1. University of MiamiAdvanced Practice Preparation

2. Principles of Drug Action Drugs modify existing functions within the body; they do not create function. No drug has a single action. Drug effects are determined by the drugs interaction with the body. 3. Pharmaceutical Equivalents FDA definition : Drugs that contain the same active ingredient Contain the same active ingredients Same dosage form Same route of administration Identical in strength or concentration 4. Pharmaceutical Alternatives Drugs products that: Contain the same therapeutic moiety, or its precursor,but not necessarily in the same amount or dosage for oras the same salt or ester. Each product meets applicable standard of: Identity Strength Quality and Purity Potency Content Uniformity Dissolution/Disentigration Rates 5. Bioequivalence The absence of a significant difference in the rate andextent to which the active ingredient inpharmaceutical equivalents or alternatives becomeavailable at the site of action. The drug is administered at the same dose and undersimilar conditions. Important when considering generic formulations andaltered formulations of a parent moeity. Drugs are considered bioequivalent as long as there isno significant difference in the degree. 6. Therapeutic Equivalents Drugs that have the same clinical effect and safety profile when given to patients under the conditions indicated by the labeling. If therapeutic equivalence is not shown, the FDA will take no position on considering the drug without further investigation and review. 7. Drug Constituents Drug is made up of one or more active ingredients andvarious additives that act as the vehicle or to maintainstability of the active ingredient. They are categorized based on chemical and physicalproperties. The constituents are used to influence certainproperties of the final formulation. 8. Drug Formulations Drugs are formulated to produce either local orsystemic effects. Local c0nfined to one area of the body. Antiseptics, Anti-inflammatories, Local Anesthetics Systemic drug is absorbed and delivered to body tissues by way of the circulatory system. Antibiotics, Anti-hypertensives, Analgesics 9. Drugs for Local Use Can have effects on the skin, mucous membranes, andrespiratory tract. May be water or oil based. Water based preparations are readily absorbed. Oil based preparations are more slowly absorbed. Oil based drugs are not used in the respiratory tract since oil may be carried to the alveoli, resulting in lipid pneumonia. 10. Systemic Drugs Absorbed into the circulation to affect one or moretissue groups. Administered: PO - SL Topically Parenterally IV, SQ, IM, ID Applied to Mucous Membranes 11. Transport Mechanisms The majority of drugs cross cell membranes by simplepassive diffusion. Only non-ionized (uncharged) lipid molecules diffuseeasily. Movement of drug molecules also occur by Carrier-mediated diffusion Active transport Pinocytosis Filtration 12. Simple Passive Diffusion Drugs move from high to low concentration. Absorption occurs as drugs move from highconcentrations in the original compartment to areas oflower concentration in another. Accounts for absorption of most drugs from: GI tract Circulation Target Cells 13. Carrier Mediated Diffusion Also known as Facilitated transport A carrier is needed. Occurs in harmony with concentration gradients. High Low Concentration A driving force is not required Transportation of Glucose, Certain Vitamins, Amino Acids and Organic Acids Example B12 Intrinsic Factor Complex in GI tract. 14. Filtration Small drug molecules move along with fluid throughpores in cell walls. No passage through the lipid matrix of cell. Capillary membrane pores act as barriers to only verylarge drug molecules. Water soluble drugs and some electrolytes are absorbedthrough tissue pores 15. Pinocytosis Drug is engulfed and moved across cell membrane. Cell wall invaginates, forms vacuole. Vacuole breaks off and moves into the cell. Fat soluble Vitamins A, D,E,K 16. Active Transport Moves drug molecules against a concentrationgradient. Uses metabolic energy ATP ATP-Drug Complex forms on cell membrane surface. Complex carries drug through the membrane, thendissociates. The rate of active transport is proportional to the drugconcentration. When carrier mechanisms are saturated, transfer ratescannot increase. 17. Molecular Size of Drug Size of drug molecule affects drug transport. Urea molecules pass easily through cell membranes. Smaller, lipid-soluble, non-ionized Glucose molecules are larger and pass with more effort. Larger, water-soluble, ionized Once drug concentrations on both sides of the cellmembrane are equal, drug movement ceases. 18. Factors Affecting Absorption Bioavailability Rate and extent to which an active drug or its metabolite is absorbed and becomes available at site of action. Ionization Solubility Absorbing Surface Pre-systemic Biotransformation 19. Bioavailability The percentage of Drug available (absorbed), after oneroute of administration that produces a pharmacologiceffect. Determined by measuring the drug concentration inplasma and by assessing the magnitude of response. 20. Bioavailability Chemical instability affects bioavailability example:penicillin G is unstable to the pH of gastric secretions. Nature of Drug Formulation bioavailability may bedecreased based on the formulation of the drug Particle size Salt form Crystal polymorphism Presence of excipients binders, dispersing agents 21. Ionization Movement of drug by one or more transport mechanisms is influenced by: polarity of the cell membrane polarity of the drug molecule Substances of like charge repel each other. Unlike charges attract each other. Drugs are usually weak acids or weak bases. 22. Ionization of Drugs Positively Charged Negatively Charged Alkaloids Acids Bases Acid Radicals Metallic Radicals 23. Drug Ionization Non-ionized drug molecules are usually lipid-solubleand able to cross cell membranes. Ionized drug molecules are unable to penetrate lipidcell membranes. A charge on a drug similar to that of the membranewill delay absorption. Both the dissolution and ionization of drugs areaffected by the pH of body solutions. 24. Drug Ionization The ratio of non-ionized drug to an ionized drug is related to two factors: The pH of the aqueous medium in which it is dissolved. The pKa value Ionization Constant The pH of of an environment in which exactly half of the drugmolecules are charged and the other half is uncharged. 25. Ionization of Aspirin Aspirin weak acid pKa value of 3.5 pH of solution in which the aspirin is dissolved isgreater than 3.5 ionized relatively insoluble in lipidenvironments. pH of solution is less than 3.5, almost entirely non-ionized lipid soluble. 26. Ionization of Drugs Ion Trapping pH dependent Drug molecules accumulate on pH favorable side of cell membrane. Example acid drug/acid environment Aspirin non-ionized in the stomach. Crosses cell membranes into plasma pH 7.4 ionized andlipid insoluble -Trapped in plasma Used therapeutically in drug overdose and poisoning 27. Ion Trapping Alkalinizing urine promotes ionization of an acid drugsuch as Phenobarbitol pKa of 7.4 Elimination is facilitated by trapping it in the urine. 28. Basic Drug Ionization Basic drugs act opposite from acidic drugs. Accumulate in a more acidic environment when a pHdifference exists. A weak organic base codeine Placed in stomach acid environment - ionized Not lipid soluble not absorbed Any drug can be absorbed to some extent in the stomachand intestines. 29. Solubility Ability of the drug to dissolve and form a solution. Must be similar to polar characteristics of theabsorption site (electrical charges). Lipid soluble cross lipid cell membranes more rapidly. Drug must be largely hydrophobic yet have solubilityin aqueous solution to be readily absorbed. 30. Absorbing Surface Blood flow areas of rich circulation promoteabsorption stomach vs. intestine. Total Surface Area intestinal absorption is mostefficient with villi and micro-villi increasing surfacearea. Example: Drugs tend to be absorbed more in theduodenum, less in the jejunum and least in the ileum Surface area decreases proximal to distal Contact Time at Absorption Site delayed orenhanced transport. 31. First Pass Hepatic Effect Drug absorbed across GI tract, must enter portal systembefore entering systemic circulation. This is not true of the mouth or rectum. If drug is rapidly metabolized by liver, the amount ofunchanged drug that gains access to the systemiccirculation is decreased. Many drugs, such as propanalol, undergo a significantbiotransformation during a single pass through the portalsystem. Drugs with significant first pass effects require much largeroral than parenteral doses. Example: Tricyclic Antidepressants, Analgesics and Anti-arrhythmics 32. Distribution Several factors influence drug distribution of an absorbed drug: Blood flow Protein binding Tissue binding Solubility Drugs are distributed through circulation to Inert plasma and tissue binding sites Site of action Organs of elimination 33. Blood FlowThe time required for a drug to be distributed to body tissues is influenced by:Cardiac OutputBlood FlowWell perfused tissues kidney, heart, liver, brain fasteruptake.Poorly perfused tissues muscle, adipose sloweruptake. 34. Blood Flow Drugs leave circulation fluid compartment crosscapillary membrane site of action. Drug concentrations equalize between organsdependent on blood flow to the area. IV Barbiturate for anesthesia pt. will awaken withinminutes half life is several hours. Rapid awkening due to decline of drug levels in thebrain drug redistributed to adipose tissue. Redistribution rather than elimination that terminatesanesthetic effect. 35. Protein Binding Once absorbed, drugs are bound to various tissues inthe body. Only free unbound drug is available to cross cellmembranes to site of action. The release of a drug from protein binding site occursdue to falling drug concentration. Release doesnt always increase drug action. 36. Protein Binding Bound drugs are pharmacologically inactive . Bound drugs cannot be bio-transformed or excreted. 2 Exceptions High-hepatic Clearance Drugs Drugs Eliminated by Renal Tubular Secretion 37. Protein Binding SitesAlpha-1-acid AlbuminGlyocoproteins Basic Drugs The most abundant plasma Quinidine protein Meperidine Acid Drugs Imipramine Warfarin Dipyridamole Penicillin Chlorpomazine Sulfonamides 38. Protein Binding A number of disease states alter the concentration of plasma proteins which affects distribution. Hypoalbuminemia low serum protein drug toxicity The stronger the bond, the longer the duration of drugaction. As drug molecules are released from their bonds, theybecome free acting. If two drugs are given the one with stronger proteinbinding or higher concentration will bind morereadily. 39. Drug-Protein Binding Expressed as a percentage, 0-100%. Percentage of binding in circulation depends largely onchemical nature of the drug. Acetaminophen - ~0% protein bound Short duration of action More drug reaches site of action TID-QID administration Wafarin 99% protein bound 1% pharmacologicallyactive. Long duration of action Once daily administration 40. Solubility Lipid soluble drugs distributed rapidly. Lipid insoluble drugs distributed slowly. 41. Barriers to Distribution Placental Membranes Non-ionized, lipid soluble drugs readily reach fetus through maternal circulation. Placenta is not a barrier to drugs as once thought. Fetus is exposed to same drug concentrations as those in the mother, possibly higher. 42. Barriers to Distribution Blood Brain Barrier - BBB Highly ionized and protein bound drugs cannot enter CNS Drugs that are lipid soluble and poorly bound to plasma proteins can cross BBB and produce effects in the CNS. BBB has active transport system pumps drug molecules out of the brain that may have entered by diffusion. Important to consider in infection antimicrobials must be able to cross BBB. Meningitis active transport fails large amounts of PCN are allowed to remain in the brain. 43. Blood-Brain Barrier Brain capillaries are covered by glial cells(astrocytes) Assist in forming tight junctions Endothelial cells form tight junctions Limits the size and type of molecules that can enterthe brain 44. Dilaudid What is the dose of oral Dilaudid? What is the dose of Dilaudid IV? Why the difference? 45. Volume of Distribution An estimate of the concentration of drug in the plasmaor blood. VdVd = the amount of drug administeredplasma drug concentration (one hour after administration) The amound of fluid necessary to contain the entiredrug in the body in the same concentration as in theblood. 46. Vd Lipid soluble drugs, the Vd is greater than the entirebody fluid volume (over 0.6 L/kg). Drugs with extensive tissue binding can have a greaterVd than total body volume (over 1 l/kg). Vd is influenced by: Age Gender sex body mass differences, pregnancy Extent of protein binding Solubility 47. Volume of Distributionand Body FluidsTotalBody Interstitial Fluids Total (21%)Weight BodyPlasma (4%)100% Water Intracellular Fluids (35%) 60% 48. Fig. Body Fluid Distribution (in the normal 70 kg adult male) proteinsTotal Body Water (42 L) lipids ICV (28 L) ECV (14 L)Intracellular Volume Extracellular carbohydrates Volume Blood Volume (5L) membranes RBCPlasma nucleiVolume VolumeIFV microtubules(2L) (3L)(11 L) mitochondria Interstitial Fluid actin Volume etc. IFV = ECV PV40% Total Body Water = 60% of body weight ICV = 40% ECV = 20%PV = 4%IFV = 16% 49. % of Body WaterCompartmentInfantAdultTotal Body Water73% 60%ICF 33% 40%ECF 40% 20% 50. Case 70 kg male given 500mcg of IV digoxin. Vd in liters = amount of drug adminstered in mcgPlasma drug concentration in mg/L645L = 500mcg digoxin 0.775 mg/LPt has 9 times total body fluid volume of a healthy 70 kg male 51. Vd Vd Pool of body fluids that is required to evenly distribute the drug to all portions of the body. Does not represent a real volume Example Digoxin Hydrophobic Distributes rapidly to muscle and adipose Very small amount is in the plasma 52. Vd High lipid solubility & High tissue binding Large Vd and lower drug levels Less frequent dosing High water solubility & Highplasma protein binding Small Vd and high blood levels More frequent dosing 53. Examples of apparent Vds for some drugsDrug L/KgL/70 kgSulfisoxazole0.1611.2Phenytoin0.6344.1Phenobarbital0.5538.5Diazepam 2.4 168Digoxin7 490 54. Post-Test