Cardiovascular Drugs - UW Canvas

Carol Jacobson RN, MN – 2014 www.cardionursing.com 1

Cardiovascular Drugs UW School of Nursing

Carol Jacobson RN, MN

www.cardionursing.com

Types of Cardiovascular Drugs

• Antiarrhythmics

• Beta Blockers

• Calcium Channel

Blockers

• Nitrates

• Diuretics

• Anticoagulants

• Platelet Inhibitors

• ACE Inhibitors

• ARBs

• SARAs

• Anti-lipid Agents

• Vasoactive Drugs

• Antihypertensives

• Thrombolytics

• Inotropes

Cardiovascular System

Function is to deliver

oxygenated blood to all

parts of the body

Heart – pump

Arteries – deliver

Veins – return

Volume – must be

adequate for tank size

All must work well in

order for CV system to

do its job


Drugs that keep blood from clotting: ASA

Plavix

Reopro, Integrilin, Aggrastat

Coumadin, Heparins

Drugs that increase

contractility: Dobutamine

Dopamine

Milrinone

Digitalis

Drugs that dilate veins (preload

reducers): Nitrates (NTG, etc.)

ACEI

ARBs

Aldosterone blockers

Neseritide

Drugs that reduce blood volume: Diuretics

ACEI

ARBs


Drugs to treat angina: Nitrates (NTG, etc)

Beta blockers

Ca++ blockers

Drugs that dilate arteries &

lower BP (afterload reducers): Ca++ blockers

Antihypertensives

ACEI

ARBs

Milrinone

Nipride

Nesiritide

Drugs that cause

vasoconstriction

and support BP: Neosynephrine

Levophed

High dose dopamine

Epinephrine

Vasopression

CO = HR x SV

Preload Afterload Contractility

Determinants of Cardiac Output

Blood Volume Distribution of

Blood volume Atrial Kick LV Function

PRELOAD

Venous Tone Body Position

Intrathoracic

pressure

Intrapericardial

pressure


Circulating vasodilator or

vasoconstrictor mediators

AFTERLOAD

SVR

Aortic Pressure

and Compliance

Aortic Stenosis

HOCM

Arteriolar Tone

Sympathetic NS

CONTRACTILITY

Ventricular

Muscle Mass Catecholamines Metabolic

State

Drugs

SNS Adrenals H+ CO2 O2 Hypoxia

Ischemia

CO = HR x SV

Atropine

Pacing

Beta blockers

Ca++ channel blockers

Digoxin

Adenosine

Antiarrhythmics Other drugs that increase HR:

dopamine, dobutamine,

epinephrine, norepinephrine


CO = HR x SV

Preload

Fluids

Blood Products

Volume Expanders

Diuretics

Venous Dilators

NTG

ACEI, ARBs

Nesiritide

Morphine


CO = HR x SV

Afterload

Arterial Dilators

Nitroprusside (Nipride)

Milrinone (Primacor)

Ca++ blockers (“pines”)

Antihypertensives

ACEI, ARBs

Nesiritide

Vasopressors

Norepinephrine (Levophed)

Dopamine (high dose)

Epinephrine

Phenylephrine (Neosynephrine)

Vasopressin

The down side of using a vasopressor is

the increase in afterload for the heart.

CO = HR x SV

Contractility

Inotropes Dobutamine

Dopamine

Epinephrine

Norepinephrine

Milrinone

Digoxin

Beta blockers

Ca++ channel blockers

Others: Antiarrhythmics

Anesthetics

Sedation agents

Chemo agents


O2 Supply --------------O2 Demand

Open arteries

CO

paO2

Hb, Hct

Heart Rate

Preload

Afterload

Contractility

Demand Supply

↓Preload

Diuretics NTG

ACEI

ARBs


Nesiritide

Morphine

↓Afterload ↓Contractility

Ca++ blockers

ACEI

ARBs

Arterial dilators

Beta blockers

Ca++ blockers

O2 Drugs to ↑ blood flow

Open occluded coronaries

NTG

Ca++ blockers

ASA

Platelet inhibitors

Anticoagulants

Thrombin Inhibitors

Factor Xa Inhibitors

Fibrinolytics

PTCA

Stents

Atherectomy

Rotablation

CABG Heart Rate:

Slower is better in CAD

BP value does not tell you WHY the BP

is low – must evaluate determinants of

BP and treat the cause

Low BP could be due to: Low CO

HR too slow or too fast

Preload too low or too high

Contractility low

Low SVR

Vasodilation due to sepsis, drugs, anaphylaxis

BP = CO x SVR


BP = CO x SVR

Drugs to ↑ CO Volume

Inotropes

Dobutamine

Dopamine

Milrinone*

Epinephrine

Drugs to ↑ SVR Vasopressors

Norepinephrine

Phenylephrine

Vasopressin

Epinephrine

Dopamine

*Milrinone is also a vasodilator.

Drug Therapy to Decrease BP

BP = CO x SVR

Drugs to ↓CO

• Diuretics

• Beta Blockers (“olols”)

• Calcium Channel Blockers

Drugs to ↓ SVR • Peripheral Alpha Blockers (prazosin, terazosin, regitine etc)

• Direct Arterial Dilators (hydralazine, minoxidil)

• ACEI (“prils”), ARBs (“sartans”)

• PDE inhibitors (milrinone)

• Calcium Channel Blockers (“pines”: amlodipine, felodipine, etc)

• nitric oxide in vascular tissue (nitroprusside, nitrates)

•Centrally Acting Agents (clonidine, guanabenz, guanfacine)

Role of Kidney in HF


Renin-Angiotensin System

Renal blood flow ( BP, Na+, diuresis) Renin release Angiotensinogen Angiotensin I Angiotensin II

Vasoconstriction Aldosterone release ↑Na+ & H2O retention

BP & Organ perfusion

(converting enzyme)

More pressure

More volume

↓ Renal blood flow Renin release Angiotensinogen Angiotensin I (converting enzyme)

Angiotensin II Vasoconstriction Aldosterone release Na+ & H2O retention ↑ BP & Organ perfusion

Beta Blockers

ACEI

ARBs


Renin Blockers


Angiotensin I

(converting enzyme)

Angiotensin II

Vasoconstriction Aldosterone release

Na+ & H2O retention

Mechanism of Action

ACEI

ARBs

Venous dilation = preload

Arterial dilation = afterload preload

Aldosterone Blockers

Drugs That Block

The RAAS


ACE INHIBITORS Block conversion of Angiotensin I

to Angiotensin II

Preload

Afterload

Levels of Bradykinin

Prostaglandin Production

Ventricular Remodeling

Heart Failure – all stages

Hypertension Especially effective in patients with renal

disease or diabetes

Acute MI

Early phase for high risk patients to prevent HF

All post-MI patients with reduced EF

Renal Failure

Slow progression of diabetic and nondiabetic

nephropathy

Cough (5-20%) – due to increased bradykinin level

Hypotension – due to arterial and venous dilation

Hyperkalemia (3%) – due to decreased aldosterone (which increases K+ reabsorption)

Angioedema (0.1-0.7%) – due to vasodilation and increased vascular permeability resulting from increased bradykinin level

Decreased glomerular filtration in some patients with renal disease or heart failure Due to dilation of efferent arteriole and to hypotension

which reduce glomerular perfusion pressure

May also protect basement membrane in the glomerulus in diabetics

Side Effects of ACE Inhibitors


History of angioedema with ACEI therapy

Pregnancy

Prior worsening of renal function with ACE

inhibitors

Acute kidney injury

Use with caution: Hypotension (SBP < 80 mmHg)

Markedly increased creatinine (> 3 mg/dL)

Serum potassium > 5.0 mEq/L

History of bilateral renal artery stenosis

The presence of impaired renal function alone is not a

contraindication to the use of ACE inhibitors or ARBs

Combination Therapy with ACEI

• Diuretics

– Thiazides & lasix OK

– Risk of ↑K+ with K+ sparing diuretics

– DC diuretic for 2-3 days on initiation of ACEI

therapy if possible

• Digoxin (good combination in HF)

- Captopril increases Dig levels

• Beta Blockers

– Additive effects on decreasing renin activity

Combination Therapy with ACEI

• Ca++ Blockers (good combination for HTN)

– Additive effects on BP (vasodilation)

• Nitrates

– Additive effects on preload reduction

• NSAIDS

– Decrease cough side effect

– Decrease effects of ACEI


Patient Teaching Issues • Report swelling of face, eyes, lips, tongue; difficulty

breathing or swallowing (angioedema)

• Report lightheadedness (may indicate ↓BP)

• Report to MD if nausea or vomiting

– Vomiting, diarrhea, or excessive sweating can cause

hypovolemia and result in hypotension

• Get up slowly, move ankles & feet prior to standing to

prevent postural hypotension

• Do not take K+ containing salt substitutes (risk of ↑K+)

• Report signs of infection: sore throat, fever

• Report jaundice

– ACE inhibitors have been linked to hepatic necrosis (rare)

Class I – active as is, metabolized to active

metabolites

Captopril

Class II – prodrugs (converted to active form in liver)

Benazepril (Lotensin), Enalapril/Enalaprilat (Vasotec

oral and injectable), Fosinopril (Monopril), Moexipril

(Univasc), Perindopril (Aceon), Quinapril (Accupril),

Ramipril (Altace), Trandolapril (Mavik)

Class III – water soluble

Lisinopril


Block effects of angiotensin II at its receptor

site

Blocks angiotensin II formed in all pathways

Results in vasodilation (↓ preload & afterload) and

decreased volume (↓ preload)

No effect on bradykinin Much less cough than ACEI

Less angioedema – although this occurs in about

0.1% of patients

Similar reduction in mortality and

hospitalization in heart failure

Similar effects in treatment of hypertension

Slow the progression of proteinuric diabetic

and nondiabetic chronic renal failure

Considered a reasonable alternative to ACEI

for all indications (especially if ACE cough)

Angiotensin II Receptor Blockers

• Losartan (Cozaar)

– 25-100 mg once or twice a day

• Irbesartan (Avapro)

– 150-300 mg once a day

• Candesartan (Atacand)

– 8 – 32 mg once or twice a day

• Eprosartan (Teveten)

– 400 – 800 mg/day (once or twice daily)

• Telmisartan (Micardis)


• Valsartan (Diovan)


• Olmesartan (Benecar)

– 20 -40 mg once a day

– Possible increased risk of death from MI or stroke?


• ACE Inhibitors (“Prils”) – Captopril

– Enalapril

– Fosinopril

– Lisinopril

• Inhibit conversion of Angiotensin I to Angiotensin II in the lungs

• Result in arterial and venous dilation, decreased Na+ & H2O reabsorption – Preload and afterload

reduction • Side Effects: cough, K+,

hypotension

• ARBs (“Sartans”) – Losartan

– Valsartan

– Candesartan

– Irbesartan

• Directly block angiotensin receptors – Block effects of

angiotensin formed in multiple locations

• Same effects as ACEI – Preload and afterload

reduction

• Side effects: less cough,

K+, hypotension (more common than with ACEI)

Effects of Aldosterone in Heart Failure

Contributes to the pathophysiology of heart failure:

• Promotes retention of Na+

• Loss of Mg++ and K+

• Activation of SNS

• Inhibition of parasympathetic NS

• Myocardial and vascular fibrosis

• Dysfunction of endothelium (formation of endothelin – powerful vasoconstrictor)


↓ morbidity and mortality

In patients with LV dysfunction post MI

LV dysfunction in diabetics

Chronic systolic heart failure

↓ hospitalizations for heart failure

↓ incidence of SCD

Aldosterone Blockers

Spironolactone (non-selective)

• 30% reduction in mortality and reduced risk of SCD and HF hospitalizations in patients with chronic HF and EF <35%.

• Vasodilator properties

• Decreases cardiac norepinephrine release

• Blocks aldosterone and androgen, stimulates progesterone

• Major side effects: gynecomastia, sexual dysfunction and menstrual problems

• Causes K+ reabsorption – risk of hyperkalemia

SARAs Selective Aldosterone Receptor Antagonists

Eplerenone (Inspra)

• Indicated for treatment of hypertension and heart failure.

• Reduces mortality and hospitalizations in patients with HF.

• 1000 fold less binding to androgen receptor.

• 100 fold less binding to progesterone receptor.

• Results in blockade of aldosterone receptors without side effects associated with spironolactone.


Recommendations for Drugs that

Block the RAAS

• Heart Failure – ACEI or ARBS to prevent HF in patients with history

of MI and all patients with reduced EF

– ACEI in all patients with systolic heart failure (or ARB if ACEI intolerant)

– Aldosterone antagonists in HFrEF patients who are NYHA class II-IV with EF <35%

• Acute Coronary Syndromes (STEMI, NSTEMI)

– ACEI within 24 hours to all patients with anterior wall STEMI, HF, or ejection fraction <40% (ARB if ACEI intolerant)

– Aldosterone blocker in patients who have ejection fraction <40% and either symptomatic HF or diabetes.

Cardiovascular Effects of SNS

Alpha Receptors Beta Receptors (Arteries & Veins)

Vasoconstriction

Beta 1 Beta 2 (Heart) (Arteries, Veins)

(Lungs)

Heart rate

Contractility

Automaticity

Conduction velocity

Vasodilation

Bronchodilation

Renin release (kidney)


Sympathomimetic Drugs

Alpha Receptors Beta Receptors (Arteries & Veins)

Beta 1 Beta 2 (Heart) (Arteries, veins)

(Lungs) Vasoconstriction heart rate Vasodilation

contractility Bronchodilation

automaticity

conduction velocity

Renin release

Neo-synephrine

Isoproterenol

Dobutamine

Dopamine

Epinephrine

Norepinephrine

Adrenergic Effects of

Sympathomimetic Drugs

Drug Alpha-1 (vasoconstriction)

Beta-1 (cardiac stimulation)

Beta-2 (vasodilation)

Epinephrine (Adrenalin)

++ (>0.2 mcg/kg/min)

+++ +++ (<0.01 mcg/kg/min)

Norepinephrine (Levophed) +++ ++++ +

Dopamine ++

(>10 mcg/kg/min) +++ +

Dobutamine 0/+ +++ +

Phenylephrine (Neosynephrine) ++++ 0 0

Isoproterenol (Isuprel)

0 ++++ +++

Beta Blockers


Effects of Beta Blockers

Beta Receptors

Beta 1 Beta 2 (Heart) (Arteries, Veins)

(Lungs)

Heart rate

Contractility

Automaticity

Conduction velocity

Renin release (kidney)

All Beta Blockers: Non-cardioselective

Beta Blockers:

Vasodilation

Bronchodilation

Use Mechanism of Action

Hypertension ↓ heart rate = ↓CO = ↓BP ↓ contractility = ↓CO = ↓ BP ↓ renin release in kidney = ↓ angiotensin II formation

Classic Angina ↓O2 demand by ↓HR, ↓contractility, ↓BP

↑O2 supply by ↓HR which ↑diastolic filling time and ↑ coronary perfusion time

Acute Coronary Syndromes

↓ automaticity in ventricle so ↓ risk of VF early in MI

Preserves ischemic myocardium by ↓O2 demands

↓ mortality rates

Heart Failure Upregulation of beta receptors, decrease circulating vasoconstrictors, ↓ LV remodeling, improve O2 supply & demand, ↓ SCD and A Fib

Arrhythmias ↓ automaticity so ↓ VT and VF

↓ AV conduction to slow ventricular rate in A Fib or flutter, may terminate SVTs

Hypertrophic

Cardiomyopathy

↓ contractility so reduces outflow track obstruction

↓ HR allows longer diastolic filling time, more blood in ventricle decreases outflow tract obstruction

BP = CO x SVR

Beta Blockers in ACS

• Should be given to all patients without contraindications (STEMI & NSTEMI) – Contraindications: PR interval greater than 0.24

seconds, second- or third-degree heart block, active asthma, or reactive airway disease

• Oral within 24 hours if tolerated

• IV if ongoing chest pain, hypertension, or tachycardia not caused by heart failure

• Metoprolol or atenolol preferred

• Continue indefinitely for secondary prevention


Why Do We Use Beta Blockers in HF?

• Chronic SNS stimulation is cardiotoxic and

contributes to the progression of HF

– Beta blockers increase survival and decrease mortality

and progression of HF

• Chronic beta stimulation → downregulation of beta

receptors → decreased responsiveness of beta

receptors to SNS stimulation

– Beta blockade upregulates beta receptor density and

restores inotropic and chronotropic responsiveness to

improve contractility

• Beta blockers reduce circulating levels of

vasoconstrictors (norepinephrine, endothelin, renin)

Shown to slow progression of HF, improve survival,

decrease hospitalizations for HF and improve

symptoms and exercise capacity

Carvedilol, metoprolol, or bisoprolol are preferred (proven benefit in studies)

Give with diuretics if recent fluid retention (beta

blockers can cause fluid retention)

Begin with low doses and titrate to maximum

tolerated dose

Symptoms may increase for 2-3 months before

improvement is noted

Beta Blockers

• Nonselective: Block both Beta 1 & Beta 2 Propranolol (Inderol) Nadolol (Corgard) Timolol (Blocadren) Sotalol (Sotacor)

Penbutolol (Levatol) (ISA) Oxprenolol (Trasicor)

Pindolol (Visken) (ISA)

• Cardioselective: Block Beta 1 Acebutolol (Sectral) (ISA) Atenolol (Tenormin)

Metoprolol (Lopressor) Esmolol (Brevebloc)

Bisoprolol (Zebeta) Nebivolol (Bystolic)

• Combined Alpha & Beta Blocking: Labetalol (Trandate, Normodyne) - nonselective

Carvedilol (Coreg) - nonselective


Side Effects of Beta Blockers

• Cardiac – Bradycardia, AV block

– Heart Failure

– Hypotension

• Pulmonary – Bronchoconstriction

– Pulmonary edema

• Peripheral Vascular – Vasoconstriction

• Metabolic – Mask signs of

hypoglycemia

– Augment hypoglycemic actions of insulin

– Increase serum triglycerides

• Other – Fatigue, sleep

disturbances

– Depression

– Sexual dysfunction

– Weight gain

Calcium Channel Blockers

• Depolarization of SA node and AV node cells (“slow current” calcium dependent cells)

• Facilitates contraction of heart and smooth muscle layer of blood vessels – Facilitates actin-myosin interaction in muscle)

Effects of Ca++ on

Heart & Blood Vessels

Muscle layer of

blood vessel

Sinus node

AV node


Effects of Ca++ Channel Blockers

• Heart:

↓ heart rate (except Nifedipine-like agents)

↓ AV conduction velocity

↓ contractility (especially verapamil)

• Blood Vessels:

Coronary vasodilation (prevent vasopasm)

Peripheral vasodilation (afterload reduction)

• Dihydropyridines have most peripheral vascular effect

CCB and BB have the same effects on the heart

but opposite effects on blood vessels

Clinical Uses of Ca++ Channel Blockers

Use Mechanism of Action

Angina: Coronary Spasm Classic Angina

Prevents vasoconstriction by decreasing amount of Ca++ available for contraction. Coronary vasodilation increases collateral blood flow. ↓ MVO2 by ↓HR, ↓contractility, ↓afterload

Hypertension

BP = CO x SVR ↓CO by ↓contractility, ↓SVR by vasodilation

Arrhythmias: SVT

Slows AV conduction so ↓ventricular response to atrial fib & flutter. Can terminate AV nodal active arrhythmias.

Hypertrophic Cardiomyopathy

↓ contractility lessens outflow tract obstruction. ↓ HR allows longer diastolic filling time, more blood in ventricle keeps outflow tract open

Ca++ Channel Blockers

• Heart Rate Lowering:

– Verapamil (Calan) – most depression of contractlitiy

– Diltiazem (Cardizem)

• Dihydropyridines (potent vasodilators, little or no depression

of contractility)

– Clevidipine – ultra-short acting (IV only)

– Nifedipine (Procardia, Adalat) – short acting, comes in sustained

release form for longer action

– Felodipine (Plendil)

– Isradipine (DynaCirc)

– Nicardipine (Cardene)

– Nisoldipine (Sular)

– Amlodipine (Norvasc) – long acting, no cardiac depression, safest

one in HF

Longer acting, little

cardiac depression


Side Effects of

Ca++ Channel Blockers

• Bradycardia (Diltiazem, Verapamil)

• AV Block (Diltiazem, Verapamil)

• Hypotension (especially Nifedipine)

• HF (especially Verapamil)

• Flushing, headaches

• Peripheral edema

• Constipation (especially Verapamil)

Pathogenesis of ACS

Plaque Rupture: • Spontaneous

• Induced by PCI

Platelet Activation

Platelet Aggregation


Antiplatelet Drug Site of Action

Clopidogrel (Plavix)

Prasugrel (Effient)

Ticagrelor (Brilinta)

Heparin

Bivalirudin (Angiomax)

Dabigatran (Pradaxa) ASA

IIb/IIIa Inhibitors

IIb-IIIa Inhibitors

• Reopro

• Integrilin (eptifibatide)

• Aggrastat (tirofiban)

Clopidogrel (Plavix)

Prasugrel (Effient)

Ticagrelor (Brilinta)

Indications:

reduce rate of

MI, stroke, and

vascular deaths

and stent

thrombosis

Patients with recent MI or

stroke.

Patients with STEMI, UA,

or NSTEMI managed

medically or with PCI or

with CABG.

Patients with STEMI,

UA, or NSTEMI

managed with PCI.

NOT for patients treated

medically.

Patients with STEMI,

UA, or NSTEMI

managed medically

or with PCI.

Dose Loading: 600 mg prior to

PCI, 300 mg in UA or

NSTEMI & with

fibrinolytics.

Maintenance: 75 mg qd

for 12 months.

Loading: 60 mg once

anatomy known, no

later than 1 hour after

PCI.

Maintenance: 10 mg qd

for 12 months.

Loading: 180 mg

Maintenance: 90 mg

bid for 12 months.

Comments Binds irreversibly to ADP

receptor: inhibits platelets

for their lifetime (10 days).

Prodrug – converts to

active form in liver.

PPIs inhibit enzyme that

converts plavix so ↓ effect.

Binds irreversibly to

ADP receptor; platelet

function returns 5-9

days. Contraindicated in

patients with Hx of TIA

or stroke.

Faster onset of action

than clopidogrel.

Binds reversibly to

ADP receptor.

Dose of ASA >100 mg

decreases effect.

Side effects: dyspnea,

bradycardia.

Faster onset of action

than clopidogrel.

Bleeding is a major risk with all these drugs. Contraindicated with active pathological bleeding,

history of intracranial hemorrhage; severe hepatic impairment.


Aspirin

Interferes with formation of TXA2 inside the platelet by irreversibly inhibiting cyclo-oxygenase (COX-1) for the lifespan of the platelet

Also has anti-inflammatory effects which may contribute to its beneficial effect in preventing MI

Dose of ASA

• 162-325 mg chewed at onset of ACS

• 75 – 162 mg maintenance (81 mg in US )

Indications for ASA

Secondary prevention in all patients with prior cardiovascular event (ACS, ischemic stroke, PAD)

• Reduces risk for subsequent event by average of 25% (up to 53% in coronary angioplasty)

In ACS, should be given in both acute and follow-up phase for medically treated and PCI patients

Not recommended as primary prevention except in high-risk patients

GP IIb/IIIa Inhibitors

Abciximab (Reopro) - adjunct to PCI to reduce incidence of reocclusion during PCI or in patients with ACS in whom PCI is planned within 24 hours

• Not used for medically treated patients (no PCI)

• Infusion can be continued for 12-24 hours after PCI

Eptifibitide (Integrilin) – adjunct to PCI or in medically treated patients with recurrent ischemia

• Platelet function returns to near normal 6 hours after drug discontinued

• Infusion continued up to 20-24 hours after PCI

Tirofiban (Aggrastat) - adjunct to PCI or in medically treated patients with recurrent ischemia


Anticoagulants

Plaque rupture

VII VIIa Tissue

Factor

X Xa

Prothrombin

Activator

Ca++

Prothrombin Thrombin

Ca++

Fibrinogen Fibrin Thrombus Factors formed in liver

and inhibited by warfarin

Indirect Xa inhibitor: fondaparinux (Arixtra)

Heparin (indirect)

LMWH: enoxaparin (Lovenox)

dalteparin (Fragmin)

Direct Xa inhibitor: apixaban (Eliquis)

rivaroxaban (Xarelto)

Heparin (indirect)

Direct thrombin inhibitors:

argatroban (Novastat)

bivalirudin (Angiomax)

lepirudin (Refludan)

dabigatran (Pradaxa)

Heparin is an indirect inhibitor of Factor Xa

and thrombin. It works by binding to

antithrombin which inhibits Xa and thrombin

Dabigatran (Pradaxa)

(direct thrombin inhibitor)

Rivaroxaban (Xarelto)

(Factor Xa inhibitor)

Apixaban (Eliquis)

(Factor Xa inhibitor)

Indications FDA approved for

prevention of stroke

and systemic

embolism in

nonvalvular AF.

Not yet approved

for DVT/PE

treatment or

prophylaxis.

FDA approved for


and systemic

embolism in

nonvalvular AF.

DVT/PE prophylaxis

post hip or knee

surgery. Treatment of

DVT/PE.

FDA approved for


and systemic embolism

in nonvalvular AF.

DVT/PE prophylaxis

post hip or knee

surgery. (Treatment

approval expected in

August.)

Dose 150 mg bid.

75 mg bid for CrCl

15-30 mL/min.

Take with or without

food.

Atrial Fib:

20 mg daily with

normal renal fx.

15 mg daily if CrCl 15-

50 mL/min.

Treatment DVT/PE:

15 mg bid for the first

21 days for initial Rx,

then 20 mg qd.

DVT prophylaxis:

10 mg qd.

Atrial Fib:

5 mg bid.

2.5 mg bid if at least 2

of following: > 80 yrs,

< 60 kg, creatinine >

1.5 mg/dL.

DVT prophylaxis:

2.5 mg bid.

Take with or without

food.


Dabigatran (direct thrombin inhibitor)

Rivaroxaban (Factor Xa inhibitor)

Apixaban (Factor Xa inhibitor)

Comments

Major side

effect of all

these drugs

is bleeding!

Inhibits both free and

fibrin-bound thrombin.

Inhibits thrombin

induced platelet

activation.

Oral prodrug that is

converted to active

form. Requires acidic

environment for

absorption (take PPIs 2

hrs apart).

No routine monitoring.

No reversal agent.

Does not cause HIT.

Swallow capsules

whole with a full glass

of water.

Discontinue 1-2 days

prior to surgery or

interventional

procedures.

Take with evening

meal. 10 mg dose with

or without food.

Inhibits free and

platelet-bound factor

Xa.


No reversal agent.

Does not cause HIT.

Discontinue 24 hrs

prior to surgery or

interventional

procedures.

Risk of spinal or

epidural hematoma

with spinal/epidural

anesthesia or

catheters.

Duration of Rx is 35

days following hip

replacement; 12 days

following knee

replacement; first

dose 12-24 hrs after

surgery.


No reversal agent.

Does not cause HIT.

Discontinue 24- 48 hrs

prior to surgery or

interventional

procedures.

Risk of spinal or

epidural hematoma

with spinal/epidural

anesthesia or

catheters.

Major side effect of all these drugs is bleeding!

Antiarrhythmics


TP

Phase 4: TRP

Phase 0: Depolarization

Phase I: Early Rapid

Repolarization Phase 2:

Plateau

Phase 3:

Repolarization Na+

K+

Ca++

Cardiac Action Potential

Na+ K+

Antiarrhythmic Drug

Sites of Action

Ca++

Class IV:

Ca++ Blockers

Class I:

Na+ Channel Blockers

Class III:

K+ Channel Blockers

Class Examples

IA Quinidine

Procainamide

Disopyramide

IB Lidocaine

Mexilitine

IC Propafenone

Flecainide

II Beta blockers (“olols”)

III Amiodarone Dronedarone

Ibutilide Sotalol

Dofetilide

IV Calcium channel blockers:

Verapamil, Diltiazem


Class Action ECG Effect

IA Sodium channel blockade

Prolong repolarization time

Slow conduction velocity

Suppress automaticity

QRS

QT

IB Sodium channel blockade

Accelerate repolarization

QT

IC Sodium channel blockade

Marked slowing of conduction

No effect on repolarization

QRS

II Beta blockade HR PR

III Potassium channel blockade

Prolong repolarization time

QT

IV Calcium channel blockade HR PR

Amiodarone • Indications (licensed in US)

– Life-threatening recurrent VF or hemodynamically unstable VT refractory to other antiarrhythmic agents

• Unlabeled uses:

– Atrial Fib • Pharmacologic conversion of AF and maintenance of

NSR

• Heart rate control of AF in patients with heart failure or in patients with hypertrophic cardiomyopathy

• Prevention of postoperative AF associated with cardiac surgery

– Supraventricular tachycardia (not initial drug of choice)

• More unlabeled uses

– Ventricular tachyarrhythmias: • Hemodynamically-stable monomorphic VT

• Polymorphic VT with a normal baseline QT interval

– Wide-complex tachycardia of uncertain origin

– WPW in pre-excited atrial arrhythmias (oral only?)

– Adjunct to ICD therapy to suppress symptomatic ventricular tachyarrhythmias

• Oral Dosing (varies with arrhythmia)

– 800 - 1600 mg qd for 1-3 weeks

– Then 600 - 800 mg qd for 4 weeks

– Maintenance = 100 - 400 mg qd

– 200 mg/day recommended maintenance to ↓ SE


Amiodarone Side Effects

– Bradycardia

– AV block

– Proarrhythmia

– Hypotension (IV form)

– Pulmonary fibrosis

– Thyroid dysfunction (hypo & hyper)

– Liver dysfunction

– Corneal microdeposits

– Photosensitivity

– Blue skin tone

– Tremor, poor coordination

– GI upset

• Unusual Features – Onset of action: oral- 2 days to 3 weeks; IV- may

be more rapid

– Peak effect: 1 week to 5 months

– Duration after discontinuing therapy: 7-50 days

– Half-life: 26-107 days (average = 53 days)

• Recommended Baseline Tests for Elective Therapy – Chest X-ray

– Renal, liver, thyroid, pulmonary function tests

• Drug Interactions – Increases protime with coumadin

– Increases dig levels

– Additive effects with class IA drugs, beta blockers, Ca++ blockers

Speed Sinus Rate:

Atropine

Epinephrine

Slow Sinus Rate:

Beta blockers

Ca++ blockers

Digoxin

Antiarrhythmics

Speed AV Conduction:

Atropine

Epinephrine

Slow AV Conduction:

Beta blockers

Ca++ blockers

Adenosine

Digoxin

Vagal Maneuvers

Suppress Atrial Arrhythmias:

Procainamide

Flecainide

Propafenone

Sotalol

Amiodarone

Dronedarone

Ibutilide

Dofetilide

Slow or Block AP:

Procainamide

Flecainide

Amiodarone (oral only)

Propafenone

Sotalol

Suppress Ventricular Rhythms:

Lidocaine

Procainamide

Amiodarone

Sotalol

Magnesium


Drug Therapy for

Dyslipidemias

LDL – “Bad” Cholesterol

• LDL is the major cholesterol-carrying

lipoprotein and so is most atherogenic

– 2/3 of blood cholesterol is carried by LDL

HDL – “Good” Cholesterol

• High HDL is protective against CHD and is

considered “antiatherogenic”

ATP III Classification (mg / dl)

• Total Cholesterol – < 200 = desirable

– 200-239 = borderline high

– > 240 = high

• LDL Cholesterol – < 100 = optimal

– 100-129 = near or above optimal

– 130-159 = borderline high

– 160-189 = high

– > 190 = very high

• HDL Cholesterol

– < 40 = low

– > 60 = high (desirable)

• Triglycerides

– < 150 = normal

– 150-199 = borderline

high

– 200-499 = high

– > 500 = very high


Benefits of Cholesterol Lowering (especially with statins)

• Primary and secondary prevention of CHD • Plaque stabilization

– Statin therapy can reduce the rate of progression of plaque development and stabilize atherosclerotic plaques that are vulnerable to rupture (stabilize fibrous cap)

• Anti-inflammatory effects (inflammation contributes to atherosclerosis and plaque rupture)

– Statins reduce CRP levels within 14 days of therapy (mechanisms not understood)

• Reverse endothelial dysfunction – Statins can attenuate vasoconstriction associated with

endothelial dysfunction, improve coronary vasodilation and myocardial blood flow

• Reduce thrombus formation at site of plaque rupture

• Reduce incidence of ventricular arrhythmias and cardiac death

Non-cardiovascular Benefits

of statins?

• May decrease risk of dementia and slow

progression of dementia

• May preserve renal function in patients with

moderate chronic renal insufficiency and in patients

with normal renal function

• May decrease risk of sepsis and mortality in sepsis

• May decrease risk of venous thromboembolism

• May increase bone formation and reduce the risk of

osteoporotic fractures

• May lower BP and improve outcomes in HF

2013 Cholesterol Guidelines

• Statin therapy consistently reduces ASCVD events in secondary and primary prevention populations, EXCEPT for patients with NYHA class II-IV heart failure or those receiving maintenance hemodialysis.

• No evidence to support titrating cholesterol-lowering drug therapy to achieve target LDL–C or non-HDL-C levels

• Appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit.


Four Major Statin Benefit Groups

1. Presence of clinical ASCVD

– ACS, or a history of ACS, coronary or other arterial

revascularization, stroke, TIA, or peripheral arterial

disease presumed to be of atherosclerotic origin

2. LDL–C >190 mg/dL

3. Diabetics aged 40 to 75 years with LDL– C =

70 -189 mg/dL and without clinical ASCVD

4. No clinical ASCVD or diabetes with LDL–C =

70 -189 mg/dL and estimated 10-year ASCVD

risk >7.5%

Intensity of Therapy

• Moderate-intensity therapy

– Lowering LDL–C by 30% to <50%

• High-intensity statin therapy

– Lowering LDL–C by ≥50%

Not recommending to treat LDL-C to a specific

target level but to lower LDL-C by a percentage

High-intensity Statin Moderate-intensity Statin

Lower-intensity Statin

Daily dose lowers LDL–C on average, by ≥50%

Daily dose lowers LDL–C on average, by 30% to <50%

Daily dose lowers LDL–C on average by <30%

Atorvastatin 40–80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20–40 mg‡ Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg

Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg

Drugs and doses in bold were evaluated in RCTs. Drugs and doses that are approved by the FDA but were not tested in the RCTs reviewed are listed in italics. ‡ Simvastatin 80 mg not recommended due to increased risk of myopathy.


Comparison of Statins

Rosuvastatin

Atorvastatin

Simvastatin

Lovastatin Pravastatin

Fluvastatin

X = Pitavastatin

Side Effects of Statins

• Hepatic dysfunction

– 0.5 to 3.0% occurrence of persistent liver enzyme

elevation (usually within 3 months and dose dependent)

– FDA recommends liver function testing prior to initiation

of statin therapy and to only repeat for clinical indications

• Muscle injury (myalgias, myositis, rhabdomyolysis)

– Uncommon with statins alone

– More common with hypothyroidism, renal failure, and

obstructive liver disease

– Risk lowest with pravastatin and fluvastatin (water soluble)

• Cognitive dysfunction and memory loss – No proof of association but may be more likely with lipophilic

statins (simvastatin, atorvastatin, fluvastatin, lovastatin)

• Cancer

– No convincing evidence that statins increase or

decrease the risk of cancer

• Diabetes

– Small increased risk of developing diabetes

– Risk is slightly greater with intensive statin therapy

than moderate statin therapy

• Other: cataracts, neuropathy, lupus – no proof of

association

Cardiovascular Drugs - UW Canvas

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