DRUG-DOSE ADJUSTMENT IN PATIENTS WITH HEPATIC DISEASES

DRUG DOSE ADAPTATION IN
PATEINTS WITH HEPATIC
DISEASES
Dr. AMREEN SABA ATTARIYA
POST GRADUATE STUDENT, DEPT OF PHARMACOLOGY
M.R. MEDICAL COLLEGE, GULBARGA
INDIA
103/20/16 Dr.A.S.Attariya:DoseAdjustmen

OUTLINE OF TALK
INTRODUCTION
EPIDEMIOLOGY
HEPATIC PATHOPHYSIOLOGY
FEATURES OF LIVER DISEASE
ALTERED PK & PD
GENERAL GUIDELINES
RECOMMENDATIONS
SPECIAL AGE GROUP CONSIDERATIONS
SUMMARY
REFERENCES 2
03/20/16
Dr.A.S.Attariya:DoseAdjustmen
tInHepaticDis

INTRODUCTION
• Liver plays a central role in PK of drugs
• Site for drug biotransformation
• Liver blood flow, binding to plasma protein &
biliary excretion influences PKdepend on
normal functioning of liver
• Hepatic dysfunction increased sensitivity to both
desired & AEDosage 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
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tInHepaticDis

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]

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.

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
tInHepaticDis

MANIFESTATIONS
Esophageal varices
Edema, ascites
Impaired liver parenchymal function
Hepatic encephalopathy
1103/20/16
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EFFECT ON OTHER ORGANS
Intestine
Lungs
Kidneys

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
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
HEPATIC CLEARANCE*
Cli is the intrinsic hepatic clearance and fu the fraction of
a drug not bound to serum proteins (free fraction).
03/20/16
*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
“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)

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)”

“ 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.
03/20/16 18Dr.A.S.Attariya:DoseAdjustmen

DIFFERENT CLASS OF DRUGS
• HED [E= >0.7]
• LED[E= <0.3]
• IED[E= 0.3-0.7]

21
HED OR FLOW LIMITED DRUGS
Clhep ≈ Q
All 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)

23
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 ? 3003/20/16 Dr.A.S.Attariya:DoseAdjustmen

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

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

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

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.

03/20/16 41Dr.A.S.Attariya:DoseAdjustmen

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

50
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)
51
*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**
52
*Frye RF et al(2006) :In Clin Pharmacol Ther
**Elbekai RH et al(2000)

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

EFFECT ON PD
• The most important changes in PD with
β-blockers
diuretics
opioid analgesics
anxiolytics 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)
59
*Drug-Induced Hepatotoxicity, Nilesh Mehta in MEDSCAPE

60
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
liverno 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

DRUGS CONTRAINDICATED IN
CHILDREN WITH LIVER DISEASES
• CHLORAMPHENICOLGrey baby syndrome
• ASPIRIN Reye’s syndrome
• PHOTOTHERAPY Bronze baby syndrome
• PCT Pct induced hepatotoxicity

64
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
68
OXIDATION,
HYDROXYLATION
DEALKYLATION REDUCTION
NITROREDUCTION
Alprazolam
Barbiturates
Carbamazepine
Ibuprofen
Phenytoin
Warfarin
Propranolol
Diazepam
Lidocaine
Theophylline
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 diseasedose modification for renally
cleared drugs is also needed.
• Utmost care while prescribing in special age groups

70
HED
Bromocriptin
Ldopa
Morphiene
Verapamil
sumatriptan
IED
Ciproflox
Carvedilol
Diltiazem
Atorva, Prava,
Simva
Omeprazole
Midazolam
codiene
LED(low PPB)
Alprazolam
Doxycycline
Metronid
INH
PCT
Mpredni
LED(high PPB)
Diazepam
Tolcapone
Ceftriaxone
Rifampicin
Prednisolone

DRUGS C/I IN LIVER DISEASE
71
Methotrexate
Niacin
Naltrexone
Metformin
Tolcapone
Statins
Tacrine
Valproic acid
Methyldopa
Clonazepam

POTENTIAL CHANGES IN DRUG
HANDLING IN CIRRHOSIS

EFFECTS OF CIRRHOSIS ON
THERAPEUTIC DRUG
RESPONSE

74
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

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