drug-dose adjustment in patients with hepatic diseases

DRUG DOSE ADAPTATION IN PATEINTS WITH

HEPATIC DISEASESDr. AMREEN SABA ATTARIYA

POST GRADUATE STUDENT, DEPT OF PHARMACOLOGYM.R. MEDICAL COLLEGE, GULBARGA

INDIA

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OUTLINE OF TALK

INTRODUCTIONEPIDEMIOLOGYHEPATIC PATHOPHYSIOLOGYFEATURES OF LIVER DISEASEALTERED PK & PDGENERAL GUIDELINESRECOMMENDATIONSSPECIAL AGE GROUP CONSIDERATIONSSUMMARYREFERENCES 2

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Dr.A.S.Attariya:DoseAdjustmentInHepaticDis

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


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

05/02/23


LEADING CAUSES FOR CHRONIC LIVER DISEASE*

• In west- alcohol & HCV• In India- alcohol & HBV

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*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]


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


• 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.


http://emedicine.medscape.com/article/177354-overview

HEPATIC PATHOPHYSIOLOGY

• Numerous pathophysiologic changes in the liver that may influence PK*

• Results in 1.reduction in liver blood flow2.presence of intra- and extrahepatic portal-systemic

shunting3.reduction in number & activity of hepatocytes

8*Le Couteur DG et al 200505/02/23 Dr.A.S.Attariya:DoseAdjustmentInHepaticDis

MANIFESTATIONSEsophageal varicesEdema, ascitesImpaired liver parenchymal functionHepatic encephalopathy

1105/02/23


EFFECT ON OTHER ORGANSIntestine

LungsKidneys


DIAGNOSIS OF LIVER DISEASE

• Unfortunately-No simple endogenous marker available

• Child Pugh Score


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

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*Veerbeck RK, Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction review article: Eur J Clin Pharmacol (2008)05/02/23 Dr.A.S.Attariya:DoseAdjustmen

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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

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“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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“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)”


“ 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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DIFFERENT CLASS OF DRUGS

• HED [E= >0.7]

• LED[E= <0.3]

• IED[E= 0.3-0.7]


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HED OR FLOW LIMITED DRUGS

Clhep ≈ QAll disease that reduce Blood flow across the liver may

impair hepatic clearance of HED.


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)2205/02/23 Dr.A.S.Attariya:DoseAdjustmen

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ADJUSTMENT FOR HED

Hence for HED administered orally, both the initial

and the maintenance doses have to be reduced.


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.


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 ?3005/02/23 Dr.A.S.Attariya:DoseAdjustmen

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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


32

Pugh Modification Of Child’s Classification Of Liver

Disease Severity


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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 hasbeen demonstrated in clinical trials and/or whose kinetics is not affected by liver disease or for which therapeutic drug monitoring is available05/02/23 Dr.A.S.Attariya:DoseAdjustmen

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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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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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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


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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EFFECT ON PPB


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)

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*Touny M et al PK of cefodizime in patients with liver cirrhosis and ascites.


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**

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*Frye RF et al(2006) :In Clin Pharmacol Ther**Elbekai RH et al(2000)05/02/23 Dr.A.S.Attariya:DoseAdjustmen

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EFFECT ON RENAL EXCRETION

• Defn of hepatorenal syndrome• Reduced renal excretion of diuretics, H2

antagonists, levetiracetam in advanced cirrhosis*

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* Gonzales G, Eur J Clin Pharmacol


EFFECT ON PD

• The most important changes in PD with β-blockersdiureticsopioid analgesicsanxiolytics and sedatives.


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


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


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


DRUGS WITHDRAWN FROM THE MARKET SECONDARY TO HEPATOTOXICITY*

• Bromfenac(NSAID)• Troglitazone(OHA)• Kava Kava(antianxiety herb)• Pemoline(for ADHD & narcolepsy)• Felbamate(for partial seizures)• Tolcapone (Antiparkinson)• Trovafloxacin(antibiotic)• Tienilic Acid(diuretic)• Zileuton(asthma)

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*Drug-Induced Hepatotoxicity, Nilesh Mehta in MEDSCAPE


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SPECIAL AGE GROUPS


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


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

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*Seth SD:Drugs in pregnancy & pediatrics


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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BRONZE BABY SYNDROME

GREY BABY SYNDROME


PREGNANCY

CAUTIOUS USE OF drugs that cross placenta to avoid toxic effects(LA, narcotics used during labor)


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.


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


DRUGS WHOSE HEPATIC METABOLISM IS REDUCED IN ELDERLY

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OXIDATION, HYDROXYLATION

DEALKYLATION REDUCTIONNITROREDUCTION

AlprazolamBarbituratesCarbamazepineIbuprofenPhenytoinWarfarinPropranolol

DiazepamLidocaineTheophylline

Nitrazepam


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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HED

BromocriptinLdopaMorphieneVerapamilsumatriptan

IED

CiprofloxCarvedilolDiltiazemAtorva, Prava, SimvaOmeprazoleMidazolamcodiene

LED(low PPB)

AlprazolamDoxycyclineMetronidINHPCTMpredni

LED(high PPB)

DiazepamTolcaponeCeftriaxoneRifampicinPrednisolone


DRUGS C/I IN LIVER DISEASE

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Methotrexate Niacin Naltrexone MetforminTolcapone StatinsTacrine Valproic acidMethyldopaClonazepam


POTENTIAL CHANGES IN DRUG HANDLING IN CIRRHOSIS


EFFECTS OF CIRRHOSIS ON THERAPEUTIC DRUGRESPONSE


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STAY HEALTHY


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 7505/02/23 Dr.A.S.Attariya:DoseAdjustmentInHepaticDis

drug-dose adjustment in patients with hepatic diseases

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