Antibiotics

folic acid,DAN,and RAN Inhibitors

by
Dr. Safia Alrezami

CONTENTS
PART(2)
1-QUINOLONES&FLUOROQUINOLONES
-MECHANISM OF ACTION
-PHARMACOKINETIC
-CLASSIFICATION
-SPECTRUM AND THERAPEUTIC
-ADVERSE EFFECTS
-CONTRAINDICATIONS
2-NITROFURANTOIN
3-METRONIDAZOLE
4-RIFAMPICINE

This drugs may be act on :
1. Cell wall
2.Protein synthesis
3.Nucleic acid metabolism. Drugs may interfere
directly with microbial DNA or its replication or
repair, e.g. quinolones metronidazole, or with
RNA, e.g. rifampicin
indirectly on nucleic acid synthesis,
e.g. sulphonamides, trimethoprimfolic acid,DAN,and RAN Inhibitors

Pteridine precursor+ p-amino benzoic acid (PABA)
Dihydropteroate synthetase
Dihydrofolic acid
Tetrahydrofolic acid
glutamate
Sulfonamides
Di hydrofolate reductase
Trimethoprim
PROTEIN DNA+RNA DNA

Silver sulfadiazine(used topically to reduce microbial colonization
and incidence of infections of wounds from burns)to avoid UT
complication.
• Child dose ( 50–100 mg/kg/day in
four doses).
• Adult dose 500-1000 mg qid
• Adultdose:1g BID
Child dose ( 60 mg/kg/day in
two doses)

D Sulfa drugs
distributed
throughout all
tissues and
cerebrospinal
fluid(BBB) They can
also pass the
placental barrier
and enter fetal
tissues.
Eexcert
by kidney
it may also
be
eliminated
in breast
milk
M metabolism
in the liver. The
sulfa drugs are
acetylated
A absorbed via the
small intestine after
oral administration(
Cmax in plasma 4-6
hours)…

Sulfonamides are not usually prescribed alone, mostly combination therapy is
preferred, indications are:
Urinary Tract Infections:
inhibit both gram (+ve, -ve) bacteria (active against selected enter bacteria in the urinary tract)
Nocardiosis :(respiratory infections).
Toxoplasmosis: Combined with pyrimethamineis treatment of choice.
Pyrimethamine: Loading dose 75 mg
Followed by 25 mg orally/ day
Sulfadiazine:1 g orally/ 6 hourly
3 – 6
weeks

Crystalluria.
Hypersensitivity
( Skin Rashes, mucous membrane rashes)
Hemopoietic disturbances (Acute Hemolytic Anemia,
Agranulocytosis , Aplastic Anemia).
Kernicterus This disorder may occur in newborns because sulfa
drugs displace bilirubin from binding sites on serum albumin,
due to deposition of bilirubin in basal ganglia and substantia
nigra lead to neonatal jaundice; may cause hemolysis in G6PD
baby.

preganacy,
lactation
people with
G6PD
Renal
failure
hypersensevity
Hepatic
failure

Only organisms that synthesize their folate
requirements de novo are sensitive to the
sulfonamides,
Thus, humans, who synthesize critical folate
cofactors from dietary folic acid, are not affected,
and bacteria that can obtain folates from their
environment are naturally resistant to these drugs,
• Acquired bacterial resistance to the sulfa drugs
can arise . Usually by random mutation.
•By transfer through plasmids

-
cotrimoxazole shows greater antimicrobia
activity than equivalent quantities of either drug
used alone. The combination was selected
because of the similarity in the half-lives of the
two drugs. M.O.A……(See figure1
Adult dose: (160 + 800 mg Q 12 hr or 0.48 + 2.4 gsingle dose)
Child dose:10 mg/kg/day TMP component in two doses)

Figure
No drugs
Trimethoprim only
Sulfamethoxazole
Both drugs
hours
No . of bacteria

.

1 - Prolonged prothrombin times in patients
receiving both trimethoprim and warfarin have
been reported(Oral anticoagulants)
2-The plasma half-life of phenytoin may be
increased due to an inhibition of its metabolism.
Methotrexate levels may rise due to displacement
from albumin-binding sites by sulfamethoxazole.
3. Sulfonylurea

can used alone
M.O.A………………See Figure 1
Therapeutic Uses………..UTI
Adverse effects: can produce the effects of folic
acid deficiency.6 These effects include
megaloblastic anemia, leukopenia, and
granulocytopenia.
Dose Peds. 4 mg/kg/d
in 2 ÷ doses
Adult dose100 mg/d PO bid
or 200 mg/d PO.

Contraindaction
Megaloblastic
anemia due to folate deficiency
Resistance
Resistance in gram-negative bacteria is due to the
presence of an altered dihydrofolate reductase that
has a lower affinity for trimethoprim.
Overproduction of the enzyme may also lead to
resistance, because this can decrease drug
permeability.

:
The first quinolone, nalidixic acid, was isolated as a by-
product of the synthesis of chloroquine. introduction
of fluorinated 4-quinolones, such as ciprofloxacin ,
moxifloxacin, gatifloxacin represents a particularly
important therapeutic advance because these agents
have broad antimicrobial activity and are effective
after oral administration for the treatment of a wide
variety of infectious diseases. Relatively few side
effects appear to accompany the use of these
fluoroquinolones, and microbial resistance to their
action does not develop rapidly.

M.O.A
interfering with the action of DNA gyrase
(topoisomerase II) and (topoisomerase IV)

After oral administration, the fluoroquinolones
-A---are well absorbed (bioavailability of 80-
95%)
-D---distributed in body tissue
-M---Inactivation by hepatic metabolism
-e---Renal and biliary excretion
Pharmacokinetics

classification
The quinolones are now often classified into
generations
first
•nalidixic acid and cinoxacin
second
•norfloxacin, ciprofloxacin, ofloxacin, enoxacin,
•and lomefloxacin
Thrid •levofloxacin , sparfloxacin , gatifloxacin
fourth
•trovafloxacin and moxifloxacin.
•the Several of the newer quinolones have been recently removed
from market

Adult dose (900 mg every 6 hours.)
Child dose (50 mg/kg daily in divided doses)
Use effective for urinary tract, effective against anaerobes.
In general quinolones are extremely active against Gram-
negative or including. coli, Salmonella sp., Shigella sp.
Neisseria sp. and Haemophilus influenza.
and they have useful activity against Pseudomonas aeruginosa
and
Legionella pneumophila. They are less active against
Gram-positive organisms (resistance commonly emerges).
Antibacterial Agent
1.nalidixic acid

dose
Oral: (100 - 750 mg) bid tablets.
suspension: 50, 100 mg/mL.
Lower RT
UTI
Prostatis
Complicated intra abdominal inf
BONE and joint inf
Inf diarrh
Typhoid fever
infSkin and skin structur -
Therapeutic Use
2-ciproofloxacin
NOTES

Dose: Oral: 400 mg bid tablets.
USED :is effective against both gram-negative and
gram-positive organisms in treating complicated
and uncomplicated UTIs.
3-Norfloxacin

Dose: 400 mg bid tablets
Parenteral: 200 mg in 50 mL for IV 20, 40
mg/mL for IV injection .
Ophthalmic : 3 mg/mL solution
Used in treatment of prostatitis due to E coli ,
gonorrhea inf .used also lower RT inf &skin
infection.
4-ofloxacin

5-Levofloxacin
Does: Oral: 250, 750 mg tablets; 25 mg/mL solution
Parenteral: 5, 25 mg/mL for IV injection
Ophthalmic :5 mg/mL solution
Used
in the treatment of prostatitis due to
E. coli and of sexually transmitted diseases, S.pn
UTI.‫و‬RTI

Dose: Oral: 400 mg24h. tablets
Parenteral: 400 mg in IV
Used
not only has enhanced activity against gram-positive
organisms (for example, S. pneumoniae) but also has
excellent activity against many anaerobes. It has very poor
activity against P. aeruginosa.
6.Moxifloxacin:

Adverse reactions
• gastrointestinal upset nausea, vomiting, and diarrhea.
• allergic reactions (rash, pruritus , photosensitivity and
anaphylaxis)
• CNS effects May develop with dizziness, headache and
confusion.
should not be used in pregnancy in nursing mother and
childten under 18 years of age.
contraindications

• The effect of antacids and cations on the absorption of these
agents was considered above. Ciprofloxacin and ofloxacin can
increase the serum levels of theophylline by inhibiting its
metabolism . This is not the case with the third- and fourth-
generation fluoroquinolones, which may raise the serum levels of
warfarin, caffeine, and cyclosporine.
Altered target : Mutations in the bacterial DNA gyrase
Decreased accumulation: Reduced intracellular concentration of the
drugs in the bacterial cell is linked to two mechanisms.
Resistance
Drug interactions

Nitrofurantoin
3member of Nitrofurantoin group used clinically
Nitrofurantoin ---UTI
furazoline ---GIT infection
Nitrofurazone----topical
M.O.A
Sensitive bacteria reduce the drug to an active
agent that inhibits various enzymes and damages
DNA. Antibiotic activity is greater in acidic urine.

Antimicrobial spectrum
The drug is bacteriostatic. It is useful against
E. col, enterbacter,klebsiella.chornic(100-200)mg daily for
several month
Dose acute
Adult dose(200-400)mg day for7-10
mg100-200))Child dose
chornic(100-200)mg daily for several month

A bsorption:well absorbed orally .-
D istribution: distributed throughout the body.-
-M etabolism: in liver and tissue
-Excretion: from kidney
-Gastrointestinal disturbances(N,V)
-Acute pneumonitis (Fibrosis)
-Neurologic problems
-Hemolytic anemia with G-6-P-D

-antiacid  - absorption--
action--sulfinopyrazine or probenecid
action of phenytoinnitrofuration
Baby and preganacy.
G.P.6 Deficieny
from mutation associated loss of bacterial nitroredutase
activity

In obligate anaerobic microorganisms
metronidazole is converted into an active form by
reduction of its nitro group: this binds to DNA and
prevent nucleic acid formation; bacteriostatic
The t1/2, is 8 h Metronidazole is well absorbed
after oral or rectal administration and distributed
to achieve sufficient concentration to eradicate
infection in liver, gut wall and pelvic tissues.
DOSE
it is mouth 400 mg 8-hourly;
by rectum 1 g 8-hourly for 3 days followed by 1 g
12-hourly; or by i.v. infusion 500 mg 8-hourly..

• Treatment of sepsis
• Antibiotic-associated pseudomembraneous colitis (caused
by Clostridium difficile)
• Trichomoniasis of the urogenital tract in bothsexes
• Acute ulcerative gingivitis ,dental infections
(Fusobacterium spp. and other oral anaerobic flora)
• Anaerobic vaginosis (Gardnerella vaginalis and
vaginal anaerobes).

nausea, diarrhoea,
vomiting,
furred tongue
unpleasant metallic
taste
headache, dizziness and
ataxia
Rashes, urticaria and
angioedema occur
Peripheral
neuropathy occurs if treatment is
prolonged
epileptiform seizures if the dose is
high folic acid,DAN,and RAN Inhibitors

is similar to metronidazole but has a
longer tl/2 (13 h).
It is excreted mainly unchanged in the urine.The
longer duration of action of tinidazole may be an
Advantage
Dose of tinidazole is
2 gby mouth in a single dose

(Rifadin_Rimactan_Rifampin)
inhibiting DNA dependent RNA polymerase
protein synthesis inhibition.
:
Rifampicin is bactericidal and more effective against
staphylococcus-aureus-streptococcus-E coli-proteus and
Mycobacterium.

A bsorption:well absorbed orally .-
D istribution:distributed throughout the body.-
-M etabolism: in liver and converted to
compound called Desacetylerifampin
-Excretion: from kidney (25% active form and
85% binds to plasma protein).

Dose
oral : 600_900mgkg B.W:
Use
1_T.B
2_leprosy
3_diphtheroid
4_meningitis
5_legionella infection.folic acid,DAN,and RAN Inhibitors

1-flushing and itching
2-thrombocytopenia
3-haemolytic anemia
4-renal failure
5-colour of urin-tears and sputum become red
6-cirrhosis

Rifampicin is powerful hepatic enzyme
inducer and speed the metabolism of
other drugs such as warfarin-steroid
contraceptive-analgesic-and phenytoin.

• PHARMACOLOGY LIPPINCOTT′S.(4 TH edition)
• NMS PHARMACOLOGYWILLIAMS AND WILKINS.
• MANULA OF PHARMACOLOGY .
• BASIC AND CLINICAL PHARMACOLOGY LANGE.
• CLINICAL PHARMACOLOGY(lorance.(NINTH edition)
• MEDICAL PHARMACOLOGY at glance.(4 TH edition
• BNF
REFRENCES

The End

Antibiotics

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