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TETRACYCLINES - Coggle Diagram
TETRACYCLINES
- Crystalline amphoteric substances of low solubility
- Their hydrochlorides→ more soluble
- Acidic solutions, fairly stable
- Chelate divalent metal ions→ interfere with absorptions & activity
- Tigecycline→glycylcycline & semisynthetic derivative of minocycline
MOA :check:
- Bacteriostatic
- Inhibit protein synthesis
Bind reversibly to 30S subunit of bacterial ribosome
↓
block binding of aminoacyl tRNA to Acceptor site of mRNA-ribosome complex
↓
Prevents addition of a. acids to growing peptide
ANTIMICROBIAL SPECTRUM :check:
Cocci :
- All G+ & G-ve were sensitive, now only few.
- Strep. pyogenes, Staph. aureus (&MRSA) & enterococci
- Few N. gonorrheae, N meningitidis
Most G+ bacilli
- Clostridia & other anaerobes
- Listeria, Corynebacteria, Propionibacterium acnes, B. anthracis
Sensitive G-ve bacilli
- H. ducreyi, Calymmatobacterium granulomatis, V. cholerae
- Yersinia pestis, T. enterocolitica, Campylobacter, Brucella, Pastuerella multocida, F. tularensis & many anaerobes
Spirochetes
All rickettsiae & chlamydiae
Mycoplasma & actinomycete
Protozoa like E. histolytica & plasmodia
RESISTANCE :recycle:
3 mechanisms described
- Impaired influx / increased efflux by an active transport protein pump
- Ribosome protection d/t pdn. of proteins that interfere with Tetr. binding to ribosome
- Enzymatic inactivation
- Tet(AE)efflux pump-expressing G-ve species→ resistant to older Tetr.( doxy/ mino)
○ But susceptible to Tige.
- Tet(K) pump of Staph. → resistance to Tetr but not doxy, mino, tigecycline→ none are pump substrates though.
- Tet(M) ribosomal protection protein
○ G+ organisms
○ Tetra, doxy, mino resistance
○ Tigecycline not resistant→ steric hindrance to bulky t-butylglycylamido component
- Tigecycline→ substrate for chr. encoded Multidrug efflux pumps
○ Seen in Proteus & Ps. aeruginosa
○ Intrinsic resistance to all Tetr & Tige.
- Partial cross resistance b/w Tetracyclines & chloramphenicol
PHARMACOKINETICS :check: Absorption
- Older Tetr.→ incomplete absorption & interference by food (60-80%)
- Doxy/mino→ complete abs (95-100%) & No interference by food
- Chelating property
○ Milk, Fe preparations, non-systemic antacids, sucralfate ↓ Absorption
Distribution
- Widely distributed
- Vd> 1L/kg
- Variable degree of PPB
○ High for doxy/ mino/demeclo
- Conc. in Liver & spleen, CT in bone & teeth
- Minocycline→ high lipid soluble→ accumulate in fat
- CSF conc. ¼ of plasma conc.
Metabolism & excretion
- Excr. in urine by GF
○ Dose ↓ in renal failure
○ Doxy, Tige-exception : Non renal mechanisms
- Partly metabolised & enter bile→ enterohepatic circulation
- Drug conc. in bile> serum by 10fold
- Secreted in milk→ affect baby
- Enzyme inducers ↑ metabolism & ↓ T½ of Doxy
○ Phenobarbitone, carbamazepine
ADMINISTRATION :check:
- Oral capsule taken ½ hr before / 2hr after food
- No IM inj→ painful
- Slow IV in severe cases→ allowed
PRECAUTIONS :no_entry:
- Not to be used in pregnancy/ lactation/ children
- Avoided in patients on diuretics
○ Blood urea↑
- Catious use in renal/ hepatic insuff.
- Never to be used beyond expiry date
- Do not mix injectable Tetr→ Penicillin
○ Inactivation occurs
- Do not inject Tetr. IM/ intrathecally
ADVERSE EFFECTS :warning: IRRITATIVE EFFECTS
- Epigastric pain, nausea, vomiting, diarrhea
- Odynophagia, esophageal ulceration
- Thrombophlebitis of inj. vein
ORGAN TOXICITY1. Liver Damage
- Fatty infiltration of liver & jaundice
- Oxytetracycline & tetracycline→ safer
- Pregnant women→ ppt. fatal a/c hepatic necrosis
2. Kidney Damage
- Patients with kidney disease→ tetr. induced kidney damage
- Doxy esp. accumulate→ worsen RF
- Reversible Fanconi syndrome like condition
○ Outdated/degraded tetracyclines
○ Degradation pdts→ epitetracycline, anhydrotetracycline & epianhydrotetracycline damage Proximal tubules
- Exposure to acidic pH, moisture & heat → degradation favored
3. Phototoxicity
- Skin reactions
- Sun-burn like
- With demeclo/ doxy
4. Teeth & Bones
- Ca-tetracycline chelate→ deposit in developing teeth & bone
- Given from mid-pregnancy → 5 months EUL→
○ affects deciduous teeth
- Brown discoloration, ill-formed teeth
- Tetr. given 3month→ 6yrs age→
○ affect crown of permanent anterior dentition
- Given at late pregnancy/childhood
○ Temporary bone growth suppression
5. Antianabolic Effect
- ↓ Protein synthesis
- Induce Negative Nitrogen balance
- ↑ Blood urea
6. ↑ Intracranial pressure
7. Diabetes Insipidus
○ Demeclocycline8. Vestibular toxicity
- Minocycline→ ataxia, vertigo, nystagmus
HYPERSENSITIVITY
- Skin rashes, urticaria, glossitis, pruritis ani & vulvae, exfoliative dermatitis
- Complete cross sensitization exhibited
SUPERINFECTION
- More marked suppression of resident flora
- Most prominent
○ Intestinal superinf. by Candida albicans
○ Pseudomembranous enterocolitis rare but serious
○ Proteus & Pseudomonas may also grow in bowel
USES
1. Empirical therapy
- Initial trt. of mixed infections
2. First choice drugs in
◘ a. Venereal diseases
- Chlamydial non-specific urethritis/ endocervicitis
○ Doxy-7days ~ single dose Azithro
- Lymphogranuloma venerum
- Granuloma inguinale
○ Tetr for 3 wks
◘ b. Atypical Pneumonia
- Psittacosis→ 3 wks
◘ c. Cholera
- adjuvant value
◘ d. Brucellosis
- Rapid symptomatic relief
- Doxy 200mg/d + Rifampin 600mg/d x 6wks
- Gentamicin + doxy→ a/c case
◘ e. Plague
- Both bubonic & pneumonic plague
◘ f. Relapsing fever
- Borrelia recurrentis
◘ g. Rickettsial infections
- Typhus, rocky mountain spotted fever, Q fever
3. Second Choice drugs in
- To Penicillin/ ampicillin→for tetanus, anthrax, actinomycosis, listeria inf.
- To Ceftriaxone, amoxicillin & azithro for gonorrhea, in penicillin allergic patients
- To ceftriaxone for syphilis
- To penicillin for leptospirosis
○ Doxy 100mg BD for 7 days curative
○ Weekly 200mg Doxy→ prophylactic
- To azithro for pneumonia (chlamydia)
- To ceftriaxone/ azithro for chancroid
- To streptomycin→ tularemia
4. Other Uses
- UTI
- CAP
- Amoebiasis( c/c intestinal)
- Adjuvant to quinine/ artesunate for CQ res. falciparum malaria
- Acne vulgaris
TIGECYCLINE
SPECTRUM :check:
- Broadest spectrum
- Most G+ & G-ve cocci & anaerobes
- Incl. tetr. resistant strains of
○ Strep. pyogenes, Strep. pneumoniae, Staph. aureus, MRSA, VRSA, Enterococcus fecalis, VRE,
○ Most enterobacteriaceae, Acinetobacter
- Tetr. sensitive strains of
○ Rickettsiae, Chlamydia, Mycoplasma, Legionella
- Nonresponsive to Pseudomonas & Proteus
RESISTANCE :recycle:
- Lack of cross resistance
○ Tetr. efflux pumps in resistant bacteria→ low affinity for Tige→ unable to pump it out
○ Ribosomal protection protein cannot protect binding site from Tige
PHARMACOKINETICS :check:
- Poor abs. from GIT
○ Route of admn. → Slow IV infusion
- Widely distributed in tissues
- Vd >7L/kg
- Plasma conc. low
- Elmn via bile→ dose adj. in renal insuff. not needed
- Elmn. T½ 36-60hrs
USE :check:
- Serious patients of CAP
- Complicated skin structure inf.
○ Not diabetic foot
- Complicated intraabdominal inf.
○ by enterococci, anaerobes, enterobacteriaceae
DOSE :check: 100mg loading dose, followed by 50mg 12hrly by slow IV inf. over 30-60min, x5-14days
ADVERSE EFFECTS :warning:
- Nausea, vomiting
- Epigastric distress, diarrhea
- Skin reactions
- Photosensitivity
- Inj. site complications
- Superinfections
- Not recommended for children/ pregnancy
- Tetracycline
- Oxytetracycline
- Demeclocycline
- Doxycycline
- Minocycline