Chemotherapy Class Note

CHEMOTHERAPY
60. INTRODUCTION AND GENERAL COSIDERATIONS

Chemotherapy: It is study of drugs which selectively inhibit or destroy specific agents
of diseases like bacteria, viruses, fungi and parasites including neoplastic cells.
Paul Ehrlich first coined the term chemotherapy in 1913 to describe drugs which attack
invading organisms without harming the host (magic bullet).
Chemotherapeutic agents are one of the most frequently used as misused class of drugs.
 TERMS AND CONCEPTS
Chemotherapeutic agents: Drugs or substances which are used to interfere with the
functioning of any type of foreign cells. These include all antibacterial, antifungal, antiviral,
antiprotozoal, anthelmintic and antineoplastic drugs.
Antibiotics: Antibiotics are agents (chemical) which are produced by various species of
microorganisms (e.g. bacteria, fungi and actinomycetes) and are used to kill or suppress
growth of other microorganisms or foreign cells. Synthetic agents are not antibiotics, but it is
antimicrobials or antibacterials.
Antimicrobials: All chemical substances, whether natural, synthetic or semi-synthetic which
are used to kill or suppress the growth of microorganisms.
Selective toxicity
Selective toxicity is the ability of an antimicrobial agent to kill an invading microorganism
without harming the cells of its host.
A drug that disrupts a microbial function not found in eukaryotic animal cells often has a
greater selective toxicity and a higher therapeutic index.
Bacteriostatic activity: It is the ability of an antibacterial agent to inhibit the growth and
multiplication of bacteria. The inhibited growth in time results in the death of organism
and/or the removal of organism by the host's defence cells.
Bactericidal activity: It is the ability of an antibacterial agent to cause death of bacteria.

The distinction between static and cidal actions is narrow for certain drugs as some
bacteriostatic (e.g. erythromycin and nitrofurantoin) becomes bactericidal at higher
concentrations.
Some bactericidal drugs (e.g. streptomycin) are only bacteriostatic under certain
circumstances.
It is also possible for an antimicrobial agent to be static for one organism and cidal for
another. e.g. chloramphenicol is bacteriostatic against Gram negative rods and bactericidal
for pneumococci.
Antimicrobial (Antibacterial) spectrum: It is the range of pathogenic organisms (e.g.

bacteria) against which an antimicrobial agent is active.
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
They are often classified as broad spectrum or narrow spectrum.
The broad spectrum antimicrobials are active against a wide variety of orgasms (e.g. both
gram-positive and gram-negative bacteria), while narrow range antimicrobials are active
against a few class/type of organisms (e.g. gram negative or gram positive bacteria).
Extended spectrum is the term applied to antimicrobials those are effective against gram-
positive bacteria and also against a significant number of gram-negative bacteria (e.g.
ampicillin + sulbactam).
Potency
It is the antimicrobial activity per milligram (microgram) of a chemotherapeutic agent.
Potency is usually expressed on the basis of minimum inhibitory concentration (MIC),
minimum bacterial concentration (MBC) or minimum antibiotic concentration (MAC). All
these indices are determined in vitro.
Minimum inhibitory concentration (MIC): It is the lowest concentration of an

antimicrobial drug that prevents visible growth of bacteria when grown against sequentially
diminishing drug concentrations in vitro.
The MIC is the most commonly used standard by which activity of a particular antimicrobial
agent is judged, but the reported MIC for a particular bacterial species is not always constant.
The MIC of bacteria may differ with a subsequent infection by the same bacteria and also
may change during the course of infections.
MIC90: It is the MIC necessary to inhibit 90 percent of the organism tested.
Minimum bactericidal concentration (MBC): It is the lowest concentration of an

antimicrobial drug that kills the bacteria. The MBC is also determined in vitro in a fashion
similar to the MIC.
Minimum antibiotic concentration (MAC): It is the concentration of an antimicrobial drug

that reduces the growth of an organism in vitro by a factor of 10 (e.g. one log).
The MAC may be one-quarter or one-tenth of the MIC depending on the drug and the
organism.
Post-antibiotic effect (PAE): It is the persistence of the antimicrobial effect for a longer
period (few hours) after brief exposure to or in absence of detectable concentration of an
antimicrobial drug.
PAE varies with each drug and each organism. e.g. aminoglycosides are given at 12 to 24
hours intervals, although their half-lives are much shorter.
Biphasic (Eagle) effect: It is a phenomenon in which low doses of an antibacterial in vitro

against certain bacteria (e.g. staphylococci and streptococci) produce lysis whereas high
doses do not.

Chemotherapeutic index: The ratio of toxic dosage level to the therapeutic dosage level is
termed the chemotherapeutic index. The higher this number safer is the drug.
 Properties of an Ideal Antimicrobial Agent

An ideal antimicrobial agent (AMA) should possess following characteristics.
1) It should have a powerful action against microorganisms.
2) It should have selective toxicity i.e. acts specifically on invading organisms without
any toxicity to host.
3) It should not be inactivated rapidly by tissue enzymes or GIT microflora.
4) It should have good oral bioavailability and penetrate efficiently to various body
tissues and fluids.
5) It should have long elimination half-life and not rapidly excreted by kidneys bile.
6) It should not favour bacterial resistance.
7) It should not interfere with host immune mechanisms.
8) It should be non-allergenic.
9) It should not show adverse drug interactions with other antimicrobial drugs.
10) It should have no/short withdrawal time in food-producing animals.
11) It should have a long shelf-life.
12) It should be easily available and cheap.
 CLASSIFICATION OF ANTIMICROBIAL DRUGS
The antimicrobial drugs can be classified in several ways based on mechanism of

action, chemical structure, type of organism/therapeutic use, spectrum of activity, type of
action and Sources.
A. Based on mechanism of action:
1.Agents that inhibit cell wall synthesis
e.g. Penicillins, cephalosporins, monobactams, carbapenems,
cycloserine,bacitracin,vancomycin and clotrimazole.
2.Agents that inhibit cytoplasmic membrane function
e.g. Polymyxins,amphotericin-B and nystatin.
3.Agents that inhibit protein synthesis
e.g. Chloramphenicol and macrolides (50S), tetracyclines and aminoglycosides (30S).
4.Agents that affect nucleic acid metabolism and synthesis
e.g. Fluoroquinolones,rifampicin,idoxuridine and acyclovir.
5.Agents that interfere with intermediary metabolism
e.g. Sulphonamides and trimethoprim.
B. Based on chemical structure:

1.Sulphonamides: e.g. Sulphadimidine,sulphadiazine and sulphanilamide.

2.Diaminopyrimidines: e.g. Trimethoprim,ormethoprim and baquiloprim.
3.Quinolones: e.g. Nalidixic acid,enrofloxacin, moxifloxacin & ciprofloxacin.
4.Beta-lactam antibiotics: e.g. Penicillins, cephalosporins, monobactams & carbapenems.
5.Aminoglycosides: e.g. Streptomycin, gentamicin,amikacin and tobramycin.
6.Tetracyclines: e.g.oxytetracycline,tetracycline,doxycycline and minocycline.
7.Macrolide antibiotics: e.g. Erythromycin and azithromycin.
8.Polypeptide antibiotics: e.g. Polymixin-B,colistin and bacitracin.
9.Nitrofuran derivatives: e.g. Nitrofurantoin and furazolidone.
10.Nitroimidazoles: e.g. Metronidazole and tinidazole.
11.Polyene antibiotics: e.g. Nystatin and amphotericin-B.
12.Imidazole derivatives: e.g. Ketoconazole,fluconazole and clotrimazole
C. Based on type of organism affected/therapeutic uses:
1.Antibacterials: e.g. Penicillins,aminoglycosides,tetracyclines & chloramphenicol.
2.Antifungals: e.g. Amphotericin-B,griseofulvin and ketoconazole.
3.Antivirals: e.g. Idoxuridine,vidaravine,zidovudine and ribavirin.
4.Antiprotozoals: e.g. Metronidazole,quinapyramine and diminazine.
5.Anthelmintics: e.g. Albendazole,levamisole,niclosamide and praziquantel.
6.Ectoparasiticides: e.g. Deltamethrin, cypermethrin, lindane &amitraz.
D. Based on spectrum of activity:
1.Narrow spectrum antimicrobials: e.g. Penicillin-G, streptomycin,erythromycin &
vancomycin.
2.Broad-spectrum antimicrobials: e.g. Tetracycline,chloramphenicol,cephalexin,
gentamicin & ampicillin.
E. Based on type of action:
1.Bacteriostatic: e.g. Sulphonamides,chloramphenicol,erythromycin,trimethoprim&
clindamycin.
2. Bactericidal: e.g. Penicillin-G,cephalexin,streptomycin,vancomycin,bacitracin&
potentiated sulphonamides.
F. Based on Sources:
1. Natural and semi-synthetic:
a) Fungi: e.g. Penicillin-G, griseofulvin and cephalexin.
b) Actinomycetes: e.g. Streptomycin, tetracycline, erythromycin & chloramphenicol.
c) Bacteria: e.g. Polymyxin-B, colistin & bacitracin.
2. Synthetic:
e.g. Sulphonamides,trimethoprim, fluoroquinolones,nitrofurans and nitroimidazoles.

 FACTORS AFFECTING CHOICE OF AN ANTIMICROBIAL AGENT
Choice of an antimicrobial agent depends mainly on three factors:

1. Organisms related factors
2. Drug related factors
3. Host related factors
1. Organisms related factors

Target organism:
• Identification of causative organism can be made from historical data and
experience or by cultural method.
• A rapid identification by Gram-stain.
Sensitivity pattern:
• It is important to select right antimicrobial drug.
• This is useful when there is wide variation in the susceptibility of different bacterial
species to antimicrobial agent.
• Disc diffusion test/bacterial sensitivity testing is the most commonly used method to
determine susceptibility to antimicrobials.
2. Drug related factors
Spectrum of activity:
• When target organism is known then a narrow spectrum drug that selectivity
affect the concerned organism is preferred.
• If serious life-threatening infections, causative organism is not known then to cover
all likely organisms with a broad spectrum drug may be used.

• Polymicrobial/mix infection requires a broad-spectrum antimicrobial agent or
combination of two or more agents.
Type of activity required:
• A bactericidal drug may be preferred over bacteriostatic drug in the treatment of life-
threatening infections, endocarditis, infections at less accessible sites and in impaired
host defence status.
• As bacteriostatic drugs should be used only when host immunity is strong and
systems are functioning normally.
Pharmacokinetic profile:
 The PK profile determines the effective concentration of drugs at site of infection for
adequate length of time.
 E.g. Chloramphenicol and macrolides are extensively metabolized and so are not used
to treat urinary tract infections (e.g. nalidixic acid, nitrofurantoin are preferred).
 The fluoroquinolones have excellent tissue penetration and attain high concentrations
in body tissues.
 Sulphonamides and chloramphenicol are readily enter into CSF, whereas penicillins
and aminoglycosides penetrate poorly into CSF.
Route of administration:
• For critically ill patients, a parenteral route, in particular intravenous route, is
preferred.
• Intrathecal injection prefer to attain effective concentration in the CSF.
• Oral route is preferred for long-term administration, for non-hospitalised animals and
when target is GIT infection.
• Aminoglycosides, penicillin G, many cephalosporins and vancomycin have to given
by injection only.
Drug interactions:
• Antimicrobials are often used in combination with analgesics and anti-inflammatory
agents, in some cases decrease efficacy or enhance toxicity of antimicrobial agents
may observed.
• E.g. NSAIDs enhance CNS toxicity of fluoroquinolones.
• Concurrent use of procaine antagonises action of sulphonamides.
Relative toxicity:
• Penicillins are among the least toxic of all antimicrobial drugs, so should be preferred
over aminoglycosides and chloramphenicol.
• However, penicillins are contraindicated in patients those are hypersensitive to the
group.
• Drugs like chloramphenicol and clindamycin are reserved for specific or life-
threatening infections because of their potential for serious toxicity.
Antimicrobial policy:
• In general, a narrow spectrum and specific antimicrobial should be used and newer
and broad spectrum drugs should be reserved for situations where they are
specifically intended.
• E.g. Fluoroquinolones are not recommended in food-animals due to increase chance
of developing bacterial resistance in humans.
Cost of therapy:
• Several drugs may show similar efficacy in treating an infection, but vary widely in
cost.
• In such cases, a less costly and easily available drug should be preferred in
veterinary.
3. Host related factors
Host-defence mechanisms:
• Elimination of infecting organism depends on the status of host defence mechanisms.
• If good immune status, bacteriostatic drugs are preferred whereas poor immune status
then bactericidal drugs are preferred.
• Higher than usual doses of bactericidal agents and longer treatment are required to
eliminate infecting organisms in immuno-compromised patients.
Pathological conditions:
• Renal insufficiency, hepatic dysfunction and meningitis often alter response and toxic
potential of some antimicrobial agents.
• Renal disease: Predispose to toxic effects of the aminoglycosides.
• Hepatic dysfunction: e.g. tetracyclines are contraindicated in treating patients with
liver diseases.
• Meningitis: Penicillins should not be used in meningitis because they concentrate
more in CNS and increases chances of CNS seizures.
Local factors:
• Pus: Presence of pus, tissues debris and body secretions decreases efficacy
ofsulphonamides and aminoglycosides.
• Haematomas: It favour bacterial growth and impair activity of penicillins,
cephalosporins and tetracyclines.
• pH: The pH of body fluid determines the efficacy of certain drugs. E.g.
Aminoglycosides are more active in alkaline urine whereas methenamine and
nitrofurantoin are more active in acidic urine. Penicillin G is inactivated in acidic
pH.
Age:
• Renal and hepatic elimination processes are often poorly developed in newborns
therefore are more susceptible to toxic effects of chloramphenicol and
sulphonamides.
• Tetracyclines are contraindicated in young animals because they accumulate in
developing bone and teeth and discolour and weaken them.
• Fluoroquinolones are contraindicated in growing dogs because they damage joint
cartilage.
Species:
• E.g. Tetracyclines by any route may be associated with enterocolitis in horses, hence
TCs should not be used in horses.

• Broad-spectrum antimicrobial agents are usually not administered by oral route in
ruminants because they disrupt bacterial fermentation.
• Cats are more susceptible to chloramphenicol toxicity due to deficient glucuronide
conjugation (glucuronide transfersae enzyme absent).
Pregnancy:
• Antimicrobials should be avoided in pregnant animals except when essentially
required, because many drugs cross placenta.
• Aminoglycosides causes hearing loss and tetracyclines decreases bone growth in
foetus.
• Some anthelmintics are embryotoxic and teratogenic.
Genetic factors:
• Certain genetic abnormalities must be considered while choosing antimicrobial
agents.
• E.g. sulphonamides and chloramphenicol may produce acute haemolysis in patients
with glucose-6-phosphate dehydrogenase deficiency.
 COMBINATION OF ANTIMICROBIAL DRUGS
The combined use of two or more antimicrobial drugs is occasionally required to treat certain
infections.
Advantages of Combination of AMA:
 To broaden the spectrum of antibacterial activity.
 To treat mixed bacterial infections in which organisms are not susceptible to a single
antimicrobial drug.
 To achieve synergistic antimicrobial activity against some resistant strains of bacteria.
 To prevent emergence of resistant strains of bacteria.
 To minimise toxicity of an antimicrobial drug
Disadvantages of Combination of AMA:
 Two drugs may interfere with each other's action.
 It increases chances of superinfection and also bacterial resistance.
 It may also increase the cost of therapy.
Guidelines (Rules) for combination of antimicrobial drugs
1) Bactericidal drugs + bactericidal drugs = synergistic effect (1+1= >2)
e.g. penicillin G + streptomycin; sulphamethoxazole + trimethoprim
2) Bacteriostatic drugs + bacteriostatic drugs = additive effect (1+1= 2)
3) Bactericidal drug + bacteriostatic agent = antagonistic effect (1+1= <2)
e.g. tetracyclines (or chloramphenicol) + penicillins
Bactericidal Drugs Bacteriostatic Drugs

Penicillins Chloramphenicol
Cephalosporins Tetracyclines
Aminoglycosides Macrolides
RESISTANCE TO ANTIBACTERIAL DRUGS

Since the 1940s, the development of effective and safe drugs to deal with bacterial
and other infections has revolutionised treatment and the morbidity and mortality associated
with these diseases has been dramatically reduced. Unfortunately, the development of
effective antibacterial drugs has been accompanied by the emergence of drug-resistant
organisms. The phenomenon of resistance imposes serious constraints on the options
available for the treatment of many bacterial infections.
Antibiotic resistance in bacteria spreads in three ways:
 by transfer of bacteria between animals

 by transfer of resistance genes between bacteria (usually on plasmids)
 by transfer of resistance genes between genetic elements within bacteria, on
transposons.
GENETIC DETERMINANTS OF ANTIBIOTIC RESISTANCE
CHROMOSOMAL DETERMINANTS: MUTATIONS
The spontaneous mutation rate in bacterial populations for any particular gene is very low,
and the probability is that approximately only 1 cell in 10 million will, on division, give rise
to a daughter cell containing a mutation in that gene. However, as there are likely to be very
many more cells than this over the course of an infection, the probability of a mutation
causing a change from drug sensitivity to drug resistance can be quite high with some species
of bacteria and with some drugs.
Resistance resulting from chromosomal mutation is important in some instances, notably

infections with methicillin-resistant S. aureus (MRSA) and in tuberculosis, but this type of
resistance is of limited clinical relevance, possibly because the mutants often have reduced
pathogenicity
EXTRACHROMOSOMAL DETERMINANTS: PLASMIDS
In addition to the chromosome itself, many species of bacteria contain extrachromosomal

genetic elements called plasmids that exist free in the cytoplasm. These are also genetic
elements that can replicate independently. Structurally, they are closed loops of DNA that
may comprise a single gene or as many as 500 or even more. Only a few plasmid copies may
exist in the cell but often multiple copies are present, and there may also be more than one
type of plasmid in each bacterial cell. Plasmids that carry genes for resistance to antibiotics (r
genes) are referred to as R plasmids. Much of the drug resistance encountered in clinical
medicine is plasmid-determined. It is not known how these genes arose.
THE TRANSFER OF RESISTANCE GENES BETWEEN GENETIC ELEMENTS

WITHIN THE BACTERIUM
Transposons

Some stretches of DNA are readily transferred (transposed) from one plasmid to another and
also from plasmid to chromosome or vice versa. This is because integration of these segments
of DNA, which are called transposons, into the acceptor DNA can occur independently of the
normal mechanism of homologous genetic recombination. Unlike plasmids, transposons are
not able to replicate independently, although some may replicate during the process of
integration resulting in a copy in both the donor and the acceptor DNA molecules.
Transposons may carry one or more resistance genes (see below) and can 'hitch-hike' on a
plasmid to a new species of bacterium. Even if the plasmid is unable to replicate in the new
host, the transposon may integrate into the new host's chromosome or into its indigenous
plasmids. This probably accounts for the widespread distribution of certain of the resistance
genes on different R plasmids and among unrelated bacteria.
Gene cassettes and integrons
Resistance-in fact, multidrug resistance-can also be spread by another mobile element, the
gene cassette, which consists of a resistance gene attached to a small recognition site. Several
cassettes may be packaged together in a multicassette array, which can, in turn, be integrated
into a larger mobile DNA unit termed an integron. The integron (which may be located on a
transposon) contains a gene for an enzyme, integrase (recombinase), which inserts the
cassette(s) at unique sites on the integron. This system-transposon/integron/multiresistance
cassette array-allows particularly rapid and efficient transfer of multidrug resistance between
genetic elements both within and between bacteria.
THE TRANSFER OF RESISTANCE GENES BETWEEN BACTERIA
The transfer of resistance genes between bacteria of the same and indeed of different species
is of fundamental importance in the spread of antibiotic resistance. The most important
mechanism in this context is conjugation. Other gene transfer mechanisms, transduction and
transformation, are of little importance in spreading resistance genes.
Conjugation
Conjugation involves cell-to-cell contact during which chromosomal or extrachromosomal

DNA is transferred from one bacterium to another, and is the main mechanism for the spread
of resistance. The ability to conjugate is encoded in conjugative plasmids; these are plasmids
that contain transfer genes, which, in coliform bacteria, code for the production by the host
bacterium of proteinaceous surface tubules, termed sex pili, that connect the two cells. The
conjugative plasmid then passes across from one bacterial cell to another (generally of the
same species). Many Gram-negative and some Gram-positive bacteria can conjugate. The
transfer of resistance by conjugation is significant in populations of bacteria that are normally
found at high densities, as in the gut.
Transduction

Transduction is a process by which plasmid DNA is enclosed in a bacterial virus (or phage)
and transferred to another bacterium of the same species. It is a relatively ineffective means
of transfer of genetic material but is clinically important in the transmission of resistance
genes between strains of staphylococci and of streptococci.
Transformation
A few species of bacteria can, under natural conditions, undergo transformation by taking up
DNA from the environment and incorporating it into the genome by normal homologous
recombination. Transformation is not of importance clinically
BIOCHEMICAL MECHANISMS OF RESISTANCE TO ANTIBIOTICS

1) THE PRODUCTION OF AN ENZYME THAT INACTIVATES THE DRUG
Inactivation of β-lactam antibiotics : The most important example of resistance caused by
inactivation is that of the β-lactam antibiotics. The enzymes concerned are β-lactamases,
which cleave the β-lactam ring of penicillins and cephalosporins. Cross-resistance between
the two classes of antibiotic is not complete, because some β-lactamases have a preference
for penicillins and some for cephalosporins
Inactivation of chloramphenicol : Chloramphenicol is inactivated by chloramphenicol

acetyltransferase, an enzyme produced by resistant strains of both Gram-positive and Gram-
negative organisms, the resistance gene being plasmid-borne. In Gram-negative bacteria, the
enzyme is produced constitutively, resulting in levels of resistance fivefold higher than in
Gram-positive bacteria, in which the enzyme is inducible.
Inactivation of aminoglycosides : Aminoglycosides are inactivated by phosphorylation,

adenylation or acetylation, and the requisite enzymes are found in both Gram-negative and
Gram-positive organisms. The resistance genes are carried on plasmids, and several are found
on transposons.
2) ALTERATION OF DRUG-SENSITIVE OR DRUG-BINDING SITE
The aminoglycoside-binding site on the 30S subunit of the ribosome may be altered by
chromosomal mutation. A plasmid-mediated alteration of the binding site protein on the 50S
subunit also underlies resistance to erythromycin , and decreased binding of
fluoroquinolones because of a point mutation in DNA gyrase A has recently been described.
An altered DNA-dependent RNA polymerase determined by a chromosomal mutation is
reported to be the basis for rifampicin resistance.
In addition to acquiring resistance to β-lactams susceptible to β-lactamase, some strains of S.

aureus have even become resistant to some antibiotics that are not significantly inactivated
by β-lactamase (e.g. methicillin), because they express an additional β-lactam-binding protein
coded for by a mutated chromosomal gene.
3) DECREASED DRUG ACCUMULATION IN THE BACTERIUM
An important example of decreased drug accumulation is the plasmid-mediated resistance to
tetracyclines encountered in both Gram-positive and Gram-negative bacteria. In this case,
resistance genes in the plasmid code for inducible proteins in the bacterial membrane, which
promote energy-dependent efflux of the tetracyclines, and hence resistance. This type of
resistance is common and has greatly reduced the therapeutic value of the tetracyclines in
human and veterinary medicine. Resistance of S. aureus to erythromycin and the other
macrolides, and to fluoroquinolones, is also brought about by energy-dependent efflux.
Multidrug resistance
 Many pathogenic bacteria have developed resistance to the commonly used

antibiotics. Examples include:
o some strains of staphylococci and enterococci that are resistant to virtually all
current antibiotics, the resistance being transferred by transposons and/or
plasmids; such organisms can cause serious and virtually untreatable
nosocomial infections
o Some strains of Mycobacterium tuberculosis that have become resistant to
most antituberculosis agents.
SULPHONAMIDES
 Sulphonamides (Sulfonamides) are a group of synthetic antibacterial drugs (they are not
antibiotics).
 They were the first chemotherapeutic agents used systemically for prevention and
treatment of various bacterial infections.
 Sulphonamides was first discovered by Domagk in 1935, who demonstrated that
prontosil dye is effective against streptococcal infection in mice and its antibacterial
activity is due to the release of an active metabolite, the sulphanilamide.
 For this discovery, he was awarded with noble prize in 1938.
 Sulphanilamide was synthesised and introduced in market as the first sulphonamide for
antibacterial use.

 Since then, a large number of sulphonamides with variable pharmacokinetic and
antibacterial spectrum have been developed for use in human and veterinary
medicines.
Chemical Properties and Solubility
 Sulphonamides are weak organic compounds.
 Most of these compounds are relatively insoluble in water, but their sodium salts are
water-soluble.
 The sodium salts have an alkaline pH (except sulphacetamide) and sulphonamides are
about twice or more soluble in alkaline pH.
 In acidic urine, sulphonamides may form crystals because of their decreased solubility.
Structure-Activity Relationship:
 Sulphonamides possess a common chemical nucleus, which is closely related to
para-aminobenzoic acid (PABA).
 This nucleus is essential for antibacterial activity.
 Sulphonamide nucleus possesses two amine groups, which have been designated as N4
and N1.
 The para-amino group (NH2) is designated as N4; the Sulphamoyl (SO2NH2) as N1.
 Presence of para amino group is essential for antibacterial activity
 Substitution at N1 leads to systemic acting where as N4 leads to gut acting.
 Substitution at N1 by heterocyclic aromatic nuclei yield high potent compound
(sulphadimidine)- Systemic acting.
 Any substitution on benzene ring results in loss of antibacterial activity.
 Acetylation at N1 may not alter chemotherapeutic activity but such compound become
more water soluble and less toxic. e.g. sulphacetamide.
 Acetylation at N4 may decrease water solubility and increase renal toxicity
Classification
A) Based on their site of action
1. Gut-acting sulphonamides
e.g. succinylsulphathiazole, phthalylsulphathiazole, phthalylsulphacetamide,
sulphaguinidine and sulphasalazine.
2. Topically acting sulphonamides
e.g. sulphacetamide, mafenide and silver sulphadiazine.
3. Renal sulphonamide
e.g. Sulfisoxazole
4. Opthalmic sulphonamide
e.g. Sulphacetamide
B) Based on their duration of action

1) Short acting sulphonamides (duration <12 hours)
e.g. sulphadiazine, sulphafurazole, sulphamerazine, sulphachlorpyridazine,
sulphathiazole and sulphanilamide.
2) Intermediate acting sulphonamides (duration 12-24 hours)
e.g. sulphadimidine, sulphamethoxazole, sulphamoxole and sulphaphenazole
3) Long-acting sulphonamides (duration 24 - 48 hours).
e.g. sulphadimethoxine, sulphaethoxypyridazine, sulphamethoxypyridazine and
sulphabromomethazine.
4) Ultra-long acting sulphonamides (duration > 48 hours)
e.g. sulphadoxine and sulphamethopyrazine.
Mechanism of Action
 Sulphonamides are structural analogues of para-aminobenzoic acid (PABA).
 PABA is an essential component of folic acid (Vitamin B9). Mammals require
preformed folic acid in their diet whereas many bacteria utilise PABA for the synthesis
of folic acid & this folic acid is vital for bacterial multiplication and growth.
 When a sulphonamide is given then due to its structural similarity with PABA, it
blocks utilisation of PABA in susceptible bacteria and, thus, inhibits synthesis of
folic acid.
 Sulphonamide act by competitively inhibiting dihydropteroate synthetase enzyme
in folic acid biosynthesis path.
 The sulphonamides are primarily bacteriostatic and have no effect on resting bacteria
(mature).
 Sulphonamides are more effective in acute stage of infection because in acute
infections bacteria multiply at a much faster rate utilising large amounts of PABA.
 Pus and tissue debris may also contain large amount of PABA therefore,
sulphonamides are less effective in the presence of necrotic tissues, pus and tissue
extracts.
 Sulphonamides do not affect animal cells because mammalian cells utilise the
preformed folic acid.

Figure: Mechanism of Action of Sulphonamides and Trimethoprim
 Note: Sulphonamides show synergistic action with trimethoprim. Trimethoprim is a
potent and selective competitive inhibitor of dihydrofolate reductase enzyme in
susceptible microorganisms. Thus combination of sulphonamide and trimethoprim
produces sequential blocks in the synthesis of folic acid. This combination showed
bactericidal action.
Antimicrobial Spectrum
 Sulphonamides are broad-spectrum antimicrobial drugs.
 They are primarily bacteriostatic with moderate to good activity against many gram-
positive and gram-negative bacteria including Streptococcus spp., Haemophilus
influenzae, Actinomyces spp., Bacillus spp., Brucella spp., C hl amydi a spp.,
Past eurel l a spp., K l ebsi el l a spp., Enterobacteriaceae and some Clostridium
spp.
 Leptospira, Pseudomonas, Mycobacterium, Mycoplasma and Rickettsia species and
spirochetes are resistant to sulphonamides.
 Some protozoa like Coccidia and Toxoplasma are also sensitive to sulphonamides.
Bacterial Resistance
Bacterial develop resistance to sulphonamides is very fast. Acquired bacterial resistance to
sulphonamides is common.
Various mechanism includes:
a) An alteration in the enzymes those utilise PABA i.e. the dihydropteroate synthase
enzyme.
b) Adoption of alternate pathway for synthesis of folic acid.
c) An increase capacity of bacteria to destroy or inactivate sulphonamides.
d) An increased production of PABA or essential metabolites.
e) Decreased drug permeability into the bacterial cell or active efflux of drug from the
target bacteria.
To reduce bacterial resistance, sulphonamide therapy should be initiated in acute stage
of disease & it should be continued atleast for 3 days or till compete recovery. Give high
initial doses and followed by smaller maintenance doses of sulphonamide.
Pharmacokinetics
 Systemically acting sulphonamides are usually well absorbed (70-100%) following
oral administration mainly from the small intestine.
 The absorption rate is affected by the solubility of sulphonamides and presence of
ingesta in the GI tract. In general, dogs, cats and birds absorb sulphonamides rapidly,
pigs take some time, and cattle require much longer time.
 Parenteral administration of sulphonamides can be painful, as the solutions of
sulphonamides are strongly alkaline.
 After absorption, sulphonamides diffuse well into body tissues and fluids. All
sulphonamides bind to plasma proteins (albumin) to variable extent.
 The sulphonamides are primarily metabolised by acetylation process.
 The acetylated metabolites can conjugate with glucuronic acid or sulphate which do
not have any antimicrobial activity.
 Acetylation of sulphonamides reduces their solubility thus promoting crystallization
 In cattle sulphonamides are more toxic due to extensive acetylation.
 Dogs lack in the ability to acetylate sulphonamides., therefore, toxicity of
sulphonamides is comparatively less in dogs.
 The main metabolic pathway of sulphonamides in dogs is glucuronide conjugation and
the conjugate metabolites are soluble.
 Sulphonamides or their metabolites are excreted mainly by kidney through glomerular
filtration although renal tubular secretion and reabsorption also occur
 Alkalinisation of urine favours ionisation of sulphonamides and its rapid elimination.
Sulphonamides are also excreted in tears, faeces, bile and sweat.
 Gut acting sulphonamides are poorly absorbed from GIT and mainly excreted in
faeces.
Side effects/Adverse effects
The most important toxic effects of sulphonamides are on kidneys.
Acute Toxicity:
a. Renal toxicity:
 Renal toxicity occurs due to precipitation of the sulphonamide in the glomerular
filtrate leading to crystallisation, haematuria and obstruction of renal tubules, ureter
and even bladder.

 Chances of crystalluria are more in dehydrated animals as the urine may contain drug
concentrations above solubility limits resulting in crystal formation.
 Clinical use of less water soluble sulphonamides or rapidly excreting sulphonamides
(e.g. sulphathiazole) have greater tendency to get precipitated in the renal tubules.
 In general, carnivores and omnivores (acidic urine- dogs & cats) are more prone to
renal toxicity than herbivores (alkaline urine). Drug crystalised in acidic urine.
Crystalluria can be minimised or prevented by
 Appropriate doses and frequency of administration
 Supply enough drinking water .1.e"
 Do not continue therapy more than 7 days

 Use of urinary alkalizer e.g. sodium bicarbonate in dogs or cats.
 Use of combination of sulphonamide e.g. sulphonamides mixture (e.g. triple sulpha=
sulphapyridine + sulphamerazine + sulphadiazine) or sulphonamides whose acetylated
forms are more soluble (e.g. sulphadiazine or sulphadimidine).
b. Blood dyscrasias:
 Dyscrasia: Constituents of blood are abnormal or are present in abnormal quantity.
E.g. Leukemia, hemophilia
 Sulphonamides leads to haemolytic anaemia may occur either due to sensitisation or in
individuals with glucose-6-phosphate dehydrogenase deficiency.
c. Hypersensitivity reactions:
 Allergic skin rashes are frequent complication of sulpha therapy.
 Exfoliative dermatitis or cutaneous eruption may occur and are more common with
long acting sulphonamides.
 Sulphadiazine containing preparations may promote a reversible immune-mediated
sterile polyarthritis in Doberman breed. A syndrome similar to serum sickness or
immediate reactions of anaphylactoid type may also occur.
d. Other effects
 These include anorexia, vomiting, nausea and abdominal discomfort.
 Too rapid IV injection of a large dose of sulphonamide may produce ataxia,
convulsions, collapse and even death.
2. Chronic toxicity: Chronic toxicity occurs in dose-dependent manner
a) Hypoprothrombinaemia:
 Prolonged administration of certain sulphonamides may lead to vitamin K deficiency
due to inhibition of enzyme vitamin K epoxide reductase.
 This results in hypoprothrombinaemia and deficiency of other vitamin K dependent
clotting factors causing prolongation of bleeding and clotting time.
 It is mostly seen in poultry with sulphaquinoxaline (used for coccidiosis).
b) Kerato-conjunctivitis sicca (KCS) (Dry eye)

 Prolonged treatment with certain sulphonamides (e.g. sulphasalazine, sulphadiazine
and sulphamethoxazole) may cause keratoconjunctivitis sicca in dogs.
c) Inhibition of carbonic anhydrous enzyme - poultry
 Inhibition of carbonic anhydrous enzyme resulting in accumulation of carbon dioxide
leading to acidosis.
 Carbonic anhydrous is also involved in eggshell production in poultry, so its inhibition
by sulphonamides may result in thin egg shells or even absence of egg shells.
d) Hepatic necrosis - dogs
 The slow acetylation often results in increased sulphadehydroxylamine metabolite,
which is hepatotoxic.
 Since dogs are slow acetylators, they are more susceptible to hepatic injury.
 Commonly observed with the use of Sulphadiazine + Trimethoprim or
Sulphamethoxazole + Trimethoprime or potentiated sulphonamide therapy.
e) Aplastic anaemia and thrombocytopenia:
 It may occur from a direct myelotoxic effect or due to an immune-mediated
component.
 Reduction in serum folate concentration, presumably by inhibition of folate production
by intestinal bacteria may also induce anaemia.
f) Other effects:
 Several other adverse effects of sulphonamides reported in domestic animals include
reduction in weight gain, decrease in egg production, formation of methaemoglobin,
drug-induced fever, hypoglycaemia or cardiomyopathy.
 In lab animal sulphamethazine leads to thyroid cancer.
Clinical Uses
 Sulphonamides are used in the treatment of various systemic and local infections
caused by susceptible bacteria in all species of animals. Also useful in Chlamydia,
Toxoplasma & Coccidia infection.
Route of administration
Sulphonamides are administered by various routes depending on the type of salt, solubility,
action required and species.
a. Oral route: It is commonly used to administer sulphonamides in domestic animals. The

drug may be administered orally in the form of tablet, bolus, powder or mixed in feed and
water.
b. Intravenous route: IV route is generally used for treatment of acute infections. It may be
followed by oral dose for maintenance therapy.
c. Intramuscular or Subcutaneous route: Sulphonamide preparations buffered to a neutral
pH may be administered by IM or SC route. Strong alkaline solutions must not be given by
IM or SC because they may cause severe irritation and sloughing of tissues.
d. Intrauterine route: Sulphonamide combined with urea is occasionally prescribed for
uterine infections.
e. Intramammary route: Oily suspensions of some sulphonamides are occasionally used for
the treatment of mastitis.
f. Topical route: Sulphonamides are generally not considered suitable for wound treatment
because of tissues debris.
Sulphacetamide solution is used for eye infection.
Mafenide and silver sulphadiazine are used topically to treat severe burns.
POTENTIATED SULPHONAMIDES
 Potentiated sulphonamides are the combinations of sulphonamides with 2,4-
diaminopyrimidines and related agents.
The combinations commonly used are
(1) sulphamethoxazole and trimethoprim (co-trimoxazole)
(2) sulphadiazine and trimethoprim (cotrimazine)
(3) sulphadimethoxine and ormetoprim
(4) sulphadimethoxine and baquiloprim
 Other 2,4-diaminopyrimidine derivatives used for combination with sulphonamides
include aditoprim, brodimoprim, iclaprim, methoprim, tetroxoprim and pyrimethamine.
 The choice of the sulphonamide and 2,4- diaminopyrimidine for combination depends
largely on their having similar pharmacokinetic (absorption and distribution) properties.
Mechanism of action
 The combination of sulphonamide with 2,4-diamino-pyi-imidine derivative results in
synergistic effect via blockade of sequential stages in the synthesis of tetrahydrofolate.
 Selective toxicity for microorganisms is achieved in two ways and the combination
becomes bactericidal [sulphonamides and 2,4-diaminopyrimidine (trimethoprim) when
used separately are bacteriostatic].
 The combination reduces by several folds the MIC of both drugs against a wide variety
of pathogenic organisms. This reduces the dose of sulphonamide required for
therapeutic effect and also chances of dose-dependent adverse effects.
 This combination also broadens the antibacterial spectrum and reduces chances of
bacterial resistance to drugs.
 Selectively inhibits the dihydrofolate reductase enzyme of microorganisms with
no/negligible effect on the enzyme of mammals. This is vitally important because
mammals also utilise dihydrofolate reductase enzyme in folic acid metabolic pathways.
1. Trimethoprim + Sulphamethoxazole (Co-trimoxazole)

 The combination of trimethoprim with sulphamethoxazole, called co-trimoxazole. It is
widely used in therapeutics in human and veterinary practices.
 It contains 5 parts of sulphamethoxazole and 1 part of trimethoprim (ratio-5:1).
 The combination has broad spectrum activity against many gram-positive and gram-
negative organisms.
 In susceptible organisms, resistance usually develops due to acquisition of a plasmid
that codes for an altered dihydrofolate reductase.
 Absorption of co-trimoxazole is rapid with peak blood levels occurring between 1-4
hours after oral administration.
 It has a good distribution in the body as trimethoprim is more lipid soluble.
 In ruminants the combination is not given orally.
 Side effects are the same as observed with sulphonamides.

Clinical uses
 Co-trimoxazole is used in human and veterinary medicines for the treatment of a
variety of upper and lower respiratory tract infections, renal and urinary tract
infections, GIT infections, skin and wound infections, septicemia and infections caused
by sensitive bacteria.
 It is also used for treatment of coccidiosis in small animals.
 Cotrimoxazole is marketed in powder and tablets forms for oral administration and in
injectable formulation for parenteral use.
2. Trimethoprim + Sulphadiazine (Co-trimazine)
 Combination of trimethoprim + sulphadiazine (1:5).
 Its pharmacological properties, adverse effects and clinical uses are similar as Co-
trimoxazole. Co-trimazine is commercially available as injection.
 Commercially available in injection form contains 400 mg sulphadiazine and 80 mg
trimethoprim/ml of injection.
 Oral preparation like powder, tablet, oral paste, oral suspension, oral granules
and bolus are also available.
3. Ormatoprim + Sulphadimethoxine
 This is a newer combination, it has a longer duration of action than trimethoprim-
sulphamethoxzole combination.
 This is mainly used for the treatment of skin and soft tissue infection caused by
susceptible bacteria esp. in dogs.
 It is also approved for treatment and prophylaxis of coccidiosis in small animals.
4. Baquiloprim + Sulphadimethoxine
 It is used for dog and cats.
5. Baquiloprim + Sulphadimidine
 This combination is used clinically for the treatment of bacterial infections in cattle
and swine.

 The combination usually contains 5 parts sulphadimidine and 1 part baquiloprim
Examples of Potentiated Sulphonamides
I. Trimethoprim Combinations
1. Trimethoprim + Sulphamethoxazole
2. Trimethoprim + Sulphadiazine
3. Trimethoprim + Sulphadoxine
4. Trimethoprim + Sulphachlorpyridazine
5. Trimethoprim + Sulphadimethoxine
6. Trimethoprim + Sulphadimidine
7. Trimethoprim + Sulphafumzole
8. Trimethoprim + Sulphamerazine
9. Trimethoprim + Sulphamethoxypyridazine
10. Trimethoprim + Sulphatroxazole
II. Baquiloprim Contbinations

1. Baquiloprim + Sulphadimethoxine
2. Baquiloprim + Sulphadimidine
III. Ormetoprim Combinations
1. Ormetoprim + Sulphadimethoxine
IV. Pyrimetbamine Combinations
1. Pyrimethamine + Sulphadoxine
Individual Sulphonamides (self study):
 Sulphadiazine: widely used with trimethoprim, Treat Toxoplasmosis, form crystalluria
 Sulphisoxazole: Treat UTI in dogs & cats
 Sulphathiazole: used P.O. & Inj.
 Sulphadimidine: Widely used in ruminants & swine. Bolus, IV & SC. Metabolites are
soluble- less chance of crystalluria.
 Sulphadimethoxime: Systemic infection in animal, coccidiosis in poultry.
 Sulphachlorpyridazine: Treat diarrhea in cattle, swine (caused by E.coli)
 Succcinyl Sulphathiazole, Phthalyl Sulphathiazole:Gut-acting drug- treat gut infection,
Inactive, prodrug for sulphathiazole.
 Sulphaguinidine: Gut-acting drug- treat gut infection
 Sulphasalazine: metabolized to sulphapyridine
 Sulphacetamide: used to treat eye infection.
 Mafenide: Used for burn dressing.
 Silver sulphadiazine: used topically to treat severe burns & ulcer.
 Sulphadoxine: Single dose effect remain for a week, Used to treat malaria &
toxoplasmosis in human.

SULFONE:
Antibacterial agent chemically related to sulphonamide. e.g. Dapsone. Effective against
Mycobacterium leprae. Sulfone (Dapsone) is drug of choice for treatment of Leprosy in man.
PENICILLINS (BETA-LACTAM ANTIBIOTICS )
 Beta-lactam antibiotics constitute one of the most important and frequently used
groups of antimicrobial agents.
 According to their core molecular structure they have been mainly categorized into
four subgroups are there
1. Penicillins
2. Cephalsporins
3. Carbapenems
4. Monobactams
PENICILLINS
 The penicillins are a large group of naturally occurring and semi-synthetic
antibiotics.
 They have a common nucleus, the 6-aminopenicillanic acid (6-APA) and belong to
the sub-group of penam beta-lactam antibiotics.
History
 Sir Alexander Fleming discovered Penicillins from penicillium notatum in 1928.
 Subsequently, Australian pathologist Howard Florey and British biochemist Ernst
Boris Chain isolated and purified penicillin in the late 1930s, and by 1941 an
injectable form of the drug was prepared for therapeutic use.
 Since then, numerous (>50) penicillins have been discovered and many are being
used in clinical practice.

Figure: Basic structure of penicillin and their hydrolysis
Chemistry
 All penicillins contain the basic structure of a 5 member thiazolidine ring (A)
connected to a beta-lactam ring (B) having a secondary amine group (-NH-) to form
6-aminopenicillanic acid (6-APA), so called the basic nucleus of penicillins.
 The beta-lactam ring is a four membered ring in which an amide linkage joins a
carbonyl group and a nitrogen.
 A side chain (R) is attached to the beta-lactam ring, which mainly determines type of
penicillin.-COOH attached to thiazolidine ring is the site for salt formation.
Properties of Penicillin
• The beta-lactam ring is the key structural feature of all beta-lactam antibiotics.
Cleavage of beta-lactam ring destroys antibiotic activity; some resistant bacteria
produce betalactamases (penicillinases) which cleaves ß-lactam ring.
• The 6-aminopenicillanic acid (6-APA) found in all penicillins is responsible for
antibacterial activity and determines the type of penicillin group. Chemical alteration
of 6-APA nucleus leads to loss of antibacterial activity.
• The side chain attached to ß-lactam ring determines mainly the individual penicillin
characteristics.
• The carboxyl group attached to thiazolidine ring is the site of salt formation (e.g.
sodium, potassium and procaine).

• 6-APA is commonly used in producing semi-synthetic penicillins.
Solubility
• They are poorly soluble, weak organic acids those are sensitive to heat, light,
extremes in pH, heavy metals, strong alcohols, and oxidising and reducing agents.
• A pH of 6-6.5 is optimal for stability of penicillins in aqueous solution with a
practical range of 5.5-7.5.
• Prolonged exposure of penicillin to water promotes hydrolysis, therefore some
penicillins are available in powder form which are reconstitution.
• Some penicillins are rapidly hydrolysed and inactivated by gastric acid & beta-
lactamase.
• The sodium and potassium salts of natural penicilllins eanhance water solubility
& therefore it is given parenterally.
• The trihydrate forms of the semi-synthetic penicillins have high water solubility and
are usually administered by both parenteral and oral routes.
Classification of Penicillins
Based on their chemical nature
(A) Natural Penicillins
Penicillin-G (Benzyl penicillin)
Penicillin-V (Phenoxymethyl penicillin)
Phenathicillin (Phenoxy ethyl penicillin)
(B) Broad spectrum penicillins: also known as Aminopenicillin

Ampicillin
Amoxycillin
Metapicillin
Bacampicillin / Pivampicillin / Hetacillin
(C) Penicillinase-resistant penicillin or β -lactamase resistant penicillins or Anti
Staphylococcal penicillins
Cloxacillin
Oxacillin
Flucloxacillin
Methicillin,
Dicloxcillin
Nafcillin
(D) Extended spectrum penicillins
Carboxy penicillins - Carbenicillin, Ticarcillin
Ureido-penicillins - Mezlocillin, Azlocillin
Piperazine penicillins - Piperacillin
(E) Potentiated penicillins/Beta-lactamase protected penicillins
Amoxicillin-clavulanic acid
Ticarcillin- clavulanic acid

Ampicillin-sulbactam,
Ampicillin-flucloxacillin piperacillin-tazobactam.
Unitage of Penicillin
 1 I.U. of Penicillin G is the specific penicillin activity contained in 0.6µg crystalline
sodium penicillin-G
1mg of sodium Pen-G= 1667 I.U
 Potency of Pen-G is expressed in terms of units
 All other semi-synthetic penicillins their potency and doses are expressed in mg
Pharmacodynamic of penicllin/MOA
 Penicillins and other beta-lactam antibiotics are bactericidal agents and interfere
primarily with the synthesis of the peptidoglycan layer of bacterial cell walls (inhibit
bacterial cell wall synthesis).
 The antibacterial effects of penicillin are due to binding to a family of proteins called
penicillin-binding proteins (PBPs).
 There are about 7 types of PBP have been identified: PBPs- 1A, 1B, 2, 3, 4, 5 and 6.
 Inhibition of one or more of these PBPs by β-lactam antibiotics produces antibacterial
effects.
 PBP 1B performs the role of transpeptidase enzyme responsible for formation of
cross-links between peptidoglycan strands in the cell wall.
 Due to inhibition of transpeptidase enzyme leads to formation of defective bacterial
cell wall.
 Inhibition of PBP 1A and 1B resulting in lysis of the bacterium.
 Beta-lactam antibiotics are most active against rapidly growing and replicating
bacterial cells.
 The efficacy of beta-lactam antibiotics is time-dependent. Therefore, the plasma tissue
concentrations must be maintained above the MIC for long period of time to achieve
maximal efficacy.
 In general, gram-positive bacteria are more ssusceptible to penicillins because cell
wall is located close to the cell surface and is readily cross by penicillins.
 In contrast, gram-negative bacteria contain a capsule and outer lipopolysaccharide
membrane surrounding the cell wall that prevents many penicillins to reach cell wall
and target PBPs.
 Narrow spectrum penicillins (e.g. penicillin G) are active against only gram-positive
organisms.
 Broad-spectrum penicillins are active against a large number of gram-positive
(mainly) and gram-negative organisms.
 Penicillins and other beta-lactam antibiotics are inactive against organisms which do
not possess cell wall such as mycobacterium, fungi, protozoa and viruses.
Acquired resistance to penicillins is a serious problem and occurs mainly through transfer of
plasmids (also chromosomes).

a. Beta-lactamase activity:
 Inactivation of ß-lactam antibiotics by ß-lactamase (penicillinase) enzymes by
bacteria is the most important and clinically significant mechanism of acquiring
resistance.
 Several types (at least 6) of ß-lactamase are produced by bacteria, some are active
exclusively against penicillins (called penicillinases), some are active against
cephalosporins (called cephalosporinases), and others are active equally against
both penicillins and cephalosporins (called broad-spectrum ß-lactamases).
 G+ve bacteria generally produce large amount of ß-lactamases whereas G-ve bacteria
produce ß-lactamases in small quantities.
b. Decreased permeability to drug:
 Decreased penetration of through outer membrane prevents the drugs from reaching
the target penicillin binding proteins.
 Some gram-negative bacteria become resistant to penicillins by loss or alteration of
aqueous channels (porins) in the outer membrane.
 Active efflux of antibiotics through cell membranes also serves as another mechanism
of acquiring resistance.
c. Altered penicillin-binding proteins:
 Some microorganisms acquire resistance because of modified PBPs. As this
proteins have lower affinity for β-lactam antibiotics.
 This mechanism may explain meticillin-resistant staphylococci, which have
acquired PBP possessing low affinity for ß-lactam
Pharmacokinetics
Absorption:
 The penicillins are weak acids, which favour oral absorption. However, many types of
penicillin are destroyed by the gastric acid and hence cannot be given orally.
 Most penicillins in aqueous solution are rapidly absorbed from IM or SC site with
peak plasma concentration occurring in 15-30 minutes.
 Absorption is slow and prolonged when depot preparations (e.g. procaine penicillin G
and benzathine penicillin G) are used.
 The prolonged absorption from depot penicillins results in longer persistence of
plasma and tissue drug concentration, but the peak concentrations may not be
sufficiently high to produce antibacterial effect unless the MICs are low.
 Oral absorption of some penicillins (e.g. penicillin G and penicillinases resistance
penicillins) is decreased by food.
 Sodium and potassium penicillin remain effective for 18 hrs
 Procain penicillin maintained for several days following single injection
 Benzathine penicillin G absorbed very slowly & a single injection remains effective for 7 or
more days. This preparation is also called as Repository form of penicillin
Distribution:
 After absorption, penicillins are widely distributed throughout the body.

 Therapeutic concentration of penicillins is readily achieved in body tissues and fluids,
but they do not penetrate into some sites such as brain, bone, cartilage, cornea, CSF
and bronchial secretions, unless these sites are inflamed.
 During inflammation such as meningitis, pleuritis and peritonitis, the drug
penetrability barrier is generally impaired and penicillins easily enter the inflamed
site.
 Penicillins do not penetrate living phagocytic cells to a significant extent.
 Penicillins are bound to plasma proteins to variable extent (20-80%).
Metabolism:
 Penicillins do not undergo significant biotransformation and are generally excreted
unchanged.
 Some Penicillins like Pen-G, Pen-V, Nafcillin, Ticarcillin & Aminopenicillin get
metabolised to some extent & metabolites are inactive.
 Hetacillin or Bacampicillin (pro drug) metabolized to Ampicillin (Active metabolite)
Excretion:
 Penicillins are excreted rapidly in urine mainly by glomerular filtration (20%) and
renal tubular filtration (80%).
 Some excretion of penicillins also occurs in milk.
 Renal tubular secretion can be deliberately inhibited by probenecid and other weak
organic acids to prolong the effective levels of penicillins in body.
 Elimination half-lives of most penicillins vary between 30-120 minutes.
 E.g. Penicillin-G-30 min in dog
Carbenicillin-120 min in cattle
Side Effects/Adverse Effects

Penicillins are among the safest antimicrobial drugs. Organ toxicity with penicillins is rare.
(1) Hypersensitivity:
 Most important and serious adverse effect of penicillins.
 The major antigenic determinant of penicillin hypersensitivity reaction is its
metabolite penicilloic acid, which reacts with proteins and serves as a haptan to cause
an immune reaction ranging from maculopapular rash to angioneurotic oedema;
anaphylaxis is rare, but could be fatal.
 Important manifestations of allergic reactions in animals, particularly cattle, may
include rash, urticaria, drug fever, angioedema, serum sickness, vasculitis and rarely
anaphylaxis.
(2) GIT disturbances:
 The use of broad-spectrum penicillins may cause Gl disturbances, particularly diarrhoea and
superinfection due to disruption of normal balance of Gl microflora
(3) Platelet dysfunction:
 Some penicillins (e.g. antipseudomonal penicillins) may cause thrombocytopenia and
decreased agglutination.
 It is generally a concern when treating patients predisposed to haemorhage or those
receiving anticoagulant therapy.
4) Organ toxicity:
 Irritate neuronal tissue and cause seizures when administered in high doses or when
injected intra-thecally
 High dose or prolonged use may cause neurotoxicity and ataxia in dogs
 As penicillins are accumulated in renal tissues at high concentrations, they have a potential to
cause acute interstitial nephritis.
5) Cation toxicity:
 Observed with Na and K salts of penicillins
 Sodium excess may aggravate the congestive heart failure
 Rapid IV administration of K penicillin may cause hyperkelemia
Contraindications and Precautions
 Patients those are hypersensitive to penicillin
 High doses of sodium or potassium penicillins with a pre-existing electrolyte abnormality,
renal disease or CHF should be avoided as they may precipitate the existing condition.
Clinical Uses
 Penicillins are widely used in both human and veterinary medicines for a wide range
of systemic infections caused by susceptible bacteria.
 They are also used topically in eye, ear and on skin to treat or prevent local infections.
 Intramammary administration of penicillins is widely used to prevent or treat bovine
mastitis.
INDIVIDUAL PENICILLINS:
Penicillin-G:
 Also known as benzyl penicillin.
 Obtain from penicillium chrysogenum.
 It was the first penicillin for clinically used and still it is useful.
 Na+, K+, procaine & benzathine penicillin G commercially available.
 Penicillin G not administered orally because it is inactivated by gastric acid.
 Potency of penicillin G expressed in I.U./ Units
 1 I.U.=0.625µg Pen. G
 1mg = 1667 I.U.
 Streptomycin + Penicillin G= choice for many bacterial infecions.
Penicillin –V:
 It is also called phenoxymethyl penicillin
 It is Orally effective because adding of phenoxymethyl group impart more acid
stability.
 Potency expressed in mg.
Pheneticillin
 It is a first clinically useful true semi-synthetic penicillin.
 Now a days it is not useful.
Cloxacillin:
 It is semi-synthetic penicillin.
 It is useful in case of skin, bone, soft tissue infection, bovine mastitis.
 Ophthalmic preparation is also available.
Oxacillin
 Same as cloxacillin
 Intra mammary & ophthalmic preparation is used.
Dicloxacillin & Flucloxacillin: Same as above
 Used orally in severe penicillinase resistant staphyloccal infection in dog & cats.
Methicillin:
 Used incase of st. aureus infectins.
 It is inactive orally as it is destroyed by the gastric acid.
 Now, it is rarely used due to its limitations because of MRSA production
Nafcillin: Mastitis by st. aureus
Ampicillin
 Widely used in all domestic animals
 Mostly in gram negative aerobs.
Amoxycillin: Similar as ampicillin.
Hetacillin & bacampicillin: metabolised to ampicillin in body.
Carbenicillin:
 Rapidly excreted within 1 hrs through urine.
 Treatment of serious psudomonas & proteus infection in dogs.
Ticarcillin
 Treatment of psudomonas aerginos infection.
 2-4 times potent than carbencillin.
Mezlocillin & Azlocillin
 Both are used in case of psudomonas aerginos and klebsiella infection
Pipracillin
 Usually combined with aminoglycoside
Amoxycillin + clavulanic acid (Co-amoxiclav):
 Ratio is 4:1
 It is not destroyed by gastric acid.
 Treatment of skin , soft tissue, urinary, biliary , Resp. tract infection, canine dental
disease, mastitis in cow.
Ampicillin+Sulbactam:
 Sulbactam is a semi-synthetic β-lactamase inhibitor
 Combined with ampicillin & given parentrally
 Used in mixed aerobic-anaerobic infection including intra-abdominal, surgical and
skin and soft tissue infections
CEPHALOSPORINS , CARBEPENEMS and MONOBACTAMS

 Cephalosporins are a class of frequently used ß-lactam antibiotics which are
structurally and pharmacologically related to the penicillins.
 Cephalosporins are derived semi-synthetically from 'cephalosporin-C' obtained from a
fungus Cephalosporium acremonium.
 Like the penicillins, they possess a beta-lactam ring structure and interfere with
synthesis of the bacterial cell wall.
Chemistry
All cephalosporins contain the basic structure of a dihydrothiazine ring fused to a beta-
lactam ring having a secondary amine to form 7-aminocephalosporanic acid, the
cephalosporin nucleus.
 By addition of different side chains to position 7 of the ß-lactam ring (R1) and
position 3 of dihydrothiazine ring (R2) a large number of semisynthetic antibiotics
have been produced.
 The modifications at position 7 are generally associated with alterations in the
spectrum of antibacterial activity
 Substitutions at position 3 of the cephalosporin nucleus are associated with changes in
the pharmacokinetic properties.
 The physical and chemical properties are generally similar to those of penicillins,
although cephalospoüns are more water soluble and acid stable.
 Cephalosporins are used either as the free base form for oral administration or as
sodium salt in aqueous solution for parenteral administration. Some antibiotics such
as aminoglycosides inactivate cephalosporins when mixed in vitro.
Classification of Cephalosporins
Based on chronology & antibacterial spectrum
I. First-generation cephalosporins
 High activity against gram-positive bacteria but weaker activity against gram-
negative bacteria.
 e.g. cefadroxil, cefazolin, cefalexin, cefalothin, cefapirin, cefaloridine
II. Second generation cephalosporins
 Greater activity against gram-negative organisms, but somewhat less activity
against gram-positive bacteria.
 e.g cefaclor, cefuroxime, cefamandole, cefonicid, ceforanide, cefotiam and
cefprozil.
III. Third-generation cephalosporins

 Most active against gram-negative bacteria, especially enteric bacteria, but are less
active against gram-positive cocci & active against strains of Pseudomonas
aeruginosa.
 e.g. cefotaxime, ceftiofur, ceftriaxone, ceftazidime, cefoperazone, cefovecin,
cefixime, cefpodoxime and ceftizoxime.
IV. Fourth-generation cephalosporin
 Broad-spectrum of activity, which include gram-positive cocci, gram-negative
bacilli and Pseudomonas aeruginosa.
 Highly resistant to β-lactamases hence they are useful against many bacteria
resistant to earlier drugs.
 e.g. cefepime, cefpirome (for human uses) and cefquinome (for vet./animal use only).
V. Fifth-generation cephalosporins
 Recently introduced, active against MRSA.
 Have powerful antipseudomonal characteristics and are less susceptible to
development of resistance.
 e.g. ceftobiprole and ceftaroline.
 Mechanisms of bacterial resistance to cepholosporins are essentially the same the
penicillins.
 These include:
a. Beta lactamases (cephalosporinases) enzyme which destroy cephalosporins.
b. Alterations in target proteins which reduce affinity for cephalosporins.
c. Decreased permeability to cephalosporins so that drugs do not reach their site of
action in sufficient quantity.
Mechanism of Action
 All cephalosporins are bactericidal.
 They inhibit bacterial cell wall synthesis in a manner similar to that of penicillins.
 However, they bind to different proteins (PBP) than those required by penicillins
and are less susceptible to penicillinases.
 More effective against actively growing bacteria.
Pharmacokinetics
Absorption
 Only a few cephalosporins are acid stable and are given orally.
 Most of them given parenterally either intramuscularly or intravenously.
 The orally administered cephalosporins are well absorbed with bioavailability values
of 75-90%.
 Absorption from IM injection site is achieved within 30 minutes of dosing.
Distribution
 Widely distributed in body tissues and fluids including lungs, kidneys, bone, placenta,
and soft-tissues and pleural, pericardial and joint fluids.
 Some third generation agents (e.g. cefoperazone) also cross the blood-brain barrier in
significant amount and are drugs of choice for meningitis due to gram-negative
bacteria.
 Most cephalosporins have poor penetration into prostatic tissue and aqueous and
vitreous humours.
 The plasma protein binding of cephalosporins is highly variable (20-80%) and species
specific. Cephalosporins enter milk in low concentrations.
Biotransformation
 Most of them do not undergo significant biotransformation and are excreted
unchanged.
 Some agents (e.g. cefalotin, cefotaxime) are actively deacetylated in the liver and
some other tissues and are excreted as inactive or mildly active metabolites.
Excretion
 Cephalosporins and their metabolites (if any) are excreted mainly by the kidneys in
urine via tubular secretion (mainly) and glomerular filtration.
 Plasma half-lives are usually 30-120 minutes, but some third-generation
cephalosporins tend to have longer plasma half lives.
 Blood levels are usually maintained for only 6 to 8 hours.
 Like penicillins, probenecid increases half lives of cephalosporins.
 Cephalosporins has low frequency of allergic reactions/ hypersensitivity
 About 10% of the penicillin sensitive individuals show some cross-reactivity to
cephalosporins. Other adverse reactions include Gl disturbances (nausea, vomiting
and diarrhoea), superinfection, pain at IM injection site and lethargy.
 Hypersensitive patients to them or penicillins.
 Prolonged administration of cephalosporins should be avoided in animals, particularly
cats, as they may lead to anaemia or superinfection.
 Dosage adjustment may be required in patients with renal insufficiency
Clinical Uses
 The high cost of cephalosporins has limited their frequent use in veterinary medicine
in particular in large animal medicine.
 The first-generation cephalosporins, in particular, have proved useful in veterinary
medicine for many infections including skin, soft tissues, and urinary and respiratory
tract infections.
 1st generation cephalosporins (cephalexin) are use for treatment of stapylococcus
infection and for surgical prophylaxis
 Ceftiofur sodium is used for bovine respiratory disease and urinary infection in dogs
 Cephapirin benzathine salts:- used for prevention of mastitis in dry cow.
 Cephapirin sodium salts:- used for treatment of clinical mastitis in cattle.
INDIVIDUAL CEPHALOSPORINS
1. Cefalothin- G+ve aerobes, injectable, widely used
2. Cefazolin- Inj. Preferred, long half life
3. Cefalexin- G+ve cocci, P.O.
4. Cefadroxil-One of the most commonly used, P.O.
5. Cefapirin-requires less frequency of dosing, used in mastitis (dry & lactating cow)
6. Cefaclor-P.O., not used in vety
7. Cefamandole- Inj. cause hypoprothrombinaemia
8. Cefotaxime- Meningitis by G-ve in small animals
9. Ceftiofur-
10. Ceftriaxone-Lyme‘s disease
11. Ceftazidime- Pseudomonas, G-ve bacteria
12. Cefoperazone- Pseudomonas, G-ve bacteria
13. Cefepime-
14. Cefquinome-Vet use only, Bovine mastitis pneumonia
15. Cefaloridine-most nephrotoxic
16. Cefalonium-I/mammary in dry cow, persistence in udder
17. Cefuroxime- Inj. Meningitis by G-ve bacteria in human
18. Ceftobiprole-5th generation recently introduced, available for human medicine
19. Ceftaroline-5th generation recently introduced, Pseudomonas & MRSA
Figure: Basic structure of four important beta-lactam antibiotics
CARBAPENEMS
 It is a new class of beta-lactam antibiotics.
 They contain a fused ß-lactam ring and a 5 membered ring which differs from
penicillins in being unsaturated and having a carbon on the five membered ring instead
of a sulphur
 They have very broad-spectrum of activity and are resistant to most ß-lactamases.
 They are derived from Streptomyces species.
Mechanism of Action
 They are bactericidal ß-lactam antibiotics.
 Similar to penicillins and cephalosporins.
 They disrupt peptidoglycan synthesis in cell wall formation by binding to penicillin
binding PBP-1 & PBP-2 results in cell lysis & death
Antibacterial Spectrum
 They have a broader specttum of activity than do most other β-lactam antibiotics
 Antibacterial Spectrum includes
Many aerobic and anaerobic gram-positive bacteria
Enterobacteriaceae
Pseudomonas aeruginosa and
Listeria spp.
 High antibacterial activity of carbapenems is attributed mainly due to their stability
against most of the beta lactamases and to their unique chemical structure. which
allows penetration through porin channels usually exclude other drugs.
Imipenem
 Imipenem is commonly used in combination with cilastatin, (an inhibitor of renal
tubular dipeptidase enzyme).
 It is derived from Streptomyces cattleya.
 The imipenem- cilastatin sodium is marketed in two formulations -a preparation for
IV infusion and a suspension for IM injection (do not used interchangeably).
Antibacterial spectrum
 Its range of activity includes almost all bacteria which may be resistant to other
drugs like Pseudomonas aeruginosa, Enterobacteriaceae, streptococci (including
penicillinase producing strains), staphylococci (including penicillinase producing
strains), most enterococci and Listeria Spp.
 Imipenem is not active against meticillin resistant staphylococci
Pharmacokinetics
 Imipenem is not absorbed orally, so it must be given parenterally.
 After IM injection, bioavailability is >95% and widely distributed throughout the
body with exception of CSF.
 Imipenem when given alone is hydrolysed rapidly by the dipeptidase enzyme found
in brush border of the proximal renal tubule resulting in low urinary drug levels,
which are inadequate for an antibacterial action& therefore cilastatin is given along
with it.
 Cilastatin induced decreased renal metabolism of imipenem also protects the
kidneys from proximal tubular necrosis that occurs when imipenem is used alone.
 When used with cilastatin. imipenem is eliminated by both renal (75%) and non-
renal (25%) mechanisms.
 Half life-1 to 3 hrs.
Side effect/Adverse effects
 GI disturbances (vomiting, diarrhoea, anorexia)
 CNS toxicity (tremors, seizures)
Clinical uses
 The combination is very useful in genito-urinary and lower respiratory tract
infections.
 In veterinary medicine, it may be used in small animal or equine medicine for
serious infections. Very costly combinations.
Meropenem
 Meropenem is another carbapenern antibiotic with an extremely broad spectrum of
activity.
 It does not require coadministration with cilastatin as it is not hydrolysed by renal
dipeptidase enzyme.
 It is more soluble than imipenem hence it requires less fluid for dilution and can be
administered IV in less volume.
 Used IV or SC in dogs & cats. SC injection causes slight hair loss at site of
injection.
 Among all the available antibiotic it is most expensive drug available today
MONOBACTAMS
 Monobactams are simple monocyclic ß-lactam compounds.e.g. Aztreonam
 It has also mild affinity for negative aerobic bacteria with no action against gram-
positive organisms or anaerobes.
 Their antibacterial spectrum, therefore, resemble more closely to that of
aminoglycosides than that to pemcillins.
 They are resistant to most ß-lactamases.
 Currently, only one drug aztreonam is available for clinical use.
Aztreonam
 Aztreonam is a monocyclic ß-lactam antibiotic isolated from Chromobacterium
violaceum.
 It interacts with penicillin-binding protein 3 (PBP-3) of susceptible organisms and
induces formation of long-filamentous bacterial structures and inhibition of cell
wall synthesis.
 It is poorly absorbed when given via the oral route, so it must be administered as
an intravenous or intramuscular injection. It has plasma half-life of about 2
hours in man
 It does not cross-react immunologically with penicillins or cephalosporins.
Therefore it may be used in penicillin-sensitives individuals.

BETA-LACTAMASE INHIBITORS
 Beta-lactamase inhibitors are agents which bind to and inactivate ß-lactamase enzyme
produced by many gram-positive and gram-negative bacteria.
 Usually administered with penicillins or cephalosporins.
 This includes (1) Clavulanic acid
(2) Sutbactam
(3) Tazobactam
Clavulanic acid
 ß-lactam ring containing compound obtained from Streptomyces clavuligens.
 It has no antibacterial activity of its own but it enhances antibacterial activity of some
penicillins by inhibiting a wide variety of ß-lactamases produced by bacteria.
 Combinations of clavulanic acid with amoxicillin and ticarcillin are available for clinical use.
Mechanism of action
 It contains a ß-lactam ring in its structure & because of structural similarities with penicillins,
it binds to and inactivates ß-lactamase enzyme produced by certain bacteria.
 Clavulanic acid is called a progressive inhibitor because its binding with ß-lactamase
enzyme is reversible initially but becomes irreversible after some time.
 It is also called a ―suicide inhibitor” because clavulanic acid itself gets degraded after
binding to the enzyme.
Pharmacokinetics
 Clavulanic acid is well absorbed from Gl tract after oral administration and from parenteral
injection sites.
 Clavulanic acid is eliminated primarily after metabolism in the urine via glomerular filtration.
Its elimination half-life in human beings is about 1 hour.
Clinical uses
 Amoxicillin + Clavulanic acid (Co-amoxiclav) is available for oral use (4:1 ratio).
 Clavulanic acid + Ticarcillin is available for parenteral use.
Sulbactam
 Sulbactam is a semi-synthetic ß-lactamase inhibitor.
 It resembles clavulanic acid structurally as well as pharmacologically.
 However, it is 2 to 3 times less potent than clavulanic acid.
 It is preferably given parenterally.
 E.g. Ampicillin+Sulbactam, Cefoperazone+Sulbactam, Cefotaxime+Sulbactam.
Tazobactam
 It is ß-tactamase Inhibitor similar in activity to clavulanic acid and sulbactarm.
 It has been combined with piperacillin and is available for parenteral use.
 The combination has the broadest antibiotic spectrum of the penicillins.
 E.g. Piperacillin+Tazobactam, Ceftriaxon+Tazobactam.

AMINOGLYCOSIDES
History
 Streptomycin was the first member of aminoglycoside antibiotics discovered in
1944 by Waksman from Streptomyces griseus.
 Neomycin in 1949 followed by kanamycin in 1957 and gentamicin in 1963.
 Amikacin was the first semi-synthetic compound.
 Presently, aminoglycosides have many members used extensively in veterinary
medicine.
Source
 Most aminoglycosides are obtained from Streptomyces spp. (soil
actinomycetes).
 Few aminoglycosides are obtained from Micromonospora spp. (e.g. gentamicin,
netilmicin and sisomicin).
 Few are semi-synthetic: Amikacin, arbekacin
 Aminoglycosides derived from Streptomyces carry the suffix -mycin, where
those obtained from Micromonospora have names ending with -micin.
Aminoglycosides produced from Streptomyces spp :
• Streptomycin - Streptomyces griseus,
• Neomycin - Streptomyces fradiae,
• Kanamycin - Streptomyces kanamyceticus,
• Tobramycin - Streptomyces tenebrarius,
• Paromomycin - Streptomyces paromomycinus
Aminoglycosides produced from Micromonospora spp.
 Gentamicin - Micromonospora purpurea,
 Sisomicin - Micromonospora inyoensis,
 Netilmicin - semisynthetic derivate of Sisomicin
Chemistry
 Aminoglycosides (Aminocylitols) are a group of natural and semi-synthetic
antibiotics having aminosugars linked to an aminocyclitol ring by glycosidic
bond.
 They are mostly bactericidal drugs.
 The presence of amino group in the structure imparts basic nature to
aminoglycosides and the hydroxyl group on sugars provide high water solubility
(or poor lipid solubility) to the drugs.
 If these hydroxyl groups are removed (e.g. tobramycin), the drug becomes more
active.
 Minor differences in the chemical structure of these drugs may lead to
differences in efficacy and toxicity.
Properties
Some common properties of the aminoglycoside group are:
 Water soluble and polar compounds which generally ionise in solution.
 Not absorbed orally, distribute only extra-cellularly and excrete mainly
unchanged in urine.

 Bactericidal in action and are more active against gram-negative bacilli
 Poorly penetrate into mammalian cells and limited action in infections caused
by intracellular bacteria.
 Interfering with protein synthesis in susceptible bacteria
 Mainly used as sulphate salts, which are highly water soluble
 Aqueous solutions of aminoglycosides are stable for months.
 More active in alkaline pH.
 Have a tendency to cause ototoxicity and nephrotoxicity.
 Narrow margin of safety
 Bacterial resistance to many aminoglycosides develop rapidly.
 Synergistic antibacterial effect with beta-lactam antibiotics.
Classification
Classify on the basis of Antibacterial spectrum :-
1. Narrow spectrum aminoglycoside
Streptomycin
Dihydrostreptomycin
2. Broad spectrum aminoglycoside
Neomycin and framycetin
Kanamycin
Paromomycin
Arbekacin
3. Extended spectrum aminoglycoside
Gentamicin
Tobaramycin
Amikacin
Sisomicin
Netilmicin
Mechanism of Action
 Aminoglycosides acts by inhibiting protein synthesis in susceptible bacteria
by binding with 30 S ribosomal subunit.
 They are bactericidal in nature and its effect is concentration dependent.
Two major steps required to produce their action
1. Entry of aminoglycoside into bacterial cell
2. Binding of aminoglycoside to bacterial ribosome
1. Entry of aminoglycoside into bacterial cell:
 Aminoglycoside reach to the periplasm of G -ve bacteria via aqueous channel
by concentration dependent manner.
 Now aminoglycosides are carried from periplasmic space to the bacterial
cytoplasm with help of O2 dependent process (hence AG are ineffective against
anaerobic bacteria)
2. Binding of aminoglycoside to bacterial ribosome
 Aminoglycoside interact with bacterial ribosome (mostly 30S ribosomal
subunit) and inhibit protein syntesis.

 By binding aminoglycoside affect number of steps in protein synthesis;
Interference with protein synthesis. Distortion of m-RNA (misreading of the
codon), Incompletely synthesized proteins or inhibit ribosomal translocation.
This leads to synthesis of abnormal structural and functional proteins in
bacteria.
The important antimicrobial feature of aminoglycosides includes:
 Concentration dependent bactericidal action, therefore single large dose is more
effective instead to divided dose.
 More effective against rapidly multiplying bacteria.
 Aminoglycosides show a long post-antibiotic effect (PAE).
 Aminoglycosides show synergistic effect with beta-lactam antibiotics (because cell
wall injury increases entry of aminoglycosides). e.g. Streptomycin + Penicillin G
 Narrow-spectrum AGs are mainly active against G-ve bacteria.
 Broad spectrum AGs are active against many G-ve and G+ve bacteria, but not
Pseudomonas.
 Extended-spectrum AGs are active against Pseudomonas aeruginosa and a variety of
aerobic bacteria.
 They are mostly ineffective against fungi and viruses.
 The susceptible microorganisms may develop resistance by several mechanisms. The
resistance may be plasmid mediated or acquired by mutation.
1. Production of inactivating enzymes: The susceptible microorganisms produces
transferase enzymes and inactivate most AGs except amikacin.
2. Impaired transport: Impaired transport of aminoglycosides across the cell
wall/membrane may occur due to changes in the pore size that becomes less permeable
to AGs. Anaerobes are inherently resistant to aminoglycosides.
3. Alteration in ribosomal structure: Alterations in the ribosomal structure leads to
decreasing the binding of aminoglycosides with their target sites. e.g. Some strains of E.
coli develop resistance to streptomycin by this mechanism.
Pharmacokinetics
 For most of the aminoglycoside the theraputic range is very narrow so chances of
toxicity are more than others antimicrobial.
Absorption:
 Aminoglycosides are poorly absorbed from GIT (<10%). Absorption from GI tract
takes place only in presence of inflammation or ulceration.
 The absorption from IM injection site is rapid and Cmax are achieved within 30 to 45
minutes of administration.
 IV and IP routes produce rapid effects but are generally avoided because of serious
side effects.
 The repeated intrauterine administration in endometritis may result in sufficient
absorption to achieve bactericidal concentration.


Distribution:
 AGs are extensively distributed in extracellular fluid, but do not readily enter into
cells due to their polar nature (water soluble).
 Therefore, they are largely excluded from brain, CSF, eye and most body tissue
except the kidneys and inner ear.
 Accumulation of aminoglycosides in high concentrations in kidney cause
nephrotoxicity and in inner ear ototoxicity
 Aminoglycosides may cross placental barrier causing deafness in young ones
(foetus).
 The aminogtycosides bind poorly to plasma proteins (<20%).
Biotransformation and excretion:
 AGs are not metabolised in body and are excreted unchanged in urine by glomerular
filtration.
 Plasma half-lives are vary between 2 to 4 hours in patients with normal renal function
& in renal insufficiency, half-lives may increase to 24-48 hours.
Toxicity /Adverse effects
Three main adverse effects observed with aminoglycosides includes nephrotoxicity,
ototoxicity and neuromuscular blockade.
1. Nephrotoxicity:
 Nephrotoxicity occurs as a result of excessive accumulation of aminoglycoside (40 to
50 times higher than blood) in the proximal tubular cells in kidneys.
 Nephrotoxicity is reversible in the initial stages because of the regenerative capacity
of tubular epithelium but on prolonged exposure causes permanent renal damage.
 Manifestations of nephrotoxicity include presence of enzymes of brush border in
urine, proteinuria, presence of casts and low GFR.
 Nephrotoxic potential of AGs: neomycin (most nephrotoxic) > tobramycin and
gentamicin > dihydrostreptomycin (least nephrotoxic).
 Nephrotoxicity can be prevented by avoiding use of potentially nephrotoxic AGs,
ensuring adequate hydration status of patient and avoiding concurrent use of other
nephrotoxic drug.
2. Ototoxicity:
 Administration of aminoglycosides can produce both vesicular and auditory
dysfunctions.
 Ototoxicity is greater when the plasma concentration of drug is persistently high.
 Ototoxicity once occur is usually irreversible .
 Ototoxicity leads to nystagmus, incoordination , vertigo, head tilt, ataxia and loss of
righting reflex
 Deafness may be produced by permanent damage and loss of organ of Corti.
 Cats are more susceptible to ototoxic effect of AGs than dogs.
 Impaired renal function increases chances of ototoxicity.
 Ototoxic potential of AGs: Streptomycin (most ototoxic) > gentamicin & neomycin >
kanamycin and amikacin.

3. Neuromuscular blockade:
 All aminoglycosides have potential to produce neuromuscular blockade with curare-
like action.
 The effect is produced mainly by interference with acetylcholine release and
chelation of Ca++ that is normally required for exocytosis.
 However, concomitant administration of neuromuscular blocking agents and general
anaesthetics with aminoglycosides may increase this toxicity.
 Muscular weakness, apnoea, respiratory arrest have been associated when
aminoglycosides, used in very high doses.
 Neomycin and streptomycin have high propensity to cause neuromuscular blockade.
 Neuromuscular blockade may be treated by IV administration of calcium salts or
neostigmine.
4. Other effects:
 Other toxic effects include allergic reaction, peripheral neuritis (by streptomycin)
and dysfunction of optic nerve.
 Toxicity may occur when they are applied topically for long period, especially on
wounds, bums or skin ulcers.
 Contraindicated in hypersensitive patients.
 Drugs should be used with extreme caution in pre-existing renal disease and in
neonatal or geriatric animals.
 Dose rates should be reduced in renal failure and in neonate, geriatric and obese
animals.
 Aminoglycoside not given to animals with myasthenia gravis.
 Not given during pregnancy (toxic to foetus)
 Not prefer for cats.
 Plasma concentration and renal function (BUN & creatinine) should be monitored
during therapy.
Drug Interactions
 Concurrent use of AG with loop diuretics (e.g. furosemide) and osmotic diuretics
(e.g. mannitol) may increase the nephrotoxic and ototoxic effects.
 AG are used with inhalant anaesthetic or neuromuscular blocking drugs (e.g. d-
tubocurarine) than increase chances of neuromuscular blockade and respiratory
paralysis.
 AG + halothane increases cardiovascular depression.
Clinical Uses
 AGs are widely used in veterinary practice to treat local and systemic infections
caused by susceptible bacteria, generally gram-negative bacteria.
 Used to treat infections of GIT, urinary tract, respiratory tract and skin.
 They are also effective against septicaemia, osteoarthritis, mastitis and wounds. Also
used intrauterine to treat endometritis and intramammary to treat mastitis.
 Some time used topically eyes and ears infection.

INDIVIDUAL ANIINOGLYCOSDES
Streptomycin:
 Oldest aminoglycoside obtained from Streptomyces griseus.
 First antibiotic used to treat tuberculosis.
 Water-soluble, use has declined in veterinary.
 It is mainly active against aerobic gram-negative bacilli.
 Streptomycin + penicillin combination used to treat mastitis. (Dose: lactating cows-
100 mg/quarter; dry cows- 500 mg/quarter, intramammary infusion)
Dihydrostreptomycin:
 Ototoxic, restricted its use in veterinary and medical practices.
Neomycin
 Broad-spectrum AG obtained from Streptomyces fradiae.
 Highly toxic to internal ear (mainly auditory) and kidneys.
 Used topically for skin, eye or ear infections.
 Combined with penicillins used intramammary in mastitis.
Framycetin/Neomycin B
 Used with corticosteroids for treatment of skin, nose, ears and eyes infections.
Paromomycin
 Effective in G-ve and G+ve bacteria, tapeworm, amoebiasis and Giardia infection
Gentamicin:
 Most widely used AG with extended spectrum of antibacterial activity.
 It is obtained from Micromonospora purpurea.
 Freely water soluble, low cost
 Used most of animal by all routes i.e. IM, SC, Intra-uterine, Intra-mammary
 Effective against a wide-range of G-ve and G+ve infections of respiratory tract,
urinary tract, GIT, bones, soft tissue and skin infections.
 Used topically for skin, ear and eye infections.
 Not given in food producing animals due to prolonged residues.
 Heat-stable antibiotics & remain active even after autoclaving (121°C).
Amikacin
 Semi-synthetic AG, have broadest spectrum.
 Used to treat serious G-ve infections resistant to gentamicin.
Arbekacin:
 Semi-synthetic AG, Used to treat G-ve and G+ve bacteria & meticillin-resistant
Staphylococcus aureus (MRSA) infection.
Tobramycin
 Very similar to those of gentamicin.
 Used clinically to treat serious G-ve infections those resistant to gentamicin.
Sisomicin and Netilmicin:
 Extended spectrum AG used primarily in human practice.
 These drugs are presently undergoing clinical trials for use in veterinary practice.

TETRACYCLINE
Tetracycline are broad spectrum antibiotics having a nucleus of four cyclic rings.
Sources:
 They are either obtained naturally from Streptomyces spp. (soil actinomycetes) or
prepared semi-synthetically.
 Chlortetracycline derived from Streptomyces aureraciens introduced in 1948.
 Oxytetracycline obtained from Streptomyces rimosus.
 Removal of chlorine atom from chlortetracycline produced semi-synthetic tetracycline
introduced in 1952 like metacycline, doxycycline and rolitetracycline.
 Doxycycline and minocycline are relatively newer tetracyclines with high lipid
solubility and longer duration of action.
 Tigecycline is new subgroup of tetracyclines (glycylcyclines) was introduced to treat
infections which are resistant conventional tetracyclines.
Chemistry and Properties
 They are four ringed amphoteric compounds
 TCs are acidic and hygroscopic compounds in which aqueous solution form salts with
both acids and bases.
 Tetracyclines form insoluble chelate with cations like Ca++, Mg++, Fe++ and Al+++
 Tetracyclines are stable as powders but their aqueous solutions are not stable so
parenteral injection are formulated in propylene glycol or polyvinyl pyrrolidine to
prolong elimination half-life (Single Inj. OTC-LA effect remain for 3-4 days while
OTC plain < 1 day).
 TCs are formulated as injections, boluses, capsules, powders, feed additives and
ointments for veterinary use.
Classification
Classify according to their duration of action.
1. Short-acting TCs (Half life = <8 hours)
e.g. oxytetracycline, tetracycline and chlortetracycline
2. Inter-mediate acting TCs (Half life = 8- 16 h )
e.g. demeclocycline and metacycline
3. Long-acting TCs (Half life = >16 hours)
e.g. doxycycline, minocycline and tigecycline.
Mechanism of action
 Tetracyclines inhibit bacterial protein synthesis by binding with 30 S ribosomal
subunit and are primarily bacteriostatic.
 Action of TCs can be divided into two processes passage of tetracyclines into
bacterial cell and interaction of TCs with bacterial ribosomes (similar to AGs).
 TCs enter into bacteria by passive or active transport process. The more lipid soluble
members (e.g. doxycycline and minocycline) pass directly through the lipid bilayer by
passive diffusion.
 Once the TCs gain enters into bacterial cell, they bind to the 30S ribosomal subunit &
this prevents addition of amino acids to the growing peptide chain resulting in
inhibition of protein synthesis in bacteria.

 Tetracyclines are highly effective against multiplying microorganisms and are more
active at pH 6-6.5.
 Responsive host-defence system is essentially required to remove static bacteria (b/c
bacteriostatic effect)
 Penetration of TCs in host/ mammalian (eukaryotic) cells through cell membrane is
poor due to lacking of specific carrier transport system. (Q: Why mammalian cell
protein synthesis are less sensitive to TCs).
 TCs are broad-spectrum antibiotics.
 They are active against a wide range of G+ve and G-ve, aerobic, anaerobic bacteria.
 They are also active against Mycoplasma, Rickettsia, Chlamydia and some protozoa
like anaplasma, haemobartonella and amoebae.
 Presently, many strains of bacteria become resistant to TCs.
 TCs are ineffective against fungi and viruses.
Microbial Resistance
 Resistance to TCs develops slowly in a graded manner.
 Resistance to TCs may be acquired by three mechanisms: decreased penetration into
cells, enzymatic inactivation and ribosomal alterations.
 Resistance to TCs is primarily plasmid mediated.
 Microorganisms those have become resistant to one tetracycline are usually resistant
to other members of the group (showed cross resistance) except minocycline.
Pharmacokinetics
Absorption:
 The oral absorption of tetracyclines is variable with older drugs being less
bioavailable and newer lipid soluble tetracyclines being 100% bioavailable.
 Absorption of tetracyclines from GIT is decreased in presence of polyvalent cations
(Ca++, Mg++, Fe++ and Al+++ ) which are present in food milk and milk products (hence
TC given before meal/ not given with food/milk).
 All TCs produce varying degree of tissue irritation on parenteral administration,
especially chlortetracycline (most irritating drug).
 Therefore for parenteral administration, buffered solutions are prepared. Procaine is
added to tetracyclines solution for IM administration in small animals.
Distribution:
 TCs bind to plasma proteins to varying degrees and are widely distributed in most
tissues including kidneys, liver, lungs, bile and bones.
 Exception as doxycycline & minocycline do not penetrate the CSF and brain.
 TCs are stored in the reticulo-endothelial cells of liver, spleen and bone marrow.
 They are also incorporated into growing bone & teeath in yough animals.
 TCs cross the placenta and enter foetal circulation and amniotic fluid.
 TCs are not metabolised to a significant extent in the body (except lipid soluble TCs).
 Most TCs are excreted in urine (60%) via glomerular filtration pathway and in faeces
(40%) via biliary excretion.

 Tetracyclines undergo enterohepatic circulation, which may affect their duration of
action.
Side effects/ Adverse effects
TCs have a relatively low toxicity at normal dosage levels
1. Gastrointestinal upsets:
 All tetracyclines produce GI irritation to varying degree-in some patients, particularly
after oral administration.
 Anorexia, abdominal pain, diarrhoea, and nausea and vomiting in small animals may
occur.
 Superinfection of Candida albicans is common with TCs.
 The oral administration of tetracyclines may lead to fatal diarrhoea in horses and
deleterious effect on rumen microbes in ruminants (Why TCs are not administered
orally in horse/ cattle?).
2. Effect on bones/teeth:
 TCs are deposited in growing teeth and bones due to their chelating properties with
calcium (decrease bone growth in foetus).
 They form tetracycline-calcium complex which inhibits calcification and results in
permanent discolouration (first yellowish then brownish) of the teeth.
 High concentrations of TCs can interfere with the calcium deposition in bones and
delay fracture healing.
3. Hepatotoxicity:
 TCs in excessive doses produce fatty infiltration of liver.
 Hepatotoxicity with jaundice due to large doses of TC been reported in pregnant
women and in some animals.
4. Nephrotoxicity:
 Tetracyclines are potentially nephrotoxic, particularly in renal insufficiency &
increase blood urea nitrogen (BUN) levels .
 The administration of expired tetracycline products may lead to acute tubular
nephrosis in animals.
5. Hypersensitivity reactions:
 Not common. Rarely, TCs may produce skin rashes, urticaria, pruritus and exfoliative
dermatitis.
 Angioedema and anaphylaxis are extremely rare.
6. Cardiovascular effects
 The rapid IV administration of TCs may result in hypotension, collapse and sudden
death in animals.
 This has been related to rapid chelation of blood calcium.
 Pre-treatment with calcium borogluconate and slow rate of IV infusion prevent these
unwanted effects.
7. Other effects:
 TCs cause irritation, swelling, necrosis and yellow discolouration usually occur at
injection site.

 In patients having hepatic insufficiency, renal diseases and hypersensitive to them.
 Oral administration of TCs to ruminants and horses.
 Not given during last trimester in pregnant animals and up to 4 weeks in neonates.
 Never used beyond their expiry date because they cause 'Fanconi syndrome‗ damage
to the proximal renal tubule. [In Fanconi syndrome glucose, amino acids, uric acid,
phosphate and bicarbonate are passed into the urine, instead of being reabsorbed].
 TCs should never be administered with food/milk because they reduce bioavailability
of TCs so they generally given at least 1-2 hours before or after food.
 Doxycycline and minocycline may be taken with food
 TCs should not be given intrathecally.
 Note: TCs should not be administered mixed with IV fluids (RL and calcium
preparations).
Clinical Uses
 Tetracyclines are used in treatment of infection caused by bacteria, mycoplasma,
chlamydiae and rickettsiae, anaplasma, hemobartonella, ehrlichia and borrelia.
 Used in the treatment of psittacosis in birds.
 Used to treat number of infection include bronchopneumonia, urinary tract infections,
metritis, mastitis, prostatitis, cholangitis and pyodermatitis.
 Actinomycosis and actinobacillosis also respond to TCs.
 Chlortetracycline used in food producing animals as growth promoters.
Administration of TCs
 TCs may be administered by oral, parenteral, topical or intramammary route.
 Most of TCs can be administered by slow IV or deep IM route (cause tissue
irritation).
 Sometimes local application of TCs in ophthalmic ointments or buffered solutions is
employed for conjunctivitis.
 Intramammary infusion of TCs for mastitis in dairy animals is extensively used in
veterinary medicine.
INDIVIDUAL TETRACYCLINES (Self Study)
Oxytetracycline:
 One of the most commonly used TC in veterinary practice.
 Obtained from Streptomyces rimosus.
 Broad-spectrum TC effective against bacteria, mycoplasma, spirochetes, chlamydia
and rickettsia.
 F=60-80%, OTC LA (Depot preparation in 2-pyrrolidone) remain effective for 3-4
days.
 OTC produces irritation at injection site.
 Drug withdrawal and milk discard time for OTC in cattle and swine: 14-22 days and
in poultry: 5 days.
Tetracycline:
 Broad spectrum obtained from Streptomyces aureofaciens.
 Almost similar to OTC, irritate at injection site.

Chlortetracycline:
 First TC isolated from Streptomyces aureofaciens.
 AM spectrum similar to OTC.
 Due to irritant action IM injection is not recommended, used orally (No Inj.).
 Mainly use as a growth promoter in food-producing animals.
Demeclocycline and metacycline:
 Currently less used in veterinary practice (Demeclocyclin inhibit ADH effect,
photosensitivity reactions in human).
Doxycycline:
 Semi-synthetic TC, Lipid soluble TC, longer duration of action.
 Oral F= 90-100%, Half life= 16-20 h, excreted in faeces.
 Used in treatment of ehrlichiosis in dogs, psittacosis in poultry and anaplasmosis in
calves.
 Used in the treatment and prophylaxis of Bacillus anthracis infection (Anthrax).
Minocycline:
 Almost similar to doxycycline but limited used in Veterinary.
 Most lipid-soluble TC, longer duration of action
 Undergoes enterohepatic circulation which prolonged half-life in the body.
Tigecycline
 Newly introduced TC antibiotic (glycylcycline antibiotic)
 Derivative of minocycline.
 Broad spectrum like TC, also active against MRSA.
 Used in human medicine, available as an injection form.

AMPHENICOL (CHLORAMPHENICOL AND RELATED DRUGS)
 Amphenicols are a group of broad-spectrum bacteriostatic drugs which act by
blocking protein synthesisis of susceptible bacteria
 Amphenicols include chloramphenicol and its related drugs thiamphenicol,
florfenicol and azidamfenicol.
CHLORAMPHENICOL
 It is a broad-spectrum bacteriostatic antibiotic obtained from Streptomyces
venezuelae in 1947, but now is manufactured synthetically.
 It is first synthetic antibiotic.
 It is used in a variety of infections in human and Veterinary medicines, particularly
those caused by anaerobic Bacteria.
Properties:
 Highly lipid soluble antibiotic, yellowish white crystalline solid.
 It is freely soluble is alcohol and acetone, fairly soluble in ether, less soluble in water
and insoluble in benzene.
 Aqueous solutions are neutral and quite stable, but need protection from light.
 It is marketed either as a free base or in ester forms (e.g. palmitate, succinate or
panthothenate salts).
 Chloramphenicol palmitate is insoluble is water and sparingly soluble in alcohol, so is
used for oral administration.
 Chloramphenicol succinate (sodium succinate) is freely soluble in both acetone and
water and, therefore, is used for parenteral injection
Chemistry and SAR
 It is a derivative of nitrobenzene and of dichloroacetic acid.
 It is unique among natural compounds having a nitrobenzene moiety in its structure.
 The para-nitro group is not important for antibacterial activity.
 The p-nitro phenyl group may be changed to ortho-or meta-nitro compounds or even
be replaced by halogens without significant loss of activity .
 The p-nitro group has been implicated in the irreversible suppression of bone
marrow.
Mechanism of action
 Chloramphenicol inhibits protein synthesis by binding to 50S ribosomal subunit in
susceptible bacteria.
 It readily penetrates into bacterial cells, probably both by passive and facilitated
diffusions.
 The effect of chloramphenicol is usually bacteriostatic, but at high concentrations it
can be bactericidal.
Antimicrobial spectrum
 It is a broad-spectrum antimicrobial agent.
 It is active against many G+ve and G-ve bacteria, and both anaerobes and aerobes
including Staphylococcus, Streptococcus, Salmonella, BruceIla, Shigella, Neisseria
and Haemophilus species.

 Its efficacy against Salmonella is very useful (to treat typhoid).
 It is also has active against Nocardia, Chlamydia and Mycoplasma.
 It has no activity against Mycobacterium, protozoa, fungi and viruses.
 Main three mechanisms of resistance to chloramphenicol: inactivate by
chloramphenicol acetyltransferase enzyme, reduced membrane permeability and
mutation of the 50S ribosomal subunit.
 This type of resistance is usually acquired through plasmids.
Pharmacokinetics
 It is a highly lipid-soluble drug, so it is very rapidly and efficiently absorbed after oral
administration.
 Cmax is generally achieved within 30 minutes after oral dosing.
 In ruminants, it is not available for absorption after oral administration because
ruminal microflora readily reduces the nitro group and inactivates the
chloramphenicol.
 The water soluble succinate form is well absorbed after IM or SC injection, but it also
requires hydrolysis in plasma and liver to release the active antibiotic.
 After absorption, It diffuses throughout the body and reaches sites of infection.
 It readily crosses cellular barriers and achieves high levels in most tissues and fluids
including CSF, brain, aqueous humour, placenta and synovial fluid.
 It is primarily eliminated by liver via glucuronide conjugation.
 Mainly excreted in urine.
 Cats are deficient in glucuronide conjugation, so elimination of chloramphenicol is
slower in cats than in dogs.
 Half life in cats: 4-8 h (long) while in small horse: < 1 h (unsuitable for treatment)
Bone marrow depression:-
 Chloramphenicol may produce dose-dependent (reversible) and dose-independent
(irreversible) bone marrow depression.
 The reversible bone marrow depression may be observed in all species of animals.
 The p-nitro phenyl group is responsible to cause irreversible bone marrow depression.
 The bone marrow is often hypoplastic or aplastic.
 The signs of bone marrow toxicity includes vacuolation of many of the early cells of
myeloid and erythroid series, lymphopenia and neutropenia.
 Aplastic anaemia develops and peripheral blood shows pancytopenia.
Gastrointestinal effects
 It may produce vomiting, diarrhoea and anorexia in animals.
Cardiovascular effects
 Rapid IV infusion of chloramphenicol especially that containing propylene glycol
may result in collapse, haemolysis and death in large animals.
Hypersensitivity reactions
 Some dogs and cats may show hypersensitivity reactions to chloramphenicol & may
produce rashes and fever.

Other effects
 In human neonates and premature infants, chloramphenicol produces Gray-baby
syndrome characterised by vomiting, hypothermia, as grey cyanosis, cardiovascular
collapse and death (it is b/c of lack of necessary liver enzymes to metabolized
chloramphenicol in neonates).
Contraindications and precautions
 In hypersensitive patients.
 Unsuitable for patients with pre-existing haematological disorders.
 In patients with impaired hepatic and renal functions.
 Avoided in neonates because of less developed metabolising enzymes, especially in
kittens.
 Not be given to nursing bitches and queens (first week after parturition).
Drug interactions
 It is not used with beta-lactam and aminoglycoside (bactericidal drugs).
 It may impair immune response to vaccines (vaccine should be postponed)
Clinical Uses:
 It is useful in the treatment of anaerobic bacterial infection, salmonellosis
Bacteroides spp., chronic respiratory infections.
 It is most effective against Salmonella typhi in humans (in typhoid).
 Used topically (as ointments and eye drops) in bacterial conjunctivitis.
 Chloramphenicol is not approved for use in food animals in many countries.
THIAMPHENICOL
 Thiamphenicol is semi-synthetic derivative of chloramphenicol.
 It is produced by replacing the p-nitro phenyl group of chloramphenicol by methyl-
sulfonyl group.
 It is more water soluble, less potent & less toxic (safe) than chloramphenicol (devoid
of irreversible bone marrow suppression)
 Not metabolised to significant extent in liver.
 It is safe & effective antimicrobial for use in food producing animals (cattle, swine,
poultry).
FLORFENICOL
 Florfenicol is a fluorinated analogue of thiamphenicol in which the hydroxy group
oxide chain is replaced with fluorine.
 It is effective against certain bacteria which are even resistant to chloramphenicol
 It is more active than either chioramphenicol or thiamphenicol.
 It is safe alternative of chloramphenicol for use in food producing animals.
AZIDAMFENICOL
 It is another amphenicol antibiotic, with profile to chloramphenicol
 Used only topically as eye drops and ointment for susceptible bacterial infections.

MACROLIDES AND LINCOSAMIDES
MACROLIDES
 The macrolides (macrocyclic lactones) are a group of bacteriostatic antibiotics.
 Exert their antibacterial effect by inhibiting proteins synthesis in susceptible bacteria
mainly by binding irreversibly to the 50S ribosomal subunit.
 The macrolide contain large lactone ring attached to one or more deoxy sugars by
glycosidic linkages.
Sources:
 Macrolides are mostly obtained from various species of Streptomyces.
 Some are prepared semi-synthetically.
Natural sources are:
 Erythromycin: Streptomyces erythreus
 Tylosin: Streptomyces fradiae
 Spiramycin: Streptomyces ambofaciens
Properties:
 All macrolide antibiotics are weak bases & this basic nature is due to the presence of
dimethylamine group in their structures.
 Macrolide concentrated in acidic fluids such as milk and prostatic fluid by process of
―ion trapping‖.
 Colourless crystalline substances, poorly soluble in water
 Maximum activity seen at pH 7.8 to 8.
 They are lipid soluble but are often used in ester forms to enhance oral bioavailability
and to improve oral tolerance.
Classification
I. Macrolide antibiotics.
1. Older macrolide antibiotics: E.g. Erythromycin, tylosin, tilmicosin, spiramycin,
oleandomycin and troleandomycin
2. Newer macrolide antibiotics: E.g. Clarithromycin and roxithromycin
II. Azalide antibiotics: e.g. Azithromycin and Tulathromycin.
III. Ketolide antibiotics: e.g. Telithromycin.
Mechanism of action
Macrolides inhibit bacterial protein synthesis by binding to 50S ribosomal subunit in
susceptible bacteria (Usually in G+ve).
MOA divided into two processes:
1. Passage of macrolides into bacterial cell.
2. Interaction of macrolides with bacterial ribosomes.
1. Passage of macrolides into bacterial cells:
 Macrolides are transported into bacteria by an active transport system.
 G+ve bacteria accumulate about 100 times more antibiotics than do G-ve.
 Macrocyclic showed enhanced antimicrobial activity at alkaline pH.
2. Interaction of macrolides with bacterial ribosomes.
 The macrolides bind to 50S ribosomal subunit and interfere with bacterial protein
synthesis.

 The effect is more pronounced on rapidly dividing bacteria and mycoplasma.
 Macrolides generally do not bind to mammalian ribosomes.
 Macrolides are effective against most aerobic and anaerobic G+ve bacteria.
 Antibacterial spectrum similar to or slightly wider than that of penicillin (Substitute to
penicillin).
 Beta- haemolytic Streptococci, Pneumococci, Staphylococci and Enterococci are
susceptible to macrolide.
 Generally not active against G-ve bacteria except some strains of Pasteurella,
Haemophilus and Neisseria species.
 Also active against Mycobacterium, Mycoplasma, Chlamydia and Rickettsia species.
 Macrolides ineffective against protozoa, viruses and fungi.
 Acquired resistance in susceptible G+ve bacteria result mainly from changes in 50S
ribosomal subunit and loss of macrolide affinity.
 This is associated primarily to decreased permeability into bacteria, active efflux of
drug, increased production of inactivating enzyme.
 The bacterial resistance is mostly plasmid mediated that may develop rapidly (e.g.
erythromycin) or slowly (e.g. tylosin).
 Cross-resistance with other macrolides, lincosamides and chloramphenicol may occur
due to their similar binding sites on the ribosome.
Pharmacokinetics
Absorption:
 Macrolides are lipid soluble which are rapidly absorbed from the GI tract. If not
inactivated by gastric acid.
 Oral preparations are often enteric-coated to prevent gastric acid inactivation.
 Presence of food usually interferes with the GI absorption.
 Cmax of macrolide occur within in 12 hours after oral dosing.
 Absorption of macrolides after IM or SC injection is rapid.
Distribution:
 Macrolides are widely distributed in tissues
 Accumulate in macrophages and leukocytes because of ion trapping & also showed
high tissue concentrations than plasma.
 They cross the placenta, but not blood-brain barriers.
 Their concentration in milk is usually several times greater than in plasma, especially
in mastitis.
 Macrolide are 70-80% protein bound mainly to alpha-1-acid glycoproteins and not to
albumin.
 Macrolide are extensively metabolized (>80%) in liver through microsomal enzyme
system.
 Excreted in both active form and inactive metabolites in bile (>60%) and undergo
enterohepatic cycling.

 Plasma half-lives is 1 to 3 hours in domestic animals.
Side Effects / Adverse Effects
 GIT disturbances:
 Vomiting, anorexia, diarrhoea, regurgitation and epigastric pain.
 Horses are more susceptible to the macrolide-induced GIT disturbances.
 Hypersensitivity:
 Other effects:
 Commonly produce pain and swelling at the injection site.
 Tylosin and Tilmicosin have tendency to produce cardiovascular toxicity.
 In hypersensitive patients.
 In patients with pre-existing liver dysfunction.
 In horses and rabbits, due to chances of a reaction causing fatal digestive disturbance.
 Avoided in lactating animals (concentrate in milk)
Drug Interactions
 Not used with chloramphenicol or lincosamides b/c they compete for 50S ribosomal
subunit.
 Macrolides inhibit microsomal enzymes and depress metabolism of many drugs.
 Activity decreases in acidic environment.
Clinical Uses
 Macrolide are widely used in human and veterinary to treat both systemic and local
infections.
 They are often used as penicillin substitutes (in penicillin allergic patient).
 Macrolides are mainly used in upper respiratory tract infections, bronchopneumonia,
enteritis, metritis, urinary tract infections, mastitis and arthritis.
INDIVIDUAL MACROLIDES:
Erythromycin:
 Most widely used, obtained from Streptomyces erythreus in 1952.
 Pain & swelling at injection site- IM, SC.
 Used in dogs and cats, sheep, cattle & swine.
 Drug of choice for Campylobacter & Rhodococcus equi in foals.
 Not recommended in adult horses (cause fatal diarrhea)
Tylosin:
 Obtained from Streptomyces fradiae.
 Pharmacologically (PD, MOA, PK) related to the erythromycin.
 Drug of choice for CRD in poultry, CBPP in cattle, CCPP in goats (Mycoplasma
infections).
 Clinically use to treat pneumonia, foot rot and metritis in cattle; pneumonia,
erysipelas and dysentery in swine.
Tilmicosin:
 Used to treat pneumonia acused by Pasteurella spp. in cattle, sheep & swine (HS).
 Not recommended by IV route (Used SC route)
 High affinity for lung tissues, single injection remain effective for 3 days.

 Clarithromycin:
 Used to treat Helicobacter pylori infections in humans.
 Used to treat Rhodococcus equi infection in combination with rifampin.
Roxithromycin
 Longer acting and more stable than erythromycin.
 Mostly used as an alternative to erythromycin in the treatment of respiratory tract,
skin, soft tissues and genital tract infections.
Tulathromycin:
 Long half-life of 92 hours in cattle, remain effective for long duration.
 Recommended for treatment of bovine respiratory disease (BRD) in cattle.
 Not recommended in meat producing animals.
 Swelling, irritation and pain at injection site may be observed.
Azithromycin:
 Recently introduced, acid stable- orally effective with no need of protection from
gastric acid.
 Longer half life 18 h in horse, 30 h in dogs.
 Ability to concentrate in respiratory tissues so used in respiratory tract infections.
Telithromycin:
 Semi-synthetic, acid stable, used in respiratory tract infection in human.
LINCOSAMIDES
 Lincosamides are a group of monoglycoside antibiotics containing an amino acid like
side chain.
Chemistry and properties
 They are more stable in salt forms.
 They are basic compounds, so are more concentrated in acidic fluids.
 The first lincosamide to be discovered was lincomycin, isolated from Streptomyces
lincolnensis in a soil sample from Lincoln (USA).
Mechanism of Action
 Lincosamides inhibit the bacterial protein synthesis by binding with the 50S
ribosomal subunit (similar to macrolides) and are primarily bacteriostatic.
 Lincosamides, macrolides and chloramphcnicol are not structurally related, they all
act at sites with close proximity.
 Lincosamides are more active at an alkaline pH and may become bactericidal at high
concentration.
 Lincosamides have antibacterial spectrum similar to that of macrolides
Bacterial resistance
 Resistance appears gradually and slowly.
 Alteration of 50S ribosomal subunit is mostly involved for resistance against
lincosamides.
 Lincosamides show cross-resistance with macrolides.

Pharmacokinetics
 Lincosamides are absorbed to variable extent (60-90%) after oral administration.
 In many species these drugs have the ability to diffuse across the placenta.
 Lincosamides do not produce serious adverse effects in all animals, but GIT
disturbances (diarrhoea, vomiting and anorexia) are common.
 Lincosamides may inhibit neuromuscular transmission and cause paralysis of skeletal
muscle.
 Hypersensitivity reactions and pain at injection site is common.
 Contraindicated in animals with fermenting GIT like ruminants and horses due to
development of fatal colitis.
 Do not prescribe to neonates, lactating animals, rodents & rabbit.
Drug Interaction
 Lincosamides increase the neuromuscular blocking effect of general anaesthetics and
skeletal muscle relaxants.
 Concurrent use of chloramphenicol or macrolide antibiotics reduces the efficacy of
lincosamides.
INDIVIDUAL LINCOSAMIDES
Lincomycin:
 Obtained from Streptotnyces lincolnensis.
 Used to treat infections caused by Staphylococci, Streptococci, anaerobes
Erysipelothrix and Mycoplasma.
 Growth promoter in poultry.
Clindamycin:
 Used primarily to treat anaerobic infections.
 Used in patients - hypersensitivity to penicillins.
 Useful in the treatment of bone, joint & deep tissue infections.
 Used to treat toxoplasmosis in dogs.
 Not used in horses, ruminants and rabbits due to serious GI disturbances.
Pirlimycin
 Useful against Staphylococcus aureus and Streptococcus spp. (G+ve) infection in
human.
 Limited used in animals

QUINOLONES/ FLUOROQUINOLONES
 They are most recent (latest) antibacterial drug group.

 They are synthetic antibacterial agents having a 4- quinolones structure.
 They are primarily active against G-ve bacteria, although newer fluorinated agents
also inhibit selected G+ve bacteria.
 They are minimally toxic and are very important in veterinary medicine.
History
 Nalidixic acid was first member of quinolones family introduced in 1964.
 Oxolinic acid and rosoxacin with more potency but limited spectrum were introduced
in 1970.
 Pipemidic acid and cinoxacin were also introduced in the 1970.
 These were followed by second-generation quinolones called fluoroquinolones with
extended spectrum and systemic antibacterial effects in 1980.
 Since then (1980 onwards), structural modifications have resulted in several second,
third and fourth generation fluoroquinolones, which have found valuable place in
human and veterinary practices.
Chemistry and Structure Activity Relationship
 Quinolones contain a basic structure of 4-quinolone with a carboxylic acid moiety at
position 3.
 Various modifications on the basic ring structure leads to produces compounds with
differing physical, chemical, pharmacokinetic and antimicrobial properties.
 The majority of quinolones in clinical use belong to the subset fluoroquinolones,
which have fluorine atom attached at the C-6 position.
Basic structure of fluoroquinolone

 The carboxyl group (-COOH) at position 3 and ketone group at position 4 are
essential for antibacterial activity.
 Substitution at position 6 with a fluorine moiety markedly enhances activity against
G-ve and G+ve bacteria as well as mycoplasma and chlamydia.
 All fluorinated 4-quinolones are called fluoroquinolones.
 Addition to piperazine ring at position 7 on fluoroquinolones significantly increases
tissue and bacterial penetration and improves spectrum of activity to include
Pseudomonas (e.g. ciprofloxacin and enrofloxacin).
 Substitution with an oxygen atom at position 8 improves activity against G+ve and
anaerobic organisms without affecting the bactericidal profile.
Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

Properties
 Quinolones are amphoteric compounds.
 They exhibit poor water solubility (high lipid solubility) between pH 6 and 8.
 In concentrated acidic urine, some quinolones form needle-shaped crystals.
 Quinolones are available for oral and parenteral administration and can be given as
water-soluble salts or as free bases.
Classification
 Quinolones are classified on the basis of their pattern of evolution (generation) and
antibacterial spectrum.
 The first generation quinolones consist of older non-fluorinated quinolones, whereas
the later generation quinolones are predominantly fluorinated compounds.
1) First-generation quinolones:
e.g. nalidixic acid, oxolinic acid, flumequine, cinoxacin, pipemidic acid, piromidic
acid and rosoxacin.
2) Second-generation quinolones:
e.g. enrofloxacin & danofloxacin (animal use only), ciprofloxacin & norfloxacin
(human use only), difloxacin, orbifloxacin, marbofloxacin, ofloxacin, pefloxacin,
sarafloxacin lomefloxacin and enoxacin.
3) Third-generation quinolones:
e.g. levofloxacin, sparfloxacin, pradofloxacin, ibafloxacin, grepafloxacin,
balofloxacin, pazufloxacin, temafloxacin and tosufloxacin.
4) Fourth-generation quinolones:
e.g. moxifloxacin, gatifloxacin, gemifloxacin, sitafloxacin, besifloxacin, clinafloxacin,
garenoxacin, trovafloxacin and prulifloxacin.
Mechanism of Action
 Quinolones inhibit the replication of bacterial DNA by interfering with action of
DNA gyrase (topoisomerase II) enzyme.
 They are bactericidal drugs.
 Drugs enter in susceptible microorganisms by the passive diffusion through porins in
the outer membrane. Once inside bacterial cell, quinolones target the enzyme DNA
gyrase, which is responsible for introducing negative supercoils into DNA.
 [Super coiling is a process where double stranded DNA molecule coils on itself so
that DNA can be tightly and compactly packed inside the bacterial cell].
 This negative supercoiling introduced by DNA gyrase is essentially required to
relieve the super helical tension while double-stranded DNA is being unwound by
helicase.
 The negative supercoiling introduced by DNA gyrase is an energy dependent reaction.
 Bacterial DNA gyrase is composed of A and B subunits.
 The A subunits carry out the strand-cutting function, whereas the B subunits cause the
ATP hydrolysis necessary for gyrase supercoiling.
 The A subunits are the primary site of action of quinolones.
 The DNA gyrase is inhibited by quinolones than the negative supercoiling not take
place that leads to disruption in bacterial DNA replication. This leads to bactericidal
effect.

 Mammalian DNA gyrase has 1000 times less affinity than bacterial DNA gyrase.
 FQs are highly effective at very low concentration.
 First-generation quinolones (e.g. nalidixic acid) have moderate G-ve activity and
minimal systemic distribution.
 Fluoroquinolones are broad spectrum drug effective against a wide range of G-ve
& G+ve bacteria, Mvcoplasma and Chlamydia.
 However, spectrum of activity varies with the type of fluoroquinolone.
 Second-generation FQs have expanded G-ve activity but limited gram-positive
activity. These agents are most active against aerobic gram negative bacilli.
 Third-generation FQs have expanded G-ve and atypical intracellular activity &
also improved G+ve coverage.
 Fourth-generation FQs show improved G+ve coverage, maintain G-ve coverage,
and gain anaerobic coverage.
 FQs showed concentration dependent antibacterial activity.
 Fluoroquinolones have long post-antibiotic effect.
 Growing bacteria are more susceptible & co-administration of bacteriostatic drugs
may decrease the efficacy.
 Anaerobic and acidic environments (e.g. abscesses) decrease the AB activity.
 Bacterial resistance develops rapidly to nalidixic acid and older quinolones.
 Staphylococcus aureus, enterococci and Streptococcus pyogenes now exhibit
resistance worldwide.
 Resistance is either due mutation in bacterial DNA gyrase or reduced permeability to
FQs.
 Efflux of drugs out of the bacteria is also possible.
 FQs have been recommended to be reserved for the use in patients those are seriously
ill and may soon require immediate hospitalization.
Pharmacokinetic
 Pharmacokinetic of quinolones varies with type of drug and Species.
 Absorption:
 Quinolones have good bioavailability after oral administration in monogastric
animals and pre-ruminating calves.
 Bioavailability is often >80% for most quinolones, except in ruminates and peak
levels are achieved in 0.5-2 hours after administration.
 However, presence of aluminium, magnesium, calcium, iron and zinc reduces
absorption and bioavailability of FQs.
 Absorption from IM or SC injection is rapid.
 Distribution:
 FQs distribute well into all body tissues and fluids including CNS, bone and prostrate.
 Tissue penetration is higher than the concentration achieved in plasma, stool, bile,
prostatic tissue and lung tissue.

 They also accumulate in macrophages and leucocytes thus being effective against
intracellular microorganisms.
 Quinolones also penetrate well in urine and kidneys when renal clearance is the route
of drug elimination.
 The degree of PPB is extremely variable. e.g. 10% for norfloxacin while >90% for
nalidixic acid.
 Biotransformation and excretion:
 Some quinolones are eliminated unchanged (e.g. ofloxacin), some are partially
metabolised (e.g. ciprofloxacin), and a few are completely metabolised (e.g.
pefloxacin).
 Metabolites of a few quinolones are active i.e. enrofloxacin metabolized to
ciprofloxacin (active metabolite).
 Pefloxacin is metabolized to norfloxacin (active metabolite).
 Renal excretion is the major route of elimination for most quinolones.
 Renal tubular secretion results in high urinary concentration.
 The alkaline urine increases reabsorption of FQs and may prolong elimination half-
life.
 The half-lives of most FQs range from 3 to 6 hours.
 FQs show significant post-antibiotic effect. Therefore, most of these drugs are
administered every 12 to 24 hours.
 FQs appear in the milk of lactating animals in high concentration.
 Side effects with older quinolones are relatively common, but newer quinolones are
generally well tolerated.
 Cartilage deformities, chondro-destruction (chondrotoxicity) and joint growth
disorders have been documented in young animals, particularly in dogs and foals,
after administration of FQs.
 In heavy breed dogs, the weight bearing joints are specifically susceptible often
leading to permanent damage.
 FQs may causes seizures or convulsion at high dosage.
 They can produce crystalluria in dogs due to their low solubility in acidic urine.
 Haemolytic anaemia has been reported in some animals with FQs.
 Recently blindness in cats caused by high doses of FQs has attracted attention.
 Sometime GIT disorders resulting in nausea, vomiting and diarrhoea.
 IM injection of some quinolones causes pain at site of injection.
 Large doses in pregnant animals may cause foetal toxicity.
 In humans, FQs are sometimes causes cardiac arrhythmias, CNS effects and
hypoglycemia.
 Contraindicated in hypersensitive patients
 FQs are not recommended in growing dogs under 12-18 months of age.
 Used with extreme care in pregnant animals and in patients with seizures disorders.
 In dehydrated patients.
 In patients with cardiac arrhythmia.

 Drug Interactions
 They are potent chelators of Mg++, Ca++, Zn+++, Fe+++ and Al+++, so products
containing cations, including sucralfate, non systemic antacids, nutritional
supplements and multivitamin and mineral supplements orally (within 2-4 h) may
interfere FQs absorption.
 FQs inhibit theophylline metabolism leads to increase chance of toxicity.
 Sometime combination of FQs with NSAIDs increases seizure threshold.
 Simultaneous use of corticosteroids has increase tendon rupture in animals.
Clinical Uses
 FQs are become drug of choice for treatment of G-ve bacterial infections.
 Older quinilones like nalidixic acid primarily used as urinary antiseptic.
 FQs are effective in the treatment local and systemic infections caused by susceptible
organism especially for intracellular and deep seated infections.
 Useful in treatment of respiratory tract, intestine, urinary and prostrate infections.
 Also useful in the treatment of meningoencephalitis, osteomyelitis and arthritis and
staphylococcal endocarditis.
INDIVIDUAL FLUOROQUINOLONES (Self Study):
Nalidixic acid:
 Non-fluorinated first-gen. drug, Used primarily as a urinary antiseptic, used orally in
dogs & cats.
Oxolinic acid: Non-fluorinated, CNS toxicity, used to treat fish diseases.
Flumequine: Withdrawn from clinical use in several countries.
Enrofloxacin:
 Excellent drug, Animal/Vet Use only, Broad spectrum, bactericidal, approved for use
in dogs, cats, cattle, buffalo, sheep, goat, horse, swine and poultry. Dose: 2.5 - 5
mg/kg.
 Avoid high dose in cats-retinotoxic.
Ciprofloxacin:
 Active metabolite of enrofloxacin, Similar to enrofloxacin, widely used in human
medicine.
Difloxacin:Mainly used in dogs, poultry, sometimes in horse, orally.
Orbifloxacin:Mainly used in dogs & cats, Also sheep, goats, horse, orally/IM.
Danofloxacin:Treat respiratory tract infections in cattle, chick, and pigs (vet. use only).
Pefloxacin:Metabolized to norfloxacin (active metabolite), used in human medicine
Gatifloxacin:
 Banned for systemic use in India (cause serious hyperglycemia), ophthalmic use-safe.
Marbofloxacin:Long elimination half life- 10 h
Moxifloxacin:
 Increase usage in clinical practice, potent against TB, Drug of last resort when all
other antibiotics have failed.
Note: Enro, Dan: Vet. use only while Cipro, Pe, Nor: Human medicine.

MISCELLANEOUS ANTIBACTERIALS & URINARY ANTISEPTICS
Classification of other Antibacterials:

I. Natural and semi-synthetic antibacterials
1. Polypeptide antibiotics e.g. polymyxins (polymyxin B and colistin), bacitracins
2. Glycopeptide antibiotics e.g. vancomycin, teicoplanin
3. Aminocyclitol antibiotics e.g. spectinomycin and apramycin.
4. Rifamycins e.g. rifampicin.
5. Pleuromutilins e.g. tiamulin, valnemulin and retapamulin
6. Streptogramins e.g. streptogramin, virginiamycin
7. Amonocoumarins e.g. novobiocin
8. Miscellaneous antibiotics e.g. fusidic acid, mupirocin, daptomycin, fosfomycin and
cycloserine
II. Synthetic antibacterials
1. Nitrofurans e.g. nitrofurantoin, furazolidone, nitrofurazone
2. Nitroimidazoles e.g. metronidazole and dimetridazole.
3. Oxazolidones e g linezolid, torezolid and eperezolid.
4. Arsenicals e.g. arsanilic acid and sodium arsanilate
5. Hydroxy quinolines e.g. clioquinol
1. POLYPEPTIDE ANTIBIOTICS
• Polypeptide antibiotics have low molecular weight produced by various bacterial
species.
• They possess strong bactericidal action, but are not used systemically due to toxicity.
• E.g. polymyxins, bacitracins
Polymyxins
• Polymyxins is a generic name used for a group of six strongly basic cyclic
polypeptides namely polymyxins A, B C, D, E and M.
• Polymyxin B and polymyxin E (called colistin) are therapeutically useful.
Polymyxin B
• Bactericidal antibiotic obtained from Bacillus polymyxa.
• Used only by topical and oral administration because parenteral administration often
leads to toxicity.
• MOA: Polymyxin B is a rapid acting bactericidal agent with a detergent like action
on the bacterial cell membrane.
• Polymyxin B strongly interacts with negatively charged lipopolysaccharide (LPS) in
the outer membrane of Gram-negative bacteria causing permeability changes and
disruption of bacterial cell membrane.

• Antimicrobial spectrum
• It effective against gram-negative bacteria only due to presence of LPS in outer cell
memberane.
• It is active against Enterobacter, Klebsiella, Salmonella, Pasteurella, Bordetella,
Pseudomonas, E coli and Shigella.
• Bacterial resistance: very slow development
• Pharmacokinetics
• Not absorbed following topical & oral administration.
• Metabolized and excreted in urine as inactive metabolites.
• Plasma half-lives in animals are about 3-6 hours.
• Adverse effects:
• Adverse effects are minimal on topic application because of its complete lack of
absorption from the site.
• Parenteral administration produces nephrotoxicity and neurotoxicity.
• Clinical uses
• Used topically to treat gram-negative infections of skin, eye and ear (e.g. otitis
externa) in all species.
• Treatment of bovine mastitis caused by Pseudomonas aeruginosa and Klebsiella.
• It is mostly used with bacitracin.
Colistin (Polymyxin E)
• Colistin obtained from Bacillus colistinus.
• It is available as colistin sulphate for oral use and colistin sodium methanesulphonate
for parenteral use.
• Colistin has an antibacterial spectrum, mode of action, pharmacokinetic patterns,
clinical uses and toxicity similar to those of polymyxin B.
• However, colistin is more potent on Pseudomonas, Salmonella and Shigella.
Bacitracin
• Bacitracin is isolated from Bacillus subtilis.
• Bacitracin A is the most active and major component.
• It is used either topically or by oral administration.
MOA:
• Bacitracin is a bactericidal drug that acts by inhibiting the cell wall synthesis in
susceptible bacteria.
• Similar to penicillin, but it is also effective against penicillinase producing
Staphylococcus aureus. Bacitracin is effective against gram-positive bacteria and
spirochetes.
Clinical Uses:
• Bacitracin is mostly used topically for susceptible skin, ear and eye infections.
• often used in combination with neomycin and/or polymyxin B
• Bacitracin as zinc or magnesium is also added to swine and poultry ration to prevent
and treat clostridial enteritis and also as growth promoter.
Toxicity: Nephrotoxicity, pain at the site of injection

2. GLYCOPEPTIDE ANTIBIOTICS
Vancomycin
• Obtained from Streptococcus orientalis.
• freely soluble in water
• MOA: Vancomycin is a bactericidal antibiotic that acts by inhibiting the bacterial
cell wall synthesis.
• AB Spectrum: Vancomycin is effective against gram-positive bacteria include
Staphylococcus, Streptococcus, Enterococcus, Clostridium and Corynebacterium
species.
• PK: vancomycin is not absorbed from GI tract after oral administration. After IV
administration, it is widely distributed in body tissues and fluids, except the CNS.
• It is excreted unchanged in urine.
• Toxicity: It produce dose-and time-dependent ototoxicity and nephrotoxicity.
Intramuscular injection is often painful and irritating.
• Clinical uses
• Used for meticillin-resistant Staphylococcus aureus (MRSA) infections of the bones
and soft tissues in dogs and cats.
Teicoplanin
• Mixture of several related compounds extracted from Actinoplanes teichomyceticus.
• Teicoplanin can be administered IM.
• Used in the treatment of MRSA infections, penicillin-resistant enterococcal
infections and in penicillin allergic patients.
3. AMINOCYCLITOL ANTIBIOTICS
• Chemically related to aminoglycosides
• The amino groups are present on the cyclitol ring hence called aminocyclitols.
• e.g. Spectinomycin and apramycin are the clinically useful drugs
Spectinomycin
• It obtained from Streptomyces spectabilis.
• soluble in water and alcohol
• Spectinomycin is bacteriostatic, binds to the 30S ribosomal subunit and inhibits the
bacterial protein synthesis.
• It is active against many gram-negative bacteria and mycoplasma.
• Resistance in susceptible bacteria develops rapidly.
• The pharmacokinetics behaviour of spectinomycin is similar to that of
aminoglycosides. No significant adverse effects.
• Spectinomycin is used in dogs, cats, horses, pigs and poultry for treatment of enteric
and respiratory infections caused by the susceptible bacteria.
Apramycin
• It obtained from Streptomyces tenebrasius.
• It is bactericidal against many gram-negative bacteria.
• Used for treatment of colibacillosis and salmonellosis in calves and pigs.
4. RIFAMYCINS
• Rifamycin are produced by Streptomyces mediterranei.
• They are effective against gram-positive bacteria (mycobacteria)
• Used to treat tuberculosis & leprosy.
• Semi-synthetic rifamycin derivatives are clinically useful includes rifampicin &
rifabutin
Rifampicin/Rifampin
• Lipophilic , slightly soluble in water and alcohol, red solid in colour.
• Rifampicin act by inhibiting DNA-dependent RNA polymerase in susceptible
bacteria.
• Rifampicin is bactericidal drug.
• Effective against Gram positive bacteria and Mycobacterium tuberculosis.
• Staphylococcus, Haemophilus, Neisseria and Chlamydia org are also susceptible.
Bacterial resistance develops quickly.
• PK: well absorbed (40-70%) from the GI tract after oral administration, C achieve
max
within 2-4 hours. Absorption from IM injection site is rapid.
• Rifampicin is rapidly distributed in body tissues and fluids.
• Rifampicin is metabolised by liver.
• It is primarily excreted in bile and to a lesser extent in urine.
• Active metabolites undergo enterohepatic cycling, which may enhance the duration
of action.
• Toxicity: Rifampicin is generally well tolerated in normal doses.
• Hepatotoxicity may occur in animals with pre-existing liver disease. Some time
Gastrointestinal disturbances & CNS depression may also seen.
Rifabutin
• Semi-synthetic rifamycin.
• Mechanism of action similar to rifampicin.
• It is effective against Gram-positive and some Gram-negative bacteria.
• It is primarily used in human medicine in the treatment of tuberculosis.
5. PLEUROMUTILINS
Tiamulin
• It obtained from Pleurotus mutilis.
• It act by inhibiting protein synthesis in bacteria by binding to 50S ribosomal subunit.
• Broad-spectrum antibacterial activity.
• Mainly used for the treatment of enzootic pneumonia in pigs.
• Used as growth promoter in swine.
Valnemulin
• MOA similar to tiamulin, Used in treatment of swine dysentery in pigs.
Ritapamulin
• First drug in the class to be approved for human use.
• Used in methicillin-resistant Staphylococcus aureus (MRSA).
• It is marketed as an ointment for topical use on skin.
6. STREPTOGRAMINS
• e.g. streptogramin & virginiamycin
• Novel class of antibiotics which act by inhibiting the protein synthesis by binding to
50S ribosomal subunit.

• Streptogramin & virginiamycin obtained from Streptomyces virginiae.
• Mostly used as a growth promoter in swine and poultry.
7. AMINOCOUMARINS
Novobiocin
• Obtained from the Streptomyces niveus.
• Freely soluble in water.
• MOA: Inhibition of bacterial DNA gyrase, thereby interference with bacterial protein
and nucleic acid synthesis.
• Mostly active against gram-positive bacteria.
• It is well absorbed orally with peak plasma levels reaching in 1-4 hours.
• Toxicity: GI disturbances and blood dyscrasias. Fever, rashes and hypersensitivity
reactions are occasionally observed.
• Novobiocin is mostly used in combination with procaine penicillin G in the
treatment of mastitis.
• Also used in the treatment of MRSA.
8. MISCELLANEOUS ANTIBIOTICS
• e.g. fusidic acid, mupirocin, daptomycin, fosfomycin and cycloserine.
Fusidic acid
• Obtained from Fusidium coccineum.
• It acts by inhibiting protein synthesis in bacteria.
• Primarily effective on gram-positive bacteria (MRSA, Staphylococcus species,
Streptococcus species and Corynebacterium species)
II. SYNTHETIC ANTIBACTERIALS
1. NITROFURANS
• e.g. Nitrofurantoin & furazolidone
• It acts by inhibiting carbohydrate metabolism in susceptible bacteria.
• Broad-spectrum of activity & also active against coccidia, trichomonads, amoebae
and giardia.
• More active in acidic environment
• Used topically for cutaneous infections and wound dressings in all species & orally as
urinary antiseptics in dogs and cats.
• Adverse effects: Several toxic effects in animals include GI disturbances and CNS
signs. Depression of spermatogenesis. hypersensitivity reaction can also occur.
Carcinogenic in laboratory animals.
Nitrofurantoin
• It is a synthetic nitrofuran used mainly for prevention and treatment of urinary tract
infections.
Furazolidone
• Synthetic nitrofuran used orally for enteric infections & topically on skin.
• It has wide spectrum of antibacterial activity & also active against Giardia,
Trichomonas, Coccidia and Histomonas.
•

2. NITROIMIDAZOLES
• Antiprotozoal and antibacterial activities.
• E.g. Metronidazole and dimetridazole
• Metronidazole
• Widely used in the treatment of trichomoniosis, giardiasis and amoebiasis.
• Bactericidal used to treat most gram-negative and gram positive anaerobic bacterial
infections.
• Metronidazole acts mainly by disrupting DNA synthesis in the susceptible
.
microorganisms.
• Dimetridazole is a synthetic 5-nitroimidazole antiprotozoal drug similar to
metronidazole.
URINARY ANTISEPTICS
• Urinary antiseptics are drugs which attain useful antibacterial concentrations only in
the urine and are used exclusively for urinary tract, bladder or renal pelvis
infections.
• E.g. nalidixic acid, nitrofurantoin and methenamine.
Methenamine (Hexamine)
• Synthetic compound
• Their salts are freely soluble in water
• MOA: The antibacterial activity of methenamine occurs due to release of
.
formaldehyde gas in water.
• Methenamine → Formaldehyde gas
• PH dependent hydrolysis reaction.
• Methenamine is primarily a bacteriostatic agent, but it becomes bactericidal in acidic
urine.
• Used in urinary tract infections in dogs & cats.

Chemotherapy of Tuberculosis
 Cattle : Mycobacterium bovis

Dogs : Mycobacterium tuberculosis / Mycobacterium avium complex
Pigs : Mycobacterium avium complex
Man: Mycobacterium tuberculosis / Mycobacterium avium complex
Mycobacterium kansasii / Mycobacterium fortuitum complex
Mycobacterium leprae cause Leprosy
Sheep, Horse and cat – Relatively Resistant
 First line drugs for TB: Isoniazid, Rifampin, Pyrazinamide, Ethambutol and
Streptomycin.
1. Isoniazid
 Primary drug for tuberculosis.

 Discovered in 1945 by chorine.
 It is hydrazide salt of isonicotinic acid
 Resting bacilli-bacterioststic, Rapidly dividing bacilli – bactericidal
 MIC: 0.025 – 0.05 µg/ml.
 Penetrates bacterial cell easily.
 MOA: Several hypothesis includes effects on lipids, nucleic acid biosynthesis and
glycolysis.
 Primary action is to inhibit biosynthesis of mycolic acid which is important
constituent of mycobacterial cell wall.
 Mycolic acid – unique to mycobacteria so high degree of selectivity.
 Rapid absorption following oral or parenteral administration.
 Distributed to tissues and body fluids. Therapeutic concentration achieved in CSF,
Pleural and ascetic fluid.
 75-90% metabolized and mainly excretion through urine
 Major Metabolites- 1) Acetyl isoniazid (acetylation)
2) Isonicotinic acid (hydrolysis)
 Globally the most preferred drug to treat all types of T.B.
 Isoniazid alone for prevention whereas isoniazid + other drugs for treatment.
 Dose: 3-5 mg/kg PO/IM. May be given with Pyridoxine/ Vitamin B6 (15 – 50 mg/kg)
to minimize side effects of isoniazid
 Prominent reactions – Rash, fever, jaundice and peripheral neuritis
 Peripheral neuritis is common.
 Isoniazid causes pyridoxine (vitamin B6) deficiency.
2. Rifampin
 Rifamycins – complex macrolcyclic antibiotics (Streptomyces mediterranei)

 Rifampin – Semisynthetic derivative of Rifamycin B
 High activity against Mycobacterium tuberculosis and other mycobacterium spp.

 Active against most G+ve (High activity against S. aureus) and some G-ve bacteria
(E.coli, Pseudomonas, Proteus & Klebsiella). Also active against Neisseria and
Hemophillus.
 Bactericidal action on intra and extra cellular microorganisms.
 Inhibits DNA-dependent RNA-polymerase enzyme – suppress initiation of RNA
synthesis in mycobacterium and other microorganisms.
 Less affinity for eukaryotic nuclear RNA-polymerase.
 High concentration inhibits viral RNA-polymerase and reverse transcriptase.
 Variable oral absorption, widely distributed including CSF.
 Metabolized to active deacetylated metabolites.
 Rifampin (150mg) + isoniazid (300 mg): most effective drugs for treatment of TB.
 Side effects: Rash, fever, nausea and vomiting.
 Potent inducer of hepatic microsomal drug metabolizing enzyme system.
 Decrease half-life of digitoxin, quinidine, ketoconazole, propanolol, metoprolol,
clofibrate, verapamil, barbiturate, halothane etc.
3. Ethambutol
 All strains of M. tuberculosis and M. avium complex are sensitive.

 No activity against other bacteria.
 MOA: Inhibits incorporation of mycolic acid in to the mycobacterial cell wall.
 Bioavailability: 75-80 % (PO), 75% excreted unchanged in urine (24h).
 Treatment of TB: Isoniazid + ethambutol.
 Replaced use of para-aminosalycylic acid (PAS).
 Side effects: rash, fever, optic neuritis-dose related and resolve following withdrawal
of drug
4. Streptomycin
 First drug used to treat TB, Bactericidal

 Use for pulmonary TB has reduced.
 Side effects: Rash, fever, dysfunction of auditory and vestibular function.
5. Pyrazinamide
 High activity on intracellular tubercle bacilli

 Following oral administration, well absorbed and distributed.
 Hydrolyzed into pyrazinoic acid & 5-hydroxy pyrazinoic acid
 Used as component of short term (6 month) multi drug therapy of TB
 Side effect – Hepatic damage.
6. Ethionamide
 Effective against M. tuberculosis.

 Use: secondary line drug for treat of T.B.
 Side effects: Anorexia, nausea and vomiting.
7. Para Amino Salicylic Acid (PAS)
 Bacterioststic (M. tuberculosis), Second line drug.

 Structural analog of PABA- inhibit folic acid synthesis in mycobacterium
 Side effects: GI upsets, nausea, epigastric pain and diarrhea.
8. Cycloserine
 Antibiotic : obtain from Streptococcus orchidaceus, Second line drug.

 Inhibits M. tuberculosis (MIC : 2-20 µg/ml)
 Side effects: CNS disturbances (headache, tremors, vertigo, confusion, nervousness
etc.)
TB chemotherapy - Strategies
 Treatment – Always use two drug combinations.

First 2 months: Isoniazid+ Rifampin + Pyrazinamide, Nest 4 months: Isoniazid+
Rifampin
Note:
 DOTS: Directly Observed Treatment (short-course)

 DOTS is the most effective strategy available for controlling TB.

69. ANTIVIRAL DRUGS
INTRODUCTION
 Antiviral drugs are agents that used to limit growth and replication of viruses.
 One of the least use drugs in veterinary practices.
 Development of effective and safe antiviral therapy is difficult. So far limited antiviral
drugs for animals and human were available.
 The conventional approach is to develop effective vaccines.
 The treatment of viral infection in animals are usually consists of nursing, control of
secondary bacterial infections, use of analgesics and other symptomatic
therapies.
[Virus: Obligate intracellular parasites, need host genetic machinery for replication,
narrow therapeutic index and lack enzymes that function in energy metabolism. Virus
shows cell dependant replication. Hence they multiply only within the cells. Virus lack
both cell wall & cell memberane.
 Viruses are the smallest infective agents with size ranging from 20 nm
(Picornaviruses) to 300 nm (Poxviruses).
 Animal viruses may be single stranded or double stranded RNA or DNA viruses.]
Difficulties in development of antiviral drugs/ Reasons for failure of antiviral therapy
 Viruses are intracellular pathogen therefore antiviral drugs that target viral process
must penetrate the host cell.
 Viral biochemistry is not fully understood in all types of viruses.
 Lack of broad spectrum antiviral drugs.
 Lack of in vitro susceptibility testing procedures.
 Viruses utilize host cell machinery for replication so antiviral drugs may injure host
cell resulting in narrow margins of safety.
 Chances of easier development of resistance due to mutation
 Inhibits only actively replicating virus, unable to eliminate non replicating/latent viral
infection.
 Mostly virustatic, hence success depends on host immune response.
 They are effective prophylactically and in early stage.
CLASSIFICATION OF ANTIVIRAL AGENTS

1) Agents preventing attachment and penetration: Gamma-globulin, Interferon,
Arbidol, Pleconaril
2) Inhibitors of viral assembly: Amantadine, Rimantadine, Tromantadine
3) Nucleoside analogues:
DNA virus-Idoxuridine, Trifluridine (pyrimidine analogues), Aciclovir Valaciclovir,
Ganciclovir,
Vidarabine (purine analogues) and Foscarnet (Pyrophospahte analogues).
RNA virus- Ribavirin
4) Inhibitor of reverse transcription: Zidovudine
5) Inhibitor of mRNA translation: Antisense oligopeptides
6) Protease inhibitors: Saquinavir, Ritonavir, Indinavir
7) Immunomodulators: Interferons, Inosiplex, levamisole, Poly I (Polyriboinosinic
acid) and Poly C (Polyribocytidylic acid)
8) Inhibitors of viral release: Zanamivir and Oseltamivir

9) Other agents: Methisazone, Rifampicin, Dactinomycin, Suramin and Dextran
sulphate.
Figure: Mechanism of Action / Targets for Antiviral Drugs
AMANTADINE
 Amantadine and its derivative Rimantadine are synthetic tricyclic amine.
 They lead to inhibition or delay of the uncoating process and also interfere with early
stage of viral mRNA transcription, inhibit viral assembly.
 At usual concentration inhibit replication of different strains of Influenza virus.
 Almost completely absorbed from GIT and 90% is excreted unchanged in urine.
 It produces fever, side effects related to CNS. Aerosol administration reduces the
toxicity.
 Veterinary uses: Prophylaxis in equine influenza.
IDOXURIDINE, VIDARABINE AND TRIFLURIDINE

 Potent inhibitors of DNA synthesis of Herpes virus. Inhibition takes place during
synthesis of DNA strand. These drugs are incorporated into the growing chain of viral
DNA, resulting in misinterpretation of genetic code.
 Inhibit DNA polymerase and defective viral proteins are synthesized.
 Toxicity- Anemia, neutropenia, loss of hair etc.; Because of toxicity reserved for
topical application.
 Idoxuridine, Trifluridine - analog of thymidine; Trifluridine is less toxic and better
penetration than Idoxuridine.
 Vidarabine- analog of adenosine; Acts on Herpes, Pox, Rhabdo, Vaccinia viruses.
 50% excreted in urine

 Used for the treatment of Herpes simplex, Keratitis, Encephalitis, Mucocutaneous
infection and Cytomegalo viral infection
 Veterinary use: Feline herpes keratitis, bovine vulvovaginitis and kerato-
conjunctivitis, local herpes infection
 Vidarabine: Local bovine herpes, Vaccinia teat lesions.
 Dose: Idoxuridine: 1 drop of 0.1% sol, every hour in infected eye. Trifluridine: 1 drop
of 0.1% sol, 4-6 times/day in infected eye.
ACYCLOVIR
 Synthetic, one of the most prescribed drug, available as sodium salts - water soluble.
 It is selective for viral rather than normal cells.
 Less cytotoxic, breakthrough in antiviral chemotherapy.

 Acyclovir is not phosphorylated in normal cell because of lack of viral thymidine
kinase, non toxic to uninfected cell.
 Valacyclovir, Desiclovir are prodrugs developed because of 90% of acyclovir is
excreted in urine intact
 Human use - Herpes simplex 1 and 2, Varicella Zoster virus – chicken pox
 Veterinary use - Equine herpes in foals
 Available in oral, topical and IV preparations.
 Topical - Local herpes, bovine herpes mammillitis, equine coital exanthema, feline
rhinotracheitis, viral kerato conjunctivitis
 Dose: Dogs & cats: 3mg/kg, PO, 5 time daily for 10 days than 10 mg/kg for next 10
days. Horses: 10 mg/kg, slov IV, 2 time daily; Birds: 80 mg/kg, PO, 3 time daily
GANCICLOVIR
 Guanosine analogue, more active against cytomegalo herpes virus than acyclovir in
immune compromised patients.
 Administration through I/V. Neutropenia and thrombocytopenia are adverse effects.
 Veterinary use: Cytomegalovirus infection
RIBAVIRIN
 Guanosine analogue
 It is activated by viral phosphorylation and subsequently prevents the formation of
mRNA and translation of viral genome. Broad antiviral activity against many RNA &
DNA virus. Resistance is rare.
 Aerosol- Respiratory syncytial virus broncholitis and influenza.
 Veterinary use: Influenza, parainfluenza, bovine herpes virus, canine distemper, blue
tongue, marek's disease, feline calcivirus.
 Topical: Local herpes infection (not feline), vaccinia teat lesions.

AZIDOTHYMIDINE/ZIDOVUDINE
 Zidovudine effective against retrovirus – HIV virus (AIDS).
 Act by selectively inhibition of viral reverse transcriptase enzyme (RNA dependent
DNA polymerase).
 Toxicity- Dose dependent Anemia, neutropenia, hepatotoxicity & GIT disturbances
 Veterinary Use: Retrovirus, feline leukemia virus (FeLV), feline immunodeficiency
virus (FIV), Equine infectious anemia (EIA)
 In HIV patients – First line of drug in treatment of AIDS in human being.
ANTISENSE OLIGONUCLEOTIDE
 The sequence of a nucleotide chain containing information for protein synthesis is
called sense sequence. The complementary strand is called antisense sequence.
 Antisense drugs recognize and bind to sense sequence of specific mRNA and thereby
prevent synthesis of specific proteins
 Destruction of mRNA by ribonuclease in cell and inhibit viral mRNA translation.
IMMUNIZATION AND INTERFERONS

Immunization
 Passive immunization by IM, IV or SC injection with immunoglobulin can prevent
entry of virus into cells (orally ineffective).
 This is useful to control CD, rabies, gastroenteritis in swine, ICH, Measles,
Poliomyelitis, chicken pox.
 If hyper immune serum is not available pooled sera from the recovered or vaccinated
animals may be used.
 To avoid anaphylactic shock only one injection should be given.
 Gamma globulins (concentrated antibodies= IgG) extracted from normal blood may
also be useful in preventing viral infections in animals.
Interferons
 Interferons are potent cytokines or interrelated group of proteins released by cells
infected by virus. They are highly species specific.
 Interfron (IFN) possesses antiviral, immunomodulatory and antiproliferative actions.
 Liberated from host cells infected by viruses and make other cells to resist the virus.
 Their effect results from binding to specific viral surface receptors and thus
preventing uncoating or penetration by the virus or inhibition of sythesis of viral
proteins.
 Three types are recognized: α, β and γ interfrons.
 IFN-α – Leucocytes.
 IFN-β - Fibroblasts antiviral action in response to RNA virus infection.
 IFN-γ or lymphokines – Lymphocytes, antigen/mitogen stimulation, immuno
modulation.
 They inhibit all the steps in viral multiplication. Bind to specific cell surface receptors
and inhibit viral penetration, uncoating, synthesis of mRNA, translation, assembly and
release.
 It can be administered SC, IM or IV. It is an important part of defense mechanism.
 Its activity expressed as International Units (I.U.).
 Clinical use: Rhino virus, Papilloma virus and herpes simplex infections, Cat- Feline
leukemia virus. Bovine IFN α, γ produced by Genetic engineering.
Interferons inducers/ Host modulators
 Interferon production in host cells can be induced by viruses, bacteria, bacterial
products, Poly-I, Poly-C and Inosine. It induce production of its own interferon.

ANTINEOPLASTIC DRUGS
Cancer: Disease of cells characterized by loss of regulatory mechanisms which control cell
growth and maturation required for homeostasis in complex multicellular organisms.
Neoplasm/tumour: Uncontrolled growth of cells coupled with malignant behavior, invasion
and metastasis.
VARIOUS PHASES OF CELL CYCLE:

G1 phase (Pre synthetic phase)
 It is interval following cell division to DNA synthesis starts.
 It lasts for 10-72 hrs where in cell sends growth signals / mitogens start the process of
cell division.
 Protein synthesis and RNA transcription occurs during this stage.
S phase (synthesis phase)
 DNA synthesis period for chromosome doubling.
 It lasts for 10-20 hrs in preparation for mitosis and is the target for many
antineoplastic drugs.
G2 phase (Post synthetic phase)
 RNA and protein synthesis period; cell activity increases.
 The duration is 1- 3 hrs.
M phase (Mitotic phase)
 The duration is very short < 1 hr.
Go Phase (Resting/non proliferative phase)
 Antineoplastic drugs are rarely effective in this stage.
 Cells like myocytes and neurons enter Go and rarely / never cycle again (Muscle &
nerve cell not regenerate).
[M=Mitotic phase, S=Synthetic phase, G1=Pre synthetic phase, G2= Post synthetic phase,
G0= True resting phase.]
 Antineoplastic agents are broadly divided into two classes.
a) Cell cycle phase specific drug
 This group act at a certain phase of the cell cycle, usually at S or M phase. The effect
is more when the cells are actively proliferating.

 Cells in the Go phase are troublesome because they are not susceptible to cytotoxic
drugs.
 e.g. Methotrexate , Pyrimidine and Purine analogues, Hydroxyurea and Vincristine.
b) Cell cycle phase non specific drugs
 This group act at all stages except Go phase. Increased drug level kills the cells.
 These drugs are given in large doses for a short period but capable of causing bone
marrow suppression.
 e.g. Cyclophosphamide, Nitrogen mustard and Chlorambucil.
ANTINEOPLASTIC DRUGS
 Antineoplastic drugs are agents that are used to either kill or modify or arrest growth
of tumour cells.
 Their uses are becoming increasingly important in veterinary practice.
 These drugs are often used in combination with surgery and/or radiotherapy.
 It must possess selective toxicity to malignant cells at normal dose than the host cells.
They react with important substrates of enzymes that are related to DNA or RNA
synthesis. Hence they are selectively toxic to cells that are rapidly dividing or those
with high mitotic index.
CLASSIFICATION OF ANTINEOPLASTIC AGENTS
1) Alkylating agents
 Nitrogen mustard: Mechlorethamine, Cyclophosphamide, Melphalan, Uracil, Mustard
& Chlorambucil
 Alkyl Sulfonates: Busulfan
 Nitrosoureas: Carmustine, Lomustine, Semustine, Streptozocin.
 Triazene: Dacarbazine
2) Antimetabolites
 Folic acid analogues: Methotrexate
 Pyrimidine analogues: Fluorouracil, Floxuridine, Cytarabine
 Purine analogues: 6 mercaptopurine, 6 thioguanine.
3) Natural products:
 Vinca alkaloids: Vincristine, Vinblastine
 Antibiotics:
Dactinomycin (Actinomycin D)
Anthracycline antibiotics – Daunorubicin, Doxorubicin
 Glycopeptides – Bleomycin, Mitomycin
 Enzymes : L-asparaginase
4) Hormones and their antagonists
 Adrenocorticosteroids - Glucocorticoid
 Progestins: Hydroxy progesterone
 Estrogens: Diethylstilbesterol
 Anti estrogens: Tamoxifen
 Androgens: Testosterone
5) Miscellaneous
 E.g. Cisplatin, Carboplatin, Mitotane, Hydroxyurea and Procarbazine
TOXICITY OF ANTINEOPLASTIC AGENTS
 Antineoplastic drugs are among the most toxic drugs because they lack selectivity and
affects neoplastic as well as normal proliferating cells.
 Bone marrow depression resulting in leucopenia, increased incidence of infection,
thrombocytopenia and uncontrolled bleeding.

 GI disturbances including anorexia, nausea, vomiting, diarrhea, stomatitis and
ulcerative enteritis. Antiemetics can be administered before the commencement of
treatment.
 Suppression of immune response
 Alopecia, Superinfection
 Secondary malignancy due to the use of antineoplastic agent
 Teratogenicity and infertility
 Hypersensitivity
DOSE:
2
 The dose is calculated based on body surface area and expressed as m . Since
chemotherapeutic agents are highly toxic to other normal cells and certain parameters
like BMR, blood volume, cardiac output and renal function were found to correlate
better with BSA (body surface area) than body weight, the dose is expressed in m2.
BSA= B.Wt0.67 x K/104 [BSA in m2, B.Wt in g and K= 10 for cat; 10.1 for dogs]
1) AKYLATING AGENTS
 These compounds are highly reactive intermediates that are able to transfer alkyl
group to DNA. They add alkyl / methyl group to DNA.
 Miscoding of DNA - Strand leakage or disruption leads to cell death.
 Cross resistance between alkylating agent exists.
Monofunctional Alkylating agent

 Transfer single alkyl group (7-N guanine residue).
 Inhibit correct utilization of base pair instead of AT CG.
 Guanine pairs with thymine.
 Miscoding of DNA.
 Strand breakage or disruption.
 Cell death/ mutagenesis/ carcinogenesis.
Polyfunctional alkylating agents
 Alkyl group is added to both the strands of DNA.
 Cross linking of DNA strand prevents uncoiling.
 Inhibition of cell growth, apoptosis leads to cell death.
 Alkylating agents are activated by CYP450 and resistance to one alkylating agent
induces resistance to others.
 Though not cell cycle specific rapidly dividing cells are more affected.
Side effect
 Bone marrow depression.
 Nausea and vomiting, some degree of GI toxicity.
 Reversible hair loss.
NITROGEN MUSTARDS
 Limited use in combination with other agents for lymphoma, lymphoreticular
neoplasia, pleural and peritoneal effusions and mast cell tumor.
 Extremely short duration of action. GI toxicity is prominent unlike other alkylating
agents.
2
 Dose of mechlorethamide in dogs: 5 mg/m , IV.
Cyclophosphamide
 It is a cytotoxic and immunosuppressive drug

 A broad spectrum anticancer drug given alone or in combination and is widely used in
veterinary medicine.
 Indication: Lymphoma, Lymphoreticular neoplasm, sarcomas, carcinoma of lung,
ovary, mammary gland and multiple myeloma.
 Can be given orally or parenterally. At normal dose it is cell cycle specific and at high
dose – Cell cycle non specific
 Toxicity: Neutropenia, bladder damage, necrotising haemorrhagic cystitis (bleeding)
Melphalan
 Phenylalanine derivative of Mechlorethamine. Recommended for oral administration
before food.
 Widely used for neoplastic diseases like mammary carcinoma, malignant melanoma,
multiple myeloma, ovarian carcinoma and testicular seminoma.
Side effect: Dose limiting bone marrow depression & GI disturbances.
Chlorambucil
 Slowest acting and least toxic.
 Substitute for cyclophosphamide when haemorrhagic cystitis is exhibited.
 Indications: Chronic lymphocytic lymphoma, multiple myeloma, ovarian carcinoma
ALKYL SULPHONATES: Busulfan

 Indications – Chronic granulocytic leukaemia.
 Well absorbed orally and also be given through intravenously.
 Patients should be premedicated with phenytoin. Since it crosses BBB.
NITROSOUREAS
Carmustine, Lomustine, Semustine
2
 Oral administration – Dog: 50 mg/m – Single dose every 6 weeks.
 Need biotransformation, highly lipid soluble and crosses the BBB.
 Indication: Brain tumours, cancer of lung, stomach and Colon.
 Streptozocin: Obtained from Streptomyces acromogens. Used for treatment of
malignant pancreatic insulinoma.
TRIAZENE
Dacarbazine
 Indication: Malignant myeloma and soft tissue carcinoma
 Not much used in veterinary practice
 Side effects: Nausea, vomiting, bone marrow depression, hepato & neurotoxicity.
2) ANTIMETABOLITIES
 Resemble normal cellular metabolites and therefore interfere with normal metabolic
pathways in a toxic manner.
 Tetrahydro folate deficiency blocks reaction requiring folate coenzymes and inturn
disrupt DNA and RNA synthesis.
 It is cell cycle specific - S phase is most sensitive
 Side effect: Bone marrow suppression, Severe GI toxicity
FOLIC ACID ANALOGUE

 E.g. Methotrexate (Oldest & highly efficacious drug- widely used in dog, cats)
 Folic acid analog used against a variety of neoplasms.
 Inhibits dihydrofolate reductase enzyme & prevent the formation of tetrahydro folate
and thereby the purine and pyrimidine nucleotides.
 Administration– Parenteral or intrathecal in CNS neoplasia
 Excreted in urine and at high dose precipitate in renal tubules.

 Side Effect: Bone marrow suppression following high dose
PYRIMIDINE ANALOGUE
5-Fluorouracil
 It is converted to active phosphate form and inhibits thymidylate synthase and inturn
causes DNA and RNA synthesis inhibition.
 Indication: GI, liver, skin and mammary carcinomas
 Administration: IV as well as topical, Metabolized in the liver and enters into the CSF
 Side Effect: CNS disturbance, neurological signs, seizures and death
 GI disturbance, oral ulceration & mild myelosuppression.
Cytarabine/Cytosine arabinoside
 Analogue of deoxycytidine and must be activated by conversion to monophosphate
nucleotide Cytarabine.
 Administration: IV or SC.
 Indication: Canine and feline lymphomas & leukemia.
 Toxicity: Leucopenia with megaloblastic changes and GI disturbances.
PURINE ANALOGUE
Mercaptopurine
 Sulphydryl Substituted analogue of hypoxanthine.
 Needs intracellular activation and inhibits a number of enzymes of purine nucleotide
inter conversion leading to inhibition of DNA and RNA synthesis.
 Administration: oral. Undergoes rapid degradation and some renal excretion.
 Side Effect: Bone marrow suppression, GI disturbances, Nausea and Vomition.
 Indication: Acute lymphocytic leukemia & granulocytic leukemia.
Thioguanine
 Similar to 6 – Mercaptopurine
 Inhibits several enzymes in purine nucleotide pathway, inhibition of nucleotide
interconversion, decreased intracellular guanine and interference with DNA and RNA
synthesis.
 Indication: Acute non lymphocytic leukemia & adult acute leukemia.
3) NATURAL PRODUCTS
Vince alkaloids: Vincristine & Vinblastine
 Mitotic inhibitors.
 These are large and complex molecules derived from Vinca rosea.
 Vincristine active only in M phase.
 Bind to the tubulin and interfere with mitotic spindle formation and thus segregation
of chromosomes in metaphase is arrested.
 Administration: IV, metabolised in the liver, partially excreted unchanged in urine.
 Indication: Transmissible venereal tumour (Vincristine), Lymphoreticular neoplasm
 Soft tissue sarcoma - Vincristine + Doxorubicin + Cyclophosphamide
 Vinblastine – used as a substitute for vincristine when the vincristine-induced
neuropathy is noted.
2
 Dose: Vincristine - 0.5 to 0.75 mg/m IV once weekly.
Antibiotics
 Dactinomycin (Actinomycin-D): Obtained from various Streptomyces.
 Binds with the double stranded DNA – intercalate and blocks the actions of RNA
polymerase prevent transcription.
 Administration: IV infusion.

 Indication: Lymphoreticular neoplasm, testicular carcinoma, rhabdomyo sarcoma and
malignant melanomas.
Anthracycline antibiotics:
 E.g. Doxorubicin, Daunorubicin
MOA:
 It blocks DNA and RNA synthesis, strand break.
 Inhibits topoisomerase II.
 Alteration in cell membranes transport.
Doxorubicin: One of the most widely used cytotoxic drug in small animals.
 solid tumors – breast cancer and hematologic malignancies
Daunorubicin
 Cell cycle non specific, maximum effect during S phase.
 Side effect: Myelosuppression, cardio toxicity, phlebitis and urticaria (Should be
premedicated with corticosteroids and antihistamines.)
Glycopeptide
 E.g. Bleomycin: Obtained from Streptomyces verticillus.
 Cell cycle specific (G2 & M phase)
 MOA: It inhibit DNA repair enzymes
 Indication – Testicular tumors, squamous cell carcinoma, lymphoma and seminoma
 Side Effect – Lung toxicity and little myelosuppression.
Enzymes
 L-asparaginase enzyme derived from E-coli.
 G1 phase specific drug.
 Side effects: Anaphylaxis and hypersensitivity
 Indication: Lymphoreticular neoplasm.
4) HORMONES AND THEIR ANTAGONISTS

 E.g. Estrogens, antiestrogens, androgens, antiandrogens, progestogens & GnRH
analogues.
 Glucocorticoids: Cell cycle non specific agent.
 Prednisone and prednisolone: Lymphoreticular neoplasm in combination with other
chemotherapeutic agent.
 Dexamethasone, prednisone & prednisolone: Leukemia and lymphoma of the CNS.
 Immunomodulators used are corticosteroids and interferons.
 Estrogens (Diethyl stilbesterol, Oestradiol): Prostatic hyperplasia, Peri anal glandular
neoplasm.
 Complications: Life threatening bone marrow suppression and aplastic anemia,
Feminization and fluid retention.
Tamoxifen
 Antiestrogen
 Indication: Early stage and metastatic breast cancer.
 Chemopreventive agent in women at high risk of breast cancer & endometrial cancer.
Progestins (Megestrol, Medroxy progesterone)

 Oppose the effects of hormones in endometrial, prostatic, breast, renal cell and
ovarian carcinoma.
 Androgens: Breast carcinoma & hypernephroma.
 Antiandrogen: Prostatic tumor.

5) MISCELLANEOUS AGENTS
Carboplatin
 It‘s a derivative of platinum, causes inter and intra strand DNA alkylation.
 Cell cycle non specific drug administered IV with mannitol to promote dieresis.
Mitotane
 Used in adrenal tumor. It act by inhibiting ACTH steroid production and causes
atrophy of inner zones of adrenal cortex.
Hydroxyurea
 Inhibits ribonucleotide reductase, leading to depletion of essential DNA precursors.
 Indication: Granulocytic leukemia & management of polycythemia vera in dogs &
cats.
NEWER APROACHES
 Hematopoietic stem cell transplant for hematologic malignancies like myeloma,
lymphoma and leukemia.
 Isolated infusion approaches to overcome toxicity but not useful in metastasis.
 Isolated limb perfusion, Isolated infusion into lung and liver for solid tumors.
 Specially targeted drug delivery - vehicle specific and target tumor cells.
 Nanoparticles - useful vehicle for poorly soluble agents such as Paclitaxel.

ANTHELMINTICS
INTRODUCTION
 Antiparasitics are drugs that reduce the parasitic burden by killing (vermicide) or
inhibiting their growth (vermifuge).
 Anthelmintics are drugs or agents that eliminate the worms from gastrointestinal
tract, other tissues and organs of body.
 Anthelmintics are broadly divided into 3 groups:
o Anti-nematodal drugs: Effective against Nematodes / round worms
o Anti-cestodal drugs: Effective against Cestodes / tapeworms
o Anti-trematodal drugs: Effective against Trematodes / flukes
CHARACTERISTICS OF IDEAL ANTHELMINTICS

1) It should have broad spectrum of activity.
 It should be active against a large variety of helminths in all animals and also
effective against mature, immature worms and larval stages.
o Antinematodal - Effective against hypotactic and migrating larva.
o Fasciolicide – It should kill immature flukes.
o Anticestodal – It should be able to remove the scoleces and strobilae.
 An ideal broad spectrum anthelmintic should be active against all the three categories.
e.g. Albendazole, closantel, Netobomin.
2) It should have wide margin of safety: Safety margin of at least six fold is expected for
modern anthelmintics
3) No residue period in tissue
 The drug should not have a tendency to accumulate in tissue or secreted in milk.
 The withdrawal period should be minimal. However in non-food animals prolonged
persistence may be beneficial by providing extended period of protection against
reinfection.
4) Easy to administer to herd/flock: It should be effective on a single dose.
5) Economical: Easily available, cheap and stable under normal storage conditions.
6) Compatible with food/feed
MECHANISM OF ACTION OF ANTHELMINTICS

 The mode of action of anthelmintics can be broadly categorised into two types:
a) Interference with energy metabolism of parasite
b) Neuromuscular paralysis of the worm.
a) Drugs affecting energy metabolism
 The normal metabolic process is affected.
Inhibition of fumarate reductase in mitochondria
 Failure to synthesize ATP. The worms die in the absence of energy. e.g
Benzimidazoles and its pro drugs (Albendazole, Fenbendazole, flubendazole).
Inhibition of tubulin polymerisation
 Binding of drugs with tubulin block polymerisation and microtubule formation. As a
result inhibition of mitosis, embryonation, egg hatching, secretory function etc. e.g.
Benzimidazole (Mebendazole).
Inhibition of mitochondrial phosphorylation/uncoupling of oxidative phosphorylation
 These act as protonophores, allowing hydrogen ions to leak through the inner
mitochondrial membrane and interfere with ATP synthesis eg. Salicylanilide‘s
(oxyclozanide, rafoxanide) and substituted phenols which are mainly flukicides.
Inhibition of glycolysis

 Glycolytic enzymes like phosphoglycerate kinase and mutase are selectively inhibited
leading to depletion of energy eg. Clorsulon (flukicide) and Thiacetarsamide (heart
worm).
b) Drugs causing neuromuscular paralysis of the worm
 Interfere with the normal neuromuscular function of worms and induce spastic or
flaccid paralysis, the parasites are removed from the host and expelled out. The killing
is generally rapid.
 The drug categories are:
Acetyl cholinesterase (AChE) inhibitors
 Increased concentration of Ach at neuromuscular junction leads to spastic paralysis
eg. Organophosphates (OP): Coumaphos, dichlorovos. trichlorofon, haloxon etc.
 OP irreversibly inhibit AchE enzyme.
Cholinergic agonist
 It acts as agonist at nicotinic receptor of nematode. Ganglionic stimulation causes
sustained muscle contraction initially followed by depolarizing neuromuscular
blockade which in turn leads to spastic paralysis. E.g. Levamisole, Butamisole,
Pyrantel and Morantel.
Muscle hyperpolarization
 Block neuromuscular transmission in parasite by hyperpolarising the nerve membrane
leading to flaccid paralysis and expelled by peristalsis eg. Piperazine. It also blocks
succinate production by the worm. It may also act through GABA.
Potentiation of inhibitory transmitters / GABA agonists
 They act as agonist at GABA receptor -> Opens chloride channel -> flaccid paralysis.
e.g. Piperazine
 Ivermectin causes paralyse the pharynx (unable to feed), the body wall and uterine
muscles of nematodes.
 It is not active against cestodes/ trematodes since they do not have receptor at
glutamate gated chloride channel.
OTHER MECHANISMS
 Affecting the permeability of the cell and vacuolation of tegument e.g. Praziquantal
increases the permeability of trematode tegument to calcium and result in spastic
contraction of muscle.
 Disruption of tegument e.g. Bunamidine, Espirantel, Praziquantal.
 Inhibit glucose metabolism of Fasciola e.g. Diamphenethide, Clorsulon
 Interferes with Arachidonic acid metabolism of filarial parasite e.g.
Diethylcarbamazine Citrate (DEC).
Endectocide:
 An antiparasitic drug that is active against both endoparasites and ectoparasites.
 e.g. Avermectins (ivermectin, abamectin, doramectin & eprinomectin) and
Milbemycins (moxidectin). They are active against both internal nematodes and
ectoparasites/arthropods.
Note: Albendazole is teratogenic, not recommended during first trimester of pregnancy.

TABLE: CLASSIFICATION OF ANTHELMINTIC DRUGS AND ITS SPECTRUM
Group Drug Anthelmintic activity

Benzimidazoles Thiabendazole Nematodes (Also mites & fungi)
Parbendazole Nematodes
Oxibendazole Nematodes
Flubendazole Nematodes (Pigs)
Canbendazole Nematodes and cestodes
Fenbendazole Nematodes and cestodes
Mebendazole Nematodes and cestodes
Oxfendazole Nematodes and cestodes
Luxabendazole Nematodes and Flukes (sheep)
Triclabendazole Trematodes
Albendazole Nematodes, Cestodes, mature flukes
Benzimidazole Febantel (Fenbendazole) Nematodes

Pro- drugs Thiophanate (Lobendzole) Nematodes
Netobimin (Albendazole)
Imidazothiazoles Levamisole Nematodes

Butamisole Nematodes
Tetramisole Nematodes
Salicylanilides Closantel Broad spectrum
Niclosamide Cestodes and intestinal trematode
Oxyclozanide Mature flukes
Rafoxanide Trematode and some nematodes.
Substituted phenols Diamphenethide N, T, C
Niclofolan Trematode
Bithionol C, T
Nitroxynil N, T
Nitroscanate N, C (dogs)
Disophenol Hookworm in dogs &cats
Clorsulon Adult & immature flukes.
Tetra hydro Pyrantel Nematode & Horse tape worm
pyrimidines
Morantel Nematodes
Oxantel Nematodes

Macrocyclic lactones Ivermectin
Nematodes & ectoparasites
Doramectin
(Endectocide)
Moxidectin
Milbemycin oxime
Heterocyclic Piperazine Nematodes (Ascarids)
compounds Diethyl carbamazine Nematodes (dogs), Heart Worm,
(DEC) Microfilaria
Isoquinolones Praziquantel Trematode & cestode

Epsiprantel Cestodes
Miscellaneous Phenothiazine Nematodes
Arecoline Cestodes (dogs)
Bunamidine Cestodes
CCl4 Trematodes
ANTHELMINTIC RESISTANCE
 It is commonly seen in Haemonchus, Trichostrogylus, Ostertagia, Nematodirus and
Oesophagastomum.
 Cross resistance is common between members of the same group.
 The predisposing factors for development of anthelmintic drug resistance by parasites
are
o Use of drug below the therapeutic / recommended dose.
o Continuous use of particular group for a long period.
o Overuse /unwarranted use
o Extensive use of anthelmintic with long withdrawal period.
o Poor management practices
 Measures to overcome resistance:
o Rotational use of anthelmintics
o Avoid indiscriminate use and follow the dosing schedule
o Narrow spectrum compound suitable for developing stage.
ANTI-CESTODAL DRUGS:
Classification: Three types
1. Natural organic compounds e.g. Arecoline, male fern
2. Synthetic compounds e.g. Praziquantel, epsiprantel, niclosamide
3. Inorganic compounds e.g. Lead arsenate, tin oxide, tin chloride
1) PRAZIQUANTEL
 It is a novel anthelmintic with excellent activity against all spp of Schistosomes and
larval cestodes of both animals and humans.
 MOA: It interferes with cell memberane permeability causing rapid influx of Ca++
and it produce spastic paralysis of the parasites.
 It is quickly and almost completely absorb from the alimentary canal.
 In dogs 60-80% of drug is excreted in urine and remaining from faces.

 Main site of inactivation is liver.
 Adverse effects: It is safest anti-cestodal drug available for clinical use in animals
 Dose: Dogs & Cats – 5mg/kg orally.
2) NICLOSAMIDE
 Highly effective against tape worm like Diphylidium caninum, Taenia spp and
Echinococcus spp in dogs, Moniezia spp of cattle, sheep and dogs.
 It has taeniacidal action.
 MOA: Anti-cestodal activity is due to inhibition of absorption of glucose by the
tapeworm and inhibiting oxidative phosphorylation process in the mitochondria of
cestodes.
 Niclosamide is poorly absorbed from the host GI tract, which perhaps accounts for its
low toxicity.
 Small quantities absorbed are transformed into an inactive metabolite.
 It is administered orally after 12 hrs fast. Saline purgative is required to remove all
dead segments.
 Adverse effects: It has wide margin of safety i.e. safety indexis more than 40 times
than the therapeutic dose. No embryotoxic or teratogenic effect.
 Dose: Cattle- 50 mg/kg orally, 70mg/kg in feed
Sheep/Goats/Dogs/Cats– 100 mg/kg orally
3) EPSIPRANTEL
 It has excellent activity against tape worm of cattle, dog, sheep and horses.
 It has less activity against Schistosome.
 It is very safe drug having safety index more than 90%.
 Dose: – Dog. : 5.5mg/kg orally, Cattle 2.25mg/kg orally.
4) BUNAMIDINE
 Bunamidine is use to treat tape worm infestation in dog and cat, also can be given to
pregnant bitch.
 Its activity against Diphylidium caninum is varies about 50-90%.
 It acts by decreases glucose uptake in the susceptible worm.
 It affects the integument of the parasite and cause death of parasite.
 Dose: Dogs/Cats- 25-50mg/kg orally as single dose after fasting of 3 to 4 hrs.
ANTI-TREMATODAL DRUGS
1) HEXACHLOROPHENE
 It has high efficacy against mature forms of Fasciola hepatica & Fasciola gigentica
in cattle & sheep.
 It is excreted in bile as glucuronide metabolites which are also highly active against
adult form since they occupy the bile duct.
 Dose: Cattle/Sheep- 25 mg/kg, orally
 Overdosing produce nervous symptoms such as excitability or depression and
impairment of vision.
2) OXYCLOZANIDE
 It is active against adult and immature form of liver flukes.

 It is also excreted as glucuronide metabolites in bile & is also active.
 This drug require 0 day withdrawal period for milk in cattle, so can be given to
lactating animals.
 Safety index is more than 4 (Low toxicity). Dose: Cattle/Sheep – 15 mg/kg, orally
 The maximum tolerance dose in cattle and sheep is up to 60 mg/kg.
3) RAFOXANIDE
 It is active against immature and mature liver fluke in cattle and sheep.
 Following oral administration peak plasma concentration observe within 24-48hrs.
 It is contraindicated in lactating animals (not used).
 Dose : Cattle/Sheep: 7.5 mg/kg, orally
4) NITROXYNIL
 It is active against mature form of liver flukes.
 It is given parenterally because if it is given orally than reduction of nitro-group by
rumen micro-organism make the drug inactive.
 Dose– Cattle/Sheep : 10 mg/kg, SC
5) CLORSULON
 It is anthelmintic sulfonamide, active against immature and mature liver fluke of
cattle and sheep
 Dose: Cattle: 7 mg/kg, orally or given by S/C route @ 4 mg/kg.
6) DIAMPHENETHIDE
 High activity against immature larval stage of F. hepatica of sheep.
 It has no activity against liver fluke of cattle.
 Amine metabolites of this drug are also more active against immature form of fluke.
 Dose: Sheep- 100 mg/kg, orally.
ANTIPROTOZOAL DRUGS
INTRODUCTION
 Parasitic protozoa are responsible for a wide range of diseases in both animals and
man and protozoal diseases are difficult to eliminate as they are frequently transmitted
by ticks, flies and mosquitoes.
Disease Therapeutic drug
Anaplasmosis Imidocarb, tetracyclines
Babesiosis Diminazene aceturate, Trypan blue, Acriflavin, Amicarbalide
Imidocarb, Phenamidine, Tetracycline
Theileriosis Buparvaquone, Parvaquone, Tetracycline
Trypanosomiasis Quinapyramine (sulphate/chloride salt), Diminazine, Suramin, Trypan
blue
Rickettsia Tetracycline
1) DIAMIDINES
 The diamidines are a group of chemotherapeutic compounds found to have a
trypanocidal activity related directly to the guanyl organic group.
 Mechanism of action: Interferes with aerobic glycolysis and DNA synthesis.

 The diamidines are used either as free bases or as one of the three salts:
dihydrochloride, dimethylsuphonate or isethionate. In veterinary field isethionate are
used most commonly.
 When administered internally, the diamidines cause an arterial dilatation, lowering of
blood pressure and increase tone of the intestinal muscles.
 Kidney and liver damage are the main toxic effects.
 E.g. Imidocarb, Phenamidine, Propamidine, Pentamidine and Diminazene.
Diminazine aceturate (Brand name: Berenil)

 In addition to trypanocidal activity, it is babesicidal and bactericidal (mainly
Brucella and Streptococcus species).
 Dosage is in the form of injection which consists of 8.75% phenazone and 7%
diminazene aceturate and may be administered either by intramuscular or
subcutaneous route.
 For Babesia infection single dose at the rate of 3.5 mg/kg, body weight will be
adequate in horse, cattle, sheep and dogs. Disappearance of symptoms may be
expected within 24 hours.
 For Trypanasoma vivax infections the same dosage as babesia may be given but the
dosage rate should be doubled for T. brucei infections.
 Local reactions may occur at the site of infection, they may be severe in horse.
Phenamidine Isothionate
 The use of phenamidine is confined to the treatment of Babesia infection in cattle,
horse and dogs.
2) QUINAPYRAMINE COMPOUNDS
Quinapyramine chloride and sulphate
 There are two quinapyramine compounds of use – the sulphate which is rapidly
absorbed and mainly trypanocidal with low prophylactic value and the chloride which
is more slowly absorbed and has a strong prophylactic effect.
 It is administered as 10 % solution by SC injection @ 4.4 mg/kg.
 Overdosage may cause trembling, sweating, salivation, increase in respiration, heart
rate, collapse and death.
Suramin
 This is a complex aromatic organic compound, freely soluble in water.
 It has good activity against Trypanosomia evansi in horse, camels, cattle and dogs;
against T. brucei in horse, dogs and cattle and against T. equinum in horses.
 It has been used in veterinary practice for both curative and prophylactic control of
trypanosomiasis.
 IM or SC injection often causes localized reaction and necrosis of tissues, so it is
given only by IV route.
 Suramin is potentially toxic, because the therapeutic index is very narrow. Horse and
donkeys are very susceptible, but camels are quite resistant. Symptoms are those
associated with liver, kidney, spleen and adrenal gland damage.
3) IMIDOCARB DIPROPIONATE
 Mechanism of action: Vacuolization of the cytoplasm and alteration in size of the
nucleus. Interfere with DNA synthesis.
 Well absorbed and distributed through out the body

 Bound to plasma protein and detectable amounts are found in all major tissues up to 4
weeks after IM administration.
 Excreted unchanged in urine and 10% in faeces.
 Recommended for the treatment and prophylaxis of babesiosis, anaplasmosis and
ehrlichiasis.
 Administered through subcutaneous and intramuscular route but not through
intravenous route.
 Narrow margin of safety. In cattle, a dose of 10 mg/kg body weight can cause death.
 Dose:
Babesiosis Cattle 1-3 mg/kg, body weight, IM or SC
Horse 2-4 mg/kg, body weight, IM or SC
Dog 6.6 mg/kg, body weight, IM, single dose
Anaplasmosis Cattle 3 mg/kg, body weight, SC

4) QUINURONIUM SULPHATE
 The drug is used against babesiosis.
 If it is used in early febrile stages of the disease, clinical cure achieved in 24-48 hours,
though a second injection may be needed on the next day.
 The course of treatment should not be repeated for a period of at least 2 weeks,
preferably 3 months; this is due to occasional development of sensitization, which
may result in severe shock and death when treatment is repeated.
 This drug only clinically cures the animals but not eradicate the infection. So on
recovery, these animals retain a number of organisms in their system which maintains
the resistance of the animal to reinfection. This phenomenon is known as premunition.
5) TRYPAN BLUE
 It is an azo dyes and related to the sulfonamides
 It was one of the older agents used against babesiosis, but ineffective against B. equi,
B. bovis and B. gibsoni.
 The drug is relatively non-toxic but stains tissues and secretions, including milk, a
blue green colour which may persist for several weeks.
6) NAPTHOQUINONES
 These drugs are recently introduced for use in theileriosis.
 Causes marked degeneration of macro schizonts and suppression of parasitemia.
Parvaquone
 Most cost effective synthetic compound in the series of napthoquinones.
Buparvaquone
 A parvaquone analogue in which cyclohexyl moiety is substituted by an alkyl group,
this substitution slows down the metabolic degradation of parent compound.
 Most active during incubation period and also after the outbreak of bovine
theileriosis.
 Withdrawal period for milk and edible tissue is 2 and 42 days respectively.
 Dose: Cattle- 2.5 mg/kg, IM as a single dose (Costly).
ANTICOCCIDIAL CHEMOTHERAPY
INTRODUCTION
 Coccidiosis mostly causes bloody diarrhea and heavy mortality in poultry.
 It also affects cattle, sheep, goat, pigs, dogs and cats.
 Two intestinal protozoan parasites of coccidia namely Eimeria (poultry, cattle, sheep,
goat) and Isospora (dog, cat & man) with numerous species have been identified.

 In broiler Eimeria tenella and E. necatrix are the most commonly encountered
protozoans.
 Solid immunity develops following exposure and it is species and strain specific.
 Control is possible by continuously feeding a coccidiostat for a prolonged period.
 In layer immunization procedure would be most suitable e.g., administration of
coccivac (vaccine) containing 7 species of protozoan oocyst.
 Preventive anticoccidial may be given for 6-22 weeks
 Two programmes are followed.
o Shuttle programme– Use of two or more drugs subsequently during the early
growth period of birds (single growout).
o Rotation programme– Use of pharmacologically different anticoccidials in
relation one after another in succeeding growout of birds.
ANTI COCCIDIAL DRUGS

 A large number of anticoccidial drugs are available for prevention and treatment of
coccidiosis in animals.
st nd
 Most of the drugs show the greatest activity during 1 or 2 asexual cycle and some
inhibit the sexual stage.
st
o 1 asexual cycle: Clopidol, Quinolones, Monensin, Robenidine, Amprolium
nd
o 2 asexual cycle: Zoalene, Nicarbazine, Sulfonamide, Dinitolmide
Amprolium
 It is a thiamine (Vitamin B1) antagonist. Acts on the early first generation schizonts
and merozoites.
 It is used prophylactically in combination with other anticoccidial inorder to increase
the spectrum against E. Brunetti and E. Maxima.
 It has good activity against E. tenella and E. acervulina.
 It is used for the treatment of coccidiosis in chicken, turkey and ruminants.
 The major advantage of this drug is slow development of resistance.
Clopidol
 It is a pyridine derivative active only against the sporozoites of Eimeria. Hence it is
not effective if given after the day of exposure of coccidial oocyst. It is a coccidiostat
and does not allow natural immunity to develop.
 Dose: 125 g/tone feed in chickens and 200g/ tone feed in rabbits.
 Withdrawal period is about 5 days in chickens.
Quinolones
 They act on Sporozoite stage and selectively inhibit electron transport and thus
respiration in coccidial mitochondria, not in the host.
 They are insoluble in water, poorly absorbed hence non-toxic.
 Rapid development of resistance.
 Eg., Decoquinate – not suitable for laying and breeding birds but suitable for calves.
 Methyl benzoquate – most potent quinolones.
Sulfonamide
 More effective against intestinal than caecal species of coccidia.
nd
 They are effective against 2 generation schizonts. Hence it is effective when
outbreak is noticed.
nd
 2 generation schizonts are important for developing immunity, hence natural
immunity develops in chicken on sulphonamides prophylactic program.
 Sulphaquinoxaline is used for treatment alone and with amprolium in turkey, chicken
and rabbit.

 Withdrawal period is about 5 days in chickens.
Ionophores (Polyether antibiotics)
 Most effective and widely used anticoccidials (growth promoter)
 They interfere with the transport of ions through membranes, causing an influx of
positively charged ions. This upsets the osmotic balance of the cell. Mainly active
towards Sporozoites and 1st generation Schizonts and Merozoites. Hence it should be
fed continuously and not recommended for established infection.
Monensin
 Source: Streptomyces cinnamonensis
 It forms complex with Na and K ions, affects permeability of membrane
 Low therapeutic index
 Highly effective against all species of coccidian in field.
 It is used for prevention of coccidiosis in broilers, cattle and sheep.Not recommended
for laying hens and equines.
 Withdrawal period is 3 days in chickens.
Lasalocid
 Source: Streptomyces lasaliensis
 Not recommended for other birds and animals except broilers and replacement layers
 Least toxic at normal dosage but net litter may be a problem because
Narasin
 Source: Streptomyces aurefaciens
 Effective against intestinal and caecal coccidia in broiler if administered continuously.
 Not effective in layers and other animals
Salinomycin
 Source: Streptomyces albus
 Similar to Narasin
 Prophylaxis in broiler. Withdrawal period is not required.
Maduramycin
 Source: Actinomadura yumaense
 Most potent ionophore for broilers.
 Withdrawal period is of 5 days.
Robenidine
 A guanidine derivative inhibits oxidative phosphorylation, primarily coccidiostat
against first generation schizont and some coccidiocidal effect against second
generation schizont.
 Recommended for broiler, turkey and rabbit continuously in feed.
 Contraindicated in laying hens and not to be combined with other anticoccidials.
 Withdrawal period: 5 days.
 Side effect: Unpleasant taste of meat and egg.
Dinitolmide
 It is a dinitrobenzamide with greatest activity against asexual stage of coccidian.
 Prolonged treatment induces coccidiocidal effect.
 It is highly active against E. tenella and E. necatrix.
 It is also used for prophylaxis of coccidiosis in chicken
 It is contraindicated in layers.
 Withdrawal period is 3 days.
Nicarbazin
 Predominantly coccidiocidal, suppressing second generation schizonts.
 It is also used for prevention rather than treatment.
 It can be used to overcome heat stress during hot climate in broilers.

 Contraindicated in layers and with other anticoccidials.
 Withdrawal period is about 4 days.
Arprinocid
 It is a purine analogue.
 Highly active against the early invasive and intracellular stages of Eimeria and affects
sporulation of oocyst.
 Inhibit microsomal metabolism & DNA synthesis in coccidia.
 Rapid development of resistance.
Halofuginone
 Highly toxic to all coccidia of chicken and turkey.
 It has both static and cidal activity against early developing stages (asexual).
 Contraindicated in layers.
 Withdrawal period is about 5 days in chickens and turkeys.
Toltrazuril
 Potent coccidiocidal, active against both sexual and asexual stage of Eimeria in
chickens, turkey and rabbits.
 Withdrawal period is about 21 days.
Diclazuril
 Safe and potent coccidiocidal drug has a zero day withdrawal period. Effective
against both schizonts and gametocytes
 Recommended at the rate of 1 ppm in feed for broiler, turkey and rabbits.
ECTOPARASITICIDES
INTRODUCTION
 Ectoparasiticides are used on animals to control ticks, mites, fleas, lice and flies
infecting the external surface of body.
 They are widely used in veterinary medicine to control severe parasitic infestations
and prevent spread of external parasite borne diseases.
1) ORGANOPHOSPHATES (OP)
 E.g. Coumaphos, malathion, parathion, fenthion, diazinon, ethion, famphur,
dicholorovos and chloropyriphos.
Mechanism of action
 The OP insecticides inhibit Ach breakdown by inhibiting AChE enzyme
irreversibly.
 Compounds are lipophilic, well absorbed through the skin.
 Metabolism of OP occurs mainly in the liver. Compounds have no residue problem.
 Used topically in animals.
Adverse effects
 Toxic signs include salivation, lacrymation, urination, defecation, fasciculation, ataxia
and convulsion.
 Chronic toxicity or delayed toxicity seen with some OP compounds with a delayed
onset of paralysis due to progressive demylination of motor neurons.
 Organophosphate Induced Delayed Neuropathy (OPIDN)
 Treatment involves administration of atropine sulphate, pralidoxime (2-PAM),
DAM.

2) CARBAMATES
 E.g. Carbaryl and propoxur. They are used in the treatment of ectoparasites in small
animals as powder, shampoo and collar formulations.
 Mechanism of action – It reversibly inhibits AChE enzyme. Their effects are more
reversible than those of OPC since the binding between carbamates and cholinesterase
is noncovalent.
 Adverse effects similar to OP poisoning. Atropine sulphate is an effective antidote.
3) ORGANOCHLORINE/CHLORINATED HYDROCARBONS
 E.g. DDT, BHC, methoxychlor, lindane, aldrine, dialdrine, endrine, endosulfan &
chlordane.
 DDT and methoxychlor are very effective synthetic insecticides. Environmental
Protection Agency (EPA) banned these compounds.
Mechanism of action
 These insecticides increase intracellular sodium and calcium via two mechanisms.
 High sodium cause depolarization and calcium will over stimulate neurotransmission,
which paralyze the insects.
Pharmacokinetic properties
 Highly lipophilic, fat in feed promotes absorption however, obese animals are more
resistant to insecticide toxicity, because fat adsorbs lipophilic chemicals.
 DDT is metabolized into DDD and DDE which is water soluble and is excreted in the
urine.
 DDE is permanently stored in the adipose tissue of animals, causing residue problems.
Adverse effects
 CNS stimulation lead to convulsion, cardiac arrhythmia may be induced.
 Egg shell thinning results from the ability of DDT to block estrogen receptors that
mediate the deposition of calcium into the egg shell.
Lindane
 It increases excitability of excitable cells by blocking GABA gated chloride channels
to induce depolarization.
 Lindane is more toxic than DDT. Young animals, especially, calves and toy breeds of
dogs are sensitive to poisoning.
4) PYRETHROIDS
 E.g. Allethrin, permethrin, Deltamethrin, cypermethrin, fenvalerate.
 They are alkaloids of pyrethrum which increases excitability of ectoparasite neurons
by prolonging the opening of sodium channels, thereby causing arthropod paralysis.
They are generally safe but may cause local irritation hypersalivation and vomition.
 Pyrethroids should not be used in cats.
 They are widely used in veterinary practices. They posses wide spectrum of
parasiticidal action with minimal residual action.
5) INSECT DEVELOPMENT INHIBITORS

Diflubenzuron
 This drug inhibits chitin synthesis in larvae and eggs of insects. They have no effects
on adult insects.
Insect growth regulators
 Cyromazine & Pyriproxyfen : They interfere with reproductive organ differentiation.
Cyromazine is administered orally for 4-6 wks to control fecal maggots in poultry. It
is also used as a spray on to surface of manure.

6) OTHER ECTOPARASITICIDES
Amitraz
 It is ectoparasiticides use in dogs, pigs and cattle.
 It activates octopamine receptors in arthropods, which inhibits neurotransmission,
resulting in flaccid paralysis.
 Amitraz should not be applied to swine before 3 days of slaughter.
Disease Causative Organism Drug of Choice
Protozoal disease
Babesiosis Babesia spp. Diminazene aceturate
Theileriosis Theileria spp Buparvaquone
Trypanosomiasis Trypanosoma spp Quinapyramine sulphate and chloride
Anaerobes protozoa Amoeba/Giardia Metronidazole, Tinidazole
Malaria Plasmodium spp. Chloroquine
Endoparasites
Lung worm infection Dictiocaulas viviparous Albendazole + oxbendazole
Tape worm infection Tape worm Praziquantel
Fascillosis Fasciolla. Spp. Oxyclozanide, Rafoxanide
Anaplasmosis Anaplasma spp. Imidocarb
Microfilariasis Dirophylaria immitis Diethyl carbamazine (DEC)
Heart worm- Adult Dirophylaria immitis Thiacetarsamide

ANTIFUNGAL DRUGS
 Eukaryotic
 Yeast: Unicellular Oval/Spherical form e.g. Candida albicans
 Mold: Multicellular filamentous form e.g. Aspergillus spp.
 Commonly two types of fungal infections occurred : Superficial & Systemic
INTRODUCTION
 Antifungal (Antimycotic) drugs are agents which are used to prevent growth and
multiplication of fungi (Fungistatic) or kill the fungi (Fungicidal).
 In general, fungal infections are more difficult to treat, are slowly eradicated, and
the antifungal drugs are more toxic to host than antibacterial drugs.
CLASSIFICATION
Antifungals are classified based on the chemical structure and clinical use:
I. Antifungal antibiotics
1. Polyenes e.g. amphotericin B, nystatin, natamycin, hamycin and candicidin.
2. Heterocyclic benzofurans e.g. griseofulvin.
II. Antimetabolites e.g. flucytosine.
III. Azoles
1. Imidazoles
e.g. ketoconazole, miconazolc. enilconazole, tiabendazole, clotrimazole, econazole,
butoconazole, oxiconazole and sulconazole.
2. Triazoles
e.g. fluconazole, itraconazole, voriconazole, posaconazole and terconazole.
IV. Allylamines e.g. terbinafine, butenafine and naftifine
V. Echinocandins e g caspofungin, anidulafungin and micafungin.
VI. Iodides e g. sodium iodide and potassium iodide.
VII. Miscellaneous agents
1) Organic acids e.g. benzoic acid and salicylic acid.
2) Fatty acids and salts e.g. propionates and undecylenate.
3) Dyes e.g. gentian violate
4) Phenols and phenolic ethers e.g. phenol, thymol and haloprogin.
5) Hydroxy quinolines e.g. clioquinol
6) Thiocarbamate e.g. tolnaftate
7) Sulphur and sulphur preparations e.g. sulphur and sulfiram.
8) Copper preparations e.g. copper sulphate and copper naphthenate.
9) Others antifungal drugs e.g. Ciclopiroxolamine, dichlorophen, hexitidine, tiacetin,
sodium thiosulphate, benzoyl disulphide, selenium sulphide and nitrofuroxine.

Figure: Mechanism of Action (Fungal Targets) of Antifungal Drugs
History :
 Two important antifungal drugs like Amphotericin B for Systemic mycoses and
Griseofulvin for dermatophytosis introduced around 1960.
 Flucytosine and Imidazoles in 1970s and Triazoles in 1980.
 Terbinafine introduced recently.
Sources:
Antifungal Drugs Sources
Amphotericin B Streptomyces nodosus
Nystatin Streptomyces noursei
Natamycin Streptomyces natalensis
Griseofulvin Penicillium griseofulvum
Hamycin Streptomyces pimprina
I. ANTIFUNGAL ANTIBIOTICS
1. Polyenes / Polyene Antibiotics
• Polyene antibiotics obtain from actinomyces
• MOA: The polyenes bind to ergosterol in the fungal cell membrane and promote
leakiness which may contribute to fungal cell death.
• They are poorly soluble in water and common organic solvents.
• Amphotericin B is the prototype drug of this group.
Amphotericin B
• Amphotericin B is obtained from Streptomyces nodosus
• Two types A & B but only B is used clinically because it is significantly more active
in vivo.

• B is insoluble in water & is often used intravenously for systemic fungal infections.
• Rapidly decomposes on exposure to light.
Mechanism of action
• The amphotericin B and other polyene antibiotics have high affinity for ergosterol,
present in fungal cell membranes.
• High concentration of amphotericin B directly disrupts the fungal cell membrane
permeability and leakage of cellular contents.
• Amphotericin B is fungistatic at normal dosages, but it can become fungicidal at
higher concentrations.
• Amphotericin B have broad-spectrum antifungal against is useful against several
systemic fungi including Candida, Histoplasma, Cryptococcus, Blastomyces,
Coccidioides, Aspergillus and Sporithrix spp.
• Some algae and protozoa (e.g. Leishmania, Trypanosoma, Trichomonas and
Entamoeba spp.) are sensitive to the polyene antibiotics.
• Amphotericin B is not effective against clinical dermatophytosis.
Pharmacokinetics
• Amphotericin B is poorly absorbed from the GI tract and, therefore, oral used only
for gastrointestinal fungal infection. For systemic infection, it is given by repeated
daily slow IV injections because it is not absorbed after IM or other parenteral routes.
• It distribute very unevenly throughout the body & can not pass the CSF, vitreous
humour and amniotic fluid.
• For fungal meningitis, it has to be given intrathecally.
• It is extensively bound to plasma lipoproteins, longer terminal half-life of about 15
days.
• Drug eliminate via urine & bile.
Side effects
• The nephrotoxicity generally occurs via two mechanisms intense renal
vasoconstriction and binding of drug to membrane cholesterol in the renal tubular cell
membrane.
• Other adverse effects includes anorexia, nausea, vomiting, anaemia, cardiac
arrhythmias, CNS signs (if given intrathecally), hepatic dysfunctions and
thrombophlebitis at injection site.
• Cats are more sensitive to the renal toxic effects.
• During the therapy monitored patient's renal function by urine analysis of BUN
& creatinine.
Clinical uses
• Amphotericin B is effective antifungal agent mainly in dogs & other spp. for serious
life-threatening systemic infections.
• It is usually diluted in 5% dextrose and administered IV.
• Oral preparations are used to treat thrush (oral candidiasis).
Nystatin
• Nystatin is produced by Streptomyces noursei.

• It is structurally similar to amphotericin & has same mechanism of action.
• It is used topically and orally.
• Nystatin is primarily used for skin, mouth, intestinal or vaginal candidiasis in dogs,
cats and birds.
Dose:
• Dogs : 50,000- 150,000 Units (total), PO,3 times daily.
• Cats: 1,00,000 Units (total), PO, 4 times daily.
Natamycin (Pimaricin)
• It is obtained from Streptomvces natalensis found in soil.
• Natamycin is used to treat fungal infections, including Candida, Aspergillus,
Cephalosporium, Fusarium and Penicillium.
• Used to treat fungal kerati
• tis in eye infection.
• Mainly used topically.
Hamycin
• It from Streptomyces pimprina.
• It is similar to nystatin and is used mainly topically for oral thrush, cutaneous
candidiasis and Trichomonas vaginitis.
2. Heterocyclic Benzofurans
Griseofulvin
• It is a systemic antifungal obtained from Penicillium griseofulvum.
• Odourless, bitter tasting, white powder that is very slightly soluble in water and
most organic solvents.
• Particle sizes of griseofulvin vary from 1μm (ultramicrosized) to up to 10 μm
(microsized) in diameter.
Mechanism of action
• Fungistatic drug that enters into the susceptible fungi through an energy-dependent
transport system.
• It acts by interfering with the polymerisation of microtubules that leads to interferes
with the spindle formation in dividing cells thereby arresting the metaphase of
cell division in susceptible fungi.
• This leads to production of multinucleate fungal cells.
• Narrow-spectrum antifungal agent active Only against dermatophytes i.e.
Microsporum, Trichophyton and Epidermophyton.
• Griseofulvin is unique among all antifungal which on oral administration
accumulates into keratin and produces action against superficial fungi.
Pharmacokinetics
• After oral administration, the absorption, in general, depends of the particle size and
preparation; and a fatty diet facilitate its absorption (F= 25% to 70% in microsized ,
100% for ultramicrosized).
• It is concentrated in skin, hair, nails, fat, skeletal muscle and liver.
• It has high affinity for keratinised tissues & found within 4-8 hours of dosing.
• For this reason, the new growth of hair or nails is the first to become free of fungal
infection.
• The drug action is slow requiring 4 to 6 weeks of therapy for skin infections and up
to 1 year for toenails infection.

• It is metabolised by the liver via oxidative demethylation and conjugation to inactive
metabolites.
• one-half of the drug is excreted in urine; remain in faeces.
• It remains in the skin for a much longer period.
• Less toxic, Gastrointestinal disturbances, hepatotoxicity, CNS signs and haemolytic
alterations have been reported.
• Cats, particularly kittens, are more susceptible to adverse effects than other species
(produce teratogenic and carcinogenic effects in cats).
• Griseofulvin is a potent inducer of microsomal enzymes.
• Clinical uses
• primarily used for treatment of dermatophytic fungal infections (ring worm) of
skin, hair and claws in dogs, cats, calves, horses and some other species.
• Treatment should continue up to at least one week after disappearance of clinical
signs.
• At least 4 weeks, and sometimes 3 months or more, may be needed for successful
therapy.
Dose
• Dogs &cats : 20- 50 mg/kg (microsized), PO, once daily or in 2 to 3 divided doses
with fatty meal or corn oil.
• Cattle &horses:5 -10 mg/kg, PO, once daily for 4 to 6 weeks or longer.
• Sheep &goats : 10 -20 mg/kg, PO, once daily.
• Swine : 20 mg/kg, PO, once daily for 6 weeks.
II. ANTIMETABOLITES
• Flucytosine
• It was originally synthesised as an antineoplastic drug, but later on it was found to
have good antifungal activity.
• White crystalline powder, stored in air tight container and protected from light to
prevent decomposition.
Mechanism of action of flucytosine:
[5-FC: 5-Fluorocytosine, 5-FU: 5-fluorouracil, 5-FUMP: 5-fluorouracil ribose mono-phosphate, 5-FUDP: 5-fluorouracil
ribose diphosphate , 5-FUTP: 5-fluorouracil ribose triphosphate , 5-FdUMP: 5-fluorodeoxyuracil ribose monophosphate]

• It is fungistatic.
• Its spectrum of activity is limited and includes Cryptococcus, Candida, Aspergillus,
Sporothrix and few other pathogenic fungi.
Pharmacokinetics
• Flucytosine is rapidly and almost completely absorbed after oral administration.
• Cmax achieved in 1-2 hours after oral dosing.
• Flucytosine is distributed widely throughout the body and has good penetration into
CSF, synovial fluid and aqueous humour.
• Only about 2-4% of the drug is bound to plasma protein.
• About 80-95% of the drug is excreted unchanged in urine.
Side effect/Adverse effects
• It has relatively low toxicity, Bone marrow depression & other side effects may be
seen.
Clinical uses
• Useful in systemic infections caused by Candida albicans and Cryptococcus
meningitis.
• It is mostly combined with amphotericin B the treatment of cryptococcosis in dogs
and cats.
• It is used alone in treating aspergillosis and candidiasis in birds.
Dose : Dogs & cats : 25-50 mg/kg, PO, 3-4 times daily in combination with amphotericin B.
III. AZOLES
• The important antifungal azoles consist of two subgroups — imidazoles and
triazoles.
• Imidazoles contain two, whereas triazoles have three nitrogen atoms in the basic five-
membered ring structure.
• Relatively non-toxic and effective antifungal compounds.
Mechanism of action of Azoles:
1. Imidazoles
• Synthetic drugs
• They are active against fungi, bacteria, helminths and protozoa.
• Generally poorly soluble in water
• Mechanism of Action
• Azoles acts by inhibiting 14α-demethylase enzyme on the fungal cell membrane and
alter the membrane permeability of susceptible fungi by inhibition of ergosterol

synthesis.
• Fungistatics
Ketoconazole
• Synthetic imidazole antifungal drug for systemic use.
• It was the first azole given orally to treat systemic fungal infections and is still
considered the prototype drug.
• Broad-spectrum of antifungal activity includes Candida, Cryptococcus, Coccidioides,
Blastomyces,Hisptoplasma species.
• Also effective Microsporum, Trichophyton, Aspergillus and Sporothrix.
Pharmacokinetic
• Oral absorption of ketoconazole is variable.
• Widely distributed in body except CNS. It has high PPB (>95%), mostly to albumin.
• Metabolised mainly in liver & excreted through bile & urine.
• Gastrointestinal disturbances, hepatotoxicity & has antiandrogenic effect.
• Cats are more susceptible to the hepatotoxic effects than dogs.
• Ketoconazole is cytochrome P450 inhibitor.
Clinical Use:
• Ketoconazole has been used to treat systemic mycosis in dogs, cats, horses, birds and
some other species.
Dose :
• Dogs & Cats : 5 -20 mg/kg, PO, 2 to 3 times daily
• Cats : 5 -20 mg/kg, PO, 1 to 2 times daily, Horses : 10 mg/kg, PO, once daily.
Miconazole
• Primarily used topically & persists for about 4 days in the stratum corneum.
• Miconazole is available as a 2% cream and a 1% lotion for treatment of local
dermatophytosis in dogs and cats.
• Also used for oral or vaginal thrush (yeast infection).
Enilconazole
• Topical antifungal agent with action similar to miconazole.
• It has excellent antifungal activity and a good residual effect after topical
application.
Clotrimazole
• Topical antifungal agent used for candidiasis, trichomoniosis and dermatophyte
infections of the skin and vagina.
2. Triazoles
• Like imidazoles, have same mechanism of action and antifungal spectrum.
Fluconazole
• Synthetic, white crystalline powder that is slightly soluble in water.
• Used in the treatment and prevention of many superficial and systemic fungal
infections.
Pharmacokinetics
• Completely absorbed after oral dosing.
• Fluconazole is readily distributed into body tissues and fluids and its concentrations in
the CSF, eye, peritoneal fluid, saliva and urine are good.
• Mainly excreted in urine and sweat.
• Side/Adverse effects similar to ketoconazole.
Clinical uses

• Use for treatment and prophylaxis of fungal infections where other antifungals have
failed in dermatophytes, yeasts and a variety of systemic fungi.
Itraconazole
• It having both topical and systemic actions.
• Broader spectrum of antifungal activity than ketoconazole or fluconazole
• Itraconazole is used primarily in veterinary practice.
• Voriconazole
• New drug structurally similar to fluconazole .
• Orally effective (F=96%) , used to treat serious fungal infections like aspergillosis.
IV. ALLYLAMINES
Terbinafine
• Synthetic drug , recently introduced
• White fine crystalline powder, freely soluble in methanol, ethanol and slightly
soluble in water.
• Highly lipophilic in nature and tends to accumulate in skin, nails and fatty tissues.
Mechanism of action
• Terbinafine is a fungicidal drug.
• It acts by selectively inhibiting squalene epoxide enzyme, leads to decrease
synthesis of ergosterol from squalene in the fungal cell wall.
• Terbinafine is more selectively (1000 fold) inhibited fungal enzyme as compared to
the mammalian cell wall enzyme.
Pharmacokinetics
• Terbinafine is well absorbed after oral administration, but it undergoes significant
first-pass
• It is highly plasma protein bound (-99%). metabolism that decreases its bioavailability
to about 40%.
• Its lipophilic nature permits wide distribution in body metabolised in the liver.
• The metabolites are excreted in urine (80%) and faeces (20%).
• Terbinafine is usually well tolerated with few adverse effect.
Clinical uses
• Used for treatment of dermatophyte infection in dogs, cats, birds and some exotic
species. Used orally (tablets) or topically (as 1% solution or cream).
V. ECHINOCANDINS
• Newer group which inhibit synthesis of fungal cell wall.
• fungicidal against some yeasts, Fungistatic against some moulds.
Caspofungin
• First echinecandin, approved for clinical usage in 2006.
Mechanism of action
• It inhibits β-glucan synthesis in the fungal cell wall.
• Caspofungin and other echinocandins are relatively-selective in their action because
glucan synthase enzyme is not present in mammalian cells.
Antifungal actions
• Mainly effective against Candida & Aspergillus spp.
Pharmacokinetics
• Administered only IV due to low oral bioavailability.
• Distributed to most tissues and organs & metabolites are excreted in the urine and

faeces.
Clinical uses
• Caspofungin is largely used in the treatment of candidiasis and aspergillosis.
VI. IODIDES
• Sodium Iodide & Potassium Iodide
• Occasionally used in the treatment of fungal infections like sporotrichosis in dogs
and cats.
VII. MISCELLANEOUS ANTIFUNGAL AGENTS

Benzoic acid
• Benzoic acid has both bacteriostatic and fungistatic actions.
• For fungal infections, it is mostly combined with salicylic acid to make Whitfield
ointment.
• Useful in dermatophytosis (ringworm infection)
Salicylic acid
• Used topically as keratolytic, anti-seborrhoeic, antiseptic and fungistatic.
• Its keratolytic action helps in the dermal penetration of drugs.
Gentian violet
• It has antibacterial, antifungal and anthelmintic activity.
Tolnaftate
• Synthetic topical antifungal agent with significant activity against Trichophyton spp.
infection.
Sulphur
• Sulphur is externally used as ointment, powder or lotion to treat ringworm and
eczema.
Copper sulphate
• Used topically in ringworm infection- fungicidal action.
Table: List of systemic & Topical antifungal agents

INDIGENOUS DRUGS WITH PROVEN PHARMACOLOGICAL &
THERAPEUTIC EFFICACY
Introduction:
Indigenous drugs refer to pharmacologically active principles primarily obtained from the
medicinal plants with proven therapeutic value.
 A large number of medicinal plants have been recognized to possess therapeutic value
in the treatment of a variety of diseases.
 The medicinal plants contain pharmacologically active principles such as alkaloids,
glycosides, resins, tannins, fixed oils, volatile oils etc.
 Ethno-veterinary medicine (EVM) is commonly defined as a system of folk beliefs,
knowledge, skills, methods and practices relating to the health care of animals.
MEDICINAL PLANTS AND ITS PHARMACOLOGICAL ACTIONS
Name of the plant Active principle Pharmacological action

Rauwolfia serpentine (Sarpagandha) Reserpine Tranqulizer and Antihypertensive
Vinca rosea (Barmasi) Vincristine and Anticancer drug – common used
Vinblastine for the treatment of transveneral
tumour in dogs.
Withania somnifera (Ashwagandha) Somniferine General tonic and
Immunostimulant
Laptadenia reticulate (Dodi, Jivanti) Laptadine Galactagogue
Zingiber officinalis (Ginger) Gingerol Carminative and Stomachic
Ricinus communis (E:Castor, H: Ricin Purgative
Arandi, G: Divel)
INDIGENOUS ANTIBACTERIAL/ANTISEPTIC AGENTS

 Curcuma longa (Turmeric/Haladi)
 Azadirachta indica (Neem)
 Allium sativum (Garlic)
 Ocimum sanctum (Tulsi)
 Zingiber officinalis (Ginger)
 Asparagus racemosus (Shatavari)
 Glycirrhiza glabra (Licorice /Jethi-madh)
INDIGENOUS ANTIFUNGAL AGENTS

 Curcuma longa
 Pongamia glabra (S:Karanja; E: Pongam)
 Azadirachta indica
 Ocimum basilicum (Sweet Basil/Tulsi)
 Cassia tora (E:Foetid cassia)

INDIGENOUS ANTICANCER AGENTS
 Catharanthus roseus (G-Barmasi, H-Sadabahar) Vinca alkaloids, vinblastine and
vincristine
 Podophyllum peltatum (G- Venivel, H- Ban kakari, E- Mayapple)
 Taxus brevifolia
 Taxus baccata and Taxus cuspidata
INDIGENOUS ANTHELMINTIC
 Areca catechu (G-Sopari, E-betel nut palm) - Anti-cestodal
 Azardirachta indica
 Carica papaya
 Cucurbita maxima (G-Lal kolu) - Anti- trematodal action
 Embelia ribes (G-Vavding, E-Embelia) - very effective in treatment of ascarides
 Butea frondosa (G-Khakaro/Palas) seeds exhibits good activity against ascarides
 Punica granatum (G-Dadam, E-Pomegranate)
 Ocimum basilicum (Sweet Basil/Tulsi)
 Pongamia glabra (S:Karanja; E: Pongam)
INDIGENOUS ARTHROPODE REPELLANTS/ INSECTICIDAL AGENTS

Acorus calamus (Sweet Flag) Repellant of Ixodid ticks
Azadirachta indica wide range insecticidal
Curcuma longa Against ticks and mites
Chrysanthemum indicum Against scabies
Pongamia glabra (G, H -Karanja) Against sarcoptic mange
Ricinus communis (E:Castor, H: Arandi, G: Divel) Against mites
Tinospora cordifolia (Galo/Gado) Against scabies

GROWTH PROMOTERS
 Growth promoters are agents which increase growth rate and feed conversion
ability of animals.
 These agents are often used in food animals in which high conversion of feed into
animal tissues is required at short time.
Classification
I. Antibiotics
a. lonophore antibiotics e.g. monensin, lasalocid and salinomycin.
b. Non-ionophore antibiotics e.g. zinc bacitracin, flavomycin, virginiamycin, tylosin,
avilamycin, spiramycin and avoparcin.
2. Synthetic antimicrobials e.g. carbadox and olaquindox.
II. Probiotics
e.g. Lactobacilli and Streptococci.
III. Prebiotics
e.g. fructo-oligosaccharides, xylo-oligosaccharides and manno-oligosaccharide
IV. Hormones
1. Steroidal sex hormones and analogues
e.g. estradiol, progesterone, testosterone, melengestrol acetate, zeranol and
diethylstilbestrol.
2. Growth hormone
e.g. naturally occurring growth hormone and recombinant growth hormone.
V. Miscellaneous drugs
1. Beta2-adrenoceptor agonists
e.g. clenbuterol, salbutamol, terbutaline, cimaterol and ractopamine.
2. Metallic compounds
e.g. copper and arsenic.
3. Enzymes
e.g. amylases, lipases, phytases, galactosidases and proteases.
I. Antibiotics
 Antibiotics are widely used in therapeutics for their antimicrobial purposes in
animals and humans.
 In ruminants, they act primarily on rumen microflora and alter rumen
fermentation.
 They enhance the microbial production of gluconeogenic fatty acid propionate
and to some extent acetate, at the cost of butyrate.
 The altered rumen fermentation also decreases production of methane with less loss
of high-energy in rumen.
 In monogastric animals, similar action may be observed in small intestine.
a. Ionophore Antibiotics
 Ionophore antibiotics are fermentation products of Streptomyces species and are
primarily used as anticoccidial drugs.

 Some agents such as monensin, lasalocid and salinomycin also possess growth
promoter activity when used in beef and dairy cattle.
 These compounds mainly modify the movement of cations across the biological
membrane to produce their antimicrobial action.
Monensin
 Monensin obtained from Streptomyces cinnamonensis.
 Monensin is widely used in veterinary practice as an anticoccidial in poultry and as
a growth promoter in cattle.
 Monensin is toxic to ruminants and other species at high doses.
Lasalocid
 Lasalocid obtained from Streptomyces lasaliensis.
 It is widely used in the control of coccidiosis and to increase feed conversion
efficiency in cattle.
Salinomycin
 Salinomycin used for prophylaxis of coccidiosis in poultry and to improve growth
rate and feed conversion efficiency in pigs.
 It is toxic to horses and other equidae and should not be used in turkeys.
b. Non-lonophore Antibiotics
 These agents selectively modify the microbial population of animals to improve
production efficiency.
 Non-ionophore antibiotics can be administered in milk replacers for young
animals or in supplementary concentrates.
Zinc bacitracin
 Bacitracin is a topically used polypeptide antibiotic obtained from a strain of Bacillus
subtilis.
 Zinc bacitracin is permitted for veterinary use as a feed additive for growth
promotion purposes.
 Used as a growth promoter in feed to young ruminants, piglets and pigs, broiler
and laying hens, and fur-bearing species excluding rabbits.
 It should not be used in lactating cows.
Tylosin
 Tylosin is a macrolide antibiotic isolated from a strains of Streptomycetes fradiae.
 Tylosin is active against mainly gram-positive organisms and is used as an
antibacterial and growth promoter.
 It concentrates in milk for a long time; therefore it should not be administered to
lactating cows.
 Withdrawal period for slaughter may vary from 0 to 14 days, depending on the use
and species.
2. Synthetic Antimicrobials
Carbadox
 It is primarily active against gram-positive bacteria and is more effective under
anaerobic conditions than aerobic conditions. It is marketed both as growth
promoter and antibacterial agent for use in swine.

 Carbadox possesses several adverse/toxic effects when used as daily feed additive in
concentration more than 100 ppm.
Olaquindox
 Olaquindox is another synthetic antibacterial drug used for increasing growth rate
and feed conversion efficiency in animals.
II.PROBIOTICS
 Probiotics are products containing live micro-organisms which are thought to be
beneficial to the host organism.
 Probiotics are used clinically in cases of digestive upsets (e.g. diarrhoea), to improve
digestion, to enhance growth rate and feed efficiency and to overcome stress due to
weaning or transport of livestock.
 Probiotics are safe to use with zero day slaughter withdrawal period.
III. PREBIOTICS
 Prebiotics are carbohydrates that cannot be digested by the human body.
 They are food for probiotics.
 Prebiotics are mainly dietary products which are selectively fermented by beneficial
gut bacteria and therefore, support a healthy gut microflora.
IV. HORMONES
 Steroidal sex hormones such as estradiol, progesterone and testosterone have been
used for anabolic purposes in animals.
 Testosterone increased protein synthesis, enhanced muscle development and
better feed efficiency resulting in net-weight gain.
 Estradiol is used as growth promoter in ruminants.
 Synthetic analogues of testosterone or progesterone possess significant anabolic
growth promoter activity in farm animals.
 Growth hormone (Somatotropin) promotes growth of all organs. It is more useful in
cattle and sheep, but not in poultry.
V. MISCELLANEOUS DRUGS
 Beta2-adrenoceptor agonists are occasionally used in cattle, pigs and poultry as
growth promoter.
 Copper salts may also be used in dairy cattle and goats (not sheep) for production
enhancing and growth promoting effect.
 Many enzymes (amylases, lipases, phytases, galactosidases, glucanases, xylanases,
proteases, pepsin and polygalacturonase) are supplemented in human and animals
diets for promoting the growth and enhancing the production.

ANTISEPTICS AND DISINFECTANTS
Antiseptics: A substance that prevents the growth of micro organism on living tissue either
by inhibiting their activity or by destroying them (use on skin or mucous membrane).
Disinfectant: An agent that destroying the disease causing microorganism on inanimate (non
living) objects.
Germicide: An agent that kill microorganisms, especially pathogenic organisms.
IDEAL PROPERTIES OF ANTISEPTICS

 It should have a broad spectrum of activity, including bacteria, fungi and virus.
 It should be rapidly effective and should be germicidal.
 It should not allow the emergence of resistant pathogens.
 It should not be inactivated by protein or organic matter or tissue debris.
 It should be non-staining, non irritant and non-corrosive or non toxic.
 It should be odorless and deodorizing.
 It should have detergent property
 It should have residual action after rinsing.
 It should be simple, easily available, stable and economical to use.
CLASSIFICATION OF ANTISEPTICS AND DISINFECTANTS

1) Oxidizing agents
a. Peroxides – Hydrogen peroxide, Potassium permanganate
b. Halogens – Chlorine, Iodine, Iodophores
2) Reducing agents - Formaldehyde, Glutaraldehyde, Sulphur dioxide
3) Acids and Alkalies – Sulphuric acid, Sodium hydroxide, Boric
acid, Benzoic acid, Quick lime, Salicylic Acid
4) Alcohols - Ethyl alcohol, Isopropyl alcohol
5) Phenols and cresols
6) Dyes - Acriflavine, Gentian violet
7) Surfactants/Detergents e.g. Cetrimide, Benzalkonium chloride & Biocides
8) Biguanides: Chlorhexidine
9) Others: EDTA, ethylene oxide etc.
10) Physical agents: Dry and moist heat, Radiation (UV light)
1) OXIDIZING AGENTS
 Two types of oxidizing agents are
o Those which release gaseous oxygen – Hydrogen peroxide.
o Those which cause oxidation without the release of oxygen – Potassium
permanganate, halogens.
Solution of hydrogen peroxide (3%)
 Produces nascent oxygen in contact with organic mater, which is partly due to the
enzyme catalase.
 In turn is responsible for oxidizing effect.
 Organic matter affects the action.
Benzoyl peroxide
 Slowly release oxygen, oxidizing antiseptic, keratolytic and antiseborrheic – useful in
pyoderma in dogs.

 Skin irritation limits its use.
Sodium perborate
 White crystalline powder; decompose in solution to give sodium metaborate and
hydrogen peroxide which in turn release nascent oxygen.
Potassium permanganate
 Dark purple crystals with metallic luster forming pink or deep purple solutions in
water (Widely used for wound washing).
 1 in 1000 (0.01%) solution is used to clean the wound and as mouth lotion (antiseptic
and deodorizer)
 5% solution reduces excess granulation.
 Once the solution turns brown it is inactive (Prepare fresh and used).
 Stains the tissues (Destainer - oxalic and sulphurous acid).
HALOGENS
Chlorine
 Inexpensive, easily available, bactericidal and broad spectrum.
 Strong oxidizing agent, oxidation of peptide links and denaturation of protein.
 It accumulation inhibits essential enzyme system.
 It is inactivated in the presence of organic matter.
 Two derivatives of chlorine are
o Inorganic compound
 Eg. Na hypochlorite – Dakin‘s Solution ( 0.4 % available chlorine )
 It is unstable and releases Cl- slowly when exposed to the atmosphere or
organic material.
 It can be used as teat dip at a concentration of 4% available chlorine.
o Organic derivatives
 Eg. Chloramine T and Chlorinated lime (Bleaching powder)
 Chloramine T - slowly release oxygen, disinfection of udder and sanitation of
dairy utensils.
 Chloramine releases Cl- and HoCl which acts as oxidizing agent. They are also
used to treat swimming pool and drinking water.
 Mixture of calcium hypochlorite and CaCl2 yields 30% chlorine and is used
for disinfection of water supply, live-stock premises, disposal of carcasses etc.
Iodine
 Used for antiseptic wound dressing, but it is an irritant and retards wound healing.
 Interacts with proteins of cytoplasmic membrane.
 Two forms
o Those releasing free iodine
 Lugol‘s Iodine
 Tincture of iodine - Weak and Strong
o Iodophors - Complex between iodine and vehicle polyvinyl pyrrolidone –
povidone iodine (Betadine).
 Increases the solubility of iodine
 Sustained release
 Improves the activity of Iodine
 Use: Skin scrub, low iodine concentration prevents staining hence used in mastitis
control as teat dip (0.5 % available iodine).
 Toxicity: Cutaneous and systemic absorption leads to iodism.

2) REDUCING AGENT /ALDEHYDES
 Formaldehyde
 Glutaraldehyde
 Sulphur dioxide
Formaldehyde
 Highly bactericidal and action is not affected by organic matter.
 Formalin – strongly astringent and antiseptic, precipitates protein on the skin and
hardens it.
 Fumigation: 10% formaldehyde solution is used for room disinfection followed by
closing the room for 24 hrs.
 In combination with KMnO4 (3:5) or boiling formaldehyde alone.
 It is an irritant and has corrosive action on the skin. The irritant vapours can be
neutralised with ammonia solution.
Glutaraldehyde (gold standard antiseptic)
 Chemo sterilizing agent, less irritant and active against bacteria, fungi, virus & spores.
 MOA – Denaturation of protein and is an alkylating agent.
 Use: Disinfection for lensed clinical equipment (endoscope or cryoscope) and
treatment of blood products. It is more active at alkaline pH- 7.5 to 8.5.
Sulphur dioxide
 Liberates gas when sulphur is ignited, 0.5 kg should be burned/100 sq.ft. and
atmosphere should be moist and ventilation should be sealed.
3) ACIDS AND ALKALIES

+ -
 Release H & OH ion and denature protein, potent bactericidal except mycobacteria.
Acids
Boric acid
 Mild germicidal activity does not irritate the skin or tissues.
 2% solution is used as eye cleanser and mouth wash.
 Borax glycerine (12% W/V borax with glycerine) and boro glycerine (31% boric acid
in glycerine) is used for treating wound lesions.
 Boric acid (2.5 g) with Salicylic acid (1.5 g) and talc (upto 50 g) is used as dusting
powder.
Benzoic acid
 Along with salicylic acid it acts as a fungicide on skin (treat ring worm).
Acetic acid
 2-5 % solution is used as antiseptic wound dressing and possesses bacteriostatic
property.
Alkalies
 Sodium carbonate (Washing soda)
 4% solution is used as antiseptic cleansing for wound.
 Calcium oxide (Lime)
 It is used as general disinfectant in farm yard by scattering in the drains or by
sweeping on the floors.
 Calcium hydroxide (Milk of lime)
 For disinfecting the areas contaminated with excreta.
4) ALCOHOLS
Ethyl alcohol
 70% is used as skin antiseptic at injection site and as preoperative skin swab. It is
virucidal and less toxic.

Isopropyl alcohol
 50% possess bactericidal action and is used as skin antiseptics.
Uses
 Alcohol acts by denaturing the protein and inhibition of cell metabolites
 It is used alone or in combination with Iodine, Phenol or Chlorhexidine.
 Not active in the presence of physical dirt and not recommended for surgical
instruments (not sporicidal).
5) PHENOL AND CRESOL
Phenols
 First disinfectant and antiseptic used by Joseph Lister in 1867.
 It is coal tar derivative.
 It acts by denaturing the bacterial protein. It acts as a protoplasmic poison when
applied to tissues and may even cause necrosis.
 Act on cytoplasmic membrane and cause leakage.
n
 It is mainly used as a general disinfectant (1-2% sol ) and chemical sterilizer (5%)
 Phenol is used as a standard to measure the effectiveness of other disinfectants and
antiseptics in terms of phenol coefficient.
Cresol
 Impure mixture of ortho, meta and para methyl deriatives of phenol and is obtained
from coal tar distillation
 It is a better disinfectant and less toxic than phenol
 2% solution of cresol with soap is commercially available as Lysol and is used as
disinfectant
Toxicity
 Both phenol and cresol are toxic to dogs and cats hence should not be used to
disinfect the kennels or cat cages (Not use for feline)
 Cats and dogs should NOT be bathed with soaps containing carbolic acid.
 Toxic signs include convulsion, coma and death due to respiratory and cardiac failure.
6) DYES
 Acridine dyes possess antibacterial activity and are occasionally used as antiseptics.
 They are more active against G+ve bacteria & gonococci. They remain active in
presence of pus, serum and organic matter.
 Acriflavin is mostly used as 0.1% emulsion, solution, lotion, cream or jelly.
 Gention violet possesses antiseptic & antifungal activities. More active against G+ve
bacteria. It is used as 0.5% in form of jelly, lotion or solution on burns.
 Equal parts of gention violet & brilliant green are used in treatment of ringworm,
eczema and chronic ulcers.
7) DETERGENTS
 Detergents are surface active agents, reduce surface and interfacial tension and act
as cleansing- emulsifying agents with antibacterial property. They are also called
as surfactants and are of two types:
o Ionic - Anionic and Cationic
o Nonionic - not antibacterial
 Detergent antiseptics are non irritant and non toxic at the recommended
concentration.
 Their activity is reduced in the presence of organic matter and has no effect on
spores, virus and fungi.
Cetrimide
 It acts as a foaming agent

 1% solution is used for skin cleansing and wound dressing
 0.1% solution is used to disinfect dairy equipments, utensils, clothes and hands
 0.5% cream is used as a prophylactic agent against mastitis
Benzalkonium chloride
 0.1% alcoholic solution is used for skin antiseptics.
 0.01-0.05% solution is used on mucous membrane and to clean deep wounds
8) OTHERS
Chlorhexidine hydrochloride
 It is a potent bactericidal agent and acts by disrupting the bacterial cell wall.
 Active against both G+ve and G-ve bacteria.
 Incompatible with soap and anionic detergents.
 Ineffective against fungi, virus and spores.
 0.5% alcoholic or 1% aqueous solution is used as skin antiseptic.
 1% aqueous solution is used as antiseptic teat dip.
 Toxicity is low and irritation is uncommon.
 Useful in prophylaxis and treatment of oral diseases.

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CHEMOTHERAPY

60. INTRODUCTION AND GENERAL COSIDERATIONS

Bactericidal activity: It is the ability of an antibacterial agent to cause death of bacteria.

Antimicrobial (Antibacterial) spectrum: It is the range of pathogenic organisms (e.g.

Minimum inhibitory concentration (MIC): It is the lowest concentration of an

MIC90: It is the MIC necessary to inhibit 90 percent of the organism tested.

Minimum bactericidal concentration (MBC): It is the lowest concentration of an

Minimum antibiotic concentration (MAC): It is the concentration of an antimicrobial drug

Biphasic (Eagle) effect: It is a phenomenon in which low doses of an antibacterial in vitro

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Properties of an Ideal Antimicrobial Agent

 CLASSIFICATION OF ANTIMICROBIAL DRUGS

The antimicrobial drugs can be classified in several ways based on mechanism of

B. Based on chemical structure:

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Choice of an antimicrobial agent depends mainly on three factors:

1. Organisms related factors

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Bactericidal Drugs Bacteriostatic Drugs

RESISTANCE TO ANTIBACTERIAL DRUGS

 by transfer of bacteria between animals

GENETIC DETERMINANTS OF ANTIBIOTIC RESISTANCE

CHROMOSOMAL DETERMINANTS: MUTATIONS

Resistance resulting from chromosomal mutation is important in some instances, notably

EXTRACHROMOSOMAL DETERMINANTS: PLASMIDS

In addition to the chromosome itself, many species of bacteria contain extrachromosomal

THE TRANSFER OF RESISTANCE GENES BETWEEN GENETIC ELEMENTS

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Gene cassettes and integrons

THE TRANSFER OF RESISTANCE GENES BETWEEN BACTERIA

Conjugation involves cell-to-cell contact during which chromosomal or extrachromosomal

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

BIOCHEMICAL MECHANISMS OF RESISTANCE TO ANTIBIOTICS

Inactivation of chloramphenicol : Chloramphenicol is inactivated by chloramphenicol

Inactivation of aminoglycosides : Aminoglycosides are inactivated by phosphorylation,

2) ALTERATION OF DRUG-SENSITIVE OR DRUG-BINDING SITE

In addition to acquiring resistance to β-lactams susceptible to β-lactamase, some strains of S.

 Many pathogenic bacteria have developed resistance to the commonly used

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

B) Based on their duration of action

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Do not continue therapy more than 7 days

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

a. Oral route: It is commonly used to administer sulphonamides in domestic animals. The

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

II. Baquiloprim Contbinations

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

PENICILLINS (BETA-LACTAM ANTIBIOTICS )

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

(B) Broad spectrum penicillins: also known as Aminopenicillin

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Side Effects/Adverse Effects

CEPHALOSPORINS , CARBEPENEMS and MONOBACTAMS

III. Third-generation cephalosporins

Figure: Basic structure of four important beta-lactam antibiotics

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019