Focus on mechanisms, pharmacological targets, and drug classes affecting blood pressure.
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.
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.
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.
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.
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).
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.
Blocks conversion of angiotensin I to II, impacting arteriolar vasoconstriction and reducing blood pressure.
Inactivates bradykinin, leading to increased NO production.
First-line for hypertension, heart failure, post-MI recovery.
Variable metabolization; patient-specific dosing.
Cough due to bradykinin accumulation, risk of angioedema, contraindicated in pregnancy.
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.
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.
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.
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.