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DRUG-DOSE ADJUSTMENT IN PATIENTS WITH HEPATIC DISEASES
1. DRUG DOSE ADAPTATION IN
PATEINTS WITH HEPATIC
DISEASES
Dr. AMREEN SABA ATTARIYA
POST GRADUATE STUDENT, DEPT OF PHARMACOLOGY
M.R. MEDICAL COLLEGE, GULBARGA
INDIA
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2. OUTLINE OF TALK
INTRODUCTION
EPIDEMIOLOGY
HEPATIC PATHOPHYSIOLOGY
FEATURES OF LIVER DISEASE
ALTERED PK & PD
GENERAL GUIDELINES
RECOMMENDATIONS
SPECIAL AGE GROUP CONSIDERATIONS
SUMMARY
REFERENCES 2
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tInHepaticDis
3. INTRODUCTION
• Liver plays a central role in PK of drugs
• Site for drug biotransformation
• Liver blood flow, binding to plasma protein &
biliary excretion influences PKdepend on
normal functioning of liver
• Hepatic dysfunction increased sensitivity to both
desired & AEDosage adjustment
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4. EPIDEMIOLOGY OF LIVER DISEASES
INDIA : LIVER DISEASE*
LIVER diseases rank no.10 in top 20 causes of death
in India
4*WHO Publish Date: May 2014
Deaths % Rate World
Rank
216,865 2.44 21.96 61
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tInHepaticDis
5. LEADING CAUSES FOR CHRONIC
LIVER DISEASE*
• In west- alcohol & HCV
• In India- alcohol & HBV
5
*Ray G:Trends of Chronic Liver Disease in a Tertiary Care
Referral Hospital in Eastern India--www.ijph.in on
Monday, February 08, 2016, IP:125.17.185.146]
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6. RISK OF LIVER DAMAGE BY DRUGS IS
THOUGHT TO BE INCREASED BY
• Age 18 years or over
• Obesity
• Pregnancy
• Consumption of alcohol
• A genetic make-up that makes people more
susceptible to a drug's effects
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7. • In the US, approximately 2000 cases of
acute liver failure occur annually
• Drugs account for over 50% of them (39% are due
to acetaminophen, 13% are idiosyncratic ).
• Drugs account for 2-5% of cases of patients
hospitalized with jaundice and approximately 10%
of all cases of acute hepatitis.
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8. HEPATIC PATHOPHYSIOLOGY
• Numerous pathophysiologic changes in the liver
that may influence PK*
• Results in
1.reduction in liver blood flow
2.presence of intra- and extrahepatic portal-systemic
shunting
3.reduction in number & activity of hepatocytes
8*Le Couteur DG et al 200503/20/16
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tInHepaticDis
12. EFFECT ON OTHER ORGANS
Intestine
Lungs
Kidneys
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13. DIAGNOSIS OF LIVER DISEASE
• Unfortunately-No simple endogenous
marker available
• Child Pugh Score
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14. FEATURES OF LIVER DISEASE*
• hepatic clearance of drugs
• plasma protein production
• First Pass Metabolism Bioavailability
• drug metabolising enzymes activity
• Impaired renal function
• Higher sensitivity of central AE of opioids & renal
AE of NSAIDs
14
*Veerbeck RK, Pharmacokinetics and dosage adjustment in
patients with hepatic dysfunction review article: Eur J Clin
Pharmacol (2008)03/20/16 Dr.A.S.Attariya:DoseAdjustmen
15. 15
HEPATIC CLEARANCE*
Cli is the intrinsic hepatic clearance and fu the fraction of
a drug not bound to serum proteins (free fraction).
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*Wilkinson, G.R., and Shand, D.G. 1975 A physiological approach to hepatic
drug clearance, Clin. Pharmacol. Ther., 18, 377-90Dr.A.S.Attariya:DoseAdjustmen
tInHepaticDis
16. 16
“FLOW-LIMITED”
When (fu x Cli) >> Q, equation
can be simplified to Clhep ≈ Q
In this case, hepatic clearance is said to be blood flow-
limited and the drugs are called flow-limited or “high
extraction” drugs(HED)
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17. 17
“ENZYME-LIMITED”
When (fu x Cli) is << Q , equation
can be simplified to Clhep ≈ (fu x Cli)
In this case, hepatic clearance is said to be “enzyme-
limited” and the drugs are called enzyme-limited or
“low extraction drugs(LED)”
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18. “ FLOW AND ENZYME LIMITED"
When (fu x Cli) ≈ Q The hepatic clearance of these
drugs is determined by both Q and (fu x Cli).
Drugs are therefore called Intermediate extraction
Drugs (IED)and cannot be assigned to either group.
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19. DIFFERENT CLASS OF DRUGS
• HED [E= >0.7]
• LED[E= <0.3]
• IED[E= 0.3-0.7]
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21. 21
HED OR FLOW LIMITED DRUGS
Clhep ≈ Q
All disease that reduce Blood flow across the liver may
impair hepatic clearance of HED.
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22. DISEASES THAT INCREASE BA OF HED
1. CIRRHOSIS and/or PORTAL HYPERTENSION
are likely to have intra- and extra hepatic porto
systemic shunt
2. Diseases that impair blood flow to the liver (heart
failure, shock, major surgery, drugs like
EPINEPHRINE, B-BLOCKERS)
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23. 23
ADJUSTMENT FOR HED
Hence for HED administered orally, both the initial
and the maintenance doses have to be reduced.
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24. DOSE ADJUSTMENT OF HED GIVEN IV
a normal initial dose can be administered and the
maintenance doses has to be reduce according to
hepatic blood flow.
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29. LED : DOSE ADJUSTMENT
• For these drugs hepatic clearance is mainly
determined by the activity of drug metabolizing
enzymes (Cli).
• Clhep ≈ (fu x Cli)
• In liver disease The maintenance dose of these
drugs should be reduced, whereas therapy can be
started with a normal dose.
• But how to adjust the maintenance dose ? 3003/20/16 Dr.A.S.Attariya:DoseAdjustmen
30. LOW EXTRACTION DRUGS :
ADJUSTMENT OF MAINTENANCE DOSE
• The reduction in Cli associated with liver disease
appears to be function of the Child’s score, an
useful classification scheme that is used to
formulate drug dosing recommendations for
patients with liver disease
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31. 32
Pugh Modification Of Child’s Classification Of
Liver
Disease Severity
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33. 34
LOW EXTRACTION DRUGS: ADJUSTMENT
OF MAINTENANCE DOSE
Patients with Child class A a maintenance dose of 50% of nor.
patients with Child class B a maintenance dose of 25% of nor.
Patients with Child class C use of drugs whose safety has
been demonstrated in clinical trials
and/or whose kinetics is not
affected by liver disease or for
which therapeutic drug monitoring
is available03/20/16 Dr.A.S.Attariya:DoseAdjustmen
34. LED with high binding to Albumin ≥ 90%
• It represent an exception to the rule that say for
LED,hepatic clearance is mainly determined by the
activity of drug metabolizing enzymes (Cli)
• Clhep ≈ (fu x Cli)
• Liver disease can reduce Sr.Alb concentration
• Therefore increase the unbound fraction of the
drug fu
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35. 36
LED WITH A HIGH
BINDING TO ALBUMIN (≥90%)
In order to avoid toxicity by overdosing, free drug levels
should be determined and used to guide therapy of such
drugs in livers disease.
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45. IED: DOSE ADJUSTMENT
• Since BA slowly rises in case of blood
flow reduction, therapy has to be
started with INITIAL LOW DOSE
• But for MAINTENANCE DOSE it has
to be calculated as that for LED
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48. ALTERED ABSORPTION
• BA of the sedative/hypnotic agent
CLORMETHIAZOLE is increased more than
10fold in cirrhosis*
• CARVEDILOL therapy should be started in
cirrhotic patients at about 1/5th
of the normal
dosage**
49
*Pentikäinen PJ et al Eur J Clin Pharmacol
**Neugebauer G, et al: PK & BA of carvedilol in patients with liver cirrhosis
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50. EFFECT ON PPB & DISTRIBUTION contd…
• Decreased PPB of certain drugs
• aVd of β-lactam antibacterial CEFODIZIME was
shown to be 3 times larger in cirrhosis*(thus needs
larger loading dose)
51
*Touny M et al PK of cefodizime in patients with liver cirrhosis and ascites.
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51. ALTERED METABOLISM
• CYP450 enzyme activity is differentially affected
in liver disease*.
• Several PK studies have shown a decrease in the
clearance of drugs metabolized by CYP3A4/3A5
such as MIDAZOLAM,NIFEDIPINE ,
EVEROLIMUS
• Glucuronidation reactions are often considered to
be affected to a lesser extent by liver cirrhosis than
CYP450-mediated reactions**
52
*Frye RF et al(2006) :In Clin Pharmacol Ther
**Elbekai RH et al(2000)
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53. EFFECT ON RENAL EXCRETION
• Defn of hepatorenal syndrome
• Reduced renal excretion of diuretics, H2
antagonists, levetiracetam in advanced cirrhosis*
54
* Gonzales G, Eur J Clin Pharmacol
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54. EFFECT ON PD
• The most important changes in PD with
β-blockers
diuretics
opioid analgesics
anxiolytics and sedatives.
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55. GENERAL GUIDELINES
1.Clinical signs & symptoms for hepatotoxicity
should be sought
2.Hepatotoxic drugs should be avoided if possible
Monitoring LFTs
1. Sr.Bilirubin levels >4-5mg/dl
2. PT >1.5 times control
3. Sr.Albumin <2.0g/dl
4. Elevated ALT & AST
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56. RECOMMENDATION
FDA and the European Medicines Evaluation
Agency (EMEA) aimed at generating, if possible,
specific dosage recommendations for patients with
hepatic dysfunction
NEED TO DEVELOP MORE SENSITIVE
LIVER FUNCTION TESTS
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57. DRUGS REPORTED (OR PREDICTED) TO HAVE AN
INCREASED RISK OF HEPATOTOXICITY IN PATIENTS
WITH LIVER DISEASE
• ATT (INH, pyrazinamide, rifampicin)
• HAART (e.g. nevirapine)
• Methimazole
• Methotrexate
• Nefazodone
• Propoxyphene
• Valproate
• Vitamin A
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60. PEDIATRIC AGE GROUP
• Pharmacokinetics differs in neonates, especially
prematures, because their organs are not fully
developed.
• Until 1 year, liver function is still immature.
• Children of 1 to 12 years have increased activity of
metabolizing enzymes
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61. HEPATIC DISEASE IN NEONATES AND
INFANTS*
• Poor intrinsic metabolic capacity of enzymes
• Decreased albumin binding of drugs
• Viral hepatitis will not affect blood flow to
liverno interference with clearance
• Avoid PCT & other NSAIDs metabolised by liver,
instead use IBUPROFEN(excreted by kidney) in
low dose
62
*Seth SD:Drugs in pregnancy & pediatrics
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62. DRUGS CONTRAINDICATED IN
CHILDREN WITH LIVER DISEASES
• CHLORAMPHENICOLGrey baby syndrome
• ASPIRIN Reye’s syndrome
• PHOTOTHERAPY Bronze baby syndrome
• PCT Pct induced hepatotoxicity
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64. PREGNANCY
CAUTIOUS USE OF drugs that cross
placenta to avoid toxic effects(LA,
narcotics used during labor)
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65. GERIATRIC AGE GROUP
• In elderly, physiologic changes alters all
pharmacokinetic processes in the liver.
• Many drugs are metabolized more slowly and
accumulate with chronic administration.
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66. AIM OF PK STUDIES IN ELDERLY
TO STUDY PARAMETERS :
• Plasma t1/2
• Plasma drug clearance
• Time to peak plasma concentration
• Area under curve
• aVd for individual drugs
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68. SUMMARY
• Cirrhosis results in numerous pathophysiological changes
influences PK of drugs.
• Be cautious while prescribing drugs in liver diseases
• Thorough knowledge of hepatic pathology for dose
adjustment
• Benefits vs AE are to be weighed.
• Need to develop sensitive LFT which serves as a
cornerstone for dosage adjustment
• Advanced liver diseasedose modification for renally
cleared drugs is also needed.
• Utmost care while prescribing in special age groups
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74. REFERENCES…
• Herrine SK: Effects of Liver Disorders on Drugs, MSD(Merck Manuals
in the United States and Canada) manual of diagnosis & therapy
• Ray G:Trends of Chronic Liver Disease in a Tertiary Care Referral
Hospital in Eastern India--www.ijph.in on Feb 08, 2016, IP:
125.17.185.146
• Wilkinson GR, Shand DG. 1975 A physiological approach to hepatic
drug clearance, Clin. Pharmacol. Ther., 18, 377-90
• Nicholas HG, Holford: In Katzung Basic And Clinical Pharmacology,
McGraw Hill Education 13th ed P.No 80-84
• Veerbeck RK, Pharmacokinetics and dosage adjustment in patients
with hepatic dysfunction review article: Eur J Clin Pharmacol (2008)
64:1147–1161 DOI 10.1007/s00228-008-0553-z
• Sharma HL, Sharma KL:In Principles of pharmacology 2nd
ed P.No.38
• Seth SD:Drugs in pregnancy & pediatrics, 2nd
ed P.No.721
• Jorge L. Herrera, University of South Alabama College of Medicine,
Mobile, AL – Published November 2007. Updated December 2012
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Editor's Notes
INTRODUCTION
1. The liver plays a central role in the absorption, distribution,and elimination kinetics of most drugs and many active or inactive drug metabolites
2. It is the most important biotransformation site for drugs
3. parameters such as liver blood flow, binding to plasma proteins, and biliary excretion which can all potentially influence drug pharmacokinetics, depend on the normal functioning of the liver
4. patients with hepatic dysfunction may also be more sensitive to the effects, both desired and adverse, of several
Drugs
5. Dosage adjustment in patients with liver dysfunction is therefore essential for many drugs to avoid excessive accumulation of the drug, and possibly of active drug metabolite(s), which may lead SAR.
According to the latest WHO data published in may 2014 Liver Disease Deaths in India reached 216,865 or 2.44% of total deaths. The age adjusted Death Rate is 21.96 per 100,000 of population ranks India #61 in the world.
HEPATIC PATHOPHYSIOLOGY
1. results in numerous pathophysiologic changes in the liver that may influence drug pharmacokinetics
2. Histologically, cirrhosis is a diffuse process characterized by fibrosis and a conversion of normal liver architecture into structurally abnormal nodules.
3. These modifications are associated with or are responsible for a reduction in liver blood flow, the presence of intra- and extrahepatic portal-systemic shunting, a capillarization of the sinusoids and a reduction in the number and in the activity of the hepatocytes
Cirrhosis may also exert a major influence on other organs such as the intestine, the lungs, and the kidneys. The function of these organs will be directly influenced by the modifications induced by cirrhosis on the vascular hemodynamics, such as the hyperkinetic state found in alcoholic cirrhosis or the potential occurrence of a hepatorenal syndrome, which is associated with a severe impairment of renal function.
DIAGNOSIS OF LIVER DISEASE
1. there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs
2. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has
gained widespread clinical use to adjust dosage regimens for drugs.
3. The semiquantitative Child-Pugh score is frequently used to assess the severity of liver function impairment
4. but it only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs
HEPATIC CLEARANCE
1. To fully appreciate the impact of hepatic dysfunction on the pharmacokinetic behavior of a particular drug, a thorough understanding of the underlying determinants of hepatic clearance is absolutely necessary
2. Hepatic drug clearance (CLH), defined as the volume of blood from which drug is removed completely by the liver per unit time, is a function of hepatic blood flow (QH) and the hepatic extraction ratio (EH) of the drug
CLH = QH * EH
3. EH depends on liver blood flow, the intrinsic clearance of unbound drug (CLint), and the fraction of unbound drug in blood (fu), the following fundamental equation for CLH has been derived:
CLH =QH * fu * CLint
QH + fu *CLint
This equation is based on the “well-stirred” or “venous equilibration” model, a kinetic model used most frequently to describe the relationship between hepatic drug clearance and the three primary determinants of hepatic drug elimination, i.e., blood flow, drug binding in blood, and the intrinsic clearance
ALTERED ABSORPTION
1. The oral bioavailability of a number of drugs with intermediate to high hepatic extraction ratios has indeed been shown to be significantly increased in patients with liver cirrhosis
2.bioavailability of the sedative/hypnotic agent CLORMETHIAZOLE is increased more than 10-fold in patients with cirrhosis necessitating an important reduction in administered dose.
3. CARVEDILOL therapy should be started in cirrhotic patients at about 1/5th of the normal dosage
CHLORMETHIAZOLE– HED
CARVEDILOL– IED
EFFECT ON PPB & DISTRIBUTION
1. Many drugs that are highly bound to albumin or α1-acid glycoprotein have a significantly higher fu in patients with chronic liver disease
2. Mechanisms for decreased binding of certain drugs to plasma proteins include
(1)reduced albumin and α1-acid glycoprotein synthesis
(2) accumulation of endogenous compounds, such as bilirubin, inhibiting PPB of certain drugs
(3)possible qualitative changes in albumin and α1-acid glycoprotein
3. As a result of the lower plasma binding,vd of certain drugs may be larger in these patients
4. water-soluble drugs will have a significant increase in their volumes of distribution in patients with ascites possibly necessitating larger loading doses. For example, the apparent volume of distribution of the β-lactam antibacterial CEFODIZIME was shown to be three times larger in patients with cirrhosis compared to
healthy individuals
METABOLISM
1, chronic liver disease in general is associated with impaired metabolism of a number of drugs.
2.Indeed, in chronic liver disease, a reduction in absolute liver cell mass or a decrease in enzyme activity due to alteration in the function of surviving cells may lead to impaired drug metabolism
3. Frye et al. used a validated cocktail approach to study the effect of liver disease on multiple CYP450 enzymes. A mixture of caffeine, mephenytoin, debrisoquine, and chlorzoxazone was orally administered to measure the in vivo activity of CYP1A2, CYP2C19, CYP2D6, and CYP2E1, respectively, in healthy subjects and patients with different
aetiologies and severity of liver disease. The results confirmed that CYP450 enzyme activity is differentially affected by the presence of liver disease.
Sequential progressive model of hepatic dysfunction. The
ordinate shows how plasma clearance, starting at 100% when hepatic
function is normal (normal HF), decreases for substances eliminated
predominantly by metabolism via individual CYP450 isoforms in the
liver. CYP450 enzyme activity in general decreases as liver function
decreases. However, some CYP450 isoform enzyme activities show
relative preservation as liver function deteriorates (e.g., CYP2E1 and
to a lesser extent CYP2D6), whereas others (e.g., CYP2C19) are
particularly sensitive to the presence of liver disease. In general,
patients with hepatic decompensation suffer from the hepato-renal
syndrome. (Reprinted with permission from the American Society for
Clinical Pharmacology and Therapeutics from Frye et al. [45])
NORMAL ENZYME ACTIVITY*
CYP3A4 & 3A5(50-60%drugs)
CYP2D6(25-30%) & 2C8 2C9(10%)
CYP1A1 & 1A2(5%).
EFFECT ON RENAL EXCRETION
1.The hepatorenal syndrome may be defined as unexplained progressive renal failure occurring in patients with chronic liver disease in the absence of clinical, laboratory, or anatomical evidence of other known causes of renal failure
2. Reduced renal excretion has been reported for a number of drugs mainly excreted in unchanged form by the kidneys such as the diuretics furosemide and bumetanide, the H2-receptor antagonists cimetidine and ranitidine, and the antiepileptic levetiracetam, in patients with advanced cirrhosis accompanied by impaired renal function
EFFECT ON PD
1. The most important changes in PK observed in cirrhosis are with β-blockers, diuretics, opioid analgesics, anxiolytics, and sedatives.
2.A decreased therapeutic effect is observed with β-blockers and diuretics
3.whereas the opposite effect is found with analgesics, anxiolytics, and sedatives.
RECOMMENDATION
1. Both the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have published a
guidance for industry on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function
2. The primary objective of such a study is to identify patients at risk and to assess whether a dosage adjustment is required for patients with impaired hepatic function
3. These guidelines recommend that the Child-Pugh classification be used to categorize patients according to their degree of hepatic impairment. In addition, they encourage the use of exogenous markers to assess the elimination capacity of the patients by different mechanisms
Bronze baby syndrome is the dark grey-brown pigmentation of skin, mucous membrane and urine following phototherapy. Hepatic dysfunction has to be there for this condition to be present