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Glucocorticoids (GCs)

Glucocorticoids (GCs)
•Reduce inflammation and immune responses,
• Used clinically since 1948
• $10,000,000,000./year market size in US (10 billion)


Glucocorticoids (GCs) Classification

Glucocorticoids (GCs) are a class of steroid hormones that bind to the glucocorticoid receptor (GCR).
The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure.


Physiological effects of GCS

Regulation of carbohydrate, protein and lipid metabolism
Maintenance of fluid and electrolyte balance Preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system and the nervous system
Preservation of organism homeostasis


Systemic Glucocorticoids (oral)

CH2OH= bonding sight
Blue= attached to bonding sight and OH. effects the lipophysity
Hydrocortisone (cortisol)


Inhaled Glucocorticoids

Trimcrinolone Acetonide
Beclomethasone dipropionate
--> No active bonding site.
--> Pro-drug (will become a drug onsite (Inhaled as CH2OCOC2H5 side chain --> separate into CH2OC on site)
--> reduced systematic effects, increases pulmonary retention time
Fluticasone propionate
Mometasone furoate


Pharmacokinetics of GC

Ideal GCs should have:
Increased lung deposition and pulmonary retention
Increased residence time and high receptor-binding affinity
Rapid clearance, and have an on-site activation of the pro-drug to promote safety


Cellular and Molecular Effects of GCs

GCs suppress (inflammatory cells) circulating eosinophils, basophils, monocytes, mast cells, dendritic cells, and to a smaller degree lymphocytes (particularly T lymphocytes).
Principal effects: (reduced inflammatory responses) inhibit the synthesis, release, and expression of cytokines, inflammatory peptides, chemokines, growth factors, adhesion molecules, and lipid mediators involved in the inflammatory response


Pharmacodynamics of Glucocorticoids

GCs and Glucocorticoids receptor (GCR) binding:
– GC receptors are not transmembrane receptors. Locate in the cell cytoplasm.


Pharmacokinetics of GC diagram

1. GC diffuse through membrane and bind to GC receptor (GR) located in plasma
2.. Travels through hole reaching the Nucleus
a) causes Gene activation
--> Increased Inflammatory gene transcription
--> Increased inflammatory protein (anti-inflammatory mediator release) (GM-CSF, IL-8)
b) causes Gene Repression
--> Decreased Inflammatory gene Transcription (reduces some mediator gene transcription)


GC effect on cells and regulation

Reduce inflammatory cell numbers including inhibition of recruitment or migration, activation, survival, and proliferation of cells.
(when combined with B2 agonist) Up-regulation of beta-adrenergic receptors on airway smooth muscle cells (prevent the Polymers of B2 agonists)


GCs in chronic asthma treatment

Inhaled GCs treatment can decrease asthma symptoms, number of uses of bronchodilator (decreases chance of tolerance), and frequency of acute asthma symptoms; and can improve lung function and bronchial hyperresponsiveness.
Onset of response: improvement in lung function may be within 1 month (still doesnt immediately stop acute symptoms);
improvement in airway inflammatory markers can be seen as early as 2 weeks.



It has no mineralocorticoid effects and has 25 times more potency than hydrocortisone. (oral)


Oral GCs (Prednisone)

– Prednisone is an inactive pro-drug and it is metabolized in liver to form prednisolone (good to take orally in emergency situation)
– The drug has less mineralocorticoid effects, so decreases swelling of ankle, retaining of water and salt.


Inhaled GCs delivery statistics

Inhaled GCs: around 20% of the drug is inhaled to the lung while 80% is deposited in the mouth and swallowed, reaching the systemic circuit and metabolized by liver.


Adverse effect of GCs
Systemic adverse effects List

Osteoporosis with loss of collagens and increased risk of fracture
-Increase blood pressure
-Affect central nervous system which decrease depression but become euphoric (happy) -Maybe verbally psychotic
-Increase risk of cataract
-Increase chance to have TB (supresses immune responses, increasing chance of having infection)
-Salt water retention
-Cushing Syndrome
- Long term GC use: Increase gluconeogenesis with high glucose level; cause diabetes and protein/muscle breakdown; cause proximal weakness.


Cushing Syndrome

Cushing syndrome:
-long term use of GCs
-hypercortisolism promotes distribution of body to trunk, back of neck (buffalo hump) and also face (moon-face), i.e. central obesity with thin arms and legs


One common problem of using GCs

A lot of patients or parents are allergic to a word "steroid"
-baby --> hulk
-steriods are a common structure. GC are different to other steroids (doesnt cause addictive effects)


GC's Local Adverse Effects

Hoarseness or dysphonia, cough, and oral candidiasis (thrush) are the most commonly reported problems associated with inhaled GCs, due to immunosuppressant effect and myopathy of the vocal cords.


Prevention Local Adverse Effects from GCs

Rinse mouth to prevent thrush (can be taken just before brushing your teeth) (when use inhaler)
Spacer: easier administration of drug to the lung and less chance to cause thrush


Outgrow of asthma

Only 6% of the kids fully "outgrew" their asthma. this means they had no asthma symptoms for atleast one full year
An additional 39% of the kids had improvement in their asthma. These kids only sometimes had asthma symptoms.
Effects of ICS treatment on % of the outgrowing asthma are still not very clear.
Relationship between long-term use of ICS and airway remodelling is not clear


Role of CysLTs in Asthma

1. Mucus secretion= LTC4 & LTD4. dose dependant. increase mucus. Submucosal glands and goblet cells.
2. Ciliary paralysis= CysLTs. Decreased activity of human respiratory cilia.
3. Macro-molecules= LTD4. Increased blood flow. increased vascular permeability.
4. Eosinophil Recruitment= LTD4. Increased venopermeability --> extravasation. Increased Edema --> eosinophil infiltration.
5. Smooth muscle contraction and proliferation = LTC4 and LTD4. Dose dependant - contractile of peripheral and central airways.
6. Oedema


Overall Target of CysLTs in Asthma

Target LTC4 or LTD4 (reverse all the effects)
=receptors creating mucus secretion
=dose dependant - increase mucus
-submucosal glands
-goblet cells


Leukotriene-Modifying Drugs for the Treatment of Asthma

1. ZYFLO: 5-Lox Inhibitor
2. SINGULAIR: Leukotrien-receptor antagonist


Leukotriene Receptor Antagonists SINGULAIR

Given orally
No studies available for use in critical patients
Use as add-on or alone therapy for mild to moderate asthma
Side effects:
– Headache
– GI disturbance
– Reversible hepatitis and hyperbilirubinemia


Leukotriene Receptor Antagonists Prevention and Relaxation

1. Prevent
– Aspirin induced asthma
– Exercise induced asthma
– Decrease both early and late responses to ` allergen
2. Relax airway in mild asthma
– Bronchodilator effect = 1/3 of salbutamol
– Additive bronchodilation effect with B2-agonist


Mast cell stabilizer

Mast cells have a role in the 1. acute responses (as allergin when directly stimulates muscle cells to release leukotriene, histamine and PGD2)
2. Laste phase responses still have to go through mast cells (further activate them)
-if can stabilise mast cells can essentially reverse effect
1. Cromolyn sodium
2. Nedocromil sodium


Cromolyn Sodium

-Non-steroidal (advantage. keeps parents happy)
-Inhibits IgE mediated mediator release from mast
cells (prevents degranulation)
-4-6 week trial therapy may be required (takes alot of time to see if really works)
-Minimal local side effects – cough
-Almost no systemic effects. (stabilizers muscle cells)
-Prevent both early and late asthmatic responses to inhaled allergens.


Cromolyn Sodium Effects

• Prevent both early and late asthmatic responses to inhaled allergens such as pollen
•Reduce airway reactivity resulting from exposure to a range of inhaled irritants such as sulfur dioxide and cold air


Other treatments and future directions

Anti-IgE therapy
Magnesium sulfate
Therapies against TNF-a
Anti–interleukin-5 (IL-5)
Gene therapy


Management of Asthma

Lots of different drugs available
Done on the basis of patients:
1. condition
2. different stage


Asthma Prevention

Remarkable progress in pharmacotherapy (alot of drugs availble to treat), education and environmental measures in treating asthma
However, no single action has been demonstrated to decrease the risk of developing asthma (real cause of asthma still isnt clear)
--> therefore need more research to improve
Prevention will depend on factors influencing the development and progression of asthma