Anti-inflammatory Drugs part 1

ANTI-INFLAMMATORY DRUGS

• Overview of anti-inflammatory drugs for veterinary pharmacology (Part 1, VET 2024).

INFLAMMATION

Normal Protective Function

• The inflammatory response is crucial for protection against pathogens, serving as a first line of defense.

• Tissue damage introduces bacteria into wounds, triggering a cascade of immune responses.

• Cells in the wounded area release a variety of chemical mediators that stimulate specific immune responses.

  • Mast Cells: Specialized immune cells that release histamine and other substances, playing a central role in the inflammatory response.

  • Histamine: A potent vasodilator that increases capillary blood flow and permeability, facilitating the movement of immune cells to the site of injury or infection.

The Inflammatory Response

• Phagocytes, including neutrophils and macrophages, leave the capillaries and ingest bacteria and dead cells, effectively cleaning the wound.

• Wounded cells communicate damage through signaling molecules called cytokines, leading to the recruitment and activation of additional immune cells, thereby amplifying the inflammatory process.

ANTI-INFLAMMATORIES

Types

• Steroids: Corticosteroids that mimic hormones produced by the adrenal glands.

  • Examples: Prednisone, Dexamethasone - known for their potent anti-inflammatory effects but also potential systemic side effects.

• Non-steroidal Anti-inflammatory Drugs (NSAIDs): A diverse group of medications providing pain relief and anti-inflammatory effects by inhibiting enzyme pathways involved in inflammation.

  • Examples: Aspirin, Rimadyl, Deramaxx, Metacam - differing in their mechanisms, efficacy, and side effect profiles.

INFLAMMATION PATHWAY

Arachidonic Acid Cascade

• Phospholipids in cell membranes respond to tissue injury, initiating the inflammatory cascade.

• Phospholipase: An enzyme inhibited by corticosteroids, converting membrane phospholipids to arachidonic acid, which leads to the formation of:

  • Prostaglandins: Important mediators that contribute to nociception, fever, and further recruitment of inflammatory cells.

  • Thromboxanes: Involved in platelet aggregation and vasoconstriction.

  • Leukotrienes: Potent mediators of bronchoconstriction and recruit additional immune cells.

MECHANISM OF ACTION

• Anti-inflammatory drugs relieve pain by blocking various steps in the inflammatory process.

  • Steroids: Inhibit phospholipase, thus halting the production of arachidonic acid and its downstream mediators.

  • NSAIDs: Inhibit cyclooxygenase (COX) and lipoxygenase (LOX) pathways, interrupting the synthesis of prostaglandins and leukotrienes, respectively.

CORTICOSTEROIDS (CCS)

General Information

• Also known as Adrenocorticosteroids, produced primarily by the adrenal cortex.

• Two main types with significant physiological roles:

  • Mineralocorticoids: Regulating electrolyte and water balance.

  • Glucocorticoids: Regulating metabolism and immune response.

  • Each corticosteroid exhibits both mineralocorticoid and glucocorticoid effects, albeit to varying degrees.

GLUCOCORTICOID EFFECTS

Stress Response System

• The hypothalamus plays a central role in maintaining cortisol levels through a tightly regulated hormonal response:

  • CRH (Corticotropin-releasing hormone) activates ACTH (Adrenocorticotropic hormone), which stimulates cortisol release from the adrenal gland, impacting numerous physiological processes related to stress and inflammation.

SYNTHETIC GLUCOCORTICOIDS

Classification

• Analogs of natural hormones classified by:

  • Mechanism of action (glucocorticoid vs. mineralocorticoid properties).

  • Potency and efficacy at suppressing inflammation.

  • Duration of action relevant to clinical use.

• Often combined with saline to enhance solubility and absorption.

INHERENT LENGTH OF ACTION

Types of Glucocorticoids

• Short Acting (up to 48 hrs): Dexamethasone, betamethasone, flumethasone, isoflupredone (PREDEF®).

• Typically used for rapid control of acute inflammatory responses.

ENHANCED DURATION OF ACTION

Very Soluble (Hydrophilic or Lipophilic?)

• Released minutes after injection, suitable for immediate response.

  • Examples: Methylprednisolone sodium succinate (SoluMedrol®) - indicated for acute inflammatory conditions.

Moderately Soluble

• Released over days to weeks; must be shaken before administration due to larger suspended crystals.

  • Example: Methylprednisolone acetate (DepoMedrol®) - used for prolonged therapeutic effects in chronic conditions.

Poorly Soluble

• Released over weeks, suitable for long-term management without frequent dosing.

  • Example: Triamcinolone acetonide (Vetalog®) - available in topical and parenteral forms for versatile applications.

THREE DOSAGE TYPES

Types of Administration

• Supraphysiologic: High doses used temporarily to manage severe inflammation.

• Physiologic (Low): Normal hormone replacement doses.

• Anti-inflammatory (Medium): Therapeutic doses targeting inflammation relief without suppressing normal function.

• Immunosuppressive (High): Used for managing autoimmune disorders and severe allergies.

INFLAMMATORY BOWEL DISEASE IN PETS

Overview

• Characterized by an abundance of inflammatory cells infiltrating the gastrointestinal tract, disrupting normal function and digestion.

• Symptoms include:

  • Vomiting: Indicative of gastrointestinal distress or obstruction.

  • Weight loss: Resulting from malabsorption or reduced food intake due to discomfort.

  • Changes in appetite (increased/decreased) reflecting the animal's discomfort.

  • Diarrhea & excessive flatulence: Common signs of poor digestion and absorption.

  • Commonly affects middle-aged to older animals.

  • Can affect various segments of the intestines: stomach, small intestine, and large intestine (colon and rectum).

EFFECTS OF GLUCOCORTICOIDS

• Catabolic effects resulting in enhanced protein breakdown, leading to increased blood glucose levels through mechanisms of gluconeogenesis and glycogenolysis, which can affect glucose metabolism over time.

NEGATIVE EFFECTS OF GLUCOCORTICOIDS

• Potential side effects include:

  • Delays healing process by affecting cellular regeneration.

  • Immune system suppression, increasing the risk of opportunistic infections.

  • Muscle wasting and atrophy due to catabolic effects on skeletal muscle.

  • Risk of induced abortion or parturition in pregnant animals due to hormonal changes.

  • Hyperglycemia concerns in diabetic animals, indicating the need for close monitoring and management.

  • Alters hemogram leading to stress leukogram changes, complicating diagnostic assessments.

GLUCOCORTICOIDS - USES

• Treatment of non-infectious inflammation includes:

  • Allergies and allergic reactions that are unresponsive to other treatments.

  • Immune-mediated diseases like autoimmune hemolytic anemia or immune-mediated polyarthritis.

  • Anaphylactic shock requiring immediate management.

  • Spinal cord trauma, wherein rapid control of inflammation can preserve neurological function.

  • Certain neoplasia cases that benefit from inflammatory control.

GLUCOCORTICOIDS CONTRAINDICATIONS

• Should not be used in:

  • Undiagnosed conditions, particularly when the underlying issue is infectious.

  • Fungal infections where immune suppression could worsen the condition.

  • During modified live virus vaccination, which relies on robust immune response.

  • In cases of corneal ulcers where healing is crucial, as corticosteroids can delay closure.

  • In pregnant animals due to potential adverse effects on fetal development.

  • In immature animals and those with pre-existing liver disease due to their compromised metabolic capacity.

SIDE EFFECTS OF GLUCOCORTICOIDS

• Issues may arise such as:

  • GI clinical signs, including nausea and gastric ulcers, necessitating preventive measures.

  • Immunosuppression, raising concern for infectious diseases.

  • Challenges for diabetic patients, requiring ongoing glucose monitoring.

  • Complications in pregnant animals, including teratogenic effects.

SAFE USE OF CORTICOSTEROIDS

• Recommendations for glucocorticoid therapy include:

  • Use alternatives like NSAIDs if possible to minimize adverse effects.

  • Administer the smallest effective dose and taper as soon as feasible to prevent rebound inflammation.

  • Avoid continuous use; instead, consider alternating day regimens to mitigate negative impacts.

  • Prefer short-acting glucocorticoids when possible to facilitate easier recovery and monitoring.