CHEMOTHERAPY

Introduction
By Firewoin B.

Dec.30, 2009

 Objective

At the end of this lesson the trainee will be able understand:

The definition of some terminology in chemotherapy. Principle of antimicrobial therapy Problems that arise with the use of antimicrobials Classification of chemotherapeutic agents.

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INTRODUCTION
The term chemotherapy was coined by Ehrlich

at the beginning of the century to describe the use of synthetic chemicals to destroy infective agents. Now refers more broadly to the use of any chemical compound that selectively acts on microbes or cancer.

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INTRODUCTION (CONT.)
Antibiotics are substances produced by

various species of M.O (bacteria, fungi, and actinomycetes) that suppress the growth of other M.O. at low con. Antimicrobial agents (AMAs) is generalized one to designate synthetic as well as naturally obtained drugs that attenuate M.O.

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INTRODUCTION (CONT.)
AMAs differ markedly in; Physical properties, Chemical properties, Pharmacological properties, Antimicrobial spectra, and Mechanisms of action. Knowledge of molecular mechanisms of

bacterial replication has greatly facilitated rational development of cpds that can interfere with their replication.
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INTRODUCTION (CONT.)
Antimicrobial agents are among the most

dramatic examples of the advances of modern medicine.

Many infectious diseases once considered

incurable and lethal are now amenable to treatment with a few pills.

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INTRODUCTION (CONT.)
The remarkable specific activity of AMAs is

due to their selectivity for targets that are either unique to MO or much more important in them than in humans.
Among

these targets are:-

Bacterial and fungal cell wallsynthesizing enzymes, The bacterial ribosome , the enzymes required for nucleotide synthesis and DNA replication, and The machinery of viral replication.

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INTRODUCTION (CONT.)
Sources of antimicrobial
1.

Microbial

Penicillin,Streptomaycin, Chloramphenicol Oral penicillin INH, Sulphonamides, Qunolons

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2.

Semisynthetic

3.

Synthetic

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Problems that arise with the use of antimicrobials

1.

Toxicity
1.

Local irritation

At the site of administration

GI irritation Pain and abscess formation at the site of Im injection Thrombophlebitis of the injected vein

2.

Systemic toxicity

Practically all AMAs produces dose related and predictable organ toxicity.
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Problems that arise with the use of antimicrobials (Cont.)

2.

Hypersensitivity reaction

It is unpredictable and unrelated to dose The whole rang of reaction from rashAnaphylactic shock can be produced.
It refers to unresponsiveness of a m.o to AMAs and is kin to the phenomena of tolerance seen in higher organisms.

3.

Drug resistance

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Problems that arise with the use of antimicrobials (Cont.)

Type of resistance Natural resistance

Some microbial have always been resistance to certain AMAs.

They lack the metabolic process or the target site which is affected by the particular drugs.

It is generally a group or species characteristic.

Gram -ve bacilli are normally unaffected by pencillin G.

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Problems that arise with the use of antimicrobials (Cont.)

Acquired resistance It is the development of resistance by an organism (which was sensitive before) due to the use of an AMAs over a period of time. This can happen with any microbe and is a major clinical problem.

It depends on the microorganism as well as the drug Some bacteria are notorous for rapid acquisition of resistance
Eg staphyloccoccui, coliforms, tubercle bacilli.

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Problems that arise with the use of antimicrobials (Cont.)

Resistance may be developed by mutation or gene

transfer.

Resistance once acquired it become prevalent due to

the selection pressure of a widely used AMAs.

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Problems that arise with the use of antimicrobials (Cont.)

Resistant organism can be: Drug tolerant Loss of affinity of the target biomolecule of the MO for AMA. Acquisition of an alternative metabolic pathway Drug destroying B- lactamase, CAF acetyl transfrase Drugs impermeable

Efflux pump

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Mechanisms of AMA resistance

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Problems that arise with the use of antimicrobials (Cont.)

Cross resistance Acquisition of resistance to one AMAs conferring resistance to another AMA to which the organism has not been exposed. This is more commonly seen between chemically or mechanistically related drugs,

Eg. Resistance to one sulfonamide means resistant to all other.

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Problems that arise with the use of antimicrobials (Cont.)

One Cause of resistance is misuse of the AMAs

1. 2. 3. 4. 5.

Treatment of untreatable infection Therapy of fever of undetermined origin. Improper dosage. Improper reliance on chemotherapy alone. Lack of adequate bacteriological information.

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Problems that arise with the use of antimicrobials (Cont.)

To prevent or reduce bacterial resistance:

Use antibiotic only when necessary. Make sure that the indication, dose, and duration of treatment are correct. Combine antibiotic when indicated. Monitor pattern of resistance. Limit the use of newest antibacterial.

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Problems that arise with the use of antimicrobials (Cont.)

4.

Super infection

This refer to the appearance of a new infection as result of antimicrobial therapy The use of most AMAs cause some alteration in the normal microbial flora of the body

The normal flora contributes to host defense.

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Problems that arise with the use of antimicrobials (Cont.)

5.

Nutritional Deficiencies

Some of the B complex group of vitamins and vit K synthesized by intestinal flora is utilized by man

Prolonged use of AMA which alters the flora may result in vit deficiency.

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Problems that arise with the use of antimicrobials (Cont.)

6. Masking of an infection A short course of AMA may be sufficient to treat one infection but only briefly suppress another one contacted concurrently.

The infection will be masked masked initially, only manifest later in a sever form. Single dose of Penicillin
Mask syphilis Cure gonorrhea

Short course Streptomycin

Mask TB Cure trivial respiratory infection

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CLASSIFICATION OF ANTIMICROBIALS
Antimicrobial agents are classified based on

chemical structure and proposed mechanism of action, as follows.

1.

The Antimetabolites,

Including trimethoprim and the sulfonamides, which block essential enzymes of folate metabolism.

2.

Agents that affect bacterial nucleic acid metabolism,

Rifamycins which inhibit RNA polymerase, and The Quinolone, which inhibit topoisomerases;

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CLASSIFICATION OF ANTIMICROBIALS (CONT.)

3.

Agents that inhibit synthesis of bacterial cell wall.

Including

The -lactam class (Penicillins, cephalosporins, and carbapenems) and Dissimilar agents such as cycloserine, vancomycin, and bacitracin

4.

Agents that bind to the 30S ribosomal subunit and alter protein synthesis, which generally are bactericidal.

The aminoglycosides
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CLASSIFICATION OF ANTIMICROBIALS (CONT.)

5.

Agents that disrupt function of 30S or 50S ribosomal subunits to reversibly inhibit protein synthesis, which generally are bacteriostatic.

Chloramphenicol, tetracyclines, erythromycin, and clindamycin,

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CLASSIFICATION OF ANTIMICROBIALS (CONT.)

6.

Agents that act directly on the cell membrane of the microorganism, increasing permeability and leading to leakage of intracellular compounds,

Including Detergents such as polymyxin; Polyene antifungal agents (e.g., nystatin and amphotericin B) which bind to cell-wall sterols; and the lipopeptide.
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Dec.30, 2009

CLASSIFICATION OF ANTIMICROBIALS (CONT.)

According to target MO affected they can be

classified as;1. 2. 3. 4. 5.
6.
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Antibacterial Antifungal Antihelementics Antiprotozoal Anticancer

Antiviral
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CLASSIFICATION OF ANTIMICROBIALS (CONT.)

According to antibacterial spectrum they

can be classified as: Narrow

spectrum Extended spectrum

Gram +ve, and certain gram ve.

Wide

spectrum

Gram -ve, gram +ve, and certain bacterial specious

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CLASSIFICATION OF ANTIMICROBIALS (CONT.)

According to the type of action they can be classified as:1.

2.

Bacteristatic agents:- that slow protein synthesis or prevents microbial cell division. Bactericidal agents:- that mediate complete killing of the bacteria.

Generally bacteriostatic and bactericidal

combination is not advisable.

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Summary
.

. .

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Thank u

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