Antimalarial

• Anti-malarial drugs


  • Cinchona alkaloids
  • 4-Aminoquinolines
  • 8-Aminoquinolines
  • Polycyclic Antimalarials
  • Fixed Combinations
• Epidemiology of malaria


  P. falciparum > 70%, P. vivax < 30%
• Malaria diagnosis


  Microscopy (gold standard), thin and thick blood smears stained with Giemsa or Wright's stain
• Quinine Sulfate


  Source: Cinchona alkaloids, lethal for all Plasmodium schizonts and gametocytes from P. vivax and P. malariae, indicated for malaria caused by chloroquine-resistant P. falciparum strains, used for nocturnal leg cramps, side effects: abortifacient, toxic: protoplasmic poison, DOC for babesiosis (malaria-like) but with combination with clindamycin
• Quinidine


  More potent anti-malarial, stereoisomer of quinine but is primarily indicated for cardiac arrythmias
• Cinchonism


  Toxic syndrome characterized by tinnitus, headache, nausea and disturbed vision
• Chloroquine


  Main antimalarial drug for prophylaxis and treatment of malaria, DOC for erythrocytic falciparum malaria, monitor: QT prolongation
• Amiodaquine


  Prophylaxis for malaria
• Mefloquine


  Effective single agent for suppressing and curing multidrug resistant form of P. falciparum, DOC for malarial suppression
• Primaquine


  Narrowest spectrum of activity, most effective against malarial parasite in the liver but not effective against parasites within erythrocytes, DOC for acute attack of P. vivax
• Quinacrine


  Most toxic antimalarial drug, treatment for malaria and a sclerosing agent, use in "liver stage", toxic if combined with Primaquine
• Doxycycline


  Prophylaxis for malaria
• Halofantrine


  Arrest tissue condition in cardiac muscles
• Lumefantrine


  Inhibition of B-hematinin
• Artesiminin


  Semi-synthetic antimalarial agent
• Sulfadoxine + Pyrimethamine


  Prophylaxis and treatment of chloroquine resistant malaria
• Atovaquone + Proguanil


  Effective against erythrocytic and exoerythrocytic plasmodium
• Artemether + Lumefantrine


  Interfere heme metabolism
• Tuberculosis is also known as "Koch Disease"
• Causative agent of tuberculosis

  Mycobaterium tuberculosis
• Gram staining of Mycobacterium tuberculosis

  Appears as "ghost" impervious to gram staining
• Acid-Fast staining of Mycobacterium tuberculosis

  Zeihl-Neelsen stain
• Cell wall anatomy of Mycobacterium tuberculosis

  • Contains peptidoglycan (murein) but 60% of the cell wall is a complex lipid, complex lipid: MYCOLIC ACID, cord factor and wax D
• Properties of Mycobacterium tuberculosis due to high concentration of lipids in cell wall


  • Impermeability to stains and dyes
  • Resistance to many antibiotics
  • Resistance to killing by acidic and alkaline compounds
  • Resistance to osmotic lysis via complement deposition
  • Resistance to lethal oxidations and survival inside of macrophages
• Signs and symptoms of tuberculosis


  1. 3 weeks cough, night sweats, on/off fever, haemoptysis
• First line anti-TB drugs

  • Rifampicin
  • Isoniazid
  • Pyrazinamide
  • Ethambutol
  • Streptomycin
• Rifampicin


  Most active against clinical use for the treatment of tuberculosis, source: Streptomyces mediterranei, unstable to moisture: requires desiccant, affects liver function, enzyme inducer, binds strongly to the subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis, does not affect mammalian polymerases, causes red-orange body secretion & is hepatotoxic, used in the prophylaxis of Neisseriae meningitidis
• Isoniazid


  Isonicotinic acid hydravzide, Isonicontinyl hydrazide, structural similarity to pyridoxine/Vit B6 (manage peripheral neuritis), inhibits the synthesis of mycolic acid that constitute important components of the cell walls of mycobacteria, toxic reactions are peripheral neuritis, gastrointestinal disturbances (constipation, loss of appetite) and hepatotoxicity
• Pyrazinamide


  Synthetic analogue of nicotinamide, pyrazinoic acid (active form), essential component of the multidrug short-term therapy of tuberculosis, hepatotoxic: increase uric acid level acute gouty arthritis
• Ethambutol


  Inhibition of the incorporation of mycolic acids into the cell wall of organisms (inhibition of arabinosyl transferase enzymes that are involved in cell wall biosynthesis), not recommended to use alone (should be combined with other anti-TB drugs), retrobulbar neuritis (optic neuritis) impairing visual acuity and red-green color discrimination, hyperuricemia
• Streptomycin


  Inhibits protein synthesis, indicated as a fourth drug in combination with isoniazid, rifampicin, and pyrazinamide in patients at high risk for drug resistance, also used in the treatment of streptomycin-susceptible MDR tuberculosis, first antibiotic effective in the treatment of TB, ototoxic
• Second-line anti-TB drugs


  • Para-amino salicylic Acid (PAS)
  • Ethionamide
  • Cycloserine
  • Capreomycin
  • Clofazimine
• Para-amino salicylic Acid (PAS)


  Structural analogue of paminobenzoic acid (PABA) just like sulfonamides, it is a folate synthesis antagonist that interferes with the incorporation of PABA into folic acid
• Ethionamide


  Derivative of isonicotinic acid and is chemically related to isoniazid, MOA: inhibition of oxygen-dependent mycolic acid synthesis, GI disturbances: nausea, vomiting and intense gastric pain, neurological side effects (confusion, peripheral neuropathy, psychosis and seizures, neurological effects can be minimized by pyridoxine supplementation
• Cycloserine


  Been isolated from the fermentation beer of three different Streptomyces species, MOA: it acts through a competitive inhibition of the D-alanine that is involved in bacterial cell wall synthesis, toxicity: dizziness, confusion, irritability, psychotic behavioral changes and even suicidal ideation, contraindicated in patients with underlying psychiatric and seizure disorders
• Capreomycin & Viomycin


  Capreomycin: isolated from Streptomyces capreolus, ototoxic (destroys 8th cranial nerve) and nephrotoxic, resembles Viomycin in activity, Viomycin: for MDR strains of tuberculosis, no longer available
• Amikacin and Kanamycin


  Considered in the treatment of MDR tuberculosis after streptomycin and capreomycin, disadvantage: very expensive
• Clofazimine


  As a last resort drug for the treatment of MDR tuberculosis
• Clarithromycin and azithromycin


  Demonstrated in vitro activity against mycobacteria, although they have limited activity against M. tuberculosis, clarithromycin is four times as active as azithromycin against M. avium-intracellulare in vitro
• Why combination therapy is given in TB?