PHARMACOLOGY BY: DR.

ASHISH RANJAN

ANTIMALARIAL DRUGS
(used for the treatment and prevention of malaria infection)

Life cycle of Plasmodium& the stage at which drug acts(mentioned in bracket)

I. Quinoline derivatives:

1. Chloroquine: 4-aminoquinolinesderivative.

Mechanism of action:

 Prevents polymerization of heme to hemozoin causing accumulation of heme which is toxic for the erythrocytic
form of the parasites (erythrocytic schizonticides).Malarial parasites flourish in host erythrocytes by digesting
hemoglobin; this generates free radicals and iron-bound heme as highly reactive by-products.
 It is NOT active against liver stage parasites.

Mechanism of resistance:

 Mutations in the gene encoding the chloroquine-resistance transporter protein (PfCRT), located in the food
vacuole of parasite.

Pharmacokinetics:

 Typically given orally. Intravenous infusion is associated with significant toxicity (severe hypotension & respiratory
& cardiac arrest).
 Largest volume of distribution (>1300 L)

Indications: [RED LIP MG]

 Rheumatoid arthitis
 Extraintestinal amebiasis
 Discoid lupus erythematosis
 Lepra reaction

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 Infectious mononucleosis
 Photogenic reactions
 Malaria
 Giardiasis

Adverse Drug Reaction:

 Well tolerated.

 Therapeutic doses (acute malarial attack): headaches, dizziness, abdominal discomfort, vomiting, diarrhea&
urticaria (not responsive to antihistamines).

 Supra-therapeutic doses (prolonged use): retinopathy (Bull’s eye maculopathy), hypotension, confusion,
arrhythmias and death. Rare reactions include hemolysis in G6PD-deficient patients, seizures, ECG changes
(QRS widening & T wave abnormalities).

Pregnancy: Safe

2. Quinine and quinidine : 4-methanolquinolines derivative

 Quinine is a derivative from the bark of the South American Cinchona tree and exists in oral and parenteral forms.
 Quinidine is a stereoisomer of quinine available in parenteral formulation.

Pharmacokinetics:

 Quinine has a short half-life. When given orally, it must be administered three times per day.

 Both have narrow therapeutic window. Overdosage- cardiotoxicity (arrhythmias & hypotension), blindness, or
deafness. Quinidine is the more cardiotoxic.

 Blood sugar levels should be monitored with intravenous infusion, as both quinine and quinidine stimulate insulin
production

Indications:

 Quinine : Cerebral malaria (falciparum)

 Quinidine: Anti- arrhythmic

Adverse Drug Reaction:

 CINCHONISM (a combination of headache, tinnitus, high tone deafness, blurred vision, vertigo, nausea, vomiting
and GI distress).
 Increased risk for cardiac arrhythmias (Torsade de pointes) due to block of cardiac K & Na channels.
 Antimuscarinic side effects

Pregnancy: – In first trimester, parenteral quinine is the drug of choice for cerebral malaria.

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3. Mefloquine:4-methanolquinolines derivative

Mechanism of action:

 Active against the hepatic stages of all human malarial parasites.

 Highly reactive metabolites of primaquine causes extensive oxidative damage that interferes with mitochondrial
electron transport in parasites. (NOTE: primaquine is also known to increase the oxidative stress on human red
blood cells, an effect that contributes to its hemolytic side effects)

Pharmacokinetics:

 Oral
 Never given parentally because of marked hypotension

Indications:

 For therapy of acute vivax and ovale malaria, it is given as a 14 day drug regimen to eradicate liver hypnozoites
following acute therapy with chloroquine (which eradicates erythrocytic forms).

Adverse Drug Reaction:

 Usually well tolerated.

 Therapeutic doses: nausea, vomiting, etc. may be reduced by dosing after meals.
 May cause hemolysis (hemolytic anemia) or methemoglobinemia (cyanosis), especially in patients with G6PD
deficiency.

Contraindications:

 G6PD deficiency
 Pregnancy
 Neurologic (Seizure) and psychiatric disorders
 cardiac conduction abnormalities.

II. Antifolates

1. Sulfadoxine-pyrimethamine

Mechanism of Action:

 Target enzymes involved in folate synthesis; pyrimethamine targets dihydrofolate reductase (DHFR), and
sulfadoxine acts on dihydropteroate synthase (DHPS)- synergistic effect

Adverse drug reaction:

 Mild side effect like gastrointestinal upset and headache.

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 Mild bone marrow suppression may occur, and sulfadoxine can precipitate hemolysis in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency. Severe cutaneous toxicity due to the sulfa moiety can
occur, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrosis

2. Atovaquone-proguanil

Mechanism of action:

 Interferes with two separate pathways involved in the biosynthesis of pyrimidines, which are essential for nucleic
acid replication.

 Atovaquone blocks the parasite mitochondrial electron transport chain, and proguanil inhibits parasite
dihydrofolate reductase through its active metabolite, cycloguanil.

 Proguanil also appears to act via a direct mechanism outside the folate pathway, enhancing atovaquone's
mitochondrial membrane toxicity

Adverse drug reaction:

 Abdominal pain, vomiting, diarrhea, headache, and pruritus

III. Artemisinins derivative:

 Derived from the leaves of the Chinese sweet wormwood plant, Artemisia annua.

 Formulations of arteminsinis: artemether, arteether, dihydroartemisinin, and artesunate.

Mechanism of Action:

 Act by production of free radicals upon iron-catalyzed cleavage of the artemisinin endoperoxide bond in the
parasite food vacuole.

 Rapid acting (fastest acting), killing blood stages (erythocytic schizonticide) of all Plasmodium species and
reducing the parasite biomass but no activity against the hepatic stages of the malarial parasite.
 Artemisinins have the fastest parasite clearance times of any antimalarial

Pharmacokinetics:

 Administered either orally (30% bioavailability) or parenterally.

 Half life 1-3 hrs. Artesunate is water soluble. Artemether is lipid soluble.

 Artesunate & artemether- Rapidly metabolized to dihydroartemisinin, the active form of the drugs.

Indications:

 Multidrug resistant malaria

 Cerebral malaria ( superior to quinine), most preferred is artesunate

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Adverse drug reaction:

 Well tolerated.

 Side effects include nausea, vomiting and diarrhea.

Pregnancy: Safety not know (Not used in Ist trimester)

Artemisinin-based combination (ACT) therapies

 Artemisinins should not be used as a single agent to prevent emergence of drug resistance (Injectable
artemisinin derivatives should be used only in severe malaria)

 It combines the highly effective short-acting artemisinins with a longer-acting partner to protect against artemisinin
resistance and to facilitate dosing convenience.

 Five ACTs recommended by WHO for the treatment of uncomplicated malaria:

 artemether-lumefantrine,
 artesunate-amodiaquine,
 artesunate-mefloquine,
 artesunate-sulfadoxine-pyrimethamine, and
 dihydroartemisinin-piperaquine

New ACT formulation: Pyronaridine-artesunatefor treatment of uncomplicated P. falciparum malaria

IV. Antimicrobials: Tetracycline, doxycycline, and clindamycin.

 In malaria parasites, these drugs appear to target the apicoplast, an organelle derived from prokaryotic ancestors.

 It has relatively slow antimalarial activity because they exert their toxic effects in the subsequent cycle of cell
division

 Usually paired with fast-acting antimalarials (usually quinine)

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 PHARMACOLOGY BY: DR. ASHISH RANJAN

ANTIULCER MEDICATIONS

1. Proton pump inhibitors (PPIs)- drugs ending in "prazole"

Mechanism of action:
 Prodrugs
 They form covalent disulfide bonds with the H/K ATPase ( final step of gastric acid secretion by parietal cells), which causes
irreversible inactivation.

Pharmacokinetics:
 PPIs differ in their pKa, bioavailability, peak plasma levels, and route of excretion
 PPIs are most effective when taken 30 to 60 minutes before the first meal of the day because the amount of H/K ATPase
present in the parietal cell is greatest after a prolonged fast.
 Maximal acid secretory capacity may not be restored for 24 to 48 hours- due to the irreversible effect on the proton
pump
 metabolized via hepatic cytochrome P450 enzymes, with CYP2C19 having the dominant role

Indications

 Peptic ulcer disease-first-line

 Gastroesophageal reflux disease
 Zollinger-Ellison syndrome
 NSAID-associated ulcers
 Eradication of Helicobacter pylori

Drug interactions:
 Clopidogrel- decreased activation of clopidogrel when used in conjunction with omeprazole due to shared hepatic
cytochrome P450-mediated metabolism
 HIV protease inhibitors -PPIs may decrease the absorption of certain HIV protease inhibitors.
 Warfarin
 should not be administered concomitantly with antisecretory agents including histamine-2 receptor antagonists,
misoprostol

Adverse effects:
 Long-term PPI use may cause a) Diarrheal illnesses- Clostridium difficile and other enteric infections b)
Malabsorption of minerals and vitamins- Magnesium malabsorption, Calcium and fracture risk, Vitamin B12
malabsorption

Potassium-competitive acid inhibitors (PCABs): Revaprazan

MOA: Works by competing for potassium on the luminal side of the parietal cell, and cause rapid and reversible
inhibition of H/K ATPase and therefore acid secretion

AFMG (DELHI, CHENNAI, UDAIPUR, TRIVANDURM, HYDERABAD, PUNE)

Helpline: 9810308460, 9810608460 visit us at: www.afmg.co.in, f: afmgmciscreening