The purpose of drug metabolism
To elimination of foreign substances (drugs)
out of the body. But as we know, the drug molecules are soluble in fat, not
ionized, easily absorbed through the cell membrane, attached to plasma proteins
and retained in the body. Want eliminated, the body must metabolize these drugs
so that they become the polar compound, easily ionized, thus becoming less
soluble in fat, protein attached to hard, hard absorbed into the cells, and
because so, than in water soluble, easily eliminated (by the kidney, feces). Without
the process of transformation, a number of very lipophilic drugs (such as
pentothal) may be retained in the body for over 100 years.
Where metabolism and enzymes catalyze the
metabolism
Intestinal mucosa: protease, lipase,
decarboxylase
Serum: esterase
Lungs: oxydase
Enterococci: reductase, decarboxylase
Central nervous system: monoaminoxydase,
decarboxylase
Hepatic metabolism is the main place,
contains most of the enzymes participating in drug metabolism, will present at
the following
The main metabolic reactions
A substance taken into the body will follow
one path or the following:
Are absorbed and excreted unchanged dump:
bromide, lithium, saccharin.
Metabolized B (Phase I), and C substances
(phase II) and elimination
Metabolized D (phase II) and elimination
A substance that may or inactive, born
substance B or no activity. Agent C and D is not inherently biological
activity. A mother nature can generate a lot of metabolite B or C.
The response in phase I
Through this phase, in the form of the drug is
soluble in fat will become more extreme, more water-soluble. But in terms of
biological effects, the drug can be inactivated, or reduced activity, or
sometimes increased activity, becomes active.
The key reaction in this phase include:
Oxidative reactions: very common reaction,
catalyzed by the microsomal liver enzymes, especially hemoprotein, cytocrom
P450.
Hydrolysis by the enzyme esterase, amidase,
protease ... In addition to the liver, serum and other tissues (lung, kidney
...) also have this enzyme.
Reduction reaction.
Oxidation reactions. This is the most common
reaction, catalyzed by oxidative enzymes (mixed - function oxidase enzymes
System- MFO), that many of microsomal liver enzymes, especially cytochrome P
450 they (Cyt- P450), is the membrane protein containing hem (hemoprotein)
localized in the smooth endoplasmic reticulum of hepatocytes and several other
tissues. In the human body is seen with type 17 and type cytochrome P450 lot
less participation metabolism of endogenous and exogenous substances from the
environment, medicine. Oxidation reactions of this type requires NADPH and O2.
The reaction was carried out in several
steps:
1) The substance (drugs, RH) reacts with
oxidized form of Cyt P 450 (Fe 3+) complexes formed Rh-
P450 (Fe 3+)
2) Rh- P450 complex (Fe 3+) received one
electron from NADPH, reduced to RH - P450 (Fe2 +)
3) Then, complex Rh- P450 (Fe2 +) react with
oxygen molecules 1 and 2 electrons from NADPH 1
to form reactive oxygen compound.
4) Finally, one oxygen atom is released, creating
H 2O. 2 oxygen atoms also be oxidized
substrate (medicine): RH ROH, and Cyt.P450
be reconstructed.
Reduction reaction. Reduction of nitro
derivatives, aldehydes, carbonyl by the enzyme nitroreductase, azoreductase,
dehydrogenase ...
Hydrolysis reaction. The ramp ester and amide
hydrolysis by the enzyme being esterase, amidase in plasma, liver, and other
tissues of the gut.
The response in phase II
The material passing through this phase of
the complex problem becomes no longer active, easily soluble in water and is
excreted. However, in this phase, sulfanilamid was acetylated to become soluble
in water, forming crystals in the kidney tubules, causing hematuria or anuria.
These reactions are in phase II conjugation
reactions: an endogenous molecule (glucuronic acid, glutathione, sulfate,
glycine, acetyl) will pair with a group of drugs chemically to form strong
complexes soluble in water . Typically, the response in Phase I will create the
necessary components for functional group reactions in phase II, which is the
group - OH, -COOH, -NH2, -SH ...
The main reactions: reactions associated with
glucuronic acid, sulfuric acid, amino acids (mainly glycine), respond
acetylation, methylation. These reactions require energy and endogenous substrates,
which are characteristic of phase II.
In addition, there are a number of drugs
metabolized completely, which is highly polar compounds (such as acid, strong
base), non permeable layer of microsomal fat. Much is eliminated as quickly as
hexamethonium, methotrexate.
Some non-polar substance can not be
transformed: barbital, ether, halothane, dieldrin.
A drug may be metabolism reactions occur
simultaneously or sequentially. Examples of paracetamol and sulfo- glucuro- the
same time; chlorpromazine metabolized in the human phenothiazines over
reaction, then the branch is also through a series of reactions to last for
more than 30 different metabolites.
Factors that alter drug metabolism speeds
age
Infants lack of drug metabolizing enzymes.
Elderly people and aging enzymes.
hereditary
Do enzymes appear atypical approximately 1:
3000 people have atypical cholinesterase, very slow hydrolysis of suxamethonium
to prolong the effects of this drug.
Isoniazid (INH) was eroded by acetylation. In
one study, oral 10 mg / kg isoniazid, after 6 hours of isoniazid in the amount
of blood found in a group is 3-6 g / mL, in the other group just 2,5g / mL.
The first group is the group of slow acetylation, easy-toxic dose reductions
due to the CNS. Genetics, slow acetylation group, found 60% were white, 40%
black and 20% are yellow. Group after group acetylation is fast, need to
increase the dose, but acetyl isoniazid metabolites toxic to the liver.
The lack of glucose 6 phosphate dehydrogenase
(G6PD) is prone to haemolytic anemia when used Phenacetin, aspirin, quinacrin,
some sulphonamides ...
Externalities
Substance-induced metabolic enzymes: effects
increases in microsomal liver enzymes students, increase the activity of this
enzyme.
For example, phenobarbital, meprobamat, clorpromazin,
phenylbutazone, and hundreds of other drugs: the use of these drugs with drugs
metabolized by the enzymes were induced to reduce the effects of the drug
combination, or by itself (ng out tuo habituation).
In contrast, with the new drug must pass
metabolism becomes active ("prodrug"), when used in conjunction with
drug-induced toxicity will be increased (parathion paraoxon)
Metabolic enzyme inhibitors: a number of
other drugs such as chloramphenicol, d icumarol, isoniazid, quinine, cimetidine
... has the effect of inhibiting, reducing the activity of drug metabolizing
enzymes, thereby increasing the effectiveness of medications coordinated.
Factors pathologic
The disease liver damage department officials
will degrade students collect snails of liver metabolism: hepatitis, fatty
liver, cirrhosis, liver cancer ... easily increase the effects or toxicity
hepatic metabolism as tolbutamid, diazepam.
The disease reduces blood flow to the liver,
such as heart failure, or β blockers prolong sympathetic system will reduce the
number of liver extracts, which lasted t / 2 of the drug has a high coefficient
of extraction in the liver as lidocaine, propranolol, verapamil, isoniazid.
