Chapter 1. Introduction
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1 Chapter 1 Introduction
2 What is Pharmacology From the Greek pharmakon (=drug), logos (=study) Pharmacology is the science that deals with the mechanisms of action, uses, adverse effects and fate of drugs in animals and humans
3 Definition of drug Substance that when taken into living organism brings about a change in biologic function through its chemical actions. Activation Inhibition
4 Properties of an ideal drug Safety Fewer side effects or lower toxicity Effectiveness Better therapeutic effects Selectivity Target to desired sites or molecules
5 Names of drug Each drug has at least three names Chemical Description of the drug using chemical nomenclature Generic Non proprietary name Simpler than chemical name Trade Proprietary or brand names Created by companies to sell drugs
6 Principles of Drug Action Drugs do not produce new function No drug has a single action have both therapeutic and adverse actions Or have multiple therapeutic effects Drug vs poison dose related
7 Principles of Drug Action Therapeutic actions are interchangeable Actions can be considered therapeutic in one case and adverse in another e.g. viagra
8 Principles of Drug Action Drug s effects are variable? It depends Many sources of variability Disease state, age and sex route of drug administration, dose, drug interactions Deciding to use a drug weigh benefits vs. risks there are always risks
9 Pharmacology deals with two aspects: what the drug does to the body drug action/effect Drug pharmacodynamics pharmacokinetics Body what the body does to the drug metabolism
10 Introduction to Pharmacology-I Drug administration and absorption
11 Pharmacokinetics Locus of action receptors Bound Free Tissue reservoirs Bound Free Systemic circulation Absorption Free drug Excretion Bound drug Metabolites Biotransformation
12 Pharmacokinetic Process-ADME Absorption Distribution Metabolism Excretion It is also called ADME process Elimination is the sum of M and E
13 Drug administration Route and form in which drug is delivered to body
14 Oral administration-most most common route Governed by: surface area for absorption, blood flow, physical state of drug, concentration. occurs via passive process. In theory: weak acids optimally absorbed in stomach, weak bases in intestine. In reality: the overall rate of absorption of drugs is always greater in the intestine
15 Subject to First Pass Effect pass through liver before reaching circulation undergo metabolism by liver
16 Rate of Appearance in Blood Dependent on rate of dissolution Rate of absorption from GI tract timed release dissolve at different rates what about crushing?
17 enteric coating dissolve in alkaline fluid what about crushing?
18 Forms of Oral Drugs Fastest liquids: syrups, elixirs suspensions powders Slowest pills: capsules, tablets
19 Buccal/Sublingual absorbed though oral mucus membranes in mouth buccal = cheek
20 Buccal/Sublingual sublingual (SL) = under tongue
21 Sublingual Administration Absorption from the oral mucosa has special significance for certain drugs despite the small surface area. Nitroglycerin - nonionic, very lipid soluble. Because of venous drainage into the superior vena cava, this route protects it from first-pass liver metabolism.
22 Parenteral Route other than alimentary canal intradermal (ID) subcutaneous (SC or SQ) intramuscular (IM) intravenous (IV) How quick is onset? Slow Fast
23 Parenteral Intravenous (IV) directly into vein rapid onset of drug actions Fastest
24 Intramuscular Rapid rate of absorption from aqueous solution, depending on the muscle. Perfusion of particular muscle influences the rate of absorption: gluteus vs. deltoid. Slow & constant absorption of drug when injected in an oil solution or suspension.
25 Subcutaneous Slow and constant absorption. Slow-release pellet may be implanted. Drug must not be irritating.
26 Topical: on the skin not absorbed in appreciable amounts have local effects (keep in mind large surface area) absorbed transdermal: usually slowly over a day
27 Example not absorbed
28 Example: absorbed
29 Example: Nitroglycerin Route IV SL Onset.. immediate min Transdermal min
30 Inhalation systemic drugs: intended to absorbed into blood
31 Inhalation local drugs: designed to act on lung tissue
32 Intraarterial Administration Occasionally a drug is injected directly into an artery to localize its effect to a particular organ, e.g., for liver tumors, head/neck cancers. Requires great care and should be reserved for experts.
33 Intrathecal Necessary if the bloodbrain barrier and blood- CSF barrier impede entrance into the CNS. Used for local or rapid effects of drugs on the meninges or cerebrospinal axis, as in spinal anesthesia or acute CNS infections.
34 Rectal/Vaginal Suppositories Vaginal: usually not absorbed
35 Rectal/Vaginal Rectal: absorbed May be useful when oral administration is precluded by vomiting or when the patient is unconscious. some first pass effect, approximately 50% of the drug that is absorbed from the rectum will bypass the liver.
36 Choice of route of drug administration Consider factors Concentration in blood Rapidity of onset Duration of effects Magnitude of effects Amount delivered Patient characteristics
37 Absorption: Process of drug leaving site of administration
38 Important Properties Affecting Drug Absorption Chemical properties acid or base degree of ionization polarity molecular weight lipid solubility or... partition coefficient Physiologic variables gastric motility ph at the absorption site area of absorbing surface blood flow Pre-systemic elimination ingestion w/wo food
39 Absorption Influenced by size & thickness of absorbing surface GI tract: large with single cell layer small bowel > large bowel
40 Surface Lung: Large with single cell layer Mucus membranes: Surface small with multiple cell layers Skin: Surface large with multiple cell layers
41 Surface blood supply to surface GI, lung, mucus membranes good blood supply skin: variable
42 Factors Influencing Absorption interaction of drug with surface characteristics e.g. skin: low in water and lipid
43 Factors Influencing Absorption amount of time in contact with surface concentration gradient
44 Physicochemical Factors In Transfer of Drugs Across Membranes Cell Membranes Passive Properties Carrier-Mediated Transport
45 Cell Membranes The character of biological membrane Be composed of phospholipids and proteins -----lipid soluble molecule can cross it easily Has aqueous channel -----water and liquid soluble molecule with little molecule weight can cross it easily
46 Membranes and Absorption Small, uncharged Hydrophilic Heads Heads H 2 O, urea, CO 2, O 2, N 2 Lipid Bilayer Hydrophobic Tails Tails Swoosh! Large, uncharged Glucose Sucrose DENIED! Small charged ions H +, Na +, K +, Ca 2+, Cl -, HCO 3 - DENIED!
47 Passive difusion Passive diffusion depends on movement down a concentration gradient.
48 1. Aqueous diffusion Water-soluble, small molecular mass drugs The force of it is the liquid static pressure or osmotic pressure across the membrane Through aqueous channels
49 Molecular Size In general, smaller molecules diffuse more readily across membranes than larger ones (because the diffusion coefficient is inversely related to the sq. root of the MW). This applies to passive diffusion but NOT to specialized transport mechanisms (active transport, pinocytosis). tight junction: MW <200 for diffusion. large fenestrations in capillaries: MW 20K-30K.
50 2. Lipid diffusion The lipid-soluble drug molecule penetrates along a concentration gradient by virtue of its solubility in the lipid membrane
51 Lipid-Solubility Oil:Water Partition Coefficient The greater the partition coefficient, the higher the lipid-solubility of the drug, and the greater its diffusion across membranes. A non-ionizable compound (or the nonionized form of an acid or a base) will reach an equilibrium across the membrane that is proportional to its concentration gradient.
52 Absorbed from stomach in 1 hour (% of dose) Other things (MW, pk a ) being equal, absorption of these drugs is 0 proportional to lipid solubility. 1 barbital (pka 7.8) secobarbital (pka 7.9) thiopental (pka 7.6)
53 3. Inization Most drugs are small (MW < 1000) weak electrolytes (acids/bases). This influences passive diffusion since cell membranes are hydrophobic lipid bilayers that are much more permeable to the non-ionized forms of drugs. The fraction of drug that is non-ionized depends on its pk a, and the local biophase ph...
54 ionized = polar = water-soluble non-ionized = less polar = more lipid-soluble Think of an acid as having a carboxyl: COOH / COO _ Think of a base as having an amino: NH 3 + / NH 2 *For both acids and bases, pk a = acid dissociation constant, the ph at which 50% of the molecules are ionized. Example: weak acid = aspirin (pk a 3.5) weak base = morphine (pk a 8.0)
55 Weak acid H + HA A - extracellular ph Weak base H + B BH + HA H + A - intracellular ph B BH + H + * The ph on each side of the membrane determines the equilibrium on each side
56 A Useful Concept... Drugs tend to exist in the ionized form when exposed to their ph-opposite chemical environment. Acids are increasingly ionized with increasing ph (basic environment), whereas Bases are increasingly ionized with decreasing ph (acidic environment).
57 acid ph base HA HB + cromolyn sodium (2.0) furosemide (3.9) sulfamethoxazole (6.0) phenobarbital (7.4) phenytoin (8.3) diazepam (3.3) chlordiazepaxide (4.8) triamterene (6.1) cimetidine (6.8) morphine (8.0) A - chlorthalidone (9.4) 10 amantadine (10.1) B
58 Henderson-Hasselbalch Hasselbalch Eqn. [protonated] log = pk a -ph [unprotonated]
59 Problem: What percentage of phenobarbital (weak acid, pk a = 7.4) exists in the ionized form in urine at ph 6.4? pk a - ph = = 1 antilog of 1 = 10 take antilog of 1 to get the ratio between non-ionized (HA) and ionized (A - ) forms of the drug: if ph = pk a then HA = A - if ph < pk a, acid form (HA) will always predominate if ph > pk a, the basic form (A - ) will always predominate Ratio of HA/A - = 10/1 % ionized = A - / A - + HA X100 = 1 / (1 + 10) X 100 = 9% ionized
60 Problem: What percentage of cocaine (weak base, pk a =8.5) exists in the non-ionized form in the stomach at ph 2.5? pk a - ph = = 6 antilog of 6 = 1,000,000 take antilog of 6 to get the ratio between ionized (BH + ) and non-ionized (B) formsof the drug: if ph = pk a then BH + = B if ph < pk a, acid form (BH + ) will always predominate if ph > pk a, the basic form (B) will always predominate Ratio of BH + /B = 1,000,000/1 % non-ionized = B/ (B + BH + ) X100 = 1 X 10-4 % non-ionized or %
61 Moral of the story... Acidic drugs are best absorbed from acidic environments Basic drugs are best absorbed from basic environments
62 Other aspects. amphetamine (weak base, pk a 10) its actions can be prolonged by ingesting bicarbonate to alkalinize the urine... this will increase the fraction of amphetamine in non-ionized form, which is readily reabsorbed across the luminal surface of the kidney nephron... in overdose, you may acidify the urine to increase kidney clearance of amphetamine.
63 Certain compounds may exist as strong electrolytes. This means they are ionized at all body ph values. They are poorly lipid soluble. Ex: strong acid = glucuronic acid derivatives of drugs. strong base = quarternary ammonium compounds such as acetylcholine.
64 Membrane Transfer Passive diffusion carrier-mediated endocytosis active passive ATP ADP-Pi
65 Special carriers Substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, glucose. These kind of transport, unlike passive diffusion, is saturable and inhibitable. Active transport is characterized by a requirement for energy Facilitated diffusion needs no energy
66 Special carriers Carrier-mediated transport is important for some drugs that are chemically related to endogenous substances The transporter proteins also mediate drug efflux P-glycoprotein /MDR1 MRP transporters Function as a barrier system to protect cells
67 P-glycoprotein Epithelial cell in GI tract GI tract: limit the absorption Kidney: promote the renal excretion Liver: promote the biliary excretion Brain: limit entry to brain Function as a barrier system to protect cells
68 Facilitated Diffusion This is a carrier-mediated process that does NOT require energy. In this process, movement of the substance can NOT be against its concentration gradient. Necessary for the transport of endogenous compounds whose rate of movement across membranes by simple diffusion would be too slow.
69 Active Transport Occurrence: - neuronal membranes, choroid plexus, renal tubule cells, hepatocytes Characteristics - carrier-mediated - selectivity - competitive inhibition by congeners - *energy requirement - saturable - *movement against concentration gradient *differences from facilitated diffusion
70 Endocytosis, Exocytosis, Internalization Endocytosis (or pinocytosis): a portion of the plasma membrane invaginates and then pinches off from the surface to form an intracellular vesicle. Ex: This is the mechanism by which thyroid follicular cells, in response to TSH, take up thyroglobulin (MW > 500,000).
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