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DOSAGE ADJUSTMENTS OF
HEPATIC, RENAL FAILURE
Presented by:
k.Sowmya
12AB1ROO41
Guided by:
k.Pallavi
Assistant professor
1
...
Table of contents
 Renal failure:
• Causes
• Classification
• Dosing adjustments
• Measurement of GFR-Creatinine clearanc...
• Renal failure or kidney failure (formerly called renal insufficiency)
describes a medical condition in which the kidneys...
Causes of renal failure
• Common causes :condition comment
Pyelonephritis Inflammation of pyelonephrons due to infection
H...
Classification
• Renal failure can be divided in to two categories:
 Acute renal failure (ARF),
 Chronic renal failure(C...
Acute kidney injury(AKI)
• AKI , previously called acute renal failure (ARF), is a rapidly
progressive loss of renal funct...
Chronic kidney disease(CKD)
• CKD is along term consequence of irreversible acute disease or part
of a disease progression...
Drug dosing incase of ARF:
• Drug therapy optimization in ARF is a challenge confounding
variables include residual drug c...
Dosing adjustments in CKD:
• Loading doses do not need to be adjusted in patients with CKD.
• Some guide lines suggest met...
National Kidney Foundation
Kidney Disease Outcomes Quality
Initiative (K/DOQI)
Stage Description GFR (mL per minute
per 1....
Antihypertensive Agents: Dosing
Requirements in patients with
Chronic Kidney Disease
Drug Usual
dosage
Dosage Adjustment b...
Hypoglycemic Agents:
Dosing Requirements in patients
with Chronic Kidney Disease
DRUG USUAL DOSAGE SPECIAL CONSIDERATIONS
...
Antimicrobial Agents: Dosing
Requirements in patients
with Chronic Kidney Disease
Drug Usual dosage Dosage adjustment base...
Other Common Agents: Dosing Requirements
in patients with Chronic Kidney Disease
Drug Usual dosage Dosage adjustment based...
Measurement of glomerular
filtration rate:
 Several drugs and endogenous substances have been used as
markers to measure ...
Creatinine clearance
 Creatinine clearance may be defined as the volume of plasma
cleared of creatinine per unit time .
...
17vignan pharmacy college,vadlamudi,gunturdist.A.P.
Measure of GFR-
creatinine clearance
 The clearance of creatinine is used most extensively as a
measurement of GFR .
 Cr...
19
vignan pharmacy college,vadlamudi,gunturdist.A.P.
Serum creatinine concentration
and creatinine clearance:
• Under normal circumstances , creatinine production is roughly e...
Calculation of
creatinine clearance from
serum creatinine concentration:
• Serum creatinine concentration , 𝑐 𝑐𝑟, is relat...
Cockcroft and Gault method:
• Adults:
 The method of cockcroft and gault is used to estimate creatinine
clearance from se...
Children:
• There are a number of methods for calculation of creatinine
clearance in children , based on body length , and...
Cockcroft-Gault equation-
IBW AND ABW:
• For obese patients , generally defined as patients more than 20%
over ideal body ...
Estimated GFR(e GFR) using
modification of diet in
renal disease(MDRD):
• Various approaches for the estimate of GFR from ...
LIVER FAILURE
• Liver failure or hepatic insufficiency is the inability of the liver to
perform its normal synthetic and m...
ACUTE LIVER FAILURE
• It is defined as the rapid development of hepatocellular dysfunction,
specifically coagulopathy and ...
ETIOLOGY
• The liver can be damaged in a variety of ways:
 Cells can become inflamed(such as hepatitis).
 Bile flow can ...
Considerations in
dosing patients
with hepatic impairment
ITEM COMMENTS
Drug elimination Drugs eliminated by the liver >20...
Liver function tests
and hepatic metabolic
markers
Drug markers used to measure residual hepatic function may correlate
we...
31
vignan pharmacy college,vadlamudi,gunturdist.A.P.
Useful hepatic marker
compounds
1.Aminotransferase (AST):Normal AST value for males is 10-55 U/L;
and for females is 7-30 ...
Effect of hepatic
disease on
pharmacokinetics
• Drugs are often metabolized by one or more enzymes located in
cellular mem...
Hepatic blood flow
and
intrinsic clearance:
• Blood flow changes can occur in patients with chronic liver disease.
• Hepat...
Child-pugh
Classification
• This classification indicates severity of liver disease:
35vignan pharmacy college,vadlamudi,g...
Severity classification
schemes for liver disease:
Grade a Grade b Grade c
Bilirubin <2 2-3 >3
Albumin >3.5 3-3.5 <3
Ascit...
Drugs with significantly
decreased metabolism
in chronic liver failure
DRUGS DRUGS
Chloramphenicol Diazepam
Antipyrine Hex...
Hepatic impairment and
dose adjustment
• The drug is metabolized in the liver to a small extent (<20%) and
the therapeutic...
Dosage considerations in hepatic failure:
:
• Several physiologic and pharmacokinetic factors are relevant
in considering ...
Dosing in liver disease
• For severe liver dysfunction (albumin<30g/L, INR > 1.2):
(a) If the drug is a high clearance dru...
Dosing in liver disease
(b) If the drug is low clearance (flow-independent - includes all
other metabolised drugs) reduce ...
Formulas:
• Model for end stage liver disease(MELD):
MELD=3.78× 𝑠𝑒𝑟𝑢𝑚 𝑏𝑖𝑙𝑖𝑟𝑢𝑏𝑖𝑛(𝑚𝑔/𝑑𝑙)+
11.20× 𝑙𝑛𝐼𝑁𝑅 + 9.57 ×
ln serum cre...
• Pediatric end stage liver disease(PELD):It is a disease severity
scoring system for children under 12 years of age .
PEL...
Hepatic vs Renal failure:
• Dose adaptation for patients with liver disease is more difficult than
for patients with impai...
conclusion
• The liver and kidneys are important for the body’s ability to break
down and excrete medication.
• Diseases o...
RFERENCES:
1. Leon shargel, susanna wu-pong,Andrew Yu,Applied
biopharmaceutics and pharmacokinetics, 6th edition,617-653.
...
RFERENCES:
4.Palmer BF. Managing hyperkalemia caused by inhibitorsof the
reninangiotensin-aldosterone system. N Engl J Med...
vignan pharmacy college,vadlamudi,gunturdist.A.P. 48
I would like to express my gratitude to all those
who gave me the pos...
49vignan pharmacy college,vadlamudi,gunturdist.A.P.
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Dose Adjustment in renal and hepatic failure

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the presentation deals with dose adjustments to be done in case of hepatic and renal failure

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Dose Adjustment in renal and hepatic failure

  1. 1. 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.
  2. 2. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  3. 3. • 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.
  4. 4. 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.
  5. 5. Classification • Renal failure can be divided in to two categories:  Acute renal failure (ARF),  Chronic renal failure(CRF) 5 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  6. 6. 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. 6vignan pharmacy college,vadlamudi,gunturdist.A.P.
  7. 7. 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. 7vignan pharmacy college,vadlamudi,gunturdist.A.P.
  8. 8. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  9. 9. 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. 9vignan pharmacy college,vadlamudi,gunturdist.A.P.
  10. 10. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-1
  11. 11. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-2
  12. 12. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-3
  13. 13. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-4
  14. 14. 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% 14vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-5
  15. 15. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  16. 16. 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. 16vignan pharmacy college,vadlamudi,gunturdist.A.P.
  17. 17. 17vignan pharmacy college,vadlamudi,gunturdist.A.P.
  18. 18. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  19. 19. 19 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  20. 20. 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%. 20vignan pharmacy college,vadlamudi,gunturdist.A.P.
  21. 21. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  22. 22. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  23. 23. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  24. 24. 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). 24vignan pharmacy college,vadlamudi,gunturdist.A.P.
  25. 25. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  26. 26. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  27. 27. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  28. 28. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  29. 29. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-6
  30. 30. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  31. 31. 31 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  32. 32. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  33. 33. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  34. 34. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  35. 35. Child-pugh Classification • This classification indicates severity of liver disease: 35vignan pharmacy college,vadlamudi,gunturdist.A.P. 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
  36. 36. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-8
  37. 37. Drugs with significantly decreased metabolism in chronic liver failure DRUGS DRUGS Chloramphenicol Diazepam Antipyrine Hexobarbitol Erythromycin Theophylline Verapamil Promazine Caffeine Metronidazole 37 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-9
  38. 38. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  39. 39. 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. 39vignan pharmacy college,vadlamudi,gunturdist.A.P.
  40. 40. 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 40vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-10
  41. 41. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P. Table-11
  42. 42. 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
  43. 43. • 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. vignan pharmacy college,vadlamudi,gunturdist.A.P. 43
  44. 44. 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. 44vignan pharmacy college,vadlamudi,gunturdist.A.P.
  45. 45. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  46. 46. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  47. 47. 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 vignan pharmacy college,vadlamudi,gunturdist.A.P.
  48. 48. vignan pharmacy college,vadlamudi,gunturdist.A.P. 48 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
  49. 49. 49vignan pharmacy college,vadlamudi,gunturdist.A.P.

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