INTRODUCTION:

Following the development of penicillin G and sulphonamides, tetracycline antibiotics were produced. Pfizer developed doxycycline as a semi-synthetic oxytetracycline congener. It was first offered for sale in 1967. It has superior oral bioavailability and serum half-life than other drugs in the tetracycline family. Doxycycline is effective against various kinds of bacteria, including gram-negative, gram-positive, and "atypical" strains, in addition to protozoa like malaria.

As a result, it is largely used around the world, "especially for the treatment of sexually transmitted infections, respiratory infections, malaria prophylaxis, and some arthropod-borne rickettsia disorders"^1.

Antimicrobial Activity:

Anthrax and leptospirosis can be treated and prevented using doxycycline. Ehrlichiosis, Lyme disease, and Rocky Mountain spotted fever can all be treated with this medication. Yersinia pestis can also be treated with Doxycycline².

Doxycycline is no longer effective against some gramme-positive bacteria. Tetracycline-resistant strains of Streptococcus thermophilus and Streptococcus faecalis were found in 40% and 74% of samples, respectively. Doxycycline has been shown to be ineffective against up to 57% of Propionibacterium acnes strains³.

Chemical Structure

Figure 1: Structure of Doxycycline

Molecular Mass: - 444.4g/mol

Molecular Formula: - C22H24N2O8

IUPAC Name: ‘(4S, 4Ar, 5aR, 6R, 12As)-4-(dimethyl amino)-3,5,10,12,12a, -pentahydroxy-6-methyl-1, -11-dioxo-1,2,3,4,4a, 5a, 6,11,12a -decahydrotetracene-2-carboxamide’

Dose of Doxycycline:

Doxycycline is available in various dosage forms, like doxycycline injection, doxycycline syrup, doxycycline suspension, doxycycline capsules, and tablets^4,5.

Mechanism of Action of Doxycycline:

Doxycycline is an antibiotic with a broad range of effects. Doxycycline decreases the production of micro-bacterial proteins by attaching to the ‘30S ribosomal subunit’. Doxycycline Add amino acids to bacteria's polypeptide chains, resulting in the creation of new proteins as well as binding failure between transfer and messenger RNA on the ribosome's subunit. The immune system has time to slaughter and eliminate microorganisms from your body during this period⁶.

Figure 2: MOA of Doxycycline

Pharmacokinetic Property:

Absorption:

Almost all of the material is absorbed by the top portion of the small intestine. It reaches its maximal plasma concentration after one to two hours⁷.

Doxycycline is best taken without food because food decreases its absorption. However, this can induce esophageal and stomach lining irritation. Furthermore, the presence of ‘trivalent or divalent cations like, magnesium, calcium, iron, zinc, and aluminum’ can chelate doxycycline and create inactive complexes, limiting absorption. Within 2 hours of dosing, the highest doxycycline concentrations in the bloodstream can be detected, with serum levels ranging from 1.7 to 3 g/ml.

Protein binding Doxycycline binds to plasma protein at a high rate, approximately 80–90%⁸.

Distribution:

Doxycycline can enter practically all human tissues and bodily fluids. Doxycycline is found in high concentrations in the liver, lungs, kidneys, gallbladder, breast milk, genitals, and bone marrow. Doxycycline levels are low in cerebrospinal fluid, aqueous humor, and saliva, but other tetracycline antibiotics, such as minocycline, enter the CSF much better⁹.

Elimination:

Doxycycline is removed from the body by another route other than the renal route. Doxycycline concentrations in bile are near fifty grammes per millilitre. The urinary system accounts for 20% of doxycycline elimination. Passive diffusion transports 75% of the doxycycline from the blood to the lumen of the intestine, while the remaining 5% is transported from the bile and eliminated through faeces¹⁰.

Metabolism:

Doxycycline is broken down in the liver, bile, as well as in the GI tract. The key metabolic routes for doxycycline have yet to be discovered. On the other hand, it is found that enzyme inducers retard the half-life of doxycycline ^11.

INTERACTION:

Oral ferrous sulphate (200-600mg) blocks doxycycline absorption in the GI tract, decreasing antibiotic and iron salt levels in the blood¹². The half-life of doxycycline may be shortened if you take it with carbamazepine, phenytoin, or barbiturates. Tetracycline may cause nephrotoxicity in those who are under methoxyflurane anaesthesia before or after surgery. An antacid decreases the absorption of doxycycline. When we take the doxycycline by intravenous then what is the effect of antacid i.e., aluminium hydroxide on the pharmacokinetics was investigated.⁶ healthy male subject received two infusion of 200mg every 7days. Volume of distribution, nonrenal clearance, urine recovery, and urine pH did not change between the therapy. When patient received 30ml of aluminium hydroxide for quarter of a day for quarter of time, starting two days before starting treatment with doxycycline. After infusion the drug the blood and urine sample were collected for microbiological analysis 48 and 96 hr. After infusion, the half-life decreased to 16.2 hours (p=0.003), while the systemic clearance increased to 54.1±12.3mL/min (p=0.008). While the area under the serum concentration-time curve decreased by 18% to 44%, renal clearance increased by 22% to 41%. The difference was not significant (P = 0.07) due to greater variability. The clearance of doxycycline can be enhanced with oral antacids¹³.

Adverse Effects:

The side effects are comparable to those of other tetracycline antibiotics. Doxycycline is an antibiotic that can cause gastrointestinal upset. Tablet esophagitis can occur when oral doxycycline is not taken with enough water or when people have difficulty swallowing or have limited mobility. It is less likely to cause. difficile colitis than other antibiotics. Doxycycline, an antibiotic, is the least likely^14,15,16.

It's been reported that people using doxycycline for malaria prevention get an erythematous rash on exposed areas of their bodies. The tolerability of malaria prevention regimens was investigated in a study. Doxycycline caused no more or less skin reactions than other antimalarials (photosensitivity was not stated). The rash goes away when the drug is stopped¹⁷.

You won't be able to use many tetracycline medications if you have kidney problems. This one can be used even if you have kidney problems¹⁸.

According to a study, doxycycline users are more prone to developing inflammatory bowel disease^. According to one large study, people who took doxycycline for acne had a 2.25-fold higher chance of acquiring regional enteritis^19,20.

CONTRAINDICATION:

Pregnancy and lactation:

The FDA classifies doxycycline as a pregnancy category D medication. Doxycycline is found in breast milk^. Antibiotics containing tetracycline are also not recommended for pregnant women or children whose age is less than. Some of the negative effects include tooth discolorations and decreased enamel formation in infants exposed to tetracycline during pregnancy, lactation, or early childhood.The Food and Drug Administration has said that the chances of doxycycline-induced primary tooth discoloration are unknown. Doxycycline is suggested by the Centers for Disease Control and Prevention for the treatment of typical pneumonia as well as tick-borne rickettsia infections in young children, and other people recommend it for malaria^21,22,23.

Other

Tetracyclines are not suggested for people who have severe liver illness or who are taking isotretinoin or other retinoids at the same time because both tetracyclines and retinoids might increase the pressure around the brain, called intracranial hypertension²⁴.

Teratogenic Study of Doxycycline:

To investigate doxycycline's teratogenic potential in humans. From 1980 to 1992, the Hungarian case control surveillance of congenital abnormalities data set was paired-analysed. During the study period, 63(0.19 percent) of the 32,804 pregnant women who had healthy babies were given doxycycline. Doxycycline was given to 56 out of 18,516 pregnant women with congenital abnormalities, which was a higher rate than the control group (P =.01). In the second and third months of pregnancy, no group with congenital abnormalities had a significantly higher rate of doxycycline treatment.

Doxycycline has a low teratogenic risk for the foetus when taken during pregnancy. Doxycycline medicine appears to have no contraindications during pregnancy ²⁵.

Indication:

Antimalarial:

Doxycycline prevents plasmodium falciparum merozoites from invading red blood cells^. It is used to prevent malaria^. Even if the parasite is doxycycline-sensitive, doxycycline is not given as a first-line treatment for malaria since its antimalarial action is delayed ^26,27,28. According to WHO guidelines, artesunate or quinine can be administered in addition to doxycycline to treat uncomplicated malaria caused by Plasmodium falciparum or after intravenous therapy for complicated malaria.

Anthelmintic:

Doxycycline kills the Wolbachia bacteria in filarial parasite genital tracts, rendering the parasites infertile and reducing the spread of disorders like onchocerciasis. In trials conducted in 2005, doxycycline treatment in the field was proven to virtually eliminate microfilariae release^29,30.

CONCLUSION:

Among the tetracycline antibiotics, doxycycline shows broad spectrum activity and is used in the treatment of infections which are caused by bacteria as well as parasites. Pneumonitis, acne, herpes, cancroid, clap, Lyme disease, cholera, typhus, and syphilis are among the germs it treats. In conjunction with quinine, it is also used to prevent malaria.

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Received on 30.06.2022 Modified on 08.08.2022

Res. J. Pharmacology and Pharmacodynamics.2022;14(4):253-256.

DOI: 10.52711/2321-5836.2022.00043