Malaria Life Cycle - Stages Flowchart

Diagram 1 - Complete Life Cycle (Goodman & Gilman's Pharmacological Basis of Therapeutics)

Diagram 2 - Detailed Cellular Mechanisms (Robbins & Cotran Pathologic Basis of Disease)

The Three Main Stages

Stage 1 - Mosquito Bite (Sporozoite Inoculation)

• Female Anopheles mosquito takes a blood meal
• Sporozoites are released from salivary glands into the human bloodstream
• Within minutes, sporozoites travel to the liver, binding to hepatocytes via circumsporozoite protein + heparan sulfate proteoglycan and thrombospondin-related adhesive protein

Stage 2 - Hepatic (Exo-erythrocytic) Stage

Key difference for relapse: P. vivax and P. ovale form dormant hypnozoites in hepatocytes. These reactivate weeks to months later, causing relapses. P. falciparum and P. malariae do NOT form hypnozoites.

Stage 3 - Erythrocytic (Blood) Stage - The Cyclic Stage

Merozoite → invades RBC
    ↓  (binds Glycophorin via sialic acid residues)
Ring trophozoite (early)
    ↓
Trophozoite (late, with digestive vacuole - digests hemoglobin)
    ↓
Schizont (multinucleated, forms knobs/PfEMP1 on RBC surface)
    ↓
RBC ruptures → releases new Merozoites
    ↓
→ Reinvade new RBCs (cycle repeats every 48-72 hrs)
    OR
→ Some become Gametocytes (sexual forms)

• P. vivax / P. ovale: 48-hour cycle (tertian fever)
• P. malariae: 72-hour cycle (quartan fever)
• P. falciparum: irregular (can infect RBCs of all ages)

Stage 4 - Mosquito (Sexual) Stage - Completing the Cycle

Why P. falciparum is Most Dangerous

• Infects RBCs of all ages (others only infect young or old RBCs - a smaller pool)
• Sequestration: infected RBCs express PfEMP1 knobs that bind endothelial receptors (ICAM-1, CD36, VCAM-1), blocking microvascular flow - causes cerebral malaria
• High parasitemia leading to severe anemia, renal failure, pulmonary edema

Host Genetic Resistance (Protective Mutations)

• HbS (sickle cell trait) and HbC
• Thalassemias (alpha and beta)
• G6PD deficiency
• Absence of Duffy antigen (DARC) - protects against P. vivax (90% of West Africans lack it)

ACT - Which Stages Does It Target?

Direct Answer

Stage-by-Stage Breakdown (Drug Activity Table)

Mechanism of Action Against the Erythrocytic Stage

• Promiscuously alkylate parasite proteins
• Oxidize macromolecules within the parasite
• Cause a 4-log₁₀ (10,000-fold) reduction in parasite burden per 48-hour erythrocytic cycle

Why ACT is Used as Combination Therapy

Comparison with Other Antimalarials (Stage Activity)

Key takeaway: ACT treats and clears active blood-stage infection + reduces mosquito transmission via gametocytes. To prevent relapse in P. vivax or P. ovale (due to hypnozoites), you must add primaquine (or tafenoquine) to the ACT regimen.

• Goodman & Gilman's Pharmacological Basis of Therapeutics, p. 1312-1313

Bicarbonate (NaHCO₃) Dosing for Low Bicarbonate / Metabolic Acidosis

Step 1 - First Ask: WHY Is the Bicarbonate Low?

Step 2 - The Formula

Standard HCO₃ Deficit Formula (Adults)

HCO₃ deficit (mEq) = Volume of Distribution × Weight (kg) × (Desired HCO₃ − Measured HCO₃)

Worked Example

• Patient: 70 kg adult
• Measured HCO₃: 12 mEq/L
• Desired HCO₃: 22 mEq/L (target, not full normal - see below)
• Formula: 0.4 × 70 × (22 − 12) = 0.4 × 70 × 10 = 280 mEq

Step 3 - How to Give It (Critical Rules)

Rule 1: Give HALF first, then reassess

Give ½ of the calculated deficit → recheck ABG/electrolytes → recalculate if needed.

Rule 2: Target HCO₃ 22 mEq/L, NOT 24-25 mEq/L

Rule 3: Give it SLOWLY as an IV infusion

• Dilute to 0.5 mEq/mL (isotonic bicarb) - avoid full-strength (hyperosmolar, risks IVH in neonates)
• Infuse over 30-60 minutes minimum, never as a fast IV push except in cardiac arrest

Rule 4: Monitor electrolytes during infusion

• Risk of hypokalemia (bicarb drives K⁺ into cells)
• Risk of hypocalcemia (alkalosis reduces ionized Ca²⁺)
• Risk of hypernatremia (each mEq NaHCO₃ contains 1 mEq Na⁺)

Special Situations

DKA (pH <7.00 only)

• 50 mEq NaHCO₃ diluted in 300 mL NS, infused over 30-45 minutes
• Target: HCO₃ 10-12 mEq/L, pH ~7.20 - do NOT normalize
• Monitor K⁺ closely as urine output reestablishes

Cardiac Arrest / CPR

• Give ½ the corrective dose as IV bolus, other half given slowly

Chronic Metabolic Acidosis (e.g. CKD, RTA)

• Oral NaHCO₃ tablets 650 mg twice daily, titrated upward
• Or Shohl's solution (sodium citrate/citric acid)
• Goal HCO₃ ≥22 mEq/L

Quick Reference Summary

HCO₃ deficit (mEq) = 0.4 × Wt(kg) × (22 − measured HCO₃)

Give HALF the dose first → reassess → give rest if needed
Rate: slow IV infusion (dilute to 0.5 mEq/mL)
Watch: K⁺, Ca²⁺, Na⁺, pH
Target: HCO₃ = 22 mEq/L (not full normal)

When NOT to Give Bicarb

• Lactic acidosis or DKA with pH >7.00 - treat the underlying cause
• Respiratory acidosis - bicarb is wrong here; improve ventilation
• Post-cardiac arrest (routine use not recommended)

What Do You Mix NaHCO₃ With?

Short Answer

Standard Diluents - What to Use

Classic "Isotonic Bicarb Drip" Recipe:

150 mL of 8.4% NaHCO₃ added to 850 mL D5W → 1 litre bag ≈ 150 mEq/L (isotonic, ~300 mOsm)

Why Not Just NS?

1. Sodium load - NS + NaHCO₃ together give a very high Na⁺ load (both are ~154 mEq/L Na⁺). This risks hypernatremia and volume overload
2. Chloride load - NS adds chloride, which can worsen hyperchloremic acidosis - counterproductive
3. D5W is electrolyte-free - the dextrose is quickly metabolized, effectively delivering free water that dilutes the bicarb without adding Na⁺ or Cl⁻

What NaHCO₃ Must NEVER Be Mixed With

Key clinical rule: Never run NaHCO₃ through the same IV line as calcium or magnesium - always flush the line with NS between them if using the same access.

Concentration to Use

Summary

✅ Mix with: D5W (preferred) or ½NS
✅ Mix with: NS if volume replacement also needed (e.g. DKA)
❌ Never mix with: Calcium, Magnesium, Lactated Ringer's
❌ Peripheral line: dilute to 0.5 mEq/mL max

Treatment of Drug-Induced Lupus (DIL)

Step 1 - STOP the Offending Drug (Cornerstone of Treatment)

"The diagnosis is typically clinical and confirmed by resolution of symptoms with the withdrawal of the offending medication." - Rosen's Emergency Medicine

• Symptoms: resolve within weeks to months after stopping the drug
• Anti-histone antibodies: may persist for months to years even after symptoms resolve
• ANA: can remain positive long-term - a persistently positive ANA alone is NOT a reason to restart or avoid treatment

Step 2 - Symptomatic Treatment (While Awaiting Resolution)

Step-by-Step Management Algorithm

Patient presents with lupus-like features
              ↓
Review all medications - identify likely culprit
              ↓
STOP the offending drug
              ↓
        Mild symptoms?          Moderate/severe?
        ↓                       ↓
      NSAIDs                Hydroxychloroquine
      (e.g. ibuprofen,      ± NSAIDs
      naproxen)             ↓
                        Not improving?
                            ↓
                    Corticosteroids
                    (prednisolone 0.5-1 mg/kg/day)
                            ↓
                    Taper as symptoms resolve

Key Clinical Features That Guide Treatment

Common Causative Drugs to Know

Note: Biologic-induced DIL (especially from TNF-α inhibitors) can be more persistent and may require longer courses of corticosteroids even after stopping the biologic.

Drug-Induced Subacute Cutaneous Lupus (SCLE) - Special Subset

• Proton pump inhibitors, diltiazem, HCTZ, terbinafine, interferons, paclitaxel, docetaxel, aromatase inhibitors

What Does NOT Need Treatment

• Asymptomatic positive ANA alone in a patient on a known causative drug - no need to stop the drug just for a positive ANA unless symptoms develop
• Persistent positive ANA after drug cessation without symptoms - observe only