Antihypertensive Medications

• Lecture provided by Gretchen Ray, PharmD, PhC, CDCES Associate Professor at UNM College of Pharmacy on March 28, 2025.
• The lecture focuses on antihypertensive medications.

Lecture Objectives

• Describe the pharmacology/mechanism of action of antihypertensive medications
• Identify common and serious side effects of antihypertensive medications
• List monitoring parameters for antihypertensive medications
• Discuss the selection of medication based on a patient's medical history and co-morbidities.

Lecture Overview

• Hypertension guidelines are reviewed.
• Pathophysiology of hypertension and pharmacotherapy targets are examined.
• First-line agents include ACE inhibitors, ARBs, Calcium Channel Blockers, and Thiazide Diuretics.
• Other agents include Beta blockers, other diuretics, Alpha-2 agonists and Vasodilators.
• Clinical cases are presented.

Hypertension

• Elevated blood pressure is often the only sign of hypertension.
• Hypertension is often asymptomatic.
• Signs and symptoms may arise due to cardiovascular, cerebrovascular, retinal, and renal complications.
• Hypertension is the silent killer
• For heart attacks 7 in 10 have high blood pressure
• For strokes 8 in 10 have high blood pressure
• For chronic heart failure, 7 in 10 have high blood pressure

Diagnosis and Goals

• All individuals age 18+ should be screened for hypertension yearly
• Diagnosis is based on the average of two or more properly measured blood pressure readings, taken 1-2 minutes apart.
• Blood pressure must be elevated when measured at two or more visits spaced 1-4 weeks apart.
• Except for individuals with HTN emergency with certain elevated blood pressure readings or known end-organ damage
• Blood pressure lowering is associated with a 35-40% reduction in stroke, 20-25% reduction in myocardial infarction and more than 50% reduction in heart failure.
• An optimal blood pressure goal is still unclear or controversial

BP Monitoring

• Quiet room, comfortable temperature
• No smoking, coffee, exercise for 30 minutes
• Relax for 3-5 minutes
• Take 3 measurements at 1 minute intervals
• Use average of the last 2 measurements
• Back supported
• No talking during and between measurements
• Cuff to fit arm size
• Arm bare and resting
• Mid-arm at heart level
• Feet flat on floor
• Use validated electronic upper-arm cuff, or manual auscultatory
• Inflatable bladder of the cuff must cover 75-100% of the individuals arm circumference for manual auscultatory devices.

BP Cuff Sizes

• Small adult cuff size is recommended for arm circumference of 22-26cm
• Standard adult cuff size is recommended for arm circumference of 27-34cm
• Large adult cuff size is recommended for arm circumference of 35-44cm
• Thigh cuff size is recommended for arm circumference of 45+ cm

Goals of Treatment with 2017 ACC/AHA Guidelines

• Includes direction on screening for masked or white coat hypertension.
• Includes American College of Cardiology and American Heart Association
• Includes ASCVD risk scoring.

Blood Pressure Values

• Normal blood pressure is defined as less than 120/less than 80 mmHg.
• Elevated blood pressure is defined as 120-129/less than 80 mmHg.
• Stage 1 hypertension is defined as 130-139 or 80-89 mmHg.
• Stage 2 hypertension is defined as greater than or equal to 140/greater than or equal to 90 mmHg.

Approach to Treatment

• Decide if the drug therapy is indicated
• Establish a treatment goal
• Encourage lifestyle modifications
• Select drug therapy
• Patients with stage 2 hypertension will need more than one drug to reach blood pressure goals
• Monitoring and follow-up is required
• ACC/AHA Guideline: BP greater than or equal to 130/80 mmHg with clinical CVD or diabetes
• ACC/AHA Guideline: BP greater than or equal to 130/80 mmHg with 10-year ASCVD risk greater than or equal to 10%.
• ACC/AHA Guideline: BP greater than or equal to 140/90 mmHg
• The BP should be targeted at less than 130/80 mmHg
• This includes patients with stable ischemic heart disease, diabetes, heart failure, CKD, renal transplant, and peripheral arterial disease.

Blood pressure, mm Hg, 10-year risk and Recommendation

• Normal: BP less than 120/less than 80, N/A 10-year risk, Reassess in 1 year and promote optimal lifestyle habits.
• Elevated: BP 120-129/ and <80, N/A 10-year risk, Non-pharm and reassess in 3-6 months
• Stage 1: BP 130-139/ or 80-89, Less than 10% 10-year risk, Non-pharm and reassess in 3-6 months
• Stage 1: BP 130-139/ or 80-89, Greater than or equal to 10% OR diabetes, CKD, or ASCVD 10-year risk, Non-pharm + Med and reassess in 1 month.
• Stage 2: BP greater than or equal to 140/greater than or equal to 90, N/A 10-year risk, Non-pharm + Meds (2) and (2) 10-year risk.

Nonpharmacologic Intervention Details

• Healthy diet using the Dietary Approaches to Stop Hypertension (DASH) dietary pattern: Dose rich in fruits, vegetables, whole grains, and low-fat dairy products with reduced content of saturated and total fat.
• Weight loss is best to focus on losing excess weight/body fat, ideal body weight is best goal, but aim for at least 1 kg body weight reduction for most overweight adults and expect about 1 mm Hg for every 1 kg reduction in body weight.
• Reduce intake of dietary sodium with less than 1500 mg/day is optimal goal, but aim for at least 1000 mg/day reduction in most adults.
• Increase intake of dietary potassium with 3500-5000 mg/day, preferably by consumption of a diet rich in potassium.
• Physical activity by adding aerobic exercises to weekly routine with 90-150 min/week and 65%-75% heart rate reserve.
• Physical activity by adding dynamic resistance training to weekly routine, 90-150 min/week, 50%-80% heart rate reserve, 1 rep maximum and 6 exercises, 3 sets/exercise, 10 repetitions/set.
• Physical activity by adding isometric resistance training to weekly routine with 4 × 2 min (hand grip), 1 minute of rest between exercises, 30%-40% maximum voluntary contraction, 3 sessions/week and 8-10/week.
• Reduce consumption of alcohol and for those who drink alcohol, the recommended daily consumption is no more than 2 drinks for men and 1 drink for women.

Pharmacotherapy Targets

• Arterial blood pressure is the target
• Left ventricle ejects blood into the Systemic vasculature.
• Systemic vasculature provides resistance to cardiac output.
• Mean arterial pressure is calculated by (Cardiac Output X Systemic Vascular Resistance) + Central Venous Pressure.
• Any increase in CO, CVP, and/or SVR will increase blood pressure
• Essential or primary hypertension has no identifiable underlying cause.
• Secondary hypertension is attributable to underlying condition such as renal artery disease, thyroid disease, hyperaldosteronism, pregnancy, medications, &etc.
• Primary hypertension is treated with antihypertensives that reduce blood volume, reduce systemic vascular resistance/produce vasodilation, and reduce cardiac output.

Reducing blood volume

• Diuretics

Reducing Systemic Vascular Resistance/Produce Vasodilation

• ACE inhibitors
• ARBs
• Vasodilators
• Dihydropyridine calcium channel blockers
• Alpha 1 blockers
• Alpha Agonists

Reducing Cardiac Output

• Beta Blockers
• Non-dihydropyridine calcium channel blockers

Pharmacotherapy Selection

• For patients with BP greater than 20/10 mmHg above target, chose two different classes and do not combine ACE inhibitors and ARBs
• Includes First-line and Secondary agents

First-Line Agents

• Thiazide diuretics
• ACE inhibitors
• Angiotensin receptor blockers (ARB)
• Calcium channel blockers, both dihydropyridines and non-dihydropyridines

Secondary Agents

• Loop diuretics
• Potassium-sparing diuretics
• Aldosterone antagonist diuretics
• Beta blockers
• Alpha 1 blockers which are generally reserved as secondary for patients with concomitant BPH
• Alpha agonists and other centrally acting agents
• Vasodilators

Thiazide Diuretics

• Chlorthalidone is a preferred agent with a long half-life and excellent evidence to support use
• Hydrochlorothiazide (HCTZ) is historically most commonly prescribed and is available in many combo pills, but is somewhat less potent than chlorthalidone

Thiazide Diuretic Mechanism of Action

• Inhibit sodium-chloride transporter in distal tubule in the kidney which will increase sodium and chloride excretion
• Produce less diuresis/natriuresis than other diuretics because only around 5% of filtered sodium is reabsorbed.
• It is more effective at blood pressure control than other diuretics.

Thiazide Diuretics Side Effects

• Hypokalemia, hyponatremia, hypomagnesemia and hypophosphatemia
• Hypercalcemia and hyperglycemia
• Hyperuricemia
• Sun sensitivity

Thiazide Diuretics Contraindications

• Not appropriate for patients with active gout, and caution with history of gout
• Less effective in patients with CrCl < 30ml/min

Thiazide Diuretics Monitoring

• Monitor blood pressure
• Electrolytes (potassium, sodium, magnesium, calcium) within 1-2 weeks of initiation or dose change.
• Renal function baseline, then 1-2 times per year.
• Blood glucose, baseline and at least once per year.

ACE-Inhibitors and Angiotensin Receptor Blockers (ARBs)

• Blocks the action of Angiotensin converting enzyme to inhibit the formation of angiotensin II.

ACE Inhibitors Examples

• Lisinopril, fosinopril, enalapril, captopril

ACE Inhibitor Mechanism of Action

• Blocks the action of angiotensin converting enzyme to inhibit the formation of angiotensin II as a vasoconstrictor, this results in vasodilation.

ACE Inhibitors Side Effects

• Side effects include dry cough, hyperkalemia, and transient rise in SCr
• Severe side effects include angioedema

ACE Inhibitors Monitoring

• Monitor potassium and SCr within 2 weeks of initiation or dose change.

ACE Inhibitors Contraindications

• Contraindicated in pregnancy and patients with history of angioedema.
• This is the preferred agent for diabetes and albuminuria.

Angiotensin II Receptor Blockers (ARBs) Mechanism of Action

• Block angiotensin II receptors on blood vessels and in tissues in the heart.

Angiotensin II Receptor Blockers (ARBs) Examples

• Valsartan, losartan, irbesartan

Angiotensin II Receptor Blockers (ARBs) Side Effects

• Side effects: hyperkalemia and transient rise in SCr
• Severe side effects: angioedema

Angiotensin II Receptor Blockers (ARBs) Monitoring

• Monitor potassium, SCr within 2 weeks of initiation or dose change, and blood pressure.

Angiotensin II Receptor Blockers (ARBs) Contraindications

• Contraindicated in pregnancy and patients with history of angioedema.
• This is the preferred agent for diabetes and albuminuria.
• ARBs are like an ACE inhibitor without a cough.

Common Meds Affecting the Kidneys

• NSAIDs Constrict Afferent arteriole which can cause potential kidney damage.
• ACEI/ARBs Dilate Efferent arteriole which can cause kidney protection.

Calcium Channel Blockers Mechanism of Action

• Bind to L-type calcium channels on vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue to block entry of calcium into the cells.
• Dihydropyridines are more selective for vascular cells and minimal direct cardiac effects
• Non-dihydropyridines are more selective for cardiac myocytes with less effects on systemic vasodilation

Dihydropyridine Calcium Channel Blockers Information

• More effective as antihypertensives
• Examples: Amlodipine, nifedipine, felodipine
• Side effects: Hypotension, dizziness, peripheral edema
• Monitoring: Blood pressure, signs of lower extremity edema

Non-dihydropyridine Calcium Channel Blockers Information

• Non-dihydropyridines are effective as antihypertensive as well as anti-arrhythmics (reduce heart rate)
• Examples: Diltiazem, verapamil
• Side effects: Hypotension, dizziness, lower extremity edema, constipation, and bradycardia
• Monitoring is of blood pressure and heart rate.
• Avoid use in patients with heart failure and bradycardia.

ACEI, ARB, CCB, Thiazide Diuretics Key Takeaways

• First-line antihypertensives for most patients
• Chlorthalidone is the thiazide of choice but HCTZ is more commonly prescribed
• ACE inhibitors and ARBs are basically the same except that ARBs are less likely to cause cough
• ACE inhibitors and ARBs are contraindicated in pregnancy
• CCBs and thiazides are preferred as first-line for black patients
• ACE-I have been shown to be less effective in preventing heart failure and stroke compared with CCBs in black patients
• OK to add an ACE-I or ARB after starting a thiazide or CCB first
• Dihydropyridine CCBs are more effective in blood pressure reduction and non-dihydropyridine CCBs have more effects on heart rate
• Non-dihydropyridine CCBs should be avoided in patients with heart failure

Approach to Treatment with Key Takeaways

• Per ACC/AHA guidelines, most patients should be treated to a goal blood pressure of less than 130/80 mmHg.
• Thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers are first-line for most patients.
• For patients with BP greater than 20/10 mmHg over their goal initiate two first-line agents of different classes.
• Do not combine ACE inhibitors and ARBs.

"Other Agents" to Treat

• Aldosterone antagonists
• Beta blockers
• Loop diuretics
• Potassium-sparing diuretics
• Alpha-2 blockers
• Vasodilators

Aldosterone Antagonist Diuretics

• Often grouped with "potassium-sparing" diuretics but mechanism is different
• A few are spironolactone with more side effects such as gynecomastia with and erectile dysfunction, but it is often less expensive than eplerenone.
• Other is Eplerone

Aldosterone Antagonist Diuretics Mechanism of Actions

• Block the action of aldosterone at distal segment of the distal tubule.
• Compete for the aldosterone-dependent sodium-potassium exchange site in distal tubule cells.
• Increase the secretion of water and sodium
• Beneficial in primary aldosteronism and resistant hypertension
• Preferred 4th line agent for resistant hypertension and used in patients with heart failure

Aldosterone Antagonist Diuretics Indication

• Secondary agent for treatment of hypertension

Aldosterone Antagonist Diuretics Side Effects

• Hyperkalemia, gynecomastia (spironolactone), hyperglycemia, hyponatremia, hypomagnesemia

Aldosterone Antagonist Diuretics Contraindications

• Presence of hyperkalemia and renal dysfunction.
• Use caution when used withother K+ sparing diuretics or potassium supplements

Potassium-Sparing Diuretics

• Triamterene with often found in combination tabs with HCTZ.
• Amiloride

Potassium-Sparing Diuretics Mechanism of Action

• Directly inhibit sodium channels in distal renal tubule
• Small effects on sodium balance and blood pressure
• Generally used along with other diuretics to prevent hypokalemia

Potassium-Sparing Diuretics Side Effects

• Hyperkalemia
• Hyperuricemia

Potassium-Sparing Diuretics Contraindications and Uses

• Not appropriate for anuric patients and patients with hyperkalemia.
• Use caution when used with other potassium-sparing agents or potassium supplements
• Not used as monotherapy for treatment of hypertension

Loop Diuretics

• Include furosemide, bumetanide, and torsemide.

Loop Diuretics Mechanism of Action

• Inhibit sodium-potassium-chloride cotransporter in the thick ascending limb.
• Around 25% of sodium is reabsorbed here which equals significant diuresis/natriuresis
• Less effective in treatment of hypertension generally used in symptomatic heart failure

Loop Diuretics Side Effects

• Profound diuresis/dehydration (acute kidney injury), hypomagnesemia, hypokalemia, hyperuricemia, and sun sensitivity
• Serious side effects include ototoxicity that is dose-related, anemia, and thrombocytopenia

Loop Diuretics Contraindications

• Use caution in history with gout because increased uric acid is less common than with HCTZ
• Not generally used in treatment of hypertension only used for edema

Loop Diuretics Monitoring

• Monitor electrolytes which are potassium, sodium, magnesium, calcium within 1-2 week of initiation, frequently during first few months, and yearly thereafter
• Monitor renal function baseline and requently during first few months, then 1-2 times per year
• Monitor fluid status

Beta Blockers Mechanism of Action

• Bind to beta-adrenergic receptors and inhibit the effects of catecholamines (norepinephrine and epinephrine) at these receptors.

Beta Blockers Side Effects

• Bronchospasm, bradycardia, dizziness, fatigue, and depression

Beta Blockers Contraindications & Warnings

• Boxed warning: Abrupt cessation of therapy may lead to angina, myocardial infarction, and death
• Avoid sudden interruption of therapy; when discontinuing therapy, gradually reduce dosage over 1-2 weeks and monitor patient
• May worsen heart failure and do not initiate in decompensated heart failure
• May mask symptoms of hypoglycemia in diabetes
• Caution in bronchospastic disease (asthma)
• Contraindicated in bradycardia (less than 50 bpm) and heart blocl

Beta Blockers Monitoring and Examples

• Monitoring includes blood pressure, heart rate, symptoms of worsening heart failure in patients with CHF, and symptoms of breathing difficulties in patients with airway disease.
• Examples: metoprolol, carvedilol, bisoprolol, propranolol
• Not first-line for HTN unless patient has stable ischemic heart disease or heart failure
• Metoprolol succinate, carvedilol, and bisoprolol are BB of choice for heart failure with reduced ejection fraction

Alpha-2 Agonists

• Secondary agent ("last line") for treatment of hypertension
• Clonidine
• Methyldopa for patients that are preferred in pregnancy
• Guanfacine
• Alpha-2 receptor agonists act as vasodilators.

Alpha-2 Agonists Mechanism of Action

• Act in the central nervous system to reduce sympathetic outflow from the CNS which decreases peripheral resistance, renal vascular resistance, heart rate and blood pressure

Alpha-2 Agonists Side Effects

• Dry mouth
• Dizziness
• Sedation/fatigue
• Hypotension
• Serious side effects: heart block and rebound hypertension, which is with abrupt discontinuation with clonidine
• Not appropriate in elderly patients; usually last line for HTN due to CNS adverse effects

Vasodilators

• Secondary agent for treatment of resistant hypertension

Vasodilators and Hydralazine Mechanism of Action

• Highly specific action on arterial vessels reduces vascular resistance and arterial pressure
• Several theorized actions such as opening of K+ channels to cause smooth muscle hyperpolarization, inhibition of calcium release in smooth muscle, and stimulates formation of nitric oxide to produce vasodilation.

Vasodilators and Hydralazine Side Effects

• Hypotension
• Edema
• Palpitations
• Reflex tachycardia
• Headaches
• Flushing
• Serious side effects include lupus-like syndrome at around 10%
• Usually dosed 2-3 times daily which limits use.
• Used inpatient for acute BP reduction or outpatient for resistant hypertension

Important Key Takeaways for Other Agents

• Aldosterone antagonists are preferred add-ons for resistant hypertension after addition of other first-line agents.
• Beta blockers may be a part of antihypertensive treatment for patients with stable ischemic heart disease or heart failure, but are not first-line antihypertensives for other patients.
• Loop diuretics are ineffective in hypertension treatment and they are generally used in heart failure for fluid retention.
• Potassium-sparing diuretics are used in combination with thiazide diuretics to prevent hypokalemia and they are not effective as monotherapy
• Alpha agonists have high rates of CNS side effects and are considered “last line” which is due to side effects.
• Vasodilators are considered last line for resistant hypertension, after addition of other first-line agents.
• But these need to be dosed multiple times per day

Combination pills

• Many patients will require more than one drug to control hypertension
• Simplified dosing regimens and reduced pill burden improve patient adherence
• Drawbacks include less flexibility in dosing
• May be more expensive than individual agents
• May be less readily available in pharmacies and covered by insurance