COR CHRISTI 0 MEDICINE 2014 TRANX LECTURER: DOC PANGANIBAN

(ALL FROM KAZTUNG 11TH EDITION)

TRANX-NIST: MIU

Tetracycline
Chemistry:

metal ions, which can interfere with their absorption and activity. A newly approved tetracycline analog, tigecycline, is a glycylcycline and semisynthetic derivative of minocycline.

All tetracycline has this kind of structure. However, they differ on R6. Free tetracyclines are crystalline amphoteric substances of low solubility. They are available as hydrochlorides, which are more soluble. Such solutions are acid and, with the exception of chlortetracycline, fairly stable. Tetracyclines chelate divalent

Tetracyclines enter microorganism in part by passive diffusion and in part by energy dependent process of active transport. Once inside the cell, tetracycline bind reversibly to the 30s subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex. This prevents addition of amino acid to the growing peptide.

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COR CHRISTI 0 MEDICINE 2014 TRANX LECTURER: DOC PANGANIBAN

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Resistance to Tetracycline is due to:

1. Decreased intracellular accumulation a. impaired influx b. increased efflux 2nd to active transport protein pumps 2. Ribosome protection production of proteins which interfere with drug binding to ribosome 3. Enzymatic inactivation Note: The 2 most impt mechanism for resistance are decrease intracellular accumulation and Ribosome protection

b. Susceptible to Tigecycline (because of its bulky t-butylglycylamido substituent and has a steric hindrance effect on Tet(M) binding to the ribosome.

Classification based on half.lives

1. Short acting 6- 8 hours: chlortetracycline, tetracycline, oxytetracycline 2. Intermediate acting 12 hours: demeclocycline and methacycline 3. Long-acting 16-18 hourss: doxycycline and minocycline ***Tigecycline has a half life of 36 hours and almost complete absorption and slow excretion of doxycycline and minocycline allow for once-daily dosing. Refer to table 1. Tetracycline for drug comparison -------------------------------------------------------------------------------------------------------------

Types of Efflux
1. Tet-AE of Gram (-)bacteria a. Resistant to Tetracyclines, Doxycycline & Minocycline; b. Susceptible to Tigecycline (because this is not a substrate of these pumps)

QUINOLONE
Nalidixic Acid First Quinolone (1963) Not fluorinated Rapidly excreted (weak systemic antibacterial effects) Useful for Urinary tract infection Oxolinic Acid Piromidic Acid Pipemidic acid 2|P a ge

2. Tet K of Staphylococcus a. resistant to Tetracycline b. Susceptible to doxycycline, minoccline and tigecycline 3. Tet M ribosomal protection protein of Gram (+) bacteria: a. Resistance to Tetracyclines, Doxycyclne & Minocycline

COR CHRISTI 0 MEDICINE 2014 TRANX LECTURER: DOC PANGANIBAN Drugs: Ciprofloxacin (prototype) Clinafloxacin Enoxacin Gatifloxacin Levofloxacin Lomefloxacin Moxifloxacin Norfloxacin Ofloxacin

(ALL FROM KAZTUNG 11TH EDITION)

TRANX-NIST: MIU

Mechanism of Action Sparfloxacin Trovafloxacin 1. Blocks bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) & topoisomerase IV 2. Prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication *Inhibition of topoisomerase IV : interferes with separation of replicated DNA into respective daughter cells during cell division

Chemistry:

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COR CHRISTI 0 MEDICINE 2014 TRANX LECTURER: DOC PANGANIBAN

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Resistance
A. One or more point mutations in the Quinolone-binding region of the target enzyme B. Change in the permeability of the organism porin in the cell wall of the bacteria changes its shape, thus the drug cannot penetrate and reach DNA where gyrase or topoisomerase is located Two types of plasmid-mediated resistance: The enzyme binds to two segments of DNA (1) creating a node of postive superhelix. The enzyme then introduces a doulbe-strand break in the DNA and passes the front segment through the break (2). The break is then resealed (3), creating a negative supercoil. Quinolones inhibit the nicking and closing activity of the gyrase and also block the decatenating activity of topoisomerase IV As a general rule: G ( - ) activity = inhibition of DNA gyrase G ( +) activity = inhibition of DNA type IV topoisomerase 1. Qnr proteins: protect DNA gyrase from the FQs. 2. Variant of aminoglycoside acetyltransferase = may modify Ciprofloxacin

REFER TO TABLE 2 FOR DRUG COMPARISON Yay! By finishing this part, parang binasa niyo na rin ang libro kasi lahat sa libro gulo kasi ni doc hahaha. Ung kinuha ko lng sa ppt nia ung may model of formation of negative DNA at mga pictures hahaha :p Game QUINOLONES naman!

Quinolone Spectrum of Activity

Atypical pneumonia: Mycoplasmas & Chlamydia Legionella spp. Mycobacterium tuberculosis Mycobacterium avium complex

PHARMACOKINETICS QUINOLONE IN GENERAL

1. Good oral bioavailability (80-95%) almost the same as IV o 50% can be adequately absorbed in the GIT (up tp 90%)

2. Wide distribution: o Low protein binding and High lipid solubility characteristic makes the drug reach CNS and prostrate 4|P a ge

COR CHRISTI 0 MEDICINE 2014 TRANX LECTURER: DOC PANGANIBAN ACCEPTED CLINCAL USES: A. Urinary Tract Infections Disease Complicated UTI Drug Generation Ciprofloxacin Ofloxacin Enoxacin Gatifloxacin (5-10 days to weeks if really complicated Lomefloxacin Levoflaxin Norfloxacin Ofloxacin Levofloxacin Ciprofloxacin

(ALL FROM KAZTUNG 11TH EDITION) C. Respiratory Tract Infection Disease Acute bacterial bronchitis

TRANX-NIST: MIU

Uncomplicated pyelonephritis Complicated UTI and Pyelonephritis

CAP 1. Hospitalized (ward) px acquired from the community and now hospitalized or ICU Otitis media D. GIT infection Disease Shigella spp Enterotoxigenic E. coli Campylobacter jejuni

Drug Levofloxacin Ofloxacin Sparfloxacin Gatifloxacin Moxifloxacin Macrolide (erythro, clinda, cepha, or Blactam + B-lactam inhibitor) + FQ Levofloxacin Gatifloxacin Moxifloxacin

Generation

B. Sexually Transmitted Disease Disease Drug Generation Uncomplicated N. Ceftriaxone or gonorrhea Gatifloxacin (banned) Ciprofloxacin or Ofloxacin if PCNallergic Chancroid Ciprofloxacin Chlamydia trachomatis Ofloxacin Sparfloxacin

Drug Norfloxacin Ciprofloxacin

Generation

E. Skin, Bone, Soft Tissue Infection o 2nd line drugs only (meaning 1st line drugs must be given first)

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ADVERSE DRUG REACTION

NOTE: SORRY D KO MADISTINGUISH KUNG SPECIFIC DRUG ANG ADVERSE EFFECT, GULO KASI NI DOC KATULAD SA TETRACYLINE, U MAY LOOK AT IT AS ADVERSE EFFECT OF TIGECYCLINE PERO SA TETRACYCLINE PALA, BUTI N LANG MAY KATZUNG KASO ETONG QUINOLONE WALA SA KATZUNG EH SO IM PUTTING THIS ADVERSE EFFECT UNDER QUINOLONE IN GENERAL. OPPORTUNISTIC INFECTION a. If given in long term, can cause superimposed infection (2ndary infection) like candidiasis GASTROINTESTINAL TRACT a. Nausea b. Vomiting c. Diarrhea d. Abdominal pain CENTRAL NERVOUS SYSTEM Headache Dizziness Drowsiness Confusion Insomnia Fatigue Depression Somnolence Seizure Vertigo Lightheadedness Restlessness Tremor

SKIN REACTION Rashes Pruritus Photosensitivity reaction (discoloration of skin upon sun exposure) HEPATIC o Elevation of Liver Enzyme o Trovofloxacin acute hepatitis and hepatic failure (thats why it is withdrawn) Miscellaneous (rare): o QTc prolongation (causes arrhythmia) o Myalgia, joint swelling o Tendonitis => tendon rupture o Abnormal or bitter taste o From past tranx: Granulocytopenia Teratogenicitiy o Cartilage erosions = arthropathy; Therefore Contraindicated in < 18 yrs., in pregnant, or breastfeeding women o Reversible

DRUG INTERACTION
Drugs FQ + Antacid Effect Reduced bioavailability of 1. Ofloxacin 73% 2. Ciprofloxacin 91% Decreases Theophylline clearance accumulation of methylxanthine may cause seizure 6|P a ge

FQ + Theophylline Ciprofloxacin, Pefloxacin & Enoxacin

COR CHRISTI 0 MEDICINE 2014 TRANX LECTURER: DOC PANGANIBAN Decreased clearance of Theophylline with Norfloxacin by inhbiting hepatic enzyme as theophylline eliminated primarily by metabolism in the liver involving CYP450 Reduces FQ clearance because it inhibits oxidative enzyme Chelate formation (assoc with Aluminum) thus decreasing FQ aborption Prolong QTC Torsades de pointes Risk of CNS Stimulation seizure Hypo or hyperglycemia (mostly hypo) Warfarin anticoagulant effects Caffeine levels Cyclosporine levels Increase serum digoxin, hence should not be given for patients with failure a. absorption b. effect of oral trovafloxacin Increase rate of absorption by 50% Concomitant administration of Theophylline and FQ results in the displacement of GABA seizure From past tranx

(ALL FROM KAZTUNG 11TH EDITION)

TRANX-NIST: MIU

It takes a lot of work from the muscle of the face to let out a smile, but just think what good smiling can bring to the most important muscle of the bodythe heart ---author unknown Love is sweet when it is new, but it IS sweeter when its true ---unknown You have to love something before you can hate it ---Nicholas Sparks, the last song A fool is quick tempered, but a wise person stays calm when insulted. ---Proverbs 12:16 Start by doing what's necessary; then do what's possible; and suddenly you are doing the impossible. ----St. Francis of Assisi Albert Einstein, three rules of work 1. Out of clutter, find simplicity. 2. From discord, find harmony. 3. In the middle of difficulty lies opportunity. Happy aral 2014 !!!
***Hello ke ate des, ate joyce, jc,, Sheila, kate, love team ace <3 tin, pao, soler brothers, jobell, shar and to me? LOL

FQ + Cimetidine (gastric ulcer) FQ + Sucralfate

FQ + Anti-Arrythmics (Class !A or III) Cisapride FQ + NSAID FQ + Antidiabetic agents FQs + _______ = increase (Weird to haha blank!!! Sa past tranx wala nito!) Gatifloxacin a. Trovafloxacin + Na+ Citrate Citric acid oral soulution b. Trovafloxacin + IV morphine FQ + Metclopramide (accelerates gastric emptying) FQ + GABA

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COR CHRISTI 0 MEDICINE 2014 TRANX LECTURER: DOC PANGANIBAN

(ALL FROM KAZTUNG 11TH EDITION)

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