Tetracyclines!

September 28, 2019 dr. ovais omer 1

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History:
 TC are broad spectrum antibiotics
 Have a nucleus of four cyclic rings
 Naturally from soil actinomycetes or prepared
semi-synthetically
 In 1948, first member introduced was
chlortetracycline derived from soil
actinomycetes Streptomyces aureofaciens
 Followed by oxytetracycline.
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 Removal of chlorine atom from
chlortetracycline produced semi-synthetic
tetracycline introduced in 1952.
 Other semisynthetics are metacycline,
doxycycline, rolitetracycline etc.
 Doxycycline and minocycline are newer
tetracyclines with high lipid solubility and
longer duration of action.
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 Chlortetracycline was introduced in 1948
followed by oxytetracycline and tetracycline
in 1950 and 1952 respectively.
In 2005, tigecycline, the first member of a
new subgroup of tetracyclines named
glycylcyclines was introduced to treat
infections caused by resistant strains.

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Chemistry

 The basic tetracycline structure consists of four

benzene rings with various constituents on each ring.
 The crystalline bases are faintly yellow, odorless,
slightly bitter compounds. They are only slightly
soluble in water at pH 7 but they can form soluble
sodium salts and hydrochloride.

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Other Properties:
 Acidic
 Hygroscopic
 In aqueous solution form salts with both acids and
bases.
 Stable as powder, aqueous solutions are not stable
(pvp=polyvinyl pyrolidine or propylene glycol etc.)
 Available in injections, bolus, capsules, powder, feed
additives, ointments.

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Classification:
Short acting: t1/2=<8hrs.
 Oxytetracycline, tetracycline,
chlortetracycline
Intermediate acting:t1/2=8-16hrs.
 Demeclocycline, metacycline

Long acting:t1/2= >16hrs.

 Doxycycline, minocycline, tigecycline.

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Mechanism of Action:
 Inhibit bacterial protein synthesis
1.Passage into bacterial cell
2. Interaction with bacterial ribosomes.
 Bacteriostatic

 More effective against multiplying

microorganisms
 More active at PH 6-6.5

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 Effects of TC are mostly reversible
 Also shows bactericidal effect at high
concentrations as they also affect the
functional integrity of bacterial cell
membranes.
 Mammalian protein synthesising apparatus is
less sensitive to TC.

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a. Passage of TC into bacterial cell
 Enter into G- bacteria by two transport
mechanisms
 1. is through passive diffusion th. Hydrophilic
channels formed by porin proteins in outer
cell membrane.
 2. Mechanism involves an energy dependent
active transport system that pumps all TC
across cytoplasmic membrane
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b. Interaction of TC with bacterial ribosomes
 TC bind to the 30S ribosomal subunit. They
prevent addition of amino acids to the
growing peptide chain resulting in inhibition
of protein synthesis (Fig 58.11) page 914.

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Antimicrobial Spectrum:
 Broad spectrum (aerobic/anaerobic G- and
G+)
 Active against mycoplasma, rickettsia,
chlamydia, and some protozoa like
anaplasma, amoebae etc.
 Ineffective against fungi and viruses.
 Pseudomonas, aeruginosa, proteus, klebsiella,
salmonella, staph., corynebacterium are
resistant.
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Microbial resistance:
 Decreased penetration of drug into cells
 Enzymatic inactivation of drug
 Production of proteins by bacteria that protect
ribosomes by binding with tetracyclines

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 Effects of tetracyclines are reversible as the
bact. protein synthesis is restored when the
drug is removed
 Host defense system is required to remove
static bact.
 Primarily static but at higher concs. act as
bactericidal (affect functional integrity of cell
membrane)
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Pharmacokinetics:
Absorption:
 Minoycline and doxycycline being 100%
bioavailble orally
 All produce varying degree of tissue irritation
on parenteral administration especially
chlortetracycline
 Procaine is added for IM administration of TC
in small animals
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 All TC are adequately but incompletely absorbed
from the G.I. tract.
 Most absorption takes place from the stomach and
upper small intestine (greater in a fasting state).
 Absorption of TC is impaired by food in the
stomach, milk products, aluminum OH gels, Na+
bicarbonate, Ca++ & Mg++, and Fe++ preparations.

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 After a single oral dose peak plasma
concentrations are achieved in 2-4 hours.
 The mechanisms responsible for decreased
absorption appear to be chelation and an
increase in gastric pH.

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Distribution:
 Widely distributed in kidneys, liver, lungs,
bile, bones.
 With exception of lipid soluble members like
doxycycline and minocycline, tetracyclines do
not penetrate the brain and CSF.
 Cross placenta.
 Bind with Ca in the teeth and bones.

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 They are bound to plasma protein in varying degree.
 Penetration of these drugs into most tissues and body
fluids is excellent.
 All TC are concentrated in the liver and excreted by
way of the bile into the intestine from which they are
partially reabsorbed (enterohepatic circulation)

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 TET crosses the placental barrier and can
accumulate in fetal bones, thus delaying bone
growth. They are also excreted in breast milk.
 Binding action with Ca++ is the result of
dental enamel

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Biotransformation:
 With exception of lipid solubles, the TC are
not metabolized to a significant extent in the
body

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Excretion:
 All the TC are excreted in the urine and the
feces, the primary route for most being the
kidney.
 The mechanism of renal exertion is
glomerular filtration.
 60% are excreted in urine and 40% in faeces

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 The drug is excreted in the feces, largely as an
inactive conjugate. Thus one of the safest of
the TET for the treatment of extrarenal
infections.

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Adverse Effects

 Have relatively low toxicity at normal dosage

levels
 TC can produce a variety of adverse effects
ranging from minor inconvenience to life-
threatening.

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Side effects

Gastrointestinal upsets:
 All produce GI irritation, mostly after oral
administration and anorexia, abdominal pain,
diarrhea, nausea and vomiting.

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 Oral dose may lead to fatal diarrhea in horses
& indigestion due to deleterious effect on
rumen microbes in ruminants

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Effect on Bones/teeth:
 Deposited in growing teeth and bones due to
chelating properties with calcium
 Form tetracycline-calcium orthophosphate
complex which inhibits calcification
 So permanent discoloration of the teeth.
 Delay fracture healing

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 Children receiving long-or short term therapy
with TC may develop brown discoloration of
the teeth.
 The drug deposits in the teeth and bones
probably due to its chelating property and the
formation of a TC -calcium orthophosphate
complex.
 Avoid giving to pregnant animals.
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Hepato toxicity:
 Fatty infiltration of liver due to excessive
doses
 Hepatotoxicity with jaundice

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Nephrotoxicity:
 Potentially nephrotoxic particularly in renal
insufficiency

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Hypersensitivity reaction:
 Not common.
 Skin rashes, urticaria, pruritis, dermatitis etc.

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Cardio vascular effects:
 Rapid IV inj. results in hypotension, collapse
and sudden death.
 Due to rapid chelation of blood calcium

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Other Effects:
 Cause irritation on parenteral administration
 Swelling, necrosis, yellow discoloration at inj.
site.
 Drug fever, photoallergic dermatitis etc.
 Prolong blood coagulation

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Contra indications/Precautions:
 Contra indicated in hepatic insufficiency,
renal diseases and in hypersensitive patients
 Oral administration to ruminants and horses is
not recommended as they inhibit the normal
bacterial fermentation of plant fibers.
 Should not be used in the last 2-3 months of
gestation

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 Should never be given with food, milk and
milk products
 Oral TC are given at least 1-2 hrs. before or
after food and milk.

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Drug Interactions:
 Antacids, iron preparations, saline purgatives,
kaolin, pectin, sodium bi carbonate decrease
absorption of tetracyclines from GI tract.
 May interfere with bactericidal activity of
penicillins, cephalosporins and
aminoglycosides.
 Should not be mixed with ringer lactate and
calcium preparations
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Clinical Uses:
 Bronchopneumonia
 UTI
 Metritis
 Mastitis
 Prostatitis
 Cholangitis etc.

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 Chlortetracycline used in food producing
animals as growth promoters
 In birds, TC are used in the treatment of
psittacosis

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Administration:
 Oral, Parenteral, Topical, Intramammary
 All can be given IV or IM
 Local ophthalmic ointments are used in
conjunctivitis
 Intramammary infusion is most commonly
used in mastitis

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Short-acting TC:
 Oxytetracycline: Obtained from
actinomycetes Streptomyces rimosus.
 After oral administration, bioavailability is
60-80%
 After IM, peak plasma levels are achieved in
0.5-2 hours.
 With the exception of brain and CSF, it is
distributed well in tissues and fluids
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 Excreted unchanged in urine and bile and also
excreted in milk
 Half life varies in different species
 Used to treat infections of respiratory and
urinary tract, skin etc.
 Best to be given in patients hypersensitive to
penicillins or macrolides.
 Available in combination with piroxicam to
alleviate pain at site
 Drug withdrawal/milk discard time in cattle is
14-22 days
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Tetracycline:
 Broad spectrum
 Obtained from Streptomyces aureofaciens or
semi-synthetically from oxytetracycline.
 Oral route is more common than parenteral
 Pharmacokinetic and pharmacodynamic
characteristics are similar to that of
oxytetracycline

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Chlortetracycline:
 Obtained from Streptomyces aureofaciens
 Orally absorbed 30%
 IM injection is painful
 Due to irritation, orally, it shows nausea,
vomiting and diarrhea.
 Mainly used as growth promoters in food
producing animals
 Drug withdrawal time in cattle is 10 days.
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Long-acting TC:
 Doxycycline: Semi-synthetic derived from
oxytetracycline.
 More lipophilic than older ones
 Has longer duration of action
 Antimicrobial spectrum more as compared to
oxytetracycline due to more penetration into
microbial cells

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 PO, 90-100% absorbed from GI tract
 Absorption is less affected by food, milk and
calcium salts.
 Also penetrates in brain and CSF
 Shows 90% plasma protein binding
 Significantly metabolised in the body (upto
40%).
 Excreted as inactive metabolites in faeces.
 Also used in psittacosis in birds and
anaplasmosis in calves and anthrax
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Minocycline:
 Semi-synthetic derivative of oxytetracycline
 More lipid soluble like doxycycline
 Efficient oral absorption (95-100 %)
 Higher tissue penetration
 Greater plasma protein binding
 Longer elimination half life

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 Broad spectrum antibacterial activity against
G+, G-, some protozoa, Rickettsiae etc.
 Most lipid soluble in tetracycline class of
antibiotics
 Greater penetration into brain
 Excreted mainly in faeces as inactive or
parent form

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