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Introduction
• The most widely encountered mycobacterial infections is tuberculosis
• Members of the genus Mycobacterium also cause leprosy as well as several tuberculosis-like human infections
• Mycobacterial infections are intracellular and,
generally, result in the formation of slow-growing granulomatous lesions that are responsible for major tissue destruction
3Lippincot´s Pharmacology; 2009
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Isoniazid (INH)
• Mechanism of action: INH is a prodrug that is activated by a mycobacterial catalase-peroxidase (KatG)
• Two different target enzymes for isoniazid: enoyl acyl carrier protein reductase and a β-ketoacyl-ACP synthase production of mycolic acids. The activated drug covalently binds to and inhibits these enzymes, which are essential for the synthesis of mycolic acid
• Mycolic acid is a very-long-chain, β-hydroxylated fatty acids found in mycobacterial cell walls.
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Antibacterial spectrum
• For bacilli in the stationary phase - bacteriostatic
• For rapidly dividing organisms – bactericidal
• Effective against intracellular bacteria
• INH specific for treatment of M. tuberculosis, although M. kansasii may be susceptible at higher drug levels
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Pharmacokinetics
• Orally administered isoniazid is readily absorbed (absorption is impaired if INH is taken with food, particularly carbohydrates, or with aluminum-containing antacids)
• The drug diffuses into all body fluids, cells, and caseous material (necrotic tissue resembling cheese that is produced in tubercles) including CSF
• It undergoes N-acetylation (fast and slow acetylators)
• Excretion is through glomerular filtration
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Adverse effects • Peripheral neuritis: (paresthesias of the hands and feet) -
appears to be due to a relative pyridoxine deficiency. (supplementation of 25-50 mg per day of pyridoxine (vitamin B6).
• Hepatitis and idiosyncratic hepatotoxicity: Potentially fatal hepatitis is the most severe side effect (toxic metabolite of monoacetylhydrazine. Higher risk - elderly, among patients who also take rifampicin, or alcoholics
• Other adverse effects: Mental abnormalities, convulsions in patients prone to seizures, and optic neuritis have been observed. Hypersensitivity reactions include rashes and fever.
• Drug interactions: Because isoniazid inhibits metabolism of phenytoin - potentiates the adverse effects of that drug (nystagmus and ataxia). Slow acetylators are particularly at risk.
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Rifampicin • Derived from Streptomyces, has a broader
antimicrobial activity than isoniazid
• Mechanism of action: it blocks transcription by interacting with the β subunit of bacterial but not human DNA-dependent RNA polymerase.
• The drug is thus specific for prokaryotes
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Antimicrobial spectrum
• it is bactericidal for both intracellular and extracellular mycobacteria, including M. tuberculosis, M. kansasii.
• It is effective against many G+ and G- organisms and is frequently used prophylactically for individuals exposed to meningitis caused by meningococci or H. influenzae
• Rifampicin is the most active antileprosy drug at present
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Pharmacokinetics • Good absorption p.o.
• Distribution – all fluids and organs including CFS
• Elimination of metabolites and the parent drug is via the bile into the feces or via the urine
• Urine and feces as well as other secretions have an orange-red color; patients should be forewarned. Tears may permanently stain soft contact lenses orange-red
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Adverse effects
• Generally well tolerated
• The most common adverse reactions include nausea, vomiting, and rash
• Hepatitis and death due to liver failure is rare (attention in patients who are alcoholic, elderly, or have chronic liver disease)
• Often, when rifampicin is dosed intermittently, or in daily doses of 1.2 grams or greater, a flu-like syndrome is associated with fever, chills, and myalgias
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Pyrazinamide
• synthetic, orally effective, bactericidal agent
• mechanism of its action is unknown
• It must be hydrolyzed to pyrazinoic acid (active form)
• It is active against tubercle bacilli in the acidic environment of lysosomes as well as in macrophages
• It distributes throughout the body, penetrating the CSF
• 1-5% patients taking isoniazid, rifampicin, and pyrazinamide may experience liver dysfunction.
• Urate retention can also occur and may precipitate a gouty attack
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Ethambutol
• Bacteriostatic, specific for most strains of M. tuberculosis and M. kansasii.
• It inhibits arabinosyl transferase—important for the synthesis of the mycobacterial arabinogalactan cell wall
• It can be used in combination with other anti-TBC
• Absorbed after p.o. administration, well distributed throughout the body. Penetration into CNS -therapeutically adequate in tuberculous meningitis.
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• Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion.
• The most important adverse effect is optic neuritis, which results in diminished visual acuity and loss of ability to discriminate between red and green.
• Discontinuation of the drug results in reversal of the optic symptoms. In addition, urate excretion is decreased by the drug; thus, gout may be exacerbated
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Lippincot´s pharmaology, 2009
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Alternate second-line drugs
• Streptomycin: it is the first antibiotic effective in the treatment of TBC; its action is directed against extracellular organisms.
• Capreomycin: This is a peptide that inhibits protein synthesis. It is administered parenterally. Reserved for the treatment of MDR TBC. Careful monitoring of the patient is necessary to prevent its nephrotoxicity and ototoxicity.
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• Cycloserine - orally effective; it antagonizes the steps in bacterial cell wall synthesis; distributed well throughout body fluids, including the CSF. Accumulation occurs with renal insufficiency. Adverse effects involve CNS disturbances, and epileptic seizure activity may be exacerbated. Peripheral neuropathies are also a problem, but they respond to pyridoxine.
• Ethionamide: This is a structural analog of isoniazid, but it is not believed to act by the same mechanism. It is effective after p.o. and is widely distributed throughout the body, including the CSF. Adverse effects that limit its use include gastric irritation, hepatotoxicity, peripheral neuropathies, and optic neuritis. Supplementation with vitamin B6 (pyridoxine) may lessen the severity of the neurologic side effects.
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• Fluoroquinolones: The fluoroquinolones, such as moxifloxacin and levofloxacin, have an important place in the treatment of multidrug-resistant tuberculosis. Some atypical strains of mycobacteria are also susceptible.
• Macrolides: The macrolides, such as azithromycin and clarithromycin, are part of the regimen that includes ethambutol and rifabutin used for the treatment of infections by M. avium-intracellulare complex. Azithromycin is preferred for HIV-infected patients because it is least likely to interfere with the metabolism of antiretroviral drugs.
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1. line• Dapson
• Clofazimine
• Rifampicin
MDT – multidrug therapy
Chemotherapy for Leprosy
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2. line• Ofloxacin
• Minocycline
• Claritromycine
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• Dapsone - structurally related to the sulfonamides and similarly inhibits folate synthesis via dihydropteroate synthetase inhibiton
• It is bacteriostatic for Mycobacterium leprae
• Dapsone is also employed in the treatment of pneumonia caused by Pneumocystis jiroveci in patients infected with the HIV.
• The drug is well absorbed from the gastrointestinal tract and is distributed throughout the body, with high levels concentrated in the skin.
• enterohepatic circulation; eliminated through the urine.
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• Adverse reactions include hemolysis, especially in patients with G-6-PD deficiency, as well as methemoglobinemia, peripheral neuropathy, and the possibility of developing erythema nodosum leprosum (a serious and severe skin complication of leprosy).
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• Clofazimine - phenazine dye that binds to DNA and prevents it from serving as a template for future DNA replication
• Its redox properties may lead to the generation of cytotoxic oxygen radicals that are also toxic to the bacteria.
• Clofazimine is bactericidal to M. leprae and has some activity against M. avium-intracellulare complex.
• Following oral absorption, the drug accumulates in tissues, allowing intermittent therapy, but it does not enter the CNS.
• Patients may develop a red-brown discoloration of the skin. Eosinophilic enteritis has been reported as an adverse effect.
• The drug also has some anti-inflammatory activity
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Antifungal, antiparasitic, antiviral chemotherapeutics
and antihelmintics
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Mycoses – caused by fungi - often chronic.
Many are superficial (only involve the skin - cutaneous mycoses).
Fungi may also penetrate the skin - subcutaneous.
Systemic mycoses - often life- threatening.
Unlike bacteria, fungi are eukaryotic - they have rigid cell walls composed of N-acetylglucosamine- rather than peptidoglycan (typical for most bacterial cell walls).
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• The fungal cell membrane contains ergosterol (cholesterol in mammalian membranes) - useful in targeting agents against fungal infections.
• Fungal infections - generally resistant to antibiotics used in bacterial infections, and conversely, bacteria are resistant to antifungal agents.
• Rise in fungal infections (candidemia = the fourth most common cause of septicemia) - associated with numbers of chronic immune suppression (organ transplant, chemotherapy, HIV.
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Antifungal drugs
• POLYENES: AMPHOTERICIN NYSTATIN GRISEOFULVIN
• AZOLES : CLOTRIMAZOLE MICONAZOLE, KETOCONAZOLE FLUCONAZOLE, ITRACONAZOLE
• OTHER: FLUCYTOSINE
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Polyenes
Mechanism of action
AMPHOTERICIN, NYSTATIN
cell membrane sterol binding
ergosterol cholesterol
cell wall synthesis inhibition
GRISEOFULVINnucleic acid synthesis
inhibition
Pharmacokinetics
• poor GI absorption nystatin – p.o., vag., topical
amphotericin – p.o, i.v.
• absorption with milk, fat ingestion; concentration in skin, hair, nails (griseofulvin)
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Indications
AMPHOTERICIN • generalised fungal infections
(cryptococcuc, candidosis)
NYSTATIN• p.o. in GI mycosis• vaginal mycosis
• locally (skin, mucosa)
GRISEOFULVIN• dermatophytes
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Side effects
AMPHOTERICIN• frequent: fever, headache, flebitis,
nephrotoxicity, anemia• rare: anaphylaxis, hepatotoxicity, vertigo,
thrombocytopenia
NYSTATIN
p.o. localy: no side effects
GRISEOFULVIN
GI troubles, cutaneous
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Azoles
Mechanism of action
ergosterol synthesis by fungal cyt P450 binding
KETOKONAZOLMIKONAZOL
FLUKONAZOLITRAKONAZOL
Pharmacokinetics
• variable GI absorption• good diffusion (except CNS)• biliary elimination
• good GI absorption• good tissue diffusion• excretion: unchanged -urinary
(fluconazole) metabolites: urine bile (itraconazole)
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Indications side effects
KETOCONAZOLE superfitial visceral
mycoses
MICONAZOLE superfitial skin
mycoses
FLUCONAZOLE ITRACONAZOLE
large scale of s.c. systemic mycoses
KETOCONAZOLEMICONAZOLE
rare GI problemsskin intolerance
FLUCONAZOLE ITRACONAZOLE well tolerated,
nausea, headache
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Voriconazole
Broad- spectrum agent.
Treatment of invasive aspergillosis and serious infections caused by Scedosporium apiospermum and fusarium species.
Orally active; penetrates well, incl. CNS.
Metabolised (CYP450 2C19, 2C9 a 3A4) – possibility of drug interactions.
Adverse effects: - similar to other azoles - transient visual disturbance shortly after a dose of the drug
Newer azoles
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Posaconazole
Oral, broad-spectrum, structure similar to itraconazole. Approved to prevent Candida and Aspergillus infections in severely immunocompromised and for the treatment of oropharyngeal candidiasis. Relatively well tolerated. To be effective, posaconazole must be administered with a full meal or nutritional supplement (increased bioavailability).
Adverse effects:-GI (nausea, vomiting, diarrhea, abdominal pain) - headache, elevation of liver function tests, - in patients with concomitant cyclosporine or tacrolimus for management of transplant rejection - rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and pulmonary embolus
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Other antifungal drugs
Mechanism of actionFLUCYTOSINE
a) interacts with RNA - disturbs the building of certain proteins
b) inhibits fungal DNA synthesis
drug has to be intrafungally converted into the cytostatic fluorouracil
Pharmacokinetics
• good absorption• good CNS penetration
(75%)• renal elimination in
unchanged form
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Indications side effects
FLUCYTOSINE
• systemic candidosis• septicemies
Side effects
• GIT• hematologic
• hepatal
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Antiparasitic drugs
• Antimalarial agents
• Antiamebiasis agents
• Antitrichomoniasis agents
• Antitrypanosomiasis agents
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Antimalarial agents
Anopheles
Plasmodium
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Malaria treatment
• Aim: prevention of mortality decrease in morbidity by safe effective drugs
• Malaria remains the world’s most devastating human parasitic infection, afflicting more than 500 million people and causing from 1.7 million to 2.5 million
deaths each year.
• monotherapy was usually used in malaria treatment, e.g.
quinine, quinidine, cloroquine, primaquine, mefloquine, sulfadoxine-pyrimethamine (SP)
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Pharmacokinetics side effects
Pharmacokinetics
• total GI resorption• good tissue diffusion• hepatal metabolism• renal excretion
Side effects
• hemolytic anemia (G-6-P-dehydrogenase deficit)
• cloroquine free of teratogenic effect
• SP second line drug in pregnancy (more effective because of less resistance)
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Resistance to antimalarials 2003:South America South-East Asia
cloroquine, SP, mefloquine, quinine
cloroquine, SP
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Intensification of resistance to cloroquine in Africa (1980-2003)
In Africa CQ resistance has spread rapidly since first identified in Kenya and Tanzania in 1979.
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Prevention of resistance spreading
• WHO – alternative combination therapy instead of monotherapy in countries with increasing appearance of resistance
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Artemisinin
• Artemisinin and its derivatives - potent antimalarial activity.
• Immediate onset and rapid reduction of parasitaemia with complete clearance in most cases within 48 hours• Efficacy is high even in areas with multidrug resistant
strains.
• Artemisinin is the extraction product from the herb Artemisia annua L.
• It was used in traditional Chinese Medicine for the treatment of febrile diseases.
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Artemisinin Mechanism of action• it contain peroxide group• iron-mediated cleavage of the peroxide bridge and generation
of an free radical • the artemisinin radical binds subsequently to membrane
proteins, and alkylation reactions eventually cause destruction of the parasite
NÚ• artemisinin is extremely well tolerated and virtually without
adverse effects • There has been no reports of clinical resistance to the
artemisinin so far
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Antiamebiasis agents
Entamoeba histolytica
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Effective drugs
• Drugs acting in intestine
paromomycine
• Drugs acting in tissues
emetin
metronidazole
cloroquine
Entamoeba histolytica
• in intestinal lumen• in intestinal mucosa
(ulcerations)• absces (liver)
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Antitrichomoniasis agents
Trichomonas vaginalis
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Metronidazole
Mechanism of action• trichomonadocidal without known resistance
Pharmacokinetics• good absorption after p.o. • systemic local (intravaginal) combination therapy• Side effects• rare, nausea, glossitis, constipation• headache• urticaria
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Antitrypanosomiasis agents
Trypanosoma gambiense
Tse-tse
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Mechanism of action
African trypanosomiasis
(T. gambiense rhodesiense)
suramin pentamidine melarsoprol
Chagas´s disease(T. crusi; American
trypanosomiasis)
nifurtimox
enzyme inhibition of DNA synthesis
energy metab. disorder
free radical formation
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Pharmacokinetics
Suramin, pentamidine • i.v. apl.• slow renal elimination
(months)• negligible metab.• minimal CNS penetration
Melarsoprol• important CNS
penetration
Nifurtimox • p.o. aplication • treatment period -
90 - 120 days
(acute or chronic form)
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Indications
Suramin, pentamidine • initial stages of African
type trypanosomiasis
Melarsoprol• lymphatic, blood
meningo-encephalic stages
Nifurtimox• a unique drug for
Chagas´s disease treatment
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Side effectsSuramín, pentamidín, melarzoprol, nifurtimox
• frequent• nausea• febrility• purpura• diarrhoea• collaps• shock
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Antihelmintic agents
Ascaris
Taenia
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Effective drugs
Mechanisms of
action• narcotising paralytic effects
• inhibition of protein secretion glucose
transport
• interference with microtubular
integrity
Presence of parasites
•in intestine•in tissues
•benzimidazoles•ivermectin•pyrantel palmoate•praziquantel
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Pharmacokinetics
• benzimidazolesmebendazol – GI absorption- less than 10%
albendazol – incomplete absorption
tiabendazol – rapid complete GI absorption
• ivermectin – absorption after oral appl.
• praziquantel – oral appl.
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Indications
Disease Drug
Helmintoses in general albendazol, mebendazol
Lymphatic fillariosis albendazol, ivermectin
Onchocercosis ivermectin
Schistosomiosis praziquantel
Strongyloidosis ivermectin
Ascariosis mebendazole
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Side effects
benzimidazoles – GIT, headache, sleepness, confusion, alergy
praziquantel – GIT, artralgia, myalgia, fever, rash
ivermectin – most common - skin rash, headache, fever, myalgia
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Antiviral agents
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Mechanisms of action
• block virus attachment to the cell• block uncoating of virus • inhibit viral protein synthesis• inhibit specific virus enzymes• inhibit virus assembly• inhibit virus release• stimulate host immune system
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Inhibitors of viral reverse transcriptase
ZIDOVUDINE
• inhibition of reverse transcriptase
• incorporation in proviral DNA, disturbance of
elongation
AIDS therapy
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Pharmacokinetics side effects
Pharmacokinetics
• p.o., i.v.• 65% bioavailability
p.o.• renal excretion• 75% as glucuronide
rest unchanged
Side effects
• fever• myalgia• headache, vertigo• anorhexia• leukopenia, anemia• pseudoflu sy.
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Protease inhibitors
INDINAVIR
competitive inhibition of viral proteases
inhibition of replication
AIDS therapy
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Pharmacokinetics side effects
Pharmacokinetics
• p.o.• 30% bioavailability
strongly decreased with protein rich food
• metabolised at P450 3A4
• renal excretion less than 20% of dose
Side effects
• nausea, vomiting• diarrhea, abdominal
pain• headache, asthenia• dry skin, rash• loss of appetite• vertigo
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Protease inhibitors
ACYCLOVIR
• guanine analogue
• activation through acyclovir-triphosphate
• only in cells with virus, containing thymidine kinase (herpes)
• inhibition of viral DNA polymerase
Indications• herpes simplex (labialis,
ocularis, genitalis, neonatal)
• herpes zooster• herpetic encephalitis,
hepatitis
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Pharmacokinetics side effects
Pharmacokinetics
• p.o., i.v., topical• incomplete absorption
p.o., unabsorbed in topical appl.
• high concentrations in kidney, liver, lungs, heart
• poor metabolism, renal excretion of majority of unchanged drug
Side effects
• rare local irritation (eye)• flebitis - i.v.• neurological symptoms -
i.v. (very rare)
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Protease inhibitors
VIDARABINE
• inhibition of virus DNA-polymerase
selective inhibition of virus DNA synthesis
Herpetic
local generalised infections
(encephalitis)
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Pharmacokinetics side effects
Pharmacokinetics
• i.v., local (eye)
• tissue distribution - liver, kidneys
• metabolised in plasma erythrocytes
• renal excretion approx. 60% as metabolite or unchanged
Side effects
• peripheral neuropathies
• myalgia• tremor (high doses)
• GI (rare)
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Other antiviral drugs
AMANTADINE
• no direct virocidal effect• inhibits cell penetration
uncoating of virus• acts on: myxovirus,
mainly influenza virus AIndications
INFLUENZA:• prophylaxis • therapy
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Pharmacokinetics side effects
Pharmacokinetics
• p.o.
• rapid complete GI absorption
• renal excretion mainly in unchanged form
Side effects
• orthostatic hypotension
• dysuria, edema• dry mouth• GI (nausea, vomiting,
constipation)
• restlessness, insomnia, halucinations
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Other antiviral drugs
INTERFERONS
• complex antiviral immunomodulatory effect
Indications
• hepatitis B C
• sclerosis multiplex
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Pharmacokinetics side effects
Pharmacokinetics
• s.c.• no oral absorption • 50% bioavailability
(s.c.)• rapid metabolism
Side effects
• frequent• pseudoflu sy.• fever, sweating,
asthenia• myalgia• cough• local pain (site of
appl.)
