Module 1 Flashcards

Question

DISTRIBUTION

Answer 1

* Concentration of blood is indicator of pharmacological effect * If concentration at site of action is equilibrium with concentration In blood * If concentration in blood drops bewlo any distribution site * Drug will move from site of distribitium to blood to maintain equilibrium * Example ○ After intravenous injection ○ Concentratrion in brain of thiopental ○ Concentration in muscles and fat will be low ○ After a few minutes concnetrations in aux places increases ○ Causes drug to leave brain and move ○ When the concentration of drug in brain decreases patient will awake 15 to 30 minutes later Action of thiopental has been terminated by drug redistribution from brain into muscle even though has not been removed from body

Answer 2

* At all distribution sites has 2 forms * Free drug and drug bound to protein When it is bound to protein is cannot cross membranes and is unable tp produce pharmacological effect or be excreted by kidney

Answer 3

* Brain ○ Blood brain barrier prevents many drugs access * Placenta ○ Very permeable and most drugs will reach * Fat cells ○ Fat soluble drugs will accumulate fat cells and since blood flow there is limited ○ Drugs will leave fatty tissue is limited Drugs will leave fat tissue slowly

Answer 4

* Called biotransformations * Converion of drug to different compound * Can result in detoxification or bioactivation of a compound * Example ○ Codeine is converted in the body to morphine Causes pain relief through bio transformations

Answer 5

* Where most occur * Involve convsersion of drugs into more water soluble compounds * Once water soluble drugs can be eliminated from the body * Kidneys without biotransfomations some chemicals that are very lipid soluble cannot be removed from the body * Drug biotransformation reactions are divided into phase 1 and 2

Answer 6

* Unmask functional group so phase 2 can add large water soluble groups * Oxidative reactions from cytochtome P450 ○ Enzymes located on smooth ER in liver ○ Perform most biotransformations ○ 18 enzymes of the CYP family ○ CYP 3A4 biotransforms 50% of the drugs used clinically which can lead to drug interactions ○ They bind to substrate and activate oygen ○ Chemistry for activation of oxygen is identical for all CYPs ○ All substrates which explains why CYP 3A4 has thousands of subsrtates * CYP genetic variability ○ Some genes coding for enzymes exist in multiple forms ○ Some people the gene that codes for the enzyme produces and ineffective one ○ A gene in population that exists in more than 1 form is called a genetic polymorphism * Other oxidative reactions ○ Not mediated by CYP and oxidation of amines and dehydrogenation of alchol groups ○ Mediated by alternative enzymes ○ Amines such as epinephrine and norpinephrine are oxidized by the enzyme monoamine oxidase ○ Dehydrogenation of alchol to aldehyde an acid occurs through action of enzyme alchol dehydrogenase and subsequently aldehyde dehydrogenase * Hydrolysis of esters and amids ○ Number of drugs are these ○ Converted to acid and corresponding alcohol or amine by carboxylase esterases in the liver ○ Blood and Gi tract and other tissues ○ Muscle relaxant succinylcholine is metabolised by the enzymes

Answer 7

* Add large water soluble groups to phase 1 biotransformations product making the metaboliy water soluble for excretion by kidney * 4 main phase conjugation enzymes are EDP glucurosyltransferase forms a glucuronide * Sulfotransferase SULT forms a sulphate * GST forms a gluthionine conjugate N-acettyl transferase forms an N acetylated metabolite

Answer 8

* Biotransformations and inactivation of drug during absorption from intestine * Consider drug administered orally * Will have to pass through intestinal cells into the blood * May be biotransformed as the cells in inestine have some drug biotransformations * Will then enter liver from the portal vein * Called frist pass effect and reduce the amount fo drug reacting the rest of the body

Answer 9

* Very cimportant clinically * Many factors affect them * Any disease that affects the liver will affect biotransformation enzymes * Alcholic hepatitis bilary disease, liverm cancer Drug interactions can occur between 2 competing drugs for the same enzyme or when 1 drug inhibits the biotransformation of anotehr drug

Answer 10

* Remove drug and metabolites out of the body * Main route of elimination for drugs is through the kidneys * Drugs can be elinated through the GI tract Glandular activity milk sweat saliva and lungs

Answer 11

* Receive 20% of blood from heart * Very efficient at excretion * Kidney filters drugs that are not bound to proteins through the glomerulus and into tubular fluid

Answer 12

* Glomerular filtration ○ Glomerulus is a big vein and passes into bowmans capsule ○ GFR is how much blood that passesthrough the glomeruli every minute ○ In kidney disease the GFR is decreased ○ Any disease that affects blood flow will also affect the excretion of drugs * Passive tubular reabsorption ○ Drugs move form areas of high concentrattion to low concentration ○ Concentration of drug is higher in renal tubules than in blood ○ Some lipid soluble drugs can be reabsorbed back into the blood as they are moving down ○ Reabsorption of drugs can be modiefied by altering pH of urine ○ Basic urine will increase excretoom of acific drugs acidic urine will increase excretion of basic drugs * Active tubular secretion ○ Move drug from blood into urine ○ Penicillin is actively excreted into the renal tubule ○ 80% dose of penicillin is cleared from the body within 3-4 hours after administration ○ Drugs probencid can be given to block secretion of pencillin andf increase concentration of penicillin in blood

Answer 13

* GI tract ○ Number of drugs are excreted via bile for elimination with feces ○ Drugs that bind to proteins in GI will not be absorbed * Other body fluids ○ Drugs found in all body fluids ○ Milk saliva and sweat ○ Have minor role ○ Some level of drug can be detected through these routes * Lungs ○ Votalitle drugs can be inhaled through here ○ Phase I will add functional group or mask it ○ Phase II add large water soluble groupe so it can be excreted

Answer 14

* Body made of several compartments * Drug can be in all or some compartments this is called VD * dose of drug/ drug in plasma (Concentration) * Apparent because does not represent the actual value

Answer 15

* 42L total * Intracellular fluid - 28L * Extracellular fluid 14L * Intravascular fluid - 3L * Intersitial fluid - 11L

Answer 16

* Removing drug from body * 2 main sites Kidneys and GI tract

Answer 17

* Rate of elimination of a drug is directly proportional to the concentration of the drug * IF CONCENTRATION OF DRUG IS HIGHER MORE IS EXCRETED * AS Liver and kindey have higehr amounts o drugs available to eliminate If concentration is low then the opposite is true

Answer 18

* Most drugs follow first order * Few drugs eliminated by 0 order * As enzymes repsonsible for elimination are saturated there is more drug that can be transformed * Alcohol is eliminated following 0 order elimination kinetics Regardless of how much alchol is consumed only 10 to 13 ml of absolute ethanol can be metabolised by the liver in an hour

Answer 19

* Time needed for kidney and liver to remove 50% of the drug from blood * Dose to always maining effective concentration of the drug Half lives can be used to calculate the drug concentration in blood after each half life in the blood

Answer 20

* Tells when a drug is administered repeatedly plasma concentration of drug will increase until rate of administration is equal to the rate of elimination * Drug input is equal to drug output * Takes 5 elimination half lives for drug put = drug output Time to reach concentration of drug in blood however the time to reach the new pleateau is still 5 half lives

Answer 21

* Chronic dosing until output = input * Must administer a dose to replace the drug that is lost from the body * Sicne drug is lost every half life you must administer a dose after ever half life Established to create drug dosage in the therapeutic range

Answer 22

* Administered by weight or volume * Expressed in mL or L * Each step is 1000 fold change * House hold measures ○ Administer drugs that are liquid form especially at home ○ Sometimes measuring device droppers and cupes grduated in the medtric system ○ Come with the liquid form of the drug for ease of measuring * Units ○ Some drugs are adminsitered by weight or volume ○ Based on biological activity of the drug ○ Some vitamins are dosed in units * Body weight or surface area ○ Perscribed by body weight ○ Doses of anticancer drugs are often based on bod ysurface area Drugs are generally more toxic than other classes of drugs and doses based on body surface are are more precise than body weight

Answer 23

* Adult dose cannot be adminstered * Cannot be calculated proportional to the reduction of a child * Child bodies respond much differently * Organs are not as well dveelopped * ADME may be different * Methdos used on children are based on ○ Age ○ Weight Body surface area

Answer 24

* Body surface area is the most accurate method * Determined by nomogram using formuka Child dose = adult body surface area(m2)/1.73 * adult dose

Answer 25

* Not effective is the patient does not take the drug correctly * When medication is self administered compliance is 20 to 90% * If a compliance is only 50% then they onlu take the drug correctly 50% of the time * Reasons ○ Dissatsifaction with diagnosis ○ Cost of drug ○ Incovience of having to take it several times a day ○ Having to take several different drugs daily Onset of minor adverse effects

Answer 26

* Entirely safe drug does not exist * TD50 = toxic dose in 50% of the population * Therapeutic index = TD50/ED50 * Tells how safe the drug is * Relates to the dose of drug required to produce beneficial effect to the dose required to produce and adverse effect * Higher the Therapeutic index the safer the drug When drug has low Therapeutic index tocoitties are likely to be observed

Answer 27

* Extension of therapeutic effect ○ When too much drug is in the blood ○ Benzodiazepeine is taken for sedative effects ○ Overdose will produce over sedation ○ To stop adverse reaction rude the dose of the drug * Allergic reactions ○ Mediated by immune system ○ Antigen-antibody combination provokes adverse reactions ○ Can be mild rash or anaphylaxis ○ May be genetic ○ Most adverse reaction to penicillin are allergic in nature ○ Solution is to avoid the drug * Effects in non target tissuesof organs ○ When receptors for drug exist in more area than the target tissue ○ Morphine reduces analegeris effect by acting on opid recpetor in the CNS ○ Can also cause constipation by opoioid receptprs in the GI ○ Reducing dose will reverse this * Adverse biotransformation reaction ○ When drug is converted to chemically reactive metabolite that can bind to ytissue component and cause tissue or organ damage ○ Acetaminophen converted to harmless metabolites and excreted ○ Overdose of it leads to production of chemically reactive metabolite that binds to the tissue component and cause liver injury ○ To avoid these reactions drugs should only be taken at recommended doses * Unrelated to main drug action ○ Effects that are unexpected and unrelated to the intended pharmacological action of the drug ○ Digitalis used to treat heart failure ○ Causes nausea and vomiting and colour vision ○ Unrelated to the main treatment ○ Activates different receptor than the therapeutic ones ○ May or may not include gradula withdrawal from the drug or additional pharmacological or non pharmacological supports * Drug idosyncrasy ○ Unusualy response to drug, only observed in small number of people ○ Usually from Genetic make up of an individual ○ Succinylcholine is used to produce muscle relaxation ○ 1/3000 patients lack enzyme that normally inactivates the drug causeing it to act for long perioids of time * Teratogensis ○ Birth defects ○ Drugs inducing defects on a developing fetis ○ Babies exposed to sedative drugs such as thalidomide during pregancny are born with abnormal limbs

Answer 28

* Drugs said to have little or no adverse effects tend to see them later on * Adverse events may be rare ○ Phase 3 clinical trials are 1-2k patients ○ Adverse events are only detected oncet he drug is widely used ○ Antibiotic chloramphenicol used for several years before it was recognized that 1/40k patients will cause fatal bone marrow damage * Toxic reactions appear after prolonged use of the drug ○ Some adverse effects may only appear after long term use of the drug ○ Appears that toxicitiy of the drug accumulates ○ Stremucin and antibootic used to treat tubeculosis causes deafness after long term use * Toxic effects not detectable in animals ○ Headache or nausea or mental distrbances are difficult to detect in animal tests ○ These adverse effects are only detected when administered to humans * Adverse effects are unique to particular period or circumstance ○ Until thalidomide was not necessary to test on preganant animals ○ Even if they are tested on animals there is no certainty that it will carry over to humans

Answer 29

* Age ○ Newborns and individuals > 60 years of age are more likely to experience an adverse drug reaction than middle aged individuals ○ Due to immature or damaged organs livers and kidneys that make the individual more sensitive to the drug * Genetics ○ Enzymes biotransform and inactivate drugs ○ Can exist in different forms based on the genes that code for the nezymes ○ Reuslting ing slow normal and fast metabolites of some drugs ○ At the suual dose, the slow metabolizer will have higher blood concentration of the drug and increase risk for an adverse drug reaction * Multiple disease in the same patient ○ Presence of more than 1 disease can increase the chance f an adverse drug reaction occuring ○ Presence of kidney disease drugs used to treat other diseases may be removed from the body more slowly tha expected ○ Causing higher than normal concentration in blood increasing the risk of adverse drug reaction

Answer 30

* Modification os pharmacological effect on one drug by the presence of another drug in the body * Potential for drug to drug interaction increases dramatically as the number of drugs taken by the patient increases * Average perscriptions of an 80yo is 8-10 * Drug interactions can lead to altered absorption distribution and biotransformation or excretion of drugs Consequences of interactions may be beneficial by increasing the effectiveness or decreasing the toxicity of drug or they may be detrimental by increasing effectiveness or increase toxocity of a drug

Answer 31

* Additive ○ Combined pharmacological effect of 2 drugs is the sum of the individual effects of 1 ○ 2 different drugs form the benzodiazepine drug calss will produce an additive effect because 2 drugs bind to the same receptor * Synergistic ○ Combined physiological effect of drugs is greater than the sume of individual effects ○ 2 drugs that bind to different receptors but produce same pharmacological effect ○ CNS depression prodcued by combination of 2 sedatives sucg as alchol and barbiturate * Potentiation ○ Effect of 1 drug increased by a second drug even though the second drug is devoid of intended therapeutic effect ○ Adminsitration of a sedative togetehr with a drug that inhibits biotransofrmations and inactivation of sedative resulting in higher than expected blood levels of the sedative * Antagonism ○ One drug reduces the pharmacological effect of another by competing for the same receptors ○ Morphine and naloxone compete for the same receptor and is used to treat morphine overdose * Altered physiology ○ One drug may alter physiology of the body so that the response to another drug is altered ○ Administration of diurectic hydrochlorothiazide combined with heart drug digoxin can increase the toxicty of digoxin

Answer 32

* Most drug drug interactions have pharmacokinetic basis and one drug alters the concentratoon of other drug in the blood and at the site of action * Absorption ○ Drug can combine with another drug in the stomach or intestine and form a complex - cause it to not be absorbed in the blood ○ Tetracyline group of antibiotics which combine with antacids, contain calcium, Mg and Al,f or this reason they should not be taken the same time as antacids ○ Some drugs increase intestinal motility to such an extent that other drugs cannot be absorbed ○ Some drugs hinder the movements of intestine and prevent the mixing of intestinal contents which normally brings a drug to contact wit habsorbings urface of the inestinal wall thereby decreasing absorption * Distribution ○ One drug may alter distribution of a second drug ○ Number of drugs use the same binding sites on proteins in the blood ○ Addition of second drug may comepet ewith the first drug for binding sites on the blood proteins ○ Displacing first drug form the proteins thereby increasing the amount of unbound drug in the blood ○ Example ○ Blood thinner warfarin extensively bound to blood proteins ○ Adding as second drug that is also protein bound such as sulphonmuide will displace warfarin from its binding sites increasing the amount of unbound warfarin in the blood reuslting in the patient bleeding

Answer 33

* Age ○ Liver and kiney function decrease with age ○ Affect ability metabolize and eliminate drugs ○ Elderly are more suspectible to drug to drug interactions * Genetic factors ○ Certain genetic traits will make certain idividuals more likely to have a dug to drug interaction than most of the population ○ Variability of genes coding for CYP result in different rates of metabolism of certain drugs * Polypharmacy - multiple drugs taken by patient ○ More drugs the person takes the greater the chance of a drug-drug interaction

Answer 34

* Some drug properties make them likely to be involved in drug to drug ineractions * Narrow therapeutic index * Saturated metablism at therapeutic doses - metabolism occurs at maximal dose * Active transport is required to reach the site of action or to be eliminated * Drug elimination by only 1 biotransformation or renal excreteion * Site of action in an organ with high blood flow * Computer databases prevent these

Answer 35

* Simialr to drug drug interactions * Foods can affect drugs * Grapefruit ○ Casues increase bioavailability ○ Compounds that inhibit CYP 3A4 and p450 found in GU wich contribute to first pass effect ○ When CYP 3A4 inhibits first pass effect is removed and more drug stays in the system ○ Patienst are recommended not to take this before taking drugs * Tyramine ○ Antidepressants of monoanime oxidase inhibitor class of any food ○ Such as aged cheddar cheese Prevent inactivation of tyramine and can increase blood pressure

Answer 36

* Identify biological targets ○ A receptor that causes a desired effect * Identify pharmacological effects ○ At molecular cellular and organ and whole animal leve; * Conduct more studies ○ If compound shows promise, leads to a more detailed survey ○ Drug might be tested for harmful side effects

Answer 37

* Prior to testing drugs on humans * Range from molecular and cellualr studies to tissue and animal studies * Pharmacology studies - determiend mechanism of action and pharmacological effects * Toxicology studies - determine the safety of the drug ○ Acute toxicology study ○ Determine toxicty of a drug after single administration ○ Or after a limited number of them ○ Short period of time ○ Determine dose that does not cause toxcity ○ Sub chronic toxicity study ○ Last few weeks to months ○ Conducted with different doses of drugs found to be well tolerated from acute study ○ 2 species of animals are given the drug daily ○ Chronic toxicity study ○ 6-12 months to 2 years with 2 species at 3 doses or more ○ Toxic effects aof the drug are measured throughout the study and any organ damage is determined at the end of the study

Answer 38

* Phase I (50 people) ○ Limiuted number of human volunteers ○ Patients with disease may be used ○ Several doses will be tested buteach subject will receive just 1 dose * Phase II (500 people) ○ Drug is administered to patients with the disease ○ Determine whether it is effective at treating the disease or not ○ Subjects divded into different groups ○ Control group will be given the gold standard ○ If the gold standard is not available than a placebo will be givem ○ Single blind ○ Person administering the drug knows but the patient does not ○ Double blind ○ Researcher and patient are blind ○ Length of study depends on the disease being studied ○ Monitor adverse effects and ADME * Phase III (thousands of people) ○ Many drugs fail I and II ○ III is to determine whether it is safe in large quantities of people ○ Most expensive ○ Can cost 1-50 million Drug companies retain the service of a contract research organizations to conduct the study

Answer 39

* Manufacturers submit Phase III Is regulatory scientist are happy with the results they will be granted approval

Answer 40

* Formal chemical compound name is gay and annoying * Will be given a generic name * Effective patient life of a drug ranges from 10-12 years after the patent ends on the drug and different companies can produce it as well * * Bioavailability studies ○ Brand name and generic will have the same active ingredients ○ Study will compare bioavaibility of both drugs ○ Ensure that both drugs are equal ○ Strict regulations are in place so that drugs made by different manufacturers are of same bioavailability as the original Ibuprofen - Advil, motrin, IBU, proprinal Acetaminophen - Tyleno, tactinal, vitapap, actamin Diphenhydramine - allergy reloef, allermax, banophen, benadryl

Answer 41

* Information on safetry and efficacy of drug after marketing * Some drug toxicities will occur 1/10k * Only be detected when the drug has been in use for a long time on a number of patients * These are phase IV studies Patients perscribed the drug in post market surveillance may be voluntary

Module 1 Flashcards

(65 cards)