Anti malarial drugs Pharma 2nd mbbs

Reading File

Finding Sources

Reading File

I now have all the key content needed. Let me compile a comprehensive, well-structured answer for 2nd MBBS pharmacology on antimalarial drugs.

Antimalarial Drugs - Pharmacology (2nd MBBS)

Life Cycle Relevance to Drug Action

Understanding where drugs act in the malaria life cycle is the foundation of this topic:

Stage	Location	Drugs Effective
Pre-erythrocytic (liver) schizogony	Hepatocytes	Proguanil, primaquine, pyrimethamine
Erythrocytic schizogony	RBCs	Chloroquine, quinine, artemisinins, mefloquine
Hypnozoites (dormant liver forms)	P. vivax / P. ovale only	Primaquine (only reliable drug)
Gametocytes (sexual stage)	Blood	Primaquine (most effective)

Key concept: P. falciparum and P. malariae have NO hypnozoites - blood schizonticides alone can cure them. P. vivax and P. ovale have hypnozoites - must add primaquine for radical cure.

Classification of Antimalarial Drugs

1. 4-Aminoquinolines

Chloroquine, Amodiaquine

2. Quinoline Methanols

Quinine, Quinidine, Mefloquine

3. 8-Aminoquinolines

Primaquine, Tafenoquine

4. Antifolates

Pyrimethamine, Proguanil, Sulfadoxine-pyrimethamine (Fansidar)

5. Artemisinin (Sesquiterpene Lactone Endoperoxides)

Artesunate, Artemether, Arteether, Dihydroartemisinin

6. Antibiotics

Doxycycline, Tetracycline, Clindamycin

7. Combination Preparations

Artemether + Lumefantrine (Coartem) - 1st line for uncomplicated P. falciparum
Artesunate + Mefloquine
Atovaquone + Proguanil (Malarone)
Artesunate + Sulfadoxine-pyrimethamine

Drug-by-Drug Details

CHLOROQUINE

Class: 4-Aminoquinoline

Pharmacokinetics:

Oral bioavailability: almost complete absorption from GI tract
Peak plasma conc: ~3 hours
Very large volume of distribution (100-1000 L/kg) - concentrates in tissues
Half-life: initial 3-5 days; terminal half-life 1-2 months
Excreted in urine

Mechanism of Action: Chloroquine concentrates in the parasite's food vacuole. It prevents biocrystallization of heme (a hemoglobin breakdown product) into hemozoin (malaria pigment). The resulting buildup of free heme is toxic to the parasite. It is a blood schizonticide - NOT active against liver stages or gametocytes.

Clinical Uses:

Drug of choice: uncomplicated P. vivax, P. malariae, P. ovale (sensitive strains)
Chemoprophylaxis in chloroquine-sensitive areas
Amebic liver abscess (adjunct; high liver concentration)
Terminates fever in 24-48 hours, clears parasitemia in 48-72 hours

Resistance (P. falciparum): Mutation in PfCRT (P. falciparum chloroquine resistance transporter) gene. Can be partially reversed by verapamil, desipramine, chlorpheniramine (no established clinical value).

Adverse Effects:

Common: pruritus (especially in Africans), nausea, headache, blurred vision
Rare but important: retinopathy (with prolonged high-dose use), hemolysis in G6PD deficiency, ototoxicity, ECG changes (QT prolongation), psychosis

Contraindications: Retinal disease, G6PD deficiency (caution), psoriasis (may worsen)

QUININE

Class: Quinoline methanol (natural alkaloid from Cinchona bark)

Pharmacokinetics:

Oral and IV forms available
Well absorbed orally; peak in 1-3 hours
Protein-bound (~80%)
Metabolized in liver; half-life ~11 hours

Mechanism of Action: Same as chloroquine - inhibits heme polymerization in parasite food vacuoles. Blood schizonticide. Also has antipyretic, analgesic, and oxytocic effects.

Clinical Uses:

Severe/complicated P. falciparum malaria (IV quinine - still a fallback)
Oral treatment of chloroquine-resistant P. falciparum (usually combined with doxycycline or clindamycin)
Less commonly used now due to artemisinins

Adverse Effects - CINCHONISM (characteristic toxicity):

Tinnitus, headache, nausea, vomiting, abdominal pain, diarrhea
Visual disturbances (blurring, color vision changes)
Hypoglycemia (stimulates insulin release - important in pregnancy)
Cardiac toxicity: QT prolongation, ventricular arrhythmias
Blackwater fever: massive intravascular hemolysis + hemoglobinuria (rare, severe)
Hypersensitivity: flushing, urticaria, thrombocytopenia

Contraindications: Tinnitus, optic neuritis, concurrent mefloquine use, cardiac disease (use with caution), renal insufficiency (reduce dose)

PRIMAQUINE

Class: 8-Aminoquinoline

Mechanism of Action: Active against liver stages (hypnozoites and tissue schizonts) and gametocytes. The only drug effective for radical cure of P. vivax and P. ovale by eliminating hypnozoites. Requires hepatic conversion to active quinoline-quinone metabolites that generate reactive oxygen species toxic to parasites.

Clinical Uses:

Radical cure of P. vivax and P. ovale (to eliminate hypnozoites and prevent relapse)
Terminal prophylaxis after returning from endemic areas
Causal prophylaxis (alternative) - kills exoerythrocytic forms
Gametocytocidal for P. falciparum (prevents transmission)

Adverse Effects:

GI disturbances (nausea, abdominal cramps)
Most important: Hemolytic anemia in G6PD-deficient patients (check G6PD before use - mandatory)
Methemoglobinemia
Leukopenia (rare)

Contraindications:

G6PD deficiency (absolute)
Pregnancy (fetus may be G6PD deficient)
Concomitant potentially hemolytic drugs

MEFLOQUINE

Class: Quinoline methanol (synthetic, related to quinine)

Pharmacokinetics:

Oral only (parenteral use causes severe local irritation)
Peak plasma levels in ~18 hours
Highly protein-bound, extensively distributed
Very long half-life: ~20 days (allows weekly dosing for prophylaxis)
Excreted mainly in feces

Mechanism: Blood schizonticidal activity against P. falciparum and P. vivax. Not active against liver stages or gametocytes. Exact mechanism unknown.

Clinical Uses:

Chemoprophylaxis in chloroquine-resistant areas (weekly dose)
Treatment of uncomplicated P. falciparum
Part of artesunate + mefloquine ACT combination

Adverse Effects:

GI: nausea, vomiting, diarrhea, abdominal pain
Neuropsychiatric (most notable): dizziness, insomnia, nightmares, anxiety, depression, confusion, hallucinations, psychosis, seizures (boxed warning in some countries)
Cardiac: bradycardia, QT prolongation
Teratogenic concerns (avoid in 1st trimester)

Resistance: Uncommon except in Southeast Asia (Thailand-Myanmar border)

ARTEMISININS

Class: Sesquiterpene lactone endoperoxides (derived from Artemisia annua)

Members:

Artesunate (water-soluble; IV/IM/oral)
Artemether (oil-soluble; oral/IM)
Arteether (IM)
Dihydroartemisinin (active metabolite)

Mechanism of Action: The endoperoxide bridge is cleaved by intraparasitic heme-iron, generating free radicals and reactive oxygen species that alkylate parasite proteins and damage membranes. Acts on all asexual erythrocytic stages including young ring forms. Fastest acting antimalarials; most rapidly reduce parasite burden.

Clinical Uses:

Severe/complicated P. falciparum malaria: IV artesunate is drug of choice (replaced quinine as first-line per WHO)
Uncomplicated P. falciparum: only as ACTs (artemisinin-based combination therapies) - NEVER as monotherapy (prevents resistance)
Artemether + Lumefantrine (Coartem) - most widely used ACT, first-line in most endemic countries

Adverse Effects:

Generally very well tolerated
GI disturbances, headache, dizziness
Neutropenia, reticulocytopenia (transient)
Neurotoxicity (mainly in animal studies; not established in humans at therapeutic doses)
QT prolongation (especially artemether-lumefantrine)

Special Note - WHY COMBINATIONS? Artemisinins have a very short half-life (~1 hour for artesunate). Used alone, parasites surviving the short drug exposure will repopulate. A partner drug with a longer half-life eliminates remaining parasites. This also prevents resistance.

PYRIMETHAMINE + SULFADOXINE (Fansidar)

Mechanism:

Pyrimethamine: Inhibits dihydrofolate reductase (DHFR) - blocks folate synthesis
Sulfadoxine: Inhibits dihydropteroate synthase (DHPS) - blocks earlier step in folate pathway
Together: sequential blockade of folate synthesis - synergistic activity

Uses:

Intermittent preventive treatment in pregnancy (IPTp)
Treatment of chloroquine-resistant P. falciparum (with artesunate as ACT)

Adverse Effects: Stevens-Johnson syndrome, bone marrow suppression, megaloblastic anemia

PROGUANIL (Chloroguanide)

Mechanism: Prodrug - metabolized to cycloguanil, which inhibits parasite DHFR. Also has intrinsic activity on parasite mitochondrial membrane.

Uses:

Chemoprophylaxis (combined with atovaquone as Malarone)
Causal prophylaxis (inhibits pre-erythrocytic stages)

ATOVAQUONE + PROGUANIL (Malarone)

Atovaquone: Inhibits mitochondrial electron transport (Complex III) - collapses mitochondrial membrane potential
Combined action disrupts both folate synthesis and mitochondrial function
Uses: Chemoprophylaxis, treatment of uncomplicated P. falciparum
Advantage: Start 1-2 days before travel (vs. 1-2 weeks for mefloquine)
Adverse effects: nausea, vomiting, abdominal pain, headache

DOXYCYCLINE

Use in malaria:

Chemoprophylaxis (start 1-2 days before, continue 4 weeks after)
Treatment: combined with quinine for chloroquine-resistant P. falciparum
Slow-acting; never use alone for treatment

Adverse Effects: Photosensitivity, GI upset, esophagitis, teratogenic (avoid in pregnancy and children <8 years), candida overgrowth

Treatment Summary Tables

Uncomplicated P. falciparum Malaria

Situation	Drug of Choice
Chloroquine-sensitive area	Chloroquine
Chloroquine-resistant	Artemether + Lumefantrine (Coartem) or other ACT
Pregnant (1st trimester)	Quinine + clindamycin
Pregnant (2nd/3rd trimester)	ACT (artemether-lumefantrine)

Severe/Complicated P. falciparum Malaria

Drug	Route
IV Artesunate (1st choice)	IV
IV Quinine (alternative if artesunate unavailable)	IV infusion

P. vivax / P. ovale

Component	Drug
Blood stage (acute attack)	Chloroquine
Radical cure (hypnozoites)	Primaquine (after G6PD testing)

P. malariae

Chloroquine (no hypnozoites, no primaquine needed)

Chemoprophylaxis Regimens

Drug	Regimen	Advantage
Chloroquine	Weekly (1 week before, 4 weeks after)	Sensitive areas only
Mefloquine	Weekly (2 weeks before, 4 weeks after)	Resistant areas
Doxycycline	Daily (1-2 days before, 4 weeks after)	Cheap, widely available
Atovaquone-Proguanil	Daily (1-2 days before, 7 days after)	Short pre-travel start
Primaquine	Daily	Terminal prophylaxis

High-Yield Points for Exams

Radical cure of P. vivax/ovale - Primaquine (only drug that kills hypnozoites)
Check G6PD before primaquine - can cause severe hemolytic anemia
Chloroquine resistance - mediated by PfCRT mutation
Cinchonism - quinine toxicity (tinnitus, nausea, headache, visual disturbance)
Blackwater fever - massive hemolysis with quinine in P. falciparum
ACT = artemisinin-based combination therapy - never use artemisinins as monotherapy
IV artesunate - drug of choice for severe malaria (replaced IV quinine)
Mefloquine - neuropsychiatric side effects, very long half-life (~20 days)
Fansidar (SP) - double blockade of folate synthesis; used in IPTp
Malarone - short pre-travel start (1-2 days); mitochondrial electron transport inhibition
Doxycycline - contraindicated in pregnancy and <8 years; photosensitivity
Artemisinin mechanism - endoperoxide bridge + heme Fe²⁺ → free radicals

Source: Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 52

This is a shared conversation. Sign in to Orris to start your own chat.