steroidal anti-inflammatory drugs (glucocorticoids) lecture 22 FIRST LECTURE FOR EXAM 4

Inflammation

is a useful and normal process that consists of a series of events, including vascular changes and release of chemicals that help destroy harmful agents at the injury site and repair damaged tissue

increases

Vasodilation ___________ permeability of blood vessels in the early phase

additional damage to the body

Severe inflammation must be reduced to avoid ...

Steroidal anti-inflammatory drugs block the action of phospholipase

-Corticosteroids are hormones produced by the adrenal cortex

-Two groups of corticosteroids, the glucocorticoids and the mineralocorticoids, are clinically used

Nonsteroidal anti-inflammatory drugs block the action of cyclooxygenase

what are the two main groups of anti inflammatory drugs

action of phospholipase

Steroidal anti-inflammatory drugs block the...

action of cyclooxygenase

Nonsteroidal anti-inflammatory drugs block the ....

glucocorticoid: stress response and negative feedback

glucocorticoid: stress response and negative feedback

adrenal cortex: hormones

adrenal cortex: hormones

1. ligand

2. DNA

3. activated

4. proteins

5. widely distributed

GLUCOCORTICOID MOA:

1. ________ binds (steroid/glucocorticoids) to the cytosolic receptor

2. Ligand/receptor complex translocates to the nucleus and binds to ______

3. Transcription of mRNA is ____________

4. __________ are translated that induce biological effects of Glucocorticoids

5. Glucocorticoid receptor is __________ __________

1. promote normal intermediary metabolism

2. increase resistance to stress

3. alter levels of circulating blood cells

4. anti-inflammatory actions

5. effects on other endocrine hormones

what are the 5 effects of glucocorticoids

Promote normal intermediary metabolism - utilize other substance to make glucose

liver: anabolic:

Increasing gluconeogenic enzymes and amino acid uptake by the liver and kidney

Promote normal intermediary metabolism - utilize other substance to make glucose

Extrahepatic tissue:

Stimulate protein catabolism to provide energy needed for glucose synthesis

Increase activity of hormone-sensitive lipase to generate fatty acid fuel

Increase resistance to stress

Elevated glucose levels provide energy required to combat stress: trauma, disease, fight or flight

Can cause a modest rise in blood pressure (mineralocorticoid effects)

Adrenal insufficiency: individuals may become hypotensive during severe stress

alter levels of circulating blood cells

Decreases eosinophils, basophils, monocytes, and lymphocytes by redistributing them from circulation to lymphoid tissue

Increases the levels of hemoglobin, erythrocytes and platelets in the circulation

anti-inflammatory actions

Inhibits NF-𝜅B, a transcription factor considered the master regulator of inflammatory responses

Inhibits phospholipase A2, via activation of Lipocortin

Decreases activity of peripheral lymphocytes and macrophages

Interfere in mast cell degranulation resulting in decreased histamine and bradykinin to reduce capillary permeability

want to reduce redness and reduce pain

glucocorticoid : inflammation

glucocorticoid : inflammation

Effects on other endocrine hormones

Negative feedback inhibits further glucocorticoid synthesis

Reduces thyroid-stimulating hormone

Production of growth hormone is increased

important points

What is the mechanism of action of glucocorticoids at the cellular level?

What are the mechanisms that glucocorticoids inhibit the inflammatory response?

What is the effect of glucocorticoids in the liver vs extrahepatic tissues, on the metabolism of carbs, lipids, and proteins?

90%

____% Cortisol is bound to plasma proteins

- Corticosteroid binding globulin (75%)

- Albumin (25%)

Remaining 10% is free and accounts for activity

albumin

Synthetic corticosteroids are bound primarily by ...

hepatic dysfunction

Glucocorticoid therapy should be monitored in individuals with ....

Pharmacokinetics (PK)

Pharmacokinetics (PK)

Relative Potencies

Relative Potencies

1. Orally (tablets or liquids)

2. Intravenously or intramuscularly

3. Topically (creams, ointments)

4. Inhaled (for respiratory conditions)

5. Local injections (e.g., joint injections)

6. When possible, local treatments are preferred over systemic administration to reduce the risk of side effects

Glucocorticoid can be administered in various ways:

alter circulating glucose, and minor mineralocorticoid effects

Glucocorticoid effects are measured by the ability to ...

Aldosterone

The primary mineralocorticoid is ..

Mineralocorticoids

promote sodium retention in the Kidney and affect blood pressure

salt retention

Mineralocorticoid effects based on ...

1. Glucocorticoid vs. mineralocorticoid activity

2. Duration of action

3. Time of day that steroid is administered - cortisol is highest in the morning, so give drug in morning to lower cortisol

what are 3 important dosage points

suppression of the HPA axis

Large doses over an extended period of time can cause ...

recover on days that the hormone is not taken

A regimen of alternate day therapy is useful, in allowing the HPA axis to ....

important points

How much cortisol is bound to proteins and why is this important?

What is the difference between the plasma and biological half life?

How glucocorticoid may have mineralocorticoid characteristics?

Inflammatory diseases

-Skin: eczema and dermatitis

-Rheumatic: Arthritis, bursitis, tenosynovitis

-Bowel: ulcerative colitis, Crohn's disease

-Respiratory diseases: Asthma, COPD

what are the therapeutic uses: anti-inflammatory

- Autoimmune diseases

- Organ transplants

- During surgery

- Allergic conditions

- Lupus

what are the therapeutic uses: inhibition of the immune system

- Cerebral edema

- Premature delivery: reduces respiratory stress and neonatal mortality

- Eye injury (Inhibit fibrosis)

- Replacement therapy (Addison's disease)

what are some other therapeutic uses

adverse effects

BE CAREFUL WITH DIABETES/HYPERTENSION PATIENT

Increased protein catabolism: decreased growth in children, Osteoporosis, impaired wound healing, muscle wasting…

Disturbed lipid metabolism: centripetal distribution of body fat-fatty belley, buffalo hum, moon face…

Increased hepatic gluconeogenesis: hyperglycemia, cataract…

Suppressed immune response and reduced WBC: increased risk of infection…

Disturb ion balance: negative calcium balance, hypokalemia…

Increased gastric acid secretion: appetite, ulcer…

Emotional disturbances: euphoria, depression…

Weak mineralocorticoid action: Peripheral edema, hypertension…

Androgenic activity: hirsutism

adrenal suppression

adrenal suppression

addisons disease - adrenal gland malfunction

Etiology: Insufficient Glucocorticoid production

Primary adrenal insufficiency

-- Autoimmune

-- Infections (Tuberculosis)

Secondary adrenal insufficiency

-- ACTH deficiency

Can develop after cessation of treatment with Glucocorticoids

addison's disease - adrenal gland malfunction

Symptoms

- Chronic fatigue

- Muscle weakness

- Loss of appetite

- Weight loss

Treatment

- Replacement therapy with Glucocorticoids

alternate date therapy - adrenal gland malfunction

dont give every day

Greater reduction in side effects than can be achieved by dose reduction alone:

-- 200 mg given every other day has the same efficacy as 90 mg given every day

-- 200 mg given every other day produces the same adverse effects as 25 mg per day

Used with intermediate acting glucocorticoids

cushing's syndrome - adrenal gland malfuncition

Etiology: Excess glucocorticoids

-- Adrenal cortex tumor (Primary)

-- Cushing’s disease: Pituitary over-secretion of ACTH (Secondary)

-- Ectopic secretion of Cortisol

Long term treatment with Glucocorticoids can mimic Cushing’s Syndrome

cushing's syndrome - adrenal gland malfuncition

Clinical features:

-- Rapid weight gain in trunk, and face, and growth of fat pads along the collarbone

-- Central obesity; buffalo hump; moon face

-- Easy bruising, skin atrophy and thinning

-- Acne

-- Hirsutism

important points

What is the cause and treatment for Addison's Disease?

What causes Cushing's Syndrome?

Primary vs Secondary: Cushing's Syndrome vs Cushing's disease

summary : know moa and side effects as well as info on glucocorticoids

summary : know moa and side effects as well as info on glucocorticoids