Pharmacotherapy: Chronic Hypertension

Definitions and Classification

Blood pressure is defined as the force exerted by circulating blood against the walls of the arteries and is determined by cardiac output and peripheral vascular resistance. Hypertension is sustained elevation in resting systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg based on the average of two or more properly measured seated blood pressure readings on two or more office visits.

Hypertension is classified into stages based on severity:

• Normal: Systolic <120 mmHg and diastolic <80 mmHg
• Elevated: Systolic 120-129 mmHg and diastolic <80 mmHg
• Stage 1: Systolic 130-139 mmHg or diastolic 80-89 mmHg
• Stage 2: Systolic ≥140 mmHg or diastolic ≥90 mmHg

Patients with hypertension are further stratified into low, moderate or high-risk groups based on the presence of target organ damage, cardiovascular comorbidities and risk factors.

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Goals of Treatment

The primary goals of treating hypertension are to:

• Reduce cardiovascular morbidity and mortality
• Control blood pressure to guideline-recommended targets
• Prevent progression of target organ damage
• Manage other cardiovascular risk factors such as dyslipidemia and diabetes

The optimal target for blood pressure reduction is controversial, especially in certain subpopulations, but for most patients with essential hypertension the goal is <130/80 mmHg. Lower targets may be appropriate in some high-risk groups if tolerated.

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Lifestyle Modification

Non-pharmacological therapy through lifestyle changes is recommended for all patients with hypertension. Lifestyle modification can effectively lower blood pressure, enhance efficacy of antihypertensive medications, reduce cardiovascular risk, prevent or delay medication initiation, and mitigate medication side effects. The major lifestyle recommendations include:

• Weight loss – Losing as little as 10 lbs can significantly reduce blood pressure in overweight individuals. Waist circumference should be <40 inches for men and <35 inches for women.
• Dietary changes – A heart healthy diet low in sodium, saturated/trans fats, cholesterol, refined carbohydrates and high in fruits, vegetables, fiber, potassium, calcium, magnesium and protein has been shown to lower blood pressure. The DASH (Dietary Approaches to Stop Hypertension) and Mediterranean diets are commonly recommended. Sodium reduction lowers blood pressure in a dose-dependent fashion and intake should be limited to <2.3 grams per day.
• Physical activity – At least 150 minutes per week of moderate intensity exercise such as brisk walking helps lower blood pressure and reduce cardiovascular risk. Resistance exercises should also be incorporated 2-3 times per week.
• Alcohol moderation – Limit intake to no more than 2 drinks per day for men and 1 drink per day for women and lighter weight individuals.
• Smoking cessation – Tobacco intake acutely raises blood pressure and quitting smoking is strongly recommended to reduce cardiovascular risk.
• Stress management – Chronic stress and anxiety activate the sympathetic nervous system and RAAS, leading to acute elevations in blood pressure. Stress management techniques such as meditation, yoga, tai chi, deep breathing and biofeedback help mitigate these effects.

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Pharmacotherapy

Drug therapy should be initiated along with lifestyle changes in adults with stage 2 hypertension or stage 1 hypertension at high risk based on age ≥75 years, known cardiovascular disease, target organ damage such as kidney disease, diabetes, or 10-year ASCVD risk ≥10%. Most patients will require multi-drug regimens to achieve blood pressure targets.

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The choice of initial antihypertensive agent depends on the clinical scenario:

• For most patients, preferred first line agents include a thiazide diuretic, ACE inhibitor, ARB or dihydropyridine CCB based on trial data demonstrating efficacy and safety.
• In diabetics, an ACE inhibitor or ARB is recommended first line.
• In patients with heart failure, an ACE inhibitor or ARB is recommended along with a beta blocker and diuretic.
• In patients with a recent myocardial infarction, a beta blocker and ACE inhibitor are recommended first line.
• In patients with chronic kidney disease, an ACE inhibitor or ARB is first line to slow disease progression.
• In elderly patients, a thiazide, long-acting CCB or ACE inhibitor may be preferred initial agents.

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Two agents can be started initially in stage 2 hypertension or in high risk stage 1 patients if blood pressure is more than 20/10 mmHg above goal. Preferred combinations include an ACE inhibitor or ARB with a CCB or thiazide diuretic. Single pill combinations may improve adherence over taking two separate agents. Most patients will eventually require multiple drugs to achieve blood pressure targets.

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Thiazide diuretics

• Examples:
  • Hydrochlorothiazide – 12.5-25 mg once daily, max 50 mg/day
  • Chlorthalidone – 12.5-25 mg once daily, max 50 mg/day
  • Indapamide – 1.25-2.5 mg once daily
• Absorption: Rapidly absorbed, onset within 2 hours
• Distribution: Extensive tissue distribution
• Metabolism: Hepatic, inactive metabolites
• Excretion: Urine (unchanged drug and metabolites)
• Adverse effects: Electrolyte abnormalities (hypokalemia, hyponatremia, hyperuricemia), hyperglycemia, hyperlipidemia, hypotension, rash
• Clinical pearls:
  • Most effective antihypertensive as monotherapy
  • Chlorthalidone preferred over hydrochlorothiazide due to longer duration of action
  • Start with lowest dose and titrate gradually
  • Supplement potassium if serum K+ < 3.5 mEq/L
  • Monitor renal function, electrolytes and uric acid
  • Avoid in severe kidney dysfunction (GFR <30 mL/min)

Angiotensin converting enzyme (ACE) inhibitors

• Examples:
  • Lisinopril – 10-40 mg once daily
  • Enalapril – 5-40 mg once daily
  • Ramipril – 2.5-20 mg once daily
• Absorption: Well absorbed, reduced with food
• Distribution: Extensively bound to tissues
• Metabolism: Hepatic to active metabolite
• Excretion: Urine (60-70% unchanged)
• Adverse effects:
  • Cough (15%), angioedema, hyperkalemia, acute kidney injury
  • Avoid in pregnancy and bilateral renal artery stenosis
• Clinical pearls:
  • Preferred for heart failure, diabetes, chronic kidney disease
  • May cause acute decrease in GFR
  • Monitor potassium and renal function
  • Dry cough is class side effect
  • Avoid potassium supplements
  • Twice daily dosing may be better for blood pressure control

Angiotensin receptor blockers (ARBs)

• Examples:
  • Losartan – 25-100 mg once daily
  • Valsartan – 80-320 mg once daily
  • Irbesartan – 150-300 mg once daily
• Absorption: Well absorbed, reduced with food
• Distribution: Highly bound to proteins
• Metabolism: Hepatic, inactive metabolites
• Excretion: Biliary and fecal
• Adverse effects:
  • Generally well tolerated
  • Increased risk of hyperkalemia and kidney injury
  • Avoid in pregnancy
• Clinical pearls:
  • Similar benefits as ACE inhibitors without the cough
  • Preferred for diabetic nephropathy and proteinuria
  • Monitor potassium and renal function
  • Avoid potassium supplements
  • Good option if ACE inhibitor not tolerated

Calcium channel blockers (CCBs)

• Dihydropyridines (preferred):
  • Amlodipine – 2.5-10 mg once daily
  • Nifedipine extended release – 30-90 mg once daily
• Non-dihydropyridines:
  • Diltiazem extended release – 120-360 mg once daily
  • Verapamil extended release – 120-480 mg once daily
• Absorption: Well absorbed, high bioavailability
• Distribution: Extensive distribution, high protein binding
• Metabolism: Hepatic, CYP3A4 substrate
• Excretion: Urine and feces
• Adverse effects:
  • Dihydropyridines – headache, edema, flushing
  • Non-dihydropyridines – constipation, heart block, worsened heart failure
• Clinical pearls:
  • Preferred in elderly patients
  • Avoid short acting nifedipine capsules
  • Amlodipine less likely to cause reflex tachycardia
  • Monitor heart rate and rhythm with non-dihydropyridines
  • Avoid verapamil or diltiazem combined with beta blockers

Beta blockers

• Cardioselective:
  • Metoprolol succinate – 50-200 mg once daily
  • Atenolol – 25-100 mg once daily
  • Bisoprolol – 2.5-10 mg once daily
• Non-cardioselective:
  • Carvedilol – 12.5-50 mg twice daily
  • Propranolol – 80-320 mg twice daily
• Absorption: Well absorbed but high first pass metabolism
• Distribution: Low lipid solubility, minimal CNS penetration
• Metabolism: Hepatic, CYP2D6
• Excretion: Urine and feces
• Adverse effects:
  • Fatigue, sexual dysfunction, reduced exercise tolerance
  • Bronchospasm in asthma
  • Masks hypoglycemia in diabetes
  • Contraindicated in heart block
• Clinical pearls:
  • Avoid abrupt discontinuation
  • Start at low dose and titrate slowly
  • Monitor heart rate and rhythm
  • Assess for fatigue and sleep disturbances
  • Not recommended as first line for uncomplicated hypertension

Combination Therapy

• Most patients require ≥2 medications to reach BP targets
• Combinations provide complementary mechanisms
• Improves efficacy and reduces dose-dependent side effects
• Preferred combinations:
  • RAS blocker + CCB
  • RAS blocker + thiazide
  • CCB + thiazide
• Avoid combining RAS blockers (ARB with ACE inhibitor)

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Resistant hypertension

• Failure to reach BP goal on 3 agents including a diuretic
• Confirm adherence and exclude pseudoresistance
• Mineralocorticoid receptor antagonists (e.g. spironolactone) or hydralazine often added
• Consider loop diuretics for patients with CKD

Monitoring

• Assess for orthostatic hypotension initially
• Monitor electrolytes 1-2 weeks after starting or changing diuretics
• Follow renal function after initiating ACEI/ARB
• Obtain ECG to check for arrhythmias
• Monitor blood pressure routinely; adjust medications to reach targets
• Assess for adherence and side effects at each visit

Special Populations

• Elderly: Start with low doses, lower blood pressure gradually
• CKD: RAS blockers to slow disease progression
• Diabetes: ACEI/ARB first-line, monitor potassium
• HF: Beta blockers, ACEI/ARB titrated to target doses
• Prior stroke: Thiazide diuretic ± ACE inhibitor

Clinical Pearls

• Don’t let perfect be the enemy of good – some BP lowering is better than none
• Lifestyle modification is always indicated, even with medications
• Measure BP correctly – wrong cuff size is common error
• Assess response and adjust medications promptly
• Combination therapy is key – don’t just increase doses
• Pick one thing at each visit to discuss and improve

Counseling Points for Antihypertensives

• Thiazide diuretics: Take in the morning to avoid nocturia. Report muscle cramps, frequent urination or weakness which may indicate electrolyte disturbances. Avoid NSAIDs which can worsen potassium loss.
• ACE inhibitors: Take at the same time each day. Notify doctor if you have a chronic cough or swelling of the lips/tongue which could indicate angioedema. Limit potassium-rich foods and salt substitutes due to hyperkalemia risk. Report sudden muscle weakness or cramping.
• ARBs: Take with or without food. Do not crush or chew tablets. Notify doctor if you have swelling of the lips/tongue. Limit potassium-rich foods and salt substitutes due to hyperkalemia risk. Report sudden muscle weakness or cramping.
• CCBs: Report swelling in lower extremities, lightheadedness, constipation or heart palpitations. Avoid grapefruit and grapefruit juice which can increase drug levels. Take non-dihydropyridines at the same time daily.
• Beta blockers: Do not stop this medication abruptly. Report symptoms of fatigue, depression, insomnia, dizziness or worsening of heart failure. Notify your doctor if you have asthma or wheezing which could be exacerbated.

Role of the Pharmacist

• Identify uncontrolled hypertension through prescription records and follow-up monitoring
• Provide convenient blood pressure checks and education in accessible retail pharmacy settings
• Assess medication adherence and optimize regimens to be simplified with once daily dosing and fixed-dose combinations
• Recommend appropriate non-pharmacological lifestyle modifications such as dietary changes and exercise plans
• Collaborate with physicians for medication initiation, titration, switching under protocol to help patients attain blood pressure targets
• Order and interpret laboratory tests when appropriate to monitor for medication side effects and adjust therapy accordingly
• Perform comprehensive medication reviews to optimize antihypertensive therapy, identify drug interactions, and improve patient safety

Example of Pharmacist-Led Intervention

A study evaluated a pharmacist-led transitional care clinic (TCC) model for improving blood pressure control in underserved patients referred from the emergency department (ED)1. The TCC pharmacist saw patients for a series of 5 visits over 6 months under a collaborative practice agreement with an ED physician. During the TCC visits, the pharmacist obtained blood pressure measurements, initiated and adjusted antihypertensive medications as needed, assessed medication adherence and provided hypertension education. At 6 months, 76% of patients achieved the blood pressure target <140/90 mmHg compared to only 43% at baseline. The TCC program demonstrated that pharmacist-led hypertension clinics can significantly improve outcomes, especially among high-risk populations.

• Stewart B, Brody A, Garwood CL, Zhang L, Levy PD. Implementation of Outpatient Pharmacist-led Hypertension Management for Under-Resourced Patients: A Pilot Study. Innov Pharm. 2021 Apr 27;12(2):10.24926/iip.v12i2.3895. doi: 10.24926/iip.v12i2.3895. PMID: 34345511; PMCID: PMC8326696.

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Conclusion

In summary, essential hypertension is a highly prevalent condition and a major reversible risk factor for cardiovascular morbidity and mortality. Treatment involves both pharmacological and non-pharmacological interventions tailored to the individual patient’s risk factors and comorbidities. Thiazide diuretics, ACE inhibitors, ARBs, CCBs and beta blockers are the cornerstones of antihypertensive therapy for most patients. Lifestyle modification importantly complements medication use. A multipronged approach focusing on proper blood pressure monitoring, control and reduction of other cardiovascular risk factors provides the optimal strategy to improve outcomes in hypertensive patients