Dose Adjustment in renal and hepatic failure

DOSAGE ADJUSTMENTS OF
HEPATIC, RENAL FAILURE
Presented by:
k.Sowmya
12AB1ROO41
Guided by:
k.Pallavi
Assistant professor
1
vignan pharmacy college,vadlamudi,gunturdist.A.P.

Table of contents
 Renal failure:
• Causes
• Classification
• Dosing adjustments
• Measurement of GFR-Creatinine clearance
• Dosage adjustments in different drugs
• Serum creatinine concentration
• Formulas
 Liver failure:
• Classification
• Etiology
• Liver function tests
• Dosage calculations
2

• Renal failure or kidney failure (formerly called renal insufficiency)
describes a medical condition in which the kidneys fail to
adequately filter toxins and waste products from the blood.
• Renal failure is described as a decrease in glomerular filtration rate
(GFR).
Renal failure
3vignan pharmacy college,vadlamudi,gunturdist.A.P.

Causes of renal failure
• Common causes :condition comment
Pyelonephritis Inflammation of pyelonephrons due to infection
Hypertension Chronic overloading of kidney with fluid and
electrolytes lead to kidney insufficiency
Diabetes mellitus The disturbance of sugar metabolism may lead to
degenerative renal disease
Nephrotoxic
drugs/metals
certain drugs like aminoglycosides,
Phenacetin cause irreversible kidney disease
Hypovolemia Any condition that causes a reduction in renal blood
flow leads to renal damage.
4
vignanpharmacycollege,vadlamudi,gunturdist.A.P.

Classification
• Renal failure can be divided in to two categories:
 Acute renal failure (ARF),
 Chronic renal failure(CRF)
5

Acute kidney injury(AKI)
• AKI , previously called acute renal failure (ARF), is a rapidly
progressive loss of renal function, generally charecterized by
oliguria(decreased urine production) and fluid and electrolyte
imbalance.

Chronic kidney disease(CKD)
• CKD is along term consequence of irreversible acute disease or part
of a disease progression.
• It is a progressive loss of function over several months to years ,
characterized by gradual replacement of normal kidney architecture
with interstitial fibrosis.

Drug dosing incase of ARF:
• Drug therapy optimization in ARF is a challenge confounding
variables include residual drug clearance , and fluid accumulation.
• Volume of distribution for water soluble drugs is significantly
increased due to edema . Use of dosing guidelines for CKD does not
reflect the clearance and volume of distribution in critically ill ARF
patients.
8

Dosing adjustments in CKD:
• Loading doses do not need to be adjusted in patients with CKD.
• Some guide lines suggest methods for maintaining dosing adjustments:
dose reduction , lengthening the dose interval or both.
• Dose reduction maintains more constant drug concentrations but
associated with high risk of toxicities if the dosing interval is inadequate
to allow for drug elimination.
• Lengthening the dosing interval - lower risk of toxicities but a higher risk
of sub therapeutic drug concentrations.

National Kidney Foundation
Kidney Disease Outcomes Quality
Initiative (K/DOQI)
Stage Description GFR (mL per minute
per 1.73 m2)
1. Kidney damage with normal or
increased GFR
≥90
2. Kidney damage with a mild
decrease in GFR 60 to 89
60-89
3. Moderate decrease in GFR 30 to 59
4. Severe decrease in GFR 15-29
5. Kidney failure < 15 (or dialysis)
10
Table-1

Antihypertensive Agents: Dosing
Requirements in patients with
Chronic Kidney Disease
Drug Usual
dosage
Dosage Adjustment based on GFR
>50 10 to 50 <10
ACE
INHIBITORS:
 Captopril
10 mg
daily
100% 50 to 75% 50%
BETA
BLOCKERS:
 Atenolol
5 to 100 mg
daily
100% 50% 25%
DIURETICS:
 Furosemide
No
adjustment
needed
_ _ _
11
Table-2

Hypoglycemic Agents:
Dosing Requirements in patients
with Chronic Kidney Disease
DRUG USUAL DOSAGE SPECIAL CONSIDERATIONS
Acarbose (Precose) Maximum: 50 to 100 mg
three times daily
Lack of data in patients with a serum
creatinine level higher than 2 mg per
dL (180 µmol per L); therefore,
acarbose should be avoided in these
patients1
Chlorpropamide
(Diabinese)
100 to 500 mg daily Avoid in patients with a glomerular
filtration rate less than 50 mL per
minute because of the increased risk
of hypoglycemia19
Glipizide (Glucotrol) 5 mg daily Dosage adjustment not necessary in
patients with renal impairment
12
Table-3

Antimicrobial Agents: Dosing
Requirements in patients
with Chronic Kidney Disease
Drug Usual dosage Dosage adjustment based on GFR
>50 10 to 50 <10
ANTIFUNGALS:
Fluconazole
200 to 400 mg
every 24 hours
100% 50% 50%
ANTIVIRALS:
Acyclovir
5 to 10 mg per
kg every
100% 100% every 12
to 24 hours
50% every 12 to
24 hours
PENICILLINS:
Amoxicillin
250 to 500 mg
every 8 hours
Every 8
hours
Every 8 to 12
hours
Every 24 hours
TETRACYCLINES
Doxycycline
No adjustment
needed
_ _ _
OTHERS:
Nitrofurantoin
500 to 1,000
mg every 6
hours
100% Avoid Avoid
13
Table-4

Other Common Agents: Dosing Requirements
in patients with Chronic Kidney Disease
Drug Usual dosage Dosage adjustment based on GFR
>50 10 to 50 <10
Allopurinol 300 mg daily 75% 50% 25%
Famotidine 20 to 40 mg at bedtime 50% 25% 10%
Metoclopramide 10 to 15 mg three times
daily
100% 75% 50%
omeprazole no adjustment needed _ _ _
Ranitidine 150 to 300 mg at
bedtime
75% 50% 25%
Table-5

Measurement of glomerular
filtration rate:
 Several drugs and endogenous substances have been used as
markers to measure GFR.
 These markers carried to the kidney by the blood via the renal artery
and are filtered at the glomerulus.
 Therefore, the rate at which these drug markers are filtered from the
blood in to urine per unit of time reflects the GFR of the kidney.
 Changes in GFR reflects changes in kidney function.
15

Creatinine clearance
 Creatinine clearance may be defined as the volume of plasma
cleared of creatinine per unit time .
 It can be calculated by the following formula:
𝑐𝑙
𝑐𝑟=
𝑟𝑎𝑡𝑒 𝑜𝑓 𝑢𝑟𝑖𝑛𝑎𝑟𝑦 𝑒𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑜𝑓 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒
𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
 It is expressed in mL/min.

Measure of GFR-
creatinine clearance
 The clearance of creatinine is used most extensively as a
measurement of GFR .
 Creatinine is an endogenous substance formed from creatinine
phosphate during muscle metabolism.
 Creatinine production varies with age, weight, gender of the
individual.
 In humans, creatinine is filtered mainly at the glomerulus, with no
tubular re-absorption.
 It tends to be decrease in elderly patient.
18

19

Serum creatinine concentration
and creatinine clearance:
• Under normal circumstances , creatinine production is roughly equal
to creatinine excretion, so the serum creatinine level remains
constant.
• In a patient with reduced glomerular filtration , serum creatinine will
accumulate in accordance with the degree of loss of glomerular
filtration in the kidney.
• The serum creatinine concentration alone is frequently used to
determine creatinine clearance, 𝑐𝑙 𝑐𝑟 .
• Creatinine clearance from the serum creatinine concentration is a
rapid and convenient way to monitor kidney function.
• Serum creatinine is expressed in mg/dL or mg%.

Calculation of
creatinine clearance from
serum creatinine concentration:
• Serum creatinine concentration , 𝑐 𝑐𝑟, is related to creatinine
clearance measured routinely in clinical laboratory.
• Therefore , creatinine clearance 𝑐𝑙 𝑐𝑟 , is most often estimated from
the patient’s 𝑐 𝑐𝑟.
• Several methods are available to calculate 𝑐𝑙 𝑐𝑟 from 𝑐 𝑐𝑟, in which
accurate methods are based on the patient’s age, height, weight,
gender.
21

Cockcroft and Gault method:
• Adults:
 The method of cockcroft and gault is used to estimate creatinine
clearance from serum creatinine concentration . This method
considers both the age and the weight of the patient.
 For males,
𝑐𝑙 𝑐𝑟= 140−𝑎𝑔𝑒 𝑦𝑒𝑎𝑟𝑠 ×𝑏𝑜𝑑𝑦𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔) /72𝑐 𝑐𝑟
 For females use 90% of the 𝑐𝑙 𝑐𝑟 value obtained in males.
22

Children:
• There are a number of methods for calculation of creatinine
clearance in children , based on body length , and serum creatinine
concentration.
• It is a method developed by schwartzand associates :
𝑐𝑙
𝑐𝑟=
0.55 𝑏𝑜𝑑𝑦 𝑙𝑒𝑛𝑔𝑡ℎ(𝑐𝑚)
𝑐 𝑐𝑟
Where 𝑐𝑙 𝑐𝑟 is given in mL/min/1.73𝑚2
.
• The value 0.55 represents a factor used for children ages 1 to 12
years.
23

Cockcroft-Gault equation-
IBW AND ABW:
• For obese patients , generally defined as patients more than 20%
over ideal body weight(IBW) creatinine clearance should be based
on ideal body weight .
• Males : IBW=50 kg+2.3 kg for each inch over 5 feet
• Females : IBW=45.5kg+2.3 kg for each inch over 5 feet.
• ADJUSTED BODY WEIGHT(ABW):
• Studies have shown ABW is the best approach for calculating
creatinine clearance in the elderly patients.
 𝑐𝑙 𝑐𝑟=[(140-age)× 𝐴𝐵𝑊)/(𝑆𝑐𝑟 × 72) × 0.85 𝑓𝑜𝑟 𝑓𝑒𝑚𝑎𝑙𝑒𝑠
 ABW=IBW+0.3*(TBW-IBW).

Estimated GFR(e GFR) using
modification of diet in
renal disease(MDRD):
• Various approaches for the estimate of GFR from serum creatinine
have been derived .
• For example,
 eGFR(mL/min/1.73𝒎 𝟐)=175× 𝒔 𝒄𝒓.std)-
1.154×age(years)-0.203×(0.742 if female)×(1.212 if
African or American.
Where eGFR is estimated GFR using the MDRD equation.
25

LIVER FAILURE
• Liver failure or hepatic insufficiency is the inability of the liver to
perform its normal synthetic and metabolic function as part of
normal physiology.
• Two forms are recognized;
 Acute liver failure,
 Chronic liver failure
26

ACUTE LIVER FAILURE
• It is defined as the rapid development of hepatocellular dysfunction,
specifically coagulopathy and mental status changes
(encephalopathy) in a patient without known prior liver disease.
CHRONIC LIVER FAILURE
• It usually occurs in the context of cirrhosis , itself potentially the
result of many possible causes, such as excessive alcohol intake,
hepatitis B or C , auto immune , hereditary and metabolic causes.
27

ETIOLOGY
• The liver can be damaged in a variety of ways:
 Cells can become inflamed(such as hepatitis).
 Bile flow can be obstructed (such as cholestasis).
 Cholesterol or triglycerides can accumulate (steatosis).
28

Considerations in
dosing patients
with hepatic impairment
ITEM COMMENTS
Drug elimination Drugs eliminated by the liver >20% are less
likely to be affected by liver disease.
Protein binding Drug protein binding may be altered due to
alteration in hepatic synthesis of albumin.
Therapeutic range Drugs with a wide therapeutic range will be
less affected by moderate hepatic impairment.
29
Table-6

Liver function tests
and hepatic metabolic
markers
Drug markers used to measure residual hepatic function may correlate
well with hepatic clearance of one drug which correlate poorly with
substrate metabolized by a different enzyme with in the same
cytochrome p-450 subfamily .
30

31

Useful hepatic marker
compounds
1.Aminotransferase (AST):Normal AST value for males is 10-55 U/L;
and for females is 7-30 U/L.
2.Alkaline phosphatase (AP):Normal AP values for males is 45-115
U/L and for females is 30-100 U/L ,
 Marked AP elevations may indicate hepatic tumors or biliary
obstruction in the liver.
3. Bilirubin : Normal value is 0-1mg/dl
 Unconjugated hyperbilirubinemia results from increased bilirubin
production.
 Conjugated hyperbilirubinemia results from defects in hepatic
excretion.
4. Prothrombin time : Normal value is 11.2-13.2 sec , with the
exception of factor 8 , all coagulation factors are synthesized by the
liver ; therefore hepatic disease can alter the coagulation.
32

Effect of hepatic
disease on
pharmacokinetics
• Drugs are often metabolized by one or more enzymes located in
cellular membranes in different parts of the liver
• Drugs and metabolites may also be excreted by biliary secretion.
• Liver disease may also alter kidney function, which can lead to
accumulation of a drug and its metabolite's even when the liver is
not primarily responsible your elimination.
• Hepatic disease can alter the pharmacokinetics of a drug including
the absorption and disposition and the pharmacodynamics including
efficacy and safety.
33

Hepatic blood flow
and
intrinsic clearance:
• Blood flow changes can occur in patients with chronic liver disease.
• Hepatic arterial venous shunts may lead to reduced drug fraction of
drug excreted and an increase in the bio avilability of drug.
• In other patients , resistance to blood flow may be increased as a
result of tissue damage and fibrosis , causing a reduction in intrinsic
hepatic clearance. The following equation may be applied to
estimate hepatic clearance of a drug after assessing changes in blood
flow and intrinsic clearance (𝑐𝑙𝑖𝑛𝑡): 𝑐𝑙ℎ=Q.𝑐𝑙𝑖𝑛𝑡/Q+𝑐𝑙𝑖𝑛𝑡
• Alternatively, when both Q and the extraction ratio ER, are known in
the patient , clearance(cl) may also be estimated : cl=Q(ER)
Where Q=Amount of blood flows to liver.
34

Child-pugh
Classification
• This classification indicates severity of liver disease:
Parameter 1(absent) 2(slight) 3(medium)
Ascites 2 2-3 3
Bilirubin mg/dL 3-5 2.8-3.5 2.8
Albumin g/dL 1-3 4-6 6
Prothrombin time 1.8 1.8-2.3 2.3
Encephalopathy None 1-2 3-4
Table-7

Severity classification
schemes for liver disease:
Grade a Grade b Grade c
Bilirubin <2 2-3 >3
Albumin >3.5 3-3.5 <3
Ascites none easily controlled poorly
controlled
Neurological
disorder
none minimal advanced
Nutrition excellent good poor
36
Table-8

Drugs with significantly
decreased metabolism
in chronic liver failure
DRUGS DRUGS
Chloramphenicol Diazepam
Antipyrine Hexobarbitol
Erythromycin Theophylline
Verapamil Promazine
Caffeine Metronidazole
37
Table-9

Hepatic impairment and
dose adjustment
• The drug is metabolized in the liver to a small extent (<20%) and
the therapeutic range of the drug is wide so that modest impairment
of the drug directly or by increasing its interaction with other
drugs.
• The drug is gaseous or volatile , and the drug and its active
metabolites are primarily eliminated via the lungs.
• For each drug case , the physician needs to assesses the degree of
hepatic impairment and consider the known pharmacokinetics and
pharmacodynamics of the drug.
• Starting therapy with low doses and monitoring response or plasma
levels provides the best opportunity for safe, efficacious treatment
38

Dosage considerations in hepatic failure:
:
• Several physiologic and pharmacokinetic factors are relevant
in considering dosing of a drug in patients with hepatic
disease.
• Chronic disease and tissue injury may change the accessibility
of some enzymes as a result of re-direction of hepatic blood
circulation.
• Drugs with flow dependent clearance are avoided otherwise
the dose of those drugs need to be reduced to as low as one-
tenth of conventional dose , for an orally administered agent.
• Starting therapy with low doses and monitoring response or
plasma levels provides the best opportunity for safe,
efficacious treatment.

Dosing in liver disease
• For severe liver dysfunction (albumin<30g/L, INR > 1.2):
(a) If the drug is a high clearance drug (liver blood flow dependent)
reduce dose by 50%:
High Clearance Drugs Example
Antipsychotics Opioids (most)
Beta-blockers (most) Tricyclic antidepressants
Lignocaine statins
Nitrates SSRIs
Table-10

Dosing in liver disease
(b) If the drug is low clearance (flow-independent - includes all
other metabolised drugs) reduce dose by 25%:
Low clearance drugs Examples
Anticonvulsants (most) Sulphonylureas
Spironolactone Theophylline
Paracetmol Warfarin
NSAID’s Steroids
41
Table-11

Formulas:
• Model for end stage liver disease(MELD):
MELD=3.78× 𝑠𝑒𝑟𝑢𝑚 𝑏𝑖𝑙𝑖𝑟𝑢𝑏𝑖𝑛(𝑚𝑔/𝑑𝑙)+
11.20× 𝑙𝑛𝐼𝑁𝑅 + 9.57 ×
ln serum creatinine (mg/dl)+
6.43(constant for liver disease etiology).
Where INR=International normalized ratio,
NOTE : If the patient has been dialyzed twice with in the last 7 days ,
then the value for serum creatinine used should be 4.0.
vignan pharmacy college,vadlamudi,gunturdist.A.P. 42

• Pediatric end stage liver disease(PELD):It is a disease severity
scoring system for children under 12 years of age .
PELD=4.80× [𝑙𝑛 𝑠𝑒𝑟𝑢𝑚 𝑏𝑖𝑙𝑖𝑟𝑢𝑏𝑖𝑛(𝑚𝑔/𝑑𝑙]+
18.57[ ln INR]-6.87[ln albumin(g/dl)+
4.36(<1 year old)+6.67(growth failure)
• A higher score correlates with a more critical condition . Thus , liver
donations are allocated by UNOS(United network for organ sharing)
according to the PELD score to maximize the life aving capability
of each donated liver.

Hepatic vs Renal failure:
• Dose adaptation for patients with liver disease is more difficult than
for patients with impaired renal function.
• Unlike creatinine clearance for the kidney ,for liver there is no
invivo surrogate to predict the drug clearance.

conclusion
• The liver and kidneys are important for the body’s ability to break
down and excrete medication.
• Diseases of the liver or the kidneys, in addition to aging , often
require doses to be lowered in order to avoid adverse drug reactions.
• Patients with markedly reduced liver function should avoid certain
medications and dietary supplements.
• Moderately impaired kidney function may require lower
medication doses; severely impaired function requires avoidance of
certain medications.
45

RFERENCES:
1. Leon shargel, susanna wu-pong,Andrew Yu,Applied
biopharmaceutics and pharmacokinetics, 6th edition,617-653.
2.Fisher MB, Paine MF, Strelevitz TJ, Wrighton SA (2001) The role of
hepatic and extrahepatic UDP-glucuronosyltransferases
inhumandrug metabolism. Drug Metab Rev 33:273–297.3.
3. National Kidney Foundation. K/DOQI clinical practice
guidelines for chronic kidney disease: evaluation, classification,
and stratification. Am J Kidney Dis 2002;39(2 suppl 1):S1-266.
4.Clinical pharmacology and pharmacotherapeutics by
K.Ravishankar,G.V.N.Kiranmayi , page no:345-352.
46

RFERENCES:
4.Palmer BF. Managing hyperkalemia caused by inhibitorsof the
reninangiotensin-aldosterone system. N Engl J Med 2004;351:585-92.
5. Palmer BF. Angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers: what to do if the
serum creatinine and/or serum potassium concentration
rises. Nephrol Dial Transplant 2003;18:1973-5.
6.Kappel J, Calissi P. Nephrology: 3. Safe drug prescribing
for patients with renal insufficiency. CMAJ
2002;166:473-7.
7. Snyder RW, Berns JS. Use of insulin and oral hypoglycemic
medications in patients with diabetes mellitus and
advanced kidney disease. Semin Dial 2004;17:365-70.
47

I would like to express my gratitude to all those
who gave me the possibility to complete this seminar .
A special thanks to the principal sir and seminar
committee.
I express deep and sincere gratitude to my guide
whose encouragement , suggestion have contributed
immensely to complete my seminar.
ACKNOWLEDGEMENT

Dose Adjustment in renal and hepatic failure

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