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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Respiratory Diseases-Pharmacotherapy (Asthma and COPD)

Summary Diagrams:

Asthma and COPD drugs 3Asthma and COPD drugs 2Asthma and COPD drugs

(SABA, LABA and AMA)                                                    (Steroids)                                                                        (Other prophylatic agents)

Refer to them!!!

Class 1 and 2: SABA and LABA

SABA (selective short acting beta-2 receptor agonist)

SalbutamolSalbutamol

-Indicated for management of astham exacerbations or other Chronic obstructive airway diseases.

-Very similar in structure to terbutaline (+ Unlike terbutaline, salbutamol exhibits less cardiac stimulation and more prolongefd bronchodilation than isoproterenol or metaproterenol).

 

(a) Salbutamol

Mechanism of action: Stimulates B2 receptors found in uterus, blood vessels, and lungs–>Bronchodilation (Reduced airway resistance and facilitates mucous drainage). Prevents mast cell degranulation

*Use as an adjunct for the treatment of hyperkalemia (Stimulates Na+/K+ ATPase pump and thus K+ excretion via kidneys).

-Levabuterol/R-Salbutamol is commonly administered, Similar to Terbutaline structure (but exhibits less cardiac stimulation)

-Comes in the form of oral tabs and oral inhalation [More common form] (90% swallowed and goes into GIT)]

*Onset of action (oral inhalation)-5-15 mins and DOA: 2-6 hours

-If SABA is required more than 2 days a week or if significant symptoms reoccur, then start to treat persistant asthma with ICS

-ACUTE SYMPTOM CONTROL!!!

 

(b) Terbutaline

*Indications: (a) Bronchospasm in asthma, COPD (b) Premature labour

 

Note: More than 12 months use will lead to tolerance and decreased lung function

-May stimulate B2 receptors found on the heart (Affect Cardiac-Causes stimulation)

-Terbutaline is less cardiostimulatory than other B2 agonists

Note: May cause hyperglycemia, stimulate uterine relaxation and dilation of arterioles

 

2. LABA (Long acting B-agonists)

 

(a) Salmeterol (Sell me to all)

Mechanism of action: Lipophilic side chain increases hydrophobicity and side chain appears to only bind to exosite (site near B2 receptor). Binding to this exosite allows the the continuous engagement and disengagement with the receptor, thus increasing duration of action. Exosite binding contributes to salmeterol’s inhibition of late phase antigens.

Highly selective to B2

*Indications: Maintenance treatment of asthma, Prevention of bronchospasm in COPD

-Long DOA, thus twice a day dosing is possible. However OAA of salmeterol is prolonged, thus therapeutic effect is limited.

*Never use Salmeterol for Acute asthma attacks (OAA too long). Useful for prophylatic therapy.

-Administered by oral inhalation.

-Onset of therapeutic effects is measured by 15% improvement in FEV1 within 14 mins.

 

(b) Eformoterol

(c) Indacaterol

 

3. Anti-muscarinic agents

(a) Ipratropium

-Synthetic quaternary compound that is similar in structure to atropine

-Administration via nasal spray or oral inhalation (most commonly used as a bronchodilator for cholinergic mediated bronchospasm associated with COPD)

*Much less effective than B2 agonists in reducing exercise induced asthma.

Mechanism of action: Antagonises the action of Acetylcholine on muscarinic receptors in the cholinergic neurons. In airways, this ultimately reduces contractility of smooth muscle. It is not muscarinic selective!!!

Intranasal adminstration of ipratropium produces a localised parasympatholytic effect which reduces watery hypersecretion from mucosal glands (Alleviates rinnorrhea associated with rhinitis or common cold)

(BAD) *Since it is quaternary (charged), it is not readily absorbed into systematic circulation. After intranasal dosing, less than 20% ipratropium dose is absorbed from the nasal mucosa into systemic circulation.

 

(b) Tiotropium

-Long acting N-quaternary structure, selective anti-muscarinic agent (Highly SELECTIVE TO M3 receptors in smooth muscles)

-Very slow dissociation from receptors, long DOA, long half life

-improved lung function (FEV1 and FVC) significantly within 30 mins after first dose administered and improvement was maintained for 24 hours.

 

4. Inhaled Corticosteroids (ICS)

-Anti-inflammation effect. MOST POTENT AND EFFECTIVE CLASS FOR ASTHMA TREATMENT!


-Administration as a MDI with spacer (Metered dose inhaler+Spacer). *Remember to wash and rinse mouth with water, gargle and spit out after each inhalation. *Oral candidasis is a common side fungal infection due to prolonged ICS use. 

Mechanism of action: Inhibits PLA2 which prevents the conversion of Arachidonic Acid to Prostaglandins, Leukotrienes, PAF etc. Thus inflammatory mediators are reduced and downstream effects inhibited.

-Inhibits both late phase (Recruitment of eosinophils, inflammatory cells) and intermediate phases (Bronchospasm, Production of leukotrienes, chemotaxins by mast cells) of asthma.

 

Glucocorticoid comparion table (DOA, minero-effects) (Refer to slide 21 of notes)

(a) Beclomethasone

-Synthetic halogenated glucocorticosteroid

Indications: Treatment of steroid-dependent asthma, Relieves symptoms associated with asthma and non-asthma rhinitis, Prevention of nasal polyps after surgical removal

-When used intranasally, the anti-inflammatory and vasoconstrictive effects are 5000x more potent than hydrocortisone

Mechanism of action:

1. Naturally occuring hormones that suppress inflammation and immune responses when administered at pharmacological doses.

2. At the molecular level, unbound glucocorticoids readily cross into cell (lipid soluble) and binds to nuclear receptors present on the nuclear membrane. Steroid-Receptor complex taken into nucleus and gene transcription is altered. New proteins are formed and released into systemic circulation. [TIME CONSUMING-SLOW PROCESS]

3. Protein alteration: Inhibition of leukocyte infiltration at the site of inflammation (less adhesion molecules made), Less inflammatory mediators made, Suppression of humoral response (Innate)

 

*Oral inhaled corticosteroid hormones reduce the intermediate and late phase allergic response associated with chronic bronchial asthma.

4. Decreased IgE synthesis

5. Increased number of B-adrenergic receptors on leukocytes

6. Decreased Arachidonic Acid production, Downstream effects of prostaglandin and leukotriene production inhibited (Refer to top)

 

Pharmacokinetics:

-Nasal inhalation absorption. Minimal amounts absorbed systematically.

-Oral inhalation absorption. After oral inhalation, drug is absorbed rapidly from the lungs and GIT. Some absorbed into systemic circulation but not sufficient to exert systemic effects.

OAA:  Occurs in a few days but may take 1-4 weeks to reach full, maximum effect

-Without spacer, approx 10-25% of orally administered dose enters the respiratory tract. The rest is deposited into mouth and is swallowed. Thus the use of spacer increases the amount of drugs that is deposited into the lungs.

 

(b) Budesonide

-Administered either intranasally or oral inhalation. Oral dosage form (tablets) usually for symptom management in Crohn’s diasease, allergic rhinitis and asthma

-Potent glucocorticoid and weak mineralocorticoid activity.

-Intranasal budesonide allows 1x daily dosage but has a less desirable side effect profile than the other intranasal steroids

*High anti-inflammatory effect when applied topically and has low systemic effect!

Pharmacokinetics:

-After nasal inhalation, approx 20% of the dose reaches systemic circulation

-After oral inhalation or nebulisation, approximately 6-13% and 6% of dose respectively reaches systemic circulation.

 

(c) Fluticasone

-Might cause a significant decrease in adrenal cortex production of glucocorticoid.

-Medium-potency corticosteroid

Indications: Used topically to relieve the inflammatory and pruritic (itching) symptoms of dermatoses and psoriasis. Used intranasally for symptom management of allergic and non-allergic rhinitis. Oral inhalation for asthma. Used clinically in some patients for COPD.

 

Pharmacokinetics:

-Administered by intranasal inhalation.

-Most of a dose following intranasal administration of fluticasone is swallowed with metabolism in gut and partial absorption with extensive first pass-metabolism in the liver. Thus, the systemic effect is negligible.

-Absorption following topical administration is minimal.

-Oral inhalation aerosol has a systemic bioavailability of about 3% of delivered dose. Bioavailability of the oral inhalation is roughly 14%.

 

 

(d) Ciclesonide

-Non-halogenated corticosteroid

*Beneficial in treating inflammatory conditions allergic rhinitis and asthma. May be beneficial in treatment of COPD.

-Low systemic bioavailability (Intranasal and oral inhalation). This limits systemic effects such as cortisol suppression.

*Administered by intranasal or oral inhalation. Oral bioavailability is negligible.

 

Pharmacokinetics:

-Ciclesonide is a produg drug with an active metabolite des-ciclesonide (100x-120x more potent)

-Esterases in the nasal mucosa hydrolyse ciclesonide to a biologically active des-ciclesonide

-Des-ciclesonide undergoes furthur metabolism in the liver via CYP3YP (MAJOR) and CYP2D6 (Minor)

-OAA: (Intranasal) 24-48 hours, with additional effects observed in 1-2 weeks for those with seasonal allergic rhinitis and 5 weeks in those with perennial allergic rhinitis.

 

 

(e) Hydrocortisone/Cortisol

(f) Prednisolone (Active metabolite), Prednisone (Prodrug)

-Prednisolone, including derivatives, are synthetic glucocorticoids used as an anti-inflammatory or immunosuppressive agent.

-(Opthalmic solutions) Can be used to treat allergic various inflammatory eye conditions.

*Can be administered with systemic corticosteroids for the maintainence treatment of uncontrolled persistant asthma

-Once stablisation of asthma is achieved, dose should be reduced or eliminated due to side effects associated with chronic use.

 

 

 

5. Cromones

(a) Sodium cromoglycate

Mechanism of action: Inhibits antigen induced bronchospasm. Prophylatic agent in the treatment of mild to moderate asthma. Intranasal inhalation to treat seasonal allergic rhinitis. Opthalmic solution to treat allergic and vernal conjunctivits.

Oral treatment for mastocytosis (too many mast cells in the body) and ulcerative collitis.

*Approved for use in adults and children as young as 2 years of age.

*An alternative to ICS in the treatment of mild persistent asthma.

  • Mechanism of action: Cromolyn works at the surface of the mast cell to inhibit its degranulation (Mast cell stabilisation occurs). This prevents release of histamine, slow reacting substance of anaphylaxis (SPS-A) and mediators of Type 1 allergic reactions.

-May reduce the release of inflammatory leukotrienes. However, it does not interfere with the binding of IgE to the mast cells or antigen to IgE.

-They can reduce hypersensitivity of the bronchi and asthmatic responses to environmental triggers.

-It is not a bronchodilator. Largely prophylatic actions.

 

  • Pharmacokinetics:

-Systemic bioavailability of oral cromolyn is 1%. However, it is still administered orally to treat systemic mastocytosis and ulcerative collitis. 

-Minimal systemic absorption occurs after intranasal and opthalmic use.

-Roughly 5%-10% of an inhaled dose reaches lungs [Amount that reaches lungs depends on extent of bronchoconstriction present]

-Several weeks of therapy may be required before improvement is obvious (hence 1 month wait to see improvements when administered ocularly)

 

 

(b) Nedocromil Sodium

*Mast cell stabiliser

-Available as opthalmic solution (For allergic conjunctivis). Available as oral inhalational aerosol (Respiratory anti-inflammatory agent for the long-term treatment of mild-moderate asthma).

*Nedocromil is an alternative to ICS in the treatment of mild persistent asthma in children 5 years of old.

-Actions similar to cromoglycate.

  • Mechanism of action:

-Although both nedocromil and cromoglycate works similarly (inhibits mast cell degranulation), nedocromil PREVENTS BRONCHOCONSTRICTION primarily (at lower doses than cromoglycate)

-Interferes with mast cell degranulation thus histamine not released. However it does not inhibit chemotaxis of eosinophils by PAF and LTB4.

-Inhibits the activation and release of PAF, leukotriene B4 and histamine from mast cells.  ***NOTE: PAF and Leukotriene B4 causes acute bronchoconstriction and increased vascular permeability (late phase of allergen-induced asthma).

-Prevents migration and recruitment of eosinophils, neutrophils, macrophages and platelets that causes airway inflammatory changes.

Does not interfere with binding of antigen to IgE or IgE to mast cells.

 

  • Pharmacokinetics

-Administered via oral inhalation or by ocular administration.

-Systemic bioavailability of inhaled nedocromil is approximately 6% to 9%

-After ocular administration, less than 4% of the total dose of 2% is systemically absorbed [Absorption is mainly through the nasolacrimal duct]

 

 

6. Leukotriene antagonists

(a) Montelukast (Prophylatic agent)

-Prophylatic agent and chronic treatment of asthma and allergic rhinitis.

-Alternative but not preferred substitute for ICS in treating mild persistent asthma.

-Efficacy shown in children as young as 12 months old and infants as young as 6 months old for allergic rhinitis.

*Available in tablet form (chewable tablet) and oral granule formulations.

 

  • Mechanism of action: Potent and selective antagonist of the receptor CYSLT1 receptor found in airways.

-Mast cells and eosinophils release LTD4, LT4, LTE4 (Bronchoconstrictors). Montelukast inhibits LTD4 from binding.

-Leukotrienes cause increased endothelial membrane permeability, peripheral edema, smooth muscle contraction and hypersecretion of viscous mucus

.-They are also associated with symptoms of allergic rhinitis (e.g. sneezing, nasal itching, rhinitis and late-stage congestion)

Montelukast inhibits both early and late-phase bronchoconstriction due to antigen challenge. Also helps in alleviating the above symptoms.

 

  • Pharmacokinetics

-Administered orally. Chewable tablet has an oral bioavailability of 63% (after being reduced by food). However, the clinical efficacy is not affected!

*ALL ORAL FORMS OF MONTELUKAST MAY BE TAKEN WITHOUT REGARD TO FOOD (i.e. taking after, before, during food is allowed)

-It is 99% bound to serum albumin.

-Undergoes extensive first pass metabolism in the liver via CYP3A4 and CYP2C9. Half life is 2.7-5.5 hours in average healthy, young adults.

(b) Zirfirlukast

 

 

7. Anti-IgE antibodies

 

Omalizumab

-First monoclonal humanised (chimaeric) antibody directed against IgE. Treats moderate to severe allergic asthma (i.e. due to allergens)

-Addition of this drug to patient’s drug regimen reduced the frequency of allergic asthma exacerbations. More patients can also discontinue or reduce dosage of corticosteroids.

*Anaphylatic shock may/may not develop after first dose or during ongoing treatment.

  • Mechanism of action:

-Binds to human IgE antibody (Fc-Constant region). This prevents the binding of IgE to various cells (BUT NOT ANTIGEN). Antigen can still bind to IgE.

-Omalizumab thus lowers free serum IgE concentrations (more than 90% decrease)

-Avoiding the bridging between IgE and cells prevents Ag-Ab induced cross-linking or receptors. No degranulation of mast cells occur, no inflammatory mediators produced.

-Suppresses eosinophil induced sputum and blunt both early and late phase allergic responses.

 

  • Pharmacokinetics:

-Administered by subcutaneous (SC) injection. Every 3 weeks, 1 injection.

-Serum free IgE levels are reduced in a dose-dependent manner within 1 hour of the first dose of omalizumab and are maintained between doses.

 

Pros: The IgE levels do not return to pre-treatment levels after discontinuation of Omalizumab (up to 1 year)

-Slow elimination t1/2 is 22+/- 9 days

 

 

8. Methylxanthine derivatives

(a) Theophylline

-Used both orally and IV to treat asthma and bronchospasm.

*Narrow therapeutic range-Thus careful monitoring of serum levels is required!

  • Mechanism of action:

1. Believed to inhibit PDE 3 and PDE 5 in smooth muscle cells. Thus, cAMP levels increase and less Ca2+ is formed–>Vasodilation.  However, other PDE inhibitors (e.g. dipyridamole, papaverine) don’t have a bronchodilating effect…(suggests an alternative mechanism)

2. Adenosine antagonism. Adenosine is a CNS stimulant, thus antagonising it will stimulate the medullary respiratory centre (increases sensitivity to carbon dioxide)

3. Inhibition of histamine release

4. Can stimulate cardiac and skeletal muscle (Opposite effect to smooth muscles)

 

  • Pharamokinetics:

-Children more than 1 years of age and adults metabolise theophylline hepatically via CYP1A2, 2E1 and 3A4

-Forms active metabolites (caffeine and 3-methylxanthine)

 

***Monitoring Parameters

-Monitor heart rate, CNS effects (insomnia and irritability), respiratory rate

-Patients often have elevated respiratory rates (due to increased sensitivity to Carbon dioxide)

 

Reference Range– Asthma (5-15 mcg/ml)–>Therapeutic Range                   >20mcg/ml–>Toxic

(b) Aminophylline