Pharmacology: Basic Cardiovascular Pharmacology (McCauley)
DIURETICS:
· Basic Pharmacological Effects: all diuretics increase the loss of sodium into the forming urine, which results in increased urine flow and loss of water
· Drugs in this Class:
- Loop Diuretics:
o Furosemide
- Thiazide and Thiazide-Like Diuretics:
o Hydrochlorothiazide
o Metolazone
o Chlorthalidone
- Potassium Sparing Diuretics:
o Amiloride
o Spirinolactone
· Mechanism Based on Sites of Action:
- Proximal Tubule:
o Normal Physiology:
§ Basically all filtered organic metabolites are reabsorbed in the proximal tubule
§ Water is passively reabsorbed and tubular fluid maintains a constant osmolarity
§ Na Reabsorption:
Ø Na in the lumen exchanged for intracellular H+ using the Na/H+ exchanger
Ø Once in the cell, Na pumped into interstitium/blood using the Na/K ATPase
§ Bicarbonate Reabsorption:
Ø Excreted H+ combines with bicarbonate in the lumen to form carbonic acid
Ø Carbonic acid is hydrolyzed by carbonic anhydrase found in the luminal membrane, resulting in the formation of water and CO2
Ø CO2 diffuses back into the cell where it combines again with water (using a different CA enzyme) to form carbonic acid
Ø Intracellular carbonic acid dissociates into H+ (pumped back into lumen in exchange for Na) and bicarbonate (reabsorbed into the blood)
§ Cl/Base Exchanger:
Ø Bicarbonate is reabsorbed faster/more extensively than Na, and as a result, H+ being pumped into the lumen in exchange for Na no longer buffered
Ø Tubule fluid becomes acidic and activates this exchanger, which promotes the reabsorption of Cl- in exchange for base being pumped into lumen
§ Water Reabsorption:
Ø Volume of water that is reabsorbed exceeds the permeability of the cell membrane
Ø Water also passes through specialized water channels (aquaporin I)
o Drugs that Work Here:
§ Carbonic Anhydrase Inhibitors: reduce the activity of the Na/H exchanger, leading to loss of NaHCO3 and water; not often used in CV diseases
Ø Dorzolamide: topical CA inhibitor used locally (ie. in the eye to reduce intraocular pressure)
§ Osmotic Diuretics: do not permeate luminal membrane, increasing the osmolality of the forming urine and reducing the reabsorption of water; similar to glucose in diabetics
Ø Mannitol: osmotic diuretic given by IV to avoid osmotic diarrhea
- Loop of Henle:
o Normal Physiology:
§ Thin Loop: more water passively reabsorbed into the hypertonic interstitium
§ Thick Ascending Loop: impermeable to water
Ø NaK2Cl Symporter: transports Na, K and 2 Cl into the cell from the lumen
o Na pumped into interstitium/blood using Na/K ATPase
o Intracellular K+ increases (coming in from lumen AND interstitium)
o K+ diffuses back into lumen as a result (back diffusion of K+), resulting in a more positive luminal potential
Ø Positive Luminal Potential: driving force for NaK2Cl symporter, as well as the reabsorption of Ca++ and Mg++ from the tubular fluid
o Drugs that Work Here:
§ Loop (High Ceiling) Diuretics: direct inhibitors of the NaK2Cl transporter; diuretic effect can be severe and is primarily due to sodium loss (35% if filtered Na usually reabsorbed here)
Ø Furosemide
Ø Ethacrynic acid
- Juxtaglomerular Apparatus:
o Normal Physiology:
§ Juxtaglomerular Apparatus: microscopic structure in kidney located between the vascular pole of the renal corpuscle and the distal convoluted tubule of the same nephron
Ø Juxtaglomerular Cells: located in the afferent arterioles of the glomerulus; act as intra-renal pressure sensory and secrete renin*
Ø Macula Densa: cells lining the distal convoluted tubule who sense changes in concentration of sodium chloride
Ø Extraglomerular Mesangial Cells: communicate via gap junctions with structural mesangial cells that surround glomerular capillaries
§ Renin Secretion: inversely proportional to NaCl load delivered to macula densa (ie. if NaCl load is low, renin secretion increases)
o Importance in Diuretic Use:
§ Detection of NaCl load depends on action of NaK2Cl transporter: if using a loop diuretic (and to a lesser extent, a thiazide diuretic), the NaCl will not be able to be transported into the cells of the macula densa due to the blockage of this receptor
Ø Macula densa will perceive it as low NaCl load and stimulate renin release
Ø As a result, these drugs are typically given along with an ACE inhibitor, to prevent the downstream effects of renin
- Distal Convoluted Tubule:
o Normal Physiology:
§ DCT is impermeable to water
§ NaCC (Na/Cl- Symporter): electrically neutral pump that reabsorbs Na and Cl
Ø Na+ pumped back into interstitium/blood using Na/K ATPase
Ø Unlike in the TAL, there is no back diffusion of K+ and therefore lumen is not positively charged (no driving force for reabsorption of cations)
§ Ca++ Reabsorption:
Ø Ca++ channel AND a Ca/Na exchanger
Ø Both of these under the control of PTH (receptors for it located on membrane of tubular cells)
o Drugs that Work Here:
§ Thiazide and Thiazide-Like Diuretics: inhibit the Na+/Cl- symporter (NaCC) of the distal convoluted tubule; diuresis not as profound as that cause by loop diuretics, and will have additive effects if used with one (can be used in combination)
Ø Hydrochlorothiazide
Ø Metolazone
Ø Chlothalidone
- Late Distal Tubule/Collecting Duct:
o Normal Physiology:
§ Na+ Reabsorption by Principal Cells: controlled by aldosterone*
Ø Contain an epithelial Na channel (ENaC) that allows Na to enter the cell (driven by continuous expulsion of Na by Na/K ATPase on the basolateral side of the cell)
§ K+ Loss via Prinicipal Cells: controlled by aldosterone (Na+ reabsorption)*
Ø Na reabsorption creates a negative lumen potential that promotes the reabsorption of Cl- and the secretion of K+
Ø Therefore, the more Na+ that reaches the distal tubule, the more K+ lost (ie. loop and thiazide diuretics can cause hypokalemia)
Ø K+ loss worsened if bicarbonate also present (ie. due to CA inhibitors) because it increases negative lumen potential but cannot be reabsorbed
§ H+ Loss via Intercalated Cells: negative lumen potential contributes to expulsion of protons using ATP-dependent proton pump
§ Water Reabsorption: ADH stimulates the expression AQP2 on apical membrane to increase water reabsorption (Lithium dramatically reduces this effect à polyruria, polydipsia)
o Drugs that Work Here: potassium sparing diuretics (all may cause HYPERkalemia)
§ Amiloride: specific inhibitor of ENaC with mild diuretic action; used more commonly to blunt hypokalemic side effects produced by diuretics (however, can also be managed by oral KCl supplements)
§ Spironolactone: competitive antagonists of aldosterone with mild diuretic action
· Loop Diuretics (High Ceiling):
- Drugs in this Class:
o Furosemide*
o Bumetanide
o Ethacyrnic Acid
o Torsemide
- Clinical Use/Effects:
o Edema associated with:
§ Heart failure
§ Liver disease (cirrhosis)
§ Renal disease (nephrotic syndrome, chronic and acute renal insufficiency)
o Increases RBF
o Appears to have direct effects that relieve pulmonary congestion and left ventricular pressure in heart failure (ie. these effects occur prior to diuresis)*
o Acute hypercalcemia (in combination with saline)
o Mild hyperkalemia
o Elimination of bromide, fluoride, and iodine ions in toxic OD (halogens reabsorbed in ascending limb)
o Acute renal failure (increase urine flow and K+ excretion, may help flush intratubular casts)
- Pharmacokinetics:
o Well absorbed orally
o Eliminated by tubular secretion and filtration (by the kidneys)
o Half life depends on renal function (usually 1.5 hours)
§ Short half life is the reason why these agents are typically not good for tx of HTN
- Adverse Effects:
o Hypokalemia (increased Na+ to collecting duct causes K+ secretion)
o Alkalosis (increased Na+ to collecting duct causes H+ secretion)
§ Both managed with administration of potassium sparing diuretics or KCl
o Hypomagnesia (controlled with Mg supplementation)
o Dehydration (+/- hypercalcemia)
o Hyperuricemia and gouty attacks (hypovolemia-enhanced reabsorption of uric acid in the proximal tubule)
o Dose related hearing loss and allergic reactions (rare)
- Drug Interactions:
o NSAIDs decrease diuretic effects
· Thiazide and Thiazide-Like Diuretics:
- Drugs in this Class:
o Hydrochlorothiazide*
o Chlorthalidone*
o Metolazone*
o Quinethazone
o Indapamide
- Clinical Use/Effects:
o Edema associated with cardiac, hepatic and renal conditions
o Hypertension (most important CV application)
§ Use of low doses recommended (increasing can lead to unwanted SEs and extreme diuresis)
§ Lower peripheral resistance without significant effect on either HR or CO
Ø Indirect action on smooth muscle cells by depletion of Na, which leads to reduction in intracellular Ca (Na/Ca exchanger brings in Na), making SMCs refractory to contractile stimuli
§ Marginally decrease plasma volume and RBF
§ Increase plasma renin activity
§ Equally effective in African and European-American populations (Asians may be more sensitive)
o Chronic heart failure (often in combination with ACE inhibitors or loop diuretics)
o Idiopathic hypercalcuria with kidney stones
§ Inhibit NCC and lower Na+ reabsorption in DCT, leading to increased activity of basal Na/Ca exchanger that moves Na into cells and Ca into interstitium
§ Also leads to reabsorption of Ca++ from tubule through apical channel
o Nephrogenic diabetes inisipidus (ie. caused by lithium)
§ Results in paradoxical decreased urine flow that has not be explained (MOA unclear)
§ Need to monitor Li levels because it may reduce Li clearance
- Pharmacokinetics:
o Well absorbed orally
o Excreted in the urine via organic acid secretory system in the proximal tubule
o Half life varies (majority of them are long enough for once daily dosing)
- Adverse Effects:
o Hypercalcemia (not by itself, but can unmask subclinical hypercalcemic conditions)
§ Hyperparathyroidism
§ Sarcoidosis
§ Paraneoplastic syndromes
o Hypokalemia (same mechanism as loop diuretics)
o Alkalosis (same mechanism as loop diuretics)
§ Both reversed by potassium sparing diuretics or KCl supplements
o Hyperuricemia (competes with uric acid for secretion by the organic acid secretory system in the proximal tubule)
o Induce hyperglycemia (use with caution in patients with diabetes)
§ Impaired pancreatic release of insulin and reduced peripheral utilization of glucose
o Alter lipid profile (use with caution in patients with dyslipidemia)
§ 5-15% increase in total cholesterol and LDL
o Hypnatremia (severe but rare side effect that only occurs in predisposed individuals; can be fatal)
- Drug Interactions:
o NSAIDs reduce diuretic effects
· Spironolactone:
- Clinical Use/Effects:
o Severe (late) congestive heart failure
§ Reduces morbidity and mortality
§ Appears to be due to antagonism of aldosterone, which facilitates myocardial fibrosis
o In conjunction with thiazide and loop diuretics to prevent K loss
o Primary and secondary aldosteronism
o Edema (particularly due to hepatic cirrhosis)
- Adverse Effects:
o Hyperkalemia
o Endocrine like effects (gynecomastia, impotence, peptic ulcers)
§ Epleranone: more specific antagonist and causes less of these effects
AGENTS THAT INTERFERE WITH ANGIOTENSIN II:
· Pharmacological Effects of Angiotensin II:
- Structure and Production: octapeptide produced by serial proteolytic cleavage of angiotensinogen
o Angiotensinogen à(Renin)à Angiotensin I à(ACE)à Angiotensin II
§ Renin: cleaves the amino terminal decapeptide from the plasma protein angiotensinogen to give angiotensin I (highly dependent on the concentration of angiotensinogen, which is produced in and secreted by the liver)
Ø Factors Affecting Production/Secretion of Angiotensinogen:
o Corticosteroids
o Estrogens (oral contraceptives)
o Thyroid hormones
§ Angiotensin Converting Enzyme (ACE): cleaves two C-terminal residues from angiotensin I to produce angiotensin II (located in the vascular endothelium of most organs- esp. lungs and kidney)
Ø Also catalyzes the degradation of bradykinin
- Control of Secretion of Renin:
o NaCl Load (Macula Densa): release of renin INVERSELY proportional to NaCl load that is detected by the macula densa; NaCl is transported into the macula densa to be detected using NaK2Cl symporter (TAL) and the NaCC symporter (DCT)
o Changes in Renal BP (Juxtaglomerular Cells): changes in renal BP detected by these cells in the afferent arterioles of the glomeruli; increased pressure inhibits the release of PGs and stimulates renin secretion
§ NSAIDs and other inhibitors of PG synthesis DECREASE renin secretion
o Activation of Beta-1 Adrenergic Receptors: by SS postganglionic stimuli (powerful force for renin secretion)
- Effects of Angiotensin II:
o General Effects: all mediated by AT1 receptor and involve many mechanisms of signal transduction
§ Increased arterial pressure
§ Na and fluid retention (directly and indirectly- induce release of aldosterone)
§ Vascular and cardiac remodeling
o Effects on Peripheral Resistance:
§ Direct Effects: acts directly on arteriolar smooth muscle cells to cause constriction and increase in vascular resistance (more potent than NE)
Ø Most pronounced in kidney
Ø Least pronounced in skeletal muscle beds
§ Indirect Effects: also act to increase BP
Ø Enhances release of NE from SS nerves and EPI from the adrenal glands
Ø Reduces neuronal NE uptake
Ø Increases vascular sensitivity to NE
Ø Acts on areas of CNS that are not protected by BBB to increase sympathetic tone (ie. area postrema)
o Effects on Renal Function:
§ Increased Na retention:
Ø Stimulated Na/H exchange in proximal tubule
Ø Enhances aldosterone secretion
Ø Decreased renal blood flow (AT1 mediated contraction of renal smooth muscle and enhance SS tone)
§ Decreased GFR
Ø Constricts mesangial cells in glomerulus
Ø Constricts both afferent and efferent arterioles of glomerulus (exert opposing effects on GFR)
o Effects on Cardiovascular Structure:
§ Direct Effects: contribute to increased wall-to-lumen ratio in vessels and the concentric cardiac hypertrophy seen in HTN
Ø Increases migration, proliferation and hypertrophy of smooth muscle cells
Ø Hypertrophy of cardiac myocytes
Ø Increases ECM synthesis by both cardiac and vascular fibroblasts
§ Indirect Effects: involved in cardiac hypertrophy and remodeling
Ø Increased cardiac preload (volume expansion)
Ø Increased afterload (greater peripheral resistance)
Ø Increased aldosterone causes myocardial fibrosis
· Angiotensin Converting Enzyme (ACE) Inhibitors:
- General Pharmacological Effects: