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Tetracyclines,Biological sources,History,Sturctures,SAR,Mechanism of action,Spectrum of activity,Important structural units and the three acidity constants in the tetracycline molucule,amphoteric......

Tetracyclines,Biological sources,History,Sturctures,SAR,Mechanism of action,Spectrum of activity,Important structural units and the three acidity constants in the tetracycline molucule,amphoteric nature,epimerisation, chelation with metals,toxicity and uses.

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  • 1. Prof.P.RavisankarVignan pharmacy collegeVadlamudi.Guntur Dist. Andhra Pradesh, India,Phone: 09059994000.Email: banuman35@gmail.copm
  • 2. Definition:Tetracyclines are octahydro napthacene derivatives whichare bacteriostatic and broad spectrum antibiotics that killscertain infection- causing microorganisms and are used totreat wide variety of infections.Introduction: Tetracyclines are introduced 50 years ago as potentbroad spectrum antibiotics.They are biosynthesized from acetic acid and propionicacidunits in microorganisms.Tetracyclines possess a wide specturm of acitivty i.e.gram+ve and gram-ve bacteria.They are mainly designed for oral route but parenteraland topical forms are available.
  • 3.  ClassificationAccording to duration of action:Short-acting (Half-life is 6-8 hrs)TetracyclineChlortetracyclineOxytetracyclineIntermediate-acting (Half-life is ~12 hrs)DemeclocyclineMethacyclineLong-acting (Half-life is 16 hrs or more)DoxycyclineMinocyclineTigecycline
  • 4. According to source:Naturally-occurringTetracyclineChlortetracyclineOxytetracyclineDemeclocyclineSemi-syntheticDoxycyclineLymecyclineMeclocyclineMethacyclineMinocyclineRolitetracycline
  • 5. Historical background: In 1945 Chlortetracycline(prototype) of tetracyclines wasdiscovered byDr.Benjamin,M.Duggar,under the guidance of yellapragada subba Rao. He was an employee of Lederle Laboratories in U.S.A. Dr. Duggar produced chlortetracycline (Aureomycin) form golden –colored soil bacterium called Streptomyces aureofaciens byfermentation technology. In 1950 oxytetracycline (Terramycin) was discovered by Findalayetal. From a similar bacterium called Streptomyces Rimosus. In 1950Pfizer company received US patent for tetracycline. Later wood ward determined the structure of oxytetracycline andmade it easy to L.H Conover of Pfizer Research dept. for producingtetracyclines as a synthetic product. Doxycycline, minocycline are the semi synthetic derivatives oftetracyclines. In 2005 a new subgroup of tetracycline was introduced withtigecycline as the first member. Because of the structural similarity tetracyclines are referred to asclose congeners of polycyclic naphthacene corboxamide.
  • 6. Sources Tetracyclines are obtained from variousspecies of Streptomyces bacteria byfermentation technology. Chlortetracyclin(aureomycin) which wasisolated in 1948 from mud-growingmicroorganism called streptomycesaureofaciens– so called because of itsgolden colour. Oxytetracycline (Terramycin)– fromStreptomyces rimosus. Tetracyclines also obtained
  • 7. ChemistryStereochemistry of tetracyclines is very complex.Carbon atoms at 4,4a,5,5a,6,12a are potentically chiral depending on substitutionMethacycline ,Oxytetracycline ,Meclocycline, Doxycycline posssess 5-hydroxySubstituent have 6 chiral corbon and others have only 5 chiral carbon atoms.Note that the carbons that join the rings aren’t numbered and referred to as Xa,where X is the carbon in front of the joining carbon. There is not a 6a at all
  • 8. Chemistry These drugs have 5 or 6 chiral centers,anywhere with a substituent without adouble bond can be a chiral center. If thestereochemistry is changed, activity andpotency is changed Extended conjugation- if you look at thestructure as drawn, there appears to bethree acids and one base, but only 3 pKa’s.However, due to conjugation, there arereally only two acids and one base These drugs are amphoteric and exist as zwitterions in solution, which decreasessolubility. The hydrochloride salt is soluble, but it will crystallize out on standing due tozwitterion formation, therefore, excess acid must be used. The hydrochloride form isavailable in capsules, and sodium or potassium salts could also be used. However, theywouldn’t be as stable Copper, magnesium, aluminum, and fluorine ions chelate the tetracyclines, whichdecreases water solubility. This is why tetracyclines aren’t taken with milk or vitamins
  • 9. O OOHNH2CH3HOCOOHOHOHCH3H3CNH3CCH3H3CHNONHCH3H3CNO OOHNH2COHOHOHCH3H3CNOCH3H3CNO OOHNH2COHOHOHCH3H3CNOO OOHNH2COHCH2OOHOHOHCH3H3CNNH3C CH3OH OHOHOOHCHO CH3NH2OHOONH3C CH3ClOH OHOHOCH2 OHCNH2OHOOO OOHNH2CH3HOCClOOHOHOHCH3H3CNO OOHNH2HCCl HOOOH OHOHCH3H3CNO OOHNH2CH3C OHHOOH OHOHCH3H3CN121110987654321MECLOCYCLINEMeclanMINOCYCLINEArestin, Dynacin,Vectrin, MinocinMETHACYCLINE[Rondomycin]DOXYCYCLINEVibramycin, Vibra–TabsDoryx, Doxy,DEMECLOTETRACYCLINEDeclomycinOXYTETRACYCLINETerramycin, (Urobiotic)CHLORTETRACYCLINEAureomycinTETRACYCLINEAchrommycin, Sumycin,Panmycin, Teracap, Tetracyn, TetralanTIGECYCLINETygacil™Structures of important tetracyclines
  • 10. The keto-enol tatomerismBetween c2 and c3 are veryimportant for biologicalactivity.‘D’ ring should bealways aromaticChanges in this ringLeads to biologicalinactivation of the molecule. Conversion ofcorboxamide group tonitriles cause a 20 foldloss of activity.Epimerization at c4and dehydration at 5aresults loss of activity.Elimination of 6-OH groupCauses increase lipophilicityAnd more stable to acids.Ex: Doxycycline.The linearly fused tetracyclicnucleus is most importantfor the antibiotic activity.Inviolate zone is essentialLittle informationavailable.Substitution of-N(CH3)2 at 7increase the activity.Ex: Minocycline.(=CH2 at c6 increases theAntibacterial activity Ex: Methacycline).(any modification atC3 loss of activity.)Electron donating (or)electron withdrawinggroups at c7 increasedAntibacterial activity Substitution with –OH Producewater soluble derivatives which canbe administered orally.Additional glycyl aminosubstitution at the 9thPosition leads to the newClass of antibioticsthe glycylcyclines.EX: Tigecycline.(Tygacil)Presence 0f-N(CH3)2 group atC4 Tetracyclines exists Ziwitter ionWhich can be posible to distribute inThe body.Removal of this group lossof activity.Replacement of –No2 group Givesmore potent but carcinogenic compounds.ABCD
  • 11. SAR summarization
  • 12. Important structrual units and the three acidityconstants in the tetracycline molecule.(conjugatedTrione systemIs acidic nature)(Conjugated phenolicEnone system is slightlybasic)Strong alkaline.pka1 (2.8-3.4)pka(7.2-7.8)Pka3 (9.1-9.7)
  • 13. AMPHOTERIC NATURE 3 structural units (3 groups are responsible for the amphotericnature of tetracyclines.Amphoteric nature of tetracyclines:The tetracyclines are amphoteric compounds.Amphoteric,meaning they will form salts with both strong acids and bases. Thus,they may exist as salts of sodium or chloride.Three structrual units of tetracyclines reprasenting 3pkavalues.Pka1--- Conjugated trione system extending from C1 to C3 ofring A is acidic nature of Pka 2.8-3.4.Pka2--- Conjugated phenolic enone system from C10-C12 isassociated with weak basic Pka values ranging from 7.2-7.8.Pka3-- C4 atom and its substituents exhibits Pka3 ranging from9.1 to 9.7. which represents strong alkaline natue.Because of the amphoteric nature tetracyclines formswater soluble salts with strong acids such as Hcl and strongbases such NaOH,KoH.
  • 14. Epimerization One of the important property oftetracyclines is their ability toundergo epimerisation at C4position. These isomerts are calledepitetracyclines. By providing acidic conditions onlong standing about one dayequilibrium can be establishedbetween the isomers. Under acidic condition,tetracycline decline to theelimination reaction of givingoff H2O from the C-6 hydroxyland C-5a hydrogen togenerate the inactive 4-epitetracyclines. These epitetracyclines are lessactivie than Natural tetracyclines.Natural form (more active) (less active(Or)inactive
  • 15. Most of the natural tetracyclines have tertiary benzylic hydroxyl group at c-6.Aromatization of ring C under acidic condition (to prevent zwitterion ionformation) occurring as a result of dehydration reaction, which is accelerated byelevated temperatures. The elements of H2O derive from the 6-OH and 5a-Hatom.65a-H2o-H2o(acid)ABCD(Napthalene derivative)
  • 16. Base-catalyzed instability of tetracylines Under alkaline condition, OH at C-6 change into oxygenanion and then attacks the C-11 lead to intramolecularnuclear reaction, by electron transfer, C ring rupture togenerate inactive lactone isomer isotetracycline Putting the tetracyclines in a basic solution leads tocleavage of ring C from ring B, which leads to theformation of inactive isotetracyclineIsotetracyclineOH--H20
  • 17. Chelation Chelation is an important feature of the chemical and clinical properties ofthe tetracyclines. The acidic functions of the tetracyclines are capable of forming salts throughchelation with metal ions. Tetracyclines are able to form complexes with divalent and trivalent metalions such as Ca2+,Fe2+,Mg2+,Ni2+,Co2+,Zn2+,Mn2+and Al3+,Fe3+.and with salicylates,phosphates,citrates,polyvinylpyrrolidine,Thiourea,lipoproteins,serum albumin,globins and RNA. These salts of metal ions are insoluble in water at neutral PHs. This insolubility not only is inconvenient for the preparation of sloutions butalso interfers with blood levels on oral administration. The tetracyclines are incompatible with coadministered,multivalent ion-richantacids and with hematinics and concamitant cosumption of daily productsrich in calcium ion also is contraindicated. Further the bones,of which the teeth are the most visible, are calcium-richstruchtures at nearly neutral pHs and so accumulate tetracyclines inproportion to the amount and duration of therapy when bones and teeth arebeing formed. Because the tetracyclines are yellow,this leads to a permanent discoloration.
  • 18.  and the teeth are evenbrown.(photochemicalprocess). When so much antibiotic istanen up that the structureod bone is mechanicallyweakened. To avoid thistetracyclines are not normallygiven to children at the ageof 6 to 12 years.(In severecases the teeth can betreated with dil.Hcl sloutionto dissovle away the coloredantibiotic.Infact it must berepaired by plasticimpregnation. When concomintat oraltherapy with tetracyclinesand incompatable metal
  • 19. Mechanism of action of tetracyclines Tetracyclines inhibit protein synthesis by binding to the bacterial ribosomeinvolved in the translation(protein synthesis) process and making thembacteriostatic. The bacterial ribosome is a 70s particle made up of 30s subunit and 50ssubunit.(the term 50s etc..refer to the sedimentation properties of thevarious structures.These are related to the qualitatively to size and mass butnot quantitatively-that’s why a 50s and 30s units combine to form 70sribosome). The 30s subunit binds mRNA and initiates the protein synthesis. The 50s subunit combines with the 30s subunit-mRNA complex to form aribisomethen binds aminoacyl tRNA and catalyses the building of the protein chain.. There are two main binding sites for the tRNA molecule. The peptidyl(p-site) binds the tRNA bearing the peptide chain The acceptor aminoacyl site (A-site) Tetracyclines reversibly bind to the 30S subunit at the A-site toprevent attachment of the amino acyl tRNA, terminating thetranslation process. They have excellent selective toxicity due to better binding to the 70 Ssubunit in comparison to the 80 S subunit . Tetracyclines also show efficient transportation into the bacterial cell. Theyenter through porins in Gram negative bacteria and lipophilicity allows themto enter in Gram positive bacteria. Once they have entered through an active transport, the bacteria mistakesthe antibiotic as food.
  • 20. l(t-RNA interprets the codedMessage in mRNA. It containAnticodon of 3-nucleic acidBases which binds to tripletOn mRNA.Tetracycline blocks.Tetracyclines blocks orinhibit(prevent) theBinding ofAmino acyl t-RNA to themRNA ribosomal complexpeptidyl site(P-site).(A-site)AnticodonTranscription is the process by whichA segemnt of DNA is copied as mRNA.M-RNA carries the genitic informationrequired for the synthesis of a proteinfrom the nucleus to the endoplasmiccalled translation. The growing proteinchain is transferred from one t-RNA to the aminoacid on thenext tRNA andis released once the completeproten molecule has been synthesized.Triplet code tobeRead here.(aminoacyl)
  • 21. There are two mainBinding sites for t-RNAMolecule.The Peptidyl(p-site)binds thet-RNA bearing the peptideChain.The acceptor aminoacyl site(A-site) binds the t-RNABearing the next amino acidto which the peptide chainWill be transferred.Peptide transferA-site(p-site)Tetracyclines works byslowing the growth ofsensitive bacteria byinterfering with theproduction of proteinsneeded by the bacteria.To grow slowing thebacterias growth allowsthe bodys defensemechanisms to destroythem.
  • 22. Animation Illustrating the Role of Tetracyclines in Blocking Translationduring Bacterial Protein SynthesisThe tetracyclines (tetracycline, doxycycline, demeclocycline, minocycline, etc.)block bacterial translation by binding reversibly to the 30S subunit anddistorting(give a misleading account and pullor twist out of shape) it in such away that the anticodons of the charged tRNAs cannot align properly with thecodons of the mRNA.
  • 23. Spectrum of activity of tetracyclines Tetracyclines are broad spectrumantibiotics active againstGram+ve and Gram-ve bacteriaincluding1. Staphylococci2. Streptococci3. Enterococci4. Bacillus anthraces5. Hemophilus influenzae6. Yersenia pestis7. Acne vulgaris8. Shigella species9. Klebsiella species10. spirochetes11.mycoplasmas,12.rickettsiae,13.Candida albicans14.Mycoplasma pneumoniae15.Chlamydia trachomatis16.Borrelia recurrentis.17.Vibrio cholerae18. Campylabacter fetus19.Brucella specie20.Streptococcuspneumoniee.21.Neisserie gonorrhoeaeIt is used in the treatment of lifethreatening infections such as Septicemia Endocarditis meningitis.
  • 24. Toxicity of tetracyclines/Adverse effects of tetracyclines. Majour toxic effects of tetracyclines are—Binding of tetracyclines to the developing bones and teeth and discoloration of teethwhile in development (<8 years of age): accumulation occurs in Calcium rich tissuessuch as bones and teeth, which turns the teeth brown via a photochemical process thatis permanent .(Tetracycline use should be avoided in pregnant or lactating women, and in children withdeveloping teeth because they may result in permanent staining (dark yellow-grayteeth with a darker horizontal band that goes across the top and bottom rows of teeth). Common side effects associated with tetracyclines include cramps or burning of thestomach, diarrhea, sore mouth or tongue. Tetracyclines can cause skin photosensitivity, which increases the risk of sunburnunder exposure to UV light. This may be of particular importance for those intending totake doxycyline long-term doxycyline on holidays as a malaria prophylaxis. Photosensitivity: exposure to the sunlight results in the formation of free radicals,especially with a chloride substitution at the 7-positionRarely, tetracyclines may cause allergic reactions. Very rarely severe headache andvision problems may be signs of dangerous secondary intracranial hypertension.These antibiotics should not be used in children under the age of 8, and specificallyduring periods of tooth development. Tetracyclines are classed as pregnancy category D. Use during pregnancy may causealterations in bone development. There is little evidence that tetracyclines reduce the efficacy of the birth control pillunless they cause gastrointestinal upset.
  • 25.  Tetracyclines should be used with caution in those with liverimpairment and may worsen renal failure (except doxycycline andminocycline). Antacids and milk reduce the absoption of tetracyclines. Drugs inthe tetracycline class become toxic over time, so expiredprescriptions of these drugs should be discarded after theexpiration date has passed. Administration of expired or degraded tetracyclines may causeNausea,vomiting,acidosis,poly urea.some tetracyclines may cause diabetes insipidus.In patients suffering with myasthenia gravis tetracyclines mayincrease muscle weakness.In case of liver impairment or liver failure tetracyclines may causeazotemia(presence of urea excessive amonts ie.nitrogenous watematerials in the blood.Tetracyclines cause extremely dry and flaky skin when appliedexternally.The breakdown products of tetracyclines are toxic and can causeFanconi syndrome, a potentially fatal disease affecting proximaltubular function in the nephrons of the kidney.
  • 26. Uses of tetracyclines Tetracyclines are called "broad-spectrum" antibiotics, becausethey can be used to treat a wide variety of infections. Physicians may prescribe these drugs to treat eye infections Tetracyclines are generally a low-cost alternative amongantibiotics. Interestingly, a form of tetracycline has recently been used inprevention of cancer recurrence They inhibit certain enzymes and processes that normallyencourage cancer growth. By making cancer cells lessaggressive, these drugs may show potential for long-termmanagement of some cancers. Syphilis. Tetracyclines may be used in the treatment of infections ofthe respiratory tract, sinuses, middle ear, intestines. Gonorrhoea
  • 27.  Acne Rosacea Acne vulgaris Actinomyces Israelii Actinomycosis Anthrax Bacillus Anthracis Bacterial Conjunctivitis Balantidium coli Bartonella Bacilliformis Bartonellosis Bordetella Pertussis Borrelia Burgdorferi Borrelia Recurrentis Bronchitis- acute Brucella Sp. Brucellosis Burkholderia Mallei BurkholderiaPseudomallei Campylobacter Fetus Cervicitis Chancroid Chlamydia Psittaci Chlamydia Trachomatis Chlamydial Conjunctivitis Chlamydia Trachomatis Chlamydial Conjunctivitis Clostridium Tetani Coxiella Burnetii
  • 28.  Duodenal Ulcer EntamoebaHistolytica Francisella Tularensis Fusobacterium Fusiforme Gonorrhea Granuloma Inguinale Haemophilus Ducreyi Haemophilus Influenzae (beta-lactamase Negative) Haemophilus Influenzae (beta-lactamase Positive) Helicobacter Pylori Klebsiella Granulomatis Legionella Pneumophila Leptospira Sp. Leptotrichia Buccalis Listeria Monocytogenes Lower Respiratory TractInfections Listeria Monocytogenes Lower Respiratory TractInfections Lower Respiratory TractInfections Listeria Monocytogenes Lower Respiratory TractInfections Lymphogranuloma Venereum Murine Typhus Mycobacterium Fortuitum Mycoplasma Hominis Mycoplasma Pneumoniae Neisseria Gonorrhoeae Neisseria Meningitidis Nocardia Sp. Non-gonococcal Urethritis (NGU) Ophthalmia NeonatorumProphylaxis Otitis Media Pasteurella Multocida Periodontitis Pharyngitis
  • 29.  Plague Plague Prophylaxis Plasmodium Falciparum Pneumonia Proctitis Propionibacterium Acnes Propionibacterium Propionicum Psittacosis Q Fever Relapsing Fever Rickettsia Akari Rickettsia Prowazekii Rickettsia Rickettsii Rickettsia Tsutsugamushi Rickettsial Pox Rocky Mountain Spotted Fever Shigella Sp. Shigellosis Sinusitis Skin And Skin Structure Infections The tetracyclines will not work forcolds, flu, and other infections causedby viruses Spirillum Minus Streptobacillus Moniliformis Syphilis Treponema Pallidum Tularemia Upper Respiratory Tract Infection Ureaplasma Urealyticum Urinary Tract Infection Vibrio Parahaemolyticus Yaws Yersinia Enterocolitica Yersinia Pestis Amebiasis Anthrax Prophylaxis Bejel Biliary Tract Infections Cholera Dentoalveolar Infection Dyspepsia Endodontic Infection Enterocolitis Gastric Ulcer Legionnaires Disease Lyme Disease Malaria Pinta Tertiary Syphilis
  • 30. Cautions, contraindications, side-effectsAre as those of the tetracycline antibiotics group:Can stain developing teeth (even when taken by the mother during pregnancy)Can cause permanent teeth discoloration (yellow-gray-brown); infancy and childhoodto eight (8) years oldInactivated by Ca2+ ion, not to be taken with milk, yogurt, and other dairy productsInactivated by aluminium, iron and zinc, not to be taken at the same time as indigestionremediesInactivated by common antacids and over-the-counter heartburn medicines.Skin photosensitivity; exposure to the Sun or intense light is not recommendedDrug-induced lupus, and hepatitisCan induce microvesicular fatty liver.TinnitusMay interfere with methotrexate by displacing it from the various protein binding sitesCan cause breathing complications as well as anaphylactic shock in some individualsShould be avoided during pregnancy as it may affect bone growth of fetus.Passes into breast milk and is harmful to breast-fed infants, and should therefore beavoided during breastfeeding if possible.
  • 31. The Future of Tetracyclines:The future of tetracyclines looks promising in respect to decreasingresistance, due to the addition of substituents at the 9-position. Neweragents with less side effects and an increased spectrum of activity arecurrently being studied to increase popularity in treatment usingtetracyclines. Two new agents that are being studied are 9-nitromethyldeoxytetracycline and 9-nitrominocycline which areglycylcyclines. They look to promise treatment of infections caused bybacteria resistant to previous tetracyclines.3
  • 32.  Tetracyclines should therefore beavoided in pregnant or lactatingwomen, and in young childrenwith developing teeth. A pregnantwoman who takes tetracyclinemight cause stains to thedeciduous teeth of her baby. Achild who takes tetracycline mightcause stains to his developingadult teeth. Those stains areusually internal and cannot beeasily removed with conventionaltooth whitening. It is thereforerecommended not to givetetracycline to children under 12years of age. They are howeversafe to use in the first 18 weeksof pregnancy. Even though tetracyclines causetooth discolouration for onlydeveloping teeth, they areconsidered very safe for adults,including women who are notpregnant. The tetracycline groupis the only family of antibioticsthat can stain developing teeth.All other antibiotics are not
  • 33.  Tetracycline cancause skinreaction(fixed durgeruptions)Skin lesions
  • 34. What are the possible side effects of Tetracycline? Get emergency medical help if you have any of these signs of anallergic reaction: hives; difficulty breathing; swelling of your face,lips, tongue, or throat. Stop using tetracycline and call your doctor at once if you have anyof these serious side effects: severe headache, dizziness, blurred vision fever, chills, body aches, flu symptoms severe blistering, peeling, and red skin rash urinating less than usual or not at all pale or yellowed skin, dark colored urine, fever, confusion orweakness severe pain in your upper stomach spreading to your back, nauseaand vomiting, fast heart rate loss of appetite, jaundice (yellowing of the skin or eyes); or easy bruising or bleeding, unusual weakness Less serious side effects may include: sores or swelling in your rectal or genital area mild nausea, vomiting, diarrhea, or stomach upset white patches or sores inside your mouth or on your lips swollen tongue, trouble swallowing; or
  • 35. What other drugs affect Tetracycline? Before taking tetracycline, tell your doctor if you are takingany of the following drugs: cholesterol-lowering medications such as cholestyramine(Prevalite, Questran) or colestipol (Colestid) isotretinoin (Accutane) tretinoin (Renova, Retin-A, Vesanoid) an antacid such as Tums, Rolaids, Milk of Magnesia, Maalox,and others a product that contains bismuth subsalicylate such as Pepto-Bismol minerals such as iron, zinc, calcium, magnesium, and over-the-counter vitamin and mineral supplements a blood thinner such as warfarin (Coumadin); or a penicillin antibiotic such as amoxicillin (Amoxil, Trimox,others), penicillin (BeePen-VK, Pen-Vee K, Veetids, others),dicloxacillin (Dynapen), carbenicillin (Geocillin), oxacillin(Bactocill), and others
  • 36. What warnings do you have forTetracycline? The following warnings are available for thismedication: Finish the prescription. Take on empty stomach. Take with plenty of water. Shake well. Do not take with milk, antacids, or iron. Avoid exposure to sun. Do not take if pregnant
  • 37.  What is the most important information I should knowabout Tetracycline? Do not use this medication if you are pregnant. It couldcause harm to the unborn baby, including permanentdiscoloration of the teeth later in life. Tetracycline canmake birth control pills less effective. Use a secondmethod of birth control while you are taking tetracyclineto keep from getting pregnant. Tetracycline passes into breast milk and may affect boneand tooth development in a nursing baby. Do not takethis medication without telling your doctor if you arebreast-feeding a baby. Do not give tetracycline to a child younger than 8 yearsold. Tetracycline can cause permanent yellowing orgraying of the teeth, and it can affect a childs growth. Avoid exposure to sunlight or artificial UV rays(sunlamps or tanning beds). Tetracycline can make yourskin more sensitive to sunlight and sunburn may result.Use a sunscreen (minimum SPF 15) and wear protectiveclothing if you must be out in the sun. Do not take iron supplements, multivitamins, calciumsupplements, antacids, or laxatives within 2 hoursbefore or after taking tetracycline. These products canmake tetracycline less effective. Throw away any unused tetracycline when it expires orwhen it is no longer needed. Do not take anytetracycline after the expiration date on the label haspassed. Expired tetracycline can cause a dangeroussyndrome resulting in damage to the kidneys