Antihypertensive Drugs and Hypertension Management

Pharmacology of AntiHypertensives

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Learning Objectives

• Identify examples of antihypertensive drugs in each class.
• List major antihypertensive drugs and their clinical uses.
• Explain the mechanism of action of major antihypertensive drugs.
• Discuss the pharmacokinetics and drug interactions of antihypertensive drugs.
• Describe common and severe adverse effects of antihypertensive medications.
• Summarize major contraindications of antihypertensive drugs.

Renin-Angiotensin-Aldosterone System

• Regulates blood pressure (BP), sodium (Na), and water balance.
• Plays a role in cardiovascular and renal homeostasis.

Angiotensin Receptors

• AT1R subtype is the most well-understood Ang II receptor.
• G-protein coupled receptors embedded in the plasma membrane of target cells (smooth muscle, adrenal gland).

BP Regulation

• BP = Cardiac Output (CO) x Systemic Vascular Resistance (SVR).
• β-blockers decrease CO. Thiazide diuretics decrease SVR.

Drugs Relevant to Hypertension

• Diuretics (loop, thiazide)
• RAAS Inhibitors (renin inhibitors, ACE inhibitors, ARBs)
• Calcium channel blockers
• Sympatholytics
• Nitrates

ABCDs of Antihypertensives

• ACE inhibitors: 'pril' (e.g., lisinopril)

• ARBs: 'sartan' (e.g., losartan)

• Alpha blockers: 'osin'

• Beta blockers: 'lol' (e.g., metoprolol)

• Calcium channel blockers: 'dipine' (e.g., amlodipine)

• Diuretics, Dilators

• ACE inhibitors and ARBs are contraindicated in pregnancy.

• Other options are safe.

Multifactorial Disease

• Essential Hypertension (93% of cases).
• Does not have a known cause
  • Risk factors include genetics, smoking, stress, poor diet, obesity, family history, and sedentary lifestyle.
• Secondary Hypertension (7%):
  • Caused by other medical conditions (renovascular disease, adrenal disorders, thyroid issues, medications).

HTN Emergencies

• Sudden, life-threatening elevation of BP.
• Intravenous vasoactive medications (labetalol, esmolol, nicardipine, nitroglycerin) are typically used in emergencies.
• Oral medications (clonidine, nifedipine) are not useful in emergencies.

Pregnancy

• Labetalol is the preferred treatment.
• Hydralazine or methyldopa can also be used.
• Avoid ACE inhibitors and ARBs.

Patient with Asthma

• Low-dose diuretics, ARBs, and calcium channel blockers are acceptable options.
• Avoid beta-blockers and alpha-2-blockers.
• ACE inhibitors are not recommended due to dry cough and increased airway sensitivity.

Renin Inhibitors

• High-renin hypertension (~15% of cases), commonly in young men.
• Aliskiren blocks renin.
• Block the synthesis of all angiotensin peptides.

Aliskiren

• MOA: Direct renin inhibitor.
• Ultimately blocks conversion of Angiotensinogen.
• Often combined with other drugs (e.g. Hydrochlorothiazide).

ACE Inhibitors

• Beneficial in patients with diabetes, heart failure, chronic kidney disease, and hyperuricemia.

Angiotensin Converting Enzyme (ACE)

• ACE converts inactive Ang I into Ang II.
• A zinc-metalloenzyme that can be inhibited by metal-chelating agents.
• Also degrades bradykinin.

Drugs Inhibiting ACE

• Used to reduce circulating and local levels of Ang II, and aldosterone & ADH secretion.
• Often end in "pril" (e.g., lisinopril, ramipril).
• Used for hypertensive patients with renal disease.

Captopril

• Treatment for hypertension (normal or impaired renal function)
• MOA: Inhibits conversion of Ang I to Ang II.
• Keeps vessels dilated and prevents aldosterone secretion.
• PK: Renal elimination.
• AE: Proteinuria, skin rashes, altered taste, neutropenia, worsening proteinuria.

ACE Inhibitors: Adverse Effects

• Dry cough, often due to increased bradykinin.
• Angioedema, severe swelling under the skin in mucous membranes.

Lisinopril

• Longer half-life
• Hydrophilic, does not bind to proteins.
• Not broken down by the liver.
• Excreted unchanged by the kidneys.

ARBs

• Treatment for hypertension when patients cannot tolerate ACE inhibitors.
• Losartan, valsartan, candesartan are examples.
• Do not affect bradykinin metabolism.

Losartan

• Common ARB.
• Works well with low-dose hydrochlorothiazide.
• Blocks Ang II receptor (AT1).
• Oral, once daily. Extensively metabolized by the liver.

Sacubitril-Valsartan

• 1^st agent in a new class: angiotensin receptor neprilysin inhibitor (ARNI).
• An alternative to ACE inhibitors or ARBs
• Approved for pediatric patients with heart failure.
• MOA: Blocks neprilysin (prevents the breakdown of natriuretic peptides), lowers blood pressure, reduces aldosterone. Valsartan blocks Angiotensin receptor

α-agonists & antagonists

• Treatment for hypertension in pregnancy (a-methyldopa).
• a-blockers (prazosin) can cause orthostatic hypotension when first started.

α-adrenergic Receptor Modulators

• MOA: affects the sympathetic nervous system to decrease systemic vascular resistance.
• Lowering BP
• Adverse effects: orthostatic hypotension, bradycardia
• Examples: methyldopa, clonidine, prazosin

Methyldopa

• Centrally acting alpha-2 adrenergic agonist.
• Treatment for hypertension, especially in pregnancy.
• No teratogenic effects.

Clonidine

• Centrally acting alpha-2 adrenergic agonist.
• Treatment for hypertension and ADHD.
• Often used to manage severe hypertension.

Prazosin

• Alpha-1 adrenergic antagonist.
• Treatment for hypertension (not first-line)
• Marked effects: First dose orthostatic hypotension.

Beta-Blockers

• Treatment for hypertension in patients with heart disease history
• 'lol' (e.g., metoprolol, atenolol, carvedilol, labetalol, esmolol)
• MOA: blocks beta receptors.
• Side effects: bradycardia, contraindicated in bronchial asthma.

Labetalol

• Combined beta- and alpha- blocker.
• Non-selective.
• Also promotes glucose uptake and reduces glycogenolysis/gluconeogenesis.
• Used for hypertensive emergencies and in pregnancy.

Atenolol

• Selective beta-1 blocker.
• Used for hypertension and atrial fibrillation.
• Does not cause postural hypotension.

Other Beta-Blockers

• Metoprolol
• Carvedilol
• Esmolol

Calcium Channel Blockers

• Treatment for hypertension in patients with asthma
• Blocks the system causing contraction, relaxes vessel muscles
• Examples: verapamil, diltiazem, nifedipine, amlodipine
• Side effects include flushing, syncope, peripheral edema, constipation

Nicardipine

• Short-acting dihydropyridine calcium channel blocker.
• Treatment for hypertensive emergencies.
• MOA: Lowers BP by reducing Ca2+ influx into vascular smooth muscle cells.

Direct-Acting Vasodilators

• Treatment for severe refractory hypertension, malignant hypertension, and hypertensive emergencies.
• Examples: hydralazine, minoxidil

Hydralazine

• Dilates arterioles, decreases systemic vascular resistance.
• Used for hypertension and chronic heart failure when combined with nitrates.

Minoxidil

• Arterial vasodilator.
• Treatment for severe hypertension.

Nitrates

• Cause vasodilation by releasing nitric oxide (NO).
• Used for hypertension (especially hypertensive emergencies).
• Nitroglycerin (short-acting), isorbide dinitrate (long-acting), and nitroprusside (IV).

Nitroprusside

• Non-selective vasodilator to prevent end-organ damage during severe hypertension.
• Water-soluble salt comprised of ferrous iron complexes with nitric oxide (NO) and five cyanide ions.
• MOA: Acts as a prodrug, reacts with sulfhydryl groups on erythrocytes and other proteins to produce nitric oxide (NO).
• PK: IV infusion (rapid onset <1').
• AE: Cyanide accumulation.

Fenoldopam

• Dopamine-1 receptor agonist.
• Treatment for hypertensive emergencies.
• MOA: Affects dopamine-1 receptors in mesenteric, coronary and renal arteries, thus increasing renal perfusion.
• PK: Short half-life (10 minutes), administered by a continuous IV infusion.

Diuretics

• Treatment for newly diagnosed hypertension.
• Thiazide diuretics (hydrochlorothiazide, chlorthalidone, indapamide)
• K+-sparing diuretics (spironolactone, eplerenone) are used for refractory hypertension and counteract potassium depletion from other diuretics.

Hydrochlorothiazide

• Diuretic that reduces peripheral vascular resistance.
• Reduces blood volume via inhibiting Na-Cl symporter.
• Often used as first-line treatment for essential hypertension.

NSAIDS and ACEI

• NSAIDs reduce ACEI efficacy.

First-Line Agents

• ACEI, ARBs, CCBs, thiazide diuretics

  • Patients with pre-existing diabetes: ACEIs or ARBs.
  • Patients not with pre-existing diabetes: Thiazide diuretics.
  • Patients with migraine: Nifedipine
  • Patients with MI: Beta-blocker
  • Pregnancy and Children should avoid ACEI drugs.

When to Treat Hypertension

• BP thresholds and recommendations for treatment.
• A stepped approach

Site of Drug Action

• Summary of drug action locations in the body, categorized by drug mechanism

Untreated Hypertension

• Angiotensin II can remodel cardiomyocytes, leading to heart attacks.