Pharmacy 303 Lecture 2 Essentials of Pharmacokinetics PDF

Lecture 2 Pharmacy 303 Essentials of Pharmacokinetics Hamdah M. Al Nebaihi, Ph.D Outlines Administration routes overview Modeling: one compartment model  Administration route: overview Choice depends on intended effect: local or systemic ...

Lecture 2 Pharmacy 303 Essentials of Pharmacokinetics Hamdah M. Al Nebaihi, Ph.D Outlines Administration routes overview Modeling: one compartment model  Administration route: overview Choice depends on intended effect: local or systemic  Local Effects Desire the effect to be restricted to one accessible anatomical site Dermatologic application (creams, lotions, emulsions, ointments, etc.) Therapeutic product applied to skin Example: psoriasis Inflammatory condition affecting skin Corticosteroid therapy  Local Effects Other routes used for local effect: Otic (solution/suspensions) Ophthalmic (solution, ointments) Rectal (solutions/suspensions, suppositories) Nasal (solutions)  Systemic Effect Oral administration: usually used for systemic effect of drug A few notable exceptions: e.g. prophylactic antibiotic therapy before gastrointestinal (GI) surgery - oral vancomycin - Effect is restricted to the GI lumen as drug is NOT ABSORBED Sulfasalazine for ulcerative colitis  PK and local effects Not very important for understanding pharmacokinetics of drugs given for local effects Critical for understanding SYSTEMIC effects If the drug does not get into the bloodstream, physicochemical properties of the drug formulation mostly dictate level and duration of effect of the drug  Systemic effects Refers to an effect that can only be attained by introduction of drug into the bloodstream Drug in dosage form Drug in bloodstream Tissues Most drugs require systemic administration e.g. a drug used for treatment of Parkinson’s disease Desired target organ, the central nervous system (nigrostriatal pathway neurons in the brain) Drug must be delivered to the site of action by the blood  Systemic effects Parenteral routes of administration Introduction of drug directly through the skin →→→ injection  Systemic effects 1. Intravenous or intraarterial injection As bolus injection, fastest rate possible of systemic drug administration 100% of the dose is delivered virtually instantaneously into the bloodstream Rate of input can be slowed by infusing the drug slowly into the blood vessel NO ABSORPTION STEP  Systemic effects 2. Intramuscular injection As Dose is injected into muscle tissue Drug distributes from site of injection to surrounding vessels Absorption step  Systemic effects 3. Subcutaneous injection Drug is injected into the fatty layer just under the dermal layers of the skin Drug can distribute to surrounding vessels  Depot injections Can enter blood directly from adjoining capillaries (mostly small molecular weight compounds) Larger compounds (proteins) and fat-soluble drugs gain access to the blood by first passing into the adjoining lymph vessels Lymph eventually drains into the blood These can get retained by cells in the lymph nodes … could be useful for drugs affecting the immune system  Non-oral, non iv/ia routes Parenteral routes (non iv / ia): e.g. intramuscular, subcutaneous Lymphatics Dose Tissue Depot Systemic Capillaries  Parenteral route Must be used to gain systemic effects for drugs that have negligible oral absorption (e.g. insulin, vaccines, aminoglycoside antibiotics) Other less common routes intrasynovial Intracardiac intraperitoneal  Oral administration Most common Oral route is convenient and is less expensive Most ideal route for ambulatory care Many cellular barriers may need to be crossed for drug action cellular barriers  Drug access to target receptors Most drugs act by interacting with specific receptor targets: Enzymes or other proteins Often these receptors are within cells or tissues Access to & interaction with receptors is a requirement for drug response Beneficial response (indication) or side effect (toxicity) Drug Enzyme Enzyme  Dissolved drug Absorption (for non-intravascular routes) ADME = PK Elimination Distribution Metabolism Organ/tissue uptake Excretion Drug Removal Drugs do not stay in the body indefinitely; they are eliminated Metabolism (usually in the liver) by enzymes Urinary excretion Most drug metabolizing enzymes are intracellular Renal excretion of drugs may have a transcellular requirement DRUG PASSAGE ACROSS CELL MEMBRANES IS AN ESSENTIAL REQUIREMENT OF ALL ADME PROCESSES  Permeability The ability of a dissolved substrate to move across a cell membrane depends on the membrane’s permeability for that substrate Permeability depends on physicochemical properties of a drug and the membrane  Biological membranes Biological membranes are very lipid-like in nature: Contain phospholipids, triglyceride, cholesterol and protein Generally, permeability is higher if the substrate has a higher logP (oil:water coefficient)  Diffusion Most transcellular drug transport occurs via diffusion across cell membranes Extracellular Intracellular fluid fluid Dissolved drug Can determine a rate of diffusion of a solute across a membrane  Factors positively correlated with diffusion rate 1. Concentration difference () of solute between the 2 sides of the membrane Relative rates (left to right): Extracellular Intracellular Extracellular Intracellular fluid fluid fluid fluid  Factors positively correlated with diffusion rate 2. Temperature (very constant in the body) 3. Cross sectional area (cell surface area)  Factors positively correlated with diffusion rate 4. Molecular radius: Smaller the size, the faster the rate 5. Distance between the 2 halves of the membrane (cell membrane thickness)  Factors positively correlated with diffusion rate 𝑅𝑎𝑡𝑒 ≅ ∆ 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 × 𝑐𝑒𝑙𝑙 𝑐𝑟𝑜𝑠𝑠 𝑠𝑒𝑐𝑡𝑖𝑜𝑛𝑎𝑙 𝑎𝑟𝑒𝑎 × 𝑡𝑒𝑚𝑝𝑒𝑟𝑎𝑡𝑢𝑟𝑒 +ve 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑟𝑎𝑑𝑖𝑢𝑠 × 𝑐𝑒𝑙𝑙 𝑡ℎ𝑖𝑐𝑘𝑛𝑒𝑠𝑠 -ve Equation linking these factors to rate of diffusion (Fick’s law)  Factors positively correlated with diffusion rate ∆ 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 × 𝑐𝑒𝑙𝑙 𝑐𝑟𝑜𝑠𝑠 𝑠𝑒𝑐𝑡𝑖𝑜𝑛𝑎𝑙 𝑎𝑟𝑒𝑎 × 𝑡𝑒𝑚𝑝𝑒𝑟𝑎𝑡𝑢𝑟𝑒 𝑅𝑎𝑡𝑒 ≅ 𝑀𝑜𝑙𝑒𝑐𝑢𝑙𝑎𝑟 𝑟𝑎𝑑𝑖𝑢𝑠 × 𝑐𝑒𝑙𝑙 𝑡ℎ𝑖𝑐𝑘𝑛𝑒𝑠𝑠 Only factor that can significantly changes in a mammalian system Diffusion is bi-directional Extracellular Intracellular fluid fluid Dissolved drug  Transcellular transport of solutes It has been known for many years that transporters exist for physiological solutes ⁻ Amino acids ⁻ Glucose ⁻ Na+/K+/H+ ions Some of these require energy (ATP) Sodium-potassium ATPase Others act as facilitated transporters (non-ATP consuming)  Proteins may be involved in drug transport Transport proteins may facilitate the movement of drugs across biological membranes This may influence the ADME of compounds, and/or their biological potency Will cover later in the course  Therapeutic margin 25 Side effects 20 Concentration 15 Safe & Effective 10 5 Insufficient effect 0 0 10 20 30 40 50 So, you measure a concentration. What do you do with it? What to do with a concentration when the drug is not working optimally? Pharmacokinetic models are available Allows an understanding of the relationship between dose and concentration Models are TOOLS useful for altering the dose regimen to keep a patient’s drug levels safe and effective PK models incorporate: ₋ Physiological (simple or complex) concepts ₋ Associated mathematical relationships Components of these models → express as equations: ₋ Relate factors controlling elimination and distribution to the administered dose and the blood fluid  Principles of pharmacokinetics Compartmental pharmacokinetics Simple but effective way to model pharmacokinetic data One compartment open model Treat body as being a square box ONE COMPARTMENT CLOSED MODEL: Body What happens if we quickly intravenously inject the person with drug? Drug fills up body (box) Then what??? Body Elimination occurs  Dose Drug in body Excreted drug One compartment open model How can we describe the loss of drug from the body? Rates and rate constants  Rate constant Dose Drug in body Rate constant Excreted drug Thank you