ADME Lecture PDF

An Overview of ADME Jared Rocco, PharmD PGY-2 Ambulatory Care Pharmacy Resident UNM College of Pharmacy [email protected] 1 1 Objectives Describe the relationship between the dose-response cu...

An Overview of ADME Jared Rocco, PharmD PGY-2 Ambulatory Care Pharmacy Resident UNM College of Pharmacy [email protected] 1 1 Objectives Describe the relationship between the dose-response curve of a drug and its therapeutic index. Compare and contrast the effects of various routes of administration on the onset, intensity and duration of pharmacologic effect Describe the first pass effect and the consequences for drug bioavailability Describe factors that affect drug absorption Describe factors that affect drug distribution Describe the pharmacokinetic consequences of drug metabolism Recognize the major enzymatic reactions within Phase I and Phase II processes Describe the contributions of filtration, secretion, and reabsorption on renal excretion of drugs Predict route(s) of drug excretion based on molecular properties of drugs Describe the relationships between drug elimination and steady-state drug concentrations 2 Key Terms Pharmacology: the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes Drug: a substance that affects a change in biologic function Pharmacokinetics (PK): process by which bioactive substance is absorbed, distributed, metabolized and eliminated (ADME) by the body Pharmacodynamics (PD): the action or effects of bioactive substances on living organisms 3 Absorption, Distribution, Metabolism, & Excretion Absorption - the process of a substance entering the blood circulation Distribution - the dispersion or dissemination of a substance through the fluids and tissues of the body Metabolism - the irreversible transformation of the parent compound into daughter metabolites Excretion - the removal of substances from the body 4 The Core of ADME Active drug must reach the drug target (receptor) at sufficient levels and for sufficient duration to therapeutically modify biological response Defines biological response to drug Related to individual variations in response to drug Understanding pharmacokinetic/pharmacodynamics parameters is critical for making dose adjustments or drug selection Also related to toxicity of drugs 5 Dose Response Curve Shows the relationship between drug dose on the x-axis and response on the y-axis A minimum dose is required to produce a significant response The response increases with dose until a maximum effect is reached, beyond which no further response occurs. Variability and slope indicate the range of responses and how quickly the effect changes with increasing dose. 6 Therapeutic Index Therapeutic index (TI) - the range of doses at which a medication is effective without unacceptable adverse events Determined using quantal dose-response curves. Therapeutic window: Clinically useful range between minimum effective and minimum toxic doses. 7 Therapeutic Index Which drug might be safer? 8 Therapeutic Index Which drug might be safer? The drug on the left graph has a wider therapeutic window, indicating a greater difference 9 between the effective dose (ED₅₀) and the toxic dose (TD₅₀), suggesting it may be safer Everything is Interconnected! 10 Quick Visual of Drug Administration 11 Other specialized parenteral routes: intra-arterial, intraperitoneal, intrathecal, etc. Factors Affecting Absorption Absorption: Movement of a drug from its site of administration à circulatory blood stream Place of entry (route) Surface area Blood flow Number and type of membranes Physiochemical properties of the membrane and drug (i.e., size lipophilicity, charge) Chelation pH changes 12 Routes of Drug Administration Consider the site of action for treatment and the physiological and biochemical barrier drugs may encounter! 13 Enteral/Parenteral Administration Enteral (intestine) administration Placement of a drug directly into any part of the gastrointestinal tract. Includes oral, sublingual and rectal. Parenteral (non-intestine) administration Includes injection (subcutaneous (sc), intramuscular (im) and intravenous (iv), topical application and inhalation through the lungs. Rate & amount of blood flow to an area is a main determinant of the rate of absorption and distribution of drugs. Surface area for drug absorption is another important determinant of uptake 14 Routes of Drug Administration Route of Administration influences: How quickly a drug reaches its target Whether the drug distribution is broad or narrow 15 Cells are More Than a Lipid Bilayer Passive transport: Concentration gradient No energy requirement Uncharged Not saturable Facilitated diffusion: Energy independent, but uses a protein carrier Saturable Compound/structure specific Active transport: Energy dependent, and uses a protein carrier Saturable Compound/structure specific 16 Passive vs. Facilitated/Active Transport 17 pH Matters At different sites, drugs exist in different ionized/unionized ratios The ratio of the two forms at a particular site influences the rate of absorption and is also a factor in distribution and elimination. 18 Other Drugs Can Alter Absorption Effect Drug Changes in gastric or intestinal pH H2 blockers, antacids, proton pump inhibitors Changes in gastrointestinal motility Laxatives, anticholinergics, metoclopramide Changes in gastrointestinal perfusion Vasodilators Chelation Tetracycline, calcium, magnesium, aluminum 19 Bioavailability Used to indicate the fractional extent to which a dose of drug reaches its site of action or a biological fluid from which the drug has access to its site of action (typically bloodstream). The fraction (%) of an administered dose that reaches the systemic circulation, relative to an IV bolus (which represents 100% bioavailability). Reflects how efficiently a drug is absorbed and becomes available at the site of action. Therefore, the choice of the route of administration for a specific drug influences bioavailability 20 What Percentage of a Parent Drug Reaches the Systemic Circulation? IV administration = 100% Transdermal = 80-100% Subcutaneous = 75-100% Intramuscular = 75-100% Oral, rectal, and inhalational – Highly variable Bioavailability via oral route is highly dependent on “first-pass” metabolism 21 First Pass Metabolism Drugs absorbed via GI tract enter the portal vein and pass through the liver before reaching the systemic circulation For certain drugs, liver metabolism (and excretion) substantially reduces drug bioavailability (first pass effect). 22 First Pass Effect 100 mg 80 mg Systemic circulation 20 mg Not absorbed 60 mg 20 mg 23 Distribution The movement of a drug from the blood stream à different body compartments 24 Factors Affecting Distribution Factors affecting absorption Tissue permeability (hydro- vs lipophilic) Blood flow Binding to plasma proteins 25 Protein Binding Albumin, β-globulin, and α-acid glycoprotein Bound drugs have no activity! Amount of bound drug determined by: Free drug concentration Protein concentration Affinity for binding sites What could change the % bound drug concentrations? 26 Protein Binding Albumin, β-globulin, and α-acid glycoprotein Bound drugs have no activity! Amount of bound drug determined by: Free drug concentration Protein concentration Affinity for binding sites What could change the % bound drug concentrations? Severe malnutrition and other conditions that affect the production of proteins 27 How is Drug Distribution Defined in Pharmacology? Apparent Volume of Distribution (Vd) C = concentration of drug and can be defined for blood, plasma, or water Vd can be greater than actual physical volume in the body 28 Apparent Volume of Distribution Indicates the extent of drug distribution beyond the bloodstream into tissues and compartments. Highlights where the drug accumulates: in the blood or in tissues. High Vd: Extensive tissue distribution. Low Vd: Primarily bound to plasma proteins. Guides dosing decisions and predicts drug duration in the body. 29 Metabolism Refers to the body's transformation of the drug through chemical reactions 30 Metabolism Goal is to enhance elimination from the body Mostly occurs in the liver by reactions that increase water solubility Metabolites are secreted back into blood or into bile (emptied into GI tract) Two main types of chemical reactions involving drug metabolism o Phase 1 o Phase II 31 Metabolism Can form inactive metabolites Can form active metabolites (e.g., prodrug or modifications that still have affinity for the parent drug receptor) 32 Metabolism Can form inactive metabolites Can form active metabolites (e.g., prodrug or modifications that still have affinity for the parent drug receptor) How might you adjust codeine in a patient with extremely functional CYP2D6? 33 Phase I Metabolism Adds a handle for larger, more water-soluble compounds to attach Includes oxidation, reduction and hydrolysis, etc. Enzymes catalyze these reactions Special populations may have decreased or increased phase I metabolism 34 Phase II Metabolism Often referred to as conjugation reactions Phase I metabolites are conjugated, link to endogenous molecules and can undergo Glucuronidation, acetylation, and sulfation reactions The conjugation makes the molecular more polar and thus easily excreted Phase II metabolism does not necessarily have to follow phase I metabolism. Conjugates generally inactive, but in certain cases can lead to drug activation or toxic 35 metabolites Changes in Pharmacokinetics Changes in pharmacokinetics (or concentration-time curves) result from variation in metabolism. Graph A could result from a polymorphism making the person a poor metabolizer or coadministration of an enzymatic inhibitor resulting in less production of 36 the metabolite. Why is Enzyme Induction Important? Failure of therapy (ex. Oral contraceptives, epilepsy, HIV) Drug tolerance with auto-induction Complicated dosing regimen Increased toxic effect 37 Why is Enzyme Inhibition Important? Blocks the usual effect Inhibitor Competitive o Competes for same site as agonist o Can be overcome with higher concentrations of agonist Noncompetitive o Binds to other site besides agonist o Cannot be detached by agonist 38 Consequences of P450 Enzyme Inhibition Decreased drug elimination Rapid and profound increases in blood levels of a drug Exaggerated pharmacological or toxicological response and symptoms of drug overdose Inhibition can occur immediately and can result in a complete loss of one or more P450 activities 39 Excretion 40 Excretion Removes an unchanged drug from the body and prevents drug accumulation. The liver and kidney are the primary sites of excretion. Metabolism is an important component of excretion. o Drug metabolites are generally charged (ionized) and hydrophilic (water- soluble) o Drug metabolites are often conjugated (hence larger) o Metabolism alters the physico-chemical properties of the drug 41 Renal vs Biliary excretion is a consequence of drug properties (ionization, adducts, etc.) Renal – excretion into urine Glomerular filtration Active secretion Passive reabsorption Hepato/Biliary – excretion into bile Diffusion Active transport 42 Renal Drug Excretion Many drugs can be excreted unchanged. Metabolites may be excreted in the urine (depending on physiochemical properties). Three Key Transport Mechanisms Controlling Renal Excretion: o Glomerular Filtration o Tubular Secretion o Tubular Reabsorption 43 Kidney 44 Nephron 45 Glomerular Filtration Non-selective, size limited Most (‘free’) drugs are small enough to be filtered specialized pores/fenestrations MW cut-off ~1000-2000 size, charge, shape affect filtration. What happens to protein-bound drug? Pressure gradient regulates filtration Renal excretion is very sensitive to BP. 46 Tubular Secretion Active transport for large, ionized molecules allows for high urine concentration Depends on specific transport systems (carriers) o Transporters can be saturated or inhibited o Transport requires: energy (ATP), specific carriers, free drug 47 Tubular Reabsorption Reabsorption is mediated by passive diffusion. The concentration gradient (urine/plasma) usually favors reabsorption. Passive reabsorption favors small, neutral, lipophilic molecules 48 Biliary Drug Excretion Drugs enter hepatocytes by diffusion and active transport Hepatocytes secrete bile which flows to duodenum for elimination. Biliary excretion favors drugs >300 mw Conjugation (Phase II metabolism) aids biliary excretion: increasing molecular size Excretion is into the bile and then into feces. About 5% of the administered dose of a drug will enter the bile by passive diffusion alone active secretion may increase this to 95%. 49 Questions? 50