THERAPEUTICS OF HYPERTENSION

Management of Normal Blood Pressure

Promote optimal lifestyle habits - Healthy diet, Physical activity

Monitor risk factors

Reassess BP in 1 year

Management of Elevated Blood Pressure

Nonpharmacological management - Weight loss, DASH diet, sodium and potassium balance, physical activity

Reduce alcohol intake

Smoking cessation

Assess secondary drug causes (e.g., decongestants, NSAIDs)

Reassess BP in 3-6 months

Step 1: When to Treat Stage 1 HTN

Initiate 1 antihypertensive + nonpharmacologic in Stage 1 patients with ANY of the following: Clinical ASCVD, ASCVD risk core of > 10%, diabetes, chronic kidney disease

Anytime an antihypertensive is initiated → reassess BP in 1 month to evaluate need for dose titration and/or sequential addition of another antihypertensive agent

Patients without any of the above: initiate nonpharmacologic therapy alone; reassess BP in 3-6 months - consider antihypertensive if BP is still uncontrolled

Step 1: When to Treat Stage 2 HTN?

Initiate 1 antihypertensive + nonpharmacologic for all patients regardless of clinical ASCVD or ASCVD risk score, diabetes, and/or chronic kidney disease

Initiate 2 antihypertensives + nonpharmacologic in those: With average BP > 20/10 mmHg above their BP goal; Two agents should be of different classes – either as separate agents or in a combination pill

Anytime an antihypertensive is initiated → reassess BP in 1 month to evaluate need for dose titration and/or sequential addition of another antihypertensive agent

When to Reassess BP after Starting Therapy

HTN Stage 1: If nonpharmacologic therapy, reassess in 3-6 months. If started on BP-lowering medication, reassess in 1 month

HTN Stage 2: Reassess in 1 month

For both: After the 1 month, if the BP goal is met, reassess in 3-6 months. If not, then assess and optimize therapy; also consider intensification of therapy

< 130/80 mmHg

Goal BP in:

Uncomplicated HTN

Co-morbid diabetes

Co-morbid CKD

HTN in the “older adult” (>65 years?)

First-line agents, in no particular order (comorbidities may influence choice)

Thiazide/thiazide-like diuretics

Calcium channel blockers

ACE-I or ARBs

Later-line agents, in no particular order, or MAY become preferred agents depending on comorbidities

Beta blockers

Mineralocorticoid antagonists

Loop diuretics

Potassium-sparing diuretics

Alpha-1 blockers

Central alpha-2 agonists

Direct vasodilator

Direct renin inhibitor

Hydrochlorothiazide or HCTZ

(Microzide)

12.5-50 mg, daily

Commonly used outpatient

Chlorthalidone

(Thalitone)

12.5-25 mg, Daily

Preferred of thiazide considering prolonged half-life and CVD reduction

Metolazone

(Zaroxolyn)

Thiazide-like Diuretic

2.5-5 mg, frequency varies

More seen inpatient for volume overload due to increased diuretic potency; if used outpatient, more commonly given QOD

Indapamide

(Lozol)

1.25 - 5 mg daily

More commonly used in elderly patients

Thiazide and Thiazide-like Diuretics Precautions

Sulfa allergy

History of acute gout

Systemic lupus erythematosus

Thiazide and Thiazide-like Diuretics ADEs

dose related

Increasing HCTZ to 50 mg has minimal benefits in comparison to increased ADE risk

Photosensitivity

Dizziness or lightheadedness

Electrolyte disturbances - Decreased Na, K, Mg, increased calcium

Other disturbances - increased uric acid; increased glucose and lipids (not clinically relevant)

Thiazide and Thiazide-like Diuretics Monitoring

Blood pressure

Basic metabolic panel - electrolytes, SCr, BUN obtained after 1-2 weeks

Uric Acid

Thiazide and Thiazide-like Diuretics Drug Interactions

NSAIDs - decrease antihypertensive effects

Lithium - Increases risk of lithium toxicity due to reduced clearance

Dofetilide - Increased risk of QT prolongation due to increased dofetilide concentrations

Thiazide and Thiazide-like Diuretics Pearls

Better BP lowering efficacy in black patients compared to ACEi/ARB

Ineffective when CrCl <30 mL/min (except metolazone)

Mild diuretic – take in the morning

If taken with loop diuretics, give thiazide 30 minutes before loop

Calcium Channel Blockers - Dihydropyridines

Amlodipine (Norvasc)

Felodipine ER (Plendil)

Nifedipine ER (Procardia XL)

Amlodipine

Norvasc

2.5-10 mg daily

Commonly used; in various combo products

Felodipine ER

(Plendil)

2.5-10 mg daily

Nifedipine ER

(Procardia XL)

30-90 mg daily

Medication option in pregnancy

Calcium Channel Blockers - Non-dihydropyridines

Diltiazem ER (Cardizem LA/CD)

Verapamil ER (Calan SR)

Diltiazem ER

(Cardizem LA/CD)

Daily dose 120-360 mg daily

More commonly used with co-morbid indications (i.e., atrial fibrillation, angina)

Verapamil ER

(Calan SR)

120-480 mg daily-BID

More commonly used with co-morbid indications (i.e., atrial fibrillation, angina)

Dihydropyridines CCBS ADEs

Peripheral edema - dose related, women > men

Dizziness

Reflex tachycardia

Headaches

Flushing

Nausea

Gingival hyperplasia

Dihydropyridines CCBs Monitoring

Blood pressure

Heart rate

Dihydropyridines CCBs Drug Interactions

Major substrates of CYP3A4 – check for strong inhibitors or inducers

Minor inhibitor of CYP3A4 – ex. why simvastatin has a 20 mg dose limit

Felodipine: 2x increases in peak concentration with meal high in fat or carbohydrates

Non-dihydropyridines CCBs Contraindications/Warnings

HF w/reduced ejection fraction (HFrEF)

2nd or 3rd degree heart block

Hepatic impairment

Non-dihydropyridines CCBs ADEs

Bradycardia

1st degree heart block

Dizziness

Headache

Constipation (verapamil > diltiazem)

Gingival hyperplasia

Non-dihydropyridines CCBs Drug Interactions

Monitor Blood Pressure and Heart Rate

Drugs with additive HR-reducing effects

Major substrates of CYP3A4 – check for other strong inhibitors or inducers

Moderate inhibitors of CYP3A4 – ex. why simvastatin has a 10 mg limit

Substrate of P-gp

Inhibitor of P-pg (verapamil only) - Significantly increases levels of dofetilide, colchicine, digoxin and cyclosporine

Calcium Channel Blockers Pearls

Better BP lowering efficacy in black patients compared to ACEi/ARB

Non-dihydropyridines specifically: Avoid use in HFrEF, Typically reserved for those with certain co-morbid conditions (i.e., atrial fibrillation, angina)

ACE-Inhibitors

Lisinopril (Zestril, Prinivil)

Benazepril (Lotensin)

Quinapril (Accupril)

Enalapril (Vasotec)

Ramipril (Altace)

Captopril (Capoten)

Lisinopril

(Zestril, Prinivil)

2.5-40 mg Daily

Most commonly used outpatient

Benazepril

(Lotensin)

5-40 mg daily

Quinapril

(Accupril)

5-40 mg daily

Enalapril

(Vasotec)

5-40 mg Daily-BID

Ramipril

(Altace)

2.5-20 mg daily

Captopril

(Capoten)

12.5-100 mg BID

Shortest half-life

ACE-Inhibitors Contraindications

Pregnancy - teratogenic

History of angioedema from ACEi

Bilateral renal artery stenosis

ACEi ADEs

Angioedema (increased risk in blacks)

Dry cough (increased risk in blacks)

Dizziness

Hyperkalemia (increased risk in CKD)

Acute kidney injury (rare)

ACE-Inhibitors Drug interactions

Monitor BP and basic metabolic panel - obtain after 1-2 weeks

K+ salts, K+ supplements, K+-sparing drugs - increased hyperkalemia risk

Entresto (sacubitril/valsartan) – separate by 36 hours due to increased angioedema risk

NSAIDS – decrease antihypertensive effects

Lithium - increased lithium toxicity due to reduced clearance

Do not use multiple RAAS inhibitors (ACEi, ARB, aliskiren) - increased ADE Risk

ACE-Inhibitors Pearls

Lower response rates in black patients (often low renin-producers)

Lacking evidence of superiority of any particular ACEi – select based on cost/frequency

Mild diuretic – take in the morning, Often held when patients are inpatient due to increased risk of acute kidney injuries

Have reno-protective and cardio-protective benefits in addition to BP-lowering

ARBs

Losartan (Cozaar)

Valsartan (Diovan)

Candesartan (Atacand)

Irbesartan (Avapro)

Olmesartan (Benicar)

Telmisartan (Micardia)

Losartan

(Cozaar)

25-100 mg daily

Most commonly used outpatient

Studies in various co-morbidities

Valsartan

(Diovan)

80-320 mg daily

Also a component in Enteresto (heart failure combination product)

Candesartan

(Atacand)

8-32 mg daily

Irbesartan

(Avapro)

75-300 mg daily

Olmesartan

(Benicar)

10-40 mg daily

Unique ADE of sprue-like enteropathy (severe/chronic diarrhea)

Telmisartan

(Micardia)

40-80 mg daily

ARBs Contraindications

Pregnancy - teratogenic

History of angioedema from ARB (rare) - Those with angioedema from an ACEi can receive an ARB (cautiously) after 6 weeks

Bilateral renal artery stenosis

ARBs ADEs

Angioedema and dry cough (much less)

Dizziness

Hyperkalemia (increased risk in CKD)

Acute kidney injury (rare)

ARBs Drug Interactions

Monitor BP; basic metabolic panel (after 1-2 weeks)

K+ salts, K+ supplements, K+-sparing drugs - increased hyperkalemia risk

NSAIDS – decrease antihypertensive effects

Lithium - increased lithium toxicity due to reduced clearance

Do not use multiple RAAS inhibitors (ACEi, ARB, aliskiren) - increased ADE Risk

NO wash-out period needed with Entresto

ARBs Pearls

same as ACE-i class, (including the reno-protective and cardio-protective benefits in addition to BP-lowering), PLUS:

Often the substitute given following an ACEi-induced cough

Less widely investigated than ACEi – may choose certain ARBs (e.g., losartan, valsartan) with certain comorbidities

Chronic kidney disease Comorbidity

Stage 1 or 2 WITH severe albuminuria (> 300 mg/g ACR): ACEi (or ARB)

Stage > 3 (regardless of albuminuria): ACEi (or ARB)

BP lowering + reno-protective (decreased intraglomerular pressure = decreased further kidney injury)

Remember… CKD patients are higher risk for hyperkalemia, and you can expect a transient increase in Scr when first starting

Other considerations: Most thiazides have reduced efficacy when CrCl < 30 mL/min

Diabetes Co-morbidity

WITH moderate albuminuria (> 30 mg/g ACR): ACEi (or ARB)

BP lowering + reno-protective (decreased intraglomerular pressure = decreased further kidney injury)

Other considerations: All other first-line agents are effective

Increase glucose potential of thiazide is often not clinically relevant

Secondary stroke prevention Co-morbidity

ACEi (or ARB) and/or thiazides (listed in NO particular order)

BP lowering + reduced risk of recurrent stroke

Other considerations: All other first-line agents are effective

Ischemic heart disease (e.g., CAD) Co-morbidity

Beta blocker AND ACEi (or ARB) (listed in NO particular order +/- CCB (lower level of evidence) if BP still not at goal despite the above

ACEi/ARBs – reduce CV events and death

Beta blockers – prevent angina, CV events and death; however, avoid those with intrinsic sympathomimetic activity

+/- CCBs – prevent angina when added to beta blockers

Heart failure Co-morbidity

Beta blocker AND ACEi (or ARB or Entresto) AND mineralocorticoid receptor antagonist (listed in NO particular order) +/- loop diuretic when patient has s/sx of fluid retention

Beta Blockers - Cardio-selective agents (β1 blocker only)

Metoprolol tartrate (Lopressor)

Metoprolol succinate (Toprol XL)

Bisoprolol (Zebeta)

Atenolol (Tenormin)

Metoprolol tartrate

Lopressor

50-200 mg BID

Metoprolol succinate

(Toprol XL)

25-200 mg daily

Evidence based option in HFrEF

Bisoprolol

(Zebeta)

2.5-10 mg daily

Evidence based option in HFrEF

Atenolol

Tenormin

25-100 mg daily - BID

Non-selective agents (β1 & β2 blockers)

Carvedilol (Coreg)

Propranolol (Inderal)

Labetolol (Trandate)

Carvedilol

(Coreg)

12.5 mg-50 mg BID

Evidence based option in HFrEF

α1 blockade: increased BP lowering

Propranolol

(Inderal)

80-160 mg Daily-QID

Most lipophilic: Increased CNS effects

Labetolol

(Trandate)

200-800 mg BID

α1 blockade: increased BP lowering

Medication option in pregnancy

Beta Blockers Contraindications/Warnings

Severe bradycardia

2nd or 3rd degree heart block

Cardiogenic shock

Warning for: Bronchospastic diseases, Decompensated (acute) heart failure

Beta Blockers ADEs

Dizziness

Bradycardia

Exercise intolerance

CNS: depression, fatigue, sexual dysfunction

Beta Blockers Drug interactions

Monitor BP and HR'

Drugs with additive HR-reducing effects

Clonidine – withdraw beta-blockers before stopping clonidine to prevent unopposed α1 agonism

Take metoprolol with food to increase absorption

Take carvedilol with food to decrease risk of orthostatic hypotension

Beta Blockers pearls

Not a first-line HTN agent, but SHOULD be a PREFFERED choice in either co-morbid:

Ischemic heart disease or Heart Failure

Rebound hypertension can occur if abruptly stopped - gradually reduce dose over several weeks

Can mask hypoglycemia symptoms (except sweating

Mineralocorticoid Antagonists

Spironolactone (Aldactone)

Eplerenone (Inspra)

Spironolactone

(Aldactone)

25-100 mg daily

Nonselective: aldosterone + sex-hormone antagonism

Eplerenone

(Inspra)

50-100 mg daily-BID

Selective to aldosterone antagonism

Mineralocorticoid Antagonists Contraindications

Hyperkalemia

Severe renal insufficiency

Mineralocorticoid Antagonists ADEs

Hyperkalemia, Renal insufficiency

Spironolactone > eplerenone: Gynecomastia, breast tenderness, impotence, irregular menses

Mineralocorticoid Antagonists Drug Interactions

Monitor BP; basic metabolic panel (within 1 week)

K+ salts, K+ supplements, K+-sparing drugs – increased hyperkalemia risk

NSAIDS – decreased antihypertensive effects

Lithium - Increased lithium toxicity risk due to reduced clearance

Eplerenone only = major substrate of CYP3A4 – check for other strong inhibitors or inducers

Mineralocorticoid Antagonists Pearls

Not a first-line HTN agent, but SHOULD be a PREFFERED choice in in co-morbid: Heart Failure

Also a preferred ADD-ON agent in resistant hypertension - Potent BP-lowering if hypertension is secondary to hyperaldosteronism

Mild diuretic – take in the morning

Management of Resistant Hypertension

Last-line pharmacological therapies

Mineralocorticoid antagonists – Decrease BP by up to 25/12 mmHg in this setting

Other options: Beta-blockers (if not already using) or central alpha-2 agonists – both target sympathetic drive

Direct vasodilators – side effects require concomitant use of HR-reducing agent and a diuretic

Infrequently used: alpha-1 blockers, direct renin inhibitor

Refer to a hypertension specialist in BP remains uncontrolled after 6 months

Last-Line Pharmacologic Therapies - Central alpha-2 agonists

Clonidine (Catapres)

Methyldopa (Aldomet)

Clonidine

(Catapres)

0.2-2.4 mg daily-BID

Caution in elderly; avoid abrupt discontinuation

ADE (reduced with patch): dizziness, bradycardia, CNS effects, and anticholinergic effects

Methyldopa

(Aldomet)

250-3000 mg BID-TID

Medication option in pregnancy

Last-Line Pharmacologic Therapies - Direct Vasodilators

Hydralazine (Apresoline)

Minoxidil (Loniten)

Hydralazine

(Apresoline)

25-300 mg

BID-QID

Contraindicated in CAD

ADE: reflex tachycardia, fluid retention, lupus-like reaction (> 200 mg/day)

Minoxidil

(Loniten)

5-100 mg Daily

Caution in renal insufficiency

ADE: reflex tachycardia, fluid retention, hypertrichosis, ECG changes, pericardial effusions

Last-Line Pharmacologic Therapies - Alpha-1 blockers

Doxazosin (Cardura)

Terazosin (Hytrin)

Doxazosin

(Cardura)

1-16 mg daily

Consider in comorbid benign prostatic hyperplasia (BPH), but NOT appropriate as monotherapy for HTN

ADE: orthostatic hypotension (first-dose syncope)

Terazosin

(Hytrin)

1-20 mg Daily- BID

Same comments and side effects as Doxazosin

Last-Line Pharmacologic Therapies - Aliskiren

(Tekturna), Direct renin inhibitor

150-300 mg daily

Rarely used

Contraindicated in Pregnancy

Do NOT use with other RAAS inhibitors (similar ADE - hyperkalemia, cough, acute kidney injury)