Basics of Glucocorticoids and its Use in Dental Clinic

Basics of Glucocorticoids and its Use in Dental Clinic

Inflammation Process and the Necessity of Anti-inflammation Medication

Inflammation is a primary defense mechanism designed to protect and promote healing, and to restore homeostasis of injured tissues, ultimately leading to resolution and tissue repair.  An inflammation process consists of primarily vascular changes as well as cellular events in concert with the immune system. The familiar clinical signs, including redness, heat, pain, and swelling comes from vascular changes. Inflammation is initiated at the site of injury by resident mast cells and macrophages which release pro-inflammatory mediators including bioactive amines, lipid mediators and cytokines (eg. TNF-alpha and IL-1) causing i) vasodilation that saccommodates hyperemia, producing redness and heat; ii) increase in capillary permeability that allows  exudation of plasma, generating swelling and pain; and iii) chemotactic gradient to recruit leukocytes to the site of injury ( a process called chemotaxis), performing phagocytosis and other processes conventiaonally atrriuted to the immune response.

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If its intensity and duration are inappropriate, the inflammatory response, as a normal protective process may become destructive and result in inflammatory disease, where drugs with anti- inflammatory actions are indicated. By interrupting the synthesis and/or release of mediators that initiate vascular changes, anti-inflammatory drugs thereby suppress the cardinal signs like redness, heat, pain and swelling. Glucocorticoids not only suppresses the cardinal signs of inflammation as anti-inflammatory drugs but also depress leukocyte function, especially lymphocytes as immunosuppressant agents. 

Mechanism of Action

The anti-inflammatory and immunosuppressive properties of glucocorticoids are largely used in clinic via i) inhibiting the vasodilation and the increased vascular permeability that occurs following inflammatory insult ii) decreasing leukocyte emigration into inflamed sites by altering leukocyte distribution and trafficking; iii) inhibiting phagocytosis of macrophages; iv) reducing the number and activity of specific subsets of T lymphocytes. At molecular level, glucocorticoids bind to their receptors of target cells to form functioning complex that migrate into the nucleus, where the complex binds to DNA and alters genetic synthesis of proteins. By a mechanism termed “transrepression”, glucocorticoids down regulate gene transcription commonly overexpressed during chronic non-resolving inflammation, including NF-kapaB and AP-1. These genes encode pro-inflammatory cytokines (eg IL-10) and chemokines, cell adhesion molecules and key enzymes involved in the initiation and/or maintenance of the host inflammatory response. However, it should also be mentioned that it is within minutes from the injury for some anti-inflammatory effects of glucocorticoids to occur, which may be independents of the transcriptional effects of receptor-steroid complex.

Phamacokinetics and Pharmacodynamics

Only less than 30% of the synthetic glucocorticoids are free and pharmacologically active while the rest of them are moderately to highly (more than seventy percent) protein bound as pharmacologically inactive forms. Currently, dosing regimens are based on total drug concentrations rather than free plasma concentrations. In linear kinetics the free drug concentration increases proportionally with increasing total concentration whereas in the case of nonlinear kinetics this relationship is unproportional leading to higher free concentrations.

Prednisolone has a higher potency, efficacy and longer duration of action than hydrocortisone (about four times). The systemic availability of prednisolone is as high as eighty percent and limited not by incomplete absorption but by first-pass liver metabolism. However, prednisolone has nonlinear pharmacokinetics in humans, which make it hard to calculate the plasma concentration of free drugs. Prednisolone binds to two proteins, albumin and human corticosteroid binding globulin (CBG, transcortin), leading to its nonlinear pharmacokinetics. Albumin has a low affinity but high capacity for prednisolone while transcortin (a glycoprotein) has a high affinity but low capacity for binding prednisolone. At low concentrations a constant free fraction of prednisolone was observed because it binds to both proteins transcortin and albumin. As concentrations approach and exceed the binding capacity of transcortin, a nonlinear free fraction was shown increasingly until transcortin is saturated. With saturation of transcortin the binding becomes linear again as only linear binding to albumin occurs. As a result, it may be more accurate and predictable to use the free, unbound concentration of prednisolone to predict its concentration-time profile, to calculate pharmacokinetic parameters, and to evaluate the degree of systemic side effects by determining the suppression of endogenous cortisol.

Prednisolone has a half-life 2.1 to 3.5h and has duration of action of 18 to 36h and low mineralocorticoid activity. It takes four biological half-lives (144 hours) to totally eliminate of prednisolone, which means that maximumly prednisolone can persist in the organism for six days. Plasma concentrations of prednisolone vary markedly among individuals. In fact, rate of elimination of prednisolone could be decreased by oral contraceptives. Topical ointments or rinses are usually preferred for treating mucosal lesions; A five day regimen (in the morning either at once or in 2 divided doses, once in the morning and once at noon) can be used for systemic administration to manage traumatic neuritis of dental nerve trunks caused by surgery or local anesthesia as well as phlebitis following intravenous sedation or anesthesia. Patient should be discouraged to take evening doses due to the circadian rhythm of endogenous steroid secretion at the highest level at night, which may lead to insomnia.

Management of the Dental Patient Receiving Glucocorticoid Medications.

The reason for patients to receive chronic therapy with glucocorticoids are because of their primary inflammatory disorders, especially those attributed to immunologic mechanisms, eg, autoimmune disease, asthma, and rheumatoid arthritis. Their anti-inflammatory efficacy surpasses that of the NSAIDs, but their potential for side effects is also greater. Although short-term use about one week is relatively safe, chronic use may cause many concerns regarding side effects.

Osteroporosis and osteonecrosis are well recognized complications for about fifty percentage of patients treated with glucocorticoids for longer than twelve months. It is shown that glucocorticoids inhibit osteoblast function and cause apoptosis of osteocytes, which leads to a rapid and focal deterioration of bone quality and has been implicated in the pathogenesis of the condition. However, what determines the individual susceptibility is still unknown When planning complex extractions or placement of dental implants, conditions including the possibility of steroid-induced osteoporosis, osteonecrosis and increased serum glucose concentrations associated with chronic glucocorticoid use, may compromise treatment outcome. Plus, all patients receiving chronic supraphysiologic doses of glucocorticoids will have a compromised immune status. There is increased risk for delayed healing and postoperative infection when planning surgical procedure for those patients. Thus prophylactic antibiotics may be indicated  Glucocorticoids, as a product of the adrenal cortex, produce physiological effects essential for life. The synthesis and release of cortisol normally appears highest in the morning and declines throughout the day until a new cycle begins. Although the normal daily secretion is ten to twenty mg, the cycle changes when the hypothalamic-pituitary region is excited by some conditions require more cortisol production, including stress, trauma, hypoglycemia. For patients who are receiving daily dosage (more than fifteen mg/d of prednisone or its equivalent) of exogenous glucocorticoid for more than three weeks, varying degrees of adrenal atrophy are observed due to decreased function of patients’ own adrenal cortex via negative feedback. However, the complications caused by the long-term usage of small dosage of glucocorticoids are highly variable among individuals. The dental provider should take it into consideration that the prescribed steroid not only provides therapeutic effects (anti-inflammatory), but also fulfills normal physiological requirements for those patients who potentially have some degree of adrenal dysfunction. This introduces two important considerations.

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Firstly, for patients who have an abrupt discontinuation of chronic therapy with glucocorticoids. the hypothalamus-pituitary-adrenal axis will attempt to stimulate cortisol production in order to sustain normal cardiovascular function and glycemic control. However, those patients may not have enough adrenal tissues to respond to the stimulation from hypothalamus-pituitary axis due to adrenal atrophy caused by chronic usage of glucocorticoid. As a consequence, those patients may experience irritability, nausea, arthralgia, dizziness, and hypotension, as common symptoms of acute adrenal insufficiency. One regiment that can be applied to avoid this complication is to withdrawn steroid medication gradually by tapering the doses over 8months in order to promote the atrophied adrenal cortex to regain function. A complimentary dosage of glucocorticoid should be administered intravenously pre-operatively if normal oral medication consumption is limited.

Secondly, supplymentary steroid may be required to equal a cortisol surge caused by stressful events such as severe infection or surgery, which may put patients into jeopardy. This extra need for cortisol can be easily produced by a functional adrenal cortex of a healthy patient. However, for a patient who has chronic therapy with glucocorticoids that may cause adrenal atrophy, it is indicated to double or triple the patient’s dose on the morning of surgery as an arbitrary regiments. Then the dose is gradually modified to baseline over the next two days.

Ultimately, a regimen of alternate-day steroid dosing is known to lessen the adverse impact of chronic steroid therapy. It may promote the adrenal cortex to regain function during the drug free day in between. It has been shown that patients who receives this regimen will seldom develop significant adrenal atrophy or immunocompromise.

Use in dental practice

Due to their excellent anti-inflammatory and immuno-modulatory effects, they have been used extensively in managing many oral diseases. However, chronic use of supraphysiologic dosages of glucocorticoids unavoidably results in a series of side effects. Termed as “double-edged “sword in medicine, their successful use depends on the comprehension of the disease process, including appropriate diagnosis, types of treatment prognosis and a clear view of purpose of the treatment-whether it is for managing a chronic disease or accelerating resolution of a short-term condition.

Management of oral lesions with glucocorticoid are considered at different level of applications, from topical to intralesional to systemic, or a combination of any two or three of those applications, depending the severity and stages of the condition. Those conditions treated by long term therapy with glucocorticoid includes recurrent aphthous stomatitis, Behcet’s disease, oral lichen planus, erythema multiforme, pemphigus, mucous membrane pemphigoid and bullous pemphigoid.

Controlling postoperative edema is the most common use of glucocorticoids in dental practice for short-term condition.  Ideally, regimens should be initiated pre-operatively and coverage extended post-operatively. This may be only a day or two for minor procedures, or as long as a week for more traumatic procedures. Because of its low cost, prednisolone is commonly prescribed in dental clinic. It was shown that a combination of a single dose of prednisolone and

NSAID (eg. diclophenac, ketoprofen and ibuprofen) is well shown for treatment of postoperative pain, trismus and swelling after dental surgical procedures. Prednisolone is available in both oral and injectable (intramuscular, and submucosal) forms. Oral administration may be unpredictable in term of systemic availability and usually associated with gastrointestinal disturbances; Submucosal administration on the other hand is fast in effect without the possibility of associated gastrointestinal disturbances. However, due to their extreme irritation to tissues, prednisolone should not be administered near nerve branches exiting the mandible or maxilla.

Another short term use of glucocorticoid in restorative dentistry is to dress deep cavities with exposed pulp tissue to control the inflammatory pulp response and decrease postoperative pain. Studies show that glucocorticoid can be applied as cavity liner to decrease or prevent postoperative thermal sensitivity. Furthermore, intracanal use of the combined regime of glucocorticoid and antibiotic has been reported to successfully control the post endodontic pain. Just to be clear, it has not been shown that this brief use of glucocorticoids would increase the risk of postoperative infection, thus it is unwarranted to prescribe additional antibiotic coverage solely for this purpose.

References:

1. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med. (2005); 353:1711–1723.
2. Ibikunle AA, Adeyemo WL, Ladeinde AL. Oral health-related quality of life following third molar surgery with either oral administration or submucosal injection Oral Maxillofac Surg. (2016) 20:343–352
3. Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. (2011) Mar 15; 335(1): 2–13.
4. Sanghavi J, Aditya A., Application of Corticosterids in Dentistry. Journal of Dental and Allied Science. (2015); 4:19–24
5. Gibson N., Ferguson JW.  Steroid cover for dental patients on long-term steroid medication: proposed clinical guidelines based upon a critical review of the literature.British Dental Journal. (2004), 197(11):681–685