Drug Handling in kidney and liver disease

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Drug Handling in kidney and liver disease
Dr. Geoff Isbister
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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

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Drug Action

• ENZYME example Angiotensin Converting enzyme
  inhibitors A I ----X----------gtA II lowered
  A II -----gt Reduced BP
• ION CHANNELS example Local Anesthetics Bloc
  k Na channels---gtAnesthesia

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• 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

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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

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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

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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

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Type of Disease

• Renal disease the nature of the disease doesnt
  matter very much, the main determinant is the
  decline in GFR

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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

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Practical issues - treating real patients

• Assessing kidney function is straightforward
• serum creatinine reflects GFR
• relationship between serum creatinine and GFR
  changes with age

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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?

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Effects of age on renal function (constant serum
creatinine of 0.10 mmol/l)
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Multiple Dosing - renally excreted drug
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 polar products (filtered without
  reabsorption)

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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

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Practical Examples of dosing in renal failure
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Gentamicin

• Practice is changing - trend to once/daily dosing
• The interval between doses may be gt24 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

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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

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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

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Hepatic Disease

• Metabolism by the Liver
• role of metabolism
• types of metabolism
• Clearance
• hepatic clearance
• Liver disease

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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

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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

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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.)

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Drugs with Active Metabolites
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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.

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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

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Phase I - P450 System

• FRAGILE
• High specificity
• Low volume
• Energy dependent
• First affected by liver disease

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Cytochrome P450 System

• Not a single entity
• Family of related isoenzymes (about 30)
• Important for drug interactions
• Enzyme induction
• Enzyme inhibition
• Genetic polymorphism

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Phase II ReactionsConjugation

• Glucuronidation
• Sulfation
• Acetylation
• Glutathione
• Glycine

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Phase II ReactionsConjugation

• ROBUST
• High volume
• Low specificity
• Not energy dependent
• Less effected by liver disease

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Paracetamol toxicity failure of Phase II
Conjugation pathway saturates
? oxidation by P450 cytochrome pathway
Formation of toxic metabolite NAPQI
Initially detoxified by glutathione
NAPQI accumulates and binds to tissue
macromolecules - cell death
Glutathione depletion
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Sites of Biotransformation

• Liver
• Lung
• Kidney
• Large and small intestine
• Placenta

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Hepatic Clearance
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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

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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

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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

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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.

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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

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Recent theories to account for impaired
metabolism in cirrhosis

• Intact hepatocyte mass
• Sick cell theory
• Impaired drug uptake/shunting theory
• Oxygen limitation theory

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Type of Metabolism

• Phase I, mainly P450
• Affected first
• Phase II
• Severe disease before any effect
• Eg. Paracetamol poisoning.

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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