Chapter 4 - Pharmacokinetics

‭Crossing a Cell Membrane‬ ‭Channels and Pores‬ ‭●‬ ‭Very few drugs‬ ‭●‬ ‭Only very small (ex. K, Na)‬ ‭Transport Systems‬ ‭●‬ ‭Some require energy; some do not‬ ‭●‬ ‭Whether a transporter carries a drug depends on its particular structure‬ ‭●‬ ‭Oral drugs may need these to move from the intestinal lumen to blood‬ ‭●‬ ‭Many drugs need these to move across the cell membrane to‬‭intracellular‬‭sites of action‬ ‭Transport Systems: P-Glycoprotein‬ ‭●‬ ‭Multidrug transporter protein (PGP)‬ ‭●‬ ‭Transports drugs out of cells‬ ‭●‬ ‭Liver:‬‭Into bile‬‭for elimination‬ ‭●‬ ‭Kidneys: Aids in quickening excretion; from blood to‬‭renal tubules‬ ‭●‬ ‭Placenta: Back into‬‭maternal‬‭blood‬ ‭●‬ ‭Intestines: Into the intestinal lumen,‬‭reducing absorption‬‭in the blood‬ ‭●‬ ‭Brain capillaries: Into the‬‭blood‬‭, limiting access‬‭to the brain‬ ‭Direct Membrane Penetration‬ ‭●‬ ‭Most drugs are too large to pass through channels/pores and lack transport systems‬ ‭●‬ ‭Able to penetrate membranes:‬‭Lipid-soluble‬‭(lipophilic),‬‭non-ionized‬ ‭●‬ ‭Unable: Water-soluble, polar, ionic, quaternary ammonium compounds‬ ‭Polar Molecules‬ ‭●‬ ‭Uneven distribution of electrical charge‬ ‭●‬ ‭Ex. gentamicin‬ ‭●‬ ‭Dissolve in polar solvents‬ ‭Ions‬ ‭●‬ N ‭ et positive/negative electrical charge‬ ‭●‬ ‭Except for very small ones, unable to cross‬ ‭Quaternary Ammonium Compounds‬ ‭●‬ ‭Molecules with at least one atom of nitrogen and carry a positive charge at all types‬ ‭○‬ ‭Atypical bonding to nitrogen (four bonds instead of three)‬ ‭○‬ ‭Ex. Tubocurarine‬ ‭pH-Dependent Ionization‬ ‭●‬ ‭When an acid gives up a proton, it becomes‬ ‭negatively charged‬ ‭●‬ ‭When a base accepts a proton, it becomes‬ ‭positively charged‬ ‭●‬ ‭Ex. aspirin (acid) and amphetamine (base)‬ ‭●‬ ‭Extent of ionization depends on environment‬ ‭○‬ ‭Acids ionize in basic media‬ ‭○‬ ‭Bases ionize in acidic media‬ ‭●‬ ‭Aspirin in the stomach (acidic) remains nonionized‬ ‭○‬ ‭Can be absorbed across membrane‬ ‭●‬ ‭Aspirin that passed from the stomach to the small intestine (basic) becomes ionized‬ ‭○‬ ‭Cannot be absorbed across membrane‬ ‭pH Partitioning‬ ‭●‬ ‭A drug‬‭accumulates‬‭on the side of a membrane where‬‭the pH most‬‭favors ionization‬ ‭●‬ ‭Ion trapping of aspirin:‬ ‭○‬ ‭Most ASA remains nonionized in the stomach since it is acidic‬ ‭○‬ ‭Since they are lipid-soluble, they can readily cross‬ ‭○‬ ‭Concentration gradient causes nonionized ASA to move into the plasma‬ ‭○‬ ‭ASA becomes ionized in the basic plasma‬ ‭○‬ ‭Ionized ASA cannot diffuse back to the stomach‬ ‭○‬ ‭More nonionized ASA molecules move to the plasma to replace them‬ ‭○‬ ‭At equilibrium, there are equal amounts of nonionized ASA but a much higher‬ ‭concentration of ionized ASA in the plasma‬ ‭●‬ ‭Can influence drug movement (ex. Manipulating urinary pH draws toxic substances from‬ ‭the blood into the urine)‬ ‭Absorption‬ ‭Factors Affecting Absorption‬ ‭Rate of Dissolution‬ ‭●‬ ‭Rapid dissolution → faster absorption‬ ‭Surface Area‬ ‭●‬ ‭Larger surface area → faster absorption‬ ‭●‬ ‭Oral drugs usually absorbed in SI rather than stomach‬ ‭High Blood Flow‬ ‭●‬ ‭Blood containing a newly absorbed drug is replaced rapidly by drug-free blood‬ ‭●‬ ‭Creates large‬‭concentration gradient‬‭between drug outside and inside the blood‬ ‭○‬ ‭Greater concentration gradient → faster absorption‬ ‭Lipid Solubility‬ ‭●‬ ‭Can readily cross membranes → faster absorption‬ ‭pH Partitioning‬ ‭●‬ ‭Depends on difference between the pH of the plasma and site of administration‬ ‭●‬ ‭Allows drugs to be‬‭ionized in the plasma‬‭→ faster‬‭absorption‬ ‭Common Routes of Administration‬ ‭IV Administration‬ ‭Large Volumes of Fluids‬ ‭●‬ ‭Only parenteral administration allowing large volumes‬ ‭●‬ ‭Some drugs are poorly soluble in water and must be dissolved in a large volume‬ ‭Irritant Drugs‬ ‭●‬ ‭Can be rapidly diluted and reduce the risk for injury‬ ‭Slow Injection‬ ‭●‬ ‭Most must be‬‭injected slowly‬‭(1 minute or more) since‬‭all blood is cirulated in that time‬ ‭●‬ ‭The drug is diluted in the largest volume of blood possible‬ ‭●‬ ‭Reduces CNS toxicity; any signs of toxicity to appear by the time a fourth of the total‬ ‭dose is administered (15 seconds)‬ ‭Embolism Risk‬ ‭●‬ ‭Insertion of IV needle can injure the venous wall‬ ‭●‬ ‭Injecting hypotonic or hypertonic fluids can destroy RBCs, becoming debris‬ ‭●‬ ‭Drugs that are not fully dissolved can become embedded‬ ‭Importance of Route Confirmation‬ ‭●‬ ‭SubQ administration is‬‭concentrated‬‭(more barriers);‬‭IV administrations are dilute‬ ‭●‬ ‭SubQ dose IV → heart and bv overstimulation (HTN, cerebral hemorrhage, CVA, death)‬ ‭●‬ ‭IV dose subQ → below MEC, no therapeutic effect‬ ‭Intramuscular Administration‬ ‭Barrier‬ ‭●‬ ‭Capillary wall with large spaces (do not need to penetrate cells)‬ ‭Absorption Pattern‬ ‭●‬ ‭Rate determined by water solubility of drug and blood flow at site‬ ‭Poorly Soluble Drugs‬ ‭●‬ ‭Little harm from suspension of an undissolved drug in interstitial space of muscle tissue‬ ‭Depot Preparations‬ ‭●‬ ‭Drug is absorbed slowly over time‬ ‭●‬ ‭Single injection can last days, weeks, or months‬ ‭●‬ ‭Ex. benzathine penicillin G (depot) lasts for a month, single penicillin G injection lasts‬ ‭for a day‬ ‭IM Contraindications‬ ‭●‬ ‭Patients undergoing anticoagulant therapy due to bleeding risk‬ ‭Oral Administration‬ ‭Barriers‬ ‭●‬ ‭Can be absorbed from stomach, intestines, or both‬ ‭●‬ ‭Two barriers: GI epithelium and capillary wall‬ ‭●‬ ‭GI epithelium is tightly packed; drugs must pass through cells‬ ‭●‬ ‭Intestinal absorption may be reduced by PGP‬ ‭Factors Influencing Absorption‬ ‭●‬ ‭Solubility and stability of the drug‬ ‭●‬ ‭Gastric and intestinal pH‬ ‭●‬ ‭Gastric emptying time‬ ‭‬ F ● ‭ ood in the gut‬ ‭●‬ ‭Coadministration of other drugs‬ ‭●‬ ‭Coatings on the drug preparation‬ ‭Drug Movement After Absorption‬ ‭●‬ ‭Must pass through liver via portal blood →‬ ‭circulation‬ ‭●‬ ‭May undergo extensive hepatic metabolism‬ ‭●‬ ‭May experience enterohepatic recirculation‬ ‭○‬ ‭Liver → duodenum via bile duct → back to‬ ‭liver via portal blood‬ ‭Safety‬ ‭●‬ ‭Preferred for self-medication‬ ‭●‬ ‭No risk for fluid overload, infection, or embolism‬ ‭●‬ ‭Reversible (ex. Activated charcoal)‬ ‭Variability‬ ‭●‬ ‭Difficult to control onset, intensity, and duration of responses‬ ‭Inactivation‬ ‭●‬ ‭Gastric acidity (ex. penicillin G)‬ ‭●‬ ‭Digestive enzymes (insulin)‬ ‭●‬ ‭First-pass effect/hepatic enzymes (ex. nitroglycerin)‬ ‭When Parenteral is Preferred‬ ‭●‬ ‭Emergencies requiring rapid onset‬ ‭●‬ ‭Need for controlled plasma drug levels‬ ‭●‬ ‭Drugs that would be destroyed‬ ‭●‬ ‭Drugs that would cause severe local injury‬ ‭●‬ ‭Drugs that cannot cross membranes‬ ‭●‬ ‭Depot preparation‬ ‭●‬ ‭Patient cannot/will not take drug PO‬ ‭Pharmaceutical Preparations for Oral Administration‬ ‭●‬ ‭Chemically equivalent: Same amount of the identical chemical compound (drug)‬ ‭●‬ ‭Bioavilability: Absorbed at the same rate and extent‬ ‭Tablets‬ ‭●‬ ‭Mixture of a drug, binders, and fillers‬ ‭●‬ ‭May differ in rates of disintegration and dissolution → varying bioavailability‬ ‭Enteric-Coated‬ ‭●‬ ‭Material that dissolves in the intestine but not‬ ‭the stomach‬ ‭●‬ ‭Protects drugs from gastric acid/pepsin;‬ ‭protects from drugs causing gastric discomfort‬ ‭●‬ ‭Time of onset can be altered by variations in‬ ‭gastric emptying (minutes - 12 hours)‬ ‭●‬ ‭May fail to dissolve; pass through GI tract‬ ‭without absorption‬ ‭Sustained-Release‬ ‭●‬ ‭Capsules with individual spheres; each have coatings that dissolve at variable rates‬ ‭●‬ ‭Reduces number of daily doses‬ ‭Blood Flow to Tissues‬ ‭‬ D ● ‭ rug is carried by the blood to its site of action‬ ‭●‬ ‭Abcess: Pus-filled pocket of infection with no internal bvs‬ ‭○‬ ‭Must be surgically drained for effective drug therapy‬ ‭●‬ ‭Solid tumors: Blood flow to outer regions is high but gets lower toward the core‬ ‭○‬ ‭Resistant to drug therapy‬ ‭Additional Administration Routes‬ ‭‬ T ● ‭ opical: Local therapy of the skin, eyes, ears, nose, mouth, rectum, and vagina‬ ‭●‬ ‭Transdermal: Absorption into systemic circulation (ex. Nitroglycerin, nicotine,‬ ‭testosterone, estrogen)‬ ‭●‬ ‭Inhaled: Elicits local effects in the lungs (ex. bronchodilators)‬ ‭●‬ ‭Rectal suppositories: Local effects or effects throughout the body‬ ‭●‬ ‭Vaginal suppositories: Treating local disorders‬ ‭●‬ ‭Direct injection into a specific site (ex. Heart, joints, nerves, CNS)‬ ‭Distribution‬ ‭Factors Affecting Distribution‬ ‭‬ B ● ‭ lood flow to tissues‬ ‭●‬ ‭Ability to exit the vascular system‬ ‭●‬ ‭Ability to enter cells‬ ‭Exiting the Vascular System‬ ‭●‬ ‭Most drugs do not produce effects within the blood; must leave‬ ‭●‬ ‭Necessary for metabolism and excretion to occur‬ ‭Typical Capillary Beds‬ ‭●‬ ‭Most offer no resistance do to pores in the capillary wall‬ ‭●‬ ‭Lipid-soluble compounds can also directly‬ ‭pass through cells‬ ‭Blood-Brain Barrier (BBB)‬ ‭●‬ ‭Tight junctions between cells‬ ‭●‬ ‭To reach sites of action in the brain, drug must‬ ‭be able to pass through (lipid-soluble or with‬ ‭transport system)‬ ‭●‬ ‭PGP may pump drugs back into the blood‬ ‭●‬ ‭Protects brain from injury but prevents drug‬ ‭therapy of CNS disorders‬ ‭●‬ ‭BBB not fully developed at birth‬ ‭Placental Drug Transfer‬ ‭●‬ ‭Not an absolute barrier‬ ‭●‬ ‭Lipid-soluble, nonionized compounds pass from maternal bloodstream to fetus‬ ‭●‬ ‭Ionized, polar, protein-bound, PGP substrate compounds are excluded‬ ‭●‬ ‭Habitual use of opioids → fetal drug dependence‬ ‭●‬ ‭Use of respiratory depressants during delivery‬ ‭(anesthetics and analgesics) → neonate respiratory‬ ‭depression‬ ‭Protein Binding‬ ‭●‬ ‭Drugs can form reversible bonds with proteins‬ ‭●‬ ‭Mostly albumin, which remains in the blood (large‬ ‭size)‬ ‭●‬ ‭Only unbound drugs leave the vascular system‬ ‭●‬ ‭Bound molecules are too large to fit through‬ ‭capillary pores; may prolong distribution and‬ ‭increase half-life‬ ‭●‬ ‭The percentage of drug molecules bound is determined‬ ‭by the strength of attraction between it and albumin‬ ‭(more attraction → less free drug/bioavailability)‬ ‭●‬ ‭Source of drug interactions; binding sites are limited‬ ‭○‬ ‭Drugs may compete or displace one another‬ ‭(free concentration of the displaced drug rises)‬ ‭Entering Cells‬ ‭●‬ ‭Some cells need to enter cells‬ ‭●‬ ‭Others produce effects by binding with receptors on the external cell membrane‬ ‭Metabolism‬ ‭‬ B ● ‭ iotransformation; chemical alteration of drug structure‬ ‭●‬ ‭Most takes place in the liver‬ ‭Hepatic Drug-Metabolizing Enzymes‬ ‭‬ M ● ‭ ost metabolism in the liver performed by the hepatic microsomal enzyme system‬ ‭●‬ ‭(Cytochrome) P450 system made of 12 closely related enzyme families‬ ‭●‬ ‭CYP1, CYP2, and CYP3 metabolized drugs; the rest‬ ‭metabolize endogenous compounds‬ ‭○‬ ‭Each metabolizes only certain drugs‬ ‭●‬ ‭Drug metabolism can result in the synthesis of a‬ ‭molecule that is smaller or larger than the parent drug‬ ‭Therapeutic Consequences of Drug Metabolism‬ ‭‬ ● ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭●‬ ‭ ccelerated renal excretion of drugs‬ A ‭Drug inactivation‬ ‭Increased therapeutic action‬ ‭Activation of “prodrugs”‬ ‭Increased toxicity‬ ‭Decreased toxicity‬ ‭Accelerated Renal Drug Excretion‬ ‭●‬ ‭The kidneys are unable to excrete drugs that are‬ ‭highly lipid-soluble‬ ‭●‬ ‭Converting these drugs to more hydrophilic forms can‬ ‭accelerated excretion‬ ‭○‬ ‭Ex. Addition of a hydroxyl group to convert pentobarbital into a more polar form‬ ‭○‬ ‭Ex. Glucoronidation to make phenytoin hydrophilic‬ ‭■‬ ‭Glucuronic acid (a hydrophilic glucose derivative) is attached‬ ‭■‬ ‭Not all glucuronides are excreted by the kidneys (bile → feces or‬ ‭enterohepatic recirculation)‬ ‭Drug Inactivation‬ ‭●‬ ‭Converting pharmacologically active compounds into inactive forms‬ ‭Increased Therapeutic Action‬ ‭●‬ ‭Increased effectiveness‬ ‭●‬ ‭Ex. codeine → morphine; the formation of morphine may account for virtually all the‬ ‭pain relief that occurs after codeine administration‬ ‭Increased/Decreased Toxicity‬ ‭●‬ ‭Conversion of drugs into inactive forms‬ ‭●‬ ‭Ex. acetaminophen → hepatotoxic metabolite‬ ‭●‬ ‭The metabolite, rather than acetaminophen, causes injury with acetaminophen overdose‬ ‭Special Considerations‬ ‭Age‬ ‭●‬ T ‭ he liver does not develop its full drug-metabolizing capacity until 1 year old‬ ‭●‬ ‭The ability of older adults to metabolized drugs is commonly decreased‬ I‭ nduction and Inhibition of Drug-Metabolizing Enzymes‬ ‭Substrates‬ ‭●‬ ‭Drugs metabolized by P450 hepatic enzymes‬ ‭Inducers‬ ‭●‬ ‭Drugs that act on the liver to increase rates of drug metabolism‬ ‭○‬ ‭Plasma drug levels fall‬ ‭●‬ ‭If the inducer is also a substrate, it can increase the rate of its own metabolism‬ ‭○‬ ‭May necessitate an increase in its dosage‬ ‭●‬ ‭Can accelerate the metabolism of other concurrently used substrates‬ ‭Inhibitors‬ ‭●‬ ‭Drugs that act on the liver to decrease rates of drug metabolism‬ ‭○‬ ‭Increase in active drug accumulation‬ ‭●‬ ‭Can lead to an increase in adverse effects an toxicity‬ ‭First-Pass Effect‬ ‭●‬ ‭Rapid hepatic inactivation of certain oral drugs‬ ‭●‬ ‭Capacity to metabolize a drug is high → drug can be wholly inactivated on its first pass‬ ‭○‬ ‭Ex. orally administered nitroglycerin (given sublingually)‬ ‭●‬ ‭Circumvented through parenteral administration‬ ‭Nutritional Status‬ ‭●‬ ‭Hepatic drug-metabolizing enzymes require cofactors‬ ‭●‬ ‭Malnourishment → lack of cofactors‬