hypertension
HYPERTENSION
Hypertension is the medical term for high blood pressure. Persistent high blood pressure can lead to increased strain to the heart and arteries that can eventually cause organ damage.
To classify the blood pressure, it must be based on ≥2 properly measured, seated blood pressure readings on each of ≥2 office visits.
Patients who have a blood pressure reading of 140 SBP or 90 DBP or both can be diagnosed as hypertensive patients.
Goals of therapy are to manage hypertension that can maintain the patient's normal blood pressure and identify and treat all reversible risk factors.

Principles of Therapy

Treatment Goals

  • To manage hypertension
    • To achieve and maintain BP goal based on age, presence/absence of comorbidities (eg DM and chronic kidney disease)
  • To prevent complications through identification and management of all other identified risk factors for CVD (DM or glucose intolerance, lipid disorders, obesity, smoking)
    • Identification and treatment of all reversible risk factors
    • Management of concomitant disorders (eg DM, established CV or renal disease)

Target BP

  • In the general adult population without DM or chronic kidney disease (CKD):
    • Aged ≥60 years: Treat patients to a goal of SBP <150 mmHg and DBP <90 mmHg
      • If pharmacologic treatment resulted in a lower achieved SBP and is not associated with adverse effects on quality of life or health, no treatment adjustment is necessary
    • Aged <60 years: Treat patients to a goal of SBP <140 mmHg and DBP <90 mmHg
  • Presence of DM and/or chronic kidney disease (CKD) in adult patients (≥18 years old): Treat to a goal of SBP <140 mmHg and DBP <90 mmHg 
    • Same target blood pressure for patients ≥60 years of age with clinical history of stroke or transient ischemic attack and those at high risk for cardiovascular disease

General Principles

Initiating Treatment

  • Decision to initiate therapy is based on the untreated BP level and presence of TOD or concomitant disorders
  • In the general population aged ≥60 years, initiate treatment at SBP ≥150 mmHg or DBP ≥90 mmHg
    • However, in patients with CKD or DM, initiate treatment at SBP ≥140 mmHg or DBP ≥90 mmHg
  • In the general adult population aged <60 years, including those with CKD or DM, initiate treatment at SBP ≥140 mmHg or DBP ≥90 mmHg
  • Implement lifestyle changes throughout management
  • Six to 12 months of lifestyle changes may be initially attempted in patients with hypertension no greater than 140/90 mmHg and without associated CV abnormalities or risk factors
    • May however start drug therapy earlier if BP is clearly not responding to lifestyle modifications
  • Start drug treatment in patients with BP >140/90 in whom lifestyle treatments have not been effective
  • Start drug treatment immediately after diagnosis for patients with BP ≥160/100 mmHg, usually with a 2-drug combination
  • Start drug treatment in all patients for whom it is necessary to achieve a more rapid control of BP

Treatment Regimen

  • Most patients will need >1 drug to achieve BP control
  • Assessment of BP and adjustment of treatment regimen is continuous until BP goal is reached
  • Different strategies may be considered based on individual circumstances, preferences of physician and patient:
    • Maximize first medication before adding a second drug
      • If BP goal is not reached within one month of treatment, increase the dose of the drug
    • Add a 2nd drug prior to reaching the maximum dose of the 1st drug
      • Add new drugs at approximately 2- to 3-week intervals, but may also depend on the physician’s judgment
      • If goal BP cannot be achieved using 2 drugs, add and titrate a 3rd drug
    • Start with a fixed-dose combination or with 2 separate drug classes
      • Consider starting immediately with 2 drugs if the untreated BP is at least 20/10 mmHg above the goal BP
  • Initial doses of drugs should be at least half the maximum dose so only one dose adjustment is needed to be done thereafter
  • In general, it is expected to reach the effective regimen within 6-8 weeks, regardless whether 1, 2 or 3 drugs were employed
  • Referral to a hypertension specialist may be necessary when goal BP cannot be achieved despite above strategies or when managing patients for whom additional consultation is warranted

Choice of Antihypertensive Agents

  • Choice is influenced by the following factors:
    • Patient’s age, ethnicity/race
    • Patient’s previous history with antihypertensive medications
      • Monitor for adverse reactions to avoid patient’s noncompliance to medications
    • Presence of other medical conditions
      • Eg coronary diseases, DM, renal disease, pregnancy, thiazide
    • Possibility of drug interactions with drugs used for other conditions
    • Patient preference
    • Cost (affordability) and availability of the drugs
      • Cost consideration should not predominate efficacy and tolerability
  • Long-acting drugs or preparations providing 24-hour efficacy that can be given once daily are preferred
    • Improves compliance and minimizes BP variability
    • Once-daily drugs can be taken at any time during the day (either morning or evening)
  • When >1 drug is needed, the use of a combination product (2 appropriate medications in a single tablet) can simplify the regimen for patients

Pharmacotherapy

ACE Inhibitors (ACEI)

  • Block the conversion of angiotensin I to angiotensin II by inhibiting angiotensin-converting enzyme (ACE)
  • ACE inhibitors are suitable for initiation and maintenance of therapy
  • Have established clinical outcome benefits in patients with chronic heart failure (CHF) and post myocardial infarction (MI) patients with reduced LV ejection fraction; also effective in reducing LV hypertrophy and preserving kidney function
  • Are well-tolerated; most common side effect is dry cough (most common in women and among Asian and African patients) related to effects of bradykinin or prostaglandin metabolism
  • There is a risk of hypotension when starting treatment with ACE inhibitors in patients who are already on diuretics, or are on low salt diet or are dehydrated
    • For patients on diuretics, skipping a dose prior to starting ACE inhibitor may help prevent this sudden drop in BP
  • Should not be combined with angiotensin receptor blockers as their combination may have adverse effects on kidney function
  • Drug effects do not seem to have dose-dependent effects, except for hyperkalemia which may occur more frequently with high doses
    • Allows patient to initiate treatment using medium or even approved high doses

Alpha-Blockers

  • Reduce BP by blocking arterial alpha-adrenergic receptors, in effect, preventing the vasoconstrictor actions of these receptors
  • Less widely used as first-line agents due to limited evidence for their clinical outcome benefits
  • Are useful in treating resistant hypertension when used in combination with other agents such as beta-blockers, diuretics and ACE inhibitors
  • Are beneficial part of treatment regimens for older hypertensive men with benign prostatic hypertrophy
  • Have favorable effects on blood glucose and lipid levels

Angiotensin II Antagonists (also called Angiotensin Receptor Blockers or ARB)

  • Act by blocking the action of angiotensin II on its AT1 receptors, preventing the vasoconstrictor effects of this receptor
  • Provide the same CV and renal benefits as ACE inhibitors
  • Should not be combined with ACE inhibitors as their combination may have adverse effects on kidney function
  • Are well tolerated; do not cause cough and only rarely cause angioedema
  • Drug effects do not appear to have dose-dependent effects
    • Allows patient to start with medium or even maximum approved doses
  • For patients on diuretics, skipping a dose of the diuretic prior to starting ARBs may help prevent sudden drop in BP

Beta-Blockers

  • Beta-blockers have a long history in the treatment of hypertension
  • For patients without conditions warranting beta-blockade, beta-blockers should not be used as initial therapy
  • Drug of choice in patients with history of MI and heart failure
    • Useful in patients with effort angina, tachyarrhythmia and have been shown to reduce CV morbidity and mortality in post-MI patients and risk of exacerbations and mortality in patients with chronic obstructive lung disease
  • Studies show that Celiprolol, Carvedilol and Nebivolol (3rd generation of beta-blockers) can reduce central pulse pressure and aortic stiffness as compared to Metoprolol and Atenolol (2nd generation of beta-blockers); Nebivolol has less effects on insulin sensitivity than Metoprolol
  • Act as competitive antagonists of the effects of catecholamines at beta-adrenergic receptor sites
    • Beta2-blockade can increase bronchial resistance and inhibition of catecholamine-induced glucose metabolism
    • Beta-blockers have different affinities for beta1- or beta2-blockade but as doses are increased, activity of beta2 receptors can become apparent in beta1-selective inhibitors
  • Combination with thiazide diuretic is shown to have dysmetabolic effect and increased incidence of new onset diabetes among patients and is therefore, not recommended in patients at risk for diabetes

Calcium Antagonists

  • Act by blocking the inward flow of calcium ions through the L channels of arterial smooth muscle cells
  • Calcium antagonists are powerful antihypertensive agents, especially when given in combination with ACE inhibitors or with ARBs
  • Main side effect is peripheral edema, most especially at high doses; though a clinical rather than a laboratory approach most often is enough to eliminate a renal or hepatic etiology for the edema
    • Reduced by combining with ACE inhibitors or ARBs

Dihydropyridine Ca Antagonists

  • Eg Amlodipine, Cilnidipine, Felodipine, Nicardipine, Nifedipine
  • Usually used for their antihypertensive and anti-anginal effects
  • Dihydropyridines have shown beneficial effects on stroke and CV outcomes in hypertension trials
  • Dihydropyridines (but not nondihydropyridines) can be safely combined with beta-blockers
  • Have greater selectivity for vascular smooth muscle than for myocardium and their main effect is vascular relaxation
    • They have little or no effect at the SA or AV nodes and negative inotropic activity is not typical at therapeutic doses

Benzothiazepine and Phenylalkylamine Ca Antagonists (Non-dihydropyridine Ca Antagonists)

  • Eg Diltiazem, Verapamil
  • Typically used for their antiarrhythmic, anti-anginal and antihypertensive properties
  • Tend to have less selective vasodilatory activity than dihydropyridine Ca antagonists
    • They have direct effect on myocardium causing depression of SA and AV conduction
  • Nondihydropyridines are preferred in patients with fast heart rates and rate control for atrial fibrillation patients who cannot tolerate beta-blockers
  • A randomized controlled trial revealed that Verapamil + Trandolapril was as clinically effective as Atenolol + Hydrochlorothiazide in hypertensive patients with coronary artery disease
  • Preferred in patients with proteinuria due to the additional antiproteinuric effect in Diltiazem and Verapamil

Direct Renin Inhibitors

  • Eg Aliskiren
  • Found to be as effective as angiotensin receptor blockers (ARB) and ACE inhibitors without dose-related increase in side effects in the elderly; combination with ACE inhibitor or ARB is not recommended
  • Current available data show that Aliskiren:
    • As monotherapy, lowers systolic BP and diastolic BP in younger and elderly hypertensive patients
    • Has a greater BP lowering effect when used in combination with a thiazide diuretic, a renin angiotensin blocker or a calcium channel blocker
    • Prolonged use in combination treatment can have a favorable effect on asymptomatic organ damage
  • Appears well tolerated among patients >75 years of age, including those with renal disease (with estimated GFR ≥30 mL/min/1.73 m2)
  • Main side effect is mild diarrhea

Diuretics

  • Use of diuretics has been well-established in the treatment of hypertension and diuretics are suitable for initiation and maintenance of therapy
    • When used in combination, diuretics may enhance the efficacy of concurrently used antihypertensive drug
    • Reduce the risk of fatal and nonfatal stroke and have been shown to reduce CV morbidity and mortality and all-cause mortality
    • Drug of choice in the elderly with no comorbid conditions
  • Combination treatment with potassium-sparing diuretics (eg Amiloride, Triamterene), mineralocorticoid antagonists (eg Spironolactone, Eplerenone), and epithelial sodium transport channel antagonists with other agents are useful in treating hypertension by reducing vascular stiffness and SBP

Aldosterone Antagonists

  • Eg Spironolactone, Eplerenone
  • Have recently been part of standard treatment of heart failure
  • Can be effective in lowering BP when added to standard 3-drug regimens (ACEI or ARB/Calcium antagonist/Diuretic) in treatment-resistant hypertension
    • Aldosterone excess can contribute to resistant hypertension

Loop Diuretics

  • Eg Furosemide, Torasemide
  • Loop diuretics are preferred over thiazide diuretics in patients with renal insufficiency

Thiazide and Thiazide-like Diuretics

  • Eg Chlorthalidone, Hydrochlorothiazide, Indapamide
  • Act by increasing elimination of sodium by kidneys and may have some vasodilator effects
  • Inexpensive and are the most widely used of the antihypertensive agents
  • With proven clinical outcome benefits in reducing strokes and major CV events
    • Chlorthalidone has powerful effects on BP and longer duration of action
  • Main side effects (metabolic, such as hypokalemia, hyperuricemia, hyperglycemia) are reduced by lowering the doses or combining them with ACE inhibitors
  • Used in combination with potassium-sparing diuretic to prevent thiazide-induced hypokalemia
  • Most effective in BP reduction when combined with ACE inhibitors or ARBs
    • Also effective when combined with calcium channel blockers

Other Antihypertensives

Centrally-Acting Agents

  • More often used nowadays as part of multiple drug combinations
  • Act by reducing sympathetic outflow from the central nervous system
  • Methyldopa
    • May be considered in resistant hypertension in combination with other antihypertensive agents
    • Safe to use in pregnancy

Direct Vasodilators

  • Are most effective in reducing BP when combined with diuretics and beta-blockers or sympatholytic agents
  • Usually used only as 4th line or later additions to treatment regimens
INDICATIONS AND PREFERRED ANTIHYPERTENSIVE TREATMENT

Indication

Preferred Antihypertensives

Angina pectoris

  • Beta-blocker
  • Ca antagonist

Asymptomatic atherosclerosis

  • ACE inhibitor
  • Ca antagonist

Atrial fibrillation

Recurrent:

  • Angiotensin II antagonist
  • ACE inhibitor
  • Beta-blocker
  • Aldosterone antagonist

Permanent:

  • Beta-blocker
  • Ca antagonist (Non-dihydropyridine)

Diabetes mellitus

Combination of ≥2 drugs are typically needed to reach target BP

  • ACE inhibitor or Angiotensin II antagonist
  • Beta-blocker
  • Thiazide
  • Ca antagonist

Heart failure

Asymptomatic patients with ventricular dysfunction:

  • ACE inhibitor

Symptomatic ventricular dysfunction or end-stage heart disease:

  • ACE inhibitor
  • Angiotensin II antagonist
  • Aldosterone antagonist
  • Beta-blocker
  • Thiazide diuretic

Isolated systolic hypertension (ISH) (elderly)

  • Diuretics
  • Direct renin inhibitor
  • Ca antagonist

LV hypertrophy

  • Angiotensin II antagonist
  • ACE inhibitor
  • Ca antagonist

Metabolic syndrome

  • ACE inhibitor
  • Angiotensin II antagonist
  • Ca antagonist

Microalbuminuria

  • ACE inhibitor
  • Angiotensin II antagonist
  • Direct renin inhibitor

Peripheral arterial disease

  • Ca antagonist
  • Beta-blocker (if with arterial hypertension)
  • ACE inhibitor

Post MI

  • ACE inhibitor
  • Aldosterone antagonist
  • Angiotensin II antagonist
  • Beta-blocker

Post stroke

  • Any BP lowering agent
  • Ca antagonist

Proteinuria/End-stage Renal Disease

  • ACE inhibitor
  • Loop diuretics
  • Angiotensin II antagonist


Effective Antihypertensive Combinations

Combination therapy can be initiated in hypertension stage 2 and above or hypertension within those at higher risk for CVD. In 15-20% of hypertensive patients, BP control cannot be achieved with a two-drug combination; in this case, a three-drug combination may be used.

  • Diuretic + (ACE inhibitor OR angiotensin II antagonist OR Ca antagonist)
  • Angiotensin II antagonist + Ca antagonist
  • ACE inhibitor + Ca antagonist
  • Beta-blocker + Ca antagonist

Many antihypertensive combinations are available. Please see the Product Section and the latest MIMS for specific formulations and prescribing information.

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