Thiazides/ACE/ARBs/DRI

• Overview of the circulatory system

  • Delivery of oxygen, nutrients, hormones, electrolytes, and other essentials to the cells
  • Removal of carbon dioxide, metabolic wastes, and other detritus from the cells
  • Two major divisions: Pulmonary circulation and systemic circulation
• What makes blood flow

  Force that drives flow is greater than resistance
• Cardiac output

  • Average adult, 5 L/min
  • Cardiac output = Heart rate × Stroke volume
• Determinants of cardiac output

  • Heart rate
  • Stroke volume
  • Myocardial contractility
  • Cardiac afterload
  • Cardiac preload
• Preload

  End-diastolic volume or end-diastolic pressure
• Afterload

  Arterial pressure that the left ventricle must overcome to eject blood
• Regulation of cardiac output

  1. Control of stroke volume by venous return

  2. Starling law of the heart

  3. Factors that determine venous return

  4. Starling law and maintenance of systemic-pulmonary balance
• Arterial pressure

  AP = Peripheral resistance × Cardiac output
• Regulation of arterial pressure

  1. Autonomic nervous system (ANS)

  2. Renin-angiotensin system

  3. Kidneys
• Steady-state control by the ANS

  • Regulates AP by adjusting cardiac output (CO) and peripheral resistance
• Rapid control by the ANS: The baroreceptor reflex


  1. Constriction of nearly all arterioles

  2. Constriction of veins

  3. Acceleration of heart rate
• Renin-angiotensin-aldosterone system


  1. Constriction of arterioles and veins (angiotensin II)

  2. Retention of water by the kidney (aldosterone) through the retention of sodium
• Postural hypotension (orthostatic hypotension)

  Renal retention of water
• Three principal natriuretic peptides

  • Atrial natriuretic peptide (ANP)
  • B (brain)-natriuretic peptide (BNP)
  • C-natriuretic peptide (CNP)
• Basic functional unit of the kidney: Nephron


  • Glomerulus
  • Proximal convoluted tubule
  • Loop of Henle
  • Distal convoluted tubule
• Three basic functions of diuretics

  • Cleansing of extracellular fluid (ECF) and maintenance of ECF volume and composition
  • Maintenance of acid-base balance
  • Excretion of metabolic wastes and foreign substances
• Three basic renal processes

  1. Filtration: Occurs at the glomerulus

  2. Reabsorption: 99% of water, electrolytes, and nutrients undergo reabsorption

  3. Active tubular secretion
• Processes of reabsorption that occur at specific sites along the nephron

  1. Proximal convoluted tubule

  2. Loop of Henle

  3. Distal convoluted tubule (early segment)

  4. Late distal convoluted tubule and collecting duct (distal nephron)

  5. Sodium-potassium exchange

  6. Regulation of urine concentration
• How diuretics work: Mechanism of action

  Blockade of sodium and chloride reabsorption
• Site of action


  Proximal tubule produces greatest diuresis
• Adverse effects of diuretics

  • Hypovolemia
  • Acid-base imbalance
  • Electrolyte imbalances
• Classification of diuretics


  • Loop: Furosemide
  • Thiazide: Hydrochlorothiazide
  • Osmotic: Mannitol
  • Potassium-sparing: Aldosterone antagonists (spironolactone), Nonaldosterone antagonists (triamterene)
  • Carbonic anhydrase inhibitors
• Furosemide (Lasix): Most frequently prescribed loop diuretic

  • Mechanism of action: Acts on ascending loop of Henle to block reabsorption
  • Pharmacokinetics: Rapid onset (PO 60 min; IV 5 min)
  • Therapeutic uses: Pulmonary edema, Edematous states, Hypertension
• Adverse effects of furosemide

  • Hyponatremia, hypochloremia, and dehydration
  • Hypotension
  • Hypokalemia
  • Ototoxicity
• Drug interactions with furosemide

  • Digoxin toxicity - increased from K+ loss
  • Ototoxic drugs
  • Potassium-sparing diuretics - counterbalance K+ loss
  • Lithium - decrease lithium excretion
  • Antihypertensive agents
  • Nonsteroidal antiinflammatory drugs - decrease effectiveness
• Other high-ceiling (loop) diuretics

  • Ethacrynic acid [Edecrin]
  • Bumetanide [Bumex]
  • Torsemide [Demadex]
  • approved for HF, CKD, and cirrhosis
• Thiazides and related diuretics

  • Effects similar to those of loop diuretics
  • Increase renal excretion of sodium, chloride, potassium, and water
  • Elevate levels of uric acid and glucose
  • Maximum diuresis is considerably lower than with loop diuretics
  • Not effective when urine flow is scant (unlike with loop diuretics)
• Hydrochlorothiazide [HydroDIURIL]


  • Most widely used
  • Action: Early segment distal convoluted tubule
  • Peaks in 4 to 6 hours
  • Therapeutic uses: Essential hypertension, Edema, Diabetes insipidus
• Adverse effects of hydrochlorothiazide

  • Hyponatremia, hypochloremia, and dehydration
  • Hypokalemia
  • Hyperglycemia
  • Hyperuricemia
  • Impact on lipids, calcium, and magnesium
• Drug interactions with hydrochlorothiazide

  • Digoxin - use caution because of K+
  • Augments effects of hypertensive medications
  • Can reduce renal excretion of lithium (leading to accumulation)
  • NSAIDs may blunt diuretic effect
  • Can be combined with ototoxic agents without increased risk of hearing loss
• Potassium-sparing diuretics


  • Useful responses: Modest increase in urine production, Substantial decrease in potassium excretion
  • Rarely used alone for therapy
• Spironolactone [Aldactone]


  Mechanism of action: Blocks aldosterone in the distal nephron, Retention of potassium, Increased excretion of sodium
• Therapeutic uses of spironolactone

  • Hypertension
  • Edematous states
  • Heart failure (decreases mortality in severe failure)
  • Primary hyperaldosteronism
  • Premenstrual syndrome
  • Polycystic ovary syndrome
  • Acne in young women
• Adverse effects of spironolactone


  • Hyperkalemia
  • Benign and malignant tumors
  • Endocrine effects - gynecomastia, menstrual irregularities, impotence, deepening of the voice
• Drug interactions with spironolactone

  • Thiazide and loop diuretics - combined to help with k+ loss
  • Agents that raise potassium levels - ACE, ARBs, and K+ supplements
• Triamterene (nonaldosterone antagonists) MOA

  Disrupts sodium-potassium exchange in the distal nephron, Direct inhibitor of the exchange mechanism

  decrease sodium reabsorption and reduction of potassium secretion

  inhibits ion transport
• Potassium-Sparing Diuretics


  • Useful responses
  • Modest increase in urine production
  • Substantial decrease in potassium excretion
  • Rarely used alone for therapy
• Triamterene [Dyrenium]


  
  

  Therapeutic uses: Hypertension, Edema
• Adverse effects of Triamterene [Dyrenium]

  • Hyperkalemia
  • Leg cramps
  • Nausea
  • Vomiting
  • Dizziness
  • Blood dyscrasias (rare)
• Amiloride [Midamor]


  Mechanism of action: Blocks sodium-potassium exchange in the distal nephron

  Therapeutic use: Counteracts potassium loss caused by more powerful diuretics

  Adverse effects: Hyperkalemia