SELECTIVE TOXICITY.ppt
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About This Presentation
Toxicity
Slide Content
SELECTIVE TOXICITY,
ADVERSE DRUG
REACTIONS &
INTERACTIONS
ADVERSE DRUG
REACTIONS &
INTERACTIONS
Human parasitism falls into three groups:-
Infection of organs with metazoa
(insects, arachnids, worms)
Infection of tissues or cells with unicellular
organisms (protozoa, fungi, bacteria, rickettsia
chlamydae, viruses)
Invasion of organs or tissues by aberrant
human cells (malignant neoplasms)
Antiparasiticagents are cytotoxic
Cytotoxicity (direct injury to or disturbance of
function of cells) may result in death of the cells
(cytocidaleffect) or may result in prevention of
the parasites multiplication (cytostatic effect)
without death of the cell.
Infection of organs with metazoa
(insects, arachnids, worms)
Infection of tissues or cells with unicellular
organisms (protozoa, fungi, bacteria, rickettsia
chlamydae, viruses)
Invasion of organs or tissues by aberrant
human cells (malignant neoplasms)
Antiparasiticagents are cytotoxic
Cytotoxicity (direct injury to or disturbance of
function of cells) may result in death of the cells
(cytocidaleffect) or may result in prevention of
the parasites multiplication (cytostatic effect)
without death of the cell.
Antiparasitic Chemotherapy 3
The cytotoxic action of a drug may exhibit
selectivityi.e. the drug affects one kind of cell
more than another.
The cytotoxic action of drug may exhibit
qualitative selectivityi.e. the drug affects one
kind of cell but does not affect a second kind of
cell.
The cytotoxic action of a drug may exhibit
quantitative selectivity when the drug at a given
dose injures one kind of cell more than a second
kind of cell or the drug injures one kind of cell at a
dose lower than that required to injure a second
kind of cell.
The cytotoxic action of a drug may exhibit
selectivityi.e. the drug affects one kind of cell
more than another.
The cytotoxic action of drug may exhibit
qualitative selectivityi.e. the drug affects one
kind of cell but does not affect a second kind of
cell.
The cytotoxic action of a drug may exhibit
quantitative selectivity when the drug at a given
dose injures one kind of cell more than a second
kind of cell or the drug injures one kind of cell at a
dose lower than that required to injure a second
kind of cell.
Antiparasitic Chemotherapy 4
The scale of measurement of selective
toxicity is the chemotherapenticindex,
which in animal models of parasitism
= the median toxic dose to host
the median curative dose
In patient terms the chemotherapenticindex
= the threshold dose toxic to some patients
the minimum dose curative for most of patients.
The scale of measurement of selective
toxicity is the chemotherapenticindex,
which in animal models of parasitism
= the median toxic dose to host
the median curative dose
In patient terms the chemotherapenticindex
= the threshold dose toxic to some patients
the minimum dose curative for most of patients.
Antiparasitic Chemotherapy 5
The basic assumption of human antiparasitic
chemotherapy is that parasite cells differ from
human cells.
By exploitation of these differences,
toxicity to the parasite can be achieved
without harm to the host
A two way classification into biochemical
and distributionalbases of selectivity will
be used.
The basic assumption of human antiparasitic
chemotherapy is that parasite cells differ from
human cells.
By exploitation of these differences,
toxicity to the parasite can be achieved
without harm to the host
A two way classification into biochemical
and distributionalbases of selectivity will
be used.
Antiparasitic Chemotherapy 6
Biochemical selectivity
The given drug is more toxic to the parasite than to
the host cells, even when the sites of toxic action in
both are exposed to the same drug concentration.
Mechanism of action.
The chemotherapeutic agent may be cytotoxic only to
the parasites in the rapid growth and multiplication
phase of their life cycle (cell wall synthesis, nucleic acid
synthesis and replication, protein synthesis)
Alternatively the drug may be cytotoxic to all phases of
the parasites life cycle including the adult phase
(cytoplasmic membrane, energy yielding metabolism,
muscle).
Biochemical selectivity
The given drug is more toxic to the parasite than to
the host cells, even when the sites of toxic action in
both are exposed to the same drug concentration.
Mechanism of action.
The chemotherapeutic agent may be cytotoxic only to
the parasites in the rapid growth and multiplication
phase of their life cycle (cell wall synthesis, nucleic acid
synthesis and replication, protein synthesis)
Alternatively the drug may be cytotoxic to all phases of
the parasites life cycle including the adult phase
(cytoplasmic membrane, energy yielding metabolism,
muscle).
Antiparasitic Chemotherapy 7
(A) Cytotoxicity in cells undergoing rapid growth and
multiplication.
1. Inhibitonof cell wall synthesis
Bacterial and fungal cells provide themselves with an
exoskeletalcell wall, mammalian cells do not have this.
The cell wall performs the important function of protecting
the cell from osmotic damage.
Penicillins, cephalosporinsand vancomycininhibit the
formation of the insoluble mucopeptidepeptidoglycan
(murein) which is a major constituent of the cell wall of
Gram positive bacteria and Gram negative cocci.
It is in part formed of d-alanine. Penicillinsand the closely
related cephalosporinsare structural analogues of d-alanyl
–d –alanine.
(A) Cytotoxicity in cells undergoing rapid growth and
multiplication.
1. Inhibitonof cell wall synthesis
Bacterial and fungal cells provide themselves with an
exoskeletalcell wall, mammalian cells do not have this.
The cell wall performs the important function of protecting
the cell from osmotic damage.
Penicillins, cephalosporinsand vancomycininhibit the
formation of the insoluble mucopeptidepeptidoglycan
(murein) which is a major constituent of the cell wall of
Gram positive bacteria and Gram negative cocci.
It is in part formed of d-alanine. Penicillinsand the closely
related cephalosporinsare structural analogues of d-alanyl
–d –alanine.
Antiparasitic Chemotherapy 8
Resistant bacteria secrete a -lactamase enzyme
(penicillinaseor cephalosporinase) that hydrolyses and
inactivates the drug.
Vancomycinbinds to the d-alanyl-d-alanine portion of the
final soluble precursor of peptidoglycan and inhibits its
cleavage from a membrane phospholipid carrier
2. Inhibition of nucleic acid synthesis
Interference with the supply of precursors
Many bacteria unlike mammalian cells cannot absorb
folateand so utilize aminobenzoateto synthesize
dihydrofolate(DHF)
Resistant bacteria secrete a -lactamase enzyme
(penicillinaseor cephalosporinase) that hydrolyses and
inactivates the drug.
Vancomycinbinds to the d-alanyl-d-alanine portion of the
final soluble precursor of peptidoglycan and inhibits its
cleavage from a membrane phospholipid carrier
2. Inhibition of nucleic acid synthesis
Interference with the supply of precursors
Many bacteria unlike mammalian cells cannot absorb
folateand so utilize aminobenzoateto synthesize
dihydrofolate(DHF)
Antiparasitic Chemotherapy 9
(a) Drugs that interfere with the synthesis of DHF from
aminobenzoate.
Since mammalian cells do not synthesize DHF from
aminobenzoate, inhibitors of dihydropteroatesynthetase
necessarily show qualitative biochemical selectivity.
Such inhibitors include sulphonamidesand sulphones
which are structural analogues of aminobenzoate(PABA)
Sulphonamidesare bacteriostatic and have antimalarial
activity.
They may cause renal toxicity unrelated to their effect on
aminobenzoatemetabolism.
Sulphones(egdapsone) are used in the treatment of
leprosy and the protozoal infection (malaria).
(a) Drugs that interfere with the synthesis of DHF from
aminobenzoate.
Since mammalian cells do not synthesize DHF from
aminobenzoate, inhibitors of dihydropteroatesynthetase
necessarily show qualitative biochemical selectivity.
Such inhibitors include sulphonamidesand sulphones
which are structural analogues of aminobenzoate(PABA)
Sulphonamidesare bacteriostatic and have antimalarial
activity.
They may cause renal toxicity unrelated to their effect on
aminobenzoatemetabolism.
Sulphones(egdapsone) are used in the treatment of
leprosy and the protozoal infection (malaria).
Antiparasitic Chemotherapy 10
.(b) Drugs that interfere with the synthesis of
tetrahydrofolate(THF) from (DHF).
Methotrexate, pyrimethamine, proguaniland
trimethoprim can only show a quantitative
biochemical selectivity.
They are all structural analogues of DHF that
inhibit DHF reductase.
.(b) Drugs that interfere with the synthesis of
tetrahydrofolate(THF) from (DHF).
Methotrexate, pyrimethamine, proguaniland
trimethoprim can only show a quantitative
biochemical selectivity.
They are all structural analogues of DHF that
inhibit DHF reductase.
Antiparasitic Chemotherapy 11
Methotrexateis a large and complex analogue
that cannot penetrate into bacteria and
protozoa.
It enters mammalian cells by the folate
uptake mechanism.
It shows quantitative selectivity for cells
with highest THF turnover (most rapid cell
division).
It has a much higher affinity than DHF for
DHF hydrogenase.
Methotrexateis a large and complex analogue
that cannot penetrate into bacteria and
protozoa.
It enters mammalian cells by the folate
uptake mechanism.
It shows quantitative selectivity for cells
with highest THF turnover (most rapid cell
division).
It has a much higher affinity than DHF for
DHF hydrogenase.
Pyrimethaminehas a simpler structure and can
penetrate into parasites.
It inhibits DHF hydrogenasefrom malaria
parasites much more than the same enzyme in
mammalian and bacterial sources.
It shows quantitative biochemical selectivity.
There is a long lag before inhibition of growth
and multiplication is effected.
It is a valuable prophylactic agent for non
immune persons.
Proguanil.
Is a prodrug, the active principle formed from
it in the body has properties very like those of
pyrimethamine.
penetrate into parasites.
It inhibits DHF hydrogenasefrom malaria
parasites much more than the same enzyme in
mammalian and bacterial sources.
It shows quantitative biochemical selectivity.
There is a long lag before inhibition of growth
and multiplication is effected.
It is a valuable prophylactic agent for non
immune persons.
Proguanil.
Is a prodrug, the active principle formed from
it in the body has properties very like those of
pyrimethamine.
Antiparasitic Chemotherapy 13
Trimethoprim.
This is a simple DHF analogue which is able to
diffuse into parasite cells.
It inhibits DHF hydrogenase from bacterial
sources and malaria parasites much more than
the same enzyme from mammalian sources.
It shows quantitative biochemical selectivity
with is a long lag before inhibition of growth
and multiplication is effected.
It is combined with a sulphonamide
(sulphamethoxazole) as co-trimoxazole to
achieve very efficient synergism by sequential
blockade of the THF synthetic pathway.
Trimethoprim.
This is a simple DHF analogue which is able to
diffuse into parasite cells.
It inhibits DHF hydrogenase from bacterial
sources and malaria parasites much more than
the same enzyme from mammalian sources.
It shows quantitative biochemical selectivity
with is a long lag before inhibition of growth
and multiplication is effected.
It is combined with a sulphonamide
(sulphamethoxazole) as co-trimoxazole to
achieve very efficient synergism by sequential
blockade of the THF synthetic pathway.
Antiparasitic Chemotherapy 14
(c)Drugs that interfere with the supply of
nucleoside and nucleotide precursors of DNA.
(i)Purine analogues.
Acyclovir is a guanine analogue
(acycloguanosine) that has much higher affinity
for virally coded than mammalian thymidine
kinase isoenzyme.
This enzyme phosporylatesacyclovir so much
higher concentrations of acycloGTP are
produced in virally infected cells.
This then selectively inhibits viral DNA
polymerase much more than it does to host
polymerase and becomes incorporated into
functionless DNA analogues.
(c)Drugs that interfere with the supply of
nucleoside and nucleotide precursors of DNA.
(i)Purine analogues.
Acyclovir is a guanine analogue
(acycloguanosine) that has much higher affinity
for virally coded than mammalian thymidine
kinase isoenzyme.
This enzyme phosporylatesacyclovir so much
higher concentrations of acycloGTP are
produced in virally infected cells.
This then selectively inhibits viral DNA
polymerase much more than it does to host
polymerase and becomes incorporated into
functionless DNA analogues.
Mercaptopurine
Inhibits many steps in the synthesis and
interconversionof purines.
Cytotoxic effects are expressed in the most
rapidly dividing cells.
Is particularly employed as an
immunosuppressant in organ transplant
recipients. .
Inhibits many steps in the synthesis and
interconversionof purines.
Cytotoxic effects are expressed in the most
rapidly dividing cells.
Is particularly employed as an
immunosuppressant in organ transplant
recipients. .
Antiparasitic Chemotherapy 16
Azathioprine
This is a prodrug from which mercaptopurine is
released in the body.
It is particularly employed as an
immunosuppressant in organ transplant
recipients.
(ii)Pyrimidine analogues
Fluorouracil
Incorporated into a false nucleotide that blocks
deoxyribonucleotide (especially thymidylate
synthesis)
Azathioprine
This is a prodrug from which mercaptopurine is
released in the body.
It is particularly employed as an
immunosuppressant in organ transplant
recipients.
(ii)Pyrimidine analogues
Fluorouracil
Incorporated into a false nucleotide that blocks
deoxyribonucleotide (especially thymidylate
synthesis)
Flucytosine.
A prodrugdeaminatedintracellularlyto
fluorouracil.
It shows distributional selectivity for fungi
Cytarabine
Generates derivatives that compete with
cystidinederivatives and cause profound
inhibition of DNA synthesis.
Like fluorouracil it shows toxicity limited to
rapidly multiplying cell populations and is
useful in the palliative treatment of malignant
neoplasms.
A prodrugdeaminatedintracellularlyto
fluorouracil.
It shows distributional selectivity for fungi
Cytarabine
Generates derivatives that compete with
cystidinederivatives and cause profound
inhibition of DNA synthesis.
Like fluorouracil it shows toxicity limited to
rapidly multiplying cell populations and is
useful in the palliative treatment of malignant
neoplasms.
Antiparasitic Chemotherapy 18
(d) Drugs that directly interfere with nucleic
acid synthesis
Alkylating agents
Nitrogen mustards (cyclophosphamide,chlorambucil).
These cause functional damage to the DNA, perhaps by
cross-linking it to other macromolecules.
Any unbound cyclic cation is spontaneously hydrolysed
to an inactive alcohol.
They show toxicity limited to rapidly multiplying cell
populations and the expected problems for the host.
All effective antineoplastic drugs in this class possess
two alkylating groups.
(d) Drugs that directly interfere with nucleic
acid synthesis
Alkylating agents
Nitrogen mustards (cyclophosphamide,chlorambucil).
These cause functional damage to the DNA, perhaps by
cross-linking it to other macromolecules.
Any unbound cyclic cation is spontaneously hydrolysed
to an inactive alcohol.
They show toxicity limited to rapidly multiplying cell
populations and the expected problems for the host.
All effective antineoplastic drugs in this class possess
two alkylating groups.
(i) Cyclophosphamide:
A prodrugmetabolically activated by ring
cleavage in the liver to produce
phosphoramide
The highly reactive cyclic cationsformed
spontaneously in watery solution bind to side –
chains of large molecules especially the
guanine codon of DNA.
A prodrugmetabolically activated by ring
cleavage in the liver to produce
phosphoramide
The highly reactive cyclic cationsformed
spontaneously in watery solution bind to side –
chains of large molecules especially the
guanine codon of DNA.
(ii) Cisplatin.
Diffuses into cells, the molecule dissociates
yielding Cl
-
ions and revealing two reactive
sites which bind particularly to the guanine
base of DNA cross linking both within and
between strands.
(iii) Busulphan.
Does not ionize, it alkylates –SH in cysteine
and is the treatment of choice in chronic
myelogenousleukaemia.
(iv) Procarbazine.
Is a hydrazine derivative that binds convalently
to DNA.
Diffuses into cells, the molecule dissociates
yielding Cl
-
ions and revealing two reactive
sites which bind particularly to the guanine
base of DNA cross linking both within and
between strands.
(iii) Busulphan.
Does not ionize, it alkylates –SH in cysteine
and is the treatment of choice in chronic
myelogenousleukaemia.
(iv) Procarbazine.
Is a hydrazine derivative that binds convalently
to DNA.
Antiparasitic Chemotherapy 21
Intercalating agents.
Doxorubicin.
A basic antibiotic that intercalates into DNA between
layers of base pairs of the double helix.
The intecalationresults in disturbance of structure and
function of the starter DNA employed by DNA
polymerase thus inhibiting DNA synthesis.
Inhibition of DNA polymerase.
Acyclovircan be regarded as a prodrugfrom which is
generated the selective viral DNA polymerase inhibitor
(acycloGTP)
Inhibition of RNA polymerase.
Rifampicin combines with and inhibits the RNA
polymerase in bacteria but not that in mammalian cells.
It is bactericidal to Gram positive bacteria and M.
tuberculosisand lepraeand has low host toxicity.
Gram negative bacteria have a low permeability to
rifampicin.
Intercalating agents.
Doxorubicin.
A basic antibiotic that intercalates into DNA between
layers of base pairs of the double helix.
The intecalationresults in disturbance of structure and
function of the starter DNA employed by DNA
polymerase thus inhibiting DNA synthesis.
Inhibition of DNA polymerase.
Acyclovircan be regarded as a prodrugfrom which is
generated the selective viral DNA polymerase inhibitor
(acycloGTP)
Inhibition of RNA polymerase.
Rifampicin combines with and inhibits the RNA
polymerase in bacteria but not that in mammalian cells.
It is bactericidal to Gram positive bacteria and M.
tuberculosisand lepraeand has low host toxicity.
Gram negative bacteria have a low permeability to
rifampicin.
Antiparasitic Chemotherapy 22
3. Inhibition of mitosis.
The vinca alkaloids (vincristine, vinblastine)
and etoposide (related to podophyllotoxin)
bring about an arrest of mitosis in metaphase.
In each case this is due to specific and
reversible combination with the protein
tubulin though the binding sites differ.
This prevents polymerization into
microtubules and hence formation of a
mitotic spindle.
Abnormal nuclear structures result and cell
function is so disturbed that cell death often
ensues.
Cells with the highest replication rate are the
most and earliest affected.
3. Inhibition of mitosis.
The vinca alkaloids (vincristine, vinblastine)
and etoposide (related to podophyllotoxin)
bring about an arrest of mitosis in metaphase.
In each case this is due to specific and
reversible combination with the protein
tubulin though the binding sites differ.
This prevents polymerization into
microtubules and hence formation of a
mitotic spindle.
Abnormal nuclear structures result and cell
function is so disturbed that cell death often
ensues.
Cells with the highest replication rate are the
most and earliest affected.
Antiparasitic Chemotherapy 23
4. Inhibition of protein synthesis
Quantitative biochemical selectivity for
bacterial rather than mammalian protein
synthesis is possible because bacteria
contain only 70S (a measure of the density)
ribosomes whereas most mammalian
ribosomes are 80S.
4. Inhibition of protein synthesis
Quantitative biochemical selectivity for
bacterial rather than mammalian protein
synthesis is possible because bacteria
contain only 70S (a measure of the density)
ribosomes whereas most mammalian
ribosomes are 80S.
Antiparasitic Chemotherapy 24
(i) Drugs that inhibit tRNA binding to
ribosomes.
•Aminoglycoside antibiotics
(gentamicin, streptomycin) bind
irreversibly to the acceptor part of the
30S sub unit and distort it so that
aminoacyl-tRNA can not bind to its
acceptor site.
(i) Drugs that inhibit tRNA binding to
ribosomes.
•Aminoglycoside antibiotics
(gentamicin, streptomycin) bind
irreversibly to the acceptor part of the
30S sub unit and distort it so that
aminoacyl-tRNA can not bind to its
acceptor site.
Antiparasitic Chemotherapy 25
(ii) Peptide bond formation.
Chloramphenicol.
A dipeptide one molecule of which binds to each sub unit and
blocks peptidyltransferaseactivity.
It has a broad spectrum but use by the systemic route is reserved
for typhoid fever and H. influenzaemeningitis.
One patient in 40,000 is hypersensitive and suffers total
irreversible bone marrow depression.
Clindamycin.
Also a dipeptide that binds reversibly and blocks peptidyl
transferase.
In vivo it affects mainly Gram-positive bacteria including
Bacteroidesbut it is active on all isolated bacterial
ribosomes.
(ii) Peptide bond formation.
Chloramphenicol.
A dipeptide one molecule of which binds to each sub unit and
blocks peptidyltransferaseactivity.
It has a broad spectrum but use by the systemic route is reserved
for typhoid fever and H. influenzaemeningitis.
One patient in 40,000 is hypersensitive and suffers total
irreversible bone marrow depression.
Clindamycin.
Also a dipeptide that binds reversibly and blocks peptidyl
transferase.
In vivo it affects mainly Gram-positive bacteria including
Bacteroidesbut it is active on all isolated bacterial
ribosomes.
Antiparasitic Chemotherapy 26
(iii) Translocation.
Erythromycin.
One molecule binds to the donor site of each 50S
subunit and blocks translocation.
Development of resistance to erythromycin is associated
with loss of this binding ability.
Erythromycin has a narrow spectrum similar to
benzylpenicillin.
Sodium fusidate.
Chemically unrelated to but has properties very like
erythromycin.
It is useful in infection by penicillin resistant
staphylococci especially of bone.
(iii) Translocation.
Erythromycin.
One molecule binds to the donor site of each 50S
subunit and blocks translocation.
Development of resistance to erythromycin is associated
with loss of this binding ability.
Erythromycin has a narrow spectrum similar to
benzylpenicillin.
Sodium fusidate.
Chemically unrelated to but has properties very like
erythromycin.
It is useful in infection by penicillin resistant
staphylococci especially of bone.
Antiparasitic Chemotherapy 27
(B) Cytotoxicity effective in all phases of the
cellular growth cycle.
Increased permeability of the
cytoplasmic membrane:
Damage to the cell membrane allowsleakage of
vital intracellular solutes.
This exerts cytocidaleffect on non growing cells
but limits selectivity.
(B) Cytotoxicity effective in all phases of the
cellular growth cycle.
Increased permeability of the
cytoplasmic membrane:
Damage to the cell membrane allowsleakage of
vital intracellular solutes.
This exerts cytocidaleffect on non growing cells
but limits selectivity.
Polyeneantibiotics:
Amphotericin binds to sterols in the cell
membrane.
Sterols are abundant in fungal membranes
and largely comprise ergosterol.
Intermediate amounts of sterols are found in
mammalian membranes and mainly
comprise cholesterol.
Sterols are absent from bacterial membranes.
The drug enters the membrane to form an artificial
pore or ionophoreincreasing the membranes
outward permeability to intracellular solutes.
Amphotericin binds to sterols in the cell
membrane.
Sterols are abundant in fungal membranes
and largely comprise ergosterol.
Intermediate amounts of sterols are found in
mammalian membranes and mainly
comprise cholesterol.
Sterols are absent from bacterial membranes.
The drug enters the membrane to form an artificial
pore or ionophoreincreasing the membranes
outward permeability to intracellular solutes.
Antiparasitic Chemotherapy 29
Imidazoles.
Miconazole.
Exhibits some biochemical selectivity.
It shows in vitro antifungal activity (fungicidal at high
concentrations) but also attacks some bacteria and
protozoa.
They impair synthesis of membrane ergosterols.
The affected fungal cell membrane becomes disorganized
and shows secondary impairment of the uptake of
nutrients.
Miscellaneous.
Aminoglycosides also damage cell membranes. This
aspect of their action contributes to the bactericidal effect
and also to the host toxicity
Imidazoles.
Miconazole.
Exhibits some biochemical selectivity.
It shows in vitro antifungal activity (fungicidal at high
concentrations) but also attacks some bacteria and
protozoa.
They impair synthesis of membrane ergosterols.
The affected fungal cell membrane becomes disorganized
and shows secondary impairment of the uptake of
nutrients.
Miscellaneous.
Aminoglycosides also damage cell membranes. This
aspect of their action contributes to the bactericidal effect
and also to the host toxicity
Antiparasitic Chemotherapy 30
Energy yielding metabolism.
Anaerobes differ significantly from human
host so selective interference with their
anaerobic pathways is possible.
Nitroimidazoles:
Metronidazole interferes with the function of
ferrodoxin (a Fe-S-protein acting as an
electron transfer agent in plants, anaerobic
bacteria and protozoa) by acting as an
electron acceptor.
Energy yielding metabolism.
Anaerobes differ significantly from human
host so selective interference with their
anaerobic pathways is possible.
Nitroimidazoles:
Metronidazole interferes with the function of
ferrodoxin (a Fe-S-protein acting as an
electron transfer agent in plants, anaerobic
bacteria and protozoa) by acting as an
electron acceptor.
Metronidazole is a prodrug in that its
reduced form is lethal to anaerobic
protozoa (Trichomonas, Giardia,
Entamoeba) and bacteria (Bacteroides.
Cl. Difficileand Borrelia vincenti).
The cell is also deprived of reducing
power by this diversion of electrons
from their normal recipient.
The drug shows very little host
toxicity.
reduced form is lethal to anaerobic
protozoa (Trichomonas, Giardia,
Entamoeba) and bacteria (Bacteroides.
Cl. Difficileand Borrelia vincenti).
The cell is also deprived of reducing
power by this diversion of electrons
from their normal recipient.
The drug shows very little host
toxicity.
Antiparasitic Chemotherapy 32
Muscle.
Roundworms (Ascaris) and threadworms
(Enterobius) need their motility to stay in their
intestinal environment.
Paralysis therefore leads to their expulsion.
Piperazine is antagonist of ACh. at worm
neuromuscular junction with little effect at those of
mammals.
It is well absorbed from the gut and host toxicity is
negligible.
Muscle.
Roundworms (Ascaris) and threadworms
(Enterobius) need their motility to stay in their
intestinal environment.
Paralysis therefore leads to their expulsion.
Piperazine is antagonist of ACh. at worm
neuromuscular junction with little effect at those of
mammals.
It is well absorbed from the gut and host toxicity is
negligible.
Antiparasitic Chemotherapy 33
Distributional selectivity.
Even a drug that is equally toxic at its
biochemical sites of action in the host and in
the parasite cells may neverthelessbe
useful as chemotherapeutic agent if the sites
of action in the parasitizing cells can be
exposed to a higher concentration than those
in the host cells.
There are three ways in which this can come
about.
Distributional selectivity.
Even a drug that is equally toxic at its
biochemical sites of action in the host and in
the parasite cells may neverthelessbe
useful as chemotherapeutic agent if the sites
of action in the parasitizing cells can be
exposed to a higher concentration than those
in the host cells.
There are three ways in which this can come
about.
Antiparasitic Chemotherapy 34
1.Selective accumulation by the parasite.
(a) Tetracyclines (oxytetracycline):
Sensitive organisms accumulate tetracyclines to
high intracellular concentration by a carrier
mediated transport process requiring ATP
After selective intracellular accumulation
tetracyclines bind reversibly to acceptor part of
the smaller submit of the ribosome and prevent
the binding of aminoacyl tRNA and therefore
protein synthesis.
1.Selective accumulation by the parasite.
(a) Tetracyclines (oxytetracycline):
Sensitive organisms accumulate tetracyclines to
high intracellular concentration by a carrier
mediated transport process requiring ATP
After selective intracellular accumulation
tetracyclines bind reversibly to acceptor part of
the smaller submit of the ribosome and prevent
the binding of aminoacyl tRNA and therefore
protein synthesis.
Unlike aminoglycoside antibiotics tetracyclines
bind in both 70S and 80S isolated ribosomes.
Tetracyclines are broad spectrum antibiotics
{activity includes many bacteria but not
Pseudomonas or Proteusbut Rickettsia and
Chlamydia(large viruses) are sensitive} with
low host toxicity.
bind in both 70S and 80S isolated ribosomes.
Tetracyclines are broad spectrum antibiotics
{activity includes many bacteria but not
Pseudomonas or Proteusbut Rickettsia and
Chlamydia(large viruses) are sensitive} with
low host toxicity.
Antiparasitic Chemotherapy 36
(b) 4-Aminoquiolines.
Chloroquine and quinine:
These are concentrated in all nucleated cells but more concentrated
by malaria parasites.
Chroroquine resistance is associated with a loss of this
concentrating mechanism.
These drugs intercalate into DNA between layers of base pairs of
the double helix.
The intercalation disturbs the structure and function of the starter
DNA employed by DNA polymerase.
They inhibit DNA synthesis at the same high concentration in
isolated systems from all cells.
In amoebic liver abscess the accumulation by liver cell nuclei
can be regarded as a selective distribution into the parasites
environment.
The amoeba selectively further accumulates the chloroquine by
engulfing nuclei material.
(b) 4-Aminoquiolines.
Chloroquine and quinine:
These are concentrated in all nucleated cells but more concentrated
by malaria parasites.
Chroroquine resistance is associated with a loss of this
concentrating mechanism.
These drugs intercalate into DNA between layers of base pairs of
the double helix.
The intercalation disturbs the structure and function of the starter
DNA employed by DNA polymerase.
They inhibit DNA synthesis at the same high concentration in
isolated systems from all cells.
In amoebic liver abscess the accumulation by liver cell nuclei
can be regarded as a selective distribution into the parasites
environment.
The amoeba selectively further accumulates the chloroquine by
engulfing nuclei material.
Antiparasitic Chemotherapy 37
(c) Prodrugs:
Acycloviris a prodrugwhich is selectively activated
in the cells infected with herpes virus.
Its metabolite acycloGTP accumulates in the viral
parasite and also within the infected host cells that
is the parasites environment.
Flucytosine:
This is also a prodrugthat is accumulated by
certain fungi.
It is selectively deaminatedto the pyrimidine
analogue fluorouracil by fungi.
It is a narrow spectrum antifungal drug.
(c) Prodrugs:
Acycloviris a prodrugwhich is selectively activated
in the cells infected with herpes virus.
Its metabolite acycloGTP accumulates in the viral
parasite and also within the infected host cells that
is the parasites environment.
Flucytosine:
This is also a prodrugthat is accumulated by
certain fungi.
It is selectively deaminatedto the pyrimidine
analogue fluorouracil by fungi.
It is a narrow spectrum antifungal drug.
Antiparasitic Chemotherapy 38
Malathion:
Activated to the organophosphorus
anticholinesterase compound malaoxon
selectively by insects which also inactivate
malaoxonmore slowly than mammals.
Thus it is the malaoxonrather than the
prodrugwhich is selectively accumulated by
the parasites.
Malathion:
Activated to the organophosphorus
anticholinesterase compound malaoxon
selectively by insects which also inactivate
malaoxonmore slowly than mammals.
Thus it is the malaoxonrather than the
prodrugwhich is selectively accumulated by
the parasites.
Antiparasitic Chemotherapy 39
2Selective distribution into a limited compartment that
forms the parasites’ environment.
Liver.
The liver cells accumulate chloroquine
which intercalates into their nuclei.
When entamoeba histolytica infection
becomes localised in the liver (forming an
abscess) the amoebae engulf liver cell and
their nuclei and hence further accumulate
chloroquine.
2Selective distribution into a limited compartment that
forms the parasites’ environment.
Liver.
The liver cells accumulate chloroquine
which intercalates into their nuclei.
When entamoeba histolytica infection
becomes localised in the liver (forming an
abscess) the amoebae engulf liver cell and
their nuclei and hence further accumulate
chloroquine.
Skin.
Griseofulvin:
Poorly absorbed from the gut but that small
proportion of the dose that is absorbed is
selectively concentrated in keratin precursor cells
of the skin.
As these differentiate it is strongly bound to
keratin. It is a mitotic inhibitor and it is fungistatic
to ringworm fungi that parasitize keratin skin,
nails, hair.
It is also accumulated by these fungi. The keratin
formed during treatment resists invasion by fungal
hyphae but treatment must be continued until
staticfungus and infected keratin have been shed.
Griseofulvin:
Poorly absorbed from the gut but that small
proportion of the dose that is absorbed is
selectively concentrated in keratin precursor cells
of the skin.
As these differentiate it is strongly bound to
keratin. It is a mitotic inhibitor and it is fungistatic
to ringworm fungi that parasitize keratin skin,
nails, hair.
It is also accumulated by these fungi. The keratin
formed during treatment resists invasion by fungal
hyphae but treatment must be continued until
staticfungus and infected keratin have been shed.
Antiparasitic Chemotherapy 41
Urinary tract–Urinary antiseptics:
Nalidixicacid:
(i) Disposition:
It is rapidly and completely absorbed from the
gut. Healthy kidneys clear the drug quickly by
glomerular filtration.
Normal therapeutic doses do not produce
accumulation to an antibacterial blood
concentration but renal tubular abstraction of
water from the nascent urine results in a
bactericidal concentration in the urine.
Urinary tract–Urinary antiseptics:
Nalidixicacid:
(i) Disposition:
It is rapidly and completely absorbed from the
gut. Healthy kidneys clear the drug quickly by
glomerular filtration.
Normal therapeutic doses do not produce
accumulation to an antibacterial blood
concentration but renal tubular abstraction of
water from the nascent urine results in a
bactericidal concentration in the urine.
(ii) Mechanism of action:
It shows some biochemical selectivity (it
inhibits DNA synthesis, by inhibition of DNA
gyrasewhich reverses the supercoiling of DNA
strands in Gram negative bacilli).
This action is reinforced in use by
distributional selectivity based on the
concentrating activity of the kidney.
It shows some biochemical selectivity (it
inhibits DNA synthesis, by inhibition of DNA
gyrasewhich reverses the supercoiling of DNA
strands in Gram negative bacilli).
This action is reinforced in use by
distributional selectivity based on the
concentrating activity of the kidney.
Antiparasitic Chemotherapy 43
3 Selective administration to a limited compartment that forms
the parasites’ environment.
Lumen of the gut:
Drugs which when swallowed are poorly
absorbed from the gut either because they are
water, but not lipid soluble or because they are
water insoluble.
They therefore provide a high exposure to
parasites within the gut lumen.
3 Selective administration to a limited compartment that forms
the parasites’ environment.
Lumen of the gut:
Drugs which when swallowed are poorly
absorbed from the gut either because they are
water, but not lipid soluble or because they are
water insoluble.
They therefore provide a high exposure to
parasites within the gut lumen.
Neomycin.
An aminoglycoside antibiotic which is toxic to bacteria
but when given systemically is toxic to the host too.
Gut absorption is negligible because it is highly polar.
It is used in bowel preparation for intestinal surgery to
reduce the bacterial content of any spills and of wall
seams with the intention of reducing postoperative
infective complications.
Neomycin along with dietary restriction reduces the
bacterial ammonia and amine production that is
responsible for the encephalopathy (disturbance of
consciousness, coma) of liver failure.
The liver normally clears the portal blood burden of
ammoniacalcompounds arising from the gut
commensal bacterial.
An aminoglycoside antibiotic which is toxic to bacteria
but when given systemically is toxic to the host too.
Gut absorption is negligible because it is highly polar.
It is used in bowel preparation for intestinal surgery to
reduce the bacterial content of any spills and of wall
seams with the intention of reducing postoperative
infective complications.
Neomycin along with dietary restriction reduces the
bacterial ammonia and amine production that is
responsible for the encephalopathy (disturbance of
consciousness, coma) of liver failure.
The liver normally clears the portal blood burden of
ammoniacalcompounds arising from the gut
commensal bacterial.
Antiparasitic Chemotherapy 45
Niclosamide.
Is a water insoluble drug that kills intestinal metazoa, probably by
damaging their membranes.
It is useful for tapeworm infestations
Mebendazole.
Is a water soluble drug that kills intestinal metazoa, propablyby
interference with glucose uptake. It is useful for threadworm
infestations.
Pyrental.
Is a water –insoluble agonist at nicotinic receptors of muscle,
causing depolarizing neuromuscular blockade (like suxamethonium)
and spastic paralysis of worms.
A polyeneantibiotic,istoo toxic for systemic use.
It is not absorbed from the gut because it is only slightly
soluble in water.
Nystatin
A polyeneantibiotic that is not absorbed from the gut
Niclosamide.
Is a water insoluble drug that kills intestinal metazoa, probably by
damaging their membranes.
It is useful for tapeworm infestations
Mebendazole.
Is a water soluble drug that kills intestinal metazoa, propablyby
interference with glucose uptake. It is useful for threadworm
infestations.
Pyrental.
Is a water –insoluble agonist at nicotinic receptors of muscle,
causing depolarizing neuromuscular blockade (like suxamethonium)
and spastic paralysis of worms.
A polyeneantibiotic,istoo toxic for systemic use.
It is not absorbed from the gut because it is only slightly
soluble in water.
Nystatin
A polyeneantibiotic that is not absorbed from the gut
Antiparasitic Chemotherapy 46
Skin:
Antibacterial antibiotics:
So little of a drug applied to the unbroken skin is
absorbed into the systemic circulation that the
more systemically toxic antibiotics can safely be
used on the skin–
framycetin,neomycin,chlortetracycline.
The advantages of such a reliance on distributional
selectivity are that pathogens are less likely to
develop resistance to systemically valuable
antibiotics and it avoids the need for –Penicillins,
sulphonamides, streptomycin and
chloramphenicol to be applied to the skin (all have
a strong tendency to induce allergy).
Skin:
Antibacterial antibiotics:
So little of a drug applied to the unbroken skin is
absorbed into the systemic circulation that the
more systemically toxic antibiotics can safely be
used on the skin–
framycetin,neomycin,chlortetracycline.
The advantages of such a reliance on distributional
selectivity are that pathogens are less likely to
develop resistance to systemically valuable
antibiotics and it avoids the need for –Penicillins,
sulphonamides, streptomycin and
chloramphenicol to be applied to the skin (all have
a strong tendency to induce allergy).
Antiparasitic Chemotherapy 47
Antiseptics:
Chlorhexidineand cetrimide.
These are cationic detergents that act at all cell
membranes and rely for any selectivity they have an poor
penetration of the unbroken skin.
Hexachlorophane
Is a chlorinated phenol which is bactericidal to Gram-
positive bacteria.
Regularly applied to the skin it gradually accumulates;
the number of organisms in the surface layers is gradually
but substantially reduced.
Misuse by whole body immersion of babies in strong
solutions, allows sufficient to be absorbed through the
skin to give CNS toxicity even death.
Antifungal drugs:
Nystatinis useful for mucocutaneouscandidiasis.
Imidazolescan be applied locally in fungicidal doses.
Antiseptics:
Chlorhexidineand cetrimide.
These are cationic detergents that act at all cell
membranes and rely for any selectivity they have an poor
penetration of the unbroken skin.
Hexachlorophane
Is a chlorinated phenol which is bactericidal to Gram-
positive bacteria.
Regularly applied to the skin it gradually accumulates;
the number of organisms in the surface layers is gradually
but substantially reduced.
Misuse by whole body immersion of babies in strong
solutions, allows sufficient to be absorbed through the
skin to give CNS toxicity even death.
Antifungal drugs:
Nystatinis useful for mucocutaneouscandidiasis.
Imidazolescan be applied locally in fungicidal doses.
Antiparasitic Chemotherapy 48
Arachnidesand insecticides:
These include carbaryland lindane.
Selectivity is great and while some show a biochemical
component the dominant basis is distributional.
Spread on the skin as powder or emulsion, the dose per
unit of body mass received by the ectoparasiteis much
greater than that received by the host.
This is due both to the differing body mass, surface area
ratios of the host and parasite and also to the more ready
penetration of the chitinousexoskeleton of the
ectoparasitethan of the intact human skin.
In addition the parasite engulfs some of the material.
Arachnidesand insecticides:
These include carbaryland lindane.
Selectivity is great and while some show a biochemical
component the dominant basis is distributional.
Spread on the skin as powder or emulsion, the dose per
unit of body mass received by the ectoparasiteis much
greater than that received by the host.
This is due both to the differing body mass, surface area
ratios of the host and parasite and also to the more ready
penetration of the chitinousexoskeleton of the
ectoparasitethan of the intact human skin.
In addition the parasite engulfs some of the material.
Eye
Similar considerations apply to the choice of antibiotics for
skin use.
Framycetin, neomycin, chlotetracyclineand chloramphenicol
are examples.
Idoxuridine.
Is a pyrimidine analogue that shows slight biochemical
selectivity based on metabolic acceptance as a
pyrimidine and incorporation into a functionless DNA.
Its main selectivity is based on distributional
consideration (site of administration –eye, skin).
It inhibits the replication of certain DNA viruses.
Similar considerations apply to the choice of antibiotics for
skin use.
Framycetin, neomycin, chlotetracyclineand chloramphenicol
are examples.
Idoxuridine.
Is a pyrimidine analogue that shows slight biochemical
selectivity based on metabolic acceptance as a
pyrimidine and incorporation into a functionless DNA.
Its main selectivity is based on distributional
consideration (site of administration –eye, skin).
It inhibits the replication of certain DNA viruses.
ADVERSE DRUG REACTIONS 50
ADVERSE DRUG
REACTIONS
ADVERSE DRUG
REACTIONS
ADVERSE DRUG REACTIONS 51
Any undesired or unintended effect of drug
treatment is an adverse drug reaction.
•Examples:-(i) Many allergic reactions.
(ii)Osteoporosis after long-term
corticosteroid therapy.
(iii)Phocomelia in children of
mothers exposed to thalidomide during
early pregnancy.
.
Any undesired or unintended effect of drug
treatment is an adverse drug reaction.
•Examples:-(i) Many allergic reactions.
(ii)Osteoporosis after long-term
corticosteroid therapy.
(iii)Phocomelia in children of
mothers exposed to thalidomide during
early pregnancy.
.
ADVERSE DRUG REACTIONS 52
Predictable adverse reactions:
(a) Excessive pharmacological effects:-
(i) Respiratory depression in patients given
morphine, benzodiazepines.
(ii) Stroke or myocardial infarction following
doses of antihypertensive drugs.
(iii) Bradycardia in patients receiving
excessive digoxin.
Predictable adverse reactions:
(a) Excessive pharmacological effects:-
(i) Respiratory depression in patients given
morphine, benzodiazepines.
(ii) Stroke or myocardial infarction following
doses of antihypertensive drugs.
(iii) Bradycardia in patients receiving
excessive digoxin.
(b) Withdrawal symptoms or rebound
responses after discontinuation of
treatment:
(i) Extreme agitation, tachycardia, confusion,
delirium and convulsions may follow
discontinuation of long term use of cns
depressants egbarbiturates,
benzodiazepines and alcohol.
ADVERSE DRUG REACTIONS 53
responses after discontinuation of
treatment:
(i) Extreme agitation, tachycardia, confusion,
delirium and convulsions may follow
discontinuation of long term use of cns
depressants egbarbiturates,
benzodiazepines and alcohol.
ADVERSE DRUG REACTIONS 53
ADVERSE DRUG REACTIONS 54
(ii) Acute Addisonian crisis after abrupt
cessation of corticosteroids.
(iii)Severe hypertension after abrupt
discontinuation of clonidine.
Unpredictable adverse effects:
(a) Allergic responses:-The reaction does
not resemble the expected
pharmacological effect:
•There is a delay between first exposure to
the drug and development of the reaction.
•The reaction recurs upon repeated
exposure even to traces of the drug.
(ii) Acute Addisonian crisis after abrupt
cessation of corticosteroids.
(iii)Severe hypertension after abrupt
discontinuation of clonidine.
Unpredictable adverse effects:
(a) Allergic responses:-The reaction does
not resemble the expected
pharmacological effect:
•There is a delay between first exposure to
the drug and development of the reaction.
•The reaction recurs upon repeated
exposure even to traces of the drug.
ADVERSE DRUG REACTIONS 55
(b) Genetically determined effects:
(i) Atypical or pseudo cholinesterase
(prolonged muscle paralysis following a
standard dose of suxamethonium)
(ii) Glucose-6-phosphate dehydrogenase
deficiency results in the risk of developing
acute haemolyticanaemiaafter exposure to
primaquine or sulphonamidesor to
quinidine.
(iii) Acetylator polymorphism shown by
Procainamide (L E), Hydralazine (LE) and
Isoniazid (peripheral neuropathy).
(b) Genetically determined effects:
(i) Atypical or pseudo cholinesterase
(prolonged muscle paralysis following a
standard dose of suxamethonium)
(ii) Glucose-6-phosphate dehydrogenase
deficiency results in the risk of developing
acute haemolyticanaemiaafter exposure to
primaquine or sulphonamidesor to
quinidine.
(iii) Acetylator polymorphism shown by
Procainamide (L E), Hydralazine (LE) and
Isoniazid (peripheral neuropathy).
ADVERSE DRUG REACTIONS 56
(c) Idiosyncratic drug reactions:
(i) Analgesic abuse may rarely cause
cancer of the renal pelvis.
(ii) Long term oestrogenswithout
coincidental progestoronemay induce
uterine cancer.
(iii) Immunosuppressive drugs may induce
lymphoid tumors.
(iv) Intramuscular iron preparation may
cause sarcomata at the site of injection.
(v)Thyroid cancermay develop in patients
who have received
131
Itherapy in the past.
(c) Idiosyncratic drug reactions:
(i) Analgesic abuse may rarely cause
cancer of the renal pelvis.
(ii) Long term oestrogenswithout
coincidental progestoronemay induce
uterine cancer.
(iii) Immunosuppressive drugs may induce
lymphoid tumors.
(iv) Intramuscular iron preparation may
cause sarcomata at the site of injection.
(v)Thyroid cancermay develop in patients
who have received
131
Itherapy in the past.
ADVERSE DRUG REACTIONS 57
Reduction of the risk:
(i) Always include a detailed drug history as part of
the clinical history.
(ii) Only use drug treatment when there is a clear
indication for it and there is no non-pharmacological
alternative.
(iii) Avoid multiple drug regimens and combination
tablets whenever possible.
(iv) Pay particular attention to drug dose and
response in the young and those with coexisting
renal, hepatic or cardiac disease.
Review the need for continuing treatment regularly
and stop drugs which are no longer necessary.
Reduction of the risk:
(i) Always include a detailed drug history as part of
the clinical history.
(ii) Only use drug treatment when there is a clear
indication for it and there is no non-pharmacological
alternative.
(iii) Avoid multiple drug regimens and combination
tablets whenever possible.
(iv) Pay particular attention to drug dose and
response in the young and those with coexisting
renal, hepatic or cardiac disease.
Review the need for continuing treatment regularly
and stop drugs which are no longer necessary.
ADVERSE DRUG REACTIONS 58
Drug intolerance:
Factors which may give rise to intolerance
include:-
(i)Effects of age:
•In the young and the old renal and hepatic
function are generally impaired.
•In the elderly impaired cardiovascular
reflexes may alter drug effects.
Drug intolerance:
Factors which may give rise to intolerance
include:-
(i)Effects of age:
•In the young and the old renal and hepatic
function are generally impaired.
•In the elderly impaired cardiovascular
reflexes may alter drug effects.
(ii) Genetic factors:
•Fast and slow acetylation may produce
different effects when isoniazid or
hydralazine are administered.
•Similarly there are plasma cholinesterase
variants in the metabolism of
suxamethonium.
•Idiosyncratic reactions may be genetic eg
primaquinesensitivity.
(iv) Disease:
Gastric stasis in migraine and digoxin
toxicity in poor renal function
ADVERSE DRUG REACTIONS 59
•Fast and slow acetylation may produce
different effects when isoniazid or
hydralazine are administered.
•Similarly there are plasma cholinesterase
variants in the metabolism of
suxamethonium.
•Idiosyncratic reactions may be genetic eg
primaquinesensitivity.
(iv) Disease:
Gastric stasis in migraine and digoxin
toxicity in poor renal function
ADVERSE DRUG REACTIONS 59
ADVERSE DRUG REACTIONS 60
Drug overdose:
Most cases of drug overdose can be
managed by supportive measures.
•The following drugs have particular clinical
features and therapeutic measures are
warranted.
1. Barbiturates:
•Butobarbitone and Amylobarbitoneare
metabolisedin the liver but
haemoperfusionmay be effective in
severe poisoning.
•Phenobarbitone toxicity may be alleviated
by forced alkaline diuresis.
Drug overdose:
Most cases of drug overdose can be
managed by supportive measures.
•The following drugs have particular clinical
features and therapeutic measures are
warranted.
1. Barbiturates:
•Butobarbitone and Amylobarbitoneare
metabolisedin the liver but
haemoperfusionmay be effective in
severe poisoning.
•Phenobarbitone toxicity may be alleviated
by forced alkaline diuresis.
ADVERSE DRUG REACTIONS 61
2. Glutethimide:
•Causes raised intracranial pressure and
apnoea.
•Urgent dexamethasone 8mg iv and 4mg
four times daily, supplemented by the
osmotic diuretic mannitol 200ml of 20%
mannitol solution infused over 30 minutes.
3. Monoamine oxidase inhibitors:
•Produce severe hypertension.
•Hypereflexia and convulsions are also
relatively common
•Treat hypertension and convulsions.
2. Glutethimide:
•Causes raised intracranial pressure and
apnoea.
•Urgent dexamethasone 8mg iv and 4mg
four times daily, supplemented by the
osmotic diuretic mannitol 200ml of 20%
mannitol solution infused over 30 minutes.
3. Monoamine oxidase inhibitors:
•Produce severe hypertension.
•Hypereflexia and convulsions are also
relatively common
•Treat hypertension and convulsions.
ADVERSE DRUG REACTIONS 62
4. Tricyclic antidepressants:
•Inhibit noradrenaline uptake, they block
parasympathetic muscarinic receptors and
have a quinidine like effect.
•Most of the symptoms produced are due
to parasympathetic blockade.
•Treat with a cholinesterase inhibitor eg
physostigmine 2mg by slow iv injection.
•Effect lasts for 20 min when the dose of
physostigmine can be repeated.
4. Tricyclic antidepressants:
•Inhibit noradrenaline uptake, they block
parasympathetic muscarinic receptors and
have a quinidine like effect.
•Most of the symptoms produced are due
to parasympathetic blockade.
•Treat with a cholinesterase inhibitor eg
physostigmine 2mg by slow iv injection.
•Effect lasts for 20 min when the dose of
physostigmine can be repeated.
ADVERSE DRUG REACTIONS 63
5. Salicylates:
•A severely poisoned patient may be alert
even aggressive.
•It is easy to underestimate the severity of
salicylate poisoning on clinical grounds.
•Metabolic acidosis caused by the drug
may be complicated by respiratory
alkalosis induced by hyperventilation.
.
5. Salicylates:
•A severely poisoned patient may be alert
even aggressive.
•It is easy to underestimate the severity of
salicylate poisoning on clinical grounds.
•Metabolic acidosis caused by the drug
may be complicated by respiratory
alkalosis induced by hyperventilation.
.
•Aspirin may still be recovered from the
stomach 12 hrs after ingestion because of
gastric stasis induced by the drug.
•Forced alkaline diuresis is very helpful.
•Haemodialysis is favoured for its beneficial
effect on electrolyte and acid base
balance.
ADVERSE DRUG REACTIONS 64
stomach 12 hrs after ingestion because of
gastric stasis induced by the drug.
•Forced alkaline diuresis is very helpful.
•Haemodialysis is favoured for its beneficial
effect on electrolyte and acid base
balance.
ADVERSE DRUG REACTIONS 64
ADVERSE DRUG REACTIONS 65
6. Opiates:
Pentazocineand Dextropropoxypheneare
available in tablet form dextropropoxypheneis
widely prescribed in combination with paracetamol.
Dextropropoxypheneoverdose:
•Profound respiratory depression.
•Naloxone is given as an antidote as 0.4 mg dose
iv repeated at 2—3 min. intervals as required.
•Naloxone has a shorter T½ than most opiates
hence monitoring is required even after apparent
complete reversal of the overdose
6. Opiates:
Pentazocineand Dextropropoxypheneare
available in tablet form dextropropoxypheneis
widely prescribed in combination with paracetamol.
Dextropropoxypheneoverdose:
•Profound respiratory depression.
•Naloxone is given as an antidote as 0.4 mg dose
iv repeated at 2—3 min. intervals as required.
•Naloxone has a shorter T½ than most opiates
hence monitoring is required even after apparent
complete reversal of the overdose
ADVERSE DRUG REACTIONS 66
7. Paracetamol(acetaminophene) overdose
causes hepatotoxicity.
•Paracetamolnormally is metabolisedby
the liver to glucuronide and sulphate
conjugates.
•A smaller proportion is metabolisedby
microsomal mixed function oxidases and a
product of this pathway is detoxified by
combination with glutathione in overdose,
•Greatly increased amounts of paracetamol
are metabolisedby this 2
ndary
pathway,
which exhausts glutathione stores and
leaves an excess of a toxic metabolite.
7. Paracetamol(acetaminophene) overdose
causes hepatotoxicity.
•Paracetamolnormally is metabolisedby
the liver to glucuronide and sulphate
conjugates.
•A smaller proportion is metabolisedby
microsomal mixed function oxidases and a
product of this pathway is detoxified by
combination with glutathione in overdose,
•Greatly increased amounts of paracetamol
are metabolisedby this 2
ndary
pathway,
which exhausts glutathione stores and
leaves an excess of a toxic metabolite.
ADVERSE DRUG REACTIONS 67
•This then combines covalently with protein
macromolecules in the liver to produce
hepatic necrosis with centrilobular pattern.
•If the patient survives normal liver function
is usually restored in a few months.
•A paracetamol T½ of more than 4hrs
indicates saturation of the major routes of
conjugation and potential toxicity.
•This then combines covalently with protein
macromolecules in the liver to produce
hepatic necrosis with centrilobular pattern.
•If the patient survives normal liver function
is usually restored in a few months.
•A paracetamol T½ of more than 4hrs
indicates saturation of the major routes of
conjugation and potential toxicity.
•Paracetamol plasma concentration of
more than 1mmol/ℓ 4hrs or more after
ingestion suggests that hepatic necrosis is
likely.
•Treatment involves giving methionine
orally or N-acetylcystein intravenously.
•Methionine enhances glutathione
synthesis by donating thiol groups.
•N-acetylcystein is hydrolysed in vivo to
cysteine a glutathione precursor.
ADVERSE DRUG REACTIONS 68
more than 1mmol/ℓ 4hrs or more after
ingestion suggests that hepatic necrosis is
likely.
•Treatment involves giving methionine
orally or N-acetylcystein intravenously.
•Methionine enhances glutathione
synthesis by donating thiol groups.
•N-acetylcystein is hydrolysed in vivo to
cysteine a glutathione precursor.
ADVERSE DRUG REACTIONS 68
ADVERSE DRUG REACTIONS 69
8. Iron:
•Produces gastritis which may be erosive
or haemorrhagic.
•Initial gastritis resolves and the condition
appears satisfactory 12—24 hrs or even
longer.
•Third stage is entered about 24—48hrs
post ingestion.
•It is caused by widespread tissue
poisoning by free iron.
•The prognosis is poor.
•Convulsions and coma may follow.
8. Iron:
•Produces gastritis which may be erosive
or haemorrhagic.
•Initial gastritis resolves and the condition
appears satisfactory 12—24 hrs or even
longer.
•Third stage is entered about 24—48hrs
post ingestion.
•It is caused by widespread tissue
poisoning by free iron.
•The prognosis is poor.
•Convulsions and coma may follow.
ADVERSE DRUG REACTIONS 70
At presentation:
•Give 2gm desferrioxaminei.m.
•Gastric lavage 1gm for each lavage.
•At the end of lavage leave 5gm in the
stomach to prevent absorption of any
residual iron.
•Then 15mg/kg to a maximum of
80mg/kg/hriv until serum iron drops
to 200mmol/ℓ.
At presentation:
•Give 2gm desferrioxaminei.m.
•Gastric lavage 1gm for each lavage.
•At the end of lavage leave 5gm in the
stomach to prevent absorption of any
residual iron.
•Then 15mg/kg to a maximum of
80mg/kg/hriv until serum iron drops
to 200mmol/ℓ.
DRUG INTRERACTIONS 71
DRUG INTERACTIONS
DRUG INTERACTIONS
DRUG INTRERACTIONS 72
The administration of one drug can alter the
action of another drug by one of two
general mechanisms.
•(i) Modification of the pharmacological
effect of B without altering its concentration
in the tissue fluid (Pharmacodynamic
interaction).
•(ii) Alteration of the concentration of B that
reaches its site of action
(Pharmacokinetic interaction).
The administration of one drug can alter the
action of another drug by one of two
general mechanisms.
•(i) Modification of the pharmacological
effect of B without altering its concentration
in the tissue fluid (Pharmacodynamic
interaction).
•(ii) Alteration of the concentration of B that
reaches its site of action
(Pharmacokinetic interaction).
DRUG INTRERACTIONS 73
•For pharmacodynamic interactions to
be important clinically it is necessary that
the therapeutic range of drug B is narrow
(ie that a small reduction in effect will lead
to loss of efficacy and/or a small increase
in effect will lead to toxicity.
•For pharmacokinetic interactions to be
clinically important it is necessary that the
concentration-response curve of drug B is
steep (so that a small change in plasma
concentration leads to a substantial
change in effect.
•For many drugs these conditions are not
met.
•For pharmacodynamic interactions to
be important clinically it is necessary that
the therapeutic range of drug B is narrow
(ie that a small reduction in effect will lead
to loss of efficacy and/or a small increase
in effect will lead to toxicity.
•For pharmacokinetic interactions to be
clinically important it is necessary that the
concentration-response curve of drug B is
steep (so that a small change in plasma
concentration leads to a substantial
change in effect.
•For many drugs these conditions are not
met.
DRUG INTRERACTIONS 74
•Drugs like penicillins are unlikely to give rise to
clinical problems because there is usually a
comfortable safety margin between plasma
concentrations produced by usual doses and
those resulting in either loss of efficacy or
toxicity.
•Several drugs do have steep concentration—
response relationships and narrow therapeutic
margins and drug interactions can cause major
problems eg antithrombotic, antidysrhythmic,
antiepileptic drugs, lithium, several antineoplastic
drugs and immunosupressant drugs.
•Drugs like penicillins are unlikely to give rise to
clinical problems because there is usually a
comfortable safety margin between plasma
concentrations produced by usual doses and
those resulting in either loss of efficacy or
toxicity.
•Several drugs do have steep concentration—
response relationships and narrow therapeutic
margins and drug interactions can cause major
problems eg antithrombotic, antidysrhythmic,
antiepileptic drugs, lithium, several antineoplastic
drugs and immunosupressant drugs.
DRUG INTRERACTIONS 75
Pharmacodynamic interactions:
•β-adrenoceptor antagonists diminish the effectiveness of
β-adrenoceptor agonists such as salbutamol or
terbutaline.
•Many diuretics lower plasma potassium concentration
and thereby enhance some actions of cardiac glycosides
and predispose to glycoside toxicity.
•Monoamine oxidase inhibitors increase the amount of
noradrenaline stored in NA nerve terminals and thereby
interact dangerously with drugs such as ephedrine or
tyramine that work by releasing stored NA–this can also
occur with tyramine rich foods eg camembert & marmite.
Pharmacodynamic interactions:
•β-adrenoceptor antagonists diminish the effectiveness of
β-adrenoceptor agonists such as salbutamol or
terbutaline.
•Many diuretics lower plasma potassium concentration
and thereby enhance some actions of cardiac glycosides
and predispose to glycoside toxicity.
•Monoamine oxidase inhibitors increase the amount of
noradrenaline stored in NA nerve terminals and thereby
interact dangerously with drugs such as ephedrine or
tyramine that work by releasing stored NA–this can also
occur with tyramine rich foods eg camembert & marmite.
DRUG INTRERACTIONS 76
•Warfarin competes with vitamin K, preventing hepatic
synthesis of various coagulation factors.If vitamin K
production in the intestine is inhibited (eg by
antibiotics),the anticoagulant action of warfarin is
increased.
•Drugs that cause bleeding by distinct mechanisms (eg
aspirin which (i) inhibits platelet thromboxane A
2
biosynthesis (ii) and inhibits PGE
2 and PGI
2 synthesis
can damage the stomach) increase bleeding caused by
warfarin.
•Sulphonamides prevent the biosynthesis of folic acid by
bacteria and other microorganisms, trimethoprim inhibits
its reduction to tetrahydrofolate. Given together the drugs
have a synergistic action in treating bacterial infections.
•Warfarin competes with vitamin K, preventing hepatic
synthesis of various coagulation factors.If vitamin K
production in the intestine is inhibited (eg by
antibiotics),the anticoagulant action of warfarin is
increased.
•Drugs that cause bleeding by distinct mechanisms (eg
aspirin which (i) inhibits platelet thromboxane A
2
biosynthesis (ii) and inhibits PGE
2 and PGI
2 synthesis
can damage the stomach) increase bleeding caused by
warfarin.
•Sulphonamides prevent the biosynthesis of folic acid by
bacteria and other microorganisms, trimethoprim inhibits
its reduction to tetrahydrofolate. Given together the drugs
have a synergistic action in treating bacterial infections.
DRUG INTRERACTIONS 77
•Nonsteroidal antiinflammatory drugs (NSAIDs)
such as ibuprofen or indomethacin inhibit
biosynthesis of prostaglandins including renal
vasodilator/natriuretic prostaglandins (PGE
2
PGI
2).If administered to patients receiving
treatment for hypertension,they cause a variable
but sometimes marked increase in blood
pressure.
•NSAIDs given to patients being treated with
diuretics for chronic heart failure can cause salt
and water retention and hence cardiac
decompensation(in this example there is a
pharmacokinetic component of interaction
NSAIDs compete with weak acids (including
diuretics) for tubular secretion.
•Nonsteroidal antiinflammatory drugs (NSAIDs)
such as ibuprofen or indomethacin inhibit
biosynthesis of prostaglandins including renal
vasodilator/natriuretic prostaglandins (PGE
2
PGI
2).If administered to patients receiving
treatment for hypertension,they cause a variable
but sometimes marked increase in blood
pressure.
•NSAIDs given to patients being treated with
diuretics for chronic heart failure can cause salt
and water retention and hence cardiac
decompensation(in this example there is a
pharmacokinetic component of interaction
NSAIDs compete with weak acids (including
diuretics) for tubular secretion.
DRUG INTRERACTIONS 78
•H
1-receptor antagonists (mepyramine) cause
drowsiness.This is more troublesome if such
drugs are taken with alcohol and may lead to
accidents at work or on the road.
Pharmacokinetic interactions:
•All of the major processes that determine
pharmacokinetic behaviour of a drug–
absorption, distribution, metabolism and
excretion can be affected by co-administration
of other drugs.
•H
1-receptor antagonists (mepyramine) cause
drowsiness.This is more troublesome if such
drugs are taken with alcohol and may lead to
accidents at work or on the road.
Pharmacokinetic interactions:
•All of the major processes that determine
pharmacokinetic behaviour of a drug–
absorption, distribution, metabolism and
excretion can be affected by co-administration
of other drugs.
DRUG INTRERACTIONS 79
Absorption:
•Gastrointestinal absorption is slowed by drugs
which inhibit gastric emptying ( atropine or
opiates) or is accelerated by drugs
(metoclopramide) which hasten gastric emptying.
•Drug A may interact with drug B in the gut to
inhibit absorption of B. Calcium and iron form
insoluble complexes with tetracycline and retard
their absorption.
•Cholestyramine, a bile acid binding resin used to
treat hypercholesterolaemia binds several drugs
(warfarin, digoxin) preventing their absorption if
administered simultaneously.
Absorption:
•Gastrointestinal absorption is slowed by drugs
which inhibit gastric emptying ( atropine or
opiates) or is accelerated by drugs
(metoclopramide) which hasten gastric emptying.
•Drug A may interact with drug B in the gut to
inhibit absorption of B. Calcium and iron form
insoluble complexes with tetracycline and retard
their absorption.
•Cholestyramine, a bile acid binding resin used to
treat hypercholesterolaemia binds several drugs
(warfarin, digoxin) preventing their absorption if
administered simultaneously.
DRUG INTRERACTIONS 80
•Addition of adrenaline to a local anaesthetic
injection results in vasoconstriction which slows
absorption of the anaesthetic thus prolonging its
local effect.
Distribution:
•Displacement of a drug from binding sites in
plasma or tissues transiently increases the
concentration of free(unbound) drug but this is
followed by increased elimination so that a new
steady state results in which total drug
concentration in plasma is reduced but the free
drug concentration is similar to that before
introduction of the second displacing drug.
•Addition of adrenaline to a local anaesthetic
injection results in vasoconstriction which slows
absorption of the anaesthetic thus prolonging its
local effect.
Distribution:
•Displacement of a drug from binding sites in
plasma or tissues transiently increases the
concentration of free(unbound) drug but this is
followed by increased elimination so that a new
steady state results in which total drug
concentration in plasma is reduced but the free
drug concentration is similar to that before
introduction of the second displacing drug.
DRUG INTRERACTIONS 81
Consequences of potential clinical importance
are:-
•Toxicity from the transient increase in
concentration of free drug before the new steady
state is reached.
•If the dose is being adjusted according to
measurements of total plasma concentration,it
must be appreciated that the target therapeutic
concentration will be altered by coadministration
of a displacing drug.
•When the displacing drug additionally reduces
elimination of the first, so that not only is the free
drug concentration increased acutely but also
chronically at the new steady state, severe
toxicity may ensue.
Consequences of potential clinical importance
are:-
•Toxicity from the transient increase in
concentration of free drug before the new steady
state is reached.
•If the dose is being adjusted according to
measurements of total plasma concentration,it
must be appreciated that the target therapeutic
concentration will be altered by coadministration
of a displacing drug.
•When the displacing drug additionally reduces
elimination of the first, so that not only is the free
drug concentration increased acutely but also
chronically at the new steady state, severe
toxicity may ensue.
DRUG INTRERACTIONS 82
•Protein bound drugs that are given in large
enough dosage to act as displacing agents
include aspirin and various sulphonamides as
well as chloral hydrate whose metabolite
trichloracetic acid binds very strongly to plasma
albumin.
•Displacement of bilirubin from albumin by such
drugs in jaundiced premature neonates could
have consequences.
•Bilirubin metabolism is undeveloped in the
premature liver, and unbound bilirubin can cross
the blood brain barrier (which is also
incompletely developed) can causekernicterus
(staining of the basal ganglia by bilirubin).
•Protein bound drugs that are given in large
enough dosage to act as displacing agents
include aspirin and various sulphonamides as
well as chloral hydrate whose metabolite
trichloracetic acid binds very strongly to plasma
albumin.
•Displacement of bilirubin from albumin by such
drugs in jaundiced premature neonates could
have consequences.
•Bilirubin metabolism is undeveloped in the
premature liver, and unbound bilirubin can cross
the blood brain barrier (which is also
incompletely developed) can causekernicterus
(staining of the basal ganglia by bilirubin).
DRUG INTRERACTIONS 83
•This causes a distressing and permanent
disturbance of movement known as
choreoathetosis, characterised by involuntary
writhing and twisting movements in the child.
•Phenytoin dose is adjusted according to
measurement of its concentration in plasma.
•Introducing a displacing drug in an epileptic
patient stabilised on phenytoin reduces the total
plasma phenytoin concentration owing to
increased elimination of free drug but no loss of
efficacy because the concentration of unbound
(active) drug in the new steady state is
unaltered.
•This causes a distressing and permanent
disturbance of movement known as
choreoathetosis, characterised by involuntary
writhing and twisting movements in the child.
•Phenytoin dose is adjusted according to
measurement of its concentration in plasma.
•Introducing a displacing drug in an epileptic
patient stabilised on phenytoin reduces the total
plasma phenytoin concentration owing to
increased elimination of free drug but no loss of
efficacy because the concentration of unbound
(active) drug in the new steady state is
unaltered.
DRUG INTRERACTIONS 84
There are instances where drugs that alter protein
binding additionally reduce elimination of the
displaced drug.
Examples include:-
•(i) Phenylbutazone displaces warfarin from
binding sites on albumin and at the same time
selectively inhibits the metabolism of the
pharmacologically active S-isomer.This results in
prolonging prothrombin time and increased
bleeding.
•(ii) Salicylates displace methotrexate from
binding sites on albumin and reduce its
secretion into the nephron by competing with
anion secretory carrier.
There are instances where drugs that alter protein
binding additionally reduce elimination of the
displaced drug.
Examples include:-
•(i) Phenylbutazone displaces warfarin from
binding sites on albumin and at the same time
selectively inhibits the metabolism of the
pharmacologically active S-isomer.This results in
prolonging prothrombin time and increased
bleeding.
•(ii) Salicylates displace methotrexate from
binding sites on albumin and reduce its
secretion into the nephron by competing with
anion secretory carrier.
DRUG INTRERACTIONS 85
•(iii) Quinidine and several other antidysrhythmic drugs
including verapamil and amiodarone displace digoxin
from tissue binding sites while simultaneously reduce its
renal excretion and can consequently cause severe
dysrhythmias due to digoxin toxicity.
Metabolism:
Enzyme induction (eg by barbiturates, ethanol or
rifampicin) is an important cause of drug interactions.
•Enzyme induction usually decreases the
pharmacological activity of a range of other drugs.
•Conversely enzyme induction can increase toxicity of a
second drug whose toxic effects are mediated by a
metabolite.
•(iii) Quinidine and several other antidysrhythmic drugs
including verapamil and amiodarone displace digoxin
from tissue binding sites while simultaneously reduce its
renal excretion and can consequently cause severe
dysrhythmias due to digoxin toxicity.
Metabolism:
Enzyme induction (eg by barbiturates, ethanol or
rifampicin) is an important cause of drug interactions.
•Enzyme induction usually decreases the
pharmacological activity of a range of other drugs.
•Conversely enzyme induction can increase toxicity of a
second drug whose toxic effects are mediated by a
metabolite.
DRUG INTRERACTIONS 86
•Paracetamol toxicity is caused by N-acetyl-p-
benzoquinone imine, a metabolite formed by cytochrome
P
450. activity.
•Administration of phenobarbitone to premature babies to
induce glucuronyl transferase and therefore increase
bilirubin conjugation and reduce the risk of kernicterus.
•Grapefruit juice contains a psoralen that inhibits CYP3A
and reduces the metabolism of terfenadine, cyclosporin
and several calcium channel antagonists.
•Paracetamol toxicity is caused by N-acetyl-p-
benzoquinone imine, a metabolite formed by cytochrome
P
450. activity.
•Administration of phenobarbitone to premature babies to
induce glucuronyl transferase and therefore increase
bilirubin conjugation and reduce the risk of kernicterus.
•Grapefruit juice contains a psoralen that inhibits CYP3A
and reduces the metabolism of terfenadine, cyclosporin
and several calcium channel antagonists.
DRUG INTRERACTIONS 87
Some inhibitors of drug metabolism influence the
metabolism of different stereoisomers.
Drugs that inhibit the metabolism of the active Sand less
active R isomers of warfarin are shown below.
Drugs that are enzyme inducers
•Enzyme inducer Drug whose metabolism is
affected.
•Phenobarbitone Warfarin
•Rifampicin Oral contraceptives
•Griseofulvin Corticosteroids
•Phenytoin Cyclosporine
•Ethanol
•Carbamazepine
Some inhibitors of drug metabolism influence the
metabolism of different stereoisomers.
Drugs that inhibit the metabolism of the active Sand less
active R isomers of warfarin are shown below.
Drugs that are enzyme inducers
•Enzyme inducer Drug whose metabolism is
affected.
•Phenobarbitone Warfarin
•Rifampicin Oral contraceptives
•Griseofulvin Corticosteroids
•Phenytoin Cyclosporine
•Ethanol
•Carbamazepine
DRUG INTRERACTIONS 88
•Enzyme inhibitor Drug whose metabolism is
affected
•Allopurinol Mercaptopurine,azathiopr.
•Chloramphenicol Phenytoin
•Cimetidine Amiodarone,phenytoin,pethi.
•Ciprofloxacin Theophylline
•Corticosteroids TCA, cyclophosphamide
•Disulfiram Warfarin
•Erythromycin Cyclosporin, theophylline
•MAOIs Pethidine
•Ritonavir Saquinavir
•Enzyme inhibitor Drug whose metabolism is
affected
•Allopurinol Mercaptopurine,azathiopr.
•Chloramphenicol Phenytoin
•Cimetidine Amiodarone,phenytoin,pethi.
•Ciprofloxacin Theophylline
•Corticosteroids TCA, cyclophosphamide
•Disulfiram Warfarin
•Erythromycin Cyclosporin, theophylline
•MAOIs Pethidine
•Ritonavir Saquinavir
DRUG INTRERACTIONS 89
Stereoselective inhibitors of clearance of S isomer of
warfarin:
•Phenobarbitone
•Metronidazole
•Sulphinpyrozone
•Co-trimoxazole
•Disulfiram
Stereoselective inhibition of clearance of R isomer of
warfarin:
•Cimetidine
•Omeprazole
Stereoselective inhibitors of clearance of S isomer of
warfarin:
•Phenobarbitone
•Metronidazole
•Sulphinpyrozone
•Co-trimoxazole
•Disulfiram
Stereoselective inhibition of clearance of R isomer of
warfarin:
•Cimetidine
•Omeprazole
DRUG INTRERACTIONS 90
Non-stereoselective inhibition of clearance
of R and S isomers of warfarin:
•Amiodarone.
Haemodynamic effects:
•Variations in hepatic blood flow influence
the rate of inactivation of drugs that are
subject to presystemic hepatic metabolism
eg lignocaine or propranolol.
•Negative inotropes (eg propranolol)
reduce the rate of metabolism of
lignocaine by this mechanism.
Non-stereoselective inhibition of clearance
of R and S isomers of warfarin:
•Amiodarone.
Haemodynamic effects:
•Variations in hepatic blood flow influence
the rate of inactivation of drugs that are
subject to presystemic hepatic metabolism
eg lignocaine or propranolol.
•Negative inotropes (eg propranolol)
reduce the rate of metabolism of
lignocaine by this mechanism.
DRUG INTRERACTIONS 91
Excretion:
1. Inhibition of tubular secretion:
•Probenecid inhibits excretion of penicillin and
azidothymidine (AZT)
•Diuretics act from within the lumen, drugs that
inhibit their secretion into tubular fluid such as
NSAIDs can reduce their effects.
2. Alteration of urine flow and pH:
•Loop and thiazide diuretics indirectly increase
proximal tubular reabsorption of lithium (which is
handled in a similar way to sodium) and this can
cause lithium toxicity in patients treated with
lithium carbonate for mood disorders.
Excretion:
1. Inhibition of tubular secretion:
•Probenecid inhibits excretion of penicillin and
azidothymidine (AZT)
•Diuretics act from within the lumen, drugs that
inhibit their secretion into tubular fluid such as
NSAIDs can reduce their effects.
2. Alteration of urine flow and pH:
•Loop and thiazide diuretics indirectly increase
proximal tubular reabsorption of lithium (which is
handled in a similar way to sodium) and this can
cause lithium toxicity in patients treated with
lithium carbonate for mood disorders.
DRUG INTRERACTIONS 92
The effect of urinary pH on excretion of weak acids and
bases is put into use in treatment of poisoning but is not
a cause of accidental interaction.
Renal tubular secretion inhibitorsDrugs withT½ affect.
•Probenecid,Sulphinpyrozone→ Penicillin
•Phenylbutazone, Sulphonamides Azidothymidine,In-
Aspirin, thiazide diuretics → domethacin
•Verapamil Amiodarone Quinidine→ Digoxin
•Diuretics → Lithium
•Aspirin NSAIDs → Methotrexate
The effect of urinary pH on excretion of weak acids and
bases is put into use in treatment of poisoning but is not
a cause of accidental interaction.
Renal tubular secretion inhibitorsDrugs withT½ affect.
•Probenecid,Sulphinpyrozone→ Penicillin
•Phenylbutazone, Sulphonamides Azidothymidine,In-
Aspirin, thiazide diuretics → domethacin
•Verapamil Amiodarone Quinidine→ Digoxin
•Diuretics → Lithium
•Aspirin NSAIDs → Methotrexate
DRUG INTRERACTIONS 93
Pharmaceutical interactions:
Examples:
•Formation of a complex between
thiopentone and suxamethoniumwhich
must not be mixed in the same syringe.
•Heparin interacts in this way with many
basic drugs.
•Heparin is used to keep intravenous lines
or canulae open and can inactivate basic
drugs if they are injected without first
cleaning the line with saline.
Pharmaceutical interactions:
Examples:
•Formation of a complex between
thiopentone and suxamethoniumwhich
must not be mixed in the same syringe.
•Heparin interacts in this way with many
basic drugs.
•Heparin is used to keep intravenous lines
or canulae open and can inactivate basic
drugs if they are injected without first
cleaning the line with saline.
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