Download 8-Anti-mycobacterial drugs

Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-47,p815-824;
LEARNING OBJECTIVES
• Antimycobacterial agents
• Appreciate the consequences of the mycobacterial life
cycle in regard to chemotherapy
• Know mechanisms of action for antimycobacterial
drugs
• Know the distinction between "first-line" and "secondline" anti-TB drugs, and why this distinction is
disappearing
• Know the pharmacogenetics of isoniazid metabolism
• Know the appropriate use of drug combinations in
antimycobacterial chemotherapy
The ten leading causes of dalys at ages 15–44 years, the world,
1990
Ranking
Causes
Total Dalys
(Millions)
% Of total
dalys
1
unipolar major depression
43.0
10.3
2
tuberculosis
19.7
4.7
3
road traffic accidents
19.6
4.7
4
alcohol use
14.8
3.5
5
self-inflicted injuries
14.6
3.5
6
bipolar disorder
13.2
3.1
7
war
13.1
3.1
8
violence
13.0
3.1
9
schizophrenia
12.5
3.0
10
iron-deficiency anemia
12.5
3.0
419.1
100
all causes
adapted from murray cjl, lopez ad, editors: global burden of disease.
harvard school of public health on behalf of the world health organization, cambridge, 1996.
Clinical Picture: (Primary & Secondary TB)
• Pulmonary infection (most common site)
• Non-pulmonary infection (lymph nodes,
skin, bones, kidneys, peritoneum,
pericardium,meninges,et..)
Predisposing factors:
• Malnutrition, overcrowding, poor hygienic
condition, contact with TB patient,
ingestion of raw milk, diabetes, HIV
infection (immune deficiency)
• Immunosuppressive drugs & anti-cancer
chemotherapy.
Characteristics of Myobacteria
• Slow growing
• Can become dormant
• Mostly reside inside macrophage, not all drugs
reach
• Cell wall is impermeable to many drugs
• Develop resistance (more if single or two drugs
used)
• Combination therapy needed (usually 3-4 drugs)
• Slow response, treatment requires months to
years (Usually 6 or 9 months, or up to 2 years for
TB bones).
• Poor compliance due to prolonged Treatment, cost
& Symptomatic relief.
G.Antimycobacterial drugs
FIRST-LINE ANTI-TB DRUGS
ISONIAZID
ETHAMBUTOL
RIFAMPIN
RIFABUTIN
PYRIZINAMIDE
STREPTOMYCIN
SECOND-LINE ANTI-TB DRUGS
CYCLOSERINE
ETHIONAMIDE
AMIKACIN
CIPROFLOXACIN
OFLOXACIN
CAPREOMYCIN
PARA-AMINOSALICYLIC ACID
Anti-TB Chemotherapy
Tuberculosis
• Chronic infections with long dormant periods separating
intermittent active (symptomatic) periods
• Mycobacteria are intracellular pathogens
Anti-Tuberculosis-• Requires prolonged constant treatment
– "Uncomplicated" TB
– Chemoprophylaxis
– Tuberculosis meningitis,
Miliary tuberculosis
6-9 months
1 year
2 years
• Resistance develops rapidly to single drugs
• Combination chemotherapy is the general rule
Anti-Mycobacterial Chemotherapy:
Isoniazid (INH)
Mechanism
•
Blocks synthesis of Mycolic Acids for mycobacterial cell wall
•
Bactericidal in growing cells only
Pharmacokinetics
• Well absorbed and distributed after oral administration
•
CNS levels ~20% of serum level; Intracellular = extracellular
•
Metabolism key factor in pharmacokinetics-- acetylated in the liver
•
Genetic differences (polymorphism) in acetylation
•
Fast acetylators may require higher doses
•
"Fast" acetylators--50% of US Blacks and Whites, most Eskimos, Asians, Native
Americans
•
t1/2 for “Fast acetylators < 1.5 hrs, "slow" acetylators-- t1/2 > 3 hrs
•
Excretion-- Urine (INH and acetylated product)
•
Alter dosing in hepatic, not renal disease
Anti-Mycobacterial Chemotherapy:
Isoniazid (INH)
Clinical use
• Prophylaxis-- Used alone for TB exposure, tuberculin convertors
•
Combination chemotherapy for TB–
–
With ethambutol, rifampin, or pyrazinamide
Adverse effects
• Dose- and duration-dependent
•
Hepatotoxicity-–
–
–
–
Increases with age of patient
more common in alcoholics
May increase during pregnancy
Increases with age after 35YO; use rifampin for prophylaxis in older patients
•
Peripheral and central neuropathy-- Treat with pyridoxine (Vitamin B6),common in
slow acetylators
Resistance-- Can develop rapidly, or is already present
• 10% of isolates in US resistant
•
Higher in Caribbean, Asia (approaching 20%)
•
Deletion of katG gene in mycobacterium
• How INH causes peripheral & central
neuropathy?
Anti-Mycobacterial Chemotherapy:
Ethambutol
Mechanism
• Inhibits synthesis of mycobacterial cell wall glycan
Pharmacokinetics
• Well absorbed and distributed
• CNS level variable, 4-60% of serum
• Most excreted in urine-- accumulates in renal failure
Adverse effects
• Dose-dependent optic neuritis, decreased acuity, loss of redgreen differentiation
Resistance-- Rapid, use in combination
• A patient diagnosed with TB was
prescribed conventional anti TB regimen
comprised with 3 drugs. After 6 months of
therapy patient developed periocular dull
pain, decreased acuity, loss of red-green
differentiation. Which drug has caused
this?
Anti-Mycobacterial Chemotherapy:
Rifampin
Mechanism
• Inhibits bacterial RNA synthesis
• Bactericidal
Pharmacokinetics-• Well absorbed and distributed
• Excreted in bile
Adverse effects-• Inducer of microsomal enzymes
• Alters t1/2 of anticoagulants, oral contraceptives
• Hepatotoxic
• "Flu-like" syndrome
• Gives orange color to body fluids
Clinical Use
• Combination chemotherapy for active disease, single agent prophylaxis for
INH-intolerant patients
• Meningococcal infection prophylaxis
Discuss 3 virtual therapeutic situations potentially
invite D-D interactions
• Patient on both
antiepileptic &
conventional anti TB
regimen
• Patient on both Oral
contraceptive &
conventional anti TB
regimen
• Patient receiving
multidrug cocktail
prescribed a
conventional anti
TB drug regimen
Anti-Mycobacterial Chemotherapy:
Pyrazinamide and Streptomycin
Pyrazinamide-• Oral, absorbed, distributed
• Bacteriostatic
• Mechanism unknown, but activated by mycobacterium
• Rapid resistance
• Cause hyperuricemia
Streptomycin-• Was only for severe (life-threatening) cases, now used
more frequently
• Pharmacokinetics, adverse effects typical of
aminoglycoside
During a course of ATT patient took some
high purine containing diet/other foodstuffs
and developed
• Or clinic-patho• Gout
biochemical features
of gout-severe pain,
redness & swelling
involving big joints
(1st MTP being the
commonest).S.Uric
acid was >>7mg/dl
Which drug probably has caused this ? What is the possible mechanism?
Rifabutin
Rifabutin, also a derivative of Rifamycin, inhibits DNAdependent RNA polymerase in E. coli, and interferes
with DNA synthesis in M. tuberculosis.
Prevention and Treatment of disseminated atypical
mycobacterial infection AIDS patients.
Adverse Effects
Rifabutin is both a substrate and inducer of CYP450, but a
less potent inducer than Rifampin.
• Clinical Scenario: A 50 years old patient was recently
diagnosed with pulmonary tuberculosis . He is already
on multidrug cocktail for his other concomitant
conditions. What precautions would you like to take while
prescribing combination therapy for TB for him ?
Second Line Anti-TB Drugs
Toxicity outweighs therapeutic effects except
for highly resistant strains
– Para-aminosalicylate (PAS), Cycloserine,
Ethionamide
– Other drugs—Amikacin, Ciprofloxacin,
Ofloxacin
• Currently a major resurgence in TB, highly
resistant strains are common
• 2nd line may become 1st line
Key features of 2nd generation drugs
ETHIONAMIDE
chemically related to Isoniazid, blocks the synthesis of mycolic acid
Adverse Effects
Intense gastric irritation, Neurologic symptoms (Pyridoxine given)
and Hepatotoxicity.
CYCLOSERINE
Inhibits cell wall synthesis
• Adverse Effects
• Most serious side effects during the 1st 2 weeks of treatment (25%)
are peripheral neuropathy and CNS dysfunction, including
depression and psychosis.
• Neurologic toxicity is minimized by giving pyridoxine 150mg/d.
CIPROFLOXACIN and LEVOFLOXACIN
• Fluoroquinolones must be used in combination with other
antitubercular drugs to which the strains are susceptible
Understanding biology of TB Infection
There is continuous shifting of bacilli between those below
subpopulation.
1.Rapidly growing -High bacillary load-+nt in areas where oxygen
tension is high +PH is neutral
Susceptibility to drugs-H>>>R,E,S
2.Slow growing- +nt in low PH sites(intracellularly+inflamed site)
Succeptibility to ATT- Z>>>H,R,E
3.Spurter –Oxygen tension low +PH neutral
ATT that is susceptible is R
4.Dormant- inactive for prolonged period
No ATT is useful.
H-INH,R-Rifampin,E-Ethambutolol,S-Streptomycin,Z-Pyrezinamide
Of the first-line agents for Mycobacterium
tuberculosis, only pyrazinamide requires an
acidic environment (as is present within
macrophage phagolysosomes) to exert
antimicrobial effects. Isoniazid, rifampin, and
ethambutol are more active than PZA
against extracellular mycobacteria.
GOAL OF ATT
• 1.KILL DIVIDING BACILLI
-to give him symptomatic relief
-to make him sputum negitive
• 2.KILL PERSISTING BACILLI
-depends upon sterilizing effect of the drug
• 3.PREVENT EMERGENCE OF RESISTENCE
-H,R-Cidal,effective against almost all population
-Z-Cidal,effective on Intracellular bacilli + inflamed site but with
sterilizing activity
-S-Cidal, on rapidly dividing extracellular bacilli
-E-Static,prevent resistance and hasten sputum conversion
ATT PROFILE
• Includes combination of several anti TB drugs to
-check the resistance
-to have enhanced efficacy
-to reduce incidences of A/E
Conventional regimens-
H+Tzn/E+-S(for initial 2 months) x12-18
months- OBSOLETE
Short course Chemotherapy-Introduced by WHO in 1997
-All first line drugs are standardized on body weight basis both for
children and adult.
-All regimens have INITIAL INTENSIVE PHASE 2-3 months-(to reduce
bacilli load ,to prevent transmission and to give symptomatic relief )
followed by CONTINUATION PHASE of 4-6 months or even longer till
patient is completely sterile,no relapses .
DRUGS FOR LEPROSY
-Treatment for several months to a person’s lifetime.
WHO now recommends multidrug therapy for most patients
with leprosy.
Multidrug therapy hastens the eradication of bacteria,
reduces the duration of active disease, and prevent
worsening of disabilities.
Multidrug therapy also appears to reduce overall cost,
increase patient’s compliance, and increase the motivation
and availability of leprosy workers.
DAPSONE & OTHER SULFONES
Sulfones are structurally related to Sulfonamides and have
similar mechanism of action.
Sulfones inhibit the synthesis of folic acid by M. leprae, and
exhibit a bacteriostatic action.
Dapsone is used in combination with Rifampin, with or
without Clofazimine to prevent the emergence of
resistance.
Dapsone
Administered orally (100mg daily), well absorbed from the gut and widely
distributed throughout body fluids and tissues.
The drug tends to be retained in skin, muscle, liver and kidney.
Skin heavily infected with M. leprae may contain several times as
much Dapsone as normal skin.
Sulfones are metabolized by acetylation and excreted in urine. Renal failure
requires dosage adjustment.
Sulfones are also excreted into bile and are reabsorbed.
Adverse Effects: G.I.T. disturbances, Peripheral Neuropathy, Optic neuritis,
Blurred vision, Proteinuria and Nephrotic syndrome, Lupus-like syndrome and
Hematologic toxicity.
Patients with G-6-P Dehydrogenase deficiency may exhibit hemolytic anemia
due to oxidation of erythrocyte membranes by Dapsone.
CLOFAZIMINE
Clofazimine is a phenazine dye with Antimycobacterial and Antiinflammatory effect.
Clofazimine is bactericidal against M. tuberculosis, is bacteriostatic
against M. leprae, and is active against M. avium intracellulare.
The drug enhances the phagocytic activity of Neutrophils and
Macrophages, and reduces the motility of Neutrophils and the
ability of Lymphocytes to transform.
Clofazimine is approved for use in combination with Dapsone and
Rifampin for the treatment of Lepromatous leprosy.
Its use is chiefly limited to Sulfone-resistant patients or intolerance to
sulfone.
Slowly and incompletely absorbed from the gut and primarily
distributed to adipose tissue and RE cells, but accumulated in the
liver, lungs, lymph nodes, spleen and other tissues.
Anti-inflammatory and Immunologic effects may be responsible for its
efficacy in the prevention and treatment of Erythema Nodosum
Leprosum, a type II hypersensitivity reaction seen during or after the
treatment of Lepromatous Leprosy.
The drug has a long half-life (about 70 days) and some of it remains in
the body for years after the therapy is discontinued.
Adverse Effects
G.I.T. disturbances such as anorexia, N/V, abdominal pain and
diarrhea.
Photosensitivity, skin discoloration (ranging from red-brown to nearly
black) and discoloration of bodily secretions, such as sweat, tears,
sputum, feces, and urine during therapy.
Clofazimine may elevate hepatic enzyme levels and may cause
hepatitis; its use is generally avoided in patients with hepatic disease.
Antibiotics of Choice for Various Infections
Drug
Organism (Disease)
Amoxicillin, clarithromycin (omeprazole*) Helicobacter pylori (peptic ulcer)
Ampicillin
Listeria (meningitis)
Ceftriaxone, Cefexime
Neisseria gonorrhoeae (gonorrhea)
Cephalosporins (third-generation)
Haemophilus influenzae
(pneumonia, meningitis)
Klebsiella (meningitis)
Doxycycline
Borrelia burgdorferi (Lyme disease)
Rickettsiae (Rocky Mountain spotted
fever)
Erythromycin
Legionella (legionnaires’ disease)
Fluconazole, miconazole, nystatin
Candida (candidiasis)
Isoniazid, rifampin, ethambutol,
pyrazinamide
Mycobacterium tuberculosis
(tuberculosis)
*Omeprazole is not an antibiotic but is used in combination with antibiotics for treatment of H. pylori.
Antibiotics of Choice for Various Infections
Drug
Organism (Disease)
Macrolides
Mycoplasma pneumoniae (atypical
pneumonia)
Legionella (legionnaires’ disease)
Corynebacterium diphtheriae; Chlamydia
Metronidazole
Trichomonas (trichomoniasis)
Penicillin G
Neisseria meningitidis (meningitis)
Treponema pallidum (syphilis)
Infections caused by streptococci,
pneumococci, other meningococci,
Bacillus anthracis,
Clostridium,
Bacteroides (except B. fragilis)
Fluroquinolones
Campylobacter (diarrhea); Shigella
Tetracycline
Vibrio cholerae (cholera)
Other tetracyclines
Chlamydia (pneumonia, lymphogranuloma
venereum)
Trimethoprim-sulfamethoxazole
Salmonella; Shigella (diarrhea)
Metronidazole or vancomycin (oral)
Clostridium difficile (diarrhea)
Prophylactic Use of Anti-infective Drugs
Drug
Cefazolin
Use
Surgical procedures
Cefoxitin, Cefotetan
Surgical procedures where
anaerobic infections are
common
Ampicillin or penicillin
Group B streptococcal infections
Trimethoprim-sulfamethoxazole
Pneumocystis carinii pneumonia (PCP)
UTIs
Rifampin
Haemophilus influenzae type B
Meningococcal infection
Chloroquine
Malaria
Isoniazid
Tuberculosis
Azithromycin
Mycobacterium avium complex (MAC) in patients
with AIDS
Ampicillin or azithromycin
or clindamycin
Dental procedures in patients with valve
abnormalities
AIDS = Acquired immunodeficiency syndrome; UTI = urinary tract infection.
Which of the following would be the
most appropriate for tuberculosis
prophylaxis, in order to minimize the risk of
hepatotoxicity and drug-drug interactions, in
a 51-year-old man on HIV antiretroviral
medications?
A.
B.
C.
D.
E.
Clarithromycin
Isoniazid
Pyrazinamide
Rifabutin
Rifampin
Answer: D
Isoniazid should not be
used in patients over 50 yo
A 20-year-old male college student
living in the dormitory has a close contact
friend who developed a meningococcal
infection. Which of the following
medications is recommended for
meningococcal prophylaxis in this patient?
A.
B.
C.
D.
E.
Amoxicillin
Cefaclor
Ceftriaxone
Penicillin G
Rifampin
Answer: E
Rifampin is used
prophylactically against
possible exposure to
meningococci
PowerPoint Slides
 Several of the PowerPoint slides are Copyright © 2002-04,
the American Society for Pharmacology and Experimental
Therapeutics (ASPET). All rights reserved.
 Some of slides in this session are from the above mentioned format
and are free for use by members of ASPET.
 Some others are from various sources like text book, recommended
books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA).
 Core concepts of various USMLE High yield review series like
Kaplan ,BRS etc. are thoroughly explored & integrated whenever
necessary