATHY
(HCM) -2
Beta Blockers: Advantage is taken of their cardio-depressant
actions. Decreased heart rate allows increased diastolic filling
decreased contractility lowers oxygen consumption of the
myocardium. Propranolol is effective but may require high doses.
Standard doses of atenolol or metoprolol are used more commonly.
When used in children or adolescents with HCM the beta blockers may
impair academic performance and lead to depression.Verapamil: The
negative inotropic action of this calcium channel blocker improves
ventricular filling in diastole and relieves chest pain. Recall its
constipating actions! In addition, some HCM patients on verapamil
may develop pulmonary edema or cardiogenic shock!
HYPERTROPHIC CARDIOMYOPATHY (HCM) -3Disopyramide (generic,
Norpace and Rythmodan): This is usually classified as an
antiarrhythmic class IA drug (see Drugs for Cardiac Arrhythmias
lecture, May 15). It has minimal effects on adrenergic receptors,
but has a negative inotropic effect on the heart . Its usually
considered to be a back-up drug in HCM, if beta blockers or
verapamil are ineffective or contraindicated. Unfortunately
disopyramide can have marked antimuscarinic effects, so it is
advisable to use the drug together with low doses of a beta
blocker. Side effects include blurred vision, constipation, dry
mouth & urinary retention. Summary of Vasodilators
Nitrates & nitroglycerin: form NO - cGMP, v; Rx CAD, HF,
Raynauds disease
Hydralazine: a; Rx HF (with nitrate), HTN
Nitroprusside: a & v; Rx acute HF or HTN emergency
Captopril & other -prils: Inhibit ACE, a & v; Rx HF,
HTN
Losartan & other -sartans: AT-1 receptor block; Rx HTN
Prazosin & other -osins: Alpha1 receptor block; a & v;
Rx: HTN, Raynauds disease
Nifedipine & other dipines: Ca2+ channel block: a > v;
Rx. CAD, HTN, Raynauds disease
Minoxidil: K+ channel activation; a; Rx refractory HTN
Sildenafil & other -afils: Inhibit PDE-5; a & v; Rx male
impotence
a = arteriolar dilationv = venous dilationANTIARRHYTHMICSClass I
Drugs NA+ CHANNEL BLOCKERS IA:QuinidineProcainamideDisopyramide
(Norpace)IB:LidocaineIC: Flecainide (Tambocor)Propaphenone
(Rythmol)Class II Drugs BETA BLOCKERSPropranolol (Inderal)Esmolol
(Brevibloc)Metoprolol (Lopressor)Class III Drugs - K+ CHANNEL
BLOCKERSAmiodarone (Cordarone)Dronederone (Multaq)Sotalol
(Betapace)Dofetilide (Tikosyn)Class IV Drugs - Ca2+ CHANNEL
BLOCKERSVerapamil (Calan)Diltiazem (Cardizem)Unclassified
antiarrhythmic drugsAdenosine (Adenocard)Digoxin (Lanoxin)Magnesium
sulfateAtropineOther/Misc DrugsEpinephrineVasopressin
BRENNER TABLE 14-1 Electrophysiologic Properties of Selected
Antiarrhythmic Drugs
TERMSAbnormal automaticityPacemaker activity that originates
anywhere other than in the sinoatrial (SA) node.Reentrant
arrhythmiasArrhythmias of abnormal conduction; they involve the
repetitive movement of an impulse through tissue previously excited
by the same impulseAbnormal conductionConduction of an impulse that
does not follow the normal path or re-enters tissue previously
excited.Selective depressionThe ability of certain drugs to
selectively depress areas of excitable membrane that are most
susceptible, leaving other areas relatively unaffectedAtrial,
ventricular fibrillation(AF & VF)Arrhythmias involving rapid
re-entry and chaotic movement of impulses through the tissue of the
atria or of the ventricles.
Ventricular fibrillation is fatal if not terminated within a few
minutes.Supraventricular tachycardia (SVT)A reentrant arrhythmia
that travels through the AV node; it may also be conducted through
atrial and ventricular tissue as part of the reentrant
circuitEffective refractory period (ERP)The period that must pass
after the upstroke of a conducted impulse in a part of the heart
before a new action potential can be propagated in that cell or
tissueVentricular tachycardia(VT)An arrhythmia often associated
with myocardial infarction. May involve abnormal automaticity or
abnormal conduction which impairs cardiac output, and may
deteriorate into ventricular fibrillation (with inadequate
contraction); for these reasons it requires prompt managementGroup
I, II, III, and IV antiarrhythmic drugsA method for
classifyingantiarrhythmic drugs, sometimescalled the Vaughan
Williamsclassification; based loosely on thechannel or the receptor
that is the drug target
Sodium channel blockers Beta receptor blockers Potassium channel
blockersCalcium channel blockers
See also Wells, Table 6-1 BACKGROUND:
ARRHYTHMIASARRHYTHMIAS/DYSRHYTHMIASThese are any abnormal cardiac
rhythms resulting from structural or electrical/conduction changes
in the heart. Causes include chronic heart failure, electrolyte
abnormalities, hypertension, hypoxemia, myocardial ischemia,
thyroid dysfunction, valvular heart disease and drug side effects/
toxicities. The major mechanisms resulting in arrhythmias are
abnormalities in impulse formation (increased automaticity) and
abnormalities in impulse conduction (reentry).Management? Treat or
correct abnormality if possible. Use antiarrhythmic drugs
temporarily or chronically. Consider non-pharmacologic
therapies.
TREATABLE CONDITIONS THAT MAY CAUSE ARRHYTHMIASElectrolyte
imbalance Renal failure Hypovolemia MIThyroid dysfunction Metabolic
acidosis Pulmonary embolism Fevers Valvular defects Drug/drug
interactionsARRHYTHMIAS AMENABLE TO DRUG THERAPYParoxysmal
supraventricular tachycardia (PSVT)Atrial fibrillation (AF)Atrial
flutterVentricular premature contractions (VPC)Ventricular
tachycardia (VT)
NON-PHARMACOLOGIC THERAPY OF ARRHYTHMIASRadiofrequency (RF)
catheter ablation Implantable cardioverter-defibrillators (ICDs)DC
cardioversion (Direct current cardioversion)The increasing use of
these therapies has reduced the need for long-term drug therapy in
many patients.
AUTOMATICITY Spontaneous depolarization (automaticity) occurs in
cells of SA & AV nodes & in the HIS-Purkinje system. Order
of rate of depolarization: SA node (the pacemaker) > AV node
> His-Purkinje.Both SA & AV nodes are innervated by PANS
(inhibitory, M2 receptors) & SANS (excitatory), but the cardiac
muscle cells are mostly innervated by SANS (1 receptors).Increased
automaticity can reflect functional changes in the molecular events
underlying the ionic mechanisms of myocardial cell
excitability.Abnormal impulse formation is usually due to
after-depolarizations which generate new A.P.s. It can occur with
intracellular calcium overload (eg, electrolyte imbalance) &
with use of cardiotoxic drugs. BRIEF REVIEW OF CARDIAC PHYSIOLOGY
RELEVANT TO ANTIARRHYTHMIC DRUG ACTIONS
4 FUNDAMENTAL CONCEPTS TO UNDERSTAND
Ionic basis of Action Potentials in Fast-Response fibers
(cardiac muscle & the His-Purkinje system)
Ionic basis of Action Potentials in Slow-response fibers (SA
& AV nodes)
Features of voltage-gated Na+ channels that render them
susceptible to certain drugs
Actions of the 2ND messenger cAMP on cardiac function that are
susceptible to drugs
BACKGROUND: ARRHYTHMIAS DRUGS THAT ACT ON FAST-RESPONSE CARDIAC
CELLS(Present in atrial & ventricular cardiac muscle & the
His-Purkinje system)DRUGS THAT ACT ON SLOW-RESPONSE CELLS (SA &
AV nodes)
Class I Antiarrhythmics (Na+ channel blockers) slow or block
phase 0 (depolarization phase) this class has 3 drug subclasses (A,
B & C)
Class II Antiarrhythmics ( blockers) slow phase 3 (the delayed
rectifier current) prolonging the ERP and AP duration
Class III Antiarrhythmics (K+ channels blockers) also slow phase
3 prolonging the ERP and AP duration
Class II Antiarrhythmics ( blockers) - slow both phase 0 and
phase 4 currents* PLUS they also decrease the delayed rectifier
currents (phase 3)
Class IV Antiarrhythmics (Ca2+ channel blockers) slow phase 0
and phase 4 (pacemaker currents*)
*Pacemaker currents are the basis for automaticity. They involve
a complex of an increased influx of Na+ and Ca2+ and a decreased
efflux of K+The double-gated Na+ channels can exist in 3 states
resting, open, or refractory. Most class I antiarrhythmic drugs
block these channels when the M gate is open a state-dependent
action.
Depolarization (phase 0) in the slow-response fibers of the SA
& AV nodes as well as the pacemaker currents (phase 4)) are
slowed by beta blockers (class II) and by calcium channel blockers
(class IV).
BACKGROUND: ARRHYTHMIASDRUGS & ANS REGULATION OF HEART RATE
SA & AV nodes have M2 receptors (which decrease cAMP) & 1
receptors (which increase cAMP).
Vagal stimulation (via ACh) increases outward K+ current thus
inhibiting depolarization M receptor agonists & AChE inhibitors
enhance these effects and thus cause bradycardia, while M receptor
blockers oppose these effects and cause tachycardia.
Activation of 1 receptors(1) increases the slope of phase 4, (2)
increases the upstroke velocity in pacemakers, and (3) shortens AP
duration by increasing the delayed rectifier currents.
Beta activators (eg, isoproterenol) initiate this action,
causing tachycardia - the beta blockers (Class II antiarrhythmics)
antagonize these effects and cause bradycardia!
CARDIAC EFFECTS OF SERUM POTASSIUM LEVELS
Changes in serum potassium can have effects on cardiac function
that are somewhat paradoxical they do not follow simply from
considering the electrochemical gradient and the role of the ion in
the repolarization phase of the cardiac action potential.
Hyperkalemia can reduce action potential duration, slow
conduction and decrease pacemaker rate!
Hypokalemia can prolong action potential duration, increase
pacemaker rate & increase pacemaker arrhythmogenesis.
The bottom line?
Maintain plasma K+ between 3.5-5.0 mEq/L
CLASS IA NA+ CHANNEL BLOCKERS Intermediate OnsetCLASS IA:
increase Action Potential Duration (APD)block fast Na+ channels
(state-dependent) decreasing slope of phase 0 & also block K+
channels decreasing slope of phase 3; APD & ERP1A drugs have a
broad spectrum are used in both supraventricular & ventricular
arrhythmias.Quinidine*(Quinidex, Quinaglute, Cardiqion):*optical
isomer of quinine200-600 mg PO qid, as sulfate or gluconate salt.
Broad activity & as been used in atrial flutter, AF & AV
nodal re-entry. The IV form has been used in VT. Also blocks
cardiac M receptors so need initial beta blocker (or verapamil) to
slow AV nodal conduction. Causes peripheral vasodilation via an
alpha blocking action hypotension Toxicity: GI distress (common),
cinchonism (dizziness, tinnitus, blurred vision), hypersensitivity,
thrombocytopenia; QT interval (torsades); heart block.
Procainamide (generic, Pronestyl, Procanbid): Both IV & PO
forms, with doses depending on specific circumstance
Broad activity - like quinidine in its actions, but no M block.
Metabolism via N-acetyltransferase (genetic variations) to an
active metabolite, NAPA, which has class III actions; short
half-life requires frequent dosing; PO & IV forms.Used in both
atrial (SVTs) & ventricular arrhythmias (used in CCU as back-up
to lidocaine post-MI). Toxicity: GI distress; SLE-like syndrome is
common (especially in slow acetylators); agranulocytosis; CV
toxicity includes torsades (more likely in fast acetylators). Serum
levels must be monitored. Contraindicated in renal
dysfunction.Disopyramide (generic, Norpace, PO):Use limited due to
marked M receptor block, hypoglycemia & possible ventricular
arrhythmias!
CLASS IB NA+ CHANNEL BLOCKERS Fast OnsetCLASS IB: decrease
Action Potential Duration (APD)Block fast Na+ channels especially
in ischemic cells, bundle of His, Purkinje fibers & ventricular
myocardium. (Interestingly, they shorten APD in normal cardiac
cells!)1B drugs are more effective in ventricular
arrhythmias.Lidocaine (generic, Xylocaine)IVuse for ventricular
arrhythmias especially post-MI; also used in heart surgery & in
digoxin OD. No therapeutic effect in most SVTs.Toxicity: Least
cardiotoxic drug BUT causes CNS toxicity (sedation, dizziness,
paresthesias, seizures, respiratory arrest), especially if used
>24h and especially in elderly.CLASS IC NA+ CHANNEL BLOCKERS
Slow OnsetCLASS IC: No effects Action Potential Duration (APD)Block
fast Na+ channels (esp. His-Purkinje); no effects on APD or on the
ANS. Several drugs in this class, but problems 1C drugs can be used
in both supraventricular & ventricular arrhythmias BUT there is
a risk of pro-arrhythmic action!Flecainide (generic, Tambocor,
PO)Approved for VTs, but shown in CAST* to increase mortality! Now
used mainly for pharmacologic cardioversion of AF (if no form of
structural heart disease or HF) the so-called pill in the pocket
approach. Toxicity: pro-arrhythmogenic (sudden death)Propafenone
(generic, Rythmol, PO)Similar, but also has nonselective beta
blocking actions (type II). Approved for VTs, but mainly used in
SVTs and for cardioversion in AF. Not studied in CAST, but
suspicions linger * CAST = Cardiac arrhythmia suppression
trial32CLASS II ANTIARRHYTHMIC DRUGS: BETA BLOCKERSMetoprolol
(Lopressor): 25 mg bid or 50mg SR form qd also IV
Propranolol (Inderal): 10-20 mg tid PO as tabs or soln - also
IV
Esmolol (Brevibloc): IV only
SA & AV nodal activity; slope of phase 4 in pacemakers;
negative inotropic effects (decrease contractility & oxygen
consumption). Also treat underlying causes of some arrhythmias (eg,
ischemic heart disease; exercise or stress-related sinus
tachycardia). Wide range of Rx uses with established efficacy:
SVTs, AF & atrial flutter, VTs, post-MI.Drugs: Most drugs have
equivalent efficacy based on CAST resultsToxicity: bradycardia,
bronchospasm, depression, fatigue, hypotension, impotenceCLASS III
ANTIARRHYTHMIC DRUGS: K+ CHANNEL BLOCKERS delayed rectifier current
slowing repolarization APD & ERP (effective refractory
period)Amiodarone (Cordarone): PO & IV forms; dosing (may
require initial hospitalization!) depends on both specific
arrhythmia and the need for loading & maintenance regimens -
its half-life is > 2 months!
Rx Uses:mimics all 4 classesnot a negative inotrope safe in
patients with left ventricular dysfunction.effective in atrial and
ventricular arrhythmiasused in AF in patients with structural heart
disease.QT prolongation (Torsades) is rare despite amiodarone being
a K+ channel blocker that can prolong QT interval!Toxicity: Most
serious is pulmonary toxicity which can be life-threatening
(baseline lung function tests & chest X-ray needed annually)
Black Box Warning!Contains 38% iodine and may cause hypo- or
hyperthyroidism (test baseline & q. 6 months). Benign corneal
& lens opacities, but with long-term use vision-threatening
optic neuritis may occur (test baseline & annually). Increases
LFTs, but hepatitis is rare. Photosensitivity reactions occur (use
sunscreens) and blue-gray skin discolorations. Drug interactions:
Inhibits several CYP450 isoforms eg, increases blood levels of
warfarin (commonly used in AF) and several statins used in
hyperlipidemias.
Dronederone (Multaq)
Like amiodarone, but contains no iodine! It has a much shorter
half-life (24h), does not require a loading dose and is reported
not to affect the thyroid, visual functions, or warfarin activity
(its labeling states no Interaction!). has been used commonly in
atrial fibrillation (though 4x more costly than amiodarone) and is
reported to reduce hospitalization & mortality. Only to
patients with normal sinus rhythm
However, the drug increases mortality in severe heart failure!
Some warfarin patients report INR increases and there have also
been warnings of liver failure (check liver enzymes at 6 months)
and reports of renal toxicity & torsades. risk of serious
cardiovascular events, including death, in patients with atrial
fibrillation monitor ECG every 3 months with appropriate
antithrombotic therapyDrug Interactions: digoxin, beta-blockers,
calcium channel blockers, some statins, strong 3A4 inhibitors,
grapefruit, and others.
33CLASS III ANTIARRHYTHMIC DRUGS: K+ CHANNEL BLOCKERS delayed
rectifier current slowing repolarization APD & ERP (effective
refractory period)Sotalol (Betapace, Betapace AF): PO 80mg bid, or
qd if CCl < 60 mL/min
Consist of 2 isomers - one IK (potassium current) & the
other is a nonselective beta blocker (class II). Renal
elimination.Rx Uses: Both atrial & ventricular arrhythmias.
Need hospitalization when starting treatment to monitor &
possibly to resuscitate!Toxicity: Torsades (dose-dependent) is NOT
rare! Avoid if QT interval > 440 msec. Black Box warning.Watch
renal function and diuretics since hypokalemia and hypomagnesemia
can both increase the risk of torsades. Contraindications: LV
dysfunction, HF, asthmaDofetilide (Tikosyn): 500 mg bid PO (lower
in renal dysfunction).
Most selective drug in this class, with few hemodynamic effects
& no negative inotropy (safe in LV dysfunction). Used for
conversion and/or maintenence in atrial flutter and AF.
Toxicity: May cause headache or dizziness. Torsades problematic
(like sotalol) avoid if QT interval > 440 msec. Suggest initiate
Rx for 3 days where cardiac monitoring & resuscitation
facilities are available!Drug Interactions: Levels increased by
azoles, cimetidine, diltiazem, erythromycin, grapefruit juice,
ketoconazole and SSRIs.
CLASS IV ANTIARRHYTHMIC DRUGS: Ca2+ CHANNEL BLOCKERSBlock slow
calcium channels: phases 0 & 4 in nodal pacemakers.Decrease AV
nodal conductionVerapamil (generic, Calan, Isoptin): PO &
IV.
Diltiazem (generic, Cardizem, Dilacor):PO/IVRx Uses: SVTs mainly
of re-entry origin.
Toxicity: Dizziness, headache, flushing, hypotension, peripheral
edema, bradycardia, AV block & constipation
(verapamil).Contraindications: Heart block, LV dysfunction; careful
in SA nodal disease, or if used with beta blockers.UNCLASSIFIED
ANTIARRHYTHMIC DRUGSDigoxin (generic. Lanoxin)Vagotomimetic action
slows AV conduction in atrial flutter or AF.Though ok in LV
dysfunction, with exercise it elicits SANS stimulation limiting its
effectiveness! Interactions:Check Heart Failure lecture for more re
toxicity & drug interactions.Adenosine (generic Adenocard) IV
administration (half-life < 20s)inhibits AV & SA node
activity and is effective in PSVTs & AV nodal arrhythmias. May
cause bronchoconstriction & flushingAdverse EffectsMay cause
bronchoconstriction & flushingMagnesium sulfate:IV Used IV in
digoxin-caused arrhythmias & in torsades, even if Mg levels
normal. Mechanism unclear!Atropine:IVOnly used (IV) in monitored
clinical setting for slow arrhythmias causing symptomatic
bradycardia. 34ARRHYTHMIASLong QT SyndromeOccurs as a familial
condition with increased risk of ventricular arrhythmias. Etiology
unclear, but some evidence of mutations in certain genes encoding
cardiac K+ channels.Risk of problems is increased by class IA &
class III antiarrhythmic drugs (and by many other drugs including
tricylic antidepressants see next frame. Higher risk in females,
elderly, bradycardia, low K+, low Mg2+
TreatmentCorrect hypokalemia & hypomagnesemiaDiscontinue
QT-prolonging drugsShorten APD with isoproterenol or electrical
pacingMg sulfate 1g/IV
DRUGS ASSOCIATED W/ QTc
PROLONGATIONAntibioticsazithromycinclarithromycin*erythromycinlevofloxacinmetronidazoleOfloxacinAntifungalsfluconazole(in
cirrhosis)Itraconazole*ketoconazoleAntiviralsnelfinavir
Antimalarialschloroquinemefloquine
AnaestheticshalothaneAntiarrhythmicsamiodarone*disopyramideflecainide
procainamidequinidinesotalol*Antidepressants
amitriptylinecitalopramclomipramine fluoxetineimipraminetrazodone
Antipsychoticsclozapine*
fluphenazinehaloperidolrisperidonethioridiazine*ziprasidonepimozideBronchodilatorsalbuterolsalmeterolAntiemeticsondansetron
et al
*Black box warnings Rx ATRIAL FIBRILLATION/FLUTTERAtrial
fibrillation (AF) is a common form of arrhythmia that affects over
2 million Americans. Risk of developing AF increases with age, is
more prevalent in men, and often is associated with underlying
heart disease. Severe symptoms are usually managed by direct
current cardioversion (DCC).Options for the drug management of AF
are rhythm control and rate control strategies. The rhythm control
strategy (restores sinus rhythm) involves cardioversion with
antiarrhythmic drugs or DC electrical current, followed by drugs
for maintenance of sinus rhythm. With the rate-control strategy,
the ventricular rate is controlled by the use of drugs without
restoring sinus rhythm.See algorithm Fig 6-1 in Wells (p.70)Rx
ATRIAL FIBRILLATION/FLUTTER (1)Ventricular rate-control drugs:
Diltiazem, verapamil, beta blocker, or digoxin if LVEF > 40%;
digoxin or amiodarone are preferred drugs if LVEF < 40%Drugs for
conversion to sinus rhythm rhythm control: amiodarone, dofetilide,
flecainide, propafenone, or ibutilide. Most are available both PO
and IV.CAUTION: Antiarrhythmic drugs (or DC cardioversion) should
NOT be used in persistent AF (> 48h ?) or recurrent AF BEFORE
anticoagulation Rx, due to a high risk of thromboembolism
strokes.Management of patients with atrial fibrillation also
includes antithrombotic therapy which may include aspirin, warfarin
or newer antithrombotic agents (see below). WHY USE DRUGS IN
AF?
The results of DC cardioversion in patients with chronic atrial
fibrillation indicate a high initial effectiveness, but poor
long-term effectiveness.70-90% patients with chronic atrial
fibrillation will convert to sinus rhythm with application of DC
cardioversion.BUT! 60-75% of successfully cardioverted patients
will revert to atrial fibrillation within one year! Rx ATRIAL
FIBRILLATION/FLUTTER (2) Warfarin (INR 2-3) is usually given for
3-4 weeks before attempted cardioversion and for at least 4 weeks
after. In high risk patients anticoagulants become a chronic
necessity. Dabigatran (Pradaxa) a direct thrombin inhibitor (DTI)
& rivaroxaban (Xarelto) a direct factor Xa inhibitor are
alternatives to warfarin. (see Anticoagulants lecture Jan 30 2014
& a recent Prescribers Letter, May 2014).ARRHYTHMIAS TREATMENT
OF PSVTs
Paroxysmal supraventricular tachycardia is usually due to
activity of AV nodal reentrant circuits.
1. First approach: Vagal stimulation (cough, carotid sinus
massage, valsalva, etc.)
2. Second approach: Adenosine IV
3. Third approach:If LVEF > 40% : IV diltiazem, or verapamil,
or beta blocker or digoxin. If no good try DC cardioversion. If
that fails try IV amiodarone or procainamide.If LVEF 40%
procainamide (IV), LVEF 10%), leukopenia, angioedema (can be
life-threatening), agranulocytosis ( 5.5 mEq/L, creatinine > 3
mg/dL, systemic BP < 80 mm Hg
Symptomatic improvement may take several months, despite which
the risk of HF progression is reduced.
ACEIs also decrease mortality if given post-MI.
DRUG INTERACTIONS WITH ACEIs
Antacids decrease GI absorption of captopril & possibly
others
Aspirin antagonizes hemodynamic effects of ACEIs
Capsaicin triggers or worsens the cough
Lithium ACEIs increase lithium toxicity
NSAIDs increase salt & water retention
K+ supplements increased risk of hyperkalemia
K+ sparing diuretics - increased risk of hyperkalemia
Rifampin decreases effects of enalapril
Tetracycline GI absorption is decreased by ACEIsAngiotensin II
Receptor Blockers (ARBs)MORE ABOUT ARBs IN HFIn one large study of
efficacy in heart failure losartan was shown equivalent to the ACE
inhibitor enalapril in terms of effectiveness judged by similar
clinical endpoints in terms of exercise tolerance, dyspnea-fatigue
index, lab evaluations, etc and like the other -sartans was less
likely to cause cough! In several recent clinical studies ARBs
(like ACEIs) were shown to decrease hospitalizations in HF.In
addition there have been reports that certain ARBS (eg,
candesartan) decreases mortality in HF, so the ARBs seem to be
equivalent to the ACEIs in this regard!
WHAT ABOUT ACEIs & ARBs IN HF DUE TO DIASTOLIC
DYSFUNCTION?Although diastolic dysfunction (stiff heart) is an
important clinical problem, its treatment is less well-defined than
for systolic dysfunction. Theheartmuscles do not relax in a normal
manner and theheartmay fill too slowly, asynchronously or with an
elevation in filling pressure only.Diastolic dysfunction can result
in HF, though not generally as severe as systolic dysfunction.
However, subsequent morbidity and mortality rates are quite
high.
Control of hypertension & coronary artery disease is a
requirement in most patients. Evidence so far suggests ACEIs and
ARBs can reduce symptoms and hospitalizations, but these drugs have
NOT been shown to decrease mortality in diastolic heart failure
(yet!).DrugCharacteristicsAdverseLosartan (Cozaar) 25-100 mg
qd/bid
Valsartan (Diovan) 80-320 mg qd
Candesartan (Atacand)
Mechanism:Bind to AT-1 receptors in kidney and blood vessels
preventing their activation by angiotensin II. Do NOT block
bradykinin metabolism by ACE!
Uses in HF:ARBs are increasingly competitive with prils as 1st
choice drugs in patients with HF
Contraindications: Pregnancy (category D), bilateral renal
stenosis
Adverse effects: Somewhat less than prils eg, less cough and
hyperkalemia; angioedema (very rare)
THIAZIDE DIURETICSInhibit the Na+/Cl- co-transporter in the
distal convoluted tubule (DCT)
Thiazides: In past were often the first drug type used in HF.
Most effective if CrCL > 30 mlL/min. Now mostly adjunctive to
ACEIs.
Chlorthalidone (Hygroton): 12.5-50 mg qdHydrochorothiazide
(Diuril): 12.5 50 mg qd Metolazone (Zaroxolyn): 2.5-10 mg qd
Contraindicated in anuria (creatinine clearance < 30mL/min).
Adverse effects:
Hypokalemia (note this may balance the effects of ACEIs if used
adjunctively!), hyperuricemia, hyperglycemia, hyperlipidemia,
hypercalcemia, rash. K+ leads to cardiac toxicity Ca2+ leads to
cardiac toxicity
POTASSIUM-SPARING DIURETICS Spironolactone (Aldactone) 12.5 50
mg qdBlocks aldosterone receptors in collecting ducts. Valuable
adjunctive use (at low dose) with ACEIs in HF 36% decrease in
hospitalization and 27% reduction in mortality.Toxicity: GI
distress, hyperkalemia (avoid if K+ > 5mEq/L), acidosis,
hirsutism, gynecomastia, menstrual irregularities
Amiloride (Midamor) 5-20 mg qd/bid
Triamterene (Dyrenium) 50-150 mg qd/bidBlock Na+ channels in
collecting ducts. Rx use: to offset hypokalemia caused by other
diureticsToxicity: Hyperkalemia (as above, avoid if K+ >
5mEq/L), acidosis, nephrolithiasis.
LOOP DIURETICS LOOP DIURETICS
Bumetanide (Bumex): 0.5-5 mg qdEthacrynic acid (Edecrin): 25-100
mg, bid-tidFurosemide (Lasix): 20-32- mg, bid-tidTorsemide
(Demadex)
Effective even if CrCl < 30 mL/minCan monitor effects by
weight change. IV administration may be needed with persistent
volume overload
Adverse effects: Dehydration (?circulatory collapse),
hypokalemia (note may balance the effects of ACEIs!), hypocalcemia,
hypomagnesemia, hyperuricemia, hyperglycemia, metabolic
alkalosis
Interactions: NSAIDs may antagonize the diuresis &
necessitate dose increase. Potential enhanced ototoxicity with
drugs like aminoglycosides.
46BETA BLOCKERS FOR HFBETA BLOCKERS IN HF (1)
How can drugs that decrease heart rate, decrease cardiac
contractility and even possibly oppose peripheral vasodilation be
of any value in HF? Good question!
Carvedilol (Coreg) was the 1st beta blocker approved for HF it
slowed disease progression, decreasing both hospitalization and
mortality (a 65% reduction) was its efficacy due to the drug also
being an alpha blocker?
Apparently not! a long-acting form of metoprolol (generic,
Lopressor, a selective 1 receptor blocker) decreases mortality in
HF and this drug has no alpha receptor blocking action!
Bisoprolol (generic, Zebeta) has also been shown to decrease
mortality in HF it too lacks any alpha antagonism! BETA BLOCKERS IN
HF (2)
Increased sympathetic tone occurs in HF and it has been
suggested that chronic SANS activation of the heart accelerates the
progression of HF. This idea may originate more from the fact that
some beta blockers work in HF than from direct evidence for the
connection between SANS activation and heart deterioration!
Other notions of how some beta blockers have efficacy in HF
include slowing/reversing ventricular remodeling, blocking
catecholamine-induced necrosis, decreasing HR & hence
myocardial oxygen demand, and inhibiting the release of renin.
Whatever!
Selected beta blockers are recommended for stable NYHA class
II-IV patients with LV dysfunction (EF < 35 - 40%) as add-ons to
ACEIs, ARBs and diuretics. IMPORTANT: The three beta-blockers shown
to improve survival in HF are metoprolol succinate, carvedilol,
& bisoprolol. DrugCharacteristics/MechanismAdverse
ReactionsCarvedilol (Coreg, Coreg ER): 3.125-50 mg bid; CR 10-80 mg
qd.
Metoprolol ER (Toprol XL): 50-100 mg qd/bid
Bisoprolol (generic, ZeBeta): start 5 mg qd; range 5-20 mg
Are started slowly watching for 1 hr with each dose change
Toxicity: bradycardia, AV block, postural hypotension,
dizziness, fatigue, depression, bronchoconstriction, hepatic
dysfunction, fluid retention (check weight) if withdrawal is needed
it is done slowly!
Contraindications: Asthma, heart block (unless pacemaker used),
sinus bradycardia
VASODILATORS & NITRATESUsually considered as alternatives in
combination therapy, with the following exception studies in
African-American HF patients showed decreases in hospitalizations
and in mortality rate in the long-term (>3y) and, if used
together WITH ACEIs, they may further decrease mortality!
DrugCharacteristics/MechanismAdverse ReactionsIsosorbide
dinitrate (ISDN, Isordil): 10-40 mg tidThe nitrate ISDN venodilates
(decreases preload).May cause headache, flushing, postural
hypotension, tachycardia, blurred vision. Need nitrate-free
periods! Avoid in nitrate hypersensitivityHydralazine (Apresoline):
25-75 mg tid Hydralazine dilates arterioles (decreases
afterload)May cause postural hypotension & tachycardia. May
cause a lupus-like syndrome. Avoid in CAD or aortic
stenosis.Nitroprusside (generic, Nitropress, IV infusion):Acts like
other nitro-vasodilators. Can improve cardiac output in
decompensated heart failure. Used short term
Used short-term, due to possible CN or SCN toxicity.
Nitroglycerin (IV):Coronary dilator used in severe HF &
ischemic heart disease.
Tolerance may develop to these nitrates and rebound can occur
with abrupt withdrawal.Nesiritide (Natrecor, IV): Recombinant form
of human B-type natriuretic peptide increases cGMP causing rapid
& intense vasodilation, but is very short-acting. Though
approved for Rx of acute decompensated HF concerns have arisen
recently over its nephrotoxic potential.
Bidil
Hydralazine (Apresoline)+Isosorbide dinitrate (ISDN,
Isordil)
Marketed specifically for African-American patients*, the agent
is a fixed combination of hydralazine (37.5 mg) and isosorbide
dinitrate (20 mg). Use of the individual drugs in combination is
less expensive but the dosage regimen of 2 tabs TID with need for a
nitrate-free interval can make adherence difficult. *It remains
uncertain whether this combination can improve survival in other HF
patients, but it is an alternativeregimen if ACEIs and ARBS are
contraindicated due to renal insufficiency, or hyperkalemia.
Headache dizziness and GI distress commonly occur.
POSITIVE INOTROPESCARDIAC GLYCOSIDESDigitalis glycosides
(together with diuretics) had been the mainstay of treatment of HF
until the ACEIs & ARBs arrived! Digitalis improved symptoms
& quality of life and decreased hospitalizations, especially in
HF patients with very low ejection fraction, or enlarged hearts.BUT
digitalis glycosides do NOT decrease mortality in HF AND they have
a narrow therapeutic index with risk of severe toxicity in overdose
including myocardial infarction and cardiac arrhythmias ANDMany
drug interactionsThe only glycoside now available in the USA is
digoxin.DrugCharacteristics/MechanismAdverse ReactionsDigoxin
(Lanoxin): 0.0625 - 0.25 mg qd. Recommended in HF due to LV
systolic dysfunction in conjunction with ACEIs &
diuretics.Kinetics: Long half-life (48 hr) reaching steady state in
about 10 days check serum levels, electrolytes, BUN &
creatinine at that time. Enters most tissues (high Vd) and
eliminated mainly via the kidney. Narrow therapeutic
window!Toxicity: Anorexia, nausea, headache, fatigue, ECG changes;
higher doses cause disorientation & visual effects. Cardiac
symptoms can take the form of most known arrhythmias and include
paroxysmal atrial tachycardia, ventricular tachycardia & heart
blockImportant: diuretics may alter electrolytes - potassium level
is critical! K+ leads to cardiac toxicity Ca2+ leads to cardiac
toxicity
Overdose toxicity is managed with Fab antibody (Digibind) +
electrolyte adjustments & antiarrhythmic drugs avoid attempted
cardioversion!
Contraindications: allergy, ventricular arrhythmias, renal
dysfunction
Drug Interactions: Blood levels are increased by many drugs
including anticholinergics, quinidine, spironolactone &
verapamil. GI absorption may be decreased by antacids and
kaopectateMechanismThe drug is a positive inotrope. It stimulates
cardiac function by complex mechanisms including inhibition of the
Na+-K+-ATPase that pumps out sodium in exchange for potassium. This
leads to intracellular Na+ which in turn results in Na+/Ca2+
exchange intracellular Ca2+ which causes Ca2+ release from
sarcoplasmic reticulum which increases the interaction between
actin-myosin which leads to contractile force!Phew!Milrinone
(generic, Primacor):Used primarily IV in acute decompensated
failure, or for severe exacerbation in chronic
failurePhosphodiesterase inhibitor that increase the levels of cAMP
resulting in the enhancement of cardiac contractility plus
vasodilation, the latter decreasing ventricular afterload. Less
thrombocytopenia than the older drug amrinone; some hepatotoxic
potential.
Dobutamine (Dobutrex) & Dopamine (Intropin): used IV in mgmt
of acute decompensated failure, especially if there is a need to
BP.These agents are sympathomimetics which activate cardiac beta
receptors
HEART FAILURE RECOMMENDATIONSGENERAL RECOMMENDATIONS (1)An ACE
inhibitor should be given to all patients with heart failure unless
there are contraindications. An ARB is an alternative.In
symptomatic patients with heart failure, specific beta-blockers are
recommended to reduce mortality rates.The aldosterone antagonist
(spironolactone) is recommended to reduce mortality rates in
certain patients with heart failure. These include patients with
current or recent history of dyspnea at rest, and patients with
recent myocardial infarction who have systolic dysfunction with
either clinically significant signs of heart failure or with
concomitant diabetes mellitus.GENERAL RECOMMENDATIONS (2)For
persistently symptomatic African-American patients with heart
failure, direct-acting vasodilators (eg, isosorbide dinitrite)
reduce overall mortality rates when added to background therapy
with ACE inhibitors, beta-blockers, and diuretics (if needed).
Direct-acting vasodilators are also an alternative for patients
with heart failure who are intolerant of ACE inhibitors.For HF
patients with volume overload, diuretics are recommended.TREATMENT
RE HEART FAILURE STAGES
For Stage A patients the emphasis is on modifying risk factors
including diet, smoking & treatments of HTN, diabetes mellitus
& dyslipidemias. If hypertensive then ACEIs or ARBs are
optimal.
For Stage B patients with prior MI (or ejection fraction