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Drug Handling in kidney

and liver disease

Dr. Geoff Isbister


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 Action
ENZYME: example Angiotensin
Converting enzyme inhibitors
A I ----X---------->A II
lowered A II -----> Reduced BP
ION CHANNELS: example Local
Anesthetics
Block Na channels--->Anesthesia
Receptor Binding
Receptors are specialised binding sites - often on cell
surface- which have specificity for certain substances
(incl drugs). Drugs may activate or block the receptor
Activation of the receptor changes the activity of the cell:
eg adrenaline activates the beta 1 receptors in the heart
and speeds up the heart
Drugs have selectivity for receptors: eg Histamine2
antagonists- reduce histamine-induced acid secretion and
heal peptic ulcers
Pharmacokinetics

The study of the action of the body on the drugs


Pharmacokinetics is the study of the time course
of concentrations of drug in the body
The way the body handles drugs determines the
dose, route and frequency of administration
The handling of drugs by the body can be split
into absorption, distribution and elimination
Pharmacokinetics
Rate of absorption
determines the time
to the peak
concentration
The extent of
absorption
determines the height
of the peak
concentration and
the AUC
Pharmacodynamics
The response of the tissue to the active free
concentration of drug present at the site of
action
May also be changed by disease processes
Type of Disease
Renal disease the 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 are eliminated
directly by the kidney
Molecules with MW below 20000 diffuse into glom filtrate.

examples: gentamicin, digoxin, atenolol


involves no chemical change to the drug
in most cases occurs by filtration (and depends on the GFR)
in a few cases (eg penicillin) some tubular secretion
contributes to elimination
Highly lipid-soluble drugs are filtered into the tubules
and then rapidly re-absorbed
High protein binding will reduce filtration
Practical issues - treating real
patients

Assessing kidney function is straightforward


serum creatinine reflects GFR
relationship between serum creatinine and GFR
changes with age
Effects 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?
Effects of age on renal function
(constant serum creatinine of 0.10
mmol/l)
Multiple Dosing - renally excreted drug

Approx 5 half-lives to reach steady state


Elderly
Drug Types
Water soluble - excreted unchanged (by
the kidney)
Lipid soluble
- filtered but fully reabsorbed in the kidney
- metabolised to polar products (filtered
without reabsorption)
A number of drugs are handled
by tubular mechanisms
Two mechanisms
Active tubular secretion important
Acidic drugs frusemide, methotrexate, penicillins, salicylate,
uric acid, probenecid
Bases amiloride, morphine, quinine
Passive diffusion
After filtration lipid-soluble drugs will be re-absorbed
passively.
Will depend on degree of ionization at certain pH levels
Practical Examples of dosing in
renal failure
Gentamicin
Practice is changing - trend to once/daily dosing
The interval between doses may be >24 hours in
the presence of renal failure and in the elderly
Toxicity relates to trough concentrations,
particularly with prolonged therapy
Toxicity mainly affects the kidney and 8th
cranial nerve
Digoxin
In the presence of renal impairment 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
Summary
Reduced elimination of drugs from the body
in the elderly will lead to accumulation and
toxicity
Disease and old age lead to reduced renal
elimination of water-soluble drugs
Co-morbidity and concomitant drug therapy
Hepatic Disease
Metabolism by the Liver :
role of metabolism
types of metabolism
Clearance
hepatic clearance
Liver disease
Type of Disease
In liver disease the type of disease does
matter:
Hepatitis not much effect
Biliary obstruction not much effect (initially)
Cirrhosis has major effects on drug handling
Assessing Function
Assessing liver function is hard - no single
test of how well the liver metabolises drugs
Drug metabolism most likely to be impaired
when the patient has cirrhosis, 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 active
active metabolites
more toxic (mutagenic, teratogenic etc.)
Drugs with Active Metabolites
Types of Metabolism
Phase 1 Reactions
usually convert the parent drug into a more polar
metabolite by introducing or unmasking a
functional group (-OH, -NH2, -SH). Metabolite is
usually inactive.
Phase 2 Reactions - Conjugation
an endogenous substrate (glucuronic acid, sulfuric
acid, acetic acid, or amino acid) is attached to a
functional group on the drug or phase I metabolite.
Absorption Metabolism Elimination

Phase I Phase II
Drug conjugate

Drug metabolite conjugate


with modified
Drug activity

Inactive conjugate
drug
metabolite
Drug

Lipophilic Hydrophilic
Phase I Reactions
Mixed Function Oxidase:
P450 enzyme system
induced and inhibited
hydroxylation and demethylation
family of isoenzymes
Monoamine Oxidase : catecholamines
Dehydrogenases :eg. Alcohol dehydrogenase
Phase I - P450 System
FRAGILE
High specificity
Low volume
Energy dependent
First affected by liver disease
Cytochrome P450 System
Not a single entity
Family of related isoenzymes (about 30)
Important for drug interactions :
Enzyme induction
Enzyme inhibition
Genetic polymorphism
Phase II Reactions
Conjugation
Glucuronidation
Sulfation
Acetylation
Glutathione
Glycine
Phase II Reactions
Conjugation
ROBUST
High volume
Low specificity
Not energy dependent
Less effected by liver disease
Paracetamol toxicity failure of
Phase II
Conjugation pathway saturates
oxidation by P450
cytochrome pathway
Formation of toxic
metabolite NAPQI

Initially detoxified by glutathione


Glutathione NAPQI accumulates and
depletion binds to tissue
macromolecules - cell death
Sites of Biotransformation
Liver
Lung
Kidney
Large and small intestine
Placenta
Hepatic Clearance
Liver Systemic circulation

1.0 0.2
fraction escaping
extraction (1-E)

0.8
fraction extracted and
metabolised (E)
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
Extraction Ratio
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
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 hepatitis little effect
Biliary Obstruction little effect
Chronic Active Hepatitis major effects
Cirrhosis major effects
Indicators :
Established cirrhosis, varices, splenomegaly,
jaundice, increased prothrombin time.
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/shunting theory
Oxygen limitation theory
Type of Metabolism
Phase I, mainly P450
Affected first
Phase II
Severe disease before any effect
Eg. Paracetamol poisoning.
Other considerations
Renal function may be impaired in
moderate to severe liver disease
Creatinine levels are not predictive
Pro-drug metabolism impairment
Eg ACE inhibitors
Pharmaco-dynamic disturbances
Tissues may be excessively sensitive to even
low concentrations of the drug eg morphone
in the brain in the presence of severe liver
disease