Pharmacology

• Topics

  • DIURETICS
  • RENIN AND ANGIOTENSIN SYSTEM
  • OTHER VASOACTIVE PEPTIDES
  • ADRENERGIC AGONISTS AND ANTAGONISTS
• Diuretics


  Increase the rate of urine flow, urine contains electrolytes, it increases the rate of Na+ excretion (natriuresis) and an accompanying anion, usually Cl-
• Diuretic Braking


  Renal compensatory mechanisms bring sodium excretion in line with sodium intake, this is when the body craves for salt because of sodium excretion
• Afferent Arteriole


  Unfiltered blood flows into the glomerulus via the afferent arteriole. Prostaglandins can affect its diameter, influencing blood flow.
• Proximal Convoluted Tubule (PCT)


  About 65% of sodium is reabsorbed here. The PCT is close to the glomerulus and is efficient at reabsorbing solutes and water.
• Loop of Henle


  The thin descending limb of the loop of Henle is where water is primarily reabsorbed, concentrating the urine. Loop diuretics act here to promote diuresis.
• Distal Tubule


  Thiazide diuretics act in the distal convoluted tubule, inhibiting sodium and water reabsorption.
• Osmotic Diuretics


  Act by increasing the osmotic pressure of the filtrate, preventing water reabsorption. They typically work in the proximal tubule and the descending limb of the loop of Henle.
• Percentage of sodium reabsorption


  • PCT - 65%
  • TAL - 20-35%
  • DCT - 5-10%
• Mineralocorticoid Antagonist


  Triamterene
• Carbonic Anhydrase Inhibitors


  • Brinzolamide
  • Zonisamide
  • Acetazolamide (proximal convoluted tubule)
  • Dorzolamide
  • Diclofenamide
  • Methazolamide
  • Ethoxzolamide
• Carbonic Anhydrase


  An enzyme for the breakdown of carbonate and the combining of carbon dioxide and water to form carbonic acid
• Type 2 and Type 4 Carbonic Anhydrase


  Makes carbonic acid to form bicarbonate which is needed by the body acting as a buffer which will resist in significant change in pH, if CA is inhibited there will be no production of hydronium which acts with an antiport along w/ sodium in the urine, as a result there will be increased excretion of sodium
• Effects of Carbonic Anhydrase Inhibition


  • Rapid rise in urinary HCO-3 excretion to about (35%), fractional excretion of Na+ (5%) – (this is why it is not really used for diuresis but a different purpose), fractional excretion of K+ (70%), decreases the GFR
• Other Actions of Carbonic Anhydrase Inhibitors

  • Ciliary processes of the eye - CA mediates formation of HCO-3 in aqueous humor decreasing the water formation in the eyes decreasing the pressure
  • CNS - paresthesia and somnolence
  • Epilepsy - production of metabolic acidosis
  • Erythrocytes - increase CO2 levels in peripheral tissues and decrease CO2 levels in expired gas
  • Blood Vessels - vasodilation by opening vascular Ca2+ activated K+ channels
• Resistance to Diuretic Monotherapy

  • (Acetazolamide + HCTZ)
  • Open Angle Glaucoma (Brinzolamide and Dorzolamide)
  • Acute-angle closure Glaucoma (Preoperatively)
  • Absence Seizure
  • High-altitude sickness or Mountain Sickness
  • Familial Periodic Paralysis (Dichlorphenamide)
  • Metabolic Acidosis
• Off-Label Uses of Carbonic Anhydrase Inhibitors


  • Normal pressure hydrocephalus (high levels of CSF in the brain)
  • Idiopathic intracranial hypertension
  • Cystine renal calculi (prevention)
  • Respiratory Stimulant (for Px with stable hypercapnic COPD)
• Calcium Oxalate is the most common form of stones, ACETAZOLAMIDE is used for stones [foods high in oxalates - avocados, dates, grapefruit juice, kiwi, orange, raspberries, spinach, tomato sauce] - tx. Potassium Citrate
• Toxicity of Sulfonamide Derivatives


  • Bone Marrow Depression
  • Skin Toxicity
  • Sulfonamide-like renal lesions
  • Allergic Reactions
• Other Toxicities

  Drowsiness and Paresthesia (Large Doses)
• Adverse Effects of Carbonic Anhydrase Inhibitors


  • Diversion of ammonia of renal origin from urine into the systemic circulation - induce or worsen hepatic encephalopathy, Cl in Px with hepatic cirrhosis
  • Calculus (kidney stone) formation and ureteral colic - Precipitation of calcium phosphate salts in alkaline urine
  • Worsening of metabolic or respiratory acidosis - Cl in Px with hyperchloremic or severe COPD
  • Reduction of the urinary excretion rate of weak organic bases (because urine needs to be acidic)
• Osmotic Diuretics


  • Glycerin (PO)
  • Isosorbide (PO)
  • Mannitol (IV)
  • Urea (IV)
• Osmotic Diuretics


  Serve as a non-resorbable solutes that limit the osmosis of water into the interstitial space extracting water from intracellular compartments, (-) Mg+2 reabsorption in the TAL
• Effects of Osmotic Diuretics

  • Increase urinary excretion of nearly all electrolytes = sodium, potassium, calcium, magnesium, chloride, bicarbonate, phosphate = this is why it is prone to imbalance, increases the Renal blood Flow but Total GFR is not significantly altered [just like zero order]
• Therapeutic Uses of Osmotic Diuretics

  • Treatment of dialysis DISEQUILIBRIUM SYNDROME
  • Control intraocular pressure
  • Reduce cerebral edema and brain mass
  • Management of cystic fibrosis (Spray-dried form)
  • Diagnosis of Bronchial Hyperreactivity (PO inhalation)
  • Treatment and prevention of AKI
  • Antihemolytic urologic irrigation (During transurethral procedures)
• Toxicity and Adverse Effects of Osmotic Diuretics

  • Frank Pulmonary Edema
  • Hyponatremia/Hypernatremia
  • Dehydration
  • Cl in Anuric Px due to Severe renal disease
  • Urea - causes thrombosis or pain if there is extravasation, Cl in Px with impaired liver fxn which will increase blood NH3 level
• Loop Diuretics

  • Furosemide (PO/IV)
  • Bumetanide (PO/IV)
  • Ethacrynic Acid (PO)
  • Ethacrynic Sodium (Inj.)
  • Torsemide (PO)
• Loop Diuretics


  Inhibit Na+ K+ Cl-2 in the Thick Ascending Limb (TAL), High Ceiling Diuretics
• Why are Loop Diuretics High Ceiling?


  About 25% of the filtered sodium load normally is reabsorbed by the TAL and Nephron segments past the TAL do not possess the resorptive capacity
• Mechanism of Action of Loop Diuretics


  Inhibit Ca2+ and Mg2+ reabsorption, two types of symporters - "absorptive" symporter (ENCC2, NKCC2, or BSC1) and "secretory" symporter (ENCC3, NKCC1, or BSC2)
• Bartter Syndrome


  Like the patient is taking loop diuretic, sodium potassium 2 chloride inhibited thus these electrolytes are not reabsorbed
• Effects of Loop Diuretics on Urinary Excretion


  • Furosemide has weak carbonic anhydrase inhibiting activity - increases urinary excretion of HCO-3 and phosphate, Acute effect: increase uric acid excretion, Chronic effect: reduced uric acid excretion, asymptomatic hyperuricemia
• Effects of Loop Diuretics on Renal Hemodynamics

  • Increase total RBF, NSAIDs attenuate the diuretic response, do not decrease the GFR by activating TGF, powerful stimulators of renin release
• Other Effects of Loop Diuretics

  • Furosemide - acutely increased systemic venous capacitance, High Doses - inhibit electrolyte transport, reason for its toxicity
• Furosemide is the most used loop diuretic
• Loop diuretics


  Increase urinary excretion of HCO3- and phosphate
• Acute effect of loop diuretics


  • Increase uric acid excretion
• Chronic effect of loop diuretics


  • Reduced uric acid excretion, asymptomatic hyperuricemia
• These effects are due to the mechanisms of the loop of Henle
• Effects of loop diuretics on renal hemodynamics


  • Increase total renal blood flow
  • NSAIDs attenuate the diuretic response to loop diuretics
  • Loop diuretics do not decrease the GFR by activating TGF
  • Loop diuretics are powerful stimulators of renin release