Antimicrobial Drugs

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Antimicrobial Drugs
Faculty of Pharmacy Department of Pharmacology
5th year Pharmacy Students
Drug-Drug Interaction
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Antimicrobial Drugs
Infectious disease is defined as a disease that
is transmissible or likely to spread.
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pharmacokinetic interaction
1-Psychotropic drugs interactions with
antimicrobial Agents
A - Itraconazole (inhibitor of CYP3A4) so,
Haloperidol plasma concentrations were increased
in schizophrenic patients concurrently treated
with itraconazol and produce significant
neurological side effects . B-
increase in plasma concentration of alprazolam
during concurrent administration of itraconazole
produce significantly depressed psychomotor
function in test subjects C- Psychotropic drugs
are often used in the treatment of emotional
disorders of HIV-infected patients. For
example, CYP3A4 metabolism of the antidepressant
trazodone to its major metabolite,
meta-chlorophenylpiperazine, was inhibited by the
ketoconazole.
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2- Multidrug antiviral regimens in HIV-infected
patients
a patient is often treated with one or more
nucleoside reverse transcriptase inhibitors
(zidovudine, didanosine,, lamivudine,) and a
protease inhibitor (ritonavir, indinavir) A- The
protease inhibitors are metabolized by CYP3A4 and
several of the reverse transcriptase inhibitors
are inducers of various cytochromes, including
CYP3A4. Therefore combinations of antiviral drugs
have the potential for drug interactions . B-
Inhibition of CYP3A4 may sometimes be an
advantage. For example, higher plasma levels of
the HIV protease inhibitor, saquinavir, which is
metabolized by CYP3A4, can be achieved by
combining the drug with CYP3A4 inhibitors like
ritonavir or ketconazole).
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3- The widespread use of drugs for
gastrointestinal disorders, such as antacids and
H2 histamine receptor-blocking agents such as
ranitidine, have been reported to alter the
bioavailability of many antimicrobials . 4-
interaction between erthyromycin and cisapride
produced prolongation of the QT interval and
clinically cardiac arrhythmias were observed. 5-
The HCG-CoA reductase inhibitors commonly used to
block cholesterol biosynthesis are metabolized by
CYP3A4. Therefore, their concurrent use with the
antimicrobials that are also metabolized by
CYP3A4 should be avoided . 6- sildenafil
(Viagra) is predominately metabolized by CYP3A4.
Therefore, any other antimicrobial drug that is
metabolized by CYP3A4 has the potential to
impair sildenafil biotransformation.
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7- HERBAL AND NATURAL PRODUCT INTERACTIONS
the herbal products may either induce CYP3A4 or
be metabolized by this isoenzyme and hence have
the potential to inhibit the metabolism of drugs
. A- the naphtodiantrons flavonoid induce
CYP3A4 and therefore have the potential to
decrease the blood concentrations of any
antimicrobial also metabolized by CYP3A4. B-
garlic supplements interact with some
anti-retroviral medications the serum
concentration for saquinavir was decreased
approximately 51 when concurrently used with a
garlic supplement. C- A number of flavones
present in grapefruit juice For example,
naringenin, and quercetin are metabolized by
CYP3A4 and so The bioavailability of
erythromycin increase as a result of the
inhibitor effect of grapefruit juice on
intestinal CYP3A4 .
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8- Drug Interactions with Medications Used for
HIV/AIDS
The vast majority of drug interactions in
HIV/AIDS are due to effects on the hepatic
cytochrome P450 system, and especially the CYP3A4
isoenzyme . All protease inhibitors and non
nucleoside reverse transcriptase inhibitors are
metabolized through this system, A- Some drugs
such as rifampin, rifabutin, nevirapine, and
efavirenz are primarily inducers of the P450
system and tend to thus increase the metabolism
of other drugs, thereby lowering their levels
. B- Other drugs, such as delaviridine,
indinavir, saquinavir, itraconazole, and
clarithromycin, are primarily inhibitors of this
pathway and so usually increase levels of other
drugs metabolized by the same enzyme .
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C - The P-glycoprotein multidrug transporter is
a membrane protein, which acts as an efflux
transporter for a number of drugs and is present
in intestinal mucosa as well as several other
sites in the body. It is increasingly being
recognized as playing an important role in drug
kinetics and distribution, and as a common
pathway for potential drug interactions. For
example, changes in activity of intestinal
P-glycoprotein can result in changes of blood
levels of orally administered drugs. Protease
inhibitors and other drugs such as rifampin that
have effects on the P450 system may also be
substrates for, or inhibitors or inducers of, the
P-glycoprotein pathway
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D- Glucuronidation is another pathway for
metabolism of some drugs including digoxin,
zidovudine, and the estrogens in oral
contraceptives. The enzyme responsible,
glucuronyl-transferase, can be increased by
rifampin and by certain protease inhibitors such
as ritonavir and nelfinavir, which could lead to
reduced levels of other drugs metabolized through
this pathway E- Changes in absorption of a drug
can also result from changes in gastric pH (and
thereby solubility) caused by another drug, or
from actual chelation inside the gastrointestinal
tract by the other drug F- The nucleoside
analog antiretrovirals require activation by
phosphorylation before they can inhibit HIV
reverse transcriptase. Depending on their base,
they may compete for the same phosphorylation
enzyme and thus may competitively inhibit the
activation of each other. For example, the
combination of zidovudine and stavudine is
actually antagonistic for this reason .
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PHARMACODYNAMIC INTERACTIONS
1- Hydroxyurea
has cellular ribonucleotide reductase activity,
thereby decreasing intracellular levels of the
deoxynucleoside triphosphates that are required
for reverse transcription of the viral genome,
and enhancing the activity of nucleoside analog
reverse transcriptase inhibitors, especially
didanosine . Hydroxyurea used to be given along
with didanosine to potentiate its antiviral
activity 2- rates of anemia and neutropenia are
increased when zidovudine is used concurrently
with ganciclovir or sulfonamides. 3- high rate
of peripheral neuropathy precludes the
combination of zalcitabine with either stavudine
or didanosine .