CV DRUGS

HYPERLIPIDEMIA

HLD

DRUGS

Mechanism of Action Clinical Use Side Effects

Statins Inhibit HMG-CoA reductase,

modify platelets and

endothelium, suppress

inflammation

Lower LDL (1st line

for hyperlipidemia)

Myopathy,

hepatotoxicity, drug

interactions

Ezetimibe Inhibit NPC1L1 at brush border in

small intestine

Lower LDL (2nd line

for hyperlipidemia,

use is decreasing)

Muscle weakness,

transaminitis (worse

w/ statins)

Bile acid

resins (“C”

drugs)

Bind cholesterol in intestinal

lumen and prevent recycling to

liver

Lower LDL (3rd line

for hyperlipidemia)

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

HDL

Increases HDL,

decreases TGs

Cutaneous flushing

due to PGs (take

aspirin), insulin

resistance

Fibrates Activate PPAR-alpha to enhance

oxidation of FAs

Increases HDL,

decreases TGs

GI, myopathy,

augment effects of

oral hypoglycemic

drugs for diabetes

Fish oil Not well defined, PPAR-alpha

agonist?

Decreases TGs May prolong

bleeding time

ANTIANGINAL

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 TPR

decreased aortic pressure

decreased ejection time

(3) Dilate coronary arteries

somewhat

Short-acting

nitroglycerin: acute

treatment before

angina, prophylactic

before activity

Long-acting isosorbide:

chronic anginal

treatment

Both short- and long-

acting: headache,

nausea, dizziness,

hypotension, don’t use

with sildenafil!

Long-acting: tolerance

(need nitrate-free

interval)

Ranolazine Reduces late Na channel

current

Last-resort in refractory

angina that cannot be

treated with PCI or

CABG (pt is usually

poor surgical

candidate)

Hydralazine Unknown cellular mechanism

Vasodilates arterioles

reducing afterload

Antihypertensive that

works particularly well

in African American pts

and pregnant women

Causes reflex

tachycardia use

beta-blocker!

Headache, SLE-like

syndrome

ANTIANGINAL/

CHF DRUGS

Mechanism of Action Clinical Use Side Effects

Beta-blockers

(Non-selective and

β1 selective)

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

vasoconstriction.

Chronic angina

(mortality benefit!),

heart failure (mortality

benefit!), hypertension

Common: fatigue,

impotence, depression.

Bradyarrhythmias,

bronchospasm (β2

blockade), peripheral

arterial vasospasm (β2

blockade)

Careful with diabetics

NOT WITH

PRINZMETAL

Calcium channel

blockers (CCBs)

Non-dihydropyridines:

verapamil and diltiazem

reduce Ca channel activity in

arteries AND myocardium

(decreases TPR decreased

myocardial consumption;

decreased myocardial

contractility)

Dihydropyridines: “-ipines”

reduces Ca channel activity in

arteries, no effect on cardiac

myocytes

Non-dihyropyridines:

chronic stable angina,

variant angina, beta-

blocker intolerance,

mortality benefit in

normal LV fxn ONLY.

Dihydropyridines:

hypertension, variant

angina, sometimes in

CHF

Non-dihydropyridines:

hypotension,

bradycardia, AV block,

peripheral edema

(diltiazem)

Dihydropyridines:

peripheral edema,

hypotension, headache,

flushing

CCBs are contraindicated in HF

ANTITHROMBOTICS

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

Willebrand factor.

• 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

platelets.

• 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

plug

Central role of factors X, prothrombin, and

thrombin in the coagulation cascade.

ANTIPLATELET

DRUG

Mechanism of Action Clinical Scenario

Aspirin Irreversible, nonselective COX-1 and

-2 inhibitor

Angina, acute MI, TIA,

stroke

Dipyridamole Blocks uptake of adenosine, PDE

inhibitor

Prophylaxis (prosthetic

heart valves, stroke)

AD

P R

ecep

tor

An

tag

on

ists

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

thrombosis, PCI

Ticagrelor Reversibly inhibits ADP receptors,

not a pro-drug

Prevention of CV

thrombosis after MI

Gp

IIb/I

IIa

Inhib

itors

Abciximab Monoclonal Ab that blocks GpIIb/IIIa During PCI

Eptifibatide Small molecule that blocks Gp

IIb/IIIa

During PCI

Tirofiban Small molecule that blocks Gp

IIb/IIIa

During PCI

Aspirin

• 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

aggregation.

• 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 Inhibitors

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

hemorrhage

Clopidogrel

• 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

aspirin.

• Used after placement of coronary stents.

• Adverse effects: Bleeding, dyspepsia, diarrhea, very rare severe

neutropenia and thrombotic thrombocytopenic purpura (TTP)

Prasugrel

• 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.

Ticagrelor

• 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

• Dyspnea

• Bradyarryhthmias

GP IIb/IIIa Inhibitors

High Risk of Bleeding

Abciximab

• 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.

Eptifibatide

• 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

(PCI).

Tirofiban

• 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

PCI.

Use Warfarin instead of Antiplatelet

Agents for Atrial Fibrillation

Anticoagulants

• Unfractionated Heparin

• Low Molecular Weight Heparin

• Fondaparinaux

• Bivalirudin

• Warfarin

• Clinical Use: DVT prophylaxis and treatment, pulmonary embolism

(PE), ACS, PCI

ANTICOAGULANT Mechanism of Action Clinical ScenarioH

eparins

UFH Anti-thrombin and anti-Xa activity DVT, PE, post-MI,

UA/NSTEMI, coats stents

LMWH

(enoxaparin,

dalteparin)

Mostly anti-Xa activity Similar to UFH, but easier

dosing, no monitoring and

less.

Fondaparinux Synthetic inhibitor of factor Xa, even

more selective than LWMH

Prophylaxis after knee, hip

replacement

Dire

ct T

hro

mbin

& X

aIn

hib

itors 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

replacement

Warfarin Competitively inhibits vitamin K (II,

VII, IX, X, protein C, protein S)

VTE prevention, DVT, Afib,

prosthetic heart valves, MI

Thrombin

• 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

platelet aggregation.

• Thrombin is also known to be a mitogen for smooth muscle cell

proliferation.

UFH

• 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

thrombin.

• 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

puncture).

LMWH

• 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

sequelae.

• 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

• 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

heparin.

PF4• 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 production.

• 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.

Warfarin

• 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)

Treatment Regimens

Fibrinolytic Drugs

• 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

hours)

• 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

state

Rarely used Produced by beta-

hemolytic Streptococci,

6% allergic reactions;

see below

Urokinase

plasminogen activator

(uPA)

Not specific for fibrin, so

produces massive lytic state

Rarely used See below

Tissue-type

plasminogen activator

(tPA; alteplase)

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

infusion

See below

Reteplase (rPA) Derivative of tPA with longer

half-life

Same; can be

administered as IV

bolus

See below

Tenecteplase (TNK-

tPA)

Derivative of tPA with longer

half-life

Same; can be

administered as IV

bolus

See below

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

Primary Hemostasis• Platelets are responsible for primary hemostasis (formation of a platelet plug) by a

three-part process:

• (1) adhesion to the site of injury,

• (2) release reaction (secretion of platelet products and activation of key surface receptors), and

• (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.

Secondary Hemostasis

• 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.

Fibrinolytic System

• 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).

CHF PHARMACOLOGY

Adrenergic System

• 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

(fibrosis etc.)

Renin-Angiotensin-Aldosterone

• 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

edema.• 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 edema.

Describe how nitrates reduce dyspnea in

patients with acute CHF, and recognize

that hypotension is a possible side effect.

• Nitropaste

• 1. Dilates veins and reduces preload, so it leads to reduced

congestion.

• 2. Dilates arteries and reduces TPR and afterload, leading to

improved CO.

• 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 failure.

• Morphine

• 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.

Frank Starling Relationship

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

in patients.

Indicate the benefit of reducing cardiac

return in a volume-overloaded heart

failure patient.

• 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

congestion.

Digoxin• 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 contractile force.

• 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 arrhythmias)

• 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.

ACE Inhibitors

• Lisinopril

• 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

• SE: • 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.

Beta Blockers• Carvedilol, Metoprolol

• Action:

• Improve cardiac performance by ↓ HR, ↑diastolic ventricular relaxation & by ↓O2 consumption.

• ↓ 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

are enhanced.

• Release of NE from sympathetic terminals is increased by Ang II &

aldosterone.

• Hypoxic impulse – peripheral chemoreflex

• Muscle metaboreflex

Aldosterone Antagonists

• Spironolactone & eplerenone

• Action:

• 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

diuretic.

• Eplerenone has fewer GI and sexual side effects

MOA Thiazides

• 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.

MOA Dobutamine

• 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

MOA Dopamine

• 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.

MOA Milrinone• 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 benefits.

• PDE inhibitors cannot be used chronically because they increase mortality (probable reason: they increase contractile demand in a sick heart and they cause ventriculararrhythmias).

• SE: nausea and vomiting, cardiac arrhythmias, thrombocytopenia

Recombinant ANP/BNP

• 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 infusion.

• SE: dizziness, nausea, cardiac arrhythmias, hypotension, headache

• NOT in patients with BP<90mmHg

Diuretics reduce preload and increase CO

Acute HF Profile

Names to Know• Inotropics

• Glycosides/digitalis• Digoxin

• Digitoxin

• Phosphodiesterase inhibitors• inamrinone (Inocor), milrinone

(Primacor)

• Beta-agonists• dobutamine (Dobutrex), dopamine

• Diuretics• Thiazides

• hydrochlorothiazide (Hydrodiuril). Metolazone.

• Loop diuretics

• furosemide (Lasix), bumetanide(Bumex)

• Potassium-sparing

• spironolactone (Aldactone), eplerenone.

• Vasodilators• ACE inhibitors

• Captopril (Capoten), enalapril(Vasotec), lisinopril (Prinivil, Zestril)

• Other vasodilators• Isosorbide dinitrate (Isordil,

others)

• Hydralazine (Apresoline)

• Sodium nitroprusside

ANTI-ARRHYTMICS

Overview

• I. INa (fast sodium channels; inhibition)• 1A: Procainamide, quinidine, disopyramide

• 1B: Lidocaine, Mexiletine, Phenytoin, Tocainide

• 1C: Encainide, Flecainide, Propafenone

• II. Beta-adrenergic receptor antagonists (Ca channels all cells)• Esmolol, Metoprolol, Propanolol, Acebutolol

• III. Delayed rectifiers (K channels, inhibition)• Amiodarone, Sotalol, Dronedarone, Dofetilide, Ibutilide

• IV. Calcium channels• Diltiazem

• Verapamil

• Others• Adenosine: adenosine A1 receptors (agonist)

• Digoxin: Na/K ATPase blocker

• MgSO4

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

blockers.

• 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

pharmacologically.

• Class I and III target rhythm in the SA node, while all classes can

target rate

Hypoxia

• 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

inappropriately.

• 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 Stimulation• 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.

• BRADYCARDIA

• 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

Sympathetic Stimulation• 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

chronotropic effect).

• 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

dromotropic effect).

• Rapid diastolic depolarization plus the lowering of the AP threshold renders the AV node more excitable.

Hypokalemia and Hyperkalemia• >5.5 mM = high

• >6.5 or <3 symptoms = emergency

• >7 = arrhythmia

• Hypokalemia

• 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

• Hyperkalemia

• 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

Abnormal Automaticity

• 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

• Rx:

• 1) Reduce slope of phase 4

• 2) Make diastolic potential more negative

• 3) Raise threshold.

Triggered Activity

• 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

• Rx:

• 1) Shorten AP duration

• 2) Correct Calcium overload

Reentry

• 2 Critical Conditions

• Unidirectional Block

• Slowed conduction through reentry path

• Anatomic: atrial flutter, AVNRT, VT due to scar tissue

• Functional: Afib, polymorphic VT, Vfib

• Rx

• 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

membrane potential.

Class IA

• 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

• Drugs:

• Quinidine: GI, cinchonism, QT elongation torsades de pointes

• Procainamide: Less QT elongation, lupus like syndrome

• Disopyramide: Anticholinergic constipation, urinary retention, glaucoma

Class IB

• 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

• Drugs• Lidocaine: IV only, confusion, paresthesia, dizziness, seizures

• Mexiletine: Oral, Dizziness, tremor, slurred speech, nausea, vomiting

Class IC

• 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

• Drugs:• 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.

QRS Widening: 1B<<1A<1C

Class II

• 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 HIGH

• 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.

• Drugs:• 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

Class III

• MOA: Class III drugs block delayed rectifier K+ channels during phase 3 repolarization

• 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

• Drugs:• 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 advanced CHF

• Dofetilide: Oral, QT prolongation, torsades de pointes

• Ibutilide: IV, QT prolongation, torsades de pointes

Class IV

• 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

• Drugs:• Verapamil: hypotension, heart block

• Diltiazem: hypotension, heart block

• Contraindicated with Beta Blockers!

Adenosine

• MOA: Binds to adenosine receptors and activates potassium

channels hyperpolarization

• 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

Digoxin

• 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 heart failure.

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

• 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.

CHA2DS2VAS2

• Algorithm for Anticoagulation

• Congestive Heart Failure

• Hypertension

• >75 (2)

• DM

• Stroke/TIA (2)

• Vascular disease

• >65

• Sex category