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
30
25
20
15
10
5
0
0
1 5 9 13
Time after
dosing
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 doesn’t 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)
100
90
80
70
60
50
40
30
20
10
0
20
40
60
80
Multiple Dosing - renally excreted drug
Approx 5 half-lives to reach steady state
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Elderly
0
12
24
36
48
60
72
84
96
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
DRUG
ACTIVE METABOLITE
allopurinol
amitriptyline
codeine
diazepam
procainamide
prednisone
primidone
aspirin
oxypurinol
nortriptyline
morphine
oxazepam
N-acetyl PA
prednisolone
phenobarbitone
salicylate
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
Phase I
Phase II
conjugate
Drug
Drug
Elimination
Metabolism
Drug metabolite
with modified
activity
Inactive
drug
metabolite
conjugate
conjugate
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
depletion
NAPQI accumulates and
binds to tissue
macromolecules - cell death
Sites of Biotransformation
• Liver
•
•
•
•
Lung
Kidney
Large and small intestine
Placenta
Hepatic Clearance
Liver
Systemic circulation
0.2
fraction escaping
extraction (1-E)
1.0
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