Causes of anaphylaxis

Download Report

Transcript Causes of anaphylaxis

Antimycobactrial Drugs
Parvaneh Rahimi-Moghaddam MD PhD
Department of Pharmacology
Iran University of Medical Sciences
Epidemiology

Nearly up to 1/3 of the global population is
infected with M tuberculosis and at risk of
developing the disease.

More than eight million people develop active
tuberculosis (TB) every year, and about two
million die.
Incidence of TB (WHO 2008)
Treatment Problems (WHO)
1.
Co-infection with HIV significantly increases
the risk of developing TB.
2.
Mycobacterium avium complex is associated
with AIDS-related TB.
3.
Multidrug resistance, which is caused by
poorly managed TB treatment, is a growing
problem of serious concern.
Multidrug-Resistant TB (WHO 2008)
Extensively Drug-Resistant TB

Extensively drug-resistant tuberculosis (XDR
TB) is a relatively rare type of multidrugresistant tuberculosis (MDR TB).

It is resistant to almost all drugs used to treat
TB.
Treatment Problems




Slowly growing organisms
Lipid-rich mycobacterial cell wall
Intracellular organism
Ability to develop resistance to single
drug
G(-) bacteria
Mycobacteria
Drug Used in TB

First-line agents:
Isoniazid (INH)
Rifampin (RIF)
Pyrazinamide (PZA)
Ethambutol (EMB)
Streptomycin (SM)
Approach in TB Treatment


INH + rifampin (9 months)  95 - 98%
cure rate
Plus PZA (first 2 months)  reduce total
duration to 6 months
TB Treatment Regimen
1. Initiation of therapy
INH + rifampin + PZA + ethambutol (or
streptomycin) for 2 months
2. Continuation phase
INH + rifampin for 4 (or 7) months
Treatment Failure

Defined as positive cultures after 4 months
of treatment in patients for whom
medication ingestion was ensured

Single new drug should never be added to a
failing regimen; it may lead to acquired
resistance to the added drug
Isoniazid



Structural similarity to pyridoxine
Bactericidal for actively growing bacilli
Active against both extra- and intra-cellular
organisms
Isoniazid
Mechanism of action
 A prodrug activated by catalase-peroxidase
(KatG)

 Inhibits synthesis of mycolic acids.
Isoniazid
Resistance
Frequency about 1:106
Most commonly results from mutations in
different genes such as KatG (high-level
resistance)

Isoniazid

Pharmacokinetics
 Readily absorbed
 Well distributed (including CNS)
 Extensive metabolism (rapid & slow acetylation)
 Average half-lives are less than 1h (rapid) & 3h
(slow)
Isoniazid
Clinical uses
A. Treatment of TB (300 mg once daily or 900
mg twice weekly; pyridoxine is
recommended for patients predisposing to
neuropathy)

B. Prevention of active TB in people with latent
tuberculosis (eg, a positive tuberculin test) as
a single agent for 9 months
Adverse Reaction of Isoniazid
Allergic reactions
A.
–
–
–
B.
Fever
skin rashes
drug-induced SLE
Direct toxicity
1) Hepatitis with greater risk in alcoholics and
possibly during pregnancy & postpartum (1% of
isoniazid recipients)
2) Peripheral & central neuropathy
Adverse Reaction of Isoniazid

Peripheral neuropathy infrequently seen
with the standard 300 mg adult dose

Is due to a relative pyridoxine deficiency
Rifampin
Effective in vitro against:
 G(+) & G(-) cocci
 Some enteric bacteria
 Mycobacteria
 Chlamydia


Bactericidal for mycobacteria including
intracellular organisms
Rifampin
Antimicrobial activity
 Binds firmly to b-subunit of DNA-dependent
RNA polymerase & inhibits RNA synthesis

Rifampin
Resistance
 Polymerase gene mutations (1:106)

Pharmacokinetics
 Well absorbed & excreted mainly into the bile
(enterohepatic circulation).
 Distributed widely (crosses BBB if inflammation
present).

Rifampin

Clinical uses (600 mg/d or twice weekly)
A. Mycobacterial infections (also for prophylaxis)
B. Other indications
Rifampin
Clinical uses
B. Other indications:
1) Elimination of meningococcal carriage
2) Elimination of staphylococcal carriage
(with a second agent)
3) Staphylococcal prosthetic valve
endocarditis

Rifampin
Adverse reactions
a) A harmless orange color
b) Cholestatic jaundice & hepatitis
c) Flu-like syndrome (< twice weekly)



fever, chills, myalgia
hemolytic anemia, thrombocytopenia
e) Induction of cytochrome P450 isoforms
Ethambutol
Inhibits synthesis of arabinoglycan via inhibition
of arabinosyl transferases.
 Resistance is due to mutations in the enzyme
gene.
 Pharmacokinetics
 Well absorbed & excreted about 50% in urine in
unchanged form.
 Crosses BBB if inflammation is present.

Ethambutol
Clinical use
 Treatment of TB (single daily dose or twice
weekly)
 Tuberculous meningitis (with higher dose)

Ethambutol
Adverse reactions
 Optic neuritis resulting in:
a) loss of visual acuity
b) red-green color blindness


Contraindicated in very young children
Pyrazinamide


Is converted to pyrazinoic acid (active form) by
mycobacteria pyrazinamidase.
Drug target & mechanism of action is unknown
Resistance
a) Impaired uptake of drug
b) Mutations in pyrazinamidase gene

Pyrazinamide
Clinical uses
 An important drug used in short-course of TB
treatment (active against intracellular
organisms)

Adverse reactions
 Hepatotoxicity
 Hyperuricemia

Streptomycin

Active mainly against extracellular bacilli

Is indicated in injectable drug needed severe
TB eg, meningitis & disseminated disease
Second-Line Drugs

a)
b)
c)
d)
Usually considered only in case of:
resistance to first-line agents
failure of clinical response to conventional
therapy
serious treatment-limiting adverse drug
reactions
expert guidance is available to deal with the
toxic effects
Second-Line Drugs

Less effective and more toxic effects
Include (in no particular order):
 Amikacin
 Kanamycin
 Capreomycin
 p-amino salicylic acid
 Streptomycin
 Ethionamide
 Fluoroquinolones

Third-Line Drugs
least effective and most toxic
 Linezolid
 Rifabutin
 Rifapentine
Antifungal Agents
Licensed Antifungal Agents:
The Pace Quickens
ravuconazole
anidulafungin
posaconazole
20
micafungin
Caspofungin
voriconazole
Nyotran
AmBisome
10
Griseofulvin
ketoconazole
miconazole
5-flucytosine
Amphotec
Abelcet
itraconazole
fluconazole
terbinafine
Amphotericin B
Nystatin
1950
1960
1970
1980
1990
2000
What are the targets for antifungal therapy?
Classification of Antifungal Agents
A. Systemic drugs for systemic infections (oral
or parenteral)
B. Oral drugs for mucocutaneous infections
C. Topical drugs for mucocutaneous infections
Systemic Drugs
for
Systemic Infections
Amphotericin B

A polyene macrolide
Pharmacokinetics
 Poorly absorbed from the GI
 Serum t1/2 is approximately 15 days

Amphotericin B
Mechanism of action
Binds to ergosterol & alters the permeability
Exerts fungicidal effect

Mode of Action of Polyenes
Ergosterol
Aqueous pore
Hydrophobic
side
Hydrophilic
side
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Cytoplasmic
membrane
Amphotericin B
Polyenes Form Non-Specific Pores
in The Membrane
Extracellular
medium
Ergosterol
Amphotericin B
Aqueous pore
Cytoplasm
Amphotericin B



A.
B.
C.
Antifungal activity
The broadest spectrum of action
Clinical uses
Drug of choice for all life-threatening mycotic
infections
Empiric therapy if a systemic fungal infection is
suspected
Topical use eg, mycotic corneal ulcers
Amphotericin B
Adverse effects
A. Infusion-related toxicity
B. Cumulative toxicity
1) Renal damage (reversible & irreversible)
2) Anemia (due to reduced erythropoietin
production)
3) Abnormalities in liver function tests
4) Seizures & chemical arachnoiditis (after
intrathecal therapy)

Liposomal Amphotericin B
Advantages
Lipid packaged drug will bind to the
mammalian membrane less readily.
Furthermore, some fungi contain lipases that
may liberate free drug directly at the site of
infection.

Properties of Conventional Amphotericin B
& Some Lipid Formulations
Drug
Dosing
(mg/kg/d)
Conventional formulation:
1
Fungizone
Lipid formulations:
AmBisome
Amphotec
Abelcet
Nephrotoxicity
_
3-5

5

5

Flucytosine (5-FC)


A pyrimidine analog
Narrower spectrum of action than amphotericin B
Pharmacokinetics
 Is well absorbed
 Penetrates well into all tissues including CNS
 Eliminated by glomerular filtration with a half-life of
3-4 hours

Flucytosine (5-FC)

Mechanism of action
cytosine permease
5-FC
into the cell
2) 5-FC → 5-FU (5-fluorouracil) → phosphorylated
derivatives → inhibits DNA & RNA synthesis
 Synergy with amphotericin B
1)
Flucytosine (5-FC)
Clinical uses
 Cryptococcal meningitis (+ amphotericin B)
 Chromoblastomycosis (+ itraconazole)

Adverse effects
 Metabolism by intestinal flora (5-FC → 5-FU) 
bone marrow toxicity

Azoles (Imidazoles & Triazoles)

Imidazoles:




Ketoconazole
Miconazole
Clotrimazole
Triazoles:




Itraconazole
Fluconazole
Voriconazole
Posaconazole
Azoles
Mechanism of action
 Decrease in ergosterol synthesis by inhibition
of fungal cytochrome P450 enzymes

Acetyl CoA
Squalene
Squalene
epoxidase
Allylamine
drugs
Squalene-2,3 oxide
Lanosterol
Azoles
14-a-demethylase
Ergosterol
Azoles

Adverse effects (selective toxicity)

Clinical uses (a broad spectrum of action)
Ketoconazole
Less selectivity for fungal enzymes
 Interferes with biosynthesis of adrenal &
gonadal steroids
 Interaction with metabolism of other drugs

Itraconazole



Less interaction with human enzymes than
ketoconazole
Does not affect mammalian steroid synthesis.
Interacts with hepatic microsomal enzymes,
though to a lesser degree than ketoconazole.
Itraconazole

Azole of choice for treatment infections
due to dimorph fungi such as histoplasma.

Is used extensively in the treatment of
dermatophytoses and onychomycosis.
Fluconazole

The least effect on hepatic microsomal
enzymes

The broadest therapeutic index of the azoles
Fluconazole

Azole of choice in the treatment and
secondary prophylaxis of cryptococcal
meningitis

Prophylactic use against fungal disease in
bone marrow transplant & AIDS patients
Fluconazole

IV fluconazole equivalent to amphotericin B
in candidemia in ICU patient with normal
WBC counts.

Commonly used in mucocutaneous
candidiasis
Voriconazole




Well absorbed orally
Low inhibition of mammalian P450
Toxicities include rash, elevated hepatic
enzyme & transient visual disturbances
Azole of choice for aspergillosis
Voriconazole

Excellent activity against candida (including
fluconazole-resistant species)

Less toxic & probably more effective than
amphotericin B in aspergillosis
Posaconazole
Drug interactions have been documented.
 The broadest spectrum member of azoles.
 Currently is approved for:
 Salvage therapy in invasive aspergillosis
 Prophylaxis of fungal infections during
chemotherapy

Echinocandins
(Caspofungin)


The newest class of antifungal agents
Active against both candida and aspergillus
Caspofungin
Mechanism of action
 Inhibition of b(1-3) glucan synthesis
 This results in disruption of cell wall and cell
death

Adverse effects
 extremely well tolerated

A scheme of the structure of the yeast cell wall
S
Mannoprotein
40%
S
GPI Anchor b1-3 glucan
50%
Transmembrane
Protein
b1-6 glucan
8%
Chitin
2%
Caspofungin
Licensed for:
 disseminated and mucocutaneous candida
infections
 empiric antifungal therapy during febrile
neutropenia

Oral Drugs
for
Mucocutaneous Infections
Griseofulvin
Clinical uses
 Systemic treatment of dermatophytoses

Mechanism of action
 Deposited in newly forming skin (fungistatic)

Adverse effects
 Allergic syndrome
 Hepatitis

Terbinafine

Available in oral form
Mechanism of action
Inhibits the fungal enzyme squalene
epoxidase (fungicidal)

Clinical uses
Dermatophytoses esp. onychomycosis

Acetyl CoA
Squalene
epoxidase
Squalene
Allylamine
drugs
Squalene-2,3 oxide
Lanosterol
Azoles
14-a-demethylase
Ergosterol
Topical Drugs
for
Mucocutaneous Infections
Nystatin



A polyene macrolide
ONLY used topically
Active against most candida species
Topical azoles
Clotrimazole & Miconazole
 Effective in:
Vulvovaginal candidiasis
Dermatophytic infections

Topical Allylamines
Terbinafine & Naftifine
Available as topical creams
Effective in tinea cruris, …
