Pharmacology notes

1. ANTIPROTOZOAL DRUGS
MR. ETEMESI

2. ANTIMALARIALS
• Causative Organisms
– Plasmodium falciparum
– Plasmodium malariae
– Plasmodium vivax
– Plasmodium ovale
• Life Cycle Of Malaria Parasites
– An anopheline mosquito inoculates plasmodium sporozoites to initiate human
infection.
– Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage
tissue schizonts mature in the liver.
– Merozoites are subsequently released from the liver and invade erythrocytes.
– Only erythrocytic parasites cause clinical illness.
– Repeated cycles of infection can lead to the infection of many erythrocytes
and serious disease.
– Sexual stage gametocytes also develop in erythrocytes before being taken up
by mosquitoes, where they develop into infective sporozoites.

3. • In P falciparum and P malariae infection;
– Only one cycle of liver cell invasion and multiplication
occurs, and liver infection ceases spontaneously in
less than 4 weeks.
– Thus, treatment that eliminates erythrocytic parasites
will cure these infections
• In P vivax and P ovale infections;
– A dormant hepatic stage, the hypnozoite, is not
eradicated by most drugs, and subsequent relapses
can therefore occur after therapy directed against
erythrocytic parasites.
– Eradication of both erythrocytic and hepatic parasites
is required to cure these infections

4. Classification Of Anti-malarials
i. Tissue schizonticides- Drugs that eliminate
developing or dormant liver forms e.g
primaquine
ii. Blood schizonticides- Those that act on
erythrocytic parasites e.g chloroquine,
amodiaqiune, quinine, mefloquine,
pyrimethamine, proguanil, sulfadoxine,
halofantrine, lumefantrine,artemisinins and its
derivatives
iii. Gametocides- Those that kill sexual stages and
prevent transmission to mosquitoes e.g quinine,
primaquine

5. • No one available agent can reliably effect a
radical cure i.e. eliminate both hepatic and
erythrocytic stages
• Causal prophylactic drugs, i.e, capable of
preventing erythrocytic infection.
– All effective chemoprophylactic agents kill
erythrocytic parasites before they increase
sufficiently in number to cause clinical disease

6. CHLOROQUINE
• Has been the drug of choice for both treatment and
chemoprophylaxis of malaria since the 1940s.
• Is a blood schizonticide
• It is not used in P. falciparum due drug resistance.
• Is a synthetic 4-aminoquinoline
• Rapidly and almost completely absorbed from the gastrointestinal
tract
• Rapidly distributed to the tissues
• Principally excreted in the urine with an initial half-life of 3-5 days
but a much longer terminal elimination half-life of 1-2 months.
• MOA- acts by concentrating in parasite food vacuoles, preventing
the polymerization of the hemoglobin breakdown product, heme,
into hemozoin, and thus eliciting parasite toxicity due to the
buildup of free heme.

7. • Clinical Uses
– Treatment of nonfalciparum and sensitive falciparum malaria
– Chemoprophylactic agent in malarious regions without resistant
falciparum malaria(Eradication of P. vivax and P. ovale requires a
course of primaquine to clear hepatic stages)
– Amebic liver abscess - Chloroquine reaches high liver
concentrations and may be used for amebic abscesses that fail
initial therapy with metronidazole.
• Adverse Effects
– Usually very well tolerated, even with prolonged use
– Pruritus, Nausea, vomiting, abdominal pain, headache,
anorexia, malaise, blurring of vision, and urticaria
– Rare reactions include hemolysis in glucose-6-phosphate
dehydrogenase (G6PD)-deficient persons, impaired hearing,
confusion, psychosis, seizures, agranulocytosis, exfoliative
dermatitis, alopecia, bleaching of hair, hypotension, and
electrocardiographic changes
• Contraindications - in patients with psoriasis or porphyria

8. AMODIAQUINE
• Is closely related to chloroquine
• Shares mechanisms of action and resistance
with chloroquine
• Adverse effects- agranulocytosis, aplastic
anemia and hepatotoxicity, have limited use of
the drug in recent years

9. QUININE
– Quinine is derived from the bark of the cinchona tree
– Quinine and quinidine remain first-line therapies for falciparum
malaria, especially severe disease, although toxicity may complicate
therapy
– Resistance to quinine is uncommon but increasing
– After oral administration, quinine is rapidly absorbed, reaches peak
plasma levels in 1-3 hours, and is widely distributed in body tissues
– Quinine is highly protein bound
– The use of a loading dose in severe malaria allows the achievement of
peak levels within a few hours
– The half-life of quinine also is longer in those with severe malaria (18
hours) than in healthy controls (11 hours).
– Quinine is primarily metabolized in the liver and excreted in the urine
QUINIDINE
– Quinidine is stereoisomer of quinine, and as effective as parenteral
quinine in the treatment of severe falciparum malaria
– Quinidine has a shorter half-life than quinine.

10. • MOA
– Is a rapidly acting, highly effective blood
schizonticide against the four species of human
malaria parasites
– The drug is gametocidal against P. vivax and P.
ovale but not P. falciparum.
– It is not active against liver stage parasites

11. • Clinical Uses
– Parenteral treatment of severe falciparum malaria
• Quinine dihydrochloride or quinidine gluconate is the treatment of
choice for severe falciparum malaria
– Oral treatment of falciparum malaria
• Quinine sulfate is appropriate first-line therapy for uncomplicated
falciparum malaria
• Quinine is commonly used with a second drug (most often doxycycline
or, in children, clindamycin) to shorten quinine's duration of use
(usually to 3 days) and limit toxicity.
– Malarial chemoprophylaxis
• Quinine is not generally used in chemoprophylaxis owing to its
toxicity, although a daily dose of 325 mg is effective
– Babesiosis
• Quinine is first-line therapy, in combination with clindamycin, in the
treatment of infection with Babesia microti or other human babesial
infections
• Dose of Quinine - ?

12. • Adverse Effects
– Cinchonism- Characterized by tinnitus, headache, nausea, dizziness,
flushing, and visual disturbances,If mild do not discontinue treatment
– More severe A/Es - more marked visual and auditory abnormalities,
vomiting, diarrhea, and abdominal pain
– Hypersensitivity reactions include skin rashes, urticaria, angioedema,
and bronchospasm. Hematologic abnormalities include hemolysis
(especially with G6PD deficiency), leukopenia, agranulocytosis, and
thrombocytopenia
– Therapeutic doses may cause hypoglycemia through stimulation of
insulin release; this is a particular problem in severe infections and in
pregnant patients, who have increased sensitivity to insulin
– Quinine can stimulate uterine contractions, especially in the third
trimester.
– Intravenous infusions of the drugs may cause thrombophlebitis
– Severe hypotension can follow too-rapid intravenous infusions of
quinine or quinidine
– Blackwater fever is a rare severe illness that includes marked
hemolysis and hemoglobinuria in the setting of quinine therapy for
malaria. It appears to be due to a hypersensitivity reaction to the drug,
though its pathogenesis is uncertain.

13. • Contraindications
– Quinine (or quinidine) should be discontinued if signs of
severe cinchonism, hemolysis, or hypersensitivity occur.
– It should be avoided if possible in patients with underlying
visual or auditory problems
– Quinine should not be given concurrently with mefloquine
• Interactions
– Aluminum-containing antacids reduce absorptionfrom the
GIT
– Quinine can raise plasma levels of warfarin and digoxin.
– Dosage must be reduced in renal insufficiency.

14. MEFLOQUINE
• Is a synthetic 4-quinoline methanol that is chemically
related to quinine
• Is effective therapy for many chloroquine-resistant strains
of P. falciparum and against other species.
• Used as chemoprophylactic drugs for use in most malaria-
endemic regions with chloroquine-resistant strains
• Given only orally
• Highly protein-bound, extensively distributed in tissues,
and eliminated slowly, allowing a single-dose treatment
regimen
• Terminal elimination half-life is about 20 days, allowing
weekly dosing for chemoprophylaxis
• Excreted slowly mainly in the feces

15. • Antimalarial action
– Mefloquine has strong blood schizonticidal activity against P.
falciparum and P. vivax, but it is not active against hepatic stages or
gametocytes
• Clinical Uses
– Chemoprophylaxis against malaria
– Treatment of mild- moderate malaria.It should not be used in severe
or complicated malaria.
• A/Es
– Nausea, vomiting, dizziness, sleep and behavioral disturbances,
epigastric pain, diarrhea, abdominal pain, headache, rash, and
dizziness
• Contraindication- if there is a history of epilepsy, psychiatric
disorders, arrhythmia, cardiac conduction defects, or sensitivity to
related drugs

16. PRIMAQUINE
• Is a synthetic 8-aminoquinoline
• Is the drug of choice for the eradication of dormant liver forms of P
vivax and P ovale.
• MOA- is active against hepatic stages of all human malaria
parasites.
– It is the only available agent active against the dormant hypnozoite
stages of P vivax and P ovale
– It is also gametocidal against the four human malaria species
• Clinical uses
– In combination with chloroquine- cures malaria caused by P.vivax and
P. ovale
– In combination with clindamycin – as an alternative regimen for
treatment of PCP
• Adverse effects
– Common- Nausea, epigastric pain, abdominal cramps, and headache
– Rarely - leukopenia, agranulocytosis, leukocytosis, and cardiac
arrhythmias

17. ATOVAQUONE
• Is a hydroxynaphthoquinone
• Was initially developed as an antimalarial and as
a component of Malarone used for prophylaxis
• Used for the treatment of mild to moderate PCP.
• Only administered orally
• Absorption is increased by fatty food
• Malarone, a fixed combination of atovaquone
(250 mg) and proguanil (100 mg), is highly
effective for both the treatment and
chemoprophylaxis of falciparum malaria
• Adverse effects include abdominal pain, nausea,
vomiting, diarrhea, headache, and rash

18. ANTIMALARIALS THAT INHIBIT OF FOLATE SYNTHESIS
• Include:
– Pyrimethamine – Is a 2,4-diaminopyrimidine related to trimethoprim
– Proguanil – Is a biguanide derivative
– Sulfadoxine – Is a sulfonamide
• Pyrimethamine
– Slowly but adequately absorbed from the GIT
– Fansidar, a fixed combination of the sulfonamide sulfadoxine (500 mg
per tablet) and pyrimethamine (25 mg per tablet), is well absorbed
– Is bound to plasma proteins, and has an elimination half-life of about
3.5 days
– Is extensively metabolized before excretion
– excreted mainly by the kidneys.
– MOA- selectively inhibit plasmodial dihydrofolate reductase, a key
enzyme in the pathway for synthesis of folate.
– Antimalarial action is achieved through action against erythrocytic
forms of susceptible strains of all four human malaria species
– The average half-life of sulfadoxine is about 170 hours.

19. • Proguanil
– Also slowly absorbed from the GIT
– Proguanil is a prodrug which is converted to
cycloguanil, the active metabolite.
– Elimination half-life of about 16 hours
– MOA- also selectively inhibit plasmodial dihydrofolate
reductase
– Antimalarial activity - against erythrocytic forms of
susceptible strains of all four human malaria species.
• also has some activity against hepatic forms

20. • Sulfonamides (e.g sulfadoxine)
– are weakly active against erythrocytic schizonts
but not against liver stages or gametocytes.
– They are not used alone as antimalarials but are
effective in combination with other agents
– inhibit another plasmodial enzyme in the folate
pathway, dihydropteroate synthase

21. • Clinical uses of antifolate antimalarials
– Chemoprophylaxis against malaria - combination of
chloroquine (500 mg weekly) and proguanil (200 mg
daily) is used as an alternative to mefloquine
– Fansidar was being used as first line treatment for
uncomplicated malaria. Currently, it is being used as a
chemoprophylactic agent against falciparum malaria.
– Sulfadiazine + Pyrimethamine – 1st line treatment of
toxoplasmosis
– A/Es - Most patients tolerate pyrimethamine and
proguanil well
• Gastrointestinal symptoms, skin rashes, and itching are rare

22. HALOFANTRINE & LUMEFANTRINE
• HALOFANTRINE
– Is a phenanthrene-methanol related to quinine
– Effective against erythrocytic (but not other) stages of all four
human malaria species
– Oral absorption is variable and is enhanced with food. Because
of toxicity concerns, it should not be taken with meals.
– Half-life is about 4 days.
– Excretion is mainly in the feces
– Halofantrine is rapidly effective against most chloroquine-
resistant strains of P. falciparum
– MOA- unknown
– Should not be given as prophylaxis due to its toxicity
– Adverse effects
• Most common - abdominal pain, diarrhea, vomiting, cough, rash,
headache, pruritus, and elevated liver enzymes.
• Alters cardiac conduction, with dose-related prolongation of QT and
PR intervals

23. • Lumefantrine,
– Is an aryl alcohol related to halofantrine,
– Is available as a fixed-dose combination with
artemether (Coartem)
– Half-life of lumefantrine, when used in
combination, is 4.5 hours
– Oral absorption is highly variable and improved
when the drug is taken with food
– Uses – Coartem (artemether + Lumefantrine) is
highly effective against falciparum malaria and is
used as first-line therapy for uncomplicated
malaria.

24. ARTEMISININ & ITS DERIVATIVES
• Artemisinin
– Is an active component of a herbal medicine that has been used as an
antipyretic in China for over 2000 years
– Is insoluble and can only be used orally
– Synthetic artemisinin analogues include:
• Artesunate – Is water-soluble; useful for oral, intravenous, intramuscular, and
rectal administration
• Artemether – Is lipid-soluble; useful for oral, intramuscular, and rectal
administration
– Artemisinin and its analogs are rapidly absorbed, and have half-lives of
1-3 hours after oral administration
– The compounds are rapidly metabolized to the active metabolite
dihydroartemisinin
– Dihydroartemisinin is also available as a drug and is under study as
combination chemotherapy with piperaquine, a quinoline related to
chloroquine
– Artemisinin and analogs are very rapidly acting blood schizonticides
against all human malaria parasites.
– Artemisinins have no effect on hepatic stages

25. – Artesunate and artemether are the only drugs reliably effective
against quinine resistant strains
– The efficacy of the artemisinins is limited somewhat by their
short plasma half-lives which also limits their use as prophylactic
agents
• Clinical Uses
– Artesunate is used for the treatment of uncomplicated and
severe falciparum malaria
– Artesunate can also be combined with mefloquine to treat
highly resistant falciparum malaria
– Artemether is available alone and as a fixed-dose combination
with lumefantrine
– WHO recommended combinations for uncomplicated malaria
in regions with resistance to older drugs include:
• artemether plus lumefantrine,
• artesunate plus amodiaquine,
• artesunate plus mefloquine
• artesunate plus sulfadoxine plus pyrimethamine

26. • Most commonly reported adverse effects have
been nausea, vomiting, and diarrhea
• Artemisinins should be avoided in pregnancy if
possible because teratogenicity has been seen
in animal studies, although use in human
pregnancy has apparently not led to fetal
problems.

27. ANTIBIOTICS WITH ANTIMALARIAL ACTION
• Include
a. Sulfonamides
b. Tetracycline and doxycycline are active against
erythrocytic schizonts of all human malaria parasites.
• Doxycycline is commonly used in the treatment of falciparum
malaria in conjunction with quinidine or quinine, allowing a
shorter and better-tolerated course of quinine
c. Clindamycin is slowly active against erythrocytic
schizonts and can be used in conjunction with quinine or
quinidine in those for whom doxycycline is not
recommended, such as children and pregnant women
d. Azithromycin also has antimalarial activity and is now
under study as an alternative chemoprophylactic drug

28. TREATMENT OF AMOEBIASIS
• Amebiasis is infection with Entamoeba
histolytica.
• This organism can cause:
– asymptomatic intestinal infection,
– mild to moderate colitis,
– severe intestinal infection (dysentery),
– ameboma,
– liver abscess, and
– other extraintestinal infections

29. METRONIDAZOLE & TINIDAZOLE
• Are nitroimidazoles
• MOA and Adverse effects – (Recall in
antibacterials drugs)
• Clinical uses
– Treatment of amoebiasis, guardiasis and
trichomoniasis
• Dose- ?

30. DILOXANIDE FUROATE
• Is a dichloroacetamide derivative
• Is an effective luminal amebicide but is not active
against tissue trophozoites
• The mechanism of action of diloxanide furoate is
unknown
• Is considered as a drug of choice for
asymptomatic luminal amoebic infections
• A/Es
– Flatulence- is common
– Nausea, abdominal cramps, rashes – uncommon
• Contraindication- Not recommended in
pregnancy

31. PAROMOMYCIN
• Is an aminoglycoside antibiotic that is not
significantly absorbed from the GIT
• It is used only as a luminal amebicide and has no
effect against extraintestinal amebic infections
• A/Es
– Occasional abdominal distress and diarrhea
– May accumulate with renal insufficiency and
contribute to renal toxicity
• Contraindications
– Avoid in patients with significant renal disease
– Use with caution in persons with GIT ulcerations

32. OTHER ANTIPROTOZOAL DRUGS
1. PENTAMIDINE
– Has activity against trypanosoma protozoans and against
Pneumocystis carinii
Uses
• Treatment of pulmonary and extrapulmonary disease caused by P. carinii
• Treatment of African trypanosomiasis(Sleeping sickness)
• Used as an alternative to sodium stibogluconate in the treatment of visceral
leshmaniasis
A/Es – Occur in 50% of patients
• Rapid intravenous administration can lead to severe hypotension,
tachycardia, dizziness, and dyspnea.
• Pain at I.M injection site is common and sterile abscesses may develop.
• Hypoglycemia due to inappropriate insulin release
• Other A/Es - rash, metallic taste, fever, GIT symptoms, abnormal LFTs, acute
pancreatitis, hypocalcemia, thrombocytopenia, hallucinations, and cardiac
arrhythmias

33. 2. SODIUM STIBOGLUCONATE
– Is used as a first-line agent for cutaneous and
visceral leishmaniasis
– I.V administration is preffered to I.M route
– Mechanism of action is unknown
A/Es
• ECG changes (T wave changes and QT prolongation)
• Arrhythmias
• Rare A/Es - Hemolytic anemia and serious liver, renal,
and cardiac effects

34. 3. SURAMIN
– Is a sulfated naphthylamine
– Is the first-line therapy for early hemolymphatic African
trypanosomiasis (especially T. brucei gambiense infection)
– Can also be used for chemoprophylaxis against African
trypanosomiasis
– Mechanism of action is unknown.
– It is administered intravenously
– The drug is slowly cleared by renal excretion
A/Es
• Immediate reactions can include: fatigue, nausea, 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.