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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.