{"id":51249,"date":"2023-09-30T11:30:33","date_gmt":"2023-09-30T11:30:33","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=51249"},"modified":"2023-10-07T08:51:36","modified_gmt":"2023-10-07T08:51:36","slug":"tetracyclines-the-old-the-new-and-the-improved-a-short-review","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no3\/tetracyclines-the-old-the-new-and-the-improved-a-short-review\/","title":{"rendered":"Tetracyclines: The Old, the New and the Improved – A Short Review"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Chlortetracycline, originally known as aureomycin, was the first tetracycline discovered and was derived from the bacterium Streptomyces aureofaciens. By reversibly attaching to the bacterial 30S ribosomal subunit and preventing incoming aminoacyl tRNA from binding to the ribosome acceptor site, it has a bacteriostatic impact on bacteria. In the past 55 years, a wealth of information has been available, revealing both the advantageous and detrimental effects of tetracyclines, changing some indications, and offering new recommendations for dermatologists to take into account.1<\/sup><\/p>\n\n\n\n

Methods<\/strong><\/p>\n\n\n\n

Tetracyclines, their varied\nmodes of action, uses, side effects, drug interactions, and contraindications\nwere all well-researched in the literature. The search engines used for\nthe literature searches were PubMed and Google Scholar. Tetracyclines, uses of\ntetracyclines in dermatology, recent advances in tetracyclines, Sarecycline,\nOmadacycline, Lymecycline, Minocycline, drug interactions of tetracyclines,\ncontraindications of tetracyclines and side effects of tetracyclines were some\nof the keywords used to search for related articles. The analysis covers\narticles that were published since 2012. These studies’ results were\ncombined to create a narrative review.<\/p>\n\n\n\n

Chemical Composition<\/strong><\/p>\n\n\n\n

Tetracyclines (Tc) are built up of four-fused, six-membered rings that compose the fundamental structure originally generated from Streptomyces spp., but modern derivatives are semisynthetic.2<\/sup><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Chemical composition of Tetracyclines3<\/sup><\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Classifications of Tetracyclines<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 2: Classification of tetracyclines based on the source<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\n\n

Figure 3: Classification of tetracyclines based on the generation<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Pharmacokinetics and Pharmacodynamics<\/strong><\/p>\n\n\n\n

The oral absorption of most tetracyclines is\ninsufficient. When taken intramuscularly, bioavailability is less than 40%,\n100% intravenously, and 60-80% orally (fasting adults). Gastrointestinal\nabsorption of oral formulations of tetracycline is reduced by 50% when taken\nwith food\/milk.4<\/sup><\/p>\n\n\n\n

As the dose is increased, the amount of medicine that is\nnot absorbed increases. Absorption is hampered by the concurrent consumption of\ndivalent and trivalent cations, such as Fe2+\/3+, Al3+, Zn2+, Mg2+ and Ca2+. As\na result, the absorption of tetracyclines can be hampered by dairy products,\nantacids, aluminum hydroxide gels, zinc or iron salts, magnesium, bismuth\nsubsalicylate, calcium, and dietary zinc and iron supplements. The peak plasma\nconcentration is obtained in 2-4 hours following a single oral dosage. The\nhalf-life varies between 6 and 12 hours, and are often taken two to four times\neach day. The presence of tetracycline in body fluids, including Cerebrospinal\nfluid (CSF), is widespread. All tetracyclines have a propensity to accumulate\nin the spleen, liver, tumors, bone, and teeth. Tetracyclines cross the placenta\nand get into the amniotic fluid and fetal circulation. Breast milk contains\nquite high amounts. With the exception of doxycycline, the kidney is the main\norgan via which most tetracyclines are removed, however, they are also\nconcentrated in the liver, expelled in bile, and partially reabsorbed through\nenterohepatic recirculation. On the other hand, doxycycline is generally\nexcreted via the bile and urine.<\/p>\n\n\n\n

Mechanism of Action<\/strong><\/p>\n\n\n\n

Tetracyclines act through various mechanisms such as:<\/p>\n\n\n\n

Antibacterial Effect<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 4: Flowchart depicting the mechanism of anti-bacterial action of tetracyclines<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Tetracyclines bind to the 30S bacterial ribosome and\nblock aminoacyl tRNA from reaching the acceptor (A) site on the mRNA-ribosome\ncomplex, which inhibits the production of bacterial proteins. Both passive\ndiffusion through channels created by porins in the outer cell membrane and\nactive transport, which pumps tetracyclines across the cytoplasmic membrane,\nallow these medications to penetrate gram-negative bacteria.5<\/sup><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 5: Illustrated image depicting the mechanism of anti-bacterial action of tetracyclines 6<\/sup><\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Anti-Inflammatory Effect<\/strong><\/p>\n\n\n\n

By preventing bacterial breakdown products, which trigger\ninflammatory processes, doses below the minimal inhibitory concentration\nindirectly affect inflammation. They suppress production of\npro-inflammatory cytokines like tumor necrosis factor, interleukin-1, and IL-8.\nLeukocyte migration, which takes place in the initial phases of inflammation,\nis inhibited by them.  By binding intracellular calcium, which is\nrequired for the development of microtubules that allow for cell movement,\nit prevents cell mobility. Tetracyclines suppress the activity of\ninducible nitric oxide synthase (iNOS), which lowers nitric oxide (NO). The\nhighly cytotoxic peroxynitrite radical that iNOS ultimately produces is what\ninhibits collagen and proteoglycan synthesis and boosts matrix\nmetalloproteinases (MMP) expression. Tetracyclines reduce peroxynitrite\nradicals, which prevent protein denaturation.<\/p>\n\n\n\n

Inhibition of Matrix Metalloproteinases<\/strong><\/p>\n\n\n\n

The family of zinc-dependent proteases known as matrix\nmetalloproteinases (MMPs) produced by connective tissue cells and inflammatory\ncells are involved in a wide range of physiological and pathological processes.\nIn nearly all inflammatory human diseases, metalloproteinases are shown to be\nmore active than normal. Tetracyclines block action of metalloproteinases\nby inhibiting them from binding to zinc or calcium ion.<\/p>\n\n\n\n

Tetracyclines also block alpha-amylases, a member of the\nhydrolase group, and phospholipases in addition to metalloproteinases. A\ncrucial enzyme in the manufacture of inflammatory mediators such\nas prostaglandins is phospholipase A2.<\/p>\n\n\n\n

Antioxidant Effect<\/strong><\/p>\n\n\n\n

Tetracyclines also neutralize reactive oxygen species\n(ROS) and protect cell structures from oxidative damage. The retention of ROS\nby these compounds depends on the phenolic ring. A stable phenolic radical that\nis enclosed by the side groups of the phenolic ring and does not interact\nfurther is created when a free radical attaches to the phenolic ring.<\/p>\n\n\n\n

Spectrum<\/strong><\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 6: Spectrum of action of tetracyclines<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Recent Advances in Tetracycline<\/strong><\/p>\n\n\n\n

Tigecycline<\/strong><\/p>\n\n\n\n

Tigecycline, a glycylcycline\ngroup of antibiotics structurally related to minocycline, has a decreased\nsusceptibility to resistance compared to other drugs in the tetracycline group\nand due to its limited oral absorption, it can only be used by intravenous\nroute. It cannot be used to treat urinary tract infections, bacteremia, or\nmeningitis because of its weak concentration in blood and urine. Tigecycline is\neffective against gram-positive and gram-negative organisms as well as anaerobes,\nin contrast to other tetracyclines. A pooled evaluation of tigecycline clinical\ntrials found a modestly greater but statistically significant risk of death\ncompared to active comparator antibiotics. Therefore, tigecycline should\nnormally only be used for infections that are resistant.<\/p>\n\n\n\n

Sarecycline<\/strong><\/p>\n\n\n\n

Sarecycline\nis a brand-new, once-daily, tetracycline-derived oral antibiotic that has\nreceived FDA approval in the US for the treatment of moderate-to-severe acne\nvulgaris in patients aged 9 years and above. It can be taken with or\nwithout meals. Sarecycline exhibits modest effect against enteric aerobic\nGram-negative bacteria but has anti-inflammatory characteristics and powerful\nactivity against Gram-positive bacteria, including activity against several\nstrains of Cutibacterium acnes. Sarecycline was examined for chest and\nback acne, unlike many other research on acne. At 1.5 mg\/kg\/day of sarecycline,\na substantial decrease in inflammatory lesions was observed at week 12, with\nstatistically significant improvement visible as early as week 3. There were no\ncomplaints of phototoxicity, vertigo, pseudotumor cerebri, or lupus, but nausea\nand vaginal candidiasis of 1.2% and 1.2%, respectively, were reported.7<\/sup><\/p>\n\n\n\n

Omadacycline<\/strong><\/p>\n\n\n\n

Omadacycline (Nuzyra\n– Paratek), a semi-synthetic tetracycline derivative, has been approved by the\nFDA for the once-daily intravenous and oral treatment of acute bacterial skin\nand skin structure infections (ABSSSIs) and community-acquired bacterial\npneumonia (CAP) in adults. Gram-positive, gram-negative, atypical, and\nanaerobic pathogens are all susceptible to omadacycline’s broad spectrum of\nactivity.8<\/sup><\/p>\n\n\n\n

Lymecycline <\/strong><\/p>\n\n\n\n

Tetracyclines and L-lysine were combined to create the\nsemi-synthetic tetracycline known as lymecycline. It differs from tetracycline\nin that it has higher serum levels, improved tissue penetration, and slower\nclearance rates.<\/p>\n\n\n\n

Lymecycline is taken as a straightforward, once-daily regimen\nbecause it has the maximum oral absorption of all tetracyclines. It produces\nfewer side effects than earlier medications from this class.<\/p>\n\n\n\n

A multicenter, randomized, blinded trial comparing the\neffectiveness, safety, and cost-efficiency of using lymecycline and minocycline\nfound that both medications had a similar safety and efficacy profile, but that\nlymecycline had a 4-fold lower cost of treatment.9<\/sup><\/p>\n\n\n\n

Minocycline-Extended Release<\/strong><\/p>\n\n\n\n

After studies revealed that minocycline had a\nlonger half-life (15\u201325 hours), lower risk for resistance, less GI side\neffects, and less influence on its action from dairy consumption, it\nbecame more widely used to treat acne. However, using minocycline has been\nlinked to a higher incidence of side effects, such as drowsiness and lupus\nbrought on by medication. The standard dosage for treating acne vulgaris\nusing instant release minocycline hydrochloride 100mg twice daily, has\nbeen linked to these side effects. By allowing for a slower rise in serum\nlevels and a lower maximum concentration, extended-release minocycline has the\npotential to lessen the risk of systemic side effects linked to greater serum\nlevels of the drug.10<\/sup><\/p>\n\n\n\n

Resistance<\/strong><\/p>\n\n\n\n

Tetracycline\nresistance in cells is caused in three ways.<\/p>\n\n\n\n

Tetracycline is actively pumped out of cells by a membrane protein that is encoded by the Efflux resistance gene.<\/p>\n\n\n\n

Ribosomal defenses that prevent tetracycline from attaching to the ribosome.<\/p>\n\n\n\n

The least common type of resistance is enzymatic, in which the medicine is rendered inactive by the addition of an acetyl group to the drug’s molecule.11<\/sup><\/p>\n\n\n\n

Topical Uses of Tetracyclines<\/strong><\/p>\n\n\n\n

Due to their chronic\nnature, potential for deformity, and psychological effects, rosacea and acne\nvulgaris pose therapeutic obstacles. Both disorders have significant\ninflammatory components despite having different pathophysiologic causes.\nSystemic antibiotics are therefore frequently recommended for months at a time\nas opposed to the days or weeks that are normal for infections. In response to\nthe emergence of resistant bacterial strains, adverse events and\ncompliance issues related to chronic systemic broad-spectrum antibiotic use,\nnew treatment strategies have been developed, including the use of\nsub-antimicrobial doses, narrow-spectrum oral antibiotics and new\nformulations of topical minocycline. 4% of topical minocycline is used to treat\nacne vulgaris while 1.5% is used to treat rosacea.12<\/sup><\/p>\n\n\n\n

Indications in Dermatology<\/strong><\/p>\n\n\n\n

Table 1: Indications in Dermatology<\/strong><\/p>\n\n\n\n\n\n\n\n
\n

Indications in Dermatology<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Based on Antibacterial effect<\/strong><\/p>\n<\/td>\n

\n

Based on anti-inflammatory effect<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

\u00b7       Acne<\/p>\n

\u00b7       Syphilis<\/p>\n

\u00b7       Lyme borreliosis<\/p>\n

\u00b7       Lymphogranuloma venereum<\/p>\n

\u00b7       Granuloma inguinale<\/p>\n

\u00b7       Rickettsia<\/p>\n

\u00b7       Atypical Mycobacterial infections<\/p>\n

\u00b7       Chlamydial non-specific urethritis\/Endo cervicitis<\/p>\n

\u00b7       Atypical Pneumonia<\/p>\n

\u00b7       Cholera<\/p>\n

\u00b7       Plague<\/p>\n

\u00b7       Relapsing fever<\/p>\n

\u00b7       Recurrent aphthous stomatitis<\/p>\n

\u00b7       Acrodermatitis chronica atrophicans<\/p>\n<\/td>\n

\n

\u00b7       Acne<\/p>\n

\u00b7       Rosacea<\/p>\n

\u00b7       Autoimmune bullous disorder<\/p>\n

\u00b7       Neutrophilic disorders (Pyoderma gangrenosum, sweet\u2019s syndrome)<\/p>\n

\u00b7       Kaposi sarcoma<\/p>\n

\u00b7       Granulomatous diseases (Sarcoidosis, Necrobiosis lipoidica)<\/p>\n

\u00b7       Palmoplantar pustular psoriasis<\/p>\n

\u00b7       Hidradenitis suppurativa<\/p>\n

\u00b7       Oral lichen planus<\/p>\n

\u00b7       Prurigo pigmentosa<\/p>\n

\u00b7       Acne keloidalis nuchae<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Usage in Infectious Conditions<\/strong><\/p>\n\n\n\n

Syphilis<\/strong><\/p>\n\n\n\n

Doxycycline 100 mg BID orally for 2 weeks<\/p>\n\n\n\n

Or Tetracycline 500mg QID orally for 2 weeks<\/p>\n\n\n\n

It can be used as an alternate treatment for patients with primary, secondary, and early latent syphilis who are allergic to penicillin.<\/p>\n\n\n\n

Doxycycline 100mg orally bid for 30 days<\/p>\n\n\n\n

Or Tetracycline 500mg orally QID for 30 days<\/p>\n\n\n\n

It can be given as alternative regimen for\npenicillin allergic patients in<\/p>\n\n\n\n

late Latent syphilis<\/p>\n\n\n\n

Leprosy<\/strong><\/p>\n\n\n\n

The only antibiotic in the tetracycline family to demonstrate notable activity against M. Leprae is minocycline, which could be attributed to cell wall penetration due to its lipophilic nature.  Although the precise way that minocycline works to stop M. Leprae has not been confirmed, it is thought to be similar to other members of the tetracycline family that work by preventing protein synthesis. Minocycline has bactericidal action against M. Leprae, with a dose-dependent MIC (minimum inhibitory concentration) of 0.2 g\/ml. Minocycline has proven to have an additive impact when used with rifampin, dapsone, and clarithromycin. Minocycline has also shown promising action when combined with another fluoroquinolones such as moxifloxacin and ofloxacin with combinations such as rifapentine + moxifloxacin + minocycline (PMM), or particularly rifampin + ofloxacin + minocycline (ROM). 13<\/sup><\/p>\n\n\n\n

Lyme Disease<\/strong><\/p>\n\n\n\n

Early Lyme illness can be effectively treated with Doxycycline 100 mg BD for 14 days, but relapsing, persistent Lyme disease does not seem to be curable with this medication.<\/p>\n\n\n\n

Atypical Mycobacterial Infections <\/strong><\/p>\n\n\n\n

To stop the inducible resistance seen in several Mycobacteria spp., combination therapy is advised. Mycobacterium marinum infections have been successfully treated with immediate release formulations of minocycline (100-200 mg daily for 6\u201312 weeks) and doxycycline (100 mg twice day for 12\u201316 weeks).<\/p>\n\n\n\n

Chlamydia Trachomatis<\/strong><\/p>\n\n\n\n

C. trachomatis, which infects 100 million individuals\nworldwide each year, is the most common STI bacterial agent. Doxycycline 100 mg\ntwice daily for 7 days was effective in treating this infection.<\/p>\n\n\n\n

Usage in Inflammatory Conditions<\/strong><\/p>\n\n\n\n

Acne Vulgaris<\/strong><\/p>\n\n\n\n

The most often prescribed oral antibiotics for the management of acne vulgaris have historically been tetracyclines.<\/p>\n\n\n\n

Doxycycline is given at a dose of 50-100mg daily. It has been reported that a sub antimicrobial dose(40mg\/kg) of doxycycline given for 6 months significantly reduces both non-inflammatory and inflammatory acne without any side effects. The primary mechanism of action of sub antimicrobial dose is anti-inflammatory mechanism.<\/p>\n\n\n\n

Tetracycline is given at the dose of 1g\/day on an empty stomach. The initial dose is followed by 250-500mg for several months<\/p>\n\n\n\n

Minocycline has an advantage because of its high concentration in the pilosebaceous unit. Recommended dose is from 50-100mg twice daily.<\/p>\n\n\n\n

Rosacea<\/strong><\/p>\n\n\n\n

Table 2: Tetracyclines in Rosacea<\/strong><\/p>\n\n\n\n\n\n\n\n\n
\n

DRUGS<\/strong><\/p>\n<\/td>\n

\n

EFFECTS ON BIOLOGICAL TARGETS OR ACTIVITIES<\/strong><\/p>\n<\/td>\n

\n

CORRELATION WITH ROSACEA PATHOPHYSIOLOGY<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Tetracycline, Minocycline<\/p>\n<\/td>\n

\n

Inhibit neutrophil migration and chemotaxis<\/p>\n<\/td>\n

\n

Inflammation and oxidative stress<\/p>\n<\/td>\n<\/tr>\n

\n

Minocycline, Doxycycline<\/p>\n<\/td>\n

\n

Inhibit expression of respirator oxygen or oxidative burst from neutrophils<\/p>\n<\/td>\n

\n

Inflammation, Dermal destruction<\/p>\n<\/td>\n<\/tr>\n

\n

Chemically Modified Tetracycline, Minocycline, Doxycycline<\/p>\n<\/td>\n

\n

Inhibit expression, production or activity of matrix metalloproteinases<\/p>\n<\/td>\n

\n

Abnormal vasculature, Dermal destruction<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Erythema Nodosum<\/strong><\/p>\n\n\n\n

Tetracycline suppresses fat necrosis and lipolysis.  Reactive oxygen species have been suggested to be involved in the pathogenesis of EN. Tetracyclines have the ability to remove reactive oxygen species from the environment. This could be one of the reasons why patient\u2019s condition improved after taking tetracycline.<\/p>\n\n\n\n

Bullous Pemphigoid<\/strong><\/p>\n\n\n\n

By inhibiting neutrophil chemotaxis and inflammatory mediators in this bullous illness, tetracyclines in combination with niacinamide decrease the inflammatory response mediated by complement at the basement membrane zone.<\/p>\n\n\n\n

Pyoderma Gangrenosum<\/strong><\/p>\n\n\n\n

Tetracycline treats pyoderma gangrenosum using both anti-inflammatory and anti-chemotactic drugs rather than merely antibacterial ones. The typical dose is 100 mg daily, however in many cases larger doses of 300 mg four times daily have been needed.<\/p>\n\n\n\n

Hidradenitis Suppurativa<\/strong><\/p>\n\n\n\n

Tetracyclines taken orally are utilized as first-line oral therapy by 75% of dermatologists in the UK, according to a recent survey.<\/p>\n\n\n\n

Confluent Reticulate Papillomatosis (Crp)<\/strong><\/p>\n\n\n\n

Some studies on CRP conducted in recent years have concentrated on the pathogenesis of bacteria in causing the disease. This notion is supported by the positive response to antibiotics like azithromycin and minocycline in clinical settings. Additionally, tetracycline groups inhibit metalloproteinase, hydrolase, phospholipase A2, tumor necrosis factor alpha, interleukin (IL)-1, and IL-6 as well as reduce IL-8 and neutrophil oxidative burst and hence have both antibacterial and anti-inflammatory effects.14<\/sup><\/p>\n\n\n\n

CMT-3 (Chemically Modified Tetracycline) in Kaposi Sarcoma<\/strong><\/p>\n\n\n\n

The CMTs are successful in treating metastasis, which is responsible for more than 90% of cancer-related mortality, according to recent reports. An imbalance between the damaging enzymes and their inhibitors results from tumor cells producing too much serine proteinase and matrix-degrading MMPs. By causing cell cycle arrest and apoptosis, they suppress cell proliferation in addition to the invasive potential and MMP activity. By producing hydroxyl free radicals that penetrate and depolarize mitochondria, CMTs destroy tumor cells. Additionally, they accelerate caspase-mediated apoptosis and slow down angiogenesis. 15<\/sup><\/p>\n\n\n\n

Recurrent Aphthous Stomatitis<\/strong><\/p>\n\n\n\n

The, size, pain and duration of the ulcers are significantly reduced with treatment of tetracycline. Doxycycline 100 mg in 10 ml water used as a mouthwash for 2-4 minutes, 4 times daily for 3 days, has shown promising effects in treating ulcers in the UK, according to a clinical investigation. 16<\/sup><\/p>\n\n\n\n

Oral Lichen Planus<\/strong><\/p>\n\n\n\n

In the literature, there is a report of significant improvement in patients following one week of rinsing with a tetracycline solution (0,25%) for 2-4 minutes, three times per day. 17<\/sup><\/p>\n\n\n\n

Acne Keloidalis Nuchae<\/strong><\/p>\n\n\n\n

Tetracycline derivatives with antibacterial\nand anti-inflammatory properties, including doxycycline, minocycline, and\ntetracycline, are frequently used oral antibiotics. These medications are\neffective at reducing infection-related symptoms like inflammation. Although\nthe fibrotic lesions may still be present, the vertex lesions tend to react\nmore quickly and experience less pain and bleeding.<\/p>\n\n\n\n

Contraindications<\/strong><\/p>\n\n\n\n

After prolonged usage of tetracyclines during pregnancy,\nthere may be a risk of Tc-associated fatty liver. Due to Tc\u2019s propensity to\ndeposit in calcified tissues, which can lead to bone distortion and growth\nretardation, it is not recommended that Tc be administered to children aged\nless than 8 years. Using minocycline while lactating results in the\ndevelopment of black galactorrhea.<\/p>\n\n\n\n

Tetracyclines in Pregnancy and Lactation<\/strong><\/p>\n\n\n\n

Tetracyclines are prohibited during pregnancy because\nthey are on the list of known human teratogens. It is a medication which belongs to\npregnancy category D. The fetus is known to be at established teratogenic risk\nwhen exposed to tetracyclines and their derivatives, such as oxytetracycline.\nThey are linked to greater risks of cleft palate, neural tube anomalies, and\nother serious congenital abnormalities (MCAs). Tetracyclines are excreted in\nbreast milk in significant amounts, but are found in extremely low levels in\nbreastfed newborns, which is a result of calcium-mediated chelation. However,\nunless the advantages clearly outweigh the hazards, tetracyclines should be avoided\nduring lactation. 18<\/sup><\/p>\n\n\n\n

Tetracyclines in Paediatrics<\/strong><\/p>\n\n\n\n

Because tetracyclines can cause yellowish staining of the\nteeth and also adversely affect the development of bone, they are\ncontraindicated in children under 9 years of age.<\/p>\n\n\n\n

Tetracyclines in Morphea<\/strong><\/p>\n\n\n\n

There are two school of thoughts regarding the role of\ntetracyclines in morphea. Tetracyclines are used in the treatment of morphea\ndue to its antibacterial effect against Borrelia which is one of the causes of\nmorphea whereas recent research has also shown that tetracyclines, such as\nminocycline, may reduce angiogenesis, rendering this and MMP inhibition\nas additional intriguing potential pathways by which minocycline may cause\nor aggravate morphea. 19<\/sup><\/p>\n\n\n\n

Side Effects<\/strong><\/p>\n\n\n\n

Table 3: Side Effects of Tetracyclines<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

1.<\/p>\n<\/td>\n

\n

PHOTOSENSITIVITY<\/p>\n<\/td>\n

\n

When Tetracycline is exposed to sunlight for a lengthy period of time, a photosensitive reaction occurs.  Doxycycline has dose-related phototoxicity, but minocycline has low photosensitivity.<\/p>\n<\/td>\n<\/tr>\n

\n

2.<\/p>\n<\/td>\n

\n

SKIN PIGMENTATION<\/p>\n

 <\/strong><\/p>\n<\/td>\n

\n

Minocycline is an antibiotic that is often used to treat acne. Only a small percentage of persons who use it for a long time develop dark pigmentation. Taking larger dosages of minocycline increases your chances of developing hyperpigmentation. If you are exposed to the sun, your chances of developing darker pigmentation increase as well. Tetracycline-induced skin pigmentation normally diminishes once you stop taking the medicine.<\/p>\n

 <\/p>\n

There are four types of skin pigmentation caused by tetracyclines:<\/p>\n

Type I refers to blue-black or grey pigmentation that is restricted to acne-related scarring or inflammation on the face (which often heals slowly) and stains for iron.<\/p>\n

 <\/p>\n

Type II refers to blue-grey pigmentation of normal skin on the lower thighs and the forearms, which normally fades slowly and stains for both iron and melanin.<\/p>\n

 <\/p>\n

Type III refers to normal skin that is discoloured and muddy brown in colour, mainly in sun-exposed skin (tends to last); stains only with melanin.<\/p>\n

 <\/p>\n

Type IV is a seldom seen type that manifests as restricted blue-grey pigmentation in acne scars on the back (the long-term course is unknown). This pigment is calcium-containing but iron-free.<\/p>\n

 <\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

3.<\/p>\n<\/td>\n

\n

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)<\/p>\n<\/td>\n

\n

Tc have been suggested as potential agents linked to drug-induced SLE, however there is no evidence to support this. They probably cause photosensitivity or a latent SLE flare-up. However, recent findings suggest that minocycline may be a medication that both clinically and serologically precipitates SLE.<\/p>\n<\/td>\n<\/tr>\n

\n

4.<\/p>\n<\/td>\n

\n

PSORIASIS<\/p>\n<\/td>\n

\n

Tc may cause the beginning of psoriasis or worsen an already present condition. Exacerbation is indicated by the development of new plaques, a propensity for rapid confluence, and itching.<\/p>\n<\/td>\n<\/tr>\n

\n

5.<\/p>\n<\/td>\n

\n

GASTROINTESTINAL<\/p>\n<\/td>\n

\n

Diarrhea, Nausea, vomiting and unexplained digestive difficulties are some common gastrointestinal side effects<\/p>\n<\/td>\n<\/tr>\n

\n

6.<\/p>\n<\/td>\n

\n

NEUROLOGICAL<\/p>\n<\/td>\n

\n

Tinnitus, labyrinthine dysfunction, ataxia, vertigo, vestibular disturbance, including lightheadedness, dizziness, and unsteadiness, can all be brought on by minocycline.<\/p>\n<\/td>\n<\/tr>\n

\n

7.<\/p>\n<\/td>\n

\n

RENAL<\/p>\n<\/td>\n

\n

Acute interstitial nephritis, azotemia, and Fanconi syndrome are listed as potential adverse effects.<\/p>\n<\/td>\n<\/tr>\n

\n

8.<\/p>\n<\/td>\n

\n

BENIGN INTRACRANIAL HYPERTENSION<\/p>\n

 <\/strong><\/p>\n<\/td>\n

\n

The condition known as benign intracranial hypertension (BIH), sometimes known as pseudotumor cerebri, is an infrequent idiopathic response to TCNs. To enable early detection of BIH, a high index of suspicion when a patient presents with headache, visual abnormalities, and nausea and\/or vomiting is essential. Persistence of this illness can result in significant vision loss that may be irreversible. If BIH is suspected, it is advised to stop using the suspected agent and to seek early ophthalmologic evaluation to check for papilledema.<\/p>\n<\/td>\n<\/tr>\n

\n

9.<\/p>\n<\/td>\n

\n

SEGAL\u2019S TRIAD<\/p>\n<\/td>\n

\n

Characterized by photosensitivity, nail discoloration and onycholysis.<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Monitoring<\/strong><\/p>\n\n\n\n

Periodic\nlaboratory evaluations of organ systems, including hematopoietic, renal, and\nhepatic investigations, should be carried out in long-term therapy. However,\nthe requirement for baseline testing is not mentioned, and no explicit\nrecommendations are made regarding the nature, timing, or frequency of\n“periodic laboratory tests”.  Importantly, thorough evaluations\non the long-term management of rosacea and acne vulgaris do not outline precise\nlaboratory monitoring guidelines.<\/p>\n\n\n\n

Toxicity<\/strong><\/p>\n\n\n\n

Liver damage: Jaundice and fatty liver are occasionally seen. In this aspect, oxytetracycline and tetracycline are safer. Tetracyclines provide a risk to unborn babies because they can cause acute hepatic necrosis, which can be deadly. 20<\/sup><\/p>\n\n\n\n

Renal damage: This risk only exists in cases where kidney disease is already present. Except for doxycycline, all tetracyclines build up in the body and worsen renal failure. Outdated tetracyclines can cause a disease similar to Fanconi syndrome that is reversible. Epitetracycline, anhydrotetracycline, and epianhydrotetracycline are the degradation products that harm proximal tubules. Such deterioration is favored by heat, moisture, and acidic pH.<\/p>\n\n\n\n

Phototoxicity: Some people get a severe skin reaction on exposed portions that resembles a sunburn. Demeclocycline and doxycycline have been associated with an increased incidence. Sometimes nails may be distorted.<\/p>\n\n\n\n

Tetracyclines have a chelating effect on teeth and bones. Calcium-tetracycline chelate is deposited in growing bone and teeth. The deciduous teeth are impacted between mid-pregnancy and five months after birth, resulting in brown discoloration and malformed, more cariogenic teeth. Tetracyclines have an impact on the crown of permanent anterior dentition, when taken between 3 months and 6 years of age. Tetracyclines taken in late pregnancy or during childhood may temporarily decrease bone development. The final impact on stature is largely negligible, but with continued use, abnormalities and height loss are possible.<\/p>\n\n\n\n

Anti-Anabolic effect: Tetracyclines have a catabolic impact and decrease protein synthesis. They can raise blood urea and cause a negative nitrogen balance.<\/p>\n\n\n\n

Vestibular toxicity: Ataxia, vertigo, and nystagmus are common side effects of minocycline which subside on stopping the drug.<\/p>\n\n\n\n

Drug Interactions<\/strong><\/p>\n\n\n\n

Table 4: Drug Interactions of Tetracyclines<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

Drug category<\/strong><\/p>\n<\/td>\n

\n

Drug examples<\/strong><\/p>\n<\/td>\n

\n

Comments<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Retinoids<\/p>\n<\/td>\n

\n

Isotretinoin > acitretin<\/p>\n<\/td>\n

\n

Increases the risk of pseudotumor cerebri<\/p>\n<\/td>\n<\/tr>\n

\n

Ionotropic agents<\/p>\n<\/td>\n

\n

Digoxin<\/p>\n<\/td>\n

\n

May increase the level of digoxin in about 10% of individuals<\/p>\n<\/td>\n<\/tr>\n

\n

Xanthine bronchodilators<\/p>\n<\/td>\n

\n

Theophylline<\/p>\n<\/td>\n

\n

May increase the levels of theophylline and toxicity including CNS adverse effects<\/p>\n<\/td>\n<\/tr>\n

\n

Anticoagulants<\/p>\n<\/td>\n

\n

Warfarin<\/p>\n<\/td>\n

\n

May increase the levels\/ anticoagulant effect<\/p>\n<\/td>\n<\/tr>\n

\n

Antacids, Food<\/p>\n<\/td>\n

\n

Milk<\/p>\n<\/td>\n

\n

Decreases the absorption of tetracyclines<\/p>\n<\/td>\n<\/tr>\n

\n

Other chelating agents<\/p>\n<\/td>\n

\n

Bismuth salts, iron, zinc<\/p>\n<\/td>\n

\n

Chelation with these drugs may decrease the absorption of tetracyclines<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Tetracyclines are a steadily expanding class of\nantibiotics that are widely employed in dermatology. In this\narticle, the antibacterial and anti-inflammatory properties of\ntetracyclines are discussed in relation to cutaneous illnesses that have been\ntreated with them. Recent advances in this group of drugs have led to newer\ntetracyclines which have umpteen number of benefits over conventional\ntetracyclines. To conclude, our article highlights the latest advances in\ntetracyclines which have enabled their use in various dermatological\nconditions. <\/p>\n\n\n\n

Acknowledgements<\/strong><\/p>\n\n\n\n

None<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

There is no conflict of interest.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

There are no funding sources<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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