1/9 Pharmacology of the Respiratory System- Corticosteroids

Question 1

Describe the sympathetic control of bronchial tone.

Answer 1

No innervation- dilated by circulating adrenaline

B2 adrenoreceptors

• increase cAMP in bronchial smooth muscle
• relaxation of bronchial smooth muscle

Inhibit release of histamine from mast cells

Question 2

Describe how the parasympathetic nervous system effects bronchial tone.

Answer 2

Muscarinic acetylcholine receptors:

• M3
• constriction of bronchial smooth muscle

Question 3

How do we achieve bronchodilation pharmacologically?

aka what are the drug targets?

Answer 3

Drugs targets

• B adrenergic agonists
• anticholinergic (antimuscarinic) drugs
• methylxanthines

Using a targeted drug delivery system

• topical (can lead to local or systemic effects)
• inhalation

Question 4

Name two B-adrenoceptor agonists that are used to achieve bronchodilation.

Answer 4

Adrenaline (epinephrine)- emergency life threatening bronchoconstriction
B2 adrenoceptor specific agonists (ex. clenbuterol)

Question 5

What are the side effects of B-adrenoceptor agonists?

Answer 5

CVS: increased HR, palpitations

Skeletal muscle: tremors

Question 6

How do anticholinergic drugs work for bronchodilation?

Answer 6

Block endogenous parasympathetic tone (M3 receptors)

Question 7

What are the side effects associated with the use of anticholinergic drugs?

Answer 7

CNS stimulation

GI inhibition

Question 8

What are corticosteroids produced for in the body?

Answer 8

Glucocorticoids- immunosuppressant effects

Mineralocorticoids- help deal with water balance

Question 9

Are corticosteroids stored?

Answer 9

No- synthesised and released as needed (after stimulation from adrenal gland)

Question 10

How are corticosteroids released in the body?

Answer 10

In circadian rhythm (vary between diurnal/nocturnal animals)

- nocturnal animals have peak glucocorticoids at night

Question 11

Explain the endogenous control of glucocorticoids.

Answer 11

Cells in hypothalamus produce corticotropin releasing factor (CRF), which signal anterior pituitary gland to produce adrenocorticotropic hormone (ACTH) which goes into circulation, reaching the adrenal gland and causing release of glucocorticoids.
– Glucocorticoids and ACTH have negative feedback on hypothalamus.

Question 12

Waht are the mechanisms of action of glucocorticoids?

Answer 12

Metabolic effects
Systemic effects

Anti-inflammatory effects
Immune suppressice effects

Question 13

What effects do dose/concentration of glucorticoids have?

Answer 13

(Increasing dose/concentration)

Physiological function –> anti-inflammatory –> immunosuppression –> cytotoxicity

Question 14

What do you need to think about when choosing a steroid?

Answer 14

Duration of action (most often don’t want long acting)
Importance of formulation
–> water soluble salts: ideal for IV, quickly absorbed and excreted
–> Insoluble esters: useful for sustained therapy
–> Mixed esters: soluble and insoluble compounds

Question 15

What are the different routes of administration of glucocorticoids?

Answer 15

Topical
Directly to specific tissue (lungs)
Intra-articular injection

Question 16

What do you use topical application of glucocorticoids for?

Answer 16

On skin for allergy/inflammation

Question 17

Why is directly administering glucocorticoids to the lungs good and what can you deliver?

Answer 17

Lungs have high surface area for local delivery

Antibiotics- infection
Bronchodilators
Glucocorticoids- reduce inflammation

Question 18

What are the general principles of corticosteroid therapy?

Answer 18

Minimal mineralocorticoid activity preferred
Use as low a dose as possible
Withdraw treatment gradually
Long acting compounds greater risk for toxicity
Need to treat underlying cause of problem

Question 19

Describe how suppression of the HPA axis occurs.

Answer 19

Negative feedback of exogenous corticosteroids occurs in hypothalamus
Leads to suppression of ACTH followed by atrophy of adrenal gland (animal can no longer produce own cortiocoids)
Sudden termination of exogenous corticosteroids (Life-threatening!)

Essential: gradual reduction of corticosteroid dose!

Question 20

List some corticosteroid side effects.

Answer 20

Gastric, corneal ulcers
Iatrogenic cushings
Suppression of HPA –> addisons disease
Laminitis

Question 21

What is Addison’s Disease?

Answer 21

Deficiency of adrenocortical steroid production

Mineralocorticoid and glucocorticoid deficiency

Question 22

What are the symptoms of Addison’s Disease?

Answer 22

Anorexia, vomiting, diarrhoea, weakness, exercise intolerance, polydipsia, polyurea

Question 23

How do you diagnose Addison’s disease?

Answer 23

Circulating ACTH concentrations increased in primary Addison’s but not in central hypoadrenocorticism

Question 24

How do you treat Addison’s?

Answer 24

Hydrocortisone sodium succinate (IV)

Chronic therapy requires permanent mineralocorticoid therapy

Question 25

What is Cushings Disease?

Answer 25

Overproduction of glucocorticoids due to a pituitary adenoma (ACTH increase) or adrenal tumor (ACTH low)

Question 26

What are the two types of Cushings?

Answer 26

Pituitary (80%): increase ACTH and cortisol

Adrenal (20%): decrease ACTH, increase cortisol

Question 27

What are the common symptoms of Cushings?

Answer 27

Pot belly
Thin skin
Coat change
Muscle wastage 
Elevated liver enzymes
Polydypsia
Polyurea

Question 28

What are the tests for Cushings?

Answer 28

ACTH test: elevated corticosteroids before ACTH administration and rise after.

Low dose dexamethasone suppression test: this will not suppress cortisol in cushings

High dose dexamethasone suppression test: If pituitary, high dose will suppress cortisol, if adrenal it won’t

Question 29

What are some pharmacological interventions for Cushings?

Answer 29

(Enzyme blockers)
Trilostane- oral, well tolerated
Ketoconazole- interferes with adrenal steroid synthesis, expensive

Mitotane (reduced layers of adrenal gland)- easy to use (oral), potentially serious side effects