Corticosteroids (Week 3, Mod 9)

What is the definition of bronchial tone?

Bronchial tone:

• the dynamic equilibrium between the state of contraction or relaxation of the smooth muscle in the bronchial walls that regulate respiration

Increased bronchial tone = smooth muscle constriction = bronchoconstriction

Decreased bronchial tone = smooth muscle dilation = bronchodilation

Describe the effect of the sympathetic nervous system on bronchial tone…

No innervation but dilated by circulating adrenaline

• B2 adrenoceptors

  • increase cAMP in bronchial smooth muscle

  • relaxation of bronchial smooth muscle

Adrenaline ALSO inhibits the release of histamine from mast cells in allergic reactions

Describe the effect of the parasympathetic nervous system on bronchial tone…

Muscarinic acetylcholine receptors: M3

• increase IP3

• increase [Ca²+];

CONSTRICTION of bronchial smooth muscle

How can we achieve bronchodilation pharmacologically??

Drug Targets

• ß-adrenergic agonists

• Anticholinergic (antimuscarinic) Drugs

• Methylxanthines (PDE inhibitors) i.e. caffeine

Aim is to mimic the sympathetic OR block the parasympathetic nervous system

• Need to keep in mind how you deliver the drugs; could help you minimize systemic side effects

What are some ß-adrenergic agonists, and what are they used for? What is their mechanism of action, and their side effects?

Adrenaline (epinephrine)

• Emergency treatment of life threatening bronchoconstriction

B, adrenoceptor specific agonists

e.g. terbutaline, salbutamol, salmeterol, clenbuterol

Mechanism: Stimulate adrenergic pathways

Side effects

• CVS: increased heart rate, palpitations

• Skeletal muscle: tremors

• Tolerance

What are some anticholinergic (antimuscarinic) drugs, and what are they used for? What is their mechanism of action, and their side effects?

ATROPINE

• comes from nightshade; highly toxic

Mechanism: BLOCKS the endogenous parasympathetic constriction of the bronchi

• acts through the M3 receptor

Side effects:

• CNS stimulation

• Gl inhibition

Administration: topical vs systemic

Local effect:

Ipratropium bromide is a quaternary derivative of atropine, limited absorption therefore minimal systemic side effects

What are some methylxanthines, and what are they used for? What is their mechanism of action, and their side effects?

Methylxanthines e.g. theobromine, caffeine, theophylline, etamiphylline

Mechanism of action:

• Phosphodiesterase (PDE) inhibitors

  • Increase CAMP

  • bronchial smooth muscle relaxation

• Decrease inflammatory mediators

• Adenosine inhibition

Side effects

GI

Cardiac

CNS

What is one of the major inflammatory mediators that causes bronchoconstriction during an allergic reaction?

Arachidonic acid

Where in the inflammatory process do NSAIDs inhibit the effects of arachidonic acid? What about corticosteroids?

NSAIDS: COX-1 and COX-2 enzymes

• blocks the production of prostaglandins

Corticosteroids: PHOSPHOLIPASES on cell membranes

• Blocks the production of arachidonic acids COMPLETELY

What are the two classes that corticosteroids are divided into? Where are they produced?

• Glucocorticoids

  • Cortisol

  • Corticosterone

• Mineralocorticoids

  • Noradrenaline

  • Adrenaline

Formed in different parts of the adrenal glands…

• Glucocorticoids = cortex

• Mineralocorticoids = medulla

When giving exogenous corticosteroids, does it act as a treatment for the patient?

NO

• only treats the SYMPTOMS of conditions

• still need to address the underlying cause

Ex: DEXAMETHASONE

• helps relieve itch, doesn’t treat the allergic reaction

Know the mechanism of action for corticosteroids… Note:

• Cell HAS to contain a receptor for that particular steroid… some cells will, some cells won’t

• Steroid-receptor complex, as it binds to the DNA, only has effects at SPECIFIC regions of the DNA template

  • Called motifs

  • Acts at a signal to that specific steroid receptor… once the complex reaches the motif, the complex will either FACILITATE the transcription of that gene, or INHIBIT it

What are 3 proteins that glucocorticoids INDUCE the transcription of?

1) Angiotensin converting enzyme

2) B2-adrenoceptor - more of these = increased response to endogenous OR exogenous adrenaline

3) Lipocortin 1

(inhibits phospolipase)

What are 4 proteins that glucocorticoids INHIBIT the transcription of?

1) Cytokines

2) Cyclo-oxygenase = less prostaglandins = prevents bronchoconstriction

3) Collagenase

4) Inducible NOS

Which corticosteroids are short acting? Which are long acting?

Short acting: < 24 hrs

• Pred (prednisolone AND prednisone)

• Methylpred

Long acting: > 24 hrs

• Dex

• Betamethasone

• Triamcinolone

What are the two main formulations corticosteroids come in?

Water Soluble Salts

Insoluble Esters

What are the characteristics of a water soluble corticosteroid? Think of some examples…

• Ideal for intravenous administration

• Readily absorbed and eliminated within 8-24h (fast acting)

• Can give high concentrations, rapid effects

• Sodium phosphate salts and soluble esters (eg succinate,) examples include: Betamethasone sodium phosphate (Betsolan ™ soluble); Dexamethasone (Azium M, Colvasone, Dexadreson "™)

  • Yes, these were listen as long acting, but their composition in this form makes them fast

What are the characteristics of an insoluble ester corticosteroid? Think of some examples…

Useful for more sustained therapy

• e.g. acetate, adamantoate, dipropionate, pivalate, phenylpropionate, isonicotinate, adamantoate.

  • Dexamethasone isonicotinate (Voren 14 M)

  • Methylprednisolone acetate (Depo-Medrone V Im)

Mixed esters:

Soluble and insoluble compounds eg Dexafort

QUESTION TIME:

Why might it not be a good idea to give a glucocorticoid systemically?

Would activate a widespread response

• Multiple systems in the body would be affected

• There are multiple glucocorticoid receptors in many different types of cells all throughout the body

  • If a glucocorticoid were given systemically, all cells of varying tissues that contain the glucocorticoid receptor would respond to it

What are 3 different routes of administration for glucocorticoids? Keeping this in mind, what is one thing you should ALWAYS remember about glucocorticoids?

1) Topical

• Ex: hydrocortisone cream

2) Direct (ex: inhalant)

• For chronic obstructive pulmonary disease (COPD) or recurrent airway obstruction (RAO

  • Would reduce inflammation

3) Intra-articular injection

• Also reduces inflammation

REMEMBER: glucocorticoids don't treat underlying causes

• Simply masks symptoms

What are the 5 different general principles of corticosteroid therapy?

• Minimal mineralocorticoid activity preferred

• Use as low a dose as possible

• Withdraw treatment gradually

• Long acting compounds greater risk of toxicity

• Treat underlying cause of the problem in the meantime

It's a matter of balance!

Why is gradual withdrawal of glucocorticoid treatment essential?

The sudden termination of corticosteroid therapy could result in a life-threatening crisis

• The negative feedback that exogenous corticosteroids apply to the hypothalamus leads to suppression of the HPA axis (see image)

• Results in expression of ACTH, followed by atrophy of the adrenal glands

What are three different diseases caused by the abnormal functioning of the adrenal gland and the HPA axis?

• Addisons's Disease

• Cushing's Disease

• Congenital Adrenal Hyperplasia

Describe congenital adrenal hyperplasia… how is it different between males and females?

Congenital Adrenal Hyperplasia (CAH) is a group of inherited genetic disorders that impair the adrenal glands' ability to produce essential hormones—specifically cortisol and often aldosterone

• causes excessive testosterone production and adrenal gland enlargement, leading to ambiguous genitalia in females and early puberty in boys

• Not too bad for males, but leads to the masculinization of females

Describe Addison's disease (hypoadrenocorticism)… what is it? What causes it?

• Deficiency of adrenocortical steroid production

  • Mineralocorticoid and glucocorticoid deficiency

• Underlying pathology: usually immune mediated destruction of adrenal cortices

• Spontaneous central hypoadrenocorticism less common

• Central hypoadrenocorticism is most commonly iatrogenic

What are the symptoms and clinical signs of Addison’s disease? What breeds are the most susceptible?

Symptoms and clinical signs:

• anorexia, vomiting, diarrhoea, weakness, exercise intolerance, polydipsia and polyurea.

• may be precipitated by a stressful event (e.g. domestic change).

Breeds predisposed:

• Standard poodles

• West Highland terriers

• Great Danes

• Some collies

How do you diagnose Addison’s disease? What medications can be used to treat it?

Diagnosis:

• Circulating ACTH concentrations increased in primary (adrenal) Addison's

  • Not in central hypoadrenocorticism

• Important to take sample early in the morning; could lead to a misdiagnosis if blood sample taken late in the day

Treatment:

• Acute hypoadrenal crisis is a medical emergency!

  • Hydrocortisone Sodium succinate (iv).

• Chronic therapy requires permanent mineralocorticoid therapy (Fludrocortisone Acetate; oral).

Describe Cushing’s disease (hypERadrenocorticism)… what is it? What causes it?

Cushing's disease = overproduction of glucocorticoids due to a pituitary adenoma (ACTH increased) or due to an adrenal tumour (ACTH very low)

• latrogenic Cushing's can result from prolonged treatment with glucocorticoids

Seen more commonly in older dogs (10yrs) and older horses (20yrs)

• RARELY in cats, but can happen

BIG SIGN: Coat thickness / texture changes

What are the symptoms and clinical signs of Cushing’s disease? What breeds are the most susceptible?

Common Symptoms:

• Polydipsia

• Polyurea

• Polyphagia

• Elevated liver enzymes

• Pot belly

• Thin skin

• Coat changes

• Muscle wastage

Susceptible Breeds:

• Poodles

• Dachshunds

• Terriers

• German Shepherds

• Golden Retrievers

What are the two different KINDS of Cushing’s disease? What are the signs?

PITUITARY

• Caused by an adenoma on the pituitary gland

• 80% of Cushing’s cases are due to this

• Signs:

  • Increased ACTH

  • Increased cortisol

ADRENAL

• Caused by a tumor on the adrenal gland

• Makes up 20% of Cushing’s cases

• Signs:

  • DECREASED ACTH

    • Due to homeostatic balance from hypothalamus… increased cortisol → hypothalamus reduces production of ACTH

  • Increased cortisol

What are the 3 main pharmacological tests for Cushing’s disease?

1) ACTH test:

• Elevated corticosteroids before ACTH and a rise after administration.

2) Low dose Dexamethasone suppression test:

• In Cushing's animal this will not suppress cortisol.

3) High dose Dexamethasone suppression test: Sometimes used to differentiate between pituitary and adrenal problem. If pituitary, high dose will suppress cortisol production; if adrenal, it will not.

What are the 3 main pharmacological treatment options for Cushing’s disease? What are their advantages / disadvantages?

Trilostane (Vetoryl °): oral, well tolerated, careful monitoring required

Ketoconazole (antifungal): interferes with synthesis of adrenal steroids

(cP450 enzymes), but expensive.

Mitotane or o,p'-DDD (Lysodren) - Cytotoxic

• Advantages:

  • Easy to use (oral, with food)

  • Relatively inexpensive

• Disadvantages:

  • Potential very serious side effects

  • Requires regular monitoring

• Give with food to aid absorption