MPP II 2.6 - RENAL PHYS. & PHARM II

• Lecture #16 is about Renal Physiology and Pharmacology II, presented by Austin Fairman, OMS-II, with slides adapted from Julia Hum, PhD.

ROMK

• ROMK, or Renal Outer Medullary Potassium channel, is located in the thick ascending limb.
• It regulates potassium.
• It secretes potassium into the lumen to allow for reabsorption via the Na+/K+/2Cl- cotransporter.
• Impaired ROMK activity limits this process.

Prox Conv Tub

• In the Proximal Convoluted Tubule (PCT), Carbonic Anhydrase IV (CA IV) converts CO2 + H2O.
• CA II converts carbonic acid to bicarbonate (HCO3-) and H+.
• PCT reabsorbs bicarbonate and secretes NH3/H+ and NH4+.
• Acetazolamide inhibits Carbonic Anhydrase II & IV in the PCT.
• Loop diuretics inhibit the Na+/K+/Cl cotransporter in the Thick Ascending Limb (TAL)

Learning Objectives

• Map diuretics to the portion of the nephron each target pharmacologically.
• Categorize the classes of diuretics and identify specific drug names within a class.
• Know each class of diuretic's mechanism of action.
• Relate the mechanism of action of each diuretic to its clinical uses.
• Connect adverse effects of a diuretic to its mechanisms of aaction.
• Diagnose each diuretic's ability to promote diuresis (mild to severe).

Early Distal Tubule (TAL -> DCT)

• The Thick Ascending Limb (TAL) of the loop of Henle transitions into the Distal Convoluted Tubule (DCT).
• DCT is the hormonal regulator.
• The thick ascending limb is specialized for transport with epithelial walls that are dense with mitochondria to supply ion pumps with energy.
• The DCT actively transports NaCl out of the tubule with very low water permeability.
• Actively transports NaCl out of tubule.
• The DCTis similar to the ascending loop of Henle.
• DCT is the main site of Mg2+ and Ca2+ homeostatic regulation.

Early DCT- Na, Cl, Ca

• The Early DCT is the site of active solute reabsorption.
• Resorption occurs via apical Na+/Cl- cotransporter, followed by Na+ pumped to the interstitium by basolateral Na+/K+ ATPase.
• Cl- exits via Cl- channels.
• Interstitial Ca2+ concentrations are 10,000 times higher than intracellular.
• Calcium crosses the apical membrane via TRPV5.
• As intracellular Ca2+ rises, the Ca2+ ATPase activity increases.
• Na+/Ca2+ exchanger aids in supporting Ca2+ transport when intracellular levels are high.

PTH Regulation

• PTH (Parathyroid Hormone) increases calcium reabsorption.
• Release of calcium is incited when plasma Ca2+ is low
• PTH binds GPCR and activates AC and PLC
• Result is increase TRPV5 opening and Ca2+ reabsorption
• Vitamin D increases expression of most proteins in Ca2+ transport.

DCT targets, Thiazides

• The DCT is impermeable to water
• Ca2+ reabsorption happens via passage through TRPV5 channel.
• Ca2+ is transported by a Na+/Ca2+ exchanger into the interstitial fluid and Ca2+ excretion is regulated by PTH in this portion of the tubule.
• Thiazides are the most widely used diuretics and all thiazides affect the DCT.
• They all have equal maximum effects, the only difference being potency
• Thiazides are considered 'low ceiling diuretics' increasing the dose above therapeutic will not promote further diuresis

DCT Targets- MOA of Thiazides

• Thiazides decrease the reabsorption of Na+ by inhibiting a Na+/Cl- cotransporter on the luminal membrane of the tubules
• Increases the concentration of Na+ and Cl- in the tubular fluid
• Drugs must be excreted into the tubular lumen to be effective
• With decreased renal function thiazide diuretics lose efficacy
• Action occurs in Site of action on the luminal membrane

DCT Targets- Thiazide Actions

• Thiazides decrease urinary calcium excretion.
• Lowers Ca2+ in urine by promoting the reabsorption of Ca2+ in the DCT.
• Loop diuretics contrast as they increase the Ca2+ concentration in the urine.
• Thiazides preserve bone mineral density at the hip and spine and may reduce the risk of fractures.

Thiazide Clinical Use and Adverse Effects

• Mainstay of antihypertensive medication, well tolerated
• Loop diuretics, are the diuretics of choice in reducing extracellular volume in heart failure.
• Thiazides diuretics may be added if additional diuresis needed for these patients
• Treats Idiopathic hypocalcemia by inhibiting urinary Ca2+ excretion.
• Most adverse effects are involved in fluid and electrolyte balance like Potassium depletion
• Has the potential to cause hyponatremia, volume depletion, with orthostatic hypotension or light-headedness
• They inhibit the secretion of Ca2+, sometimes leading to hypercalcemia.

Think-Pair-Share: Thiazides

• Thiazides have a 'ceiling effect' due to only acting the the DCT
• Limited number of sodium chloride channels present.
• More thiazide dose increases risk for toxic byproduct buildup with action in different sites.

Late DCT CNT CCD (distal) collecting duct

• The site for acid/base balance and critical stage for recovery
• Location- Connecting Tubule (CNT) and Cortical Collecting Duct (CCD)
• Similar to descending loop of Henle in water permeability.
• Has similar structures and functions with intercalated cells (20-30%) that secrete acid and Na+ reabsorbing cells (70-80%).
• Regulated by Na+ homeostatic hormones, and the Collecting Duct (CCD) has principle cells.

Late DCT: Sodium and Chloride

• Transcellular reabsorption in the late distal tubule is driven by a transmembrane Na+ gradient made by basolateral Na+/K+ ATPase.
• The main pathway for Na+ reabsorption is via ENaC.
• When Nat crosses apicalmembrane leaves lumen very negative and K+ tries to offset this negative charge through ROMK.
• Creates driving force for paracellular Cl- reabsorption and the recovery also transcellularly via intercalated cells

Basolateral Cl Functions

• Cl- recovered via Apical Cl- channel allows influx.
• Basolateral Cl-/HCO3- exchanger for entering interstitium.

Principal Cell Regulation: Aldosterone

• Aldosterone regulates principal cells to recover Na+
• If increased blood pressure or increased renal flow: aldosterone stimulates a need to retain Nat or excrete K, Na reabsorption increases and secretion + excretion in that region
• Aldostrone Binds Mineralocorticoid receptor
• Result: Retains Na+ ,and gets rid of K+ via urine

Potassium Details

• Hyper- or hypokalemia adversely affect cardiac function
• Plasma K+ levels are determined in distal nephron segments and outer medullary collecting duct

Late DCT: Bicarbonate and Acid

• Responsibility of the intercalated cells (2 Types)
• Makes more acidic, ↑ secretion of H⁺.
• Bicarbonate and Acid Transporters
• Located in the Intercalated cells

Alpha Intercalated Cells

• Predominant form with secreted H+ into the tubule lumen via H+/K+ ATPase.
• Synthesized HCO3- secreted across the interstitium via Cl-/HCO3- exchanger in the basolateral membrane.

Beta Intercalated Cells

• B-Intercalated cells synthesize acid pumped into interstitium by H+/K+ ATPase, making the urine more basic
• In the Basolateral side, via apical Cl-/HCO3 - exchanger: "pendrin"

Collecting Ducts

• Collecting Ducts (CD) fluid at entrance is dilute.
• Fluid must go through corticopapillary osmotic gradient to extract water.
• Recovery of water via Aquaporins that are used when water intake is limited .
• Little water is recovered if water intake exceeds homeostatic needs

CCD Targets

• Pharm targets are responsible for Na+, K+, and water transport and Na out of lumen & ENaC
• Sodium enters the principal cells through ENaC and ROMK
• Na+ reabsorption relies on a Na+/K+-ATPase pump to be transported into the blood with a basolateral side.

Aldosterone in Principal Cells

• Aldosterone receptors present in the principal cells to influence Na+ reabsorption
• Can increase the synthesis of Sodium channels and of the Na+/K+-ATPase pump to increase Sodium reabsorption
• Generated in adrenal glands cortex

Aldosterone Antagonist: Potassium-sparing Diuretics

• Ex: Spironolactone
• Inhibits Reabsorption of Sodium and Secretion of Potassium via Aldosterone - Interferes by binding to the aldosterone receptor inhibiting its function.
• Can promote Potassium retention with decrease urine volume & sodium reabsorption
• A lack of mediator proteins prevents Na+ reabsorption and, therefore, K+ and H+ secretion

Aldosterone Antagonist- MOA

• Antagonizes aldosterone rendering the spironolactone-receptor complex inactive with Actions:
  • In most edematous states
  • Spironolactone antagonizes the activity of aldosterone, resulting in retention of K+ and excretion of Na+

Aldosterone Antagonist- Clinical uses/Effects

• Potassium sparing agents that do not promote loss of calcium
• Diuretic and for resistant hypertension.
• Prevents the remodeling that occurs with the progressing failure of the heart
• Leads to Decrease mortality associated when combined with those with HF
• The use for sex effects like chemically resembles sex steroids and may cause menstrual irregulaties and gynecomastia
• Other effects: Hyperkalemia, nausea, lethargy, and mental confusion, which can occur at low doses but should be used carefully
• Not used in patients with hyperkalemia

Sodium Channel Interruption: Triamterene and Amiloride

• Triamterene and Amiloride act to Block Na Transport channels/ resulting decrease in Na+/K+ exchange Unlike the aldosterone antagonists, Blocking the Na+/K+-exchange site in the collecting tubule does not depend on the presence of aldosterone, that do very high efficacy

Sodium Channel Interruption: Clinical Use

• Commonly used in combination with other diuretics
• Prevent the loss of K+ that thiazide loop diuretics cause
• Cause Increased uric acid, Renal stones, K+ retention

Style Question Analysis

• Involves the ineffectiveness of a thiazide diuretic, potentially due to requiring adequate renal function.
• The patient with high creatinine + BUN, has lowered K
• The patient has loop diuretics that increase calcium secretion
• The patient likely has loop diuretics-
• The patient has elevated Creatitine and BUN causing decreased GFR