Pharmacology (dra Dando)

Anti-Protozoa
30 January 08

PRINCIPLES OF ANTIPARASITIC CHEMOTHERAPHY spontaneously in less than 4weeks. Thus,

treatment that eliminates erythrocytic parasites
TARGETS OF CHEMOTHERAPHY OF PARASITIC DISEASE will cure these infection

1) unique essential enzymes found only in the parasite
Ex. Pyruvate serotoxin oxidoreductase
⇒ produce by anaerobic protozoa
↑ relapses can therefore occur after therapy
nitroimidazole
2) similar enzymes found in both host and parasite but
indispensable only for the parasite
Ex. α-Difluromethylornithine
⇒ acts on orthinine decarboxylase of
African trypanosome (sleeping
sickness)
3) common biochemical functions found in both parasite
and host but with different pharmacologic properties.
Ex. Microtubules --in helminthes
↑
Benzomidazole
------------------------ANTIPROTOZOAL
DRUGS-----------------------
TREATMENT OF MALARIA
• P. vivax & P. ovale
= a dormant hepatic stage, the HYPNOZOITE, is
not eradicated by most drugs and subsequent
directed against erythrocytic parasites
= eradication of both erythrocytic and hepatic
parasites is required to cure these infection.
ANTIMALARIAL DRUGS:SITE OF ACTION
1) Drugs used to treat acute attack
- blood schizonticidal agents
- drugs for suppressive/clinical use
2) drugs that affect the exoerythrocytic hypnologists &
results in radical cure of P.vivax & P.ovale
3) drugs that block the link between exoerythrocytic
stage & erythrocytic stage
- used for chemoprophylaxis (casual prophylactic)
- prevent the development of malarial attacks
- acts on Merozoites emerging from the liver cells
4) drugs that prevent transmission and thus prevent
increase the human reservoir of the disease
-act on gametocytes

Four species of plasmodium that cause human malaria: SUMMARY OF DRUGS USED FOR TX &
a) Plasmodium falciparum CHEMOPROPHYLAXIS OF MALARIA
= responsible for nearly all serious complication and INFECTION DRUG FOR TX DRUG FOR
deaths OF CLINICAL CHERMOPROP
= drug resistance is an important therapeutic problem INFECTION HYLAXIS
b) Plasmodium vivax
All plasmodial Oral Oral
c) Plasmodium malariae
infection chloroquine or chloroquine or
d) Plasmodium ovale
except sulfadoxine- proguanil
chloroquine pyrimethamine
PARASITIC LIFE CYCLE
resistant P. (FANSIDAR)
1) Anopheline mosquito → inoculates plasmodium
faclcifarum
porosities to initiate human infection.
Infection with Oral Oral
2) Circulating SPOROZOITES rapidly invade liver cells
chloroquine chloroquine + chloroquine +
3) EXOERYTHROCYTIC stage tissue schizonts mature in
resistant tetracycline/ proguanil/doxy
the liver
P.falciparum doxycycline/ cycline/
4) MEROZOITES release from liver and invade
oral pyrimethanine-
erythrocytes
halofantrine/ dapsone/
oral mefloquine
*** During the asexual erythrocytic stage of
mefloquine
infection, parasites develop from trophozoites to
schizonts and then rupture host erythrocytes, releasing
multiple merozoites that invade other erythrocyte to ANTIMALARIAL DRUGS
reinitiate the cycle. I. CHLOROQUINE
 DOC: treatment and chemoprophylaxis of
ERYTHROCYTIC PARASITES = causes clinical illness malaria but its utility against P.falciparum has
been seriously compromised by drug resistance
*** Sexual stage GAMETOCYTES also develop in  Synthetic 4-aminoquinoline
erythrocytes before being taken up by mosquitoes,  Oral use: formulated as a phosphate salt
where they develop into infective porosities.  T1/2: 3-5 days
 Anti-malarial action and resistance:
NOTE: a) ANTI-MALARIAL ACTION
• P. faclciparum & malariae - Blood schizonticide
= only one cycle of liver cell invasion & - Moderately effective against gametocytes
multiplication occurs, and liver infection ceases of P. vivax, P. ovale and P.malariae but not
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 Pharmacology – Endocrine Drugs by Dra Dando
against those of P.falciparum
- Not active against liver stage parasite
b) MOA
- Concentrating in parasite food vacuoles
- Preventing the polymerization of
hemoglobin breakdown product, heme,
into hemozoin and thus eliciting parasite
toxicity due to the build-up of free heme
c) RESISTANCE
- Common among strains of falciparum
- Chloroquine resistance can be reversed:
1) verapamil, 2) desipramine, and 3)
pheniramine
 Clinical uses:
a) TREATMENT
- both for treatment and prophylaxis of
non-falciparum and sensitive faciparum
malaria
- it rapidly terminates fever and clears
parasitemia cost by sensitive parasites
- with PRIMAQUINE = eliminates dormant
liver forms of P.vivax and P.ovale
b) CHEMOPROPHYLAXIS
- Preferred chemoprophylactic agent in
malarious regions without resistant
facliparum malaria\
c) AMEBIC LIVER ABSCESS
- Combination with METRONIDAZOLE
 ADR: (usually very well tolerated even with
prolonged use)
a) Pruritus is common primarily in Africans
b) N&V, abdominal pain, HA, Anorexia, Malaise,
blurring of vision and urticaria are
uncommon
c) Dosing after meals may reduce some
adverse effects
 Contraindication:
a) px w/ psoriasis and porphyria,
b) with retinal or visual field abnormalities or
myopathy
c) caution in px w/ hx of liver disease/
neurologic/ hematologic disorders
d) antidiarrheal agents: kaolin & Ca++ & Mg++
containing acids interfere w/ absorption of
chloroquine.
 Considered safe: pregnancy & for young adults
II. QUININE
 DOC: Chloroquine resistant P. Falciparum
 First-line therapies for falciparum malaria---
especially in severe disease--- though toxicity
III.
concerns complicate therapy
 T1/2: 11 hours
 Anti-malarial action:
- Rapidly acting, highly effective blood
schizonticide against four species of
human malaria parasite
- Gametocidal against P.vivax and P.ovale
- Not active against liver stage parasites
 Clinical Use:
a) PARENTERAL TX OF SEVERE FALCIPARUM
MALARIA
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- May cause cardiac toxicity in IV route,
so it should be administered w/
cardiac monitoring
b) ORAL TX OF FALCIPARUM MALARIA
- First-line therapy for uncomplicated
falciparum malaria except when
infection was transmitted in an area
w/o documented chloroquine resistant
malaria
- Less effective than chloroquine
against other human malarias and is
more toxic, and it is therefore not
used to treat infections with these
parasites
c) MALARIAL CHEMOPROPHYLAXIS
- Not generally used in chemoprophylaxis
owing to its toxicity
d) BABESIOSIS
- First line therapy, in combination w/
CLINDAMYCIN, for the treatment of
infection w/ Babesia microti or other
Human Babesial infection
 ADR:
a) CINCHONISM
- Tinnitus, HA, N&V, dizziness, flushing and
visual disturbance (constellation of
symptoms)
b) BLACKWATER FEVER
- Hemolysis(pallor & anemia) and
hemoglobinuria (pallor & bloody urine)
- Hypersensitivity to drug
c) Severe Hypotension(too rapid IV infusion;
Prolong QT (IV)
 Contraindication &Caution:
a) Visual & auditory problems
b) Cardiac abnormalities
c) Should not be given concurrently w/
mefloquine and caution in Px w/ malaria who
previously received mefloquine
chemoprophylaxis
d) Absorption may be block by aluminum-
containing antacid
e) Can rise plasma levels of warfarin & digoxin
f) Dosage must reduce in renal insufficiency
 Given in combination w/:
a) Pyrimethamine - folate antagonist that acts as
blood schizonticide given orally(t1/2=4days)
b) Dapsone – a sulfone, oral (T1/2= 24-48hrs)
c) Sulfadoxine – long-acting sulfonamide (T1/2=
7-9days)
MEFLOQUINE
 Effective therapy for many chloroquine-resistant
strains of P.falciparum and against other species
 Recommened chemoprophylactic drug use in
most malaria-endemic regions w/ chloroquine
resistant strains
 Synthetic of 4-quinoline methanol
 Given ORALLY bec svere local irritation occurs w/
parenteral use
 T ½ = 30days
 MOA: Inhibits parsites heme polymerase
 Antimalarial action:
 Pharmacology – Endocrine Drugs by Dra Dando
a) strong blood schizonticidal activity against
P.falciparum & P.vivax
b) not active against hepatic stages or
gametocyte
 ADR:
a) GI disturbance
b) Neurotoxicity
c) Psychiatric problems ( depression, confusion,
acute psychosis, or seizures)
d) Leukocytosis, thrombocytopenis and
aminotransferase elevation
e) Can also alter cardiac conduction and
arrhythmias & bradycardia have been
reported
 Contraindication:
a) Hx of epilepsy, psychiatric disorders,
arrhythmia, cardiac conduction defects, or
sensitivity to related drugs
b) Should not be coadministered w/ quinine,
quinidine,or halofantrine
c) SAFE: children, pregnancy
IV. PRIMAQUINE
 DOC: eradication of dormant liver forms of P.vivax
& P.ovale
 Synthetic 8-amino quinolone
 ORAL
 T1/2: 36 hrs
 Antimalarial action:
a) Active against hepatic stages of all human
malarial parasites
b) Dormant hypnozoite stages of P.vivax &
P.ovale
c) Gametocidal against the four malarial human
species
 Clinical Use:
a) Therapy (radical cure) of Acute Vivax and
Ovale Malaria
- Standard therapy for these infection
includes chloroquine to eradicate
erythrocyticforms and primaquine to
eradicate live hypnozoites and prevent a
subsequent relapse
b) Terminal Prophylaxis of Vivax & Ovale Malaria
c) Chemoprophylaxis of Malaria
d) Gametocidal Action
e) Pneumocystis carinii infection
- Combination w/ CLINDAMYCIN is an
alternative regimen for the tx of
pnuemocystosis, particularly mild to
moderate disease
 ADR:
a) GI disturbances
b) Methehemoglobinemia = w/ large doses; dec
oxygen capacity causing cyanosis; Fe+2 →Fe+3
c) Hemolysis = individual w/ G6PD genetic
deficiency in erythrocyte
d) Leucopenia, agranulocytosis, leukocytosis and
cardiac arrhythmias
 Contraindication:
a) Hx of granulocytopenia/
methehemoglobinemia, in those receiving
potential myelosuppressive drugs
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b) Never given parentally because it induce
marked hypotension
c) G6PD deficient
V. ATOVAQUONE
 a hydroxynaphthoquinone
 ORAL
 Initially developed as an antimalarial and as
component of MALARONE is recommended as
prophylaxis
 It has been approved by the FDA for the
treatment of mild to moderate P.jiroveci
pneumonia
 Absorption is increase by FATTY FOOD
 Resistance develop rapidly if given alone
 T1/2 = 2-3 days
 In plasmodia it appears to disrupt mitochondrial
electron transport
 MALARONE = combination of atovaquone &
proguanil highly effective as tx &
chemoprophylaxis of falciparum malaria
= use for tx of simple, acute, uncomplicated P.falciparum
 It has advantage over mefloquine & doxycycline
in requiring shorter period of tx, before and after
the period of risk of malarial transmission, but it is
more expensive than other drugs
 Taken w/ food
 Alternative therapy for p. jiroveci but its efficacy
is lower than trimethoprim-sulfamethoxazole
 ADR: fever rash, N&V, diarrhea, HA and insomnia
 Plasm concn is decrease in combination w/
tetracycline & rifampin
INHIBITOR OF FOLATE SYNTHESIS
I. PYRIMETHAMINE
 Can be given once a week for chemoprophylaxis
 Combination w/:
a) Sulfadoxine----FANSIDAR
b) Dapsone -----MALOPRIM
c) Suldiazine ---1st line tx for toxoplasmosis
II. PROGUANIL
 Biguanide derivative
 Administered daily for chemoprophylaxis
 It is Prodrug
 only its triazine metabolite: CYCLOQUANIL, is
active
 folate antagonist
 slow acting blood schizonticide
 some action on primary liver forms of vivax
 ORAL
 Have some activity against hepatic form
 SAFE: Pregnancy but folate supplements should
be coadminstered
ANTIMALARIAL ACTION & RESISTANCE
A. Antimalarial action
- Acts slowly against erythrocytic forms of
susceptible strains of all four human
malaria species
 Pharmacology – Endocrine Drugs by Dra Dando
- Neither drug is adequately gametocidal or
effective against the persistent liver
stages of P.vivax/ P.ovale
B. MOA
- Selectively inhibit plasmodial
dihydrofolate reductase
C. Resistance
- Common for P.falciparum and less
commonly to P.vivax
- Due to mutation in dihydofolate reductase
& dihydropteroate synthase
CLINICAL USE
A. Chemoprophylaxis
B. Tx of Chloroquine-Resistant Falciparum Malaria
- FANSIDAR= used to treat uncomplicated
falciparum malaria
C. Presumptive Tx of Falciparum Malaria
- FANSIDAR = used as presumptive therapy
for travellers who develop fever while
travelling in malaria-endemic regions and
who unable to obtain medical evaluation
D. Toxoplasmosis
- Combi w/ SULFADIAZINE
E. Pneumocytosis
ADR
1) GI symptoms
2) Skin rashes & itching
3) Proguanil = mouth ulcers & alopecia
ANTIBIOTICS
- MOA: inhibit protein synthesis or other
functions in two plasmodial prokaryote-
like organelles, the mitochondrion and the
newly described plastid
- None of antibiotics should be used as a
single ahents for the tx of malaria
because their action is much slower than
those of standard antimalarials
I. TETRACYCLINE
 Active against erythrocytic schizonts of all human
malaria parasites
II. DOXYCYCLINE
 Active against erythrocytic schizonts of all human
malaria parasites
 Commonly used in tx of falciparum malaria in
conjunction w/ quinine &quinidine, allowing
shorter and better tolerated quinine
 Standard prophylaxis use in areas of Southeast
Asia w/ high rates of resistance to antimalarial
drugs (mefloquine)
 ADR: GI symptoms, candidal vaginatis, &
photosensitivity
III. CLINDAMYCIN
 Slowly active aginst erythrocytic schizonts and
can be used in conjuction w/ quinine/ quinidine in
those whom doxycylcine is not recommended,
such as children & pregnant
 In combi w/ other drugs, is effective therapy for
toxoplasmosis, pneumocytosis and babeiosis
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IV. AZITHROMYCIN
 Also have antimalarial activity
V. SPIRAMYCIN
 Macrolide antibiotic that is used to treat primary
toxoplasmosis acquired during pregnacy
** Tetracycline & erythromycin = alternative therapies for
the tx of intestinal amebiasis
OTHER ANTI-MALARIAL DRUGS
I. HALOFANTRENE
 Phenathrene methanol related to quinine
 Effective against erythrocytic schizont stages of
all four human malaria parasite including
multiresistant P.Falciparum
 Not active against hepatic stage & gametocyte
 Oral absorption is variable and is enhanced by
food
 Taken w/ meals;T1/2 = 4 days
 Rapidly effective against most chloroquine-
resistant strains of P.falciparum, but its used is
limited by irregular absorption and cardiac
toxicity
 Cross-resitance w/ mefloquine
 ADR: alters drug conduction, w/ dose related
prolongation of QT & PR intervals
 CI: cardiac conduction defects, pregnancy
(embryotoxic)
II. LUMEFANTRENE
 No cardiac side effects
 Combination w/ ARTHEMETER ---called: Coartem
 Aryl alcohol
III. ARTEMISININ (Ginghaosu)
 Sesquiterpene lactone endoperoxide, the active
principle of a herbal medicine that has been used
as an antipyretic in China
 Insoluble and can only be used ORALLY
 Analogs: ( inc solubility & improve antimalarial
activity)
 Rapidly acting blood schizonticide against all
human malaria parasites
 No effect on hepatic stage
 Probably results from production of free radicals
that follows the iron-catalyzed cleavage of
artemisinin endoperoxide bridge in the parasite
food vacuole
 Only drug reliably effective against quinine-
resistant strains
a) ARTESUNATE
- Water-soluble
- Useful oral, IV, IM, rectal administration
b) ARTHEMETER
- Lipid-soluble
- Useful for oral, IM & rectal administration
TREATMENT OF AMOEBIASIS
Amoebiasis is infection with Entamoeba histolytica. This
agent can cause asymptomatic intestinal infection, mild
to moderate colitis, severe intestinal infection
(dysentery), ameboma, liver abscess, and other
 Pharmacology – Endocrine Drugs by Dra Dando
extraintestinal infections. The choice of drugs for
amebiasis depends on the clinical presentation
Treatment of Specific Forms of Amebiasis
I. Asymptomatic Intestinal Infection
• Asymptomatic carriers generally are not treated in
endemic areas but in nonendemic areas they are
treated with a luminal amebicide.
• A tissue amebicidal drug is unnecessary.
• Standard luminal amebicides are:
a) diloxanide furoate
b) iodoquinol
c) paromomycin.
II. Amebic Colitis
• Metronidazole plus a luminal amebicide
= treatment of choice for colitis and dysentery.
• Tetracyclines and erythromycin
= alternative drugs for moderate colitis but are not
effective against extraintestinal disease.
• Dehydroemetine or emetine
= can also be used, but these agents are best avoided
(when possible) because of their toxicity.
III. Extraintestinal Infections
• The treatment of choice is metronidazole plus a
luminal amebicide.
• For unusual cases where initial therapy with
metronidazole has failed, aspiration of the abscess
and the addition of chloroquine to a repeat course
of metronidazole should be considered.
• Dehydroemetine and emetine are toxic alternative
drugs.
DRUGS FOR AMEBIASIS: Extraluminal
Metronidazole
 a nitroimidazole
 drug of choice for the treatment of extraluminal
amebiasis.
 It kills trophozoites but not cysts of E histolytica
and effectively eradicates intestinal and
extraintestinal tissue infections.
 Oral metronidazole is readily absorbed and
permeates all tissues by simple diffusion.
 the half-life of the unchanged drug is 7.5 hours.
 Plasma clearance of metronidazole is decreased
in patients with impaired liver function.
 MOA: The nitro group of metronidazole is
chemically reduced in anaerobic bacteria and
sensitive protozoans. Reactive reduction products
appear to be responsible for antimicrobial activity.
 Clinical Uses
A) Amebiasis
- DOC: Tx 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.
B) Giardiasis
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- The dosage for giardiasis is much lower—
and the drug thus better tolerated—than
that for amebiasis.
- Efficacy after a single treatment is about
90%. Tinidazole is equally effective.
C) Trichomoniasis
 Adverse Effects & Cautions:
- Nausea, headache, dry mouth, or a metallic taste
in the mouth occurs commonly.
- Infrequent adverse effects include vomiting,
diarrhea, insomnia, weakness, dizziness, thrush,
rash, dysuria, dark urine, vertigo, paresthesias,
and neutropenia.
- Taking the drug with meals lessens
gastrointestinal irritation.
- Pancreatitis and severe central nervous system
toxicity (ataxia, encephalopathy, seizures) are
rare.
1. disulfiram-like effect, so that nausea and
vomiting can occur if alcohol is ingested during
therapy.
= The drug should be used with caution in patients with
central nervous system disease. Intravenous infusions
have rarely caused seizures or peripheral neuropathy. The
dosage should be adjusted for patients with severe liver
or renal disease.
2. potentiate the anticoagulant effect of
coumarin-type anticoagulants.
= Phenytoin and phenobarbital may accelerate
elimination of the drug, while cimetidine may decrease
plasma clearance.
3. Lithium toxicity may occur when the drug is
used with metronidazole.
4. mutagenic in bacteria & chronic administration
of large doses led to tumorigenicity
** Metronidazole is thus best avoided in pregnant or
nursing women, though congenital abnormalities have
not clearly been associated with use in humans.
DRUGS FOR AMEBIASIS: Luminal
I. Diloxanide furoate
 dichloroacetamide derivative
 effective luminal amebicide but is not active
against tissue trophozoites.
 In the gut, diloxanide furoate is split into
diloxanide and furoic acid;
 The unabsorbed diloxanide is the active
antiamebic substance.
 DOC: asymptomatic luminal infections, but it is no
longer available in the USA.
 It is used with a tissue amebicide, usually
metronidazole, to treat serious intestinal and
extraintestinal infections
 does not produce serious adverse effects.
 Flatulence is common, but nausea and abdominal
cramps are infrequent and rashes are rare.
 The drug is not recommended in pregnancy.
II. Iodoquinol (diiodohydroxyquin)
 halogenated hydroxyquinoline
 It is an effective luminal amebicide that is
commonly used with metronidazole to treat
amebic infections.
 against trophozoites
Pharmacology – Endocrine Drugs by Dra Dando
 It is effective against organisms in the bowel
lumen but not against trophozoites in the
intestinal wall or extraintestinal tissues.
 ADR:
a. diarrhea—which usually stops after several days
—anorexia, nausea, vomiting, abdominal pain,
headache, rash, and pruritus.
b. can produce severe neurotoxicity with
prolonged use at greater than recommended
doses.
c. taken with meals to limit gastrointestinal
toxicity.
d. caution in patients with: optic neuropathy,
renal or thyroid disease, or nonamebic hepatic
disease.
e. The drug should be discontinued if it produces
persistent diarrhea or signs of iodine toxicity
(dermatitis, urticaria, pruritus, fever).
 It is contraindicated in patients with intolerance to
iodine.
III. Paromomycin Sulfate
 an aminoglycoside antibiotic
 that is not significantly absorbed from the
gastrointestinal tract.
 It is used only as a luminal amebicide and has no
effect against extraintestinal amebic infections.
 the drug may accumulate with renal insufficiency and
contribute to renal toxicity.
 is an effective luminal amebicide that appears to
have similar efficacy and probably less toxicity than
other agents;
 in a recent study, it was superior to diloxanide furoate
in clearing asymptomatic infections.
 ADR: occasional abdominal distress and diarrhea.
 CI: renal disease and used with caution in persons
with gastrointestinal ulcerations.
IV. Emetine & Dehydroemetine
 Emetine = an alkaloid derived from ipecac
 Dehydroemetine = a synthetic analog ; preferred
over emetine because of its somewhat better
toxicity profile.
 are effective against tissue trophozoites of E
histolytica, but because of major toxicity concerns
they have been almost completely replaced by
metronidazole.
 administered parenterally because oral
preparations are absorbed erratically. They
accumulate in tissues and are eliminated slowly
via the kidneys.
 Its use is limited to unusual circumstances in
which severe amebiasis warrants effective
therapy and metronidazole cannot be used.
 The drugs should be used to treat amebic
dysentery or amebic liver abscess for the
minimum period needed to relieve severe
symptoms (usually 3–5 days).
 administered subcutaneously (preferred) or
intramuscularly(but never intravenously) in a
supervised setting.
 ADR: Serious toxicities include cardiac
arrhythmias, heart failure, and hypotension.
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 CI: patients with cardiac or renal disease, in
young children, or in pregnancy unless absolutely
necessary.
OTHER ANTIPROTOZOAL DRUGS
i. Pentamidine
 activity against trypanosomatid protozoans and
against P jiroveci, but toxicity is significant.
 an aromatic diamidine formulated as an
isethionate salt.
 only administered parenterally
 Only trace amounts of pentamidine appear in the
central nervous system, so it is not effective
against central nervous system African
trypanosomiasis
 inhaled as a nebulized powder for the prevention
of pneumocystosis.
 Clinical Uses:
A) Pneumocystosis
- alternative therapy for pulmonary and
extrapulmonary disease caused by P jiroveci.
- alternative agent for primary or secondary
prophylaxis against pneumocystosis in
immunocompromised individuals, including
patients with advanced AIDS.
B) African Trypanosomiasis (Sleeping Sickness)
- as an alternative to suramin for the early
hemolymphatic stage of disease caused by
Trypanosoma brucei (especially T brucei
gambiense).
- The drug can also be used with suramin.
- Pentamidine should not be used to treat late
trypanosomiasis with central nervous system
involvement.
- Pentamidine has also been used for
chemoprophylaxis against African
trypanosomiasis, with dosing of 4 mg/kg
every 3– 6 months.
C) Leishmaniasis
- an alternative to sodium stibogluconate for
the treatment of visceral leishmaniasis,
although resistance has been reported.
 Adverse Effects & Cautions
- Pentamidine is a highly toxic drug, with
adverse effects noted in about 50% of
patients receiving 4 mg/kg/d.
- Rapid IV: severe hypotension, tachycardia,
dizziness, and dyspnea, so the drug should be
administered slowly (over 2 hours) and
patients should be recumbent and monitored
closely during treatment.
- IM: pain at the injection site is common and
sterile abscesses may develop.
- Pancreatic toxicity is common.
- Hypoglycemia due to inappropriate insulin
release often appears 5– 7 days after onset of
treatment, can persist for days to several
weeks, and may be followed by
hyperglycemia.
- Reversible renal insufficiency is also common.
- Other adverse effects include rash, metallic
taste, fever, gastrointestinal symptoms,
abnormal liver function tests, acute
Pharmacology – Endocrine Drugs by Dra Dando
pancreatitis, hypocalcemia,
thrombocytopenia, hallucinations, and cardiac
arrhythmias. Inhaled pentamidine is generally
well-tolerated but may cause cough, dyspnea,
and bronchospasm.
ii. Sodium Stibogluconate
 Pentavalent antimonials
 first-line agents for cutaneous and visceral
leishmaniasis.
 intravenous (preferred) or intramuscular
administration
 ADR:
- common are gastrointestinal symptoms,
fever, headache, myalgias, arthralgias, and
rash.
- Intramuscular injections can be very painful
and lead to sterile abscesses.
- Electrocardiographic changes may occur,
most commonly T wave changes and QT
prolongation. These changes are generally
reversible, but continued therapy may lead to
dangerous arrhythmias. Thus, the
electrocardiogram should be monitored
during therapy
- Hemolytic anemia and serious liver, renal,
and cardiac effects are rare
iii. Nitazoxanide
 nitrothiazolyl-salicylamide prodrug
 use in children against G lamblia and
Cryptosporidium parvum
 The drug is converted to an active
metabolite, tizoxanide, which inhibits the
pyruvate:ferredoxin oxidoreductase pathway.
 Appears to have activity against
metronidazole-resistant
protozoal strains and is well tolerated.
 Unlike metronidazole, nitazoxanide
and its metabolites appear to be free
of mutagenic effects.
 Other organisms that may be
susceptible include E histolytica,
Helicobacter pylori, A lumbricoides,
several tapeworms, and Fasciola
hepatica
iv. Trypanosmoiasis & Leishmaniasis
a) SURAMIN
- sulfated naphthylamine
- first-line therapy for early hemolymphatic
African trypanosomiasis (especially T brucei
gambiense infection), but because it does not
enter the central nervous system, it is not
effective against advanced disease.
- administered intravenously
- Combination therapy with pentamidine may
improve efficacy.
- can also be used for chemoprophylaxis
against African trypanosomiasis.
- Adverse effects are common. Immediate
reactions can include fatigue, nausea,
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vomiting, and, more rarely, seizures, shock,
and death.
- Later reactions include fever, rash, headache,
paresthesias, neuropathies, renal
abnormalities including proteinuria, chronic
diarrhea, hemolytic anemia, and
agranulocytosis.
b) MELARSOPOL
- is a trivalent arsenical
- first-line therapy for advanced central
nervous system African trypanosomiasis.
- intravenous administration it is excreted
rapidly
- Melarsoprol is extremely toxic. The use of
such a toxic drug is justified only by the
severity of advanced trypanosomiasis and the
lack of available alternatives.
- Immediate adverse effects include fever,
vomiting, abdominal pain, and arthralgias.
- The most important toxicity is a reactive
encephalopathy
= that generally appears within the first
week of therapy (in 5– 10% of patients)
and is probably due to disruption of
trypanosomes in the central nervous
system.
= Common consequences of the
encephalopathy include cerebral
edema, seizures, coma, and death
- Other serious toxicities include renal and
cardiac disease and hypersensitivity reactions
c) EFLORNITHINE
- an inhibitor of ornithine decarboxylase
- second therapy for advanced central nervous
system African trypanosomiasis and is less
toxic than melarsoprol but not as widely
available.
- use as a topical depilatory cream, leading to
donation of the drug for the treatment of
trypanosomiasis.
- administered intravenously, and good central
nervous system drug levels are achieved.
- Eflornithine appears to be as effective as
melarsoprol against advanced T brucei
gambiense infection, but its efficacy against T
brucei rhodesiense is limited by drug
resistance.
- Adverse effects include diarrhea, vomiting,
anemia, thrombocytopenia, leukopenia, and
seizures. These effects are generally
reversible.
d) NIFURTIMOX
- Nitrofuran
- is the most commonly used drug for
American trypanosomiasis (Chagas' disease)
- decreases the severity of acute disease and
usually eliminates detectable parasites, but it
is often ineffective in fully eradicating
infection. Thus, it often fails to prevent
progression to the gastrointestinal and
cardiac syndromes associated with chronic
infection that are the most important clinical
consequences of Trypanosoma cruzi infection.
Pharmacology – Endocrine Drugs by Dra Dando
- does not appear to be effective in the
treatment of chronic Chagas' disease
- Adverse effects include nausea, vomiting,
abdominal pain, fever, rash, restlessness,
insomnia, neuropathies, and seizures. These
effects are generally reversible but often lead
to cessation of therapy before completion of a
standard course.
e) MILTEFOSINE
- alkylphosphocholine analog that has recently
shown efficacy for the treatment of visceral
leishmaniasis
- Vomiting and diarrhea are common but
generally short-lived toxicities. Transient
elevations in liver enzymes are also seen.
- The drug should be avoided in pregnancy
because of its teratogenic effects.
- registered for the treatment of visceral
leishmaniasis in India, and—considering the
serious limitations of other drugs, including
parenteral administration, toxicity, and
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resistance—it may become the treatment of
choice for that disease
f) AMPHOTERICIN
- This important antifungal drug
- is an alternative therapy for visceral
leishmaniasis, especially in parts of India with
high-level resistance to sodium
stibogluconate, but its use is limited in
developing countries by difficulty of
administration, cost, and toxicity.
g) BENNIDAZOL
- orally administered nitroimidazole that
appears to have efficacy similar to that of
nifurtimox for the treatment of acute Chagas'
disease.
- Important toxicities include peripheral
neuropathy, rash, gastrointestinal symptoms,
and myelosuppression.
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