5. Pharmacology of Hypertension 1

Pharmacology of Hypertension I

Overview

• Focus on mechanisms, pharmacological targets, and drug classes affecting blood pressure.

Learning Outcomes

• Identify pharmacological targets in blood pressure regulation.

• Describe the role of blood volume regulation and the related cell types and proteins.

• Compare and contrast drugs that regulate blood volume, including their mechanisms of action, pharmacokinetics, and potential side effects.

Antihypertensive Therapy

• Types of antihypertensive drugs categorized based on mechanisms:

  • Centrally Acting Agents: Moxonidine, Clonidine, Methyldopa.

  • Ganglionic Blockers: Various drugs affect neurotransmission.

  • Vasodilators: Various drugs affecting blood vessel diameter.

  • Calcium Channel Blockers: For reducing arterial pressure.

  • Beta-Blockers: To decrease cardiac output.

  • Diuretics: Affecting blood volume, including Thiazides and K+-sparing diuretics.

  • RAAS Modulators: Captopril, Aliskiren, and Spironolactone among others for direct action in the RAAS cascade.

Volume Regulation

Key Concepts

• Intravascular Volume: ~3 L, a small component of total body water.

• Feedback Systems:

  • Low-Pressure System: Atria and pulmonary vasculature influence ADH release for water reabsorption.

  • High-Pressure System: Baroreceptors to modulate sympathetic outflow and ADH.

• Natriuretic Peptides (NPs): Released during atrial wall stress to promote vasodilation and Na+ excretion.

Renin-Angiotensin-Aldosterone System (RAAS)

Components

• Key Players: Renin, Angiotensinogen from the liver, Angiotensin I, ACE in lungs converting it to Angiotensin II.

• Functions of Angiotensin II:

  • Vasoconstriction and increased blood pressure.

  • Stimulation of thirst and ADH release.

  • Aldosterone secretion leading to renal Na+ retention.

Pharmacological Classes Modifying Volume

Categories

• Agents modifying neurohormonal volume regulators.

• Direct acting agents on nephron segments altering renal Na+ reabsorption.

  • RAAS Interruption: 1. Renin inhibitors (Aliskiren) 2. ACE inhibitors (Captopril) 3. Angiotensin receptor blockers (Valsartan) 4. Mineralocorticoid receptor antagonists (Spironolactone).

Renin Inhibitors

Details

• Mechanism of Action (MoA): Inhibits conversion of angiotensinogen to angiotensin I.

• Example: Aliskiren, for patients with renal insufficiency.

• Pharmacokinetics (PK): Low oral bioavailability, T1/2 ~ 24 hrs.

• Side Effects: Include hypotension and renal impairment.

ACE Inhibitors

Mechanism

• Blocks conversion of angiotensin I to II, impacting arteriolar vasoconstriction and reducing blood pressure.

• Inactivates bradykinin, leading to increased NO production.

Clinical Uses

• First-line for hypertension, heart failure, post-MI recovery.

Pharmacokinetics

• Variable metabolization; patient-specific dosing.

Side Effects

• Cough due to bradykinin accumulation, risk of angioedema, contraindicated in pregnancy.

Angiotensin Receptor Antagonists (ARBs)

Mechanism and Use

• Allow more complete inhibition of angiotensin II effects; examples: Valsartan, Losartan.

• Used as first-line treatment for hypertension and often in combination with ACE inhibitors.

• Fewer side effects compared to ACE inhibitors.

Diuretics

• Help regulate urinary volume and composition through inhibiting ion reabsorption in nephron segments:

  • Osmotic Diuretics: e.g. Mannitol.

  • Carbonic Anhydrase Inhibitors: e.g. Acetazolamide.

  • Loop Diuretics: e.g. Furosemide, effective for significant fluid retention.

  • Thiazides: e.g. Hydrochlorothiazide, easier on the system for mild hypertension.

  • K+-Sparing Diuretics: e.g. Spironolactone, help retain potassium.

Detailed Nephron Mechanisms

Segments

• Proximal Convoluted Tubule (PCT): 2/3 of Na+ reabsorption occurs here, utilizing NHE3 Na+/H+ exchanger.

• Thick Ascending Limb of Loop of Henle: Major target for Loop diuretics (NKCC2 inhibition).

• Distal Convoluted Tubule (DCT): Modest Na+ reabsorption here affected by Thiazides.

• Collecting Duct: Final adjustments to Na+ and K+ levels, controlled by aldosterone and specific diuretics.

Conclusion

Summary of Key Points

• Blood volume regulation is essential for maintaining blood pressure.

• Key drug classes affecting RAAS include Renin inhibitors, ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists.

• Important diuretic classes affect blood volume through various nephron action sites.