VEM027 Lecture 1 PDF

Veterinary Clinical Pharmacology DEAN SIDNEY S. LEYSON, DVM Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Key Concepts Pharmacokinetics...

Veterinary Clinical Pharmacology DEAN SIDNEY S. LEYSON, DVM Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Key Concepts Pharmacokinetics Pharmacodynamics What the body does to the What the drugs do to the body.. drugs.. Veterinary Clinical Pharmacology Drug Selection & Drug Dosage & Administration Formulation What drug to use and How much of the drug how to give the drug.. and in what form.. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Goals Effective treatment Select the most appropriate drug, dosage, and administration route for each individual animal. Minimizing Adverse Effects Maximize therapeutic benefits while minimizing adverse effects. Being able to assess risk and monitor drug safety. Rational Drug Use Usage of drugs based on scientific-evidence, clinical experience, as well as, emphasizing cost-effectiveness. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Goals Animal Welfare Alleviate suffering and disease prevention. Effective pain management strategies for animals and curing illnesses. Public Health Ensuring the safety of animal-derived food products by preventing and treating diseases in livestock and control spread of zoonotic diseases. Research & Development Developing new and improved veterinary drugs and evaluation of the safety and efficacy of drugs before they are marketed. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Inflammation DEAN SIDNEY S. LEYSON, DVM Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Inflammation National Cancer Institute: - a normal part of the body’s response to injury or infection. Inflammation occurs when the body releases chemicals that trigger an immune response to fight off infection or heal damaged tissue. Once the injury or infection is healed, the inflammatory process ends. Merriam Webster: - a local response to cellular injury that is marked by capillary dilatation, leukocytic infiltration, redness, heat, pain, swelling, and often loss of function and that serves as a mechanism initiating the elimination of noxious agents and of damaged tissue. National Library of Medicine: - inflammation is the body’s immune system’s response to an irritant. The irritant might be a germ, but it could also be a foreign object, such as a splinter in your finger Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Inflammation Physiologic? Pathologic? Pathologic/Chronic inflammation is an abnormal immune response in which the inflammatory process does not end when it should or may begin when there is no infection or injury. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Cardinal Signs Calor Rubor Functio laesa Dolor Tumor Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. When do anti-inflammatory drugs come in? Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Anti-inflammatory Drugs DEAN SIDNEY S. LEYSON, DVM Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Drug classifications Anti-histamines NSAIDs Corticosteroids Chondroprotective Agents Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Histamine Background: ▪ 2-(4-Imidazolyl)ethylamine ▪ Found in all tissues but is unevenly distributed (innate immune system). ▪ Stored primarily in granules of ____ and ____ cells. ▪ Component of venoms and insect stings Functions: ✓ Mediator of immediate allergic and inflammatory reactions. ✓ Gastric acid secretions. ✓ Neurotransmitter Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Histamines Functions: Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Histamine Mechanism of release: ▪ Injury to mast cells. ▪ Sensitization of mast cells and basophils by IgE. ▪ Degranulation of mast cells. Mechanism of action: Activation of H1 Receptors (endothelial and smooth muscle) ✓ Increase intracellular Ca++ Activation of H2 Receptors (gastric mucosa, cardiac muscles, immune cells) ✓ Increase intracellular cAMP Activation of H3 Receptors (CNS) ✓ Inhibits histamine synthesis and release, release of adrenaline Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Histamine Effects on tissue and organ systems: Cardiovascular System (H1, H2) ↓ blood pressure ↑ heart rate (+chronotropic) ↑ force of contraction (+inotropic) Skin (H1, H2) Vasodilation & ↑ capillary permeability Lewis Triple Response 1. Flushing – appearance of the red line after stroking 2. Flaring – redness surrounding the red line 3. Wheal – localized edema fluid Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Histamine Effects on tissue and organ systems: Intestinal smooth muscles (H1) Contraction leading to cramps & diarrhea Bronchiolar smooth muscle (H1) Constriction leading to asthma & ↓ lung capacity Exocrine excretion (H1) ↑ production of mucus Nerve Endings (H1) Pruritus & pain Stomach (H2) ↑ HCl secretion by parietal cells Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Anti-histamines Histamine Histamine Release Antagonist Inhibitors Epinephrine Cromolyn sodium Beta-2 adrenoceptor stimulants Histamine Receptor Antagonists H1 Blockers H2 Blockers Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Epinephrine Trade & Other Name: Adrenaline Functional Classification: Adrenergic Agonist MOA: ✓ Non-selectively stimulates alpha-adrenergic and beta- adrenergic receptors (Alpha-1 & Beta-2). Effects: ↑ heart rate and force of contraction ↑ vascular resistance and potent vasopressor ↑ bronchodilation ↓ inflammatory mediators in the airways ↑ glycogenolysis and blood sugar Pupillary dilation Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Epinephrine Indications: ✓ Emergency situations to treat cardiopulmonary arrest and anaphylactic shock ✓ Test for diagnosing anhidrosis in horses ✓ Prolong DOA of local anesthetics Contraindications: ✓ DO NOT USE to treat cardiac effects caused by alpha-2 agonists. ✓ Hypersensitivity to epinephrine. ✓ Ventricular fibrillation ✓ Vasopressor contraindications ✓ Small body appendages Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Epinephrine Doses: For cardiac resuscitation Dogs & Cats: 0.01-0.02mg/kg IV; 0.1mg-0.2mg/kg IV/IO Birds: 0.1mg/kg IV/IC Newborn Foals: 0.01-0.02mg/kg IV For anaphylaxis Dogs & Cats: 0.01-0.02mg/kg IV; 0.1mg-0.2mg/kg IV/IO Horses: 3–5 mL per 450 kg of body weight, IM/SC Ruminants/Swine: 0.5–1 mL/100 lbs. body weight, IM/SC Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Histamine Release Inhibitors Chromolyn Sodium Beta-2 adrenoceptor stimulants MOA: ✓ inhibiting the release of inflammatory mediators, such as histamine and leukotrienes, from mast cells. Effects: ↑ heart rate and force of contraction ↑ vascular resistance ↑ bronchodilation ↓ inflammatory mediators in the airways ↑ glycogenolysis and blood sugar Lipolysis & Diuresis Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Beta-2 Agonists Examples: Albuterol (most commonly used) Terbutaline (large animals) Ractopamine & Zilpaterol (growth promoters) Clenbuterol (cardiotoxic, muscle tremors, lean) Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. H1 Blockers MOA: ✓ Competitively block histamine action on smooth muscles Effects: Sedation Anti-emetic Anticholinergic Hypotension Anti-inflammatory Antitussive Local anesthetic Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. H1 Blockers Ethanolamines Dimenhydrinate Diphenhydramine HCl (Benadryl®) (2-4mg/kg PO 2-3x a day) Clemastine Carbinoxamine Doxylamine Ethylenediamines Antazoline Pyrilamine Tripennamine Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. H1 Blockers Piperazine Derivatives Cyclizine Meclizine (Bonamine®) (4mg/kg PO once a day) Hydroxyzine Carbinoxamine Doxylamine Ethylenediamines Antazoline Pyrilamine Tripelennamine Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. H1 Blockers Alkylamines Brompheniramine Chlorpheniramine Dechlorpheniramine Triprolidine Phenothiazine Promethazine Trimeprazine Methclilazine Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. H1 Blockers Piperidines Azatedine Terfenadine (2nd Gen, non-sedating) Miscellaneous Loratidine (Claritin®) (2nd Gen, non-sedating) Astimizole (2nd Gen, non-sedating) Cetirizine (2nd Gen, relatively non-sedating) Dose: 1mg/kg PO once daily Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. NSAIDs NSAIDs vs Steroids Inhibit the production Suppress the immune of prostaglandins, system, reducing which are substances inflammation that promote inflammation and pain. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. NSAIDs Nonselective COX Inhibitors Dual Inhibitor Enolic Acids Tepoxalin Carboxylic Acids COX-2 Selective Inhibitors Coxibs Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Cyclooxygenase (COX) Responsible for converting arachidonic acid into prostaglandins, which play a crucial role in various physiological processes, including inflammation, pain, and blood clotting. Isoforms: COX-1, COX-2, COX-3 Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. NSAIDs COX1 vs COX2 “House keeping enzyme”. An inducible enzyme Maintains homeostatic primarily produced at processes including sites of inflammation in gastric mucosal response to injury or cytoprotection, renal infection. function, vascular homeostasis, & platelet aggregation. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Non-selective COX Inhibitors Enolic Acids Oxicams Pyrazolones Carboxylic Acids Salicylates Indoleacetic Acids Indolines Thiophenacetic Acids Propionic Acids Anthranilic Acid Aniline Derivatives Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Oxicams Meloxicam Unique Characteristics: COX-2 > COX-1 Tx/Mgt of muscoskeletal disorders and postoperative pain and inflammation. Mostly used in dogs and cats. Relatively more GIT safe than other NSAIDs. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Oxicams Piroxicam Unique Characteristics: COX-1 > COX-2 Anti-tumor effects (bladder transitional cell carcinoma) Extensive enterohepatic recycling. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Pyrazolones Phenylbutazone Unique Characteristics: COX-1 > COX-2 One of the earliest NSAID’s for horse and dogs primarily used in horses for muscoskeletal issues. Banned for use in humans due to risk of hypersensitivity Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Pyrazolones Dipyrone Unique Characteristics: COX-1 > COX-2 Relaxes GIT smooth muscle in a not well understood mechanism. Toxic effects as phenylbutazone Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Salicylates Aspirin Unique Characteristics: COX-1 > COX-2 Frequently used in veterinary medicine but extra label. With anti-platelet properties Cats are more relatively sensitive than dogs. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Indoleacetic Acids Etodolac Unique Characteristics: COX-1 sparing than COX-2 selective 2nd Gen NSAID Inhibits macrophage chemotaxis Rarely used today due to toxicity attributed to extensive enterohepatic recycling. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Indolines Indomethacin Unique Characteristics: COX-1 > COX-2 Highly toxic in dogs Causes severe ulceration, hematemesis, and melena at therapeutic doses. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Thiopheneacetic Acid Diclofenac Unique Characteristics: COX-1 > COX-2 First NSAID shown to be toxic to scavenging birds and has been banned for veterinary use. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Propionates Carprofen Unique Characteristics: COX-2 > COX-1 Used extensively in dogs, but contraindicated in dogs with bleeding disorders. Tx/Mgt associated with osteoarthritis. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Propionates Ketoprofen Unique Characteristics: Inhibits COX, LOX, and bradykinins. Short term analgesia for horses, dogs, and cats. Tx/Mgt for colic in horses as well as pain due to orthopedic and soft tissue surgery. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Propionates Ibuprofen Unique Characteristics: Not recommended for use in dogs and cats. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Propionates Naproxen Unique Characteristics: Tx/Mgt for myositis and tying-up syndrome in horses. Chondrotoxic Too toxic for dogs especially Beagles due to extensive recycling. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Anthranilic acids Meclofenamic Acid Unique Characteristics: COX-1 > COX-2 Similar with mefenamic and tolfenamic acids. More potent than phenylbutazone in inflammatory effects. Significant anti-thromboxane activity. Not recommended for use preoperatively. Avoid use in pregnancy especially near term. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Anthranilic acids Flunixin Meglumine Unique Characteristics: Only NSAID used in a variety of species especially in horses. Short-acting, long duration of action. Primary Tx/Mgt for equine colic. Tx/Mgt for mastitis and acute pulmonary emphysema in cattle. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Aniline Derivatives Acetaminophen Unique Characteristics: Extremely toxic to cats and less toxic to dogs. Not technically considered as an NSAID due to low anti-inflammatory activity. Inhibits COX-3 Depletes hepatic glutathione. The least toxic member of this group. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. COX-2 Selective Inhibitors Coxibs Deracoxib Firocoxib Rofecoxib Celecoxib Valdecoxib Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Coxibs Deracoxib Unique Characteristics: Highly selective to COX-2 Approved for dogs Alternative to piroxicam as anti-tumor for bladder cell carcinoma. Used in post-operative pain and inflammation mgt after orthopedic surgery and osteoarthritis. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Dual Inhibitor Tepoxalin Unique Characteristics: Selective inhibition for LOX Used in dogs to alleviate osteoarthritis. Rapid onset, long duration of action. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved.  Corticosteroids Glucocorticoids vs Mineralocorticoids Primarily involved in Primarily regulate stress response and electrolyte balance, immune regulation. especially sodium and potassium. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Corticosteroids Glucocorticoids Hydrocortisone/Cortisone Prednisone/Prednisolone Dexamethasone Betamethasone Flumethasone Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Glucocorticoids MOA: ✓ Inhibition of pro-inflammatory cytokines. ✓ Reduction of inflammatory mediators. ✓ Inhibition of immune cell activation. ✓ Promotion of anti-inflammatory mediators. Indications: ✓ Severe systemic inflammation ✓ Immune-mediated diseases ✓ Shock Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Glucocorticoids Effects: ✓ Overall immunosuppression. ✓ Potent anti-inflammatory effects. ✓ Stabilization of lysosomal membranes. ✓ ↑ Blood glucose ✓ ↑ Protein catabolism ✓ ↑ Lipid redistribution Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Glucocorticoids Complications: ✓ Cushing’s Syndrome (Iatrogenic Hyperadrenocorticism) ✓ Adrenal insufficiency on withdrawal ✓ Poor wound healing ✓ Severe immunosuppression ✓ Growth retardation ✓ Excessive catabolism ✓ Myopathy and muscle weakness ✓ Liver function disorder ✓ Diabetes Miletus Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Glucocorticoids Cortisol/Corticosterone Unique Characteristics: Two most important naturally occurring glucocorticoids. Cortisol Humans, Pigs, Dogs Corticosterone Rabbit, Mouse, Rat Short-acting Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Glucocorticoids Prednisone/Prednisolone Unique Characteristics: Used for long term therapy. Prednisone Inactive form – used in dogs Prednisolone Active form – used in cats and horses. Intermediate-acting Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Glucocorticoids Dexamethasone Unique Characteristics: Used in life-threatening cases. In order of potency Flumethasone > Betamethasone > Dexamethasone Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Chondroprotective Agents MOA: Inhibition of inflammatory mediators. Neutralization of free radicals. Indications: Joint problems Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Chondroprotective Agents Sodium Hyaluronate Unique Characteristics: Free salt of hyaluronic acid, extracted from rooster combs. Inhibits PGE2 synthesis, inflammatory enzymes, and reduce pain. Labeled for use in horses (return to normal function after one injection. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Chondroprotective Agents Polysulphated Glycosaminoglycan (PSGAG) Unique Characteristics: Resembles the ground substance of cartilage (chondroitin) from bovine tracheal cartilage. Inhibit inflammation and protect cartilage from degeneration. Reduce PGE2 release and inhibits catabolic enzymes (elastase, metalloproteases). Used only in non-infectious degenerative or traumatic joint diseases. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Chondroprotective Agents Pentosan Polysulphate Sodium (PPS) Unique Characteristics: An ester of xylan from beechwood plant material. Similar to PSGAG in MOA Decrease cytokine activity Resembles heparin chemically Used in interstitial cystitis in man and osteoarthritis in dogs. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Chondroprotective Agents Orgotein Unique Characteristics: Water soluble metalloprotein containing zinc and copper, found in low concentrations in the body. Has superoxide dismutase activity and scavenges oxygen free radicals. Used in soft tissue inflammation, lameness in horses, and arthritis in dogs. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Miscellaneous Agents Dimethylsulphoxide (DMSO) Unique Characteristics: Used particularly in pain and swelling from limb injuries in horses and dogs. Scavenger of free hydroxyl radicals of oxygen; osmotic diuretic Analgesic action: reduction or interference with pain impulse conduction in peripheral nerves. Potentiates activity of atropine and endogenous steroids. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved. Prepare for a 20-item quiz next meeting. Any unauthorized reproduction and/or distribution of this document is punishable by law. Ⓒ 2024 D.S. Leyson. All Rights Reserved.