Renal Exam 1

Which diuretics are classified as Natriuretics?

• Carbonic Anhydrase Inhibitor (CAIs)

• Loop Diuretics

• Thiazide & Thiazide-like Diuretics

• Potassium Sparing Diuretics

*Now Call Larry The K-angaroo*

What is the general MOA of Natriuretics?

Agents that increase renal sodium excretion

* Increase \[Na\] in urine → Increase \[H2O\] output → Decrease \[H2O\] in body

Carbonic Anhydrase Inhibitors Target

Carbonic Anhydrase

• IV (Lumen)

• II (Intracellular)

Carbonic Anhydrase Inhibitors Site of Action

Proximal Convoluted Tubule - PCT

Carbonic Anhydrase Inhibitors MOA

Inhibit BOTH isoforms of CA (IV & II) + enhance renal absorption

What are the 3 drugs in the class of CAIs?

• Acetazolamide

• Methazolamide

• Ethoxzolamide

Are CAIs highly efficacious?

NOT highly efficacious

What are the side effects of CAIs?

• Acetazolamide

• Methazolamide

• Ethoxzolamide

• Increase HCO3- in urine = Basic urine → Urinary alkalization

• Decrease HCO- in blood = acidic blood → Metabolic acidosis

• Renal stones from alkaline urine calcium phosphate

Does CAIs cause metabolic acidosis or metabolic alkalosis?

Metabolic acidosis

How does CAIs impact the potassium levels of the blood?

Hypokalemic

What are the CI for CAIs'?

Hepatic cirrhosis

• Hyperammonemia

• Hepatic encephalopathy

Hyperchloremic acidosis/ COPD

Caution w/ Sulfa Allergy

What are the drug-drug interactions of CAIs?

• Increase in amphetamine levels

• increase excretion of aspirin

  • CNS toxicity

What is the dosage form and administration for CAIs?

• Tablets & Capsules

  • Well absorbed orally

• IV solution

Loop Diuretic Target

NKCC2

Loop Diuretic Site of Action

Thick Ascending Limb (TAL)

Is the Thick ascending limb a major reabsorption location for sodium?

Yes, 25% of Na is filtered as NaCl

* But is impermeable to water

Loop Diuretic MOA

Inhibit NKCC2 @ TAL → increase renal NaCl excretion + Ca/Mg

What does NKCC2 stand for and where do these ions go after entering the cell?

• Na - reabsorbed via Na/K pump @basolateral membrane

• K - Secreted via channel back to the lumen

• Cl - reabsorbed via channel @basolateral membrane

***Ca, Mg, & Na follow the electrochemical gradient caused by the K and Cl channels

What does the K channels & Cl channels cause within the cell and what is impacted?

• Lumen-positive transepithelial potential difference

• Helps w/ Ca, Mg, and Na reabsorption

What drugs are in the class of Loop Diuretics? (Strongest)

• Sulfonamide-Based

  • Bumetanide

  • Furosemide

  • Toresmide

• Non-sulfamide deriv.

  • Ethacrynic acid

What is the dosage form for the sulfonamide-based Loop Diuretics?

• Bumetanide

• Furosemide

• Torsemide

Rapid ORAL absorption + onset

Of the loop diuretics, which is the most potent?

Bumetanide (X40)

What are the SE of Loop Diuertics?

• Abnormalities in fluid

• Electrolyte balance - ALWAYS HYPO

• OTOTOXICITY (ethacrynic acid)

Due to the inhibition of NKCC via loop diuretics, what is the impact on the ions?

• K can not cross → can not create the Lumen-positive transepithelial potential difference →

• K, Ca, Mg, Na are stuck on the lumen side

  • Hypokalemia

  • Hypocalcemia

  • Hypomagnesemia

  • Hyponatremia

  • Hypovolemia

Loop diuretics cause:

• Hyperuricemia

• Hyperglycemia

• Hyperlipidemia

• Sulfa Allergy

Loop Diuretics are contraindicated with:

• Hepatic cirrhosis

• Hyperchloremic acidosis

• COPD

• Sulfa Allergy

Loop Diuretics have DDI with:

• OTOTOXIC AGENTS

  • aminoglycosides (ABX)

  • Amphotericin B (Antifungal)

• Digitalis glycosides

• NSAIDs

• Thiazides

Thiazides + Thiazide-Like Diuretics Target

NCC

* Sodium - Chloride

Thiazides + Thiazide-Like Diuretics Site of Action

Distal Convoluted Tubule - DCT

Is the Distal Convoluted Tubule permeable to water?

No, the DCT is impermeable to water

What patient population works best w/ TZD?

Ideal for Pts w/ HPT

Drugs in the Class Thiazides

• HCTZ (prototype)

• Chlorothiazide

Drugs in the Class Thiazide-Like Diuretics

• Chlorthalidone

• Metolazone

• Indapamide

What are the SE of Thiazide & Thiazide-Like Diuretics?

• Abnormalities in fluid

• Electrolyte balance

• Sulfa allergy

Due to the inhibition of NCC via thiazide diuretics, what is the impact on the ions?

• Na & Cl can not enter →

• Na/Ca Antiporter increases to compensate →

• ENHANCES Ca2+ reabsorption →

• Hypercalcemia

Which thiazide/thiazide-like diuretic can only be administered parenteral?

Chlorothiazide

Thiazides can cause hypokalemia. What does this increase the risk of?

Cardiac arrhythmia

Drug-Drug Interactions of Thiazides

• Quinidine

  • QT Prolongation → torsade de pointes arrhythmia

• NSAIDs - reduce effectiveness

Water permeability at the cortical collecting duct, is controlled by what hormone?

Antidiuretic hormone (ADH)

How much sodium is filtered at the Cortical collecting duct?

2-3% - via Na channels → regulated by aldosterone THE

The cortical collecting duct is a major site of what ion secretion?

Potassium

* Major site where all diuretic-induced changes in K+ balance

Target of K+ Sparring Diuretics

ENac

• Aldosterone

• Mineralocorticoid receptor

Site of Action for K+ Sparring Diuretics

Cortical Collection Duct (CCD)

K+ Sparring MOA

1. Inhibits Na+ influx through ENac →

2. Inhibits interaction w/ aldosterone w/ mineralocorticoid → decrease ENaC expression

K+ Sparring Diuretics: ENaC Inhibitors

• Amiloride

• Triamterene

***EAT

K+ Sparring Diuretic: Mineralocorticoid Receptor Antagonists

• Spironolactone

  • Non-selective

• Eplerenone

  • Selective

***MS. E

SE of K+ Sparring: Triamterene

Kidney Stones → precipitate in urine

SE of K+ Sparring: Spironolactone

• Gynecomastia

• Impotence

• Decreased libido

*Eplerenone - less anti-androgenic effect

Do K+ Sparring Diuretics cause metabolic acidosis or alkalosis?

* Metabolic acidosis

What impact does K+ Sparring have on the ion potassium?

Hyperkalemia

K-Sparring Contraindications

* Pts w/ Hyperkalemia
* Renal failure

Drug-Drug Interactions of K+-Sparring

• K+ sparing diuretics

• ACEI

• K+ supplements

How do Aquaretics work?

Increase excretion of solute-free water

* ONLY WATER

What two classes are Aquaretics?

• Osmotic

• Vasopressin

Site of Action for Osmotic Diuretic

• Proximal Convoluted Tubule (PCT) +

• Thin Descending Limb (TDL)

MOA of Osmotic Diuretics

• Increase osmotic pressure w/in the tubule →

• Retention of water in lumen→

• Increased urine output

What drugs are in the class of Osmotic diurtetics?

• Mannitol

• Glycerin

How does the osmotic diuretic, Mannitol, engage with the glomerulus?

* Filtered by glomerulus but NOT reabsorbed

What dosage form is the osmotic diuretic, Mannitol given?

IV ONLY

What are the SE of osmotic diuretics?

• Mannitol

• Glycerin

• Increase extracellular fluid volume →

  • Hyponatremia (HA, N/V)

• Excessive use leads to DEHYDRATION & hypernatremia

Vasopressin (ADH) Antagonist Target

Antidiuretic Hormone

Vasopressin (ADH) Antagonist Site of Action

Renal Collecting Duct

Vasopressin (ADH) Antagonist MOA

* Direct vasopressin receptor antagonists inhibit the translocation →
* Increase water excretion

Vasopressin (ADH) Drugs

• Vasopressin (non-selective agonists)

• Desmopressin (V2 selective agonists)

• Canivaptan (non-selective)

• Tolyaptan (V2 selective)

SE of Vasopressin (ADH) Antagonist

• Vasopressin (non-selective agonists)

• Desmopressin (V2 selective agonists)

• Canivaptan (non-selective)

• Tolyaptan (V2 selective)

• Polyuria (dehydration)

• Liver issues for Tolyaptan

Drug-Drug Interactions for Vasopressin Antagonists

• CYP3A4 inhibitors

• Liver Pt or liver drugs

Functions of Kidney:

• EXCRETORY: Electrolytes / Toxins / Drugs - For both acute & chronic KF

• ENDOCRINE: Erythropoietin – Associated with CKD

• METABOLIC: Vitamin D – associated with CKD

GFR (glomerulus filtration rate):

Estimates how much glomerulus filters

GFR (glomerulus filtration rate): Normal Output

120ml/min/ 1.73 m^2

GFR Relationship w/ Age

Inverse → GFR declines with age

Populations that will have a altered GFR

• Elderly (L)

• Female (L)

• cachectic (malnutritious) (L)

• Obese

Why do we not round GFR tests?

May lead to an underestimate of renal function → overdose

SCR (serum creatine): Lab value

\- how much filtration occurring

• Creatine: product of creatine metabolism from

muscle

Low SCr for elderly with

low muscle mass

HIGH SCr

kidneys can’t get rid of Cr, working HARD would still filter out to urine

Small changes in SCr

big differences in CrCl

SCr will lag behind ___

Will lag behind GFRs decline by 1-2d

IBW Male

50kg + (2.3\* inches>5ft)

IBW female

45\.5kg + (2.3\* inches>5ft)

If actual BW > IBW x1.2 →

Use adjusted

* ▪ Adjusted BW= 0.4\* (actual BW-IBW)+ IBW

If actual BW < ideal BW

Use Actual (under-wt)

If actual BW/Ideal BW< 1.2 →

Use ideal

Cockcroft-Gault Equation.

CrCl =\[ \[(140-Age) x IBW\]/(72 x SCr) \] x 0.85 (IF FEMALE)

What is the purpose of Cockcroft-Gault Equation?

Estimate CrCl to determine drug dosages

How to detect an AKI:

• ↑ in SCr by >0.3mg/dl within 48h

• ↑ in SCr to >1.5xs baseline (known/ presumed to have occurred within 7 days)

• Oliguria: urine volume <0.5ml/kg/h for 6 hr

Staging of AKI (KDIGO): Stage 1

detect!

• SCr: 1.5-1.9xs baseline or >0.3mg/dl ↑

• UOP: <0.5ml/kg/h for 6-12h

Staging of AKI (KDIGO): Stage 2

• SCr: 2.0-2.9 sx baseline •

• UOP: <0.5ml/kg/h for >12h

Staging of AKI (KDIGO): Stage 3

• SCr: 3 X baseline OR ↑ in SCr to >4mg/dl OR initiation of dialysis

• UOP: <0.3ml/kg/h for >24h OR anuria for >12h

Risk Factors for an AKI

• DM,

• HTN,

• HF,

• CKD ,

• Age

Risk Exposures of AKI

• Volume depletion (dehydration)

• nephrotoxicity meds,

• radiocontrast agents,

• sepsis, - body shows systemic infection

  • Hypotension + Tachycardia

• urinary system obstruction - post renal

Complications AKI

• ↑K,

• Uremia,

• metabolic acidosis,

• fluid overload,

• PO4 3- in blood

Prerenal: Causes of Intravascular Volume Depletion

* Hypovolemia (vol. depletion)
* GI loss,
* hemorrhage,
* Diuretic therapy
* Dehydration
* Dry membranes, Low BP, High HR
* Extensive burns

Prerenal: Causes of Effective Circulating Blood Volume

• Decreased effective circulatory volume

  • distributive shock

  • Systemic vasodilation - SEPSIS

  • CHF

  • Decreased cardiac output

• Sx: Fluid overload

  • JVP

  • Pitting edema

  • ascites

    • Fluid build up in abdomen

  • Pulmonary crackles

Prerenal Causes: Medications

• NSAIDs

• ACEi

AKI - Prerenal Diagnostic Criteria

* UNa:

Prerenal: COMPENSATORY RESPONSES:

• stimulate the sympathetic NS (fight or flight)

• release antidiuretic hormone if hypotension is present

• stimulate RAAS (renin-angiotensin-aldosterone system)

Na reabsorbs, water follows to help w/ dehydration

Prerenal: Response of RAAS

• Renal Hypoperfusion

• Angiotensinogen

  • //Renin

• Angiotensin I

  • //Ace

• Angiotensin II

  • → Vasoconstriction

• Aldosterone

  • Increase Na reabsorption in collecting ducts

Prerenal Sodium Concentration in Urine

• Kidney holds onto Na to maintain intravascular volume (UNa >20) →

• Decrease in urine sodium concentration