Study Guide for Exam 3
Study Guide for Exam 3 PHCL2001
U of M
Popular in Basic Principles of Pharmacology: A Drug's Fantastic Voyage
Popular in Pharmaceutics
Math 32A: Calculus of Several Variables
verified elite notetaker
verified elite notetaker
verified elite notetaker
BIOL 103 - 03
verified elite notetaker
This 13 page Study Guide was uploaded by Huiyu Li on Tuesday December 15, 2015. The Study Guide belongs to PHCL2001 at University of Minnesota taught by Gregory Connell in Fall 2015. Since its upload, it has received 22 views. For similar materials see Basic Principles of Pharmacology: A Drug's Fantastic Voyage in Pharmaceutics at University of Minnesota.
Reviews for Study Guide for Exam 3
Report this Material
What is Karma?
Karma is the currency of StudySoup.
You can buy or earn more Karma at anytime and redeem it for class notes, study guides, flashcards, and more!
Date Created: 12/15/15
Lecture: End of the Voyage: Drug Elimination/Renal Clearance (November 16th) renal artery: Supply the kidneys with blood. cortex: Outer portion of the kidney. medulla: Innermost part of the kidney. ureter: The duct by which urine passes from the kidney to the bladder. Glomerulus a cluster of capillaries around the end of a kidney tubule, where waste products are filtered from the blood. Bowman’s capsule/space a capsuleshaped membranous structure (layer of epithelial cells) surrounding the glomerulus of each nephron in the kidneys of mammals that extracts wastes, excess salts, and water from the blood. Site of filtration. *gave example of it is like a glove around your hand* Podocyte cells in the Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. They keep large particles out and allow small molecules to be let in. Collecting Duct system of the kidney consists of a series of tubules and ducts that connect the nephrons to the ureter. It participates in electrolyte and fluid balance through reabsorption and excretion. Nephrons drain into the collecting duct. Nephrons each of the functional units in the kidney, consisting of a glomerulus and its associated tubule, through which the glomerular filtrate passes before emerging as urine. Questions discussed in class: Q1 : What is the filtration rate in ml/min GFR if 20% of the cardiac output goes to kidneys and 20% of this is filtered? Cardiac output= 6L blood/minute= 3L plasma/minute 1/5 of cardiac output goes to renal artery (kidney): 3000ml*(1/5)= 600ml plasma/min 1/5 of plasma entering renal artery is filtered: 600ml*(1/5)= 120ml plasma/ min (GFR) Q2 : What causes a person to have low GFR? Kidney failure, low cardiac output, anaphylactic shock, low vessel tone (vessels dilate, lower blood pressure) Q3 : Why is the GFR relevant clinically? Lifetime of drug in plasma may be in the body much longer (from toxic overdose) because of low GFR. Q4 : If a drug is able to bind to a plasma protein like albumin, what could be the effect on its halflife? As long as the equilibrium is reversible, its halflife will extend Q5 : Approximately what volume of plasma is filtered daily in a healthy adult? 170 Liters daily. (120 ml/min x 60 min/day x 24 hours/day) Q6: If you were the pharmacologist developing drugs to lower blood pressure, what would be some potential targets? Lowering Na+ transport, causes water to follow> increasing the elimination of water in urine> lower blood volume> lower blood pressure Q7 : Why does alcohol consumption increase rate of urination? When alcohol is consumed, the body excretes the drug through renal function. The proximal and distal tubules of the kidney undergo passive reabsorption depending on the pH levels. They also have antidiuretic hormones (ADH) produced from the hypothalamus and released from the pituitary gland. The ADH controls the amount of water released from the kidneys into the urine. Alcohol causes the tubular urine to be more alkaline which means the weak acid is being largely ionized and are thus excreted more rapidly. Alcohol also prevents the ADH from releasing which causes an increase in urine production. Mechanism of uric acid Lecture: Review of Exam 2/ Renal Clearance/ Liver Clearance (November 18th) Drug Clearance (C): the volume of plasma cleared of drug each minute to account for amount in urine. C= (U*V)/P (ml/min) U concentration of drug in urine (mg/ml) V urine volume collected per min (ml/min) P concentration of drug in plasma (mg/ml) Drug Elimination: Organic Anion Transporters (OATs): actively transport the drug into the nephron i.e. Penicillin excreted by filtration and active transport, thus made it have a short half life, so it would be safe even give a high dosage. Organic Cation Transporters (OCTs): also actively transports drugs into the nephron. Only difference is it transports drugs that are organic bases rather than acids. Aspirin Toxicity: changes in acidbase balance 1. Increased O2 consumption and CO2 production as a result of uncoupling of oxidative phosphorylation; 2. Increased O2 consumption stimulates respiration balancing production and maintaining plasma CO2; 3. Salicylates directly stimulate the respiratory center in the medulla resulting in hyperventilation; 4. Compensated by renal excretion of bicarbonate (compensated respiratory alkalosis); 5. After toxic doses or prolonged exposure, salicylates have a depressant effect on the medulla; What conditions favor increased elimination through urine? To increase drug elimination through urine, give a charged form of the drug. Ex: ● give a weak base to force drug into the negatively charged form ● give under acidic conditions to force into positive form Lecture: Drug Biotransformation Part 1 (November 23rd) What is a pharmacokinetic explanation for the generalization that consuming no more than one standard alcoholic drink every hour will keep the bloodalcohol level from rising no matter the starting level? Alcohol dehydrogenase actually saturates at a very low EtOH concentration which results in zero order kinetics. Under zero order kinetics most people metabolize 1 drink per hour. As long as consumption rate is less than this the plasma concentration should not rise. first order kinetics The amount of drug that is metabolized/excreted in a given unit of time is directly proportional to the concentration of drug in systemic circulation zero order kinetics Saturation kinetics. The rate of absorption or elimination is constant. Based on transporters. Amount of drug absorbed or eliminated is a linear function of the time elapsed, not exponential. Biotransformation (affect enzyme) vs. Metabolism (increase water solubility) Phase I reactions add in a functional group. Usually a hydroxylOH group (Sometimes increases metabolism but also has a chance of increasing hydrophobic property of the drug decreasing elimination of drug). Phase II reactions add in highly water soluble group to functional group usually hydroxyl group (Increases metabolism of drug, makes drug more water soluble). Biliary Secretion drugs moved/transported in bile ducts in the liver. Water soluble drugs eliminated through feces in this process. Clearance (total) Clearance (renal) + Clearance (hepatic) + Clearance (other) Lipid soluble drug not eliminated efficiently, secreted into the bile ducts, reabsorbed back into the livers Drug clearance: volume of plasma filtered at the glomerulus per minute that would be needed to account for the amount of the drug in the urine Describe a complete route through which the following drug could be efficiently eliminated from the body: The drug undergoes phase one biotransformation which is the hydroxylation of the drug via cytochrome p450’s. This adds a functional group such as an hydroxyl group. It then needs to undergo phase 2 biotransformation in order for the drug to be efficiently excreted. Lecture: Drug Biotransformation Part 2 (November 25th) 1. A patient who recently began taking phenytoin, an anti seizure drug, endedup pregnant even though she was taking oral contraceptives. Provide a possible pharmacokinetic explanation. P450 can be induced in undesirable and unpredictable ways. Drugs that are hydrophobic or lipophilic can bind to xenobiotic (foreign material with no purpose of being in the body). The phenytoin induces CYP3A4 and CYP2C19. Estrogen is biotransformed by CYP3A4, causing the half life of estrogen to decrease. 2. . What is a pharmacokinetic explanation for alcoholics being able to consume more alcohol with fewer side effects than the occasional drinker? Ethanol induces CYP450 2E1 which oxidizes alcohol to acetic acid. 3. A patient who is taking 6mercaptopurine for the treatment of leukemia is prescribed allopurinol for the treatment of gout. Provide a pharmacokinetic explanation as to why the patient died. People who overproduce uric acid take allopurinol to inhibit xanthine oxidase. This can be used to treat people with gout. 6mercaptopurine is normally metabolized (biotransformed) by xanthine oxidase, allopurinol inhibit xanthine oxidase. They both compete for binding. The leukemia drug builds up toxic levels in the plasma and kills the patient. Lecture: Pharmacogenetics (November 30th) Pharmacogenetics: The study of the role of inherited and acquired genetic variation in drug response. Genotype: unit of heredity, genetic makeup of a person. Phenotype: traits you can see in someone Genome: the haploid set of chromosomes in a gamete or microorganism, or in each cell of a multicellular organism. the complete set of genes or genetic material present in a cell or or ganism. Inheritance: Born with the trait, comes from parents. Acquired genetic variation acquired later on in life (ex: cancer) Unit heredity: Blending heredity: the expression in offspring of phenotypic characters (as pink flower color from red and white parents) intermediate between those of the parents; also : inheritance in a now discarded theory in which the genetic material of offspring was held to be a uniform blend of that of the parents. Superficial traits: Traits you can observe. Influenced by genetic variation and multiple different loci (different genes). Manhattan Plot: genome (xaxis). Probability, PValue (yaxis). On chromosome #11, the CYP2C9 is located. Think of it like this the taller the building, the more likely the “Ttest” is not due to chance. Association people who have variations at these loci. Example: warfarin. very narrow therapeutic index (too much or too little could be fatal), so CYP2C9 is the therapeutic approach. Association Loci only looking where they want to look, don’t know about other places to look so they don’t look there. Unbiased search: looks at the whole genome, “genome wide association,” association predicts cause and effect, does not prove the association, con: takes time/money Candidate search: have an idea of where it is so you look there, con: only going to find something where you’re looking, you might miss something somewhere else Take home message: Why establish association? ● make more accurate predictions about who should take a drug, who shouldn’t, how much they should take, an alternate drug they should take, etc. (drug resistance, drug induced toxicity, dosage requirements) Know this cycle: The liver uses vitamin K to make blood clotting proteins. In doing so, vitamin K plays a role in your body's natural clotting process. Warfarin works against vitamin K. Specifically, warfarin reduces your liver's ability to use vitamin K to produce normally functioning forms of the blood clotting proteins. By reducing the liver's ability to use vitamin K to produce normally functioning forms of the blood clotting proteins, warfarin reduces your risk of forming a blood clot. So how does my intake of vitamin K affect warfarin therapy? A significant change in your intake of vitamin K can result in a significant, and potentially dangerous, change in your INR. For example, if you reduce the amount of vitamin K in your diet, your INR will increase. Also, reducing the amount of vitamin K in your diet may make it more difficult to manage your warfarin therapy. Patients who have a low intake of vitamin K have been found to have more fluctuation in their INR, which is the test used to measure the effect of warfarin and to adjust the dose of warfarin. Variable Outcomes drug resistance, toxicity, need more than normal amount. By studying this relationship, there are better outcomes in patients. Know the study of hospitalization in patients with VKORC1: Know this process: Patients with Reduced UGT1A1 Activity. Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia (abnormally low count of a certain type of white blood cells that helps to fight off infections) following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele(see DOSAGE AND ADMINISTRATION). Heterozygous patients (carriers of one variant allele and one wildtype allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses. Lecture: Drug Discovery (December 2nd) FDA Mission Statement (does not include dietary supplements) Safety, Efficacy and Security. Aspirin Main drug people were taking in 1905. *In the early 1900s, congress passed the Pure Food & Drug Act foods/drugs had to be what they were labeled as. (nothing about safety and efficacy) *”Shirley Amendment” of 1910 prohibits knowingly false therapeutic claims. *1938 (30 years later), Food Drug & Cosmetic Act = requires drugs be shown to be safe prior to approval (after the sulfanilamide tragedy sweet, oral drug caused 100 children’s deaths from liver failure). *DurhamHumphrey Amendemnt, 1951 distinction between OTC and prescriptions. *KefauverHarris Amendment, 1962 proves drug efficacy because of thalidomide diaster. (thalidomide disaster was marketed as depression drug. It affected pregnancies by shortening arms/legs of babies) When testing drugs in mice it is hard for them to test for efficacy. Subacute toxicity : tested the Max Tolerated Dose, which is the max amount to give a mouse everyday where they won’t fail to thrive. Lecture: Drug Developement (December 7th) History of Drug Development: Early days used natural products Aspirin was the birth of modern drug industry Sulfanilamide: triumph and tragedy Thalidomide disaster US Drug Law: Pure food and drug act of 1906 (just remember early 1900s) 1911 US vs Johnson, supreme court rules that the 1906 act does not prohibit false therapeutic claims but only false and misleading statements about the ingredients or identity of a drug. 1912, Congress enacts the Sherley Amendment to overcome the US vs Johnson. Prohibits labeling medicines with knowingly false therapeutic claims intended to defraud the purchaser (which was difficult to prove). 1938, Food Drug and Cosmetic Act. (after the Sulfanilamide tragedy) Required drugs to be shown to be safe prior to approval. Subjects being tested not patients, because in an experiment they are not sick people trying to get better. Phase I Trial Who to do phase I trials on young, healthy adults who volunteer (informed consent given). This is because they more likely need the money to get paid, probably healthier than older adults (greater safety margin). *** safety is the sole goal! (rarely efficacy tested in phase I) watching for adverse effects ( like high bp, high hr, hypertension, mood, nausea) IRB makes sure the subjects being tested are protected and that the tests are ethical. Waited for FDA to either approve or deny to go on to phase II trials. Phase II Trial Efficacy and safety tested. Use people that would benefit the most from this trial (have the disease the medication is treating) 100300 participants Phase III Trial Make sure people are not reporting wrong therapeutic problems than what really happens. double blind = placebo controlled 10003000 participants PostMarketing Surveillance (Phase IV Trials) “med watch” must report any known adverse effects or drugdrug interactions Lecture: Toxicology (December 9th) Many overdoses of opioid drugs because of prescriptions. Mainly middleage to older people most commonly affected. Common Toxic Mechanisms: Reversible binding Receptor mediated: Opiate overdose Nonspecific: Heavy metals Electrophilic attack Reactive electropositive regions within molecules Acetaminophen Free radical generation Reactive unpaired electrons Paraquat, ionizing radiation Xenobiotic metabolism Metabolic activation: Aflatoxin, methanol, diethylene glycol Inhibition or induction of metabolism Allergy Most drugs too small, but peptide and proteins immunogenic Drugs linked to proteins may be immunogenic Naloxone/Narcan/Naltrexone Treat acute opiate exposure, don’t need a prescription for this medication. Its mechanism is that it is more potent and has a higher affinity antagonist. If a person goes into respiratory depression, they are given this drug and then they can start breathing again because of the agonist properties. Also gives them acute withdrawal and makes brings them down from their “high”. Carbon Monoxide poisoning. Hemoglobins carry oxygen, carbon monoxide replaces the oxygen and takes over the cells. Carbon monoxide binds reversibly to Hemoglobin It is produced by automobiles, space heaters, furnaces. When the levels are above 20% coHb will die, below that level people can live. It can be reversible, at 2.5 atm and 1 atm. Acetaminophen Tylenol. Could unintentionally cause an overdose because APAP is in so many drugs. Causes liver failure (one symptom we talked about with this is jaundice). (Know this process, don’t need to memorize the structures but know what they are doing) When given a therapeutic dose of APAP, 90% of acetaminophen(APAP) becomes glucuronide through phase II metabolism. 10% goes through the toxic intermediate because of CYP450. Then glutathione converts the toxic intermediate to a nontoxic form. (cysteine conjugate) When a person overdoses acetaminophen (a high dose), the phase II enzymes become saturated. This causes the CYP450 to be converted more to the toxic intermediate. Their livers run out of glutathione when they overdose. Doctors will then give a person NAC (N acetylcystein) so that they can live. NAC has a high LPC which can get into the cells to replenish the glutathione levels. Doctors cannot give the patient glutathione because glutathione does not have a high enough lipid partition coefficient so they cannot get into the cells.
Are you sure you want to buy this material for
You're already Subscribed!
Looks like you've already subscribed to StudySoup, you won't need to purchase another subscription to get this material. To access this material simply click 'View Full Document'