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American Nephrology Nurses Association (ANNA). PHARMACOLOGY IN RENAL DISEASE Timothy V. Nguyen, BS, PharmD, CCP, FASCP Assistant Professor of Pharmacy Practice Arnold & Marie Schwartz College of Pharmacy, LIU Adjunct Pharmacology Professor Saint Peter’s College May 7, 2011. Overview.

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American Nephrology Nurses Association (ANNA)


Timothy V. Nguyen, BS, PharmD, CCP, FASCP

Assistant Professor of Pharmacy Practice

Arnold & Marie Schwartz College of Pharmacy, LIU

Adjunct Pharmacology Professor

Saint Peter’s College

May 7, 2011

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  • Effect of CKD on Metabolism and Elimination of Pharmacologic Agents

  • Classifications of Drugs to Treat Patients with Chronic Kidney Disease

  • Hypoglycemic Agents

  • Interdialytic Agents

  • Effect of Dialysis on Drug Therapy

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Diseases of the kidney are among the most common and complex of all diseases of man.

The kidneys are 0.5% of the body weight, but consume 7% of total body oxygen.

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  • Acute Kidney Injury

  • Acute Nephritis

  • Chronic Kidney Disease

  • Nephrotic syndrome

  • Urinary Tract Infections & Obstructions

  • Renal Tubule Effects – medication induced

    • Acyclovir, MTX, triamterene, indinivir, sulfonamides

  • Hypertension

  • Nephrolithiasis

  • End stage renal failure

    • End stage renal failure is defined as the condition in which the kidneys fail to remove metabolic waste products, regulate pH, or control fluid balance.

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End Stage Renal Disease In The United States *:

  • More than 20 million Americans (1in 9 adults), have chronic kidney disease

  • 470,000 Americans receiving treatment for ESRD

    • 335,000 dialysis patients

    • 136,000 with a functioning kidney transplant

    • Each year about 70,000 Americans die from kidney failure

      A profile of kidney failure patients in the U.S. follows: (2000)

  • There are approximately 3,600 dialysis facilities and 255 transplant facilities in the U.S.

  • Only 260 dialysis units are hospital-based.

  • The current annual cost of treating kidney failure in the U.S. is approximately $17.9 billion.

    * National Kidney Foundation 2005

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Leading causes of kidney failure in the US *

  • Diabetes –

    • 44% new cases

    • 36% of all cases

  • Uncontrolled or poorly controlled high blood pressure

  • Glomerulonephritis & inflammatory diseases

    National Kidney Foundation data 2003

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  • Maintain water & electrolyte balance

  • Secrete renin by the cells of the juxtaglomerular apparatus

    • Important regulatory mechanism for controlling blood flow

  • Production & metabolism of prostaglandins & kinins

  • Production & secretion of erythropoietin by the interstitial cells in response to decreased 0xygen in the blood

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Renal Function – processes of

  • Filtration

  • Secretion

  • Reabsorption

  • Endocrine & Metabolic Fx’s

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Renal physiologic functions affecting Pharmacology


  • Occurs at the glomerulus

  • Determinants of a drug’s capacity to be filtered

  • Most drugs are small enough for filtration except for high molecular weight dextrans i.e. volume expanders

    Protein Binding

  • Displacement of highly bound drugs

  • Only free drug can pass through the glomerulus

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NEPHRON (1 million)/kidney

Is the functional unit

of the kidney

Regions of the nephron

  • Glomerulus

  • Proximal tubule

  • Loop of Henle

  • Distal Tubule

  • Collecting Duct

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  • At the nephron is where we see the passing of anions & cations through active & passive diffusion.

  • Na+, K+, Cl-, HCO3-, & H20.

  • Reabsorption denotes transport from the urine back to the blood.

  • Secretion is the movement of solutes or water from the blood to the nephron tubule lumen.

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Measurement of Renal Function

  • Quantify renal fx to use as a diagnostic indicator to monitor therapy.

    • success vs. failure

  • Measurement of renal function is an indicator of the body’s ability to eliminate drugs from the body.

  • Single best measure of renal fx = GFR

  • Volume of plasma filtered across the glomerulus per unit of time

  • Responsible for keeping the renal blood flow constant

  • Normal GFR = 120 mL/min/1.73m2

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Mechanism of Kidney Clearance

  • Measurement of GFR

  • Serum creatinine level, eCrCl

  • MDRD

  • Cystatin C

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  • Measurement of GFR

  • Inulin clearance

    • fructose polysaccharide obtained from plant tubers of the Jerusalem artichoke, chicory & dahlia plants.

    • Urine & blood samples

  • Iothalamate clearance

    • I-Iothalamate radiolabeled form

      Intermittent availability, high cost, invasiveness, sample preparation, & assay variability limits its use in the clinical setting.

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Estimation of Creatinine Clearance

  • CrCl is the single most common clinical test for the assessment of renal fx.

  • Cr is a product of creatinine metabolism on muscle mass.

  • Normal Cr = 0.5 – 1.5 mg/dL

  • Cockcroft and Gault Formula:

    (140-age)(body weight in kg)

    (72)(serum creatinine)

    Women x 0.85

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(140-79)(65)x 0.85 (1.2)(72)

Est. CrCl = 39 mL/min


Calculating the CrCl

  • 79 YO, Female

  • Serum creatinine =1.2 mg/dL

  • 65 Kg

    Important to note there is a normal loss of nephrons due to the aging process.

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Modification of Diet in Renal Disease (MDRD) Study Formula

GFR (mL/min/1.73m2) = 186x(Scr)-1.154 x (age) -0.203 x (0.742, if female) x (1.212, if black)

  • Does not require weight as a variable

  • More accurate for patients whose GFR is less than 90 mL/min

    Other Methods: CKD-EPI, Cystatin, etc…

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Renal Disease Classifications

National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl)

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measures rise and fall of drug concentrations in the serum and tissue





T1/2 : the time it takes to eliminate 50% of the drug from the body


What the drug does to the body

incorporates kinetics

integrates microbiological activity focusing on biological effects, particular growth inhibition and killing of pathogens


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  • Establish a therapeutic outcome for a specific patient

  • Monitor patient’s therapy for effectiveness & clinical responses

  • Evaluate potential side effects

  • Drug Interactions:

    • Additive effect

    • Synergistic effect

    • Incompatibility

    • Adverse drug events

  • All drugs are potentially toxic & can have cumulative effects. Knowledge of organs responsible for metabolizing & elimination will allow us to dose appropriately.

    • Especially in pts with compromised organ function

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DRUGS significantly effected by Renal Failure







DRUGS exhibiting sensitivities to Renal Insufficiencies



Narcotic analgesics

Meperidine (Demerol)



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Drug dosing in CKD

  • Anticipate problems

  • Minimize polypharmacy

  • Strategies

    • Decrease dose

    • Increase Dosing Interval or BOTH

  • Methods

    • Estimate CrCl

    • Consult Dosing recommendations – guidelines

    • Individualize Dose

    • Monitor Serum Drug Concentrations

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Drug Dosing in Dialysis

Influencing factors

  • Protein Binding – unbound drug for diaysis

  • Volume of Distribution-lge VD less dialyzable

  • Molecular Weight – MW > 500 not dialyzable

  • Dialyzer Membrane Permeability – allow passage of drugs

  • Dialyzer Surface Area – larger areas achieve greater clearance

  • Blood Flow Rate – fast BFR may allow increased clearance

Johnson et al. 2005 Dialysis of Drugs

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Drug Dosing In Dialysis

  • Maintenance dose based on anephric status

  • Supplemental Dose - Replace amount of lost drug

  • Establish Serum Drug Concentration Monitoring

  • Water-soluble vitamins are dialyzable

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Antihypertensive in CKD: ACEIs & ARBs(HTN, a common complication of CKD)

Angiotensin Converting Enzyme Inhibitors

Captopril (Capoten), enalapril (Vasotec), enalaprilat (Vasotec IV), lisinopril (Prinivil, Zestril), ramipril (Altace), benazepril (Lotensin), quinapril (Accupril), fosinopril (Monopril), moexipril HCl (Univasc), spirapril (Renormax), trandolapril (Mavik), perindopril (Aceon).

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  • Beneficial in pts with HTN & diabetic damage to the kidneys & heart.

  • HF – ↓ systemic vascular resistance, BP (afterload), preload; also ↑ CO & exercise tolerance time; Also block the sympathetic nervous system & therefore prevent ventricular remodeling (?end stage HF after an MI) (↓’ed mortality from CHF by 25 to 31%)

  • Preventing diabetic nephropathy – ↓’ed GFR, improved renal hemodynamics, ↓’ed proteinuria, retarted glomerular hypertrophy, & a slower rate of decline in GFR.

  • Excreted primarily by the kidney

  • Half-life is prolonged in RD

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ACEIs: Precautions

  • First dose effect (a profound drop in BP); used in 2nd & 3rd trimesters of pregnancy is associated with fetal injury & death; cautious in RD (~20% associated with nephrotic syndrome); hyperkalemia.

  • CI: bilateral renal artery stenosis, angioedema, pregnancy

  • AE’s: orthostatic hotn, angioedema

  • Dry, hacking cough (15 – 20%) (seem to be related to bradykinin & substance P)

  • Elevations of liver enzymes, BUN/SrCr, K

  • DI: Potassium-sparing diuretics, NSAIDs

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Angiotensin Receptor Blockers (ARBs)

  • Losartan potassium (Cozaar), candesartan (Atacand), eprosartan (Teveten) , irbesartan (Avapro), olmesartan (Benicar), telmisartan (Micardis), valsartan (Diovan)

  • MOA: Blocks the vasoconstriction & aldosterone effects of angiotensin, selectively blocking the binding of angiotensin II to angiotensin receptors.

  • Have no effect on bradykinin metabolism & therefore more selective blockers of angiotensin effects than ACEIs; potentially have a more complete inhibition of angiotensin action compared with ACEIs b/c there are enzymes other than ACE that are capable of generating ACEII

  • AE’s: angioedema, diarrhea, dizziness, cough (less than ACE inhibitors)

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HTN: Diuretics

  • Thiazides – early renal failure

    (In the treatment AKI, large randomized trials have failed to prove diuretics to be effective)

  • Loop diuretics – effective in pts with residual renal fx

    • Furosemide (Lasix), Torsemide (Demadex)

  • Thiazide-like Diuretics – potent, use in CKD/ESRD

    • Indapamide (Lozol), metolazone (Zaroxoline)

  • Osmotic – Mannitol

  • K-Sparing – spironolactone (Aldactone), amiloride (Midamor) [avoid in hyperKalemia]

  • Monitor: I/O, kidney function, lytes, ototoxicity, lipid profiles, uric acid, allergy

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Beta Adrenergic Blocking Drugs

  • Propranolol HCl (Inderal)

  • Acebutolol (Sectral)

  • Metoprolol (Lopressor)

  • Nadolol (Corgard)

  • Atenolol (Tenormin)

  • Pindolol (Visken)

  • Betaxolol (Kerlone)

  • Acarteolol (Cartrol)

  • Penbutolol (Levatol)

  • Timolol (Blocadren)

  • Carvedilol (Coreg)

  • Esmolol (Brevibloc)

  • Sotalol (Betapace)

  • Nebivolol (Bystolic)

  • ↓ HR

  • Bronchospasm

  • Masked hypoglycemia

  • ↑ triglycerides w/↓HDL

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Calcium Channel Blockers

  • Also used as: antiangina, arrhythmias

  • Cause negative inotropic

  • Dizziness, HoTN

  • Amlodipine (Norvasc)

  • Nifdipine (Adalat, Procardia)

  • Isradipine (Dynacirc)

  • Felodipine (Plendil)

  • Nnisoldipine (Sular)

  • Verapamil (Calan, Isoptin)

  • Diltiazem (Cardizem)

  • Others

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Analgesics in CKD

  • Mild (1-4): APAP, +/- adjuvants prn

  • Moderate (5-6): Tramadol (Ultram), Hydromorphone (Dilaudid)?

  • Severe (7-10): Fentanyl, Methadone, +/- adjuvants

  • Not recommended: Codeine, Oxycodone, Morphine, NSAIDs

  • AVOID: Meperidine, Propoxyphene

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Dyslipidemias Management in CKD

NKF-K/DOQI. Am J Kidney Disease. 2003;41(suppl 3)

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CKD & Anemia Management

  • Transfusions

  • Androgen tx – 1970

    • Modest success

    • Only 50% of pts respond with a 5% increase in HCT’s

  • Recombinant erythropoietin

    • EPO, Darbepoetin alfa

  • Iron Therapy

    • Iron dextran (Infed), Sodium ferric gluconate (Ferrlecit), Iron Sucrose (Venofer)

  • Adjuvants

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NKF-KDOQI Guidelines

Monitor: Hb at least monthly

Iron Indices at every 1-3 months

NKF-KDOQI. Am J Kidney Dis. 2006;47(5):suppl 3., Am J Kidney Dis. Sept. 2007

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FDA Public Health Warning Issued for ESAs

  • Hb target >12 g/dL may  risk of CV events & death

  • Lowest dose of ESAs should be used

  • Hb should be gradually raised to avoid need for transfusion

  • Monitor Hb during dose titration

  • Withhold the dose if the Hb  exceeds 12 g/dL or rises by 1 g/dL in any 2-wk period

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Iron Physiology

  • Is a key constituent of Hb & necessary as adjunctive thx to enhance the effectiveness of ESA

  • Ferritin: Liver is the main storage site of Fe & in the form of ferritin

    • Acute-phase reactivity (’ed in acute/chronic inflammation, malnutrition, liver disease)

  • Transferrin (TSAT): immediate iron on board is essential for erythropoiesis

    • Acute-phase reactivity (significant fluctuations, low in malnutrition/chronic disease)

  • Reticulocyte hemoglobin content

    • “Real time” assessment of Fe status

    • Measures immediated incorporation of Fe into reticulocytes (in circulation for only 1 day)

    • Less variable/more accurate than sferritin/TSAT

NKF-KDOQI. Am J Kidney Dis. 2006; Kalantar-Zadeh, et al. Nephrol Dial Transplant. 2004;19:141-149

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NKF-KDOQI. Am J Kidney Dis. 2006; Fishbane. Am J Kidney Dis. 1997;29:319-333

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IV Iron administration

Oral – not effective (HD)

Iron Dextran: anaphylactic risk (0.6-2.3%), ~0.7% w/life-threatening rxns

Iron Sucrose & Gluconate: better safety profile, similar efficacy

Iron & Infection: microbes synthesize iron transport proteins that compete with transferrin for free iron; Depress sIron values have been documented during infectious diseases

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NKF-K/DOQI Guideline: Fe Administration

  • If TSAT <20% and/or Ferritin <100 ng/mL, give IV iron 100-125 mg qHD x8-10 doses

  • Repeat TSAT & Ferr 1-2 weeks later, if still <20% and/or <100 ng/mL, repeat IV Fe course

  • Once TSAT 20% & Ferr 100 ng/mL, give IV Fe 50-100 mg qweek MD

    Monitor: every 1 to 3 months

    May monitor during iron maintenance schedule, no need to interrupt dosing

    Usually 1-2 wks after course completed

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Hyporesponsive Issues

Comobidities: DM, HTN, Cardiovascular disease,

Frequent hospitalizations, blood loss, CA, AIDS

Infection, Inflammation

Iron deficiency (Absolute & Functional)

Aluminum toxicity

Pure Red Cell Aplasia (PRCA)


Elevated C-reactive protein level

Temporary & permanent catheter insertions

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Overcoming Hyporesponsive Issues?


  • A carrier involved in the transport of fatty acid

  • HD patients may have low level

  • No pathogenic mechanism that may contribute to anemia

    Vitamin C (Ascorbate)

  • May help  the release of Fe from ferritin & the reticuloendothelial system, which  Fe utilization during heme synthesis

    Conclusion: Insufficient evidence

    Not recommended: Androgens

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Mineral & Bone Disorders

  • Severe Hyperparathyroidism (sHPT)

  • Vitamin D’s analogs

  • Phosphate-binding drugs

  • Cinacalcet (Sensipar)

    • Calcium sensing receptors

    • Decrease PTH hormone

    • Lowering serum calcium levels

    • Dose sHPT – 30mg po daily; increase q2-4w, prn

    • AE’s: N/V, hypocalcemia, seizures

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NKF-KDOQI Target Treatment Goals for CKD Stage 5

NKF-KDOQI. Am J Kidney Dis. 2003;42(suppl 3)

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Mineral & Bone Metabolism

  • Vitamin D’s

    • Calcitriol - Calcijex

    • Paricalcitol - Zemplar

    • Doxercalciferol - Hectorol

  • Monitoring

    • Ca, Phosphorus

    • Ca x PO4 products

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Mineral & Bone Metabolism

  • Phosphate Binding Agents

    • Aluminum base binders

    • Calcium base binders (1500 mg/day)

    • Non Calcium/Aluminum binders

      • Sevelamir HCl (Renagel)

      • Lanthanum Carbonate (Fosrenol)

  • Monitoring

    • Ca, PO4

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  • Gram positives coverage: Cefazolin, nafcillin, vancomycin, linezolid (Zyvox), quinupristin/dalfopristin (Synercid), daptomycin (Cubicin), Tigecycline (Tygacil), others

  • Gram negative coverage: aminoglycosides, fluoroquinolones, 3rd gen cephalosporins, others

  • AntiFungals: e.g. Amphotericin, Fluconazole

  • AntiVirals: e.g. Acyclovir

    Dosages must be adjusted for renal failure

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Antimicrobial: Cefazolin (Ancef, Kefzol)

SOA: sensitive staph & strep

Dose: nl 0.5-1.5 g, q8-6h, crcl <10 mL/min, q24-48h.

PKs: renal excretion (56-100%), t1/2 1.5-2.5 hrs (nl), 11-13 hrs (renal failure), 40-70 hrs (anephric)

Dialyzable: Yes

HD: moderately dialyzable (20-50%), dose post-HD, or 0.5-1 g supplemental dose post-HD

PD: 0.5 g, q12h

CAVH/CAVHD: removes 30 mg/liter of filtrate/day

AE’s & Precautions: GI (diarrhea), renal impairment

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Antimicrobial: Vancomycin

SOA: MRSA, Staph & Streph PCN allergic patients


PK: Renal excretion, t1/2 4-6hrs (nl RF), 7.5 days (avg anephric pts)

Dialyzability: Conventional membranes - not dialyzable (0-5%), no longer used.

Newer high-flux filter – dialyzable, dose post-HD

Not significantly removed by CAPD, Clearance ~10-15 mL/min (CAHD)

AE’s: rash (red neck), chills, drug fever.

Slow infusion, not exceeding 10 mg/min, extremely irritating & may cause tissue necrosis

Precautions: avoid IM, presence of renal impairments/drugs, pre-existing hearing loss, slow IV infusions

Monitor: Trough, Random levels (avoid level w/in 6hr post-HD; wait ~20hrs)

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Vancomycin Serum Levels in Patients Receiving High flux Dialysis

Matzke G. ACCP 2007 Spring Meeting

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Aminoglycosides: Gentamycin, Tobramycin, Amikacin Dialysis

SOA: serious infections, gram negative, staph

PK: Renal excretions (60-85%), t1/2 1.6-3 hrs (nl), 53 hrs (anephric)

Dialyzable (HD, PD, Hemoperfusion): Yes, dose post-HD

AE’s: ototoxicity, nephrotoxicity, neurotoxicity, edema, rash, GI’s

Precautions: other nephro/ototoxicity agents, impair renal function.

Monitor: Peak & trough, random levels

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CKD & Hypoglycemic Agents Dialysis

What to do?

Initiate low dose

Monitor closely

Avoid (many agents)


Decreased clearance

Impaired glucogenesis



Active metabolites

Lactic acidosis

Worsen fluid retention


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Interdialytic Agents Dialysis

  • Hypertonic Solutions: 23.5% NS, 5%, NS, 3% NS

    • Warning – JC Patient Safety High Alert

  • Normal Saline (NS)

  • Plasma expanders: Albumin, Mannitol

  • Sympatholytics: Midodrine

    • Alpha agonist, activates phospholipase C, effects smooth muscle contraction increasing BP

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Multidisciplinary Care of CKD Patients Dialysis

Joy et al. Am J Kidney Dis. 2005;45(6):1105-1118

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  • The kidney is the major excretory organ for many therapeutic agents and their metabolites.

  • It is imperative to consider renal function when reviewing drug therapy.

    • Maximize therapeutic effects while minimizing toxicity.

  • Estimated CrCl is the only clinical tool available for renal function.

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Nurse’s Roles Dialysis

  • The processes of assessments, implementation, & monitoring should be reassessed regularly

  • The treatment plan (pharmacotherapy) should be changed to accommodate the needs of the patient

  • Neglecting may results in ineffective tx

  • Nurse’s Role: More than just memorization of the names or pharmacologic agents, their use, but requires a sound comprehension & application of the knowledge to a variety of clinical situations.

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ANNA’s Jersey North: CNN Certification Review Course Dialysis


Timothy Nguyen, BS, PharmD, CCP, FASCP