Pharmacokinetics Lecture Notes PDF

Pharmacokinetics Dr.Leila Alblowi Lecture Objectives: 01 Define pharmacokinetics and differentiate it from pharmacodynamics Understand and explain the processes involved in pharmacokinetics, 02 including absorption, distribution, metabolism, and excretion (ADME). 03 Identify the f...

Pharmacokinetics Dr.Leila Alblowi Lecture Objectives: 01 Define pharmacokinetics and differentiate it from pharmacodynamics Understand and explain the processes involved in pharmacokinetics, 02 including absorption, distribution, metabolism, and excretion (ADME). 03 Identify the factors that influence drug absorption and bioavailability. Analyze the significance of first-pass metabolism and its impact on drug 04 dosing. Explore the metabolic pathways involved in drug elimination and the role of 05 enzymes like CYP450 in drug metabolism.  Pharmacokinetics vs Pharmacodynamics Pharmacokinetics What the body does to the drug Pharmacodynamics What the drug dose to the body. Therapeutic effect and side effects Pharmacokinetics Drug Body Pharmacodynamics Pharmacokintecs The process of movement of unchanged drug from Absorption: the site of administration to systemic circulation to reach the site of action. Transfer the drug from one location to another within the Distribution: body Process by which the drug is altered and broken down Metabolism: into smaller substances (metabolites). Elimination Excretion is the removal of drug from body fluids (Excretion): Urine, bile, sweat, saliva, tears, feces, breast, milk..etc  Absorption: Defined as the passage of the drug from the site of administration into circulation  Mechanisms of absorption of drugs 1. Passive diffusion: The drug moves from a region of high concentration to one of low concentration, the vast majority of drugs are absorbed by this mechanism. 2. Facilitated diffusion: Protein carrier mediated system moving the drug from an area of high concentration to an area of low concentration. e.g Tetracycline Both Passive and facilitated diffusion: ✓Move the drugs from an area of high concentration to an area of low concentration. ✓They do not require energy  Mechanisms of absorption of drugs 3. Active transport: It is transfer of drugs against a concentration gradient and need energy , it is carried by a specific carrier protein 4. Endocytosis and exocytosis: Engulf large molecule e.g. protein e.g; Vitamin B12 is transported across the gut wall by endocytosis..used to transport drugs of exceptionally large size across the cell membrane. Factors influence the rate and extent of absorption of drug 1. Disintegration and dissolution Liquids are absorbed faster than solids Delay in disintegration and dissolution, as with poorly water soluble drugs like aspirin, result in delayed absorption 2. Particle size Small particle size is important for better absorption When drug has to act on the gut, it particle size should kept large to avoid absorption, e.g., anthelmintics drugs 3. Lipid solubility Lipid soluble drugs are absorbed faster and better by dissolving in the phospholipids of the cell membrane  Factors influence the rate and extent of absorption of drug Acidic pH at absorptive site: Weak acid>more unionized> more lipid soluble 4. pH and ionization Weak base>less unionized> less lipid soluble Ionized drugs are poorly absorbed while Alkaline pH at absorptive site: unionized (uncharged) drugs are lipid soluble and Weak acid>less unionized> less lipid soluble well absorbed. Weak base>more unionized> more lipid soluble Most drugs are either weak acids or weak bases that are present in solution 5. Area and vascularity of the absorption site The greater the absorbing surface area and vascularity, the better the absorption. Most drugs are absorbed in the small intestine. 6. Gastrointestinal motility If gastric emptying time is faster, the drug moves to the intestines more quickly, resulting in faster absorption. When intestinal motility is increased, as in the case of diarrhea, drug absorption is decreased. Factors influence the rate and extent of absorption of drug 7. Presence of food It delays gastric emptying Drugs can form complexes with food components; for example, tetracycline can chelate with calcium in food, reducing its bioavailability. 8. Metabolism Some drugs may degraded in the gut, e.g., nitroglycerine, insulin. 9. Disease The diseases of the gut like malabsorption result in reduced absorption of drugs First-pass hepatic metabolism It is also called pre-systemic metabolism or first pass effect Drugs given orally may be metabolized in the gut wall and in the liver before reaching the systemic circulation Drugs like insulin undergoes complete first pass metabolism it should not be given orally Highly metabolized drugs in the liver or intestine reduce the amount of unchanged drug that reaches the systemic circulation, thereby decreasing the bioavailability of oral drugs.  Bioavailability (F) F is the fraction of the drug that reaches the systemic circulation following administration by any route F= -------- % for IV admin drug E.g. 100mg of drug taken orally F for oral administered drug is lower due to uncompleted absorption and first pass metabolism (PO), and 70 mg of this drug absorbed unchanged, what is F = ??? Important for calculating drug dosages.  Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and tissues.  Distribution Factors determine the rate and extent of distribution: 1. Lipid solubility Lipophilic drugs easily cross most biological membranes. They dissolve in the lipid layers of the membranes, allowing them to penetrate the entire cell surface. 2. Ionization 3. Blood flow kidney and liver higher than skeletal muscles and adipose tissues. 4. Binding to plasma proteins and cellular proteins only free or unbound drug is available for action, metabolism, and excretion, e.g. warfarin is 99% protein bound while lithium is 0%,i.e., totally free) Drugs bound are pharmacologically inert. Some drugs can displace others from their binding sites on the plasma proteins Volume of Distribution ▪ Vd is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. Q: if 10 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C0 = 1 mg/L what is the Vd? Metabolism Metabolism(Biotransformation) Is the process by which the body chemically altered the drug and broken it down into smaller substances (metabolites) Mainly in liver Metabolism transforms drugs into more polar, water-soluble compounds, making them easier to excrete through the kidneys. The rate of metabolism determines the duration and intensity of a drug's pharmacological action. Sites of Drug Metabolism The main organ for drug biotransformation is the liver Drugs are also metabolized by kidney, gut, lungs, skin and the brain (extrahepatic metabolism) Some oral drugs are transported directly to the liver , where they undergo hepatic metabolism before reaching their sites of action through systemic circulation. such as lidocaine which has a bioavailability of only 3% when taken orally. This process is known as first-pass or pre-systemic metabolism.  Results of Drug metabolism Drug metabolism usually leads to deactivation or detoxification, it may leads also to the formation of a metabolite having therapeutic or toxic effects Metabolism Inactive/ low More active Active Toxic Active metabolites metabolites metabolites metabolites Same Activity Different activity  Pathways of Drugs Metabolism 1. Phase I reaction: (functionalization reactions) This involves oxidation, reduction, and hydrolysis reactions which introduce or unmask a functional group on the drug molecule. This phase makes the drug more polar and can either active, unactive or have no change on the drug's pharmacological activity. 2. Phase II reaction: (conjugation reactions) The drug undergoes conjugation reactions where it combines with an endogenous substance to form a more water-soluble compound, making it easier to excrete. These conjugation products are usually in active. Detoxifying pathways in drug metabolism. The Biotransformation of Drug  Phase 1 Metabolism In this phase non-polar drugs undergo reactions that make them more polar. This occurs through two pathways: 1. Introduction of a more polar functional group into the drug molecule(-OH, - NH2, COOH –SH....etc.). 2. Modification of an existing group and converting it to a more polar one. by: I.Oxidations (Cytochrome P450-Dependent and Cytochrome P450-Independent* * non-microsomal oxidation enzymes :such as alcohol and aldehyde dehydrogenase, mono-amine oxidases, diamine oxidases and other enzymes.) II.Reductions III.Hydrolysis  CYP450 enzymes Phase I reactions in drug metabolism are most commonly catalyzed by the cytochrome P450 (CYP) enzyme system. Cytochrome P450 enzymes are a superfamily of heme protein monooxygenases that catalyze the hydroxylation, oxidation, or reduction of a wide range of structurally diverse drugs. These enzymes are primarily found in the smooth endoplasmic reticulum membrane of hepatocytes Cytochrome P450 enzymes (CYP) are involved in the metabolism of approximately 75% of all drugs used today  CYP450 enzymes There are many CYP enzymes that facilitate the metabolism of both endogenous and exogenous compounds; however, the key families involved in drug metabolism include CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, CYP3A4, and CYP4A11. CYP3A4 is the most important CYP enzyme in drug metabolism  CYP450 enzymes Enzyme induction: Induction of selected CYP isozymes by some drugs (i.e. enzyme inducers) e.g. phenobarbital, rifampin and carbamazepine, also smoking, ethanol. Leading to: Increased rate of drug metabolism Decrease in drug plasma concentration Decrease drug activity > decrease therapeutic effect (if metabolite is inactive) Dose adjustment is required (often increase dose)  CYP450 enzymes Enzyme inhibition Inhibitors of CYP> e.g. erythromycin, ketoconazole, and grapefruit. Leading to: Increase plasma concentration of parent drug Exaggerated and prolonged pharmacological effects Increased risk of drug-induced toxicity Prodrugs > loss of activity* Dose adjustment (reduction) is required/ avoid concomitant use  Other Phase I enzymes non-microsomal enzymes Alcohol dehydrogenase: It oxidase alcohols to their aldehyde derivatives as part of excretion These enzymes are the basis for the toxicity of methanol Methanol is oxidized by alcohol dehydrogenase to acetaldehyde (structurally similar to formaldehyde) which can cause significant tissue damage. Formaldehyde, and methanol poisoning can result in blindness. Monoamine oxidase (MAO): This enzyme is responsible for the oxidation of amino –containing endogenous compounds such as catecholamine and tryamine and some drugs Phase II Reaction When Phase I reactions do not produce metabolites that are sufficiently hydrophilic (water-soluble) or inactive for elimination from the body, the drugs or metabolites generated by Phase I reactions undergo Phase II reactions Phase II conjugation reactions converting these metabolites to more polar and water-soluble products that is inactive and easily excreted by the kidneys. Phase II Reaction Important Phase II enzymes include: 1. UDP-Glucuronosyl transferases (UGTs) 2. Sulfotransferases (STs) 3. Glutathione transferases (GSTs) 4. N-Acetyltransferases (NAT) 5. Methyltransferases 6. Amino Acid conjugate The resulting conjugated products are very polar (water soluble), resulting in rapid drug elimination from the body Acetaminophen Metabolism and Toxicity Normal Metabolism: 1. Primary Pathways: 95% of acetaminophen is metabolized via glucuronidation and sulfation. 2. Alternative Pathway: The CYP450-dependent pathway, responsible for only 5% of metabolism, involves GSH conjugation. Acetaminophen Metabolism and Toxicity Overdose Scenario: 1. In cases of excessive acetaminophen intake, the glucuronidation and sulfation pathways become saturated. 2. The CYP450-dependent pathway becomes more prominent, converting the drug into N- acetyl-p-benzoquinoneimine (NAPQI), a hepatotoxic metabolite. Hepatotoxicity Risk: 1. Under normal conditions, glutathione (GSH) conjugates NAPQI, preventing toxicity. 2. With overdose, GSH stores are depleted faster than they can be regenerated, leading to NAPQI accumulation and resulting in hepatic necrosis. Antidote: 1. Acetylcysteine: Administered as an antidote in cases of acetaminophen overdose to replenish GSH levels and prevent liver damage  Thanks! Does anyone have any questions?