Lec 1. Introduction-History-Terminology-Routes of Administration, Dr. Hoang Nguyen- Full Slides.docx

After Completion of this section of Terminology and Routes of Administration1 first year M1 students will be able to: Define basic pharmacological terms and use them properly in discussions and written evaluation of drugs Outline properties of drugs and drug development process Describe drug...

After Completion of this section of Terminology and Routes of Administration1 first year M1 students will be able to: Define basic pharmacological terms and use them properly in discussions and written evaluation of drugs Outline properties of drugs and drug development process Describe drug permeation ability Describe the different routes of administration of drugs and describe the advantages and disadvantages of each route. Pharmacology is the study of how drugs exert their effects on living systems. Pharmacologists work to: identify drug targets in order to learn how drugs work study the ways in which drugs are modified within . organisms Divisions of Pharmacology Pharmacodynamics: "What the drug does to the body" Pharmacokinetics: "What the body does to the drug" Pharmacogenomics: the influence of genetic variation on drug responses in patients Interaction of drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological function of particular organs. Steps in Pharmacodynamics: Drug-Receptor Interactions - Binding Signal Transduction Mechanism of action, Pathways Dose-Response Effect Pharmacokinetics What the body does to the drug. The magnitude of the pharmacological effect of a drug depends on its concentration at the site of action. Key Aspect of Pharmacokinetics Absorption Distribution Metabolism Elimination Optimizes drug therapy. Involves: Dose Dosage regimen - Dosage form affect an individual's response to a drug. "Personalized Medicine" Genomics may influence diminish/ enhance response, side effects or allergies Tools: High throughput data (sequencing, SNP chip, proteomics) Example: Trastuzumab (Herceptin) for breast cancer. HER2 is the genetic testing that used to determine match gene for the treatment. science concerned with the nature effect and detection of . poisons. Toxicology is the measurement and analysis of potential toxin, intoxicating or banned substances, and prescription medications presence in the person's body. Toxicity is adverse effects of a drugs on biological processes In 1938, the "Food, Drug, Cosmetic Act" was passed giving authority of the Food and Drug Administration (FDA) to oversee the safety of food, drugs, and cosmetics. • In 1970 the "Comprehensive Drug Abuse Prevention and Control Act" was passed which requires the pharmaceutical industry to maintain security and record keeping of drugs. (controlled substances) • 1994 "Dietary Supplement Health and Education Act": it regulates labeling, production, and claims regarding dietary supplements Drugs can be defined as chemical agents that uniquely interact with specific target molecules in the body, thereby producing a biologica I effect. Drugs can be stimulatory or inhibitory Drugs interact with biological systems in ways that mimic, resemble or otherwise affect the natural chemicals of the body. Drugs can produce effects by virtue of their properties: acidic or basic (e.g. antacids, protamine) surfactant (amphotericin) ability to denature proteins (astringents) osmotic properties (laxatives, diuretics) physicochemical interactions with membrane lipids Size and Molecular Weight: Drugs vary in size with molecular weights between 100 and 1000 too small= lack of selectivity too large= poor absorption and distribution Drug-Receptor Bonds: covalent bonding (usual irreversible) electrostatic bonds (between a cation and an anion) hydrogen, van der Waals, and hydrophobic bonds. Covalent Bond:-very strong, extremely stable Examples: DNA-alkylating chemotherapy agents (cyclophosphamide) » These drugs are chemically highly reactive, forming covalent bonds with DNA functional groups » The covalently-modified DNA may be incompatible with successful tumor cell division. Electrostatic:--very common in drug-receptor Interactions Ionic bonding: (Skcal/mol) Strong electrostatic interactions occur between permanently charged ionic molecules (cations and anions) Hydrogen: (1-7kcal/mol) bonds between hydrogen atoms and polar functional groups (eg. nitrogen, oxygen, sulfur) Van der Waals forces: (0.5-1 kcal/mol) positive or negative charges are induced in a molecule due to shifts in electron density. Opposite charges attract. Hydrophobic interactions: due to tendency to avoid the aqueous environments: weak interactions: between lipophilic drugs and the lipid component of biological membranes between drugs and relatively nonpolar receptor regions Drugs have three or more names: Chemical: assigned according to the rules of nomenclature of chemical compounds (e.g. (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid ) Proprietary (brand/trade): given by the manufacturer, upper case (e.g. Advil, Motrin) Generic: a common established name irrespective of the manufacturer. Lower case (e.g. Ibuprofen) Drug Development Process In vitiro1 s,tudies Biologic products Phase 1, 20-100 subjects CHnical testing (Is it,safe, pharmacokine1ics?-) '""r'keting Generics Lead compound ,c:: fficacy, selectivi17, mechanism Phase 2 100-200 atients (Does it work in patients?' Phase 3 I Chemical synthesis, optimization (Does it wo double blind?} 000-6000 patients Drug metaborismi safety assessment Phase A (Postmarketing surveiilance 0 2 Years (average,11 IND (t,nvestigationa, New Drug) 8-9 NDA ,,New Drug AppHcatron',, 20 (Patent expires 20 years after filing ol application Souroo: Bertr.am G. Katzung; sas,c & a1n1cal Pharmacology, Fourteenth Edition Copyright © McGraw-Hill Education. All rights reserved. https://www.youtube.com/watch?v=JVNDgfCT1pg A. Passive diffusion: aqueous diffusion or lipid diffusion B. Carrier-mediated transport: active transport or facilitated diffusion C. Endocytosis and Exocytosis Aqueous Diffusion Lipid Diffusion Active Transport Endocytosis (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Aqueous Di us1• on Aqueous Diffusion: movement of molecules through the watery extracellular and intracellular spaces capillaries have small water-filled pores (blood and extravascular space) governed by Fick's law aqueous solubility is a function of the electrostatic charges, water molecules are attracted to charged drug molecules forming an aqueous shell around them. Plasma protein-bound drugs cannot diffuse through aqueous pores Fick's Law of Diffusion predicts the rate of mvmt of molecules across a barrier the concentration gradient (C1-C2) permeability coefficient for the drug area thickness of the barrier membrane Interpretation: drugs are absorbed faster from organs with large surface areas and thinner membranes Important for movement of drugs that are too large/ insoluble to diffuse passively through membranes - Active transport: requires energy to move molecules against a concentration gradient, selective and saturable {limited number of binding sites) □ Ex: L-dopa uptake by large neutral amino acid {LNAA) transport system - Facilitated diffusion--requiresa carrier to facilitate transport along a concentration gradient, saturable, and not energy dependent □ Ex: glucose entry into cells by GLUTl/GLUTS Endocytosis Exocytosis Binding to receptors on cell membranes (a very selective process), Subsequent internalization by in folding of that area of membrane contents are released into the cytoplasm of the cell Ex: iron: transferrin Vitamin B12 : intrinsic factor move across the intestinal wall into the blood Exocytosis is the transport of materials out of a cell using a vesicle that first engulfs the material and then extrudes it through an opening in the cell membrane e.g. expulsion of neurotransmitters into the synaptic cleft Lipid Diffusion Charge and Absorption Ionized drugs = more water soluble non-ionized drugs = more lipid soluble Since membranes are composed of lipids, non-ionized drugs are absorbed and ionized drugs are excreted. Drugs may exist in either ionized or non- ionized form depending upon the pH of the environment and whether the drug is a weak acid or a weak base. An acid in an acidic environment favors absorption (more uncharged molecules) Acid in basic/ alkaline environment favors excretion (more charged molecules) Lipid Diffusion A base in an acidic environment favors excretion (more charged molecules) A base in alkaline environment ft1vors► absorption (more uncharged molecules) (ionized = charged) (nonionized = uncharged) faster in acidic urine. Weak bases are excreted fasted in acidic urine and reabsorbed faster in basic urine To acidify urine, give ammonium chloride; to alkalinize urine, give sodium bicarbonate Weak Bases: Examples: TCAs, amphetamines. Trapped in acidic environments. Treat Weak Acids: Examples: phenobarbital, methotrexate, aspirin {salicylates). Trapped in basic environments. Treat overdose with sodium bicarbonate to alkalinize urine. overdose with ammonium chloride to acidify urine. TCA toxicity is genera Ily treated with sodium bicarbonate to overcome the sodium channel blocking activity of TCAs, but not for accelerating drug elimination. Routes of Administration li figure 1,2 Cor..i.mmlfy l!::SEt'I rqUies iJf Grug administrc!io:iL. IV = .mtr ; IM= imramaSirular,SC= bD!IW£!DllS.. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) OraI Entera I Routes Advantages: safest, most convenient, and economical Disadvantages: limited absorption, vomiting, destruction of drug by digestive enzymes or low pH, variation of absorption, and patient complia nee. The membranes which the drug must cross are the digestive epithelium and the vascular endothelium. The digestive tract goes from the mouth to the rectum. The membranes which the drug must cross are the digestive epithelium and the vascular endothelium. Digestive absorption can take place at any level of the digestive tract. Oral administration usually requires 30 minutes to 60 minutes before significant absorption from the GI tract occurs, therefore, the onset of drug action is delayed. Food also delays drug absorption and therefore delays the onset of drug action. Another advantage of oral administration is that drugs given orally can be removed (within the first few hours) by gastric lavage or induced vomiting. This procedure is often employed in drug overdose (sleeping pills) or accidental . . po1son1ng. Sublingual route: mucosal membrane beneath the tongue Eg: Nitroglycerinangina pectoris Buccal route: refers to the area between the gums and cheek and has the same characteristics as sublingual absorption Stomach: pH of the gastric fluid is acidic ranging from 1-4. Neutral molecules and acids not ionized in an acid pH are absorbed from the stomach. Intestine: the area of the small intestine is large: from 200 to 300m2. The pH is alkaline: 6 to 8. The majority of drugs are absorbed at small intestine. Drug formulations ■ Gelatin capsules: are used to administer drug powders or liquids. Gelatin capsules Aqueous (Syrup): is a solution of dissolve in the stomach, thereby releasing water and sugar to which a drug is the drug added. Addition of flavoring agents ■ Delayed-Release products: contain the eliminates the bitter taste of many drugs. Little of alcohol is added of equivalent of two or three single dose units. They are designed to produce drug effects over an extended time. (ie. helping for drug dissolved. Verapamil ER, Morphine SR) Troches and Lozenges: these ■ Enteric-Coated produc : The drug tablet flattened tablets are allowed to or capsule is coated with an acid-resistant dissolve in the mouth, they are substance that will dissolve only in the commonly used for colds and sore less-acidic portions of the intestines. throats. Enteric coated products should be taken on an empty stomach with water. Suppositories: these are drugs mixed Transdermal products: are administered with a substance (cacao butter) that through a bandage or patch system; is will melt at body temperature. released from the bandage or patch and is Suppositories are intended for then absorbed through the skin into the insertion into the rectum, urethra, or systemic circulation. This will provide a vagina. continuous source of drug over 24hrs or more. Irregular and incomplete absorption half of the drug will bypass the liver, decreasing the potential for hepatic first-pass metabolism useful when oral ingestion is precluded (unconscious, vomiting, young children, distasteful drugs). When patient can't take oral medications and parenteral isn't indicated, also for local effect Drug may irritate the rectal mucosa Examples: Analgesics, laxatives, anti-emetic Usually delivered into the gluteal or deltoid muscles. Extreme caution should be observed with gluteal injections to avoid injury to sciatic nerve The onset of action with IM administration is relatively short, usually within several minutes. Contraindications: th rom bocytopenia, coagulopathy For drugs that are inactivated by the GI tract Onset of action within several minutes Suitable for slow-release drug Absorption through simple diffusion Intravenous Injection (IV) is usually restricted to use in the hospital. Appropriate for emergency, comatose, or non- compliant patients Fastest means of drug absorption because the drug is delivered directly into the circulation; therefore, the onset of drug action is almost immediate. However to pay attention to the speed of administration because it should not be: too rapid, and risk of severe reactions Inject solutions slowly as a rule of thumb. too slow, then the effective therapeutic concentration cannot be reached. Oily solutions should not be given by intravenous route. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) exam pie is testing for TB An injection given into the dermis Used only for small very small volumes of drugs {0.1 ml or less) primarily for diagnostic skin testing. injection directly into the spinal subarachnoid space. Bypass the blood-brain barrier and the blood- cerebrospinal fluid (CSF) barrier Advantages: quick entry into the central nervous system (CNS). When local and rapid effects of drugs on the meninges or cerebrospinal axis are desired, as in anesthesia or treatment of acute CNS infections Expert administration only; severe adverse effects are possible. Inhalation Gaseous and volatile drugs may be inhaled and absorbed through the pulmonaryepitheliumand mucous membranes of the respiratory tract. Involves administration through the nose or mouth and into lungs during respiratory inspiration. Access to circulation is rapid (almost instantaneous absorption) because of the large surface area of the Iungs. Common route for drugs of abuse Bypasses hepatic first-pass metabolism Disadvantages: rapid dissipation of effects and toxicity due to systemic absorption Transdermal Absorption: dependent upon the surface area over which they are applied and their lipid solubility, temperature, lesions, age Convenient dosage form that provides continuous absorption and systemic effects over many hours a,_ I Skin e,aw b,ackin.g 01'1"-9,1r,@5 ·rvoir l:7r g-,re,lea_s:e m;en1bra_n,e Contact adheS'ive Controlled-release topical patches nicotine withdrawal, scopolamine for motion sickness, nitroglycerin for angina pectoris, testosterone and estrogen replacementtherapy, and estrogens and progestins for birth control. avoid first-pass metabolism but have the possibility of skin irritations. IDl!'ug diffusing ·fro.,n re:servoJI'· intc;;i, subCiU!talll.ll!!CJ<US US$!UII!' m Fligu£e JL.'1.A. :i?m£IDaJ::iic tan"'°' .o;' a ttam:sden:Il:aIpa,tcb_B. T patchapplied ED W:e-,ilill!L nfcorn:,e, Mucous membranes- Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, and urethra for their local effects. Absorption occurs rapidly. Eye- Topically applied ophthalmic drugs are used primarily for their local effects, which require absorption through the cornea. Systemic absorption from drainage through the nasolacrimal canal is undesirable. Nasal route can be used for local treatment (anti-allergic drugs) or for general treatment (desmopressin). The nasal route avoids first-pass metabolism. 1. Basic and clinical pharmacology by Katzung, 15th edition. 2. Videos: https://sketchy.com/