Drug Class 13: Corticosteroids/Glucocorticoids

13.1: Inhaled corticosteroids (ICS) [For Asthma]

-Beclomethasone, Budesonide, Ciclesonide (Active metabolite-Des-ciclesonide), Fluticasone, Prednisolone (Solo-Active metabolite of Prednisone)

*Most potent and consistently effective class of medications for long-term control of asthma in both adults and children.

  • Mechanism of Action (Corticosteroids)

1. Glucorticoids readily cross cell membranes and bind with high affinity to specific nuclear receptors. Following binding, transcription  and protein synthesis altered.

-May inhibit leukocyte infiltration at the site of inflammation.

-Reduce/Inhibit mediators of inflammation

-Suppression of the humoral immune responses.

2. Regulate gene expression which results in glucocorticoid effects

-Glucocorticoid effects: Gluconeogenesis, proteolysis (breaks down proteins), lipolysis (breaks down fats), Suppression of inflammation and immune responses (useful in asthma)

-Unwanted mineralocorticoid effects:  Hypertension, sodium and water retention, potassium loss

3. Inhibits Phospholipase A2 which prevents downstream production of inflammatory mediators (e.g. Prostaglandins-PGI2, PGE2, PGD2, Thromboxane A2, Leukotrienes such as LTE4, LTC4, LTD4)

-Reduces inflammation which is evident in asthma.

Note: Corticosteroids may have predominantly glucocorticoid effects but tend to have some/minimal mineralocorticoid effects as well (becomes side effects when treating asthma)

For ICS Mechanism of action,

1. Decreased IgE synthesis (triggers mast cell degranulation)

2. Increased number of b-adrenergic receptors on leukocytes

3. Decreased Arachidonic acid metabolism (Decreases PGs and LTE released)

  • Precautions (ICS has a predominant systemic action so these precautions are less crucial)

1. Latent TB– May be reactivated. Consider treatment with isoniazid

2. Peptic ulcer disease-Corticosteroids may increase the risk of peptic ulcers

***3. Diabetes-Corticosteroids worsen diabetes control and may cause hyperglycemia in non-diabetics.

4. Hypertension, Heart failure

-May be worsened due to sodium and water retention side effects (mineralocorticoid effects)

5. Psychiatric disorders-May be exacerbated

6. Glaucoma-Intraocular pressure may be increased

7. Osteoporosis

8. Myasthenia gravis

-Increased muscle weakness may occur during the first few weeks of treatment with corticosteroids, seek specialist advice.

9. Infections (Corticosteroids are immunosuppressive)

-Increase the risk and severity of infection.

*Use with caution if patient has a history of recurrent infections. 

-The decision to start or continue corticosteroids in a patient depends on various factors e.g. type of infection (active or latent), its severity, whether the infection can be treated or controlled and the indication for the drug.

*Seek specialist advice if unsure.

10. Intra-articular injection (Not applicable here-ICS)

Contraindicated in patients with infective arthritis, skin or soft tissue infections near joint (risk of introducing bacteria into joint) or a prosthetic joint.

11. Surgery

-Patients with hypothalamic-pituitary adrenal (HPA) suppression due to corticosteroids or taking replacement doses of corticosteroids for adrenal insufficiency should be given corticosteroids for protection against adrenal crisis during surgery and for 24-48 hours afterwards. 

-Wound healing may be delayed by pharmacological doses of corticosteroids.

12. Children (Effects do not apply to ICS)

-Chronic use of corticosteroids (at pharmacological doses) may retard growth (Effects do not apply to ICS).

-Follow growth and development carefully.

-Catch-up growth may occur after corticosteroid withdrawal

13. Pregnancy

*Use the lowest safest dose for the shortest possible time. Budesonide is the preferred ICS for pregnancy (Most gestational data available)

-No treatment is more serious for fetus and ongoing pregnancy.

-Corticosteroid use in early pregnancy (before 12 weeks) may slightly increase risk of orofacial clefts.

-ICS-(CAT A-AUS)

*Hydrocortisone, prednisone, prednisolone, methylprednisolone are preferred for maternal disorders as placental transfer is limited.

*Betamethasone and dexamethasone are preferred for fetal disorders as placental transfer is greater.

  • Adverse effects/Side effects (ICS related)

-These adverse effects occur when corticosteroids are used at pharmacological doses.

Note: *Inhaled corticosteroids only have systemic actions when given in high doses.

-Short courses of high dose systemic treatment cause fever adverse effects than prolonged courses of lower doses.

Practice points: Reduction of systemic absorption can be achieved by using Metered dose inhaler with a spacer. Then, rinse mouth with water and gargle. Spit out water to reduce oral side effects.

Practice points:  Monitor Dosage and side effects.

(a) Systemic Side effects (Common):

1. Mineralocorticoid effects (Na+ reabsorption and K+ excretion, Increases BP). Sodium and water retention.

-Prednisolone, Prednisone, Methylprednisolone, Hydrocortisone (most significant) and cortisone has mineralocorticoid effects.

2. Adrenal suppression (adrenal cortex does not see the need for adrenal production of corticosteroids)

3. Increased susceptibly to infections, Masking of signs of infection

4. Edema (relatd to mineralocorticoid effects)

5. Hypertension (related to mineralocorticoid effects)

6. Hypokalemia (related to mineralocorticoid effects)

7. Hyperglycemia (Increased gluconeogenesis)

8. Dyslipidemia (Increased lipolysis)

9. Osteoporosis (Inhibition of collagen/cartilage formation), Fractures

10. Increased appetite

11. Delayed wound healing (Immunosuppression), Skin atrophy

12. Bruising

13. Acne

14. Hirsutism

15. Growth retardation in children

16. Myopathy

17. Muscle weakness and wasting

18. Fat redistribution (Cushing’s syndrome-Fat distributes around waist/abdomen area). Classical moon face appearance. Buffalo hump.

19. Weight gain

20. Amneorrhea- absence of a menstrual period in a woman of reproductive age

21. Psychiatric effects-Euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour. Delirium and psychosis are less common.

22. Posterior subcapsular cataracts-Cataracts that affect the back of the lens

*Amenorrhea-Absence of menstruation in women of reproductive age.

(b) Systemic side effects (Infrequent):

-Osteonecrosis (particularly of the femoral and humeral heads, Ocular hypertension, glaucoma

-For intra-articular injection: Refer to AMH 2012.

(c) Systemic side effects (Rare):

-Peptic ulceration, hypersensitivity reactions, tendon rupture (especially of Archilles tendon), Central serous chorioretinopathy

***Specific side effects for ICS: Important for asthma

1. Dysphonia (Hoarseness)

-Caused by deposition of ICS on vocal cords and myopathy of laryngeal muscles (occurs up to 1/3 of those using ICS)-Very common

-Less occurance with breath-activated delivery (BAI)

-Method of inhalation leads to protection of vocal cords by false cords.

2. Oral candidasis (Opportunistic Fungal infection due to Candida Albicans)

-Can be prevented by using spacer device or by gargling after use of the inhaler.

  • Comparative information

-Corticosteroids with minimal mineralocorticoid properties (e.g. Prednisolone and prednisone) or no mineralocorticoid properties (e.g. Beclomethasone, Dexamethasone and triamcinolone) are generally preferred for use as immunosuppressants or anti-inflammatory agents.

Acronym: TBe De But-To be debuted (no mineralocorticoid effects). P and P-Partially (some mineralocorticoid effects)

*Higher levels of fluticasone causes significant reduction in adrenal cortisol production

  • Counselling points

-Take the tablets or oral liquid with food to help reduce stomach upset.

-Tell the doctor immediately if patient has any signs of infection.

-This medication may affect patient’s mood (psychiatric effects). Cause problems with sleeping. Talk to the doctor if patients have any concerns.

*Do not stop taking this medication suddenly unless doctor tells patient otherwise. The doctor may need to be reduce dose gradually when intending to stop treatment (avoid withdrawal symptoms-Fatigue, Weakness, body aches, Joint pain)

-Tell all health professionals (doctors, dentists, surgeons, pharmacists, nurses etc) that the patient is treated with corticosteroids (or have taken them in the past). If patient becomes ill or intending to have surgery, the dose of medicine may need to be increased.

-Consider wearing a Medic Alert (r) Bracelet/ Steroid card detailing treatment (Only required when treated with high doses of corticosteroids)

*Warn patient that medication of ICS is not instantaneous. Time is required (since transcription is altered). Tell patient it will take days to see maximal response. 

  • Practice points

-Measure blood glucose, weight, BP acid and electrolytes at baseline. Then do so each week for the first month of treatment

-Watch for signs/symptoms of infection. Signs of infection may be masked.

-Measure BMD at baseline if likely to require chronic treatment (>3 months) or repeat courses. Evaluate and manage other risk factors for osteoporosis and consider need for drug treatment to prevent bone loss.

-Monitor for cataracts and glaucoma in patients on long term corticosteroids.

-Adrenal suppression (MINIMISE RISK OF ADRENAL SUPPRESSION BY GIVING CORTICOSTEROIDS IN THE MORNING)

-Under periods of stress (e.g. trauma, surgery, infection, blood loss), dose of corticosteroids may need to be increased.

*Refer to AMH 2012 for specific points on Intra-articular injection (used for joints-RA)

  • Types of ICS (In alphabetical order)

1. Beclomethasone

-Synthetic halogenated inhaled glucocorticoid (has Cl)

Beclomethasone structure (Contains Cl halogen so beClomethasone)

  •  Clinical Indications:

(a) Treatment of steroid-dependent asthma (unusually hard to control type of asthma)

(b) For relieving symptoms associated with allergic or non-allergic rhinitis

(c) Preventing recurrent nasal polyps following surgical removal

(d) Prevention of neo-natal respiratory distress syndrome

(e) Intradermal administration of dermatological disease [not relevant for ICS form]

(f) Adjunctive treatment for inflammatory arthritis (e.g. rheumatoid, osteoarthritis, acute gout, tendonitis [not relevant for ICS form]

  • Precautions

-Breast feeding: Safe to use

-Pregnant women: Safe to use (CAT A-AUS)

  • Pharmacokinetics

-Nasal inhalation absorption (minimal absorption systemically)

-Oral inhalation absorption (Drug is absorbed rapidly from lungs and GIT). Some of the oral inhaled dose is absorbed systemically, but usually not sufficient to exert therapeutic effects.

-OAA: typically occurs in a few days but full effects can take as long as 1-4 weeks to be apparent.

Note: Without a spacer, approximately 10-25% of a spacer device, approx 10-25% of the orally inhaled dose will enter the respiratory tract. The rest will be deposited in the mouth or oropharynx and swallowed.

∴ Use a spacer to maximise percentage of medication delivered into lungs.

  • Practice Points

-Can be injected directly into affected soft tissue (e.g. bursitis, myostitis)

-Symptom relief usually occurs 2-4 hours for intra-articular injection, and is maintained for at least 4 weeks.

2. Budesonide (Not found in AMH 2012)

Budesonide structure(Budesonide)

-May be Administered via intranasal inhalation (once a day dosing), oral inhalation or orally for various conditions

-Potent glucorticoid with weak mineralocorticoid activity.

-Less desirable side effect profile when compared to other Intranasal steroids.

-Inhaled budesonide (via oral or nasal) possess high topical anti-inflammatory activity but low systemic activity.

  • Clinical indications: (a) Allergic rhinitis (Intranasal inhalation) (b) Asthma (oral inhalation) (c) Crohn’s disease (orally)
  • Pharmacokinetics: 

1. First pass metabolism after oral absorption (oral inhalation/nebulisers). Inactivated extensively in the liver.

-Very low systemic effects (6% of the dose reaches systemic circulation)

∴ Preferred for children or when high doses of ICS are required.

2. Only 20% of the dose reaches the systemic circulation (nasal inhalation)

3. Ciclesonide (Modern and recent version)———Prodrug

Ciclesonide structure (ciclesonide-Notice the ester group present, it is a pro-drug)

-Non-halogenated glucocorticoid which is beneficial in treating inflammatory conditions such as allergic rhinitis and asthma.

Clinical indications: (a) Asthma (b) Allergic rhinitis

+Drug has a low systemic bioavailability following intranasal or oral inhalational administration which limits systemic side effects such as adrenal suppression.

The active metabolite of ciclesonide, des-ciclesonide is 100-120x more potent than ciclesonide.

  • Pharmacokinetics:

1. Lung/Mucosal Metabolism: Esterases in the nasal and lung mucosa hydrolyse ciclesonide to a biologically active metabolite, des-ciclesonide (100-120x more potent than parent)

2. Hepatic Metabolism (Liver): CYP3A4 and CYP2D6 metabolises des-ciclosonide furthur.

3. Administered by intranasal inhalation or oral inhalation.

4. Oral bioavailability is negligible.

5. OAA: following intranasal administration is 24-48 hours. Desired effects observed after 1-2 weeks in those with seasonal allergic rhinitis and 5 weeks in those with perennial allergic rhinitis. 

4. Dexamethasone (Indications not specific)-Not for asthma or COPD

Dexamethasone structure

-Halogenated corticosteroid

  • Clinical indications: (a) Multiple myeloma (b Lymphoma (c) Some leukemias (Need to research on this) (d) Post-operative or chemotherapy induced nausea and vomitting (d) CROUP (e) Cerebral edema due to malignancy
  • Precautions: 

1. Breastfeeding-Limited data avilable. Consider using alternative corticosteroid (e.g., prednisolone or budesonide)

  • Adverse effects/Side effects

Common

1. Transient itching

2. Burning or tingling in perineal area (after IV bolus)

*Perineal- region of the body and surrounding structures

  • Administration advice

-Give IV injection over 1-3 minutes

  • Practice points

-Can be given by intra-articular or soft tissue injection for local effect.

-Use of adjuvant IV dexamethasone (starting for bacterial meningitis is controversial). Recommended if S.pneumoniae is suspected in adults or H.influenza in children

-When treating penicillin-resistant pneumococcal meningitis, consider reduced CSP penetration of vancomycin due to corticosteroids.

5. Fluticasone (for asthma, COPD treatment and other conditions)

Fluticasone structure

-Contains fluorine (so Fluticasone). Synthetic Steroid with medium potency.

  • Clinical indications:

(a) Relieve inflammatory and puritic manifestations of dermatoses (skin diseases) and psoriasis. [TOPICAL]

(b) Allergic and non-allergic rhinitis [Intranasal inhalation-Fluticasone furoate]

(c) Asthma [Oral Inhalation]

(d) Used clinically for certain patients with COPD.

fluticasone furoate (Intranasal inhalation-Allergic Rhinitis)

  • Pharmacokinetics

-Most of a dose following intranasal adminstration of fluticasone is swallowed with metabolism in the gut and partial absorption with extensive first pass metabolism (CYP3A4)

*First pass metabolism eliminates all/most of the systemic effects. 

-Absorption following topical administration to the skin is usually minimal and depends on such factors as the vehicle and integrity of the epidermis.

-Due to primary absorption from the lungs, the oral inhalation aerosol usually results in systemic bioavailability of about 30%  of the delivered dose.

-Bioavailability of the oral inhalation powder is approx 14%

6.  Hydrocortisone/cortisol —(Indications not specific but can be used for Asthma)

Hydrocortisone.Cortisol structure

  • Clinical Indications: (a) Autoimmune or inflammatory conditions (b) Adrenal insufficiency (Glucocorticoid replacement) (c) Anaphylaxis (as an adjunct to management) (c) Asthma
  • Precautions: Breast feeding (safe to use). Pregnancy-Safe to use (May cause maternal disorders so avoid use over long periods of time) 

7. Methylprednisolone (given as methylprednisolone sodium succinate or methylprednisolone acetate)-For severe asthma and other conditions

Methylprednisolone (Additional methyl group attached at C6)

  • Clinical indications (for MTP sodium succinate): (a) Anaphylaxis (as an adjunct to management) (b) Acute severe asthma (c) Autoimmune or inflammatory disease (d) Acute transplant rejection (e) Acute exacerbation of multiple sclerosis (MS)
  • Clinical indications (for MTP acetate): (a) Autoimmune or anti-inflammatory conditions (Intramuscular) (b) Adjunctive treatment for inflammatory arthritis (e.g. osteoarthritis, rheumatoid) (c) Gout (d) Tendonitis (intra-or peri articular injection)
  • Precautions:

– IV administration of methylprednisolone acetate-CONTRAINDICATED       WHY? Release acetate ions?

-Breastfeeding (safe to use). *Give dose immediately after a feed and wait 4 hours before the next feed.

  • Administration advice

Methylprednisolone sodium succinate

-Rapid IV administration of high doses may cause arrhythmia, cardiovascular collapse or cardiac ARREST.

-Infuse IV doses of >250 mg over at least 30 mins and doses of <250 mg over at least 5 mins.

  • Practice points 

-Improves rate of recovery from exacerbation of MS.

Methylprednisolone acetate can also be given by intradermal injection for local effect.

8. Prednisolone/Prednisone (Can be used for acute asthma and various other conditions)

*Need to know which is the active metabolite and which is the prodrug

Prednisolone vs Prednisone

(Notice that prednisone has the ketone group at C11 whereas prednisolone has an OH/hydroxyl group at C11)

*Prednisone is the prodrug (needs to be reduced to OH in the liver). Prednisolone is the active metabolite (Has the OH group)

Prenisolone (Solo steroid-Active-metabolite).  Prednisone (Still a son, needs to grow up-Prodrug)

-Hepatically activated prodrug.

  • Clinical indications:

(a) Severe, persistant, Acute asthma  (b) Autoimmune and inflammatory diseases (c) Acute transplant rejection (d) Acute gout (e) CROUP (f) Inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe-[OPTHALMIC SOLUTIONS] (g) May be used for multiple myeloma, lymphoma, some leukemias [CHECK TREATMENT PROTOCOL]

Note: Systemic corticosteroids may be added to other long-term maintenance medications in the managment of uncontrolled severe persistent asthma.

  • Precautions:

-Breastfeeding: Safe to use. Take dose immediately after a feed and wait 4 hours before the next feed. Doses up to 80mg have been studied.

  • Practice Points:

-Prednisone is converted to active prednisolone in the liver and vice versa (via CYP3A4 inducer)

Prednisolone (Active metabolite) is used for CROUP when dexamethasone oral liquid is unavailable.

*CROUP-respiratory condition that is usually triggered by an acute viral infection of the upper airway. The infection leads to swelling inside the throat, which interferes with normal breathing and has symptoms of coughstridor, and hoarseness

Note: Systemic corticosteroids may be added to other long-term maintenance medications in the managment of uncontrolled severe persistent asthma.

-When asthma is stabilised, dose should be reduced or eliminated due to the side effects associated with chronic administration.

-Short courses of treatment may be used in moderate to severe exacerbations.

-If long term therapy is required, the lowest possible effective dose should be used.

9. Triamcinolone (can be used for asthma and other conditions)

Triamcinolone structure

-Long acting, synthetic corticosteroid given topically, orally, injection or by inhalation.

  • Clinical indications: 

(a) Autoimmune or Inflammatory diseases (Intramuscular injection) (b) Dermatological disease (Intradermal injection) (c) Adjunctive treatment for inflammatory arthritis (e.g. rheumatoid or osteoarthritis) (d) Acute Gout (e) Tendonitis (intra- or peri-articular injection)

  • Precautions

-Breastfeeding (data is limited). Diffusion into breast milk is low?

  • Adverse effects/Side effects

-Systemic adverse effects may arise from intra-articular and intra-dermal administration.

Common:

Local administration: Intra-articular pain, flare, hyperpigmentation

  • Practice Points

-Use triamcinolone 10mg/ml for intra-articular injection of doses <5 mg and for intradermal injection

-Intravitreal (injection into eye) triamcinolone is used to treat conditions such as diabetic macular edema, indication is not recommended by manufacturer!

Risk of adverse effects such as: Increased intraocular pressure, cataract formation, endophthalmitis and visual disturbances

*Endophthalmitis-is an inflammation of the internal coats of the eye

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