Drugs Affecting the Respiratory System: Anti-Inflammatory Agents

Respiratory tract inflammation is the body’s immune response to

irritants, pathogens, or allergens (part of the defense system).

Inflammation in the Respiratory Tract can cause what illness

It can be in the form of: Rhinitis, Laryngitis, Tracheitis, Bronchitis, Pneumonia, Asthma, RAO, IAD, and

Airway epithelial cells and macrophages detect the invaders, and release what

cytokines (IL-1, IL-6, TNF-alpha, granulocyte/macrophage colony-stimulating factor [GM-CSF]), recruiting immune cells, and release histamine from mast cells.

The cytokines stimulate what

arachidonic acid release from membrane lipids, leading to production of eicosanoids, which further stimulate mucus secretion by goblet cells and tissue inflammation.

What are examples of Anti-inflammatory Drugs

1. Glucocorticoids

2. NSAIDS

What is the role of Glucocorticoids (GC)

the role is the management of metabloism of glucose

What do we use Glucocorticoids for animals to treat

from Addisson’s dis. to Inflammatory, Allergic, and Autoimmune Disorders

What are the different forms of Glucocorticoids

from Systemic application to topical applications: ophthalmic, intraarticular, otic, topical , ...

GC-Mechanism of Action Three cellular mechanisms:

(i) Genomic Mechanisms

(ii) Inhibition of Phospholipase A2

(iii) Nongenomic Nonspecific Mechanisms

Genomic mechanism by cGR what does this do

• Glucocorticoids are lipid-soluble, they easily pass through the cell membrane.

• Inside the cell, they bind to a cytoplasmic glucocorticoid receptor (cGR).

• The GC-receptor complex moves into the nucleus.

• In the nucleus, it binds to specific DNA regions called glucocorticoid response elements (GREs).

• This changes gene transcription, causing some proteins to be produced and others to be suppressed.

Inhibition of Phospholipase A2 does what

• One of the most clinically important effects of GCs is induction of lipocortin-1.

• Lipocortin inhibits phospholipase A2 (PLA2).

• Damages and stimuli activate PLA2→Release of Arachidonic acid (AA) from cell membrane phospholipids

Arachidonic acid is then converted into:

• Prostaglandins

• Leukotrienes

Prostaglandins. and Leukotrienes cause what

• Pain

• Fever

• Swelling

• Vasodilation

• Leukocyte recruitment

So Prostaglandins. and Leukotrienes cause • Pain

• Fever

• Swelling

• Vasodilation

• Leukocyte recruitment

by inhibition of what blocks those effects

By inhibition of PLA2, GCs will block all these effects!

Nongenomic Nonspecific what is the mechanism

• At higher doses, glucocorticoids can act much faster.

• Instead of changing gene transcription, they interact with:

  • Cytoplasmic glucocorticoid receptors (cGR)

  • Membrane glucocorticoid receptors (mGR)

  • Cell membrane

Nongenomic Nonspecific They cause changes in

• phosphorylation, transmembrane currents, and calcium levels (Stabilize Membranes)

• These contribute to the immediate immunosuppressive effectts for emergencies.

What are the GC-Characteristics

• short acting

• intermediate

• long acting

What is an example of GC-Characteristics:short acting

• hydrocortisone

• coritsone

What is an example of GC-Characteristics:intermediate acting

• triamcinolone

What is an example of GC-Characteristics:long acting acting

• flumethasone

• dexamethasone

• betamethasone

What is Dexamethasone Phosphate used for

fast-acting. It is the gold standard for iv or im injection in emergency

settings for respiratory distress.

What is the drug of choice for dogs

Oral prednisolone or prednisone is usually the drug of choice when a corticosteroid is needed for treating chronic airway disease (0.5–1.0 mg/kg).

What is the drug of choice for cats

Oral prednisolone initial dosages of 2–4 mg/kg/day have been used for 10–14 days, followed by chronic doses of 1 mg/kg/day for the treatment of feline asthma.

What is the drug of choice for horses

In horses, for management of recurrent airway obstruction (RAO) and inflammatory airway disease (IAD). Both prednisolone and dexamethasone, when combined with environmental control, had beneficial effects. Prednisolone tablets are the preferred drug for oral administration. Initial dose of 2 mg/kg oral, once a day then tapered to 1 mg/kg.

Prednisolone not prednisone can be administered to cats and horses.

WHY?

• The answer is in their liver!

• They lack the enzyme “11beta- hydroxysteroid dehydrogenase type 1”, which is responsible to activate prednisone.

Is prednisone a prodrug?

yes

GC-Inhaled advantages are

 Rapid onset of action

 Fewer systemic side effects

Which GC inhaled drug is considered most potent

Fluticasone is the most potent (18 × dexamethasone) and is usually the one used in veterinary medicine!

GC-Adverse Effects

• Metabolic/Endocrine: Iatrogenic Cushing’s dis., Diabetes, Hypertension

• GI/Hepatic: Stimulate appetite, GI ulcers at high doses

• Dermatological: ↓ collagen synthesis, ↓wound healing, bilateral symmetrical alopecia, calcium deposition in skin (calcinosis cutis)

• Immunologic: exacerbation of infections!

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) Mechanism of Action: is

The principal action is inhibition of COX, the enzyme with a pivotal position in the AA cascade; NSAIDs occupy the hydrophobic part of COX, preventing AA access to its active site. This leads to the effect of inhibition of synthesis of proinflammatory mediators, including PGE2.

Which is the good COX

COX1

• COX 2 is the bad one

What is the role of COX-1

inhibition producing toxic effects

What is the effect of COX2

inhibition providing therapeutic effects.

NSAIDS-Adverse Effects

• Gastrointestinal irritation: vomiting, ulceration, melena (PGI2), Prolonged use in horses causes Right Dorsal Colitis.

• Nephrotoxicity: acute renal failure (PGI2)

• Hepatotoxicity: idiosyncratic, not dose-dependent! Type B!

• Inhibition of hemostatic mechanisms: leading to hemorrhage (TXA2)

• Delayed parturition: (PGF2)

• Delayed healing: (PGE2)

Flunixin meglumine is an NSAIDs what is it use for

is registered for cattle to treat inflammatory respiratory problems such as bovine respiratory disease (BRD) and is included in one of the antibiotic combinations used to treat BRD (flunixin meglumine and florfenicol in Resflor Gold®).

Meloxicam and ketoprofen are also NSAIDs what do we use them for

are frequently introduced via injection or water systems to manage Swine Respiratory Disease Complex, decreasing the clinical severity of herds.

For chronic conditions, like chronic bronchitis and asthma, in equine, feline, and canine cases,

Glucocorticoids are preferred.

Classification is Selective COX-1 inhibitors what are the examples and key characteristics ?

• Aspirin, ketoprofen (cat),

  flunixin (cow)

• COX-1 inhibitory potency ≥5-fold

  greater than COX-2 inhibition

Classification is Nonselective COX inhibitors inhibitors what are the examples and key characteristics ?

• carprofen (horse),

  flunixin, ketoprofen (dog,

  horse), phenylbutazone

• No significant biological or clinical

  differences in concentrations

  producing COX-1 vs. COX-2

  inhibition

Classification is Slightly/moderately selective COX-2 inhibitors what are the examples and key characteristics ?

• carprofen (dog, cat),

  deracoxib, etodolac,

  etoricoxib, meloxicam,

  mavacoxib

• COX-2 inhibition 5–30× greater

  than COX-1 inhibition. At higher

  concentrations, significant COX-1

  inhibition may occur.

Classification is Highly/very highly selective COX-2 inhibitors what are the examples and key characteristics ?

• Cimicoxib, firocoxib,

  robenacoxib, valdecoxib

• COX-2 inhibition >50× greater than

  COX-1 inhibition. Limited COX-1

  inhibition in vivo at maximum

  therapeutic doses.