TETRACYCLINES

Alduheza, Shynne B.
Banaa, Mae Anne S.

I. DOXYCYCLINE
((4S,4aR,5S,5aR,6R,12aS)-4-(dimethylamino)3,5,10,12,12a-pentahydroxy- 6-methyl- 1,11dioxo- 1,4,4a,5,5a,6,11,12aoctahydrotetracene- 2-carboxamide or
C22H24N2O8)

Doxin (Biofemme), Vibramycin (Pfizer)

II.CHEMISTRY and STABILITY

Pharmacology
protein synthesis inhibitor
bacteriostatic
high lipid solubility and low affinity for
calcium binding
highly stable in normal human serum
Categorized as a long acting tetracycline

III. MECHANISM OF ACTION

inhibits bacterial protein synthesis by
binding to the 30S ribosomal subunit, thereby
blocking access of the amino acyl-tRNA to the
mRNA-ribosome complex at the receptor site.
entry is mediated both by passive diffusion and
by an energy-dependent transport protein
unique to the bacterial inner cytoplasmic
membrane

SPECTRUM
gram-positive and gram-negative
Bacillus anthracis, Staph.aureus,Listeria

monocytogens, Mycoplasma
pneumoniae,Neisseria
gonorrhoea,Haemophilus influenzae

44% of strains of Streptococcus pyogenes

and 74% of Streptococcus faecalis have
been found resistant to tetracyclines
active against the asexual erythrocytic forms of
Plasmodium falciparum but not against the
gametocytic form of this organism.

IV. PHARMACOKINETICS
IVa. Absorption
readily and almost completely absorbed from
the GI tract (90-100%) after oral
administration
food and milk products may decrease
absorption
time to peak plasma concentration: 2 hr.

IVb. Distribution
liver, kidney, spleen, skin
bind to tissues undergoing calcification or to
tumors having a high calcium content
cross the placental barrier and concentrate in
fetal bone and dentition
80-90% bound to serum proteins
IVc. Elimination/Excretion
partially inactivated in GI tract by chelate
formation.
via urine (23%) and feces (30%); Plasma
half-life: 15-25 hr.
30-42% is excreted unchanged in the urine

V. USES
It is a drug of choice in infections caused by:
Mycoplasma: Pneumonia
Rickettsiae: Rocky mountain spotted fever
and Reckettsial pox
Chlamydia :Trachoma & Psittachosis
Vibrio : Cholera
Bacillus anthracis:Anthrax
Spirochetes: Lyme disease
it is use in a regimen for treatment of gastric ulcer
caused by Helicobacer pylori
Used with Aminoglycoosides for plague, tularemia,
bruceloosis

 Dental:
1. reduce bacteria associated with periodontal
disease
2. adjunct to scaling and root planning to promote
attachment level gain and reduce pocket depth
in adult periodontis
Others:
1. gram-negative: chancroid, tularemia, plague,
cholera
2. gram-positive: chlamydial infections, lyme
disease, relapsing fever

VI. CAUTION
Adverse Drug Events
A. Gastrointestinal Adverse Effects
anorexia, diarrhea, nausea, vomitting

B. Bone structures and teeth

Fluorescence,discoloration of the teeth

C. Liver toxicity
Hepatic toxicity leading to hepatic necrosis
D. Others:
Anemia,arthralgia, myalgia,headache, benign
intracranial hypertension, tinnitus,dyspnea,
tachycardia,asthma, anaphylaxis, anaphylactic shock

Precautions and Contraindications

Known hypersensitivity to tetracyclines or to
any component of the product.
Patients who are pregnant, breastfeeding,
infants and children below 8 yrs old (except for
use as an alternative treatment for inhalational
anthrax post-exposure)
Patients with myasthenia gravis
Patients with systemic lupus erythematosus

Pediatric
doxycycline forms a stable calcium complex in any
bone-forming tissue.
A decrease in the fibula growth rate
Use of tetracycline class during tooth development
(last half of pregnancy; infancy and childhood to the
age of 8 years) may cause permanent
discoloration of the teeth (yellow-gray-brown).
Doxycycline, therefore, should not be used in these
groups of patients unless other drugs are not
available, are not likely to be effective or are
contraindicated.

Pregnancy
It should not be used in pregnant women unless, in
the judgment of the physician. (Pregnancy
category D)
Results of animal studies indicate that tetracyclines
cross the placenta, are found in fetal tissues and can
have toxic effects on the developing fetus (often
related to retardation of skeletal development).
Evidence of embryotoxicity has also been noted in
animals treated early in pregnancy.
Doxycycline should be avoided in nursing mothers

Chronic toxicity
Chronic toxicity of doxycycline was evaluated in rats at
oral doses up to 500 mg/kg/day for 18 months.
Findings revealed no adverse effects on growth,
food consumption, or survival.
Yellow ultraviolet fluorescence of bone, teeth
and/or kidneys was seen in rats at all levels.
Chronic studies in dogs at oral doses up to 100
mg/kg/day for one year showed some functional and
histopathological changes in the liver. However,
effects were reversible after cessation of exposure to
the material.

Acute toxicity
Acute overdosage with tetracyclines is extremely rare,
and if it occurs, no specific treatment is required. Any
gastrointestinal
upset
should
be
treated
symptomatically. As tetracyclines form insoluble
complexes with cations, antacids may be administered
in appropriate circumstances.
Dialysis does not alter serum t1/2 and thus would not
be of benefit in treating cases of overdosage.

Drug Interactions
anticoagulants: prolongation of prothrombin time
penicillins: interfere bactericidal action of
penicillins
antacids: impaired doxycycline absorption
alcohol, barbiturates, anticonvulsants:
decrease half-life of doxycycline
methoxyflurane: fatal renal toxicity
oral contraceptives: less effectivity of
contraceptives, increase breakthrough bleeding

 Atovaquone: may decrease plasma concentration

of atovquone
Ciclosporin: increased plasma concentration of
ciclosporin
Ergot alkaloids and methotrexate: increased
toxic effects
Isotretinoin: may result in pseudomotor cerebri
(benign intracranial hypertension)
Sodium bicarbonate, colestipol,
cholestyramine and kaolin-pectin: decrease
doxycycline absorption
Laboratory Test Interactions: False elevations
of urinary catecholamine levels may occur due to
interference with the fluorescence test.

Pharmaceutical dosage forms

Capsules, delayed release capsules, oral suspension, syrup,
tablet, IV
Adult: First day, 100 mg q12h
Maintenance: 100-200 mg/day, depending on severity of
infection
Children over 8 years (45 kg or less): first day,4.4 mg/kg in 12 doses; then 2.2-4.4 mg/kg/day in divided dose depending
on severity of infection
Children over 45 kg should receive the adult dose.
Adminstration
oral, intravenous
Preparation
100 mg caps

VII. Clinical Studies Done

Two randomized phase III clinical trials evaluating
anti-inflammatory
dose
doxycycline
(40-mg
doxycycline, USP capsules) administered once daily for
treatment of rosacea
Phase 3
Methodology: In two phase III, parallel-group,
multicenter, randomized, double-blind, placebocontrolled studies (studies 301 and 302), patients
received 40-mg of controlled-release doxycycline (n =
269) or placebo (n = 268) for 16 weeks. The primary
efficacy end point was the mean change from baseline
in facial inflammatory lesion count.

 Rationale: to evaluate the efficacy and safety of

once-daily anti-inflammatory dose doxycycline
for the treatment of rosacea
Results: The mean lesion count at baseline was
approximately 20 in each study arm. At week
16, the mean change from baseline in lesion
count in the active-treatment groups was -11.8
in study 301 and -9.5 in study 302 compared
with -5.9 and -4.3, respectively, in the placebo
groups (P < .001 for both comparisons). Antiinflammatory dose doxycycline was well
tolerated; the most common adverse events
were nasopharyngitis (4.8%), diarrhea (4.4%),
and headache (4.4%).

Sources:
Lippincotts Illustrated Reviews
Pharmacology (5th edition)
PDR Nurses Drug Handbook (2003
edition)
http://www.nlm.nih.gov/medlineplus/drugin
fo/meds/a682063.html