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ANTITUBERCULAR DRUGS

Classification

• Fluoroquinolones: Moxifloxacin, Levofloxacin, Ofloxacin, Ciprofloxacin
• Injectable agents: Amikacin, Kanamycin, Capreomycin
• Ethionamide / Prothionamide
• Cycloserine
• Para-aminosalicylic acid (PAS)
• Linezolid
• Bedaquiline
• Delamanid
• Clofazimine (used in MDR-TB)

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Mechanism of Action (MOA) of First-Line Drugs

1. Isoniazid (INH)

• MOA: INH is a prodrug activated by the mycobacterial catalase-peroxidase enzyme KatG. The activated form inhibits InhA (enoyl-ACP reductase) and KasA enzymes involved in mycolic acid synthesis - a critical component of the mycobacterial cell wall. Also inhibits synthesis of mycolic acids by blocking fatty acid synthase II (FASII) system.
• Active against rapidly dividing bacilli (extracellular) and intracellular bacilli.
• NOT active against "persisters" (dormant bacilli).
• Resistance: Mutation in katG (reducing activation) or inhA (reducing drug binding).

2. Rifampicin (RMP)

• MOA: Binds to the beta-subunit of DNA-dependent RNA polymerase (encoded by rpoB gene) and inhibits transcription (mRNA synthesis). Does NOT inhibit mammalian RNA polymerase.
• Bactericidal against both intracellular AND extracellular bacilli.
• The only drug active against "persisters" (dormant bacilli in caseous lesions).
• Resistance: Mutation in the rpoB gene.

3. Pyrazinamide (PZA)

• MOA: Converted to pyrazinoic acid by mycobacterial pyrazinamidase (PncA enzyme). Pyrazinoic acid disrupts mycobacterial membrane energy metabolism and inhibits fatty acid synthase I (FASI). Active only in acidic environment (pH 5-6), such as within macrophage phagolysosomes.
• Active against slow-multiplying intracellular bacilli - acts as a "sterilizing" agent allowing short-course therapy.
• Resistance: Mutations in pncA gene.

4. Ethambutol (EMB)

• MOA: Inhibits arabinosyl transferase enzymes (embA, embB, embC genes), blocking arabinogalactan synthesis - a key component of mycobacterial cell wall. This prevents incorporation of mycolic acids into the cell wall.
• Bacteriostatic. Primarily used to prevent emergence of resistance to other drugs.
• Resistance: Mutations in embB gene.

5. Streptomycin (SM)

• MOA: Aminoglycoside. Binds to 30S ribosomal subunit (specifically 16S rRNA), causing misreading of mRNA and inhibiting protein synthesis. Active only against extracellular, rapidly dividing bacilli. Cannot penetrate cell membranes or the blood-brain barrier.

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Indications for Chemoprophylaxis in Tuberculosis

Indications:

1. Household contacts of smear-positive pulmonary TB cases, especially children under 5 years
2. HIV-positive individuals with TST/IGRA positive (strongly indicated - reduces TB risk by 60-90%)
3. TST/IGRA converters (recent skin test conversion within 2 years)
4. Immunosuppressed patients on corticosteroids, TNF-alpha inhibitors, post-transplant immunosuppression
5. Diabetics with positive TST
6. Silicosis with positive TST
7. Children under 5 years who are close contacts of open (smear +ve) TB cases - regardless of TST status
8. Newborns of mothers with active TB - INH prophylaxis; BCG given after INH course completed
9. Healthcare workers with TST conversion
10. Patients starting biologic therapy (e.g., infliximab) - screen and treat LTBI first

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DOTS (Directly Observed Treatment, Short-course)

Definition

Five Core Elements of DOTS (WHO)

1. Government commitment to sustained TB control
2. Case detection by sputum smear microscopy among symptomatic patients
3. Standardized short-course chemotherapy given under direct observation
4. Regular, uninterrupted drug supply of all essential anti-TB drugs
5. Recording and reporting system allowing assessment of treatment outcomes

DOTS Regimens (RNTCP/National TB Elimination Programme - India)

• Intensive Phase (IP): 2 months - HRZE (daily) or HRZE3 (thrice weekly)
• Continuation Phase (CP): 4 months - HR (daily) or HR3 (thrice weekly)
• Total: 6 months (2HRZE + 4HR)

• IP: 3 months HRZES (streptomycin in first 2 months), then 1 month HRZE
• CP: 5 months HRE
• Total: 8 months

• All new patients: 2HRZE/4HR (daily)
• Severe forms (TB meningitis, spinal TB with neurological deficit): 2HRZE/10HR (12 months total)
• Childhood TB: same regimen, weight-based dosing

DOTS Advantages:

• Ensures patient compliance - prevents development of resistance
• Reduces treatment failures and relapses
• Most cost-effective strategy for TB control
• Community-based delivery possible

DOTS categories (Old RNTCP):

• Category I: New smear +ve, seriously ill smear -ve, severe extra-pulmonary TB
• Category II: Previously treated (relapses, failures, default)
• Category III (abolished): New smear -ve, less severe extra-pulmonary TB

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XDR-TB - Drugs

Drugs used in XDR-TB (Group allocation):

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MDR-TB - Treatment

Treatment Principles:

• At least 4 effective drugs in intensive phase
• Longer treatment: traditionally 18-20 months; newer short regimens 9-12 months

WHO Recommended Regimens:

• Bedaquiline + Pretomanid + Linezolid + Moxifloxacin (BPaLM) for 6 months, then BPaL for 2 more months
• 9 months total; high cure rates

• Intensive Phase (6 months): Bedaquiline + Levofloxacin/Moxifloxacin + Clofazimine + Cycloserine + Linezolid
• Continuation Phase (12-14 months): Levofloxacin/Moxifloxacin + Clofazimine + Cycloserine

Causes of Treatment Failure in TB (see section below)

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Failure of Drug Treatment of TB - Causes

1. Patient-related:
   • Non-compliance - most common cause
   • Irregular drug intake
   • Premature stoppage of treatment
   • Poor absorption (malabsorption, HIV enteropathy)
2. Drug-related:
   • Inadequate regimen (wrong drug combination, under-dosing)
   • Drug interactions (e.g., RIF reduces blood levels of many drugs)
   • Poor drug quality
3. Bacillary factors:
   • Primary drug resistance (patient infected with resistant strain)
   • Acquired resistance (due to inadequate therapy)
   • Slowly growing "persisters" surviving drug therapy
4. Host factors:
   • HIV coinfection - impaired immunity
   • Severe malnutrition
   • Diabetes mellitus
   • Malabsorption
5. Pharmacokinetic issues:
   • Fast acetylators metabolize INH quickly - lower peak levels
   • Drug-drug interactions reducing drug bioavailability

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RIFAMPICIN - Detailed Profile

Antimicrobial Spectrum / Actions:

• M. tuberculosis - primary use; most potent bactericidal first-line drug
• M. leprae - most bactericidal drug against leprosy
• Atypical mycobacteria - M. kansasii, M. avium complex
• Gram-positive: Staphylococcus aureus (including MRSA), Streptococcus, Enterococcus
• Gram-negative: N. meningitidis, N. gonorrhoeae, H. influenzae, Legionella
• Others: Brucella (with doxycycline), Chlamydia, Rickettsia
• Active against intracellular organisms due to excellent cell penetration

MOA (reiterated):

Pharmacokinetics:

• Absorption: Well absorbed orally. Absorption reduced by food (take 30-60 min before meals or 2 hours after).
• Distribution: Wide distribution into all tissues and fluids including CSF, pleural fluid, tears, saliva, urine (all turn orange-red). Crosses blood-brain barrier and placenta. Protein binding ~80%.
• Metabolism: Undergoes auto-induction of hepatic CYP3A4 - accelerates its own metabolism. Deacetylated in liver to active desacetyl-rifampicin. Undergoes enterohepatic circulation.
• Excretion: Primarily biliary/fecal; some renal excretion. Half-life: 2-5 hours (shortened with repeated dosing due to auto-induction).
• Colour: Turns urine, tears, sweat, saliva orange-red - useful as compliance marker.

Adverse Effects:

1. Hepatotoxicity - most serious; jaundice, hepatitis; elevated transaminases; risk increased with concurrent INH, pre-existing liver disease, alcoholism
2. Influenza-like syndrome - fever, chills, headache, myalgias; especially with intermittent high-dose regimens (immune complex mediated)
3. Thrombocytopenic purpura - with intermittent therapy (immune-mediated)
4. Cholestatic jaundice and hyperbilirubinemia
5. GI effects - nausea, vomiting, anorexia, abdominal cramps
6. Hypersensitivity - rashes, urticaria, eosinophilia; rarely anaphylaxis
7. Hemolytic anemia - with intermittent therapy
8. Renal impairment - hemoglobinuria, hematuria (rare)
9. Orange-red discoloration of all secretions - harmless but distressing; permanent staining of soft contact lenses
10. Drug interactions (very important) - Potent enzyme inducer (CYP3A4, 2C9, 2C19, P-glycoprotein):
    • Reduces efficacy of: OCPs (breakthrough pregnancy), warfarin, digoxin, phenytoin, corticosteroids, cyclosporine, HIV protease inhibitors, NNRTIs, methadone, oral hypoglycemics, antifungals (azoles), beta-blockers

Precautions / Contraindications:

1. Liver disease - use with caution; LFTs monitored; avoid in severe hepatic dysfunction
2. Pregnancy - use only if benefit outweighs risk (crosses placenta); risk of hemorrhagic disease of newborn due to Vit K deficiency - give Vit K to mother and neonate
3. Drug interactions - always review concurrent medications
4. Intermittent dosing - risk of immunological reactions; do not restart if hypersensitivity occurred, or wait at least 3 weeks
5. PAS co-administration - delays RMP absorption; avoid co-administration
6. Alcoholism - increased hepatotoxicity risk
7. Warn patients about orange discoloration of body fluids
8. Never use alone for TB - always in combination (to prevent resistance)

Other Therapeutic Uses (beyond TB):

1. Leprosy - component of WHO MDT regimen; monthly 600 mg
2. Meningococcal prophylaxis - rifampicin 600 mg BD x 2 days (eradicates nasal carriage of N. meningitidis)
3. H. influenzae type b (Hib) prophylaxis - household contacts of Hib meningitis
4. MRSA - in combination with other agents (never monotherapy)
5. Brucellosis - with doxycycline
6. Legionellosis - in combination
7. Pruritus of cholestasis - rifampicin reduces bile acid levels
8. Staphylococcal prosthetic joint/device infections - in combination
9. Non-tuberculous mycobacterial (NTM) infections

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MULTIBACILLARY LEPROSY - TREATMENT

WHO MDT Classification:

• Paucibacillary (PB): 1-5 skin lesions; smear negative
• Multibacillary (MB): 6 or more skin lesions OR any smear positive; includes lepromatous leprosy (LL), borderline lepromatous (BLL), mid-borderline (BB)

WHO MDT Regimen for Multibacillary Leprosy:

Role of Individual Drugs in MB Leprosy:

• Most potent bactericidal drug against M. leprae
• Single dose 1500 mg OR 3-4 consecutive daily doses of 600 mg kills 99% of viable organisms
• Effective at monthly intervals - unique advantage
• Given monthly (supervised) to reduce cost and toxicity while maintaining efficacy
• Mechanism: Inhibits RNA polymerase
• Prevents selection of RMP-resistant mutants when combined with dapsone/clofazimine
• ADRs: Hepatotoxicity, GI upset, orange discoloration, influenza-like syndrome

• Diaminodiphenylsulfone - MOA: Structurally similar to PABA; competitively inhibits dihydropteroate synthetase, blocking folate synthesis (same as sulfonamides)
• Weakly bactericidal against M. leprae
• Cheap, effective, well-absorbed orally
• Dose: 100 mg/day (adults); 1-2 mg/kg in children
• ADRs: Hemolytic anemia (most common - dose-dependent), methemoglobinemia, agranulocytosis, hepatitis, peripheral neuropathy, psychosis, lepra reactions. Rare "DDS syndrome" - fever, lymphadenopathy, exfoliative dermatitis, hepatitis, maculopapular rash

• Riminophenazine dye
• MOA: Binds to mycobacterial DNA (guanine bases), inhibiting template function. Also has anti-inflammatory and immunosuppressive properties (suppresses lepra reactions - added advantage)
• Less potent than RMP but suppresses both bacterial replication AND type 2 lepra reactions (ENL)
• Dose: 300 mg/month (supervised) + 50 mg/day
• ADRs: Red-black skin discoloration (major concern; cosmetically unacceptable to some patients, especially fair-skinned) - affects skin, conjunctiva, mucous membranes; discoloration of urine, sweat. GI: nausea, diarrhea, abdominal pain. Ichthyosis. Reversible on stopping.
• If unacceptable: Replace with ethionamide 250 mg/day or prothionamide

Lepra Reactions (management note):

• Type 1 (Reversal reaction, T-cell mediated): Prednisolone 40-60 mg/day tapered
• Type 2 (ENL, immune complex mediated): Thalidomide (first choice - not in women of childbearing age) or prednisolone; clofazimine also suppresses ENL

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ANTIMALARIAL DRUGS

Classification (KD Tripathi / Katzung)

Based on Chemical Structure:

1. 4-Aminoquinolines: Chloroquine, Amodiaquine, Piperaquine (bisquinoline)
2. Quinoline methanols: Quinine, Quinidine, Mefloquine
3. 8-Aminoquinolines: Primaquine, Tafenoquine
4. Sesquiterpene lactone endoperoxides (Artemisinins): Artemisinin, Artesunate, Artemether, Dihydroartemisinin (DHA)
5. Antifolates:
   • DHFR inhibitors: Pyrimethamine, Proguanil, Trimethoprim
   • DHPS inhibitors: Sulfonamides (sulfadoxine), Dapsone
   • Combinations: Sulfadoxine-pyrimethamine (SP/Fansidar), Atovaquone-proguanil (Malarone)
6. Antibiotics: Doxycycline, Tetracycline, Clindamycin, Azithromycin
7. Naphthoquinones: Atovaquone
8. Aryl aminoalcohols: Lumefantrine, Halofantrine

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Terms Used to Describe Antimalarial Drug Action in Relation to Life Cycle of P. vivax

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Chloroquine - Detailed Profile

MOA:

Pharmacokinetics:

• Well absorbed orally
• Extensively distributed (large Vd 200-800 L/kg) - accumulates in tissues, especially liver, spleen, kidneys, melanin-containing tissues (retina)
• Long half-life: 1-2 months (allows weekly dosing for prophylaxis)
• Metabolized in liver to desethylchloroquine
• Excreted by kidneys

Therapeutic Uses:

1. Treatment of uncomplicated P. vivax, P. malariae, P. ovale malaria (where chloroquine sensitivity retained) - Drug of choice
2. Treatment of chloroquine-sensitive P. falciparum (rare now due to widespread resistance; still effective in Central America west of Panama Canal, Haiti, Dominican Republic)
3. Chemoprophylaxis - 500 mg (base) once weekly, 1-2 weeks before, during, and 4 weeks after travel
4. Extraintestinal amoebiasis (hepatic amoebiasis) - 500 mg BD x 2 days then 500 mg/day x 21 days (alternative)
5. Rheumatoid arthritis - disease-modifying; 250 mg/day
6. Systemic Lupus Erythematosus (SLE) - skin and systemic manifestations; 250 mg/day
7. Infective mononucleosis - to reduce fever
8. Porphyria cutanea tarda - low dose chelates hepatic porphyrins

Adverse Effects:

1. GI: Nausea, vomiting, epigastric distress, diarrhea (most common, take with food)
2. CNS: Headache, dizziness, tinnitus, vertigo, irritability, psychosis (rare)
3. Retinopathy (most serious - dose-related): Macular degeneration with long-term use (RA/SLE); "bull's eye" maculopathy; irreversible visual loss if not detected early. Baseline and annual ophthalmologic exams needed for long-term use. Rarely occurs with malaria prophylaxis doses.
4. Skin: Pruritus (very common in dark-skinned Africans), bleaching of hair, exacerbation of psoriasis, lichenoid eruptions, exfoliative dermatitis
5. Hemolysis in G6PD-deficient patients
6. Cardiac toxicity: QTc prolongation (rare with standard doses), cardiomyopathy with long-term high doses
7. Neuromyopathy: Proximal myopathy and neuropathy with prolonged use
8. Hypotension: With parenteral administration

Precautions:

1. Retinopathy monitoring - baseline ophthalmic examination; avoid >6.5 mg/kg/day for long-term use
2. G6PD deficiency - use with caution (mild hemolysis)
3. Psoriasis - may exacerbate
4. Epilepsy - lowers seizure threshold
5. Cardiac disease - monitor ECG; avoid in arrhythmias
6. Hepatic disease - use cautiously
7. Pregnancy - considered safe for malaria treatment/prophylaxis at standard doses
8. Do not use alone for P. falciparum in chloroquine-resistant areas

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ARTEMISININ DERIVATIVES

Drugs in this group:

• Artemisinin (from Artemisia annua - qinghao/sweet wormwood)
• Artesunate (water-soluble; IV/IM/oral)
• Artemether (lipid-soluble; oral/IM)
• Dihydroartemisinin (DHA) - active metabolite of all artemisinins; oral

MOA:

1. Alkylate heme and parasite proteins (particularly PfATP6 - sarcoplasmic reticulum Ca2+-ATPase / SERCA)
2. Cause oxidative damage to parasite membranes and cellular proteins
3. Rapidly kill all asexual stages (rings, trophozoites, schizonts) AND young gametocytes

• Fastest-acting antimalarials
• Kill ~99.9% parasites per asexual cycle
• Reduce parasite biomass rapidly - prevent severe disease

Pharmacokinetics:

• Artesunate: Water-soluble, IV formulation available for severe malaria; converted to DHA
• Artemether: Lipid-soluble, oral and IM; converted to DHA
• DHA: Active metabolite; short half-life (1-2 hours) - this is why they must be combined with longer-acting partner drug in ACT
• Poor oral bioavailability of artemisinin itself; derivatives have better bioavailability
• No significant CYP induction

Adverse Effects:

1. Generally well tolerated - one of the safest antimalarials
2. Neurotoxicity - animal studies showed neurotoxicity at high doses; clinical significance in humans at therapeutic doses is debated; rare case reports of ototoxicity
3. GI: Nausea, vomiting, abdominal pain (mild)
4. Dizziness, headache
5. QTc prolongation - mild; artemether-lumefantrine has the most significant effect (mainly lumefantrine)
6. Embryotoxic/teratogenic - in animal studies; avoid in 1st trimester if possible; benefit-risk analysis for severe falciparum in pregnancy (artesunate IV used for severe malaria in pregnancy)
7. Post-artesunate delayed hemolysis - occurs 1-3 weeks after IV artesunate for severe malaria (rare)
8. Reticulocytopenia - transient
9. Elevated transaminases - mild, transient

Precautions:

1. Never use as monotherapy - rapid resistance selection; must use in ACT
2. First trimester pregnancy - avoid if alternative exists; use for severe falciparum (no alternative)
3. Neurotoxicity concern - avoid very high doses; standard therapeutic doses appear safe
4. QTc monitoring - especially artemether-lumefantrine in cardiac patients
5. Drug interactions - artesunate induces CYP (mild); check interactions
6. Short half-life requires ACT combination

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Artemisinin-Based Combination Therapy (ACT)

Rationale / Justification for ACT:

1. Pharmacokinetic complementarity: Artemisinins have very short half-life (1-2 hours) - they rapidly kill the bulk of the parasite biomass (99.9%/cycle) but cannot eliminate all parasites before being cleared. The long-acting partner drug (t½ 2-6 weeks for lumefantrine/mefloquine) clears the residual parasites that survive after artemisinin is gone.
2. Synergy: Two different mechanisms of action → enhanced killing; prevents emergence of resistance to either drug (reduces parasite selection pressure for either drug)
3. Resistance prevention: If a parasite mutates resistance to artemisinin, it is killed by the partner drug, and vice versa. The probability of simultaneous mutations to both drugs is extremely low (10⁻²² for independent mutations).
4. Faster parasite clearance compared to any single drug → fewer days of fever, less transmission
5. Reduction of gametocyte carriage → artemisinins kill young gametocytes → reduced transmission even if treatment is partly incomplete
6. Reduced recrudescence rates vs artemisinins alone

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ACT Regimens for Uncomplicated P. falciparum Malaria

WHO/NVBDCP Recommended ACT Regimens:

• Artemether 20 mg + Lumefantrine 120 mg per tablet
• Adults (>35 kg): 4 tablets twice daily x 3 days (total 6 doses)
• Or weight-based: given at 0, 8, 24, 36, 48, 60 hours
• Take with fatty food (increases lumefantrine absorption by 3-16 fold)
• Lumefantrine t½ ~3-6 days; provides adequate tail cover
• Contraindicated in: 1st trimester pregnancy (use quinine+doxy), severe hepatic disease
• ADRs: QTc prolongation (monitor in cardiac patients), dizziness, nausea

• Artesunate 100 mg + Amodiaquine 270 mg once daily x 3 days
• Amodiaquine: 4-aminoquinoline; MOA same as chloroquine
• ADRs of amodiaquine: Agranulocytosis, hepatitis (rare but serious with long-term use; safe for 3-day course)
• Widely used in Africa

• Artesunate 100 mg/day x 3 days + Mefloquine 25 mg/kg split over 2 days
• Alternatively: Mefloquine 15 mg/kg day 2 + 10 mg/kg day 3 with daily artesunate
• Used in Southeast Asia
• ADRs of mefloquine: Neuropsychiatric effects (vivid dreams, anxiety, psychosis), GI effects, QTc prolongation

• DHA 40 mg + Piperaquine 320 mg, once daily x 3 days
• Piperaquine: bisquinoline; very long t½ (~5 weeks) = long post-treatment prophylactic effect
• Take on empty stomach (piperaquine absorption better without food, but check formulation)
• High efficacy; increasingly used as WHO-recommended first-line
• ADRs: QTc prolongation (piperaquine most QTc-prolonging partner drug)

• AS 60 mg + Pyronaridine 180 mg, once daily x 3 days
• Newer combination; approved in Europe and some endemic countries

India (NVBDCP) Current Protocol:

• Uncomplicated P. falciparum: ACT - Artemether + Lumefantrine (AL) with single dose primaquine 0.75 mg/kg on Day 2 (for gametocyte clearance)
• Severe falciparum malaria: IV Artesunate 2.4 mg/kg at 0, 12, 24 hrs then daily; switch to oral ACT when tolerating

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ACT in Acute Uncomplicated Falciparum Malaria

Rationale:

• Falciparum malaria kills through rapid parasite multiplication, sequestration of parasitized RBCs in capillaries, severe anemia, cerebral malaria, acute respiratory distress, multi-organ failure
• ACT provides: (a) fast parasite clearance via artemisinin's rapid action, (b) sustained elimination via long-acting partner drug, (c) gametocyte reduction reducing transmission, (d) protection against resistance
• WHO recommends ACT as first-line for ALL cases of P. falciparum malaria

Three ACT Regimens (Detailed):

• Mechanism: Artemether (endoperoxide → free radical damage to parasite proteins) + Lumefantrine (4-aminoquinoline-like; inhibits heme polymerization, similar to chloroquine)
• Dose: 20/120 mg tablets; 4 tabs at 0, 8, 24, 36, 48, 60 hours (adults)
• Duration: 3 days
• Take with food (especially lumefantrine absorption)
• Efficacy: >95% cure rates in most regions
• Advantages: WHO first-line; well-studied; widely available fixed-dose combination
• Contraindications: First trimester; QTc >500 ms; known hypersensitivity

• Mechanism: Artesunate (endoperoxide) + Mefloquine (quinoline methanol; inhibits hematin polymerization; may inhibit DNA synthesis)
• Dose: Artesunate 100 mg/day x 3 days + Mefloquine 25 mg/kg split over 2 days (typically 8 mg/kg/day x 3 days with AS)
• Efficacy: High in Southeast Asia (Thailand-Cambodia border); where chloroquine resistance is high
• Disadvantage: Neuropsychiatric ADRs of mefloquine; more expensive
• Avoid in: Epilepsy, psychiatric history, cardiac conduction defects

• Mechanism: DHA (artemisinin derivative) + Piperaquine (bisquinoline; inhibits hemozoin formation)
• Dose: DHA 2-4 mg/kg + Piperaquine 16-32 mg/kg once daily x 3 days
• Long t½ of piperaquine (5 weeks) provides post-treatment prophylaxis
• Efficacy: Very high cure rates (>97% in most settings)
• Advantage: Once daily dosing; long protective effect
• QTc monitoring important

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Advantages of ACT Over Other Antimalarials:

1. Fastest parasite clearance - artemisinins clear >99.9% of parasites per cycle; fever resolution in 24-48 hours
2. Active against all asexual stages including rings (early trophozoites) which are resistant to most other drugs
3. Gametocytocidal - reduce transmission
4. Protection against resistance - two mechanisms = low probability of dual resistance
5. High efficacy against multidrug-resistant P. falciparum - artemisinins retain activity even against chloroquine/SP resistant strains
6. Good tolerability - artemisinins among the best-tolerated antimalarials
7. Short treatment course - 3 days vs 7 days for quinine
8. Rapid symptom resolution - important for patient adherence
9. No cross-resistance with older antimalarials
10. Reduces parasite biomass quickly - prevents progression to severe malaria

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Summary Table: Important Antimalarial Drugs

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PART 1: ANTITUBERCULAR DRUGS

Classification

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Mechanism of Action of First-Line Drugs

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Indications for Chemoprophylaxis in Tuberculosis

1. Household contacts of smear-positive pulmonary TB cases, especially children under 5 years - regardless of TST status
2. HIV-positive patients with positive TST/IGRA (reduces TB risk by 60-90%)
3. TST/IGRA converters - recent conversion within 2 years
4. Immunosuppressed patients - corticosteroids, TNF-alpha inhibitors (infliximab, etc.), post-transplant immunosuppression - screen and treat LTBI before starting biologics
5. Diabetics with positive TST
6. Silicosis with positive TST
7. Newborns of mothers with active TB - INH prophylaxis; BCG given after completing INH course
8. Healthcare workers with TST conversion
9. Patients with fibrotic lesions on chest X-ray consistent with old healed TB

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DOTS (Directly Observed Treatment, Short-course)

Five Core Elements of DOTS (WHO):

1. Government commitment to sustained TB control
2. Case detection by sputum smear microscopy in symptomatic patients
3. Standardized short-course chemotherapy under direct observation
4. Regular, uninterrupted drug supply of all essential anti-TB drugs
5. Standardized recording and reporting system to monitor treatment outcomes

DOTS Regimens (National TB Elimination Programme, India):

• New patients: 2HRZE/4HR (2 months Isoniazid+Rifampicin+Pyrazinamide+Ethambutol, then 4 months Isoniazid+Rifampicin), given daily
• Previously treated: 2HRZES/1HRZE/5HRE (total 8 months)
• TB meningitis / spinal TB with neurological deficit: 2HRZE/10HR (12 months total)
• Paediatric TB: Same regimen with weight-based dosing (FDC paediatric formulations)

DOTS Advantages:

• Ensures compliance - major prevention of drug resistance
• Reduces treatment failure, relapse, and default
• Most cost-effective TB control strategy
• Community-based delivery; reduces healthcare burden

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XDR-TB - Drugs

Drugs Used in XDR-TB:

• Bedaquiline + Pretomanid + Linezolid ± Moxifloxacin for 6-9 months
• Cure rates ~90% in ZeNix/TB-PRACTECAL trials

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Failure of Drug Treatment of TB - Causes

1. Patient non-compliance - most common; irregular intake, premature stoppage
2. Inadequate regimen - wrong drug combinations, under-dosing, inappropriate duration
3. Primary drug resistance - infected with resistant strain from the outset
4. Acquired resistance - inadequate or irregular therapy selects resistant mutants
5. Drug absorption problems - malabsorption syndromes, HIV enteropathy
6. HIV coinfection - impaired cell-mediated immunity; altered drug pharmacokinetics
7. Drug interactions - rifampicin enzyme induction reduces co-drug levels
8. Fast acetylators - rapid INH metabolism → subtherapeutic INH levels
9. Severe malnutrition, diabetes mellitus
10. Poor drug quality / substandard drugs

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MDR-TB Treatment

WHO Recommended Approach (current):

• Bedaquiline + Pretomanid + Linezolid + Moxifloxacin (BPaLM) x 6 months

• Intensive Phase (6 months): Bedaquiline + Levofloxacin/Moxifloxacin + Clofazimine + Cycloserine + Linezolid
• Continuation Phase (12-14 months): Levofloxacin/Moxifloxacin + Clofazimine + Cycloserine
• At least 4 effective drugs in intensive phase

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PART 2: RIFAMPICIN - Detailed Profile

Antimicrobial Spectrum:

• Mycobacterium tuberculosis (first-line, most potent)
• M. leprae (most bactericidal drug in leprosy)
• Atypical mycobacteria (M. kansasii, MAI/MAC)
• Gram-positive: S. aureus (including MRSA - in combination), Streptococcus, Enterococcus
• Gram-negative: N. meningitidis, N. gonorrhoeae, H. influenzae, Legionella
• Brucella, Rickettsia, Chlamydia

Pharmacokinetics:

• Absorption: Good oral bioavailability; food reduces absorption - take 30-60 min before meals or 2 hours after
• Distribution: Wide distribution; crosses BBB, placenta, all tissue fluids; excreted in tears, saliva, sweat, urine (orange-red discoloration). Protein binding ~80%
• Metabolism: Hepatic; undergoes autoinduction of CYP3A4 (accelerates its own metabolism over first 2 weeks); enterohepatic circulation; active metabolite = desacetyl-rifampicin
• Excretion: Primarily biliary/fecal; some renal; t½ = 2-5 hours (shortens with repeated use due to autoinduction)

Adverse Effects:

1. Hepatotoxicity - elevated transaminases, jaundice, hepatitis (most serious); risk with concurrent INH, alcohol, pre-existing liver disease
2. Influenza-like syndrome - fever, chills, myalgia, headache (immune complex-mediated; especially with intermittent high-dose regimens)
3. Thrombocytopenic purpura - immune-mediated; with intermittent therapy
4. GI effects - nausea, vomiting, anorexia, abdominal cramps
5. Cholestatic jaundice and hyperbilirubinemia
6. Hemolytic anemia - with intermittent therapy
7. Hypersensitivity - rashes, urticaria, eosinophilia; rarely anaphylaxis
8. Renal impairment - hemoglobinuria, hematuria (rare)
9. Orange-red discoloration of urine, tears, sweat, saliva - harmless but stains soft contact lenses permanently
10. Drug interactions (major - potent enzyme inducer CYP3A4, 2C9, 2C19, P-gp): Reduces levels of OCPs (breakthrough pregnancy), warfarin, digoxin, phenytoin, corticosteroids, cyclosporine, HIV antiretrovirals (PIs, NNRTIs), azole antifungals, oral hypoglycemics, methadone, beta-blockers

Precautions:

1. Liver disease - caution; monitor LFTs; avoid in severe hepatic dysfunction
2. Pregnancy - use when benefit > risk; risk of hemorrhagic disease of newborn (Vit K deficiency); give Vit K to neonate
3. Drug interactions - always review all concurrent medications
4. Do not restart within 3 weeks if stopped (risk of hypersensitivity reaction)
5. PAS co-administration - delays absorption; avoid or separate by 8-12 hours
6. Alcoholism - increased hepatotoxicity
7. Warn patients about orange body fluid discoloration
8. Never use as monotherapy in TB or leprosy (rapid resistance development)

Other Therapeutic Uses:

1. Leprosy (most bactericidal drug against M. leprae) - monthly 600 mg in WHO MDT
2. Meningococcal carrier eradication - 600 mg BD x 2 days (prophylaxis for close contacts of meningococcal meningitis)
3. H. influenzae type b prophylaxis - household contacts of Hib meningitis
4. MRSA - in combination with other antibiotics (for biofilm-forming infections, prosthetic joint infections)
5. Brucellosis - with doxycycline for 6 weeks
6. Legionellosis - in combination with fluoroquinolone
7. Pruritus of cholestasis (primary biliary cholangitis)
8. Non-tuberculous mycobacterial infections

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PART 3: MULTIBACILLARY LEPROSY - Treatment

WHO Classification:

• Paucibacillary (PB): 1-5 skin lesions, smear negative
• Multibacillary (MB): 6+ skin lesions OR any smear positive (LL, BLL, BB)

WHO MDT Regimen for Multibacillary Leprosy:

Drugs in Detail:

• Most potent bactericidal drug against M. leprae; single dose of 1500 mg or 3-4 days of 600 mg daily kills 99% of viable M. leprae
• Given monthly (supervised) - cost-effective, maintains efficacy, reduces toxicity risk
• MOA: Inhibits DNA-dependent RNA polymerase (rpoB)
• ADRs: Hepatotoxicity, GI symptoms, orange discoloration, influenza-like syndrome, thrombocytopenic purpura
• Given alone: rapid resistance develops - must use in combination

• MOA: Competitively inhibits dihydropteroate synthetase (DHPS) - same as sulfonamides; blocks folate synthesis in M. leprae
• Cheap, well-absorbed, weakly bactericidal
• ADRs: Hemolytic anemia (dose-related), methemoglobinemia, agranulocytosis, hepatitis, peripheral neuropathy, lepra reactions. Rare DDS syndrome: fever, lymphadenopathy, exfoliative dermatitis, hepatitis, maculopapular rash
• Precaution: Check Hb before and during therapy; iron supplements routinely given

• Riminophenazine dye
• MOA: Binds to guanine bases in mycobacterial DNA; inhibits template function; also has anti-inflammatory and immunosuppressive effects
• Added advantage: Suppresses Type 2 lepra reactions (ENL)
• ADRs: Red-brown/black skin discoloration (most troublesome - affects skin, conjunctiva, mucous membranes; urine, sweat discolored; reversible on stopping but may take months/years). GI: nausea, diarrhea, abdominal pain. Ichthyosis. Enteropathy at high doses.
• If unacceptable cosmetically: Replace with Ethionamide 250-375 mg/day OR Prothionamide

• Ofloxacin 400 mg/day - 22 doses kill 99.9% of M. leprae; used in WHO alternative single-dose regimen (ROM - Rifampicin+Ofloxacin+Minocycline) for single-lesion PB leprosy
• Minocycline 100 mg/day - lipid-soluble tetracycline; bactericidal; part of ROM regimen; avoid in children <8 yrs and pregnancy
• Clarithromycin - bactericidal; alternative second-line drug
• Thalidomide - for ENL (Type 2 reaction); strictly contraindicated in women of childbearing age

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PART 4: ANTIMALARIAL DRUGS

Classification

• DHPS inhibitors: Sulfadoxine, Dapsone
• DHFR inhibitors: Pyrimethamine, Proguanil, Trimethoprim
• Combinations: Sulfadoxine-Pyrimethamine (SP/Fansidar), Atovaquone-Proguanil (Malarone) 7. Antibiotics: Doxycycline, Tetracycline, Clindamycin, Azithromycin 8. Naphthoquinones: Atovaquone 9. Others: Lumefantrine (aryl aminoalcohol), Halofantrine, Pyronaridine (Mannich base acridine)

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Terms Used to Describe Antimalarial Drug Action (in relation to Life Cycle of P. vivax)

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Chloroquine - Detailed Profile

MOA:

Pharmacokinetics:

• Well absorbed orally; food enhances absorption
• Large volume of distribution (200-800 L/kg); accumulates in tissues (liver, spleen, kidney), melanin-containing tissues (retina - causes retinopathy)
• Long t½ (1-2 months) - allows weekly prophylaxis dosing
• Metabolized in liver to desethylchloroquine
• Excreted in urine (acidification increases renal elimination)

Therapeutic Uses:

1. Drug of choice for uncomplicated P. vivax, P. ovale, P. malariae malaria (CQ-sensitive)
2. Uncomplicated CQ-sensitive P. falciparum (rare; Central America west of Panama Canal, Haiti, DR)
3. Chemoprophylaxis - 500 mg (base) weekly (1-2 weeks before → 4 weeks after travel)
4. Radical cure of P. vivax/P. ovale - combined with primaquine (CQ for blood stages + primaquine for hypnozoites)
5. Extraintestinal amoebiasis (hepatic abscess) - alternative
6. Rheumatoid arthritis - 250 mg/day (DMARD)
7. SLE - 250 mg/day (skin and systemic manifestations)
8. Porphyria cutanea tarda - low dose chelates hepatic porphyrins

Adverse Effects:

1. GI: Nausea, vomiting, epigastric distress, diarrhea - most common (take with food)
2. Pruritus - very common in dark-skinned patients (especially Africans)
3. CNS: Headache, dizziness, tinnitus, vertigo; blurred vision (acute)
4. Retinopathy (most serious; with long-term high-dose use as in RA/SLE) - "bull's eye" maculopathy; retinal pigmentation; irreversible visual loss; annual ophthalmic exam mandatory for long-term use
5. Skin: Bleaching of hair, exacerbation of psoriasis, lichenoid drug eruption
6. Hemolysis in G6PD-deficient patients
7. Cardiac: QTc prolongation (rare with standard doses); cardiomyopathy with long-term high-dose use
8. Neuromyopathy - proximal muscle weakness and neuropathy with prolonged use
9. Hypotension - with rapid parenteral administration

Precautions:

1. Retinopathy monitoring - baseline and annual ophthalmology for long-term use; do not exceed 6.5 mg/kg/day base
2. G6PD deficiency - mild hemolysis; use cautiously
3. Psoriasis - may precipitate severe exacerbation; relative contraindication
4. Epilepsy - lowers seizure threshold
5. Cardiac disease - ECG monitoring; avoid in arrhythmias
6. Avoid rapid IV injection - can cause hypotension and cardiac arrest
7. Pregnancy - considered safe for malaria treatment and prophylaxis at standard doses

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Artemisinin Derivatives

Drugs: Artemisinin (parent), Artesunate (water-soluble), Artemether (lipid-soluble), Dihydroartemisinin/DHA (active metabolite)

MOA:

1. Alkylate heme and critical parasite proteins (PfATP6 - calcium ATPase / SERCA analogue in parasite)
2. Cause severe oxidative damage to parasite membranes and organelles
3. Inhibit hemoglobin digestion

• Fastest acting - kill all asexual stages (rings, trophozoites, schizonts) AND young gametocytes
• Reduce parasite biomass by 99.9% per cycle
• Resistance: K13 (Kelch13) propeller domain mutations → delayed ring clearance (partial artemisinin resistance, especially Southeast Asia and now East Africa)

Pharmacokinetics:

• Artesunate: Water-soluble; IV/IM/oral; rapidly converted to active DHA; t½ ~1-2 hours (parent and DHA)
• Artemether: Lipid-soluble; oral/IM; converted to DHA; absorbed with food
• DHA (dihydroartemisinin): Active metabolite of all artemisinins; oral formulation available; t½ ~1-2 hours
• Very short half-lives necessitate ACT (partner drug provides residual parasite elimination)
• Good CNS penetration
• Minimal drug interactions

Therapeutic Uses:

1. Severe/complicated P. falciparum malaria - IV artesunate (2.4 mg/kg at 0, 12, 24 hours then daily) - replaces IV quinine as drug of choice
2. Uncomplicated P. falciparum malaria - as part of ACT (never as monotherapy)
3. Severe vivax malaria - artesunate may be used
4. In ACT: artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, DHA-piperaquine

Adverse Effects:

1. Generally very well tolerated - among safest antimalarials
2. GI: Nausea, vomiting, abdominal pain (mild, transient)
3. Dizziness, headache
4. Neurotoxicity - shown in animal studies at suprapharmacological doses; clinical significance at therapeutic doses uncertain; rare case reports of ototoxicity
5. QTc prolongation - mild (mainly with artemether-lumefantrine, primarily due to lumefantrine component)
6. Embryotoxic/teratogenic in animal studies - avoid in 1st trimester if alternatives exist; use for severe malaria in pregnancy when life-saving
7. Post-artesunate delayed hemolysis - 1-3 weeks after IV artesunate for severe malaria (immune-mediated)
8. Transient reticulocytopenia, transient elevation of transaminases

Precautions:

1. Never as monotherapy - rapid resistance selection
2. 1st trimester pregnancy - avoid if possible; use IV artesunate if life-threatening severe malaria
3. QTc prolongation - caution in cardiac patients on artemether-lumefantrine
4. Neurological monitoring in high-dose protocols
5. Short t½ demands complete 3-day course - stopping early causes recrudescence

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Artemisinin-Based Combination Therapy (ACT)

Indication: First-line treatment for ALL cases of uncomplicated P. falciparum malaria (WHO), and P. vivax where chloroquine resistance is documented.

Justification for Combining Two Drugs in ACT:

1. Pharmacokinetic complementarity: Artemisinin (short t½, 1-2 hours) rapidly destroys the bulk of parasites (>99.9% per cycle). Residual parasites surviving after artemisinin clearance are eliminated by the long-acting partner drug (t½ 2-6 weeks)
2. Synergy: Two different mechanisms → enhanced killing
3. Resistance prevention: Two independent mechanisms make it virtually impossible for a parasite to develop resistance to both drugs simultaneously (probability ~10⁻²²)
4. Rapid gametocyte reduction (artemisinins kill young gametocytes) → reduces onward transmission even with partial treatment failure
5. Reduces total parasite load so rapidly that progression to severe malaria is prevented
6. Mutual protection - if resistance to one partner emerges, the other drug eliminates resistant mutants

Advantages of ACT Over Other Antimalarials:

1. Fastest parasite clearance - fever resolution in 24-48 hours
2. Active against all asexual stages including rings (resistant to most other drugs)
3. Reduces gametocyte carriage - public health benefit
4. High efficacy against MDR P. falciparum
5. No cross-resistance with older antimalarials
6. Short treatment course (3 days vs 7 for quinine)
7. Excellent tolerability
8. Prevents progression to severe disease by rapid parasite kill

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Three ACT Regimens (Detailed)

Regimen 1: Artemether-Lumefantrine (AL) - Coartem

• Artemether: Endoperoxide → Fe²⁺ cleavage → free radicals → oxidative parasite death
• Lumefantrine: Inhibits heme polymerization (similar to chloroquine/quinine); inhibits phospholipid digestion

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Regimen 2: Artesunate-Mefloquine (ASMQ)

• Artesunate: As above
• Mefloquine: Quinoline methanol; inhibits hematin polymerization; may interfere with DNA replication

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Regimen 3: Dihydroartemisinin-Piperaquine (DHA-PPQ) - Eurartesim

• DHA: Active artemisinin metabolite; same endoperoxide mechanism
• Piperaquine: Bisquinoline; inhibits hemozoin formation; very long t½ (~5 weeks) provides prolonged post-treatment prophylaxis

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India NVBDCP Current Protocol:

• Uncomplicated P. falciparum: AL (Artemether-Lumefantrine) + single dose primaquine 0.75 mg/kg on Day 2 (for gametocytocidal action)
• Severe falciparum: IV Artesunate 2.4 mg/kg at 0, 12, 24 hours then daily; switch to oral ACT when able to tolerate
• P. vivax: Chloroquine 25 mg/kg over 3 days + Primaquine 0.25 mg/kg/day x 14 days (radical cure); test G6PD first

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Other Important Antimalarials - Summary

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