Principles of Inflammation and Immune Pharmacology PDF

Inflammation Dr. Fatemah Alherz PHS 310 1 Objectives Briefly review the inflammatory process Discuss the pharmacologic strategies of managing inflammation Explain mechanisms of action of anti- inflammatories with emphasis on actions on eicosanoids and...

Inflammation Dr. Fatemah Alherz PHS 310 1 Objectives Briefly review the inflammatory process Discuss the pharmacologic strategies of managing inflammation Explain mechanisms of action of anti- inflammatories with emphasis on actions on eicosanoids and histamine. Describe major features of some anti- inflammatory agents. 2 What is Inflammation? A complex set of responses to tissue injury and infection, characterized by the classic signs of redness, heat, swelling, pain and loss of function. The immune system includes the cells and soluble factors, such as antibodies and complement proteins, which mediate the inflammatory response; Thes cells and factors both eliminate the inciting inflammatory stimulus and initiate immunologic memory. 3 Triggers of Inflammation Triggered by a variety of stimuli such as: Trauma Exposure to a foreign substance Infectious agents Ischemia Immune reactions 4 Any benefit of inflammation? For combating foreign invaders. To remove the inciting stimulus and resolve tissue damage. 5 Inflammation (cont.) Inflammation can inadvertently cause local tissue damage, Sometimes can persist for too long → chronic injury, Either because of a long-term inappropriate response to a stimulus (e.g., allergies) or Because the offending agent is not removed (e.g., chronic infection, transplantation, and autoimmunity). 6  Mediators of Inflammation An insult (trigger) → Stimulates a local cytokine cascade (IL- Interleukins; or TNF – Tumor Necrosis Factor) → in turn stimulate enzymes (e.g. COX-2, LOX) → in turn facilitate the production of pro-inflammatory mediators (e.g. PGs & LTs) → in turn promote the infiltration of inflammatory cells → more mediators production ……….. 7 8 Feedback Mechanisms Purpose: To ensure that the inflammatory response cannot proceed unchecked. Help resolve inflammation and the return of the tissue to homeostatic conditions. 9 Feedback Mechanisms (cont.) Lipoxins Some eicosanoids PGE2- by inhibiting functions of B & T lymphocytes and NK cells; LTs by regulation of T cell proliferation 10 Overview of Arachidonic acid Pathways 11 Arachidonic Acid A common precursor to the majority of eicosanoids. Is biosynthesised from the essential fatty acid precursor linoleic acid. Alfa-linolenic acid, EPA, and DHA are called Omega-3 fatty acids. EPA: Eicosapentaenoic Acid DHA: Docosahexaenoic acid 12 Arachidonic Acid (cont..) In the cell arachidonic acid exists as esterified to membrane phospholipids. Released from the phospholipids by the enzyme Phospholipase A2 (the rate determining step in the generation of eicosanoids) 13 14 Products of the COX Pathway PGE2- Mast cells, macrophages Potentiation of responses to painful stimuli, vasodilation, bronchoconstriction, fever, inflammatory cell activation, mucus production. 15 Products of the COX Pathway PGF2alpha- Bronchial smooth muscle, Uterine smooth muscle, vascular smooth muscle Vascular tone, bronchoconstriction, abortion PGD2- Neuron, mast cells Bronchoconstriction (asthma) Sleep control functions Alzheimer’s disease 16 Products of the COX Pathway PGI2- Endothelium Vasodilation, inhibition of platelet aggregation TXA2- Platelets Vasoconstriction, platelet activation The local balance between TxA2 and PGI2 levels regulates arterial resistance (and thus blood pressure) and thrombogenesis. 17 Products of the LOX Pathway LTB4- Neutrophils Activation of neutrophils (migration, degranulation, Superoxide generation, eicosanoid synthesis) Potentiate the action of natural killer cells. 18 Products of the LOX Pathway LTC4, LTD4 (cysteinyl leukotrienes ) Bind to CysLT1 receptors to cause: Vasoconstriction, bronchospasm, and increased vascular permeability. Cysteinyl leukotrienes are responsible for the hyperreactivity to stimuli and the airway and vascular smooth muscle contraction that occur in asthmatic, allergic, and hypersensitivity processes. 19 Lipoxins Sequential action on arachidonic acid by LOX followed by hydrolysis → lipoxins LXA4 & LXB4 Have anti-inflammatory and pro-resolving roles. Are counter-regulators of Leukotriene actions 20 Some Inflammatory Diseases Asthma Rheumatoid arthritis Inflammatory bowel disease Glomerulonephritis Inflammation is also contributory to: CV disease Cancer 21 Pharmacologic Anti-inflammatory Strategies 1. Targeting the mediators of inflammation or components of the immune system. 2. Modification of the underlying pathophysiologic cause. 22 Targeting the mediators of inflammation or components of the immune system 23  Pharmacologic Classes of Anti-inflammatories Glucocorticoids COX inhibitors Leukotriene inhibitors Thromboxane Antagonists (no clinical utility yet) Cytokine inhibitors Lipoxins/protectins/maresins- Under study. 24 Glucocorticoids Lowering & inhibition of lymphocytes & macrophages. Indirect inhibition of phospholipase A2 (by elevation of lipocortin) →blocks release of arachidonic acid (precursor of PGs and LTs) Reduction COX-2 synthesis Interfere with mast cell degranulation → decreased histamine release 25 26 NSAIDs NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) Inhibit the activity of cyclooxygenase enzymes: COX-1 and COX-2 are necessary for the production of prostaglandins (PGs). Except for aspirin, all NSAIDs act as reversible, competitive inhibitors of cyclooxygenase. The antipyretic activity of NSAIDs is likely related to their ability to decrease the levels of PGE2, particularly in the region of the brain surrounding the hypothalamus. 27 Leukotriene Inhibitors CysLT1(Cysteinyl leukotriene receptor 1) receptor antagonists: Montelukast & Zafirlukast Use: in treatment of asthma 28 Leukotriene Inhibitors (cont.) 5-LOX inhibitor: zileuton (acts by chelating the non-heme iron) Limited use in asthma FLAP (5-Lipoxygenase Activating Protein) inhibition: not available for clinical use. 29 Cytokines Pro-inflammatory cytokines TNF-α and IL-1 Enhance PG production Upregulate COX-2 30 Cytokine inhibitors TNF-α antagonists: Infliximab: a humanized mouse monoclonal antibody directed against TNF-α Adalimumab: human IgG1 monoclonal antibody that specifically binds to tumor necrosis factor (TNF)-alpha Uses: Rheumatoid arthritis, inflammatory bowel disease, autoimmune diseases. Adverse effects: increased risk of serious infections 31 Cytokine inhibitors (contd..) IL-1 antagonist: Anakinra In rheumatoid arthritis Adverse effects: increased risk of serious infections 32  Interplay of Inflammatory cells and mediators The complexity is reflected in the complex inflammatory diseases such as Rheumatoid Arthritis, Inflammatory bowel disease, Asthma, Gout ….. Management of such diseases is thus dependent on tackling the pathologic conditions by various mechanisms. E.g. Drugs for Rheumatoid Arthritis 33 Drugs used in Rheumatoid Arthritis NSAIDs Glucocorticoids DMARDs Disease Modifying Anti-Rheumatic Drugs E.g. methotrexate, azathioprine, cyclosporine Through their immunosuppressive/immunomodulatory effects. IL-1 antagonist: Anakinra 34 Drugs used in Rheumatoid Arthritis (cont.) Biologics T-cell modulating : abatacept B-cell cytotoxic agent: rituximab Anti-IL-6 receptor antibody: tocilizumab TNF-alpha blocking agents: e.g., adalimumab, infliximab 35 Histamine Is an autocoid A major mediator of immune, allergic & inflammatory processes Histamine also plays a role in: Regulation of gastric acid secretion Neurotransmission Immune modulation 36  Systemic mast cell degranulation can cause the Histamine life-threatening condition known as anaphylaxis. and Typically, anaphylactic shock is initiated in a previously sensitized individual by a Anaphylaxis hypersensitivity reaction to an insect bite, an antibiotic such as penicillin, or ingestion of certain highly allergenic foods such as peanuts. 37  Histamine Receptors Involved in Inflammation H1 receptors: Expressed primarily on vascular endothelial cells & smooth muscle cells Mediate inflammatory and allergic reactions Result in edema, bronchoconstriction, sensitization of primary afferent nerves 38  1. Administration of Antihistamines Strategies of Inhibition of 2. Prevention of mast cell degranulation Actions of Histamine 3. Functionally counteracting the effects of histamine 39 40 Antihistamines Act on H1 receptor Are inverse agonists Bind to the inactive conformation of H1 & shift the equilibrium towards the inactive state. Are Classified as First and Second Generation Antihistamines. 41  First Generation H1-Antihistamines Include: Diphenhydramine, Promethazine Cross the BBB & block the actions of histaminergic neurons. Are less selective; may bind to: Cholinergic, alpha-adrenergic, & serotonergic receptors. Major Adverse effects: drowsiness, dry mouth. 42  Second Generation H1-Antihistamines Include: Loratadine, fexofenadine, olopatadine High albumin binding and Low lipophilicity, → therefore do not cross the BBB significantly → less CNS adverse effects More selectivity toward H1 receptors →less adverse effects 43 Clinical Uses of H1-Antihistamines Allergy: Relieve symptoms of rhinitis, conjunctivitis, urticarial, & pruritus H1-antihistamines strongly block the increased capillary permeability necessary for forming edema and are therefore, more effective when used prophylactically than after an allergic reaction has begun. Oral, & sometimes topical (e.g. olopatadine eye drop for allergic conjunctivitis ) may be used Generalized itching: The potent anti-pruritic agents Hydroxyzine Have significant CNS effects 44 Clinical Uses of H1-Antihistamines Nausea & Motion Sickness: First generation H1-antihistamines E.g. Promethazine MOA: inhibiting histaminergic signals from vestibular nucleus to vomiting center of medulla. Insomnia: Through their CNS depressive effects First generation: e.g. diphenhydramine 45 Limitations of H1-Antihistamines Antihistamines Not used as monotherapy in asthma Other mediators like leukotrienes have significant contributions to asthma, whereas antihistamines have minimal effects. No application in many complex immune/inflammatory diseases. Ineffective in anaphylaxis Other local mediators of anaphylaxis are unaffected by antihistamines. Epinephrine – treatment of choice for anaphylaxis. 46 Summary Drugs that modulate the Inflammatory/immune responses play very important roles in the treatment of various inflammatory/immune diseases and allergic conditions. Some conditions can be alleviated by a single agent, as in a simple allergic reaction; and many complex conditions such as rheumatoid arthritis may need to be tackled by the use of different agents depending on the severity of the disease. 47 Question? 48