Lecture 5 - Pharmacokinetics Part 2

‭Absorption‬ ‭●‬ ‭Passage of drug into the systemic circulation; determines bioavailability‬ ‭●‬ ‭Bioavailability:‬‭How much of the drug is present to‬‭have an effect‬ ‭●‬ ‭Factors affecting bioavailability:‬ ‭○‬ ‭Routes of administration‬ ‭○‬ ‭Drug solubility (lipophilic or hydrophilic)‬ ‭○‬ ‭1st pass effect‬ ‭pH-Dependent Ionization‬ ‭●‬ ‭Some drugs are only absorbed in acidic (aspirin) or basic environments‬ ‭Lipid-Soluble vs. Water-Soluble‬ ‭●‬ ‭Lipid-soluble: More rapid-absorption, sooner onset‬ ‭Distribution‬ ‭●‬ ‭Reversible movement of drug from‬‭circulation to fluid/tissues‬ ‭○‬ ‭Can come off protein‬ ‭●‬ ‭Affected by:‬ ‭○‬ ‭Protein binding‬ ‭○‬ ‭Capillary permeability‬ ‭○‬ ‭Blood flow‬ ‭Protein Binding‬ ‭●‬ ‭Most significant is albumin‬ ‭●‬ ‭Drug that is protein-bound has no effect‬ ‭●‬ ‭Competitive binding‬ ‭Capillary Permeability‬ ‭●‬ ‭Little resistance; can go between‬ ‭●‬ ‭Can go in if protein-bound, lipophilic, non-polar‬ ‭Blood Flow‬ ‭●‬ ‭Lower blood flow and vessels in tumors and abcesses, less drug distribution‬ ‭Metabolism/Biotransformation‬ ‭●‬ ‭Irreversible alteration of drug structure‬ ‭●‬ ‭Primary routes:‬ ‭○‬ ‭GI tract‬ ‭○‬ ‭Hepatic‬ ‭○‬ ‭Biliary‬ ‭○‬ ‭Renal‬ ‭Consequences of Metabolism‬ ‭●‬ ‭Accelerated renal excretion‬ ‭●‬ ‭Drug inactivation‬ ‭●‬ ‭Increased therapeutic action‬ ‭●‬ ‭Activation of “prodrugs”‬ ‭○‬ ‭No effect until metabolized‬ ‭●‬ ‭Increased or decreased toxicity‬ ‭Metabolic Processes‬ ‭●‬ ‭First pass effect‬ ‭●‬ ‭Phase I metabolism (cytochrome P450)‬ ‭●‬ ‭Phase II reactions‬ ‭●‬ ‭All occur in the liver‬ ‭First-Pass Effect‬ ‭●‬ ‭If high, less bioavailable (ex. testosterone)‬ ‭●‬ ‭Rapid GI or hepatic inactivation of oral drugs before effect is had‬ ‭●‬ ‭Does not reach circulation or is made inactive when it does‬ ‭Bioavailability‬ ‭●‬ ‭Fraction of drug administered reaching the systemic circulation‬ ‭●‬ ‭Significance: Dosage of drugs with a high hepatic extraction‬ ‭Phase I Metabolism‬ ‭●‬ ‭Alteration in the chemical structure of a drug by‬‭P450‬ ‭●‬ ‭Occurs in:‬ ‭○‬ ‭Hepatic circulation‬ ‭○‬ ‭GI system‬ ‭○‬ ‭Skin‬ ‭○‬ ‭Kidneys‬ ‭○‬ ‭Lungs‬ ‭●‬ ‭Results in:‬ ‭○‬ ‭Increasing‬‭polarity‬ ‭○‬ ‭Inactivation‬‭of drugs‬ ‭○‬ ‭Activation‬‭of prodrugs‬ ‭●‬ ‭Located in the liver, where most drug metabolism takes place‬ ‭●‬ ‭Consists of 12 enzymatic families (P450):‬ ‭○‬ ‭Key enzyme: Cytochrome‬ ‭○‬ ‭3 primary groups metabolize drugs (CYP1, CYP2,‬ ‭CYP3)‬ ‭○‬ ‭CYP3A4‬‭metabolizes 50% of drugs‬ ‭Disruption of Phase I: Inducers‬ ‭●‬ ‭Many drugs can activate or inhibit P450 metabolism of substrate‬ ‭drugs‬ ‭●‬ ‭Substrates:‬‭Drugs metabolized by P450‬ ‭●‬ ‭Inducers:‬‭Activate P450 metabolism; stimulation of‬‭enzymes‬ ‭increases metabolism‬ ‭○‬ ‭Decreased plasma concentration‬ ‭○‬ ‭Decreased drug activity‬ ‭○‬ ‭Decreased therapeutic effect‬ ‭●‬ ‭Ex. phenytoin and warfarin‬ ‭Disruption of Phase I: Inhibitors‬ ‭●‬ ‭Many drugs can induce or inhibit P450 metabolism of‬ ‭substrate drugs‬ ‭●‬ ‭Inhibitors:‬‭Slow P450 metabolism‬ ‭○‬ ‭Lead to increased plasma concentrations‬ ‭○‬ ‭Increased risk for toxicity and adverse effects‬ ‭●‬ ‭Inhibitors can also be foods/substances (‬‭grapefruit‬‭juice)‬ ‭●‬ ‭Ex. warfarin and erythromycin‬ ‭Phase II Metabolism‬ ‭●‬ ‭Biotransformation of drugs that‬‭does not involve‬‭the‬ ‭hepatic‬‭P450‬‭system‬ ‭●‬ ‭Almost always results in a‬‭polar form‬‭of the drug‬ ‭●‬ ‭Glucuronidation‬‭: Addition of glucose derivative molecule‬ ‭to a drug to expedite elimination of drug (lipophilic to‬ ‭hydrophilic‬‭)‬ ‭○‬ ‭Unable to be reabsorbed‬ ‭Factors Influencing Metabolism‬ ‭●‬ ‭Age‬ ‭●‬ ‭Nutrition‬ ‭●‬ ‭Drug interactions‬ ‭Excretion‬ ‭●‬ ‭Removal of drugs from the body‬ ‭●‬ ‭Excretion can occur in:‬ ‭○‬ ‭Kidneys‬ ‭○‬ ‭GI tract‬ ‭○‬ ‭Lungs‬ ‭○‬ ‭Saliva, sweat‬ ‭○‬ ‭Breastmilk‬ ‭Excretion: Kidney‬ ‭●‬ ‭Renal excretion involves 3 processes:‬ ‭○‬ ‭Glomerular filtration‬ ‭○‬ ‭Passive resorption‬ ‭○‬ ‭Active secretion (PGP)‬ ‭Factors Affecting Renal Excretion‬ ‭●‬ ‭Age‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ ipid solubility‬ L ‭Protein binding‬ ‭pH and ionization‬ ‭Competition of active transport‬ ‭Renal dysfunction‬ ‭Single-Dose Curve‬ ‭●‬ ‭Minimum effective concentration:‬‭The‬ ‭serum drug level under which no‬ ‭therapeutic effects take place‬ ‭●‬ ‭Toxic concentration:‬‭The serum drug‬ ‭level at which toxic effects start to occur‬ ‭●‬ ‭Therapeutic range:‬‭A range between‬ ‭the minimum effective concentration and‬ ‭toxic concentration, in which there is enough of the drug available to have a therapeutic‬ ‭effect but not enough to induce toxicity‬ ‭●‬ ‭Peak:‬‭The highest level of plasma drug concentration‬ ‭●‬ ‭Onset of action:‬‭The amount of time taken for a drug‬‭to begin demonstrating its effects‬ ‭●‬ ‭Duration of action:‬‭The range of time from the onset‬‭of action to which a drug no longer‬ ‭exerts any effects on the body; how long its effects are present‬