Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Chapter 2 PHARMACOKINETI CS “What the body does to the drug” Lei Wang Department of Pharmacology Pharmacology Drug - Body Interactions Pharmacodynamics Pharmacokinetics What drug does to the body What body does to the drug Three Phases of Pharmacokinetics ELIMINATION Adapted from Lehne, RA, Pharmacology for Nursing Care, 7th ed., 2009, Elsevier, p. 26 3 Part 1 Transmembrane transport of drugs Filtration Simple Diffusion Facilitated Diffusion Active Transport Simple Diffusion (Passive Diffusion ) (down hill movement) Most drugs move down their concentration gradients until the concentration of the drug reaches equilibrium. Greater the difference in the concentration of the drug on the two sides of the membrane, faster of its diffusion (Fick’s law) Simple Diffusion (Passive Diffusion ) Passive diffusion requires no energy expenditure but does depend on the size of the drug and the lipid solubility of the drug. Most drugs cross biologic barriers by passive diffusion Simple Diffusion (Passive Diffusion) Cell Membrane Structure Biological membranes are bilayer, phospholipids matrices containing cholesterol, protein, and other constituent. Due to the cell membrane's hydrophobic nature and like dissolves like, lipid soluble drugs can diffuse by dissolving in the lipoidal matrix of the membrane Simple Diffusion (Passive Diffusion) For drugs that cross membrane by passive diffusion, the lipid solubility of the drug is a key determinant. In order to directly penetrate cell membranes by simple diffusion, a drug must be lipid soluble Polar molecules and ions are not lipid soluble and so cannot penetrate membranes by simple diffusion Simple Diffusion (Passive Diffusion) The drugs which are unionized, low polarity and higher lipid solubility are easy to permeate membrane. The drugs which are ionized, high polarity and lower lipid solubility are difficult to permeate membrane. Weak Electrolytes and Influence of pH Many drugs are weak acids or weak bases Weak acids and weak bases exist in both non-ionized form and ionized form in solution HA H+ + A(unionized) (ionized) Weak Acids and Weak Bases Cross Membranes in Their Non-ionized State 12 Effect of the environment pH on the degree of ionization Most of drugs are weak acids or weak bases. The ionization of drugs may markedly influence their ability to penetrate membranes. The ratio of ionized versus un-ionized fraction of drug (the degree of ionization) depends on the pKa (ionization constant) of the drug and the pH of the surrounding tissues or fluids. pKa: the pH at which 50% of the drug is ionized and 50% is un-ionized. Effect of the environment pH on the degree of ionization When the pH of a solution is below the pKa, acids are preferentially un-ionized. When the pH of a solution is higher than the pKa, acids are mostly ionized. HA H+ + A(unionized) (ionized) Handerson-Hasselbalch Equation For acids (A): For bases (B): Effect of the environment PH on the degree of ionization A weak acid is most likely to be unionized when in an acidic environment, and an alkaline drug is preferentially unionized in an alkaline environment. A weak acid is most likely to be ionized when in an alkaline environment, and an alkaline drug is preferentially ionized in an acidic environment. Filtration Filtration is passage of drugs through aqueous pores in the membrane or through paracellular spaces. Aqueous Diffusion Filtration Aqueous Diffusion Water can cross cell membranes through aqueous pores. Bulk flow of water can carry with it drug molecules. Aqueous Diffusion Bulk Flow Aqueous Diffusion Cell membrane works like a sieve Depends on the size of the membrane pores Majority of cells have very small pores Small and water soluble molecules move through the pores of the membrane while drug with molecular weights (MW) exceeds 100 to 200 daltons are not able to penetrate. Paracellular Transport Paracellular transport refers to passing through the intercellular space between the cells. Capillaries (except those in brain) have large paracellular space and most drug can filter through these. Paracellular movement generally is limited to unbound drug Carrier-Mediated Membrane Transport Active transport Facilitated diffusion Active Transport Cells use ENERGY (ATP) to transport materials that cannot diffuse across a membrane Move a substance against its concentration gradient Accumulates some molecules that the cell needs Sodium-potassium pump The excretion and secretion of renal tract Facilitated diffusion Requires a carrier molecule No energy is needed Drugs move down their concentration gradients Cephalexin undergo facilitated diffusion by an oligopeptide transporter protein located in intestinal Absorption 24 Absorption Drug absorption refers to the passage of a drug from its site of administration into the circulation Intravascular administration does not involve absorption intravenous oral rectal sublingual transdermal Absorption inhalation Absorption circulation 25 Which route is the fastest route of absorption? The rate of absorption: Inhalation→Sublingual→Rectal→intramuscular →subcutaneous→oral→transdermal The rate of absorption determines how soon the effects will begin. The amount of absorption determines how intense the effects will be. Absorption The absorption of a drug is influenced by the physical and chemical properties of the drug itself and by the physiologic and anatomical factors at the site of absorption. Absorption Ionization Drug absorption requires that drugs cross one or more layers of cells and cell membranes Most Only drugs are absorbed by passive diffusion the nonionized form of the drugs is sufficiently soluble in membrane lipids to cross cell membranes Ionization In the stomach (pH 2.0),which will be better absorbed, a weak acid (pK 6.8) or a weak base (pK 7.1)? A weak acid is most likely to be unionized when in an acidic environment An alkaline drug is preferentially ionized in an acidic environment. Weak acid Ionization Weak acids can also be absorbed more readily from the intestines than from the stomach, despite their greater ionization in the intestines Most drugs are absorbed in the intestines The greater surface area in the intestines outweighs the influence of greater ionization in the intestines. Dosage Form Absorption The formulation of a drug affects the drug’s absorption and onset of action. Drugs that are available as liquid formulations are absorbed faster than drugs that are suspensions, suspensions are absorbed more rapidly than capsules, and capsules are absorbed more rapidly than tablets Routes of Administration Routes Of Drug Administration Enteral Parenteral Injection Topical Respiratory Rectal Subling ual Oral Routes of Administration Oral Administration ©2006 Twentieth Century Fox Film Corporation Clinical sketch A man with angina has not understood instruction on the use of glyceryl trinitrate tablets. He swallows them instead of putting them under his tongue. There is no therapeutic benefit. Comment: this drug is subject to extensive first-pass metabolism. First-Pass Metabolism Before the drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine. As a result, the concentration of drug in the systemic circulation will be reduced. First-pass elimination The result of first pass metabolism means that only a proportion of the drug reaches the circulation. First-pass elimination The liver is usually assumed to be the major site of first-pass metabolism of a drug administered orally. Broadly, first-pass elimination takes place when a drug is metabolized between its site of administration and the site of sampling for measurement of drug concentration. Other potential sites are the gastrointestinal tract, blood, vascular endothelium, lungs, and the arm from which venous samples are taken. Bypassing First Pass Metabolism Injection Sublingual route Effects of Food on Oral Drug Absorption Food tends to slow the rate of gastric emptying and results in slower absorption of many drugs. Drugs are often administered on an empty stomach. Penicillin V should be administered on an empty stomach. Metoprolol and propranolol should be taken with meals Oral Administration Advantages: It is convenient. It is the cheapest available route. It is easy to use. It is safe and acceptable. Routes of Administration Sublingual Administration ©2006 Twentieth Century Fox Film Corporation Sublingual Administration In sublingual administration the drug dissolves in salivary secretions and diffuses through mucous membrane beneath the tongue. Advantages: Rapid absorption takes place. Drug is dissolved easily Drug enters the blood directly Less first pass effect. Sublingual Administration Disadvantages: Irritation of the mucous membrane might occur Person may swallow the drug Might be unpleasant in taste Routes of Administration Rectal Route ©2006 Twentieth Century Fox Film Corporation The rectal route of administration (ROA) is a way of administering drugs into the rectum to be absorbed by the rectum's blood vessels and into the body's circulatory system. Approximately 50% of the drug that is absorbed from the rectum will bypass the firstpass metabolism. The upper part is connected with the portal system, whereas the lower part is directly connected with the systemic circulation. Drugs inserted in the lower part can bypass hepatic portal circulation and firstpass elimination of the drugs is partially avoided. Rectal Route Advantages: This route is preferred in unconscious or uncooperative patients. This route avoids nausea or vomiting Disadvantages: It is not preferred by patients. Rectal absorption often is irregular and incomplete. Many drugs can cause irritation of the rectal mucosa. Acetaminophen Suppository Routes of Administration Parenteral Administration ©2006 Twentieth Century Fox Film Corporation The parenteral routes of administration include any routes that bypass the gastrointestinal tract entirely. Intravenous Intravenous Intramuscular or IM Drugs administered intramuscularly enter the blood through gaps in capillary walls. The rate of absorption: Intramuscular→subcutaneous Slow releasing drugs can be given by this route. Oily preparations can be used. Intramuscular Disadvantages: Uncomfortable and inconvenient Irritating substances may cause muscle necrosis Irritating substances or improperly placed injections may damage nerves Intramuscular The absorption rate of intramuscular administration is directly affected by blood flow at the site of injection. Application of heat, exercise and activity at the injection site increase blood flow, which speeds drug absorption. Absorption may be reduced by immobilizing the limb, applying ice, administering a vasoconstrictive agent (adrenaline +local anaesthetic). Clinical sketch A patient with extensive burns is given intramuscular opiate for the pain. His blood pressure is very low. Adequate pain relief is not achieved for over half an hour. Comment: muscle blood flow is reduced by shock, and the rate of drug absorption can be affected. Subcutaneous Injection Subcutaneous (SQ) Route Used for solutions, emulsions and suspensions Absorption is usually slower for SQ than IM Highly irritating or corrosive substances should not be given subcutaneously Subcutaneous Insulins 57 Topical Application A topical effect, in the pharmacodynamic sense, may refer to a local, rather than systemic, target for a medication. Routes of Administration Inhalation ©2006 Twentieth Century Fox Film Corporation Inhalation Inhaled drugs are often given to directly affect bronchial and alveolar targets, thus achieving efficacy with minimal systemic effects. Drugs used involve volatile drugs, gases and dry-powder. Anesthetic gases, inhaled glucocorticoids and β-adrenergic agonists Inhalation Inhalation can be thought of conceptually as a topical administration A proportion of inhaled drugs still reaches the systemic circulation. Inhaled drugs with systemic sites of action include the anesthetic gases and some drugs of abuse that are smoked. Routes of Administration Eye ©2006 Twentieth Century Fox Film Corporation Eye Drops Eye drops often mean a local medication. However, because drug is absorbed via nasolacrimal canal, undesirable systemic absorption occurs. Such risk can be minimized by occluding the lacrimal punctum, for a short while after instilling drops. Routes of Administration Skin (Transdermal absorption) ©2006 Twentieth Century Fox Film Corporation Skin (Transdermal absorption) Not all drugs readily penetrate the intact skin. Drugs applied on the skin may be used either for their local effects or for systemic effects. Drugs for transdermal delivery must have suitable skin penetration characteristics and high potency. Transdermal patches : for birth control, hormone replacement therapy, and prevention of motion sickness. Transdermal controlled-release forms are designed to release the drug for extended periods.