1/9 Pharmacology of the Respiratory System- Corticosteroids Flashcards
Describe the sympathetic control of bronchial tone.
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
Describe how the parasympathetic nervous system effects bronchial tone.
Muscarinic acetylcholine receptors:
- M3
- constriction of bronchial smooth muscle
How do we achieve bronchodilation pharmacologically?
aka what are the drug targets?
Drugs targets
- B adrenergic agonists
- anticholinergic (antimuscarinic) drugs
- methylxanthines
Using a targeted drug delivery system
- topical (can lead to local or systemic effects)
- inhalation
Name two B-adrenoceptor agonists that are used to achieve bronchodilation.
Adrenaline (epinephrine)- emergency life threatening bronchoconstriction
B2 adrenoceptor specific agonists (ex. clenbuterol)
What are the side effects of B-adrenoceptor agonists?
CVS: increased HR, palpitations
Skeletal muscle: tremors
How do anticholinergic drugs work for bronchodilation?
Block endogenous parasympathetic tone (M3 receptors)
What are the side effects associated with the use of anticholinergic drugs?
CNS stimulation
GI inhibition
What are corticosteroids produced for in the body?
Glucocorticoids- immunosuppressant effects
Mineralocorticoids- help deal with water balance
Are corticosteroids stored?
No- synthesised and released as needed (after stimulation from adrenal gland)
How are corticosteroids released in the body?
In circadian rhythm (vary between diurnal/nocturnal animals)
- nocturnal animals have peak glucocorticoids at night
Explain the endogenous control of glucocorticoids.
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.
Waht are the mechanisms of action of glucocorticoids?
Metabolic effects
Systemic effects
Anti-inflammatory effects
Immune suppressice effects
What effects do dose/concentration of glucorticoids have?
(Increasing dose/concentration)
Physiological function –> anti-inflammatory –> immunosuppression –> cytotoxicity
What do you need to think about when choosing a steroid?
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
What are the different routes of administration of glucocorticoids?
Topical
Directly to specific tissue (lungs)
Intra-articular injection
What do you use topical application of glucocorticoids for?
On skin for allergy/inflammation
Why is directly administering glucocorticoids to the lungs good and what can you deliver?
Lungs have high surface area for local delivery
Antibiotics- infection
Bronchodilators
Glucocorticoids- reduce inflammation
What are the general principles of corticosteroid therapy?
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
Describe how suppression of the HPA axis occurs.
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!
List some corticosteroid side effects.
Gastric, corneal ulcers
Iatrogenic cushings
Suppression of HPA –> addisons disease
Laminitis
What is Addison’s Disease?
Deficiency of adrenocortical steroid production
Mineralocorticoid and glucocorticoid deficiency
What are the symptoms of Addison’s Disease?
Anorexia, vomiting, diarrhoea, weakness, exercise intolerance, polydipsia, polyurea
How do you diagnose Addison’s disease?
Circulating ACTH concentrations increased in primary Addison’s but not in central hypoadrenocorticism
How do you treat Addison’s?
Hydrocortisone sodium succinate (IV)
Chronic therapy requires permanent mineralocorticoid therapy
What is Cushings Disease?
Overproduction of glucocorticoids due to a pituitary adenoma (ACTH increase) or adrenal tumor (ACTH low)
What are the two types of Cushings?
Pituitary (80%): increase ACTH and cortisol
Adrenal (20%): decrease ACTH, increase cortisol
What are the common symptoms of Cushings?
Pot belly Thin skin Coat change Muscle wastage Elevated liver enzymes Polydypsia Polyurea
What are the tests for Cushings?
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
What are some pharmacological interventions for Cushings?
(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
