tuberculosis by jitendra bhangale

8/16/2012

1

© 2010 Delmar, Cengage Learning1

By- Jitendra Bhangale

Assistant Professor & Head,

Department of Pharmacology,

Smt N. M. Padalia Pharmacy College,

Ahmedabad


By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad

“Tuberculosis is defined as an infectious disease caused by

a bacterium; that most commonly affects the lungs.”

It can also be a crippling and deadly disease, and is on the

rise in both developed and developing worlds.

Globally, it is the leading cause of deaths resulting from a

single infectious disease.

Currently, it kills “three million people” a year and could

claim up to 30 million lives if not controlled.

8/16/2012

2



TB germs are passed through the air when a person who is

sick with TB disease coughs, sings, sneezes, or laughs

To become infected with TB germs, a person usually needs

to share air space with someone sick with TB disease

(e.g., live, work, or play together)

The amount of time, the environment, and how sick the

person is all contribute to whether or not you get

infected

In most cases, your body is able to fight off the germs



Mycobacterium which is carried by humans.

Mycobacterium T.B. can present it self in the human

body in different forms effecting any where from “the

intestines, bones, joints, skin, and the genitourinary,

lymphatic, and nervous systems.”

8/16/2012

3



Avian which is carried by birds

Transmitted by ingestion and inhalation of aerosolizedinfectious organisms from feces.

Oral ingestion of food and water contaminated with feces isthe most common method of infection.

Once ingested, the organism spreads throughout the bird'sbody and is shed in large numbers in the feces.

If the bacterium is inhaled, pulmonary lesions and skininvasions may occur

Transmission of avian TB is from bird to human not fromhuman to human.



Bovine tuberculosis is carried by cattle.

People contract Bovine TB today,by eating food that has

been contaminated by the bacteria or from drinking

un-pasteurized milk from cows that are infected with

the virus.

Bovine TB is most likely going to effect the joints and bones.

8/16/2012

4



The primary stage of the disease may be symptom-free, or

the individual may experience a flu-like illness. This is

called the “inactive stage.”

Within the active stage of the disease, there might be a

slight fever, night sweats, weight loss, fatigue.

The symptoms may vary depending on what type of

tuberculosis you contract.



This is an example of tuberculosis of the skin it is normally

referred to as Warty T.B. and someone will only

contract this type of tuberculosis if they have had prior

exposure to tuberculosis.

8/16/2012

5



There is a difference between TB “infection” and TB

“disease”

TB infection: TB germs stay in your lungs, but they do

not multiply or make you sick

You cannot pass TB germs to others

TB disease: TB germs stay in your lungs or move to

other parts of your body, multiply, and make you sick

You can pass the TB germs to other people



TB infection is treated with medicine, usually for 4-9

months.

If TB infection is not treated, it can turn into TB

disease.

It is important to take all your medicine, even though

you don’t feel sick.

8/16/2012

6



TB disease is treated with medicine to kill the TB

germs.

Usually, the treatment will last for 6-9 months.

TB disease can be cured if the medicine is taken as

prescribed, even after you no longer feel sick.



First line: These drugs have high antitubercular efficacy

as well as low toxicity; are used routinely.

Second line: These drugs have either low antitubercular

efficacy or high toxicity or both; are used in special

circumstances only.

8/16/2012

7



First line agent

Isoniazid

Rifampin

Ethambutol

Streptomycin

Pyrazinamide

Second line agent

Moxifloxacin

Gatifloxacin

Ethionamide

Aminosalicylic acid

Cycloserine

Amikacin

Kanamycin

Capreomycin



Isoniazid is the hydrazide of isonicotinic acid.

Isoniazid is a prodrug; mycobacterial catalase-peroxidase converts

isoniazid into an active metabolite.

A primary action of isoniazid is to inhibit the biosynthesis of mycolic

acids, branched lipids that are attached to a unique polysaccharide,

arabino galactan, to form part of the mycobacterial cell wall.

The mechanism of action of isoniazid is complex, with resistance mapping

to mutations in at least five different genes (katG [coding for the

catalase-peroxidase that activates the prodrug isoniazid], inhA,

ahpC, kasA, and ndh).

8/16/2012

8



The preponderance of evidence points to inhA as the primary drug target.

Indeed, the catalase-peroxidase-activated isoniazid, but not the

prodrug, binds to the inhA gene product enoyl-ACP reductase of fatty

acid synthase II, which converts D2-unsaturated fatty acids to saturated

fatty acids in the mycolic acid biosynthetic pathway.

Mutations of the katG gene that result in an inactive catalase-peroxidase

cause high-level isoniazid resistance, since the prodrug cannot be

activated by the catalase-peroxidase.

Isoniazid also inhibits mycobacterial catalase-peroxidase (the isoniazid-

activating enzyme), which may increase the likelihood of damage to the

mycobacteria from reactive oxygen species and H2O2.



Adverse effect:

Fever

Jaundice

Peripheral neuritis

Hypersensitivity

Skin eruptions

Hepatitis

Arthritic symptoms

Convulsions

8/16/2012

9



The rifamycins (rifampin, rifabutin, rifapentine) are a group of

structurally similar, complex macrocyclic antibiotics produced by

Streptomyces mediterranei .

Antibacterial Activity:- Rifampin inhibits the growth of most

gram-positive bacteria as well as many gram-negative

microorganisms such as Escherichia coli, Pseudomonas, indole-

positive and indole-negative Proteus, and Klebsiella. Rifampin is very

active against Staphylococcus aureus and coagulase-negative

staphylococci.



Mechanism of Action. Rifampin inhibits DNA-dependent RNA

polymerase of mycobacteria and other microorganisms by forming a

stable drug-enzyme complex, leading to suppression of initiation of

chain formation in RNA synthesis.

More specifically, the β subunit of this complex enzyme is the site

of action of the drug, although rifampin binds only to the

holoenzyme.

8/16/2012

10



Nuclear RNA polymerases from a variety of eukaryotic cells do not

bind rifampin, and RNA synthesis is correspondingly unaffected in

eukaryotic cells.

High concentrations of rifamycin antibiotics can inhibit RNA

synthesis in mammalian mitochondria, viral DNA-dependent RNA

polymerases, and reverse transcriptases.

Rifampin is bactericidal for both intracellular and extracellular

microorganisms.



Adverse effect:-

Hepatitis and deaths

Chronic liver disease

Alcoholism

Respiratory syndrome

Cutaneous syndrome

Flu syndrome

Abdominal syndrome

8/16/2012

11



Antibacetrial spectrum:-

M. tuberculosis and M. kansasii

Mechanism of action

Ethambutol inhibits arabinosyl transferases involved in

arabinogalactan synthesis and to intefere with mycolic acid

incorporation in mycobacterial cell wall.

Mechanism of resistance

Bacterial resistance to the drug develops in vivo via single

amino acid mutations in the embA gene when ethambutol is

given in the absence of other effective agents.



Adverse effect:-

Flu syndrome

Abdominal syndrome

Hyperuricemia

8/16/2012

12


H. dureyi

Brucella

Yersinia pestis

Francisella tularensis

Nocardia

Calym. granulomatis

M. tuberculosis

It is the oldest aminoglycoside antibiotic obtained fromStreptomyces griseus.It is a narrow spectrum antibiotic that active against aerobic gram-negative bacilli

E. coli

H. influenzae

V. cholerae

Shigella

Klebsiella

enterococci

Antibacterial spectrum



By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad

Streptomycin binds to the 30S ribosomal subunit and interfereswith initiation of protein synthesis by fixing the 30S-50Sribosomal complex at the start codon (AUG) of mRNA.

As 30S-50S complexes downstream complete translation ofmRNA and detach, the abnormal initiation complexes, so-called streptomycin monosomes, accumulate, blockingfurther translation of the message.

8/16/2012

13



Streptomycin binding to the 30S subunit also causes misreadingof mRNA, leading to B. premature termination of translation withdetachment of the ribosomal complex and incompletelysynthesized proteinC. incorporation of incorrect amino acids (indicated by the X),resulting in the production of abnormal or nonfunctional proteins.


Resistance microorganisms

Notable bacilli that are not inhibited are

E. coli,

H. Influenzae

Str. Pneumonine,

Str. Pyogens,

Staph. aureus


8/16/2012

14


Streptomycin is highly ionized.

It is neither absorbed nor destroyed in the g.i.t.

However, absorption from injection site in muscles is rapid.

Adverese effect:-

Vestibular disturbances, Hypersensitivity reactions are rare;

rashes, eosinophilia, fever and exfoliative dermatitis




Mechanism of action:-

It inhibits mycolic acid synthesis, but by interacting with a

different fatty acid synthase encoding gene.

Mechanism of resistanace:-

Resistance to pyrazinamide develops rapidly if it is used

alone, and is due to mutation in the pncA gene which encodes for

the enzyme generating the active metabolite of pyrazinamide.

Adverse effect:-

Hepatotoxicity, Hyperuricaemia, arthralgia, flushing, rashes,

fever and loss of diabetes control.

8/16/2012

15



The C-8-methoxy-fluoroquinolones, such as gatifloxacin and

moxifloxacin are the most active agents.

Mechanism of action

The FQs inhibit the enzyme bacterial DNA topoisomerase IV,

which nicks double-stranded DNA, introduces negative supercoils

and then reseals the nicked ends.

This is necessary to prevent excessive positive supercoiling of the

strands when they separate to permit replication or

transcription.

The DNA gyrase consists of two A and two B subunits: The A

subunit carries out nicking of DNA, B subunit introduces

negative supercoils and then A subunit reseals the strands.



FQs bind to A subunit with high affinity and interfere with its

strand cutting and resealing function.

Recent evidence indicates that in gram-positive bacteria the major

target of FQ action is a similar enzyme topoisomerase IV

which nicks and separates daughter DNA strands after DNA

replication.

8/16/2012

16



Mechanism of Action

In the manner of isoniazid, ethionamide is also an inactive prodrug that is

activated by a mycobacterial redux system.

EtaA, an NADPH-specific, FAD-containing monooxygenase, converts

ethionamide to a sulfoxide, and thence to 2-ethyl-4-aminopyridine.

Although these products are not toxic to mycobacteria, it is believed that a

closely related and transient intermediate is the active antibiotic.

Ethionamide inhibits mycobacterial growth by inhibiting the activity of the

inhA gene product, the enoyl-ACP reductase of fatty acid synthase II.

This is the same enzyme that activated isoniazid inhibits.

Although the exact mechanisms of inhibition may differ, the results are

the same: inhibition of mycolic acid biosynthesis and consequent

impairment of cell-wall synthesis.



Adverse effect

Anorexia

Nausea and vomiting

Gastric irritation

Postural hypotension

Mental depression

Drowsiness

Olfactory disturbances

Blurred vision

Diplopia

Dizziness

Paresthesias

Headache

Restlessness,

Tremors

allergic skin rashes

purpura,

Stomatitis

Gynecomastia

Impotence

Menorrhagia

Acne

Alopecia

8/16/2012

17



Aminosalicylic acid is bacteriostatic.

Mechanism of Action

Aminosalicylic acid is a structural analog of para-aminobenzoic

acid, and its mechanism of action appears to be very similar to that

of the sulfonamides.

The sulfonamides are ineffective against M. tuberculosis, and

aminosalicylic acid is inactive against sulfonamide-susceptible

bacteria.

This differential sensitivity presumably reflects differences in the

enzymes responsible for folate biosynthesis in the various

microorganisms.



Adverse effect

Gastrointestinal problems

Anorexia

Nausea

Epigastric pain

Abdominal distress

Diarrhea

Hematological abnormalities

8/16/2012

18



Cycloserine is a broad-spectrum antibiotic produced by

Streptococcus orchidaceus.

Mechanism of Action

Cycloserine and D-alanine are structural analogs; thus, cycloserine

inhibits reactions in which D-alanine is involved in bacterial cell-

wall synthesis.

The use of medium free of D-alanine reveals that the antibiotic

inhibits the growth in vitro of enterococci, E. coli, S. aureus, Nocardia

species, and Chlamydia.



Adverse effect:-

Somnolence

Headache

Tremor

Dysarthria

Vertigo

Confusion

Nervousness

Irritability

Psychotic states

Paranoid reactions

Twitching

Hyperreflexia

Visual disturbances

Paresis

Tonic-clonic or absence

seizures.

8/16/2012

19



Capreomycin is an antimycobacterial cyclic peptide elaborated by

Streptococcus capreolus.

It consists of 4 active components¾capreomycins IA, IB, IIA, and

IIB.

The agent used clinically contains primarily IA and IB.

Capreomycin must be given intramuscularly.

Adverse effect:-

Hearing loss, tinnitus, transient proteinuria, cylindruria, nitrogen

retention, leukocytosis, leukopenia, rashes, and fever



tuberculosis by jitendra bhangale

Education