Brief explanation of drugs acting on the kidney.

1. Drugs Acting on The Kidney
The kidneys are major organs of urine formation
Regulate the ionic composition, volume & pH of urine/body
fluid by three major processes;
Urine formation = glomerular filtration - tubular reabsorption +
active tubular secretion
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2. Functions of Renal System
Excretory function: metabolic wastes, drugs, toxins, NTs,
water soluble metabolites, hormones
Regulatory function:
Water/fluid/ balance: diluting & concentrating urine
Electrolyte balance: K+, Na+, Ca2+, Mg2+, Cl-, Pi-
Acid base balance: H+, HCO3
-
Endocrine function: EPO, renin, PGs
Metabolic function: activation of Vitamin-D, gluconeogenesis
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3. Urine formation
 An important interplay b/n RBF & nephron function
 CO  RBF  RPF  GFR  tubular flow  urine
CO = HR  SV
= 72 beats (strokes)/minute  70 mL/beat(stroke)
= 5040 mL/minute
 5 Liters/minute
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4. RBF to both kidneys = 20-25% of CO
Out of 5 Liters; 20% = 1 L/minute
In the 1 L blood; 40% (400 mL) are cells & 60% (600 mL) is
plasma
Cells (RBCs, WBCs, platelets) do not filtered, simply circulate
through the blood vessels
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5. Out of 600 mL plasma 20% (120 mL/min) filtered in the
glomeruli in both kidneys (60 mL/min/kidney) as it is passing
in the glomerular capillaries i.e. GFR
Out of 120 mL:
65% of fluid is reabsorbed in the PCT
10-15% of fluid is reabsorbed in the thin descending loop of
Henle (water permeable site)
Water permeability of the collecting tubule system is ADH
dependent
Finally 1 mL/minute urine is produced
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6. 6

7. Diuretics
Increase urine volume by promoting renal excretion of salt &
water
Principally used to remove excess ECF from the body
180 liters of fluid is filtered from the glomerulus into the
nephron per day
The normal urine out put is 1-5 liters per day
The remaining is reabsorbed in d/t areas of nephron
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10. Classification of Diuretics
Carbonic anhydrase inhibitors
Loop (high ceiling) diuretics
Thiazides (Benzothiadiazides) & thiazide like diuretics
Potassium-sparing diuretics:
ENaC blockers, aldosterone antagonists
Aquaretics: osmotic diuretics, ADH antagonists
Adenosine A1-receptor antagonists
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11. Carbonic anhydrase inhibitors
 Acetazolamide, dorzolamide, methazolamide, brinzolamide
 MOA: carbonic anhydrase inhibition, results in:
 H+ formation inside PCT cell
 Na+/H+ antiport
 Na+ & HCO3
– in lumen
 diuresis
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13.  Uses:
Glaucoma:  aqueous humor production
Mountain sickness: reducing the formation as well as the pH of
CSF – it can also be used for prophylaxis
Metabolic alkalosis: enhances HCO3
– excretion
Alkalinization of urine
Idiopathic intracranial hypertension:  CSF secretion
Epilepsy: acetazolamide (adjuvant) as it  seizure threshold
Hyperphosphataemia:urinary phosphate excretion
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14.  Side effects:
Bicarbonaturia & acidosis
Hypokalemia
Hyperchloremia
Paresthesia /unusual or unexplained tingling, pricking, or
burning sensation on the skin/
Renal stones: Ca2+ is lost with HCO3
–  hypercalciuria
Sulfonamide hypersensitivity
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15. Loop Diuretics
 Furosemide, ethacrynic acid, torsemide, bumetanide
 MOA: Na+/K+/2Cl– transporter inhibition, results in:
 intracellular K+ in the TALH
 back diffusion of K+
 positive potential
 reabsorption of Ca2+ & Mg2+
 diuresis
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18.  Uses:
Edema of cardiac, hepatic or renal origin: e.g. CHF
Acute pulmonary edema & acute LVF: IV furosemide
Acute renal failure or acute kidney injury (AKI):  urine output
& K+ excretion
Hypertension
Forced diuresis: in drug poisoning & anion overdose
Acute hypercalcemia & hyperkalemia
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19. 19
Furosemide in pulmonary edema

20.  Side effects:
Sulfonamide hypersensitivity (furosemide)
Hypokalemia & metabolic alkalosis
Hyponatremia, dehydration, hypovolemia & hypotension
Hypocalcemia, hypomagnesemia
Hyperuricemia (actively secreted by the OAT)
Ototoxicity (tinnitus & vertigo): ethacrynic acid > furosemide
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21.  Drug interactions:
Furosemide & ethacrynic acid are highly protein bound:
displacement
Aminoglycosides generate free radicals within the inner ear,
with subsequent permanent damage to sensory cells &
neurons  permanent hearing loss (enhanced ototoxicity)
Lithium: chronic loop administration   Li+ clearance
Digoxin:  toxicity due to hypokalemia
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23.  MOA: Na+/Cl– transporter inhibition, results in:
 luminal Na+ & Cl– in DCT
 diuresis
Thiazides (derived from acetazolamide) inhibit CA at the PCT
(weak diuretic effect)
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24.  Uses:
Hypertension
CHF (edema)
Nephrolithiasis (calcium stones)
Nephrogenic diabetes insipidus (rarely)
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26. 26

27.  Side effects:
Sulfonamide hypersensitivity
Hypokalemia & alkalosis (due to H+ excretion)
Hypercalcemia, mild hypomagnesemia (unknown)
Hyperuricemia (actively secreted by the OAT into the PCT)
Hyperglycemia: due to hypokalemia b/c insulin release
depends on K+ level ( insulin release)
Dose dependent hyperlipidemia ( cholesterol, LDL, TG);
worsened insulin sensitivity &/reflex RAAS & SNS activation
Impotency (rare): is likely a result of reduced volume
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28. Potassium-sparing Diuretics
 Spironolactone: aldosterone-receptor antagonist
 Uses:
Hyperaldosteronic state
Adjunct to K+ wasting diuretics
Antiandrogenic uses (female hirsutism)
Congestive heart failure
 SEs: hyperkalemia & acidosis, antiandrogen
 Eplerenone: selective, devoid of antiandrogenic effect
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 Canrenoate is not active but is converted to canrenone

30.  Amiloride & triamterene: Na+ channel blockers
 Use:
Adjunct to K+ wasting diuretics
Lithium-induced nephrogenic diabetes insipidus (amiloride)
 SEs: hyperkalemia & acidosis
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32. Osmotic Diuretics
Mannitol, Glycerin, Isosorbide, Sorbitol, Urea
 After IV administration mannitol ECF: extracting fluid from the
cell (fluid shift) results in;
Renal blood flow by;
Viscosity of blood
Inhibition of RAAS as ECF ed
Sympathetic tone no activation of 1
➨Diuresis 32

33. Clinical indications
To ICP in ABI, hemorrhagic stroke
To IOP before ophthalmologic procedures
 Adverse Effects
Extracellular volume expansion (prior to diuresis)
Dehydration (hypovolemia) & hypernatremia
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36. ADH Antagonists
ADH: octapeptide produced in the hypothalamus
Medical conditions (CHF, SIADH) stimulate ADH secretion 
water retention
Patients with CHF who are on diuretics frequently develop
hyponatremia secondary to excessive ADH secretion 
dangerous hyponatremia
 Use: treatment of hypervolemic & euvolemic hyponatremia
Ethanol, water: inhibit ADH secretion from hypothalamus
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37.  ADH receptors: V1 (V1a, V1b) & V2
V1: expressed in the vasculature & CNS
V2: expressed specifically in the kidney
 Antagonists:
Non specific agents: Lithium & demeclocycline
Now replaced by vaptans due to ADR (renal failure)
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38. Conivaptan (available in IV): act on both V1a & V2
Orals (tolvaptan, lixivaptan & satavaptan): V2 selective
Tolvaptan: FDA-approved, very effective for hyponatremia
Lixivaptan & satavaptan: under clinical dev’t
t½ of conivaptan & demeclocycline: 5-10 hrs, tolvaptan 12-24
hrs
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39.  Clinical indications:
Syndrome of Inappropriate ADH Secretion
If water restriction is not successful
Other causes of elevated ADH
Thirst: IV conivaptan is effective by blocking V1a
Refractory ascites
Autosomal dominant polycystic kidney disease
Cyst development in polycystic kidney disease is mediated
through cAMP
ADH is a major stimulus for cAMP production in the kidney via
V2: tolvaptan
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40.  Adverse Effects
Nephrogenic diabetes insipidus: caused by Li+
Can be treated with thiazides & amiloride
HCTZ causes ed osmolality in the inner medulla (papilla) & a partial
correction of the Li+-induced reduction in aquaporin-2 expression
Amiloride blocks Li+ entry into collecting duct cells & reverses Li+-
induced polyuria
Acute renal failure: Li+ & demeclocycline
Chronic interstitial nephritis: in long-term Li+ therapy
Hypotension & elevation in liver function tests: tolvaptan
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41. Adenosine A1-Receptor Antagonists
Renal adenosine concentrations rise in response to hypoxia &
ATP consumption
In the hypoxic kidney, adenosine actually decreases blood flow
and GFR
Adenosine increases Na+ reabsorption from the reduced flow in
the cortex, so that delivery to medullary segments will be even
further reduced
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42. Adenosine is known to affect ion transport in the PCT, the
medullary TAL, and collecting tubules
Reduces blood flow to the glomerulus & GFR via A1 receptors
on the afferent arteriole
Is also the key signaling molecule in the process of
tubuloglomerular feedback (TGF)
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43.  Adenosine A1–Receptor Antagonists
Prevent tubuloglomerular feedback
Interfere with the activation of Na+/H+ exchanger in the PCT
Interfere the adenosine-mediated enhancement of collecting
tubule K+ secretion (K-sparing)
Several naturally occurring methylxanthines (e.g., caffeine,
theophylline, and theobromine) are A1 receptor antagonists
(albeit nonselective) and consequently cause diuresis
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44.  Pamabrom:
Is a mild diuretic consisting of a one-to-one mixture of 8-
bromotheophylline & 2-amino-2-methyl-1-propanol
8-bromotheophylline (a methylxanthine), is the active
component of pamabrom
 Use: for the treatment of premenstrual syndrome (PMS)
symptoms (water weight gain, bloating, swelling, muscle
cramps/pan, tension, fullness feeling)
Works by increasing the production of urine which eliminates
unwanted water retention
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45. ADH/AVP (Vasopressin) Agonists
Vasopressin & desmopressin are used in the treatment of
central diabetes insipidus
DI is due to either deficient production of ADH (neurogenic or
central DI) or inadequate responsiveness to ADH (nephrogenic
diabetes insipidus (NDI))
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46.  ADH secretion is regulated by
serum osmolality & by volume
status
AQP2, apical aquaporin water
channels
AQP3,4, basolateral aquaporin
water channels
V2, vasopressin V2 receptor
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47. V2 Receptor Agonist: Vasopressin
 Major Therapeutic Uses
 V1 receptors cause GI & vascular smooth muscle contraction
Postoperative abdominal distention
Abdominal roentgenography (X-ray)
Bleeding, cardiac arrest, hypovolemic shock
Contraindicated in nephrogenic diabetes insipidus
Not for long-term therapy of central diabetes insipidus
Use with extreme caution in patients with vascular disease
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48. V2 Receptor Agonist: Desmopressin
V2 receptors cause water conservation & release of blood
coagulation factors (von Willebrand factor)
 Uses:
Central diabetes insipidus (DOC)
Primary nocturnal enuresis
Prevention of blood loss in patients with specific bleeding
disorders
Can be administered orally at high doses
 ADR: water intoxication
 CI: in nephrogenic diabetes insipidus
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49. Diuretic Resistance
Is inability to reduce plasma sodium levels despite using full
therapeutic dose of diuretics
Could be due to multiple reasons like higher sodium intake,
reduced absorption of the diuretic, inadequate renal blood flow
as in CCF leading to lower amounts of it reaching the kidney
Chronic renal failure & nephrotic syndrome patients may also
be refractory to diuretics
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50.  Diuretic resistance may be managed with:
Upgradation from a lower to a higher efficacy diuretic
Using a suitable combination
Reduced salt intake
Timing the diuretic intake 30 – 60 minutes before food also
works because renal diuretic levels would be high enough to
avoid slat retention
Avoid NSAIDs, b/c they can cause salt & water retention & are
a common cause of diuretic resistance
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51. Drug Interactions with Diuretics
Hypokalaemia induced by diuretics enhance digitalis toxicity
NSAIDs blunt the effect of diuretics b/c of inhibition of PG
synthesis in the kidneys
Diuretics enhance lithium toxicity by reducing renal excretion
of lithium
Drugs that cause hyperkalemia (ACEIs/ARBs) & oral K+
supplements should be avoided with K+ sparing diuretics
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52. Diuretics potentiate the antihypertensive effects of drugs used
in hypertension
Probenecid competes with furosemide & thiazides for tubular
secretion & counter their diuretic effect as smaller amounts of
these diuretics reach the tubular fluid
Diuretics also counter the uricosuric effects of probenecid as
they cause hyperuricemia
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53. Contraindications for Diuretics
 Toxaemia of pregnancy (preeclampsia):
Diuresis induced in pregnancy results in reduced fetal
circulation which may result in fetal death
Hence diuretics are contraindicated in pregnancy-induced
hypertension
 Hepatic cirrhosis: diuretics can cause mental disturbances &
hepatic coma in cirrhosis patients
The combined effect of raised NH3 levels, alkalosis &
hypokalemia may be responsible for this
Cautiously used!
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