Transcript Antimycobacterials.19.Apr.2011

Antimycobacterials
J. Mojžiš
1
Introduction
• The most widely encountered mycobacterial
infections is tuberculosis
• Members of the genus Mycobacterium also
cause leprosy as well as several tuberculosislike human infections
• Mycobacterial infections are intracellular and,
generally, result in the formation of slowgrowing granulomatous lesions that are
responsible for major tissue destruction
2
Lippincot´s Pharmacology; 2009 3
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.
4
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
5
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
6
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.
7
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
8
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
10
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
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myalgias
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.
13
• 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
14
Lippincot´s pharmaology, 2009
15
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.
17
• 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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Chemotherapy for Leprosy
MDT – multidrug therapy
1. line
• Dapson
• Clofazimine
• Rifampicin
19
2. line
• Ofloxacin
• Minocycline
• Claritromycine
20
• 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.
21
• 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).
22
• 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
23
Antifungal, antiparasitic,
antiviral chemotherapeutics
and antihelmintics
24
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).
25
• 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.
26
Antifungal drugs
• POLYENES:
AMPHOTERICIN
NYSTATIN
GRISEOFULVIN
• AZOLES :
CLOTRIMAZOLE
MICONAZOLE, KETOCONAZOLE
FLUCONAZOLE, ITRACONAZOLE
• OTHER:
FLUCYTOSINE
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Polyenes
Mechanism of action
Pharmacokinetics
AMPHOTERICIN, NYSTATIN
cell membrane
sterol binding
ergosterol  cholesterol
cell wall synthesis inhibition
GRISEOFULVIN
nucleic acid synthesis
inhibition
• 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
30
Azoles
Mechanism of action
 ergosterol synthesis by fungal cyt
P450 binding
KETOKONAZOL
MIKONAZOL
FLUKONAZOL
ITRAKONAZOL
Pharmacokinetics
• variable GI absorption
• good diffusion (except CNS)
• biliary elimination
• good GI absorption
• good tissue diffusion
• excretion: unchanged -urinary
(fluconazole) metabolites: urine
 bile (itraconazole)
31
Indications  side effects
KETOCONAZOLE
superfitial  visceral
mycoses
MICONAZOLE
superfitial skin
mycoses
FLUCONAZOLE
ITRACONAZOLE
large scale of s.c. 
systemic mycoses
KETOCONAZOLE
MICONAZOLE
rare GI problems
skin intolerance
FLUCONAZOLE
ITRACONAZOLE
well tolerated,
nausea, headache
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Newer azoles
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
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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
34
Other antifungal drugs
Mechanism of action
FLUCYTOSINE
Pharmacokinetics
a) interacts with RNA disturbs the building of certain
proteins
• good absorption
• good CNS penetration
(75%)
• renal elimination in
unchanged form
b) inhibits fungal DNA
synthesis
drug has to be intrafungally
converted into the cytostatic
fluorouracil
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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
cloroquine, SP,
mefloquine, quinine
41
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.
42
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
46
Effective drugs
Entamoeba histolytica
• in intestinal lumen
• in intestinal mucosa
(ulcerations)
• absces (liver)
• Drugs acting in
intestine
paromomycine
• Drugs acting in
tissues
emetin
metronidazole
cloroquine
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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
49
Antitrypanosomiasis agents
Tse-tse
Trypanosoma gambiense50
Mechanism of action
African
trypanosomiasis
(T. gambiense  rhodesiense)
suramin
pentamidine
melarsoprol
enzyme inhibition
 of DNA synthesis
energy metab. disorder
Chagas´s disease
(T. crusi; American
trypanosomiasis)
nifurtimox
free radical formation
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Pharmacokinetics
Suramin, pentamidine
• i.v. apl.
• slow renal elimination
(months)
• negligible metab.
• minimal CNS penetration
Nifurtimox
• p.o. aplication
• treatment period 90 - 120 days
(acute or chronic form)
Melarsoprol
• important CNS
penetration
52
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 effects
Suramín, pentamidín,
melarzoprol, nifurtimox
•
•
•
•
•
•
•
frequent
nausea
febrility
purpura
diarrhoea
collaps
shock
54
Antihelmintic agents
Ascaris
Taenia
55
Effective drugs
Presence of parasites
•in intestine
•in tissues
•benzimidazoles
•ivermectin
•pyrantel palmoate
•praziquantel
Mechanisms of
action
• narcotising 
paralytic effects
• inhibition of protein
secretion  glucose
transport
• interference with
microtubular
integrity
56
Pharmacokinetics
• benzimidazoles
mebendazol – GI absorption- less than 10%
albendazol – incomplete absorption
tiabendazol – rapid  complete GI absorption
• ivermectin – absorption after oral appl.
• praziquantel – oral appl.
57
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
59
Antiviral agents
60
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
61
Inhibitors of viral reverse
transcriptase
ZIDOVUDINE
•
inhibition of reverse
transcriptase
•
incorporation in
proviral DNA,
disturbance of
elongation
AIDS therapy
62
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.
63
Protease inhibitors
INDINAVIR
competitive inhibition of
viral proteases 
inhibition of
replication
AIDS therapy
64
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
65
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
66
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)
67
Protease inhibitors
VIDARABINE
• inhibition of virus DNApolymerase 
selective inhibition of virus DNA
synthesis
Herpetic
local  generalised infections
(encephalitis)
68
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)
69
Other antiviral drugs
AMANTADINE
•
•
•
no direct virocidal effect
inhibits cell penetration
 uncoating of virus
acts on: myxovirus,
mainly influenza virus A
Indications
INFLUENZA:
• prophylaxis
• therapy
70
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
71
Other antiviral drugs
INTERFERONS
•
complex antiviral 
immunomodulatory
effect
Indications
• hepatitis B  C
• sclerosis multiplex
72
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.)
73