Doxycycline | Side Effects | Overview

Introduction to Doxycycline – Overview

Doxycycline, a member of the tetracycline class of antibiotics, is a broad-spectrum bacteriostatic (antibiotic) agent synthesized from oxytetracycline, a naturally occurring tetracycline generated by bacteria of the Streptomyces species (1). Doxycycline was produced and clinically developed by Pfizer Inc. in the early 1960’s and was marketed under the trade name Vibramycin®. The Food and Drug Administration (FDA) has cleared doxycycline for the prevention or treatment of a variety of local and systemic infections. It has also been investigated as a potential cancer treatment (in which a cancer cell grows and prepares to synthesize DNA (2).

The antibiotic doxycycline, a member of the tetracycline family, has been used in medicine for more than four decades. Usually given at a dose of 100 mg once or twice daily. It penetrates tissue efficiently and is well absorbed. Generally contraindicated during pregnancy or in children because of potential effects on bone growth and gastrointestinal and dermatologic adverse effects, and effects on developing teeth (3).

Drug interactions are rare, but can occur when methotrexate and oral contraceptive pills (OCP) are used together. It is active against a wide range of species, including atypical bacteria, Gram-positive bacteria, and Gram-negative bacteria. In addition, it seems to have some anti-inflammatory effects that could be clinically beneficial (2).

Doxycycline is a useful antibiotic for the prevention and treatment of several significant potential biological warfare agents. As a result, it is widely used throughout the world, particularly for the treatment of various arthropod-borne rickettsial diseases, as well as for the prevention of malaria, respiratory tract infections (RTIs), and sexually transmitted infections (STIs). Doxycycline is also used to treat granulomatous diseases and has shown efficacy in treating these conditions (3).

Mechanism of action

Doxycycline is more lipophilic than other tetracyclines, allowing it to cross membranes to reach target molecules. Tetracyclines function as cationic coordination complexes in gram-negative bacteria to bridge the OmpF and OmpC porin channels; two porins that regulate the passive diffusion of small, hydrophobic molecules across the outer membrane, thus allowing cells to rapidly adapt to osmotic changes. Similar to this, the lipophilic and electroneutral forms of Gram-positive bacteria cross the cytoplasmic membrane. The energy-dependent proton motive force drives uptake across the cytoplasmic membrane (4).

The 30S ribosomal subunit of the bacterial ribosome is where doxycycline reversibly binds, preventing aminoacyl-tRNA from binding to the bacterial ribosome and thereby inhibiting bacterial protein production. By binding to 70S ribosomes in mitochondria, further inhibition of protein synthesis occurs. It is a bacteriostatic drug as a result.
In Plasmodium falciparum, it also inhibits apicoplast ribosomal subunits, thereby affecting heme production and fatty acid synthesis late in the malaria cell cycle.
In addition, it promotes the adhesion of gingival fibroblasts, inhibits angiogenesis and apoptosis, and accelerates wound healing, among many other things. It is also known to inhibit certain matrix metalloproteases (MMPs), which are proteolytic enzymes generated by inflammatory cells. Because of this, prospective applications have emerged in various anti-inflammatory (rheumatoid arthritis) and antineoplastic activities (5).

In periodontitis, subantimicrobial doses of doxycycline block the activity of MMPs that damage the gums and degrade collagen (6).

Pharmacokinetics and pharmacodynamics

Following oral treatment, doxycycline is virtually entirely absorbed in the stomach and proximal small intestine. Contrary to tetracycline and minocycline, the effects of food or dairy products on absorption are minimal, with blood levels just 20% lower. Doxycycline reaches the small intestine as a free medication because it forms compounds with metal ions in food that are unstable in the acidic environment of the stomach. A tiny amount of doxycycline is not absorbed due to stable metal complexes that are generated in the duodenum, however. The absorption of doxycycline will be hampered by the presence of multivalent cations. It has an extended serum half-life of 18 to 22 hours, which does not seem to affect reduced renal function. Peak serum levels are obtained after 30 minutes of intravenous dosing and 2-3 hours after oral administration. Due to doxycycline’s greater lipophilicity compared to tetracycline, large concentrations of the drug have been found in a variety of tissues, including lymphatic fluid, peritoneal fluid, prostate tissue, and breast milk (7).

Contraindications, warnings, and precautions

People with a history of tetracycline hypersensitivity should not use doxycycline. If it is administered in the latter half of the mother’s pregnancy, a child may experience permanent tooth discoloration and enamel hypoplasia during the development of their teeth. Other risks are diarrhea associated with Clostridium difficile and the associated morbidity and mortality; potential overgrowth of non-susceptible organisms, including fungi; photosensitivity; severe skin reactions, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; intracranial hypertension; potential toxic effects on the developing fetus due to the emergence of drug-resistant bacteria; the drug crossing the placenta; anti-anabolic action of the drug leading to increase in blood urea nitrogen (8).

Drug interactions

Coumarins: Doxycycline may increase the anticoagulant effect of oral anticoagulants in patients by interfering with prothrombin utilization and decreasing vitamin K generation by the intestinal flora. Participants who used doxycycline and acenocoumarin or phenprocoumon concurrently had a 2.5-fold increased risk of more bleeding events (9).

Digoxin: Digoxin blood levels may be increased in those taking doxycycline and digoxin together.

· Beta-blockers: When a patient received intravenous doxycycline plus a beta-blocker while under general anesthesia, patients may have a type I anaphylactic response with hypotension, bronchospasm, and urticaria (10).

Antacids: When doxycycline is administered together with drugs containing divalent or trivalent cations (such as antacids, laxatives, and oral iron preparations), the absorption of doxycycline is reduced (11).Antiepileptics: Induction of microsomal enzyme activity by barbiturates, carbamazepine, and phenytoin is thought to shorten the half-life of doxycycline (12).

Vaccines: Most doctors advise anyone receiving the oral typhoid vaccine to avoid taking doxycycline for 24 hours after it is given, as it can decrease the vaccine’s effectiveness.

· OCP: Concomitant use of tetracycline may reduce the efficacy of oral contraceptives. It is suggested to use complementary forms of birth control when using doxycycline (13).

Side effect profile

Particularly in comparison to the older tetracyclines and minocycline, doxycycline is generally well tolerated.

Bones and Teeth

Doxycycline accumulates in teeth and bones, causing discoloration that is more common in primary teeth than in permanent teeth. However, if given to children when their permanent teeth are still forming, it could cause lifelong discoloration. Permanent teeth can also be discolored to some degree, particularly when poor oral care and excessive sun exposure coexist (14).
In addition, it can lead to bone abnormalities, enamel dysplasia, and reduced bone development. Doxycycline treatment for preterm infants resulted in a 40% decrease in fibular bone development; however, this effect was reversible once the drug was discontinued (15).

Dermatologic and hypersensitivity

Photosensitivity is one of the most significant dermatologic adverse effects of doxycycline. Due to the fact that doxycycline is crucial for the prevention of malaria and because malaria is mainly distributed in regions with high levels of sunlight, special attention should be paid to this side effect. Doxycycline can cause photoonycholysis and photosensitivity. Patients report mild to severe discomfort or itching. Up to 80% of the body can be affected in extreme situations (16).

The initial skin symptom of a phototoxic reaction to doxycycline is typically a sensation of sunburn, warmth, and erythema, on sun-exposed areas such as the nose, upper cheeks, lips, and the backs of the forearms, hands, and fingers (similar to pseudoporphyria) occurring in less than 24 hours of exposure to relatively intense sunlight without scarring or hirsutism as seen in true porphyria. Subsequently, barely perceptible erythematous plaques emerge and may be accompanied by tiny papules in the aforementioned locations. Symptoms resolve on their own within 10 to 14 days after cessation of doxycycline therapy (17).

Due to its lower cost compared to other preventative antimalarials, doxycycline is preferred by many travelers. However, since the area of exposure to malaria infections is mainly near the equator with high levels of solar radiation, special attention should be paid to sun protection during doxycycline prophylaxis. Sun protective clothing or sun protection should be worn to reduce sun exposure. Sunscreens should have a factor 50+ and cover the entire UVA1 spectrum (340-400 nm) (18).
Skin eruptions of many different types can occur, including erythematous, maculopapular, and pustular rashes, pruritus, urticaria, and fixed drug eruptions. Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity responses to serum sickness are extremely rare. When doxycycline is used to treat spirochetal infections, the Jarisch-Herxheimer response may occur. Reports of anaphylaxis have also emerged (16).

Gastrointestinal disorders

Commonly nausea, vomiting, diarrhea, and epigastric heartburn are Esophagitis, esophageal ulceration, and mediastinitis are examples of severe responses. By using enteric-coated medications and monohydrate (rather than hydrochloride) formulations, the risk of esophageal ulcers can be decreased. To relieve discomfort, patients should take doxycycline with plenty of water and stand upright for 30 minutes after taking it.
In people with esophageal compression or obstruction, doxycycline should be avoided entirely. Other gastrointestinal side effects include Clostridium difficile, although this occurs less frequently than with other antibiotics such as clindamycin.
Hepatic failure increases the risk of tetracycline-induced hepatotoxicity; however, doxycycline presents negligible or very low risk compared to other tetracyclines (19).

Neurological side effects

Benign intracranial hypertension has also been associated with the use of doxycycline. Most patients obtain improvement in symptoms after stopping the drug, but some patients experience irreversible loss of visual acuity or visual field, requiring optic nerve fenestration or CSF shunting (20).

Genitourinary side effects

Tetracyclines may increase the virulence factors linked to the bacterium and are thought to decrease the vaginal bacterial flora, causing an excess of Candida albicans. A typical symptom of vaginal and oropharyngeal candidiasis is fungal overgrowth. Taste disturbances, rhinitis, hiccups, and blood dyscrasias are rare side effects. Women who use oral contraceptives or who have a history of candidal vulvovaginitis should consider antifungal therapy while taking doxycycline (21).

Conclusion

Doxycycline is frequently referred to as the “hidden weapon of the infectious diseases for the physician” because of its broad range of activity and the variety of therapeutic uses it has, particularly for some disorders that are more uncommon and challenging to detect. Lyme disease, brucellosis, anthrax, Q fever, and atypical respiratory pathogens, as well as the prevention of malaria, are just a few of the sexually transmitted infections it has excellent clinical activity. It is also generally well tolerated and has a side effect profile that must be watched for.

See Also

Lisinopril Side Effects

Lexapro Side Effects

What is Meloxicam Used For?

Blood Thinners Side Effects

Is Tylenol A Blood Thinner?

Side Effects of Folic Acid

References

1. Kundu CN, Das S, Nayak A, Satapathy SR, Das D, Siddharth S. Antimalarials are anticancer and vice versa: one arrow, two sparrows. Tropic Act. 2015;149:113-27.

2. Styka AN, Savitz DA, National Academies of Sciences E, Medicine. doxycycline. Evaluation of long-term health effects of antimalarial drugs when used for prophylaxis: National Academies Press (USA); 2020.

3. Holmes NE, Charles PG. Safety and efficacy review of doxycycline. Clinical Medicine Therapeutics. 2009;1:CMT. S2035.

4. Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiology and molecular biology reviews. 2001;65(2):232-60.

5. Di Caprio R, Lembo S, Di Costanzo L, Balato A, Monfrecola G. Anti-inflammatory properties of low and high doses of doxycycline: an in vitro study. Inflammation mediators. 2015;2015.

6. Preshaw PM, Hefti AF, Jepsen S, Etienne D, Walker C, Bradshaw MH. Subantimicrobial dose doxycycline as adjunctive treatment for periodontitis: a review. Journal of clinical periodontics. 2004;31(9):697-707.

7. Saivin S, Houin G. Clinical pharmacokinetics of doxycycline and minocycline. clinical pharmacokinetics. 1988;15(6):355-66.

8. Czeizel AE, Rockenbauer M. Teratogenic study of doxycycline. Obstetrics and Gynecology. 1997;89(4):524-8 (https://pubmed.ncbi.nlm.nih.gov/9083306/).

9. Caraco Y, Rubinow A. Enhanced anticoagulant effect of coumarin derivatives induced by co-administration of doxycycline. Annals of Pharmacotherapy. 1992;26(9):1084-6.

10. Hamilton LA, Guarascio AJ. Allergy to tetracyclines. Pharmacy. 2019;7(3):104.

11. Nguyen VX, Nix DE, Gillikin S, Schentag JJ. Effect of oral administration of antacids on the pharmacokinetics of intravenous doxycycline. Antimicrobial agents and chemotherapy. 1989;33(4):434-6.

12. Penttilå O, Neuvonen P, Aho K, Lehtovaara R. Interaction between doxycycline and some antiepileptic drugs. Br Med J. 1974;2(5917):470-2.

13. Kaneshiro B, Edelman A, Carlson NE, Nichols M, Forbes MM, Jensen J. A randomized controlled trial of doxycycline at subantimicrobial doses to prevent unscheduled bleeding with continued use of oral contraceptive pills. Contraception. 2012;85(4):351-8.

14. Cohlan SQ, Bevelander G, Tiamsic T. Growth inhibition of preterm infants receiving tetracycline: a clinical and laboratory investigation of tetracycline-induced bone fluorescence. American journal of diseases of children. 1963;105(5):453-61.

15. Ayaslioglu E, Erkek E, Oba A, Cebecioglu E. Doxycycline-induced staining of the adult permanent dentition. Australian dental journal. 2005;50(4):273-5.

16. Goetze S, Hiernickel C, Elsner P. Doxycycline phototoxicity: a systematic review on clinical manifestations, frequency, cofactors, and prevention. Pharmacology and physiology of the skin. 2017;30(2):76-80.

17. Habif TP. Doxycycline-induced phototoxicity. New England Journal of Medicine. 2006;355(2):182-.

18. Elsner P, Hölzle E, Diepgen T, Grether‐Beck S, Hönigsmann H, Krutmann J, et al. Recommendation: daily sun protection in the prevention of chronic skin damage induced by UV rays. JDDG: Journal of the Deutschen Dermatologischen Gesellschaft. 2007;5(2):166-73.

19. Thiim M, Friedman LS. Hepatotoxicity of antibiotics and antifungals. Clinics in liver diseases. 2003;7(2):381-99.

20. Friedman DI, Gordon LK, Egan R, Jacobson DM, Pomeranz H, Harrison A, et al. Doxycycline and intracranial hypertension. Neurology. 2004;62(12):2297-9.

21. Maraki S, Margioris A, Orfanoudaki E, Tselentis Y, Koumantakis E, Kontoyiannis D, et al. Effects of doxycycline, metronidazole, and their combination on colonization by Candida species of the human oropharynx, intestinal lumen, and vagina. Chemotherapy Magazine. 2003;15(4):369-73.

 

Follow us