Advanced Pharmacology - Module 1 Solved 100%

Drug - ANSWER-any chemical that can affect living processes. Pharmacology - ANSWER-the study of drugs and their interactions with living systems. or the total knowledge of drugs including history, chemistry, source, biochemical & physical effects Clinical Pharmacology - ANSWER-the study of drugs in humans, this discipline includes the study of drugs in patient's and healthy volunteers (during drug development) Therapeutics - ANSWER-AKA: pharmacotherapeutics; is defined as the use of drugs to diagnose, prevent, or treat disease of to prevent pregnancy. A simplified definition is "the medical use of drugs" 3 most important characteristics for drugs - ANSWER-Effectiveness, safety, selectivity Effectiveness - ANSWER-When the drug elects the response for which it was administered. Effectiveness is the most important property a drug can have. Current US law states all new drugs must be proven effective prior to release for marketing. Safety - ANSWER-A safe drug is defined as one that can't produce harmful effects; even if administered in very high doses and for a very long time. ALL DRUGS HAVE ABILITY TO CAUSE INJURY Selectivity - ANSWER-A selective drug is defined as one that elicits only the response for which it is given. There is NO such thing as a WHOLLY selective drug; because all drugs cause side effects. Steps in New Drug Development - ANSWER-1. Pre-Clinical testing (occurs in animals) **Evaluating** a.Toxicity b.Pharmacokinetics c.Possible Useful Effects 2. Investigational New Drug Staus (IND) 3. Clinical Testing (occurs in humans) Phase 1 - healthy volunteers and tests metabolism, pharmacokinetics, biologic effects Phase 2 - patients and tests therapeutic utility and safe dosing ranges Phase 3 - patients and tests safety and effectiveness Phase 4 - Conditional Approval of New Drug application (NDA) Phase IV - Post marketing surveillance To be approved by the FDA for marketing - ANSWER-a drug must shown by studies to be "safe and effective" Post Marketing Surveillance - ANSWER-results may reveal rare by serious adverse reactions to drugs not previously reported in the investigational stages. This could result in a "warning" added to the drug literature (i.e. tornadoes de points with thioridazine) or the drug could all together be removed from the market (i.e. Seldane, Vioxx, Redux) Indications - ANSWER-When a new drug gets approved for marketing in the US its conditions for use are detailed in the package insert representing the compilation of data submitted by the manufacturer for FDA approval. (indications for use) Restrictions may be placed on the drug based on age groups (adults and children 12 years of age and older for example) and dosage schedules for certain pathological conditions. (i.e renal impairment) Off- Label Use or unlabeled use - ANSWER-Many drugs once marketed, often find therapeutic utility for different purposes or in populations other than those described in the package insert. Therapeutic Orphans - ANSWER-Pregnant women, women of child bearing age, infants and children. They are referred to as therapeutic orphans because they were seldom used in drug research due to ethical reasoning. recently more research is being conducted and congress has passed several laws that promote research on drug efficacy and safety in children. Prisoners and antivivisectionists - ANSWER-Prisoners Can't be used in research and antivivisectionists have made inroads on the use of animals for experimentation. Neonates & Infants - ANSWER-Companies seldom use infants in their studies, most drug literature dose not have dosage schedules for neonates and infants. Neonate dosing for medications can be located in Neofax publication. Child Bearing Age - ANSWER-FDA now encourages the use of women of child bearing age in research; the finding that the H1N1 virus caused an increased risk of mortality and morbidity in pregnant women further suggest the need for studies in pregnant women. Generic Equivalent - ANSWER-Must now prove equivalent bioavailability (bioequivalence) to the innovators drug. Meaning - equivalent release of the same drug substance from 2 or more drug products or formulations. Bioavailability - ANSWER-the percentage of the dose of the drug administered by any route that reaches systemic circulation. Bioequivalence - ANSWER-When 2 different dosage forms of the same drug are considered to be bioequivalent when they produce AUC, CMAX, TMAX values that are neither clinically nor statistically different . The FDA definition of bioequivalence is the equivalent release of the same drug substance from 2 or more drug products or formulations. BRAND NAMES - ANSWER-are CAPITALIZED in literature generic names - ANSWER-are lower case in literature There are a few drugs that may be generically equivalent (have the same active ingredient) but may not be bioequivalent - Examples of this are: - ANSWER-Levothyroxine, Phenytoin Sodium, Sustained Release dosage forms may not be bioequivalent due to the sustained release formulations i.e niacin. Federal Trade Commission - ANSWER-has reported that makers of brand name drugs have made payments to generic firms to not market a generic equivalent. Non-Inferiority Trials - ANSWER-Non-inferiority trials are conducted when a proven effective treatment already exists and assigning some patients to a placebo group would be unethical. A non-inferiority trial is a comparison with an active control to determine whether the difference in the new treatment is not less effective than the active control in achieving the primary outcome. Sources for Drug Information - ANSWER-Newsletters (The Medical Letter, The Prescriber Letter) Reference Books ( PDR, Drug Facts and Companions) Internet The American Pharmaceutical Association publishes annually "Handbook of Non-Prescription Drugs" Pharmacodynamics - ANSWER-What the drug does to the body - - is the study of the relationship between the concentration of a drug and the response obtained in a patient. Pharmacokinetics - ANSWER-what the body does to the drug - or the quantitative study of the absorption, distribution, metabolism and excretion of drugs and their metabolites. DRUG - ANSWER-any substance which, introduced to the body produces a physiological change, a decrease in population of resident or invading microorganisms, or a decrease in abnormal tissue development. Drug Names 3 types - ANSWER-1. Chemical Name: constitutes a description of the drug using the nomenclature of chemistry 2. Generic Name: name assigned by the United States Adopted Name Council. Each drug has only 1 generic name (nonproprietary name) 3. TradeName: AKA - proprietary name or brand name. Names under which the drug is marketed. Created by drug companies with the intention they will be easily pronounced and remembered by RN's, MD's and patients. Trade names must be approved of by the FDA, to ensure that no 2 trade names are too similar. Orphan Drugs - ANSWER-The Orphan Drug Act of 1983 provides incentives for the development of drugs for treatment of diseases affecting fewer than 200,000 patients in the US, or for research using commonly available (nonpatentable) chemicals for treatment of a specific diseases. The incentives (usually tax breaks) are to encourage companies to do research for which they are unlikely to recoup their costs. Clinical Pharmacology - ANSWER-The study of the effect of drugs in man as compared to animal or comparative pharmacology. The emphasis is on the drug and it's uses. Pharmacotherapeutics - ANSWER-deals with use of drugs in preventions and treatment of disease; usually to alleviate symptoms or sometimes, to alter the course of the disease. The emphasis is on the disease and the treatment thereof. Chemotherapeutic Agents - ANSWER-drugs with minimal effects in man but destroy or eliminate pathogenic cells or organisms (anticancer; anti-invectives) Toxicology - ANSWER-deals with adverse affects of the drugs Therapeutic Index - ANSWER-is the relative toxicity of a drug; in other words - in most commonly pharmacology this is the ratio of the dose capable of killing 50% of animals (LD50) over that required to achieve e beneficial effect in 50% of the animals (ED50) Small Therapeutic Index - ANSWER-when a drug has little difference between the therapeutic dose and the dose tat causes toxicity. (i.e. digoxin) Tolerance - ANSWER-hyporeactivity that occurs from chronic exposure to a drug (like opioids or alcohol). When tolerance develops, usually increasing doses are needed to provide a therapeutic effect. This is attributed to neuronal adaptation or cellular tolerance. Cross Tolerance - ANSWER-may develop between drugs within a class (i.e. opioids) or between drugs of different classes tat produce similar pharmacologic effects (i.e. alcohol and inhaled anesthetics) Metabolic Tolerance - ANSWER-is a decreased response to a dose of a drug which develops because of an increase in rate of elimination of the drug. (enzyme induction is an example) Down Regulation - ANSWER-when there is a need for increased dose of a drug because there is a decrease in the number or sensitivity of receptor cites after continues dosing. Such as with T2DM; there is an increased intake of sugar resulting in the release of large amounts of insulin. Continued exposure to the large amounts of insulin causes the insulin receptors to become less sensitive - this is "down regulation of the receptors" Up regulation - ANSWER-Opposite of down regulation; For example in response to constant depression of receptors (as with beta blockers), the body may either increase the number of receptors or increase the sensitivity of the receptors. ----- NOTE** A change in receptor numbers may also be caused by other hormones, i.e thyroid hormones increase both the beta-receptors in heart muscle and cardiac sensitivity to catecholamines. Tachyphylaxis - ANSWER-rapid tolerance to the effect of some drugs is a phenomena created by up and down regulation called tachyphylaxis Overshoot - ANSWER-phenomena that follow the withdrawal of certain drugs Idiosyncrasy - ANSWER-describes an unusual effect of a drug; usually occurs in a very small percentage of patients and may not be related to the dose of the drug. Side Effect - ANSWER-usually desc rides any action of the drug other than the desired therapeutic effect. Untoward or Adverse Effect - ANSWER-is any noxious, unintended, and undesired effect that occurs at normal drug doses(World Health Organization) Toxic Effect - ANSWER-is that effect (usually expected) produced by a large or toxic dose of the drug. Side Effect/ Adverse Effect - ANSWER-The terms side effect and adverse effect are often used synonymously. Although by definition the terms are different they are often misused. Side effects are listed as most common and additional, may include infections, liver damage, aplastic anemia and renal failure. Adverse Effects - includes somnolence, dizziness, local redness. Most drug literature describes unwanted reactions mild or serious as adverse events. Side effects may be unwanted or occasionally helpful for example - a antihistamine taken to alleviate an allergic reaction may cause drowsiness which may help the patient sleep at night. Selectivity Additional Information - ANSWER-A drug is usually described by it's most prominent effect or by the action thought to be the basis of that effect. Drugs may have a high selectivity for one receptor (i.e acetylcholine) but may produce a number of effects because of widespread locations of acetylcholine receptors. On the other hand Benadryl is classified as an antihistamine although it also has both anticholinergic and sedative effects. Thus it is nonselective in its actions. Codeine Example - ANSWER-A drugs desired effect one occasion may be a side effect on another occasion. Codeine may be used as an analgesic, constipation may be a side effect of the codeine. Codeine or a similar drug may be given because of it's constipating effect for the treatment of diarrhea. Therapeutic Index/Margin of Safety Example - ANSWER-A drug may have more than one therapeutic index, depending on the specific uses of the drug and the toxic effect being administered. The margin of safety of aspirin for relief of headache is greater than the margin of safety when sued for relief of arthritic pain. Food, Drug & Cosmetic Act and Amendments - ANSWER-are administered by the FDA. This law was initially developed to improve quality and labeling of drugs (originally the Pure Food & Drug Act). It has been updated throughout the years to include testing for toxicity and to restrict certain drugs to prescription use only and to prove the drug is safe and effective. Amendments - ANSWER-Amendments to the Federal Food, drug and cosmetic act enacted in 1962 mandate that drug manufacturers seeking federal approval to market a new drug must prove that it is safe and effective and that the proposed label is accurate and adequate. Hatch-Taxman Amendment - ANSWER-allows for generic drugs to gain FDA approval by simply showing equivalence to a reference drug that has already been approved by the FDA. Generic drug manufacturers are not required to duplicate expensive and time consuming clinical trials already performed under a brand name drug development. A generic drug application must also show safety and efficacy of its labeling equivalent to the brand name labeling. OTC - over the counter - ANSWER-can be sold without a prescription. Some OTC may require intervention by the pharmacist (i.e drugs that contain pseudo ephedrine) FDA decides what can be sold as OTC or prescription required. Important NOTE - ingredients in OTC drugs can be changed without changing the name. Comprehensive Drug Abuse Prevention and Control Act originally called the Harrison Narcotics Act - ANSWER-The controlled Substance Act -enforced by the DEA. classifies potentially addictive substances into schedules. I-V and sets requirements for documentation, storage, prescriptive orders and filling of prescriptive orders. The prescriber must register with the DEA and have a DEA number to write prescriptions. Schedule I - ANSWER-Addictive substance - no approved medicinal use - example heroin Schedule II - ANSWER-Highly addictive substance- such as morphine and amphetamines. Prescriptions must be written in ink or typed or submitted using electronic prescribing procedures and can't be refilled. in October Hydrocodone made schedule II Schedule III and IV - ANSWER-less addictive- may be prescribed orally and may be refilled up to 5 times in 6 months. Aspirin with codeine (schedule III) or diazepam (schedule IV) Schedule V - ANSWER-low addictive potential no difference in II, IV, or V Practitioners Role and Responsibilities in Prescribing - ANSWER-Responsibility to gather data, by talking through a history and performing a physical examination. Once the data is gathered and evaluated, one or more diagnoses are formulated an a treatment plan will be established. It is the practitioners responsibility to know the drug therapy they are prescribing. Prescriptions - ANSWER-MUST be legible, unambiguous, dated and signed clearly Plasma Membranes - ANSWER-Factors affecting passage across the membranes - drug factors that influence the ability of a drug to cross the plasma membranes include molecular size and shape, solubility at the site of absorption, the degree of differences in PH across the membrane, the electrochemical gradient for the lipid form of the drug, degree of ionization, vascularity of the tissue and relative solubility of ionized and nonionized forms. Composition of plasma membrane - ANSWER-The plasma membrane is composed of lipids. The cells are very close to one another, so drugs must usually pass through the cells rather than between them. 3 ways Drugs Cross Cell membranes - ANSWER-1. through channels 2. active transport 3. direct penetration of passive diffusion Passive Diffusion - ANSWER-for passive diffusion the drug must be lipid soluble and is controlled by the magnitude of concentration gradients across the membranes. Polar molecules (water soluble) and ions can not penetrate membranes and require transport systems. Propanolol and Nadolol - ANSWER-- Both are non-selective beta blockers. Propranolol is very lipid soluble(non polar) and nadolol is very water soluble(polar) -Propanolol is rapidly & completely absorbed from the gut and has a large 1st pass effect (70%); it is primarily metabolized by hepatic metabolism and can cross the blood brain barrier and produce CNS effects. -Nadolol is poorly absurd (30%) 1st pass effect, primarily eliminated by renal filtration and does not cross the blood brain barrier. Non-polar substances at a steady state - ANSWER-the concentration of free drug is the same on both sides of the membrane Weak Electrolytes - ANSWER-Strong acids and bases are completely ionized. On the other hand many drugs are weak acids or bases and represent in solution as both ionized and nonionized. The nonionized is usually lipid soluble and able to penetrate the lipid membrane while the ionized can not. A few drugs the ratio of ionized to ionized molecules is affected by pH.Ionized molecules do not readily cross the plasma membranes Ion trapping - ANSWER-A weak base (morphine) in an acid medium is predominantly in the ionized states; hence gets "trapped" in the more acidic fetus if the morphine is given to the women at term. Effect of Ph change on drug action - ANSWER-Example - Salicylic Acid - development of acidosis drives the drug to it's ionized form, which can go into tissues(brain) and cause toxicity. On the other hand, treat salicylic toxicity by alkalinizing the urine to increase the ionized form that can't be reabsorbed through the kidney tubules. Cases of aspirin toxicity are treated with "forced alkaline diuresis" i.e giving sodium bicarbonate IV and then furosemide Bulk Flow - ANSWER-through intercellular pores is major mechanism of passage of drugs across most capillary endothelial membranes. (aqueous diffusion) except in the CNS. Capillary endothelial membranes have intercellular gaps large enough that diffusion is limited by blood flow and not by lipid solubility or pH gradients. Plasma and small molecules therein filter into intercellular spaces. What is necessary to cross the cellular plans membrane and enter a cell? - ANSWER-Either passive diffusion or active transport. Blood Brain Barrier - ANSWER-tight junctions are characteristic of capillaries of CNS, which along with surrounding lipid, glial cells for the BBB Active Transport - ANSWER-active transport of some drugs (polar/water soluble) such as the Parkinsosns drug levodopa occurs across neuronal membranes, the chord plexus, renal tubular cells and hepatocytes. Active transport is characterized by selectivity, competitive inhibition by congeners(similar drugs or metabolites) a requirement for energy, satiability and movement against an electrochemical gradient. Levodopa with Food for Parkinsons - ANSWER-the absorption of levodopa is interfered with by proteins in foods, hence in the treatment of parkinsons; administration of levodopa with food may decrease absorption of levodopa because of competition for active transport mechanisms in the gut Facilitated Diffusion - ANSWER-is a carrier-mediated transport prices but there is no input of energy. The substance moves according to the electrochemical gradient (some amino acids) Entry in Cells - ANSWER-is facilitated by a large number of transported on the plasma membrane. On the other hand, some transporters such as p-glycoprotein, move chemicals out of cells. Absorption - ANSWER-is the transfer of a substance from the site of applications to the blood stream (usually systemic circulation) IV and intrathecal are the only sites were absorption is not a factor. Characteristics of Commonly used routes of Administration - ANSWER- Absorption of Drugs from the GI Tract - Things to Know - ANSWER-1. for drugs administered orally, bioavailability may be less than 100% because of either incomplete extent of absorption or 1st pass effect (in the gut and liver) 2. drugs administered via the GI tract are called enteral. 3. All other forms are called parenteral 9usually reserved for injected drugs) 4. Drugs administered topically may have a systemic affect depending on the drug, condition of the skin, or mucosa and extent or duration of application. 5.Drugs given with fluid on empty stomach will of quickly from stomach to intestine. Most drugs given with food will have delayed absorption due to delayed stomach emptying. 6. The amount of drug absorbed may or may not by influenced by food. The absorption of most drugs given orally occurs in the small intestine. 1st Pass Effect - ANSWER-this refers to the rapid hepatic inactivation of certain oral medications on their first pass through the liver. 1st Pass Elimination - ANSWER-this refers to when orally administered drugs are metabolized in the gut. The metabolism in the gut, liver or excretion into bile Solid Oral Forms - ANSWER-i.e. tablets/capsules, must 1st disintegrate, an then must dissolve in the intestinal fluids. Drugs to be absorbed must be a mix water solubility( to dissolve in GI fluids; drugs must be solubilized to be absorbed) and lipid soluble (to cross the lipid plasma membrane) Drugs may be too hydrophilic (nadolol) or lipophilic (acyclovir)to be absorbed easily. Some drugs particular water soluble like amino acids are absorbed by active transport mechanisms. Metabolized by Enzymes - ANSWER-Some drugs may be metabolized by enzymes in the gut or gut wall- like digoxin. Cytochrome P450 3A4 is found in both enterocytes as well as hepatocytes. Chemicals found in grapefruit inhibit intestinal CYP 3A4, increasing the bioavailability of a number of drugs. P-Glycoprotein - ANSWER-is a drug efflux system also found in enterocytes. It is not an enzyme, but it excretes drugs back into the intestinal lumen and decreases absorption. P-Glycoprotein is also found in the kidney and brain. Digoxin is sometimes used as a probe for p-glycoprotein activity. P-Glycoprotein appears to have an important role in decreasing drug absorption from the gut, removing drugs from the brain, transporting drugs from the blood into kidney tubules. OATP - ANSWER-rates cases of decreased bioavailability of the drugs may be due to inhibition of Organic Anion-Transporting Polypeptides in the gut. Drug Transport Systems - ANSWER-have been associated with resistance of Strep Progenies to marlines and Plasmodium falciparum to quinine. Intestinal absorption - ANSWER-when absorbed from the intestine, the drug travels via the portal vein to the liver when some drugs are extensively metabolized before reaching systemic circulations (i.e nitroglycerin and propranolol) The drug may also be metabolized in the gut wall or even in the portal blood. The metabolism of a drug on the first pass through the liver itself is 1st pass effect or first pass hepatic elimination. Sublingual & Transdermal Adminstration - ANSWER-avoids hepatic 1st pass effect. Drugs with Large 1st Pass Effect - ANSWER-have low bioavailability. Prodrugs - ANSWER-inactive until they are activated by metabolism in the liver into active compounds (many ACE inhibitors, i.e lisinopril are prodrugs) Rectal Administration - ANSWER-50% of the dose of a drug given rectally will avoid 1st pass effect. Distribution - ANSWER-the process of a substance living the blood stream and moving into cells and tissues. Can be limited by drugs binding to plasma proteins Free Drugs - ANSWER-"free" drugs are distributed to receptor sites and tissues Bound Drugs - ANSWER-bound to plasma proteins and generally not active. Blood Levels - ANSWER-drawing of blood to check levels measures both the bound and free drug in the blood but does not include drug bound in tissues or receptor cites. Concentration Gradient - ANSWER-across the plasma membrane for the diffusible fraction (lipid soluble, nonionized, unbound) determines both rate and direction of net transfer between plasma and tissues. The blood supply to the tissue may also affect the concentration gradient. (poor tissue perfusion fails to carry the drug away from the absorption site. ) Member Transport Systems - ANSWER-may play a role in entry into or exit of drug out of tissues.