Antiamoebic Drugs and Protozoal Infections
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Protozoal infections are common among
people in underdeveloped tropical and
subtropical countries, where sanitary
conditions, hygienic practices, and control
of the vectors of transmission are
inadequate. However, with increased
world travel, protozoal diseases, such as
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amebiasis, giardiasis, trichomoniasis
malaria, leishmaniasis, trypanosomiasis,
are no longer confined to specific
geographic locales.
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Protozoa are eukaryotes, the unicellular
protozoal cells have metabolic processes
closer to those of the human host than to
prokaryotic bacterial pathogens.
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Protozoal diseases are thus less easily
treated than bacterial infections, and many
of the antiprotozoal drugs cause serious
toxic effects in the host, particularly on
cells showing high metabolic activity, such
as neuronal, renal tubular, intestinal, and
bone marrow stem cells.
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Most antiprotozoal agents have not proved to be
safe for pregnant women.
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:
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1. Metronidazole
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2. Tinidazole
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3. Diloxanide furoate
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4. Iodoquinol
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5. Emetine and dehydroemetine
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6. Chloroquine., 7. Paromomycin
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The disease can be acute or chronic, with
patients showing varying degrees of
illness, from no symptoms to mild
diarrhoea to fulminating dysentery.
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The diagnosis is established by isolating
E. histolytica from fresh faeces.
•
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:
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Entamoeba histolytica exists in two forms:
cysts that can survive outside the body,
and labile but invasive trophozoites that do
not persist outside the body.
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Cysts, ingested through feces
contaminated food or water, pass into the
lumen of the intestine, where the
trophozoites are liberated. The
trophozoites multiply, and they either
invade and ulcerate the mucosa of the
large intestine or simply feed on intestinal
bacteria.
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(one strategy for treating luminal
amebiasis is to add antibiotics, such as
tetracyclines to the treatment regimen,
resulting in a reduction in intestinal flora –
the amoeba’s major food source).
•
The trophozoites within the intestine are
slowly carried toward the rectum, where
they return to the cyst form and are
excreted in feces.
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Large numbers of trophozoites within the
colon wall can also lead to systemic
invasion.
•
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Amebiasis is infection with Entamoeba
histolytica. This organism can cause;
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1. Asymtomatic intestinal infection
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2. Mild to moderate colitis
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3.Severe intestinal infection (dysentery)
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4.Amoeboma
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5. Liver abscess
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6. Other intestinal infections
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M
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:
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A nitroimidazole, is the drug of choice in
the treatment of extra luminal amoebiasis.
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It kills trophozoites but not cysts of
E.histolytica and effectively eradicates
intestinal and extra intestinal tissue
infections.
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Pharmacokinetics:
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Route of administration: oral, and I.V.
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Oral metronidazole readily absorbed and
permeate all tissues by simple diffusion.
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Intracellular concentration rapidly
approach extra cellular levels.
•
Peak plasma concentration reached in 1-
3 hours.
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Protein binding is low (10-20%)
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The half life of unchanged drug is 7.5
hours for metronidazole
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Metronidazole and its metabolites are
excreted mainly in the urine.
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:
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The nitro group of metronidazole is
chemically reduced in anaerobic bacteria
and sensitive protozoans.
•
Reactive reduction products appear to be
responsible for antimicrobial activity
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.
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It is not reliably effective against luminal
parasites and so must be used with a
luminal amebicide to ensure eradication of
the infection.
•
Dose:750mgTDS or 500mg I.V QID1odays
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:
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Metronidazole is the treatment of choice
for giardiasis.
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The dosage for giardiasis is much lower
and the drug thus better tolerated than that
for amebiasis.
•
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:
•
Metronidazole also useful in infections
caused by anaerobic bacteria for e.g.
bacteroids fragilis, fusobacterium,
clostridium perfringens.
•
5
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:
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Nausea, dry mouth, metallic taste in the
mouth and headache occurs commonly.
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Infrequent adverse effects include:
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Vomiting, Diarrhoea, insomnia, weakness,
dizziness, thrush, dysuria, dark urine ,
paraesthesias, neutropenia, pancreatitis,
ataxia, encephalopathy, seizures are rare
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I.V. infusion rarely caused seizures or
peripheral neuropathy.
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CAUTION:
•
THE DRUG SHOULD BE USED WITH CAUTION IN PATIENTS
WITH CNS DISEASE. IT SHOULD BE AVOIDED IN
PREGNANT WOMEN DUE TO RISK OF
TERATOGENICITY(NOT PROVED IN HUMANS, PROVED IN
BACTRERIA, MICE)
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D
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N
:
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Metronidazole has a disulfiram like effect,
so that nausea and vomiting can occur if
alcohol ingested during therapy.
•
It potentiate the anticoagulant effect of
coumarin type of anticoagulants.
•
Phenytoin & phenobarbitone may increase
•
elimination of the drug, cimetidine
decrease plasma clearance
T
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a
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•
Tinidazole, a related nitroimidazole, having
similar activity and a better toxicity profile
than metronidazole, and it offers simpler
dosing regimens.
•
P
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:
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Tinidazole readily absorbed and permeate
all tissues by simpler diffusion.
T
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e
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Intracellular concentration rapidly
approach extra cellular levels.
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Peak plasma level reached in 1- 3 hours.
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Protein binding is low(10- 20%)
•
The half life of Tinidazole is 12- 14 hours
•
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•
It must be used with luminal amebicide
because it is not effective against luminal
parasites.
•
Dose: 2 G daily for 3 days
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•
2
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3
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•
Diloxanide furoate is a dichloroacetamide
derivative.
•
It is an effective luminal amebicide but is
not active against tissue trophozoites.
•
Dose: 500mg three times/day for 10 days
•
P
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a
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:
•
After oral administration, in the gut,
diloxanide furoate
is split into diloxanide
and furoic acid; about 90% of the drug is
D
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•
Rapidly absorbed ad then conjugated to
form glucuronide, which is promptly
excreted in the urine.
•
The unabsorbed diloxanide is the active
antiamoebic substance.
•
M
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C
l
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s
:
•
It is considered the drug of choice for
asymptomatic luminal infections
•
It is used with a tissue amebicide, usually
metronidazole to treat serious intestinal
and extra intestinal infections.
•
A
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Iodoquinol (diiodohydroxyquin) is a
halogenated hydroxyquinoline.
Dose: 650mg TDS for 21days
P
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:
It is poorly understood
90% of the drug is retained in the intestine
and excreted in feces. The remainder
enters the circulation, and is excreted in
the urine as glucuronides.
I
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:
The mechanism of action of iodoquinol
against trophozoites is unknown.
It is effective against organisms in the bowel
lumen but not against trophozoites in the
intestinal wall or extra intestinal tissues
A
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•
Headache, rash, pruritus
•
Neurotoxicity with prolonged use with high
dosage.
•
C
a
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t
i
o
n
s
:
•
1
.
i
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q
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G
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y
•
2. it should be used with caution in
patients with optic neuropathy, renal or
thyroid disease, or non amebic hepatic dis.
I
o
d
o
q
u
i
n
o
l
3. The drug may increase protein-bound
serum iodine, leading to a decrease in
measured
131
I uptake that persist for
months.
4. It should be discontinued if it produces
persistent diarrhea or signs of iodine
toxicity( dermatitis, urticaria pruritus, fever)
C.I: It is contraindicated in patients with
intolerance to iodine.
E
m
e
t
i
n
e
a
n
d
D
e
h
y
d
r
o
e
m
e
t
i
n
e
Emetine
, an alkaloid derived from ipecac
and
dehydroemetine,
a synthetic analog,
are effective against tissue trophozoites of
E. histolytica, but because of major toxicity
concerns they have been almost
completely replaced by metronidazole.
R
o
u
t
e
o
f
a
d
m
i
n
i
s
t
r
a
t
i
o
n
:
Subcutaneous (preferred) or I.M, never I.V
E
m
e
t
i
n
e
a
n
d
D
e
h
y
d
r
o
e
m
e
t
i
n
e
C
L
I
N
I
C
A
L
U
S
E
S
:
Their use is limited to unusual
circumstances. in which severe amebiasis
warrants effective therapy and
metronidazole can not be used.
Dehydroemetine is preferred because of its
some what better toxicity profile. It should
be used for the minimum period usually 3-
5 days.
E
m
e
t
i
n
e
a
n
d
D
e
h
y
d
r
o
e
m
e
t
i
n
e
•
A
d
v
e
r
s
e
e
f
f
e
c
t
s
:
•
diarrhea is common
•
Nausea, vomiting, muscle weakness
•
Cardiac arrhythmias, heart failure,
hypotension (serious toxicity)
•
C
a
u
t
i
o
n
:
t
h
e
d
r
u
g
s
h
o
u
l
d
n
o
t
b
e
u
s
e
d
i
n
p
a
t
i
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n
t
s
w
i
t
h
c
a
r
d
i
a
c
o
r
r
e
n
a
l
d
i
s
e
a
s
e
,
i
n
y
o
u
n
g
c
h
i
l
d
r
e
n
,
o
r
i
n
p
r
e
g
n
a
n
c
y
.
•
P
a
r
o
m
o
m
y
c
i
n
Paromomycin is an aminoglycoside
antibiotic.
It is not significantly absorbed from the GIT.
The small amount absorbed, is slowly
excreted unchanged, mainly by glomerular
filtration.
Dose: 10mg/kg TDS for 7 days
P
a
r
o
m
o
m
y
c
i
n
C
l
i
n
i
c
a
l
u
s
e
s
:
It is used only as a luminal amebicide, has
no effect against extra intestinal amebic
infections.
Paromomycin is an effective luminal
amebicide that appears to have similar
efficacy and less toxicity than other
agents.
P
a
r
o
m
o
m
y
c
i
n
In a recent study, it was superior to diloxanide
furoate in clearing asymptomatic infections.
Parenteral paromomycin is under investigation in
treatment of visceral leishmaniasis.
A
d
v
e
r
s
e
e
f
f
e
c
t
s
:
abdominal distress, diarrhea.
It should be avoided in patients with significant
renal disease and cautiously used with G I
ulceration
T
e
t
r
a
c
y
c
l
i
n
e
s
Tetracyclines are broad – spectrum
bacteriostatic that inhibit protein synthesis
in susceptible microorganisms.
They are active against many gram-
positive and gram- negative bacteria
including anaerobes, rickettsiae,
chlamydiae, mycoplasma, and against
some protozoa e.g., amebas.
T
e
t
r
a
c
y
c
l
i
n
e
s
M
e
c
h
a
n
i
s
m
o
f
a
c
t
i
o
n
:
Tetracyclines enter microorganisms in part by
passive diffusion and in part by an energy
dependent process of active transport.
Susceptible cells concentrate the drug
intracellularly. Once inside the cell, tetracyclines
bind reversibly to the 30S subunit of the bacterial
ribosimes, blocking the binding of aminoacyl-
tRNA to the acceptor site on the mRNA-
ribosome complex. This prevents addition of
aminoacid to the growing peptide .
.
T
e
t
r
a
c
y
c
l
i
n
e
s
•
Dose: 250mg 3 times daily for 10 days
•
A
d
v
e
r
s
e
e
f
f
e
c
t
s
:
•
1. G I adverse effects: nausea, vomiting,diarrhea
•
2. bony structure and teeth
•
3. liver toxicity
•
4. kidney toxicity
•
5.photosensitization
•
6.vestibular reactions
•
E
r
y
t
h
r
o
m
y
c
i
n
•
Erythromycin 500mg, 4 times daily for 10
days.
•
Erythromycin inhibits protein synthesis
occurs via binding to the 50S ribosomal
RNA, which blocks the aminoacyl
translocation reaction and formation of
initiation complexes.
C
h
l
o
r
o
q
u
i
n
e
•
It is used in combination with
metronidazole and diloxanide furoate to
treat and prevent amoebic liver
abscesses.
•
It eliminates trophozoites in liver
abscesses, but it is not useful in treating
luminal amebiasis
C
h
l
o
r
o
q
u
i
n
e
•
M
E
C
H
A
N
I
S
M
O
F
A
C
T
I
O
N
:
•
Chloroquine probably acts by
concentrating in parasitic food vacuoles,
preventing the polymerization of the
hemoglobin breakdown product, heme into
hemozoin, and thus eliciting parasite
toxicity due to buildup of free heme.
C
h
l
o
r
o
q
u
i
n
e
•
A
d
v
e
r
s
e
e
f
f
e
c
t
s
:
•
pruritus is common,
•
nausea, vomiting, abdominal pain,
anorexia.
•
Headache, blurring of vision uncommon.
•
Hemolysis in G6-PD deficient patients,
impaired hearing, agranulocytosis
alopecia, hypotension.
Protozoal infections such as amoebiasis, giardiasis, and malaria are a global concern, particularly prevalent in underdeveloped regions. Antiamoebic drugs serve as the primary treatment, targeting protozoal parasites like Entamoeba histolytica. However, these drugs can pose challenges due to potential toxic effects and limited safety for pregnant women. Diagnosis of amoebiasis involves isolating E. histolytica from feces. Stay informed about the complexities of treating protozoal diseases with antiamoebic medications.
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Presentation Transcript
Antiamoebic Drugs Dr.Saeed Ahmed Sheikh Department Of Pharmacology King Saud University
Antiamoebic Drugs Protozoal infections are common among people in underdeveloped tropical and subtropical countries, where sanitary conditions, hygienic practices, and control of the vectors of transmission are inadequate. However, with increased world travel, protozoal diseases, such as
Antiamoebic Drugs amebiasis, giardiasis, trichomoniasis malaria, leishmaniasis, trypanosomiasis, are no longer confined to specific geographic locales. Protozoa are eukaryotes, the unicellular protozoal cells have metabolic processes closer to those of the human host than to prokaryotic bacterial pathogens.
Antiamoebic Drugs Protozoal diseases are thus less easily treated than bacterial infections, and many of the antiprotozoal drugs cause serious toxic effects in the host, particularly on cells showing high metabolic activity, such as neuronal, renal tubular, intestinal, and bone marrow stem cells.
Antiamoebic Drugs Most antiprotozoal agents have not proved to be safe for pregnant women. Antiamoebic drugs are as under: 1. Metronidazole 2. Tinidazole 3. Diloxanide furoate 4. Iodoquinol 5. Emetine and dehydroemetine 6. Chloroquine., 7. Paromomycin
Antiamoebic Drugs Amoebiasis: (It is also called amoebic dysentery) is an infection of the intestinal tract caused by Entamoeba histolytica. The disease can be acute or chronic, with patients showing varying degrees of illness, from no symptoms to mild diarrhoea to fulminating dysentery.
Antiamoebic Drugs The diagnosis is established by isolating E. histolytica from fresh faeces. Life cycle of E.histolytica: Entamoeba histolytica exists in two forms: cysts that can survive outside the body, and labile but invasive trophozoites that do not persist outside the body.
Antiamoebic Drugs Cysts, ingested through feces contaminated food or water, pass into the lumen of the intestine, where the trophozoites are liberated. The trophozoites multiply, and they either invade and ulcerate the mucosa of the large intestine or simply feed on intestinal bacteria.
Antiamoebic Drugs (one strategy for treating luminal amebiasis is to add antibiotics, such as tetracyclines to the treatment regimen, resulting in a reduction in intestinal flora the amoeba s major food source). The trophozoites within the intestine are slowly carried toward the rectum, where they return to the cyst form and are excreted in feces.
Antiamoebic Drugs Large numbers of trophozoites within the colon wall can also lead to systemic invasion. Classification of Antiamoebic Drugs: 1. systemic: Tinidazole, Chloroquine, dehydroemetine, emetine. They are effective against amebas in the intestinal wall and liver.
Antiamoebic Drugs Luminal: Diloxanide furoate, iodoquinol, paromomycin. They act on the parasites in the lumen of the bowel. Mixed: (luminal and systemic) Metronidazole
Antiamoebic Drugs Amebiasis is infection with Entamoeba histolytica. This organism can cause; 1. Asymtomatic intestinal infection 2. Mild to moderate colitis 3.Severe intestinal infection (dysentery) 4.Amoeboma 5. Liver abscess 6. Other intestinal infections
Antiamoebic Drugs Metronidazole: A nitroimidazole, is the drug of choice in the treatment of extra luminal amoebiasis. It kills trophozoites but not cysts of E.histolytica and effectively eradicates intestinal and extra intestinal tissue infections.
Antiamoebic Drugs Pharmacokinetics: Route of administration: oral, and I.V. Oral metronidazole readily absorbed and permeate all tissues by simple diffusion. Intracellular concentration rapidly approach extra cellular levels. Peak plasma concentration reached in 1- 3 hours.
Antiamoebic Drugs Protein binding is low (10-20%) The half life of unchanged drug is 7.5 hours for metronidazole Metronidazole and its metabolites are excreted mainly in the urine.
Antiamoebic Drugs Mechanism of Action: The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity
Antiamoebic Drugs Clinical Uses: 1.Amoebiasis: Metronidazole is the drug of choice in the treatment of all tissue infections with E.histolytica. It is not reliably effective against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection. Dose:750mgTDS or 500mg I.V QID1odays
Antiamoebic Drugs 2. Giardiasis: Metronidazole is the treatment of choice for giardiasis. The dosage for giardiasis is much lower and the drug thus better tolerated than that for amebiasis. 3. Trichomoniasis: Metronidazole is the treatment of choice. 2G,single dose is effective.
Antiamoebic Drugs 4. Anaerobic Bacterial infections: Metronidazole also useful in infections caused by anaerobic bacteria for e.g. bacteroids fragilis, fusobacterium, clostridium perfringens. 5. Dracunculosis: infection caused by guinea worm.
Antiamoebic Drugs Adverse effects: Nausea, dry mouth, metallic taste in the mouth and headache occurs commonly. Infrequent adverse effects include: Vomiting, Diarrhoea, insomnia, weakness, dizziness, thrush, dysuria, dark urine , paraesthesias, neutropenia, pancreatitis, ataxia, encephalopathy, seizures are rare
Antiamoebic Drugs I.V. infusion rarely caused seizures or peripheral neuropathy. CAUTION: THE DRUG SHOULD BE USED WITH CAUTION IN PATIENTS WITH CNS DISEASE. IT SHOULD BE AVOIDED IN PREGNANT WOMEN DUE TO RISK OF TERATOGENICITY(NOT PROVED IN HUMANS, PROVED IN BACTRERIA, MICE)
Antiamoebic Drugs DRUG INTERACTION: Metronidazole has a disulfiram like effect, so that nausea and vomiting can occur if alcohol ingested during therapy. It potentiate the anticoagulant effect of coumarin type of anticoagulants. Phenytoin & phenobarbitone may increase elimination of the drug, cimetidine decrease plasma clearance
Tinidazole Tinidazole, a related nitroimidazole, having similar activity and a better toxicity profile than metronidazole, and it offers simpler dosing regimens. Pharmacokinetics: Tinidazole readily absorbed and permeate all tissues by simpler diffusion.
Tinidazole Intracellular concentration rapidly approach extra cellular levels. Peak plasma level reached in 1- 3 hours. Protein binding is low(10- 20%) The half life of Tinidazole is 12- 14 hours Mechanism of Action: It has similar to metronidazole.
Tinidazole Clinical uses: 1. Amebiasis: Tinidazole is also a drug of choice in the treatment of all tissue infections with E. histolytica. It must be used with luminal amebicide because it is not effective against luminal parasites. Dose: 2 G daily for 3 days
Tinidazole 2. Giardiasis: Tinidazole is at least equally effective like metronidazole 3. Trichomoniasis: It may be effective against some of these resistant organisms Adverse effects: toxicity profile is better than metronidazole.
Diloxanide furoate Diloxanide furoate is a dichloroacetamide derivative. It is an effective luminal amebicide but is not active against tissue trophozoites. Dose: 500mg three times/day for 10 days Pharmacokinetics: After oral administration, in the gut, diloxanide furoate is split into diloxanide and furoic acid; about 90% of the drug is
Diloxanide furoate Rapidly absorbed ad then conjugated to form glucuronide, which is promptly excreted in the urine. The unabsorbed diloxanide is the active antiamoebic substance. Mechanism of Action: unknown
Diloxanide furoate Clinical uses: It is considered the drug of choice for asymptomatic luminal infections It is used with a tissue amebicide, usually metronidazole to treat serious intestinal and extra intestinal infections. Adverse effects: flatulence is common, nausea, abdominal cramps and rashes
Iodoquinol Iodoquinol (diiodohydroxyquin) is a halogenated hydroxyquinoline. Dose: 650mg TDS for 21days Pharmacokinetics: It is poorly understood 90% of the drug is retained in the intestine and excreted in feces. The remainder enters the circulation, and is excreted in the urine as glucuronides.
Iodoquinol mechanism of action: The mechanism of action of iodoquinol against trophozoites is unknown. It is effective against organisms in the bowel lumen but not against trophozoites in the intestinal wall or extra intestinal tissues Adverse effects: Diarrhoea, anorexia, nausea, vomiting, abdominal pain,
Iodoquinol Headache, rash, pruritus Neurotoxicity with prolonged use with high dosage. Cautions: 1. iodoquinol should be taken with meals to limit GI toxicity 2. it should be used with caution in patients with optic neuropathy, renal or thyroid disease, or non amebic hepatic dis.
Iodoquinol 3. The drug may increase protein-bound serum iodine, leading to a decrease in measured 131I uptake that persist for months. 4. It should be discontinued if it produces persistent diarrhea or signs of iodine toxicity( dermatitis, urticaria pruritus, fever) C.I: It is contraindicated in patients with intolerance to iodine.
Emetine and Dehydroemetine Emetine, an alkaloid derived from ipecac and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E. histolytica, but because of major toxicity concerns they have been almost completely replaced by metronidazole. Route of administration: Subcutaneous (preferred) or I.M, never I.V
Emetine and Dehydroemetine CLINICAL USES: Their use is limited to unusual circumstances. in which severe amebiasis warrants effective therapy and metronidazole can not be used. Dehydroemetine is preferred because of its some what better toxicity profile. It should be used for the minimum period usually 3- 5 days.
Emetine and Dehydroemetine Adverse effects: diarrhea is common Nausea, vomiting, muscle weakness Cardiac arrhythmias, heart failure, hypotension (serious toxicity) Caution: the drug should not be used in patients with cardiac or renal disease, in young children, or in pregnancy.
Paromomycin Paromomycin is an aminoglycoside antibiotic. It is not significantly absorbed from the GIT. The small amount absorbed, is slowly excreted unchanged, mainly by glomerular filtration. Dose: 10mg/kg TDS for 7 days
Paromomycin Clinical uses: It is used only as a luminal amebicide, has no effect against extra intestinal amebic infections. Paromomycin is an effective luminal amebicide that appears to have similar efficacy and less toxicity than other agents.
Paromomycin In a recent study, it was superior to diloxanide furoate in clearing asymptomatic infections. Parenteral paromomycin is under investigation in treatment of visceral leishmaniasis. Adverse effects: abdominal distress, diarrhea. It should be avoided in patients with significant renal disease and cautiously used with G I ulceration
Tetracyclines Tetracyclines are broad spectrum bacteriostatic that inhibit protein synthesis in susceptible microorganisms. They are active against many gram- positive and gram- negative bacteria including anaerobes, rickettsiae, chlamydiae, mycoplasma, and against some protozoa e.g., amebas.
Tetracyclines Mechanism of action: Tetracyclines enter microorganisms in part by passive diffusion and in part by an energy dependent process of active transport. Susceptible cells concentrate the drug intracellularly. Once inside the cell, tetracyclines bind reversibly to the 30S subunit of the bacterial ribosimes, blocking the binding of aminoacyl- tRNA to the acceptor site on the mRNA- ribosome complex. This prevents addition of aminoacid to the growing peptide . .
Tetracyclines Dose: 250mg 3 times daily for 10 days Adverse effects: 1. G I adverse effects: nausea, vomiting,diarrhea 2. bony structure and teeth 3. liver toxicity 4. kidney toxicity 5.photosensitization 6.vestibular reactions
Erythromycin Erythromycin 500mg, 4 times daily for 10 days. Erythromycin inhibits protein synthesis occurs via binding to the 50S ribosomal RNA, which blocks the aminoacyl translocation reaction and formation of initiation complexes.
Chloroquine It is used in combination with metronidazole and diloxanide furoate to treat and prevent amoebic liver abscesses. It eliminates trophozoites in liver abscesses, but it is not useful in treating luminal amebiasis
Chloroquine MECHANISM OF ACTION: Chloroquine probably acts by concentrating in parasitic food vacuoles, preventing the polymerization of the hemoglobin breakdown product, heme into hemozoin, and thus eliciting parasite toxicity due to buildup of free heme.
Chloroquine Adverse effects: pruritus is common, nausea, vomiting, abdominal pain, anorexia. Headache, blurring of vision uncommon. Hemolysis in G6-PD deficient patients, impaired hearing, agranulocytosis alopecia, hypotension.
