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1、Antimicrobial AgentsMartin VotavaOlga KroftovOverviewIf bacteria make it past our immune system and start reproducing inside our bodies, they cause disease. Certain bacteria produce chemicals that damage or disable parts of our bodies. Antibiotics work to kill bacteria.Antibiotics are specific to ce
2、rtain bacteria and disrupt their function.What is an Antibiotic?An antibiotic is a selective poison. It has been chosen so that it will kill the desired bacteria, but not the cells in your body. Each different type of antibiotic affects different bacteria in different ways. For example, an antibioti
3、c might inhibit a bacterias ability to turn glucose into energy, or the bacterias ability to construct its cell wall. Therefore the bacteria dies instead of reproducing. AntibioticsSubstances produced by various speciesof microorganisms: bacteria, fungi, actinomycetes- to suppress the growth of othe
4、r microorganisms and to destroy them.Today the term ATB extends to include synthetic antibacterial agents: sulfonamides and quinolones.HistoryThe German chemist Paul Ehrlich developed the idea of selective toxicity: that certain chemicals that would be toxic to some organisms, e.g., infectious bacte
5、ria, would be harmless to other organisms, e.g., humans.In 1928, Sir Alexander Fleming, a Scottish biologist, observed that Penicillium notatum, a common mold, had destroyed staphylococcus bacteria in culture. Sir Alexander FlemingFlemings Petri DishZone of InhibitionAround the fungal colony is a cl
6、ear zone where no bacteria are growingZone of inhibition due to the diffusion of a substance with antibiotic properties from the fungusHistoryPenicillin was isolated in 1939, and in 1944 Selman Waksman and Albert Schatz, American microbiologists, isolated streptomycin and a number of other antibioti
7、cs from Streptomyces griseus.Susceptibility vs. Resistanceof microorganisms to Antimicrobial AgentsSuccess of therapeutic outcome depends on:Achieving concentration of ATB at the site of infection that is sufficient to inhibit bacterial growth.Host defenses maximally effective MI effect is sufficien
8、t bacteriostatic agents (slow protein synthesis, prevent bacterial division)Host defenses impaired- bactericidal agentsComplete ATB-mediated killing is necessarySusceptibility vs. Resistance(cont.)Dose of drug has to be sufficient to produce effect inhibit or kill the microorganism:However concentra
9、tion of the drug must remain below those that are toxic to human cells If can be achieved microorganism susceptible to the ATBIf effective concentration is higher than toxic- microorganism is resistantSusceptibility vs. Resistance(cont.)Limitation of in vitro testsIn vitro sensitivity tests are base
10、d on non-toxic plasma concentrations cut offDo not reflect concentration at the site of infectionE.g.: G- aer.bacilli like Ps.aeruginosa inhibited by 2 4 ug/ml of gentamycin or tobramycin. Susceptible !? Antibiotic Susceptibility Testing84021 Tetracycline (g/ml)MIC = 2 g/mlDetermination of MICChlAmp
11、EryStrTetDisk Diffusion TestSusceptibility vs. Resistance(cont.)Plasma concentration above 6-10 ug/ml may result in ototoxicity or nephrotoxicityRation of toxic to therapeutic concentration is very low agents difficult to use.Concentration in certain compartments vitreous fluid or cerebrospinal flui
12、d much lower than those in plasma.Therefore can be only marginally effective or ineffective even those in vitro test states sensitive.Susceptibility vs. Resistance(cont.)Therefore can be only marginally effective or ineffective even those in vitro test states sensitive“.Conversely concentration of d
13、rug in urine may be much higher than in plasma , so resistant“ agents can be effective in infection limited to urine tractResistanceTo be effective ATB must reach the target and bind to it.Resistance: Failure to reach the targetThe drug is inactivatedThe target is alteredResistance (cont.)Bacteria p
14、roduce enzymes at or within the cell surface inactivate drugBacteria possess impermeable cell membrane prevent influx of drug.Transport mechanism for certain drug is energy dependent- not effective in anaerobic environment.ATB as organic acids penetration is pH dependent.Resistance (cont.)Acquired b
15、y mutation and passed vertically by selection to daughter cells.More commonly horizontal transfer of resistance determinant from donor cell, often another bacterial species, by transformation, transduction, or conjugation.Horizontal transfer can be rapidly disseminated By clonal spread or resistant
16、strain itselfOr genetic exchange between resistant and further susceptible strains.Resistance (cont.)Methicilin resistant strains of Staphylococcus aureus clonally derived from few ancestral strains with mecA geneEncodes low-affinity penicillin-binding protein that confers methicillin resistance.Sta
17、phylococcal beta-lactamase gene, which is plasmid encoded, presumambly transferred on numerous occasions. Because is widely distributed among unrelated strains, identified also in enterococciSelection of the ATBRequires clinical judgment, detailed knowledge of pharmacological and microbiological fac
18、tors.Empirical therapy initial infecting organism not identified single broad spectrum agentDefinitive therapy- microorganism identified a narrow spectrum low toxicity regiment to complete the course of treatment Empirical and Definite TherapyKnowledge of the most likely infecting microorganism and
19、its susceptibilityGram stainPending isolation and identification of the pathogenSpecimen for culture from site of infection should be obtain before initiation of therapy Definite therapyPenicillinsPenicillins contain a b b-lactam ring which inhibits the formation of peptidoglycan crosslinks in bacte
20、rial cell walls (especially in Gram-possitive organisms)Penicillins are bactericidal but can act only on dividing cellsThey are not toxic to animal cells which have no cell wallSynthesis of Penicillinb-Lactams produced by fungi, some ascomycetes, and several actinomycete bacteriab-Lactams are synthe
21、sized from amino acids valine and cysteineb b Lactam Basic StructurePenicillins (cont.) Clinical PharmacokineticsPenicillins are poorly lipid soluble and do not cross the blood-brain barrier in appreciable concentrations unless it is inflamed (so they are effective in meningitis)They are actively ex
22、creted unchanged by the kidney, but the dose should be reduced in severe renal failurePenicillins (cont.)ResistanceThis is the result of production of b b-lactamase in the bacteria which destroys the b b-lactam ringIt occurs in e.g. Staphylococcus aureus, Haemophilus influenzae and Neisseria gonorrh
23、oeaPenicillins (cont.)ExamplesThere are now a wide variety of penicillins, which may be acid labile (i.e. broken down by the stomach acid and so inactive when given orally) or acid stable, or may be narrow or broad spectrum in actionPenicillins (cont.)ExamplesBenzylpenicillin (Penicillin G) is acid
24、labile and b-lactamase sensitive and is given only parenterallyIt is the most potent penicillin but has a relatively narrow spectrum covering Strepptococcus pyogenes, S. pneumoniae, Neisseria meningitis or N. gonorrhoeae, treponemes, Listeria, Actinomycetes, ClostridiaPenicillins (cont.)ExamplesPhen
25、oxymethylpenicillin (Penicillin V) is acid stable and is given orally for minor infectionsit is otherwise similar to benzylpenicillinPenicillins (cont.)ExamplesAmpicillin is less active than benzylpenicillin against Gram-possitive bacteria but has a wider spectrum including (in addition in those abo
26、ve) Strept. faecalis, Haemophilus influenza, and some E. coli, Klebsiella and Proteus strainsIt is acid stable, is given orally or parenterally, but is b-laclamase sensitivePenicillins (cont.)ExamplesAmoxycillin is similar but better absorbed orally It is sometimes combined with clavulanic acid, whi
27、ch is a b-lactam with little antibacterial effect but which binds strongly to b-lactamase and blocks the action of b-lactamase in this wayIt extends the spectrum of amoxycillinPenicillins (cont.)ExamplesFlucloxacillin is acid stable and is given orally or parenterallyIt is b-lactamase resistant It i
28、s used as a narrow spectrum drug for Staphylococcus aureus infectionsPenicillins (cont.)ExamplesAzlocillin is acid labile and is only used parenterallyIt is b-lactamase sensitive and has a broad spectrum, which includes Pseudomonas aeruginosa and Proteus speciesIt is used intravenously for life-thre
29、atening infections,i.e. in immunocompromised patients together with an aminoglycoside Penicillins (cont.)Adverse effectsAllergy (in 0.7% to 1.0% patients). Patient should be always asked about a history of previous exposure and adverse effectsSuperinfections(e.g.caused by Candida )Diarrhoea : especi
30、ally with ampicillin, less common with amoxycillinRare: haemolysis, nephritisPenicillins (cont.)Drug interactionsThe use of ampicillin (or other broad-spectrum antibiotics) may decrease the effectiveness of oral conraceptives by diminishing enterohepatic circulationAntistaphylococcus penicillinsOxac
31、illin, cloxacillinResistant against staphylococcus penicillinasisCephalosporinsThey also owe their activity to b-lactam ring and are bactericidal.Good alternatives to penicillins when a broad -spectrum drug is requiredshould not be used as first choice unless the organism is known to be sensitiveCep
32、halosporinsBACTERICIDAL- modify cell wall synthesisCLASSIFICATION- first generation are early compoundsSecond generation- resistant to -lactamasesThird generation- resistant to -lactamases & increased spectrum of activityFourth generation- increased spectrum of activity CephalosporinsFIRST GENERATIO
33、N- eg cefadroxil, cefalexin, Cefadrine - most active vs gram +ve cocci. An alternative to penicillins for staph and strep infections; useful in UTIsSECOND GENERATION- eg cefaclor and cefuroxime. Active vs enerobacteriaceae eg E. coli, Klebsiella spp,proteus spp. May be active vs H influenzae and N m
34、eningtidisCephalosporinsTHIRD GENERATION- eg cefixime and other I.V.s cefotaxime,ceftriaxone,ceftazidine. Very broad spectrum of activity inc gram -ve rods, less activity vs gram +ve organisms. FOURTH GENERATION- cefpirome better vs gram +ve than 3rd generation. Also better vs gram -ve esp enterobac
35、teriaceae & pseudomonas aerugenosa. I.V. route onlyCephalosporins (cont.)Adverse effectsAllergy (10-20% of patients wit penicillin allergy are also allergic to cephalosporins)Nephritis and acute renal failureSuperinfectionsGastrointestinal upsets when given orallyAminoglycosides (bactericidal)strept
36、omycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, neomycin (topical)Mode of action - The aminoglycosides irreversibly bind to the 16S ribosomal RNA and freeze the 30S initiation complex (30S-mRNA-tRNA) so that no further initiation can occur. They also slow down protein synthesis that
37、 has already initiated and induce misreading of the mRNA. By binding to the 16 S r-RNA the aminoglycosides increase the affinity of the A site for t-RNA regardless of the anticodon specificity. May also destabilize bacterial membranes.Spectrum of Activity -Many gram-negative and some gram-positive b
38、acteriaResistance - CommonSynergy - The aminoglycosides synergize with -lactam antibiotics. The -lactams inhibit cell wall synthesis and thereby increase the permeability of the aminoglycosides.AminoglycosidesClinical pharmacokineticsThese are poorly lipid soluble and, therefore, not absorbed orally
39、Parenteral administration is required for systemic effect.They do not enter the CNS even when the meninges are inflamed.They are not metabolized.Aminoglycosides (cont.)Clinical pharmacokineticsThey are excreted unchanged by the kidney (where high concentration may occur, perhaps causing toxic tubula
40、r demage) by glomerular filtration (no active secretion).Their clearance is markedly reduced in renal impairment and toxic concentrations are more likely. Aminoglycosides (cont.)ResistanceResistance results from bacterial enzymes which break down aminoglycosides or to their decreased transport into
41、the cells.Aminoglycosides (cont.)ExamplesGentamicin is the most commonly used, covering Gram-negative aerobes, e.g. Enteric organisms (E.coli, Klebsiella, S. faecalis, Pseudomonas and Proteus spp.) It is also used in antibiotic combination against Staphylococcus aureus.It is not active against aerob
42、ic Streptococci.Aminoglycosides (cont.)ExamplesIn addition to treating known sensitive organisms, it is used often blindly with other antibiotics in severe infections of unknown cause.Streptomycin was formerly the mainstay of antituberculous therapy but is now rarely used in the developed world.Amin
43、oglycosides (cont.)ExamplesTobramycin: used for pseudomonas and for some gentamicin-resistant organisms.Some aminoglycosides,e.g. Gentamicin, may also be applied topically for local effect, e.g. In ear and eye ointments.Neomycin is used orally for decontamination of GI tract.Aminoglycosides (cont.)A
44、dverse effectsAlthough effective, aminoglycosides are toxic, and this is plasma concentration related.It is essential to monitor plasma concentrations ( shortly before and after administration of a dose) to ensure adequate concentrations for bactericidal effects, while minimising adverse effects, ev
45、ery 2-3 days. Aminoglycosides (cont.)Adverse effectsThe main adverse effects are: NephrotoxicityToxic to the 8th cranial nerve (ototoxic), especially the vestibular division.Other adverse effects are not dose related, and are relatively rare, e.g. Allergies, eosinophilia.Macrolides (bacteriostatic)e
46、rythromycin, clarithromycin, azithromycin, spiramycinMode of action - The macrolides inhibit translocation by binding to 50 S ribosomal subunitSpectrum of activity - Gram-positive bacteria, Mycoplasma, Legionella (intracellular bacterias)Resistance - CommonMacrolides (cont.)Examples and clinical pha
47、rmacokineticsErythromycin is acid labile but is given as an enterically coated tabletAbsorption is erratic and poor.It is excreted unchanged in bile and is reabsorbed lower down the gastrointestinal tract (enterohepatic circulation).It may be given orally or parenterallyMacrolides (cont.)Examples an
48、d clinical pharmacokineticsMacrolides are widely distributed in the body except to the brain and cerebrospinal fluidThe spectrum includes Staphylococcus aureus, Streptococcuss pyogenes, S. pneumoniae, Mycoplasma pneumoniae and Chlamydia infections.Macrolides (cont.)Examples and clinical pharmacokine
49、ticsNewer macrolides such as clarithromycin and azithromycin may have fewer adverse effects.Macrolides side effectsNauzea, vomitusAllergyHepatitis, ototoxicityInteraction with cytochrome P450 3A4 (inhibition)Chloramphenicol, Lincomycin, Clindamycin (bacteriostatic)Mode of action - These antimicrobia
50、ls bind to the 50S ribosome and inhibit peptidyl transferase activity.Spectrum of activity - Chloramphenicol - Broad range;Lincomycin and clindamycin - Restricted rangeResistance - CommonAdverse effects - Chloramphenicol is toxic (bone marrow suppression) but is used in the treatment of bacterial me
51、ningitis.ClindamycinClindamycin, although chemically distinct, is similar to erythromycin in mode of action and spectrum.It is rapidly absorbed and penetrates most tissues well, except CNS. It is particularly useful systematically for S. aureus (e.g.osteomyelitis as it penetrates bone well) and anae
52、robic infections.ClindamycinAdverse effectsDiarrhoea is common.Superinfection with a strain of Clostridium difficile which causes serious inflammation of the large bowel (Pseudomembranous colitis)ChloramphenicolThis inhibits bacterial protein synthesis. It is well absorbed and widely distributed , i
53、ncluding to the CNS.It is metabolized by glucoronidation in the liver.Although an effective broad-spectrum antibiotics, its uses are limitid by its serious toxicity.Chloramphenicol (cont.)The major indication is to treat bacterial meningitis caused by Haemophilus influenzae, or to Neisseria menigiti
54、dis or if organism is unknown.It is also specially used for Rikettsia (typhus).Chloramphenicol (cont.)Adverse effectsA rare anemia, probably immunological in origin but often fatalReversible bone marrow depression caused by its effect on protein synthesis in humansLiver enzyme inhibitionSulfonamides
55、 and trimethoprimSulfonamides are rarely used alone today.Trimethoprim is not chemically related but is considered here because their modes of action are complementary.Sulfonamides, Sulfones (bacteriostatic)Mode of action - These antimicrobials are analogues of para-aminobenzoic acid and competitive
56、ly inhibit formation of dihydropteroic acid.Spectrum of activity - Broad range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.Resistance - CommonCombination therapy - The sulfonamides are used in combination with trimethoprim; this
57、combination blocks two distinct steps in folic acid metabolism and prevents the emergence of resistant strains.Trimethoprim, Methotrexate, (bacteriostatic)Mode of action - These antimicrobials binds to dihydrofolate reductase and inhibit formation of tetrahydrofolic acid.Spectrum of activity - Broad
58、 range activity against gram-positive and gram-negative bacteria; used primarily in urinary tract and Nocardia infections.Resistance - CommonCombination therapy - These antimicrobials are used in combination with the sulfonamides; this combination blocks two distinct steps in folic acid metabolism a
59、nd prevents the emergence of resistant strains.p-aminobenzoic acid + PteridineDihydropteroic acidDihydrofolic acidTetrahydrofolic acidPteridine synthetaseDihydrofolate synthetaseDihydrofolate reductaseThymidinePurinesMethionineTrimethoprimSulfonamidesSulfonamides and trimethoprimMode of actionFolate
60、 is metabolized by enzyme dihydrofolate reductase to the active tetrahydrofolic acid.Trimethoprim inhibits this enzyme in bacteria and to a lesser degree in animal s, as the animal enzyme is far less sensitive than that in bacteria. Sulfonamides and trimethoprimClinical pharmacokineticsMost sulfonam
61、ides are well absorbed orally and they are widely distributed including to the CNS.Most are excreted by the kidney unchanged.They are effective against Gram-positive and many Gram-negative organism but are rarely used alone now.Sulfonamides and trimethoprimClinical pharmacokineticsTrimethoprim is al
62、so well absorbed and excreted by the kidneys, with similar spectrum.Cotrimoxazole is widely used for urinary and upper respiratory tract infections but should not be the drug of choice because of its adverse effects.Sulfonamides and trimethoprimClinical pharmacokineticsIt is the drug of choice for t
63、he treatment and prevention of pneumonia caused by Pneumocystis carinii in immunosupressed patients.Trimethoprim is increasingly used alone for urinary tract and upper respiratory tract infections, as it is less toxic than the combination and equally effective.Sulfonamides and trimethoprimAdverse ef
64、fectsGastrointestinal upsetsLess common but more serious:-sulfonamides: allergy, rash, fever, agranulocytosis, renal toxicity-trimethoprim: macrocytis anemia, thrombocytopenia -cotrimoxazole: aplastic anemiaSulfonamides and trimethoprimDrug intereactionsSulfonamides can decrease metabolism of phenyt
65、oin, warfarin and some oral hypoglycaemics, increasing their effects.Quinolones (bactericidal)nalidixic acid, ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, lomefloxacin, sparfloxacin Mode of action - These antimicrobials bind to the A subunit of DNA gyrase (topoisomerase) and prevent supercoi
66、ling of DNA, thereby inhibiting DNA synthesis.Spectrum of activity - Gram-positive cocci and urinary tract infectionsResistance - Common for nalidixic acid; developing for ciprofloxacinQuinolonesThe quinolones are effective but expensive antibiotics.With increased use, resistance to these drugs is b
67、ecoming more common.They should in general be reverse drugs and not first-line treatment.Quinolones (cont.)Examples and clinical pharmacokineticsNalidixic acid, the first quinolone, is used as a urinary antiseptic and for lower urinary tract infections, as it has no systemic antibacterial effect.Cip
68、rofloxacin is a fluoroquinolone with a broad spectrum against Gram-negative bacilli and Pseudomonas,Quinolones (cont.)Examples and clinical pharmacokineticsIt can be given orally or i.v. to treat a wide range of infections, including respiratory and urinary tract infections as well as more serious i
69、nfections, such as peritonitis and Salmonella.Activity against anaerobic organism is poor and it should not be first choice for respiratory tract infections.Quinolones (cont.)Adverse effectsGastrointestinal upsetsFluoroquinolones may block the inhibitory neurotransmitter GABA, and this may cause con
70、fusion in the elderly and lower the fitting threshold.They are also contraindicated in epileptics.Allergy and anaphylaxisQuinolones (cont.)Adverse effectsPossibly damage to growing cartilage: not recommended for pregnant women and childrenDrug interactionCiprofloxacin is a liver enzyme inhibitor and
71、 may cause life-threatening interaction with theophylline.Tetracyclines (bacteriostatic)tetracycline, minocycline and doxycyclineMode of action - The tetracyclines reversibly bind to the 30S ribosome and inhibit binding of aminoacyl-t-RNA to the acceptor site on the 70S ribosome.Spectrum of activity
72、 - Broad spectrum; Useful against intracellular bacteriaResistance - CommonAdverse effects - Destruction of normal intestinal flora resulting in increased secondary infections; staining and impairment of the structure of bone and teeth.Tetracyclines (cont.) Examples and clinical pharmacokineticsTetr
73、acycline, oxytetracycline have short half-lives.Doxycycline has a longer half-life and can be given once per day.These drugs are only portly absorbed.They bind avidly to heavy metal ions and so absorption is greatly reduced if taken with food, milk, antacids or iron tablets.Tetracyclines (cont.) Exa
74、mples and clinical pharmacokineticsThey should be taken at least half an hour before food.Tetracyclines concentrate in bones and teeth.They are excreted mostly in urine, partly in bile.They are broad spectrum antibiotics, active against most bacteria except Proteus or Pseudomonas.Tetracyclines (cont
75、.) Examples and clinical pharmacokineticsResistance is frequent.They are specially indicated for Mycoplasma, Rikettsia, Chlamydia and Brucella infections.Their most common use today is for acne, given either orally or topically.Tetracyclines (cont.) Adverse effectsGastrointestinal upsetsSuperinfecti
76、onDiscolouration and deformity in growing teeth and bones (contraindicated in pregnancy and in children 12 years)Renal impairment (should be also avoided in renal disease)MetronidazoleMetronidazole binds to DNA and blocks replication.PharmacokineticsIt is well absorbed after oral or rectal administr
77、ation and can be also given i.v.It is widely distributed in the body (including into abscess cavities) It is metabolized by the liver. Metronidazole (cont.)UsesMetronidazole is active against anaerobic organisms (e.g. Bacteroides, Clostridia), which are encountered particularly in abdominal surgery.
78、It is also used against Trichomonas, Giardia and Entamoeba infections and can be used to treat pseudomembranous colitis.Metronidazole (cont.)UsesIncreasingly, it is used as part of treatment of Helicobacter pyloris infestion of the stomach and duodenum associated with peptic ulcer disease.It is used
79、 also to treat a variety of dental infections, particularly dental abscess.Metronidazole (cont.)Adverse effectsNausea, anorexia and metallic tasteAtaxiaIn patients, who drink alcohol, may occur unpleasant reactions. They should be advised not to drink alcohol during a treatment.Possibly teratogenic
80、if taken in the first trimester of pregnancyNitrofurantoinThis is used as a urinary antiseptic and to treat Gram-negative infections in the lower urinary tract.It is taken orally and is well absorbed and is excreted unchanged in the urine.It only exerts its antimicrobial effect when it is concentrat
81、ed in the urine and so has no systemic antibacterial effect.Nitrofurantoin (cont.)It is ineffective in renal failure because of failure to concentrate.Resistance develops relatively quickly.Nitrofurantoin (cont.)Adverse effectsGastrointestinal upsetsAllergyPolyneuritisFucidinFucidin is active only a
82、gainst Staphylococcus aureus (by inhibiting bacterial protein synthesis) and is not affected b-lactamase.It is usually only used with flucloxacillin to reduce the development of resistance.It is well absorbed and widely distributed, including to boneFucidin (cont.)It can be given orally or parentera
83、lly.It is metabolized in the liver.Adverse effectsGastrointestinal upsetsHepatitis and jaundiceVancomycinThis interferes with bacterial cell wall formation and is not absorbed after oral administration and must be given parenterally.It is excreted by the kidney. It is used i.v. to treat serious or r
84、esistant Staph. aureus infections and for prophylaxis of endocarditis in penicillin-allergic people.Vancomycin (cont.)It is given orally to treat pseudomembranous colitisteicoplanin is similar but less toxicVancomycin (cont.)Adverse effectsIts toxicity is similar to aminoglycoside and likewise monit
85、oring of plasma concentrations is essential.NephrotoxicityOtotoxicityAllergyAntibiotics for leprosyLeprosy is caused by infection with Mycobacteria leprae. A mixture of drugs are used to treat leprosy, depending on the type and severity of the infection and the local resistance patterns. Antibiotics
86、 for leprosyRifampicin is used and dapsone, which is related to the sulphoamides.Its adverse effects include haemolysis, gastrointestinal upsets and rashes.Chemotherapy for virusesAntiviral drugsAntiviral chemotherapy is still in its infancy.Viruses are more difficult targets than bacteria: they are
87、 most vulnerable during reproduction, but all use host cell organelles and enzymes to do this, so that antiviral compounds are often as toxic to host cells as to virus.Antiviral drugs (cont.)Viruses have assumed increasing importance in the setting of immunosuppression - both drug induced and AIDS.A
88、ntiviral drugs (cont.)Current antiviral drugs are thought to work in one of the following ways:- inhibition of viral uncoating shortly after penetration into the cell; they are best for prophylaxis or very early in the disease course (e.g.amantadine)- interference with viral RNA synthesis and functi
89、on (e.g. ribavirin)Antiviral drugs (cont.) interference with DNA synthesis (e.g. cytarabine)inhibition of viral DNA polymerase (e.g.aciclovir and gancyclovir)inhibition of reverse transcriptase at retroviruses such as HIV (e.g.zidovudine)use of complex natural antiviral defences by employing interfe
90、ronAciclovirMode of actionIt is active against Herpes simplex and Herpes zoster.Aciclovir targets virus-infected cells quite specifically, and this explains the drugs relatively low toxicity.Aciclovir (cont.)Clinical pharmacokineticsThe drug is used topically, orally and i.v.Little drug is absorbed
91、from topical formulations, and the bioavailability of the oral drug is low (about 20%).It is widely distributed and crosses the blood-brain barrier.It is excreted in the urine and in lactating women in the breast milk.Aciclovir (cont.)Therapeutic usesIt is the drug of first choice for Herpes simplex
92、 and zoster infections, because of the great efficacy and lower toxicity than the alternatives.The drug has little activity against cytomegalovirus or Epstein-Barr virus.Aciclovir (cont.)Therapeutic usesHerpes simplex infections of skin, mucous membranes and corneaLife-threatening Herpes simplex inf
93、ections; aciclovir i.v. reduces mortalityHerpes zoster that is less sensitive to aciclovir than H. simplex .It is used for early topic or oral treatment of zoster; aciclovir i.v. is used for life-threatening zoster infections as pneumoniaAciclovir (cont.)Adverse effectsRenal impairment: mainly in hi
94、gh i.v. doses in dehydrated patientsLocal inflammation following extravascular administrationEncephalopathy: mainly in high i.v. dosesZidovudine (AZT)Mode of actionHIV virus is an RNA virus capable of including the synthesis of a DNA transcript of its genome, which can then become integrated into th
95、e host cells DNA, thereby allowing viral replication.Synthesis of the initial DNA transcript involves the enzyme reverse transcriptase.Zidovudine (AZT) cont.Mode of actionZidovudine is a potent inhibitor of reverse transcriptase.It has relatively specific toxicity for the virus.Zidovudine (AZT) cont
96、.Clinical pharmacokineticsIt is well absorbed from the gut but subject to first-pass metabolismBioavailability is about 70%The drug is widely distributed and crosses the blood-brain barrierMost of the drug is eliminated by hepatic metabolism, unchanged zidovudine accounting for about 10% of the dose
97、Zidovudine (AZT) cont.Clinical pharmacokineticsIn patients with renal or liver impairment, the drug may accumulate, and doses are usually adjusted in these disease statesZidovudine (AZT) cont.Therapeutic usesIt is used to prolong life patients with AIDS and AIDS-related complex (ACR); it probably do
98、es not delay the onset of AIDS in HIV-positive patientsThe drug usually produces a rise in CD4 cell counts, but eventual deterioration is usual in spite of zidovudineIn patients with late AIDS it is of little use.Zidovudine (AZT) cont.Adverse effectsBone marrow toxicityPolymyositisHeadache and insom
99、niaZidovudine (AZT) cont.Drug interactionsParacetamol: the risk of bone marrow suppression may increasedProbenecidPurine and pyrimidine analoguesMode of actionThese drugs are effective against DNA virusesThe compounds structurally resemble purine and pyrimidine nucleosidesThe resulting DNA molecule
100、is more easily fragmented, leading to transcription errors.They also inhibit viral DNA polymerase.Purine and pyrimidine analoguesExamples and clinical pharmacokineticsIdoxuridine: it is not absorbed from the gut, and is used topicallyVidarabine: cannot be given orally because it is metabolized in th
101、e gut- it is usually given i.v. or topicallyPurine and pyrimidine analoguesTherapeutic usesIdoxuridine: may be used topically for Herpes simplex and zoster but is too toxic for systemic use and has largely been supplanted by aciclovirVidarabine: may be used for life-threatening systemic Herpes infec
102、tionsPurine and pyrimidine analoguesAdverse effectsIdoxuridine: because it is used only topically, severe adverse effects are unusualVidarabine: anorexia, nausea, vomiting, diarroea and bone marrow suppressionPurine and pyrimidine analoguesDrug interactionsThe metabolism of vidarabine is inhibited b
103、y the xanthine oxidase inhibitor allopurinol, and toxicity may resultRibavirinIt is effective against a wide range of DNA and RNA virusesThe drug may be given by aerosol inhalation, orally or i.v.Oral biavailabity is about 40%It readily crosses the blood-brain barrier and has a very large volume of
104、distribution, mainly because of cellular uptake.Ribavirin (cont.)The drug is eliminated by both metabolism and renal excretion, with a terminal half-life of about 2 weeksRibavirin (cont.)Therapeutic usesRespiratory syncytial virus (RSV) infections: bronchiolitis and pneumonia at young childrenInfluenza A and BLassa fever
