Classify the anti malerial drugs pharmacology

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Classification of Antimalarial Drugs - Pharmacology

Overview: Classification by Stage of Action

Antimalarial drugs are classified by which stage of the Plasmodium life cycle they target:

Category	Definition	Examples
Blood schizonticides	Kill erythrocytic (blood) stage parasites	Chloroquine, quinine, mefloquine, artemisinins
Tissue schizonticides	Eliminate developing/dormant liver forms	Primaquine, tafenoquine, proguanil (partial)
Gametocides	Kill sexual stages; prevent mosquito transmission	Primaquine, artemisinins (partial)
Causal prophylactics	Prevent erythrocytic infection entirely	Very few (atovaquone-proguanil, primaquine)

No single drug reliably eradicates both hepatic and erythrocytic stages (a "radical cure").

Classification by Chemical Structure

1. 4-Aminoquinolines

Drugs: Chloroquine, Amodiaquine

Mechanism of Action:

Concentrate in parasite food vacuoles
Prevent biocrystallization of heme (from hemoglobin breakdown) into hemozoin (inert crystal)
Free heme accumulates and is toxic to the parasite
Highly effective blood schizonticides; NOT active against liver stages or gametocytes

Chloroquine:

Oral absorption is rapid and near-complete; t½ = 1-2 months (very long)
Volume of distribution: 100-1000 L/kg (extensive tissue binding)
Drug of choice for sensitive P. falciparum, P. vivax, P. ovale, P. malariae
Resistance: Widespread in P. falciparum (reduced drug accumulation via PfCRT transporter mutation)
Uses: Treatment + chemoprophylaxis in chloroquine-sensitive areas (Central America west of Panama Canal, Hispaniola, Egypt, parts of Middle East)
Adverse effects: Nausea, pruritus (especially in dark-skinned patients), ECG QT prolongation, postural hypotension; long-term high-dose: irreversible retinopathy
Serious toxicity: High doses - hypotension, cardiac arrhythmias; overdose can be rapidly fatal

Amodiaquine:

Used for some chloroquine-resistant strains
Available in fixed combination with artesunate (ASAQ)

2. Quinoline Methanols

Drugs: Quinine, Mefloquine

Mechanism of Action:

Similar to chloroquine - interfere with heme detoxification in food vacuole
Mefloquine: exact mechanism unknown but strong blood schizonticidal activity
Both are blood schizonticides only - not active against liver stages or gametocytes

Quinine:

Oral and IV administration; well absorbed orally
Binds plasma proteins; excreted in urine
Uses: Treatment of P. falciparum (oral and IV); still used in severe malaria if artemisinin resistance suspected (combined with artesunate)
Adverse effects - "Cinchonism": Tinnitus, high-tone hearing loss, headache, nausea, dysphoria, visual disturbances - occur even at therapeutic doses
Serious toxicity: Hypoglycemia (stimulates insulin release), arrhythmias, blackwater fever (massive hemolysis + hemoglobinuria)
Contraindications: Avoid with mefloquine (both prolong QT); reduce dose in renal insufficiency

Mefloquine:

Oral only (severe local irritation with parenteral use)
t½ approximately 20 days - allows weekly dosing; highly protein-bound
Uses: Chemoprophylaxis + treatment of chloroquine-resistant P. falciparum; part of artesunate-mefloquine combination (WHO-recommended ACT)
Adverse effects: Nausea, dizziness, sleep disturbances, epigastric pain; neuropsychiatric toxicity (seizures, psychosis) - FDA issued black box warning in 2013
Resistance: Uncommon except in Southeast Asia (border regions of Thailand)

3. 8-Aminoquinolines

Drugs: Primaquine, Tafenoquine

Mechanism of Action:

Active against hepatic stages (hypnozoites and liver schizonts)
Gametocidal
Exact mechanism not fully elucidated; likely involves oxidative damage via reactive metabolites

Primaquine:

Oral absorption adequate; metabolized to active products
Uses: Radical cure of P. vivax and P. ovale (eliminates hypnozoites, preventing relapse); terminal prophylaxis; alternative primary chemoprophylaxis
Dose: 52.6 mg (30 mg base) daily for 14 days
Critical toxicity: Hemolytic anemia in G6PD-deficient patients - G6PD testing MANDATORY before use
Contraindications: Pregnancy, G6PD deficiency

Tafenoquine:

Newer 8-aminoquinoline with longer half-life
Single-dose (300 mg) radical cure for P. vivax and P. ovale
Also used for chemoprophylaxis: 200 mg daily x 3 days, then weekly
Same hemolysis risk as primaquine in G6PD deficiency

4. Bisquinolines

Drug: Piperaquine

Long half-life
Available only in fixed combination with dihydroartemisinin (DHA-PPQ) - a first-line ACT
Blood schizonticide; used for P. falciparum and P. vivax

5. Artemisinins (Sesquiterpene Lactone Endoperoxides)

Drugs: Artesunate, Artemether, Dihydroartemisinin (DHA), Artemotil (arteether)

Mechanism of Action:

Endoperoxide bridge cleaved by intraparasitic heme iron, generating free radicals
Free radicals alkylate and damage parasite proteins
Fastest acting of all antimalarials; active against all blood stages including young ring forms
Also active against gametocytes of P. falciparum
NOT active against liver stages

Formulations and Routes:

Drug	Route	Notes
Artesunate (IV/IM)	IV, IM, rectal, oral	Gold standard for severe malaria; FDA-approved IV form
Artemether	IM, oral	Oil-based - erratic absorption IM; used in Coartem (oral)
DHA	Oral	Active metabolite of most artemisinins
Artemotil	IM	Oil-based; erratic absorption

Artesunate IV is first-line for severe/complicated malaria (superior to quinine in trials)
Always used in combination (ACTs) to prevent resistance; very short t½ requires partner drug

Resistance: Emerging P. falciparum resistance in Southeast Asia (kelch-13 mutations) - a major global health concern.

6. Folate Synthesis Inhibitors

Drugs: Pyrimethamine, Proguanil, Sulfadoxine, Sulphones (dapsone)

Mechanism of Action:

Pyrimethamine + Proguanil - inhibit plasmodial dihydrofolate reductase (DHFR), blocking folate synthesis
Proguanil is a prodrug - converted to active triazine metabolite cycloguanil
Sulfadoxine (sulfonamide) - inhibits dihydropteroate synthase (DHPS)
Combining DHFR + DHPS inhibitors provides synergistic blockade of folate pathway

Key Drug Combinations:

Fansidar (Sulfadoxine-Pyrimethamine, SP): Long t½ of sulfadoxine (~170 h); used for intermittent preventive therapy (IPTp) in pregnancy in endemic areas; widespread resistance limits treatment use
Malarone (Atovaquone + Proguanil): Highly effective for treatment AND chemoprophylaxis of P. falciparum; taken daily; shorter pre/post-travel dosing window than mefloquine; proguanil also has some causal prophylactic activity against liver stages

Adverse effects: Fansidar - severe cutaneous reactions (Stevens-Johnson syndrome); Malarone - GI disturbance, headache, insomnia; generally well tolerated.

7. Naphthoquinone

Drug: Atovaquone (always used in combination with proguanil = Malarone)

Mechanism of Action:

Selectively inhibits parasite mitochondrial electron transport at cytochrome bc1 complex (Complex III)
Collapses parasite mitochondrial membrane potential
Blood schizonticide; proguanil (partner drug) acts synergistically

8. Tetracyclines (Antibiotics with Antimalarial Activity)

Drug: Doxycycline, Tetracycline

Slow-acting blood schizonticides
Inhibit parasite protein synthesis (target apicoplast protein synthesis)
Used as combination therapy with quinine for P. falciparum
Used alone for chemoprophylaxis in multidrug-resistant areas (e.g., Thai-Myanmar border)
Dose: Doxycycline 100 mg daily
Contraindications: Pregnancy, children <8 years (tooth discoloration, bone effects)

9. Aryl Alcohol

Drug: Lumefantrine

Only available in fixed combination with artemether (Coartem/Riamet)
First-line treatment for uncomplicated P. falciparum malaria worldwide
t½ = 3-4 days; oral absorption improved significantly with fatty food (must be taken with food)
Blood schizonticide
Generally well tolerated; minor QT prolongation

10. Mannich Base Acridine

Drug: Pyronaridine

Available in fixed combination with artesunate (Pyramax)
t½ approximately 8 days; renal elimination
Efficacy comparable to other leading ACTs
Adverse effects: eosinophilia, transaminitis

Summary Classification Table

Class	Drug(s)	Target Stage	Key Use
4-Aminoquinolines	Chloroquine, Amodiaquine	Blood schizonts	Sensitive malaria / ACT partner
Quinoline methanols	Quinine, Mefloquine	Blood schizonts	Resistant P. falciparum
8-Aminoquinolines	Primaquine, Tafenoquine	Liver (hypnozoites), gametocytes	Radical cure P. vivax/ovale
Bisquinolines	Piperaquine	Blood schizonts	ACT partner (DHA-PPQ)
Artemisinins	Artesunate, Artemether, DHA	All blood stages, gametocytes	Severe malaria; backbone of ACTs
Folate inhibitors	Pyrimethamine, Proguanil, SP	Blood schizonts (slow)	Combination therapy, IPT, prophylaxis
Naphthoquinone	Atovaquone	Mitochondria (blood stages)	ACT partner (Malarone)
Tetracyclines	Doxycycline	Blood schizonts (slow)	Combination therapy, prophylaxis
Aryl alcohol	Lumefantrine	Blood schizonts	ACT partner (Coartem)
Mannich base	Pyronaridine	Blood schizonts	ACT partner (Pyramax)

Artemisinin-Based Combinations (ACTs) - WHO Recommended

Combination	Brand	First-line Use
Artemether + Lumefantrine	Coartem	Uncomplicated falciparum malaria (global first-line)
Artesunate + Amodiaquine	ASAQ	Africa, parts of Asia
Artesunate + Mefloquine	ASMQ	Southeast Asia
Dihydroartemisinin + Piperaquine	DHA-PPQ	Asia, parts of Africa
Artesunate + Pyronaridine	Pyramax	Falciparum and vivax malaria
Artesunate + SP (Fansidar)	Some regions	Where SP resistance is low

Sources:

Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 52 (Antiprotozoal Drugs)
Harrison's Principles of Internal Medicine 22E, Table 231-7

Classify the anti malerial drugs pharmacology. If possible give in classification tables and flow charts

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<!-- ══════════════════ HEADER ══════════════════ -->
<div class="header">
  <h1>🦟 Antimalarial Drugs</h1>
  <p>Complete Pharmacology Classification — Tables, Flowcharts &amp; Drug Profiles</p>
  <span class="badge">Sources: Katzung 16e · Harrison's 22e · Goldman-Cecil</span>
</div>

<div class="container">

<!-- ══════════════════ SECTION 1: MASTER CLASSIFICATION TABLE ══════════════════ -->
<div class="section-title">① Master Classification Table</div>

<div class="tbl-wrap">
<table>
  <thead>
    <tr>
      <th>#</th>
      <th>Chemical Class</th>
      <th>Drug(s)</th>
      <th>Mechanism of Action</th>
      <th>Stage Killed</th>
      <th>Key Use</th>
      <th>t½</th>
      <th>Route</th>
    </tr>
  </thead>
  <tbody>
    <tr>
      <td>1</td>
      <td><strong>4-Aminoquinolines</strong></td>
      <td>Chloroquine<br>Amodiaquine</td>
      <td>Inhibit heme biocrystallization → heme accumulation → parasite death</td>
      <td><span class="pill pill-blood">Blood schizont</span></td>
      <td>Tx &amp; prophylaxis (sensitive strains); ASAQ combination</td>
      <td>1–2 months</td>
      <td>Oral, IM</td>
    </tr>
    <tr>
      <td>2</td>
      <td><strong>Quinoline Methanols</strong></td>
      <td>Quinine<br>Quinidine<br>Mefloquine</td>
      <td>Interfere with heme detoxification in food vacuole (exact mechanism unclear for mefloquine)</td>
      <td><span class="pill pill-blood">Blood schizont</span></td>
      <td>Quinine: severe malaria IV; Mefloquine: prophylaxis + Rx chloroquine-resistant P. falciparum</td>
      <td>Quinine: 8–14 h<br>Mefloquine: 20 days</td>
      <td>Oral, IV (quinine/quinidine)</td>
    </tr>
    <tr>
      <td>3</td>
      <td><strong>8-Aminoquinolines</strong></td>
      <td>Primaquine<br>Tafenoquine</td>
      <td>Oxidative stress via reactive metabolites → kills liver stages &amp; gametocytes</td>
      <td><span class="pill pill-liver">Liver (hypnozoite)</span> <span class="pill pill-game">Gametocyte</span></td>
      <td>Radical cure P. vivax / P. ovale; terminal prophylaxis</td>
      <td>Primaquine: 5–7 h<br>Tafenoquine: ~14 days</td>
      <td>Oral only</td>
    </tr>
    <tr>
      <td>4</td>
      <td><strong>Bisquinoline</strong></td>
      <td>Piperaquine</td>
      <td>Similar to chloroquine — heme detoxification inhibition</td>
      <td><span class="pill pill-blood">Blood schizont</span></td>
      <td>Fixed combination with DHA (DHA-PPQ) — WHO-recommended ACT</td>
      <td>21–28 days</td>
      <td>Oral</td>
    </tr>
    <tr>
      <td>5</td>
      <td><strong>Artemisinins</strong><br><em>(Sesquiterpene lactones)</em></td>
      <td>Artesunate<br>Artemether<br>Dihydroartemisinin (DHA)<br>Artemotil</td>
      <td>Endoperoxide bridge activated by Fe²⁺-heme → free radicals → alkylate parasite proteins; fastest-acting antimalarials</td>
      <td><span class="pill pill-blood">All blood stages</span> <span class="pill pill-game">Gametocyte (partial)</span></td>
      <td>Severe malaria (artesunate IV); backbone of all ACTs</td>
      <td>Very short: 1–2 h</td>
      <td>IV, IM, oral, rectal</td>
    </tr>
    <tr>
      <td>6a</td>
      <td><strong>DHFR Inhibitors</strong><br><em>(Folate pathway)</em></td>
      <td>Pyrimethamine<br>Proguanil (→ cycloguanil)</td>
      <td>Inhibit plasmodial dihydrofolate reductase (DHFR) → block folate synthesis → no nucleotide synthesis</td>
      <td><span class="pill pill-blood">Blood schizont</span> <span class="pill pill-causal">Causal prophylaxis (proguanil)</span></td>
      <td>In combination (Fansidar, Malarone); intermittent preventive therapy (IPTp)</td>
      <td>Pyrimethamine: 3.5 days<br>Proguanil: 16 h</td>
      <td>Oral</td>
    </tr>
    <tr>
      <td>6b</td>
      <td><strong>DHPS Inhibitors</strong><br><em>(Folate pathway)</em></td>
      <td>Sulfadoxine<br>Dapsone</td>
      <td>Inhibit dihydropteroate synthase (DHPS) — synergistic with DHFR inhibitors</td>
      <td><span class="pill pill-blood">Blood schizont</span></td>
      <td>Fansidar (SP): IPTp in pregnancy; combination Tx</td>
      <td>Sulfadoxine: ~170 h</td>
      <td>Oral</td>
    </tr>
    <tr>
      <td>7</td>
      <td><strong>Naphthoquinone</strong></td>
      <td>Atovaquone</td>
      <td>Inhibits mitochondrial electron transport (cytochrome bc1, Complex III) → collapses mitochondrial membrane potential</td>
      <td><span class="pill pill-blood">Blood schizont</span> <span class="pill pill-causal">Causal prophylaxis</span></td>
      <td>Only as Malarone (atovaquone + proguanil) — Tx &amp; prophylaxis P. falciparum</td>
      <td>Atovaquone: 2–3 days</td>
      <td>Oral</td>
    </tr>
    <tr>
      <td>8</td>
      <td><strong>Tetracyclines</strong></td>
      <td>Doxycycline<br>Tetracycline</td>
      <td>Inhibit apicoplast protein synthesis → slow-acting blood schizonticide</td>
      <td><span class="pill pill-blood">Blood schizont (slow)</span></td>
      <td>Combination with quinine for P. falciparum; chemoprophylaxis (multidrug-resistant areas)</td>
      <td>Doxycycline: 18 h</td>
      <td>Oral</td>
    </tr>
    <tr>
      <td>9</td>
      <td><strong>Aryl Alcohol</strong></td>
      <td>Lumefantrine</td>
      <td>Inhibits heme polymerization (similar to chloroquine); acts on blood stages</td>
      <td><span class="pill pill-blood">Blood schizont</span></td>
      <td>Only as Coartem (artemether + lumefantrine) — global first-line ACT</td>
      <td>3–4 days</td>
      <td>Oral (with fatty food)</td>
    </tr>
    <tr>
      <td>10</td>
      <td><strong>Mannich Base Acridine</strong></td>
      <td>Pyronaridine</td>
      <td>Inhibits heme polymerization + intercalates DNA</td>
      <td><span class="pill pill-blood">Blood schizont</span></td>
      <td>Fixed combination with artesunate (Pyramax) for P. falciparum &amp; P. vivax</td>
      <td>~8 days</td>
      <td>Oral</td>
    </tr>
    <tr>
      <td>11</td>
      <td><strong>Lincosamide Antibiotic</strong></td>
      <td>Clindamycin</td>
      <td>Inhibits apicoplast ribosomal protein synthesis</td>
      <td><span class="pill pill-blood">Blood schizont (slow)</span></td>
      <td>Combination with quinine; used in pregnancy (when doxycycline CI)</td>
      <td>2–4 h</td>
      <td>Oral, IV</td>
    </tr>
  </tbody>
</table>
</div>

<div class="legend">
  <div class="legend-item"><div class="legend-dot" style="background:var(--red)"></div> Blood schizonticide</div>
  <div class="legend-item"><div class="legend-dot" style="background:var(--green)"></div> Tissue/Liver schizonticide</div>
  <div class="legend-item"><div class="legend-dot" style="background:var(--purple)"></div> Gametocide</div>
  <div class="legend-item"><div class="legend-dot" style="background:var(--teal)"></div> Causal prophylactic</div>
  <div class="legend-item"><div class="legend-dot" style="background:var(--orange)"></div> Multiple stages</div>
</div>


<!-- ══════════════════ SECTION 2: CLASSIFICATION BY STAGE OF ACTION ══════════════════ -->
<div class="section-title">② Classification by Stage of Action (Flowchart)</div>

<div class="flow-box">
<div class="mermaid">
flowchart TD
    A["🦟 ANTIMALARIAL DRUGS<br/>Classified by Stage of Action"] --> B["LIVER STAGES<br/>(Tissue Schizonticides)"]
    A --> C["BLOOD STAGES<br/>(Blood Schizonticides)"]
    A --> D["SEXUAL STAGES<br/>(Gametocides)"]
    A --> E["CAUSAL PROPHYLACTICS<br/>(Prevent Blood Infection)"]

    B --> B1["Primaquine<br/>Tafenoquine<br/><i>→ Kill hypnozoites<br/>(P. vivax, P. ovale)</i>"]
    B --> B2["Proguanil<br/>Atovaquone<br/><i>→ Kill developing liver forms<br/>(causal prophylaxis)</i>"]

    C --> C1["FAST-ACTING<br/>Artemisinins<br/>(artesunate, artemether, DHA)"]
    C --> C2["QUINOLINES<br/>Chloroquine, Amodiaquine<br/>Quinine, Mefloquine<br/>Piperaquine, Lumefantrine<br/>Pyronaridine"]
    C --> C3["ANTIFOLATES<br/>Pyrimethamine + Sulfadoxine<br/>Proguanil"]
    C --> C4["ANTIBIOTICS (slow)<br/>Doxycycline, Clindamycin"]
    C --> C5["MITOCHONDRIAL<br/>Atovaquone"]

    D --> D1["Primaquine<br/>Tafenoquine<br/><i>→ Kill P. falciparum<br/>gametocytes</i>"]
    D --> D2["Artemisinins<br/><i>→ Reduce gametocyte<br/>density (partial)</i>"]

    E --> E1["Atovaquone-Proguanil<br/>(Malarone)<br/>Primaquine, Tafenoquine"]

    style A fill:#2c3e50,color:#fff,stroke:#2c3e50
    style B fill:#27ae60,color:#fff,stroke:#27ae60
    style C fill:#c0392b,color:#fff,stroke:#c0392b
    style D fill:#8e44ad,color:#fff,stroke:#8e44ad
    style E fill:#16a085,color:#fff,stroke:#16a085
    style B1 fill:#a9dfbf,stroke:#27ae60
    style B2 fill:#a9dfbf,stroke:#27ae60
    style C1 fill:#fadbd8,stroke:#c0392b
    style C2 fill:#fadbd8,stroke:#c0392b
    style C3 fill:#fadbd8,stroke:#c0392b
    style C4 fill:#fadbd8,stroke:#c0392b
    style C5 fill:#fadbd8,stroke:#c0392b
    style D1 fill:#d7bde2,stroke:#8e44ad
    style D2 fill:#d7bde2,stroke:#8e44ad
    style E1 fill:#a2d9ce,stroke:#16a085
</div>
</div>


<!-- ══════════════════ SECTION 3: CHEMICAL CLASSIFICATION FLOWCHART ══════════════════ -->
<div class="section-title">③ Chemical Classification Flowchart</div>

<div class="flow-box">
<div class="mermaid">
flowchart LR
    ROOT["ANTIMALARIAL<br/>DRUGS"] --> QUI["QUINOLINE<br/>DERIVATIVES"]
    ROOT --> ART["ARTEMISININS<br/>(Endoperoxides)"]
    ROOT --> ANTI["ANTIFOLATES"]
    ROOT --> OTHER["OTHER<br/>AGENTS"]

    QUI --> Q4["4-Aminoquinolines<br/>━━━━━━━━<br/>Chloroquine<br/>Amodiaquine"]
    QUI --> QM["Quinoline Methanols<br/>━━━━━━━━<br/>Quinine • Quinidine<br/>Mefloquine"]
    QUI --> Q8["8-Aminoquinolines<br/>━━━━━━━━<br/>Primaquine<br/>Tafenoquine"]
    QUI --> BQ["Bisquinolines<br/>━━━━━━━━<br/>Piperaquine"]

    ART --> ART1["Artesunate (IV/oral)<br/>Artemether (IM/oral)<br/>Dihydroartemisinin<br/>Artemotil (IM)"]

    ANTI --> DHFR["DHFR Inhibitors<br/>━━━━━━━━<br/>Pyrimethamine<br/>Proguanil"]
    ANTI --> DHPS["DHPS Inhibitors<br/>━━━━━━━━<br/>Sulfadoxine<br/>Dapsone"]
    ANTI --> COMBO["Fixed Combinations<br/>━━━━━━━━<br/>Fansidar (SP)<br/>Malarone (Atov+Pro)"]

    OTHER --> NAPH["Naphthoquinone<br/>━━━━━━━━<br/>Atovaquone"]
    OTHER --> ARYL["Aryl Alcohol<br/>━━━━━━━━<br/>Lumefantrine"]
    OTHER --> MANN["Mannich Base Acridine<br/>━━━━━━━━<br/>Pyronaridine"]
    OTHER --> ABIO["Antibiotics<br/>━━━━━━━━<br/>Doxycycline<br/>Clindamycin"]

    style ROOT fill:#2c3e50,color:#fff
    style QUI  fill:#2980b9,color:#fff
    style ART  fill:#c0392b,color:#fff
    style ANTI fill:#27ae60,color:#fff
    style OTHER fill:#8e44ad,color:#fff
    style Q4   fill:#d6eaf8,stroke:#2980b9
    style QM   fill:#d6eaf8,stroke:#2980b9
    style Q8   fill:#d6eaf8,stroke:#2980b9
    style BQ   fill:#d6eaf8,stroke:#2980b9
    style ART1 fill:#fadbd8,stroke:#c0392b
    style DHFR fill:#d5f5e3,stroke:#27ae60
    style DHPS fill:#d5f5e3,stroke:#27ae60
    style COMBO fill:#d5f5e3,stroke:#27ae60
    style NAPH fill:#e8daef,stroke:#8e44ad
    style ARYL fill:#e8daef,stroke:#8e44ad
    style MANN fill:#e8daef,stroke:#8e44ad
    style ABIO fill:#e8daef,stroke:#8e44ad
</div>
</div>


<!-- ══════════════════ SECTION 4: DRUG PROFILE CARDS ══════════════════ -->
<div class="section-title">④ Drug Profile Cards</div>

<div class="cards-grid">

  <!-- CHLOROQUINE -->
  <div class="card c-blue">
    <div class="card-header"><span class="icon">💊</span> Chloroquine</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">4-Aminoquinoline</span>
        <span class="tag">Blood schizonticide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Blocks heme biocrystallization in food vacuole</li>
        <li><strong>t½:</strong> 1–2 months (very long)</li>
        <li><strong>Vd:</strong> 100–1000 L/kg (tissue binding)</li>
        <li><strong>Uses:</strong> Sensitive P. falciparum, P. vivax, P. malariae, P. ovale</li>
        <li><strong>ADRs:</strong> Pruritus, nausea, QT prolongation</li>
        <li><strong>Serious:</strong> Retinopathy (cumulative), arrhythmia</li>
      </ul>
      <div class="mech">⚠ Widespread P. falciparum resistance (PfCRT mutation)</div>
    </div>
  </div>

  <!-- QUININE -->
  <div class="card c-red">
    <div class="card-header"><span class="icon">🏥</span> Quinine</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Quinoline methanol</span>
        <span class="tag">Blood schizonticide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Interferes with heme detoxification</li>
        <li><strong>t½:</strong> 8–14 h</li>
        <li><strong>Uses:</strong> Severe P. falciparum (oral &amp; IV)</li>
        <li><strong>Cinchonism:</strong> Tinnitus, headache, high-tone hearing loss, nausea</li>
        <li><strong>Serious:</strong> Hypoglycemia (↑insulin), arrhythmia, blackwater fever</li>
      </ul>
      <div class="mech">⚠ Reduce dose in renal failure; avoid with mefloquine</div>
    </div>
  </div>

  <!-- MEFLOQUINE -->
  <div class="card c-orange">
    <div class="card-header"><span class="icon">✈</span> Mefloquine</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Quinoline methanol</span>
        <span class="tag">Blood schizonticide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Unknown; strong blood schizonticidal activity</li>
        <li><strong>t½:</strong> ~20 days → weekly dosing</li>
        <li><strong>Oral only</strong> (local irritation with parenteral use)</li>
        <li><strong>Uses:</strong> Prophylaxis + Rx chloroquine-resistant P. falciparum</li>
        <li><strong>ADRs:</strong> Neuropsychiatric (seizures, psychosis — FDA black box 2013), GI</li>
      </ul>
      <div class="mech">⚠ Avoid with quinine; resistance in SE Asia border areas</div>
    </div>
  </div>

  <!-- PRIMAQUINE -->
  <div class="card c-green">
    <div class="card-header"><span class="icon">🔬</span> Primaquine</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">8-Aminoquinoline</span>
        <span class="tag">Liver schizonticide</span>
        <span class="tag">Gametocide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Reactive oxygen species via CYP2D6 metabolites</li>
        <li><strong>t½:</strong> 5–7 h</li>
        <li><strong>Uses:</strong> Radical cure P. vivax &amp; P. ovale (kills hypnozoites)</li>
        <li><strong>Dose:</strong> 30 mg base daily × 14 days</li>
        <li><strong>CRITICAL:</strong> Check G6PD before use — hemolytic anemia in G6PD deficiency</li>
      </ul>
      <div class="mech">⚠ Contraindicated in pregnancy &amp; G6PD deficiency</div>
    </div>
  </div>

  <!-- TAFENOQUINE -->
  <div class="card c-teal">
    <div class="card-header"><span class="icon">🧬</span> Tafenoquine</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">8-Aminoquinoline</span>
        <span class="tag">Liver schizonticide</span>
        <span class="tag">Gametocide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Similar to primaquine (reactive metabolites)</li>
        <li><strong>t½:</strong> ~14 days (much longer than primaquine)</li>
        <li><strong>Uses:</strong> Single-dose (300 mg) radical cure P. vivax/ovale; weekly prophylaxis</li>
        <li><strong>Advantage:</strong> Single dose vs 14-day primaquine course</li>
        <li><strong>CRITICAL:</strong> Same G6PD hemolysis risk as primaquine</li>
      </ul>
    </div>
  </div>

  <!-- ARTESUNATE -->
  <div class="card c-red">
    <div class="card-header"><span class="icon">⚡</span> Artesunate (+ Artemisinins)</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Artemisinin</span>
        <span class="tag">Fastest-acting</span>
        <span class="tag">All blood stages</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Fe²⁺-cleaved endoperoxide → free radicals → alkylate parasite proteins</li>
        <li><strong>t½:</strong> Very short 1–2 h (partner drug needed)</li>
        <li><strong>Artesunate IV:</strong> First-line severe malaria (FDA approved; superior to quinine)</li>
        <li><strong>Coartem:</strong> Artemether + Lumefantrine (oral; #1 global ACT)</li>
        <li><strong>ADRs:</strong> Generally very well tolerated</li>
      </ul>
      <div class="mech">⚠ Always used in combination (ACTs) — never as monotherapy</div>
    </div>
  </div>

  <!-- ATOVAQUONE-PROGUANIL -->
  <div class="card c-purple">
    <div class="card-header"><span class="icon">🛡</span> Malarone (Atovaquone + Proguanil)</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Naphthoquinone</span>
        <span class="tag">DHFR inhibitor</span>
        <span class="tag">Causal prophylactic</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>Atovaquone MOA:</strong> Inhibits mitochondrial Complex III (cytochrome bc1)</li>
        <li><strong>Proguanil MOA:</strong> Inhibits DHFR (prodrug → cycloguanil)</li>
        <li><strong>Synergistic combination</strong></li>
        <li><strong>Uses:</strong> Treatment &amp; prophylaxis P. falciparum; shorter pre/post-travel window</li>
        <li><strong>Take with food</strong></li>
        <li><strong>ADRs:</strong> GI disturbance, headache, insomnia; liver enzyme elevation</li>
      </ul>
      <div class="mech">⚠ Avoid in pregnancy; levels halved by rifampin/tetracycline</div>
    </div>
  </div>

  <!-- SULFADOXINE-PYRIMETHAMINE -->
  <div class="card c-yellow">
    <div class="card-header"><span class="icon">🤰</span> Fansidar (Sulfadoxine + Pyrimethamine)</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">DHFR inhibitor</span>
        <span class="tag">DHPS inhibitor</span>
        <span class="tag">Antifolate combo</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>Pyrimethamine MOA:</strong> Inhibits DHFR (blocks folate synthesis)</li>
        <li><strong>Sulfadoxine MOA:</strong> Inhibits DHPS (synergistic antifolate block)</li>
        <li><strong>Sulfadoxine t½:</strong> ~170 h (very long)</li>
        <li><strong>Key use:</strong> IPTp — intermittent preventive therapy in pregnancy (endemic areas)</li>
        <li><strong>Serious:</strong> Stevens-Johnson syndrome, toxic epidermal necrolysis</li>
      </ul>
      <div class="mech">⚠ Widespread resistance in SE Asia; still used in Africa</div>
    </div>
  </div>

  <!-- DOXYCYCLINE -->
  <div class="card c-grey">
    <div class="card-header"><span class="icon">💉</span> Doxycycline</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Tetracycline antibiotic</span>
        <span class="tag">Blood schizonticide (slow)</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Inhibits apicoplast 70S ribosomal protein synthesis</li>
        <li><strong>t½:</strong> ~18 h → daily dosing</li>
        <li><strong>Uses:</strong> Combination with quinine for P. falciparum; prophylaxis multidrug-resistant areas (Thailand border)</li>
        <li><strong>Dose:</strong> 100 mg daily</li>
        <li><strong>ADRs:</strong> Photosensitivity, GI, esophageal irritation, candidiasis</li>
      </ul>
      <div class="mech">⚠ CI: pregnancy, children &lt;8 years</div>
    </div>
  </div>

  <!-- LUMEFANTRINE / COARTEM -->
  <div class="card c-navy">
    <div class="card-header"><span class="icon">🌍</span> Lumefantrine (Coartem)</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Aryl alcohol</span>
        <span class="tag">Blood schizonticide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Inhibits heme polymerization</li>
        <li><strong>t½:</strong> 3–4 days (as Coartem combination)</li>
        <li><strong>Only available as Coartem</strong> (artemether 20 mg + lumefantrine 120 mg)</li>
        <li><strong>Global first-line ACT</strong> for uncomplicated P. falciparum malaria</li>
        <li><strong>MUST take with fatty food</strong> (variable absorption)</li>
        <li><strong>ADRs:</strong> Well tolerated; minor QT prolongation</li>
      </ul>
    </div>
  </div>

  <!-- PIPERAQUINE -->
  <div class="card c-pink">
    <div class="card-header"><span class="icon">🔗</span> Piperaquine (DHA-PPQ)</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Bisquinoline</span>
        <span class="tag">Blood schizonticide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Inhibits heme polymerization (similar to chloroquine)</li>
        <li><strong>t½:</strong> 21–28 days (very long — post-treatment protection)</li>
        <li><strong>Only as DHA-PPQ</strong> (dihydroartemisinin + piperaquine)</li>
        <li><strong>Uses:</strong> WHO-recommended ACT for P. falciparum; P. vivax in some regions</li>
        <li><strong>ADRs:</strong> QT prolongation, GI disturbance</li>
      </ul>
    </div>
  </div>

  <!-- PYRONARIDINE -->
  <div class="card c-teal">
    <div class="card-header"><span class="icon">🧪</span> Pyronaridine (Pyramax)</div>
    <div class="card-body">
      <div class="drug-tags">
        <span class="tag">Mannich base acridine</span>
        <span class="tag">Blood schizonticide</span>
      </div>
      <ul style="margin-top:10px">
        <li><strong>MOA:</strong> Inhibits heme polymerization + DNA intercalation</li>
        <li><strong>t½:</strong> ~8 days; renal elimination</li>
        <li><strong>Only as Pyramax</strong> (artesunate + pyronaridine)</li>
        <li><strong>Uses:</strong> P. falciparum &amp; P. vivax malaria; comparable efficacy to other ACTs</li>
        <li><strong>ADRs:</strong> Eosinophilia, transaminitis</li>
      </ul>
    </div>
  </div>

</div><!-- end cards-grid -->


<!-- ══════════════════ SECTION 5: ACT COMBINATIONS TABLE ══════════════════ -->
<div class="section-title">⑤ WHO-Recommended Artemisinin-Based Combinations (ACTs)</div>

<div class="alert alert-info">
  <span class="alert-icon">ℹ</span>
  ACTs are the global standard of care for uncomplicated <em>P. falciparum</em> malaria. The short-acting artemisinin clears the bulk of parasites rapidly; the longer-acting partner drug eliminates residual parasites and provides post-treatment protection.
</div>

<div class="tbl-wrap">
<table>
  <thead>
    <tr>
      <th>ACT Combination</th>
      <th>Brand</th>
      <th>Artemisinin Component</th>
      <th>Partner Drug (t½)</th>
      <th>Key Region / Use</th>
      <th>Dosing</th>
    </tr>
  </thead>
  <tbody>
    <tr>
      <td><strong>Artemether + Lumefantrine</strong></td>
      <td>Coartem, Riamet</td>
      <td>Artemether 20 mg</td>
      <td>Lumefantrine 120 mg (3–4 days)</td>
      <td>Global first-line; FDA-approved in USA</td>
      <td>4 tabs twice daily × 3 days (with fatty food)</td>
    </tr>
    <tr>
      <td><strong>Artesunate + Amodiaquine</strong></td>
      <td>ASAQ, Coarsucam</td>
      <td>Artesunate 100 mg</td>
      <td>Amodiaquine 270 mg (days)</td>
      <td>Sub-Saharan Africa; WHO first-line</td>
      <td>Once daily × 3 days</td>
    </tr>
    <tr>
      <td><strong>Artesunate + Mefloquine</strong></td>
      <td>ASMQ, Artequin</td>
      <td>Artesunate 100–200 mg</td>
      <td>Mefloquine 400 mg (20 days)</td>
      <td>Southeast Asia (first-line Thailand)</td>
      <td>Daily × 3 days</td>
    </tr>
    <tr>
      <td><strong>Dihydroartemisinin + Piperaquine</strong></td>
      <td>Eurartesim, DHA-PPQ</td>
      <td>DHA 40 mg</td>
      <td>Piperaquine 320 mg (21–28 days)</td>
      <td>Asia, parts of Africa; long protection period</td>
      <td>Daily × 3 days (fasted)</td>
    </tr>
    <tr>
      <td><strong>Artesunate + Pyronaridine</strong></td>
      <td>Pyramax</td>
      <td>Artesunate 60 mg</td>
      <td>Pyronaridine 180 mg (8 days)</td>
      <td>P. falciparum &amp; P. vivax globally</td>
      <td>Daily × 3 days</td>
    </tr>
    <tr>
      <td><strong>Artesunate + Sulfadoxine-Pyrimethamine</strong></td>
      <td>AS+SP</td>
      <td>Artesunate</td>
      <td>SP / Fansidar (170 h)</td>
      <td>Where SP resistance is low; Africa</td>
      <td>Artesunate 3 days + SP single dose</td>
    </tr>
  </tbody>
</table>
</div>


<!-- ══════════════════ SECTION 6: TREATMENT SELECTION FLOWCHART ══════════════════ -->
<div class="section-title">⑥ Treatment Selection Flowchart</div>

<div class="flow-box">
<div class="mermaid">
flowchart TD
    START(["Patient with suspected Malaria"]) --> DIAG{"Severity?"}

    DIAG -->|"SEVERE / Complicated<br/>(altered consciousness,<br/>hyperparasitemia,<br/>organ failure)"| SEV["ARTESUNATE IV<br/>2.4 mg/kg at 0, 12, 24 h<br/>then daily × 2 days<br/>→ Follow with oral ACT"]

    DIAG -->|"UNCOMPLICATED"| SPECIES{"Species / Area<br/>of Acquisition?"}

    SPECIES -->|"P. vivax or P. ovale"| VIVAX{"Chloroquine-<br/>sensitive area?"}
    SPECIES -->|"P. falciparum"| FALCI{"Chloroquine-<br/>sensitive area?"}
    SPECIES -->|"P. malariae"| MALRI["Chloroquine<br/>(1g → 500mg at 6, 24, 48h)"]

    VIVAX -->|"Yes"| VX1["Chloroquine<br/>PLUS<br/>Primaquine (G6PD test first!)<br/>30mg base × 14 days<br/>OR Tafenoquine 300mg once"]
    VIVAX -->|"No (PNG, Indonesia)"| VX2["ACT (Coartem or DHA-PPQ)<br/>PLUS<br/>Primaquine (if G6PD normal)"]

    FALCI -->|"Yes (Central America<br/>West of Panama Canal,<br/>Haiti, Egypt)"| FX1["Chloroquine<br/>(1g → 500mg × 3 doses)"]
    FALCI -->|"No (chloroquine-resistant)"| FX2{"Specific region?"}

    FX2 -->|"Most regions"| RX1["COARTEM<br/>Artemether 20mg + Lumefantrine 120mg<br/>4 tabs twice daily × 3 days<br/><em>(with fatty food)</em>"]
    FX2 -->|"Alternative"| RX2["MALARONE<br/>Atovaquone 250mg + Proguanil 100mg<br/>4 tabs daily × 3 days"]
    FX2 -->|"Thailand border<br/>(mefloquine-resistant)"| RX3["ARTESUNATE + DOXYCYCLINE<br/>or<br/>ARTESUNATE + CLINDAMYCIN"]
    FX2 -->|"If ACT unavailable"| RX4["QUININE 650mg TID × 3–7 days<br/>+ DOXYCYCLINE 100mg BD × 7 days<br/>or CLINDAMYCIN (if pregnant)"]

    SEV --> ORAL["Complete 3-day full course:<br/>Coartem OR Malarone<br/>OR Mefloquine<br/>± Doxycycline/Clindamycin × 7 days"]

    style START fill:#2c3e50,color:#fff
    style DIAG  fill:#e67e22,color:#fff
    style SEV   fill:#c0392b,color:#fff
    style SPECIES fill:#2980b9,color:#fff
    style VIVAX fill:#27ae60,color:#fff
    style FALCI fill:#8e44ad,color:#fff
    style VX1   fill:#a9dfbf,stroke:#27ae60
    style VX2   fill:#a9dfbf,stroke:#27ae60
    style FX1   fill:#d6eaf8,stroke:#2980b9
    style FX2   fill:#d7bde2,stroke:#8e44ad
    style RX1   fill:#fadbd8,stroke:#c0392b
    style RX2   fill:#fadbd8,stroke:#c0392b
    style RX3   fill:#fadbd8,stroke:#c0392b
    style RX4   fill:#fadbd8,stroke:#c0392b
    style ORAL  fill:#fde9d9,stroke:#e67e22
    style MALRI fill:#d6eaf8,stroke:#2980b9
</div>
</div>


<!-- ══════════════════ SECTION 7: CHEMOPROPHYLAXIS TABLE ══════════════════ -->
<div class="section-title">⑦ Chemoprophylaxis Comparison Table</div>

<div class="tbl-wrap">
<table>
  <thead>
    <tr>
      <th>Drug</th>
      <th>Area / Indication</th>
      <th>Adult Dose</th>
      <th>Start Before Travel</th>
      <th>Continue After</th>
      <th>Key Advantage</th>
      <th>Key Disadvantage</th>
    </tr>
  </thead>
  <tbody>
    <tr>
      <td><strong>Chloroquine</strong></td>
      <td>Chloroquine-sensitive areas only</td>
      <td>500 mg weekly</td>
      <td>1–2 weeks</td>
      <td>4 weeks</td>
      <td>Safe in pregnancy; cheap</td>
      <td>Useless for resistant P. falciparum</td>
    </tr>
    <tr>
      <td><strong>Malarone</strong><br>(Atovaquone/Proguanil)</td>
      <td>Most malarious areas</td>
      <td>1 tablet daily</td>
      <td>1–2 days</td>
      <td>7 days (causal)</td>
      <td>Short pre/post-travel window; well tolerated</td>
      <td>Expensive; daily dosing; avoid pregnancy</td>
    </tr>
    <tr>
      <td><strong>Mefloquine</strong></td>
      <td>Most malarious areas (not SE Asia border)</td>
      <td>250 mg weekly</td>
      <td>2–3 weeks</td>
      <td>4 weeks</td>
      <td>Weekly dosing; long t½</td>
      <td>Neuropsychiatric side effects (FDA black box); avoid with quinine</td>
    </tr>
    <tr>
      <td><strong>Doxycycline</strong></td>
      <td>Multidrug-resistant areas (Thailand border)</td>
      <td>100 mg daily</td>
      <td>1–2 days</td>
      <td>4 weeks</td>
      <td>Active against P. falciparum &amp; P. vivax; cheap</td>
      <td>Photosensitivity; CI pregnancy &amp; &lt;8 years; daily</td>
    </tr>
    <tr>
      <td><strong>Primaquine</strong></td>
      <td>Terminal prophylaxis P. vivax/ovale; alternative primary prevention</td>
      <td>52.6 mg (30 mg base) daily</td>
      <td>1–2 days</td>
      <td>7 days (causal)</td>
      <td>Prevents relapse; causal prophylaxis</td>
      <td>G6PD test mandatory; CI pregnancy</td>
    </tr>
    <tr>
      <td><strong>Tafenoquine</strong></td>
      <td>Terminal prophylaxis + primary prevention (alternative)</td>
      <td>200 mg daily × 3 days loading, then 200 mg weekly</td>
      <td>3 days loading</td>
      <td>1 week</td>
      <td>Long t½; fewer doses needed</td>
      <td>G6PD test mandatory; newer drug (limited data)</td>
    </tr>
  </tbody>
</table>
</div>


<!-- ══════════════════ SECTION 8: MECHANISM SUMMARY FLOWCHART ══════════════════ -->
<div class="section-title">⑧ Mechanisms of Action — Conceptual Map</div>

<div class="flow-box">
<div class="mermaid">
flowchart TD
    P["Plasmodium Parasite<br/>🦠 Targets"] --> HV["Food Vacuole<br/>(Heme Detoxification)"]
    P --> MIT["Mitochondria<br/>(Electron Transport)"]
    P --> FOL["Folate Synthesis<br/>(DHFR + DHPS)"]
    P --> APL["Apicoplast<br/>(Protein Synthesis)"]
    P --> OXI["Oxidative Damage<br/>(Reactive Radicals)"]
    P --> DNA["DNA<br/>(Intercalation)"]

    HV --> H1["4-Aminoquinolines<br/>Chloroquine, Amodiaquine<br/>→ Block hemozoin formation"]
    HV --> H2["Quinoline Methanols<br/>Quinine, Mefloquine<br/>→ Disrupt heme processing"]
    HV --> H3["Aryl Alcohols<br/>Lumefantrine<br/>→ Inhibit heme polymerization"]
    HV --> H4["Artemisinins<br/>Artesunate, Artemether<br/>→ Fe²⁺ activates → free radicals<br/>alkylate proteins &amp; heme"]

    MIT --> M1["Atovaquone<br/>→ Inhibit Complex III (bc1)<br/>→ Collapse Δψm"]

    FOL --> F1["Pyrimethamine<br/>Proguanil (cycloguanil)<br/>→ Inhibit DHFR"]
    FOL --> F2["Sulfadoxine, Dapsone<br/>→ Inhibit DHPS<br/>Synergistic with DHFR inhibitors"]

    APL --> A1["Doxycycline<br/>Clindamycin<br/>→ Inhibit 70S ribosome<br/>(delayed death phenotype)"]

    OXI --> O1["Primaquine<br/>Tafenoquine<br/>→ CYP2D6 metabolites<br/>→ ROS in liver stages &amp; gametocytes"]

    DNA --> D1["Pyronaridine<br/>→ DNA intercalation<br/>(+ heme polymerization inhibition)"]

    style P   fill:#2c3e50,color:#fff
    style HV  fill:#c0392b,color:#fff
    style MIT fill:#8e44ad,color:#fff
    style FOL fill:#27ae60,color:#fff
    style APL fill:#2980b9,color:#fff
    style OXI fill:#e67e22,color:#fff
    style DNA fill:#16a085,color:#fff
</div>
</div>


<!-- ══════════════════ SECTION 9: ADVERSE EFFECTS TABLE ══════════════════ -->
<div class="section-title">⑨ Key Adverse Effects &amp; Contraindications</div>

<div class="tbl-wrap">
<table>
  <thead>
    <tr>
      <th>Drug</th>
      <th>Common ADRs</th>
      <th>Serious / Unique Toxicity</th>
      <th>Key Contraindications</th>
    </tr>
  </thead>
  <tbody>
    <tr>
      <td><strong>Chloroquine</strong></td>
      <td>Nausea, pruritus (dark-skinned), QT prolongation, dysarthria</td>
      <td>Irreversible retinopathy (cumulative &gt;100 g), cardiac arrhythmia, acute overdose fatality</td>
      <td>Retinal disease, G6PD deficiency (relative), pre-existing maculopathy</td>
    </tr>
    <tr>
      <td><strong>Quinine</strong></td>
      <td>Cinchonism (tinnitus, headache, nausea, hearing loss), bitter taste</td>
      <td>Hypoglycemia (↑insulin release), blackwater fever, cardiac arrhythmia, thrombocytopenia</td>
      <td>Concurrent mefloquine, severe renal failure (dose reduce), hearing impairment</td>
    </tr>
    <tr>
      <td><strong>Mefloquine</strong></td>
      <td>Nausea, dizziness, diarrhea, sleep disturbances, headache</td>
      <td>Neuropsychiatric: seizures, psychosis, depression (FDA black box warning 2013)</td>
      <td>Psychiatric history, seizure disorder, concurrent quinine, cardiac conduction abnormalities</td>
    </tr>
    <tr>
      <td><strong>Primaquine / Tafenoquine</strong></td>
      <td>Nausea, vomiting, abdominal pain, methemoglobinemia</td>
      <td>Hemolytic anemia in G6PD deficiency — potentially life-threatening</td>
      <td>G6PD deficiency, pregnancy, breastfeeding (if infant G6PD unknown)</td>
    </tr>
    <tr>
      <td><strong>Artemisinins</strong></td>
      <td>Nausea, dizziness, headache</td>
      <td>Neurotoxicity (animal data; not confirmed in humans at therapeutic doses); QT prolongation (lumefantrine minor)</td>
      <td>First trimester pregnancy (caution); no major CI at standard doses</td>
    </tr>
    <tr>
      <td><strong>Fansidar (SP)</strong></td>
      <td>GI disturbance, headache, rash</td>
      <td>Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis</td>
      <td>Sulfonamide allergy, severe renal/hepatic disease, near-term pregnancy</td>
    </tr>
    <tr>
      <td><strong>Atovaquone (Malarone)</strong></td>
      <td>GI disturbance, headache, insomnia, rash</td>
      <td>Reversible liver enzyme elevation</td>
      <td>Pregnancy (safety unknown), severe renal impairment; levels ↓ by rifampin/tetracycline</td>
    </tr>
    <tr>
      <td><strong>Doxycycline</strong></td>
      <td>Photosensitivity, GI upset, esophageal irritation, vaginal candidiasis</td>
      <td>Permanent teeth discoloration, skeletal growth inhibition in children</td>
      <td>Pregnancy, children &lt;8 years</td>
    </tr>
    <tr>
      <td><strong>Piperaquine (DHA-PPQ)</strong></td>
      <td>Epigastric pain, diarrhea</td>
      <td>QT prolongation (must take fasted)</td>
      <td>Patients at risk for cardiac arrhythmia; do NOT take with food (paradoxically ↑QT)</td>
    </tr>
  </tbody>
</table>
</div>

<div class="alert alert-danger">
  <span class="alert-icon">🚨</span>
  <strong>Always check G6PD status</strong> before prescribing primaquine or tafenoquine. Hemolytic anemia in G6PD-deficient individuals can be life-threatening.
</div>
<div class="alert alert-warn">
  <span class="alert-icon">⚠</span>
  <strong>Artemisinin monotherapy is banned by WHO</strong> for uncomplicated malaria to prevent resistance. Always use as part of an ACT.
</div>
<div class="alert alert-info">
  <span class="alert-icon">ℹ</span>
  <strong>Artemisinin partial resistance</strong> has emerged in SE Asia (kelch-13 gene mutations) and more recently in Africa — a critical global health threat requiring surveillance.
</div>


<!-- ══════════════════ FOOTER ══════════════════ -->
<div class="footer">
  Sources: Katzung's Basic and Clinical Pharmacology 16th Edition (Chapter 52) · Harrison's Principles of Internal Medicine 22E (Chapter 231) · Goldman-Cecil Medicine · WHO Guidelines for Malaria Treatment
</div>

</div><!-- end container -->

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    theme: 'default',
    flowchart: { curve: 'linear', rankSpacing: 60, nodeSpacing: 40 },
    securityLevel: 'loose'
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</body>
</html>

Running Command

ls -lh /home/daytona/workspace/antimalarial/

Here is the complete classification of antimalarial drugs with tables and flowcharts:

Download the Full Interactive File

antimalarial pharmacology

HTML File · HTML

Open this in any browser to view all rendered flowcharts (Mermaid.js), color-coded cards, and tables with full interactivity.

What's Inside (9 Sections)

① Master Classification Table

All 11 drug classes in one table: Chemical class → Drug names → Mechanism → Stage killed → Half-life → Route

② Classification by Stage of Action (Flowchart)

ANTIMALARIAL DRUGS
├── LIVER STAGES (Tissue schizonticides)
│   ├── Primaquine, Tafenoquine → Kill hypnozoites (P. vivax / P. ovale)
│   └── Proguanil, Atovaquone → Kill developing liver forms (causal prophylaxis)
├── BLOOD STAGES (Blood schizonticides)
│   ├── FAST: Artemisinins (all blood stages)
│   ├── QUINOLINES: Chloroquine, Quinine, Mefloquine, Piperaquine, Lumefantrine
│   ├── ANTIFOLATES: Pyrimethamine + Sulfadoxine
│   ├── ANTIBIOTICS (slow): Doxycycline, Clindamycin
│   └── MITOCHONDRIAL: Atovaquone
├── GAMETOCIDES (kill sexual stages)
│   ├── Primaquine, Tafenoquine (P. falciparum gametocytes)
│   └── Artemisinins (partial)
└── CAUSAL PROPHYLACTICS
    └── Malarone, Primaquine, Tafenoquine

③ Chemical Classification Flowchart

ANTIMALARIALS
├── QUINOLINE DERIVATIVES
│   ├── 4-Aminoquinolines: Chloroquine, Amodiaquine
│   ├── Quinoline Methanols: Quinine, Mefloquine
│   ├── 8-Aminoquinolines: Primaquine, Tafenoquine
│   └── Bisquinolines: Piperaquine
├── ARTEMISININS (Endoperoxides)
│   └── Artesunate, Artemether, DHA, Artemotil
├── ANTIFOLATES
│   ├── DHFR inhibitors: Pyrimethamine, Proguanil
│   ├── DHPS inhibitors: Sulfadoxine, Dapsone
│   └── Combos: Fansidar (SP), Malarone
└── OTHER AGENTS
    ├── Naphthoquinone: Atovaquone
    ├── Aryl alcohol: Lumefantrine
    ├── Mannich base: Pyronaridine
    └── Antibiotics: Doxycycline, Clindamycin

④ Drug Profile Cards (12 cards)

Color-coded cards for each major drug with: MOA, t½, uses, adverse effects, key warnings.

⑤ WHO ACT Combinations Table

All 6 WHO-recommended ACTs with partner drug t½, region, and dosing.

⑥ Treatment Selection Flowchart

Decision tree: Severe vs uncomplicated → Species → Chloroquine-sensitive vs resistant → specific drug choice

⑦ Chemoprophylaxis Comparison Table

All 6 prophylactic regimens: dose, start/stop timing, advantages, disadvantages.

⑧ Mechanisms of Action Map

Molecular targets: Food vacuole · Mitochondria · Folate pathway · Apicoplast · Oxidative · DNA

⑨ Adverse Effects & Contraindications Table

All major drugs with common ADRs, serious toxicities, and contraindications. Includes red alert boxes for:

G6PD testing (primaquine/tafenoquine)
WHO ban on artemisinin monotherapy
Artemisinin partial resistance in SE Asia/Africa

Sources: Katzung's Basic and Clinical Pharmacology 16e (Ch. 52) · Harrison's Principles of Internal Medicine 22E · Goldman-Cecil Medicine

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