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Describe the main routes of drug elimination - Kindney: urine for polar drugs Hepatobiliary: excretion of drugs as bile → back to intestine → as feces Milk and Sweat Lungs for volatile/gaseous anaesthetics Describe the main types of drug metabolism (biotransformation) - Occurs in the liver by mic...

Describe the main routes of drug elimination - Kindney: urine for polar drugs Hepatobiliary: excretion of drugs as bile → back to intestine → as feces Milk and Sweat Lungs for volatile/gaseous anaesthetics Describe the main types of drug metabolism (biotransformation) - Occurs in the liver by microsomal cytochrome CYP450 Developed as a way to combat plant toxins Lipophilic drugs are able to be metabolised since they can cross the plasma membrane Phase I reactions: General characteristics, P450 monooxygenases, other reactions - Rxtn introduces a hydroxyl (OH) which is the point of attack for the glucuronide in Phase II Prodrugs that are inactive are activated this way Make drug more reactive/toxic and carcinogenic Monooxygenation requires flavoprotein, NADH, drug subrate, O2 and P450 enzyme Inhibitors of P450 o Can be competitive (compounds that compete for the active site but are not the enzyme’s substrate o Suicide inhibition: oxidate product binds covalently and is activated by P450 → then it kills the enzyme o Non competitive inhibition: forms a tight complex with P450 Other reactions - Alcohol dehydrogenase for ethanol Xanthine oxidase Monoamine oxidase: noradrenaline, dopamine and 5-hydroxytrypatmine Reductive reactions: warfarin hydrolytic reactions: aspirin in plasma CYP - In the smooth er (microsomes) Main families are CYP 1-3 CYP enzymes may be responsible for catalyzing the same drug CYP2E1 catalyzes alcohol and paracetamol so if you take both at the same time they compete with each other and enhance the effects of toxic byproducts that cause liver damage Differ due to the amino acid sequences, inhibitors, inducing agents, drugs they catalyze Grapefruit inhibits drug metabolism, brussel sprouts and smoke induce P450 enzymes and St johns wort induces P-glycprotein a CYP isoenzyme Phase II reactions, general characteristics - Anabolic Make drugs more hydrophilic/less lipid soluble and inactive Adds conjugate: glucuronide if there is a hydroxyl, thiol or amino group o Glucuronyl is transferred from uridine diphosphate glucuronic acid Recognize the following terms: bioactive metabolites, prodrugs, microsomal enzyme induction - Prodrugs: become pharmacolgically active after metabolism and include levodopa and clopidogrel Describe stereospecificity of drugs; first-pass (presystemic) metabolism; and enterohepatic recirculation of drugs - Drugs like ibuprofen and warfarin are stereoisomers - First pass: metabolism in the liver and gut before reaching site of action, important for drugs like levodopa, morphine, aspirin, propranolol. Large dose needed per os (for therapeutic effects). Reduces bioavailability. Enterohepatic: recirculation of drugs from gut to liver (conjugated products are secreted via bile, reactivated in the intestine and then reabsorbed Characterize and compare three fundamental processes that account for renal drug excretion - Glomerular filtration: about 20% of the drug leaves through initial filtration in the glomerulus Active tubular secretion: 80% travels into the peritubular capillaries where the drug is actively pumped into the proximal tubule Passive reabsorption: drugs that are lipidsoluble will cross the membranes to back into the pertibular capillaries Proximal tubule leads to the excretion of the drug as urine Only free drugs no plasma bound will be glomerulalry filtered and make it to excretion Carrier mediated transport of the peritubulkar capillaries make sit so that plasm abound drugs can be excreted Clinical Pharmacokinetics 1. Definitions: 2. 3. 4. 5. • Drug Clearance (CL): The rate at which a drug is eliminated from the body relative to its plasma concentration, often measured in L/h. the higher the drug concentration in plasma, the higher the rate of elimination • First-Order Kinetics: The rate of drug elimination (metabolized or excreted) is directly proportional to its concentration in systemic circulation, commonly observed with most drugs. Because the clearance mechanisms for most drugs are not saturated, increases in plasma drug concentration are matched by increases in the rate of drug metabolism and excretion • Zero-Order Kinetics: Saturation kinetics where the elimination rate remains constant despite increasing drug concentration. Leads to disproportionate concentration of drug in plasma. Used by ethanol, due to oxidation of ethanol by alcohol dehydrogenase reaches a maximum at low ethanol concentrations due to limited availability of NAD+ • Saturation Kinetics: A subset of zero-order kinetics where clearance mechanisms become saturated. • Drug Half-life t(1/2): The time required for the concentration of a drug in the plasma to decrease by half. Knowledge of half life allows for the estimation of the frequency of dosing to maintain plasma conc of drug in the therapeutic range. The longer the half life the longer the drug will remain in the body after dosage • Rate of absorption: how quickly the drug gets into plasma. drugs with higher rates of absorption have more plasma concentration. Single-Compartment Model: • Represents the body as a single homogenous compartment. Dose → Volume of distribution (one compartment) → elimination via excretion and metabolism • Elimination follows first-order kinetics. So half life is dependent on clearance and volume of distribution • Describes drug distribution and elimination simplistically. Two-Compartment Model: • Involves a central compartment (plasma) and a peripheral compartment (tissues). • More realistic representation of drug distribution and elimination. • Introduces a second exponential component in the plasma concentration time course. Factors Affecting Drug Elimination Half-life: • Physiological changes such as age and disease status. Age causes skeletal muscle mass to decrease which also decreases volume of distribution • Pharmacogenomic profile, including cytochrome P450 activity. Can be induced to reduce half life or inhibited to prolong half life • Cardiac output affecting blood supply to clearance organs. • Renal function impacting drug excretion. Repeated Dosage: • 6. Half-life and Saturation Kinetics: Steady state achieved after three to five (3-5) half-lives, if that is too slow a loading dose is used. Saturation kinetics result in constant elimination despite increasing drug levels. 1. after one half-life, the concentration will have fallen to half the initial concentration 2. after two half-lives, it will have fallen to one-quarter the initial concentration 3. after three half-lives, to one eighth • Loading Dose: Larger initial dose compensating for tissue distribution, reaching therapeutic levels faster. Bolus injection • Maintenance Dose: Subsequent doses to replace metabolized and excreted drug. Relationships: • • Clearance and Steady-State Concentration: Clearance determines the rate at which a drug reaches a steady-state concentration during constant infusion. 1. Clearance (CL) is the rate at which a drug is removed from the body. It determines how quickly the drug reaches a steady-state concentration during constant infusion. 2. Steady-state concentration (Css) is achieved when the rate of drug input (infusion rate) equals the rate of drug elimination (clearance). It reflects a balance between drug intake and removal. Drug Concentration at Zero Time and Volume of Distribution: 1. Concentration at zero time (C0) is the drug concentration immediately after administration. 2. Volume of distribution (Vd) estimates the apparent volume into which a drug distributes. The relationship C0 = X / Vd, where X is the dose, helps understand the initial drug distribution in the body. • Maintenance Dose and Clearance: The rate of drug input (maintenance dose) equals the rate of drug output (clearance) at steady state. Maintenance dose is the ongoing dose needed to maintain a steady-state drug concentration. • Loading Dose and Volume of Distribution: Larger initial dose compensates for tissue distribution, dependent on the volume of distribution. Volume of distribution influences the loading dose calculation (Loading Dose = C0 * Vd), considering the initial drug distribution into tissues. NSAIDs . Introduction to Anti-Inflammatory Drugs • Definition: • • Anti-inflammatory drugs are substances that alleviate inflammation, typically used for conditions involving pain, swelling, and fever. Major Groups: • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Disease-Modifying Antirheumatic Drugs (DMARDs) and Immunosuppressants • Glucocorticoids • Anti-Cytokines and Other Biopharmaceutical Agents • Antihistamines (for allergic inflammation) • Drugs for Gout II. Comparison of COX Enzymes and Selective COX Inhibitors • COX Enzymes: • • • COX-1: • Constitutive expression in most tissues. • Role in tissue homeostasis, gastric cytoprotection, platelet aggregation, renal blood flow. COX-2: • Induced in inflammatory cells during activation. • Responsible for prostanoid mediators of inflammation. Selective COX Inhibitors: • COX-2 Selective Inhibitors (Coxibs): Vary in potency towards COX-2. • Second-generation Coxibs: Higher COX-2 vs. COX-1 inhibition ratio. III. NSAIDs: Chemical Structures and Pharmacological Actions • • 1. Chemical Structures: • Most NSAIDs are carboxylic acids. • Coxibs contain bulky groups impeding COX-1 enzyme access. Pharmacological Actions: Antipyretic Effects: • 2. Resetting the body's thermostat by affecting prostaglandin production in the hypothalamus. Analgesic Effects: • Reduction of inflammatory pain through various mechanisms. 3. Anti-Inflammatory Effects: • Suppression of components of the inflammatory response involving prostaglandins. IV. Molecular Pharmacology of NSAIDs • • Inhibition of Prostaglandin Biosynthesis: • NSAIDs inhibit prostaglandin biosynthesis by directly acting on the COX enzyme. • COX-1 and COX-2 are homodimers with distinct catalytic activities. • Most NSAIDs competitively and reversibly inhibit the initial dioxygenation reaction. Selective Inhibition: • Some drugs, especially those with bulky side groups, are more selective for COX-2. • Aspirin irreversibly inactivates COX-1 by acetylating a serine at position 530. 1. Main Side Effects of NSAIDs Gastrointestinal Effects • Gastric Cytoprotection: Prostaglandins normally inhibit acid secretion and protect the gastric mucosa. NSAIDs inhibit gastric COX-1, leading to increased risk of damage. • Gastrointestinal Damage: NSAIDs, including aspirin, can cause damage to the gastric mucosa, resulting in issues like gastric discomfort, dyspepsia, diarrhea, nausea, vomiting, bleeding, and ulceration. Renal Effects • Acute Renal Insufficiency: NSAIDs can pose a threat to kidney function, especially in susceptible individuals (neonates, elderly, patients with heart, liver, or kidney diseases). Inhibition of prostanoids involved in renal blood flow maintenance contributes to this effect. • Analgesic Nephropathy: Chronic NSAID consumption can lead to analgesic nephropathy characterized by chronic nephritis and renal necrosis. Other Side Effects • Skin Reactions: Rashes are common unwanted effects of NSAIDs, ranging from mild erythematous reactions to more serious, potentially fatal diseases. • Platelet Aggregation: Most NSAIDs, except COX-2 inhibitors, prevent platelet aggregation, potentially prolonging bleeding. Aspirin is a notable contributor to this effect. • Central Nervous System Effects: NSAIDs may cause CNS effects, bone marrow disturbances, liver disorders, and approximately 5% of patients exposed to NSAIDs may experience aspirin-sensitive asthma. • Reye's Syndrome: NSAIDs, particularly aspirin, are associated with Reye's syndrome in children. 2. Detailed Study of Aspirin Antiplatelet Action • Mechanism: Aspirin irreversibly inactivates COX-1, reducing thromboxane A2 synthesis in platelets. This antiplatelet action is exploited for thromboprophylaxis. • Dosage: Low doses (e.g., 75 mg once daily) are recommended for thromboprophylaxis, with higher doses for analgesia and anti-inflammatory purposes. Pharmacokinetics • Absorption: Aspirin is a weak acid absorbed in the ileum. • Metabolism: Rapidly hydrolyzed by esterases, yielding salicylate. • Excretion: Salicylate is excreted via urine; plasma half-life depends on the dose. Side Effects • General NSAID Effects: Aspirin shares general unwanted effects with NSAIDs, including gastrointestinal issues and platelet-related effects. • Salicylism: Overdose can lead to symptoms like tinnitus, vertigo, decreased hearing, nausea, and vomiting. • Salicylate Poisoning: Results in disturbances of acid-base and electrolyte balance, with potentially serious consequences. 3. Detailed Study of Acetaminophen (Paracetamol) Pharmacokinetics • Absorption: Well absorbed orally with peak plasma concentrations in 30-60 minutes. • Metabolism: Inactivated in the liver via conjugation to glucuronide or sulfate. • Excretion: Excreted unchanged or as metabolites in urine. Side Effects • Therapeutic Doses: Few and uncommon side effects. • Toxic Doses: Can cause potentially fatal hepatotoxicity, especially when liver enzymes are saturated. 4. Current Status with Coxibs (COX-2 Inhibitors) • Selective COX-2 Inhibitors: Include celecoxib and rofecoxib. • Goal: Provide anti-inflammatory and analgesic actions with reduced gastric damage. • Safety Concerns: Some studies showed safety benefits but raised concerns about increased cardiovascular events, leading to withdrawal of rofecoxib in 2004. Major Groups of Anti-Inflammatory Drugs: 1. 2. Drugs that Inhibit Cyclo-Oxygenase (COX) Enzyme: • Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) • Coxibs (COX-2 Selective Inhibitors) Antirheumatoid Drugs and Disease-Modifying Antirheumatic Drugs (DMARDs): • Used in autoimmune diseases • Includes some immunosuppressants 3. Glucocorticoids (Steroidal Anti-Inflammatories): 4. Anti-Cytokines and Other Biopharmaceutical Agents: 5. Antihistamines for Allergic Inflammation: 6. Drugs for Gout Control: 7. Immunosuppressants: • Used in autoimmune diseases and transplant rejection • Examples: cyclosporine, tacrolimus • Mechanism of Action: Act during the induction phase, reducing lymphocyte proliferation Features of Autoimmune Diseases: • Characterized by autoantibodies and autoreactive T cells against self-antigens. • Disease-specific autoantibodies often detected. Immunosuppressants: Clinical Uses: • Suppress rejection of transplanted organs. • Treat autoimmune conditions: idiopathic thrombocytopenic purpura, rheumatoid arthritis, lupus, etc. Immunosuppressants: Mechanism of Action: • Act during the induction phase, reducing lymphocyte proliferation. • Inhibit effector phase: drugs inhibiting IL-2 production or action, cytokine gene expression, purine/pyrimidine synthesis. Cyclosporine (CsA): • Discovered in 1972, specific T-cell immunity inhibitor. • Unique non-cytotoxic activity. • Used in whole-organ transplantation. • Derived from soil fungus Tolypocladium inflatum. Tacrolimus (FK506): • More potent than cyclosporine. • Binds to FK-binding proteins, inhibiting calcineurin. • Derived from soil bacterium Streptomyces tsukubaensis. Pharmacology of CsA vs. FK506: • CsA: Selective inhibition of IL-2 gene transcription. • FK506: Inhibits IL-2, IL-3, IL-4, IFN-γ, TNF-α production, inhibiting cell-mediated immunity. Pharmacokinetics of CsA: • Poor oral absorption, can be given orally. • Peak plasma concentrations in 3-4 hours, half-life ~24 hours. • Metabolism in the liver, excreted in bile. • Accumulates in tissues. Unwanted Effects of CsA: • Nephrotoxicity (common and serious). • Hepatotoxicity, hypertension. • Other effects: anorexia, lethargy, hirsutism, tremor, paraesthesia. • No depressant effects on bone marrow. Grapefruit Interactions: • Inhibits cytochrome P450, affecting drug metabolism. • Increases blood levels of drugs, leading to therapeutic/toxic effects. Pharmacokinetics of Tacrolimus: • Oral, intravenous, or topical use. • 99% metabolized by the liver, half-life ~7 hours. Unwanted Effects of Tacrolimus: • Similar to CsA, but more severe. • Higher nephrotoxicity, neurotoxicity; lower hirsutism. • Gastrointestinal disturbances, metabolic disturbances, thromboc General Features of Autoimmune Diseases: Autoimmune diseases are characterized by the following features: 1. 2. Autoantibodies and Autoreactive T Cells: • Presence of autoantibodies and autoreactive T cells targeting self-antigens. • Disease-specific autoantibodies frequently detected. Examples of Disease-Specific Autoantibodies: • Anti-DNA antibody in systemic lupus erythematosus (SLE). • Rheumatoid factor (autoantibody to IgG) in rheumatoid arthritis. • Anti-Jo-1 antibody in polymyositis. • Anti-Scl-70 antibody in systemic sclerosis. Clinical Use and Mechanism of Action (MOA) of Immunosuppressants: 1. Cyclosporine (Ciclosporin): • • 2. Clinical Use: • Used to suppress rejection of transplanted organs and tissues. • Employed in autoimmune diseases such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus (SLE). MOA: • Acts during the induction phase of the immunological response, reducing lymphocyte proliferation. • Selectively inhibits IL-2 gene transcription. Tacrolimus: • Clinical Use: • • 3. Utilized for immunosuppression in transplant surgeries. MOA: • Binds to FK-binding proteins, forming a complex that inhibits calcineurin. • Inhibits IL-2, IL-3, IL-4, IFN-γ, and TNF-α production. Drug Interactions with Grapefruit Juice: • • Mechanism: • Grapefruit juice contains furanocoumarins that affect the cytochrome P450 system, especially CYP3A4. • Inhibits CYP3A4, reducing drug metabolism. Effect: • Increases blood levels of drugs, leading to enhanced therapeutic and/or toxic effects. Mechanism of Action (MOA) of Cytotoxic Agents and Their Use as Immunosuppressants: 1. Cyclophosphamide: • MOA: • Alkylates DNA, interfering with DNA synthesis and cell division. • Activated by the cytochrome P450 system in the liver. • Active nucleophilic metabolites bind to DNA, disrupting replication. • • 2. Effective during all phases of the cell cycle, especially the S phase. Clinical Use: • Used in autoimmune diseases like rheumatoid arthritis and lupus. • Employed in the chemotherapy of leukemias and lymphomas. Azathioprine: • • MOA: • Metabolized to mercaptopurine, inhibiting purine synthesis and DNA synthesis. • Depresses clonal proliferation during the induction phase of the immune response. Clinical Use: • Immunotherapy in autoimmune diseases (e.g., rheumatoid arthritis). • Prevents tissue rejection in transplant surgeries. Overview of Human Glucocorticoid System: Adrenal Steroids: • Source: Synthesized and released by the adrenal cortex, regulated by adrenocorticotrophic hormone (ACTH). • Types: Two main types - mineralocorticoids (e.g., aldosterone) for water/electrolyte balance and glucocorticoids (e.g., hydrocortisone) with broad metabolic and immune effects. Immune-Adrenal Axis: • Stress Response: Cortisol release in response to stress limits the extent of inflammatory responses. • Regulation: ACTH from the pituitary gland stimulates cortisol release, essential for life. Glucocorticoids as Anti-Inflammatory and Immunosuppressive Drugs: Main Features: Molecular Pharmacology: • Receptors: Glucocorticoid receptors (GRs) in the nuclear receptor superfamily mediate effects. • Mechanism: Binding leads to conformational changes, activating transactivation and transrepression mechanisms. Metabolic and Systemic Effects: • Metabolism: Impact on carbohydrate and protein metabolism, potential hyperglycemia, and muscle wasting. • Calcium Balance: Negative influence, contributing to potential osteoporosis. • Feedback Inhibition: Exogenous glucocorticoids suppress endogenous cortisol production, leading to adrenal atrophy. Actions on Inflammatory Cells: • Neutrophils/Macrophages: Decreased egress and activation. • T Cells: Reduced activation and clonal proliferation. • Fibroblasts: Decreased function impacting healing and repair. • Cytokines: Decreased production of pro-inflammatory cytokines and increased synthesis of antiinflammatory factors. Clinical Uses: • Replacement therapy for Addison's disease. • Anti-inflammatory/immunosuppressive therapy in conditions like asthma, rheumatoid arthritis, and inflammatory bowel diseases. • Prevention of graft-versus-host disease post-transplantation. Adverse Effects: • Infection Susceptibility: Suppression of immune response, necessitating caution and timely antimicrobial treatment. • Wound Healing: Impaired healing. • Metabolic Actions: Osteoporosis, hyperglycemia, and potential iatrogenic Cushing's syndrome. Anti-Cytokine Therapies: Overview: • Advantages: Target specific aspects of inflammatory diseases. • Disadvantages: Biopharmaceuticals are expensive and difficult to produce. Drugs: TNF-α Inhibitors: • Etanercept: Binds TNF-α and TNF-β, approved for rheumatoid arthritis and other conditions. • Infliximab: Specific for TNF-α, used in rheumatoid arthritis, Crohn's disease, and more. • Adalimumab: Fully human monoclonal antibody against TNF-α. Other Biopharmaceuticals: • Rituximab: Causes B cell lysis, used in rheumatoid arthritis. • Efalizumab: Binds CD11a adhesion molecule, approved for psoriasis. • Natalizumab: Antibody against VLA-4, shows promise in multiple sclerosis. Pharmacokinetics and Clinical Use: • Administered parenterally due to protein nature. • Specific administration schedules for different drugs. • Clinical use in conditions like rheumatoid arthritis, psoriasis, and Crohn's disease. Adverse Effects: • Potential for latent disease activation or opportunistic infections. • Infliximab and adalimumab associated with tuberculosis recurrence. • Etanercept generally well-tolerated, with minimal side effects. Future Developments: • Ongoing research for new anti-cytokine therapies. • Emphasis on inhibitors of leukocyte trafficking. • Advances in IL-1 receptor antagonists and orally active TNF-α inhibitors. Lecture 13 Rheumatoid Diseases: Overview of Rheumatoid Diseases: • Common Inflammatory Conditions: Rheumatoid diseases, including rheumatoid arthritis, juvenile rheumatoid arthritis, and systemic lupus erythematosus, are prevalent chronic inflammatory conditions. • Prevalence: Over six million Canadians diagnosed with arthritis; one in three rheumatoid arthritis patients likely to become severely disabled. • Pathogenesis: Likely autoimmune reaction involving inflammation, synovial proliferation, and erosion of cartilage and bone. • Key Cytokines: Pro-inflammatory cytokines, such as IL-1 and TNF-α, play a major role in disease pathogenesis. Main Classes of Antirheumatoid Drugs: 1. 2. 3. 4. 5. DMARDs (Disease-Modifying Anti-Rheumatic Drugs): • Diverse group with unrelated structures and mechanisms. • Examples: Methotrexate, gold compounds, penicillamine, chloroquine. • Aim to improve symptoms and reduce disease activity. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): • Provide symptomatic relief but do not alter disease progression. • Commonly used for pain and inflammation. Cytotoxic Drugs/Immunosuppressants: • Examples: Azathioprine, cyclosporine. • Used in specific patient groups. Glucocorticoids: • Steroidal anti-inflammatories. • Exhibit broad anti-inflammatory effects. Newer Agents (Anticytokine Drugs): • Target specific pathways involved in rheumatoid diseases. DMARDs (Disease-Modifying Anti-Rheumatic Drugs): Overview of DMARDs: • Diverse Group: Unrelated structures and mechanisms. • Clinical Effects: Improve symptoms, reduce swollen/tender joints, pain, and disability scores. • Onset of Action: Slow (months), initiated alongside NSAIDs for cover during induction phase. • Duration of Treatment: Varies; some continue for extended periods. Examples of DMARDs: 1. 2. 3. Methotrexate (MTX): • Folate analogue used for rheumatoid arthritis, psoriasis, and graft versus host disease. • Versatile with anti-neutrophil, anti-T-cell, and antihumoral effects. Gold Compounds (Auranofin): • Organogold compounds with slow onset of action. • Mechanism not fully understood; may inhibit IL-1 and TNF-α production. Penicillamine: • Specific for rheumatoid diseases. • Putative mechanisms: Decreases immune response, affects collagen synthesis. Pharmacokinetics of DMARDs: • Methotrexate (MTX): • First-choice DMARD, immunosuppressant. • Rapid onset of action, closely monitored due to bone marrow depression and liver cirrhosis. • Anti-inflammatory activity independent of cytotoxic action. Gout: Overview of Gout: • Metabolic Disease: Raised plasma urate concentration. • Clinical Manifestation: Painful intermittent attacks of acute arthritis due to sodium urate crystal deposition in joints and tissues. • Inflammatory Response: Involves kinin, complement, plasmin systems, and cytokine production. Main Classes of Drugs for Gout: 1. 2. Allopurinol and Other Purines: • Allopurinol: Non-competitive xanthine oxidase inhibitor. • Clinical Uses: Long-term gout treatment. • Uricosuric Agents: Probenecid, sulfinpyrazone; increase uric acid excretion. Colchicine: • Mechanism: Prevents neutrophil migration by binding to tubulin. • Clinical Uses: Prevents and relieves acute gout attacks. Pharmacokinetics of Gout Drugs: • • Allopurinol: • Given orally, well absorbed, metabolized in the liver, excreted renally. • Side effects: Gastrointestinal disturbances, allergic reactions. Colchicine: • Given orally, well absorbed, excreted partly in the gastrointestinal tract and urine. Antihistamines: Three Types of Histamine Receptors: 1. H1 Receptors: Involved in various inflammatory and allergic mechanisms. 2. H2 Receptors: Mainly inhibit gastric secretion. 3. H3 and H4 Receptors: H3 receptors in the CNS; H4 receptors less studied but potentially involved in inflammation. Antihistamines: Pharmacodynamics and Pharmacokinetics: • Clinical Uses: Allergic reactions, motion sickness, sedation, antiemetic effects. • Pharmacodynamics: Decrease histamine-mediated smooth muscle contraction, inhibit vascular permeability. • Pharmacokinetics: Orally administered, well absorbed, widely distributed, metabolized in the liver, excreted in the urine. Side Effects of Antihistamines: • CNS effects (sedation, dizziness), peripheral antimuscarinic actions (dry mouth, blurred vision, constipation), gastrointestinal disturbances, allergic dermatitis. These study notes provide a comprehensive overview of rheumatoid diseases, gout, and antihistamines, covering their pathogenesis, drug classes, pharmacodynamics, pharmacokinetics, and clinical considerations. Independent Study Pharmacokinetics of Fluvastatin: • Metabolism (MOA): Fluvastatin is primarily metabolized by the liver via the cytochrome P450 (CYP) enzyme system. Specifically, CYP2C9 and CYP3A4 are involved in the metabolism of fluvastatin. • Main Route of Elimination: Fluvastatin is mainly eliminated through the liver, with excretion into bile and subsequent fecal elimination. • Half-life (t1/2) for Various Formulations: The half-life of fluvastatin varies based on the formulation. The extended-release formulation has a longer half-life compared to the immediate-release form. This is important in determining dosing intervals and overall drug exposure. Pharmacokinetics of Clopidogrel: • Metabolism (MOA) and Prodrug Nature: Clopidogrel is a prodrug that undergoes a two-step hepatic biotransformation. The first step involves cytochrome P450 enzymes, primarily CYP2C19, and results in an intermediate metabolite. The second step involves further conversion to the active form of the drug, which inhibits platelet aggregation. • Loading Dose and Maintenance Doses: Clopidogrel is administered with a loading dose to rapidly achieve therapeutic concentrations. This loading dose is followed by lower maintenance doses to sustain the antiplatelet effect. • Enzymes Involved in Metabolism: Apart from CYP2C19, CYP1A2 and CYP2B6 are also involved in the metabolism of clopidogrel. Clinical Study Specifics: • Enrolment Criteria and Volunteer Discontinuation: The criteria for volunteer enrolment likely included factors such as age, health status, and absence of contraindications. Some volunteers may have discontinued participation due to adverse events, non-compliance, or other reasons. • Pharmacokinetic and Pharmacodynamic Assessments: The study likely employed various assessments, including blood sampling for drug concentration measurements (pharmacokinetics) and platelet function tests (pharmacodynamics) to understand the effects of the drugs. • Metabolic Pathways: • • Clopidogrel (Prodrug): • Metabolized primarily by CYP2C19 to its active form. • CYP3A4 and other enzymes are also involved in its metabolism. Fluvastatin: • • Metabolized by CYP2C9 and CYP3A4. Elimination: • Clopidogrel: • • Elimination involves both renal and non-renal routes. Fluvastatin: • Mainly excreted in the feces. Pharmacokinetic Assessment: • Clopidogrel Study: • Loading Dose: 300 mg. • Maintenance Dose: 75 mg/day. • Reason for Loading Dose: • • To rapidly achieve therapeutic concentrations. Volunteer Criteria and Discontinuation: • Criteria: Specific inclusion criteria for health and age. • Discontinuation: Reasons not provided. Effects of Clopidogrel on Fluvastatin: • Pharmacokinetic Impact: • Clopidogrel did not significantly affect the pharmacokinetics of fluvastatin. • No notable alterations in fluvastatin's absorption, distribution, metabolism, or elimination. Hypothesis on Fluvastatin's Impact on Clopidogrel: • • Hypothesis: • There might be a potential interaction due to shared metabolic pathways (CYP3A4). • Changes in clopidogrel's pharmacodynamic action could be anticipated. Study Outcome: • Contrary to the hypothesis, the study did not observe significant pharmacodynamic changes in clopidogrel when co-administered with fluvastatin.