Transcript L3_protein synthesis..

Inhibitors of bacterial protein synthesis
The five general mechanisms
comprise (1) inhibition of
synthesis of cell wall,
(2) damage to cell membrane,
(3) modification of nucleic
acid/DNA synthesis,
(4) modification of protein
synthesis (at ribosomes), and
(5) modification of energy
metabolism within the cytoplasm
(at folate cycle).
Inhibitors of bacterial protein synthesis
 Drugs that inhibit protein synthesis vary considerably in terms
of chemical structures and their spectrum of antimicrobial
activity.
 Chloramphenicol, tetracyclines, and the aminoglycosides
were the first inhibitors of bacterial protein synthesis to be
discovered with broad spectrum of antimicrobial activity.
 Erythromycin, an older macrolide antibiotic has a narrow
spectrum of action.
 Azithromycin
and
clarithromycin
(semisynthetic
macrolides), clindamycin and newer inhibitors developed
lately as streptogramins, linozolid, telithromycin, and
tigecycline have activity against certain bacteria that have
developed resistance to older antibiotics.
Lists of drugs act as protein synthesis inhibitors
I : Chloramphenicol
 Chloramphenicol is a bacteriostatic antimicrobial that
became available in 1949. it was isolated from cultures of
streptomyces bacteria.
 It inhibits bacterial protein by binding to the 50S
ribosomal subunit.
 Chloramphenicol is considered a prototypical broad
spectrum antibiotic, is effective against a wide range of
gram-positive and gram-negative bacteria, including
most anaerobic organisms.
 Because of its toxicity, its use is restricted to lifethreatening infections for which no alternative exist.
 Due to resistance and safety concerns, it is no longer a
first-line agent for any infection.
Mechanism of action of chloramphenicol
Antibacterial spectrum
 It is a bacteriostatic broad-spectrum antibiotic that is active against both aerobic
and anaerobic gram positive and gram negative organisms
 It is active not only against bacteria, but also against other microorganisms, such
as Rickettsia.
(A genus of gram-negative bacteria that are carried as parasites by many ticks, fleas,
and lice and cause diseases such as typhus, scrub typhus, and Rocky Mountain
spotted fever.)
 It is bacteriostatic for most organisms but kills (bacterocidal) for Haemophilus
influenzae, Neisseria meningitidis and Bordetella pertussis (Bacteroids).

•
•
•
It is not active against Klamedia species.
P. aeruginosa is resistant to even very high concentrations of the drug.
Chlamydia is a genus of bacteria that are obligate intracellular parasites.
Chlamydia infections are the most common bacterial sexually transmitted
infections in humans and are the leading cause of infectious blindness
worldwide.[The three Chlamydia species include Chlamydia trachomatis (a
human pathogen), Chlamydia suis (affects only swine), and Chlamydia
muridarum (affects only mice and hamsters).[
Classification and Pharmacokinetics
 Chloramphenicol has a simple and distinctive structure, and no
other antimicrobials have been discovered in this chemical
class.
 Chloramphenicol is extremely lipid soluble; it remains
relatively unbound to protein and is a small molecule.
 It has a large apparent volume of distribution, and penetrates
effectively into all tissues of the body, including the brain.
 The concentration achieved in brain and cerebrospinal fluid
(CSF) is around 30 to 50%, even when the meninges are not
inflamed; this increases to as high as 89% when the meninges
are inflamed.
Pharmacokinetics
 Chloramphenicol is effective orally as well as parenterally
and is widely distributed readily crossing the placental and
blood brain barriers.
 Chloramphenicol undergoes enterohepatic cycling, and a
small fraction of the dose (10%) is excreted in the urine
unchanged.
 Most of the drug is inactivated by a hepatic
glucuronosyltransferase.
 Chloramphenicol inhibits the hepatic mixed-function
oxidases.
 Chloramphenicol increases the absorption of iron
Administration and fate of chloramphenicol
Clinical uses
 Because of its toxicity, chloramphenicol has very few uses as a
systemic drug.
 Chloramphenicol should be reserved for serious infections in
which benefit of the drug outweighs its uncommon but serious
hematological toxicity, such uses may include:
Infections caused by H. influnzae resistant to other drugs.
Meningitis in patients whom penicillin cannot be used.
 Chloramphenicol is active against the three main bacterial
causes of meningitis: Neisseria meningitidis, Streptococcus
pneumoniae and Haemophilus influenzae.
 Chloramphenicol is sometimes used for rickettsial diseases.
 The drug is commonly used as a topical antimicrobial agents
in bacterial conjunctivitis.
 It is effective in typhoid fever, but ciprofloxacin or amoxicillin
and co-trimoxazole are similarly effective and less toxic.
Clinical use in special populations
 Chloramphenicol is metabolized by the liver to chloramphenicol
glucuronate (which is inactive). In liver impairment, the dose of
chloramphenicol must therefore be reduced.
 The majority of the chloramphenicol dose is excreted by the kidneys
as the inactive metabolite, chloramphenicol glucuronate. Only a tiny
fraction of the chloramphenicol is excreted by the kidneys
unchanged. Plasma levels should be monitored in patients with renal
impairment, but this is not mandatory.
 Chloramphenicol succinate ester (the inactive intravenous form of
the drug) is readily excreted unchanged by the kidneys, more so than
chloramphenicol base, and this is the major reason why levels of
chloramphenicol in the blood are much lower when given
intravenously than orally.
 Chloramphenicol passes into breast milk, so should therefore be
avoided during breast feeding, if possible.
Adverse effects
Aplastic anemia:
 The most serious side effect of chloramphenicol treatment is
aplastic anemia. This effect is rare and is generally fatal: there
is no treatment and it is unpredictable.
 Aplastic anemia is severe idiosyncratic depression of the bone
marrow resulting in pancytopenia (a decreased in all blood cell
elements) and independent of dose and may occur after
therapy ceased.
Bone marrow suppression:
 Chloramphenicol commonly causes bone marrow suppression
during treatment; this is a direct toxic effect of the drug on
human mitochondria. This effect manifests first as a fall in
hemoglobin levels. The anemia is dose-dependent and fully
reversible once the drug is stopped.
Leukemia
 There is an increased risk of childhood leukemia, and the risk
increases with length of treatment.
Adverse effects
Gray baby syndrome
 Intravenous chloramphenicol use has been associated with
the so-called gray baby syndrome.
 This phenomenon occurs in newborn infants because they
do not yet have fully functional liver enzymes (i.e. UDPglucuronyl transferase), so chloramphenicol remains
unmetabolized in the body. This causes several adverse
effects, including hypotension and cyanosis. The condition
can be prevented by using the drug at the recommended
doses, and monitoring blood levels.
Gastrointestinal disturbances:
 These conditions may occur from direct irritation and from
superinfections, especially candidiasis (secondary to
alteration of the intestinal microbial flora).
Drug interactions
 Administration of chloramphenicol concomitantly with
bone marrow depressant drugs is contraindicated.
 Chloramphenicol is able to inhibit some of the hepatic
mixed-function oxidases and, thus, blocks the metabolism
of such drugs as: warfarin, phenytoin, tolbutamide, and
chlorpropamide, thereby increasing their elimination halflife, elevating their concentrations and potentiating their
effects.
 Conversely, other drugs may alter the drug
elimination.
Concurrent
administration
of
phenobarbital or rifampin, which potently induce
CYPs, shortens its t1/2 and may result in
subtherapeutic drug concentrations.
Inhibition of the cytochrome P450 system by
chloramphenicol
II : Macrolides
 The macrolide antibiotics are large cyclic lactone ring
structures with attached sugars.
 The main macrolide and related antibiotics are erythromycin,
clarithromycin and azithromycin.
 Erythromycin was the first of these drugs to be used clinically
as drug of choice and as alternative to penicillin in individuals
who are allergic to penicillin (mainly active against grampositive organisms).
 Clarithromycin and azithromycin are semisynthetic
derivatives of erythromycin have greater gram-negative
activity than erythromycin.
 Telithromycin a semisynthetic derivative of erythromycin, is
the first “ketolide” antimicrobial agent that has been approved.
 The Ketolides are active against macrolide-resistant grampositive strains.
Macrolide antibiotics structure
Mechanism of action of macrolide antibiotics
Antimicrobial spectrum
1. Erythromycin:
 This drug is effective against many of the same organisms as
penicillin G, and is slightly wider than that of penicillin, it
may be used in patients who are allergic to the penicillins.
 Erythromycin is used to treat infections caused by Grampositive bacteria (e.g. Streptococcus pneumoniae) and
spirochaetes, but not against most gram-negative organisms,
exceptions being N gonorrhoeae and, to a lesser extent, H
influenzae.
 Erythromycin has activity against many species of
Campylobacter, Chlamydia, Mycoplasma, Legionella.
 Erythromycin is not active against penicillin-resistant
Streptococcus pneumoniae strains (PRSP) and MRSA strains.
2. Clarithromycin:
 Clarithromycin is slightly more potent than erythromycin
against sensitive strains of streptococci and staphylococci.
 Clarithromycin is as active, and its metabolite is twice as
active, against H. influnzae as erythromycin.
 Its activity against intracellular pathogens, such as Chlamydia,
Legionella, Moraxella, and Ureaplasma species and
Helicobacter pylori, is higher than that of erythromycin.
3. Azithromycin:
 Azithromycin is far more active against respiratory infections
due to H. influnzae and Moraxella cattarhalis.
 Azithromycin is now the preferred therapy for urithritis caused
by Chlamydia trachomatis, and for Mycobacterium infections.
 It is also effective in gonorrhea, as an alternative to ceftriaxone
and in syphilis, as an alternative to penicillin G.
4. Telithromycin:
 This ketolide drug has an antibacterial spectrum similar of
that of azithromycin.
 The structural modification within ketolides neutralizes the
most common resistance mechanisms (methylase-mediated
and efflux-mediated) that make macrolides ineffective.
 The drug can be used in community-acquired pneumonia
including infections caused by multidrug-resistant
organisms.
Pharmacokinetics
Erythromycin:
 The erythromycin base is destroyed by gastric acid.
 Thus, enteric coated tablets or esterified forms of the antibiotic
are administered.
 All are adequately absorbed upon oral administration.
 Intravenous administration of erythromycin is associated with a
high incidence of thrombophlebitis.
 It distributes well to all body fluids except the CSF.
 it is extensively metabolized by the liver and is known to inhibit
the oxidation with cytochrome P450 of several drugs for example:
theophylline.
 It is primarily concentrated and excreted in an active form in the
bile.
 Partial reabsorption occurs through the enterohepatic circulation.
Inactive metabolites are excreted into the urine (15%).
Pharmacokinetics
 Clarithromycin, azithromycin, and telithromycin are stable
to stomach acid and readily absorbed.
 Food interferes with the absorption of erythromycin and
azithromycin, but can increase that of clarithromycin.
 All these drugs are concentrate in the liver and are widely
distributed in the tissues.
 Inflammation allows for greater tissue penetration.
 Azithromycin has the longest half-life and largest distribution.
 Telithromycin inhibit cytochrome P450 system, and all are
converted to active metabolites.
 Clarithromycin and its metabolites (the active 14-hydroxy
derivative metabolite) are eliminated by the kidneys as well as
the liver.
Administration an fate of the macrolide antibiotics
Some properties of the macrolide antibiotics
Clinical uses
 Erythromycin is effective in the treatment of infections
caused by M pneumoniae, Corynebacterium, Bordetella
pertussis, Ureaplasma urealyticum, and treponema pallidum.
 Erythromycin is useful as a penicillin substitute in penicillinallergic individuals with infections caused by streptococci or
pneumococci.
 Erythromycin or tetracycline is the drug of choice for
Mycoplasmal pneumonia.
 Erythromycin is an effective alternative for individuals who
are allergic to penicillin for the prophylaxis of recurrences of
rheumatic fever.
Clinical uses
 Azithromycin has a similar spectrum of activity but is
more active against Moraxella catarrhalis, Neisseria, H
influnzae, and Legionella pneumophila.
 Because of its long half-life, a single dose of azithromycin
is effective in the treatment of urogenital infections caused
by Chlamydia trachomatis.
 Clarithromycin has almost the same spectrum of
antimicrobial activity and clinical uses as erythromycin.
 Clarithromycin 500 mg, in combination with omeprazole,
20 mg, and amoxicillin, 1 g, each administered twice daily
for 10 to 14 days, is effective for treatment of peptic ulcer
disease caused by H. pylori .
Adverse effects
Gastrointestinal disturbance:
 GIT disturbances are common and unpleasant but not
serious. Anorexia, nausea, vomiting, and diarrhea
occasionally accompany oral administration (due to a
direct stimulation of gut motility).
Cholestatic jaundice:
 Cholestatic hepatitis is the most striking side effect (fever,
jaundice, impaired liver function), probably as the result of
a hypersensitivity reaction to the estolate form of
erythromycin.
Ototoxicity: Transient deafness has been associated with
erythromycin, especially at high dosages.
Allergic reactions:
 Among the allergic reactions observed are fever,
eosinophilia and skin eruptions, which may occur alone or
in combination; each disappears shortly after therapy is
stopped.
Inhibition of the cytochrome P450 system by erythromycin,
clarithromycin, and telithromycin.
“Chancroid is a bacterial infection that is spread only through sexual contact
III : Aminoglycosides
 Aminoglycoside antibiotics had been used for treatment of
serious infections due to aerobic gram-negative bacilli.
 Because their use is associated with serious toxicities, they
have been replaced to some extent by safer antibiotics, such as
the third- and fourth-generation cephalosporins, the
fluoroquinolones, and the carbapenems.
 Aminoglycosides that are derived from Streptomyces have mycin suffixes, whereas those derived from micromonospora
end in –micin.
 The polycationic nature precludes their easy passage across
tissue membranes.
 All members of this family are believed to inhibit protein
synthesis.
Aminoglycosides structure
 The aminoglycoside are a group antibiotics of complex
chemical structure composed of amino-modified sugars,
resembling
each
other
in
antimicrobial
activity,
pharmacokinetic characteristics and toxicity. The main agents
are gentamicin, streptomycin, amikacin, tobramycin, and
neomycin.
Mechanism of action of the aminoglycosides
Antibacterial spectrum
 The aminoglycosides are effective against many aerobic gramnegative bacilli (including Peudomonas aeruginosa) and some
gram-positive organisms.
 They most widely used against gram-negative enteric
organisms and sepsis.(Sepsis is an illness in which the body has a severe response
to bacteria or other germs)
 To achieve an additive or synergistic effect, aminoglycosides
are often combined with a beta-lactam antibiotic, vancomycin,
or a drug active against anaerobic bacteria.
 They may be given together with a penicillin in streptococcal
infections and those caused by Listeria spp. and P. aeruginosa.
 Gentamicin and tobramycin commonly used for P. aeruginosa.
 Amikacin has the widest antimicrobial spectrum and can be
effective in infections with organisms resistant to gentamicin
and tobramycin.
Pharmacokinetics
 Aminoglycosides are polar compounds, not absorbed after oral
administration and must be given intramuscularly, or
intravenously for systemic effect.
 Because aminoglycosides are concentration- and timedependent and also have post antibiotic effect, once-daily
dosing with the aminoglycosides can be employed. This results
in less toxicity and less expensive to administer.
 They have limited tissue penetration and do not pass the BBB.
 Glomerular filtration is the major mode of excretion, 50-60%
of a dose being excreted unchanged within 24 hr.
 The plasma half-life (2-3 hr) of these drugs are greatly affected
by changes in renal function.
 If renal function is impaired, accumulation occurs rapidly, with
resultant increase the dose related toxic effects (such as
ototoxicity and nephrotoxicity).
Administration and fate of aminoglycosides
Clinical uses
 Gentamicin, tobramycin, and amikacin are important drugs for the
treatment of serious infections caused by aerobic gram-negative
bacteria, including E. coli and Enterobacter, Klebsiella, Proteus,
Providencia, Pseudomonas, and Serratia species.
 In most cases, aminoglycosides are used in combination with a betalactam antibiotic. Examples include their combined use with
penicillins in the treatment of pseudomonal, listerial, and
entercoccal infections.
 Pseudomonal aeruginosa infections could be treated with
tobramycin alone or in combination with piperacillin or ticarcillin.
 Enterococci infections could be treated with gentamicin or
streptomycin plus vancomycin or ampicillin.
 Gentamicin is the drug of choice for the treatment of
tularemia. (Tularemia is usually a disease of animals. Humans can acquire tularemia
when they come in contact with infected animals or are bitten by insects that have fed on an
infected animal.)
Clinical uses
 Streptomycin in combination with penicillins is used in the
treatment of enterococcal carditis, tuberculosis, and plague.
 Because of the risk of ototoxicity, streptomycin should not be used
when other drugs well serve.
 Owing to their toxic potential, neomycin and kanamycin are usually
restricted to topical (for the conjunctiva or external ear) or oral use
(e.g., eliminate bowel flora). Gentamicin is also available for topical
use.
 Because of their toxicity with prolonged administration,
aminoglycosides should not be used for more than a few days unless
deemed essential for a successful or improved outcome.
 Once the microorganism is isolated and its sensitivities to antibiotics
are determined, the aminoglycoside should be discontinued if the
infecting microorganism is sensitive to less toxic antibiotics.
Side effects
Serious, dose-related toxic effects, which may increase as
treatment proceeds, can occur with the aminoglycosides.
The main hazards being ototoxicity and nephrotoxicity.
1. Ototoxicity:
 Its directly related to high peak plasma levels and the
duration of treatment. Auditory or vestibular damage (or
both) may occur with any aminoglycoside and may be
irreversible.
 Auditory impairment or deafness is more likely with
neomycin, amikacin and kanamycin while vestibular
dysfunction manifested as vertigo, ataxia, and loss of
balance is more likely with streptomycin, gentamicin and
tobramycin.
 Ototoxicity may be increased by the use of other ototoxic
drugs (e,g., loop diuretics, cisplatin, etc.).
In the case of the auditory part of CN VIII, the symptoms are deafness or tinnitus
(ringing in the ears). In the case of the vestibular part of CN VIII, the symptoms are
vertigo or imbalance.
Side effects
2. Nephrotoxicity:
 Renal toxicity usually takes the form of acute tubular necrosis.
Its reversible and more common in elderly patients and in
those taking nephrotoxic agents (e.g., 1st generation
cephalosporins, vancomycin). Gentamicin and tobramycin are
the most nephrotoxic.
3. Neuromuscular blockade:
 Paralysis caused by neuromuscular blockade may occur at
high doses of aminoglycoside. It results from inhibition of
calcium uptake. Patients with myasthenia gravis are at risk.
4. Skin reactions:
 Allergic skin reactions may occur in patients, and contact
dermatitis may occur in personnel handling the drug.
Neomycin is the agent most likely to cause this adverse effect.
Tetracycline antibiotics
 Tetracyclines are a group of broad-spectrum
bacteriostatic antibiotics that inhibit protein synthesis.
 The group includes tetracycline, doxycycline and
minocycline. They have only minor differences in their
activities against specific organisms.
 Their general usefulness has been reduced with the onset
of bacterial resistance. Despite this, they remain the
treatment of choice for some specific indications.
 They are so named for their four (“tetra-”) hydrocarbon
rings (“-cycl-”).
Classification
 All of the tetracycline have the basic structure shown below:
Mechanism of action
Tetracycline bind to the 30S ribosomal subunits, thus
preventing the binding of aminoacyl-tRNA to the ribosome.
Antibacterial spectrum
 As broad spectrum bacteriostatic antibiotics, the
tetracyclines are effective against gram-positive and
gram-negative bacteria, as well as organisms other
than bacteria such as: Mycoplasma, Rickettsia,
Chlamydia spp., spirochetes, and some protozoa (e.g.,
amoebae).
 Minocycline is also effective against N. meningitidis.
 The antibacterial activities of most tetracyclines are
similar except that tetracycline-resistant strains may
remain susceptible to doxycycline or minocycline.
Pharmacokinetics
 The tetracyclines are generally given orally but can also
be administered parenterally.
 Minocycline and doxycycline are lipid soluble and
virtually completely absorbed.
 The absorption of most other tetracyclines is irregular and
incomplete but is improved in the absence of food.
 Because tetracyclines chelate metal ions (calcium,
magnesium, iron, aluminum), forming non-absorbable
complexes, absorption is decreased in the presence of
milk, certain antacids and iron preparations.
 A portion of an orally administered dose of tetracycline
remains in the gut lumen, modifies intestinal flora, and is
excreted in the feces.
 Minocycline and doxycycline are long acting tetracycline
while tetracycline is short acting.
Pharmacokinetics
 Tetracyclines are distributed widely to tissues and they
bind to tissues undergoing calcification (e.g., teeth and
bones).
 All tetracyclines enter the CSF, but levels are insufficient
for therapeutic efficacy, except for minocycline. and can
cross the placental barrier and concentrate in fetal bones
and dentition.
 All the tetracyclines undergo enterohepatic cycling.
 Obstruction of the bile duct and hepatic or renal
dysfunction can increase their half-lives.
 Doxycycline is excreted mainly in feces; does not
accumulate significantly in renal failure, and requires no
dosage adjustment, making it the tetracycline of choice for
use in the setting of renal insufficiency
 Tigecycline, formulated only for IV use, is eliminated in
the bile and has a half-life of 30-36 hours.
Administration and fate of tetracyclines
Effects of antacids and milk on the absorption of
tetracyclines
Clinical uses
Primary uses:
 Tetracyclines are recommended in the treatment of infections
caused by Mycoplasma pneumoniae (in adults), chlamydiea,
rickettsiae, vibrios, and some spirochetes.
 Doxycycline is currently an alternative to macrolides in the
initial treatment of community-acquired pneumonia caused by
Mycoplasma pneumoniae.
Secondary uses:
 Tetracyclines are alternative drugs in the treatment of syphilis.
They are also used in the treatment of respiratory infections
caused by susceptible organisms, for prophylaxis against
infection in chronic bronchitis, in the treatment of
leptospirosis, and in the treatment of acne.
Leptospirosis is a bacterial disease that affects both humans and animals. Humans become infected
through direct contact with the urine of infected animals or with a urine-contaminated environment
ACNE
Clinical uses
Selective uses:
 Specific tetracyclines are used in the treatment gastrointestinal
ulcers caused by Helicobacter pylori (tetracycline), in Lyme
disease (doxycycline), and in the meningococcal carrier state
(minocycline).
 Doxycycline is also used for the prevention of malaria and in
the treatment of amebiasis.
Tigecycline:
 It has a broad spectrum action that includes organisms resistant
to standard tetracyclines.
 Its antimicrobial activity includes gram-positive cocci resistant
to methicillin (MRSA strains) and vancomycin-resistant
enterococci (VRE strains). Beta-lactamase-producing gramnegative bacteria, anaerobes, chlamydiae, and mycobacteria.
The drug is formulated only for IV use.
Lyme disease is a bacterial infection you get from the bite of an infected tick.
Typical therapeutic applications for tetracyclines
CHOLERA
LIME DISEASE
MYCOPLASMA
PNEUMONIAE
ROCKY
MOUNTAIN
SPOTTED FEVER
CHLAMEDIAL
INFECTIONS
Side effects
 Gastrointestinal disturbances: Nausea, vomiting, and
diarrhea are the most common reasons for discontinuing
tetracycline medication. These effects are due to direct local
irritation of the GIT.
 Superinfections: disturbance in the normal flora may lead to
candidiasis (oral and vaginal) and more rarely to bacterial
superinfections with S aureus or Clostridium difficile.
 Bony structure and teeth: because they chelate calcium,
tetracyclines are deposited in growing bones and teeth, causing
staining and sometimes dental hypoplasia and bone deformity.
 Fatal hepatotoxicity: high doses of tetracyclines, especially in
pregnant patients and those with preexisting hepatic disease,
may impair liver function and lead to liver necrosis.
Side effects
 Phototoxicity (sensitization to sunlight): tetracyclines,
especially demeclocycline, may cause enhanced skin
sensitivity to ultraviolet light.
 Vestibular disturbances: dose-dependent reversible dizziness
and vertigo have been reported with doxycycline and
minocycline.
 Tetracyclines other than doxycycline may accumulate to toxic
levels in patients with impaired kidney function.
 High doses of tetracyclines can decrease protein synthesis in
host cells, an anti anabolic effect that may result in renal
damage.
 The tetracyclines should not be employed in pregnant or
breast-feeding woman or in children less than 8 years of age.
Phototoxicity
Important information about tetracycline( summary)
Do not use tetracycline if you are pregnant. It could cause harm to the unborn baby,
including permanent discoloration of the teeth later in life.
Tetracycline can make birth control pills less effective. Use a second method of birth
control while you are taking this medicine to keep from getting pregnant.
Tetracycline passes into breast milk and may affect bone and tooth development in a
nursing baby.
Do not give this medicine to a child younger than 8 years old.
Tetracycline can cause permanent yellowing or graying of the teeth, and it can affect a
child's growth.
Avoid exposure to sunlight or artificial UV rays (sunlamps or tanning beds).
Tetracycline can make your skin more sensitive to sunlight and sunburn may result. Use a
sunscreen (minimum SPF 15) and wear protective clothing if you must be out in the sun.
Do not take iron supplements, multivitamins, calcium supplements, antacids, or laxatives
within 2 hours before or after taking tetracycline. These products can make this medicine
less effective.
Throw away any unused tetracycline when it expires or when it is no longer needed. Do
not take this medicine after the expiration date on the label has passed. Expired
tetracycline can cause a dangerous syndrome resulting in damage to the kidneys.
Inhibitors of metabolism
(antifolate drugs)
Antimicrobial agents that interfere with folate
synthesis or action (antifolate drugs)
 The antifolate drugs used in the treatment of infectious
diseases are the sulfonamides, which inhibit microbial
enzymes involved in folic acid synthesis, and
trimethoprim, a selective inhibitor of dihydrofolate
reductase.
 The importance of sulfonamides has declined due to
increasing resistance.
 The only drugs still commonly used are sulfamethoxazole
(usually in combination with trimethoprim as cotrimoxazole), sulfasalazine (poorly absorbed in the
gastrointestinal tract, used to treat ulcerative colitis) and
occasionally sulfadiazine.
Structures of two representative sulfonamides
and trimethoprim
Mechanisms of action
Sulfonamide is a structural analogue of p-aminobenzoic acid
(PABA), which is an essential precursor in the synthesis of
folic acid, required for the synthesis of DNA and RNA in
bacteria.
 Sulfonamides as antimetabolites of PABA, they are
competitive inhibitors of the enzyme dihydropteroate
synthetase .
 They can also act as substrates for this enzyme, resulting in the
synthesis of nonfunctional forms of folic acid.
 The selective toxicity of sulfonamides results from the
inability of mammalian cells to synthesize folic acid; they
must use preformed folic acid that is present in the diet.
 The action of sulfonamide is to inhibit growth of the bacteria,
not to kill them; thus it is bacteriostatic rather than
bactericidal.
Mechanisms of action
Trimethoprim is structurally similar to folic acid, and is a
selective inhibitor of bacterial dihydrofolate reductase
that prevents formation of the active tetrahydro form of
folic acid (tetrahydrofolate coenzymes required for
purine, pyrimidine, and amino acid synthesis).
Trimethoprim plus sulfamethoxazole:
 When the two drugs are used in combination,
antimicrobial synergy results from the sequential
blockade of folate synthesis.
 The drug combination is bactericidal against susceptible
organisms.
Inhibitory effects of sulfonamides and trimethoprim on
folic acid synthesis
Inhibition of tetrahydrofolate synthesis by sulfonamides and trimethoprim
Pharmacokinetics
 Sulfonamides are weakly acidic compounds, given orally and
are well absorbed (except, sulfasalazine), and widely
distributed in the body.
 The drug pass into inflammatory exudates and cross both
placental and blood brain barriers. They are metabolized
mainly in the liver, the major product being an acetylated
derivative that lacks antibacterial action and eliminated by the
kidney.
 Trimethoprim is well absorbed orally, and widely distributed
throughout the tissues and body fluids. It reaches high
concentrations in the lungs and kidneys, and fairly high
concentrations in the cerebrospinal fluid (CSF).
 When given with sulfamethoxazole, about half the dose of
each is excreted within 24 hr. Because trimethoprim is a weak
base, its elimination by the kidney increases with decreasing
urinary pH.
Administration and fate of the sulfonamides
Administration and fate of co-trimoxazole
Antibacterial spectrum
 Sulfonamides are active against selected Enterobacteria in
the urinary tract and Nocardia.
 In addition, sulfadiazine, in combination with the
dihydrofolate reductase inhibitor pyrimethamine, is
preferred form of treatment for toxoplasmosis.
 The antibacterial spectrum of trimethoprim is similar to
that of sulfamethoxaole. However, trimethoprim is 20- to
50-fold more potent than the sulfonamide.
 Trimethoprim may be used alone in the treatment of acute
urinary tract infections and in the treatment of bacterial
prostatitis (although fluoroquinolones are preferred) and
vaginitis.
Antibacterial spectrum
 Trimethoprim is more lipid soluble than
sulfamethoxazole and has a greater volume of
distribution. Administration of one part trimethoprim
to five parts of the sulfa drugs produces a ratio which
is optimal for the antibiotic effect.
 Co-trimoxazole shows greater antimicrobial activity
than equivalent quantities of either drug used alone. It
is effective in treating urinary tract infections and
respiratory tract infections as well as in pneumonia
and ampicillin- or chloramphenicol-resistant systemic
salmonella infections.
Synergism between trimethoprim and sulfamethoxazole
inhibits growth of Escherichia coli
Clinical use
I. Sulfonamides:
 The sulfonamides are active against gram-positive and gramnegative organisms, Chlamydia, and Nocardia.
- Simple urinary tract infections- Oral (triple sulfa, sulfisoxazole).
-Ocular infections – Topical (sulfacetamide).
-Burn infections – Topical (mafenide, silver sulfadiazine)
-Ulcerative colitis, rheumatoid arthritis – Oral (sulfasalazine).
-Toxoplasmosis – Oral (sulfadiazine plus pyrimethamine).
II. Co-trimoxazole:
 This drug combination is effective orally in the treatment of
urinary tract infections and respiratory, ear, and sinus
infections caused by Haemophilus influnzae and Moraxella
catarhalis.
 It is used for treatment of severe Pneumocystits pneumonia
and for gram-negative sepsis
Adverse effects
Sulfonamides may have the following adverse effects:
 Hypersensitivity: allergic reactions, including skin rashes and
fever, occur commonly.
 Gastrointestinal: nausea, vomiting, and diarrhea and mild
hepatic dysfunction may occur.
 Hematotoxicity: granlocytopenia, thrombocytopenia, and
aplastic anemia.
 Nephrotoxicity: sulfonamides may precipitate in the urine at
acidic pH, causing crystalluria and hematuria.
 Sulfonamides can displace bilirubin from plasma proteins,
with the risk of kernicterus (bilirubin-induced brain
dysfunction) in the neonate if used in the third trimester of
pregnancy.
Adverse effects
 Trimethroprim can produce the effects of folic acid
deficiency (blood disorders), including megaloblastic
anemia, leukopenia and granulocytopenia.
 These blood disorders can be reversed by the simultaneous
administration of folinic acid, which does not enter
bacteria.
 Co-trimoxazole: may cause any of the adverse effects
associated with the sulfonamides.
 AIDS patients given co-trimoxazole have a high incidence
of adverse effects, including fever, rashes, leukopenia, and
diarrhea.