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Exam 1: Pharmacokinetics
Question: If you are in an emergency room with symptoms of a potentially fatal heart attack, would you prefer to receive the medication to resolve the problem as an intravenous injection or as a tablet that should be swallowed? Question: When you pick up a prescription drug from the pharmacist, you receive instructions as to how much of the drug to take - the dose of the drug - and when to take the drug - the dose schedule. What factors are involved in setting the dose and the dose schedule? Many of the medically relevant answers to these questions are determined from pharmacokinetic studies of the drug(s) in question. Pharmacokinetics is the study of the relationship between the dose of an administered drug and the concentration of that drug in plasma over a period of time and the relevance of that relationship to the effects of a drug. Pharmacokinetics is the term used to describe how the action of a drug is time dependent and it is also the term for the study of how and why drug action is time dependent. If you think about it, we all know from experience that drug action is time dependent but we will explore this issue in some detail in this subsection of the course.
Learning Objectives
Although Learning Objectives can be useful guides for learning, the student should be careful: a list of Learning Objectives does not include all the information and concepts from a section and therefore it does not include all the information on which the student may be tested in an exam. Know the routes of drug administration and understand the advantages and disadvantages to their use in individuals of different age, general health status, and immediate health status. Know the processes by which drug molecules may cross the plasma membrane and may cross a layer of cells. Understand how lipid solubility of drug molecules affects the rate of movement of the drug across the plasma membrane. Understand how ionization of drug molecules is dependent on the characteristics of the drug and of the pH of the local environment and how pH-dependent ionization can lead to asymmetric drug distribution across a membrane. Understand the processes of absorption, distribution, metabolism and excretion. Understand the characteristics of drug elimination by zero order kinetics and by first order kinetics. Define Half-Life and understand how Half-Life is determined, why drugs do not have the same Half-Life, and what information can be obtained if the Half-Life for a drug is known.
Understand how the sum of the processes of absorption, distribution, metabolism and excretion will determine the relationship of drug concentration (in the plasma or any other body compartment) with time after a dose of drug is administered. Understand the concepts of therapeutic threshold concentration and toxic threshold concentration for a drug. Understand the consequences of different drug dose regimens and routes of administration in terms of potential therapeutic benefit and intensity of the therapeutic response, potential toxicity, latency to effect, and duration of effect of a drug given in a single dose or given in repeated doses.
Drug Processing
Unless injected intravenously, Administration of a drug by any route is followed by movement of the drug from the site of administration into the (blood) plasma through a process of Absorption. Once in the plasma, the drug may exist as Free Drug or as Bound Drug because drug molecules can bind to plasma proteins. Drug in the plasma is delivered to organs, tissues and cells in the body through the process of Distribution. The Movement of Drug Molecules Across Membranes across a cell membrane and across cell layers as it passes to or from the plasma, or into or out of cells of a particular tissue or organ, can occur through several processes. In some cells, tissues and organs, Storage of the drug may occur; in others, Metabolism of the drug may occur. Delivery of the drug to some organs may lead to Excretion of the drug. In order for its action to be terminated, a drug must either be metabolized or excreted: the sum of the processes of metabolism and of excretion is known as Elimination. The acronym ADME is often used to refer to the processes of absorption, distribution, metabolism, and excretion. Each of these processes is described in the following material.
Drug Processing Drug Administration
Drugs can be administered via several routes divided strictly into two groups: Enteral and Parenteral. Enteral administration requires that the drug be placed into the (lumen of the) gastrointestinal tract - so that the drug accesses the blood from the gastrointestinal tract. Parenteral administration requires that the drug be placed at any site other than the (lumen of the) gastrointestinal tract - the drug does not access the blood from the gastrointestinal tract. Some drugs may be administered by several of the different routes: the drug may be available in slightly different chemical forms, each appropriate for a different route of administration, and may be available in different formulations, each appropriate for one more routes of
Sublingual Administration Some drugs can be formulated in chewable and sublingual (placed under the toingue) form and are absorbed into the blkood vessels in the tongue and the cheeks. These drugs tend to have rapid onset but short duration of action (compared to a swallowable form the same drugs)which tend to have a delayed onset and a longer duration of action. Intragastric Tube Administration allows the drug be delivered (in liquid form only) directly into the stomach. This route of administration is useful in unconscious individuals or in individuals who have difficulty swallowing or who are unable to swallow. Rectal Administration allows the drug to be delivered into the lumen of the colon. Drugs delivered in this manner can be absorbed into the plasma of the systemic circulation or may have effects only within the colon. Intravenous Administration of a drug may be made by injection or infusion of drug solution. A drug can be injected in a (relatively) concentrated form, in a relatively small volume (<10ml) using a syringe. This is a suitable method if the drug is to be applied only once or is applied multiple times with relatively large time intervals between each administration. A drug can be also infused in a (relatively) dilute form, continuously over many hours (or longer) using a so called "iv drip". This is a suitable method if continuous application is required (perhaps to maintain a continuous effect) or if concentrated solutions of the drug may be an irritant at the site of injection or within blood vessels, or if the drug is eliminated (i.e., removed) from the body (by metabolism and excretion) extremely rapidly. Drugs may also be injected intravenously through a peripheral indwelling central catheter or PIC catheter. The PIC catheter is inserted through the skin into a vein and pushed up the vein so that drug enters the vein close to the heart; the end of the catheter is accessible from the skin so that drug administration by injection from a syringe through the catheter can be made repeatedly without repeated damage to the skin which occurs without an indwelling catheter. Drugs administered intravenously will be quickly directed to all tissues and organs of the body (the heart and lungs being the first organs to which the drug will be delivered) without the need for movement of the drug from the point of administration into the blood. Such rapid delivery is beneficial for therapeutic effects but is also potentially problematic regarding similarly rapid induction of a drug's undesired side effects. However, it is unusual to administer drugs by intravenous injection/infusion outside of immediate medical supervision. Intramuscular Administration by injection of drug in a (relatively) concentrated form in a relatively small volume (<10ml) is performed using a syringe;drug is injected into the extracellular/extravascular space of large muscle (usually the upperarm or shoulder, or the buttocks. This is a suitable method if the drug is to be applied only once or is applied multiple times with relatively large time intervals between each application. Drug administered by intramuscular injection can have effects at the site of injection but the drug will also be absorbed into the plasma and be directed to all tissues and organs within the body where it can have effects. Different drug forms a of a drug - the basic drug molecule with some other chemical moiety attached to it - may be available for intramuscular injection with each of the different forms having different rates of absorption (access) into the plasma and/or different half life in the plasma and thus having different latency to action and different duration of action. However, it is unusual to administer drugs by intramuscular injection outside of immediate medical supervision.
Subcutaneous Administration of a drug may be made using a syringe (<2ml) or by implantation of a capsule made from silastic (plastic) tubing. Subcutaneous injection is suitable for administration of drug in a small volumes of liquid. Drug administered by subcutaneous injection can have effects at the site of injection but will also be absorbed into the plasma and be directed to all tissues and organs within the body where it can have effects. Alternatively, implantation of a drug-containing plastic capsule under the skin allows for slow release of the drug from the capsule into the surrounding tissue so that drug effects can last months or years - the drug is put into the capsule in crystal form. Drugs administered in this way can have effects at the site of injection but will also be absorbed into the plasma and be directed to all tissues and organs within the body where it can have effects. However, it is unusual to administer drugs by subcutaneous injection outside of immediate medical supervision. Topical Administration with Local Effect includes a number of methods to apply a liquid, ointment, or cream form of the drug to a single site on the surface of the body. Drugs applied in this way are usually designed to have their effect at the site of application although (therapeutically) unnecessary and potentially undesirable side effect resulting from absorption into the systemic circulation can occur. Sites for topical administration with local effect include the eye, nasal passage, mouth, skin, and vagina. "Cutaneous" Administration with Distant Effect for some drugs permits slow but contiuous absorption of the drug into the systemic circulation from the site of administration - usually the skin - with delivery of the drug to tissues and organs throughout the body. This mechanism of administration with desired distant effect includes use of a "patch" for delivery of nicotine, contraceptive drugs and some other drugs. Inhalation Administration allows drugs to administered as a spray/mist or a gaseous component of inspired air. Administration in this way allows the drug to be targeted to the bronchial system within the lung (as with some anti-asthmatic and decongestant drugs). However, the potential for drugs applied in this way to cross into the pulmonary circulation also allows drugs targeting other tissues or organs in the body to administered in this way (as with inhalant general anesthetics). Intraspinal Administration of a drug - "spinal" or "epidural" injection - allows the drug to be targeted to the nerves in the spinal column. One advantage of this route of administration when the target of drug action is within the spine is that, although the amount of drug injected into the spine is sufficient for the desired therapeutic effect, the amount of drug passing from the spine to the plasma will be small so that potentially undesirable adverse effects of the drug elicited through effects of the drug at other sites in the body will be minimized. Drug Formulation Drugs have Different Chemical Forms Drugs may be available in several forms each of which has disadvantages and advantages. The drug molecule can exist in a form that does not produce an ionized form of the drug when put into liquid: these drugs are generally very soluble in lipid and are often insoluble (or soluble
disease of dysfunction of the liver and/or kidneys which would alter metabolism and excretion, respectively, of drugs. Is the patient able to follow instructions? Self medication may be possible in most adults but not in those with a neurodegenerative disease in which memory and cognitive function is compromised or in those where normal mental abilities arein someway impaired. Additionally, self medication is not possible for some physically disabled individuals and in the very young. Is the patient in a emergency situation? Delivery of a drug may be through a different route when the situation at hand is an emergency - in which rapid drug effects are required. Other Drugs "On Board". Are there other drugs already in the body or "on board" which may influence the route by which a second drug should be administered? A drug already in the body may influence absorption of a second drug from some sites of administration but not others. One drug may influence blood flow through an organ/tissue which is the major site of drug absorption for the second drug. One drug may also influence blood flow through the organ/tissue which is the major site of drug action of a second drug present in the plasma. Additionally, (see later section in this section), two drugs may compete for the same metabolic or excretion process and this competition will influence the availability of each drug at its sites of action. Duration of Treatment. Is the drug to be administered in a single dose on a single occasion or must it be administered repeatedly or continuously over a period of hours or longer? Latency to Effect. Is it critically important that the drug effect be essentially immediate following administration or can the drug effect be delayed (as a consequence of route of administration chosen) after administration without harm to or to the benefit of the patient? Target of Administered Drug. Will a drug administered by a particular route be delivered to the desired target site at sufficient concentration to have the desired therapeutic effect? Will a drug administered by a particular route be delivered to the desired target site to have the desired therapeutic effect but also be delivered to other sites (cells, tissues and organs) and consequently have undesired adverse side effects? Formulation of the Drug. Is the formulation of the drug suitable for the route of administration chosen? Is the formulation of the drug suitable for the patient? An adult may be able to swallow a tablet form of a drug that must be given in liquid form to a young child.
Drug Processing Drug Absorption
For all drugs, administration is followed by movement of the drug into the blood plasma, a process called Absorption.
Absorption includes movement of a drug into the blood: across the mucosa-lined epithelial surfaces of the lungs, gastrointestinal tract, nasal passages, and vagina, across the skin and the surface of the eye, and from injection sites (subcutaneous, intramuscular, and intraspinal). Absorption occurs regardless of whether or not absorption (movement of drug from point of administration to plasma) is required for the desired drug action. Some thoughts.... A drug applied orally must cross the wall of the gastrointestinal tract and enter the plasma if it is to reach sites of action such as the heart, brain, and skeletal muscle. A drug applied by inhalation with desired effects in the central nervous system must enter the plasma in order to reach the that site of action. A drug applied on the skin for a desired effect at the site of administration will still be absorbed across the skin and enter the systemic circulation. A drug which is inhaled (as an aerosol) in order to have effect on the bronchiole system will still be absorbed across the epithelium of the lungs and will enter the systemic circulation. Just as absorption of a drug may or may not be required for desired therapeutic action, we should recognize that absorption may lead to undesirableside effects. Movement of Drug Molecules across cell membranes and across layers of cells is obviously required for absorption of a drug to occur. It's important to realize that the same processes by which drug molecules move across cell membranes and cell layers during absorption into the plasma from the site of administration are also important for movement of drug molecules out of the plasma in any tissue or organ, and for movement of drug molecules across cell membranes and cell layers within a tissue or organ. Movement of Drug Molecules Across Membranes and Cell Layers In most situations, it is necessary for the drug to get from the site of administration into the plasma ( Absorption ) and then to the desired site(s) of therapeutic action ( Distribution ) before a therapeutic benefit will be noted. For all drugs, administration is followed by movement of the drug into the blood plasma, a process called Absorption. Absorption includes movement of a drug into the blood: across the mucosa-lined epithelial surfaces of the lungs, gastrointestinal tract, nasal passages, and vagina, across the skin, and
surface area across which drug movement occurs - the larger the surface area, the higher rate of movement (in terms of molecules per minute moving across the whole surface); think for example what would happen in terms of rate and total amount of drug movement from the lumen of the gastrointestinal tract to the blood if the small intestine had a lesser surface area. vascularization of the surface across which drug movement (into or out of plasma) is occurring - the higher the density of blood vessels, the higher rate of movement (in terms of molecules per minute moving across the whole surface); think for example what would happen if the small intestine had fewer blood vessels passing through it. blood flow "through" surface across which drug movement (into or out of plasma) is occurring - the higher the perfusion of or blood flow through vessels, the higher rate of movement of drug molecules across the surface; think for example what would happen if blood flow through vessels in the small intestine was reduced. Bulk Flow Drug molecules can move across cell layers without having to pass through any cell membranes by a process known as Bulk Flow. Imagine two compartments separated by a layer of cells which are relatively loosely joined together. In this situation, liquid may pass through the gaps between cells, from one compartment to the other, if there is a hydrostatic pressure difference between the two compartments or if there is an osmotic pressure difference between the two compartments. The liquid passing across the cell layer via Bulk Flow includes water, electrolytes (Na, K, Cl etc) and relatively small molecules including drug molecules in solution. Larger molecules, such as proteins, will not normally pass across cell layers in this way although in certain pathophysiological situations movement of such molecules will occur by Bulk Flow. Where are such hydrostatic pressure differences and such arrangements of cells so that Bulk Flow occurs? The wall of blood vessels allows Bulk Flow of materials from the plasma to the surrounding extravascular space around small arterioles and the arteriolar side of capillaries because the hydrostatic pressure in these vessels is greater than in the extravascular space around those vessels. Similarly, Bulk Flow of materials occurs - in the opposite diretion - from extravascular space to the plasma of small veins and the venous side of capillaries because the hydrostatic pressure in the extravascular space around these vessels is greater than in these vessels. Bulk Flow also occurs in the glomerulus of each kidney tubule where water and electrolytes and drug molecules in the plasma are filtered into the (Bowman's capsule) lumen of the tubule; this filtrate solution passes down the tubule and is processed to form urine. Where is Bulk Flow of drug molecules across cell layers prevented?
In certain organs, the cells forming the wall of the blood vessels are tightly joined together. In this situation, movement of water, electrolytes and small drug molecules by Bulk Flow across the cell layers of the blood vessel wall is restricted and perhaps essentially absent. Organs where bulk flow from/to the plasma is restricted, include the brain (where the wall of blood vessel forms part of what is known as the "blood brain barrier") and the placenta. At these sites, movement of drugs (by Bulk Flow) into the brain and to the developing fetus is reduced compared to movement (by Bulk Flow) into other tissues and organs. Bulk flow is also restricted in the kidney where the cells forming the wall of the kidney tubule(s) are tightly abutted to prevent Bulk Flow movement of molecules, including drug molecules and of electrolytes, from the lumen of the tubule(s) back to the plasma Is Bulk Flow important in terms of drug delivery within the body? Certainly. Except in those tissues and organs noted above, bulk flow is an important mechanism for drugs to move from the plasma into the extravascular space. However, bulk flow is to some extent "ignored" as a process for drug movement from the plasma because bulk flow can not be controlled by medical intervention (i.e., drugs) and because physical/chemical design changes of drug molecules are not useful to alter bulk flow movement by those drug molecules (while likely altering pharmacodynamic properties and other pharmacokinetic properties of the drug). Mechanisms for Trans-Membrane Drug Movement Drugs can be moved across membranes into and/or out of cells and thus across cell layers by three very different mechanisms: Endocytosis (aka pinocytosis) and Exocytosis , both of which require significant structural alterations of the cell to move drug molecules into or out of the cell, Membrane-embedded Transporters , and Diffusion. While these are important mechanisms in physiological processes, only diffusion is generally considered important in terms of movement of drugs across membranes and cell layers: however, drugs may ("target" and) affect these processes to produce therapeutic benefit (or undesirable side effects). Exocytosis & Endocytosis Exocytosis and Endocytosis of drugs as the mechanism to move drugs across membranes or cell layers to achieve therapeutic benefit is relatively rare (or at least not well documented). These two processes are certainly energy dependent (that is, energy is expended) and can be used to move drug molecules up or down a concentration gradient across the membrane for that drug. Exocytosis: Drug molecules are moved from the cytoplasm into the extracellular space after being packaged into vesicles (membrane bound spheres) with subsequent release of vesicular contents into the extracellular space after vesicle-plasma membrane fusion. This is the process by which neurotransmitters and protein hormones are released from cells and is therefore physiologically extremely important. Exocytosis is a critical physiological mechanism used by cells to secrete molecules into the extracellular space and may be modulated (increased or decreased) by some drugs. However, if movement of drugs into the extracellular space does occur by exocytosis, such movement is serendipitous and uncontrollable and not considered important.
Drug molecules may move across the membrane by moving within the phospholipid bilayer. This movement is energy independent. Rate of movement of drug molecules depends on several factors. Net movement of drug molecules requires that there is a difference of concentration of the drug in the solution on each side of the membrane and will occur until drug concentration on each side of the membrane is the same. It should be noted that drug molecule movement across the membrane occurs in both directions - even when concentration of the drug is the same on each side of the membrane. These animations illustrate transmembrane movement of drug molecules through the membrane by diffusion. Note that the uncharged or non-ionized drug molecules diffuse across the membrane down a concentration gradient but that charged or ionized drug molecules do not diffuse across a membrane down a concentration gradient. Diffusion of Drugs Across Membranes: Introduction Every type of drug molecule can pass across cell membranes (and thus across cell layers) by Diffusion. It is the most common and thus most important mechanism for transmembrane drug movement. The rate of transmembrane movement of drug (that is the number of molecules of the drug moving across the membrane per unit time) by diffusion can be predicted/controlled by altering the physico-chemical characteristics of the drug molecule. Like other mechanisms of movement of drug molecules across cell layers, diffusion is dependent on surface area of the "diffusion surface", on vascularization of the "diffusion surface", and blood flow through vessels in the "diffusion surface". Drug molecules can diffuse across the cell membrane in both directions, into and out of a cell. Drug molecules will diffuse across a membrane even if a concentration difference or concentration gradient of the drug across the membrane does not exist. In this situation - equilibrium - the concentration of drug on each side of the membrane is the same and movement of drug molecules in one direction occurs at the same rate as movement in the other direction. Obviously in this situation the drug concentration on each side of the membrane is maintained constant. If a concentration difference or concentration gradient for the drug exists across the membrane, then drug movement from the side with higher concentration to the side with lower drug concentration will be greater than in the opposite direction. Unequal movement driven by the concentration difference will occur until the equilibrium condition (equal concentration of drug on each side of the membrane) is reached. Rate of diffusion of a drug is dependent on concentration difference across membrane and on certain physical & chemical characteristics of the drug molecule: Size & Compactness Smaller (molecular weight) molecules crosses membrane more rapidly than large molecules More compact molecules (in terms of space occupied by each molecule) cross membrane more
rapidly than less compact molecules of the same molecular weight (These statements assume that lipid solubility and ionization of the molecules is not affected by these parameters) Lipid Solubility Drugs may be described as lipophilic (hydrophobic) or hydrophilic (lipophobic) More lipophilic: higher solubility in fat than aqueous solution More hydrophilic: more soluble in aqueous solution than in fat Lipophilic drugs diffuse across a membrane more rapidly than hydrophilic drugs - given the same concentration gradient and assuming same size and compactness. Degree of ionization Drug molecules exist in solution in ionized and non-ionized forms Extent of ionization is controlled by acidity (pH) of environment and a property of the drug nolecule (pKA) Ionized form of drug is more soluble in aqueous solution than non-ionized form Non-Ionized form of drug is more soluble in lipid (including plasma membrane) than ionized form Non-ionized form of drug can move across membranes by diffusion: the non-ionized form of a drug is the diffusable form of the drug Ionized form of drug essentially unable to diffuse across membrane: the ionized form of a drug is the non-diffusable form of a drug In totality, these factors are each important and each factor may influence the other factors At equilibrium , the non-ionized form of the drug is at the same concentration in each of two compartments separated by a membrane but the concentration of the ionized form of the drug may be the same or different in each of these compartments (see section on Ion Trapping). At equilibrium, movement of the non-ionized drug molecule across the membrane occurs at the same rate in each direction. Diffusion of Drugs Across Membranes: Size & Compactness Molecules of almost every type of drug can pass across cell membranes and thus across cell layers by Diffusion. A major factor in determining the rate of Diffusion of molecules across a membrane (and therefore across cell layers) is Size & Compactness. Size of a molecule is considered primarily to be described by molecular weight of the compound: a large molecule has a high molecular weight and a small molecule has a low molecular weight. However, in addition, a drug molecule may be described as being compact or non-compact - terms used essentially to describe the space occupied by a single drug molecule. We need to consider how rapidly (number of molecules per unit time) a drug will move across the plasma membrane. In a manner that is not at all practical (i.e. real) we'll consider size and compactness as separate issues and also as separate issues to lipid solubility
How fast does a compact compound or a non-compact compound diffuse from one compartment to a second compartment if the two compartments are filled with the same aqueous solution and separated only by a cell membrane or another lipid bilayer? ANSWER Let's assume that we are dealing with a drug that exists only in a non-ionized, membrane diffusable form and that the two drugs have the same molecular mass. The difference the two drugs is simply the space that each molecule fills. Take a look at the graph below.... The graph above shows graphically the Concentration of a drug plotted against Time after addition of the drug to one compartment when two (aqueous-solution filled) compartments are separated by a lipid membrane; before addition both compartments are drug free. Immediately after adding drug to one of the compartments at time zero, transmembrane movement of the drug will have not yet started. As time passes, the drug moves across the membrane down its concentration gradient. At equilibrium, the concentration of the drug is the same in each chamber; drug movement between the two chambers still occurs but is equal in each direction. Clearly, the compact drug comes to equilibrium more rapidly than the non-compact drug. At equilibrium, the concentration of drug in each chamber is the same; drug movement between the two chambers still occurs but is equal in each direction. So, in general terms we would recognize that smaller molecules - compactness and molecular weight - will pass more rapidly through a lipid bilayer so that equilibrium will be reach more rapidly than larger molecules.
Diffusion: Lipophilicity Molecules of almost every type of drug can pass across cell membranes and thus across cell layers by Diffusion. A major factor in determining the rate of Diffusion of molecules across a membrane (and therefore across cell layers) is Lipophilicity or Lipid Solubility. A molecule may be described as being better able to dissolve in fat or lipid than in water and this type of molecule is called lipophilic ("lipid liking") or hydrophobic ("water hating") or as better able to dissolve in water than in fat and this type of molecule is called hydophilic or lipophobic. Recall that thye plasma membrane of all cells is composed of a lipid (fat) bilayer; also, that the extracellular space and intracellular space is essentially an aqueous or water-filled environment. So we might expect that drug molecules would have to be somewhat soluble in water - to remain in solution in all the various body compartments - and also to be somewhat lipid soluble to be able to pass through the membrane of cells.. QUESTION How fast (number of molecules per unit time) does a lipophilic dug or a lipophobic drug diffuse from one compartment to a second compartment if the two compartments are filled with the same aqueous solution and separated only by a cell membrane or another lipid bilayer (given a certain concentration gradient of the drug across the membrane)? ANSWER Let's assume that we are dealing with a drug that exists only in a non-ionized form. Take a look at the graph.... Let's assume that we are dealing with a drug that exists only in a non-ionized, membrane diffusable form.
difference of the drug across the membrane. In contrast, molecules of a drug which exists in an ionized form in an aqueous solution can not move across a membrane by diffusion. In reality every drug exists in solution in ionized and non-ionized forms. Every drug molecule has sites which may be charged or uncharged. In any one environment, a certain fraction or proportion of the molecules of a particular drug present will exist in an ionized from and the remainder will exist as non-ionized molecules. The non-ionized form but not the ionized form of drug is able to diffuse across membrane. This animation illustrates the difference between a drug that exists only in the non-ionized form and a drug that exists only in the ionized form in terms of ability to diffuse across a membrane between two compartments where the two drugs are found at different concentrations. The molecules of the non-ionized drug move freely across the membrane but the molecules of the ionized drug do not. The same basic scenario is observed with ionized and non-ionized molecules of a single type of drug: non-ionized drug molecules but not ionized drug molecules move across the membrane. If the concentration of the non-ionized form of a drug on the two sides of a lipid membrane are not the same, then non-ionized molecules of the drug will diffuse across membrane (down the concentration gradient for the non-ionized form of the drug) until equilibrium (equal concentration of the non-ionized form of the drug on each side of the membrane) is attained. The concentration of the ionized form of the drug does not affect the rate of diffusion of the non-ionized molecules across the membrane - ionized molecules do not count in the assessment of the concentration of membrane diffusable molecules. Further, at equilibrium, it is the concentration of the non-ionized molecules of a drug that is the same on each side of the membrane - non-ionized molecules diffuse across the membrane down the concentration gradient until that gradient declines to zero. The concentration of the ionized drug molecules may or may not be the same on each side of the membrane at equilibrium. The rate at which a drug can cross a membrane by Diffusion and the final distribution of the drug in solution on either side of the membrane depends in part on the Degree of Ionization of the drug in the aqueous medium on each side of the membrane. Degree of ionization of drug molecule is a term expressing the fractional amounts of the total drug present which is in the ionized (charged) form and in the non-ionized (uncharged) form. Ionization is determined in part by pH of environment and in part by properties of the drug. Diffusion: Ionization II Introduction As you have read, ionized molecules can not diffuse across plasma membranes and thus can not diffuse across a cell layer. This is an important fact because diffusion is the most important mechanism for movement of drug molecules across plasma membranes and cell layers.
What's on this Page? You may already know that most drugs exist as weak acids and weak bases. It's important that you realize the consequences of this fact on the nature of the drug molecules - in terms of ionization - and on the consequences of ionization. In the following audio visual presentation (approx 18minutes; click on the right and left arrows to move the presentation forward and backward respectively), you will see how ionization of drug molecules depends on properties of the drug molecules and the environment into which they are placed. You will also be introduced or re-introduced to the Henderson Hasselbach equation and how the equation can be used to determine what proportion of the molecules of a particular drug in a particular environment are ionized and what proportion of those drug molecules are non-ionized. Click here to see a printable version of the images shown in the presentation. The "take home message": At equilibrium, for a weak acid drug, the percentage or proportion or fraction of nonionized drug present (of all of the drug present)will be greater than the percentage or proportion or fraction of ionzed drug present (of all of the drug present) if the environment is more acidic than the pKA of the drug. At equilibrium, for a weak acid drug, the percentage or proportion or fraction of nonionized drug present (of all of the drug present)will be less than the percentage or proportion or fraction of ionzed drug present (of all of the drug present) if the environment is more basic than the pKA of the drug. At equilibrium, for a weak base drug, the percentage or proportion or fraction of nonionized drug present (of all of the drug present)will be greater than the percentage or proportion or fraction of ionzed drug present (of all of the drug present) if the environment is more basic than the pKA of the drug. At equilibrium, for a weak base drug, the percentage or proportion or fraction of nonionized drug present (of all of the drug present)will be less than the percentage or proportion or fraction of ionzed drug present (of all of the drug present) if the environment is more acidic than the pKA of the drug. Note that although the pH of the environment in which a drug is placed affects the extent of the ionization of the drug, the low concentration of the weak acid or weak base drug does not actually change of the pH of the (relatively well buffered) environment in which the drug is placed. What should you have learned from the audio visual presentation? You should: (i) understand what factors contribute to determining whether a drug molecule is more likely to be non-ionized or to be ionized in a particular environment; (ii) be able to calculate what proportion of a drug with a particular pKA and placed in a particular environment is in its non-ionized form and in its ionized form; (iii) be able to recognize whether the majority of molecules of weak acid drug are ionized or non-ionized in an environment which is acidic to the pKA of the drug or is basic to the pKA of the drug; (iv) be able to recognize whether the majority of molecules of base acid drug are ionized or non-
