pkvb disease state

8/8/2019 Pkvb Disease State

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Pharmacokinetic variabilityPharmacokinetic variability--

disease statedisease state


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Pharmacokinetic variabilityPharmacokinetic variability--diseasedisease

statestate

pharmacokinetic variability is greater in sickpeople than

in healthypeople. Disease affects various organ systems

of the body and affects the way drugs are absorbed,

distributed, excreted and metabolised


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Renal impairment:

Renal impairment:

In renal impairment some drugs which are excreted by

kidney are eliminated at lower rate compared to normalperson

Causes of renal failure:

Hypertension

Diabetes Hypovolemia

Uremia


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creatinine

Renal function can be determined by measuring the GFR

CREATININEis an agent which gets excreted in

unchanged form by glomerular filteration only and is

physiologically and pharmacologically inert

Normal values range from 100-125ml/min

Creatiinine clearance values of

20-50ml/min->moderate renal failure

severe renal frailure


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CREATININECLEARANCECREATININECLEARANCE

It represents the rate at which creatinine isremoved from blood by the kidneys.

Creatinine is exclusively excreted by glomerularfiltration.

Elevation of serum creatinine concentrationindicates renal damage.

Renal clearance ratio = ClR of drug / ClR ofcreatinine


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For children (between 1 to 20 yrs)

Clcr = 0.48 H/ Scr * [W/70]^0.7

For adults (above 20 years)

Males, Clcr = (140-age) W/72*Scr

Females, Clcr = (140-age) W/85*Scr

Clcr=creatinine clearance in ml/min

Scr=serum creatinine in mg%H=height in cms

W=weight in kgs


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DRUGEXCRETION

There is a linear relationship between the renal

clearance of a drug and creatinine clearance in

patients with varying degrees of renal function

Renal clearance = A * Creatinine clearance


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Eg: Nadolol

The renal clearance of

nadolol in essentially

anephritic patients isvirtually zero


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Drug elimination

The effect of renal disease on the elimination of

drug depends on the renal status of the patient and

the elimination characteristics of drug

Total clearance = A * creatinine clearance +

nonrenal clearance


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Drug a , b, c are 10%,

50% ,90% eliminated byrenal excretion

Renal clearance is linearly

related to creatinine

clearance

In case of renal

impairment: At a

creatinine clearance of

20ml/min, tc of drug a is

decreased by 8.5% , thatof drug b by 40%, and

that of drug c by 70%


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Dosage regimen

The half-lives of some drugs are changed sufficiently in

patients with impaired renal function to warrant a change

in the usual dosage regimen to prevent accumulation ofdrug in the body to toxic levels

Changes in the regimen usually take the form of reducing

the dose per dosing interval or increasing the length of

dosing interval Eg: cephalexin


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Dosage adjustment

Dose in patients with renal impairment can be calculatedfrom the formula:

Normal dose*RF

RF= CLcr of patient/CLcr of normal person

Dosing interval in hours = Normal interval (in hours)/RF

When drug is eliminated both by renal and non renal

mechanismsDose to be administered = Normal dose

[RF*Fu + Fnr ]


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Effects on metabolised drugsEffects on metabolised drugs

Adverse effects of certain metabolised drugs

phenytoin, clofibrate is higher in renal failure

patient because of change in protein binding

Renal failure also produce a more direct inhibition

of drug metabolism

For Eg morphine


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protein binding and renalfailureprotein binding and renalfailure

Protein binding is decreased in renal failure specially aciddrugs like sulfonamide and phenytoin

Protein binding of drug is decreased because of decrease inserum albumin and accumulation of endogenous inhibitorswhich interfere in drug binding to albumin

After and before kidney transplantation warfarin andphenytoin is calculated for protein binding.


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Pharmacokinetic variabilityPharmacokinetic variability--

Liver diseaseLiver disease


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Liver diseaseLiver disease

Liver disease:

Liver disease may effect the drug binding ,hepaticblood flow, drug metabolizing enzymes

antipyrine has been used widely as a model drug

to investigate the effects of liver disease on drug

metabolism in man, it is not bound to plasmaproteins and tissues


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ANTIPYRINE

Antipyrine clearance may serve as quantitative measureof liver function

It is eliminated almost exclusively by hepatic metabolism, its half-life and clearance are considered sensitive indicators of liverfunction wrt oxidative metabolism

In usual procedure calculating antipyrine clearance involvescollection of 4 to 7 samples of blood or saliva during a 24 to 48 hr

period after oral or iv administration of a single dose Half life of antipyrine was prolonged in the patient with liver

disease compare to normal


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Hepatic Extraction Ratio (EHepatic Extraction Ratio (EHH))

Extraction Ratio tells of efficiency, not extent

EH = Ca Cv

Ca

Factors affecting EH:

Blood flow

Protein binding

Hepatic intrinsic clearance (ability of hepatocytes to removedrug from liver , when blood flow, protein binding, andtranslocation to the site of metabolism or elimination are notrate-limiting)


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Hepatic clearanceHepatic clearance

Volume of blood from which drug is removed

completely per unit time

CLH = QH EH

Hepatic clearance is not equal to systemic

clearance


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Drugs Exhibiting >20% Decrease in

Clearance in Chronic LiverDisease

Lidocaine

Meperidine

Metoprolol

Propranolol

Verapamil

Caffeine

Diazepam

Erythromycin

Metronidazole

Theophylline


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Extraction ratios

Low Extraction Ratio

Dosage adjustment only necessary when intrinsic clearancve

changes (ie cirrhosis) The elimination of drugs that have a low hepatic extraction

ratio and are largely cleared by metabolism in liver are ratelimited by activity of hepatic metabolising enzymes

Eg:antipyrine

A given liver disease , however doesn't affect all enzymepathways to the same extent

Eg: phenytoin and warfarin


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Low Extraction Ratio Drugs in Liver

Disease

Drug Clearance half-life

Diazepam 25% (half that of control)

^4 fold

Valproic Acid 50%

Metronidazole 40%

Naproxen 40%

Theophylline 30% 26hrs,where

as 7hrs in

control


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Low Extraction Ratio Drugs in LiverLow Extraction Ratio Drugs in Liver

DiseaseDisease

Decreased intrinisic clearance (hepatic cell mass andfunction ).

Often increased serum albumin

Overall, total Cl is generally reduced two to four-fold(increasing plasma levels).However, free (active) plasma levels may be increased bymuch more

Therefore, highly bound drugs may need > 2 or 4-folddosage reduction


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High Extraction Ratio Drugs in Liver

D

isease

Cirrhosis and other liver dysfunction affect not only

hepatic drug metabolizing enzymes but also liver blood

flow Thus hepatic disease can affect the disposition of high

hepatic extraction ratio drugs in 2 ways

after oral administration presystemic metabolism

will be less in cirrhotic patient compared to normal clearance will be lower in cirrhotic patients


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Indocyanine green (ICG) is eliminated so rapidly

by human liver that its clearance is often used as

an indicator of hepatic blood flow rate

The disposition of ICG and lidocaine an other

high hepatic extraction ratio drug was studied

during and after recovery from an episode ofacute viral hepatitis


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disease Half life

halthy 12hr

cirrhosis 34hr

Chronic active hepatitis 26hr

Acute hepatitis and obstructive

jaundice

Very less difference than

normal


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CHOLESTASIS

Cholestasis impairs the elimination of certain drugs.

Eg: avg half life of rifampicin was found to be 5.7hrswith patients with obstructive jaundice, double to that ofnormal subject.

Pancuronium a neuromuscular blocking agent in patients

with total biliary obstruction indicate there is doubling ofhalf life and a 50% decrease in plasma clearance of drugcompared to healthy subject


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Prediction of disease effects

Although liver dysfunction may have significant

effect on elimination of drugs. The degree of

impairment of drug elimination in an individual

being treated with specific drug cannot be

predicted

Measurement of drug kinetics can be used toprovide quantitative information of hepatic

function in patients


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Crom et al have evaluated a method to simultaneouslyassess three major processes involved in hepatic drug

metabolism (glucuronide conjugation, hepatic blood flowand microsomal oxidative metabolism)

using a single cocktail containing 3 model substrates(lorazepam, ICG, Antipyrine)

More recently, kawasaki et al measured the clearance of

antipyrine, ICG and galactose to evaluate changes inhepatic blood flow and hepatic drug metabolisingactivities in patients with chronic liver disease


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PharmacokineticPharmacokineticvariabilityvariability--

Cardiovascular diseaseCardiovascular disease


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CARDIOVASCULARDISEASE

Decreased hepatic perfusion is found in patientswith cardiac heart failure because of reduced

cardiac out put. These changes reduce theclearance of propronalol, pentazocine, lidocaine.

CV failure may alter concentration of drugbinding protein like AAG, results production of

endogenous binding inhibitors which inhibitprotein binding.


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Propronalol clearance was observed 50%less in

permanent hypertension patients than in border line

hypertension patients. Oral administration of prazosin was tested in patients

with CHF and normal subjects.AUC is twice in CHF.half

life of prazocin was 6hrs in CHF .

Mean time to reach peak delayed in CHF patients whenfurosemide, bumetanide were administered


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PharmacokineticPharmacokinetic

variabilityvariability--Thyroid diseaseThyroid disease


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THYROIDDISEASE

When thyroid function is altered there are a series

of physiologic changes that may affect drug

absorption, excretion , metabolism.


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ABSORPTION

Bioavailability of riboflavin is increased in

hypothyroidism and decreased in hyperthyroidismbecause of changes in GIT motility.

Absorption rate of propranolol and oxezepam arealso increased in hyperthyroidism due to increase

in GIT motility


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METABOLISM

Activity of hepatic microsomal drug metabolising

enzymes is reduced in hypothyroidism and

incresed in hyperthyriodism.

Thyroid disease seems to have a considerable

effect on the elimination of propranolol. Hypothyroid patients absorb and eliminate

acetaminophene more slowly, where as

hyperthyroid patients absorb and eliminate the


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EXCRETION

Renal plasma flow is reduced in hypothyroidism

and increased in hyperthyroidism.

Eg: low blood levels of digoxin in

hyperthyroidism and high blood levels in

hypothyroidism.


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