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Renal Pharmacology

Terms in this set (80)

Renal elimination of drugs
Most drugs are first metabolized prior to being excreted

1. Glomerular filtration
2. Proximal tubular secretion
3. Distal tubular reabsorption
What compounds can be excreted via the kidney without being metabolized
Polar compounds
Elimination via glomerular filtration
-Polar compounds (i.e. aminoglycosides) more hydrophilic
-Low molecular weight compounds
-Drug enters kidneys through renal arteries
-Free drug flows thru Bowman's capsule
-Excreted thru urine
Elimination via proximal tubular secretion
-Most drugs are excreted out through kidneys by tubular secretion (drugs not filtered thru glomerulus are later secreted in tubules)
-Energy dependent process
-If a drug concentration is high, it will reach its transport maximum
-There is competition between drugs for the carriers
Distal tubular reabsorption
-If drug is uncharged it can diffuse back into circulation
-manipulating pH can decrease reabsorption
Effect of drug metabolism on reabsorption in distal tubule
-Most drugs are lipid soluble
-Without metabolization, drugs could freely diffuse out of tubular lumen once concentration is high enough
-Drugs are metabolized into more polar substances (primarily in liver) to minimize reabsorption
Medications that can cause prerenal azotemia
Diuretics can cause hypoperfusion
ACEI (lisinopril, ramipril)
ARBs (Losartan, irbesartan)
NSAIDs (Ibuprofen, Naproxen)
α-adrenergic blockers (terazosin)
Management of prerenal azotemia
Give fluids to replenish volume
Effect of NSAIDs, diuretics, and ACEIs on single nephron
Reduce blood flow to glomerulus and reduce GFR

NSAIDs: block prostaglandin production, ↓ blood flow to glomerulus

Diuretics: ↓ blood flow to glomerulus

ACEIs or ARBs: ↓ GFR via efferent arteriole dilation
COX-1 and COX-2
Enzyme used to create prostaglandins

NSAID blocks COX 1, 2
Prostaglandins
↓ Na reabsorption
Stimulate renin release
Vasodilators
When does prostaglandin synthesis increase
↑ with aging
↑ with decreased kidney function

These patients can't take NSAIDs bc it will ↓ GFR too much
ACEI effects
-Vasodilation of efferent arteriole
-↓ hydrostatic pressure → less filtration
-↓ GFR
-↓ Aldosterone release
-↓ Na, H2O reabsorption
-↓ K secretion
-↑ urinary output
-↓ blood volume
What happens when ACEIs are first started
Initial serum creatinine ↑ and ↓ GFR

Over time, will turn out to be renal protective therapy
Renal function in elderly

What meds affect this
↓ blood flow and GFR

Meds:
NSAIDs
ACE inhibitors
ARBs
Diuretics
IV contrast materials
Treatment options for prerenal AKI
Elimination and avoidance of potential insults
-meds
-hypotension
-Iodinated contrast agens
-hypovolemia
-effective volume depletion (CHF or cirrhosis)
What medications can cause acute tubular necrosis
Aminoglycosides
Amphotericin B ("amp-terrible")
Cisplatin ("sick-platin")
Iodinated radio contrast material
Aminoglycosides (Drugs)
Amikin sulfate
Gentamicin sulfate
Neomycin sulfate (PO)
Tobramycin Sulfate
Aminoglycoside characteristics
-Absorbed poorly from GI tract
-Administer parenterally (except neomycin)
-Not metabolized, excreted by kidneys
-1/2 life ↑ as renal function ↓
-Do not cross BBB
Aminoglycoside toxicity
-Presents as a gradual ↑ in SCr and subsequent ↓ in CrCl after 6-10 days of therapy
-↓ of GFR due to proximal renal tubule epithelial cell damage
Risk factors for aminoglycoside toxicity?
Aggressive dosing
Synergistic drug toxicity
Pre-existing clinical condition
Management of aminoglycoside toxicity
Watch CrCl
Hydration
Discontinue other nephrotoxic drugs
Preferred dosing for aminoglycosides
The single high-dose, extended interval is generally preferred with a few exceptions (pregnancy, neonates, etc.)
-Provides the longest period with plasma concentration of the drug below threshold toxicity
Monitoring aminoglycosides
-Serum creatinine should be monitored at baseline and repeated every 1-3 days
-Serum concentrations should be determined when the patient has received therapy for 3-5 1/2 lives of the drug
-Trough concentrations are measured within 30 minutes of the next dose and peak concentrations 30-45 minutes after an IV infusion or 60 minutes after IM injection
Amphotericin B toxicity
-Amphotericin B is an antifungal agent used for life-threatening situations
-Direct tubular epithelial cell toxicity w/ increase tubular permeability and necrosis
Risk factors for amphotericin B toxicity
CKD
Higher doses
Volume depletion
CO administration of diuretics and nephrotoxins (cyclosporine)
Rapid infusion
Prevention of amphotericin B toxicity
-Use a liposomal prep (only affect fungal cell) - AmBisome
-Hydration
-Limit cumulative doses
-Avoid co-administration of other nephrotic meds
Acute interstitial nephritis
-Allergic rxn to drugs or autoimmune
-Damage is to instersitium or tubule
-Eosinophiluria supports diagnosis
-NSAIDs, ACEIs, >40 other drugs
-Antibiotics: methicillin, ciprofloxacin

therapy: discontinue offending agent
Common drugs that can cause Acute interstitial nephritis due to drug sensitivity

Know these for exam
Penicillins
NSAIDs
Sulfa drugs (i.e. Bactrim)
Cephalosporins
Ciprofloxacin
Rifampin
Allopurinol
Postrenal AKI
Typically due to obstruction of urine passage

-BPH
-Stones

Management: remove blockage
When you see anticholinergic, think
Dry, dry, dry
Treatment of nephrotic syndrome
treat underlying disease

-Proteinuria: ACEI/ARB
-Edema: Sodium restriction and diuretics (thiazides vs loops
-Hyperlipidemia: Statin and diet modification
Treatment of ADPKD
HTN: ACE inhibitors or ARBs

Lipids: aggressive tx with statins

avoid NSAIDS

Renal transplant
Key points of Drug induced nephrotoxicity
-Common manifestation of DIN is ↓GFR, ↑ Serum Creatinine, ↑BUN
-ATN: most common presentation of DIN
-ACEIs and NSAIDS are implicated in hemodynamically mediated kidney injury
-Acute allergic interstitial nephritis is implicated in <3% of acute kidney injury
Drugs that can cause DIN
Aminoglycosides
Amphotericin
ACEIs and ARBs
Diuretics and Mannitol
ASA and NSAIDs
Chemotherapeutic agents (Cisplatin, Cyclophosphamide)
Cyclosporine
Bisphosphonates
Lithium
High risk patients for DIN
Elderly
Diabetics
Pts taking other nephrotoxic drugs
Heart failure
GFR < 60 ml/min
Mannitol
Osmotic diuretic
-just moves water → ↓ extracellular fluid → hypernatremia and hyperkalemia
-vasoconstriction of glomerular afferent arteriole
Chronic kidney disease
state of irreversible kidney damage and/or progress reduction of kidney function
Criteria for CKD
-Markers of kidney damage and/or GFR <1.73 present for 3 months
Markers for kidney damage
Albuminuria
Urine sediment abnormalities
Electrolyte and other abnormalities due to tubular disorders
Abnormalities detected by histology
Structural abnormalities determined by imaging
Managing CKD
-Judacious use of ACE inhibitors, ARBs, and aldosterone agonists
-Treat hyperlipidemia
-Minimize proteinuria (ACEI/ARB)
Risk factors for progression of CKD
Proteinuria
Hypertension
Diabetes mellitus
Preventing progression of CKD: albuminuria
Angiotensin-converting enzyme inhibitors
Ace receptor blockers
Sodium glucose transporter inhibitors (SGLT2 inhibitors
ACE inhibitors and ARBs
-Recommended for all patients with proteinuria (ACR>300)
MOA of ACE inhibitors and ARBS in albuminuria
1. Inhibit RAAS
2. Vasodilation of afferent and efferent arterioles
3. ↓ intra glomerular pressure
4. ↓ both GFR and urine albumin excretion
Common ADRs of ACE inhibitors and ARBs

must know, will be on test
ACEI: cough, increased serum K
ARB: increased serum K
Contraindications of ACEI and ARBs
Pregnancy
Bilateral artery stenosis
Hx of edema
Examples of ACE I
Lisinopril
Ramipril
Quinapril
Examples of ARBs
Losartan
Irbesartan
Valsartan
When to reduce dose of ACEI and ARB?

When to discontinue ACEI and ARB?

(terms of GFR)
30-50% decrease in GFR → reduce dose

>50% decrease in GFR → discontinue
Once maximum tolerated dose of ACEI or ARB is achieved, but patient is still not at BP goal, consider adding
-Spironolactone I (↓ urine albumin excretion when -added to ACEI or ARB)
-Calcium channel blocker
-Beta-blocker
-Thiazide or loop diuretic
-Alpha blocker
T/F: Proper glucose control in diabetes can prevent or delay progression of the microvascular complications of diabetes, including diabetic kidney disease.
True
Target A1C
-Most patients ~7%

Can be extended above 7% for patients w comorbidities and limited life expectancies and/or pts at risk for hypoglycemia
Treating diabetes
1st choice: Metformin

SGLT2 inhibitors and GLP-1 RAs should be considered for patients with T2DM and CKD who require another drug added to metformin to attain target A1c or can't tolerate metformin
SGLT2 inhibitors reduce
-Renal tubular glucose reabsorption
-Weight
-Systemic blood pressure
-Intraglomerular pressure
-Albuminuria

Also slow GFR loss
SGLT2 inhibitors
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
SGLT2 inhibitor MOA
inhibits sodium glucose cotransporter
GLP-1 RAs MOA
Activates glucagon like peptide 1 receptor → increasing insulin secretion
GLP-1 RAs
Dulaglutide (Trulicity)
Exenatide (Byetta)
Liraglutide (Victoza)
Semaglutide (Ozempic)
Changes in serum chemical composition in chronic renal failure
↑:
Na+
K+
Cl-
H+
Mg++
NH4+
PO4--
PTH

↓:
Ca++
EPO
Vit D
Calcium, phosphorus and bone disease in CKD
-Maintain [phos] between 2.7-4.6 in stage 3 or 4 CKD
-Start dietary phos restriction if PTH is increased
-Use phos binders as soon as PTH increases
-If Vit D is prescribed, monitor Ca and Phos
-Bisphosphonates recommended for osteoporosis
Management of hyperphosphatemia in CKD
-Occurs when GFR falls below 25-40

1. Restriction of dietary phosphate intake
2. Phosphate binders
a. calcium containing binders (Calcium carbonate, calcium acetate)
b. Non calcium containing binders (sevelamer, lanthanum)
Calcium acetate (PhosLo)
-Binds to phosphate to ↓ serum phosphate levels
-30-40% is absorbed, but unabsorbed drug is what binds to phosphate
-more beneficial than calcium carbonate bc less affected by high gastric pH
-vascular calcification may result from positive calcium balance
-watch for hypercalcemia and watch other calcium sources
Ferric Citrate (Auryxia) MOA and ADRs
MOA: Binds to dietary phosphate in GI tract

ADRs: Diarrhea, N&V, constipation, cough
Sevelamer carbonate (Renvela)
-Binds to phosphate in intestine
-nonselective anion exchanger
-water soluble (only trace amts absorbed in from GI tract)
-also binds bile acids and lipoprotein cholesterol
-will bind to fat soluble vitamins
-ADRs: N&V, diarrhea, dispepsia, metabolic acidosis
Fat soluble vitamins
ADEK
Lanthanum carbonate (Fosrenol) MOA and ADRs
-Binds to dietary phosphate
-insoluble in water so doesn't get absorbed in GI tract
-chew or crush completely before swallowing. DO NOT SWALLOW IN TACT

-consider oral powder in pts with poor dentition

ADRs: N&V, abdominal pain
Calcitriol (Rocaltrol)
Vitamin D analog - binds and activates vitamin D receptors in kidney, parathyroid gland, intestine, and bone to stimulate calcium absorption

-Used for management of hypocalcemia
Cinacalcet (Sensipar)
MOA: increases parathyroid gland chief cell Ca sensing receptor sensitivity to calcium, ↓PTH secretion

ADRs: ↓ plasma testosterone, diarrhea, dizziness, myalgia, nausea, vomiting, hypoparathyroidism

-take with food or shortly after a meal
Relationship between Ca, PTH, and PO4
↓ Ca → ↑ PTH → resorption of Ca from bones

↑ PO4 → ↑ PTH → stimulates kidney to remove phosphate
Calcitonin (Miacalcin)
-Structurally similar to human calcitonin
-Less effective than bisphosphonates
- ↑ risk of cancer
Calcitonin MOA
↓ plasma calcium in:

1. Bone, by inhibiting osteoclasts and stimulating bone uptake of Ca
2. Kidney by stimulating secretion of calcium
Bisphosphonates info
decrease osteoclast activity

-there is an association between long term bisphosphonate use and femur fractures

-some providers discontinue temporarily after 5 years

dose adjust for kidney function
Bisphosphonates

know formulation and dosing frequency
Alendronate → daily or weekly oral tablet

Ibandronate → daily or monthly oral tablet, or every 3 months IV

Risedronate → daily or weekly oral tablet, 1-2x monthly oral delayed release tablet

Zoledronic acid → yearly IV
Dosing instruction for oral bisphosphonates

Will be tested on
-Take with 6-8 oz of plain water only
-Take at least 30 minutes before other food, drink, meds
-Remain upright and don't lie down for at least 30 mins after taking
Erythropoietin (Epogen, Procrit)
they are used to treat anemic patient due to reduced kidney production of EPO
Medication use in CKD
At GFR <50-60, need to consider dosage or dose frequency

At GFR <30 almost all doses need to be adjusted
2 types of dialysis
hemodialysis
peritoneal dialysis (chronic ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD))
Factors to consider for dosing with dialysis
Drugs with low molecular weight, limited volume of distribution, and that are water soluble are most likely to be removed by dialysis and will require extra dosing
Commonly prescribed meds for dialysis patients
Erythropoietin (Epogen, Procrit)
Iron (Ferrous Sulfate or Iron Dextran)
Vit D (Calcitriol)
Phosphorous binders (Renvela or Renagel)
B-Complex and Folic Acid
Topical cream and antihistamines
Vit E capsules
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