Chloroquine for malaria treatment

Antimalarials
Antimalarial PRCOP S D Magar
Syllabus
b) Antimalarials: Etiology of malaria.
Quinolines: SAR, Quinine sulphate, Chloroquine, Amodiaquine, Primaquine phosphate, Pamaquine, Quinacrine
hydrochloride, Mefloquine.
Biguanides and dihydrotriazines: Cycloguanil pamoate, Proguanil.
Miscellaneous: Pyrimethamine, Artesunete, Artemether, Atovoquone, Halofantrine, Lumefantrine.
[Chloroquine]
LECTURE NO-20

Malaria, one of the most widespread diseases, is caused by a
Plasmodium parasite.
Its name is derived from mala aria (bad air).
The name is based on the early knowledge that malaria was
associated with swamps and badly drained areas.
The Anopheles mosquito is the carrier of the causative
protozoa was obtained by Dr. Ronald Ross, who was recognized in
1902 with the Nobel Prize in Medicine.

Malaria is caused by four species of a one-cell protozoan
of the plasmodium genus:
1. P. falciparum:
This species is estimated to cause approximately 50% of all
malaria. It causes the most severe form and the most
debilitating form of the disease, because patients feel ill
between acute attacks. One reason why it leaves the patient so
weak is that it infects up to 65% of the patient's
erythrocytes.
Etiology of malaria.

species,
2. P. Vivax:
This species is the second most common
accounting for about 40% of all malaria cases.
3. P. malariae:
While causing only 10% of all malarial cases, relapses
are very common.
4. P. ovale:
This species is the least common.

The life cycle of malarial parasite

There are four possible sites for drug therapy:
1.Kill the sporozoites injected by the mosquito and/or prevent the
sporozoites from entering the liver.
2. Kill the schizonts residing in hepatocytes and/or prevent from
becoming merozoites.
3. Kill the merozoites in the blood and/or prevent them from
developing into gametocytes.
4. Kill he gametocytes before they can enter the mosquito and
reproduce in to zygotes.

1. Cinchona alkaloid Quinine, Quinidine
2 4-Aminoquinoline Chloroquine, Amodiaquine, hydroxychloroquine,
Piperaquine, Mefloquine.
3 8-Aminoquinoline Primaquine, Pamaquine, Pentaquine, isopentaquine
4 Biguanides Proguanil (Chloroguanide), Chlorproguanil
5 Dianinopyrimidine Pyrimethamine
6 Sulphonamides and
sulfone
Sulfadoxine, Sulfamethopyrazine, Dapsone
7 Tetracycline Tetracycline, Doxycycline
8 Sesquiterpene lactones
(ARTEMISININ DERIVATIVES)
Artesunate, Artemether, Arteether
9 Amino alcohols Halofantrine, Lumefantrine
10 Naphthoquinone Atovaquone
CLASSIFICATION

1. Cinchona alkaloid
The cinchona tree produces four alkaloids.
cinchona bark.

Quinine and Quinidine:
Quinine has been used for "fevers' in South America
since the 1600s.
The pure alkaloids quinine and cinchonine were isolated in
1820.
The stereoisomer, quinidine, is a more potent
antimalarial, but it also is more toxic.
Quinine is lethal for all Plasmodium schizonts and the
gametocytes from P. vivax and P. malariae but not for
P. falciparum.

Rubane

1. Quinine Sulphate:
QUALAQUIN (quinine sulfate) is an antimalarial drug indicated only for treatment of
uncomplicated Plasmodium falciparum malaria.
Quinine sulfate has been shown to be effective in geographical regions where resistance to
chloroquine.
(R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclooctan-2-yl]-(6-methoxyquinolin-4-yl)methanol

Mode of Action:
DNA interaction: The mechanism of action for quinine is that the drug gets intercalated
into the DNA of the parasite.
It is based on the fact that the concentration required for the inhibition of nucleic acid
synthesis is significantly higher than that necessary for the inhibition of the
plasmodium parasite.

General: fever, chills, sweating, flushing and hypersensitivity reactions.
Hematologic: agranulocytosis fever, leukopenia, aplastic anemia,
Neuropsychiatric: headache, confusion and suicide.
Dermatologic: cutaneous rashes,
Respiratory: asthma,
Cardiovascular: chest pain, vasodilatation, hypotension.
Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, gastric irritation.
Hepatobiliary: granulomatous hepatitis, hepatitis, jaundice, and abnormal liver function tests.
Metabolic: hypoglycemia and anorexia.
Musculoskeletal: muscle weakness.
Renal: hemoglobinuria, renal failure, renal impairment, and acute interstitial nephritis.
Special Senses: visual disturbances, photophobia, night blindness,
Adverse drug reactions

2 4-Aminoquinoline
The 4-aminoquinolines are the closest of the antimalarial that are based on the
quinine structure.
4-N-(7-chloroquinolin-4-yl)-1-N,1-N-diethylpentane-1,4-diamine
Chloroquine

Chloroquine:
The phosphate salt is use in oral dosage forms (tablets), and the
hydrochloride salt is administered parenterally.
It is a rapidly acting erythrocytic schizonticide against all species of
plasmodia.
It has activity against the blood stages of plasmodium ovale, P.
Malariae, and susceptible strains of P. Vivax and P. Falciparum.

MECHANISM OF ACTION :

PHARMACOLOGICAL ACTIONS
1. Antimalarial activity:
• High against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum
• Gametocytes of vivax
• No activity against tissue schizonts
• Resistance develops due to efflux mechanism.
2. Other parasitic infections:
• Giardiasis, taeniasis, extrainstestinal amoebiasis
3. Other actions:
• Depressant action on myocardium, direct relaxant effect on vascular smooth muscles,
antiinflammatory, antihistaminic , local anaesthetic

Adverse drug reactions
Intolerance:
• Nausea, vomiting, anorexia
• skin rashes, photosensitivity, pigmentation,
• Long term therapy may cause bleaching of hair
• Rarely thrombocytopenia, agranulocytosis.
Ocular toxicity:
• High dose prolonged therapy
• Temporary loss of accommodation
• Lenticular opacities, subcapsular cataract.
• Retinopathy:
• Constriction of arteries, edema, blue black pigmentation, constricted field of vision.
• CNS:
• Insomnia, transient depression seizures, & ototoxicity
• CVS:
• fall in bp & cardiac arrest in children reported

THERAPEUTIC USES
1. HEPATIC AMOEBIASIS
2. GIARDIASIS
3. CLONORCHIS SINENSIS
4. RHEUMATOID ARTHRITIS

3. Amodiaquine:
It is very similar to chloroquine and does not have any
advantages over the other 4-aminoquinoline drugs.
Studies over the past 20 years in Africa have found it to be
somewhat faster acting than chloroquine.
There is evidence now that amodiaquine maybe effective
even in areas with chloroquine-resistant P. falciparum.

4-[(7-chloroquinolin-4-yl)amino]-2-(diethyl aminomethyl)phenol
4-Aminoquinolines depress cardiac muscle, impair cardiac conductivity, and produce
vasodilatation with resultant hypotension. They depress respiration and cause diplopia,
dizziness and nausea.

4. Mefloquine:
It is marketed as the R,S isomer. It Was developed in
the I960s.
It having two trifluoromethyl moieties, at positions 2’
and 8’.
No electronegative substituents at either position 6'
(quinine) or 7' (chloroquine).
It acts asschizonticide acting before the parasite
can enter the erythrocyte.

[2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol
Mefloquine is effective against malaria parasites
resistant to chloroquine.
Mefloquine is a chiral molecule.
It is reported that while the (+) enantiomer
primarily mediates an antimalarial activity,
the (-) enantiomer contribute to the psychotrophic
effects by specifically binding to adenosine receptors
in the central nervous system.

3 8-Aminoquinoline
The first compound introduced in this series was
pamaquine.
During World War II, pentaquine, isopentaquine. and
primaquine became available.

5. Primaquine Phosphate.
Is the only 8-antinoquinoline currently in use for the treatment of
malaria
Primaquine is a poor erythrocytic schizontocide: has weak
action on P.vivax.
4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine;phosphoric acid

Primaquine is a medication used to treat and prevent malaria and to
treat Pneumocystis pneumonia.
Specifically it is used for malaria due to Plasmodium vivax and Plasmodium
ovale along with other medications and for prevention if other options cannot be
used.
It is an alternative treatment for Pneumocystis pneumonia together with clindamycin.
It is taken by mouth.
On the other hand, it is more active against the pre erythrocytic stage of P
.
falciparum than that of P
. vivax.
Its effect o primary as well as secondary tissue phases of the malarial
parasite. It is highly active against gametocytes and hypnozoites.

Common side effects include nausea, vomiting, and stomach cramps.
Primaquine should not be given to people with glucose-6-phosphate dehydrogenase
(G6PD) deficiency due to the risk of red blood cell breakdown.
It is often recommended that primaquine not be used during pregnancy.
The mechanisms of action is not entirely clear but is believed to involve effects on
the malaria parasites' DNA.

Pamaquine is an 8-aminoquinoline drug formerly used for the treatment of malaria.
It is closely related to primaquine.
6. Pamaquine.
1-N,1-N-diethyl-4-N-(6-methoxyquinolin-8-yl)pentane-1,4-diamine

USES
Pamaquine is effective against the hypnozoites of the relapsing malarias (P. vivax and P.
ovale); and unlike primaquine, it is also very effective against the erythrocytic stages of all
four human malarias.
One small clinical trial of pamaquine as a causal prophylactic was disappointing (whereas
primaquine is an extremely effective causal prophylactic).
Adverse Effect:
Like primaquine, pamaquine causes haemolytic anaemia in patients with G6PD deficiency.
Patients should therefore always be screened for G6PD deficiency prior to being prescribed
pamaquine

7. Quinacrine hydrochloride
Quinacrine Hydrochloride is the dihydrochloride salt of the 9
aminoacridine derivative quinacrine with potential antineoplastic and antiparasitic activities.
Quinacrine may inhibit the transcription and activity of both basal and inducible nuclear factor-
kappaB (NF-kappaB), which may result in the induction of tumor suppressor p53 transcription,
the restoration of p53-dependent apoptotic pathways, and tumor cell apoptosis.
4-N-(6-chloro-2-methoxyacridin-9-yl)-1-N,1-N-diethylpentane-1,4-diamine;hydrochloride

An acridine derivative formerly widely used as an antimalarial but superseded by
chloroquine in recent years.
It has also been used as an anthelmintic and in the treatment of giardiasis and malignant
effusions.
It is used in cell biological experiments as an inhibitor of phospholipase A2.

4 Biguanides
Proguanil:
It is developed in 1945 is an early example of a
prodrug. It is metabolized to cycloguanil.
cycloguanil is a dihydrofolate reductase inhibitor.
(1E)-1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine

Proguanil is a slow-acting erythrocytic schizontocide which also inhibits the
preerythrocytic stage of P
. falciparum.
Proguanil is a biguanide derivative that is converted to an active metabolite
called cycloguanil.
It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase
enzyme.
It has causal prophylactic and suppressive activity against P. falciparum and cures
the acute infection.
It is also effective in suppressing the clinical attacks of vivax malaria.
However it is slower compared to 4-aminoquinolines.

Cycloguanil

4-[(3-carboxy-2-hydroxynaphthalen-1-yl)methyl]-3-hydroxynaphthalene-2-carboxylic acid;1-(4-
chlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine
Cycloguanil pamoate

Cycloguanil Pamoate is a dihydrofolate reductase inhibitor, and is a
metabolite of the antimalarial drug proguanil; its formation in vivo has
been thought to be primarily responsible for the antimalarial activity of
proguanil.
However, more recent work has indicated that, while proguanil is
synergistic with the drug atovaquone (as in the combination Malarone),
cycloguanil is in fact antagonistic to the effects of atovaquone, suggesting
that, unlike cycloguanil, proguanil may have an alternative mechanism of
antimalarial action besides dihydrofolate reductase inhibition.
Although cycloguanil is not currently in general use as an antimalarial, the
continuing development of resistance to current antimalarial drugs has led
to renewed interest in studying the use of cycloguanil in combination with
other drugs.

5 Diaminopyrimidine
Pyrimethamine
pyrimethamine inhibits the reduction of folic acid to its active tetrahydrofolate coenzyme form.
5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine
Pyrimethamine is a competitive inhibitor of dihydrofolate reductase (DHFR). DHFR is a key enzyme in
the redox cycle for production of tetrahydrofolate, a cofactor that is required for the synthesis of
DNA and proteins.

Pyrimethamine is a synthetic derivative of ethyl-pyrimidine with potent antimalarial properties.
This agent is often used in combination with other antimalarials for the treatment of uncomplicated
falciparum malaria.
Mechanism of Action
Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines
and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear
division at the time of schizont formation in erythrocytes and liver.
Pyrimethamine

8 Sesquiterpene lactones (ARTEMISININ DERIVATIVES)
Artemisinin:
Drugs in the artemisinin series are the newest of the
antimalarial drugs and are structurally unique, compared with the
compounds in current use.
The parent compound artemisinin is a natural product
annua (sweet
extracted from the dry leaves of Artemisia
wormwood).
The plant must be grown each year from seed because
mature plants may lack the active drug.

Artemisia annua

structure characteristic appears to be a
The key
"trioxane" consisting of the endoperoxide and doxepin
oxygens. This is shown by the somewhat simpler series of 3-
aryltrioxanes.

Artesunate
4-oxo-4-1,5,9-trimethyl-11,14,15,16 tetraoxatetracyclo hexadecan-10-yl]oxy] butanoic acid

Artesunate is metabolized to the active DHA. the endoperoxide bridge of DHA reacts with heme, generating
free radicals which inhibit protein and nucleic acid synthesis of the Plasmodium parasites during all
erythrocytic stages.
Mechanism of Action
Artesunate is a water-soluble, semi-synthetic derivative of the sesquiterpine lactone artemisinin with anti-
malarial, anti-schistosomiasis, antiviral, and potential anti-neoplastic activities.
Upon hydrolysis of artesunate's active endoperoxide bridge moiety by liberated heme in parasite-infected red
blood cells, reactive oxygen species and carbon-centered radicals form, which have been shown to damage
and kill parasitic organisms.
Data regarding overdoses of artesunate are rare.
Patients experiencing an overdose may present with pancytopenia, melena, seizures, multi organ failure, and
death.
Treat overdose with symptomatic and supportive measures.
Adverse Reaction/Toxicity

In the body, artemether is metabolized into the active metabolite metabolite dihydroartemisinin.
The drug works against the erythrocytic stages of P. falciparum by inhibiting nucleic acid and protein synthesis.
Artemether is administered in combination with lumefantrine for improved efficacy.
Artemether has a rapid onset of action and is rapidly cleared from the body.
It is thought that artemether provides rapid symptomatic relief by reducing the number of malarial parasites.
Lumefantrine has a much longer half life and is believed to clear residual parasites.
Artemether
10-methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo hexadecane

Mechanism of Action
Involves an interaction with ferriprotoporphyrin IX (“heme”), or ferrous ions, in the acidic
parasite food vacuole, which results in the generation of cytotoxic radical species.
The generally accepted mechanism of action of peroxide antimalarials involves interaction of
the peroxide-containing drug with heme, a hemoglobin degradation byproduct, derived from
proteolysis of hemoglobin.
This interaction is believed to result in the formation of a range of potentially
toxic oxygen and carbon-centered radicals.

9 Amino alcohols
Halofantrine:
It is a good example of drug design that incorporates bio
isosteric principles, a evidenced by the trifluoroethyl moiety.
Halofantrine is schizonticide and has no effect on the
sporozoite, gametocyte or hepatic stages.
3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)phenanthren-9-yl]propan-1-ol

The mechanism of action of Halofantrine may be similar to that
of chloroquine, quinine, and mefloquine; by forming toxic complexes with
ferritoporphyrin IX that damage the membrane of the parasite.
Mechanism of Action
Side effects incldue coughing noisy, rattling, troubled breathing, loss of
appetite, aches and pain in joints, indigestion, and skin itching or rash.
Side Effects

Lumefantrine
Lumefantrine is a member of the class of fluorenes that is 9-(p-chlorobenzylidene)-9H-
fluorene which is substituted by chlorine at positions 2 and 7, and by a 2-(dibutylamino)-1-
hydroxyethyl group at position 4.
An antimalarial drug used in combination with artemether for the treatment of multi-drug
resistant strains of falciparum malaria.
It has a role as an antimalarial. It is a tertiary amine, a member of monochlorobenzenes, a
secondary alcohol and a member of fluorenes.
2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]fluoren-4-yl]ethanol

The exact mechanism by which lumefantrine exerts its antimalarial effect is unknown.
However, available data suggest that lumefantrine inhibits the formation of β-hematin by
forming a complex with hemin and inhibits nucleic acid and protein synthesis.
Mechanism of Action
Common side effects of combination artemether/lumefantrine therapy in adults include
headache, anorexia, dizziness, and asthenia.
Common side effects in children include pyrexia, cough, vomiting, anorexia, and headache.
Possible serious adverse effects include QT prolongation, bullous eruption, urticaria,
splenomegaly (9%), hepatomegaly (adults, 9%; children, 6%), hypersensitivty reaction, and
angioedema.
Side Effects

10 Naphthoquinone
Atovaquone:
Atovaquone's chemistry is based on it being a naphthoquinone
that participates in oxidation—reduction reactions as part of its
quinone—hydroquinone system.
The drug selectively interferes with mitochondrial electron
transport, particularly at the parasite's cytochrome site.
Atovaquone and proguanil HCI are administered in combination in an
atovaquone-to-proguanil HCI ratio of 2.5:1 measured in milligrams.

3-[4-(4-chlorophenyl)cyclohexyl]-4-hydroxynaphthalene-1,2-dione
Atovaquone is a naphthoquinone compound having a 4-(4-chlorophenyl)cyclohexyl group at
the 2-position and a hydroxy substituent at the 3-position.
It has a role as an antimalarial, an antifungal agent.

Atovaquone has been linked to serum aminotransferase elevations in a small proportion
of patients (1% to 6%).
There have also been rare reports of clinically apparent, acute liver injury due to
atovaquone.
Side Effects
In Plasmodium species, the site of action appears to be the cytochrome bc1 complex
(Complex III).
Several metabolic enzymes are linked to the mitochondrial electron transport chain
via ubiquinone.
Inhibition of electron transport by atovaquone will result in indirect inhibition of these
enzymes.
The ultimate metabolic effects of such blockade may include inhibition of nucleic acid
and ATP synthesis.
Mechanism of Action

Chloroquine for malaria treatment

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