Transcript Anti-TB - PharmaStreet

TUBERCULOSIS
CONTENTS:
•INTRODUCTION
•EPIDEMIOLOGY
•CAUSES
•PATHOGENESIS
•DIAGNOSIS
•TREATMENT
• Tuberculosis or TB is a common and often
deadly infectious disease caused
by mycobacteria, usually Mycobacterium
tuberculosis in humans.
• Tuberculosis usually attacks the lungs but can
also affect other parts of the body.
• The classic symptoms are
a chronic cough with blood-tinged
sputum, fever, night sweats, and weight loss.
CAUSES:
• The primary cause of TB, Mycobacterium tuberculosis , is a
small aerobic non-motile bacillus.
• The M. tuberculosis complex includes four other TBcausing mycobacteria: M. bovis, M. africanum, M. canetti and M.
microti.
• M. africanum is not widespread, but in parts of Africa it is a
significant cause of tuberculosis.
EPIDEMIOLOGY:
• It is currently estimated that 1/2 of the world's
population (3.1 billion) is infected with
Mycobacterium tuberculosis. Mycobacterium
avium complex is associated with AIDS related
TB.
• The proportion of people who become sick
with tuberculosis each year is stable or
falling worldwide but, because of population
growth, the absolute number of new cases is
still increasing.
• In 2007 there were an estimated 13.7 million chronic active cases,
9.3 million new cases, and 1.8 million deaths, mostly in developing
countries.
• The distribution of tuberculosis is not uniform across the globe;
about 80% of the population in many Asian and African countries test
positive in tuberculin tests, while only 5-10% of the US population
test positive.
Per 1,000,00
< 10
10 - 24
25 - 49
50 - 99
100 - 299
300 or more
No estimate
Highest estimated
TB rates per capita
were in Africa
Transmission:
• Pulmonary tuberculosis is a disease
of respiratory transmission, Patients
with the active disease (bacilli) expel
them into the air by:
• coughing,
• sneezing,
• shouting,
• or any other way that will expel
bacilli into the air
Transmission is dependent on closeness and time of
contact
• Once inhaled by a tuberculin free person, the
bacilli multiply 4 -6 weeks and spreads
throughout the body. The bacilli implant in areas
of high partial pressure of oxygen:
• lung
• renal cortex
• reticuloendothelial system
Signs and symptoms:
• When the disease becomes active, 75% of the cases are pulmonary
TB, that is, TB in the lungs.
• Symptoms include chest pain, coughing up blood, and a
productive, prolonged cough for more than three weeks.
• Systemic symptoms include fever, chills, night sweats, appetite
loss, weight loss, pallor, and often a tendency to fatigue very
easily.
Signs and symptoms:
• In the other 25% of active cases, the infection moves from the lungs,
causing other kinds of TB, collectively denoted extrapulmonary
tuberculosis. This occurs more commonly
in immunosuppressed persons and young children.
• Extrapulmonary infection sites include the pleura in tuberculosis
pleurisy, the central nervous system in meningitis, the lymphatic
system in scrofula of the neck, the genitourinary system in
urogenital tuberculosis, and bones and joints in Pott's disease of the
spine.
Pathophysiology
Infection via inhalation of droplet nuclei.
↓
Transport of bacilli to terminal alveoli (especially lower segments of
lungs)
↓
Ingestion of organisms by macrophages followed by multiplication
within macrophages
↓
Transport of organisms to regional lymph nodes by infected
macrophages with continue multiplication and minimal inflammatory
response
↓
Extension of organisms( within 4-6 weeks after inhalation) into
the bloodstream from the regional nodes
↓
Cell mediated immunity / hypersensitivity reaction
↓
Development of clinical infection
Diagnosis by X-ray:
Chest x-rays:
Multi nodular
infiltrate above
or behind the
clavicle with or
without pleural
effusion
unilaterally or
bilaterally.
Diagnosis sputum investigation:
•
Cultures will reveal the presence
of mycobacterium tuberculosis
•
Patients stay infectious for as
long as the bacilli are excreted
in the sputum
Diagnosis by tuberculin test:
Skin test. PPD (purified protein
derivative) antigens are injected
intradermally. A positive reaction is
a helpful adjunct in diagnosis.
Tuberculin test positivity indicated
hypersentivity to bacterial protein
Classification of drugs:
According to their clinical utility the drugs are:
• First line drugs : High antitubercular efficacy and low toxicity which
are used routinely.
• Second line drugs: Either low antitubercular efficacy or high toxicity
or both, used in special circumstances only.
First line drugs include:
-ISONIAZIDE
- PYRAZINAMIDE
- ETHAMBUTOL
-RIFAMPICIN
-STREPTOMYCIN
HIGH EFFICACY AND LOW TOXICITY
Second line drugs include:
-THIACETAZONE
-CAPREOMYCIN
-P-AMINOSALICYLIC ACID
-ETHIONAMIDE
-CYCLOSERINE
-KANAMYCIN
-AMIKACIN
LOW EFFICACY AND HIGH TOXICITY
NEWER SECOND LINE DRUGS:
• Flouroquinolones are active against M.tuberculosis.
Ciproflaxacin,
Oflaxacin,
• Newer macrolides and some rifampin congeners are the recent
additions.
Clarithromycin,
Azithromycin,
Rifabutin.
Isoniazid (INH)
(Isonicotinic acid hydrazide, H)
• Primarily tuberculocidal
• Tuberculocidal for rapidly multiplying bacilli
• Acts on extracellular as well as on intracellular TB
• Equally active in acidic or alkaline pH
• One of the cheapest anti-tubercular drugs
MECHANISM OF ACTION
synthesizes
Mycolic acids
Isoniazid
inhibits this
synthesis
Mechanism of Action Inhibition of synthesis of mycolic acids
Two gene products labelled ‘InhA’ and ‘ KasA’ , which function in mycolic
acid synthesis are targets of INH action
INH enters sensitive mycobacteria which convert it by a catalaseperoxidase enzyme into a reactive metabolite
then forms adduct with NAD that inhibits InhA and KasA
INH enters bacilli by passive diffusion
Drug is not directly toxic to the bacillus but must be activated to its
toxic form within the bacillus by KatG (multifunctionary , catalase –
peroxidase)
KatG catalyzes the production from INH of an isoNicotinoyl radical that
subsequently interacts with mycobacterial NAD and NADP to produce
a dozen adducts
A nicotinoyl-NAD isomer, inhibits the activities of enoyl acyl carrier
protein reductase (InhA) and β-ketoacyl acyl carrier protein synthase
(KasA)
Inhibition of these enzymes inhibits synthesis of mycolic acid -- bacterial
cell death
Another Adduct, a nicotinoyl-NADP isomer , potently inhibits
mycobacterial DHFRase ,thereby interfering with nucleic acid synthesis
MOA of H:
ISONIAZID
Active INH
AcpM & Kas
Kat G( catalase peroxidase
in mycobacteria)
AcpM- Acyl Carrier protein
KasA ( ß ketoAcyl Carrier protein
synthetase)
Block Mycolic Acid Synthesis
Other products of KatG activation of INH include superoxide,H2O2 ,
alkyl hydroperoxides and NO radical may also contribute to INH
bactericidal effect
HOW DOES INH KILLS M. TUBERCULOSIS
PRODURG ACTIVATED BY CATALYSE EANZYME PEROXYDASE (katG)
UNABLE TO ENCODE ENOYL - ACP REDUCTASE OF
FATTY ACID SYNTHASE II
NO CONVERSION OF UNSATURATED FATTY ACIDS
TO SATURATED FATTY ACIDS
NO BIOSYNTHESIS OF MYCOLIC ACID
M. TUBERCULOSIS CAN NOT SURVIVE
PHARMACOKINETICS
Absorption
• Rapid and complete; rate can be slowed with food
• Peak Plasma Time: 1-2 hr
Distribution
• All body tissues and fluids including CSF; crosses placenta;
enters breast milk
• Protein Bound: 10-15%
Metabolism
• Hepatic ( fast, slow acetylators)
Elimination
• Half-life elimination: fast acetylators: 30-100 min; slow
acetylators: 2-5 hr; may be prolonged with hepatic or
severe renal impairment
• Excretion: Urine (75-95%); feces
PHARMACOKINETICS
Absorption
• Rapid and complete; rate can be slowed with food
• Peak Plasma Time: 1-2 hr
Distribution
• All body tissues and fluids including CSF; crosses placenta;
enters breast milk
• Protein Bound: 10-15%
Metabolism
• Hepatic ( fast, slow acetylators)
Elimination
• Half-life elimination: fast acetylators: 30-100 min; slow
acetylators: 2-5 hr; may be prolonged with hepatic or
severe renal impairment
• Excretion: Urine (75-95%); feces
Mechanism of resistance
• Resistance can emerge rapidly if the drug is used alone.
• Resistance can occur due to either
1.
2.
High-level resistance is associated with deletion in the katG gene that codes for a
catalase peroxidase involved in the bioactivation of INH.
Low-level resistance occurs via deletions in the inhA gene that encodes “target
enzyme” an acyl carrier protein reductase.
Interactions with Isoniazid
• Aluminium hydroxide inhibits INH absorption
• INH retards phenytoin, carbamazepine,
diazepam, theophylline and warfarin metabolism by inhibiting
CYP2C19 and CYP3A4,and may raise their blood levels.
• PAS inhibits INH metabolism and prologs its half life.
Adverse effects of Isoniazid
• Peripheral neuritis and a variety of neurological manifestations are
the most important dose-dependent toxic effects.
• INH neurotoxicity is treated by pyridoxine 100mg/day.
• Hepatitis is major adverse effect of Isoniazid.
• Lethargy
• Rashes.
• Fever acne.
• Arthralgia.
Adverse effects:
• Hepatitis, a major adverse effect.
• Respiratory syndrome: breathlessness.
• Purpura, haemolysis, shock and renal failure.
• Cutaneous syndrome : flushing, pruritis + rash.
• Flu like syndrome : fever, headache, bone pain.
Rifampin (Rifampicin , R)
• Semisynthetic derivative of Rifamycin B obtained from streptomyces
mediterranei
• Bactericidal to M. Tuberculosis and many other gram(+) and gram (-)
bacteria like staph.aureus , N.meningitidis, H.influenza, E.coli,Kleibsella ,
Pseudomonas,Proteus and legionella
• Against TB bacilli , it is as efficacious as INH and better than all other
drugs
• Bactericidal actions covers all subpopulations of TB bacilli , but acts best
on slowly or intermittenly dividing ones (spurters)
• Both extra and intracellular organisms are affected
• Good sterilizing and resistance preventing actions
Mechanism of action of Rifampin
• Rifampin interrupts RNA synthesis by binding to beta subunit of
mycobacterial DNA-dependent RNA polymerase encoded by rpoB
gene and blocking its polymerizing function
• The basis of selective toxicity is that mammalian RNA polymerase
does not avidly bind rifampin
Mechanism of action • Interrupts RNA synthesis by binding to β subunit of mycobacterial DNA
dependent RNA polymerase (encoded by rpoB gene )
MOA OF RIFAMPIN:
 D.N.A

RIFAMPIN

DNA dependent R.N.A.polymerase
R.N.A

Protein Syn.

Cell multiplication
Rifampin bind to β S.U of D.D.R.P

Drug –Enz Complex

Supression of chain initiation
Rifampin resistance
• Mycobacteria and other organisms develop resistance to rifampin
rather rapidly.
• Rifampin resistance is nearly always due to mutation in rpoB gene
reducing its affinity for the drug.
• No cross resistance with any other antitubercular drug,except
rifampin congeners,has been noted.
Pharmacokinetics • Well absorbed orally
• Bioavailability ~ 70% , food decreases absorption
• Rifampin is to be taken in empty stomach
• Widely distributed in the body;
• penetrates intracellularly , enters tubercular cavities, caseous
masses and placenta
• It crosses meninges , largely pumped out of CNS by P–
glycoprotein
• Metabolized in liver – active deacetylated metabolite –
excreted mainly in Bile , some in urine
• Rifampin and its deacetylated metabolite undergoes
enterohepatic circulation
• T1/2 – 2-5 hrs
Interactions with rifampin
•Rifampin is a microsomal enzyme inducer-increases severalCYP3A4, CYP2D6,CYP1A2 and
CYP2C subfamily.
•It thus enhances its own metabolism as well as that of many drugs including warfarin, oral
contraceptives, corticosteroids, sulfonyl ureas, steroids, HIV protease inhibitors, non
nucleoside
reverse
transcriptase
inhibitors(NNRTIs),
theophylline,metaprolol,fluconazol,ketoconazole, clarithromycin, phenytoin etc.
•Contraceptive failures have occurred.
•It is advisable to switch over to an oral contraceptive containing higher dose (50
microgram) of
•Estrogen or use alternative method of contraception.
Adverse effects of Rifampin
oIncidence of adverse effects is similar to INH
oHepatitis , a major adverse effect, generally occurs in pts with pre-existing liver disease
and is dose related
oJaundice – discontinuation of drug – reversible
•Minor reactions, usually not requiring drug withdrawal and more common with
intermittent regimens, are:
oCutaneous syndrome: flushing, pruritus + rash (especially on face and scalp),redness
and watering of eyes.
oFlu syndrome: with chills ,fever, headache, malaise and bone pain.
oAbdominal syndrome :nausea, vomiting, abdominal cramp with or without diarrhoea.
Urine and secretions may become orange-red—but this is harmless.
Other serious but rare reactions are:
oRespiratory syndrome: breathlessness which may be associated with shock and
collapse.
oPurpura, haemolysis, shock and renal failure.
Other uses of rifampin
1.
2.
3.
4.
Leprosy
Prophylaxis of Meningococcal and H.influenza meningitis and
carrier state
Second/third choice drug for MRSA, Diptheroids and legionella
infections
Combination of doxycycline and rifampin is first line therapy of
brucellosis
Pyrazinamide (Z)
• Chemically similar to INH – Pyrazinamide was developed parallel to it
(1952)
• Weakly tuberculocidal
• more active in acidic medium and slowly replicating bacteria
• More lethal to intracellular bacilli and at sites showing inflammatory
response
• Highly effective during the first 2 months of therapy when
inflammatory changes are present
• Inclusion enabled duration of treatment to be shortened and risk of
relapse to be reduced
Mechanism of action of Pyrazinamide
• not well established
• Similar to INH – converted inside mycobacterial into active metabolite
pyrazinoic acid by pyrazinamidase encoded by pncA gene
• Gets accumulated in acidic medium and probably inhibits mycolic acid
synthesis, but by interacting with a different fatty acid synthase
• Pyrazinoic acid also appears to disrupt mycobacterial cell membrane and its
transport function
MOA OF PYRAZINAMIDE:
• Pyrazinamide
Mycobacterial Pyrazinamidase
Pyrazinoic Acid
Inhibits Mycolic Acid Synthesis
PZA : MECHANISM OF ACTION
PZA enter through passive diffusion
Bac. Pyrazinamidase
Pyrazinoic acid
inhibit myobacterial fatty acid synthase -I
INTERFERANCE IN CELL WALL SYSNTHESIS
Pyrazinamide resistance
•Resistance to Pyrazinamide develops rapidly if it is used
alone and is mostly due to mutation in pncA gene.
Pharmacokinetics of Pyrazinamide
•Pyrazinamide is absorbed orally, widely distributed, has good penetration in CSF,
because of which it is highly useful in meningeal TB; extensively metabolized in liver and
excreted ion urine; plasma t½ is 6-10 hours.
Adverse effects of Pyrazinamite
• Hepatotoxicity is the most important dose-related adverse effect
• Hyperuricaemia is common aid is due to inhibition of uric acid
secretion in kidneys; gout can occur.
• Other adverse effects are abdominal distress, arthralgia, flushing,
rashes, fever and loss of diabetes control.
Ethambutol (E)
• Selectively Tuberculostatic
• Active against MAC as well as some other mycobacteria
• Fast multiplying bacilli – more susceptible
• Added to triple regime of RHZ – hastens the rate of sputum
conversion and prevents development of resistance
Mechanism of action of Ethambutol
• The mechanism of action of E is not fully understood, but it has been
found to inhibit arabinosyl tranferases (encoded by embAB genes)
involved in arabinogalactan synthesis thereby interfering with mycolic
acid incorporation in mycobacterial cell wall.
• Resistance to E develops slowly and is most commonly associated
with mutation in embB gene, reducing the affinity of the target
enzyme for E.
• No cross resistance with any other antitubercular drug has been
noted.
ETHAMBUTOL : MECHANISM OF ACTION
EXACT MECHANISM : NOT KNOWN
PROBABILITIES :
ETHAMBUTOL
BLOCKS
ARABINOSYL TRANSFERASE (ENCODED BY emb)
NO POLYMERIZATION REACTION OF ARABINOGLYCAN
INTERFERANCE IN CELL WALL SYSNTHESIS
MOA OF E:
Mycobact. Arabinosyl Transferase

ETHAMBUTOL

Polymerisation reaction of
Arabinoglycan

Essential component of Myco.Cellwall
Pharamacokinetics of Ethambutol
• About ¾ of an oral dose of E is absorbed.
• It is distributed widely, but penetrates meninges incompletely and is
temporarily stored in RBCs.
• Less than½ of E is metabolized.
• It is excreted in urine by glomerular filtration and tubular secretion;
plasma t½ is ~4 hrs.
• Caution is required in its use in patients with renal disease.
Adverse effects of Ethambutol
• Patient acceptability of E is very good and side effects are few.
• Loss of visual acuity/colour vision, field defects due to optic neuritis is the
most important dose and duration of therapy dependent toxicity.
• With early recognition and stoppage of the drug, visual toxicity is largely
reversible.
• It is contraindicated in patients with optic neuritis.
• Ethambutol produces few other symptoms: nausea, rashes, fever, rarely
peripheral neuritis.
• Hyperuricemia is due to interference with urate excretion.
• It is safe during pregnancy.
• Ethambutol is used in MAC infection as well
Streptomycin
• Streptomycin was isolated from a strain of Streptomyces griseus.
• It was first clinically useful antitubercular drug.
• It is aminoglycoside antibiotic.
• It is tuberculocidal but less effective than INH or rifampin; acts only on
extracellular bacilli.
• Thus, other drugs and host defense mechanisms are needed to eradicate
the disease.
• It penetrates tubercular cavities,but does not cross CSF, and has poor action
in acidic medium.
• Limitation of its use
i)dose related toxicity
ii)development of resistant org.
iii)pt compliance is poor due to i. m
Streptomycin
Mechanism of action:
Irreversibly inhibits bacterial protein synthesis. Protein synthesis is inhibited in at least
three ways:
1.
Interference with the initiation complex of peptide formation.
2.
Misreading of mRNA, which causes incorporation of incorrect aminoacids into
the peptide, resulting in a nonfunctional or toxic protein.
3.
Breakup of polysomes into nonfunctional monosomes.
Streptomycin resistance
•Resistance developed rapidly when streptomycin was used alone in tuberculosis-most
patients had a relapse.
•Recent studies indicate worldwide increase in resistance to streptomycin.
•In case if streptomycin resistance infection, it must be stopped at the earliest because of
risk of streptomycin dependence in which case the infection flourishes when the drug is
continued.
•Most nontubercular mycobacteria are unaffected by streptomycin.
Pharmacokinetics
• Absorption: IM: well absorbed; not absorbed from gut
• Distribution: To extracellular fluid including serum, abscesses, ascitic, pericardial,
pleural, synovial, lymphatic, & peritoneal fluids; crosses placenta; small amounts enter
breast milk
• Protein Bound: 34%
• Half-life elimination: newborns: 4-10 hr; adults: 2-4.7 hr, prolonged with renal
impairment
• Excretion: urine (90% as unchanged drug); feces, saliva, sweat, & tears (<1%)
SIDE EFFECTS:
• OTOTOXICITY-drugs get conc. In labrynthine fluid,
both vestibular & cochlear damage
• NEPHROTOXICITY
• PARALYSIS
• Sterile abscess at the inj. site
USE
•Because of need for i.m. injections and lower margin of safety (ototoxicity and
nephrotoxicity, especially in the elderly and those with impaired renal function)
streptomycin is used only as an alternative to or in addition to other first line anti-TB
drugs
•Use is restricted to maximum of 2 months.
•It is thus also labelled as a ‘supplemental’ first line drug.
Second line drugs in TB
• Less effective
• More toxic
• Used only if organism is resistant to first line drugs
• Ethionamide , PAS, cycloserine : bacteriostatic
• Amikacin, capromycin, fluoroquinolones are used in Multi Drug
Resistant TB
Second line drugs:
• Aminoglycosides: least effective and more toxic
Capreomycin - Viomycin – Kanamycin
Adverse effects:
• These drugs are: Nephrotoxic will cause Proteinuria, Hematuria,
Nitrogen metabolism, and Electrolyte disturbances
However effect is reversible when drug is stopped
• Capreomycin has replaced viomycin because of less
toxic effects, but all three drugs have the same effects.
Cycloserine:
• Can cause CNS disturbances
• Therapeutic States :
Cycloserine should be used when re-treatment is necessary
or when the micro-organism is resistant to the other drugs.
• It must be given in combination with other anti-tuberculosis
drugs.
• Dose: 500 mg to 1g per day
• Mechanism of Action :
An analog of D- alanine synthetase, will block bacterial cell
wall synthesis.
Thioacetazone & Ethionamide:
• These are first anti tubercular drugs.
• It is a tuberculostatic drug.
• Low efficacy drug.
• Side effects:
hepatitis,
optic neuritis,
mental disturbences
impotence
Dose: 150mg per day
Para-amino salicylic acid:
• PAS is a tuberculostatic and one of least active drugs.
• It inhibits denovo folate synthesis.
• PAS is completely absorbed by oral route and distributed all over .
• Dose : 150 mg/kg/day
• Patient acceptability of PAS is poor.
• Adverse effects ;
Rashes, fever, liver dysfunction
Chemotherapy
DOTS:
To control tuberculosis requires:
• Effective, inexpensive, simple and standardised technology.
The success of the DOTS strategy depends on:
• Government commitment to a national tuberculosis programme.
• Case detection –finding by smear microscopy examination of TB
susceptible in general health services.
• Regular uninterrupted supply of essential anti-TB drugs.
• Monitoring system for programme supervised and evaluation.
Short Course Chemotherapy:
• These are regimens of 6-9 month duration.
• All regimens have an initial intensive phase lasting 2-3 months to kill the
TB bacilli and afford symptomatic relief.
• This is followed by continuation phase for 4-6 months so that relapse
does not occur.
REGIMENS :
Type of patient
Duration of treatment
Regimen
Category-1
1.New sputum positive
2.Seriously ill, sputum negative,
Pulmonary
3.Seriously ill
Intensive phase(2months)
INH+RMP+ETB+PZA
Continuation phase(4months)
INH+RMP
Category-2
Retreatment group
1.Relapse
2.Treatment failure
Intensive phase(3months)
INH+RMP+ETB+PZA
Continuation phase(5months)
INH+RMP+ETB
Category-3
1.New smear negative
pulmonary
2.extrapulmonary
Intensive phase(2months)
INH+RMP+PZA
Continuation phase(4months)
INH+RMP
Multiple Drug Resistance(MDR):
• Resistance to both Isoniazid and Rifampin and number of other anti-TB
drugs . MDR-TB has a more rapid course ,(some die in 4-16 weeks).
• Treatment is difficult as second line drugs
are less efficacious, less convenient, more expensive and toxic.
• Therapy depends on drugs used in earlier regimen, dosage and
regularity with which they have been taken.
• In India>200,000patients have been treated under DOTS by early 2001
with cure rate of 75-80%.
• In other countries 80-93%cure rates have been obtained.
Chemotherapy
Treatment of TB is categorised by:
• Site of disease (pulmonary or extra pulmonary), its severity: the bacillary
load and acute threat to life are taken into consideration.
• Sputum smear positivity/negativity :positive cases are infectious.
• History of previous treatment: risk of drug resistance is more in
irregularly treated patients.
SECOND LINE DRUGS
Para amino salicylic acid
Mechanism of action
Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively
against mycobacterium tuberculosis.
It is structurally similar to p-amino benzoic acid(PABA) and the sulfonamides.
Pharmacokinetics
Absorption
• T max is about 6 h
Distribution
• About 50% to 60% is protein bound.
Elimination
• 80% is excreted in the urine with at least 50% excreted in acetylated form.
• The t 1/2 of free aminosalicylic acid is 26.4 min.
Dose: 4g 3 times daily, children < 15yrs: 200-300mg/kg daily in 2-4 divided doses.
Adverse Reactions
GI
• Nausea; vomiting; diarrhea; abdominal pain.
Metabolic
• Goiter with or without myxedema.
Miscellaneous
• Hypersensitivity (eg, fever, skin eruptions, leukopenia, thrombocytopenia, hemolytic
anemia, jaundice, hepatitis, encephalopathy, Loffler syndrome, vasculitis).
Drug Interactions
Pregnancy
• Category C .
Lactation
• Excreted in breast milk.
Contraindications
• Severe hypersensitivity to aminosalicylate sodium and its congeners.
Precautions:
Renal Function Impairment
Drug and its acetyl metabolite may accumulate
• Digoxin- May reduce oral absorption and serum levels of digoxin.
• Rifampin- May decrease absorption of rifampin.
• Vitamin B 12 May decrease GI absorption of oral vitaminB 12 .
Hepatic Function- Use with caution.
CHF
• Use with caution because of high sodium content (55 mg of sodium per 500 mg
tablet).
Crystalluria
• Maintain urine at neutral or alkaline pH to avoid crystalluria.
Ethionamide
Mechanism of Action:
Ethionamide, like pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is
thought that ethionamide undergoes intracellular modification and acts in a similar
fashion to isoniazid.
Pharmacokinetics:
• Absorption: completely absorbed following oral administration
• Bioavailability approximately 100%.
• Volume of distribution 93.5 L.
• Protein binding :Approximately 30% bound to proteins.
• Metabolism: Hepatic . Metabolized to the active metabolite sulfoxide, and several
inactive metabolites.
The sulfoxide metabolite has been demonstrated to have antimicrobial activity
against Mycobacterium tuberculosis.
• Route of elimination: Less than 1% of the oral dose is excreted as ethionamide
in urine.
• Half life2 to 3 hours
Dose:
Tuberculosis:
• 15-20 mg/kg/day PO Max: 1000 mg/day
Renal Impairment
• CrCl <10 mL/min: decrease dose 50%
Administration
• Part of multi-drug regimen; not first-line treatment
• Take with food
Monitor:
• baseline & periodic LFTs, TFTs, glucose
Interactions
Significant - Monitor Closely
• cycloserine
• isoniazid
• magnesium oxide/anhydrous citric acid
ADRS
>10%
• Disorder of gastrointestinal tract (50%)
Frequency Not Defined
• Postural hypotension
• Dizziness
• Drowsiness
• Headache
• Peripheral neuropathy
• Psychosis
Contraindications & Cautions
Contraindications
• Hypersensitivity to ethionamide
• Severe hepatic dysfunction
Cautions
• Diabetes mellitus, thyroid disease, hepatic impairment
Pregnancy & Lactation
• Pregnancy Category: C
• Lactation: excretion in milk unknown; use with caution
CYCLOSERINE
Cycloserine is an antibiotic produced by streptomyces
orchidaceus.
Mechanism of action :
• It inhibits the incorporation of D- alanine into peptidoglycan
pentapeptide by inhibiting alanine racemase, which converts Lalanine to D- alanine, and D- alanyl-D –alanine ligase (finally
inhibits mycobacterial cell wall synthesis).
• Cycloserine used exclusively to treat tuberculosis caused by
mycobacterium tuberculosis resistant to first line agents
Dosing and uses
Active Tuberculosis
• Initial: 250 mg PO BID
• Maintenance: 500 mg -1 g/day in 2 divided doses for 18-24 months;
not to exceed 1 g/day
Renal Impairment
• CrCl 50-80 mL/min: Give q12-16hr
• CrCl 10-49 mL/min: Give q24-36hr
• CrCl <10 mL/min: Contraindicated
Administration
• Part of multi-drug regimen; not first-line treatment
Pharmacokinetics
• Distribution: CSF concentration equal to that in plasma
• Metabolism: liver
• Excretion: urine
INTERACTIONS
Significant - Monitor Closely
• ethionamide
• isoniazid
• magnesium oxide/anhydrous citric acid
ADR
Frequency Not Defined
• Confusion
• Dizziness
• Headache
• Somnolence
• Seizure
• Psychosis
Contraindications & Cautions
Contraindications
• Hypersensitivity
• Alcohol use
• Renal dysfunction, severe
• History of seizure disorder, mental depression, severe anxiety or psychosis
Cautions
• Alcoholism, anemia, impaired hepatic/renal function
Pregnancy & Lactation
• Pregnancy Category: C
• Lactation: enters breast milk; safe
Thioacetazone
Mechanism of action: Bacteriostatic- inhibits cyclopropanaton of cell wall mycolic
acids.
Uses: It continues to be used as a convenient low cost drug to prevent emergence of
isoniazid resistance, streptomycin & ethambutol.
Dose:150mg OD in adults;2.5mg/kg in children; it is frequently combine with
isoniazid
T1/2: 12 hrs
ADR: hepatitis, exfoliative dermatitis, SJS, bone marrow depression rarely
Common: Abdominal discomfort, loose motions, rashes, mild anemia, anorexia.
Azithromycin
Mechanism of Action
Binds to 50S ribosomal subunit of susceptible microorganisms and blocks
dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent
protein synthesis to arrest; does not affect nucleic acid synthesis
Absorption
• Rapidly absorbed
• Bioavailability: 37%; variable effect with food
• Peak plasma time: 2.3-4 hr
Distribution
• Extensively distributed into skin, lungs, sputum, tonsils, and cervix; penetrates
cerebrospinal fluid (CSF) poorly
• Protein bound: 7-50% (concentration dependent)
• Vd: PO, 33.3 L/kg; IV, 31.1 L/kg
Metabolism
• Metabolized in liver
Elimination
• Half-life: Immediate release, ~70 hr; extended release, 59 hr
• Excretion: Feces (50% as unchanged drug), urine (5-12%)
Dose
Mycobacterium Avium Complex Infection
Prevention
• 1.2 g PO once weekly; may be combined with rifabutin 300 mg once daily
Treatment
• 250 mg PO once daily in combination with ethambutol 25 mg/kg/day for 2
months 15 mg/kg/day plus rifabutin 300 mg/day or rifampin 600 mg/day
Interactions
Contraindicated
• pimozide
Serious - Use Alternative
• BCG- vaccine live
• Digoxin
• Fondaparinux
• heparin
• Ondansetron
• quinidine
• typhoid vaccine live
• warfarin
ADRS
>10%: Diarrhea (52.8%), Nausea (32.6%), Abdominal pain (27%), Loose stool
(19.1%)
1-10%: Cramping (2-10%), Vaginitis (2-10%), Dyspepsia (9%), Flatulence (9%),
Vomiting (6.7%), Malaise (1.1%)
<1%: Agitation, Allergic reaction, Anemia, Anorexia, Candidiasis, Chest pain,
Conjunctivitis, Constipation, Dermatitis (fungal), Dizziness, Eczema
Contraindication
• hypersensitivity
• Cholestatic jaundice or hepatic impairment
Cautions
• Bacterial or fungal overgrowth may result from prolonged use
• Prolonged QT interval: Cases of torsades de pointes have been reported.
• Renal impairment (CrCl <10 mL/min)
• Use with caution in patients with myasthenia gravis (exacerbation may occur)
Administration
IV Preparation
• Dilute 500-mg vial in 4.8 mL of SWI (100 mg/mL)
• Dilute further in NS to 1 mg/mL (500 mL) or 2 mg/mL (250 mL)
IV Administration
• 1 mg/mL solution: Infuse over 3 hours
• 2 mg/mL solution: Infuse over 1 hour
Pregnancy & Lactation
• Pregnancy category: B
• Lactation: Unknown whether drug is excreted into breast milk; use with
caution
Clarithromycin
Mechanism of Action
Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S
ribosomal subunit of susceptible organisms and may inhibit RNAdependent protein synthesis by stimulating dissociation of peptidyl tRNA from ribosomes, thereby inhibiting bacterial growth
Pharmacokinetics
• Absorption
• Highly stable in presence of gastric acid (unlike erythromycin); food
delays but does not affect extent of absorption
• Bioavailability: 50%
• Peak plasma time: 2-3 hr
Distribution
• Distributed widely into most body tissues except central
nervous system (CNS)
• Protein bound: 42-50%
Metabolism
• Partially metabolized by CYP3A4
• Metabolites: 14-OH clarithromycin (active)
Elimination
• Half-life: Immediate release, 3-7 hr; active metabolite, 5-9 hr
• Renal clearance: Approximates normal glomerular filtration rate (GFR)
• Excretion: Urine (30-55%)
Dosing & Uses
Mycobacterial Infection
• Prophylaxis and treatment
• 500 mg PO q12hr for 7-14 days
Dosing Modifications
• Renal impairment (CrCl <30 mL/min): Reduce normal dose by 50%
ADR
• >10%: Gastrointestinal (GI) effects, general (13%)
• 1-10%: Abnormal taste (adults, 3-7%, Diarrhea (3-6%), Nausea (adults, 3-6%),
Vomiting (adults, 1%; children, 6%), Elevated BUN; 4%, Abdominal pain (adults,
2%; children, 3%), Rash (children, 3%), Dyspepsia (2%), Headache (2%), Elevated
prothrombin time (PT; 1%)
• <1%: Anaphylaxis, Anxiety, Clostridium difficile colitis, Dizziness, Dyspnea,
Elevated liver function tests
Contraindications
• hypersensitivity
• Coadministration with pimozide, cisapride, ergotamine, and dihydroergotamine
• History of cholestatic jaundice or hepatic dysfunction associated with previous use
of clarithromycin
• History of QT prolongation
• Coadministration with HMG-CoA reductase inhibitors (statins) that are
extensively metabolized by CYP3A4 (lovastatin, simvastatin), due to the increased
risk of myopathy, including rhabdomyolysis
Cautions
• Severe renal impairment
• Elderly patients may be more susceptible to drug-associated QT prolongation
• Discontinue immediately if severe hypersensitivity reactions occur
• Clostridium difficile associated diarrhea reported with use of nearly all
antibacterial agents, including clarithromycin
• Exacerbation of myasthenia gravis or new onset of symptoms reported
Hepatic dysfunction
• Increased liver enzyme activity and hepatocellular or cholestatic hepatitis, with or
without jaundice, have been reported; this may be severe and is usually reversible
Pregnancy & Lactation
• Pregnancy category: C
• Lactation: Drug is excreted in breast milk; use with caution
AMIKACIN
Mechanism of Action
Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in
protein synthesis; causes growth inhibition. For gram-negative bacterial coverage
of infections resistant to gentamicin and tobramycin
Pharmacokinetics
• Absorption: IM: May be delayed in bedridden patient
• Vd: 0.25-0.4 L/kg, primarily into extracellular fluid (highly hydrophilic);
penetrates blood-brain barrier when meninges inflamed; crosses placenta.
• Excretion: urine (94-98%)
• Half-Life: 2-3 hr
• Peak Plasma Time: IM: 45-120 min
• Protein Binding: 0-11%
Dosing
15 mg/kg/day divided IV/IM q8-12hr
Renal Impairment/Elderly
• CrCl >90 mL/min & <60 years old: q8hr
• CrCl 60-90 mL/min OR >60 years old: q12hr
• CrCl 25-60 mL/min: q24hr
• CrCl 10-25 mL/min: q48hr
• CrCl <10 mL/min: q72hr
Interactions
Contraindicated
• amphotericin b deoxycholate
• cidofovir
• neomycin
Serious - Use Alternative
• Atracurium
• BCG- vaccine live
• Bumetanide
• cyclosporine
• ethacrynic acid
• Furosemide
ADR
• 1-10%
• Neurotoxicity
• Nephrotoxicity (if trough >10 mg/L)
• Ototoxicity
• <1%: Hypotension, Headache, Drug fever, Rash, Nausea, Vomiting,
Eosinophilia, Tremor, Arthralgia
Contraindications
• Documented hypersensitivity
Cautions
• Renal impairment
• Risk of neurotoxicity, ototoxicity, nephrotoxicity - risk of ototoxicity increase
with concurrent loop diuretics
Pregnancy & Lactation
• Pregnancy Category: D
• Lactation: excretion in milk unknown/not recommendedIV Preparation
• Dilute 500 mg to 100 or 200 mL sterile diluent (usu NS or D5W)
IV/IM Administration
• IM: give undiluted to upper outer quadrant of buttocks
• IV: infuse over 30-60 min in adults and children and 1-2 hr in infants
KANAMYCIN
Mechanism of Action
Bactericidal and believed to inhibit protein synthesis
by binding to 30 S ribosomal subunit.
Pharmacokinetics
•Metabolism: unknown
•Excretion: urine
Dosing & Uses
• IV Administration: 5-7.5 mg/kg/dose divided q8-12hr; not to exceed 15
mg/kg/day divided q6-12hr; administer slowly
• IM Administration: 5-7.5 mg/kg/dose divided q8-12hr; not to exceed 15
mg/kg/day IM divided q12hr at equally divided intervals;
• Renal Impairment
• CrCl 50-80 mL/min: give 60-90% of usual dose or give q8-12hr
• CrCl 10-50 mL/min: give 30-70% of usual dose or give q12hr
• CrCl <10 mL/min: give 20-30% of usual dose or give q24-48hr
ADR
Agranulocytosis, Anorexia, Diarrhea, Dyspnea, Elevated BUN, Enterocolitis,
Headache, Incr salivation, Muscle cramps, Nausea, Nephrotoxicity, Neurotoxicity,
Ototoxicity, Pruritus.
Contraindications
• Documented hypersensitivity
Cautions
• Auditory toxicity more common with kanamycin than with streptomycin and
capreomycin;
• monthly audiometry is recommended while patients are being treated with this
drug;
• renal toxicity occurs at a frequency similar to that of capreomycin; regular
monitoring of serum creatinine recommended
• Renal impairment
• Myasthenia gravis
• Nephrotoxic agents
Pregnancy & Lactation
• Pregnancy Category: D
• Lactation: usually compatible
ADMINISTRATION
• IV Preparation
• For adults, IV infusions are prepared by adding 500 mg of kanamycin to 100200 mL of usual IV infusion fluid such as NS or D5W or by adding 1 g of the
drug to 200-400 mL of diluent
• IV/IM Administration
• Administer by deep IM injection, or IV infusion
• May administer by intraperitoneal instillation, irrigation, or inhalation
• Infuse over 30-60 min
RIFABUTIN
Mechanism of Action
Inhibits DNA-dependent RNA polymerase
Pharmacokinetics
Absorption: readily, 53%
Distribution: body tissues including the lungs, liver, spleen, eyes, & kidneys
• Vd: 9.32 L/kg
• Protein Bound: 85%
• Bioavailability: absolute: HIV: 20%
• Half-Life, 45 hr (range: 16-69 hr)
• Peak Plasma Time: 2-4 hr
Metabolism: hepatic CYP3A4 to active and inactive metabolites
Excretion
• Urine: 10% as unchanged drug, 53% as metabolites
• Feces: 10% as unchanged drug, 30% as metabolites
Prophylaxis
• Indicated for prefention of disseminated Mycobacterium avium complex (MAC)
disease in paitents with advanced HIV infection: 300 mg PO qDay
• Patients with N/V diathesis: 150 mg PO BID with food
Active TB (off-label)
• 5 mg/kg PO qD or 2-3x/week + other antitubercular agents, no more than 300
mg/dose
Renal Impairment
• CrCl<30mL/min dose should be reduced by 50%
Interactions
• artemether
• Clarithromycin
ADR:
>10%: Discoloration of urine (30%), Neutropenia (25%), Leukopenia
(17%), Rash (11%)
1-10%: Incr AST/ALT (7-9%), Thrombocytopenia (5%), Abdominal pain
(4%), Diarrhea (3%), Eructation (3%), Headache (3%), Nausea/vomiting
(3%), Anorexia (2%), Flatulence (2%)
Contraindications & Cautions
Contraindications
• Hypersensitivity to rifamycins
• Concomitant live bacterial vaccines
Cautions
• Monitor hematologic status
• Eye pain, redness, loss of vision may indicate inflammatory ocular condition
• May have brown-orange color of urine, feces, saliva, sputum, perspiration, tears,
& skin
• Pregnancy Category: B
Fluoroquinolones
Ciprofloxacin, Levofloxacin, gatifloxacin, moxifloxacin can inhibit strains M
tuberculosis. They are also active against atypical mycobacteria.
Moxifloxacin is the most active against M tuberculosis.
Mechanism of action:
They inhibit bacterial DNA synthesis by inhibiting bacterial
topoisomerase II (DNA Gyrase) and topoisomerase IV.
• Inhibition of DNA Gyrase prevents the relaxation of
supercoiled DNA that is required for normal transcription and
replication.
• Inhibition of topoisomerase IV interferes with separation of
replicated chromosomal DNA into the daughter cells during cell
division.
Pharmacokinetics
Rapidly absorbed orally- but food delays absorption,
BA: C- 60-80%, L- 100%, G- 96%
PPB: C- 20-35%, L- 15%, G- 20%
Vd: C- 3-4%, L-8%,
Half life: C- 3-5hrs, L-8hrs, G- 8hrs
High tissue penetration: lungs, sputum, muscle, prostate but low in CSF
Excreted primarily in urine, urinary and biliary concentrations are 10-50 times more
than plasma
Ciprofloxacin 750mg BD,PO
Levofloxacin 500mg OD.PO
Moxifloxacin 400mg OD. PO
Dosage
Adverse effects
Nausea, vomiting,diarrhoea(most common). Headache, dizziness, insomnia,
skin rash, photosensitivity.
Damage growing cartilage and cause an arthropathy. Tendinitis, tendon
rupture.
Interactions
• All fluoroquinolones interact with aluminum- or magnesium-containing
antacids and products containing calcium, iron, or zinc. Concomitant use
invariably results in marked reduction of oral absorption of the
antimicrobial and decreased the bioavailability of these drugs by up to 98%
when given within 2 hours of antibiotic administration.
• Fluoroquinolones are administered with food, peak concentration times are usually
slightly delayed, and maximum plasma concentrations (Cmax) are decreased 8-16%.
• Reductions in renal and total systemic clearance caused by probenecid are 24% for
levofloxacin,[50% for ciprofloxacin, and 42% for gatifloxacin.
• Significantly interact with theophylline-ciprofloxacin decreased theophylline clearance
by 25-30%, and increased theophylline plasma concentrations by up to 308%.
THANK YOU
-PHARMA STREET