Beta-blockers decrease renin production by inhibiting beta-1 receptors in juxtaglomerular cells.
LO 3, 4 Clopidogrel is a “pro drug” that is metabolized in liver by CYP450 in 2 steps to highly reactive metabolite. Genetic variation in metabolism can affect clinical efficacy. Ticlopidine another example of an ADP receptor antagonist (thienopyridine) that is no longer used due to neutropenia and TTP. Clopidogrel, prasugrel, and ticlopidine are thienopyridines. Ticagrelor is not a thienopyridine, but it is an ADP receptor antagonist. ICH = intracranial hemorrhage
Lepirudin: Hirudin does not rely on ATIII, inhibits thrombin in clots.
Fibrinolytics target fibrinolysis, which normally acts to regulate coagulation in the body. Plasmin is the key protease in fibrinolysis and can cut both fibrinogen and fibrin in clots. Conversion from plasminogen to plasmin occurs with tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA), which are endogenous fibrinolytics in the body that have been exploited as drugs. Unlike the older agent streptokinase, the newer drugs bind preferentially to fibrin in a formed thrombus instead of having substrate specificity for fibrinogen AND fibrin. As a result, there is less interference with coagulation in the general circulation. PAI-I normally inactivates plasminogen to prevent widespread activation of plasminogen.
Mechanism of Action Clinical Use Side Effects
Statins Inhibit HMG-CoA reductase,
modify platelets and
Lower LDL (1st line
Ezetimibe Inhibit NPC1L1 at brush border in
Lower LDL (2nd line
use is decreasing)
Bind cholesterol in intestinal
lumen and prevent recycling to
Lower LDL (3rd line
GI (gas, diarrhea),
drug interactions, no
systemic side effects
b/c not absorbed
Niacin Decreases lipolysis in adipose
tissue, increases HDL by
decreasing hepatic removal of
due to PGs (take
Fibrates Activate PPAR-alpha to enhance
oxidation of FAs
augment effects of
drugs for diabetes
Fish oil Not well defined, PPAR-alpha
Decreases TGs May prolong
ANTIANGINAL Mechanism of Action Clinical Use Side Effects
Nitrates (1) Metabolized to NO relax
great veins decrease
venous return decrease
preload reduces work of
heart and O2 consumption
(2) Relax arterioles somewhat
decreased aortic pressure
decreased ejection time
(3) Dilate coronary arteries
Both short- and long-acting:
hypotension, don’t use
Ranolazine Reduces late Na channel
Last-resort in refractory
angina that cannot be
treated with PCI or
CABG (pt is usually
Hydralazine Unknown cellular mechanism
works particularly well
in African American pts
and pregnant women
Mechanism of Action Clinical Use Side Effects
Decrease O2 consumption by
decreasing HR and contractility.
Also decrease renin production
to some extent, decreasing BP.
Don’t use in Printzmetal angina
or cocaine intoxication β
blockade causes coronary
heart failure (mortality
arterial vasospasm (β2
Careful with diabetics
verapamil and diltiazem
reduce Ca channel activity in
arteries AND myocardium
(decreases TPR decreased
reduces Ca channel activity in
arteries, no effect on cardiac
chronic stable angina,
variant angina, beta-blocker
mortality benefit in
normal LV fxn ONLY.
angina, sometimes in
bradycardia, AV block,
Describe basic platelet physiology
• Lifespan of platelet: T ½ = 10 days
• Adhesion: Platelets adhere to exposed subendothelial collagen when there’s
endothelial damage. This occurs through glycoprotein receptors via von
• Activation: Platelets stick to exposed basement membrane proteins through
glycoproteins (VCAM-1). This activate platelets, causing ADP and serotonin to be
released and TXA2 to be synthesized and released . These will activate more
• Platelet aggregation: GP IIb/IIIa is a glycoprotein receptor on platelets responsible
for binding to fibrinogen. When the platelet is activated, GP IIb/IIIa will bind to the
RGD motif of fibrinogen. Fibrinogen is a dimer, so a second platelet can bind to
the other end, which leads to platelet aggregation and the formation of the platelet
Central role of factors X, prothrombin, and
thrombin in the coagulation cascade.
Mechanism of Action Clinical Scenario
Aspirin Irreversible, nonselective COX-1 and
Angina, acute MI, TIA,
Dipyridamole Blocks uptake of adenosine, PDE
heart valves, stroke)
Clopidogrel Irreversibly inhibits ADP receptors
(use in people allergic to aspirin)
Recent MI, unstable angina,
recent stroke, PAD, post-stenting
Prasugrel Irreversibly inhibits ADP receptors,
*metabolized more efficiently
Prevention of CV
Ticagrelor Reversibly inhibits ADP receptors,
not a pro-drug
Prevention of CV
thrombosis after MI
Abciximab Monoclonal Ab that blocks GpIIb/IIIa During PCI
Eptifibatide Small molecule that blocks Gp
Tirofiban Small molecule that blocks Gp
• MOA: Non-selective, irreversible inhibitor of both cyclooxygenase-1
and -2 (COX-1 and -2). NSAIDs block formation of TXA2 and PGI2.
Blocking TXA2 is beneficial because TXA2 normally triggers platelet
• Clinical Use: Low dose (30mg/day) used for prevention of MI, High
dose (70-375mg) used in acute cases of stable angina, unstable
angina, STEMI and NSTEMI.
• Extremely important to use in patients with known CV disease.
• Adverse effects: GI discomfort, modest increase in peptic ulcer
disease and GI/systemic bleeding (remember that prostaglandin,
which aspirin inhibits, protects the stomach)
ADP Receptor Inhibitor MOA
• Inhibit ADP-mediated activation of platelets.
• Extracellular ADP normally activates platelets by binding to two types
of purinoceptors, P2Y1 (acts via phospholipase C to increase
intraplatelet Ca) and P2Y12 (acts via inhibitory G protein to reduce
cAMP production, which increases intraplatelet Ca).
• ADP-induced platelet activation requires simultaneous activation of
both the P2Y1 and P2Y12 purinoceptors.
• The ADP receptor antagonists irreversibly block P2Y12 receptors,
inhibiting platelet aggregation.
• Contraindications for all agents in this class:
• Active pathological bleeding such as peptic ulcer or intracranial
• Clinical Use: The most commonly used agent. Pro-drug that must be
metabolized to active metabolite by the CYP2C19 enzyme in the liver.
• Slightly better than aspirin in preventing MI and stroke.
• Used as aspirin substitute for patients who are allergic/intolerant to
• Used after placement of coronary stents.
• Adverse effects: Bleeding, dyspepsia, diarrhea, very rare severe
neutropenia and thrombotic thrombocytopenic purpura (TTP)
• Clinical Use: Prasugrel has a greater antiplatelet effect than
clopidogrel because it is metabolized more efficiently.
• This drug is mainly used during percutaneous coronary interventions
(PCI) in the cath lab.
• Clinical Use: percutaneous coronary interventions
• 1. Direct acting - not a prodrug; does not require metabolic activation
Rapid onset of inhibitory effect on the P2Y12 receptor Greater
inhibition of platelet aggregation than clopidogrel
• 2. Reversibly bound - Degree of inhibition reflects plasma
concentration Faster offset of effect than clopidogrel
• Functional recovery of all circulating platelets
• Adverse effects
• Genetically engineered monoclonal antibody
• Its Fc portion has been cleaved off so it can only bind to and inhibit
platelets without splenic uptake and which reduces thrombocytopenia.
• Clinical Use:
• Adjunct (to heparin and aspirin) during percutaneous coronary
interventions (PCI: balloon angioplasty, stenting, atheroablation)
• Prevention of acute cardiac ischemic complications in patients at high
risk for abrupt closure of the treated coronary vessel
• Use in patients with unstable angina not responding to conventional
medical therapy, when PCI is planned within 24 hours.
• A synthetic cyclic heptapeptide with a KGD sequence, which more
specifically blocks GP IIb/IIIa receptors.
• Modeled after disintegrins found in snake venom, which contain the
arginine-glycine-aspartic acid (RGD) motif.
• Approved for use in patients with acute coronary syndrome (ACS):
unstable angina or acute myocardial infarction.
• Also used in patients during percutaneous coronary intervention
• First in class synthetic, non-peptide, GP IIb/IIIa inhibitor
(peptidomimetic). Based on RGD sequence.
• In patients with unstable angina, tirofiban reduced myocardial
infarctions and deaths by 22% when used with heparin and aspirin.
• Approved for use with heparin for the treatment of ACS and during
Use Warfarin instead of Antiplatelet
Agents for Atrial Fibrillation
ANTICOAGULANT Mechanism of Action Clinical Scenario
UFH Anti-thrombin and anti-Xa activity DVT, PE, post-MI,
UA/NSTEMI, coats stents
Mostly anti-Xa activity Similar to UFH, but easier
dosing, no monitoring and
Fondaparinux Synthetic inhibitor of factor Xa, even
more selective than LWMH
Prophylaxis after knee, hip
Direct Thrombin & Xa Inhibitors
Lepirudin Direct thrombin inhibitor Used in pts w/ HIT
Bivalirudin Direct thrombin inhibitor Unstable angina & PTCA,
for pts w/ HIT
Argatroban Direct thrombin inhibitor Thrombosis in pts w/ HIT
Dabigatran Direct thrombin inhibitor After hip/knee replacement,
pts w/ Afib
Ximelagatran Binds to thrombin active site Discontinued
RivaroXaban Direct Xa inhibitor—binds to free
and unbound Xa
Afib, after hip/knee
Warfarin Competitively inhibits vitamin K (II,
VII, IX, X, protein C, protein S)
VTE prevention, DVT, Afib,
prosthetic heart valves, MI
• Thrombin is produced by the enzymatic cleavage of two sites on
prothrombin by activated Factor X (Xa). Thrombin is a "trypsin-like"
serine protease protein.
• Thrombin in turn acts as a serine protease that converts soluble
fibrinogen into insoluble strands of fibrin, as well as catalyzing many
other coagulation-related reactions.
• Additionally, thrombin is the most potent of the activators of platelets
and platelet aggregation so inhibition of thrombin also diminishes
• Thrombin is also known to be a mitogen for smooth muscle cell
• MOA: binds with antithrombin III and stimulates its anti protease
activity. Once bound to UFH, the natural anticoagulant effect of
antithrombin is potentiated, resulting in accelerated binding and
inactivation of serine proteases such as coagulation factors X a and
• Antithrombin III inactivates several enzymes of the coagulation
system. It inactivates factors IIa (thrombin), IXa, XIa and Xa.
• Side Effects: Bleeding, Heparin Induced Thrombocytopenia
• Contraindications: hypersensitivity, actively bleeding, hemophiliacs,
severe hypertension, infective endocarditis, active tuberculosis, GI
ulcers, visceral carcinomas, advanced hepatic or renal disease, or
blood brain barrier is compromised (brain or eye surgery, lumbar
• Enoxaparin and Dalteparin
• LMWHs are derived by enzymatic or chemical cleavage from UFH
into a mixture of glycosaminoglycans. They inhibit factor Xa to a
greater extent because they retain the specific sequence that binds
antithrombin during the breakdown process. LMWHs are cleared
renally, so must use caution in renal failure.
• Superior bioavailability, limited nonspecific binding, and non-dose-dependent
half-lives facilitate once or twice-daily subcutaneous
dosing based solely on weight and without laboratory monitoring.
• Cleared by renal mechanisms.
• Less heparin-induced thrombocytopenia (HIT).
Mechanism of HIT and HITT
• Allergy-like adverse reaction to heparin. Occurs in about 3% of
patients treated for more than 4 days.
• Type I: occurs due to mild direct platelet activation by heparin.
Associated with early (within 4 days) decrease in platelet count,
typically recovers in 3 days, not associated with major clinical
• Type 2: occurs due to antibodies to complexes between heparin and
platelet factor 4 (PF4). Associated with substantial fall in platelet count
between days 4 and 14 of treatment. Generally causes life-threatening
thrombotic and thromboembolic complications (e.g., DVT,
PE, MI, stroke, occlusion of limb arteries that can lead to amputation).
Mortality is 20-30% without treatment.
• HIT Type I is a benign form of HIT that is not associated with an
increased risk of thrombosis. Its mechanism is unclear, but it appears
that heparin causes a non-immune-mediated platelet aggregation,
thus reducing the circulating platelet count, called thrombocytopenia.
It generally does not lower platelets less than 100,000 (normal is
150,000-300,000). It appears in the first 2 days of heparin exposure
and it can be managed expectantly without discontinuation of heparin.
• HIT Type 2 is a clinically significant syndrome that typically develops
between days 4 and 14 of heparin treatment. It is life- and limb-threatening
with mortality 20-30%. Platelets typically fall to about
60,000. All forms of heparin must be discontinued immediately. Type 2
HIT is due to antibodies to platelet factor 4 (PF4) complexed to
• PF4 is a small, positively charged molecule of uncertain biological function
normally found in the alpha-granules of platelets. When platelets are activated,
PF4 is released into circulation and some of it binds to the platelet surface.
Because of opposite charges, heparin (negatively charged) binds to the PF4
molecules, exposing epitopes that act as immunogens leading to antibody
• People who develop HIT produce an IgG antibody against the heparin-PF4
complex, which binds to the heparin-PF4 complex on the platelet surface through
the Fab region. The Fc portion of the HIT antibody can then bind to the platelet Fc
receptor, triggering the aggregation of platelets. Activated platelets release PF4,
perpetuating the cycle of heparin-induced platelet activation. Platelet activation
also leads to the activation of the coagulation cascade.
• HIT antibodies can form complexes with endogenous heparan sulfate on the
endothelial surface and induce tissue factor expression, further activating the
coagulation cascade. Thrombocytopenia is largely due to clearance of activated
platelets and antibody-coated platelets by reticuloendothelial system.
• Therefore, although there is thrombocytopenia present (normally leads to
bleeding), the huge amount of platelet activation and coagulation cascade
activation leads to thrombosis.
Direct Thrombin Inhibitors
• Bivalirudin: anticoagulant in patients with unstable angina undergoing
percutaneous transluminal coronary angioplasty
• Argatroban: used for prophylaxis or treatment of thrombosis with HIT
and recently approved for use in patients with or at risk for HIT
undergoing percutaneous coronary interventions
• Lepirudin: patients with HIT. no longer produced as of May 31, 2012
• Direct thrombin inhibitors can inhibit thrombin in clots and can be
used in patients with HIT. The action of InDirect inhibitors are
dependent on Antithrombin and can bind only “soluble” thrombin that
is unbound to Fibrin.
• Direct Thrombin Inhibitors bind to the active site of Thrombin and can inactivate
Thrombin regardless of the presence of Fibrin.
• MOA: Related to vitamin K and acts as competitive inhibitor. Blocks
vitamin K cycle by inhibiting vitamin K epoxide reductase and vitamin
K reductase, preventing gamma-carboxylation of factors II, VII, IX, X,
and proteins C and S.
• Side Effects:
• Bleeding (1% per year for major bleeds)
• Skin necrosis can occur between days 3-8.
• “Purple toe syndrome” in patients with underlying atherosclerotic
disease. Warfarin can break off cholesterol emboli and send them
to the limbs.
• Many drug interactions (cyt P450)
• Mechanism of Action: all work directly or indirectly to cut inactive
plasminogen to its active form, plasmin. Plasmin then degrades
fibrinogen and fibrin network in thrombi and blood clots, actually
dissolving the clot (the drugs we have previously discussed mostly
prevent or stabilize existing clots). There are endogenous PAs in the
body known as tissue-type PA (tPA) or urokinase (uPA). Fibrinolytics
are modeled after these drugs.
• Clinical Use: short-term treatment of multiple pulmonary emboli, DVT,
acute MI (“time is muscle” in the heart, meaning use within several
• Side Effect: bleeding!, do not use with severely elevated blood
pressures (higher risk of bleeding)
FIBRINOLYTICS Mechanism of Action Clinical Use Side Effects
Streptokinase When complexed with
plasminogen, can convert
other plasminogen molecules
into plasmin, massive lytic
Rarely used Produced by beta-hemolytic
6% allergic reactions;
Not specific for fibrin, so
produces massive lytic state
Rarely used See below
More specific for clots
because fibrin acts as
cofactor for tPA’s activation of
plasminogen (half-life = 3 min)
Thrombolytic in ACS
when no access to PCI,
ischemic stroke, PE;
administered as IV
Reteplase (rPA) Derivative of tPA with longer
Same; can be
administered as IV
Derivative of tPA with longer
Same; can be
administered as IV
All Fibrinolytics Break down plasminogen to
plasmin, which degrades
fibrinogen and fibrin.
Thrombolytic in ACS,
ischemic stroke, PE
BLEEDING!, do not use
with elevated BP
Contraindications for Fibrinolytics
• Active internal bleeding
• History of CVA
• Recent surgery or trauma
• Intracranial neoplasm or aneurysm
• Known bleeding disorder
• Severe uncontrolled HTN
• Platelets are responsible for primary hemostasis (formation of a platelet plug) by a
• (1) adhesion to the site of injury,
• (2) release reaction (secretion of platelet products and activation of key surface
• (3) platelet aggregation.
• When there is damage to the endothelial cells, basement membrane proteins are
exposed. Platelets bind to these proteins through integrin receptors and agonists
such as collagen and thrombin then bind to the platelets themselves.
• These interactions activate platelets, causing (1), the release of granules
containing ADP and serotonin (5-HT), and (2), stimulation of thromboxane A2
(TXA2) synthesis. Both (1) and (2) activate more platelets.
• ADP interacts with ADP receptors found on platelets, leading to platelet
aggregation. ADP causes the expression of GP IIb/IIIa receptors.
• GP IIb/IIIa receptor: This receptor is located on the platelets and binds fibrinogen
molecules as additional platelets are recruited. This allows the platelets to tightly
link to one another.
• The coagulation cascade is secondary hemostasis. The coagulation
cascade results in the formation of a fibrin clot that can reinforce the
primary platelet plug.
• Factor X is converted to Factor Xa via the extrinsic and intrinsic
coagulation pathways. Factor Xa converts prothrombin (aka Factor II)
to thrombin (aka Factor IIa). Thrombin can then convert soluble
fibrinogen to insoluble fibrin, which crosslinks to form the clot.
Thrombin also activates Factor XIII, which stabilizes the fibrin clot.
• The fibrinolytic system is how the body breaks down a clot. It leads to
(1), cleavage of the fibrin mesh, and (2), destruction of coagulation
factors. Plasmin is the major protease enzyme of this system – it
binds to fibrin and degrades it. Conversion from its inactive form,
plasminogen, is controlled by tissue plasminogen activator (t-PA).
• The fall in CO is sensed by baroreceptors in the carotid sinus and
aortic arch they decrease their firing, and the signal is sent through
CN IX and X to the cardiovascular control center in medulla
• This results in increased sympathetic outflow to the heart and
peripheral circulation, and parasympathetic tone is diminished.
• The immediate consequences of this are an increased heart rate,
increased ventricular contractility and vasoconstriction, sweating, skin
vasoconstriction, increased renin release, cardiac deterioration
• 1) Decreased renal perfusion, 2) Decreased salt delivery to macula
densa, 3) Direct stimulation of juxtaglomerular β2 receptors by
sympathetic nervous system Renin Secretion
• Renin cleaves angiotensinogen to angiotensin, which is cleaved by
ACE to form angiotensin II (a potent vasoconstrictor).
• constricted arterioles and raises total peripheral resistance
• Angiotensin II also increases intravascular blood pressure by
stimulating thirst and increasing aldosterone secretion.
• Aldosterone promotes sodium reabsorption from the distal convoluted
tubule of the kidney, and increases intravascular volume
Explain why heart failure can cause
pulmonary congestion and/or peripheral
• Compensations only work for a while, and eventually become
harmful. Increased circulating volume and venous return can further
engorge the lung vasculature and/or lead to peripheral edema.
• If the Left Ventricle or Right Ventricle is unable to work properly, there
will be a backup of fluid.
• LV heart failure will lead to an increased LA pressure, and increased
pressure in the pulmonary veins and capillaries, which leads to fluid
leakage and congestion.
• RV heart failure will lead to an increased RA pressure, and an
increased venous pressure in the SVC and IVC, leading to peripheral
Describe how nitrates reduce dyspnea in
patients with acute CHF, and recognize
that hypotension is a possible side effect.
• 1. Dilates veins and reduces preload, so it leads to reduced
• 2. Dilates arteries and reduces TPR and afterload, leading to
• BP must be monitored to avoid hypotension
Identify the mechanisms by which
morphine reduces dyspnea in patients
with acute congestive heart failure.
• In acute CHF, dyspnea is caused by pulmonary edema and acute LV
• 1. CNS-mediated reduction in breathing rate, and reduces discomfort
from breathing so quickly.
• 2. CNS- mediated SNA reduction leads to a reduction in TPR and
tachycardia, and increased capacity of peripheral circulation.
• 3. Vasodilation caused by peripheral histamine release, and a
convenient anxiolytic effect.
Understand why reducing peripheral
resistance increases cardiac output in a
heart failure patient but not in a normal
individual or one with hypertension but
without heart failure
• In the normal heart reducing TPR/afterload produces little change in
CO but in HF, the reduced ventricular contraction cannot overcome
outflow resistance. Reducing peripheral resistance in CHF patients
reduces the afterload on the LV which permits increased SV and CO
Indicate the benefit of reducing cardiac
return in a volume-overloaded heart
• Reducing cardiac return in a volume-overloaded heart failure patient
reduces the preload on the left ventricle, which in turn, causes
diastolic pressure to fall out of the range that promotes pulmonary
• MOA: Digoxin binds to the outward K+ binding site of the Na+/K+ ATPase and
inhibits the enzyme. This reduces the transmembrane Na+ gradient. Reduction of
the Na+ gradient reduces the action of the Na+/Ca2+ exchanger, causing
intracellular [Ca2+] to build up. This increases the sarcoplasmic reticulum [Ca2+],
which will release more Ca2+ upon release. The ultimate effect is an increase in
• Digoxin has a narrow therapeutic window of 0.7-1.2 ng/dL. It is renally excreted,
so many drugs affect its renal clearance.
• Hypercalcemia, Hypokalemia and Hypomagnesia all increase toxicity.
• Side Effects:
• GI: anorexia, vomiting, nausea, diarrhea
• CNS: visual disturbances
• Cardiac dysrhythmias (bradyarrhythmias evolving into heart block or ventricular
• Digoxin may be beneficial to patients with atrial fibrillation because it promotes AV
block, which allows the ventricular rate to slow; after which, antiarrhythmics can
be used return normal sinus rhythm.
• 3 beneficial effects: vasodilation, natriuresis (excretion of Na+),
attenuation of cardiac remodeling
• MOA: ↓ AngII and ↑bradykinin
• ↓ afterload and TPR due to ↓vasoconstrictor action of AngII, ↓ NE release by
AngII, ↑ vasodilation by bradykinin
• ↓ preload by ↓ venoconstriction and ↓ intravascular volume (natriuretic)
• ↓ aldosterone secretion
• ↓ remodeling of myocardium
• Due to bradykinin accumulation : cough, skin rashes, angiodema
• K retention (bad news in presence of K-sparing diuretic, good news in
presence of furosemide
• First dose orthostatic hypotension
• Risk of severe fetal injury if the drug is used after the first trimester.
• Acute Renal failure in patient with bilateral high grade renal artery stenosis.
• Carvedilol, Metoprolol
• Improve cardiac performance by ↓ HR, ↑diastolic ventricular relaxation & by ↓O2
• ↓ renin release and contribute to ↓Angiotensin II and Aldosterone.
• ↓ the cardiotoxic effects of NE (fibrosis, remodeling)
• Protect against arrhythmias including ventricular fib.
• Can reduce afterload
• DECREASE SYMPATHETIC NA
• 3rd line agent (after ACE inhibitors and loop diuretics).
• Indicated for treatment of stable symptomatic HF stages II & III.
• Therapy must be started only when a patient is not fluid overloaded otherwise the
reduced contractility would result in a worsening of HF due to increased preload,
venous pressure and congestion.
• Only 2nd and 3rd generations are used.
Why is SNA so increased in Heart Failure
• Inhibitory cardiopulmonary reflexes (baroreceptor /cardiac ventricular
reflex) are down-regulated.
• Excitatory sympathetic reflexes from the heart and ischemic tissues
• Release of NE from sympathetic terminals is increased by Ang II &
• Hypoxic impulse – peripheral chemoreflex
• Muscle metaboreflex
• Spironolactone & eplerenone
• K+ sparing diuretics.
• ↓effects of aldosterone
• Potentiate diuretic effect of furosemide
• Promote K retention which is anti-dysrhythmic if K is low
• ↓ direct and indirect (via NE) toxicity of aldosterone on heart
• Improve the ratio of vagal / sympathetic drive to the heart (↓sinus node
dysfunction, ↑vagal tone).
• ↓ overall mortality in HF patients already treated with ACEI + loop
• Eplerenone has fewer GI and sexual side effects
• Inhibit Na+Cl– cotransporter in the distal convoluted tubule
• ↓NaCl reabsorption
• Commonly used to ↓ ventricular preload.
• Not potent enough beyond stage II to be given as sole diuretic,
because their already small natriuretic
• Action is further decreased by the reduction in GFR.
• Potentiate effect of loop diuretics
• Hydrochlorothiazide, Metolazone
• SE: hypokalemia, hyperglycemia, hyperlipidemia, hyperuricemia,
hypercalcemia, metabolic acidosis, hypersensitivity
MOA Loop Diuretics
• Compete for the Cl- binding site on the Na-K-2Cl in loop of Henle
• ↓ NaCl reabsorption
• Commonly used to ↓ Na and H2O retention
• More effective than other diuretics in HF
• Maintain their effectiveness despite low GFR
• Effectively treats congestion and edema
• Used in stage II and beyond
• Furosemide: optimal dose 40mg IV bolus
• SE: Hypokalemia, ototoxicity, metabolic acidosis, hypovolemia,
hyperuricemia, hypomagnesia, sulfa allergy
Isosorbide Dinitrate with Hydralazine
• Isosorbide ↓preload. Hydralazine ↓afterload.
• Effective but not uniformly well tolerated (because of hydralazine).
• 3rd-line alternative and usually less effective than ACEIs or ARBs.
• Used in patients who cannot tolerate ACEIs
• This combo produces added benefits in subsets of African-Americans
when added to the standard regimen (Diuretic + BB + ACEI or ARB)
• Hydralazine: - high incidence (about 20%) of side-effects in <10% of
patients with most serious SE: reversible lupus-like syndrome.
• β1/β2 agonist with α1-AR agonist activity.
• ↑CO and ↑ SV without much ↑ in HR and, typically, a slight ↓ in TPR.
• IV administration
• Only for short term support of circulation in patients with
decompensated CHF or cardiac decompensation caused by cardiac
surgery or acute MI.
• Blocked by Beta Blockers
• Mixed DA receptor agonist (α1/β1/β2/D1).
• At low dose infusion rate (<2-10 μg/ min), D1-receptor activation predominates and
causes rather selective renal, splanchnic and coronary vasodilation relieving some
of the work of the heart.
• At intermediate doses (2-10 μg/ min) dopamine is a β1-agonist that also releases
NE from sympathetic terminals by a mechanism akin to amphetamine. This effect
produces β1-mediated ionotropic effect on heart (good) and tachycardia (bad) and
some degree of vasoconstriction and afterload increase (bad).
• This dose range may be also appropriate for acute treatment of CHF.
• At still higher doses (>10 μg/ min), DA is a powerful α1 agonist. This dose range is
inappropriate in CHF but is useful in hypotensive states such as shock.
• Side-effects (concern with hi-dose therapy): tachycardia, tachyarrhythmias.
• Inhibits type III phosphodiesterase (PDE). PDE inhibitors prevent the hydrolysis of
cAMP and cGMP.
• In the heart PDE inhibitors have a positive inotropic effect since cAMP increases
intracellular Ca release and contractility.
• In VSM PDE inhibitors generally produce relaxation because VSM contraction is
typically reduced by cAMP (e.g. caused by beta-2AR agonists)or by cGMP
(e.g. caused by NO).
• Overall effects in HF:
• Combination of inotropic effect and decreased preload/afterload has short term
• PDE inhibitors cannot be used chronically because they increase mortality
(probable reason: they increase contractile demand in a sick heart and they cause
• SE: nausea and vomiting, cardiac arrhythmias, thrombocytopenia
• Nesiritide is synthetic human natriuretic peptide (BNP). This drug is
natriuretic, diuretic, has vasodilator effects and inhibits the effects of
renin and aldosterone.
• BNP infusion improves LV function in patients with congestive heart
failure via a vasodilating and a prominent natriuretic effect.
• BNP infusion may be useful for the treatment of decompensated
congestive heart failure requiring hospitalization.
• The clinical potential of BNP is limited as it is a peptide and requires
• SE: dizziness, nausea, cardiac arrhythmias, hypotension, headache
• NOT in patients with BP<90mmHg
Rate vs. Rhythm Control
• Rate control consists of restoring the ventricular rate to normal which,
usually, restores hemodynamic stability. This may be achieved by
rendering the AV node more refractory (less excitable) using
pharmacological agents such as beta-blockers or calcium channel
• Rhythm control means returning the heart rate to sinus rhythm, i.e.
under the sole control of the SA node. This is more difficult to achieve
• Class I and III target rhythm in the SA node, while all classes can
• 1. During hypoxia, ATP production is insufficient Dysfunction of of
the Na/K ATPase potassium equilibrium potential ++++ and the
diastolic potential +++ enhanced propensity to get activated
• 2. Hypoxia-induced depolarization fast sodium channels remain
inactive during diastole fewer channels can open during phase 0 of
the action potential membrane potential changes more slowly
(reduced dV/dt) AP propagates more slowly along the ventricle.
• Increased spontaneous activation potential + the slowing of the action
potential in and around an ischemic area can lead to reentry.
• Cholinergic receptor stimulation (muscarinic) produces much the same effects in
the SA and AV node but their consequences on heart function are different.
• A. Shared effects of cholinergic receptor stimulation in the SA and AV node:
• Combined inhibition of If and activation of I K,Ach decreases the rate of diastolic depolarization
• Decreased calcium current phase 0 dV/dt is smaller and threshold of the AP is higher
• B. Consequences of these actions in the SA node:
• If inhibition, activation of I K,ACh plus increase in AP threshold slows down the action potential
frequency causing bradycardia (negative chronotropic effect).
• The reduction of phase 0 dV/dt is unimportant functionally.
• C. Consequences of the actions of ACh in the AV node:
• Decrease in phase 0 dV/dt slows action potential velocity and increases atrio-ventricular delay.
• Slower diastolic depolarization + increase of the AP threshold AV node less excitable.
• LOWER EXCITABILITY
• Beta1-adrenergic receptor stimulation of the heart occurs naturally during
exercise and emotional stress because of a rise in sympathetic tone.
• A. Shared effects of Beta1-adrenergic receptor stimulation in the SA and AV node:
• Activation of If and increased rate of diastolic depolarization (phase 4)
• Increased ICa (calcium current) phase 0 dV/dt is larger and AP threshold is lower
• B. Consequence of these actions in the SA node:
• If activation plus lowering of AP threshold speeds up the AP frequency (tachycardia, positive
• Increase in phase 0 dV/dt within the SA node is inconsequential for cardiac physiology.
• C. Consequences of these actions in the AV node:
• Increase in phase 0 dV/dt speeds up action potential velocity and reduces AV delay (positive
• Rapid diastolic depolarization plus the lowering of the AP threshold renders the AV node more
Hypokalemia and Hyperkalemia
• >5.5 mM = high
• >6.5 or <3 symptoms = emergency
• >7 = arrhythmia
• Increased AP duration → Arrhythmia
• Delayed rectifier K+ current weaker delays repolarization
• Lengthens QT interval
• Causes: Diuretics (especially thiazides or loop diuretics), Vomiting and diarrhea, Diabetes,
metabolic alkalosis, β2 agonists, xanthenes, steroids, Cushing’s syndrome, Liver cirrhosis
• EK more positive → Cells closer to AP threshold → abnormal automaticity foci
• Decreases AP duration, refractory period
• Can inactivate Na+ channels → widens QRS
• Causes: Spironolactone, ACE Inh., Ang. II receptor antagonists, Heparins, Renal failure,
Hyperaldosteronism, Tissue destruction, Metabolic acidosis
• Hypocalcemia increases AP duration and is arrhythmogenic
• Modulated by the autonomic nervous system
• Sympathetic and Parasympathetic Stimulation
• Cardiac injury may cause acquisition of spontaneous automaticity in
non pacemaker cells due to leaky membranes
• Sinus node: Sinus Tachycardia
• AV node: AV junctional tachycardia
• Ectopic focus: Ectopic atrial tachycardia and some VT
• 1) Reduce slope of phase 4
• 2) Make diastolic potential more negative
• 3) Raise threshold.
• Early afterdepolarizations
• Occur during phase 2 or 3 in condutions that prolong QT intervals
• Can de caused by Na+ or Ca+ influx
• Torsades de pointes
• Delayed afterdoplarizations
• Develop in states of high intracellular calcium
• APBs, VPBs, digitalis arrythmias, idiopathic VT
• Stimulated by preceding action potential, NOT spontaneous
• 1) Shorten AP duration
• 2) Correct Calcium overload
• 2 Critical Conditions
• Unidirectional Block
• Slowed conduction through reentry path
• Anatomic: atrial flutter, AVNRT, VT due to scar tissue
• Functional: Afib, polymorphic VT, Vfib
• 1) Decrease conduction in circuit
• 2) Increase refractory period in reentrant circuit
• 3) Suppress premature beats that can initiate reentry
AP velocity in ventricular myocytes is
defined by fast sodium currents, not by
speed of repolarization.
AP velocity through the AV node is largely
regulated via the calcium channel current.
Pacemaker cells do NOT have a resting
• MOA: Moderate blockade of fast sodium channels
• 1. Conduction through the ischemic area is already slow because few Na channels
are in the closed state. Class I drugs bind to these channels prolongs phase 0
slowing rate of conduction decreased reentry
• 2. Increases ERP of the healthy tissue adjacent to the ischemic region. K+ blockade
prolongs AP and refractory period decreased reentry
• 3. Increase threshold and decrease slope of phase 4 depolarization Inhibition of
pacemaker channels decreased automaticity
• Prolonged QRS and QT
• Use: Reentrant and ectopic supraventricular/ventricular tachycardias
• Quinidine: GI, cinchonism, QT elongation torsades de pointes
• Procainamide: Less QT elongation, lupus like syndrome
• Disopyramide: Anticholinergic constipation, urinary retention, glaucoma
• MOA: Mild blockade of fast sodium channels
• Inhibits reentrant arrhythmias by reducing slope of phase 0 depolarization and
slowing conduction velocity
• Suppresses ectopic automaticity by decreasing slope of phase 4 spontaneous
depolarization and raising threshold
• Shortens AP and RP by blocking small sodium current in phase 2
• NO QT prolongation
• Preferentially targets diseased and ischemic cells
• Lidocaine suppresses delayed afterdepolarizations
• Use: Ventricular arrhythmias due to ischemia and digitalis toxicity
• Little effect on atrial activity
• Lidocaine: IV only, confusion, paresthesia, dizziness, seizures
• Mexiletine: Oral, Dizziness, tremor, slurred speech, nausea, vomiting
• MOA: Potent block of fast sodium channels
• Decrease upstroke of AP
• Decrease conduction velocity in atrial, ventricular, and Purkinje fibers
• Prolong refractory period in AV node
• No change in AP duration
• Increased mortality shown in patients with underlying structural heart disease
• Use: Supraventricular arrhythmias without structural disease
• Avoid in patients with LV dysfunction or CAD can lead
to heart failure
• Flecainide: Oral, aggravation of ventricular arrhythmias and CHF, confusion,
dizziness, and blurred vision
• Propafenone: Also exhibits Beta blocker activity, few side effects apart from
dizziness and taste disturbance.
• MOA: Beta Blockers block decrease calcium and If currents
• Inhibits reentrant arrhythmias by reducing slope of phase 0 depolarization and
slowing conduction velocity. VERY IMPORTANT WHEN SYMPATHETIC TONE IS
• Suppresses ectopic automaticity by decreasing slope of phase 4 spontaneous
depolarization and raising threshold
• Increases refractory period of AV node.
• Afterdepolarizations caused by excessive catecholamines can also be prevented
with Beta Blockers.
• Increase PR Interval
• Use: Atrial flutter, Afib, PSVT, APBs, VPBs, Ventricular arrhythmias.
• Propanolol: bronchoconstriction, arrhythmias, fasting hypoglycemia
• Acebutolol: bronchoconstriction, bradycardia, impotence, USE FOR DIABETES
• Esmolol: bronchoconstriction, bradycardia, impotence, USE FOR DIABETES
Beta blockers affect If and Ca2+
conduction while Calcium Channel
Blockers just affect Ca2+ conduction
• MOA: Class III drugs block delayed rectifier K+ channels during phase 3
• Little effect on Phase 0 depolarization or conduction velocity
• Prolong AP of Purkinje and ventricular myocytes
• Class III antiarrhythmics increase the ERP by delaying repolarization and delaying the
return of the fast sodium channels to the closed state.
• Use: Ventricular arrhythmias, atrial flutter, Afib, Bypass tract mediated
PSVT, HIGHLY EFFECTIVE, 1st line for cardiac resuscitation, commonly
used in ventricular systolic dysfunction
• Amiodarone: class I, II, and IV effects, vasodilator, negative inotropy
• Pulmonary toxicity, bradycardia, ventricular arrhythmia, early afterdepolarization, torsades de
pointes, hypotension, hypothyroidism, GI toxicity, increased LFTs, Muscle weakness, neuropathy,
ataxia, tremors, sleep disturbance, corneal microdeposits
• Dronedarone: no liver or thyroid toxicity, mainly GI side effects, contraindicated in
• Dofetilide: Oral, QT prolongation, torsades de pointes
• Ibutilide: IV, QT prolongation, torsades de pointes
• MOA: Blockade of L-type cardiac calcium channels
• Suppress automaticity by slowing phase 4 spontaneous depolarization
• Suppress reentry by decreasing slope of phase 0 and conduction velocity
• Suppress reentry by lengthening the refractory period of the AV node
• Raise threshold potential at SA node
• Decrease HR
• Decrease rapid atrial transmission
• Use: SVT, Atrial Fibrillation, Atrial Flutter, Multifocal Atrial Tachycardia
• Verapamil: hypotension, heart block
• Diltiazem: hypotension, heart block
• Contraindicated with Beta Blockers!
• MOA: Binds to adenosine receptors and activates potassium
• Suppresses spontaneous automaticity in SA node
• Slows conduction through AV node
• Inhibits adenylate cyclase Decreases cAMP decrease If and Ca2+ currents
• Slows SA node firing and decreases AV node conduction
• First line in Afib, rapid termination of reentrant SVT
• Not effective in ventricular myocytes
• SE: headache, chest pain, flushing, bronchoconstriction, higher doses
may be needed in patients using theophylline and caffeine
• MOA: The Na/K ATPase pumps 3 K ions into the cell for every 2 Na
ions expelled outside the cell. Digoxin binds the enzyme in a region
that is close to the K binding site. Dig and K compete for this binding
site. This is important because it means that the enzyme is more
active during hypokalemia than during hyperkalemia.
• ATPase impairment produces some degree of depolarization of the
nerve terminals which is interpreted by the brain as being caused by
an elevated level of blood pressure. The abnormal activation of the
baroreceptors triggers the baroreflex namely a reduction of
sympathetic tone and an increase in vagal tone to the heart. These
effects combine to reduce AV nodal excitability and therefore protect
against ventricular tachycardia in the context of Afib.
• Digoxin’s use is reserved to cases of Afib associated with congestive
Therapeutic Management of SVTs
• Atrial fibrillation: Most common supraventricular arrhythmia
• Rate control: with AFib, we attempt to delay AV node transmission by rendering AV node more refractory.
• 1. Digoxin (not as effective)
• 2. Diltiazem (IV)
• 3. Verapamil (IV)
• 4. ß-blockers (II)
• 5. Amiodarone (III)
• 6. Adenosine IV
• Doesn't normalize the A-fib, just normalizes HR and makes heart more hemodynamically stable.
• Rhythm control: Requires alteration of the sinus node, which is difficult to do pharmacologically.
• 1. Can use class IA/C or III drugs
• 2. Electrical cardioversion
• Prevent thrombus: Anticoagulants to prevent abnormal coagulation in atria
• 1. Warfarin, heparin, etc.
• CHRONIC treatment:
• 1. AV node ablation
• 2. Ablation of re-entry areas
• 3. Chronic anticoagulation and AV-blocking drugs
• Carotid massage activates the baroreceptors. It is not recommended
on older patients who may have atherosclerotic plaques at the
bifurcation of the carotid arteries.
• The Valsalva maneuver is an alternate way to cause a vagal
discharge that may break an SVT. The maneuver consists of trying to
exhale through a closed glottis. An intense vagal discharge occurs at
the end of the maneuver.