Lecture 16 - Diuretics and Antihypertensive Drugs Flashcards
Renal Physiology
What occurs during the filtration of blood?
Waste products, toxins, and excess substances, such as electrolytes and water, are filtered from the bloodstream to form urine
Renal Physiology
What is regulated?
- Sodium, potassium, calcium, and phosphate
- Balance body fluid by adjusting the amount of water
- regulate blood pressure
Renal Physiology
What are the functions of the renal system?
- Filtration of blood
- regulation of electrolytes, fluid balance, and blood pressure
- Production of hormones
- Acid-Base balance
- Excretion of waste products and detoxification
- Pheromone secretion
Where does urine formation take place?
In the nephrons within the kidneys (includes filtration, reabsorption and secretion)
What are the steps in urine formation?
- Glomerular filtration - creates a plasmalike filtrate of the blood
- Tubular reabsorption - Removes useful solutes from the filtrate and returns them to the blood
- Tubular secretion - Removes additonal wastes from the blood and adds them to the filtrate
- Water conservation - Removes water from the urine and returns it to the blood; concentrates wastes
What substances can pass through the filter?
Water, electrolytes, glucose, amino acids, fatty acids, vitamins, urea, uric acid, creatinine (anything < 8 nm)
How are sodium and chloride ions reabsorbed?
Cation exchange and chloride ion transport
How is Water reabsorbed?
Within the proximal convoluted yubules and the collecting ducts. Water rushes toward sodium ions in the blood through aquaporins.
Role of kidney in regulating acid-base balance
How does the kidney regulate acid-base balance?
CO2 + H2O –carbonic anhydrase–> H+ + HCO-3
- H+ gets secreted
- HCO3- is reabsorbed as a buffer and added to extracellular fluid
What are diuretics used to manage?
- Anuria
- Hypertension
- Heart failure
- Edema
What are the classes of diuretics?
- Osmotic agents
- carbonic anhydrase inhibitors
- Thiazide and thiazide-like compounds
- Organic acids (loop diuretics)
- Potassium-sparing diuretics
- ADH antagonists
What is the site of action of Osmotic diuretics?
Glomerulus
What is the site of action of Carbonic anhydrase inhibitors?
Proximal convoluted tube
What is the site of action of Loop diuretics?
Ascending limb of the nephron loop
What is the site of action of Thiazide/thiazide-like diuretics?
Distal convoluted tube
Osmotic diuretics - Mechanism of action
Acts osmotically by attracting fluid from edematous tissues –> creates an osmotic gradient within the renal tubular lumen to prevent water reabsorption. Osmotic diuretics cannot cross tubular membrane. Produces a mild diuresis with no alteration in electrolyte or acid-base balance
Osmotic diuretics - Indication
Treatment of anuria, oliguria, acute kidney injury, cerebral edema, drug toxificity management
Osmotic Diuretics - Drug examples
Glycerin, isosorbide, mannitol
Carbonic Anhydrase inhibitor - Mechanism of action
Inhibition of carbonic anhydrase –> results in excretion of sodium ions into urine
Distal convoluted tubules increase the secretion of potassium ions –> leads to increased level of potassium in the urine (hypokalemia)
How do carbonic anhydrase inhibitors affect the acid-base balance?
- Prodiction of bicarbonate ions is inhibited –> metabolic acidosis (increased pH in body due to increase of bicarbonate in blood) may occur
Carbonic anhydrase inhibitors - Indication
- Weakest of the diuretics
- Main use is in the treatment of glaucoma
Carbonic anhydrase inhibitors - Drug examples
Acetazolamide - inhibits both isoforms inhibits both isoforms of carbonic anhydrase; the decreased carbonic anhydrase activity results in decreased
Na+ and HCO3– absorption
Loop diuretics - Mechanism of action
Inhibits sodium and chloride ion transport in the loop of Henle
- significant loss of sodium, potassium, chloride, and water occurs
- Targets NKCC2
-VERY efficient diuretics (highest capacity of diuresis
Loop diuretics - Drug examples
Bumetanide, ethacrynic acid, furosemide, and torsemide
Thiazide and thiazide-like diuretics - Mechanism of action
Produce diuresis by inhibiting sodium transport
- most commonly used diuretics
- Targets NCC (sodium-chloride co-transporter
- Causes hypochloremic alkalosis (low chloride in blood), hypokalemia (low potassium in blood), and hyponatremia (low sodium in blood)
Thiazide and thiazide-like Diuretics - Drug examples
Chlorothiazide, chlorthalidone, and
metolazone
Which diuretics can cause hypokalemia and metabolic alkalosis in the blood and why?
Loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule –> increases potassium loss
Reduced blood volume and arterial pressure –> activates the renin-angiotensin-aldosterone system –> increased aldosterone which stimulates sodium reabsorption and increases potassium and hydrogen ion excretion into urine –> hypokalemia and metabolic alkalosis in the blood
Potassium-Sparing Diuretics - Indications
- Controls potassium depletion
- Used to treat edema, hypertension, and primary hyperaldosteronism
- Prevents development of hypokalemia
Potassium-Sparing Diuretics - Mechanism of action
Directly targets ENaC, or regulates the expression and function of ENaC, K+ channels and Na+/K+ ATPase by antigonizing aldosterone
Potassium-Sparing Diuretics - Drug examples
Amiloride and tramterene (inhibit ENaC) and spironolactone (inhibits aldosterone)
What do antidiuretic hormone (ADH, vasopressin) antagonists do?
Regulate water balance by controlling water loss in urine
Antidiuretic hormone antagonist
Vaptans - Mechanism of action
Inhibits vasopressin receptors (V1 and V2) –> decreased expression of aquaporin –> decreased water reabsorption and increased urination
Which naturally occuring xanthine derivatives produce a mild diuretic response?
Caffeine, pamabrom, theobromine, and theophylline
What are the two main roles of the kidneys in regulating blood pressure?
- Control electrolyte balance and blood volume
- Secrete renin
Renin-angiotensin-aldosterone (RAA) system
What is the normal response to a drop in blood pressure?
- Kidney releases renin which combines with angiotensinogen from the liver to produce angiotensin I
- Angiotensin I goes through the angiotensin-converting enzyme (ACE) in the lungs to produce angiotensin II
- Angiotensin II goes to the hypothalamus to produce ADH and thirst, to the cardiovascular system to cause vasoconstriction, and to the adrenal cortex in the kidney to produce aldosterone which causes sodium and water retention
- All three conditions elevate blood pressure
How do you calculate cardiac output?
CO = heart rate (HR) x stroke volume (SV)
What is peripheral resistance (PR)?
- resistance or friction that the arteries and arterioles have against the flow of blood
- increased by vasoconstriction
How do you calculate blood pressure?
BP = HR x SV x PR
What factors contribute to blood pressure?
- Changes to HR, SV, or PR
- stimulation of the sympathetic nervous system
- high sodium intake, obesity, smoking, lack of exercise, and stress
What are the four major classes of Antihypertensive Agents?
- Diuretics
- Sympatholytics
- Vasodilators
- Renin-angiotensin system blockers
List of diuretics that act as Antihypertensive Agents
- Thiazide
- Loop diuretics
- K+ -sparing diuretics
List of sympatholytics that act as Antihypertensive Agents
- CNS sympathetic outflow blockers
- Ganglionic blockers
- Postganglionic adrenergic nerve terminal antagonists
- Alpha1-Adrenergic antagonists
- Beta1-Adrenergic antagonists
- Mixed alpha-adrenergic antagonists
- Mixed beta-adrenergic antagonists
List of vasodilators that act as Antihypertensive Agents
- Calcium channel blockers
- Minodixidil
- Hydralazine
- Sodium nitroprusside
Renin-angiotensin system blockers that act as Antihypertensive Agents
- Renin inhibitors
- ACE inhibitors
- AT1 antagonists
- Aldosterone antagonists
Antihypertensive Agents
Diuretics - Mechanism of action
- Increase excretion of sodium and water and reduces blood volume and CO
- Long-term antihypertensive effect develops –> reduced intracellular sodium concentration inside vascular smooth muscle
Antihypertensive Agents
Clonidine (centrally acting sympatholytic drug) - Mechanism of action
- Stimulates inhibitory alpha-2 receptors
- Reduces activity of sympathetic nerves that travel from the heart, kidneys, and blood vessels
Antihypertensive Agents
Prazosin and Terazorin (Alpha-1 blockers) - Mechanism of actions
Produces vasodilation effects and decreased peripheral resistance
Antihypertensive Agents
Propranolol and Atenolol (Beta-1 blockers) - Mechanism of action
Block beta-1 recpetors in the heart and the release of renin from the kidneys
Antihypertensive Agents
Vasodilator drugs - mechanism of action
- Act directly on vascular smooth muscle to cause relaxation (ex. nitrate medicines)
- Used in combination with diuretics and beta-blockers
Antihypertensive Agents
Hydralazine (vasodilator) - Mechanism of action
Mechanism unknown - may target calcium channel of smooth muscle
- used in moderate to severe hypertension
Antihypertensive Agents
Minoxidil (vasodilator) - Mechanism of action
Potassium channel activator –> causes hyperpolarization
- more potent arteriolar dilator than hydralazine
Antihypertensive Agents
Nondihydropyridines (vasodilator) - mechanism of action
Calcium channel blocker
- Ex. Verapamil and diliazem
- have direct actions to decrease heart rate, AV conduction, and myocardial contractility
Antihypertensive Agents
Dihydropyridines (vasodilator) - Mechanism of action
Calcium channel blocker
- Ex. Nifedipine and amlodipine
- Do not have direct actions on the heart
Antihypertensive Agents
Aliskiren - Mechanism of action
Inhibits enzymatic activity of renin
Antihypertensive Agents
Angiotensin-coverting enzyme (ACE) inhibitors - Mechanism of action
Inhibits formation of angiotensin II and inhibit inactivation of bradykinin (a potent vasodilator)
- Decreases release of aldosterone and antidiuretic hormone
Antihypertensive Agents
Angiotensin receptor blockers (ARBs) - Mechanism of action
Bind to the AT1 receptor and antagonize actions of angiotensin II
- orally active drugs
Antihypertensive drugs - Site of action
Methydopa, Clonidine, Guanabenz, Guanfacine
Vasomotor center
Antihypertensive drugs - Site of action
Mecamylamine
Sympathetic ganglia
Antihypertensive drugs - Site of action
Propranolol
- Beta receptors in the heart
- Beta receptors of juxtaglomerular cells that release renin
Antihypertensive drugs - Site of action
Losartan
Angiotensin receptors in vessels
Antihypertensive drugs - Site of action
Prazosin
Alpha-receptors in vessels
Antihypertensive drugs - Site of action
Hydralazine, Minoxidil, Nitroprusside, Diazoxide, Verapamil, Fenoldopam
Vascular smooth muscle
Antihypertensive drugs - Site of action
Thiazides
Kidney tubules
Antihypertensive drugs - Site of action
Captopril
Angiotensin converting enzymes
Antihypertensive drugs - Site of action
Aliskiren
Renin (first enzyme in the RAA system)
