University of MiamiAdvanced Practice Preparation
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 drug’s interaction with the body.
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
Pharmaceutical Alternatives Drugs products that: Contain the same therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage for or as the same salt or ester. Each product meets applicable standard of: Identity Strength Quality and Purity Potency Content Uniformity Dissolution/Disentigration Rates
Bioequivalence The absence of a significant difference in the rate and extent to which the active ingredient in pharmaceutical equivalents or alternatives become available at the site of action. The drug is administered at the same dose and under similar conditions. Important when considering generic formulations and altered formulations of a parent moeity. Drugs are considered bioequivalent as long as there is no significant difference in the degree.
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.
Drug Constituents Drug is made up of one or more active ingredients and various additives that act as the vehicle or to maintain stability of the active ingredient. They are categorized based on chemical and physical properties. The constituents are used to influence certain properties of the final formulation.
Drug Formulations Drugs are formulated to produce either local or systemic 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
Drugs for Local Use Can have effects on the skin, mucous membranes, and respiratory 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.
Systemic Drugs Absorbed into the circulation to affect one or more tissue groups. Administered: PO - SL Topically Parenterally – IV, SQ, IM, ID Applied to Mucous Membranes
Transport Mechanisms The majority of drugs cross cell membranes by simple passive diffusion. Only non-ionized (uncharged) lipid molecules diffuse easily. Movement of drug molecules also occur by Carrier-mediated diffusion Active transport Pinocytosis Filtration
Simple Passive Diffusion Drugs move from high to low concentration. Absorption occurs as drugs move from high concentrations in the original compartment to areas of lower concentration in another. Accounts for absorption of most drugs from: GI tract Circulation Target Cells
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.
Filtration Small drug molecules move along with fluid through pores in cell walls. No passage through the lipid matrix of cell. Capillary membrane pores act as barriers to only very large drug molecules. Water soluble drugs and some electrolytes are absorbed through tissue pores
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
Active Transport Moves drug molecules against a concentration gradient. Uses metabolic energy – ATP ATP-Drug Complex forms on cell membrane surface. Complex carries drug through the membrane, then dissociates. The rate of active transport is proportional to the drug concentration. When carrier mechanisms are saturated, transfer rates cannot increase.
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 cell membrane are equal, drug movement ceases.
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
Bioavailability The percentage of Drug available (absorbed), after one route of administration that produces a pharmacologic effect. Determined by measuring the drug concentration in plasma and by assessing the magnitude of response.
Bioavailability Chemical instability – affects bioavailability – example: penicillin G is unstable to the pH of gastric secretions. Nature of Drug Formulation – bioavailability may be decreased based on the formulation of the drug Particle size Salt form Crystal polymorphism Presence of excipients – binders, dispersing agents
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.
Drug Ionization Non-ionized drug molecules are usually lipid-soluble and able to cross cell membranes. Ionized drug molecules are unable to penetrate lipid cell membranes. A charge on a drug similar to that of the membrane will delay absorption. Both the dissolution and ionization of drugs are affected by the pH of body solutions.
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 drug molecules are charged and the other half is uncharged.
Ionization of Aspirin Aspirin – weak acid pKa value of 3.5 pH of solution in which the aspirin is dissolved is greater than 3.5 – ionized – relatively insoluble in lipid environments. pH of solution is less than 3.5, almost entirely non- ionized – lipid soluble.
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 and lipid insoluble -Trapped in plasma Used therapeutically in drug overdose and poisoning
Ion Trapping Alkalinizing urine promotes ionization of an acid drug such as Phenobarbitol pKa of 7.4 Elimination is facilitated by trapping it in the urine.
Basic Drug Ionization Basic drugs act opposite from acidic drugs. Accumulate in a more acidic environment when a pH difference 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 stomach and intestines.
Solubility Ability of the drug to dissolve and form a solution. Must be similar to polar characteristics of the absorption site (electrical charges). Lipid soluble cross lipid cell membranes more rapidly. Drug must be largely hydrophobic yet have solubility in aqueous solution to be readily absorbed.
Absorbing Surface Blood flow – areas of rich circulation promote absorption – stomach vs. intestine. Total Surface Area – intestinal absorption is most efficient with villi and micro-villi increasing surface area. Example: Drugs tend to be absorbed more in the duodenum, less in the jejunum and least in the ileum Surface area decreases proximal to distal Contact Time at Absorption Site – delayed or enhanced transport.
First Pass Hepatic Effect Drug absorbed across GI tract, must enter portal system before entering systemic circulation. This is not true of the mouth or rectum. If drug is rapidly metabolized by liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propanalol, undergo a significant biotransformation during a single pass through the portal system. Drugs with significant first pass effects require much larger oral than parenteral doses. Example: Tricyclic Antidepressants, Analgesics and Anti- arrhythmics
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
Blood FlowThe time required for a drug to be distributed to body tissues is influenced by: Cardiac Output Blood FlowWell perfused tissues – kidney, heart, liver, brain – faster uptake.Poorly perfused tissues – muscle, adipose – slower uptake.
Blood Flow Drugs leave circulation fluid compartment – cross capillary membrane – site of action. Drug concentrations equalize between organs dependent on blood flow to the area. IV Barbiturate for anesthesia – pt. will awaken within minutes – half life is several hours. Rapid awkening due to decline of drug levels in the brain – drug redistributed to adipose tissue. Redistribution rather than elimination that terminates anesthetic effect.
Protein Binding Once absorbed, drugs are bound to various tissues in the body. Only free unbound drug is available to cross cell membranes to site of action. The release of a drug from protein binding site occurs due to falling drug concentration. Release doesn’t always increase drug action.
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
Protein Binding SitesAlpha-1-acid AlbuminGlyocoproteins Basic Drugs The most abundant plasma Quinidine protein Meperidine Acid Drugs Imipramine Warfarin Dipyridamole Penicillin Chlorpomazine Sulfonamides
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 drug action. As drug molecules are released from their bonds, they become free acting. If two drugs are given – the one with stronger protein binding or higher concentration will bind more readily.
Drug-Protein Binding Expressed as a percentage, 0-100%. Percentage of binding in circulation depends largely on chemical 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% pharmacologically active. Long duration of action Once daily administration
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.
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.
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 enter the brain
Dilaudid What is the dose of oral Dilaudid? What is the dose of Dilaudid IV? Why the difference?
Volume of Distribution An estimate of the concentration of drug in the plasma or blood. Vd Vd = the amount of drug administered plasma drug concentration (one hour after administration) The amound of fluid necessary to contain the entire drug in the body in the same concentration as in the blood.
Vd Lipid soluble drugs, the Vd is greater than the entire body fluid volume (over 0.6 L/kg). Drugs with extensive tissue binding can have a greater Vd than total body volume (over 1 l/kg). Vd is influenced by: Age Gender – sex body mass differences, pregnancy Extent of protein binding Solubility
Volume of Distributionand Body FluidsTotalBody Interstitial Fluids Total (21%)Weight Body Plasma (4%)100% Water Intracellular Fluids (35%) 60%
Fig. Body Fluid Distribution (in the normal 70 kg adult male) proteins Total Body Water (42 L) lipids ICV (28 L) ECV (14 L) Intracellular Volume Extracellular carbohydrates Volume Blood Volume (5L) membranes RBC Plasma nuclei Volume Volume IFV microtubules (2L) (3L) (11 L) mitochondria Interstitial Fluid actin Volume etc. IFV = ECV – PV 40% Total Body Water = 60% of body weight ICV = 40% ECV = 20% PV = 4% IFV = 16%
% of Body WaterCompartment Infant AdultTotal Body Water 73% 60%ICF 33% 40%ECF 40% 20%
Case 70 kg male given 500mcg of IV digoxin. Vd in liters = amount of drug adminstered in mcg Plasma drug concentration in mg/L 645L = 500mcg digoxin 0.775 mg/L Pt has 9 times total body fluid volume of a healthy 70 kg male
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
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
Examples of apparent Vd’s for some drugsDrug L/Kg L/70 kgSulfisoxazole 0.16 11.2Phenytoin 0.63 44.1Phenobarbital 0.55 38.5Diazepam 2.4 168Digoxin 7 490