Pharm Ch 11 Corticosteroids

Front 1

What is the Clinical Indications for Use of Inhaled Corticosteroids?

Back 1

Maintenance, control therapy of chronic asthma

(Step 2 asthma: Symptoms > 2 days/week, but not daily and night awakenings three or four nights/month, FEV1 or peak expiratory flow (PEF) 80% predicted or greater)

COPD

Intranasal aerosol agents:

Management of seasonal and perennial allergic and nonallergic rhinitis

Front 2

Physiology of Corticosteroids

Adrenal cortical hormones

Back 2

Adrenal cortical hormones

Glucocorticoids

Glucocorticosteroids, e.g., cortisol

Mineralocorticoids

Regulate body water, e.g.,

aldosterone

Sex hormones

Androgens and estrogens

Key Point: The physiology of endogenous corticosteroids involves a sequence of stimulation of the adrenal cortex through the hypothalamic-pituitary-adrenal (HPA) axis, in which increased blood levels of corticosteroid inhibit the HPA and adrenal cortex from further secretion.

Front 3

Hypothalamic–pituitary–adrenal axis

Back 3

Pathway for release and control of endogenous corticosteroids

Stimulation of hypothalamus causes impulses to be sent to median eminence, where corticotropin-releasing factor (CRF) is released

Key Point: Corticosteroids secreted by the adrenal cortex include: glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and androgen and estrogen hormones.

Glucocorticoids, often referred to simply as steroids, exert an anti-inflammatory effect in the body.

Front 4

CRF circulates to ______ and does what?

Back 4

CRF circulates to anterior pituitary gland where corticotropin is released into the blood stream

Front 5

Corticotropin, or adrenocorticotropic hormone (ACTH), stimulates _______ to do what?

Back 5

stimulates the adrenal cortex to secrete glucocorticoids, such as cortisol

Front 6

Hypothalamic–pituitary–adrenal suppression with steroid use

Back 6

Body cannot distinguish between endogenous and exogenous

Administration of glucocorticoid drugs raises body’s level

Inhibits hypothalamus and pituitary glands

Referred to as HPA suppression or adrenal suppression

Front 7

HPA Axis Regulation of Corticosteroid Secretion key point

Back 7

Exogenous corticosteroid agents can suppress the HPA axis and the adrenal gland.

Front 8

Diurnal steroid cycle

Back 8

Production of body’s own glucocorticoids follows rhythmic cycle; termed diurnal or circadian rhythm

Cortisol levels are highest in the morning at 8 am

Examples of interference with cycle:

Jet lag

Night shift work

Front 9

Alternate-day steroid therapy

Back 9

Mimics natural diurnal rhythm by giving steroid drug early in the morning when normal tissue levels are high

On alternate day, regular diurnal secretion in the hypothalamic–pituitary–adrenal (HPA) system can resume

Front 10

Inflammation definition

Back 10

the response of vascularized tissue to injury.

Front 11

Operational Definition of Asthma

Back 11

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells.

In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning.

Front 12

Asthma episodes are usually associated with what?

Back 12

These episodes are usually associated with widespread but variable airflow obstruction often reversible either spontaneously or with treatment

The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to various stimuli.

Front 13

Mediators such as: prostaglandins, leukotrienes, histamine, and cytokines (interleukins) do what?

Back 13

further amplify the inflammatory response in asthma by attracting the cells mentioned previously to the airway and inducing the release of adhesion factors to bind inflammatory cells to the airway surface.

Arachchidonic Acid Cascade

Front 14

Inflammation

Triple response:

Back 14

Redness: Local dilation of blood vessels, occurring in seconds

Flare: Reddish color several centimeters from the site, occurring 15 to 30 seconds after injury

Wheal: Local swelling, occurring in minutes

Front 15

Nature of Inflammatory Response 4 Major Categories of Activity

Back 15

1. Increased vascular permeability

2. Leukocytic infiltration

3. Phagocytosis

4. Mediator cascade

Front 16

Increased vascular permeability

Back 16

An exudate is formed in surrounding tissues

Front 17

Leukocytic infiltration

Back 17

White cells emigrate through capillary walls (diapedesis) in response to attractant chemicals (chemotaxis)

Front 18

Phagocytosis

Back 18

White cells and macrophages (in lungs) ingest and process foreign material such as bacteria

Front 19

Mediator cascade:

Back 19

Histamine and chemoattractant factors are released at the injury site.

Various inflammatory mediators, such as complement and arachidonic acid products, are generated

Front 20

Chronic bronchitis

Back 20

(usually caused by tobacco smoking) and asthma (range of triggers) are most common

Treatment with antiinflammatory agents such as glucocorticoids is important to reduce basal level of airway inflammation, thereby reducing airway hyperresponsiveness and predisposition to acute episodes of obstruction

Front 21

Asthmatic reactions are biphasic. Early phase

Back 21

asthmatic response is caused by immunoglobulin E (IgE)

Response peaks at ~15 minutes

BRONCHOCONSTRICTION

Front 22

Asthmatic reactions are biphasic

Late phase

Back 22

Mast cell mediators and release of cytokines recruit other inflammatory cells to cause late-phase reaction

Response occurs after ~6–8 hours

Can last up to 24 hours

SUBMUCOSAL EDEMA, MUCUS PRODUCTION, AIRWAY HYPERREACTIVITY

Front 23

Types of corticosteroids

Back 23

Front 24

Aerosolized corticosteroid agents

Back 24

Beclomethasone dipropionate (QVAR)

Fluticasone propionate (Flovent HFA, Flovent Diskus) - Advair

Fluticasone Furoate (Arnuity Ellipta) – Breo Ellipta

Budesonide (Pulmicort Respules, Pulmicort Turbuhaler) - Symbicort

Mometasone furoate (Asmanex Twisthaler) - Dulera

Ciclesonide (Alvesco)- Prodrug

Front 25

Which are your combination drugs?

Back 25

Advair (Fluticasone propionate/salmeterol )

Symbicort (Budesonide/formoterol)

Dulera (mometazone furoate/ formeterol fumerate)

Front 26

Purpose of combination drugs

Back 26

Compliance

Evidence of beneficial, complementary interaction between glucocorticoids and β-adrenergic agonists

Steroids increase β2-adrenergic receptor transcription (Upregulation)

Simply stated: increases the response to a stimulus

Inhaled corticosteroid therapy can provide partial protection against the development of tolerance

Salmeterol has been shown to promote binding of the glucocorticoid receptor to the response element of the cell’s nuclear DNA

Front 27

Intranasal corticosteroids

Back 27

All steroids available as orally inhaled agents are also available in intranasal formulation

Agents will have different trade names

Used for treatment of allergic or inflammatory nasal conditions and seasonal or perennial allergic or nonallergic rhinitis and to prevent reoccurrence of nasal polyps

Front 28

Corticosteroids mode of action

Back 28

To induce gene expression for antiinflammatory proteins and receptors

To suppress gene expression for proinflammatory proteins

Front 29

Three general actions of suppression:

Back 29

1. Upregulate transcription of antiinflammatory genes for substances, such as lipocortin

2. Suppress factors such as activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), which cause transcription of genes involved in inflammation

3. Upregulate expression of inhibitors of NF-κB, such as inhibitor protein IκB

Front 30

General result

Back 30

induce gene expression for anti-inflammatory proteins and receptors and suppress gene expression for proinflammatory proteins.

Front 31

Corticosteroids effect on WOB

Back 31

Demargination: Depletion of neutrophil stores reduces their accumulation at inflammatory sites and in exudates

Overall increase in white cell count

Constriction of microvasculature to reduce leakage of cells and fluids into inflammatory sites

Front 32

Effect on β-receptors

Back 32

Beta adrenergics are potent inhibitors of mast cell release- pt may become unresponsive to tx

Restore responsiveness to β-adrenergic stimulation

Enhance β-receptor stimulation by increasing the number and availability of β-receptors on cell surfaces and by increasing the affinity of the receptor for β-agonists

Front 33

Steroid Use:Hazards and Side Effects

Back 33

Systemic administration of steroids:

Suppression of the HPA axis

Immunosuppression

Psychiatric reactions

Cataract formation

Myopathy of striated skeletal muscle

Peptic ulcer

Fluid retention

Hypertension

Increased WBC count

Dermatological changes (Cushing)

Slowing of growth in children

Hyperglycemia

Front 34

Systemic side effects with aerosol administration (of major concern):

Back 34

HPA suppression

Loss of bone density

Growth restriction in children

Front 35

Systemic side effects with aerosol administration (potential):

Back 35

Adrenal insufficiency

Allergic inflammation after cessation

Suppression of HPA function

Growth reduction in children

Front 36

Topical (local) side effects with aerosol administration:Most common:

What to do:

Back 36

Most common:

Oropharyngeal candidiasis (oral thrush)

Dysphonia (hoarseness/voice quality)

What to do:

Use of lowest effective dose

Use reservoir device

Rinse mouth after use

Front 37

Clinical Application of Aerosol Steroids Use in Asthma

Back 37

Early use in asthma

For acute severe asthma

Clinical use of inhaled corticosteroids

Front 38

Clinical Application of Aerosol Steroids use in COPD

Back 38

Relieves symptoms

Little or no effect on FEV1

Front 39

Respiratory Care Assessment of Inhaled Corticosteroid Therapy

Evaluation

Back 39

Instruct patient in correct use of delivery system

Controller … not a rescue agent!

Respiratory rate and pattern

Breath sounds

Pulse

Subjective response

Use of peak flow meter

Exacerbations, missed work/school,

ER visits

Assess for side effects

Front 40

How long until you see effects of inhaled corticosteroids?

Back 40

3-5 days