2324 MD137 Lecture IV (1) PDF

Major Classes of Eicosanoids Prostaglandins Thromboxanes Prostacyclins Leukotrienes HETES Universit y ofGalway. ie Synthesis of Eicosanoids Effects of Eicosa...

Major Classes of Eicosanoids Prostaglandins Thromboxanes Prostacyclins Leukotrienes HETES Universit y ofGalway. ie Synthesis of Eicosanoids Effects of Eicosanoids Induction of inflammation Mediation of pain signals Induction of fever Smooth muscle contraction (including uterus) Smooth muscle relaxation Protection of stomach lining Simulation of platelet aggregation Inhibition of platelet aggregation Universit y Sodium and water retention ofGalway. ie  Clinical Relevance Patient Profile: John Smith, 52Yo Male Medical History: Hypertension, hyperlipidemia. Presentation: Joint pain, stiffness, low-grade fever, and fatigue. Over-the-counter NSAIDs provide minimal relief Physical Examination: Swollen and tender joints (hands, knees) with Mild hypertension (150/90 mmHg). Laboratory Findings: Elevated erythrocyte sedimentation rate and c-reactive protein indicating inflammation. Plasma levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) are significantly elevated Diagnosis: Likely inflammatory arthritis, with elevated eicosanoids contributing to inflammation and pain Treatment Considerations: NSAIDs: A stronger prescription NSAID may be initiated. Corticosteroids: Consider for rapid inflammation reduction. DMARDs: (Disease-modifying antirheumatic drugs ) Methotrexate if RA is confirmed. Universit Eicosanoid Modulation: Targeting the eicosanoid pathway y ofGalway. Lifestyle Modifications: Increase omega-3 fatty acids (e.g., fish oil) to help modulate inflammation ie  Synthesis of Hormone Derivatives of Tryptophan Amino Acid Derived Hormones Universit y Universit ofGalway. y ie ofGalway. ie  Synthesis of Hormone Derivatives of Tyrosine Universit y Universit ofGalway. y ie ofGalway. ie  Synthesis of Hormone Derivatives of Tyrosine Universit y Universit ofGalway. y ie ofGalway. ie Transport of Hormones Peptide or Protein Hormones Dissolve Easily in Plasma Still Carried Bound to Carrier Proteins Steroid or Amine Hormones Relatively Insoluble in plasma Majority (>90%) of Steroids Transported Bound to Protein Weak Chemical Bonds - Hydrogen/ ionic bonds/van der waals Resulting Affinity can be Strong Typically Only 1-10% of Total Hormone is Free Only Free Hormone is Active Bound and Free hormone Always in Equilibrium Universit y ofGalway. ie Binding Hormones Specialised Binding proteins High Affinity but Low Capacity Present only in Small Amounts CBG-Cortisol Binding Globulin TBG- Thyroxin Binding Globulin Non-Specialized Binding Proteins Low Affinity- High Capacity Binds Steroids and Thyroid Hormnes Plasma Albumins also TBPA Universit y ofGalway. ie Consequences of Binding Prevents Over Action of Hormone Only “Free” is Biologically Active Normally only Free hormone Binds Receptor Prolongs Effect of Hormone Inactivation in Liver and Excretion in Urine is Delayed Increases Total Hormone Carrying Capacity of Blood Prevents Large Fluctuations in Active Hormone Levels Increased Reservoir of Hormone Equilibrium Between Free and Bound Forms Universit y ofGalway. ie Hormone Concentration in Blood Peptides Levels May be as Low as 10-12M ADH 10-12 to 10-11 or 10-10M Glucagon and Insulin Approx. 10-9M Steroids Much Higher Levels Cortisol at 10-7M Steroid Sex Hormones at 10-7M to 10-10M Aldosterone is an Exception 10-10M NOTE: Variation In Patterns Universit y ofGalway. ie  Patterns of Hormone Secretion Chronic hormone secretion - relatively constant concentration of hormone Acute hormone secretion in response to a stimulus Episodic (Cyclic) hormone secretion Universit y ofGalway. ie Hormone Specificity - Hormones Affect Only Target Tissues with Specific Receptors Receptors Present on Cell Membrane or Cytoplasmic Receptor Number NOT Constant - Normally degraded and replaced regularly Down-regulation Rate of synthesized decreases after prolonged hormonal exposure Prolonged hormone exposure can increase the rate at which receptor molecules are degraded. Explains the desensitization that can occur to some drugs Universit y ofGalway. ie Increase in Receptor Number- Up regulation Increase in synthesis of receptors for a hormone, thus increases sensitivity to that hormone FSH stimulation of the ovary causes an increase of LH receptors Universit y ofGalway. ie Receptor Location – Protein/Peptide Hormones Unable to pass through the plasma membrane Size and Charge Receptors must be located on the plasma membrane Extracellular Domains - Exposed to Extra-Cellular Surface Interact with & Binds Hormone - Ligand-Binding Domain Trans-Membrane Domains - Span Cell membrane Hydrophobic Stretches of Amino Acids that Anchor the Receptor in Cell Membrane Cytoplasmic or Intracellular Domains Interact with Other Intracellular Molecules, Generate of Second Messengers - Effector Region Universit y ofGalway. ie cAMP Second Messenger System Universit y ofGalway. ie Turning off of the signal: 1 Ga hydrolyzes GTP to GDP + Pi Presence of GDP on Ga so it rebinds to inhibitory bg complex Adenylate Cyclase is no longer activated 2. Phosphodiesterases catalyze hydrolysis of cAMP to AMP Universit y ofGalway. ie Universit y ofGalway. ie Amplification Universit y ofGalway. ie PI Second Messeng er System Universit y ofGalway. ie  Other Protein Hormone Receptors Trans-membrane receptors with intrinsic tyrosine kinase activity Receptor tyrosine kinase Receptors for insulin and many growth factors Universit y ofGalway. ie Steroid Hormone Action Universit y ofGalway. ie Thyroid Hormone Nuclear Receptor Universit y ofGalway. ie Universit y ofGalway. ie Universit y ofGalway. ie Universit y ofGalway. ie