For MBBS Students

1. Dr. J. N. Chaturvedi
Assoc. Prof. (Desig.), Pharmacology
S.S. Medical College, Rewa (M.P.)

2.  This disease is caused by infection with protozoan parasites of the genus Plasmodium.
 Five Plasmodium spp. are known to infect humans:
 P. falciparum,
 P. vivax,
 P. ovale,
 P. malariae, and
 P. knowlesi
 Plasmodium falciparum and P. vivax cause most malarial infections worldwide.
 Plasmodium falciparum accounts for the majority of the burden of malaria in sub-
Saharan Africa and is associated with the most severe disease.
 Plasmodium vivax accounts for half of the malaria burden in South and East Asia
 Over the past half-century, malaria parasites worldwide—primarily P. falciparum and
P. vivax—have become increasingly resistant to antimalarial drugs, including
chloroquine, quinine, sulfadoxine/pyrimethamine and atovaquone

4.  High, spiking fevers (with or without periodicity), chills, headaches, myalgias,
malaise, and GI symptoms.
 Severe headache, a characteristic early symptom in malaria caused by all
Plasmodium spp., often heralds the onset of disease, even before fever and chills.
 Plasmodium falciparum causes the most severe disease and may lead to organ
failure and death.
 Placental malaria, of particular danger for primigravidae, is due to P. falciparum
adherence to CSA in the placenta. This often leads to severe complications,
including miscarriage.
 Acute illness due to P. vivax infection may appear severe due to high fever and
prostration.

5.  Plasmodium ovale causes a clinical syndrome similar to that of P. vivax but may
be milder with lower levels of parasitemia.
 Plasmodium malariae generally causes an indolent infection with very low levels
of parasitemia and often does not produce clinical symptoms.
 An uncommon but potentially fatal complication of P. malariae is a
glomerulonephritis syndrome that does not respond to antimalarial treatment.
 Plasmodium knowlesi infection is often misdiagnosed as P. malariae by light
microscopy but has shorter erythrocytic cycle (24 h compared with 72 h for
P. malariae) and higher levels of parasitemia.
 Asymptomatic P. falciparum and P. vivax infections are common in endemic
regions and represent important potential reservoirs for malaria transmission.

6.  Based on their activities on the stage of plasmodium life cycle:
A. Agents active against erythrocytic stage:
1. Artemisinins- Artesunate, Artemether, Dihydroartemisinin
2. Chloroquine,
3. Mefloquine,
4. Quinine and quinidine,
5. Pyrimethamine,
6. Sulfadoxine, and
7. Tetracycline
B. Agents active against primary hepatic & erythrocytic stage:
1. Atovaquone
2. Proguanil
C. Agents active against primary and latent hepatic & gametocyte stage:
1. Primaquine
2. Tafenoquine

8.  It includes:
 Artemisinin,
 Dihydroartemisinin,
 Artesunate and
 Artemether.
 Effective against the asexual erythrocytic stages of P. falciparum & P. vivax.
 In addition, artemisinins possess some gametocytocidal activity, leading to a
decrease in malarial parasite transmission.
 The standard treatment of malaria employs artemisinin based combination
therapies (ACTs)-
 To increase treatment efficacy and
 reduce selection pressure for the emergence of drug resistance.

9.  Mechanism of action:
 Putative mechanisms of action are:
Artemisinin and derivatives Active form
Formation of Toxic heme-adducts Free radicals
Damage to macromolecules of parasite
Reduced heme iron

10.  Pharmacokinetics:
Available for oral (dihydroartemisinin, artesunate, and artemether); I.M. (artesunate and
artemether); I.V. (artesunate); and rectal (artesunate) routes.
A= Bioavailability after oral dosing typically is 30% or less.
D= Widely distributed with modest plasma protein binding.
M= Hepatic
E= Metabolites are excreted in urine.
T1/2= 1-2hrs.

11.  Therapeutic Uses:
1. Treatment of severe P. falciparum malaria along with other agents.
 Toxicity
1. Dose-related and reversible decreases in reticulocyte and neutrophil counts.
2. Increases in transaminase levels
3. Allergic reactions.
 Contraindications:
1. First trimester of pregnancy.
2. Children 5 kg or less.

12.  ACT Partner Drugs:
 Partner drugs for ACT are chosen for potency and t1/2 that substantially exceeds
that of the artemisinin partner. These includes:
1. Lumefantrine:
 Formulated with artemether.
 Combination is highly effective for the treatment of uncomplicated malaria.
 Large aVd & long terminal t1/2 (4-5 days). High fat meal increase absorption, thus
recommended.
2. Amodiaquine:
 Formulated with artesunate.
 Amodiaquine (t1/2= 3hrs) which is quickly converted into monodesethyl-amodiaquine
(t1/2= 9 to 18 days).

13.  ACT Partner Drugs:
3. Piperquine:
 Formulated with dihydroartemisinin.
 Large aVd and slow elimination (t1/2= 5 weeks)
4. Sulfadoxin-pyrimethamine:
 Formulated with artesunate (sulfadoxin= 25mg/kg; pyrimethamine=1.25mg/kg)
 Interferes with folate metabolism of plasmodium

15.  Chloroquine is a weak base.
 Mechanism of action:
Gets concentrated in the digestive vacuoles of susceptible plasmodium
Binds with heme and interferes with sequestration of heme to hemozoin
Oxidative damage to cell membrane & other macromolecules

16.  Mechanism of resistance:
1. Decreased entry into digestive vacuoles d/t mutation in pfcrt gene.
2. Increased efflux of drug d/t over expression of P-glycoprotein transporter
(encoded by pfmdr-1 & PfMRP)
 Pharmacokinetics:
A= well absorbed orally & from i.m/s.c. sites.
D= extensively sequesters in tissues, particularly liver, spleen, kidney, lung, and, to a
lesser extent, brain and spinal cord.
M= Hepatic CYPs
E= Metabolites (25%) & unchanged form (50%) in urine.
 Tmax= 3-5hrs
 Terminal elimination t1/2= 30-60 days

17.  Therapeutic Uses:
1. Treatment of P. vivax, P. ovale, P. malariae, P. knowlesi, and chloroquine sensitive
strains of P. falciparum malaria.
2. Chemoprophylaxis for P. vivax, P. ovale and P. malariae.
 Chloroquine rapidly controls the clinical symptoms and parasitemia of acute malarial attacks.
 Most patients become completely afebrile within 24–48 h after receiving therapeutic doses.
 If patients fail to respond during Day-2 of chloroquine therapy, resistant strains should be
suspected and therapy instituted with quinine plus tetracycline/doxycycline or with
atovaquone-proguanil, artemether-lumefantrine, or mefloquine if the others are not available.
3. Hepatic amoebiasis.
4. Manifestation of Porphyria cutanea tarda (low doses)

18.  Toxicity:
1. With high single dose or rapid i.v. administration
 Cardiovascular: hypotension, vasodilation, suppressed myocardial function, cardiac
arrhythmias, and eventual cardiac arrest.
 Neurological: Confusion, convulsions, and coma.
 I.V. dose of > 5g is usually fatal.
2. With therapeutic doses for acute malarial attack:
 Oral Chloroquine: GI upset, headache, visual disturbances, and urticaria.
3. With chronic suppressive dose for chemoprophylaxis:
 Headache, blurring of vision, diplopia, confusion, convulsions, lichenoid skin eruptions,
bleaching of hair, widening of the QRS interval, and T-wave abnormalities.
4. With chronic daily therapy (>250 mg/d leading to cumulative dose of 1g/kg/year)
 Irreversible retinopathy and ototoxicity; toxic myopathy, cardiopathy, and peripheral
neuropathy.

19.  Precautions and Contraindications:
 Not recommended for treatment of malaria in patients with:
1. Epilepsy
2. Myasthenia gravis
3. psoriasis or other exfoliative conditions.
4. Porphyria cutanea tarda
 Not recommended in pts. with Malaria in pts. with Along with mefloquine/
amiodarone/ digoxin/ cyclosporin
 Avoided/ used cautiously in pts. with severe liver/GI/neurological disease or blood
dyscrasia.
 Dose reduced in renal failure.

21.  Mechanism of action & resistance:
 Similar to Chloroquine.
 Pharmacokinetics:
A= Rapid but variable oral absorption.
D= Extensive tissue distribution & plasma protein binding (>98%)
M= Hepatic CYPs
E= Fecal (90%), unchanged in urine (10%)
T1/2= 13-24 days.
 Therapeutic Uses:
 More effective when combined with artemisinin compounds
 Reserve drug for prevention and treatment of malaria caused by drug-resistant
P. falciparum and P. vivax

22.  Toxicity and Side Effects:
1. Gastrointestinal: Nausea & vomiting
2. Neuropsychiatric: Sleep disturbance, vivid dreams, dysphoria, confusion or
decreased sensorium, acute psychosis, seizures.
 Contraindications:
1. Pregnancy.
2. Patients with a history of seizures, depression, bipolar disorder and other
severe neuropsychiatric condition.

24.  Quinidine, a stereoisomer of quinine, is more potent as an antimalarial and more
toxic than quinine.
 This drug is more toxic and less effective than chloroquine against malarial
parasites susceptible to both drugs.
 Compared to artemisinin class therapy, quinine produces poorer clinical outcomes.
 Mechanism of antimalarial action:
 Similar to Chloroquine.
 Other effects:
 Skeletal muscle relaxant effect alarming respiratory distress and dysphagia in
patients with myasthenia gravis.

25.  Pharmacokinetics:
A= Rapid oral/i.m absorption.
D= aVd ≈ 1.5L/kg
M= Hepatic CYPs
E= Renal
T1/2 = 11h (18h in severe malaria)
 Therapeutic Uses:
1. Treatment of drug-resistant P. falciparum malaria along with tetracyclines or
clindamycin.
2. Nocturnal leg cramps.

26.  Toxicity and Side Effects.
1. Quinine is associated with a triad of dose-related toxicities when given at full
therapeutic or excessive doses:
a) Cinchonism (tinnitus, high-tone deafness, visual disturbances, headache, dysphoria,
nausea, vomiting, and postural hypotension),
b) Hypoglycemia, and
c) Hypotension.
2. GI symptoms: Nausea, vomiting, abdominal pain, and diarrhea
3. Cutaneous: Flushing, sweating, rash, and angioedema, especially of the face.
4. Cardiac: QTc prolongation and other dysrhythmias s/a sinus arrest, junctional
rhythms, atrioventricular block, and ventricular tachycardia and fibrillation.
5. Blackwater fever: triad of massive hemolysis, hemoglobinemia, and hemoglobinuria
leading to anuria, renal failure.

27.  Precautions & Contraindications:
1. Patients with tinnitus or optic neuritis.
2. Patients with cardiac dysrhythmias

29.  A fixed combination of atovaquone with proguanil hydrochloride is available.
 Atovaquone is a lipophilic analogue of ubiquinone (coenzyme Q)
 Active against asexual blood and the liver stages of P. falciparum. Not active against P. vivax
hypnozoites
 Mechanism of action:
Binds to Q0 site of cytbc1
Inhibits electron transport
Collapse of mitochondrial membrane potential Inhibits regeneration of ubiquinone
Inhibition of dihydroorotate dehydrogenase Inhibition of pyrimidine
synthesis

30.  Mechanism of resistance:
 Single, nonsynonymous nucleotide polymorphisms in the cytochrome b gene located in
the mitochondrial genome.
 Pharmacokinetics:
A= Slow and variable oral absorption.
D= Highly plasma protein bound (>99%)
M= Not metabolized significantly
E= Bile Feces.
T1/2 = 2-3 days (adults), 1-2 days (children)

31.  Therapeutic Uses:
1. Mild-to-moderate attacks of chloroquine- or sulfadoxine-pyrimethamine–resistant P.
falciparum malaria.
2. Atovaquone-proguanil followed by primaquine for P. vivax malaria.
3. Chemoprophylaxis of P. falciparum malaria.
 Toxicity:
1. Gastrointestinal: abdominal pain, nausea, vomiting, diarrhea.
2. Transient elevations of serum transaminase or amylase.
 Precautions and Contraindications:
1. Children weighing less than 11 kg,
2. Pregnant women, and
3. Lactating mothers.

32.  Exerts activity against both the primary liver stages and the asexual red blood
cell stages of both P. falciparum & P. vivax infection.
 Thus adequately controlling the acute attack and usually eradicating the P.
falciparum infection but not P. vivax infection.
 Mechanism of action:
Inhibition of the bifunctional plasmodial dihydrofolate reductase–thymidylate synthetase
Inhibition of purine and pyrimidine synthesis.
 Proguanil accentuates the mitochondrial membrane-potential–collapsing action of
atovaquone against P. falciparum.

33.  Pharmacokinetics:
A= Well absorbed orally
D= Three times more as compared to plasma in RBCs
M= two major metabolites, the active cycloguanil and an inactive 4-chlorophenyl biguanide.
E= Renal (40-60%)
T1/2= 180-200 hrs
 Therapeutic Uses:
1. Proguanil in combination with atovaquone, to treat drug-resistant strains of P.
falciparum or P. vivax.
 Toxicity & Side effects:
1. Vomiting, abdominal pain, diarrhea.
2. Hematuria, and the transient appearance of epithelial cells and casts in the urine.

35.  Acts against primary and latent hepatic stages of Plasmodium spp. and prevents
relapses in P. vivax and P. ovale infections.
 Also display gametocytocidal activity against P. falciparum and other Plasmodium
species.
 Inactive against asexual blood-stage parasites.
 Mechanism of Action:
 Not Known
 Pharmacokinetics:
A= 100% oral bioavailability.
M= Hepatic
E= Renal (inactive metabolites)

36.  Therapeutic Uses:
1. Radical cure of P. vivax and P. ovale together with a blood schizonticide, usually
chloroquine.
 Simultaneous administration of a schizonticidal drug plus primaquine is more effective
than sequential treatment in promoting a radical cure.
2. Terminal chemoprophylaxis of P. vivax and P. ovale.
 Toxicity and Side Effects:
1. Mild-to-moderate abdominal distress.
2. Mild anemia, cyanosis (severe methemoglobinemia congenital deficiency of
NADH methemoglobin reductase), and leukocytosis.
3. Acute hemolysis and hemolytic anemia in humans with G6PD deficiency

37.  Precautions and Contraindications:
1. G6PD deficiency.
2. Pregnant women
3. Lactating mothers
4. Tendency to granulocytopenia (e.g., active forms of rheumatoid arthritis and
lupus erythematosus).

39.  Similar to primaquine with following differences:
1. Large volume of distribution and low clearance
2. Long terminal t1/2 (14 days)

41.  Pharmacological prevention of malaria poses a difficult challenge because P.
falciparum, has become progressively more resistant to available antimalarial drugs.
 Oral artemether-lumefantrine is likely appropriate as first-line antimalarial
treatment of uncomplicated P. falciparum malaria.
 Chloroquine remains effective against malaria caused by P. ovale, P. malariae, P.
knowlesi, most strains of P. vivax, and chloroquine-sensitive strains of P. falciparum
found in some geographic areas.
 Chloroquine-resistant strains of P. falciparum are now the rule, not the exception.
 Multidrug-resistant P. falciparum malaria is especially prevalent and severe in
Southeast Asia and Oceania.
 Drugs should not replace simple, inexpensive measures for malaria prevention s/a:
1. Avoid exposure to mosquitoes at dusk and dawn,
2. Using insect repellents containing at least 30% DEET and
3. Sleeping in well-screened rooms or under bed nets impregnated with a pyrethrin insecticide
such as permethrin.