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198 Cards in this Set

  • Front
  • Back
What is the principle symptom of ischemic heart disease?
Angina pectoris
What is the primary cause of angina?
an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels
The imbalance of myocardial oxygen demand and oxygen supplied by coronary vessels in angina is caused by?
a decrease in myocardial oxygen delivery (O2 supply)

an increase in myocardial oxygen demand (O2 demand)

or a combination of both
Stable angina is also known as:
Exertional angina
Typical or classic angina
Angina of effort
Atherosclerotic angina
What is the underlying pathology of stable angina?
usually atherosclerosis (reduced oxygen supply) giving rise to ischemia under conditions where the work load on the heart increases (increased oxygen demand)

Pipes not big enough to meet oxygen demands. Seen in exercise.
Anginal episodes precipitated by?
exercise, cold, stress, emotion, or eating
Unstable angina is also known as:
Preinfarction angina
Crescendo angina
Angina at rest
What is the difference between unstable and stable angina?
Unstable angina is associated with a change in the character, frequency, and duration of angina in patients with stable angina, and episodes of angina at rest

Unstable does not need a trigger
What is the common cause of unstable angina?
recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm (reduced oxygen supply)
What is unstable angina associated with?
myocardial infarction (acute coronary syndrome)

Acute coronary syndrome: at risk of having a MI due to the plaques
Vasospastic angina is also referred to as:
Variant angina
Prinzmetal's angina
What caused vasospastic angina?
transient vasospasm of the coronary vessels (reduced oxygen supply)
What is associated with vasospastic angina?
underlying atheromas
Four major classes of antianginal drugs:
Organic nitrates / nitrovasodilators
Calcium channel blockers
Beta-adrenergic blockers
Late sodium current inhibitors
How to organic nitrates/nitrovasodilators work in body to treat angina?
Vasodilate coronary arteries
Reduce preload and aferload
How to calcium channel blockers work in body to treat angina?
Vasodilate coronary arteries
Reduce afterload
Non-dihydropyridines (verapamil and diltiazem) also decrease heart rate and contractility
How to beta blockers work in body to treat angina?
Decrease heart rate and contractility
Decrease afterload 2° to a decrease in cardiac output
Improve myocardial perfusion 2° to a decrease in heart rate
How to late sodium channel inhibitors work in body to treat angina?
Reduces myocardial oxygen consumption during diastole
No hemodynamic effects
Organic Nitrates / Nitrovasodilators examples:
nitroglycerin
isosorbide dinitrate (ISDN)
isosorbide mononitrate (ISMN)
amyl nitrite
Chemical breakdown of Organic Nitrates / Nitrovasodilators
All breakdown to nitrous oxide, enter cell, activates guanylate cyclase, catalyzes formation of cGMP, which activates cGMP dep. protein kinase, this results in the phosphorylation of several proteins that reduce intracellular calcium and hyperpolarize the plasma membrane causing vascular smooth muscle relaxation
Effects of nitrovasodilators-peripherally
Peripheral vasodilation: predominates over arterioles (more preload than after load)
Effects of nitrovasodilators-coronary blood flow
Increased coronary blood flow: epicardial arteries dilated w/o impairing autoregulation in small coronary vessels
collateral flow may be increased
Decreased preload improves subendocardial perfusion
can relax vasospastic coronary arteries but have little effect on total coronary blood flow in patients with typical angina due to atherosclerosis
Dilation of coronary arteries can paradoxically result in aggravation of angina - a phenomenon known as “coronary steal”
Effects of nitrovasodilators-platelets
May contribute to their effectiveness in the treatment of unstable angina
Pharmacokinetic Properties of Organic Nitrates
Hepatic first pass extensive for nitroglycerin and IDSN (sublingual or transdermal)
Isosorbide mononitrate (5-ISMN) is not subject to first-pass metabolism
Hepatic blood flow and disease can affect the pharmacokinetics of nitroglycerin and ISDN
Organic Nitrates / Nitrovasodilators-Routes of administration
Amyl nitrate-gas at room temp, inhalation, Rapid onset, short duration (3-5 min)
Nitroglycerin and ISDN: rapid onset of action (1-3 min) sublingually, short duration of action (20-30 min) not suitable for maintenance therapy
IV nitroglycerin: treat severe recurrent unstable angina
Slowly absorbed preparations of nitrovasodilators (oral, buccal, transdermal): duration of action 3-10 hours, can lead to tachyphylaxis
Tolerance and Dependence with Nitrovasodilators
Transdermal nitroglycerin may provide therapeutic levels of drug for 24 hours or more, but efficacy only lasts 8-10 hrs
Nitrate-free periods of at least 8 hrs (e.g., overnight) are recommended to avoid or reduce tachyphylaxis
Enzymes that affect nitroglycerin to NO reaction.
This doe not occur in normal therapy: Monday disease and Weekend angina.
Adverse Effects of Nitrovasodilators
The major acute adverse effects of nitrovasodilators are due to excessive vasodilation
Severe throbbing headache
Orthostatic hypotension
Tachycardia
Dizziness
Flushing
Syncope
Contraindications of nitrovasodilators:
patients with elevated intracranial pressure
Nitrovasodilators: Drug Interactions
All of the PDE-5 inhibitors are contraindicated in patients taking nitrovasodilators
Causes hypotension due to PDE-5 inhibiting breakdown of cGMP.
Three classes of Ca++ channel blockers and main example:
Benzothiazepines: Diltiazem
Phenylalkylamines: Verapamil
Dihydropyridines: Nifedipine
Ca++ channel blockers and Effects on Vascular Smooth Muscle
inhibit L-type (and/or T-type) voltage-dependent Ca++ channels
“Vascular selectivity”:
Decreased intracellular Ca++ in arterial smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure)
Little or no effect of Ca++-channel blockers on venous beds -> no effect on cardiac preload (ventricular filling pressure)
Specific dihydropyridines may exhibit greater potencies in some vascular beds
Little or no effect on nonvascular smooth muscle
Calcium channel blockers and Effects on Cardiac Cells
(non-dihydropyridine vs dihydropyridine)
Negative inotropic effect (L-type channels in ventricular myocytes): Dihydropyridines have very modest negative inotropic effect
Negative chronotropic/dromotropic effects (L-type channels in nodes and conduction system): Verapamil, and diltiazem depress SA node and AV conduction while Dihydropyridines have minimal direct effects on SA node and AV conduction (but they can cause reflex tachycardia)
Desired Therapeutic Effects of Calcium Channel Blockers for Angina
Vasodilate coronary arteries: vasospastic angina esp.
Reduced myocardial oxygen demand: decrease afterload (dilates arterioles), Non-dihydropyridines (verapamil and diltiazem) also lower heart rate and decrease contractility
Dihydropyridines may aggravate angina in some patients due to reflex increases in heart rate and contractility; these sympathetic effects can be prevented by co-administration of -adrenergic blockers.
Ca++ Channel Blockers: Toxicities
Major adverse effects (non-dihydropyridines): Depression of contractility and exacerbation of heart failure AV block, bradycardia, and cardiac arrest

Minor adverse effects: Hypotension, dizziness, edema, flushing
Patients who should not use verapamil or diltiazem
ventricular dysfunction
SA node or AV conduction disturbances
WPW syndrome
systolic blood pressures below 90 mm Hg
Immediate-release forms of dihydropyridines may increase what?
mortality in patients with myocardial ischemia
Ca++ Channel Blockers: Drug Interactions
beta blockers in combination with verapamil or diltiazem: Bradycardia, AV block, depression of LV function
Some channel blockers (verapamil, diltiazem) can cause an increase in plasma digoxin levels, also AV bock with digoxin use due to increased vagal tone
Quinidine in combination with some calcium channel blockers: decreased clearance of both, bradycardia, AV block
Other antiarrhythmic drugs can also inhibit SA and AV node function and should be avoided
b-Adrenergic Blockers in the Treatment of Angina
Propanolol
do not cause coronary vasodilation
ability to decrease oxygen demand of the heart
Desired Effects of Beta-blockers in the Treatment of Angina
Reduced myocardial oxygen demand by reducing contractility and heart rate
Reducing cardiac output also reduces afterload (independent of decreased vascular resistance)
Some b-blockers can cause vasodilation directly or by acting as a-blockers (e.g., labetolol, carvedilol)
Improved myocardial perfusion by slowing heart rate (more time spent in diastole)
Adverse Effects, Contraindications and Drug Interactions of b-Blockers
Makes heart failure worse
Contraindicated in patients with asthma
Caution with diabetic patients because masks hypoglycemia (tachycardia)
May depress contractility and heart rate and produce AV block in patients receiving non-dihydropyridine calcium channel blockers, and other drugs that inhibit the SA and AV nodes (e.g., many antiarrhythmic drugs and digoxin)
Ranolazine: Late Sodium Current Inhibitor
has no hemodynamic effects
Always used in combination with other antianginal agents
Approved for use only in refractory cases of angina primarily due to concerns of safety: QT prolongation, testicular toxicity
Mechanism of Action of Ranolazine
inhibition of late sodium current which causes cardiac myocyte calcium overload by slowing the rate of myocardial calcium removal via the sodium-calcium exchanger

excess intracellular calcium ion increases contractile protein activation, giving rise to increased diastolic myocardial oxygen consumption, and reduced coronary perfusion due to reduced myocardial relaxation.
Antianginal Combination Therapies
dihydropyridine calcium channel blocker and a beta-blocker
coronary vasodilation, decreased afterload, lower heart rate, suppression of reflex tachycardia
Antianginal Combination Therapies
nitrovasodilator and a beta-blocker
coronary vasodilation, decreased preload, lower heart rate, suppression of reflex tachycardia
Antianginal Combination Therapies
A nitrovasodilator and a non-dihydropyridine calcium channel blocker
coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia
Antianginal Combination Therapies
A nitrovasodilator, a dihydropyridine calcium channel blocker, and a beta-blocker
coronary vasodilation, decreased preload and afterload, lower heart rate, suppression of reflex tachycardia
Antianginal Combination Therapies
beta-blocker and non-dihydropyridine calcium channel blocker
Bad one
bradycardia, AV block, depressed LV function
Therapeutic Consideration of treating angina
Treat conditions that might have lead to angina (hypertension and hyperlipidemia)
Modify risk factors associated with atherosclerosis (smoking, hypertension, hyperlidemia)
Patients with stable angina who are refractory to drug therapy may require surgical revascularization (bypass graft) or angioplasty (PCI)
Patients with vasospastic angina not good for surgery and should use calcium channel blocker
Platelets normally function by
Adhering to damaged endothelium
Releasing a variety of mediators that activate other platelets and non-platelets
Aggregating to each other

Can form de novo to form clots.
The most important platelet inhibitory drugs work through three basic mechanisms:
Inhibition of platelet prostaglandin (thromboxane) synthesis
Inhibition of ADP-induced aggregation
Blockade of GP IIb/IIIa receptors on platelets that mediate platelet aggregation
Aspirin-Antiplatelet Mechanism of action
Aspirin acetylates and irreversibly inhibits COX-1 enzymes and thus inhibits TXA2 and PGI2.
No TXA2 induced platelet activation and aggregation
Anti-platelet effect last about 10 days because platelets cannot regenerate COX-1.
Complete inaction of COX-1 with 75-160 mg/day.
Higher doses inhibit PGI2 and cause toxicities
Thioenopyridines (P2Y12 Inhibitors)
Clopidogrel, Prasugrel, Ticlopidine
Thioenopyridines (P2Y12 Inhibitors) mechanism of action
inhibit ADP activation of platelet function by irreversibly blocking ADP binding to platelet ADP receptors (P2Y12 receptors)
Thioenopyridines (P2Y12 Inhibitors) vs. aspirin
they are more effective than aspirin and are used when greater anti platelet effect is needed.

Additive or synergistic effects are obtained when used in combination with aspirin
Thioenopyridines (P2Y12 Inhibitors): when used.
prevent vascular events in patients with transient ischemic attacks and completed strokes
reduce risk in patients with recent myocardial infarction, acute coronary syndrome, and peripheral artery disease
reduce the risk of clots in patients undergoing angioplasty (PCI) and after stent placement
Clopidogrel (Plavix) metabolism:
prodrug that requires CYP2C19 for bioactivation
Polymorphisms reduce bioactivation in 20-30% of population
FDA 2010 "boxed warning" indicates genetic testing for CYP2C19 polymorphisms might be useful
Patients taking omeprazole (which competes for CYP2C19) have reduced anti-platelet effects of clopidogrel
Prasugrel (Effient) metabolism
more rapid onset of action than clopidogrel or ticlopidine
greater and more predictable inhibition of platelet aggregation
Prodrug, nearly 100% bioactivation
Compared to clopidogrel, prasugrel showed a significant reduction in CV death, MI, and stroke in patients with ACS scheduled for angioplasty; incidence of stent thrombosis also reduced, but increased slight bleeding.
Adverse Effects: Ticlopidine
Nausea, dyspepsia, and diarrhea in 20% of patients
Hemorrhage in 5% of patients
Leukopenia in 1% of patients (can be life-threatening)
Thrombotic thrombocytopenic purpurea (TTP)

Reason not prescribed as much
Adverse Effects: Clopidogrel
Clopidogrel has fewer adverse effects than ticlopidine
Rarely associated with neutropenia
TTP rarely occurs with this agent
When to use: Ticlopidine, Clopidogrel, Prasugrel
Because of fewer adverse effects and better dosing regimen, clopidogrel is preferred over ticlopidine

Due to more consistent and effective platelet inhibition, prasugrel is superior to clopidogrel
What do we use Platelet GP IIb/IIIa Inhibitors to treat?
acute coronary syndromes (these agents are all given parenterally)
Abciximab (ReoPro)
Platelet GP IIb/IIIa Inhibitor
humanized monoclonal antibody that binds the IIb/IIIa complex
Eptifibatide (Integrilin)
Platelet GP IIb/IIIa Inhibitor
cyclic peptide analog containing a KGD (LysGlyAsp) sequence, the portion of fibrinogen that binds the IIb/IIIa receptor
Tirofiban (Aggrastat)
Platelet GP IIb/IIIa Inhibitor
non-peptide RGD-mimetic; the RGD (ArgGlyAsp) sequence is found in fibrinogen, vWF and other integrin receptor ligands
Uses of Antiplatelet Drugs
Arterial Thrombosis: Activation of platelets big problem involving TIAs, strokes, unstable angina/ acute coronary syndrome (ACS), and MIs

Aspirin and thioenpyridines are used to prevent ischemia in patients with TIAs and strokes, unstable angina/ACS and acute MIs, and with ACS undergoing angioplasty and stent palcement

GP IIb/IIIa inhibitors are often used in combination with other antiplatelet drugs in treating ACS and acute MI

Venous thrombosis: activation of platelets not the major problem here.
AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2011 Update (Circulation 2011) Antiplatelet agents/anticoagulants
Aspirin 75–162 mg daily is recommended in all patients with coronary artery disease unless contraindicated.
Clopidogrel 75 mg daily is recommended as an alternative for patients who are intolerant of or allergic to aspirin.
Combination therapy with both aspirin 75 to 162 mg daily and clopidogrel 75 mg daily may be considered in patients with stable coronary artery disease.
2011 Update (cont.): ACS (acute coronary syndrome) & PCI (angioplasty) w/stents

Antiplatelet agents/anticoagulants
A P2Y12 receptor antagonist in combination with aspirin is indicated in patients after ACS or PCI with stent placement.
For patients receiving a stent during PCI for ACS, thienopyridine therapy should be given for at least 12 months. (Can be earlier if safer)
After PCI, it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses
2011 Update (cont.): Bypass grafts

Antiplatelet agents/anticoagulants
aspirin should be started within 6 hours after surgery to reduce saphenous vein graft closure. Dosing regimens ranging from 100 to 325 mg daily for 1 year appear to be efficacious.

clopidogrel (75 mg daily) is a reasonable alternative in patients who are intolerant of or allergic to aspirin.
2011 Update (cont.): Peripheral Artery Disease

Antiplatelet agents/anticoagulants
patients with symptomatic atherosclerotic peripheral artery disease of the lower extremity, antiplatelet therapy with aspirin (75–325 mg daily) or clopidogrel (75 mg daily) should be started and continued.

The benefits of aspirin in patients with asymptomatic peripheral artery disease of the lower extremities are not well established.
AHA 2011 Update (cont.): Anticoagulants
Antiplatelet therapy is recommended in preference to anticoagulant therapy with warfarin or other vitamin K antagonists to treat patients with atherosclerosis

If there is a compelling indication for anticoagulant therapy, such as atrial fibrillation, prosthetic heart valve, left ventricular thrombus, or concomitant venous thromboembolic disease, warfarin should be administered (to achieve appropriate INR) in addition to the low-dose aspirin (75–81 mg daily).

Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with increased risk of bleeding and should be monitored closely.
2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Circulation 110:588)
Aspirin (162 and 325 mg) should be given to the patient with suspected STEMI as early as possible and should be continued indefinitely (75 to 162 mg/d), unless allergy

Clopidogrel combined with aspirin is recommended for STEMI patients who undergo coronary stent implantation. In patients in whom aspirin is contraindicated because of aspirin sensitivity, clopidogrel is probably useful as a substitute for aspirin to reduce the risk of occlusion. Clopidogrel is not recommended for treatment before cardiac catheterization or for patients who may have CABG surgery in 5-7 days.

It is reasonable to start treatment with abciximab as early as possible in patients undergoing primary PCI (with or without stenting). Tirofiban or eptifibatide may be useful as antiplatelet therapy to support primary PCI for STEMI.
Testing the Intrinsic and Extrinsic Coagulation Pathways and drugs they monitor
Activated Partial Thromboplastin Time: Intrinsic pathway (standard heparin and parenteral direct thrombin inhibitors)

Prothrombin Time: Extrinsic Coagulation Pathway (Warfarin)
4 Classs of Anticoagulant Drugs
The heparinoids: accelerate the action of endogenous antithrombin III (AT III), including heparin and the low MW heparins. AT III binds and inactivates several clotting factors. Pentasacharide is a synthetic molecule that binds ATT III and indirectly inactivates factor Xa

Direct thrombin inhibitors (DTIs): hirudin (parenteral) and dabigatran (oral)

Direct factor Xa inhibitors: apixaban (oral) and rivaroxaban (oral)

The vitamin K antagonists (VKAs): warfarin, inhibit the synthesis of vitamin K-dependent clotting factors
Heparin
Binds to AT III and increases its rate of interaction (inhibition) with activated proteases by a factor of >1000

can catalyze the activation of many molecules of AT III

extracted from pig intestinal mucosa and bovine lung (rarely used); it is very heterogeneous-why it must be monitored.

continuous or intermittent IV infusion or by subcutaneous injection (slow delivery
2 types of heparins
unfractionated (UFH) or fractionated (HMWHs and LMWHs)
What does Standard heparin (UFH) markedly inhibits
inhibiting several activated clotting factors
Low MW fractions of heparin inhibit what?
more specific for inhibition of factor Xa, though they may also inhibit thrombin
LWMHs vs Standard Heparin
LMHS are just as efficacious, increased bioavailability SQ, less dosing, more expensive, DVT, etc.
What leads to heparin-induced thrombocytopenia
UFH binds platelets and causes their activation and aggregation, LMWH rarely happens
Why do LMWHs have longer ½ lives/bioavailability?
UFH bind to many plasma proteins and cells, LMWHs bind to less, more predictable
What does UFH and LMWHs act on?
UFH: circulating thrombin and LMWHs also act on clot-bound thrombin
What types of heparin require monitoring?
UFH: aPTT, but LMWH’s do not unless renal issues and pregnancy (factor Xa)
Enoxaprin drug class
LMWHs
Toxicities of Heparin:
Bleeding, UFH: thrombocytopenia, antibody-mediated thrombocytopenia (after 5-10 days), count platelets
Other toxicities of heparins:
Allergies, hematomas, osteoporosis long term, mineralocorticoid def long term, agranulocytosis
Contraindications of heparin
hypersensitive, actively bleeding, surgery, unable to clot blood disease, etc, pregnancy
Reversal of heparinoid
D/C drug, UFH neutralized by protamine sulfate, LMWHs not well neutralized with protamine.
Fondaparinux (pentasaccharide, Arixtra)
irreversible, more bioavailable, higher affinity for AT III, indirect factor Xa inhibitor with no thrombin inactivation, knee surgery, no cross-reaction with the heparin-induced antibody
Hirudin (lepirudin) Drug class
How administered
Direct Thrombin Inhibitors

Lepirudin (Refludan) is recombinant hirudin

Parenterally
How does lepirudin work in the body?
binds thrombin specifically and tightly
Its action is independent of AT III so it can inactivate fibrin-bound thrombin in clots
How is lepirudin monitored?
aPTT
Lepirudin is approved for whom?
patients with heparin-induced thrombocytopenia
Long-term infusions of lepirudin leads to...
antibodies directed against thrombin-lepirudin complexes; this can slow clearance by the kidneys (resulting in an enhanced anticoagulant effect)
Bivalirudin (Angiomax)
Drug class
Direct Thrombin Inhibitors- Parenteral

a bivalent semi-synthetic 20-residue peptide
Dabigatran (Pradax)
Drug class
Direct Thrombin Inhibitors - Oral
Dabigatran (Pradax)
Approved for:
with atrial fibrillation to prevent ischemic stroke and venous thrombolic events (VTEs)
Dabigatran (Pradax) vs warfarin
Dabigatran is well absorbed, little drug interactions, fixed dosing, faster onset, does not require routing coagulation monitoring.
Warfarin
Drug class
vitamin K antagonists
molecular target of warfarin
Vitamin-K oxidoreductase complex 1 (VKORC1)

inhibit coagulation by blocking the g-carboxylation of Glu residues on factors II (prothrombin), VII, IX, and X
What accounts for warfarin dose variability?
SNPs in VKORC1 account for 20-30%
Warfarin Onset of Action
8-12 hour delay
dependent upon the rates of degradation of the four vitamin K-dependent clotting factors (6-60 hours)
a 1-3 day delay in maximum hypo-prothrombinemia following peak drug concentration
How to initiate warfarin dosing? How monitored?
initiated with low doses over 1-2 weeks and monitored by prothrombin time (preferably using INR)
How frequently should warfarin be tested for PT?
daily in the beginning, until appropriate dosing is obtained and PT is stable for 2 days, then periodically (1-4 weeks) after that
Factors That Can Alter Warfarin Efficacy
Polymorphisms of CYP2C9 and VKORC1
Changes in diet
Changes in hormonal status: hyper increase efficiency and hypoparathyroidism decreases
Changes in liver or kidney function: clotting factors and altered drug metabolism
Changes in concomitant drugs
Warfarin Toxicity
Crosses placenta causes hemorrhagic disorders in the fetus as well as birth defects (bone formation needs g-carboxylglutamate synthesis)
Cutaneous necrosis with reduced activity of Protein C sometimes occurs during the first weeks of therapy
Hemorrhagic infarction due to venous thrombosis occurs more rarely
Relative Contraindications to Warfarin Therapy
Pregnancy
Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy
Uncontrolled alcohol/drug abuse
Unsupervised dementia/psychosis
How to reverse warfarin in body?
Stopping the drug
Administering large doses of vitamin K1 (phytonadione)
Administering fresh-frozen plasma or factor IX concentrates (Konyne 80, Proplex T) that contain large amounts of prothrombin complex
also could do whole blood transfusion if serious
Warfarin: Dosing & Monitoring
Start low (not with a loading dose)
5 mg daily or 2 mg daily for Elderly, frail, liver disease, malnourished
If rapid anticoagulation is required, use concurrent heparin for >/= 4 days until INR is in therapeutic range for 2 days
Check INR daily until therapeutic range has been reached and sustained for 2 consecutive days; titrate dosage to obtain desired INR
Once the INR has become stable, INR testing can be reduced to intervals as long as 4 weeks
Conversion from Heparin to Warfarin
May begin warfarin concomitantly with heparin therapy to achieve rapid anticoagulation effect
Monitor INR daily until stable for 2 days
Heparin should be continued for a minimum of four days (warfarin needs 96 hours for peak effect)
When INR reaches desired therapeutic range for 2 days, discontinue heparin (after a minimum of four days
Recent Oral Anticoagulants- Possible Replacements for Warfarin? (two of them)
Dabigatran (Pradaxa) is a direct-acting thrombin inhibitor
Rivaroxaban (Xarelto) is a direct-acting factor Xa inhibitor

rapid onset of action (1-4 hours), do not require bridge therapy with heparinoids, and do not require laboratory anticoagulant monitoring
Why is dabigatran/Rivaroxaban (Xarelto) better than warfarin?
Rapid onset of action
No known pharmacogenetic interactions; few interactions with food
Does not require laboratory anticoagulant monitoring
What is the antidote for dabigatran/Rivaroxaban (Xarelto)?
No antidote if toxicity
What is the key component of the fibrinolytic system?
What does it do?
Plasmin, a serine protease that digests fibrin
Breakdown of a clot pathway
Endothelial cells release tPA, binds with fibrin bound plasminogen and activates it, plasmin is formed, cleaves fibrinogen.
What can activated plasminogen to form plasmin?
tissue plasminogen activator (tPA), urokinase (uPA), and factor XIIa
What inactivates plasmin outside clot?
Circulating a2-antiplasmin
tPA normally only activates plasminogen in clots for several reasons:
tPA binds fibrin with high affinity where it activates fibrin-bound plasminogen
tPA is rapidly cleared from the blood
Free tPA is inhibited by circulating inhibitors, PAI-1 (plasminogen activator inhibitor-1) and PAI-2
Tissue plasminogen activator (tPA; alteplase, ACTIVASE)
Drug class
Fibrinolytic Drugs
tPA is serine protease that activates plasminogen in a fibrin-specific manner
Fibrinolytic Agents: Administration
administered IV or intra-arterially
Give as soon as possible
Agents are typically administered in combination with aspirin and heparin (abxicimab may also be administered)
Thrombolytic Agents: Toxicity
Bleeding
Intracranial hemorrhage is the most serious bleeding problem and occurs with all regimens (increases with co-adminstration of heparin)
Fibrinolytic Agents: Indications
Acute thromboembolic stroke: given within 3 hours, watch for of hemorrhagic stroke
Acute myocardial infarction: give with aspirin. Best with ST segment elevation and BBB. Angioplasty
Central deep vein thrombosis (DVT)
Fibrinolytic Therapy: Contraindications
Recent surgery, trauma, CPR wihin last 3 weeks
Serious GI bleeding or ischemic stroke within 3 months
Uncontrolled hypertension
Active bleeding or hemorrhagic disorder
Previous CVA or active intracranial process
Suspected aortic dissection
Acute pericarditis
Current use of warfarin and INR >1.7
Invasive procedures
Ideal Antiarrhythmic Drug
reduce ectopic pacemaker activity and modify critically impaired conduction

should be more effective on ectopic pacemaker and depolarized tissues than on normally depolarizing tissues

ideal antiarrhythmic drug should decrease mortality: real drugs may increase this.
Arrhythmogenic Mechanisms (3)
Enhanced automaticity

Afterdepolarizations and triggered automaticity
Normal depolarizations can trigger automaticity (DAD and calcium overload, EAD and potassium channel block)

Reentry: most common, region of non-conducting tissue and heterogeneous conduction around that region
Inhibition of Automaticity:
b-Adrenergic blockers
Decrease phase 4 slope
Inhibition of Automaticity:
Na+ and Ca++ channel blockers
Increased threshold-need to be stimulated more before firing.
Inhibition of Automaticity:
Adenosine and muscarinic agonists
Increased maximum diastolic potential
Inhibition of Automaticity:
K+ channel blockers
Increased action potential duration
Delayed afterdepolarizations (DADs)
arise from the resting potential (during diastole) and result from calcium overload (ischemia, adrenergic stress, digitalis, heart failure)
Early afterdepolarizations (EADs)
arise from phase 3 (repolarization phase) and result from prolonging action potential duration (K+ channel block/dysfunction or increased Ca++ or Na+ inward current); can lead to torsades de pointes
What drugs will inhibit the formation or maintenance of a reentrant circuit?
Antiarrhythmic drugs that slow conduction (Na+ channel blockers) or increase the refractory period (K+ channel blockers, Na+ channel blockers)
Singh-Vaughan Williams Classification (I)
Class I drug class
Sodium channel blockers
Singh-Vaughan Williams Classification
Subclass IA potency
Intermediate to high potency sodium channel blockers and prolong repolarization (prolong QT interval)
Singh-Vaughan Williams Classification
Subclass IA drugs (3)
Quinidine, procainamide, disopyramide
Singh-Vaughan Williams Classification
Subclass IB Potency
Lowest potency sodium channel blockers (liitle effect on PR, QRS, or QT interval)
Singh-Vaughan Williams Classification
Subclass IB drugs (2)
Lidocaine, mexiletine
Singh-Vaughan Williams Classification
Subclass IC Potency
most potent sodium channel blocking agents (slow conduction the most, thus prolong PR and QRS intervals); have little effect on repolarization (no effect on QT interval)
Singh-Vaughan Williams Classification
Subclass IC Drugs (2)
Flecainide, propafenone
Singh-Vaughan Williams Classification
Class II Drug class
blocking beta-adrenergic receptors (may slow sinus rhythm, prolong PR interval depending on sympathetic tone
Singh-Vaughan Williams Classification
Class II Drugs (4)
Propranolol, esmolol, sotalol, acebutolol, and others
Singh-Vaughan Williams Classification
Class III Drug class
Potassium channel blockers
prolong repolarization (increase refractoriness, prolong QT interval, no effect on QRS interval, little effect on rate of depolarization
Singh-Vaughan Williams Classification
Class III Drugs (5)
Amiodarone, dronedarone, sotalol, dofetilide, ibutilide-this blocks slow inward Na+ current
Singh-Vaughan Williams Classification
Class IV Drug class
relatively selective AV nodal L-type calcium-channel blockers (slow sinus rhythm, prolong PR interval)
Singh-Vaughan Williams Classification
Class IV Drugs (2)
Verapamil, diltiazem
Singh-Vaughan Williams Classification (Misc.)
Drugs (3)
digoxin, adenosine, magnesium sulfate
Singh-Vaughan Williams Classification
Class I toxicities
Pro-arrhythmic effects: IA-torsades, IC-CAST proarrhytmia

Negative ionotropic effects (IC)

infranodal conduction block
Singh-Vaughan Williams Classification
Class II toxicities
Sinus bradycardia
AV block
Depression of LV function
Singh-Vaughan Williams Classification
Class III toxicities
Sinus bradycardia

Pro-arrhythmic effects: torsades
Singh-Vaughan Williams Classification
Class IV toxicities
AV block

Negative inotropic effect
Torsades de Pointes associated with what drug actions?
drugs that have Class III and Class IA actions (potassium channel blockers and drugs that prolong repolarization) and that cause Drug-Induced Long QT Syndrome (DILQTS)
Common drugs that cause torsades:
Quinidine (2-8% of patients, can occur at subtherapeutic doses)
Sotalol (common, but dose-dependent)
N-acetylprocainamide (metabolite of procainamide)
Amiodarone (DILQT is common, but torsades is uncommon)
Ibutilide (4-8%)
Dofetilide (1-3%)
Other classes of drugs that torsades is seen with? (4)
Antiinfectives (e.g., erythromycin, sparfloxacine)
Antipsychotics (e.g., chlorpromazine, haloperidol)
Antiemetics (e.g., domperidone, droperidol)
Opiates (e.g., methadone, levomethadyl)
Drawbacks of the Singh-Vaughn Williams Antiarrhythmic Drug Classification System
Drugs within a class do not necessarily have clinically similar effects
Almost all of the currently available drugs have multiple actions
The metabolites of many of the drugs may contribute significantly to the antiarrhythmic actions or side effects
Due to polymorphisms in drug metabolizing enzymes, there can be large differences in efficacy and/or toxicities between patients
Use(Rate)-Dependent Channel Blockade
Enhanced sodium or calcium channel blockade in rapidly depolarizing tissue

Responsible for increased efficacy in slowing and converting tachycardias with minimal effects on tissues depolarizing at normal (sinus) rates

Class I and Class IV
negative or reverse rate-dependence
Many of the drugs that prolong repolarization (i.e., Class IA and Class III drugs)

These drugs have little effect on prolonging repolarization in rapidly depolarizing tissue
can cause prolongation of repolarization in slowly depolarizing tissue or following a long compensatory pause, leading to repolarization disturbances and torsades de pointes
Lidocaine and mexiletine (Class IB)
IV for treating arrhythmias because of rapid first-pass metabolism. Mexiletine is lidocaine's PO.
IV amiodarone before lidocaine
Mexiletine does not prolong QT interval
Don't use with amiodarone
side effects are CNS including tinnitus and seizures, and occasionally hallucinations, drowsiness, and coma
Quinidine (Class IA)
supraventricular and ventricular arrhythmias
significant risks of ventricular arrhythmia
Torsades-contraindicated in Patients with a history of long QT, torsades, or hypokalemia
Patients with heart failure can have proarrhythmias and digoxin interactions
Common side effects include hypotension, GI problems (diarrhea and vomiting), and cinchonism (tinnitus, blurred vision, and headaches).
Quinidine is a potent inhibitor of hepatic CYP2D6 and is associated with more drug interactions than any other antiarrhythmic drug.
Procainamide (Class IA)
both supraventricular and ventricular arrhythmias (including atrial arrhythmias associated with WPW syndrome)
IV and oral
metabolite, N-acetylprocainamide (NAPA), has predominantly Class III antiarrhythmic actions. (fast acetylators)
Nasty side effects: a lupus-like syndrome, which usually begins as mild arthralgia, but can be fatal if allowed to progress. Stop med if this happens
Disopyramide (Class IA)
supraventricular arrhythmias, and ventricular arrhythmias only in patients with good ventricular function because of its negative inotropic effects

anticholinergic effects which may be useful in some patients with vagally mediated paroxysmal supra ventricular tachycardias, but mainly limit therapy
Flecainide (Class IC)
fast inward sodium channel blocker
symptomatic supraventricular arrhythmias and documented life-threatening ventricular arrhythmias.
CAST proarrhytmia
lowers ventricular function in most patients.
also raises the threshold of pacing and cardiac defibrillators and should be used with caution in patients with pacemakers or ICDs.
Propafenone (Class IC)
symptomatic supraventricular arrhythmias and suppress life-threatening ventricular arrhythmias.

structurally similar to propranolol and has beta-blocking activity in addition to its sodium channel blocking activity

Could cause problems with heart failure patients
Verapamil and diltiazem (Class IV)
variety of arrhythmias of atrial or supra ventricular origin
*High doses can cause AV block or suppression of SA node, particular when used in combination with beta-blockers, digoxin or other drugs that inhibit the SA and AV nodes
*Should be used with caution in combination with drugs that inhibit SA and AV function, lower LV function, or lower blood pressure
Contraindicated in patients with heart failure, impaired LV function, sick sinus syndrome, heart block, severe hypotension or reentrant arrhythmias due to Wolf-Parkinson-White (WPW) or Lown-Ganong-Levine (LGL) syndrome
*The most common side effect of verapamil is constipation
Grapefruit juice is known to increase the plasma concentrations of verapamil because it inhibits CYP3A4 in the gut wall
Dofetilide (Class III)
relatively pure potassium channel blocker
for the conversion and maintenance of normal sinus rhythm in highly symptomatic patients with atrial fibrillation or flutter
Fewer non-cardiac toxicities than amiodarone and no negative inotropic effects
should not be used in combination with other drugs that prolong QT interval
Must screen for torsades, ECG, and kidney function and get in hospital.
Ibutilide (Class III)
blocks outward potassium
prolongs repolarization by increasing inward sodium flux
convert atrial arrhythmias to normal sinus rhythm
*Class IA or Class III drugs should not be used concurrently, or within 4 hours of ibutilide dosing, to avoid the possibility of DILQTS and torsades
*Ibutilide is contraindicated in patients with prolonged QT, torsades or other polymorphic ventricular arrhythmias, or who are taking drugs that prolong QT or are associated with torsades
Sotalol (Class III and II)
l-isomer causes the beta-blocking effects
the d-isomer causes the effects on prolonging the action potential
variety of atrial and ventricular arrhythmias
Don't use high doses-torsades
contraindicated in patients with QT prolongation, bradycardia, torsades, hypomagnesemia, hypokalemia, bronchospasm, pulmonary edema, heart failure, or AV block.
Because of the risk of arrhythmia or MI, abrupt cessation of drug therapy should be avoided
Drug combinations that enhance the pharmacological effects of sotalol (beta-blockade, QT prolongation, AV blockade) should be used with caution.
Amiodarone (Class III/other)
"broad spectrum" anti arrhythmic
it prolongs QT interval, its potential to cause proarrhythmias (torsades de pointes) is significantly lower
have consistently decreased mortality
use in refractory life-threatening ventricular arrhythmias
Used IV, amiodarone is superior to lidocaine and other agents for the treatment of ventricular fibrillation
Loading dose needed due to long half life
most common serious adverse effects are pulmonary fibrosis and interstitial pneumonitis (2-15% of patients on chronic amiodarone), which is fatal in 10% of these patients. The pneumonitis is reversible if drug is stopped early on, thus clinical assessment and chest x-rays are required every 3 months
Looks like iodine and cause problems with thyroid
Vision problems with long term use.
Dronedarone (Multaq)
non-iodinated derivative of amiodarone
use in non-permanent atrial fibrillation and flutter
less adverse effects
less effective in maintaining sinus rhythm
Reduces morbidity and mortality in patients with high-risk paroxysmal and persistent atrial fibrillation
should not be given to patients with NYHA class IV heart failure or patients who have had an episode of decompensated heart failure in the past 4 weeks, especially if they have depressed ventricular function
Digoxin (Misc.)
cardiac glycoside that acts by inhibiting the sodium/potassium ATPase
control ventricular rate in patients with atrial tachycardias
increases vagal tone, thus inhibiting AV nodal conduction
Digoxin can actually exacerbate atrial arrhythmias because it can cause calcium overload, but therapeutic efficacy is measured by the drug's ability to protect the ventricles by reducing the number of impulses passing through the AV node
relatively narrow therapeutic index and is known to interact pharmacokinetically with quinidine and other antiarrhythmic agents
Adenosine (Misc.)
endogenous compound that is an agonist for purinergic (adenosine) receptors
Activates outward K+ current in atrium, SA and AV nodes resulting in hyperpolarization
IV bolus to acutely treat paroxysmal (reentrant) supra ventricular tachycardia
It potently blocks AV nodal conduction
half-life of elimination of 1.5-10 seconds
*Common side effects, which are short-lived, including facial flushing, dyspnea, and chest pressure
signs and symptoms of heart failure
tachycardia, decreased exercise tolerance and shortness of breath, peripheral and pulmonary edema (rales), and cardiomegaly
Forms of Congestive Heart Failure
Diastolic dysfunction or diastolic heart failure
Due to inadequate ventricular relaxation which prevents adequate filling

Systolic dysfunction or systolic heart failure
Due to inadequate force generation to eject blood normally
Diastolic Heart Failure
Symptoms
some clinical signs of CHF due to low cardiac output, but lack specific characteristics of systolic dysfunction (e.g., ejection fraction may be normal)
Diastolic Heart Failure
Therapy
no uniformly agreed upon therapy

vasodilators or positive inotropes) may have no benefit or exacerbate diastolic dysfunction

In theory, ACE-I may prevent chronic diastolic heart failure in patients with systemic hypertension because of the ability of ACE inhibitors to reduce preload and afterload, and minimize myocardial and vascular smooth muscle hypertrophy
Systolic Heart Failure
Symptoms
Breathlessness and fatigue
Cardiac output is depressed at rest and increases minimally with exertion (exercise intolerance)
Elevated heart rate at rest
Large, dilated, and poorly contracting heart
Diminished stroke volume (ejection fraction <45%), even though heart is dilated
Pulmonary edema (congestion) causes dyspnea, orthopnea, and tachypnea
Peripheral venous edema, especially in lower extremities
Cerebral blood flow may be decreased enough to impair CNS function
Reduced perfusion of liver and kidneys can impair hepatic and renal function and reduce the clearance of many drugs
NYHA Heart Failure Classification: “Function/symptom-based”

Stage, symptoms, ejection fraction
Normal (No HF) ---------- 55-75%
Mild-I No symptoms 40-54%
Moderate-II Symptoms with moderate exercise 30-39%
Advanced-III Symptoms with light exercise 20-29%
Severe-IV Symptoms at rest <20%
Classification of Heart Failure Based on 2001 ACC/AHA Guidelines: “Risk/stage-based”
Stage A: high risk for CHF, no structural heart disease, no symptoms
Stage B: Structural heart disease, no signs or symptoms
Stage C: Structural heart disease, symptoms of CHF
Stage D: Refractory HF, requires specialized interventions
Pathophysiology of Congestive Heart Failure
lesion or disease that impairs the ability of the heart to pump adequately

Increased sympathetic tone
Increased release of catecholamines
Increased release of renin leading to increased angiotensin II and aldosterone
Increased release of atrial natriuretic peptide (ANF, ANP), B-type natriuretic peptide (BNP), and prostacyclin
Other Normal Compensatory Mechanisms Which May Be Deleterious in CHF
Remodeling (hypertrophy) of the heart and vasculature can reduce efficiency
Myocardial hypertrophy which can impair oxygen diffusion: increased capillary density and distance
Ventricular dilatation (Frank-Starling mechanism) increases systolic wall tension (afterload)
High catecholamine levels are cardiotoxic and arrhythmogenic: reductions in # of beta-receptors
Changes in b-Adrenergic Receptors in CHF
reduction in beta-adrenergic receptor density
"uncoupling" of myocardial beta-receptors from the stimulatory G protein (in some forms of CHF)
increase in the inhibitory G protein, Gi, which inhibits myocardial adenylyl cyclase
Traditional Goals in Treating Heart Failure
Improve hemodynamics: Increase CO with inotropic agents (Digoxin, Dobutamine/dopamine (beta-receptors), PDE inhibitors Inamrinone/mirilone (inotropy and vasodilate))
Reduce stress on heart (decrease preload and afterload) with vasodilators-Nitrovasodilators, hydrazine, ACE inhibitors
Reduce salt and water retention-diuretics
New/Non-Traditional Goals in Treating Heart Failure (Prevention and Slowing of Progression)
Reduce levels of circulating angiotensin II or block its action: ACE-I, AT1 receptor blockers (losartan, candesartan, valsartan and others)

Block beta-adrenergic receptors in the heart: Metoprolol, carvedilol, bisoprolol

Block aldosterone action: spironolactone, Eplerenone (selective aldosterone receptor antagonist)

Increase circulating B-type natriuretic peptide (BNP): Nesiritide
Rationale for Pharmacologic Intervention in Heart Failure
Long-term treatment directed towards neurohormonal factors with inhibitors of the renin-angiotensin-aldosterone system and beta-blockers can slow or stop the progression of the disease, decrease morbidity and mortality, and improve quality of life
Treatment for Patients at Risk of Developing Heart Failure
Stage A
Treat underlying issues
ACEI or an ARB
Treatment for Patients at Risk of Developing Heart Failure
Stage B
Treat underlying issues
ACEI or an ARB
Beta-blockers in appropriate patients
What is the first line therapy in treating CHF?
(ACE) inhibitors

ARBs are just as effective
Common adverse effects of ACEI
hypotension and renal insufficiency
increasing concentrations of kinins (cough and angioneurotic edema)-can be avoided with ARB substitution

Decreasing the dose of concurrent diuretic can minimize the effects of lowering angiotensin II
Vasodilators in Heart Failure
Concurrent therapy with two vasodilators, hydralazine and isosorbide dinitrate, can improve symptoms/mortality

useful in patients who cannot tolerate ACE inhibitors or ARBs

BiDil (hydralazine and ISDN) is the first race-based drug to be approved-African americans
Beta-Adrenergic Blockers in Heart Failure
now considered first-line therapy for patients with mild to moderate heart failure

Start low and go slow
Potential beneficial effects of Beta-Adrenergic Blockers in Heart Failure
Protect against catecholamine toxicity
Protect against arrhythmias (sudden cardiac death)
Prevent myocardial -receptor down-regulation
Block sympathetic stimulation of renin-angiotensin system
Beta-Blockers Used in Heart Failure
Agents currently used to treat CHF
Carvedilol: alpa1 antagonist (vasodilator), longer acting, antioxidant properties
Metoprolol succinate sustained release
Bisoprolol
Treatment of Patients with Heart Failure
Stage C
Drugs and Devices
Drugs for routine use: Diuretics, ACEI, Beta blockers
Drugs in selected patients: Aldosterone antagonist, ARBs, Digitalis, hydralazine/nitrates
Devices in selected patients: biventricular pacing, implantable defibrillators

Salt restriction
Treatment of Patients with Heart Failure
Stage D
Treatment Options
Palliative care
Heart transplant
Chronic inotropes
Permanent mechanical support
Experimental surgery or drugs
Diuretics in Heart Failure
Why used and do they help?
relieve symptoms of fluid retention
no evidence that diuretics slow the progression of the disease or decrease mortality
Diuretics in Heart Failure
Drug options
Loop diuretics (furosemide, bumetanide, torsemide) are the most effective diuretics

Thiazide diuretics act on the distal loop and are less effective than loop diuretics: can use two to increase response of a single drug class

adding spironolactone or eplerenone to standard treatment can significantly decrease mortality
common adverse effect of diuretic therapy in CHF
How prevented?
potassium depletion
prevented by use of supplemental potassium, an ACE inhibitor, ARB, or a potassium-sparing diuretic
Nesiritide (Natrecor)
Drug Class
What it does to treat CHF
Adverse Effects
Recombinant B-type natriuretic peptide
Lowers preload and afterload without increasing heart rate
Hypotension is major adverse effect, should not be used in CHF patients with low BP
Eplerenone (Inspra)
Drug class
Therapeutic use
Selective aldosterone receptor antagonist
FDA approved for use post-MI in patients with heart failure
Has fewer side effects than spironolactone
Drugs That Should be Avoided In Most Patients with Heart Failure
Antiarrhythmic drugs that reduce left ventricular function: amiodarone and dofetilide have been shown to not adversely affect survival

Calcium channel blockers: dihyrdopyridines exception

NSAIDs (except aspirin) can cause sodium retention and vasoconstriction and reduce the efficacy of diuretics and ACE inhibitors