Pharmacology presentation on Drug Metabolism

1. It is the metabolic alteration of drug molecules . This
usually involves two types of biochemical reactions
that occur sequentially in two phases known as phase
(ǀ) and phase (ǁ). Phase I reactions usually involves
oxidation ,reduction ,hydrolysis , deamination and
dealkylation reactions. This may render the
descendant drug more active and some times more
toxic than the parent drug (functionalization phase).
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2. Phase II reactions involve conjugation reactions which render the
drug inactive . Both stages will decrease the lipid solubility of the
drug and hence , Increase its renal elemination assissted by the non-
selective detoxification system of the intracellular metabolizing
enzymes.
This takes place mainly in the liver except for some drugs where
the two phases occur in the plasma (e.g. hydrolysis of
suxamethonium and procaine by plasma cholinesterases) , in the
lung (e.g. various prostanoids) or in the wall of intestines (e.g.
tryptamines ).
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3. The liver intracellular enzymes are mostly attached to
the smooth endoplasmic reticulum (microsomal
enzymes) sediment after prolonged high speed
centrifugation on homogenization. A non-polar drug
,more readily ,can pass the hepatocyte membrane and
reach these enzymes where as the highly polar drugs ,
if they do not have a carrier system , may be excreted
unchanged.
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4. Phase I Reactions
A/ Oxidation Reactions :
(Hydroxylation of nitrogen and carbon atoms , N- and O-
dealkylation and oxidative deamination) are catalyzed by
the enzymatic system mixed function oxygenase system
that resides on the endoplasmic reticulum ( e.g.
cytochrome P-450 that catalyze hydroxylation reactions)
.
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5. Some drugs may be metabolized by:
I / The soluble cytoplasm enzyme alcohol
dehydrogenase (e.g. ethanol) .
II/ The non-microsomal enzyme xanthine oxidase
(involoved in uric acid synthesis and inactivation of the
cytotoxic drug 6-mercaptopurine).
III/The monoamine oxidase enzyme ( involved in the
inactivation of many active amines e.g. tyramine and
noradrenaline ) which can occur in many tissues other
than the liver.
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6. B/ Reduction Reactions:
I/ The anticoagulant drug warfarin is inactivated by the
conversion of a ketone group to a hydoxyl one .
II/ Many steroids (e.g. cortisone and prednisone) are
activated by the reduction of the ketone group to the
corrosponding hydroxy compounds. These also
involves microsomal enzymes .
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7. C/ Hydrolytic Reactions:
These occur only in tissues other than the liver to
hydrolyse the ester and amide groups (e.g. hydrolysis of
procaine by the plasma cholinesterases).
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8. Phase II Reactions
A drug may be susceptible to a conjugation reaction (
attachment of a substituent group), if it has a handling
group (e.g. a hydoxyl , a thiol or an aminogroup) . The
conjugate is pharmacologically inactive and less lipid
soluble than the precursor ( from phase I ) is then
excreted. This conjugate formation is often involoving a
glucuroynly- , a glycyl- , a sulphate- , a methyl- , an
acetyl- or a glutamyl- group in the liver ,mostly , lung or
kidney .
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9. I/Glucronide formation involves the formation of a
high energy phosphate group (Uridine Diphospho-
Glucuronic Acid ) from which the acid part is
changed into an electron rich atom ( N-,O- OR S- )
forming and amide- , ester or thiol- bonds catalyzed
by glucuronyl-transferase.
II/ Acetylatin and methylation reactions occur with
acetyl co-A and S-adenosyl methionine respectively.
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10. Induction of Microsomal Enzymes:
Many drugs can enhance the activity of microsomal enzymes
and the conjugateing system (e.g. ethanol,phenobarbitone and
phenylbutazone) as well as some carcinogenic substances
(e.g. benzpyrine ) . This can result from an increase of :
I/ Microsomal enzymes synthesis.
II/ The rate of metabolism of inducing agent in variable
patterns (e.g. phenobarbitone is a verstile , non-selective
inducer that increase the rate of degradation of many drugs
and polycyclic hydrocarbons are selective only to oxidase
enzyme ). Induction to phase I metabolism can increase the
drug effect.Phase I induced metabolites may cause toxicity (
e.g. paracetamol and the carcinogenic polcyclic
hydrocarbons).
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11. Mechanism:
This is suspected to involve stimulation of gene
transcription leading to incearsed protien synthesis
by binding to cytosolic recteptor that in turn binds to
to specific DNA sequences associated with the
production of particular drug metabolizing enzymes.
First-pass metabolism ( Presystemic ):
-Much larger dose of the drug is required orally.
-Marked individual variation occur in the extend to
which a drug can be metabolized.
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12. Renal Excretion of Drugs & Drug Metabolites
-The kidneys handle different dugs differently (e.g.
penicillin is excreted completely after a single passage
through the kidney , where as the chlorpromazine is
excreted slowly and all the drugs excretion rates fall
between these two ranges).
-The products of phases I and II are excreted more
readily than the parent drug.
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13. -The basic processes incorporated in renal excretion
are :
I/ Glumerular Filteration :
- This allows all drugs of molecular weight less than
20000 with a concentraction in the filtrate nearly
similar to that in plasma.Drugs bound to plasma
protiens ( plasma albumin molecular weight =
68000) are less readily found in the filterate (e.g.
phenylbutazone concentrations is 98% bound to
plasma albumin and its concentration in the filtrate is
2% only )
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14. II/ Tubular Secretion & Reabsorption:
-20% of a drug is removed from blood via glumerular
filtration ,whereas the remainder 80% moves to the
pretubular capillaries of the proximal tubules to reach the two
independent , non-selective carrier systems ( one can transport
acidic drug and the other is specific for basic substances) to
be taken to the tubular lumen against an electrochemical
gradient
-Many drugs excreted via kidneys share the same carrier
system and hence , compitition occur ( e.g. probencid retard
the excretion of penicillin and inhibit the reabsorption of uric
acid , but it is useful in the treatment of gout ).
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15. III/ Diffusion Across Renal Tubules:
-Water is reabsorbed in the renal tubules ( urine
volume is 1% of that of the filtrate).drugs with
micromolecules are readily filtered in the renal
tubules( plasma concentration – filtrate
concentration) and hence , it can easily be
absorbed passively.Drugs with high lipid
solubility and high tubular permeability are also
slowly excreted.
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16. -Highly polar drugs have high urine
concentrations (e.g. gallamine and streptomycin).
-Weak acids and bases change their ionization
and hence, markedly affect excretion ( a basic
drug may be readily excreted in an acidic urine (
e.g. gaptamine )and an acidic drug can not be
reabsorped if the urine is alkaline ( e.g.
barbiturate and aspirin) due to ionization.
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17. Drug Clearance :
It is the volume of plasma containing the amount of substance that is
removed by the kidney in a unit time :
CLr = CU VU/CP
Where :
CLr = Clearance of a drug.
Cu = Drug urinary concentration.
Vu = Rate of flow of urine.
Cp = Drug plasma concentration.
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18. Factors Affecting Drug Clearance :
-Drugs that are completely filtered (not protien-bound)
may have a clearance almost similar to the glumerular
filteration (e.g. insulin CLr = 120 ml / min. ).
-Drugs that are completely excreted via the carrier
system of the renal tubule during a single passage
through the kidney (e.g. penicillin ) ,may have a CLr
nearly equal to that of P-amiohippuric acid which is
equal to renal plasma flow (700 ml/min. ).
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19. -Drugs that are excreted via passive
diffusion (e.g. barbiturates) may have a
CLr nearly equal to the rate of urine
formation (1ml / min. ).
-Clearance varies among individuals and
from time to time in the same individual
thus, affecting the values of drug safety.
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20. Billiary Excretion :
The transference of drugs and drug metabolites from
plasma to bile through liver cells.
TRANSPORT SYSTEMS:
I/ Acid and base handling systems.
II/ Transport of unchanged molecules.
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21. -Various hydrophilic drugs conjugates are delivered
into the intestines , hydrolized and then released to
be reabsorbed and recycled again ( e.g. digoxin,
morphine ,chloramphenicol and stilbosterol).
- Some drugs are considerably excreted in bile (e.g.
cromoglycate in the unchanged form and rifambicin
in the deacetylated form).
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