antimicrobial, antiparasit & antivirus [dr. edy junaedi]
DESCRIPTION
kuliah farmakologi fakultas kedokteran universitas jemberTRANSCRIPT
Antimikroba, Antiparasit & Antivirus
Edy Junaidi
Antimikroba
● Efek antibakterial :– Bakteriostatik
– Bakterisid
● Spektrum efek antibakterial– Narrow – spectrum
– Broad – spectrum
● Mekanisme resistensi– Natural resistance
– Acquired resistance
Selection of Antimicrobial agents● Optimal selection require :
– Clinical judgement
– Detailed knowledge of pharmacological properties
– Microbiological factors
● General Use of Antibiotics :– Empirical therapy
– Definitive therapy
– Prophylactic therapy
Indications Combination of antibiotic agents● Empirical Therapy of Severe Infections in Which a Cause is
Unknown
● Treatment of Polymicrobial Infections
● Enhancement of Antibacterial Activity in the Treatment of Specific Infections
● Prevention of the Emergence of Resistant Microorganisms
DisadvantagesDisadvantages :
● Increased risk of toxicity
● Selection of multiple-drug-resistant microorganisms
● Eradication of normal host flora with subsequent superinfection
● Increased cost
Misuses of Antibiotics● Treatment of nonresponsive infections● Therapy of fever of unknown origin● Improper dosage ● Inappropriate reliance on chemotherapy alone● Lack of adequate bacteriological information
General Mechanisms
Inhibitors of Cell Wall SynthesisInhibitors of Cell Wall Synthesis
● Structural stability of cell wall mainly constructed by murine (peptidoglycans) lattice, consist of:
– N-acetylglucosamine
– N-acetyl muramic acid
● Inhibitors of cell wall synthesis → bactericidal– Penicillin & derivatives
– Cephalosporins
– Bacitracin
– Vancomycin
Form a building block of cell wall
PenicillinsDerivatives of Penicillin G
● β-lactamase inhibitors :– Clavulanic acid (the only available for oral use)
– Sulbactam
– Tazobactam● Combine with Combine with ββ-lactam antibiotics to overcome -lactam antibiotics to overcome
penicillinase activitypenicillinase activity– Ampicillin – sulbactam, ticarcillin –
clavulanic acid, piperacillin – tazobactam, amoxycillin – clavulanic acid
● All except amoxycillin – clavulanic acid are parenteral formulation
Cephalosporins
● Semisynthetic antibiotics, classified according to antibacterial spectrum & stability to β-lactamase
● The cephalosporins distribute in satisfactory concentrations to most tissues except the central nervous system.
– Only cefepime, cefuroximecefepime, cefuroxime (Zinacef), cefotaximecefotaxime (Claforan), ceftriaxoneceftriaxone (Rocephin), and ceftazidimeceftazidime (Fortaz) achieve therapeutic therapeutic concentrationsconcentrations in cerebrospinal fluid
Inhibitors of Tetrahydrofolate SynthesisInhibitors of Tetrahydrofolate Synthesis● Tetrahydrofolic acid (THF) → a coenzymecoenzyme in the synthesis
of purine bases and thymidine ⇒ constituents of DNA and RNA ⇒ required for cell growthrequired for cell growth and replicationreplication
● Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim (bacteriostatic)
● Sulfonamide possess structural resemblence to PABA → false substratefalse substrate → inhibit utilization of PABA
● Trimethoprim is a highly selective inhibitor of highly selective inhibitor of dihydrofolate reductase of lower organismsdihydrofolate reductase of lower organisms; ~100,000 times more drug is required to inhibit human reductase than the bacterial enzyme
Dihydrofolate Dihydrofolate reductasereductase
Classification of Sulfonamides based on extend or rapidity of absorption and excretion
● Absorbed and excreted rapidly (sulfisoxazole, Sulfamethoxazole and sulfadiazine)
● Absorbed very poorly when administered orally and hence are active in the bowel lumenactive in the bowel lumen (sulfasalazine)
● Mainly used topically (sulfacetamide, mafenide, and silver sulfadiazine)
● Long-acting sulfonamides (Sulfadoxine)
Clinical Use● Urinary tract infections● Nocardiosis● Toxoplasmosis● Bacterial Respiratory Tract Infections● Gastrointestinal Infections● Infection by Pneumocystis jiroveci● Prophylaxis in Neutropenic Patients
Adverse Effects● May cause or precipitate megaloblastosis, leukopenia, or
thrombocytopenia in folate-deficient patients ⇒ narrowing safety margin
● Dermatologic reactions, severe cases primarily in older patients
● Transient jaundice with histological features of allergic cholestatic hepatitis
● Displacement of other plasma protein-bound drugs or bilirubin in neonates (danger of kernicterus : contraindication contraindication for the last weeks of gestation and in the neonatefor the last weeks of gestation and in the neonate)
● Hypersensitivity reactions
Inhibitors of DNA Function● Synthesis of new DNA is a prerequisite for cell
division → inhibition of reading of genetic information at the DNA template damage the regulatory center of cell metabolism
Gyrase InhibitorsGyrase Inhibitors
● Interfere supercoiling of double helical configuration → prevent specifically the resealing of opened strands →bactericidal
● Nalidixic acid (older drug) attains effective concentrations only in urine → urinary antiseptics, affects exclusively Gram-negative bacteria
● Other quinolonesquinolones (Norfloxacin, Ofloxacin, ciprofloxacin, enoxacin, and others) achieve effective concentration systemically → used for infections of internal organs
● Quinolones damage epiphyseal chondrocytes and joint cartilages → should not be used during pregnancy, lactation, and periods of growth
● Several reports on hepatic damage, prolongation of the QT-interval with risk of arrhythmias, and phototoxicity
Nitroimidazole derivatives (Metronidazole, Timidazole)Nitroimidazole derivatives (Metronidazole, Timidazole)● Reactive metabolites → attack DNA → damage DNA by
complex formation or strand breakage
● Bactericidal effect
● Occurs in obligate anaerobic bacteria & shows antiprotozoal action (Trichomonas vaginalis, Entamoeba hystolitica)
● Potentially mutagenic, carcinogenic, and teratogenic in humans, it should not be used for longer than 10 days
● Avoid use during pregnancy and lactationAvoid use during pregnancy and lactation
Inhibitors of Protein Synthesis● Protein synthesis involves amino acid assembly to form
peptides – protein, occurs at ribosomes
● Antibiotics of different groups affecting protein synthesis by interfering steps amino acid incorporation into peptide chains
Tetracycline & Its derivativesTetracycline & Its derivatives● Inhibit the binding of tRNA–AA complexes
● Bacteriostatic effect
● Broad spectrum
Aminoglycosides Aminoglycosides (Gentamycin, amikacin, streptomycin, etc)
● Induce the binding of “wrong” tRNA–AA complexes, resulting in synthesis of false proteins
● Bactericidal ( concentration-dependent), mainly Gram-negative organisms
● GIT absorption differ among derivatives of tetracycline, nearly complete for doxycycline & minocycline
● The most common unwanted effect is GI upset:
– Direct mucosal irritant
– Damage to the natural bacterial gut flora (broad-spectrum antibiotics)
● Concurrent ingestion of antacids or milk form insoluble insoluble complexescomplexes → inactivation
● The ability to chelate Ca2+ makes tetracyclines accumulates in growing teeth (irreversible discoloration) & bone (reversible growth inhibition)
● Other Adverse effects include photosensitivity, hepatic damage (mainly after IV administration)
Resistance mechanismsResistance mechanisms :
● Decreased accumulation of tetracycline (acquisition of an energy-dependent efflux pathway)
● Production of a ribosomal protein that displaces tetracycline from its target
● Enzymatic inactivation of tetracyclines
ChloramphenicolChloramphenicol● Inhibits peptide synthetase
● Binds reversibly to the 50S ribosomal subunit → prevent binding amino acyl tRNA to acceptor site → inhibiting peptide bond formation
● Broad – spectrum
● Bacteriostatic, may be bactericidal against H. influenzae, Neisseria meningitidis, and S. pneumoniae
● Completely absorbed after oral ingestion; Readily crosses diffusion barriers
● Danger of bone marrow damage
– Dose-dependent, toxic, reversible form manifested during therapy
– Non dose-dependent, frequently fatal, occurs after several weeks of latency
Macrolides Macrolides (Prototype : Erythromycin)● Binding reversibly to 50S ribosomal subunits at or very near the
site that binds chloramphenicol
● Inhibits the translocation stepInhibits the translocation step from the acceptor site on the ribosome to the peptidyl donor site
● Predominantly bacteriostatic
● mainly against Gram-positive organisms
● Effective orally
● Suitable as a substitute in allergy or resistance to penicillin
● Clarithromycin, roxithromycin and azithromycin have similar activity with slower elimination → reduce dosing & frequency of administration
● Inhibitors of CYP isozymes → potential for drug interactions
LincosamidesLincosamides● Clindamycin possess antibacterial activity ≈ erythromycin
● Bacteriostatic effect mainly on Gram-positive aerobic
● Clindamycin is a semisynthetic chloro analogue of Lincomycin
– Better absorbed
– Greater antibacterial efficacy
● Both penetrate well into bone tissue
● Macrolide resistance due to ribosomal methylation also may produce resistance to clindamycin
● Clindamycin is not substrate of efflux pumps → microbial resistance to macrolides by this mechanisms might susceptible to Clindamycin
LinezolidLinezolid● Synthetic antimicrobial agent of the oxazolidinone class● Binding to the P site of the 50S ribosomal subunit and
preventing formation of the larger ribosomal-fMet-tRNA complex that initiates protein synthesis
● Unique mode of action → no cross-resistance with other drug classes
● Active againts bacteria resistance to other drugs, including penicillin – resistance, methicillin – resistance, vancomycin-intermediate and vancomycin-resistant strains
● Resistance generally requires mutations in two or more copies of 23S rRNA genes
Antifungal AgentsImidazole derivativesImidazole derivatives● Inhibit synthesis of ergosterol, an integral constituent of
cytoplasmic membranes of fungal cells
● Fungistatic or fungicidal
● Poorly absorbed and poorly tolerated systemically
– Most imidazoles are suitable only for topical use (Clotrimazole, Econazole, Oxiconazole and other azoles)
● Fluconazole and itroconazole are newer orally effective triazole derivatives
● Fluconazole water-soluble → injectable solution
Polyene antibioticsPolyene antibiotics
(Amphotericin B and nystatin)
● Cause formation of hydrophilic channels
● Amphotericin B is active against most organisms responsible for systemic mycoses
● polyene antimycotics are nonabsorbable → it must be given by infusion → poorly tolerated
– Chills, fever, CNS disturbances, impaired renal function, phlebitis at the infusion site
FlucytosineFlucytosine● Converted in candidal fungi to 5-fluorouracil by the action of a
specific fungal cytosine deaminase
● Antimetabolite, disrupts DNA and RNA Synthesis → fungicidal effect
CaspofunginCaspofungin● Inhibits synthesis of the fungal cell wall
● Water-soluble, parenteral injection; can be used in systemic mycoses due to aspergillus fungi when amphotericin B or itroconazole cannot be employed
● well tolerated, with the exception of phlebitis at the infusion site
GriseofulvinGriseofulvin● Acts as a spindle poison to inhibit fungal mitosis
● The time required for the eradication of dermatophytes corresponds to the renewal period of skin, hair, or nails
● Its clinical use become obsolete because of its cumbersome application (require parenteral administration in the therapy of dermatophytoses)