Cardiovascular Pharmacology

Epidemiology of HTN

• Differs by Age

  • Men are more likely ages < 55

  • Equal from 55 to 64

  • Women are  more likely ages > 64

• Differs by race

  • Blacks > White > Hispanic

Factors that can cause HTN

• Modifiable

  • High sodium intake

  • Low K/Mg/Ca intake

  • Low quality diet

  • Alcohol

  • Obesity

  • Low physical activity

  • Poor sleep

  • Stress

• Fixed

  • CKD

  • FH

  • Age

  • Air pollution

  • Genetics

  • Social determinants of health

MOA of Thiazide Diuretics

• Inhibits sodium and chloride reabsorption back into the body

• Distal convoluted tubule

• Na, water, K, H+ excretion in the urine

• Initially: Decrease in stroke volume and cardiac output

• Chronic: Decrease TPR

CI, SE, and Monitoring of Thiazide Diuretics

• CI

  • Hypersensitivity to drug of sulfonamide

• SE

  • Hypokalemia, hyponatremia, hypomagnesia, hypercalcemia

  • Hyperuricemia

• Monitoring

  • Electrolytes

  • Renal function

Clinical Pearls of Thiazide Diuretics

• Dose in the morning

• Not effective if CrCl is < 30 mL/min

  • Except chlorthalidone < 20 mL/min

MOA of Loop Diuretic

• Inhibit sodium and chloride reabsorption

• Ascending loop of Henle

• Initial: Decreased stroke volume and cardiac output

• Chronic: Decreased TPR

CI, SE, Monitoring of Loop Diuretics

• CI

  • Hypersensitivity or sulfur

• SE

  • Hypokalemia

• Monitor

  • Electrolytes (K, Mg)

  • Renal function (SCr, BUN)

Clinical Pearls of Loop Diuretics

• Dose in morning

• Less effective than thiazide

• Ototoxicity at high doses

• Consider K supplement when neccessary

• Preferred when CrCl is < 30 mL/min

Thiazide/Loop and Sulfa Allergy

• Cross reactivity is low, unlikely reactions

• Ethacrynic acid is the drug of choice

MOA of Potassium Sparing Diuretics

• Interferes with sodium/potassium active transport exchange

• Distal tubule and collecting duct

• Does not produce hypokalemia

CI, SE, and Monitoring of Potassium Sparing Diuretics

• CI

  • K > 5.5 mEq/L

  • CrCl < 45 mL/min

• SI

  • Hyperkalemia (especially when combined with ACEi/ARB, K supplements, NSAIDs

• Monitoring

  • Electrolytes (Hyperkalemia)

  • Renal function (BUN, SCr)

Clinical Pearls of Potassium Sparing Diuretics

• Dose in morning

• Weak antihypertensive (not meant for monotherapy)

MOA of ACEi

• Inhibits ACE conversion in ATII

  • ATII is a potent vasocontrictor

  • Causes release of aldosterone

CI, SE, and Monitoring of ACEi

• CI

  • History of Angioedema

  • Bilateral renal artery stenosis

  • Pregnancy

• SE

  • Hyperkalemia

  • Dry cough

  • Angioedema

• Monitoring

  • Drug Interactions

    • K+ Sparing diuretics, K+ supplements,

  • Renal function (BUN, SCr)

Clinical Pearls of ACEi

• Most common first line

• Decreased morbidity and mortality

• SCr may increase upon start and can continue unless it raises above 30%

• DO NOT use in combo with an ARB

• Reduces incidence of peripheral edema in CCB use

MOA of ARBs

• Inhibits the AGII receptor from binding to angiotensin

  • Selective for AG1

  • AG2 is involved in vasodilation

CI, SE, and Monitoring for ARB

• CI

  • Pregnancy

  • Bilateral renal artery stenosis

  • Angioedema with an ARB

• SE

  • Hyperkalemia

• Monitoring

  • Renal Function, hepatic function, and electrolytes

Clinical Pearls of ARBs

• Never use in combo with ACEi or direct Renin

• SCr increase

• Better tolerated than ACEs

• ACEi may be better post MI or HFrEF

• Losartan is cheapest but not the best

  • Consider olmesartan, olmesartan, irbesartan

MOA of Direct Renin Inhibitor

• Inhibits the conversation of angiotensinogen to angiotensin 1

MOA of CCB

• Inhibits the influx of calcium in heart cells

  • Dihydropyridines: Peripheral vasodilation, no effect on heart

  • Non-dihydropyridines: Reduce HR, slow AV node conduction, and peripheral vasodilation

CI, SE, and Monitoring of CCbs

• CI

  • Afib, aortic stenosis

• SE

  • Dizziness, flushing, peripheral edema (cant be fixed by diuretics)

  • Bradycardia, AV block

• Monitoring

  • HR, angina, peripheral edema

Clinical Pearls of CCB

• DHPs

  • Great for elderly, Raynaud’s

• Non-DHPs

  • Decreased contractility and HR

  • Avoid in HF

MOA of Beta Blockers

• Decreased Renin secretion in the kidney

• Blocks the beta 1 receptors in the heart

• Causes decreased blood pressure by reducing heart rate

CI, SE, and Monitoring of Beta Blockers

• CI

  • ISA in post Mi

• SE

  • Fatigue, dizziness, bradycardia

• Monitoring

  • Can mask hypoglycemia in DM patients

  • HR, renal function

Clinical Pearls of BB

• Hypoglycemia can be masked

• Look for sweating

• Less effective for blood pressure control and preventing events

• Use beta 1 selective in patient with COPD/Asthma

MOA of A1 blockers

• Inhibits norepinephrine uptake at alpha 1 receptors in peripheral smooth muscle cells

• Results in vasodilation and BP lowering

CI, SE, and Monitoring of A1

• SE

  • Orthostatic hypotension

  • Priapism

  • Syncope, dizziness, fainting

Clinical Pearls of A1

• Not recommended as first line therapy

MOA of central A2

• Stimulates alpha 2 receptors in the brain

• Reduced sympathetic outflow

CI, SE, and Monitoring of A2

• SE

  • Anti-cholinergic effects

  • Rebound hypertension

  • Orthostatic hypotension

Clinical Pearls of A2

• Methyldopa can be used in pregnancy

• No abrupt D/C

• Must be adherent

MOA of Direct Arterial Vasodilators

• Directly relaxes muscles in arterioles

  • peripheral vasodilation

CI, SE, and Monitoring of Direction Arterial Vasodilators

• They exist, use last line

Primary HTN

• HTN without a specific cause

• No cure, but can be controlled

• Largest cause

Secondary HTN

• Known cause for HTN, usually a disease

• Main cause in children

Classification of HTN

• Elevated: 120-129 / <80

• Stage 1: 130-139 / 80-90

• Stage 2: 140+ / 90 +

Resisstent HTN

• Taking 4 or more meds

• Taking 3 optimized meds and still not at goal

Workflow for treating HTN

• Normal: Lifestyle modification, reassess in 1 year

• Elevated: Lifestyle modifications, reassess in 3-6 months

• Stage 2 HTN: Lifestyle + Drugs

• Stage 1 HTN: Lifestyle

  • If ASCVD risk is greater than 7.5% = drugs

  • If ASCVD risk is less than 7.5% = reassess in 3-6 months

  • If still at stage 1 after reassessment = drugs

Overall goal of treatment for HTN

• Reduce morbidity and morality from CV events

• Goal < 130/80

• If possible < 120/80

Nonpharmacologic Interventions for HTN

• Weight loss

• Healthy diet

• Reduced intake of dietary sodium

• Enhanced intake of dietary potassium

• Physical activity

• Moderation in alcohol intake

Choosing Drug Therapy for HTN

• Stage 2 HTN, combo therapy

  • Thiazides, DHP-CCBs, ACEi/ARBs

  • Lower doses, titrate up

• CKD

  • ACEi or ARB

• Use combo pills when possible, once daily

• Can change HCTZ to chlorthalidone

• Add spironolactone as a 4th line agent

• Alpha and beta blockers as a last line

Resistant Hypertension Treatment

• ACEi or ARB + DHP-CCB + Thiazide like diuretic

• Ensure BP meds are actually being taken and home BP is being checked

• Can change HCTZ to chlorthalidone

• Add spironolactone as a 4th line agent

• Alpha and beta blockers as a last line

Isolated Systolic HTN Treatment

• Diuretics + DPH-CCB

Treating HTN in pregnancy

• Methyldopa

• Labetalol

• Nifedipine XL

• Hydralazine

Blood Pressure Formula

BP (MAP) = CO x Total Peripheral Resistance

Cardiac Output Formula

CO = Stroke Volume x HR

Ascertaining Cardiac Output

• Normal CO is between 4-8 L/min

• Cardiac Index (CI) is CO adjusted for BSA

Systole and Diastole

• Systole: Pumping or squeezing of the heart

• Diastole: Heart relaxing and filling

Left Ventricular Ejection Fraction:

• Proportion of blood ejected from left ventricle with each contraction

• EJ = Stroke volume / End Diastolic Volume

Preload Vs Afterload

• Preload: Volume of blood in the ventricles at the end of diastole (volume overloaded)

• Afterload: The resistance that the left ventricle must overcome in order to circulate blood

Heart Failure Definition

• Progressive syndrome that can result from any abnormality in cardiac structure or function that impairs the ability of the ventricle to fill or eject blood.

Risk Factors of HF

• CAD

• DM

• HTN

• Obesity

• Cardiomyopathy

• Valvular heart disease

• Lifestyle (tobacco, alcohol, sodium intake)

Heart Dysfunction

• Systolic Dysfunction: Typically seen in lower or reduced ejection fraction

• Diastolic Dysfunction: Typically seen in preserved ejection fraction

Classification of Ejection Fraction

• Normal: LVEF 50-70%

• HFrEF: LVEF <= 40%

• HFimpEF: Previous LVEF <= 40%, and follow up >40%

• HFmrEF: LVEF 40-49%

• HFpEF: LVEF >= 50%

HF Etiologies

• HFrEF

  • CAD

  • Dilated cardiomyopathy

  • Aortic/pulmonary valvular stenosis

  • Regurgitation

• HFpEF

  • Ventricular hypertrophy

  • MI

  • Mitral valve stenosis/regurgitation

Drugs that can exacerbate HF

• Negative Inotropes

  • Amiodarone

  • Non-DHP CCBs

  • BB (cannot use in decompensated HF)

• Directly Cardiotoxic Agents

  • Antineoplastics

  • Alcohol

  • Stimulants

• Increased Sodium/water Retention

  • NSAIDs

  • Glucocorticoids

  • Androgens and estrogens

  • Sodium containing medication

• Other

  • DPPE-4

  • TNF-Alpha inhibitors

Decreased Cardiac Output

Nervous System

• Increased SNS activity

• Increased release of NE

• Increased HR/contractility

Kidney

• Decreased renal perfusion

• Renin release

• Sodium/water retention (increased preload)

Extremities

• Increased vasoconstriction

• Increased blood pressure

Cardinal Symptoms of HF

• Dyspnea

• Fatigue

• Exercise intolerance

• Fluid retention

Mostly caused by the compensatory mechanisms.

Left Vs Right Sided Heart Failure

Right Sided:

• Systemic congestion

• Peripheral edema

• Abdominal pain

• Ascites

• JVD

Left Sided:

• Pulmonary Edema

• Rales

• Dyspnea / Orthopnea

Congestion Vs Low Cardiac Output

Volume Overload

• Weight gain

• JVD, Orthopnea

• Rales, dyspnea, tachypnea

• Peripheral Edema

Low CO

• Fatigue

• Exercise intolerance

• Tachycardia, hypotension

• Low urine output

• Cool extremities, cyanosis

Lab Testing for HF

• B-type Natriuretic Peptide (BNP)

  • Increased GFR

  • Natriuresis

  • Diuresis

  • Vasodilation

• N-terminus-proBNP (NT-proBNP)

  • Precursor of BNP

This tells us that the heart is struggling

Degraded by Neprilysin

Other lab testing for HF

• Troponin T

  • Indicated heart injury

• BMP + Mg

• CBC

• Iron count

• Thyroid function

• Liver panel

• A1C

• Drug screen

• Genetic evaluation

Diagnostic Procedure and Imaging for HF

• EKG

• Echo

• Cardiovascular Magnetic Resonance (CMR)

• Chest X-Ray

Two main classifications types of HF

• ACC/AHA Stages (cannot go back)

  • Stage A is high risk of heart failure

  • Stage B is structural heart disease with no symptoms

  • Stage C is structural heart disease with current or past symptoms

  • Stage D is Refractory HF that required specialized interventions

• NYHA Functional Classification (can go back)

  • 1-4

  • Stage 3 is symptoms with less than ordinary activity

  • Stage 4 is inability to carry any physical activity without symptoms

Nonpharmacological Therapy of HF

• Life essential 8

• Sodium restriction

  • Less than 2-3 gram per day

• Fluid restriction

  • 1.5-2L per day

  • Devices in select patient

Dry weight in HG

• Weight in the morning after restroom

• Contact a physician if gain more than 2-3 pounds in 24 hours

• Or if more than 5 pounds gain in a week

Treatment for Stage A and B HF

Stage A

• Lifestyle

• Treating comorbidities

Stage B

• ACEi or ARB plus BB

• Guideline directed therapy if LVEF is <30

Pharmacotherapy of Stage C HFrEF

• ACEi

• ARBs

• ARNI

• BB

• MRAs

• SGLT2

• Bidil (hydralazine + isosorbide mono)

• Ivabradine

• Digoxin

• Verciguat

• Loop and Thiazide diuretics

General principles of management of HFrEF

• Four pillars of therapy

• Optimize therapy

• Manage volume

• Consider adjunctive therapy once optimization has been reached

Guideline Directed Medical Therapy (GDMT)

1. ACE or ARB or ARNI

2. Evidence based BB

3. MRA

4. SGLT2

5. Loop diuretics as needed for volume control

Dose of ACEi used in HFrEF

• Enalapril (Vasotec)

  • Starting Dose: 2.5 mg PO BID

  • Target Dose: 10-20 mg PO BID

• Lisinopril (Zestril)

  • Starting Dose: 2.5-5 mg PO QD

  • Target Dose: 20-40 mg PO QD

• Class effect of drugs

Dose of ARB used in HFrEF

• Valsartan (Diovan)

  • Starting Dose: 40 mg PO BID

  • Target Dose: 160 mg PO BID

Dose of ARNI used in HFrEF

Sacubitril/Valsartan (Entresto)

• Target Dose: 97 mg / 103 mg PO BID

  • Starting dose depends on dose of ACEi or ARB

Doses of BB used in HRrEF

• Metoprolol Succinate (Toprol XL)

  • Starting Dose: 12.5 to 25 mg PO QD

  • Target Dose: 200 mg PO QD

• Bisoprolol (Zebeta)

• Carvedilol (Coreg and Coreg CR)

Doses of MRA in HFrEF

• Spironolactone (Aldactone)

  • Starting Dose: 12.5 to 25 mg PO QD

  • Target Dose: 25 to 50 mg PO QD

• Eplerenone

DO not start if

• SCr is 2.5 in males or 2.0 in females

• EGFR < 30 mL/min per 1.73m²

• K > 5.0 mEq/L

Doses in SGLT2 Inhibitors for HFrEF

Doses not needed to be memorized

• Dapaglifloxin (Farxiga)

• Empagliflozin (Jardiance)

Hydralazine + Isosorbide Dinitrate in HFrEF

• Hydralazine is direct arterial vasodilator

• Isosorbide Mononitrate is direct venous vasodilator

• Contraindicated in use with PDE-5 and Verciguat

• Can be used in African American patients

• Alternative if patients cannot tolerate ACEi, ARB, or ARNI

• Reduces hospitalizations, morbidity, and mortality

Ivabradine in HFrEF

• Added after optimal GDMT

  • LVEF <= 35%

  • Normal Sinus Rhythm

  • HR >= 70 BPM while on maximally tolerated BB

• MOA: Inhibits the funny current in the SA node

  • Decreases HR without decreasing BP

• Reduces hospitalization, no effect on mortality

Digoxin in HFrEF

• MOA: Interferes is Na-K ATPase to decrease HR and increase inotropy

• Add on to GDMT to improve symptomes

• Decrease hospitalizations, no impact on mortality

• Avoid in Vfib

Verciguat in HFrEF

• MOA: Soluble guanylate cyclase stimulator leads to vasodilation

• Can be considered to reduce HF hospitalizations in patient that already are on GDMT or recent or worsening HF

• No effect on mortality

Loop Diuretics in HFrEF

• Bumetanide (Bumex)

• Furosemide (Lasix)

• Torsemide (Demadex)

• Ethacrynic Acid (Edecrin)

• IV Conversion for Dosing

  • Furosemide 40 mg PO

  • Furosemide 20 mg IV

  • Torsemide 20 mg PO

  • Bumetanide 1 mg PO

Thiazide Diuretics in HFrEF

• Metolazone

• Chlorothizide

• Not usually used in heart failure

  • When used in combo with loops, they are taken 30-60 mins before loops

Pharmacotherapy in Stage D HFrEF

• Continuous IV inotropes

• Preparation for transplant

Pharmacotherapy in HFpEF

• Loops

• SGLT2 (1st line)

• MRAs (2nd line)

• ARBs (2nd line)

• ARNI (2nd line)

• ACEi

• BB

Pharmacotherapy in HFmrEF

• Diuretics (as needed)

• SGLT2 (1st line other wise)

• ACEi

• ARB

• ARNI

• MRA

• BB

Recently approved non-steroid MRA for HF

Finerenone (Kerendia)

Pharmacological Agents used for Dyslipidemia

• HMG-CoA Reductase Inhibitors (Statins)

• Cholesterol Absorption Inhibitors

• PCSK9 Inhibitors (mAB)

• Small interfering RNA (sRNA)

• ATP-Citrate Lyase (ACL) Inhibitor

• Bile Acid Sequestrants

• Fibrates

• Omega-3 Fatty Acids

• Nicotinic Acids (Niacin)

Statins for Dyslipidemia

• Indicated for hypercholesterolemia and hypertriglyceridemia

  • Lowers LDL by 18-55%

  • Lowers TG by 7-30%

• Generally dosed once daily, taken at night

• East Asian populations

  • Start with dosing Rosuvastatin at 5mg daily

• Renal dosing cut offs for lower renal function

Statin Intensities

• Moderate Intensity (Lowers LDL by 30-49%)

  • Atorvastatin 10-20 mg

  • Rosuvastatin 5-10 mg

  • simvastatin 20-40 mg

  • pravastatin 40-80 mg

  • lovastatin 40-80 mg

  • fluvastatin 80 mg

  • pitavastatin 1-4 mg

• High Intensity (Lowers LDL by >= 50%)

  • Atorvastatin 40-80 mg

  • Rosuvastatin 20-40 mg

Important PK Parameters of Statins

• DO NOT use simvastatin 80 mg

• Hydrophilic Statin (RP)

  • Rosuvastatin

  • Pravastatin

• Statins that can be taken at any time of day (RAP)

  • Rosuvastatin

  • Atorvastatin

  • Pitavastatin

• Statins that are CYP3A4 metabolized (ASL)

  • Atorvastatin

  • Simvastatin

  • Lovastatin

Safety Considerations for Statins

• CI

  • Acute liver disease

  • Persistent increase in tranaminases

• Side Effects

  • Statin Associated Muscle Symptoms (SAMS)

  • New onset of T2DM

• Pregnancy

  • Avoid in both pregnancy and lactation

Drug-Drug Interactions with Statins

• All Statins

  • Gemfibrozil

  • Nicotinic acid

  • Cyclosporine (Simvastatin and lovastatin)

• Select CYP3A4 Inhibitors

  • Azole anti-fungal

  • Macrolide antibiotics

  • Protease inhibitors

  • Diltiazem, verapamil, amiodarone

• Simvastatin Dose Limits

  • 20 mg daily with Amiodarone

  • 10 mg daily with diltiazem, verapamil

Monitoring Parameters of Statins

• Fasting Lipid Panel (Efficacy)

  • Baseline

  • 4-12 weeks after initiation or adjustments

  • 3-12 months thereafter

• Liver enzymes (Safety)

• Creatine Phosphokinase (CPK) (Safety)

Statin Associated Muscle Symptoms (SAMS)

• Myalgia

• Myopathy

• Rhabdomyolysis

Managing SAMS

• Assess for factors that are causing symptoms

• D/C statin

• Rechallenge with hydrophilic statin (rosuvastatin and pravastatin)

• Reduce dose or frequency

• Some potential benefit from Coenzyme Q10?

Ezetimibe (Zetia) in Dyslipidemia

• Indicated for primary and secondary ASCVD, primary hyperlipidemia

  • Lowers LDL by 13-20%

• Dosed at 10 mg QD

Safety Considerations for ezetimibe

• CI

  • Hypersensitivity

• Warnings

  • Liver impairment

  • Renal impairment

• Side Effects

  • Diarrhea

  • Elevated transaminases

• Pregnancy

  • Not well studied

• DDI

  • Monitor when taking with fibrates or cyclosporin

PCSK9 Inhibitors in Dyslipidemia

• Alirocumab (Praluent)

• Evolocumab (Repatha)

• MOA: Monoclonal antibody that binds to proprotein convertase subtilisin kexin 9 to reduce LDL receptor degradation

  • Increases availability for the body to clear LDL from the blood

• Indicated for add-on therapy for primary or secondary treatment

  • LDL lowering by 43-64%

  • Given SubQ

  • Cost is a barrier

• BUD of 30 days when left at RT

• Refrigerate and protect from light

Safety Considerations in PCSK9i

• CI

  • Hypersensitivity

• Warnings and precaution

  • Latex allergy (pen cap)

• Adverse Reaction

  • Injection site reactions

  • Cold and flu like symptoms

• Pregnancy

  • No available data

Inclisiran (Leqvio) in Dyslipidemia

• MOA: Small interfering RNA that binds and degrades mRNA for PCSK9

  • Allows for more LDL to be taken from the bloodstream by preventing degradation of LDL receptors

• Add on therapy for primary and secondary prevention

  • DO NOT use with a PCSK9i

  • LDL lowering by 53%

  • Must be administered by a healthcare professional, SubQ