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Adverse Drug Reactions - Type I: allergic reactions to stings and drugs; symptoms range from mild rash to life-threatening anaphylaxis; onset is immediate Pure Food and Drug Act of (1906) The federal government (Food and Drug Administration, FDA) may enforce standards of drug strength and purity as officially designated by the USP (United States Pharmacopoeia) and NF (National Formulary). 2. Prohibits mislabeling or adulteration of drugs Harrison Narcotic Act (1914) Regulated importation, manufacture, sale, and use of opium, cocaine, and marijuana 2. Repealed and superseded by Controlled Substances Act (1970) Food, Drug, and Cosmetic Act (1938) Enforced by the FDA through registration of all parties involved in the manufacture, sale, and distribution of drugs required adequate testing of a compound to prevent marketing of a possibly toxic substance. New drugs must be a safe as well as pure in order to be introduced into interstate commerce. But this law still did not require proof of effectiveness. Durham-Humphrey Amendments (1952) 1. separated drugs into legend (prescription) and nonlegend (nonprescription, over-the-counter) categories. The "legend" must appear on every commercial container of legend drugs: "Caution: Federal Law Prohibits Dispensing without Prescription." 2. rules for dispensing legend drugs Kefauver-Harris Amendment of (1962) 1. required proof of efficacy as well as safety before any new drug could be placed in interstate commerce (Thalidomide) 2. Guidelines for conducting clinical trials 3. Established the Drug Efficacy Study Implementation (DESI) Comprehensive Drug Abuse Prevention and Control Act of 1970 (Controlled Substances Act) 1. Established rehabilitation program for drug users 2. Established control (registration) and enforcement (DEA) 3. Regulates export and import of controlled substances What is a Controlled Substance? •Prescription •Potentially addictive -Reinforcing -Physically addicting -Psychologically addicting •Use is controlled by the Federal Government and monitored by both Federal and State Governments Schedule I High abuse potential and no accepted medical use (Heroin, Marijuana, LSD, Mescaline, Peyote, Bath salts) Schedule II currently accepted medical use in U.S. with high abuse potential resulting in severe physical or psychological dependence -Written Prescription required with prescriber's actual (legal) Signature Electronic prescriptions are allowed (preferred, required) -Must be dated the same day as signed -No refills allowed -In an emergency, a verbal order may be given for a limited quantity of drug adequate to treat the emergency condition, but must be followed by a written prescription within 72 hours. -Note: There are no verbal orders allowed for schedule in Prescriptions in Alabama. Schedule III Abuse potential less than Schedule II -Written or verbal prescriptions allowed; valid for 6 months from the date written -limit of 5 refills Schedule IV Abuse potential less than Schedule III (Same Rule) -Benzodiazepines, Diazepam (Valium), Alprazolam (Xanax) -Drugs for weight loss (Qsymia) -Drugs for Sleep (Ambient) Schedule V Lowest abuse potential -Some drugs in this schedule are non legend both federally and in some states; purchase still subject to state regulations. -Antitussive and antidiarrheal narcotic drugs in limited quantities, diphenoxylate/atropine (Lomotil), Robitussin-AC -Narcotic analgesic: buprenorphine (Buprenex) Rules for Controlled Substances in Alabama Classifications determined by the State Board of Health, but may not be classified in lower schedules than federal law permits Poison Prevention Packaging Act of (1970) 1. Regulates certain "household substances" and requires that they be packaged for consumer use in a manner that will make them significantly difficult for children 5 years old to open 2. Patient may request noncomplying container 3. Child- resistant container applies to: -All controlled drugs -All legend drugs EXCEPT -Sublingual nitroglycerin -Oral contraceptives in dispenser packs -Aspirin or aspirin-containing preparations; some exceptions, effervescent tablets -Iron-containing drugs and dietary supplements Food and Drug Administration Modernization Act (FDAMA) (1997) -Allows for fast-tracking of drugs for serious illnesses to market. -Drug manufacturers have to give patients 6 months notice before they discontinue making a drug -Established a clinical trial database for drugs for critical illnesses -INFORMS OF "OFF-LABEL" USES -Incentives for pediatric drug research Best Pharmaceuticals for Children Act (BPCA) (2002) / Pediatric Research Equity Act 2003 -Both promote drug studies in children -See how existing drugs work in children and determine safety -SET UP PEDIATRIC DRUG TRIALS FDA Amendments Act of 2007 1. Drug safety legislation designed to monitor drugs once they are on the market. 2. Post-marketing safety, risk surveillance mandated to include 100 MILLION PATIENTS -Black Box Warnings - High Risk!! -Risk Evaluation Mitigation Strategies -Dear Prescriber Letters -Removal of unsafe drugs from the market quickly New Drug Laws •Drug laws are dynamic! •More than 120 new laws regarding the opioid crisis •Good Samaritan Laws -Defibrillators -Narcan (Naloxone) administration What is a Black Box Warning? -A BB Warning is the strongest safety warning a drug can have and still be on the market Ex: Acetaminophen causes liver toxicity -Compare to side effect -Compare to adverse drug reaction New Drug Development -May take years -Preclinical phase: done in animals -Phase I: Done in healthy volunteers -Phase II and III: Done in small cohorts with the disease. Groups are randomized and studies are typically double blinded -Phase IV: The drug is marketed and continually monitored for adverse effects Hospital/Institutional Orders 1. multiple-copy physician order sheet; part of permanent patient record a. orders written directly by physician Electronic Medical Record—maintained by the institution b. verbal orders from physician 2. one copy printed by pharmacy for each medication order as needed Prescription Orders - Written 1. date: required for controlled substances a. Schedules III-V: valid for 6 months from date written b. Schedule II: valid for several days to 6 months depending on individual state regulations c. prescriptions for noncontrolled medications valid for one year from date of issuance (generally accepted practice) 2. name and address of patient a. required for controlled substances b. age and weight helpful for pediatric patients 3. superscription - Rx Inscription Drug name and strength Subscription Directions to pharmacist Signatura directions to patient; transcribed by pharmacist onto label of dispensed medication Refill information Schedule II - No refills allowed Schedule III-V: Maximum of 5 refills (or 6 months from date written, whichever comes first) No limit on refills of noncontrolled drugs in Alabama. However, after one year, prescription should be renewed. Other states do place limits on refills; "prn" (as needed) refills may not be allowed. Signature a. Two signature lines required in Alabama i. "dispense as written" ii. "product selection permitted"; signing on this line constitutes permission for generic substitution b. prescriber's actual (legal) signature required for Schedule I drugs c. DEA # required for controlled substances Prescription orders - verbal 1. no verbal prescriptions allowed for Schedule II drugs in Alabama 1. verbal orders may be communicated by an "agent" of the prescriber 2. E-prescribing now allowed for schedule II agents in Alabama NOTE: abbreviations used in prescriptions - Review These on Your Own Example include: PO, IV, IM, PR, hs, pc, bid, did Drugs and the Healthcare Process •Assessment -Before a drug is administered •Analysis/Diagnosis -Is the drug appropriate? Does the patient understand it? •Planning -Goals of therapies, priorities, interventions •Implementation -Drug administration, education, interventions •Evaluation -Drug response, SE, adherence Enteral routes Oral Sublingual - tablets placed under tongue and allowed to dissolve Rectal Parenteral Routes Injectables a. general considerations i. requires sterile dosage forms ii. faster onset of action iii. skill and training required for injection iv. used for drugs which do not undergo GI absorption, or which unstable in the GI tract b. intravenous (iv) c. intramuscular (im) d. subcutaneous (sc; subQ) Oral - Advantages/Disadvantages Advantage: -relatively safe -convenient -suited for slow-release dosage forms -systemic or local effects in GI tract Disadvantages: -Delayed onset of action -GI distress -Swallowing or tube feeding -taste -Food interactions -inactivation by gastric acid -first-pass effect -take with water -schedule in relation to meals Oral -Oral- -Formulations liquids: solution, elixir, syrup, suspension (shake well before measuring dose) solids: capsules, tablets-film coats - enteric coats - crushing Sublingual, Buccal Advantages: -Rapid absorption and onset- directly absorbed into blood- avoids exposure to gastric acid and first- pass effect Disadvantages: -Must not be irritating or have bad taste- must not swallow tablet or drink liquid while tablet is in place- keep under tongue or in buccal cavity until completely dissolved Rectal Advantages: -suitable for NPO patient -systemic or local action -may avoid first-pass effect Disadvantages: -inconvenient, noncompliance Dosage forms: -suppositories, retention enemas Intravenous Advantages: -most rapid-acting -may control and titrate dosage -relatively large volumes -complete absorption Disadvantages: -requires skill for administration -cannot recall administered drug (most hazardous route) -requires water-soluble drug Intramuscular Advantages: -Relatively rapid absorption -Suitable for suspensions and depot forms Disadvantages: -Painful, Irritation -Must avoid injection into vessel -Rate of absorption dependent on blood flow at injection site Subcutaneous Advantages: -Suitable for suspensions and implants -Relatively small volumes Disadvantages: -Unsuitable for irritating drugs -Slower onset than iv or im Topical Routes a. ophthalmic (ocular) b. otic (ear) c. nasal d. respiratory (pulmonary, inhalation) e. skin (percutaneous) f. vaginal Ophthalmic Routes Considerations -Must be sterile -Drops (solutions, suspensions) -Ointment -Disk insert (Ocusert Pilo) -Used for local effects, diagnosis and treatment of eye disorders Otic -Drops (solutions, Suspensions) -Contraindicated in perforated eardrum Nasal Drops, Sprays Used primarily for local effects (decongestants) may be used for systemic effects Respiratory Route •Metered-dose inhaler (MDI)- nebulizer - intended for local effects -some systemic absorption may occur and cause side effects Dermal Routes Creams, ointments, lotions, shampoos Transdermal systems (patches) May be used for either local or systemic effects --Examples of Transdermals: -Nitroglycerin (Transderm Nitro) everyday angina -Conjugated estrogen Estraderm, Vivelle, Climara applied to abdomen twice weekly, once weekly for menopausal symptoms -Nicotine (Habitrol, Nicoderm, Prostep) everyday smoking cessation NOTE: The patient must quit smoking before starting therapy or nicotine levels may become dangerously high, What does the body do to the drug? Absorption, Distribution, Metabolism, Excretion Absorption How the drug is "picked up" from the site at which it is administered and placed in the bloodstream Distribution How the drug is carried through the body Metabolism How the drug is inactivated Excretion How the drug leaves the body Liberation of Drug -For most injectables, this is immediate (exceptions are slow-release suspensions for im or sc injection) -For PO forms, the rate-limiting step of liberating the drug from its dosage form involves DISSOLUTION of the drug particles. Capsules and tablets are slower to have an effect for this reason than are liquid forms of PO medications. Absorption The liberation phase extends from the time of drug administration to the point where the drug is dissolved in body fluids and ready for absorption. Absorption is the process of drug movement from the absorption site across one or more cell membrane barriers into the circulation. The most common mechanism for drug absorption is PASSIVE DIFFUSION. Enteral -Oral, rectal, sublingual -GI epithelial membrane barrier Parenteral -Intravenous (no barrier) -Intramuscular, Subcutaneous, (Capillary Endothelial Cell Membrane Barrier) Topical -Percutaneous (thick epithelium) -Eye lung (epithelial mucous membrane) How fast does blood get to the site? - The faster, the better the absorption - The more vascularized, the better the absorption If the drug is given orally, what it is competing with? Food will slow the absorption of PO meds -Especially fatty foods, alcohol! -Watch certain foods-especially grapefruit juice -Watch out for Coad ministration of antacids The First-Pass Effect Enzymes in the gut and the liver the "First pass" at the drug and may affect its absorption into the systemic circulation Pharmacokinetic Interactions a. GI Function-In the GI tract, the following may impact drugs in transit, affecting their absorption: i. gastric emptying ii. intestinal motility b. physicochemical processes that decrease drug absorption i. Adsorption, complexation due to charcoal, kaolin pectin (present in antidiarrheals), and aluminum or magnesium-containing antacids. Sometimes formation of a nonabsorbable complex that reduces drug absorption results. 2 hour rule for antacids! For food on "empty stomach" meds! First-Pass effect (presystemic metabolism) During the process of drug absorption from the GI tract, the drug may be altered (metabolized) in two potential sites: 1) gut wall, and 2) liver. If the drug is metabolized as it passes through either of these sites, it is said to undergo first-pass metabolism. If this happens, the drug has been changed—and will likely not be effective before it ever reaches the systemic circulation. Distribution--Practically - The patient will notice effects first—for better or worse—in rapidly perfused tissue - The patient with disease in poorly perfused tissue will need long-term or high-dose treatment (SAFETY ALERT) Binding of drug to plasma protein Reversible (noncovalent bonding) Free drug + protein ---- drug-protein complex -albumin -- our main plasma protein (binds acidic drugs) -alpha-1 acid glycoprotein (binds basic drugs) -lipoproteins -Only free drugs can diffuse to the site of action. Pharmacologic activity depends on free drug concentration in plasma for very highly bound drugs. -Reservoir effect may prolong both the duration of drug action and half-life for highly bound drugs. -There may be excess free drug present if hypoalbuminemia occurs and resulting toxicity; important only for highly bound drugs, may require dosing adjustment. Specialized Distribution Barriers a. Blood-Brain Barrier (BBB) no intercellular pores between brain capillary endothelial membranes due to the presence of tight junctions between cells effects-- severe limitation on movement of ionized of highly polar species; these substances cannot easily penetrate the BBB -in order for drugs to gain access to the brain from the capillaries, drugs must diffuse across cells (lipid-soluble nonionized form) or be actively transported by a carrier. Placental Barrier-SAFETY-ALERT drugs cross placenta by diffusion; lipid-soluble, nonionized drugs penetrate most rapidly. Usually, placental transfer of drugs is relatively slow with the equilibration time between maternal blood and fetal tissues estimated at about 15 minutes for some drugs and almost an hour for other drugs. However, virually every drug used for therapetion purposes can and does cross the placenta; effectively, no real barrier exists. In addition, many illicit drugs and other toxic substances absorbed by the mother will gain exposure to the fetus. Drug are classified on a scale (A,B,C,D,X) for safety for use into pregnancy based on their ability to harm the fetus. Detoxification (defense) mechanism Purpose of drug METABOLISM 1. chemical conversion of a toxic substance to a less toxic metabolite for termination of drug action 2. chemical conversion of a pharmacologically active substance to an inactive metabolite Metabolism! -Conversion of a relatively lipid-soluble parent drug molecule to a much more polar, water-soluble drug metabolite which can be readily excreted. -The more lipid-soluble parent form of the drug is not easily eliminated by the body's excretory mechanisms (renal and biliary excretion). -Drug metabolism produces a polar, water-soluble substance which is more easily excreted from the body. There is individual variation in metabolism -- Pharmacogenetics Liver Smooth endoplasmic reticulum in hepatocytes contain many drug-metabolizing enzymes; some enzymes are found in cytosol. b. gut wall and mucosal surface c. plasma 10% Phase I (nonsynthetic) Types of Metabolic Reactions Major types i. Oxidation by the cytochrome P450 system which is a family of drug-metabolizing enzymes in the liver. The major function of this enzyme system is to add an oxygen atom to the drug substrate. - Drug + O2 ------ drug-OH - (nonpolar, lipid-soluble) (polar, water-soluble) Phase II (synthetic) Types of Metabolic Reactions reactions occur in the liver and gut wall. The products of Phase II reactions are called conjugated metabolites, and are virtually always inactive, very polar and/or ionized, and easily excreted. Several types of conjugation may occur: i. glucuronide conjugation - Liver ii. N- acetylation - Liver, gut wall; addition of an acetate group to a nitrogen atom. Individuals are classified as either slow or fast acetylators depending on genetic factors, sulfonamides, isoniazid, procainamide. Very simple drugs Induction Certain drugs and foreign chemicals stimulate the activity of drug-metabolizing enzymes (P450 system) in the liver by inducing (increasing) the synthesis of these enzymes. The net effect of induction is to increase the metabolism of other drugs normally metabolized in the liver, and to decrease their pharmacologic effects. Inhibition certain drugs may inhibit the activity of drug-metabolizing enzymes in the liver. By interfering with the metabolism of other drugs, inhibitors may increase or prolong the activity of drugs normally metabolized in the liver. Effects of inhibition occur over a few days to a week. Major Routes Excretion a. kidney b. bile c. pulmonary d. milk e. saliva (swallowed, reabsorbed) Principles a. a drug may be excreted either as unchanged parent drug (if it is sufficiently polar) or as a metabolite b. lipid-soluble compounds are not easily excreted and must be metabolized to more polar, water-soluble substance Definition The time required for the plasma concentration of a drug to decline by 50% (that is, to decrease by one-half) -Half-Life Factors affecting half-life renal or hepatic disease may impair metabolism and/or excretion pathways and result in prolonged half-life this may cause toxicity or side effects SAFETY ALERT -Half-Life Pediatric Populations Most pharmacokinetic parameters are different here-especially early. -Absorption may not normalize until about age 2 -Plasma proteins are lower for the first year, so distribution of drugs may be affected -BBB not fully developed in infants, so CNS is sensitive -Metabolic enzymes do not fully develop until about a year -Renal function approaches adult levels at about a year. Geriatric Populations •Many pharmacokinetic changes related to organ failure -Absorption is decreased slightly -Distribution is affected by increased body fat and less lean body mass, decreased TBW and decreased serum albumin -Slight decrease in hepatic metabolism -Progressive decline in renal function and resulting drug accumulation is the MOST common cause of ADRs in the elderly! •Monitor with Creatinine Clearance (CrCL)--as this decreases, it is an indicator of renal failure Pharmacogenomic Variations •Are expressed in cytochrome P450 amount and activity -This affects ability to metabolize drugs -This impacts therapeutic effects as well as toxic response •How much? Some studies say as much as 50% of the time; for some drugs testing for polymorphisms is required •Are expressed in a transporter protein called P-glycoprotein, which normally keeps drugs from being able to cross membranes -Individuals with high PgP activity absorb drugs poorly; if activity is low, drugs cross membranes more easily. This activity can also be induced and inhibited by other drugs! What does the Drug Do to the Body? Receptor Theory, Toxicology, Drug Interactions (Receptor Theory) Receptor Portion of tissue or cell capable of interacting with a drug with resulting pharmacologic effects (Receptor Theory) Chemical Composition of Receptors a. membrane macromolecules (mostly proteins, lipids) b. intracellular macromolecules (proteins, nucleic acids) c. enzymes Agonist (Full agonist) a. Drug which interacts with a receptor to produce a pharmacologic response that is the same response produced by the endogenous compound Antagonist Drug which interacts with a receptor to block the actions of the endogenous agonist, e.g., phenoxybenzamine (adrenergic receptor antagonist) reacts with adrenergic receptors in blood vessels to block the actions of norepinephrine (endogenous agonist) - "Blockers" Partial Agonist Drug which can interact with a receptor but produces a much weaker pharmacologic response than a full agonist. These are sometimes used in pain management and in anesthesia Affinity Measure of a drug's ability to interact with a receptor Agonist - High affinity Antagonist - High affinity Partial agonist - Low affinity Efficacy Measure of a drug's ability to produce a pharmacologic response after interaction with receptor has occurred Agonist - High efficacy Antagonist - Zero efficacy Partial agonist - Low efficacy Potency -Measure of the dose of a full agonist required to produce the maximum pharmacologic response. If drugs A and B are both agonists, and drug A produces the maximum response at a lower dose than drug B, then drug A is more potent than drug B. -Look at the milligram strength of a drug to determine Additive Effects a. combination of two drugs producing a pharmacologic effect which is the sum of the two individual drug effects i. lowering of blood pressure by combined use of a diuretic and a vasodilator. ii. analgesia by combined use of aspirin (inhibits prostaglandin synthesis) and codeine (agonist at central opiate receptors) 1+1 = 2 Synergistic Effects combination of two drugs producing a pharmacological effect that is greater than the sum of the two individual effects i. CNS depression resulting from combined use of alcohol and benzodiazepines 1 + 1 = 3 Antagonism the combined effect is less than the effect produced by the active drug alone; second drug eliminates or diminishes activity of the first drug, e.g. antidotes to drug overdose: Narcan and Heroin 1 + 1 = 0 Side Effects Unwanted effects of drugs that appear at normal doses required for therapeutic response Toxicity Unwanted effects of drug that appear as drug dosage is increased beyond the dose required for therapeutic response Effective Dose 50 (ED50) dose which produces a desired therapeutic effect in 50% of test subjects Lethal Dose 50 (LD50) dose which is lethal to 50% of test subjects Therapeutic Index (TI) ratio of LD50 to ED50 Drug Allergy Generally not dose-related Adverse Drug Reactions Type I: Allergic reactions to stings and drugs; symptoms range from mild rash to life-threatening Anaphylaxis; onset is immediate Adverse Drug Reactions Type II: Autoimmune Reactions to drugs Adverse Drug Reactions Type III: Serum sickness, vasculitis -- seen with injectables Adverse Drug Reactions Type IV: Contact dermatitis from topical application ii. many "allergic" reactions to drugs may be genetic deficiency states or idiosyncratic responses that are not mediated by immune mechanism. 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