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Medication Management In Geriatric CKD
Jessica Goh
Senior Pharmacist
1
10 SEPTEMBER 2016
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Pharmacokinetic-Pharmacodynamic (PK-PD) Changes In Elderly
2
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PHARMACOKINETICS (PK)
ABSORPTION: process of drug entering blood stream
DISTRIBUTION : dispersion/dissemination of drug to fluids and tissue in body
METABOLISM : irreversible conversion of parent compounds to metabolites
EXCRETION : elimination of metabolites from body
3
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PK CHANGES IN ELDERLY Absorption
PO Meds
-Vitamin B12, Calcium and iron have absorption
in elderly due to gastric pH or GI motility
-Patients with heart failure may have blood flow
to the GIT, leading to absorption
Topical
-Skin atrophies with aging reduced blood flow,
impaired transdermal absorption
IM/SC meds
-Elderly have muscle mass poorer perfusion
4 Delafuente et al. Consult Pharm 2008
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PK CHANGES IN ELDERLY
Distribution
- total body water Affects water-soluble drugs (eg digoxin, theophylline, morphine) due to Vd Higher serum drug concentrations
- muscle mass Distribution to lean tissue is smaller Lower doses required
-Higher body fat Affects lipid soluble drugs (eg phenytoin,valproate, diazepam) as they have larger Vd Longer duration of action as they are bound to the body longer
-Lower dose or frequency interval required
5 Delafuente et al. Consult Pharm 2008
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PK CHANGES IN ELDERLY
Distribution
- albumin concentrations (malnourished/frail/prolonged illness) More unbound drugs Higher serum concentrations of free drug
-Uremic toxins protein binding
affinity for drugs (eg penicillins,
phenytoin,Theophylline) = free
(unbound)drug concentrations
6
Delafuente et al. Consult Pharm 2008
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PK CHANGES IN ELDERLY
Metabolism
-Drugs undergoes metabolism in the liver via Phase 1 and Phase 2 reactions
-Aging causes liver to be smaller poorer liver blood perfusion
-Phase 1 (oxidation/reduction/hydrolysis) liver metabolism is in older patients
-CYP system is responsible for Phase 1 reactions of many medications. >50% of drugs undergo CYP3A4 metabolism
-Phase 2 reactions : not affected with aging
7 Delafuente et al. Consult Pharm 2008
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PK CHANGES IN ELDERLY
Elimination
-as CrCl drug clearance by tubular secretion and glomerular filtration
-Renal function may be “overestimated” due to low muscle mass
8 Delafuente et al. Consult Pharm 2008
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PD CHANGES IN ELDERLY
-Blunted baroreflex responses
- inotropic and chronotropic responses to β1adrenergic stimulation
-Increased sensitivity to agents that act on the central nervous system (CNS)
9 Delafuente et al. Consult Pharm 2008
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ADJUSTING MEDICATIONS IN GERIATRIC CKD
-General rule of thumb: Start low, Go s l o w
-Avoid long acting agents in elderly
-Some dosage adjustments may be based on CrCl (derived from Cockcroft-Gault equation) or eGFR
-Beers Criteria
10
*Adjustments quoted in the following slides
are for non-dialysis CKD patients
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Antibiotics In Geriatric CKD
11
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PO ACYCLOVIR
12
Drugs Renal Fxn Dose Max Dose
Acyclovir CrCl 10-25 Recommended Dose
q8H
800mg/dose
2.4g/day
CrCl <10 Recommended Dose
q12H
800mg/dose
1.6g/day
Caution • Potential risk for crystalluria
• Nephrotoxicity risk with concurrent
nephrotoxic agents (ACE/ARB, NSAIDs,
Colchicine) or dehydration
• Potential Risk for neurotoxicity
UptoDate 2016
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13 http://www.cfps.org.sg/publications/the-college-mirror/article/994
ACYCLOVIR TOXICITY IN CKD The College Mirror, Vol 42, March 2016
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ACYCLOVIR NEUROTOXICITY IN CKD
14
The College Mirror, Vol 42, March 2016
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ANTIBIOTIC ASSOCIATED DELIRIUM
15
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ANTIBIOTIC ASSOCIATED DELIRIUM
16
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ANTIBIOTIC ASSOCIATED DELIRIUM
17
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DRUG ASSOCIATED WITH COGNITIVE IMPAIRMENT IN ELDERLY
18
Moore AR et al .Drugs Aging 1999.
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PO ANTIBIOTICS
19
Drugs Renal
Function
Dose Max Dose
Amoxicillin CrCl 10-30 500mg BD 0.5-1g/day
CrCl <10 500mg OD
Augmentin CrCl 10-30 625mg BD
CrCl <10 625mg OD
Penicillin V Use with
caution in
renal
dysfunction
Usual:
500mg q6H
4g/day
UptoDate, Micromedex 2016
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PO ANTIBIOTICS
20
Drugs Renal Fxn Dose
Bactrim Dosed based on TMP component Single Strength:(TMP 80 mg/SMX 400 mg)=480mg
Double Strength:(TMP 160 mg/SMX 800 mg)=960mg
*Maintain adequate hydration to prevent crystalluria
CrCl 15-30 50% of
dose
CrCl <15 Avoid
Nitrofurantoin
Avoid in elderly due to risk for
pulmonary toxicity
Contraindicated in
CrCl <60ml/min
(ineffective)
UptoDate, Micromedex 2016
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SULFONAMIDE CRYSTALLURIA
21
UptoDate 2016
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PO ANTIBIOTICS
22
Drugs Renal
Function
Dose Max Dose
Cefuroxime CrCl 10-30 500mg q24H 500mg/day
CrCl <10 500mg q48H 250mg/day
Nitrofurantoin Avoid in elderly due to risk for pulmonary
toxicity
Contraindicated in CrCl <60ml/min
UptoDate, Micromedex 2016
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ANTIBIOTICS NO RENAL ADJUSTMENT REQUIRED
23
Drugs Max Dose
(per day)
Azithromycin 500mg
Cloxacillin 6g
Clindamycin 1.8g
Doxycycline 200mg
Ceftriaxone 4g
Metronidazole 4g**
Moxifloxacin 400mg
**varying practice UptoDate, Micromedex 2016
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PO ANTIBIOTICS
24
Drugs Renal Fxn Dose
Ciprofloxacin CrCl <30 500mg OM
Levofloxacin CrCl 20-49 500mg/day:
500 mg STAT, then 250 mg q24H
750mg/day:
750mg q48H
CrCl 10-19 500mg/day:
500 mg STAT, then 250 mg q48H
750mg/day:
500 mg STAT, then 500mg q48H
UptoDate, Micromedex 2016
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DRUG-DRUG INTERACTIONS
25
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Oral Hypoglycemic Agents (OHGAs)
26
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METFORMIN
-First line agent for Type 2 Diabetes
-Low hypoglycemic risks
27
eGFR Dose adjustments
45 to <60 mL/min Monitor renal function
3-6monthly
≥30 to <45
mL/min
Use with caution, may
consider dosage reduction
<30 mL/min Avoid
American Diabetes Association, UptoDate, Micromedex 2016
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SULPHONYLUREAS Drug Duration Excretion Renal Adjustment
First Generation
Chlorpropamide 24-72h Urine (unchanged drug and as
hydroxylated metabolites)
T/12 : ~36 hrs; prolonged in
elderly .ESRD : 50-200 hrs
CrCl >50 mL/min: by50%.
CrCl <50 mL/min: Avoid use.
Tolbutamide 14 -16h Urine (75% -85% as
metabolites. Metabolism not
affected by age
No dosage adjustment
available
Second Generation
Glipizide 14 -16h Urine (<10% as unchanged
drug; 80% as metabolites)
Less hypoglycemia in renal
impairment than other SUs.
Start low dose.
Glicazide 24 h Urine (60% to 70%; <1% as
unchanged drug
Mild to Mod: Adjust slowly
Severe impairment: Avoid
Glibenclamide 20 -
24+h
Urine (50%)metabolites eGFR <60 mL/min: Avoid
Glimepiride 24+ h Urine (60%, 80% -90% as M1
and M2 metabolites)
Severe impairment: Avoid
28
UptoDate, Micromedex 2016
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HSA ALERT -GLIBENCLAMIDE
29
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DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
30
Drug Renal Function Elimination Dose
Adjustment
Sitagliptin CrCl ≥30 -49
mL/min
Excretion: Urine
87% (~79% as
unchanged drug,
16% as
metabolites)
50mg OD
CrCl <30 mL/min 25mg OD
Saxagliptin CrCl ≤50 mL/min Urine (75%) 2.5 mg OD
Linagliptin Regardless of
renal function
80% cleared in
feces
5mg OD
None required
UptoDate, Micromedex 2016
-Low hypoglycemic risks
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MEGLITINIDES •Faster onset and shorter duration of effect than sulfonylureas
•Low risk of hypoglycemia
•Good for patient who are sulfonamides or sulphur allergy
31
Drug Duration Renal
function
Dosage
adjustment Elimination
Repaglinide
4-6h
CrCl
20-40
Initial: 0.5 mg
with meals;
titrate carefully.
Feces
(~90%)
CrCl <20 Not studied
Nateglinide
4h
N/A No adjustment
required
Urine (83%)
UptoDate, Micromedex 2016
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OTHER OHGAs
Drug Renal function Adjustment
Alpha-Glucosidase
Inhibitors
Eg Acarbose
CrCl <25 mL/min or Scr
>2mg/dL or 177umol/L
Avoid
Sodium-Glucose Cotransporter 2 Inhibitors
Canagliflozin eGFR 45 to <60 mL/min Max 100mg
eGFR <45 mL/min Avoid
Dapagliflozin eGFR 30 to <60 mL/min Avoid
Empagliflozin eGFR <45 mL/min Avoid
Thiazolidinediones None required. Need to
adjust for hepatic
Avoid in patients with
advanced CKD, especially
those with preexisting heart
failure, given the risk of
edema and heart failure
32 UptoDate, Micromedex 2016
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SUMMARY SLIDE ON OHGAs
33
CKD
Stage
eGFR Metformin SU Meglitnide DPP4 SGLT2 Acarbose Thiazolid-
inediones
3A 45-59 √ √* √ √ √ √ √
3B 30-44 √ √* √ √* X √ √
4 15-29 X √* √* √* X X √*
5 <15 X √* √* √* X X √*
*requires renal adjustment/only certain agents in drug class
recommended-conditions apply
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PAINKILLERS IN GERIATRIC CKD
34
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PAINKILLERS
35
2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults
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PAINKILLERS
36
2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults
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PAINKILLERS
37
2012 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults
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PAINKILLERS-START LOW
38
UptoDate 2016
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DRUG ASSOCIATED WITH COGNITIVE IMPAIRMENT IN ELDERLY
39
Moore AR et al .Drugs Aging 1999.
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Antihypertensives In Geriatric CKD
40
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ACEI/ARB + DIURETICS + NSAIDS & NEPHROTOXICITY
•Acute kidney injury risk increases by 31%, with the highest risk occurring in the first month of use
• Triple whammy!
41 Lapi et al. BMJ. 2013;346:e8525
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WHAT BP TARGETS DO WE USE FOR ELDERLY?
Guidelines Population Goal BP, mm Hg Remarks
JNC8 2014 General ≥60 y <150/90
Diabetes <140/90
CKD <140/90
ESH/ESC 2013 General elderly <80 y <150/90 *For fragile
elderly, SBP
goals should be
adapted to
individual
tolerability
General ≥80 y <150/90
Diabetes <140/85
CKD no proteinuria <140/90
CKD + proteinuria <130/90
CHEP 2013 General ≥80 y <150/90
Diabetes <130/80
CKD <140/90
NICE 2011 General ≥80 y <150/90
42
Abbreviations: CHEP, Canadian Hypertension Education Program; JNC, Joint National Committee; ESC, European Society of
Cardiology; ESH, European Society of Hypertension; NICE, National Institute for Health Clinical Excellence.
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ANTIHYPERTENSIVES ARE ASSOCIATED WITH FALL RISKS!!
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ADVERSE DRUG EVENTS
44 Hanlon JT et al. J Am Geriatr Soc 1997
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POLYPHARMACY- BANE OR BOON?
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TAKE HOME MESSAGES
•Start low, Go s l o w
•Avoid polypharmacy
•Consider potential drug interactions
•Review patients & medications regularly
•Keep regimens simple
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Br J Clinc Pharmaco 1998; 46:531-533
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CASE STUDY 1
Medication list
Aspirin 100 mg OM
Metformin 250g BD
Glibenclamide 10 mg BD
Madopar 62.5mg qds during waking hours
Lactulose 10ml BD
Simvastatin 40 mg ON
68y M, was found drowsy and referred to ED for hypoglycemia.He was recently prescribed a week course of Clarithromycin 500mg BD for URTI. PMH:T2DM, Hypertension , Parkinson disease, Dyslipidaemia and CKD Stage 3 What do you think could have caused his hypoglycemia?
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HSA ALERT -GLIBENCLAMIDE
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DRUG-DRUG INTERACTIONS
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CASE STUDY 2
At the clinic, he brought his own meds from GP.
Co-Diovan(Valsartan 80mg/HCTZ 12.5mg) 1/1 OM
Allopurinol 100mg OM –withheld by GP due to ARF
Colchicine 500mcg TDS prn for gout flare
Diclofenac 50mg TDS prn
70y M, taxi driver, was referred to Nephrology clinic for AKI. Serum creatinine was 131umol/L. PMH: Gout, Hypertension What do you think could have caused his AKI?
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ACEI/ARB + DIURETICS + NSAIDS & NEPHROTOXICITY
•Acute kidney injury risk increases by 31%, with the highest risk occurring in the first month of use
• Triple whammy!
52 Lapi et al. BMJ. 2013;346:e8525