PART 1: ANTITUBERCULAR DRUGS

Classification

Mechanism of Action of First-Line Drugs

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

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

XDR-TB - Drugs

Drugs Used in XDR-TB:

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

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

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

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

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

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)

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

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

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

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

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

Regimen 2: Artesunate-Mefloquine (ASMQ)

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

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

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

Other Important Antimalarials - Summary