Renal pharm Flashcards
what happens in the kidney
- Filter
- Reabsorb
- Secrete
How do we measure Kidney fxn?
- GFR- dependent on protein load
- Tubular secretion and reabsorption
- Endocrine and metabolic fxn
-secretion of renin
-produce and metab prostaglandins and kinins
-EPO production
-activate Vitamin D
-Gluoneogensis
-Metab of insulin, steroids, xenobiotics
Lab procedures to detect kidney disease?
- Urinalysis- pH, glucose, Ketones, nitrite, leukocyte esterase, heme, protein/albumin, specific gravity
- Microscopic analysis of urine- hematuria, WBC, CASTS, CRYSTAL (uric acid crystals)
- Serum or Blood Urea Nitrogen- urea undergoes filtration and reabsorption up to 50%
- Serum and Urine creatinine- most important endogenous biomarker for kidney disease = HIGH = DYSFXN
- Serum and urine Cystatin C= LOW= DYSFXN
Measurement of Kidney fxn
- Gold standard= mGFR= early rec of CKD and drug dose adjustment
- Conditions that impact kidney fxn independent of underlying pathol-> oral protein load (vegetarians have lower GFR) or Decline in kid mass- Age, HTN, or DM
- GFR is volume of plasma filtered across glomerulus per unit of time= based on total renal blood flow and cap hemodynamics (normal values= 120 mL/min/ 1.73 m2
- mGFR is equivalent to renal clearance of the solute marker- endog or exog
Caveats to reliability of Creatinine based Kidney fxn
ONLY USEFUL FOR STABLE RENAL FXN
CrCl= (urine Cr* Urine volume)/(plasma Cr* Time)
Not used when:
unstable= pregnancy, serious comorb, hospitalizes, EXTREMES IN MUSCLE MASS AND DIET
Formulas for dosing adjustments in CKD
- Cockcroft-Gault method = CrCL
-direct measure of renal fxn
- used to be the gold standard= phasing out - Modification of diet in renal disease- MDRD= GFR
-estimates GFFR based on creatinine and patient characteristics
MAY UNDERESTIMATE ACTUAL GFR OF HEALTHY PT BY UP TO 29%
BELOW 60 GFR - CKD- EPI equation= GFR
-near or ABOVE 60 ml/min
-accounts for sex and race
CrCl= normal= 20 mg/kg/day
Nrml GFR= 100-120 mL/min
Chronic kidney disease
- ABN kidney structure or function for AT LEAST 3 MONTHS
- IRREVERSIBLE DAMAGE TO THE NEPHRONS
- Progressive decline of GFR over months to years
- Defined: Absolute GFR less than 60 or struct/functional abnormalities= hematuria, proteinuria, abn renal imagin
u/s: cysts, masses, renal artery stenosis-> Diag KD
How does CKD affect drug therapy
- pts more vulnerable to a drugs effect-> increases susceptibility
- Drug effect may be exaggerated or reduced
- may have higher steady state in renal disease-> toxicity results
-ADME- absorption, distribution, metabolism, elimination
overall: Renal disease either increases of decreases drug effect-> usually increase= TOXICITY
Drug dose should be reduced proportionally to the predicted reduction in drug clearance
- increased drug clearance= lower drug conc
-Decreased drug clearance=higher drug conc and greater drug effect=====REDUCE DOSING OF THESE DRUGS
Pharmkinetics in CKD- Drug Absorption
Absorption
-alters abso or bioavial -> highly variable
Reasons= drug interactions
- GI-» DELAYED GASTRIC EMPTYING, DECREASED GASTRIC ACIDITY, INCREASE IN GASTRIC PH
high use of antacids-> increases pH= cdkd pts freuently take
Pharmkinetics in CKD- Drug Distribution
Volume of distribution INCREASED-> DECREASING SERUM DRUG CONC
due to
-fluid overload secondary to fluid intake or administration
-decreased protein binding-> increased tissue binding
Altered plasma protein binding
-normal kidney fxn->protein binding limits drug distribution as only unbound are able to cross cellular membranes and distribute
CKD= decrease in binding= increased drug distribution
Example of drug distribution
Protein binding of phenytoin (90% protein bound-> primary to albumin) (decreased binding= not activated-> into tissues)
-decreased due to decreased plasma phenytoin binding affinity for albumin
-changes alter relationship btwn total phytoin conc and desired/toxic effects
-resulting increase in unbound fraction from values of 10% in normal to over 20% in G5 CKD= increased hepatic clearance and decreased total conc
IN CKD THERAPEUTIC RANGE BASED ON TOTAL PHENYTOIN CONC IS SHIFTED DOWNWARD FROM NORMAL VALUES OF 10-20 TO 4-8
Drawing drug level decreases bc unattached= only looking for active which has to be bound
Pharmkin in CKD: Elimation
Kidney fxn is most quantifiable determinant of drug clearance-> how quickly a drug is removed from the body
fxn is combined process of
-GFR
-tubular secretion
-reabsorption
-reduced kidney mass
-# of functioning nephrons
-Renal blood flow
alteration of fxn can have dramatic effect on drug disposition-> drugs primarily filtured thru kidneys a decrease in GFR= PROPORTIONAL DECREASE IN RENAL DRUG CLEARANCE
clearance decreased in both renally and non renally
Pharmcodynamics
pharmacodynamics= effects of drugs and the MOA on body
Decreased GFR= slows rate of drug filtration thru kidney and decreased clearance
-increased conc levels in blood= diff peak and trough serum conc
Causes of CKD requiring dose adjustments
- Age decreases fxn
- Multiple medical comorb= 1. DM 2. HTN
- Medications alter kidney fxn= 1.NSAIDS 2. Metformin
Drug dosing in CKD
- inapprop dosing can cause -> toxicity and ineffective therapy
- Special concerns in elderly-> Age related decline in GFR or polypharmacy
- Active/toxic metabolites
Renal metabolism
some drugs undergo partial renal metab-> affect adjustment
loading dose and maintenance dose
Volume distribution= increase water= increase VD so increase dose and vice versa
Drug dosing regimens for CKD pts
- loading dose is the same as pts with normal= no adjustments
-except if VD is known to be altered in presence of CKD or concomitant disease - Rapid achievement of therapeutic drug conc is important= start aggressively like in anticoag, sepsis, stroke pts
- FDA product labeling should be foundation for ongoing therapy
Renal dosage adjustment
- if pts renal fxn is markedly decreased -> drugs will need renal adjustment but varies
- online calc available for CrCl
- no simple method applies to all drugs
- Dose reduction vs longer interval
-50 mg x2 = more steady state but wont excrete fully = toxic effect
-100 mg x1= peak and trough but excrete so less toxic
Important drug considerations in CKD
- antibiotics
- Antihypertensives
- Antidiabetic agents
- Analgesic agents
Antimicrobial agents in CKD that need dosing adjustment
- Penicillin G or carbenicillin
-neuromusc toxicity, myoclonus, seizures, coma - Tetracyclines (NOT DOXY) exacerbate uremia
- Nitrofurantoin metabolites cause peripheral neuropathy
- AMINOGLYC SHOULD NOT BE USED IF POSSIBLE= NEPHROTOXIC
Problems with Fluoroquinolones
Cipro/Levaquin
Moxifloxacin - no renal adjustment
—all increase QT intervals—
1.Loading doses are okay
2. Renal dosing is 1/2 to 1/4 “normal dose”
antihypertensive agents- drug considerations diur
Diuretics
-THIAZIDE DIURETICS NOT RECOMMENDED IF SERUM CREATININE GREATER THAN 2.5 MG/DL OR CREATININE CLEARANCE LESS THAN 30 ML/MIN
–loop diuretics mc for uncomp htn in ckd
–potassium sparing diur and Aldosterone blockers= increase SERUM POTASSIUM which wont get excreted
Anti HTN agents- ACE and ARBS
ACE and ARBS
-1st line for pts with DM and Early Kidney Disease
problems
-ACE ADN ARBS DECREASE GFR AND INCREASE CREATININE
DC IF SERUM CREATININE INCREASES MORE THAN 30% OR SERUM POTASSIUM AT LEAST 5.6
Anti HTN- renal adjustment
Adjustment:
Hydrophilic BB= ATENOLOL AND NADOLOL
No adjustment: not hydrophylic
CCB, CLONIDINE, ALPHA BLOCKERS
Water loving go to increased water conc-> impaired excretion= increased build up of drug
Metabolic agents- Metformin
BBW: LACTIC ACIDOSIS W/ CERTAIN COMORB-> blocks gluconeogenesis= increases lactic acid
Do not give met if :
1. SERUM CREATININE IS GREATER THAN 1.5 MG IN MEN OR 1.4 IN WOMEN
2. Age over 80
3. CHF
dont avoid-> start low dose and titrate with close monitoring
Temp d/c metformin in pts at higher risk of lactic acidosis-> Sepsis or AKI
SE: diarrhea
Metabolic agent- other
- Sulfonylureas- (Glimepiride or glyburide)
-CAUSE HYPOGLYCEMIA NOT USED IN STAGE 3 OR HIGHER KIDNEY DISEASE
-no adjustment of GLIPIZIDE - Statins
-adjustment for all but ATORVASTATIN
Mnemonic for bad
TVBMANSIAACKFP
These-tetracycline, thiazides
Very- vancomycin
Bad- BB
Meds- metformin
Are- ACE/ARB
Not- Nitrofurantoin/nsaids
Safe-Sulfonureas
In- Imepenem
Acute- Aminoglycosides
And- Acyclovir
Chronic- Chemo drugs
Kidney- K+ sparing diuretics
Failure- Fluoroquinolones
Patients- penicillins
Insulin and CKD
- Hormone synth and secreted by pancreatic islet cells
- Decreased GFR = increased insulin levels-> kidney clears 30-80% of serum insulin
-Dose may need to be reduced to avoid hypoglycemia
-Done empirically as pts are doing daily monitoring of BF
Analgesic agents and CKD
- Opiods
- NSAIDS
acetaminophen- no adjustment needed
Opioid use and CKD
AVOID MORPHINE AND CODEINE
MEPERIDINE AND TRAMADOL METABOLITES-> affect central nervous and respiratory systems= not recommended in stage 4 or 5
-hydro morphine, oxycodone, and fentanyl are safe
Renal toxicity appears in appropriate use-> higher than needed doses, presence of other toxins, pre-existing dehydration, PROSTATE ENLARGMENT= DECREASED URINE OUTPUT LEADING OT KIDNEY FAILURE
Chronic opioid use= greater incidence of toxicity
- accumulate metabolites - cause unwanted side effects-> steady state reached and builds up
Opioid use/ overdose
Overdose= AKI
causes: dehydration, hypotension, rhabdomyolysis, urinary retention
CKD may result due to mode of administration of drug
-skin popping resulting in amyloidosis
-Heroin associated nephropathy (HAN)
Opioid and elderly
age related changes might alter opioid drug kinetics= unwanted SE
-Decreased organ fxn of liver and kidney
-Alterations in ADIPOSE TISSUE COMPOSITION ALTERING KINETICS- allow metab to accumulate and present for longer
Nonsteroidal anti-inflammatory drugs NSAIDS
Indications: Chronic inflammatory conditions, Acute and Crhonic pain, Fever
-Aspirin
-indomethacin
-Diclofenac
-ketorolac
-ibuprofen
-naproxen
-celecoxib
SE: Gastrointestinal complications, NEPHROTOXICITY, Nervous sys effects-> sodium retention, hyperkalemia, type 4 RTA, hyponatremia, AKI
—constricts afferent arteriole and decreases GFR—
NSAIDS: Renal Syndromes
AKI
Metabolic disturbances-> doesnt filter= hyponatremia, hyperkalemia, metabolic acidosis
Acute and Crhonic interstitial nephritis
decreased sodium excretion -> peripheral edema, htn, exacerbated hf
HTN-> develops or exacerbated by use
NSAIDS: AKI
linked to 3x higher risk for acute renal failure-> due to reduced renal plasma flow bc of decreased prostaglandins which reg VD at glomerular level
Adjustment if agent specific
RF make kidney dependent on prostaglandins:
1. “True” intravasc Volume depletion-> vomiting, diarrhea
2. “Effective” intravasc volume depletion-> CHF, cirrhosis, nephrotic syndrome
3. Kidney disease: acute or chronic
4.Meds: ACE and ARBS
5. Old age
NSAIDS and CKD
cause or worse? unknown
SHOULD BE AVOIDED IN PTS WITH STAGE 4 OR 5 CKD
NSAIDS overall
Antihypertensive effects of BB, ACE or ARBs= can be decreased
Short term use is well tolerated if
-well hydrated
CrCl>50%
no HF, DM, HTN
no long term use recommended
Serum creatinine should be checked every 2-4 weeks in early tx
