Use of corticosteriod in clinical practise

DEFINITION

Corticosteroids are a class of chemicals that includes steroid hormones naturally produced in the adrenal cortex of vertebrates (e.g., cortisol, corticosterone, aldosterone) and analogues of these hormones that are synthesized in laboratories. 

CORTICOSTEROIDS FUNCTIONS

Corticosteroids are involved in a wide range of physiological processes, including:

•  stress response
•  immune response and regulation of inflammation
•  carbohydrate metabolism
•  protein catabolism
•  blood electrolyte levels
•  behavior

Glucocorticoids (such as cortisol) control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms.

Mineralocorticoids (such as aldosterone) control electrolyte and water levels, mainly by promoting sodium retention in the kidney.

Therapeutic use of corticosteroids

Synthetic pharmaceutical drugs with corticosteroid-like effects are used in a variety of conditions, ranging from brain tumors to skin diseases. 

•  Dexamethasone and its derivatives are almost pure glucocorticoids. 
•  Prednisone and its derivatives have some mineralocorticoid action in addition to the glucocorticoid effect. 
•  Hydrocortisone (cortisol) is available for replacement therapy, e.g. in adrenal insufficiency and congenital adrenal hyperplasia.

Synthetic glucocorticoids are used in the treatment of INFLAMMATORY PROCESSES:

•  Joint (e.g. arthritis)
•  Blood vessels (e.g., temporal arteritis, Schonlein-Henock purpura),
•  Skin (e.g., dermatitis),
•  Lung (e.g., asthma),
•  Liver (e.g., autoimmune hepatitis)
•  Bowel (e.g. ulcerative colitis and Crohn's disease)
•  Systemic (e.g. systemic lupus erythematosus)
• Allergic reactions

Synthetic glucocorticoids are particularly useful when inflammation is caused by autoimmunity.

If inflammation is caused by infection or trauma glucocorticoids may be CAUTIOUSLY used to reduce some manifestation such as oedema or pain, BUT the patient need to be carefully monitored.

Routes of administration

•  By mouth. Tablets, capsules or syrups are used to treat the inflammation and pain associated with certain chronic conditions  (e.g. rheumatoid arthritis and lupus) or acute manifestation (e.g. allergic disorders).
•  By inhaler and intranasal spray. These forms are used to control inflammation associated with asthma and nasal allergies.
•  Topically. Creams and ointments are used to treat many skin conditions.
•  By injection. IM or IV administration may be used in patients who are not able to swallow. Articular infiltration of long-acting formulations are used to treat pain and inflammation in the case of localized articular inflammation.

Side effects

Use of corticosteroids has several severe side-effects including: 

• Water retention with weight gain. 
• Skin-thinning and easy bruising. 
• Muscle weakness. 
• Cushing's syndrome (characterized by 'moon face', striae, and acne)
•  Impaired glucose methabolism (hyperglycaemia, insulin resistance, diabetes mellitus)
•  Impaired bone turnover (osteoporosis)
•  Ocular damage (cataract and retinopathy)
• Psychiatric disorders (anxiety, irritability, depression)
•  Hypertension, stroke
• Endocrinologic disorders (erectile dysfunction, hypogonadism, hypothyroidism, amenorrhoea)
• Delayed wound healing (by inhibiting inflammation and collagen synthesis)
• GI dysfunction (e.g. Colitis, peptic ulceration with perforation and haemorrhage, dyspepsia, abdominal distention, and oesophageal ulceration)

The evidence for corticosteroids causing peptic ulceration is relatively poor, and protective prophylaxis measures should not be considered except for high risk patients.

IN CHILDREN and ADOLESCENTS prolonged corticosteroid treatment may cause irreversible growth retardation.

The immunosuppressant effect of corticosteroid treatment may predispose the patient to infections.  

Viral and fungal infections (cutaneous/mucous or systemic) are particularly frequent in this context and may be severe or fatal if misdiagnosed or untreated.

Side effects are dose- and, above all, time-related, being relatively infrequent with low doses and short courses of treatment.

With topical treatment (inhaled or dermatologic) side effects are rare but they may be present if treatment is prolonged and involve a large cutaneous surface. 

Prolonged topical treatment must be avoided because they cause cutaneous atrophy and may facilitate infection. 

Corticosteroids withdrawal

The production of corticosteroids is controlled by a "feedback mechanism," involving the adrenal glands, the pituitary gland, and brain -The Hypothalamic-Pituitary-Adrenal Axis (HPAA). 

The continuous administration of corticosteroids at doses greater than our body's natural production (about 7.5 mg of prednisone per day) inhibits this mechanism, causing the HPAA to "hibernate". The amount of the drug needed to suppress the HPAA varies from person to person. 

Note that morning doses have less inhibiting effect on HPAA. Moreover taking steroids every other morning gives the body a better chance to recover function. Thus, alternate-day therapy is ideal, if possible, once the disease is under control.

Withdrawal symptoms

 Once we begin to decrease or discontinue the dose, withdrawal symptoms may occur:

•  Weakness, fatigue
•  Decreased appetite, weight loss, 
•  Nausea, vomiting, diarrhea and abdominal pain 
•  Low blood pressure, leading to dizziness or fainting
•  Hypoglicaemia
•  Menstrual changes

Thus, steroid use cannot be stopped abruptly. 

Tapering the drug gives the adrenal glands time to return to their normal patterns of secretion. 

How quickly steroids can be tapered depends on continued control of the underlying disease with decreasing doses, and on how quickly our body adjusts to the need to produce its own hormones. 

If things go well, 4 to 6 weeks (or longer) is a reasonable period.

Some practical questions...

What should we consider when initiating oral corticosteroids?

Corticosteroids should only be used when a firm clinical diagnosis has been made. 

A trial of oral corticosteroids in people with cryptic or undiagnosed illnesses should only be undertaken under the supervision of a specialist and with close monitoring. 

When initiating oral corticosteroids, consider: 

• The person being treated → factors like age, co-morbidities, and other medications may affect the choice of oral corticosteroid. 
• Age → children and elderly people are more susceptible to the adverse effects of corticosteroids. 
• Co-morbidities → corticosteroids are contraindicated in people with an untreated systemic infection, and should be used cautiously in people with other conditions (such as diabetes, hypertension, and hepatic impairment). 
• Other medications → some drugs (such as digoxin and methotrexate) may interact with oral corticosteroids.
• The condition being treated → different corticosteroids have varying ratios of mineralocorticoid to glucocorticoid properties, and these ratios determine their potency, efficacy, and therapeutic use.

How do we withdraw or stop oral corticosteroid treatment?

Due to insufficient evidence to support any particular withdrawal regimen, the rate of withdrawal should depend on: 

• The person's response to the withdrawal (if withdrawal symptoms are reported, resume a higher dose and continue the withdrawal at a slower rate). 
•  The disease being treated. 
•  The duration of treatment. 

If stress (infection, trauma, or surgery) occurs up to 1 week after stopping the corticosteroid, additional steroid cover should be provided. 

During withdrawal, the dose of oral corticosteroids may be reduced rapidly down to physiological doses (about 7.5 mg of prednisolone or equivalent) and reduced more slowly thereafter.  

What contraindications and cautions are associated with oral corticosteroids?

Oral corticosteroids are contraindicated in: 

People with systemic infections, unless specific anti-infective therapy is given. Oral corticosteroids may mask the symptoms of the infection allowing it to get worse.

Oral corticosteroids should be used with caution in people with: 

Hepatic impairment — Plasma concentrations of oral corticosteroids may be increased in hepatic impairment. Monitor closely for increased adverse effects. 

Psychiatric disturbance — Mood disorders have been reported in people taking oral corticosteroids. Monitor people with a predisposition to mental disturbance   

Wounds — avoid corticosteroids in situations of wound repair, or use cautiously if this is unavoidable. Corticosteroids may delay wound healing and this effect is worsened in the presence of hyperglycaemia.

Pre-existing conditions — including heart failure, recent myocardial infarction, hypertension, diabetes mellitus, epilepsy, glaucoma, hypothyroidism, osteoporosis, obesity, psychosis or severe affective disorder, or peptic ulceration. Monitor the person closely, as these conditions can be exacerbated by oral corticosteroids.

Can we prescribe oral corticosteroids to a woman who is pregnant, planning a pregnancy, or breastfeeding?

Pregnancy 

Oral corticosteroids can be used in pregnancy. However, the risks of treatment (such as cleft palate) must be weighed against the potential benefits. 

Prescribe the lowest effective dose of oral corticosteroid, for the minimum period possible. 

If long-term or high-dose treatment is required, monitor fetal growth.

Breastfeeding 

Prednisolone is the glucocorticoid of choice for women that are breastfeeding. 

If high doses of prednisolone are repeatedly required: 

•  Monitor the infant for signs of adrenal insufficiency. 
•  Advise the woman that, if possible, she should wait for 3–4 hours after a dose before breastfeeding.

How do we minimize the risks of adverse effects in people taking oral corticosteroids?

• Prescribe the lowest effective dose of oral corticosteroid, for the minimum period possible. 

•  Prescribe the corticosteroid to be taken in the morning and (if the disease will allow it) on alternate days. 

•  Ensure that withdrawal from long-term (> 3 weeks) oral corticosteroid treatment is done gradually to prevent potentially fatal acute adrenal insufficiency or relapse of the condition being treated. 
•  Be alert to the signs and symptoms of adrenal insufficiency and prescribe additional steroid cover if stress (such as infection, trauma, or surgery) occurs.
•  Document the person's history of chickenpox and measles. Advise those without a history of chickenpox or measles to avoid close contact with people who have chickenpox, shingles, or measles and to seek urgent medical advice if they are exposed. 
•  Consider prescribing a proton pump inhibitor for gastrointestinal protection in people at high-risk of gastrointestinal bleeding or dyspepsia. 
•  Ensure that withdrawal from long-term (> 3 weeks) oral corticosteroid treatment is done gradually to prevent potentially fatal acute adrenal insufficiency or relapse of the condition being treated. 
•  Be alert to the signs and symptoms of adrenal insufficiency and prescribe additional steroid cover if stress (such as infection, trauma, or surgery) occurs.
•  Document the person's history of chickenpox and measles. Advise those without a history of chickenpox or measles to avoid close contact with people who have chickenpox, shingles, or measles and to seek urgent medical advice if they are exposed. 
•  Consider prescribing a proton pump inhibitor for gastrointestinal protection in people at high-risk of gastrointestinal bleeding or dyspepsia. 
•  Monitor the person regularly for adverse effects, and manage appropriately. 
•  Advise about lifestyle recommendations to minimize the adverse effects of corticosteroids. 

In children and adolescents receiving oral corticosteroids: 

•  Prescribe once daily doses on alternate days, if possible. 
•  Monitor the child's or adolescent's growth regularly. Refer the person to a paediatrician if growth retardation is suspected.

How do we monitor someone on oral corticosteroids?

Baseline measures 

Before initiating treatment with long-term oral corticosteroids, obtain baseline: 

•  blood pressure,
•  body weight,
•  height (children and adolescents),
•  ophthalmic examinations,
•  levels of glucose (fasted), triglycerides, and potassium.

Regular monitoring

•  Blood pressure — monitor at every appointment and treat if necessary. 
•  Body weight — monitor regularly, and offer weight management advice if necessary. 
•  Triglycerides and potassium — check blood concentrations 1 month after initiating oral corticosteroids, then every 6–12 months thereafter. 

Regular monitoring

•  Diabetes mellitus — Check for new onset of diabetes 1 month after initiation of oral corticosteroids, then every 3 months thereafter. If possible, dipstick test urine for glucose at each clinic visit. 

 Monitor people with confirmed diabetes more closely. Their oral anti-diabetic drugs may need to be increased, or insulin therapy started.

•  Adrenal suppression — monitor people taking long-term or regular oral corticosteroids for signs of adrenal suppression. Children who frequently use courses of oral corticosteroids should have regular checks for signs of adrenal suppression.  
• Adverse effects — ask about adverse effects at every clinic visit and manage appropriately.

What are the key drug interactions with oral corticosteroids and how do we manage them?

Anticoagulants — Corticosteroids may increase or reduce the anticoagulant effect of coumarins (such as warfarin). High-dose corticosteroids increase the anticoagulant effect and increase the risk of gastrointestinal bleeding.

Monitor the international normalized ratio (INR) or prothrombin time if high-dose corticosteroids are started or stopped in people taking oral anticoagulants. 

Anticonvulsants — Therapeutic effects of prednisolone (and probably other glucocorticoids) can be markedly reduced by carbamazepine, phenytoin, and phenobarbital. The significance of this reduction in corticosteroid level depends on the disease being treated.

Closely monitor the outcome of concurrent use of corticosteroids and carbamazepine, phenytoin, or phenobarbital. 

Anti-diabetic drugs — Corticosteroids (glucocorticoids) oppose the blood glucose lowering effects of anti-diabetic drugs. Significant hyperglycaemia can occur with systemic corticosteroids, and in some cases with inhaled corticosteroids and high-potency topical corticosteroids.

Increase the frequency of blood glucose monitoring when corticosteroids are started, and adjust anti-diabetic treatment accordingly. 

Antifungals — Some antifungal (e.g. Itraconazole and ketoconazole) may increase the levels or effects of corticosteroids. 

Monitor concurrent use for signs of corticosteroid overdose (such as fluid retention, hypertension, and hyperglycaemia). 

Bronchodilators — Bronchodilators (such as salbutamol) can cause hypokalaemia, which can be worsened by corticosteroids. In severe cases, the risk of serious cardiac arrhythmias could be increased. 

Consider monitoring potassium levels if people receiving corticosteroids also require large doses of bronchodilators (for example during an exacerbation of asthma). Monitoring should be based on the severity of the person's condition and the number of potassium-depleting drugs used. 

Digoxin — Corticosteroids can cause potassium loss, which may increase the risk of digoxin toxicity. Monitor potassium levels and watch for signs of digoxin toxicity (such as bradycardia). 

Diuretics — Diuretics can cause hypokalaemia, which can be worsened by corticosteroids. In severe cases, the risk of serious cardiac arrhythmias could be increased. 

Monitor potassium levels. Monitoring should be based on the severity of the person's condition, any predisposing disease state, and the number of potassium-depleting drugs used.

HIV protease inhibitors — monitor concurrent use for signs of corticosteroid overdose (such as fluid retention, hypertension, and hyperglycaemia). If the person is taking dexamethasone with indinavir or saquinavir, monitor antiviral efficacy (dexamethasone may increase the levels of indinavir and saquinavir). 

Live vaccines — People immunized with live vaccines while taking immunosuppressive doses of corticosteroids (equivalent to 40 mg of prednisolone daily for more than 7 days) may develop generalized (and possibly life-threatening) infections. 

Live vaccines should be postponed for at least 3 months after high-dose corticosteroids are stopped. 

Macrolides — Macrolides (especially clarithromycin and erythromycin) can reduce the clearance of methylprednisolone, thereby increasing its therapeutic and adverse effects. 

If the person is taking methylprednisolone, monitor closely (a reduction in corticosteroid dosage may be necessary). 

Rifampicin — Rifampicin can significantly reduce the effects of oral corticosteroids. 

Monitor closely and increase the dose of the corticosteroid accordingly. 

Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drugs may increase the risk of gastrointestinal bleeding and ulceration when they are given with corticosteroids. 

Consider the use of a proton pump inhibitor if the person is at high risk of gastrointestinal ulcers. 

What information and advice should we give to a person receiving oral corticosteroids?

Advise the person receiving an oral corticosteroid to: 

•  Take it as a single dose in the morning, with food. 
•  Continue taking their medication. They must not stop the corticosteroid abruptly (unless they are advised to). 
•  Be aware of any mood and behavioural changes, and to seek help if they become confused, irritable, or delusional, or have suicidal thoughts. 
•  Avoid contact with people that have shingles, chickenpox, or measles (unless they are immune). If they come in contact with these people, they must seek urgent medical advice. 
•  Visit an optician every 6–12 months (to check for ocular adverse effect of corticosteroids, such as glaucoma and cataract). 
•  Adopt lifestyle recommendations to minimize the adverse effects of corticosteroids: 

• Eat a healthy balanced diet, including adequate calcium intake. 
• Maintain a normal body weight. 
• Stop smoking. 
• Drink alcohol only in moderation. 
• Get plenty of physical exercise (within the limits imposed by the underlying disease).

PS: In the photo you can see the volunteers now helping us in Chaaria

Dr Nadia Chiapello

Dr Bro Giuseppe Gaido