Introduction To Pharmacokinetics PDF

Introduction to Pharmacokinetics Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Objectives 1. To be able to define the goal of drug therapy. 2....

Introduction to Pharmacokinetics Fadi Khasawneh, Ph.D. (361) 221-0755 [email protected] 1 Learning Objectives 1. To be able to define the goal of drug therapy. 2. Know the concept of individual variability in drug response 3. To be able to define and differentiate pharmacokinetics and pharmacodynamics and their relationship with dose-response curves. 4. To be able to understand the fundamental hypothesis in pharmacology regarding the effect of a drug and its concentration 5. To be able to describe the four main pharmacokinetic processes (ADME) and factors affecting each process. 6. Describe the four methods of drug transport. 7. Understand the use of the Henderson–Hasselbalch equation to calculate the unionized and ionized forms of a drug. 8. Describe the difference between gastric and intestinal absorption. 9. Know the general anatomy of the gastrointestinal tract. 10. To be able to define pharmacokinetic terms such as bioavailability, oral bioavailability. 11. Understand the impact of different formulations on drug bioavailability. 2 1  The Goal of Drug Therapy - Achieve a desired beneficial effect (cure a disease) with minimal adverse effects. - To achieve our goal, we should employ a rational approach that combines the principles of pharmacodynamics and pharmacokinetics to clarify the dose-effect (response) relationship  Selection of an appropriate drug  Selection of the right dose/dosing interval - A relationship exists between the beneficial or toxic effect of a drug and its plasma concentration 3 An Example Minimal Toxic concentration Therapeutic Range/Window Minimal Therapeutic concentration Regimen A is better than Regimen B (dose too high, causing toxicity). Arrows indicate doses administered. 4 2  - A drug needs to reach its target organ/tissue within our body before it is able to combat disease. - For a drug to reach its target organ, a drug must be able to cross the physiologic barriers (that exist to limit the access of foreign substances to the body). - Therefore, an appreciation of the factors that affect the ability of the drug to act within our body is important for clinical practice. 5 Individual Variations Drug: Phenytoin (Anti- seizure) Minimal Toxic concentration Therapeutic range: 10- Therapeutic Range/Window 20 mg/L Minimal Therapeutic concentratio 6 3  Dose-Response Relationship - It is determined by drug-body interactions and could be dissected into two aspects:  Pharmacokinetics: the study of what the body does to the drug; the relationship of drug dose and drug concentration  Pharmacodynamics: the study of what the drug does to the body; the relationship of drug concentration and drug effect 7 Pharmacokinetics The study of the time course of drug absorption (except for the IV route), distribution, metabolism and excretion (ADME). All of these processes require the passage of the drug across the cell membrane. Drug Disposition refers to the fate of a drug after its absorption - Distribution - Metabolism - Excretion The combined process of drug metabolism and excretion is also called drug elimination. 8 4  Absorption Definition: Movement of a drug from its site of administration to to the systemic circulation 9 Principles on Absorption Absorption of a drug is a complex process that depends on  the physicochemical nature of the drug  the formulation of the drug (drug vehicle)  the route of administration  the state of the patient 10 5 The Henderson–Hasselbalch equation 11 Gastric Vs. Intestinal Absorption 12 6 13 14 7  Oral Administration A summary of the processes involved in drug absorption, distribution, metabolism and excretion. D, drug M, metabolite(s) 15 The Anatomy of the Gastrointestinal Tract 16 8  Oral Administration Key pharmacokinetic steps following oral administration:  Disintegration of the tablet/capsule to small particles  Dissolution of small particles to drug molecules in a solution  Absorption of drug in the gastrointestinal (GI) tract  Metabolism in the GI tract  First pass through the liver  Drug distribution  Urinary excretion (and sometimes metabolism)  Hepatic metabolism (and sometimes biliary excretion) 17 Oral Administration Absorption of Drugs by the Gastrointestinal Tract (GIT) * * small intestine (duodenum, jejunum and ileum). 18 9  Bioavailability (F) Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route. The area under the concentration–time curve (AUC) is used to measure the extent of bioavailability for a drug given by a particular route. The AUC obtained following IV administration is used as the reference value. 19 Bioavailability (F) For IV route, F = 1, since the drug is directly introduced into the blood stream and there is no absorption process involved. When drugs are given by any route other than the IV route, the extent of absorption and bioavailability must be defined in order for one to prescribe it rationally and be able to make appropriate quantitative adjustments, or route of delivery changes. 20 10  Bioavailability Route Bioavailability (%) Intravenous (IV) 100 (by definition) Intramuscular (IM) 75 to 100 Subcutaneous (SC) 75 to 100 Oral (PO) 5 to < 100 Rectal (PR) 30 to < 100 Inhalation (Pulmonary) 5 to < 100 Transdermal 80 to 100 21 Notes The above information is for small molecule drugs in general. The bioavailability of large molecule drugs (e.g., peptides and proteins such as insulin) administered by non-parenteral routes is much lower (e.g., < 0.1% when dosed by the oral route). Therefore, peptide- and protein-based drugs are usually administered using parenteral routes (IV, IM and SC). 22 11  Oral Absorption The plasma concentration-time Absorption Phase profile of theophylline, a drug Cmax for the relief of asthma, in a subject following an oral dose Elimination Phase of a 600-mg controlled-release formulation. AUC tmax 23 Oral Bioavailability (F) Also known as bioavailable fraction (F) Calculation Factors determining oral bioavailability Extent of absorption First-pass elimination 24 12  Factors Affecting Extent of Oral Absorption (Oral Bioavailability) The physicochemical nature of the drug  A balance of hydrophilicity/lipophilicity is needed for a drug to be highly absorbed in the GI tract. Incomplete absorption could be due to  Too high hydrophilicity of the drug (atenolol) because it cannot pass through the lipid cell membrane.  Too high lipophilicity of the drug because it cannot dissolve in water.  Incomplete absorption may also result from activating the P- glycoprotein efflux pump in epithelial cells. P-glycoprotein efflux pump 25 Factors Affecting Extent of Oral Absorption (Oral Bioavailability) The physicochemical nature of the drug  A balance of hydrophilicity/lipophilicity is needed for a drug to be highly absorbed in the GI tract. Incomplete absorption could be due to  Too high hydrophilicity of the drug (atenolol) because it cannot pass through the lipid cell membrane.  Too high lipophilicity of the drug because it cannot dissolve in water.  Incomplete absorption may also result from activating the P- glycoprotein efflux pump in epithelial cells. Formulation has a major impact on bioavailability. 26 13  Formulation Vs. Bioavailability Toxic C. Therapeutic C. Sub-therapeutic levels 27 Conclusions Both the rate and the extent (F & Cmax) of absorption can influence the clinical effectiveness of a drug. 28 14  Rate of Absorption The rate of absorption is determined by  the physicochemical nature of the drug  the drug formulation  the route of administration The rate of absorption should not be confused with the extent of absorption (bioavailability, measured by AUC values). The rate of absorption determines the onset of action of the drug. The fast the drug is absorbed, the fast the drug acts. 29 The Time Course of Drug Effect - Temporal characteristics of drug effect and relationship to therapeutic window:  the concentration range between minimal effective concentration Cmax for adverse response (or minimal toxic concentration) and minimal effective concentration for desired therapeutic response (or minimal therapeutic concentration) tmax Lag time 30 15  Any questions? The End 31 16