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Drug elimination (metabolism, excretion)

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Title: Drug elimination (metabolism, excretion)


1
Drug elimination
(metabolism, excretion)
  • Anton Kohút

2
DRUG METABOLISM major site of drug metabolism
liver, exceptions- suxamethonium and
procaine - plasma cholinesterase-
tyramine - intestinal wall
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  • Phase 1
  • - lipophilic molecules are converted into more
    polar molecules Reactions are catalyzed by the
    cytochrome P-450 (CYP)
  • by ? oxidation
  • ? reduction
  • ? hydrolysis
  • - products are often less eactive than the parent
    compounds
  • - after metabolism may be excreted by kidneys
  • - each of the enzyme has a low specificity
  • Phase 2
  • consists of conjugation reactions
  • Most often involved groups in conjugation are
  • ? glucuronyl
  • ? sulphate
  • ? methyl
  • ? acetyl
  • ? glycyl
  • ? glutamyl

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The two phases of drug metabolism
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Metabolism of imipramine
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Involvement of some isoform of CYP
in the metabolism
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FACTORS INFLUENCING DRUG
METABOLISM
  • - systemic pathological processes - liver
    diseases, heart failure
  • - age
  • - sex
  • - body temperature
  • - genetic factors - polymorhism
  • - drug interactions? enzyme inhibition, enzyme
    induction

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Drug interactions - enzyme induction
  • Drug induction
  • increase of enzyme activity can decrease drug
    potency,
  • - result is an increased synthesis of microsomal
    enzymes after repeated use of drugs
  • - generally, metabolism of inducers itself is
    increased as well as various other compounds,
  • - increase of metabolism may increase toxicity
    of paracetamol toxic metabolites
  • Drugs that cause induction
  • barbiturates, carbamazepine, ethanol (chronic
    use), glutethimide, griseofulvin, meprobamate,
    phenytoin,
  • rifampicin, sulphinpyrazone,

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Drug interactions - enzyme inhibition
  • Drug inhibition
  • - enzyme inhibition can slow down the
    metabolism
  • - action of coadministrated drug may be
    increased and prolonged
  • Drugs that cause inhibition
  • - cimetidine,
  • - erythromycin,
  • - quinolone
  • - sodium valproat,
  • - allopurinol

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Genetic polymorphism
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Genetic polymorphism
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Genetic polymorphism
  • 1. Plymorphism in acetylation (rapid or slow
    acetylators isoniasid (INH), hydralazine and
    procainamide, sulphasalazine
  • 2. Poor oxidisers debrisoquine, metoprolol,
    timolol, haloperidol
  • 3. Glucose-6-phosphate dehydrogenase deficiency
  • G-6-PD risk of haemolysis aspirin,
    probenecid, quinine, chloroquine, nitrofurantoin,
    some sulphonamides
  • 4. Pseudocholinesterase deficiency malignant
    hyperthermia suxametonium,

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CYP 2D6
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  • Drug excretion

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- Drugs are exreted either unchanged or as
metabolites. - Lipid-soluble drugs are not
readily eliminated until they are metabolized to
more polar compounds
  • Drug excretion

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Renal excretionExtrarenal excretion
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Renal excretion
  • 1. Glomerular filtration - passive
  • Depends on fractional plasma protein binding
  • glomerular filtration rate (size
    of molecules)
  • (MW 68 000) is completely held
    back
  • by this way is removed about 20 of drugs
    from the blood
  • 2. Passive tubular reabsorption
  • ? the nonionized forms of weak acids and bases
    undergo passive reabsorption.
  • ?The concentration gradient for back-diffusion is
    created by the reabsorption of water with Na and
    other inorganic ions.

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  • When the tubular urine is made more acidic, the
    excretion of weak acids is reduced
    (alkalinization of the urine have the opposite
    effects on the excretion of weak bases).
  • Treatment of drug poisoning, the excretion of
    some drugs can be hastened by appropriate
    alkalinization or acidification of the urine.

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Renal excretion (cont.)
  • 3. Active tubular secretion
  • ?Many organic acids (such as penicillin) and
    metabolites (such as glucuronides) are
    transported by the system that secretes naturally
    occurring substances (such as uric acid).
  • ? Organic bases, such as tetraethylammonium, are
    transported by a separate system that secretes
    choline, histamine, and other endogenous bases.
  • ? The carrier systems are relatively
    nonselective, and organic ions of similar charge
    compete for transport.
  • ?Both transport systems also can be
    bidirectional, and at least some drugs are both
    secreted and actively reabsorbed. (an endogenous
    organic acid is uric acid).

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Excretion by other routes
  • Biliary and fecal excretion
  • Saliva, sweat, tears - the concentration of some
    drugs in saliva parallels that in plasma.
  • Breast milk - excretion by breast milk is
    dependent mainly upon diffusion, Milk is more
    acidic than plasma, basic compounds may be
    slightly concentrated in this fluid.

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Excretion by Other Routes
  • 1. Saliva
  • ? Excretion of drugs into sweat, saliva, and
    tears is quantitatively unimportant.
  • ? Excretion by saliva is dependent mainly upon
    diffusion
  • ? Drugs excreted in the saliva enter the mouth,
    where they are usually swallowed.
  • ? The concentration of some drugs in saliva
    parallels that in plasma.
  • ? Saliva may therefore be a useful biological
    fluid in which to determine drug concentrations
    when it is difficult or inconvenient to obtain
    blood.

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  • 2. Breast milk
  • ? Excretion by breast milk is dependent mainly
    upon diffusion
  • ? Milk is more acidic than plasma, basic
    compounds may be slightly concentrated in this
    fluid,
  • Nonelectrolytes, such as ethanol and urea,
    readily enter breast milk and reach the same
    concentration as in plasma, independent of the pH
    of the milk.
  • Excretion of drugs in breast milk are potential
    sources of unwanted pharmacological effects in
    the nursing infant.

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  • 3. Feces
  • Substances excreted in the feces are mainly
    unabsorbed orally ingested drugs or metabolites
    excreted in the bile and not reabsorbed from the
    intestinal tract.
  • 4. Biliary excretion

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Elimination
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Rate of elimination
Elimination of most drugs from the body after
therapeutically relevant doses follows
first-order kinetics. To illustrate first order
kinetics we might consider what would happen if
we were to give a drug by i.v.
bolus injection, collect blood samples at various
times and measure the plasma
concentrations of the drug. We might see a
decrease in concentration as the drug is
eliminated.
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First-order kinetics Elimination half-life
(t1/2)
Definition Elimination half-life is the time it
takes the drug concentration in the blood to
decline to one half of its initial value. It is
a secondary parameter The elimination
half-life is dependent on the ratio of VD
and CL. Unit time (min, h, day)
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First order kinetics half - life
  • ? Most drugs exhibit first order kinetics
    disappeaance of drug from plasma follows
    exponential patterns.
  • ? The rate of elimination is directly
    proportional to drug concentration.
  • ? Plasma half-life is directly proportional to
    the volume of distribution and inversely
    proportional to the overall rate of clearance
  • ? With repeated dosage or sustained delivery of a
    drug the plasma concentration approaches a steady
    state within 4-5 half-lifes.

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Rate of elimination
Elimination which follows first-order kinetics
dC/dt - kel . C kel . rate constant
of elimination rate of change
is proportional to concentration and is
therefore decreasing with time as the conc.
decreases
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Rate of elimination
monoexponential decay C(t) C0 . e- kel . t
half-life t1/2 C C0 / 2 t t1/2 ln2 / kel
0.693/ kel after 4 half-lives 6
remaining, 94 eliminated
50
Saturation kinetics
  • ? In a few cases as ethanol, phynytoin and
    salicylate disapppearance of drug from plasma
    does not follow exponential patterns.
  • ? Pattern of desappearance of drug is linear
    drug is removed at a constant rate that is
    indipendent of plasma concentration
  • ? This is often called zero order kinetics

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Use of t1/2
1/ t1/2 can be used to predict how long it will
take for the drug to be eliminated from
plasma.
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