Download PHRM 4060 Exam III Study Guide: Cholesterol & Hemophilia Therapeutics and more Exams Advanced Education in PDF only on Docsity!
PHRM 4060 Exam III Study Guide
Bile Acid Resins - Answer -Lowers plasma LDL levels by indirectly increasing rate ofLDL clearance from bloodstream -MOA: Binds to bile acids and increases fecal excretion of bile acids, decreasing theamount of bile acids returning to the liver. Stops feedback inhibition of 7alpha-hydroxylase and increases conversion of cholesterol to bile acids-Secondary MOA: Decreases hepatic cholesterol which increases LDL receptor expression, uptake of plasma LDL, induces HMG-CoA reductase, and increasesbiosynthesis of cholesterol. -Structure: Polymeric resin with crosslinking agent. Positive charge from substitutedamine acts as binding sites for bile acids -Adverse effects: Minimal side effects due to lack of oral absorption; constipation,increased frequency of loose stools due to higher fat excretion, hypoprothrombinemia, bleeding-Drug Interactions: can potentially decrease oral absorption of almost any other drug. All oral meds should be taken 1 hour before or 4 hours after taking bile acids. Caninteract with warfarin. HMG-CoA Reductase Inhibitors (Statins) - Answer -MOA: Blocks conversion ofHMG-CoA to mevalonic acid, decreasing cholesterol synthesis. Causes increased expression of HMG-CoA reductase and LDL receptors. Enhanced LDL receptorexpression and LDL uptake is primary mechanism for lowering LDL levels. -Adverse effects: GI disturbances, increase in CK levels, myalgia, myopathy.Rhabdomyolysis is rare. -Drug interactions: Increased risk of myopathy with 3A4 inhibitors Natural/semi-synthetic statins - Answer -Lovastatin (lactone/inactive prodrug form);primarily metabolized by CYP3A -Pravastatin: Not metabolized by CYP3A -Simvastatin (lactone/inactive prodrug form); primarily metabolized by CYP3A4Synthetic statins - Answer -Fluvastatin: metabolized by 2C -Atorvastatin: metabolized by 3A -Pitavastatin: metabolized mostly by 2C9 and undergoes lactonization-Rosuvastatin: partly metabolized by 2C
Which statins are prodrugs? - Answer lovastatin and simvastatin Which statins are not metabolized by CYP3A4? - Answer -Pravastatin -Pitavastatin (2C9 and lactonization)-Rosuvastatin (2C9) -Fluvastatin mostly 2C9 but some 3A4What drugs are of concern when taking statins? - Answer 3A4 inhibitors including: -Cyclosporine -Azole antifungals-Macrolides (erythromycin, clarithromycin) -HIV protease inhibitors -Nefazodone-Grapefruit juice -Verapamil PCSK9 Inhibitors - Answer Evolocumab (Repatha), Alirocumab (Praluent)-MOA: Inhibits PCSK9 that binds to LDL-receptors, preventing degradation of LDL receptors and increasing expression of LDL receptors on surface of hepatocytes,lowering plasma LDL-C -Indication: Patients with very high cholesterol levels (500-600 mg/dL), patients withmixed hyperlipidemia or hypercholesterolemia in conjunction with diet and/or statins Cholesterol Transport Inhibitors - Answer Ezetimibe (Zetia)-MOA: Lowers plasma cholesterol by inhibiting cholesterol absorption in small intestines. Binds transport protein to reduce cholesterol transport and absorption,while not interfering with the absorption of other compounds. Decrease in cholesterol causes increase in cholesterol biosynthesis and overall LDL-lowering. -Indication: Can be used alone or in conjunction with statin for patients that don'trespond to diet, exercise, or other non-pharmacologic regimens. -Metabolism: rapidly and extensively metabolized in intestinal wall and liver toglucuronide. Major metabolite is active compound that is excreted in bile and undergoes enterohepatic recirculation. -Adverse effects: well tolerated; abdominal pain, diarrhea, cramping, fatigue, backpain.
Plasma transfusions - Answer given to replace blood volume and clotting factors -Can take hours to administer -Cryoprecipitation increases concentration of clotting factors in transfusion-Risk of immunogenetic rejection if body produces neutralizing antibodies Cryoprecipitate Factor VIII - Answer Factor VIII-enriched plasma protein fractionprepared from whole blood -Indication: Hemophilia A -Preferred over lyophilized factor VIII since it preserves the polymeric structure offactor VIII and allows preparation to only need a single donor -Risk of viral infection Lyophilized Factor IX - Answer Factor IX protein extracted from plasma to activateclotting factors -Indication: Hemophilia B -Heparin is usually added to limit overactivation of thrombinMononine - Answer Factor IX purified from pooled human plasma -Monoclonal antibody specific to factor IX isolates targeted protein which is thenseparated from protein and undergoes further purification -IV administration NovoSeven - Answer Factor VIIa-Indication: Patients with VII deficiency, bleeding episodes in hemophilia patients, increases thrombin activity for both A and B -Harvested from baby hamster kidneys??? and cleaved to active form VIIa andpackaged as lyophilized single-use vials -IV administration Therapeutics for Hemophilia A - Answer -Obizur-Eloctate -Nuwiq -Kovaltry-Afstyla
-Hemlibra -Esperoct Therapeutics for Hemophilia B - Answer -Alprolix-Idelvion -RebinynObizur - Answer porcine factor VIII
-Indication: Hemophilia A -Harvested from hamster kidneys Eloctate - Answer recombinant Factor VIII-Fc fusion protein -Indication: Hemophilia A -Analog of factor VIII covalently linked to human IgG which binds to Fc receptor -Binding of IgG to Fc receptor delays degradation of IgG by lysosomes -Harvested in human embryonic kidney cells and purified Nuwiq - Answer recombinant, truncated human Factor VIII -Indication: Hemophilia A -Only heavy and light chain, no covalent attachment of chains -Harvested in human embryonic kidney cells and purified
Esperoct - Answer Antihemophilic factor, glyopegylated-exei -Factor VIII analog linked to PEG -PEG increases half-life and reduces clearance -Indication: Prevent or reduce bleeding episodes for Hemophilia A -Half life of 21.7 hours Alprolix - Answer Factor IX-Fc fusion protein -Recombinant factor IX fused to Fc fusion protein (IgG)-Delays degradation of IgG and increases half-life
-Indication: Hemophilia B -Harvested in human embryonic kidney cells and purified -Half-life: 86 hours Idelvion - Answer recombinant Factor IX fused to albumin -Indication: Hemophilia B -Single protein fusion of human factor IX and human albumin that is cleaved by activated
factor IX when needed for clotting -Prodrug -Half life: 90 hours Rebinyn - Answer GlycoPEGylated Factor IX -Indication: Hemophilia B -PEG increases circulating half-life of Factor IX, causes lower bleeding frequency andless frequent IV dosing
-Half-life: 115 hours Human insulin - Answer Two peptide chains (A and B) linked by two disulfide bridges -Created from proinsulin by cleaving at two points -A chain: 21 amino acids with internal disulfide bridge at Cys 6 and 11-B chain: 30 amino acids -6 COOH groups Porcine Insulin - Answer Rarely used due to risk of causing immunological responseand ease of access to recombinant human insulin
-differs from human insulin by only one amino acid (alanine instead of threonine) -Slightly less water soluble
-Peak: 4-12 hours -Duration: 18-26 hours (though effect is decreased after 13-15 hours) Semilente - Answer Discontinued insulin -Between short and intermediate acting -Insulin, ZnCl2, acetate buffer -Onset: 0.5-1 hours -Peak: 2-8 hours-Duration: 12-16 hours
Ultralente - Answer Humulin U (Discontinued why are we learning about it then) -Long acting -Insulin, ZnCl2, excess acetate buffer -Onset: 4-8 hours -Peak: 9-18 hours (no true peak)-Duration: >36 hours
Lente - Answer Humulin L (Also discontinued) -Intermediate acting -Onset: 1-2 hours
-Peak: 8-12 hours (no true peak) -Duration: 18-24 hours Humalog - Answer Insulin lispro Insulin analog; short-acting -2 point mutations at residues 28 and 29 of B chain -Onset: 0.25 hours -Peak: 0.5-1.5 hours-Duration: 2-5 hours
Can be taken before or just after a meal, as opposed to humulin which has to be takenhalf an hour to an hour before meals
Novolog - Answer Insulin aspart Insulin analog; short-acting -1 point mutation at residue 28 -Onset: 0.25 hours -Peak: 0.6 to 0.8 hours -Duration: 3-5 hours Apidra - Answer Insulin glulisine
-Threonine of residue 30 on B chain is deleted, C14 fatty acid added to amine side chainof lysine on residue 29 -Increase in lipid nature causes increase in binding to tissue and plasma albumin -24 hour duration, used for basal insulin since it gives a low, constant rate of delivery -Do not mix with other insulins Insulin pump - Answer portable, battery-powered device that delivers insulin throughthe abdominal wall in measured amounts
-Constant infusion of rapid-acting insulin (as opposed to slow-acting insulin for basalrate) -Bolus dose to cover food eaten -Continuous bolus dose at basal rate for between meals and at night -Changed every 3 days Exubera - Answer Inhalable insulin (withdrawn in 2007) -Fine powder that is aerosolized in inhaler -Smaller blisters deliver greater percentage of insulin than larger blisters? GLP-1 - Answer Released from cells in intestinal tract in response to carbohydrates tostimulate glucose-dependent insulin synthesis and secretion from beta cells
-Increases insulin synthesis-Lowers glucagon secretion leading to lower hepatic glucose production
Byetta - Answer Exenatide GLP-1/Incretin mimetic -39 amino acid peptide amide -MOA: Enhances glucose dependent insulin secretion to enhance glycemic control,reducing fasting and post-prandial glucose concentration. Moderates glucagon secretion, slows gastric emptying, and reduces food intake. -Indication: Type II diabetes (requires functional beta cells) -Twice daily subcutaneous injection -Adverse effects: nausea, vomiting -Can delay absorption of some drugs (notably digoxin, lovastatin, lisinopril) Victoza - Answer Liraglutide (also sold as Saxenda for weight loss) GLP-1 analog/Incretin analog -32 residues with C-16 palmitoyl group -MOA: Enhances glucose dependent insulin secretion to enhance glycemic control,reducing fasting and post-prandial glucose concentration. Moderates glucagon secretion, slows gastric emptying, and reduces food intake. -Indication: Type II diabetes
GLP-1 agonist/mimic -Modified at K26 with spacer and C-18 fatty di-acid, and modification at position 8 toresist DPP-
-MOA: Enhances glucose dependent insulin secretion to enhance glycemic control,reducing fasting and post-prandial glucose concentration. Moderates glucagon secretion, slows gastric emptying, and reduces food intake. -Prolonged activity due to albumin binding which results in decreased renal clearanceand metabolic degradation, causing it to last longer
DPP-4 - Answer Dipeptidyl peptidase 4 -Degrades incretin hormones such as GLP-1 and GIP Sitagliptin - Answer Januvia DPP4 Inhibitor -MOA: Inhibits DPP4, increasing levels of GLP-1 and GIP. Results in increased insulinsecretion, reduced glucagon secretion.
-Indication: Type II diabetes -Excreted primarily as unchanged form in urine-Low metabolism
-Adverse effects: Upper respiratory infections, headache, and sore throat
Saxagliptin - Answer Onglyza DPP-4 Inhibitor -MOA: Inhibits DPP4, increasing levels of GLP-1 and GIP. Results in increased insulinsecretion, reduced glucagon secretion.
-Indication: Type II diabetes. -More potent than sitagliptin -Low protein binding -Converted to active metabolite through 3A4; metabolite is half as potent-Primarily excreted in urine via active secretion
Linagliptin - Answer Tradjenta DPP-4 Inhibitor (more selective for DPP-4) -MOA: Inhibits DPP-4, increasing levels of GLP-1 and GIP. Results in increased insulinsecretion, reduced glucagon secretion.
-Indication: Type II diabetes. -Half life: over 100 hours -Primarily excreted in unchanged form in *feces, thus making it preferred over other
injections -Half life: 50 minutes -Adverse effects: nausea Do not mix with insulin due to pH differences Sulfonylureas - Answer Glipizide, glyburide, glimepiride, tolbutamide, chlorpropamide,acetohexamide
-MOA: Stimulate insulin release from beta cells by binding to and blocking ATPsensitive potassium channels. This increases levels of intracellular potassium, depolarizing the cell and opening calcium channels. Increased intracellular calciumcauses release of insulin from storage granules. May also increase insulin sensitivity and decrease hepatic glucose production -Extensive binding to serum and tissues and increased intestinal absorption due tolipophilic nature
-Monitor for hypoglycemia -Adverse effects: Hypoglycemia, (Chlorpropamide and acetohexamide only) Flushing,vomiting in combination with alcohol
Sulfonylureas SAR - Answer -R group should be in para position -R group can be methyl, amino, acetyl, chloro, bromo, iodo, methylthio, trifluoromethyl -Aryl arboxyamidoethyl substitution in second generation enhances potency greatly-Increases in chain length and number of carbons on R group increases lipid nature and facilitates gut absorption
First generation sulfonylureas - Answer -Tolazamide -Chlorpropamide-Acetohexamide -Tolbutamide Second generation sulfonylureas - Answer -Glipizide -Glimepiride-Glyburide
Repaglinide - Answer Prandin Glinide -MOA: Causes closing of ATP dependent K+ channels, resulting in depolarization ofthe cell and opening of Ca channels. Increased calcium causes glucose dependent insulin release. -Highly protein bound; displacement by other drugs causes increased hypoglycemiceffect
-Metabolism: 3A -Adverse effects: hypoglycemia, otherwise well tolerated Nateglinide - Answer Starlix Glinide
