Hypertension and Diuretics: A Case Study

Case Study

• A 65-year-old man presents to the emergency department with severe shortness of breath.
• His wife reports he's hypertensive but refused antihypertensive meds due to lack of symptoms, so he never took any.
• Over the past month, he's had increasing ankle edema, reduced exercise tolerance, and difficulty sleeping lying down, reporting no chest pain or discomfort.
• Pitting edema to the knees and acute discomfort are present.
• Vital signs: blood pressure is 190/140 mm Hg, pulse is 120 bpm, and respiratory rate is 20/min.
• Chest auscultation reveals loud rhonchi and an electrocardiogram is negative. Also, there's evidence of left ventricular hypertrophy.
• He receives an intravenous diuretic and is admitted to intensive care.
• The questions are: Which diuretic would be most appropriate for this man's case of acute pulmonary edema associated with heart failure, and what are the possible toxicities of this therapy?

Blood Pressure and Hypertension

• Blood pressure measures the force of blood against artery walls.
• Hypertension is defined as either a sustained blood pressure greater than 140 mm Hg or a sustained diastolic blood pressure greater than 90 mm Hg.
• Classification of hypertension based on blood pressure includes normal (< 120/80 mm Hg), prehypertension (120-135/80-89 mm Hg), hypertension (> 140/90 mm Hg), stage 1 (140-159/90-99 mm Hg), and stage 2 (≥ 160/100 mm Hg).

General Concepts of Diuretics

• A diuretic increases urine volume.
• A natriuretic agent increases renal sodium excretion. Since natriuretics usually increase water excretion, they are often called diuretics.
• An aquaretic increases excretion of solute-free water.

Pharmacological Uses of Diuretics

• Abnormalities in fluid volume and electrolyte imbalances are the main reasons for their use.
• Diuretics are used to treat hypertension, heart failure, renal failure, nephrotic syndrome, and liver cirrhosis.

Kidney and Nephron Structure

• The nephron includes the renal corpuscle, proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct.
• Filtration, reabsorption, and secretion happen in the nephron to form urine, culminating in excretion.
• Solutes such as glucose, amino acids, sodium, potassium, and urea are secreted and reabsorbed across the nephron.

Diuretic Agents Classification

• Classified as:
• Thiazides
• Potassium-sparing diuretics
• Loop diuretics
• Carbonic anhydrase inhibitors
• Agents that alter water excretion like osmotic diuretics and antidiuretic hormone antagonists

Proximal Tubule

• The contents reabsorbed include 66% of total sodium ions as NaCl, 85% of the filtered NaHCO3, 65% of K+ via a paracellular pathway, and 60% of the water by passive diffusion. Additionally, virtually all filtered glucose and amino acids.
• The most relevant to diuretic action are NaHCO3 and NaCl.

Transport Mechanism:

• Na+ enters the tubule cell through the Na+/H+ exchanger (NHE3) located on the luminal membrane of the proximal convoluted tubule (PCT).
• Na+ moves into the interstitium via the Na+/K+ ATPase pump, maintaining low intracellular Na+.
• H+ secreted combines with bicarbonate (HCO3-) to form H2CO3, that is rapidly dehydrated to CO2 and H2O by carbonic anhydrase.
• CO2 reabsorbed to form H2CO3 and bicarbonate reabsorption is dependent on carbonic anhydrase.
• Free H+ causes luminal pH to fall, activating a Cl-/base exchanger, and the net effect of parallel Na+/H+ exchange and Cl-/base exchange is NaCl reabsorption.

Other Secretions in PCT

• Organic acid secretory systems secrete uric acid, NSAIDs, diuretics, and antibiotics.
• Organic base secretory systems secrete creatinine and choline.

Drugs Acting on PCT

• Carbonic anhydrase inhibitors block NaHCO3 reabsorption.
• Mannitol prevents water reabsorption.
• Adenosine receptor antagonists block PCT absorption of NaCl in clinical investigation.

Loop of Henle

• The Loop of Henle has a thick ascending limb (TAL).
• The TAL has ion transport pathways across luminal and basolateral membranes.
• A lumen-positive electrical potential is created by K+, and back diffusion drives divalent and monovalent cation reabsorption via the paracellular pathway.
• NKCC2 is the primary transporter in the luminal membrane.

Thick Ascending Limb

• Salt reabsorption dilutes the tubular fluid in the diluting segment.
• The medullary parts of the TAL contribute to medullary hypertonicity, aiding in urine concentration.
• The NaCl transport system in the luminal membrane of the TAL is a Na+/K+/2Cl- cotransporter (NKCC2 or NK2CL).
• The Na+/K+/2Cl- transporter is electrically neutral, but its action contributes to K+ accumulation in the cell.
• Back diffusion of K+ into the tubular lumen causes a lumen-positive electrical potential, which drives the reabsorption of cations, magnesium, and calcium via the paracellular pathway.

Loop Of Henle Segments

• Water is extracted in the descending limb of Henle's loop through osmotic forces in the hypertonic medullary interstitium.
• The thin ascending limb is permeable to some solutes but impermeable to water.
• The thick ascending limb reabsorbs NaCl via active transport from the lumen, 25% of sodium, and is impermeable to water.

Drugs Acting on Loop of Henle

• Mannitol inhibits water extraction from the descending limb in the hypertonic medullary interstitium.
• Loop diuretics block NaCl transport within the TAL's luminal membrane, a Na+/K+/2Cl- cotransporter called NKCC2.

Distal Convoluted Tubule (DCT)

• NaCl reabsorption accounts for 10% of reabsorption, and it is impermeable to water.
• The mechanism of NaCl transport is an electrically neutral Na+ and Cl- cotransporter, NCC.
• Ca2+ is actively reabsorbed by the DCT epithelial cell via an apical Ca2+ channel, regulated by parathyroid hormone.
• Ca2+ is reabsorbed into the blood via a basolateral Na+/Ca2+ exchanger.

Distal Convoluted Tubule Cell

• Ion transport pathways go across the luminal and basolateral membranes.
• NCC is the primary sodium and chloride transporter in the luminal membrane.
• Na+/K+ ATPase is present in the basolateral membrane.
• Parathyroid hormone (PTH) receptor is located here.

Drugs Acting on DCT

• The Na+ and Cl- cotransporter (NCC) is sensitive to thiazide diuretics.

Cortical Collecting Tubules

• This is the nephron's final segment.
• The last tubular site of sodium reabsorption is controlled by aldosterone.
• It's responsible for 2-5% of NaCl reabsorption by the kidney, more if aldosterone is increased.
• Sodium reabsorption occurs via ENaC channels.
• The important site of K+ secretion involves a loss of K+ and H+.
• Water reabsorption occurs in the medullary collecting tubule under the control of antidiuretic hormone (ADH), also called arginine vasopressin (AVP).
• Principal cells are the major sites of Na+, K+, and water transport.
• Intercalated cells (α, β) are the primary sites of H+ (α cells) or bicarbonate (β cells) secretion.

Collecting Tubules

• Na+ reabsorption is via the epithelial Na channel (ENaC), its secretion of K+ is regulated by aldosterone.
• Na+ entry into the principal cell predominates over K+ secretion, with a 10-50 mV lumen-negative electrical potential developing.
• A relationship exists between Na+ delivery to the cortical collecting tubule (CCT) and the resulting secretion of K+ and H+, known for the hypokalemic alkalizing effect of diuretics.
• Relative magnitudes of Na+ reabsorption at different tubular sites are: Proximal Convoluted Tubule (PCT): 65-70%, Ascending Limb of the Loop of Henle(AscLH): 20-25%, Distal Convoluted Tubule (DCT): 8-9%, and Cortical Collecting Tubule (CCT): 1-2%.

Renal Autacoids

• They include adenosine, prostaglandins, and peptides.

Adenosine

• It has four distinct adenosine receptors (A1, A2a, A2b, and A3).
• Adenosine rises in response to hypoxia and ATP consumption.
• Affects ion transport in the PCT, the medullary TAL, and collecting tubules.
• Shows a biphasic effect on NHE3 activity: it enhances at low concentrations and inhibits at high concentrations.
• Decreases K+ secretion in the cortical collecting tubule.

Prostaglandins

• Five prostaglandin subtypes (PGE2, PGI2, PGD2, PGF2α, and thromboxane [TXA2] are synthesized in the kidney and have receptors.
• PGE2 acts on EP1 and EP3.
• PGE2 decreases Na+ reabsorption in the TAL of Henle's loop and ADH-mediated water transport in collecting tubules.
• These PGE actions contribute significantly to the diuretic efficacy of loop diuretics and blocking prostaglandin synthesis with NSAIDs can interfere with loop diuretic activity.

Peptides

• Natriuretic peptides (ANP, BNP, and CNP) induce natriuresis.
• ANP and BNP are synthesized in the heart, while CNP primarily originates from the CNS.
• Peptides exert both vascular and sodium transport effects in the kidney.
• Urodilatin is structurally similar to ANP but is synthesized and functions only in the kidney.
• Synthesized in distal tubule epithelial cells, urodilatin blunts Na+ reabsorption by affecting Na+ uptake channels and Na+/K+-ATPase in the downstream collecting tubule system. It also increases GFR, enhancing natriuretic activity.
• Ularitide is a recombinant peptide that mimics urodilatin.
• ANP and BNP increase GFR by affecting glomerular arteriolar vasomotor tone and show activity as a diuretic, even though CNP has very little diuretic activity.
• Agents in clinical use or under investigation: nesiritide (BNP), carperitide (ANP, Japan only), and ularitide.

Major Segments of The Nephron

• The glomerulus aids in the formation of glomerular filtrate. No diuretics act here.
• The proximal convoluted tubule helps Na+/K+/CA2+ Mg2+, Na+/K+/CA2+ Mg2+, as well as 85% of NaHCO3, and nearly 100% of glucose and amino acids to undergo reabsorption. Carbonic anhydrase inhibitors and adenosine antagonists have their effect here.
• The proximal straight tubule segment is where organic acids and bases, most diuretics and uric acid are secreted and reabsorbed.
• The thin descending limb of Henle's loop allows passive reabsorption of water.
• The thick ascending limb of Henle's loop allows active reabsorption of 15-25% of filtered Na+/K+/CI. Loop diuretics have an effect here.
• The distal convoluted tubule allows reabsorption of 4-8% of filtered Na* and CI. Thiazides have an effect here.
• The cortical collecting tubule allows Na+ reabsorption and K+ secretion. K+-sparing diuretics and adenosine antagonists (under investigation) have an effect here.
• The medullary collecting duct allows water reabsorption. Vasopressin antagonists have an effect here.

Carbonic Anhydrase Inhibitors

• Carbonic anhydrase's predominant location is in the PCT's epithelial cells.
• Carbonic anhydrase in many nephron sites catalyzes the dehydration of H2CO3 to CO2 at the luminal membrane, and rehydration of CO2 to H2CO3 in the cytoplasm.
• By blocking carbonic anhydrase, these drugs block NaHCO3 reabsorption, inducing diuresis.
• Acetazolamide is a prototypical Example and Methazolamide.

Pharmacodynamics of Carbonic Anhydrase Inhibitors

• At maximum dosage, this is 85% of the HCO3- reabsorption of PCT, although some HCO3- can still be absorbed at other nephron sites.The maximal effect equals about 45% suppression of kidney level HCO3- reabsorption.
• Carbonic anhydrase inhibition causes significant HCO3- loss and hyperchloremic metabolic acidosis.
• Reduced HCO3- leads to enhanced NaCl reabsorption by the nephron remainder. The diuretic efficacy of acetazolamide decreases significantly with consistent use.

Pharmacokinetics Carbonic Anhydrase Inhibitors

• Well absorbed orally. An increase in urine pH from HCO3- diuresis is apparent within 30 minutes, becomes maximal at 2 hours, and persists for 12 hours.
• Excretion occurs via secretion in the proximal tubule S2 segment so dosing must be reduced if renal insufficiency.

Clinical Uses of Carbonic Anhydrase Inhibitors

• GLAUCOMA: Carbonic anhydrase inhibitors are the most common treatment indication, acting as antagonists on the ciliary epithelial carbonic anhydrase.
• Dichlorphenamide (50 mg) and Methazolamide (50-100 mg) are carbonic anhydrase inhibitors used for glaucoma.
• URINARY ALKALINIZATION: Renal excretion of cystine (in cystinuria) and other weak acids can be enhanced to increase urinary pH.
• METABOLIC ALKALOSIS: Acetazolamide can correct the alkalosis.
• ACUTE MOUNTAIN SICKNESS: Acetazolamide can treat dangerous pulmonary or cerebral edema at high altitudes because it increases ventilation and diminishes symptoms by decreasing cerebrospinal fluid synthesis.

Toxicity of Carbonic Anhydrase Inhibitors

• HYPERCHLOREMIC METABOLIC ACIDOSIS: This condition is a result of body HCO3- stores reduction, thus limiting the diuretic efficacy to only 2 or 3 days.
• RENAL STONES: Phosphaturia and hypercalciuria occur during the bicarbonaturic response, and the renal excretion of solubilizing may decline with continuous use, enhancing the potential for stone formation.
• RENAL POTASSIUM WASTING: Potassium wasting happens because the lumen-negative electrical potential isn't reabsorbed, increasing lumen-negative potential, causing enhanced K+ secretion. Simultaneous administration of potassium chloride can counteract this effect.
• OTHER TOXICITIES: Drowsiness and paresthesias are common, carbonic anhydrase inhibitors can accumulate in patients with renal failure, causing nervous toxicity.
• Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur.

Contraindications and Dosage of Carbonic Anhydrase Inhibitors

• Contraindications include alkalinization of the urine, decrease urinary excretion of NH4+, and cirrhosis.
• The adult dosage of acetazolamide at more than 12 years is 250-500 mg every 12 hours, and and the paediatric dosage for 20kg is 4mg/kg q8h I/V, PO. The Neonatal (3kg) does is 4 mg/kg q8h.

Loop Diuretics

• Loop diuretics selectively inhibit NaCl reabsorption in the TAL and are are considered the most efficacious diuretics.
• Furosemide, ethacrynic acid, bumetanide and torsemide.

Pharmacodynamics of Loop Diuretics

• They inhibit NKCC2, the luminal Na+/K+/2Cl- transporter in the ascending limb of Henle's loop, reducing the reabsorption of NaCl and decreasing lumen-positive potential.
• Reducing the potential causes an increase in Mg2+ and Ca2+ excretion and induces cyclooxygenase (COX-2) expression. PGE2 then inhibits salt transport.

Pharmacokinetics of Loop Diuretics

• They are rapidly absorbed and eliminated via the kidneys by glomerular filtration and tubular secretion. Oral torsemide absorption is faster than oral furosemide.
• Furosemide's effects last 2-3 hours, while Torsemide lasts 4-6 hours.
• Half-life is dependent on the state of renal function, so diuretics with NSAIDs or probenecid should not be given, due to competition for weak acid secretion in the proximal tubule.

Clinical Indications of Loop Diuretics

• They include acute pulmonary edema, hypercalcemia, acute renal failure, and treatment of anion overdose.

Toxicity and Contraindications of Loop Diuretics

• They include Hypokalemic Alkalosis, Ototoxicity and Hyperuricemia.
• This toxicity can come in the form of dose-related hearing loss but is reversible.
• Hyperuricemia diuretics trigger gout attacks, caused by hypovolemia enhances absorption.
• Hypomagnesemia occurs most often in patients who don't eat Magnesium.
• Allergies also happen, except with ethacrynic acid; the loop diuretics are sulfonamides, so this toxicity resolves rapidly once discontinued.
• Loop diuretics are dangerous to those with cirrhosis, borderline renal or heart failure
• Furosemide, bumetanide, and torsemide may react with sulfa drugs.

Dosage of Loop Diuretics

• For Oral Edema, 40 mg initially, raised to 80mg daily, and maxed at 40mg in children daily; Injections, 20–50 mg intravenously every 2 hours, dosages going above 50 mg, can not be administered at a max of 20mg given in a day for kids.
• Otherwise its Bumetanide: (0.5–2 mg), Ethacrynic acid: (50–200 mg), Furosemide: (20–80 mg), Torsemide: (5–20 mg).

Thiazide Diuretics

• Thiazides inhibit NaCl transport. They affect DCT and retains significant carbonic anhydrase inhibitory activity, therefore Chlorothiazide (HCTZ), is the only thiazide available for parenteral administration and not very lipid-soluble so must be given, in dosages, 1–4mg for example.

Pharmacodynamics of Thiazide Diuretics

• They inhibit NaCl reabsorption along the luminal side of the DCT epithelial cells, lessening intracellular Na+ and enhancing reabsorption. High reabsorption masks hypercalcemia or sarcoidosis. Depends on renal prostaglandin levels that can hinder NSAIDs if conditions dictate.

Pharmacokinetics of Thiazide Diuretics

• All thiazides can be taken orally but are metabolized differently.
• Chlorothiazide isn't lipid-soluble so must be given in relatively large doses and is the only one prepared parenterally for use. Chlorthalidone absorbs slower, but acts for longer periods.

Clinical Indications of Thiazide Diuretics

• Hypertension: Thiazides are also useful for issues like Heart failure; Nephrolithiasis caused by idiopathic hypercalciuria or nephrogenic diabetes insipidus.

Toxicity of Thiazide Diuretics

• These are caused by loop diuretics, the main one being Hypokalemic Alkalosis.
• Hyperglycemia and the inability to utilize it, may occur to those with diabetes.
• Increase serum cholesterol levels or low-density lipoproteins might lead to hyponatremia for those reacting badly to the sulfonamides and members contained within this similar group or similar side-effects.
• Thiazide diuretics might not be helpful for those with serious renal failure or heart conditions; the dosage includes: Bendroflumethiazide (2. 5-10 mg), Chlorothiazide (0.5–2 g), Chlorthalidone (25–50 mg), Hydrochlorothiazide (25- 100 mg), Hyddroflumethiazide (12. 5-50 mg), Indapamide (2. 5-10 mg), Methyclothiazide (2. 5-10 mg), Trichlormethiazide (1-4 mg);

Potassium-Sparing Diuretics

• Potassium-sparing diuretics prevent K+ secretion by antagonizing aldosterone in the distal and cortical collecting tubules.
• Inhibition by a mineralocorticoid or through inhibition from Na+ influences.
• The inhibilitation may occur through antagonism of (spironolactone, eplerenone).
• Ularitide now is under the investigation for its uptake of Na+ but is affected from vascular affects, whereas Nesiritide is for intravenous use, affecting sodium absorption.

Pharmacodynamics Of Potassium-Sparing Diuretics

• Though Amiloride and triamterene do not block aldosterone, they interfere with the channels.
• Aldosterone antagonists also impede its effects, thus inhibiting renal prostaglandin production.

Pharmacokinetics of Potassium-Sparing Diuretics

• Spironolactone acts competitively antagonistic to aldosterone, occurring by means of the aldosterone-kinetic response, though it might inactivate in the liver because of its delayed action.
• Elperenone can then be used for aldosterone, but a smaller amount can't affect progesterone receptors.
• Amiloride interferes with influx of Na+ and triametrene metabolizes in the liver, though it has a quicker half-life.

Clinical Indications and Toxicity of Potassium-Sparing Diuretics

• K+ Sparing medication are useful due to mineralocorticoid excess conditions or hyperaldosteronism.
• One may experience endocrine abnormalities.
• Triamterene mixing, with medication causes renal failures, though a higher solubility of Triamterene forms Kydney stones, but is contraindicated.
• Using agents increases hyperkalemia.

Agents that Alter Water Excretion and Osmotic Diuretics

• The proximital Tub and descending limb is water permeable and active, as active agents don't reabsorb quickly it promotes diuresis.
• Osmotics absorbs poorly, given its parenteral makeup, not oral.
• They increase urine levels, cause hyperkalemia, and expand extracellular volume so as to dehydrate.
• To counter act it, Antidiuretic hormone antagonists are then used, reducing their affects as it excretes.
• In general connivapatan are active oral meds, for conditions like abnormal ADH.

Diuretic Combinations and Loop Agents Thiazides

• Refractoriness is excessive interval, greatly reducing retention of Na+ .
• Drugs acting act different create synergy.
• Loop, thiazides and loop are good with kidney Prox Tub meds in treating all Na. Close monitoring is needed.

Summary of Diuretic Agents

• Acetazolamide has inhibition of enzymes to assist dehydration for HCO3 helping edema. Loop meds are effective in blocking NaCl with a strong output. Thiazodine aids Na and inhibits Ca uptake.