Pharmacokinetic 1 Absorption PDF, Spring 2024, Galala University

BMS161 (1): General Pharmacology A- Introduction B- Pharmacokinetics: Absorption Professor: Ahmed Nour Eldin Hassan Ass. Prof. Nevien Fekry Abdalla Lecturer: Mai Ebeid Faculty of Medicine Spring 2024  C...

BMS161 (1): General Pharmacology A- Introduction B- Pharmacokinetics: Absorption Professor: Ahmed Nour Eldin Hassan Ass. Prof. Nevien Fekry Abdalla Lecturer: Mai Ebeid Faculty of Medicine Spring 2024  Course: Foundations of Pharmacology Pharmacokinetics Practical (Not Theoretical) Pharmacodynamics How to Do Cholinergic nervous system Skills: How to find knowledge, Adrenergic nervous system How to calculate dose General Chemotherapy How to find D.I. Autacoids Principles of cancer chemotherapy SGD: Discussion, free reading Names of Drugs??? (Just a moderator) Ahmed Nour Eldin Hassan: Professor of Clinical Pharmacology Nevien Fekry Abdalla: Assistant Professor of Clinical Pharmacology Mai Ebeid: Lecturer of Clinical Pharmacology LEARNING RESOURCES and References: Required Resource Whalen K, Finkel R and Panavelil TA, (2018). Lippincott's Illustrated reviews: Pharmacology (7th edition), Lippincott Williams and Wilkins. Optional Resources 1- Bertram G. Katzung, Suzan B. Masters and Anthony J. Trevor ( 2020). Basic and Clinical Pharmacology (15th edition), Mc Graw HILL, NY. 2- H.P. Rang , M.M. Dale J.M. Ritter, R.J. Flower and G. Henderson (2016). Rang and Dale's Pharmacology (8th edition), Churchill Livingstone Elsevier, Edingburgh, UK.  Pharmacokinetic- 1- Absorption Intended Learning Objectives: By the end of this lecture, the student should be able to: 1. Explain the difference between pharmacokinetics and pharmacodynamics 2. Realize the clinical importance of pka of a drug & pH of medium, in drug ionization, lipid solubility & subsequent absorption or excretion. 3. Summarize role of p- glycoprotein in affecting serum level of drugs 4. Compare between different routes of drug administration 5. Recall the definition of drug bioavailability 6. List the major factors that affecting bioavailability 7. Predict the effect of liver diseases on drug pharmacokinetics Drug: A chemical substance administered and used for treatment, diagnosis, prevention (prophylaxis) of diseases or a condition to suppress physiological process (suppression of ovulation by contraception) Chemical name Drug Nonproprietary (Generic) Proprietary name: "Brand name" Paracetamol (Acetaminophen) Panadol® Abimol ® Pyral ®  Sources of Drugs I. Natural Plants: e.g. atropine, morphine and peppermint Animals: e.g. insulin hormone. Microorganisms; e.g. antibiotics as penicillin. Minerals; e.g. iron, calcium. II. Semi-synthetic: III. Synthetic A. Chemical synthesis; e.g. aspirin. B. Biological synthesis: by recombinant DNA technology: It is the selective insertion of the desired DNA into another DNA of a living cell to form recombinant DNA. e.g. Human insulin, Erythropoietin. Drug Journey From Discovery to Market 3-7 years Post Marketing Animal Study Clinical Study Pharmacovigilance Pharmacologic Profile: Phase I: Small number (healthy volunteers) *Actions on all organs Non-blind. *Safety Tests: Clinical dose range in human and PhK. Acute & chronic toxicity. Reproductive. Carcinogenic Phase II: small number of patients Mutagenic Safety and efficacy. Addiction liability. Single-blind (compare with older drug) Phase III: large number of patients. Double-blind Placebo "I shall please" an inert substance given just to please the patient. Placebo Effects: reactions unrelated to the pharmacologic effects of drug. Uses of Placebo: To distinguish the pharmacodynamic effects of a drug from the psychological effects of medication. Single Vs Double-Blind Technique Double Placebo Single  Division of General Pharmacology Pharmacodynamics: Mechanism of drug action Biochemical & physiological effects: Therapeutic (intended) & Side effects ( unintended) Drug What drugs do to the body What the body does to the drug Body Pharmacokinetics: ADME Absorption Distribution Metabolism (Biotransformation) Excretion  Pharmacokinetics Not designed but we study the kinetics of effective dose Blood: Absorption: Distribution: Site of Administration 1- Site of Action 2- Other Organs Elimination Clearance Metabolism: Excretion: Main Organ Main Organ  Absorption Transfer of a drug from the site of administration to the bloodstream. Mechanisms of absorption of drugs from the GI tract: 1.Passive diffusion: With concentration gradient, No ATP, No carrier 2. Facilitated diffusion: With concentration gradient, Carrier NO ATP 3. Active transport: With or against concentration gradient, ATP, Carrier (L-dopa to brain) 4. Endocytosis Vitamin B12 absorption 5. Exocytosis: release of neurotransmitter  Carrier Transport System Drug Endogenous Substrate Saturable: Competition: Limited Absorption Amino Acids carrier to Brain L-Dopa (Drug)  Factors Influencing Absorption: Passive Diffusion 1- Effect of pH on drug absorption: 2- Blood flow to the absorption site: Blood flow to the intestines >>>>> stomach Drug administration in shock: e.g. epinephrine [Given IM Not SC] ↑Absorption of S.C. insulin by exercises 3-Total surface area available for absorption: Intestine (200 m2) 1000-fold that of the stomach. the lung (70 m2). 4- Contact time at the absorption surface: Diarrhea or food in the stomach ↓ gastric emptying (Slow absorption). 5- Expression of P-glycoprotein: is a transmembrane transporter protein. It is expressed in different tissues: the liver, kidneys, intestines and brain It “pumps” drugs out of the cells [intestine (↓ drug absorption)].  P-Glycoprotein Genetic Variability Drug Metabolizing Enzyme It is also associated with multidrug resistance as in cancer cells. Effect of pH on drug absorption: ❖Dissociation Constant [pKa]: Is the pH medium at which 50 % of drug is ionized and 50 % is unionized. The change in the pH medium will lead to change in this ratio Ionized = hydrophilic = Charged Cannot cross membrane Unionized = lipophilic = Uncharged Can cross membrane and absorbed pKa and pH Medium Clinical Significance of pKa???  Clinical Significance of pKa 1. GIT Aspirin (weak acid with pKa 3.5) is mostly non-ionized in the empty stomach →crosses the cell membrane of the gastric mucosal cells to be trapped inside cells (aspirin trap) → inflammation &“peptic ulceration”. 2. Kidney: In Aspirin drug poisoning, renal drug elimination can be enhanced by Alkalinization of urine. This increases drug ionization and inhibits tubular reabsorption: Acidification of urine (to ↓ urine pH below drug pKa) is used in basic drug poisoning, e.g. amphetamine More Absorbed in Same Media and Excreted in Opposite Media  Bioavailability Definition: It is the percentage of drug released from a formulation that reaches the systemic circulation and becomes available for biological effect. Calculation: It is calculated by dividing the Area Under the blood concentration- time Curve (AUC) after any route of administration by that after IVI. For the same dose. Factors that influence bioavailability: I- Factors affecting drug absorption from GIT Enzymes Food Blood Active Ingredient pKa Factors that influence bioavailability: I- Factors affecting drug absorption from GIT 1. Factor related to dosage form e.g. synthesis techniques & exipients added can affect disintegration of the dosage form into particles. 2. Factor related to drug: molecular weight (MW) & solubility can affect the dissolution of the drug particles into molecules. 3. Factor affecting drug stability in GIT: GIT secretions can result in drug destruction; food & co administered drugs interact with drugs. 4. Gut pH & drug's pKa affect ionization of drug molecules into ions. 5. Factor related to the absorptive system e.g. GIT motility, surface area available for absorption, presence of GIT disease can modify the rate of crossing of the absorptive surface. II-First-Pass Effect (First-Pass Metabolism; Presystemic Elimination) Definition: It is the metabolism of some drugs in a single passage through the liver, gut wall or the lungs before reaching the systemic circulation. Site: 1- Liver 2- Intestine: e.g. Estrogen 3- Lung: for inhaled drugs as nicotine II-First-Pass Effect (First-Pass Metabolism; Presystemic Elimination) Definition: It is the metabolism of some drugs in a single passage through the liver, gut wall or the lungs before reaching the systemic circulation. A. Hepatic first-pass effect: drugs absorbed from the GIT are carried first in the portal circulation to the liver. Some drugs are extensively metabolized in their first-pass e.g. nitroglycerin & propranolol. Factors reducing Hepatic 1st pass metabolism Reduction in portal blood flow: portal hypertension, propranolol. Inhibition of hepatic metabolizing enzymes: liver failure and presence of enzyme inhibitors as Erythromycin. ↑Bioavailability Routes of Administration: Practical Enteral Parentral Topical??? Intravenous For Systemic or Intramuscular local Effects?? Subcutaneous Eye: Intradermal + Intrathecal Skin Epidural Nose Intra-arterial Inhalation Lung Intraarticular Suitable Dosage Form For Each Route Rational Professional Prescription Thank You