Chemotherapy can be defined as “the use of chemical compounds in the treatment of infectious diseases, so as to destroy offending parasites or organisms without damaging the host tissues”.

The history of chemotherapy can be discussed in three periods as :

• Pre-Ehrlich era before 1891.
• Paul-Ehrlich era.
• Period after 1935 – well known by discovery of sulfonamides and antibiotics.

The various events, developments, major contribution to chemotherapy are as listed below :

• Domagk Mietsch, in 1938, introduced a dye ‘Prontosil’ inhibiting streptococci.
• Pasteur and Joubret, in 1877 – 1885, postulated that one bacterium could produce a substance that would stop the growth of another.
• Emmerich and Low, in 1889 (1899), discovered that extracts of Pseudomonas aeruginosa in high dilutions could destroy a variety of pathogenic cocci as well as diptheria, cholera, plague organism.
• Sir Alexander Fleming, in 1928, observed that one of his bacterial culture plates was contaminated by a fungus, which prevented growth of surrounding bacterial colonies.
  The fungus was later discovered as Penicillin notatum.
  Schataz, Bugie and Waksman, in 1944, reported the isolation of antibiotic streptomycin from Streptomyces griseus.

Significance of Various Terms Used in Chemotherapy :

Chemotherapeutic index : According to Ehrlich, substances used as anti-infectives, should produce greater effects on parasites (maximum parasitotropic) and minimum effects on host cells and tissues (minimum organotropic). Such anti-infective agents are defined as ‘desirable’ and posses a favourable chemotherapeutic index, which can be represented as :

Chemotherapeutic index (C.I) = Maximum tolerated dose / Minimum curative dose

Taking into consideration the various routes of administration, different hosts, the above formula is modified as :

Chemotherapeutic index (C.I)  =  L.D. 0.1 / C.D. 99.9

where,

L D. 0.1.  =  a dose which will kill all animlas except 0.1%.

C D. 99.9  =  dose which cures all animals except 0.1%.

This index indicates margin of safety of anti-infective agents.

General Mechanism of Action of Anti-infective Agents :

The various chemotherapeutic, anti-bacterial agents, used in therapy, act by either of following mechanism :

• Inhibition of bacterial cell-wall synthesis.
• Inhibition of cytoplasmic membrane function.
• Inhibition of nucleic acid synthesis.
• Inhibition of protein synthesis.
• Control of microbial enzymes.
• By competing for an essential metabolite in a substrate.

URINARY ANTISEPTICS

Introduction / Pathophysiology :

Urinary tract infection is defined as a condition characterized by presence of actively multiplying bacteria in the urinary bladder.

When 100,000 or more organisms are present in 1 ml of urine in two separately tested samples, then it is the condition referred to as urinary tract infection. Usually during infection, along with bacteria, white cells also appear.

The clinical conditions informing urinary tract infection are :

• Acute pyelonephritis – it is characterized by pain in the loins, fever, rigors and frequency of micturation. 
• Chronic pyelonephritis – characterized by asymptomatic bacteria.
• Cystitis – it is characterized by frequency of micturation, fever, tenderness over supra pubic region.
  The causative organism of urinary tract infections is Escherichia Coli.

URINARY TRACT ANTISEPTICS

Definition :

These are pharmacological agents, which when administered, inhibit the growth of causative organisms of urinary tract infection. Because these agents act locally on kidneys, urinary bladder and uterus. They are called as urinary tract antiseptics.

Classification :

1. Urinary tract antiseptics

• Methenamine mandelate
• Nalidixic acid
• Oxalinic acid
• Nitrofurantoin

2. Antibiotics

• Ampicillin
• Carbenecillin
• Cephalosporins
• Ciprofloxacin

Mechanism of Action :

The pharmacological agents, which are used as urinary antiseptics, when administered get concentrated in the renal tubules and effectively inhibit the growth of the infection causing organisms.

Adverse / Side Effect :

Gastro-intestinal tract upset is very common.

Preparation / Dose :

SULFONAMIDES

Definition :

The antimicrobial compounds containing a sulfonamide – SO₂NH₂ group are called as sulfonamides.

Classification :

Sulfonamides are classified as follows :

1. Used for the treatment of systemic infection :

• Short acting sulfonamides :
  Sulfadiazine, sulfadimidine, sulfacetamide.
• Intermediate acting sulfonamides :
  Sulfamethoxazole
• Long acting sulfonamides :
  Sulfamethoxypyridazine

2. Used for local gastro intestinal infection. Sulfagaunidine, succinyl sulfathiazole.

Anti-bacterial Spectrum :

Sulfonamides are effective against Gram positive and Gram negative organisms like :

• Streptococci, staphylococci, gonococci, pneumococci etc.
• Clostridia
• Haemophilus influenzae, vibrio, E. coli etc.
• Chlamydia

Mechanism of Action :

Folic acid derived from Para-amino-benzoic acid is essential for growth and multiplication of microorganism.

Sulfonamides inhibit folic acid synthetase enzyme; and because of its structural resemblance to para-amino-benzoic acid, removes PABA from the site and inhibits conversion of Para-amino-benzoic acid to folic acid, by attaching to the site.

Because of deficiency of folic acid, microorganism cannot multiply and grow. Thus, growth and multiplication of microorganism stops.

This is termed as ‘bacteriostatic’ action of sulfonamide. Schematically it can be represented as follows :

1. Normally when

2. When

Absorption, Fate, Excretion :

Sulfonamides used for systemic purposes are well absorbed. The main site of absorption is the small intestine.

In the blood, these drugs are loosely bound to plasma proteins.

Free, acetylated sulfonamides are mainly excreted in urine.

Adverse / Side Effects :

a. Sulfonamides cause renal complications.

In the presence of acidic urine, the acetylated form of sulfonamide is precipitated in collecting tubules and calyces. This causes renal irritation, obstruction to urinary flow, crystaluria, albuminuria, haematuria, oliguria and anuria.

These renal complications can be minimized by

• Advising high fluid intake to ensure adequate output of urine.
• By alkalinisation of urine, to increase solubility of conjugated products.
• By using sulfa combination.

b. On blood system sulfonamides causes agranulocytosis thrombocytopenia.

Clinical Application / Therapeutic Uses :

• To treat urinary tract infections –
  Urinary tract infection is caused by the microorganism E.Coli, which is highly sensitive to sulfonamides.
• To treat acute bacillary dysentery.
• In the prophylaxis of meningocaccal meningitis.
• In the treatment of trachoma and inclusion conjunctivitis.
• To treat nocardiasis.
• In the management of burns and skin disorder.

Contraindications :

Sulfonamides should be not used (contraindicated) in patients :

• With a history of sulpha hypersensitivity.
• Advanced kidney diseases with an elevated blood urea nitrogen.
• Pregnant women in last trimester.

Sulfonamide Interaction :

• Sulfonamides, if administered with oral anti-coagulents or methotrexate, increase their pharmacological effect.
• Sulfonamides, if administered with oral hypoglycemic agent like sulfonylurea, potentiates hypoglycaemic action.
• Analgesics like indomethacin and probenecid salicylates, reduce efficacy of sulfonamide by displacing it from the binding site.

Sulfa Combination :

• Sulfa combination is preferred instead of only sulfa in practice, for following reasons :

1. Combination therapy overcomes each others drawbacks (side effects).
2. In combination low doses are effective.
2. Combinations acts synergistically.

• In sulfa combination, sulfamethoxazole is combined with trimethoprim.
• Trimethoprim is a pyrimidine derivative and is effective against pathogenic bacteria.
• In this combination these agents are preferred because.

1. Trimethoprim and sulfamethoxazole act synergestically.
2. Trimethoprim is a structural anologue of dihydrofolic acid and hence inhibits the enzyme dihydrofolate reductase, which is involved in conversion of dihydrofolic acid to tetrahydrofolic acid.
3. Sulfonamides inhibit conversion of Para-amino-benzoic acid to folic acid and thus inhibits synthesis of folic acid.
4. Thus, together these drugs prevent growth of microorganisms by producing folic acid deficiency.
5. Pharmacokinetic studies make it clear, that the half lives of these two agents are identical and approximately similar.
   Half life of trimethoprim:  16 hrs
   Half life of sulfamethoxazole:  10 –12 hrs.

• Schematically, the mechanism of action of sulfa combination, can be represented as follows :

Clinical Application / Therapeutic Uses :

• As a preparation of choice in the urinary tract infection, caused by E. Coli.
• In the treatment of respiratory tract infections including acute and chronic bronchitis.
• To treat gastro-intestinal infections, specifically in the treatment of shigellosis.
• Combination is useful for the treatment of septicaemias and serious infections caused by gram –ve bacilli.
• In the treatment of plague.
• In the treatment of veneral, i.e. sexually transmitted diseases, like syphilis and gonorrhoea.
• Combination is successfully suggested in cases of neonatal meningitis.

Adverse / Side Effect :

It is postulated that trimethoprim may increase the gastro-intestinal and haematological toxicity of sulphamethoxazole.

Interactions :

• Combination increases pharmacological action of anti-coagulant warfarin and of anti-epileptic phenytoin sodium.
• It should not be administered to pregnant women, especially during the first trimester and to children below 12 years of age.

Preparation / Dose :

Trimethoprim, sulfamethoxazole are combined with each other in a ratio 1 : 5. Accordingly the various preparations available are :

ANTIBIOTICS

These are chemical compounds produced by living microorganisms like bacteria, fungi and actinomycetes, which at high dilutions, are capable of inhibiting or killing bacteria and other microorganisms.

Potency :

It is defined as activity per milligram of a chemotherapeutic agent and is expressed on the basis of “minimum inhibitory concentration, which is capable of inhibiting the multiplication of one of the susceptible microorganisms”.

Bacteriostatic Activity :

It is defined as “ability of a compound to inhibit growth and multiplication of micro-organisms” e.g. chloramphenicol, erythromycin, tetracycline, sulphonamides etc.

Bactericidal Activity :

It is defined as ability of a compound to kill microorganism.

e.g. penicillins, cephalosporins, vancomycin etc.

Antibacterial Spectrum :

This refers to the range of activity of a compound.

Usually activity of a compound is expressed either as broad-spectrum or narrow -spectrum.

PENICILLIN

Definition :

Antibiotics are chemical substances derived from various species of microorganisms, such as fungi, actinomycetes, bacteria and in higher concentrations suppress growth of other microorganism.

Penicillin is one of the most important antibiotics.

Source :

It is extracted from the mould penicillium notatum.

Structure :

Penicillins represent a large group of antimicrobial agents, consisting of a fundamental nucleus, 6 – Amino – Penicillanic – acid (6 – APA) having a Beta lactum ring.

Classification :

1. Natural penicillins

• Benzly penicillin (penicillin G)
• Phenoxy methyl penicillin (penicillin V)

2. Penicillinase resistant penicillins

• Methicillin
• Nafcillin
• Oxacillin

3. Broad-spectrum penicillin

• Ampicillin
• Amoxicillin

4. Penicillins active against pseudomonas

• Carbenicillin

Mechanism of Action :

Penicillins act by interfering with the synthesis of the cell wall mucopeptide of gram-postive cocci. This makes the cell membrane of the organism vulnerable to damage by solutes in the surrounding medium (plasma).

Thus, penicillins are bactericidal drugs and are effective mainly against multiplying organisms.

Antibacterial Spectrum :

Penicillins are mainly effective against Gram-positive and Gram-negative cocci. Streptococci, staphylococci, Gonococci, pneumococci, meningococci are sensitive to penicillin.

Absorption, Fate, Excretion :

Penicillin G, i.e. benzyl penicillin, is inactivated by gastric acid, when orally administered.

Hence, as its absorption is inadequate and irregular, benzyl penicillin is administered by intramuscular route.

Penicillin is widely distributed in the body. It crosses the placental barrier.

Penicillin is eliminated by the kidneys while small amounts appear in bile, milk and saliva.

Co-administration of probenecid delays rapid excretion of penicillin. It competes with penicillin for tubular transport and can raise plasma-penicillin level. The normal dose of probenecid, which is known to increase plasma penicillin level, is 0.5 g six hourly.

Adverse / Side Effects :

• Anaphylaxis : It is a rare but most serious reaction. Anaphylaxis can develop even with a minute quantity of penicillin and is irrespective of the route of administration. It is characterized by an acute cardio-vascular collapse, bronchospasm and edema of larynx.
• Serum sickness like syndrome with skin rash, fever, eosinophilia, asthma, etc.
• Renal complications like haematuria, albuminuria.
• Hyper Kalemia.

Preparation / Dose :

Clinical Application / Therapeutic Uses :

• To treat pneumococcal infection.
• To treat streptococcal infection.
• To treat staphylococcal infection.
• To treat meningococcal infection.
• To treat infections with anaerobes.
• Penicillin is the choice of antibiotic in the treatment of sexually transmitted diseases like syphilis and gonorrhoea.
• As a prophylactic, penicillin is used in dental procedures, bronchoscopy, tonsillectomy, surgical procedures.
• Penicillin is effective in the management of tetanus, diptheria, gangrene.

Test for Detection of Penicillin Allergy :

Skin test :

• Scratch the skin through a drop of solution containing 10,000 units of benzyl penicillin per ml.
• If a central wheel due to local edema occurs after 15 minutes, it is considered a positive reaction.

Treatment for Anaphyplactic Shock :

The hypersensitivity reaction produced by penicillin, referred to as anaphylactic shock, can be treated by using following pharmacological agents :

1. Adrenaline:0.2 to 0.5 ml I/M
2. Prednisolon:100 mg
3. Promethazine:50 mg

STREPTOMYCIN

AMINOOGLYCOSIDE ANTIBIOTIC – STREPTOMYCIN

Definition :

These are the antibiotics composed of aminosugars, connected by glycosidic linkage. Streptomycin is obtained from streptomyces griseus.

Antibacterial Spectrum :

Streptomycin is effective against M.tuberculosis, Shigella species, Brucella, H. Influenzae, H.ducreyii, Nocardia etc. Streptomycin is more effective in alkaline pH (7 – 8) than acidic pH.

Mechanism of Action :

Ribosomes prepare enzymes under messenger RNA.

It is believed that streptomycin combines with bacterial ribosome, interferes with messenger – Rna combination and compels ribosomes to prepare wrong amino acids sequence, which results in destruction of bacterial cell.

Streptomycin may be bactericidal or bacteriostatic.

Absorption, Fate, Excretion :

• Streptomycin is poorly absorbed from gastro-intestinal tract.
• Streptomycin is usually injected intramuscularly.
• Streptomycin is excreted by glomerular filtration in urine.

Adverse / Side Effects :

• Streptomycin, on oral administration, may cause nausea and vomiting.
• Intramuscular administration of streptomycin may cause abscess and fever.
• Streptomycin causes damage to 8^th cranial nerve and impairs auditory and vestibular function.
  Streptomycin may cause deafness in babies born to mothers receiving streptomycin during pregnancy, as it crosses the placental barrier.

Preparation / Dose :

Clinical Application / Therapeutic Uses :

• It is a drug of choice in the treatment of tuberculosis.
• It is useful in treatment of urinary tract injection due to E. Coli.
• It is useful in treatment of meningitis.
• Streptomycin is advised in bacteremia and bacterial endocarditis.
• It is the preferred drug in infections like tularemia.
• In the treatment of brucellosis, streptomycin is effective.

Contraindication / Interactions :

• Frusemide and ethacrynic acid, like diuretics, are potentially ototoxic and must be avoided being taken with streptomycin.
• As streptomycin causes neuromuscular blockade, it must be avoided being taken in combination with neuromuscular blocking agents.

TETRACYCLINES AND OTHER ANTIBIOTICS

BROAD SPECTRUM ANTI-BIOTICS

Definition :

These antibiotics are not only effective against gm–positive and gram–negative organisms, but also rickettsiae, mycoplasmae, chalmydia and brucella. Hence, they are called Broad Spectrum Antibiotics.

TETRACYCLINE

Definition :

Tetracyclines are broad-spectrum antibiotics and are naphthalene derivative.

Antibacterial Spectrum :

Tetracyclines are effective against Gram-positive and Gram-negative organisms, including pneumococci, gonococci, clostridia, H.indluenzae, H.pertusis. H.ducreyi, Brucella, vibrio comma etc.

Mechanism of Action :

Tetracyclines act by inhibiting certain essential enzyme systems of bacterial cell. Tetracyclines are known to inhibit protein synthesis in bacterial ribosomes.

Tetracyclines bind with magnesium, manganese and calcium to form insoluble complexes ‘chelates’, and by removing these divalent metallic cations from sites, they inhibit enzyme activation.

Thus, tetracyclines are bacteriostatic in action.

However, in higher concentrations or parenteral administration, they may exert a bactericidal effect.

Absorption, Fate, Excretion :

• Tetracyclines form insoluble complexes on chelation with calcium, magnesium and aluminium.
• Hence absorption of tetracycline on oral administration, is variable and incomplete.
• It is also advised to avoid tetracyclines with food or milk as it forms chelates, which are insoluble complexes, with divalent ions present in milk and food.
• Therefore, tetracyclines must be administered by intravenous, intramuscular, or by local application.
• Tetracyclines, administered intramuscularly, produce peak plasma level within one hour and sufficient levels are maintained for 12 hours.
• Tetracyclines are widely distributed in the body and are excreted mainly in the urine by glomerular filtration.

Adverse / Side Effects :

• Tetracyclines chelate with calcium, forming a tetracycline orthophosphate complex. This is deposited in areas of calcification in bones and teeth. This affects bone and teeth development. Tetracyclines, if administered to pregnant women, may lead to yellow staining of the teeth of infant and defective formation of enamel.
  Hence, they should not be administered to infants and children upto the age of 12 years.
• On oral administration, tetracycline causes nausea, vomiting, epigastric distress, loose stools.
• Tetracyclines develop ‘Fanconi-like’ syndrome, characterized by nausea, vomiting, proteinuria, glycosuria.
• Tetracyclines when administered in large doses intravenously, develop jaundice, hepatic dysfunction, pancreatitis.
• In infants, tetracycline administration results in Benign – intracranial hypertension, characterized by headache, photophobia.

Preparation / Dose :

Clinical Applications / Therapeutic Uses :

• Tetracyclines are very effective in rickettsial infections like murine, epidemic, scrub typhus, rickettsial pox, Q fever, Rocky mountain spotted fever.
• To treat granuloma inguinale.
• In the treatment of plague.
• In the treatment of primary atypical pneumonia.
• To treat cholera.
• To treat chalmydia infections.
• To treat bacillary infections.
• In the treatment of urinary tract infection.
• Tetracyclines are useful in acne vulgaris.
• To treat veneral diseases.

Contraindication :

• Tetracyclines are strictly contraindicated in pregnant women and children upto 12 years of age.

Interaction :

• Tetracyclines interact with milk, food by forming insoluble complexes with calcium, magnesium, manganese and aluminium.

CHLORAMPHENICOL

Definition :

It is a broad-spectrum antibiotic derived from streptomyces venezuelae.

Antibacterial Spectrum :

Chloramphenicol is a broad-spectrum antibiotic, effective against Gram-positive and Gram-negative bacteria, chlamydia, rickettsiae, salmonella typhie etc.

Mechanism of Action :

Chlorampenicol acts by inhibiting bacterial protein synthesis. It is a bacteriostatic agent.

Absorption, Fate, Excretion :

• When administered orally, it is completely absorbed in the gut.
• It can also be administered by the intramuscular and intravenous route.
• Chloramphenicol is 60% bound to plasma protein.
• It is mainly excreted in urine.

Adverse Effects :

• Chloramphenicol, due to its nitrobenzene radical, produces bone marrow toxicity, characterized by bone marrow depression, anaemia, leukopenia, thrombo-cytopenia, agranulocytosis, aplastic anemia.
  To prevent this risk of bone marrow depression – aplastic anaemia, prolonged or repeated use of chloramphenicol should be avoided.
  During treatment, blood cell count should be monitored, and if total leucocyte count drops below 4000 / cu mm blood, then treatment should be stopped.
• Neonates and premature infants, if administered by chloramphenicol in large doses, may develop ‘grey baby syndrome’ characterized by progressive abdominal distension, vomiting, refusal to feed, loose greenish stools and irregular respiration.
• During chloramphenicol theraphy, gastro-intestinal disturbances like nausea, vomiting, glossitis, stomatitis, enterocolitis may occur.

Preparation / Doses :

Clinical Application / Therapeutic Uses :

• Chloramphenicol is used to treat enteric fever.
• Chloramphenicol is indicated in H.influenzae meningitis.
• Chloramphenicol is also preferred topically for eye infections.

Note :

• Chloramphenicol therapy should not be prolonged unduly.
• Repeated therapy with chloramphenicol should be avoided.
• During chloramphenicol therapy, frequent blood cell counting should be done.
• Chloramphenicol therapy is supplemented with haematinics i.e. iron preparations.

Contraindications :

• Chloramphenicol should be avoided during pregnancy.
• It should be avoided in neonates and premature infants.

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