Prednisolone
Prednisolone
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Prednisolone
Clinical data
Trade namesOrapred, PediaPred, Millipred, others
Other names11,17-Dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one
AHFS/Drugs.comMonograph
MedlinePlusa615042
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous, topical, ophthalmic
Drug classGlucocorticoid
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life2–3.5 hours[2][3][4]
Excretionurine
Identifiers
  • (11β)-11,17,21-Trihydroxypregna-1,4-diene-3,20-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.020 Edit this at Wikidata
Chemical and physical data
FormulaC21H28O5
Molar mass360.450 g·mol−1
3D model (JSmol)
  • O=C\1\C=C/[C@]4(/C(=C/1)CC[C@@H]2[C@@H]4[C@@H](O)C[C@@]3([C@@](O)(C(=O)CO)CC[C@@H]23)C)C
  • InChI=1S/C21H28O5/c1-19-7-5-13(23)9-12(19)3-4-14-15-6-8-21(26,17(25)11-22)20(15,2)10-16(24)18(14)19/h5,7,9,14-16,18,22,24,26H,3-4,6,8,10-11H2,1-2H3/t14-,15-,16-,18+,19-,20-,21-/m0/s1 checkY
  • Key:OIGNJSKKLXVSLS-VWUMJDOOSA-N checkY
  (verify)

Prednisolone is a corticosteroid, a steroid hormone used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers, electrolyte imbalances and skin conditions.[5][6] Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthritis, dermatitis, eye inflammation, asthma, multiple sclerosis, and phimosis.[6] It can be taken by mouth, injected into a vein, used topically as a skin cream, or as eye drops.[7][8][6] It differs from the similarly named prednisone in having a hydroxyl at the 11th carbon instead of a ketone.

Common side effects with short-term use include nausea, difficulty concentrating, insomnia, increased appetite, and fatigue.[5] More severe side effects include psychiatric problems, which may occur in about 5% of people.[9] Common side effects with long-term use include bone loss, weakness, yeast infections, and easy bruising.[6] While short-term use in the later part of pregnancy is safe, long-term use or use in early pregnancy is occasionally associated with harm to the baby.[1] It is a glucocorticoid made from hydrocortisone (cortisol).[10]

Prednisolone was discovered and approved for medical use in 1955.[10] It is on the World Health Organization's List of Essential Medicines.[11] It is available as a generic drug.[6] In 2023, it was the 146th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[12][13]

Medical uses

[edit]

When used in low doses, corticosteroids serve as an anti-inflammatory agent. At higher doses, they are considered as immunosuppressants.[14] Corticosteroids inhibit the inflammatory response to a variety of inciting agents and, it is presumed, delay or slow healing.[15] They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation.[16]

Systemic use

[edit]

Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and autoimmune conditions[17] such as asthma,[18] uveitis, pyoderma gangrenosum, rheumatoid arthritis, urticaria,[19] angioedema,[19] ulcerative colitis, pericarditis, temporal arteritis, Crohn's disease, Bell's palsy, multiple sclerosis,[20] cluster headaches, vasculitis, acute lymphoblastic leukemia, autoimmune hepatitis,[21] lupus, Kawasaki disease,[22] dermatomyositis,[7] post-myocardial infarction syndrome,[23] and sarcoidosis.[24]

Prednisolone can also be used for allergic reactions ranging from seasonal allergies to drug allergic reactions.[25]

Prednisolone can also be used as an immunosuppressant for organ transplants.[7][26]

Prednisolone in lower doses can be used in cases of adrenal insufficiency due to Addison's disease.[27][28]

Topical use

[edit]

Ophthalmology

Conjunctivitis

Topical prednisolone is mainly used in the ophthalmic pathway as eye drops in numerous eye conditions,[29] including corneal injuries caused by chemicals, burns, and alien objects, inflammation of the eyes, mild to moderate non-infectious allergies, disorders of the eyelid, conjunctiva or sclera, ocular inflammation caused by operation and optic neuritis.[30][31] Some side effects include glaucoma, blurred vision, eye discomfort, impaired recovery of injured site, scarring of the optic nerve, cataracts, and urticaria.[31] However, their prevalence is not known.

Prednisolone eye drops are contraindicated in individuals who develop hypersensitivity reactions against prednisolone,[29] or individuals with the current conditions, such as tuberculosis of the eye, shingles affecting the eye, raised intraocular pressure, and eye infection caused by fungus.[32]

Prednisolone acetate ophthalmic suspension (eye drops) is prepared as a sterile ophthalmic suspension and used to reduce swelling, redness, itching, and allergic reactions affecting the eye.[33][8][34] It has been explored as a treatment option for bacterial keratitis.[35]

Prednisolone eye drops are used in conjunctivitis caused by allergies and bacteria, marginal keratitis, uveitis, endophthalmitis, which is an infection of the eye involving the aqueous humor, Graves' ophthalmopathy, herpes zoster ocular infection, inflammation of the eye after surgery, and corneal injuries caused by chemicals, radiation, thermal burns, or penetration of foreign objects.[30] It is also used in the prevention of myringosclerosis,[36] herpes simplex stromal keratitis.[37] Topical prednisolone can also be used after procedures such as Laser Peripheral Iridotomy for patients with primary angle-closure suspects (PACS) to control inflammations.[38]

Ear drops

In addition, topical prednisolone can also be administered as ear drops.[39]

Pred Forte Ophthalmic Suspension (Prednisolone acetate ophthalmic suspension) [second right]
Examples of topical prednisolone Products
Eye drops Ear drops
Prednisolone sodium phosphate ophthalmic solution[29] Prednisolone sodium phosphate 0.5% eye/ ear drops[39]
Pred forte ophthalmic suspension (prednisolone acetate ophthalmic suspension)[33]
Suspension (prednisolone mild ophthalmic)[29]
Suspension (prednisolone acetate ophthalmic)[29]

Adverse effects

[edit]

Adverse reactions from the use of prednisolone include:[40][7]

Discontinuing prednisolone after long-term or high-dose use can lead to adrenal insufficiency.[43]

Pregnancy and breastfeeding

[edit]

Although there are no major human studies of prednisolone use in pregnant women, studies in several animals show that it may cause birth defects including increased likelihood of cleft palate.

Prednisolone is found in the breast milk of mothers taking prednisolone.[43]

Local adverse effects in the eye

[edit]
Cataract

When used topically on the eye, the following are potential side effects:

  • Cataracts: Extended usage of corticosteroids may cause clouding at the back of the lens, also known as posterior subcapsular cataract. This type of cataract reduces the path of light from reaching the eye, which interferes with a person's reading vision. Consumption of prednisolone eye drops post-surgery may also retard the healing process.[29]
  • Corneal thinning: When corticosteroids are used in the long term, corneal and scleral thinning is also one of its consequences. When not ceased, thinning may ultimately lead to perforation of the cornea.[29]
  • Glaucoma: Elongated use of corticosteroids has a chance of causing a raised intraocular pressure (IOP), injuring the optic nerve, and weakening visual awareness. Corticosteroids should be used cautiously in patients with concomitant conditions of glaucoma. Doctors track patients' IOP if they are using corticosteroid eye drops for more than 103 days.[29]

Pharmacology

[edit]

Pharmacodynamics

[edit]

As a glucocorticoid, the lipophilic structure of prednisolone allows for easy passage through the cell membrane where it then binds to its respective glucocorticoid receptor (GCR) located in the cytoplasm. Upon binding, the formation of the GC/GCR complex causes dissociation of chaperone proteins from the glucocorticoid receptor enabling the GC/GCR complex to translocate inside the nucleus.[47] This process occurs within 20 minutes of binding. Once inside the nucleus, the homodimer GC/GCR complex binds to specific DNA binding sites known as glucocorticoid response elements (GREs) resulting in gene expression or inhibition. Complex binding to positive GREs leads to the synthesis of anti-inflammatory proteins while binding to negative GREs blocks the transcription of inflammatory genes.[48] They inhibit the release of signals that promote inflammation such as nuclear factor-Kappa B (NF-κB), Activator protein 1 (AP-1), nuclear factor of activated T-cells (NFAT), and stimulate anti-inflammatory signals such as the interleukin-10 gene.[49][14] All of them will collectively cause a sequence of events, including the inhibition of prostaglandin synthesis and additional inflammatory mediators. Glucocorticoids also inhibit neutrophil cell death and demargination. As well as phospholipase A2, which in turn lessens arachidonic acid derivative genesis.[50]

Pharmacokinetics

[edit]

Prednisolone has a relatively short half-life, ranging 2–4 hours. It also has a large therapeutic window, considering the dosage required to produce a therapeutic effect is a few times higher than what the body naturally produces.[14]

Prednisolone is 70–90% plasma protein bound, it binds to proteins such as albumin.[14]

Both prednisolone phosphate and prednisolone acetate go through ester hydrolysis in the body to form prednisolone. It subsequently undergoes the usual metabolism of prednisolone. Concomitant use of prednisolone and strong CYP3A4 inhibitors such as ketoconazole is shown to cause a rise in plasma prednisolone concentrations by about 50% owing to a diminished clearance.[49]

Prednisolone predominantly undergoes kidney elimination and is excreted in the urine as sulphate and metabolites of glucuronide conjugate.[14]

Prednisone

[edit]

Prednisone is a prodrug that is activated in the liver. When it enters the body, prednisone is triggered by the liver and body chemicals to turn into its active form, prednisolone.[51]

Chemistry

[edit]

Prednisolone is a synthetic pregnane corticosteroid closely related to its cognate prednisone, having identical structure save for two fewer hydrogens near C11. It is also known as δ1-cortisol, δ1-hydrocortisone, 1,2-dehydrocortisol, or 1,2-dehydrohydrocortisone, as well as 11β,17α,21-trihydroxypregna-1,4-diene-3,20-dione.[52][53]

Interactions

[edit]

Co-administration of prednisolone eye drops with ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) may perhaps exacerbate its effects, causing unwanted side effects such as toxicity.[clarification needed] The wound healing process may also be hindered.[54]

Drug interactions of prednisolone include other immunosuppressants like azathioprine or ciclosporin, antiplatelet drugs like clopidogrel, anticoagulants like dabigatran or warfarin, or NSAIDs such as aspirin, celecoxib, or ibuprofen.[55]

Special populations

[edit]

Children

[edit]

Prolonged use of prednisolone eye drops in children may lead to raised intraocular pressure. While this phenomenon is dose-dependent, it is shown to have a greater effect, especially in children under 6 years of age.[29]

Pregnancy and breastfeeding

[edit]

Research on animal reproduction has indicated that there is a trace of teratogenicity when doses are reduced by 10 times the human recommended dose.[56] There is no sufficient information on human pregnancy at this moment. Use is only recommended when the potential benefits outweigh the potential risks for the pregnant mother and the fetus.[56]

Prednisolone when delivered systemically can be found in the mother's breast milk, however, there is no data provided for the extent of prednisolone found in the system after administering eye drops.[29][56] However, the presence of corticosteroids is recorded when they are administered systemically, and it could affect the fetus' growth.[56] Therefore, the use of prednisolone during breastfeeding is not advocated.[56]

Society and culture

[edit]

Dosage forms

[edit]

Prednisolone is supplied as oral liquid, oral suspension, oral syrup, oral tablet, and oral disintegrating tablet. It may be a generic medication or supplied as brands Flo-Pred (prednisolone acetate oral suspension),[40] Millipred (oral tablets),[25] Orapred (prednisolone sodium phosphate oral dissolving tablets),[7] Pediapred (prednisolone sodium phosphate oral solution),[43] Veripred 20, Prelone, Hydeltra-T.B.A., Hydeltrasol, Key-Pred, Cotolone, Predicort, Medicort, Predcor, Bubbli-Pred, Omnipred, P-Pred (prednisolone acetate ophthalmic suspension),[8] Pred Mild,[34] Pred Forte,[33] and others.[57]

Athletics

[edit]

As a glucocorticosteroid, unauthorized or ad hoc use of prednisolone during competition via oral, intravenous, intramuscular, or rectal routes is banned under World Anti-Doping Agency (WADA) anti-doping rules.[58]

Veterinary uses

[edit]

Prednisolone is used in the treatment of inflammatory and allergic conditions in cats, dogs, horses, small mammals such as ferrets, birds, and reptiles.[59][60] Its usage in treating inflammation, immune-mediated disease, Addison's disease, and neoplasia is often considered off-label use. Many drugs are commonly prescribed for off-label use in veterinary medicine."[61] Studies in ruminating species, such as alpacas, have shown that oral administration of the drug is associated with a reduced bioavailability compared to intravenous administration; however, levels that are therapeutic in other species can be achieved with oral administration in alpacas.[62]

It is used in a broad spectrum of diseases, for example, inflammation of scleral tissues, cornea, and conjunctiva in dogs.[59] In horses, prednisolone acetate suspensions are priorly used to treat inflammation in the middle layer of the eye, also known as anterior uveitis and equine recurrent uveitis (ERU), which is the leading cause of visual impairment in horses.[60] Prednisolone acetate eye drops are not to be used in other animals such as birds.[59]

Prednisolone acetate eye drops are also prescribed to dogs and cats to lessen swelling, redness, burning, and pain sensations after surgeries of the eye.[59]

Cats with conjunctivitis usually are required to avoid using ophthalmic preparations of corticosteroids and its derivatives. The most typical infections are caused by herpes virus.[60]

References

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Prednisolone

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Prednisolone, sold under the brand name Prednezol among others, is a synthetic glucocorticoid and corticosteroid medication that mimics the effects of the naturally occurring hormone cortisol, primarily used for its potent anti-inflammatory and immunosuppressive properties to treat a wide range of inflammatory, allergic, and autoimmune conditions.[1] It works by binding to glucocorticoid receptors in cells, which inhibits the production of pro-inflammatory mediators such as cytokines and prostaglandins, thereby reducing swelling, redness, itching, and immune system overactivity.[2] Approved by the U.S. Food and Drug Administration in 1955, prednisolone is available in various oral forms including tablets, syrups, and solutions, as well as topical and ophthalmic preparations, and is typically prescribed for short-term use to minimize risks, though long-term therapy requires careful monitoring.[1] Common indications for prednisolone include endocrine disorders such as adrenal insufficiency, rheumatic diseases like rheumatoid arthritis, allergic states including severe asthma exacerbations and anaphylaxis, dermatologic conditions such as eczema, hematologic issues like certain anemias, and gastrointestinal disorders including ulcerative colitis.[2] It is also employed in the management of respiratory conditions like chronic obstructive pulmonary disease flares, renal diseases such as nephrotic syndrome, and certain cancers or to prevent organ rejection after transplants by suppressing immune responses.[3] Dosage varies by condition and patient age, generally ranging from 5 to 60 mg daily for adults and 0.14 to 2 mg/kg daily for children, often tapered gradually to avoid adrenal suppression upon discontinuation.[2] While effective, prednisolone carries significant side effects, particularly with prolonged use, including weight gain, insomnia, mood changes, increased infection risk due to immune suppression, gastrointestinal disturbances, osteoporosis, potential growth suppression in children, muscle cramps (associated with hypokalemia), numbness or tingling in the arms or legs, and proximal muscle weakness (steroid myopathy).[3][4] These symptoms should prompt medical consultation. Precautions are essential, such as avoiding live vaccines, monitoring bone density, and using protective measures against infections like chickenpox or COVID-19, with patients on long-term therapy often requiring a steroid treatment card for emergency management.[2] Its chemical structure, a derivative of hydrocortisone with a molecular formula of C₂₁H₂₈O₅, enhances its potency and duration of action compared to natural cortisol, making it a cornerstone in clinical practice for modulating inflammatory pathways.[1]

Medical uses

Systemic uses

Prednisolone is administered systemically via oral or intravenous routes to manage a wide range of inflammatory, allergic, and autoimmune conditions by suppressing immune-mediated inflammation through glucocorticoid receptor agonism. Typical oral dosing ranges from 5 to 60 mg per day, administered once daily or in divided doses of 1 to 4 times daily, preferably taken with or after a morning meal to minimize gastrointestinal issues and align with the body's natural cortisol rhythm, adjusted based on disease severity and patient response, with intravenous administration used for acute or severe cases requiring rapid onset. When transitioning from intravenous to oral administration (e.g., after acute treatment), equivalent doses are typically used due to prednisolone's high oral bioavailability (approximately 80-100%), with clinical effects monitored and doses adjusted if necessary; in some cases of chronic use, slight increases in oral doses may be required due to potential variability in bioavailability.[5][1][6][7][8][9] In rheumatoid arthritis, prednisolone serves as an adjunct to disease-modifying antirheumatic drugs, particularly in low doses of 5-10 mg daily for long-term symptom control or higher doses up to 60 mg daily for acute flares, reducing joint inflammation and improving function as demonstrated in the GLORIA trial, which showed significant pain reduction in older patients without excessive adverse events.[10] For systemic lupus erythematosus, it is indicated for moderate to severe flares, with initial doses of 0.5-1 mg/kg/day orally, tapered gradually to the lowest effective dose, supported by clinical evidence of reduced disease activity and organ damage in randomized trials.[11][12] Prednisolone is a cornerstone for treating asthma exacerbations, where oral doses of 40-60 mg daily for 5-10 days accelerate recovery and reduce hospitalization rates, as per Global Initiative for Asthma (GINA) guidelines and meta-analyses confirming efficacy in moderate to severe cases.[13][14] In inflammatory bowel disease, such as ulcerative colitis or Crohn's disease, it is used for moderate to severe flares with oral prednisolone at 40-60 mg daily for 1-2 weeks followed by tapering, achieving remission in up to 60-70% of patients in clinical studies, though not recommended for maintenance due to relapse risks.[15][16] For acute allergic reactions and anaphylaxis, intravenous prednisolone at high doses (e.g., 1-2 mg/kg) is employed to mitigate systemic inflammation and prevent biphasic responses, with evidence from emergency guidelines showing reduced symptom recurrence when administered early.[5] In organ transplantation, particularly kidney transplants, prednisolone is integral to immunosuppressive regimens, starting at 0.3-1 mg/kg/day orally and tapered to 5-10 mg maintenance, preventing acute rejection as evidenced by long-term survival data in transplant cohorts.[17][18] To minimize risks such as adrenal insufficiency, doses should be tapered gradually after prolonged therapy (e.g., >3 weeks or high cumulative exposure), typically reducing by 5-10 mg weekly once clinical stability is achieved, as recommended in endocrine and rheumatology guidelines.[5][19]

Topical and ocular uses

Prednisolone is available in topical formulations such as creams and ointments, typically at concentrations of 0.5% to 1%, for the treatment of inflammatory skin conditions including eczema, psoriasis, and contact dermatitis.[1] These formulations are applied thinly to affected areas one to four times daily, depending on the severity and location of the inflammation, with treatment duration generally limited to two weeks to minimize risks.[20] The anti-inflammatory action helps reduce redness, itching, and swelling by suppressing local immune responses in the skin.[21] In ocular applications, prednisolone acetate ophthalmic suspension (1%) is commonly prescribed as eye drops to manage anterior uveitis, allergic conjunctivitis, and inflammation following ocular surgery.[22] The standard dosing regimen involves instilling one to two drops into the affected eye two to four times daily, with potential increases in frequency during the initial 24 to 48 hours for acute cases, followed by tapering as symptoms improve.[23] This localized delivery targets inflammation in the anterior segment of the eye, alleviating pain, redness, and photophobia while preserving visual function.[24] High-potency topical or prolonged ocular use of prednisolone can lead to systemic absorption, potentially causing hypothalamic-pituitary-adrenal axis suppression, Cushing's syndrome, or hyperglycemia, necessitating monitoring of plasma cortisol levels and clinical signs in at-risk patients.[25] To mitigate these risks, clinicians recommend using the lowest effective dose and duration, particularly on large skin areas or thin-skinned regions like the face and eyelids.[20]

Adverse effects

General adverse effects

Systemic use of prednisolone, a glucocorticoid, is associated with a range of adverse effects that vary by dose, duration, and individual patient factors. Short-term effects, typically occurring within days to weeks of initiation, include increased appetite leading to weight gain, insomnia, mood alterations such as euphoria or irritability, and hypertension due to sodium and fluid retention.[26][27] Long-term administration, often defined as exceeding 3 months at doses above 5 mg/day, can result in more serious complications. Osteoporosis develops rapidly, with trabecular bone loss observable within 6-12 months and up to 40% of patients experiencing clinically significant bone density reduction or fractures.[26] Adrenal suppression occurs through hypothalamic-pituitary-adrenal axis inhibition, potentially leading to adrenal insufficiency upon abrupt discontinuation; for high cumulative doses exceeding 5 g prednisone equivalent, the median percentage of affected patients is 50% (IQR 0–100%).[28][29] The risk of diabetes mellitus increases due to glucocorticoid-induced insulin resistance and hyperglycemia; new-onset diabetes is observed in approximately 2-5% of long-term users at 1 year, particularly those with preexisting risk factors, while hyperglycemia affects up to 32%.[28][30][31] Features of iatrogenic Cushing's syndrome, such as moon facies, buffalo hump, and central obesity, emerge with prolonged high-dose therapy.[26] Musculoskeletal and neurological adverse effects are also associated with prednisolone use. Long-term administration can cause steroid myopathy, characterized by weakness and wasting of the proximal limb and girdle muscles, which is generally reversible following discontinuation of the drug. Hypokalemia, a known metabolic side effect of corticosteroids, may develop and manifest as muscle cramps, additional muscle weakness, and paresthesia. Numbness or tingling in the arms or legs (including lower limbs) is listed as a more common side effect (incidence 1% to 10%). Patients experiencing muscle cramps, numbness, tingling, or unexplained muscle weakness should promptly seek medical consultation, as these symptoms may indicate hypokalemia, steroid myopathy, or other serious complications requiring evaluation and potential intervention.[4] Immunosuppression from prednisolone impairs both innate and adaptive immune responses, elevating susceptibility to infections by approximately 1.6-fold (95% CI 1.3-1.9), with risks escalating at doses ≥10 mg/day or cumulative exposure exceeding 700 mg prednisone equivalent.[28] This heightened vulnerability includes bacterial, viral, and opportunistic infections, often masked by the drug's anti-inflammatory properties.[27] Management of these adverse effects emphasizes prevention and monitoring. For osteoporosis, calcium supplementation at 1000-1200 mg/day combined with vitamin D (800-2000 IU/day) is recommended for patients on prednisolone >5 mg/day for over 3 months, alongside bisphosphonates for high-risk individuals.[28] Adrenal suppression requires gradual dose tapering and stress-dose adjustments during illness. Hyperglycemia necessitates regular glucose monitoring and lifestyle interventions or antidiabetic agents as needed. To mitigate infection risks, prophylactic measures and vigilant surveillance are essential, using the lowest effective dose to balance therapeutic benefits.[26][27]

Reproductive and fertility effects

There is no clear evidence that short-term use of prednisolone (or its prodrug prednisone) reduces fertility in men or women. The NHS states there is no clear evidence to suggest that taking prednisolone reduces fertility in either men or women. MotherToBaby fact sheets indicate that paternal exposure is unlikely to increase risks to a pregnancy, with small studies on men taking prednisone or prednisolone (often with other immunosuppressants, e.g., transplant patients) showing no increased chance for birth defects or pregnancy complications and no reduced ability to impregnate partners. This contrasts with anabolic-androgenic steroids, which can suppress spermatogenesis and cause infertility. Long-term or high-dose use may warrant caution, but short courses (e.g., for poison ivy dermatitis) are not expected to affect conception attempts.[32]

Local adverse effects

Local adverse effects of prednisolone arise primarily from its topical, ocular, and inhaled routes of administration, where the drug's glucocorticoid activity can disrupt local tissue homeostasis despite targeted delivery. These effects are generally dose- and duration-dependent, with higher risks associated with potent formulations and prolonged use exceeding 2 weeks. Unlike systemic administration, local effects are confined to the application site but may occasionally contribute to minor systemic exposure through absorption.[33][21] Topical application to the skin, often using high-potency creams for conditions like eczema or psoriasis, commonly leads to dermal atrophy, characterized by thinning of the skin layers due to reduced collagen synthesis and epidermal hypoplasia. This can progress to striae distensae, or stretch marks, particularly in areas of friction or stretching such as the flexures, resulting from fragmentation of dermal elastin fibers. Telangiectasia, the dilation of small superficial blood vessels, often accompanies atrophy and appears as reddish lines on the skin surface, while acneiform eruptions may develop from sebaceous gland hyperplasia and follicular plugging. These changes are more pronounced with continuous use beyond 2 weeks on potent preparations and may be partially irreversible in thin-skinned areas like the face.[33][21][34] Ocular use of prednisolone acetate or sodium phosphate eye drops, typically for postoperative inflammation or uveitis, frequently elevates intraocular pressure (IOP) by altering trabecular meshwork outflow resistance, potentially leading to secondary open-angle glaucoma in susceptible patients. In the general population, 5% to 6% are high steroid responders experiencing IOP rises greater than 15 mm Hg, with risks increasing to 29% to 36% for intermediate elevations after 4 to 6 weeks of chronic use; glaucoma develops if unchecked, causing optic nerve damage. Posterior subcapsular cataracts may also form due to lens epithelial cell apoptosis and protein aggregation, particularly with long-term therapy. Additionally, delayed corneal wound healing occurs from inhibited fibroblast proliferation and collagen deposition, complicating recovery after surgery. To mitigate these, regular IOP monitoring via tonometry is essential, ideally weekly during the first month and monthly thereafter for extended courses.[35][36][37][38] For inhaled corticosteroids (though prednisolone itself is not typically administered this way; effects apply to similar glucocorticoids), used for acute respiratory exacerbations in asthma or COPD when oral routes are unsuitable, primarily affects the oropharyngeal and laryngeal mucosa. Oral thrush (oropharyngeal candidiasis) arises in up to 5% to 10% of users from local immunosuppression favoring fungal overgrowth, presenting as white plaques on the tongue or buccal mucosa. Hoarseness or dysphonia results from vocal cord edema and myopathy, affecting vocal quality in approximately 20% to 50% of patients with regular dosing due to direct irritation and muscle fiber atrophy. These effects are minimized by post-inhalation mouth rinsing and spacer use, with rare instances of systemic crossover limited to high doses in vulnerable populations.[39][40][41]

Pharmacology

Pharmacodynamics

Prednisolone exerts its effects primarily by binding to the glucocorticoid receptor (GR), a nuclear receptor located in the cytoplasm of target cells. Upon binding, the ligand-receptor complex undergoes a conformational change, dissociates from heat shock proteins, and translocates to the nucleus, where it binds to glucocorticoid response elements (GREs) in DNA to modulate gene transcription. This genomic action upregulates the expression of anti-inflammatory proteins, such as annexin-1 (also known as lipocortin-1), which inhibits the activity of phospholipase A2 (PLA2), and downregulates pro-inflammatory genes.[42][8][43] The anti-inflammatory effects of prednisolone stem from multiple mechanisms, including the inhibition of PLA2, which prevents the release of arachidonic acid from membrane phospholipids, thereby reducing the synthesis of pro-inflammatory mediators such as prostaglandins and leukotrienes. Additionally, prednisolone suppresses the production of key cytokines, including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), by interfering with their transcriptional regulation. These actions collectively dampen inflammatory cascades in conditions like autoimmune diseases and allergic responses.[27][44][45] Prednisolone's immunosuppressive properties involve the induction of T-cell apoptosis and the inhibition of the nuclear factor-kappa B (NF-κB) pathway. The activated GR complex interacts with NF-κB, preventing its translocation to the nucleus and subsequent activation of genes encoding pro-inflammatory and immune-modulatory proteins. This leads to reduced T-lymphocyte proliferation and survival, contributing to immunosuppression in transplant rejection and autoimmune disorders. Furthermore, prednisolone promotes apoptosis in lymphocytes through both genomic and non-genomic pathways, enhancing its role in controlling excessive immune responses.[46][47][48] In terms of potency, prednisolone exhibits approximately four times the glucocorticoid activity of cortisol (hydrocortisone) while possessing minimal mineralocorticoid activity, making it suitable for anti-inflammatory and immunosuppressive uses without significant sodium retention or potassium loss. This relative potency profile allows for effective dosing in systemic therapies while minimizing certain endocrine side effects associated with stronger mineralocorticoid agents.[49]

Pharmacokinetics

Prednisolone is rapidly absorbed from the gastrointestinal tract after oral administration, exhibiting nearly complete bioavailability of 80–100% (often approaching or reaching 100%). Peak plasma concentrations are typically reached within 1–2 hours post-dose. Due to this high oral bioavailability, switching from intravenous (IV) to oral administration is typically performed at equivalent doses without routine adjustment. Clinical effects should be monitored, and doses adjusted if needed. In some cases with chronic use, oral doses may occasionally require slight increases due to potential reduced bioavailability.[8][11][7] The drug distributes widely throughout the body, with a volume of distribution of approximately 0.6 L/kg. Prednisolone is highly bound to plasma proteins (80–90%), primarily to albumin and corticosteroid-binding globulin (transcortin), although binding decreases at higher concentrations due to saturation of transcortin. As a lipophilic compound, it readily crosses the blood-brain barrier and placenta. These parameters are dose-dependent, with higher doses leading to increased volume of distribution and clearance.[50][8][11][51][1] Metabolism occurs predominantly in the liver, where prednisolone is reversibly converted to the inactive prodrug prednisone through 11β-dehydrogenation catalyzed by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Further metabolism produces inactive metabolites such as 6β-hydroxyprednisolone, primarily via the cytochrome P450 3A4 (CYP3A4) enzyme. The elimination half-life ranges from 2–4 hours in adults.[8][27][11][1] Excretion is primarily renal, with metabolites (conjugated with glucuronides or sulfates) eliminated in the urine and about 20% excreted unchanged; plasma clearance rates are approximately 1–2 mL/min/kg.[8][52][27]

Relation to prednisone

Prednisone serves as an inactive prodrug that undergoes hepatic metabolism to its active metabolite, prednisolone, primarily catalyzed by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).[50] This conversion occurs efficiently in the liver of individuals with normal hepatic function, rendering prednisone pharmacologically equivalent to prednisolone once activated.[53] In clinical practice, prednisone and prednisolone are dosed on an equimolar basis, with 5 mg of prednisone approximating the potency of 5 mg of prednisolone in patients without liver dysfunction.[54] However, in cases of liver impairment, such as cirrhosis, the enzymatic conversion of prednisone to prednisolone is significantly reduced, leading to lower plasma levels of the active drug and diminished therapeutic response; thus, prednisolone is recommended to ensure reliable efficacy by avoiding dependence on hepatic activation.[55][56] Prednisone is commonly prescribed for oral administration in patients with intact liver function, where its cost-effectiveness and availability make it a standard choice for chronic conditions requiring systemic glucocorticoids.[54] Prednisolone, being the active form, is preferred for intravenous use in acute scenarios or when gastrointestinal malabsorption might impair oral drug delivery, such as in inflammatory bowel disease exacerbations or severe malnutrition.[57][16] Historically, clinical preference has shifted toward prednisolone in specific populations, including neonates, children, and those with hepatic compromise, due to its direct activity without requiring metabolic conversion and the development of palatable liquid formulations that enhance absorption and compliance in pediatric patients.[58][59]

Chemistry

Chemical structure

Prednisolone is a synthetic glucocorticoid with the IUPAC name (11β)-11,17,21-trihydroxypregna-1,4-diene-3,20-dione.[60] Its molecular formula is C21H28O5, and the molecular weight is 360.44 g/mol.[60] The core structure of prednisolone features a pregnane backbone with a Δ1,4-3-keto configuration, consisting of four fused rings (three six-membered and one five-membered) characteristic of steroids, along with a side chain at C17.[60] This Δ1,4-diene system in ring A, combined with the 3-keto group, is essential for conferring glucocorticoid activity by facilitating interaction with the glucocorticoid receptor.[61] Hydroxyl groups are attached at positions C11, C17, and C21; these substituents enhance glucocorticoid specificity, with the 11β-, 17α-, and 21-hydroxy groups playing key roles in receptor affinity and biological potency.[61] The stereochemistry of prednisolone includes critical configurations at multiple chiral centers, notably the 11β and 17α orientations of the hydroxyl groups, which are vital for proper binding to the glucocorticoid receptor and distinguishing glucocorticoid effects from mineralocorticoid activity.[61] The full stereodescriptor in the IUPAC name is (8S,9S,10R,11S,13S,14S,17R), ensuring the molecule's three-dimensional conformation aligns with receptor requirements.[60]

Physical and chemical properties

Prednisolone is a white to almost white, odorless crystalline powder.[60] It exhibits limited solubility in water, with a reported value of approximately 0.223 mg/mL at 25 °C, rendering it sparingly soluble; however, it is freely soluble in ethanol (1 g dissolves in about 30 mL) and chloroform (1 g in about 180 mL).[60] A predicted pKa of 12.4 has been reported.[62] Prednisolone is sensitive to light, undergoing photolysis upon exposure to sunlight or UV radiation, and is also susceptible to oxidation, particularly in solution.[60][63] It is slightly hygroscopic and decomposes at temperatures between 235–241 °C; for stability, it should be stored at room temperature (20–25 °C) in a tight container, protected from light.[60] Commercially, prednisolone is produced through microbiological transformation, notably by Δ¹-dehydrogenation of hydrocortisone using bacteria such as Corynebacterium simplex, which introduces the characteristic double bond between carbons 1 and 2.[60]

Interactions

Drug interactions

Prednisolone, a glucocorticoid, exhibits several drug interactions that can modify its pharmacokinetics or pharmacodynamics, leading to altered therapeutic effects or heightened adverse risks.[1] CYP3A4 inhibitors, such as ketoconazole, reduce the metabolism of prednisolone by inhibiting the CYP3A4 enzyme, thereby increasing its plasma concentrations by approximately 50% and elevating the risk of adrenal suppression and other glucocorticoid-related toxicities.[64] CYP3A4 inducers, such as rifampin or phenytoin, accelerate the metabolism of prednisolone, reducing its plasma concentrations and potentially decreasing therapeutic efficacy, requiring dosage adjustments.[27] The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, with prednisolone enhances the risk of gastrointestinal complications, including ulcers and bleeding, with the combination increasing the odds of such events by 4-fold for low- to medium-dose NSAIDs and up to 13-fold for high-dose NSAIDs compared to NSAID use alone due to synergistic mucosal damage.[65] Anticoagulants such as warfarin interact with prednisolone, potentiating anticoagulant effects and potentially elevating the international normalized ratio (INR), necessitating close INR monitoring to prevent bleeding complications.[66] Prednisolone can antagonize the effects of antidiabetic medications by causing hyperglycemia, necessitating monitoring of blood glucose and possible insulin or oral hypoglycemic dose increases.[67] Live vaccines are contraindicated in patients receiving immunosuppressive doses of prednisolone, as the drug's suppression of immune responses can diminish vaccine efficacy and heighten the risk of disseminated infection from the vaccine virus.[27]

Other interactions

Prednisolone's effects can be influenced by certain dietary and lifestyle factors, which may alter its absorption, efficacy, or risk of adverse effects. For instance, consumption of grapefruit juice does not significantly affect the metabolism or pharmacokinetics of prednisolone.[68] While there is no direct pharmacokinetic interaction, moderate alcohol consumption may be acceptable according to some guidelines like the NHS, but excessive use can exacerbate gastrointestinal irritation, such as increased risk of stomach ulcers or bleeding, and may heighten overall liver strain during long-term corticosteroid therapy. Although no direct pharmacokinetic interaction exists, the combined immunosuppressive effects can further weaken the immune system and contribute to bone density loss.[69][70][71][72] Prednisolone possesses mineralocorticoid activity that promotes potassium excretion, potentially leading to or worsening hypokalemia, particularly in patients with pre-existing low potassium levels from conditions like diuretic use or dietary deficiencies.[27][73] To mitigate this, dietary potassium supplementation or consumption of potassium-rich foods (e.g., bananas, spinach) is often advised, alongside monitoring serum levels.[74] Conversely, high-sodium intake can intensify fluid retention and hypertension risks associated with prednisolone.[73] Licorice consumption should be avoided, as its glycyrrhizin content can enhance the mineralocorticoid activity of prednisolone, exacerbating risks of hypokalemia and hypertension.[72] Smoking may diminish prednisolone's therapeutic efficacy in treating inflammatory conditions, such as asthma, by inducing systemic corticosteroid insensitivity through mechanisms like increased oxidative stress, independent of any pharmacokinetic changes.[75][76] This reduced responsiveness highlights the importance of smoking cessation to optimize treatment outcomes in responsive diseases.

Special populations

Use in children

Prednisolone is commonly used in pediatric populations for conditions such as acute asthma exacerbations, nephrotic syndrome, and juvenile idiopathic arthritis, where it provides anti-inflammatory and immunosuppressive effects to induce remission or control symptoms.[77] In acute asthma, short courses of 1-2 mg/kg/day (maximum 60 mg/day) divided into two doses for 3-10 days are effective in reducing hospitalization rates and improving lung function, as per National Heart, Lung, and Blood Institute guidelines.[77] For nephrotic syndrome, initial therapy involves 2 mg/kg/day (or 60 mg/m²/day, maximum 60 mg/day) for 4-6 weeks to achieve remission, followed by alternate-day dosing at 1.5 mg/kg (or 40 mg/m², maximum 40 mg/day) for 2-5 months to prevent relapses, according to Kidney Disease: Improving Global Outcomes recommendations.[77] In juvenile idiopathic arthritis, dosing is individualized based on weight, disease severity, and response. In Australia, initial doses are typically 0.5 mg/kg daily (in 3-4 divided doses), which can be doubled or trebled if necessary for inflammatory control; maintenance doses are 0.125-0.25 mg/kg daily, with careful tapering to minimize side effects. General doses range from 0.14-2 mg/kg/day or 4-60 mg/m²/day, titrated to the lowest effective level for symptom control.[77][78] Alternate-day regimens are preferred for maintenance therapy across these indications to minimize hypothalamic-pituitary-adrenal (HPA) axis suppression while preserving efficacy.[77] Despite its benefits, prednisolone use in children carries unique risks, particularly with prolonged or high-dose administration. Linear growth retardation is a prominent concern, with studies showing reduced height velocity of approximately 1-2 cm per year during high-dose therapy (e.g., 2 mg/kg/day), more pronounced in frequent relapsers of nephrotic syndrome; catch-up growth may occur post-treatment but persistent deficits are possible if therapy extends beyond 1-2 years.[79] Increased susceptibility to infections is another key risk, with long-course use associated with higher rates of bacterial and viral infections due to immunosuppression, necessitating prophylactic measures like avoiding live vaccines during high-dose periods.[77] Short courses (e.g., 3-5 days for asthma) also elevate infection risk modestly, alongside behavioral changes and sleep disturbances in 4-5% of cases.[80] To mitigate these risks, regular monitoring is essential in children on prednisolone. Height and weight should be tracked using standardized growth charts at each visit to detect deviations early, with adjustments to the lowest effective dose if growth velocity falls below the 25th percentile.[77] Bone age assessments via hand-wrist X-rays are recommended annually or if growth falters, to evaluate skeletal maturation and guide therapy duration, particularly in chronic conditions like juvenile arthritis or nephrotic syndrome.[81]

Use in pregnancy and breastfeeding

Prednisolone is classified as FDA Pregnancy Category C, indicating that animal reproduction studies have shown adverse effects on the fetus, but there are no adequate and well-controlled studies in humans; it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[82] In animal studies, high doses of prednisolone (≥20 mg/kg) administered during the first trimester have been associated with an increased risk of cleft palate in offspring.[5] Human data from cohort studies suggest a possible small increase in orofacial clefts (from approximately 1 per 1,000 to 3-5 per 1,000 infants) with first-trimester exposure to systemic corticosteroids like prednisolone at doses exceeding 20 mg/day, though newer reviews indicate this risk may be negligible or not causally linked after adjusting for underlying maternal conditions.[83] Prednisolone crosses the placenta, but the active form is partially metabolized by placental 11β-hydroxysteroid dehydrogenase type 2, reducing fetal exposure compared to synthetic glucocorticoids like betamethasone.[84] Despite these risks, prednisolone provides significant benefits in managing maternal autoimmune diseases during pregnancy, such as systemic lupus erythematosus (SLE), by suppressing inflammation and preventing disease flares that could lead to adverse pregnancy outcomes like preterm birth or fetal loss.[83] Guidelines recommend using the lowest effective dose, ideally less than 20 mg/day of prednisone equivalent, to balance maternal therapeutic needs with fetal safety, as higher doses have been linked to increased risks of gestational diabetes and preeclampsia in SLE pregnancies.[84] For instance, low-dose regimens (≤10 mg/day) in SLE patients have shown better fetal outcomes, including reduced prematurity and small for gestational age infants, compared to high-dose therapy.[85] During breastfeeding, prednisolone transfers into breast milk in very low amounts, typically less than 0.1-0.2% of the maternal dose, with peak levels occurring 1-2 hours after ingestion and a short half-life of about 2.5 hours.[86] It is considered compatible with breastfeeding for short-term use at doses up to 20 mg/day, as no adverse effects have been reported in breastfed infants, though maternal doses above 20 mg/day may warrant waiting 4 hours post-dose to minimize infant exposure.[86] Infants should be monitored for signs of adrenal suppression, such as poor growth or hypotonia, particularly with prolonged high-dose maternal therapy, although such effects are rare.[86] To minimize systemic exposure in pregnant or breastfeeding individuals requiring corticosteroid therapy, topical formulations of prednisolone or milder alternatives like hydrocortisone are preferred, as they result in negligible fetal or infant absorption and have not been associated with increased risks of birth defects or low birth weight.[87]

Use in the elderly

In elderly patients, prednisolone dosing should begin at the lower end of the recommended range, typically 5 mg per day, with gradual titration to minimize risks associated with age-related declines in hepatic and renal function that can prolong drug clearance.[5][2] This cautious approach accounts for slower metabolism in older adults, where reduced renal clearance may lead to higher drug exposure and amplified adverse effects.[88] Key risks of prednisolone use in the elderly include heightened susceptibility to osteoporosis, where even low doses as small as 2.5 mg daily can significantly increase fracture risk, potentially doubling incidence rates with cumulative exposure exceeding 5400 mg or prolonged use beyond 365 days.[89][90] Delirium is another concern, as oral corticosteroids may induce or exacerbate it in those at high risk, prompting recommendations to avoid use except when essential, such as during acute exacerbations, and to employ the lowest effective dose for the shortest duration.[91] Polypharmacy further complicates therapy, as elderly individuals often take multiple medications, elevating interaction risks with drugs like anticoagulants, antidiabetics, or NSAIDs.[5] Prednisolone remains valuable for conditions prevalent in the elderly, such as polymyalgia rheumatica, where initial doses of 12.5–25 mg daily often provide rapid symptom relief, or acute COPD exacerbations, treated with shorter courses like 40 mg for 5 days, potentially adjusted lower in frail patients.[92][93] To mitigate osteoporosis, co-therapy with bisphosphonates is advised, particularly for those on doses exceeding 7.5 mg daily for over 3 months or with low bone mineral density. The American Geriatrics Society Beers Criteria highlight long-term corticosteroid use as potentially inappropriate in older adults due to these risks, urging careful monitoring, bone density assessment, and fracture prevention strategies to balance benefits against harms.[91][5]

Society and culture

Available forms and dosages

Prednisolone is available in multiple pharmaceutical formulations to accommodate various routes of administration, including oral, topical, ophthalmic, and injectable forms. Oral formulations are the most commonly used for systemic therapy and include tablets in strengths ranging from 5 mg to 50 mg, orally disintegrating tablets (ODT) equivalent to 10 mg, 15 mg, and 30 mg of prednisolone base, oral solutions at various concentrations including 5 mg/5 mL (1 mg/mL) or 15 mg/5 mL (3 mg/mL) in some regions, and in Australia a common formulation is 25 mg/5 mL (5 mg/mL, brand Redipred, equivalent to prednisolone sodium phosphate 6.72 mg/mL), and syrups at similar concentrations.[77][2][5][78][94] Brand names in the United States include Prelone (syrup and solution), Orapred (ODT and solution), Pediapred (solution), and Millipred (tablets and solution); other brand names include Prednezol. Generic versions have been available since the drug's FDA approval in 1955.[95][1][96] For topical and ophthalmic use, prednisolone is formulated as a 0.5% ointment or cream for skin application and as a 1% ophthalmic suspension or solution for eye conditions.[1][97] Injectable forms include prednisolone acetate suspension at 25 mg/mL or 50 mg/mL and prednisolone sodium phosphate at 20 mg/mL, typically administered intramuscularly or intra-articularly.[77] These formulations allow for targeted delivery, with topical and ophthalmic preparations minimizing systemic exposure.[98] Although prednisolone is primarily available in oral, topical, ophthalmic, and injectable formulations, compounded intranasal preparations of prednisolone acetate exist for specific inflammatory conditions of the nasal passages. For example, prednisolone acetate 1% in NaCl nasal suspension is compounded by specialized pharmacies (such as Wedgewood Pharmacy) and is not a commercially mass-produced product.[99] A 2012 retrospective study in adult patients with refractory nasal polyposis investigated the safety of intranasal prednisolone acetate 1% nasal spray and found no statistically significant effects on serum cortisol (p = 0.89) or adrenocorticotropin hormone (ACTH) levels (p = 0.63), indicating minimal systemic absorption and low risk of adrenal suppression with this route.[100] Standard dosing schedules vary by condition and patient factors but follow general guidelines for adults and children. For acute systemic conditions such as asthma exacerbations or allergic reactions, an initial oral dose of 40-60 mg per day is common, often tapered over 5-10 days to avoid adrenal suppression; chronic maintenance therapy typically ranges from 5-10 mg per day.[77] In children, doses are weight-based, such as 1-2 mg/kg/day (up to 60 mg/day) for acute asthma, divided if necessary.[77] Ophthalmic dosing involves 1-2 drops of 1% suspension in the affected eye 2-4 times daily, while topical creams are applied as a thin layer 2-3 times daily to the affected area.[97][21] Injectable doses range from 10-40 mg intramuscularly for acute inflammation, with repeat administration based on response.[77]
FormulationStrengthsCommon Administration Tips
Oral Tablets/ODT5-50 mg; 10/15/30 mg baseTake with food or milk to reduce gastrointestinal upset; do not break ODT tablets.[5]
Oral Solution/Syrup5 mg/5 mL; 15 mg/5 mL; 25 mg/5 mL (Australia, Redipred)Shake well before use; measure with dosing device; refrigerate if specified but do not freeze.[77][101]
Ophthalmic Suspension1%Shake vigorously; instill 1-2 drops; avoid touching dropper to eye.[102]
Topical Cream/Ointment0.5%Apply sparingly to clean skin; wash hands after use unless treating hands.[21]
Injectable Suspension20-50 mg/mLAdminister deep intramuscularly; shake well for suspensions; use within 48 hours if drawn into syringe.[77]
Prednisolone products should be stored at controlled room temperature (15-30°C or 59-86°F), protected from light and moisture, in tightly closed containers; oral liquids may be refrigerated for palatability but should not be frozen.[103][27] Always follow gradual tapering for doses exceeding physiological replacement (about 5-7.5 mg/day) to prevent withdrawal symptoms.[5]

Non-medical use and regulation

Prednisolone, as a glucocorticoid, has been subject to rare instances of non-medical abuse, primarily driven by its potential to induce euphoria or hypomanic states, leading to mood alteration. Case reports have documented dependence motivated by these psychiatric effects, though such misuse is uncommon compared to anabolic steroids.[104] This abuse carries significant risks, including physical dependence due to suppression of the body's natural cortisol production, which can result in severe withdrawal symptoms upon cessation.[105] In athletics, prednisolone is prohibited by the World Anti-Doping Agency (WADA) during competition when administered systemically (orally, intravenously, or rectally), due to its anti-inflammatory properties that may enhance performance by reducing pain and fatigue.[106] Athletes with legitimate medical needs, such as those managing asthma or inflammatory conditions, may obtain a Therapeutic Use Exemption (TUE) following evaluation by anti-doping authorities. Glucocorticoids like prednisolone have appeared on International Olympic Committee (IOC) prohibited lists since the 1980s, with formal restrictions emerging in the late 1970s for competitions.[107][108] Prednisolone is regulated as a prescription-only medication in most jurisdictions to prevent misuse and ensure appropriate medical supervision. In countries like India, it is classified under Schedule H of the Drugs and Cosmetics Rules, requiring a registered medical practitioner's prescription for dispensing. In veterinary medicine, it is similarly restricted to use under the order of a licensed veterinarian, with federal laws in places like the United States limiting its administration to professional oversight.[109][110]

History

Discovery

Prednisolone's discovery was driven by the urgent need to develop glucocorticoids that retained the anti-inflammatory efficacy of cortisone—successfully used to treat rheumatoid arthritis since 1948—while minimizing undesirable side effects like sodium and fluid retention associated with its mineralocorticoid activity.[111] In 1950, Arthur Nobile and his colleagues at Schering Corporation achieved this breakthrough through microbial fermentation processes applied to corticosteroids. The team utilized bacteria to perform selective dehydrogenation, converting hydrocortisone (cortisol) into prednisolone by introducing a double bond between carbons 1 and 2 in the A-ring, enhancing glucocorticoid potency without increasing sodium-retaining effects. A parallel transformation oxidized cortisone to prednisone, the 11-keto analog of prednisolone.[112][113] The key microbiological experiment involved fermenting hydrocortisone with strains like Corynebacterium simplex, which catalyzed the Δ¹-dehydrogenation to yield prednisolone in high purity and yield, marking a pivotal advance in steroid biochemistry. This method not only streamlined production but also highlighted the potential of microbial transformations for synthesizing therapeutically superior analogs.[114] The findings were first publicly detailed in a seminal 1955 publication in Science, where Nobile and co-authors described these novel anti-arthritic steroids and their superior pharmacological profiles.

Clinical development and approval

Prednisolone's clinical development began with early trials in the mid-1950s, focusing on its efficacy in treating rheumatoid arthritis. In a 1955 study involving 141 patients with moderate to severe rheumatoid arthritis, prednisolone demonstrated anti-inflammatory effects comparable to prednisone, with both compounds showing approximately four times the potency of hydrocortisone on a milligram basis, allowing for lower maintenance doses of 5-15 mg/day orally.[115] These trials highlighted prednisolone's ability to reduce joint swelling and improve mobility over 6-9 months, though side effects such as gastric issues were noted, establishing its role as a potent glucocorticoid alternative to earlier corticosteroids.[115] The U.S. Food and Drug Administration (FDA) approved prednisolone on June 21, 1955, under the brand name Delta-Cortef for oral tablet formulations, initially indicated for a range of conditions including endocrine disorders, rheumatic diseases, allergic states, and dermatological issues.[60] This approval marked a significant advancement in corticosteroid therapy, building on the rapid transition from laboratory synthesis to clinical application within months of its development.[1] In the 1960s, prednisolone's indications expanded to include acute and chronic asthma management, with oral forms becoming standard for systemic treatment of exacerbations, reflecting growing evidence of its efficacy in reducing airway inflammation.[116] By 1977, prednisolone was incorporated into the inaugural World Health Organization (WHO) Model List of Essential Medicines, recognizing its critical role in global access to affordable anti-inflammatory therapy.[117] Patents for prednisolone expired in the 1960s, facilitating the entry of generic versions and broadening its availability worldwide.

Veterinary uses

Common applications

Prednisolone is widely used in veterinary medicine to manage inflammatory and immune-mediated conditions in various animal species, particularly where rapid suppression of immune responses is required. In dogs and cats, it is commonly prescribed for allergies, such as atopic dermatitis and flea allergy dermatitis, as well as autoimmune skin diseases including pemphigus foliaceus and lupus erythematosus.[118][119][120] For example, oral administration at 0.5-1 mg/kg/day is often employed in these cases to alleviate pruritus and inflammation. Treatment typically results in a rapid response in allergic dermatitis, with significant clinical improvement observed within days in the majority of affected animals.[121][122] In horses, prednisolone serves as a key therapeutic agent for equine asthma, formerly known as heaves or recurrent airway obstruction (RAO), where it helps reduce airway inflammation and bronchoconstriction. It can be administered systemically to improve respiratory function and alleviate symptoms like coughing and labored breathing, often as part of a multimodal approach including environmental management.[123][124] Studies have demonstrated its efficacy in enhancing lung function in affected horses.[125] Among livestock, prednisolone is applied in cattle for the treatment of mastitis, particularly to mitigate inflammation and support antibiotic therapy by reducing udder swelling and restoring milk production parameters.[126][127] In pigs, prednisolone has been studied for managing endotoxic shock induced by bacterial toxins, with a 1984 study showing that pretreatment can improve survival rates by modulating the inflammatory response, though efficacy in shock conditions remains controversial.[128][129]

Dosage considerations

Prednisolone dosages in veterinary medicine vary by species, condition severity, and therapeutic goal, typically ranging from anti-inflammatory to immunosuppressive levels, with oral administration being the most common route due to its efficacy and ease of use.[130] Anti-inflammatory doses are generally lower and used for conditions like allergic dermatitis or asthma, while higher immunosuppressive doses target autoimmune diseases or organ transplants, always requiring gradual tapering to prevent adrenal suppression.[129] In dogs, the standard anti-inflammatory dosage is 0.5–1 mg/kg orally once daily (typically in the morning to mimic natural cortisol rhythms), which may increase to 2 mg/kg for severe cases such as acute allergic reactions; although some protocols may initiate with twice-daily dosing, many dogs tolerate once-daily administration well for anti-inflammatory or immunosuppressive purposes, with treatment beginning with 5–7 days of daily dosing followed by tapering to 0.25 mg/kg every 48–72 hours; however, altering the timing or ratio of prednisolone (or prednisone, which converts to prednisolone) dosing can affect efficacy or increase risks, such as through less steady blood levels, even if the total daily dose remains the same, as dosing is tailored to the specific condition.[130][118][131] For immunosuppressive therapy, doses start at 2.2 mg/kg orally every 24 hours, potentially up to 6.6 mg/kg in critical situations, with tapering over 10–20 days to alternate-day regimens to minimize risks like iatrogenic Cushing's syndrome.[130] Dosage adjustments are essential in dogs with hepatic insufficiency, where prednisolone is preferred over prednisone due to better bioavailability, and long-term use necessitates monitoring for polyuria, polydipsia, and infections via urine cultures every 3–6 months.[129] Cats require higher relative doses owing to differences in metabolism; anti-inflammatory therapy uses 1–2 mg/kg orally every 24–48 hours for conditions like feline asthma or inflammatory bowel disease, with initial daily administration for 5–7 days before tapering.[130] Immunosuppressive doses are 4.4 mg/kg orally every 24 hours, tapered similarly after 10–20 days, with careful monitoring for hyperglycemia and diabetes, as cats are particularly susceptible to these adverse effects from prolonged corticosteroid exposure.[130] Alternate-day dosing is recommended for chronic management to reduce hypothalamic-pituitary-adrenal axis suppression.[129] For horses, anti-inflammatory dosages range from 0.8–2.2 mg/kg orally every 24 hours for issues like chronic obstructive pulmonary disease, starting with 5–7 days of daily use and tapering to 0.4–1 mg/kg every 48–72 hours.[130] Immunosuppressive protocols employ 2–4 mg/kg orally every 24 hours, with tapering after 10–20 days to avoid adrenal insufficiency, and veterinarians must consider the animal's body weight and concurrent medications to prevent gastrointestinal ulceration.[130]
SpeciesPurposeDosage (mg/kg)Route/FrequencyTapering Notes
DogsAnti-inflammatory0.5–1 (up to 2 severe)PO, q24h5–7 days initial, then to 0.25 q48–72h
DogsImmunosuppressive2.2 (up to 6.6 severe)PO, q24hAfter 10–20 days to alternate-day
CatsAnti-inflammatory1–2PO, q24–48h5–7 days initial, then taper
CatsImmunosuppressive4.4PO, q24hAfter 10–20 days to alternate-day
HorsesAnti-inflammatory0.8–2.2PO, q24h5–7 days initial, then 0.4–1 q48–72h
HorsesImmunosuppressive2–4PO, q24hAfter 10–20 days to alternate-day
General considerations across species include avoiding abrupt discontinuation to prevent hypoadrenocorticism, using the lowest effective dose for the shortest duration, and contraindicating high doses in patients with diabetes, infections, or gastrointestinal ulcers.[129] Long-term therapy (>2 weeks) should transition to alternate-day dosing to mitigate risks like immunosuppression and electrolyte imbalances, with regular veterinary monitoring essential for safety.[129]

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