year3_drug_handling_in_renal_and_liver_diseasev2

8/7/2019 Year3_drug_handling_in_renal_and_liver_diseasev2

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Drug Action

Drugs tend to be small lipid-

soluble molecules

Drugs must get access to sites

of action

Drugs tend to bind to tissues,

usually protein molecules Drugs alter the actions of

enzymes, ion channels and

receptors

Drug Handling in kidney and liver disease Geoff Isbister

ENZYME: exampleAngiotensin Converting

enzyme inhibitors

A I ----X---------->A II

lowered A II ----->

Reduced BP

ION CHANNELS:example Local

AnestheticsBlock Na

channels--->Anesthesia

liver disease affect the way the body handles drugs

curriculum.toxicology.wikispaces.net/.../Year3_drug+handling+in+renal+and

+liver+diseasev2.ppt


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Receptors are specialised bindingsites - often on cell surface-

which havespecificity for certainsubstances (incl drugs). Drugsmay activate or block thereceptor

Activation of the receptor

changes the activity of the cell:eg adrenaline activates the beta 1receptors in the heart and speedsup the heart

Drugs haveselectivity for

receptors: eg Histamine2antagonists- reduce histamine-induced acid secretion and heal

peptic ulcers

Receptor Binding

study of the action of

the body on the drugs

Pharmacokinetics is

the study of the time

course ofconcentrations of drug

in the body

The way the body

handles drugs

determines the dose,

route and frequency of

administration

Pharmacokinetics


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Pharmacokinetics

Rate of absorptiondetermines the time tothe peak concentration

The extentof absorptiondetermines the height of

the peak concentrationand the AUC

0

5

10

15

20

25

30

0 1 5 9 13

Time after

dosing

Pharmacodynamics

The response of the

tissue to the active

free concentration of

drug present at thesite of action

May also be changed

by disease processes


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Type of Disease

Renal diseasethe nature of the

disease doesnt

matter very much,the main

determinant is the

decline in GFR

Routes of elimination - Kidney

Some drugs are water-soluble and areeliminated directly by the kidney

Molecules with MW below 20000 diffuseinto glom filtrate.

examples: gentamicin, digoxin, atenolol

involves no chemical change to the drug

in most cases occurs by filtration (anddepends on the GFR)

in a few cases (eg penicillin) sometubular secretion contributes toelimination

Highly lipid-soluble drugs are filteredinto the tubules and then rapidly re-absorbed

High protein binding will reduce filtration


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Assessing kidney

function is

straightforward

serum creatinine

reflects GFR

relationship between

serum creatinine andGFR changes with

age

Practical issues -

treating real patientsEffects of age on renal function

There is a steady and

proportional decline in

average GFR with

increasing age

However the serum

creatinine remains

unchanged

Why is this?


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Effects of age on renal function

(constant serum creatinine of 0.10 mmol/l)

0

10

20

30

40

50

60

70

80

90

100

20 40 60 80

Multiple Dosing - renally excreted drug

0

0 .1

0 .2

0 .3

0 .4

0 .5

0 .6

0 .70 .8

0 .9

1

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6

Approx 5 half-lives to reach steady state

Elderly


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Drug Types

Water soluble -

excreted unchanged

(by the kidney)

Lipid soluble- filtered but fully

reabsorbed in the

kidney

- metabolised to polarproducts (filtered

without reabsorption)

A number of drugs are handled by

tubular mechanisms

Two mechanisms Active tubular secretion

important

Acidic drugsfrusemide,

methotrexate, penicillins, salicylate,

uric acid, probenecid Basesamiloride, morphine, quinine

Passive diffusion

After filtration lipid-soluble drugs

will be re-absorbed passively. Will depend on degree of

ionization at certain pH levels


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Gentamicin

Practice is changing - trend toonce/daily dosing

The interval between doses

may be >24 hours in the

presence of renal failure and inthe elderly

Toxicity relates to trough

concentrations, particularly

with prolonged therapy

Toxicity mainly affects the

kidney and 8th cranial nerve

Practical Examples of dosing in renal failure

Digoxin

In the presence of renalimpairment the dose must

be reduced

The dose is given once

daily

Elderly people almost

invariably have some

renal impairment, so they

usually require dose

reduction - normally a

halving of dose compared

with young people


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Summary

Reduced elimination of drugs from the bodyin the elderly will lead to accumulation and

toxicity

Disease and old age lead to reduced renalelimination of water-soluble drugs

Co-morbidity and concomitant drug therapy


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Hepatic Disease

Metabolism by the Liver :

role of metabolism

types of metabolism

Clearance

hepatic clearance

Liver disease

In liver disease the type

of disease does matter:Hepatitisnot much

effect

Biliary obstructionnot

much effect (initially)

Cirrhosishas major

effects on drug handling

Type of Disease


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Assessing Function

Assessing liverfunction is hard - no

single test of how well

the liver metabolises

drugs

Drug metabolism most

likely to be impaired

when the patient hascirrhosis, and has

evidence of coagulation

disturbances and low

albumin

Biotransformation

Majority produces

metabolites that are :

less active

more polar and water

soluble

Minority :

Pro-drugs that require

metabolism to be activeactive metabolites

more toxic (mutagenic,

teratogenic etc.)


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Drugs with Active Metabolites

DRUG ACTIVE METABOLITE

all ri l ri lamitri t li rtri t lic i mor i

iazepam oxazepam

procai ami e N-acet l PAprednisone prednisoloneprimidone phenobarbitoneaspirin salic late


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Cytochrome P450 System

Not a single entity

Family of related

isoenzymes (about 30)

Important for druginteractions :

Enzyme induction

Enzyme inhibition

Genetic polymorphism

Glucuronidation

Sulfation

Acetylation

Glutathione

Glycine

Phase II ReactionsConjugation

ROBUST

High volume

Low specificity

Not energy dependent

Less effected by liver disease


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Paracetamol toxicityfailure of Phase II

NAPQI accumulates and

binds to tissue

macromolecules - cell death

Conjugation pathway saturates

o oxidation by P450

cytochrome pathwayFormation of toxic

metabolite NAPQI

Initially detoxified by glutathione

Glutathione

depletion


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Hepatic Clearance

LiverSystemic

circulation

0.2fraction escaping

extraction (1-E)

1.0

0.8

fraction extracted

and metabolised

(E)

Liver

Lung

Kidney

Largeand small

intestine

Placenta

Sites of Biotransformation


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Extraction Ratio

High extraction ratio : Effectively removed by the

liver

Limited by hepatic blood

flow

High first pass metabolism

Eg. Lignocaine,

propranolol, diltiazem,

morphine

Less effected by changes in

intrinsic clearance, such as

induction and inhibition

High Extraction ratio

Clearance

approximates organ

blood flow Low Extraction ratio

Clearance

proportional to free

drug in the blood and

intrinsic clearance of

the liver


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Liver Disease

Severe disease before

major effects on

metabolism

Liver Disease :Hepatocellular disease

Decrease liver perfusion

Type of metabolism :Phase I

Phase II

Disease Factors

Disease Type :Acute hepatitislittle

effect

Biliary Obstructionlittle

effectChronic Active Hepatitis

major effects

Cirrhosismajor effects

Indicators :Established cirrhosis,

varices, splenomegaly,jaundice, increased

prothrombin time.


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Disease Factors

Poor perfursion

Cardiac failure : limits

blood flow so effects those

with high extraction ratios

Eg. Lignocaine

Combination with ischaemic

liver injury Other low perfusion states :

Other causes of shock

Recent theories to

account for impaired

metabolism in cirrhosis

Intact hepatocyte

mass

Sick cell theory

Impaired drug

uptake/shuntingtheory

Oxygen limitation

theory


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conjugate

Phase I Phase II

Drug metabolite

with modifiedactivity

Inactive

drug

metabolite

conjugate

Drug

Drug

Drug

conjugate

Lipophilic Hydrophilic

Absorption Metabolism Elimination


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Drug Handling in kidney and liver disease

Dr. Geoff Isbister

year3_drug_handling_in_renal_and_liver_diseasev2

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