Systemic Anti-Inflammation

Initial response to the stimulus; tissue damage followed by resolution

Acute inflammation

Occurs when the initial immune response does not lead to resolution but instead leads to further cellular damage; damage and repair continue in an ongoing cycle

Chronic inflammation

What kind of pain occurs from trauma (acute)?

Nociceptive

What kind of pain uses Aδ and C sensory nerve fibers?

Nociceptive pain

What kind of pain occurs in response to tissue damage and inflammation (acute or chronic)?

Inflammatory

What kind of pain occurs if the nervous system is damaged (chronic)?

Neuropathic

Innate immunity or cellular response to stress/injury?

• Infections of pathogen cause the release of pathogen-associated molecular patterns (PAMP) which bind to pattern recognition receptors (PRR) on immune cells

• Initiation of immune response to resolve infection and allow for tissue repair

Innate immunity

Innate immunity or cellular response to stress/injury?

• Damage associated molecular patterns (DAMP) are released and bind to PRR on immune cells

• Trigger intracellular signaling cascades to express a variety of proinflammatory molecules

• Should lead to allow for tissue repair and immune protection

Cellular response to stress/injury

What are the five classic signs of inflammation?

Heat, pain, redness, swelling, and loss of function

Resolution or repair?

• Restoration of normal function (acute)

Resolution

Resolution or repair?

• Functional, but altered organ (chronic)

Repair

Inflammation causes hypoxia, which stimulates the release of what from macrophages?

Vascular endothelial growth factor (VEGF) and other factors

Why can the vessels made during angiogenesis lead to edema?

New vessels are immature and cause leakage

What kind of irreversible visual impairment can angiogenesis cause in the eye?

Opacification of the cornea and permanent changes to the retina, such as proliferative diabetic retinopathy or wet age-related macular degeneration

During inflammation _____ is activated and releases arachidonic acid (ARA) from the membrane.

Phospholipase A2 (PLA2)

During inflammation Phospholipase A2 (PLA2) is activated and releases _____ from the membrane.

Arachidonic acid (ARA)

What does ARA get converted to in inflammation?

Various pro-inflammatory mediators

Leukotrienes are produced by _____ in leukocytes, mast cells, and other immune system cells.

Lipoxygenase (LOX)

LOX produces what pro-inflammatory mediator in leukocytes, mast cells, and other immune system cells?

Leukotrienes

Prostaglandins (PG) are produced by activation of _____ in all cells

Cyclooxygenase (COX-1/COX-2)

COX-1/COX-2 produce what pro-inflammatory mediator in all cells?

Prostaglandins (PG)

Which cyclooxygenase is usually active in cells (constitutional)?

• Produces cytoprotective PGs that activate platelets and protect the gastric lining

• Not involved in inflammation

COX-1

Which cyclooxygenase is induced (inducible) in cells?

• Produces inflammatory PGs that lead to pain, inflammation, and fever

COX-2

Which cyclooxygenase is found mostly in the CNS and might be important for the pain and fever modulations?

COX-3

In general, how do steroids work?

They inhibit phospholipases

In general, how do NSAIDs work?

They inhibit COX-1, COX-2, and maybe COX-3

In general, how do disease-modifying anti-rheumatic drugs (DMARD) work?

They inhibit the antigen processing to activate macrophages

In general, how do leukotriene antagonists work?

They inhibit lipoxygenases and leukotriene receptors

The hypothalamus releases _____

Corticotropin releasing hormone (CRH)

CRH stimulates the release of _____ from the anterior pituitary

Adrenocorticotropic hormone (ACTH)

ACTH stimulates the synthesis/release of _____ from the adrenal cortex

Steroids

Which basic steroid group helps regulate kidney control of water and electrolyte balance?

Mineralocorticoids (aldosterone)

Which basic steroid group regulates sexual differentiation, characteristics, and behavior?

Androgenic steroids (sex steroids)

Which basic steroid group increase glucose in blood stream to supply brain?

Glucocorticoids (cortisol)

Produced to handle stressful situations

• Mobilizing energy supplies

• Inhibits the release of ACTH and CRF

Glucocorticoids (cortisol)

When are glucocorticoid (cortisol) levels highest?

In the morning (4-8am)

When are glucocorticoid (cortisol) levels lowest?

In the evening (8pm-midnight)

What are the normal levels of release of glucocorticoid (cortisol)?

20-25 mg/day

What are the physiological effects of glucocorticoids (steroids)?

• Insulin resistance develops as well as loss of pancreatic β-cells

• Increased blood glucose (hyperglycemia)

• Increased proteolysis (proteins to amino acids) by the muscle

• Increased lipolysis to release fatty acids and glycerol

What are the pharmacological effects (doses >25 mg/day) of glucocorticoids (steroids)?

• CNS: mood changes (behavioral disturbances)

• Decreased numbers of lymphocytes and decreased immunity and inflammatory response

What are the long term effects of steroids?

• Stop ACTH production, which results in atrophy of the adrenal cortex (cannot produce aldosterone, cortisol, or sex steroids)

• No normal hormone production once long-term steroids are stopped

  • Patients could suffer/die in stressful situations (cannot increase BP or respond with a strong flight response)

• ⸫ must taper steroids instead of abruptly stopping

How do glucocorticoids decrease inflammation?

• Decreasing capillary permeability

• Decreasing migration of WBCs

• Decreasing fibroblast and capillary proliferation

• Decreasing scar formation by inhibiting fibrin and collagen

• Decreasing epithelial regeneration

How do glucocorticoids decrease inflammation at a molecular level?

They increase or decrease transcription/translation of genetic material to make new proteins or inhibit production of others, which blocks the synthesis of certain inflammatory mediators (lipocortin/annexin A1 acts to inhibit PLA2)

Which form of glucocorticoids are metabolized more quickly (alcohol or acetate)?

Alcohol

Do naturally produced agents (like cortisol and cortisone) tend to be short, intermediate, or long acting?

Short

What systemic toxicities can corticosteroids cause?

• Peptic ulcers

• Increase infections

• Decreased wound healing

• Muscle atrophy

• Osteoporosis

• Metabolism

  • Hyperglycemia

  • Increased appetite

  • Fluid retention

• Eyes

  • Increased IOP

  • PSCs

• Hypertension

• Mood changes

• Cushing’s syndrome (too much cortisol, redistribution of fat around the body)

• Pediatric complications (inhibit the normal growth process)

What are the contraindications of cortisol/steroids?

• No absolute contraindications, weigh risks/benefits related to life/sight

• No real hypersensitivities (cortisol is natural)

• Treat effects:

  • Peptic ulcer

  • Osteoporosis

  • Psychosis

  • TID/TIID

What are the advantages of systemic steroids?

• Good for systemic inflammation: many uses

• Can easily supplement topical for a stronger effect

• Easy to take

• May reach all parts of the eye

What are the disadvantages of systemic steroids?

• Adrenal suppression

• Significant systemic side effects

What are the advantages of inhalation steroids?

• Easily absorbed across bronchiolar or nasal tissue into systemic circulation

• Compared to systemic administration, smaller doses and lower risks of toxicities

What are the disadvantages of inhalation steroids?

• Systemic side effects still a risk

What do we commonly use inhalation steroids for?

Asthma, COPD, rhinitis, nasal congestion from viruses

What are the advantages of topical steroids?

• Easily absorbed into tissue, but not much reaches systemic circulation

• Compared to systemic administration, much smaller doses and very lower risks of toxicities

What are the disadvantages of topical steroids?

• Relieves symptoms so can be easily abused

• Can also be absorbed systemically, but much less

What type of drug is cortisone?

Steroid

Is cortisol short, intermediate, or long acting?

Short

What kind of activity does cortisone have?

Equally mineralocorticoid and glucocorticoid activity

What type of drug is hydrocortisone (Cortef)?

Steroid

Is hydrocortisone (Cortef) short, intermediate, or long acting?

Short

What kind of activity does hydrocortisone (Cortef) have?

Equally mineralocorticoid and glucocorticoid activity

What type of drug is prednisone?

Steroid

Is prednisone short, intermediate, or long acting?

Intermediate

What kind of activity does prednisone have?

Lower mineralocorticoid activity

What kind of drug is prednisolone (topical: Pred Forte, Pred Mild)?

Steroid

Is prednisolone (topical: Pred Forte, Pred Mild) short, intermediate, or long acting?

Intermediate

What kind of activity does prednisolone (topical: Pred Forte, Pred Mild) have?

Low mineralocorticoid activity

What kind of drug is methylprednisolone (Medrol, Dosepak, Solu-Medrol)?

Steroid

Is methylprednisolone (Medrol, Dosepak, Solu-Medrol) short, intermediate, or long acting?

Intermediate

What kind of activity does methylprednisolone (Medrol, Dosepak, Solu-Medrol) have?

Minimal mineralocorticoid activity

What type of drug is beclomethasone (Beconase AQ, QVAR)?

Steroid

Is beclomethasone (Beconase AQ, QVAR) short, intermediate, or long acting?

Long

What type of activity does beclomethasone (Beconase AQ, QVAR) have?

Minimal mineralocorticoid activity

What type of drug is fluticasone (Flonase, Flovent)?

Steroid

Is fluticasone (Flonase, Flovent) short, intermediate, or long acting?

Long

What type of activity does fluticasone (Flonase, Flovent) have?

Minimal mineralocorticoid activity

What type of drug is dexamethasone (Decadron)?

Steroid

Is dexamethasone (Decadron) short, intermediate, or long acting?

Long

What type of activity does dexamethasone (Decadron) have?

Minimal mineralocorticoid activity

What is the most potent oral steroid?

dexamethasone (Decadron)

What is Blephamide a combination of?

sulfacetamide + prednisolone

What type of drug is difluprednate (Durezol)?

Steroid

Is difluprednate (Durezol) short, intermediate, or long acting?

Intermediate

What kind of activity does difluprednate (Durezol) have?

Low mineralocorticoid activity

What type of drug is dexamethasone (Maxidex)?

Steroid

Is dexamethasone (Maxidex) short, intermediate, or long acting?

Long

What kind of activity does dexamethasone (Maxidex) have?

Minimal mineralocorticoid activity

What is Maxitrol a combination of?

neomycin + polymyxin B + dexamethasone

What is TobraDex a combination of?

tobramycin + dexamethasone

How do NSAIDs work?

Work via PG inhibition

• COX-1/2/3?

• Prevents to some degree hyperemia and disruption of the blood aqueous barrier

• Less inhibition of the healing process

What do we use NSAIDs for?

Inflammation, pain, fever, arthritis

What serious toxicities are associated with NSAIDs?

• Kidney and liver failure (in abuse)

• Ulcers (COX-1)

• Prolonged bleeding (COX-1)

What type of drug is aspirin?

NSAID for systemic pain, fever, and inflammation

What is aspirin used for besides pain, fever, or inflammation?

To inhibit clotting and prevent stroke

What can aspirin cause in children?

Reye’s syndrome

What is Aggrenox a combination of?

Aspirin + dipyridamole (more effective than either drug alone)

What is Darvocet a combination of?

Propoxyphene + aspirin (used for pain — opioid receptors + NSAID)

What activity does aspirin have?

Non-selective inhibition but COX-1 > COX-2

What type of drug is ibuprofen (Advil, Motrin)?

NSAID for systemic pain, fever, and inflammation

What activity does ibuprofen (Advil, Motrin) have?

Non-selective

What NSAID is suitable for children?

Ibuprofen (Advil, Motrin)