Tetracyclines are broad-spectrum antimicrobials classified into first, second, and third generations. First generation (naturally occurring): Oxytetracycline, Tetracycline, Demeclocycline hydrochloride Second generation (semi-synthetic): Doxycycline, Minocycline, Lymecycline Third generation (fully synthetic): Eravacycline, Tigecycline First-generation tetracyclines are mainly excreted renally, whereas the more lipophilic second- and third-generation agents penetrate tissues better and have broader activity. All tetracyclines share the suffix -cycline. They are used to treat a variety of infections such as acne, sexually transmitted infections (chlamydia, syphilis), H. pylori, pneumonia, and Lyme disease. Demeclocycline hydrochloride also has a unique role in treating hyponatraemia associated with syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The following article will describe the pharmacokinetics, adverse effects, cautions and contraindications and clinically significant drug interactions for tetracyclines. Mechanism of action Tetracyclines are bacteriostatic. They inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit, blocking the attachment of aminoacyl-tRNA to the mRNA-ribosome complex. This prevents elongation of the peptide chain and halts bacterial growth and replication. Tetracyclines are active against gram positive and gram negative bacteria, while third-generation tetracyclines also cover multidrug-resistant bacterial strains that the earlier generation tetracyclines are resistant to; the first generation tetracyclines are now used less widely due to antimicrobial resistance. The mechanism behind the use of tetracyclines in acne is not fully understood, but is expected to be in part owed to their antimicrobial action alongside other processes. As mentioned previously, demeclocycline can also be used in hyponatraemia associated with SIADH. SIADH occurs when the pituitary gland releases too much vasopressin, leading to water retention and hyponatraemia. Demeclocycline causes water diuresis by blocking the effect of vasopressin in the collecting duct (where vasopressin usually acts to concentrate urine) and restores sodium levels. It should be used cautiously in renal impairment for this reason, and can cause reversible nephrogenic diabetes insipidus. adobe stock Fig 1: Mechanisms of action of antimicrobials Cautions and adverse effects Tetracyclines should be avoided in children under 12 years of age, especially in those under 8 years, due to tooth staining and enamel hypoplasia. This is because tetracyclines bind to calcium. They should be avoided in pregnancy, as they can impair foetal skeletal development and cause tooth discolouration and in breastfeeding, where they may appear in low concentrations in milk (chelation of tetracyclines to calcium in milk occurs). Cautions: May exacerbate myasthenia gravis (due to neuromuscular blockade) and systemic lupus erythematosus Use of tetracyclines which have passed their expiry date can cause pseudo-fanconi syndrome, affecting the ability of the kidneys to reabsorb electrolytes and other substances such as bicarbonate ions. Renal tubular acidosis can occur as a result of the loss of bicarbonate ions. Adverse effects: Photosensitivity → increased risk of sunburn (especially with demeclocycline) Oesophageal irritation/ulceration → take with water while upright Benign intracranial hypertension → may cause permanent visual loss, symptoms: visual disturbance/headache GI effects (nausea, diarrhoea, pseudomembranous colitis, C. difficile) Hepatotoxicity → hepatitis, hepatic failure Renal effects → raised urea, acidosis, hyperphosphataemia, Fanconi syndrome Other rare reactions → pancreatitis Adobe stock Fig 2: closeup view of teeth with tetracycline staining. Interactions Cations (Ca²⁺, Mg²⁺, Al³⁺, Fe²⁺/³⁺, Zn²⁺, bismuth): Chelation → reduced absorption. Separate administration. Retinoids, isotretinoin, vitamin A: increased risk of benign intracranial hypertension. Warfarin: reduced prothrombin activity → warfarin dose reduction needed. Tigecycline and eravacycline may prolong prothrombin time and activated partial thromboplastin time meaning the blood takes longer to clot. Concomitant administration of tigecycline with warfarin led to a reduction in warfarin clearance and greater warfarin exposure (mechanism unknown) Methoxyflurane: Fatal renal toxicity risk when combined. Lithium: Increased levels with tetracyclines. Penicillins: Bacteriostatic mode of action of tetracyclines may interact with the bacteriostatic action of penicillins therefore the two classes should not be used together. Enzyme inducers (barbiturates, alcohol, carbamazepine, phenytoin): Reduce doxycycline/lymecycline half-life. Ciclosporin: Doxycycline may increase ciclosporin levels. Eravacycline: CYP3A4 metabolism → affected by inducers/inhibitors. Increase eravacycline dose with CYP3A4 inducers No action required with CYP3A4 inhibitors unless patient also has hepatic insufficiency and/or obesity Hypoglycaemic agents: tetracycline may enhance the hypoglycaemic effect Digoxin and methotrexate: increase levels with tetracycline Atovaquone: reduced levels with tetracycline Pharmacokinetic Properties Pharmacokinetic properties of some of the widely used tetracyclines are described below: Absorption Distribution Metabolism Excretion Doxycycline capsules (PO) Completely absorbed, unaffected by food/milk. Tmax ~2 h Limited info Not metabolised Bile & urine. No change in renal impairment Lymecycline tablets (PO) Readily absorbed, not affected by milk. Tmax ~3 h Readily distributes into tissues Minimal hepatic metabolism Half life = 10 hours. Tigecycline (IV) 100% (IV). Rapid distribution Readily distributes into tissues Weak concentration in urine and blood. <20% metabolism (non-CYP). Mainly faecal; ~13% renal Demeclocycline hydrochloride tablets (PO) Incomplete, irregular absorption. Affected by food/cations. Tmax ~3–4 h 41–90% protein bound, wide distribution Limited info Urine & faeces Half life is 12 hours Eravacycline (IV) 100% (IV). Tmax ~1 h Protein binding increases with dose CYP3A4 metabolism Urine & faeces Tetracycline tablets (PO) Incomplete absorption (F = 60–80%). Tmax ~1–3 h Wide tissue/fluid distribution, 20–65% bound to plasma proteins Not metabolised Urine & faeces. ~55% unchanged in urine References https://bnf.nice.org.uk/drugs/tetracycline/ accessed 6.2.25 https://bnf.nice.org.uk/drugs/demeclocycline-hydrochloride/ accessed 6.2.25 https://www.medicines.org.uk/emc/product/13082/smpc#gref accessed 6.2.25 https://www.medicines.org.uk/emc/product/100034/smpc accessed 6.2.25 https://bnf.nice.org.uk/drugs/doxycycline/ accessed 6.2.25 https://www.medicines.org.uk/emc/product/14071/smpc accessed 6.2.25 Tetralysal 300mg Hard Capsules. https://www.medicines.org.uk/emc/product/926/smpc Last updated on emc: 28 Nov 2022. Accessed 9.2.25. Xerava 100 mg powder for concentrate for solution for infusion, https://www.medicines.org.uk/emc/product/13327/smpc, Last updated on emc: 08 Nov 2024. accessed 9.2.25. Tetracycline 250 mg Tablets. https://www.medicines.org.uk/emc/product/15412/smpc Last updated on emc: 16 Jan 2024. Accessed 9.2.25. Manoharan D, Srinivasan S, Vignesh N R, Senthilvel A. Tetracyclines: The Old, the New and the Improved – A Short Review. Biomed Pharmacol J 2023;16(3). Kenneth N. Agwuh, Alasdair MacGowan, Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines, Journal of Antimicrobial Chemotherapy, Volume 58, Issue 2, August 2006, Pages 256–265, https://doi.org/10.1093/jac/dkl224 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Tetracyclines Question 1 of 3 Submitting... Skip Next Rate question: You scored 0% Skipped: 0/3 More Questions Available Upgrade to TeachMePharmacy Pro Challenge yourself with over 2100 multiple-choice questions to reinforce learning Learn More Rate This Article