Copy of Midterm Review.docx

Lipases – What performs lipid digestion? Lingual lipases: secreted by salivary glands Activated by stomach acid Gastric lipases Produced by infants Pancreatic lipases: Secreted into duodenum Performs most lipid digestion Lipid digestion – Why is a special pathway required for lipid digestion? Lipids...

Lipases – What performs lipid digestion? Lingual lipases: secreted by salivary glands Activated by stomach acid Gastric lipases Produced by infants Pancreatic lipases: Secreted into duodenum Performs most lipid digestion Lipid digestion – Why is a special pathway required for lipid digestion? Lipids are not water-soluble Difficult to break down Normal digestion cannot penetrate lipid Strategy: break lipid to increase surface area and suspend in aqueous environment Emulsification – How do you prevent separation of liquids and aqueous phases? Reduce size of fat droplets in duodenum Add bile lecithin (phospholipids) and bile acids (steroids) Summary: break up fat globules and coat them with bile lecithin and bile acid so they can be suspended in small droplets Micelle absorption – How are cholesterol, lipids, and other fat-soluble materials absorbed? Formation of micelles containing 20-30 molecules of bile acids, free fatty acids, monoglycerides, cholesterol, and fat-soluble vitamins Directly absorbed across cell membrane Summary: formation and absorption of micelle droplets across cell membranes Chylomicron – What is a chylomicron and what is its purpose? Formed from triglycerides, cholesterol, and phospholipids packed together with a protein coating Packaged into secretory vesicles by Golgi complexes and exocytosed Enter lymphatic system via central lacteal of intestinal villi Summary: chylomicrons are a lipoprotein package used to transport fats and lipids to lymphatic system via central lacteal Lipid metabolism – What is the exogenous pathway (part I) of lipid metabolism? Chylomicrons contain apo-B48 Secreted chylomicrons acquire apoCII and apoE from HDL ApoCII activates lipoprotein lipase Activated lipoprotein lipase are attached to endothelial cells of capillary wall and hydrolyze triglycerides within chylomicron Chylomicrons are converted to remnants Remnants are either (1) converted to IDL, or (2) removed by hepatocytes through apoE-mediated process Hepatocytes: remnants converted to VLDL VLDL exocytosed from hepatocytes and enter circulation Lipid metabolism – What is the endogenous pathway (part II) of lipid metabolism? VLDL particles acquire apoCII from HDL Lipoprotein lipase hydrolyzes triglycerides found on VLDL Lipoproteins containing apoB-100 are converted to IDL, then LDL ApoCII and apoE dissociate, then reassociate with HDL Hepatic lipases mediate IDL → LDL LDL and apoB-100 interacts with high affinity receptors on hepatocytes and peripheral cells LDL-receptor interaction causes receptor-mediated endocytosis of LDL into cell Lipid metabolism – What is the goal? Remove lipid from blood to prevent abnormal deposition in arteries Interference causes hyperlipidemia, blood perfusion issues, and narrowed arteries Cholesterol – How is synthesized cholesterol and dietary cholesterol balanced? HMG-CoA reductase is the rate-limiting step of cholesterol synthesis HMG-CoA reductase inhibition prevents cholesterol synthesis (statin drugs) Presence of dietary cholesterol → block cholesterol synthesis Absence of dietary cholesterol → permit cholesterol synthesis There is a limit to the extent which the body can naturally balance cholesterol. Lipoproteins – What are the characteristics of various lipoproteins? High density lipoprotein (HDL) Associated with apoCII and apoE released for lipid metabolism Reverse cholesterol transport to reabsorb and carry extrahepatic cholesterol to liver for removal Removal mechanism fails as atherosclerosis progresses Very low-density lipoprotein (VLDL) Synthesized in liver and regulated by diet and hormones Inhibited by chylomicrons remnants in liver VLDL later converted by lipoprotein lipase to IDL, then LDL Low-density lipoprotein (LDL) Major cholesterol transport lipoprotein – contains mainly apoB-100 which recognizes and binds to LDL receptor Cholesterol-LDL-LDL receptor interaction causes internalization Oxidized low density lipoprotein (oxLDL) Oxidization of LDL Uptaken by macrophages and not regulated by feedback mechanism OxLOL can/is: Regulate vascular tone Activate immune and inflammatory response Chemotaxic for monocytes Toxic to endothelial cells Familial hypercholesterolemia Autosomal dominant disorder; high LDL levels in blood with deposition in arteries, tendons, and skin Class 1: receptor negative – LDL receptor not produced Class 2: transport defective – LDL receptor is not transported to cell surface Class 3: binding defective – LDL receptor does not bind effectively to LDL Class 4: internalization defective – LDL receptor is not endocytosed after binding Class 5: recycling defective – LDL receptor not recycled back to cell surface Dyslipoproteinemia Apolipoprotein defects: variants or deficiencies in apolipoproteins affecting LDL levels in blood Enzyme defects: deficiencies affecting LDL levels in blood Acute Coronary Syndrome (ACS) – What are the types of myocardial infarctions and prognoses? ST elevation myocardial infarction (STEMI): transmural infarction Non-ST elevation MI (NSTEMI): non-transmural infarction Endocardial or pericardial Elderly patients have better prognosis due to collateral circulation Prognosis determined by extent and location of tissue damage Usually causes unstable angina, NSTEMI, or STEMI Angina pectoris – What is angina? What are signs and symptoms? Pain in chest (upon severe to minor exertion) induced by physical activity or emotional stress caused by insufficient myocardial perfusion May radiate to left arm, jaw, and upper abdomen Persists 1-15 minutes Relieved by rest or coronary vessel vasodilation Related to atherosclerosis, coronary vasospasm, aortic stenosis, or aortic insufficiency Types of angina – What are the 3 types of angina? Stable: myocardial ischemia due to restriction of coronary blood flow Prinzmetal: angina that may occur at rest, associated with areas adjacent to atherosclerotic plaque Spasms can contribute to, but does not cause, MI Unstable: may be unrelated to exercise, occurring at rest or sleep Related to non-occlusive thrombi formed on atherosclerotic plaque Associated with MI Angina with increasing frequency and duration within 3-4 days Normal EKG and enzymes (CK, LDH) distinguishes from actual MI No permanent muscle injury Treat as if MI has already occurred How is unstable angina diagnosed? New onset or increasing severe angina ST-depression, T-wave inversion, or both No serum biomarkers of myocardial necrosis How is NSTEMI MI diagnosed? Prolonged crushing angina with higher severity and wider radiation than usual Elevated serum biomarkers of myocardial necrosis due to myocardial damage Rise in troponins and CK-MB over several days, followed by decline Higher levels = worser prognosis EKG: ST-depression and T-wave inversion How is STEMI MI diagnosed? Prolonged crushing angina with higher severity and wider radiation than usual Elevated serum biomarkers of myocardial necrosis due to myocardial damage EKG: ST-elevation, followed by Q-wave change later on How is STEMI distinguished from NSTEMI MI? STEMI has ST-elevation indicating transmural infarction NSTEMI has ST-depression Myocardial infarction (MI) – What causes myocardial infarctions and what occurs during it? Focus of ischemic necrosis in myocardium due to blockage of blood flow to a region Duration of ischemia influences extent of infarct and tissue damage Caused by occlusion of coronary vessel or coronary artery spasm May cause death due to massive damage to heart tissue or disturbance of electrical activity causing ventricular fibrillation Atherosclerosis – What is atherosclerosis? Where is it commonly found? Disease of large and medium-sized arteries due to accumulation of smooth muscle cells, lipids, and connective tissue within the tunica intima (interna) causing reduced size and downstream flow Abnormally found at branch points to reinforce arteries due to stress of turbulent blood flow Reduces or obstructs blood flow to tissue, causing cramping, injury, and cell death Common locations: aorta, coronary artery, pulmonary artery, aortic arch What is the hypothesized pathway of atherosclerotic plaque formation? Intimal lesions at sites predisposed to lesion formation Lipid accumulation due to disruption of endothelial barrier Lipid deposition in intimal cells causes cell injury Cell injury triggers inflammatory response and macrophage accumulation Macrophages release growth factors Lymphocytes and other cells release cytokines to stimulate plaque formation Over time, endothelial wall loses anticoagulant properties Arterial wall remodels to adapt to plaque Progression of plaque and development of complications, including surface ulceration, fissures, calcification, cholesterol crystallization, and aneurysm End: occlusion of vessel blocks blood flow or vessel wall fails (hemorrhage) What are foam cells? Phagocytosis of lipids by macrophages Foam cells: lipid-filled macrophages Triglycerides – What are triglycerides? Long chain fatty acid esters of glycerol Stored in adipose tissue Hydrolyzed by lipases to form free fatty acids for energy Lipoproteins – What are lipoproteins? A structure containing hydrophilic exterior and hydrophilic interior that carries cholesterol (vesicle) Made of apoB-100 and phospholipids Cholesterol is the building block for cell walls, bile acids, and steroidal hormones. 35% is acquired through diet, while 65% is biosynthesized, mainly in the liver. It is highly lipophilic and transported by lipoprotein vesicles composed of phospholipids and apolipoproteins. LDL is a reservoir of cholesterol and disintegrated as needed. HDL transports cholesterol to the liver, kidneys, ovaries, and testes. Oxidized LDL are bad because they are recognized by macrophages and arterial endothelial lining, serving as the initial phase of atherosclerotic plaque formation. Cholesterol biosynthesis occurs by the mevalonate pathway and involves HMG-CoA reductase. Many compounds are derived from cholesterol, like cholic acid, estradiol, cortisone, testosterone, and vitamin D. Development of atherosclerotic lesions Normal vessel Hyperlipidemia leads to migration and deposition of lipids into the vessel intima. Lipids are taken up by macrophages to form foam cells. Clinically silent Further deposition of lipid causes more foam cells, apoptosed macrophages, crystallization of cholesterol, collagen formation, vascularization, and migration of smooth muscle cells into intima. This leads to thickening of the vessel wall and narrows the vessel. Presents as: angina due to increased exertion or emotional stress Presence of a massive plaque with a lipid core. The area around plaque contains T-cells foam cells, collagen, and smooth muscle cells. Eventually, the intima and vessel wall ruptures, causing the formation of a thrombus. The thrombus further narrows the vessel wall and may fragment. Presents as: unstable angina, MI, coronary death, stroke, critical leg ischemia Plasma Lipid Levels (in mg/dL) Non-HDL-Cholesterol HDL-Cholesterol LDL-Cholesterol Triglycerides < 130 130-159 160-189 190-219 ≥ 220 Desirable Above desirable Borderline High Very high < 40 < 50 > 60 Low (men) Low (women) Good < 70 < 100 100-129 130-159 160-189 ≥ 190 Optimal (high-risk) Desirable Above desirable Borderline High Very high < 150 150-199 200-499 ≥ 500 Normal Borderline High Very high 6 treatment options for hyperlipidemia Bile acid sequestering agents Niacin Cholesterol absorption inhibitors: ezetimibe Fibrates HMG-CoA reductase inhibitors PCSK9 inhibitors Non-pharmacological treatments: low-fat/sugar diet, exercise, reduce stress Bile acid sequestrants (BAS) MOA: anion-exchange resins that bind to bile acids in the small intestine for fecal elimination Why? – bile acids are end products of cholesterol metabolism and normally would be reabsorbed in small intestines Also: liver increases biosynthesis of bile salts from LCL-C from cholesterol, which increases liver cholesterol synthesis and synthesis of LDL-receptors to endocytose more LDL-C Overview Key characteristics: Bile acids are acidic and anionic in nature, so bile acid sequestrants must be basic and cationic. Can be used alone or in combination with statins Are not absorbed – excreted in stool post-binding LDL-C reduction is dose-dependent Contraindicated in severe hypertriglyceridemia Drugs: cholestyramine, colestipol, colesevelam Cholestyramine Contains a positive charge → can work in any pH environment Colestipol Contains a tertiary amine and no positive charge → requires acidic pH to become protonated & binding power depends on intestinal pH Colesevelam Contains positive charge → can work in any environment Adverse effects Gastrointestinal: upset stomach (dyspepsia), bloating, constipation, diarrhea Heartburn Impaired coagulation: malabsorption of vitamin K Drug interactions Anionic/acidic drugs: NSAIDs, anticoagulants, valproic acid, furosemide, sulfonylureas, troglitazone, HMG-CoA reductase inhibitors Non-specific binding – some thiazides, furosemide, propranolol, L-thyroxine, digoxin, warfarin, some statins Recommendation: take drugs 1 hour before or 4 hours after bile sequestrants Niacin (Vitamin B3) MOA: (1) inhibit lipolysis of stored triglycerides in adipose tissue (2) decreases activity of DGAT2 to decrease liver triglyceride and VLDL synthesis (3) increase lipoprotein lipase activity to hydrolyze VLDLs and increase formation of HDL Overview Requires much higher dose than as a vitamin Requires BID or TID dosing due to 1 hour half life Used with BAS or statin to normalize LDL in hypercholesterolemia Contraindicated in pregnancy DDIs: Statins: increase myotoxicity Anticoagulants: prolonged bleeding time ADEs Flushing/redness after each dose due to cutaneous vasodilation GI distress: dyspepsia, NVD Hepatotoxicity Can cause insulin resistance and hyperglycemia → caution with diabetes Arrhythmia → discontinue Metabolism: phase II conjugation Fibric acid / Fibrates MOA: (1) activates PPAR-α to stimulate expression of lipoprotein lipase, causing: - VLDL clearance, - HDL increase, - FFA oxidation, - inhibition of triglyceride biosynthesis (2) conversion of cholesterol to bile acid for removal from liver Overview Peroxisome proliferator-activated receptor alpha (PPAR-α) Transcription factor that regulates pathways in nucleus Activated in starvation mode to induce fatty acid oxidation, increase lipoprotein lipase synthesis, and reduce expression of apoC-III to increase VLDL clearance Drug creates more fatty acid breakdown and reduced lipid biosynthesis Not very effective in reducing cholesterol (LDL-C) Treats hypertriglyceridemia caused by treatment with HIV protease inhibitors Avoid in hepatic or renal impairment SAR (see right) DDIs: highly protein-bound Anticoagulants (coumarins) Sulfonylureas Drugs: Fenofibrate (prodrug): fenofibrate → fenofibric acid Combined with simvastatin to reduce progression of diabetic retinopathy Half-life: 20 hours More effective at increasing HDL than gemfibrozil Gemfibrozil (active) Combined with ezetimibe can increase risk of gallstones Avoid in hepatic or renal impairment Highly plasma protein bound Enterohepatic circulation Passes to placenta Half-life: 1.5 hours Adverse effects – generally well-tolerated Myopathy: risk increases if statin taken with gemfibrozil (use fenofibrate, if needed) Arrhythmia Hypokalemia Pancreatitis HMG-CoA reductase inhibitor, “statins” MOA: inhibit HMG-CoA reductase which is involved in the rate-limiting step of cholesterol biosynthesis HMG-CoA reductase: N-domain – N-terminal; embedded in ER membrane L-domain – largest domain; catalytic site binding to HMG-CoA S-domain – smallest unit; binding site for NADPH coenzyme Interactions between HMG-CoA and HMG-CoA reductase H-bonds i-dipole bonds Vander Waals bonds i-i bonds Drug overview Most effective in reducing LDL-C by increasing amount high-affinity LDL receptors in liver Small decreases in triglycerides (substantial decreases if > 250 mg/dL initially) Small increases in HDL-C (5 to 10%) Increase the stability of atherosclerotic plaques to reduce oxidative stress and vascular inflammation Reduces risk new coronary events Reduces risk of atherothrombotic stroke Contraindicated in pregnancy Only used in children with familial hypercholesterolemia SAR: requires high affinity to HMG-CoA Structural analog of HMG-CoA intermediate Dihydroxyheptanoic acid: required for enzyme binding May be cyclized into lactone → activation by esterase hydrolysis Ring: requires lipophilic substituents to create high enzyme affinity (more than HMG-CoA) Naturally derived statins Simvastatin (Zocor®) – prodrug Lovastatin (Altoprev®) – prodrug Pravastatin (Pravachol®) – inactive metabolites Synthetic statins Atorvastatin (Lipitor®) – long half life Rosuvastatin (Crestor®) – long half life Must titrate doses, starting at 5 mg Increased risk of rhabdomyolysis in East Asians Fluvastatin (Lescol®) – inactive metabolites Metabolism Key enzymes: CYP3A4 – lovastatin (dehydration), simvastatin (dehydration), atorvastatin (hydroxylation) CYP2C9 – fluvastatin (N-dealkylation, hydroxylation, oxidation) Pravastatin oxidized in liver and excreted 65% unchanged Pharmacokinetics Uptaken by OATP1B1 into the liver – more selective for hydrophilic statins Metabolites are somewhat active (except fluvastatin and pravastatin) Short half lives → take at night (except atorvastatin and rosuvastatin) Mainly eliminated through feces → no major issues with renal impairment Metabolism CYP3A CYP2C9 CYP2C9, 2C19 Largely unchanged Glucuronide conjugation Atorvastatin Lovastatin Simvastatin Fluvastatin Rosuvastatin Pravastatin Pitavastatin Adverse drug effects Hepatotoxicity: rare and unpredictable → monitor serum markers and LFTs Myopathy: ranges form mild muscle soreness/weakness to rhabdomyolysis → monitor creatinine kinase, proteinuria; if muscle pain, consider limiting dosage or switching therapies Risk increased in combined with niacin, HIV protease inhibitors, amiodarone (antiarrhythmic), nefazodone (antidepressant) Hyperglycemia: increased risk in developing T2DM Drug interactions Strong CYP3A4 inhibitors Grapefruit juice Gemfibrozil – contraindicated w/ simvastatin Cyclosporine – contraindicated w/ simvastatin Niacin Digoxin Warfarin – no interaction with pitavastatin Macrolides, azole antifungals – contraindicated w/ simvastatin Cholesterol absorption inhibitors MOA: (1) suppress absorption of dietary cholesterol by inhibiting NPC1L1 transport protein (2) suppress assembly and secretion of VLDL (liver) and chylomicrons (intestines) Goal: reduce total cholesterol, LDL, and triglycerides, while increasing HDL Overview Reduces absorption of dietary cholesterol by 54% Induces increase in cholesterol biosynthesis → inhibit with statin In the absence of dietary cholesterol, can inhibit reabsorption of cholesterol excreted in bile Allosteric, non-competitive binding Rarely used in monotherapy – only for statin-intolerant patients SAR Metabolism: Glucuronidation in gut or liver to create active drug Oxidation of benzylic -OH inactivates drugs Enters enterohepatic circulation → difficult to eliminate Drug: Ezetimibe (Zetia®) If taken with bile acid sequestrants, take ezetimibe at least 2 hrs before or 4 hrs after BAS Proprotein Convertase Subtlisin/Kesin type 9 (PCSK9) inhibitor MOA: increase LDL receptor recycling on hepatocytes to decrease serum LDL, by binding to and inhibiting PCSK9 Why? – PCSK9 binds to LDL-LDL receptor complex to enhance breakdown of LDL and LDL receptor, thus preventing receptor recycling → mAB binds to PCKS9 to block its effects Goal: increase availability of LDL receptors to internalize LDL Overview Synergistic function with statins: PCSK9i increases internalization of LDL while statin decreases cholesterol biosynthesis Contraindicated in pregnancy and breastfeeding Biologic: Alirocumab (Praluent®) Evolocumab (Repatha®) Adverse effects Alirocumab: allergic/anaphylactic-type reactions, unusual tiredness/weakness Evolocumab: injection site redness/pain, allergic-type reactions, back pain, upper respiratory tract infection Metabolism: proteolytic degradation into amino acids in endoplasmic reticulum Omega-3 Fatty Acid Ethyl Esters / Fish Oils MOA: act on PPAR-α and stimulate expression of dependent genes Overview Consumption of fish is better than taking fish oil capsules for average person Adverse effects Prolonged bleeding time – monitor esp. w/ anticoagulant therapy Arthralgia Nausea, dyspepsia Main drug treatments for ischemic heart disease Decrease oxygen demand Beta blockers Some calcium channel blockers Nitrates Increase oxygen supply Vasodilators Calcium channel blockers Statins Antithrombotic agents Anti-anginal Therapies MOA: decrease myocardial oxygen requirement by decreasing heart size, heart rate, blood pressure, or contractility Nitrates and CCBs can cause a redistribution of coronary flow, increase oxygen delivery, and reverse coronary artery spasm Molecular mechanism Increase cGMP Decrease intracellular Ca2+ Stabilize or prevent depolarizat5ion of vascular smooth muscle cell membrane Drugs Nitrates / nitrites: amyl nitrite, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin DHP CCB: amlodipine, felodipine, nicardipine, nifedipine, nisoldipine, etc. Non-DHP CCB: diltiazem, verapamil Beta blockers: atenolol, carvedilol, propranolol, metoprolol, labetalol, sotalol, etc. Other: ranolazine, ivabradine Nitrates / Nitrovasodilators MOA: release nitric oxide which interacts with heme group of soluble guanylate cyclase to activate it and increase cGMP production Why? – cGMP activates myosin phosphatase to cause vasodilation which restores blood flow and perfusion to cardiac muscle Mechanism: thiol (-SH) mediated hydrolysis Additional effect: increase in CGMP causes decreased platelet aggregation Overview Highly flammable & loses potency over time, ~6 months Store in refrigerator in glass containers All are prodrugs and must be reduced to produce NO Most effects on smooth muscles; does not affect cardiac or skeletal muscles Relaxes arteries and veins – vasodilation increases venous capacity to decrease ventricular preload (thus heart size and output) – and redistribute blood flow to ischemic areas May cause reflex tachycardia, increased heart contractility, and salt/water retention Creates cyanide toxicity by replacing CN- from hemoglobin Structure: contains –ON2O (nitrate) or –ONO (nitrite) – sequence of carbon-oxygen-nitrogen Drugs Nitroglycerin Half-life: 3 minutes Peak plasma time, sublingual: 5 minutes → rapid onset; used for anginal attack 60% plasma protein binding Metabolism: liver – produces glyceryl dinitrate and glyceryl mononitrate (active) Drug tolerance develops Isosorbide dinitrate Half-life: 40 minutes → longer DOA than nitroglycerin Peak plasma time, sublingual: 6 minutes → prophylactic therapy Active metabolites provides longer DOA Rarely used in methods other than sublingually due to high tolerance Good for those with alcohol dehydrogenase deficiency (primary enzyme for NTG) Isosorbide mononitrate Slow onset of action → prophylactic therapy Active metabolites provides longer DOA Bypasses first-pass metabolism Low chances of tolerance Metabolite of isosorbide dinitrate Amyl nitrate – almost never used; inhaled vapors DDIs: Contraindicated: phosphodiesterase 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil, etc.) Why? – PDE5 inhibitors are responsible for breaking down cGMP. Administration of nitrovasodilators and blockage of phosphodiesterases can cause excess vasodilation and massive drop in blood pressure Alteplase Antihypertensives Alcohol Adverse effects Binds to hemoglobin – toxic doses can cause tissue hypoxia and death Nitroglycerin CNS: throbbing headache, dizziness → avoid in increased intracranial pressure CV: orthostatic hypotension, reflex tachycardia GI: sublingual burning, NV Skin: contact dermatitis (patches) DOA [shortest to longest] – use sublingual NTG for acute attack; use oral/patch for prophylaxis Amyl nitrite, inhalant Nitroglycerin, sublingual Isosorbide dinitrate, sublingual Isosorbide dinitrate, oral chewable Nitroglycerin, slow-release, buccal Nitroglycerin, 2% ointment, transdermal Isosorbide dinitrate, oral Nitroglycerin, sustained-action, oral Nitroglycerin, slow-release patch, transdermal Isosorbide mononitrate, oral Pentaerythritol tetranitrate (PETN) Calcium Channel Blockers (CCBs) MOA: bind to L-type calcium channels (found in cardiac, skeletal, and smooth muscle) to reduce Ca2+ influx, causing relaxation and vasodilation Binds to a1 site of L-type calcium channel Why? – calcium controls cardiac excitation, heart rate, and release of chemical mediators Overview Drug reduces frequency of channel opening in response to depolarization to decrease transmembrane calcium current Effect on smooth muscle – long-lasting relaxation Effect on heart – negative chronotropic, ionotropic, and dromotropic Vasodilation primarily in arterial beds (not veins) Decreases peripheral vascular resistance May induce reflex tachycardia to promote increase in HR and cardiac output Only for DHP CCB since non-DHP act directly on heart and can block reflexes Relaxes coronary vasospasms to treat angina Dihydropyridine CCBs → greatest effect on vasodilation; minimal effect on cardiac contractility and SA node (heart rate); no effect on AV node (conduction/velocity) → requires very high dose to affect heart Amlodipine Nicardipine Nifedipine Felodipine Isradipine Nisoldipine Non-DHP CCBs → greatest effect at SA and AV nodes; strong effect on reducing cardiac conductility and causing vasodilation Phenylalkylamine: verapamil Benzothiazepine: diltiazem DDIs: Drugs that rely on P-glycoprotein for transport Ranolazine Often combined with CCBs, beta blockers, nitrates MOA: alters transcellular late inward sodium current to affect sodium-dependent calcium channels Why? – by blocking sodium current, it results in blocking sodium-dependent calcium channels to prevent calcium overload → prevent cardiac ischemia 76% oral bioavailability; hydrophilic, 62% protein bound Metabolism Hydroxylation of ring, then glucuronidation or sulfation O-demethylation, then O-glucuronidation or sulfation N-dealkylation Ivabradine MOA: binds to and blocks HCN “pacemaker” channels to reduce heart rate and cardiac oxygen demand Metabolism: CYP3A4 DDIs: CYP3A4 inducers and inhibitors Beta-adrenergic antagonists MOA: negative inotrope; decrease heart rate to decrease oxygen demand Drugs: Propranolol Atenolol Nadolol Carvedilol Metoprolol Labetalol AE Bronchoconstriction in patients with asthma or COPD, especially if non-selective Increase insulin release Decreases FFA release Glaucoma treatment – decreases aqueous humor production 4 classes of antiplatelet drugs Cyclooxygenase inhibitors Phosphodiesterase inhibitors ADP inhibitors GP IIb/IIIa inhibitors Cyclooxygenase (COX) inhibitors MOA: irreversible COX-1 and COX-2 inhibitor Binds to: serine 530 of COX-1 and serine 516 of COX-2 Selectivity: 10X greater binding for COX-1 Aspirin (Aggrenox®) – acetyl salicylic acid (ASA) SAR: acetate group located ortho to -COOH is essential for activity Triflusal – not US FDA approved SAR: aspirin + -CF3 group located para to -COOH MOA slightly different: blocks TxA2 to inhibit COX to prevent platelet aggregation Block NF-kB to regulate mRNA expression of cell adhesion molecule-1 used in aggregation Inhibit PDE to increase cAMP concentration and inhibit aggregation factor release from platelets Metabolism: active metabolite Phosphodiesterase (PDE) inhibitors MOA: inhibits phosphodiesterase in platelets to increase intracellular cAMP Why? – activate pathway that leads to Ca2+ chelation → when chelated, it is not available to induce the release of platelet aggregation → inhibits platelet action and clotting Dipyramidole (Aggrenox®) Cilostazol (Pletal®) Metabolism: CYP3A4, CYP2C19 → dosing adjustments Note: these PDE do not interact with nitrates Platelet P2Y Purinergic Receptor Inhibitors (adenosine diphosphate inhibitors) – irreversible type MOA: irreversibly binds to platelet P2Y12 purinergic receptor to increase cAMP levels and block ADP-induced platelet aggregation Other potential mechanism: interact with GP IIb/IIIa receptor to inhibit fibrinogen binding Prodrug: requires a free thiol (-SH) for activity Clopidogrel (Plavix®) Ticlopidine (Ticlid®) Prasugrel (Effient®) Prodrug: requires hydrolysis, then esterase activity to become active thiol intermediate Platelet P2Y Purinergic Receptor Inhibitors (adenosine diphosphate inhibitors) – reversible type MOA: reversibly binds to allosteric site, distinct from site of irreversible binding Structure: cyclopentane ring mimicking ribose sugar of ADP Ticagrelor (Brilinta®) Active metabolite also reversibly inhibits P2Y12 Cangrelor (Kengreal®) Cyclopentane ring phosphorylated → deactivated by dephosphorylation GP IIb/IIIa inhibitors MOA: inhibits fibrinogen binding by blocking glycoprotein IIb/IIIa receptors on the plasma membrane of the platelet Structure: peptidomimetic of fibrinogen Key sequence for binding: arginine-glycine-aspartic acid OR lysine-glycine-aspartic acid Abciximab (Reopro®) Eptifibatide (Integrilin®) Tirofiban (Aggrastat®) Lamifiban Roxifiban requires ester hydrolysis to reveal -COOH Lefradafiban requires ester hydrolysis to reveal -COOH Thrombolytic agents MOA: converts plasminogen to plasmin, which is a proteolytic enzyme that dissolves fibrin clots Drugs 1st generation: streptokinase, urokinase Streptokinase: binds with plasminogen to form an activator complex that activates plasminogen into plasmin Non-specific drug Short half life (~30 nins) – cannot lyse a thrombus fully Urokinase: serine protease that cleaves arginine-valine bond in plasminogen to activate to plasmin 2nd generation: prourokinase, alteplase Alteplase: human tPA serine protease with high affinity for plasminogen bound to fibrin in a thrombus 3rd generation: retaplase, tenectaplase Retaplase: deletion mutant of alteplase, missing first 172 amino acids Reduced binding and selectivity, but longer half life Tenecteplase: analog of alteplase with 3 mutations; TNKase