Quiz 1 Pharm Flashcards
HMG CoA Reductase Inhibitors
Atorvastatin Lovastatin Simvastatin Statin
HMG CoA Reductase Inhibitors; Atorvastatin Lovastatin Simvastatin Statin
Mechanism
Mechanism: Structurally similar to HMG-CoA ( acts as a reversible inhibitor
o Inhibition of an early AND rate limiting step in cholesterol synthesis→ increases need for exogenous cholesterol→ increased uptake of LDL in liver
• Increase in LDL receptor gene: reduced free cholesterol→ Sterol Regulatory element binding proteins (SREBP) cleaved by protease and translocated to nucleus
• Transcription factors bind sterol responsive element of LDL receptor gene→ enhance transcription→ increase synthesis of receptors
• Upregulation of receptors→ increased catabolism of LSL
• Decreases plasma LDL
Niacin (Nicotinic Acid)
Mechanism
o Decrease TG and decrease cholesterol
o In adipose tissue, inhibits FFA mobilization (niacin receptor in adipose tissue)
• Activation of niacin receptor-> decrease in cAMP→ decrease activation of PKA→ decrease phosphorylation of perilipin and Hormone Sensitive Lipase (HSL)
• Decrease access of HSL to TG in fat droplet→ Decrease TF breakdown
• Decreases FFA delivered to liver
o In liver: decrease synthesis of VLDL
• Inhibits DGAT2 (diacylglycerol acetyltransferase 2)—important for TG synthesis
• Inhibits synthesis and re-esterification of fatty acids
• Increase ApoB degradation
o Inhibits uptake of HDL-apoA1: Inhibition of uptake and catabolism by hepatocytes
Pharmacokinetics
o Oral administration
o Formulations: Immediate release (2-4x/day)// Long acting// Extended release (once/ bedtime)
o Dose for lowering cholesterol is much higher than those used for vitamin
• Adverse events
o Intense cutaneous flush/pruritus
o Mediated by vasodilatory PGs (use NSAIDS to block)→ decreases overtime
o GI effects
o Elevated liver enzymes→ hepatic if combined with statins
o Hyperurecemia: contraindicated in pts w/ gout
o Combined use w/ statins increases risk of myopathy
o Contraindications: peptic ulcer, gout, hepatic disease, diabetes
Bile-Acid Binding Resin
Cholestyramine
o Cholesterol is converted to bile acid (7a-hydroxylase)
o Conjugated bile acids are secreted from liver→ stored in gall bladder
o Bile acids-→ intestines→ emulsify fats→ digestion/absorption
o Bile acids reabsorbed→ returned to liver
o Excreted bile salts account for cholesterol excretion
Mechanism
o Anion exchange resins that readily exchange chloride ions for bile salts→ increase bile acid excretion
o Highly positive charge binds negative charge bile acids
o Depletes pool of bile acids
o Lowers feedback inhibition by bile acids→ increase breakdown of hepatic cholesterol
o Increased catabolism of cholesterol→ increase HMG coA reductase activity
o Lowers LDL cholesterol by increasing rate of removal of cholesterol through receptor mediated catabolism
o Liver responds by forming more LDL receptors
Pharmcokinetics
o Administered as chloride salt/ insoluble in water
o Not absorbed
o Reduction in plasma cholesterol concentration usually seen in first month of therapy
o Stop drug→ levels return to normal
Adverse effects
o Constipation/ bloating sensation
o Gritty consistency (n/v/ constipation)
o Interferes with absorption of other drugs
o Modest increase in TG (will return to baseline over time)
Use o Hypercholesterolemia o Not recommended for individuals w/ hypercholesterolemia AND high TG o Second linen agent (after statin) o Recommended for pt 11-20 yrs of age
Use:
o Primary hypercholesterolemia
o Combined with statins (Simvastatin + Ezetimibe)
• Statin inhibits cholesterol biosynthesis
• Ezetimibe inhibits intestinal cholesterol absorption
• Increased risk of myopathy in combo
Fibric acids/fibrates
PPAR Activators
Gemfibrozil
Fenofibrate
• Agents: Gemfibrozil, Fenofibrate
• Mechanism: Interacts with PPAR ( peroxisome proliferator activated receptors)
o PPAR binds as heterodimers with retinoid X receptor → alter gene transcription
• Increased lipolysis and plasma clearance of TG rich lipoproteins
• Activation of LPL
• Reduce production of LPL inhibitor, apoCIII
• Reduced FFA for TG synthesis
• Inhibition of de novo FA synthesis
• Increases in HDL
• Pharmacokinetics
o Administered orally, well absorbed
o Highly bound to plasma proteins
o T1/2: Gemfibrozil (1.1 hrs) < fenofibrate (20hrs)
o Fenofibrate metabolized to active metabolites
• Adverse effects
o Generally well tolerated
o GI sxs
o Increased CK w/ statin → leads to renal failure
o Use contraindicated in pts w/ renal impairment
o Gemfibrozil can increase systemic statin concentrations by blocking transporter
• Gemfibrozil inhibits update of active hydroxyl acid forms of statins
• First pass hepatic uptake by transporter (OATP1B1) after oral administration→ if blocked→ increases plasma concentration
• Use
o Patients w/ high TG and low HDL associated with metabolic syndrome or Type II DM
o Not used as primary therapy in pts with elevated hypercholesterolemia w/o hyperTG
Ezetimibe
• Mechanism: cholesterol absorption inhibitor
o Inhibits cholesterol transfer from intestinal lumen into intestinal cell
o Binds to Niemann Pick C1 like protein (NPCL1) within brush border membranes of intestinal cells
• Decreases rate of cholesteryl ester incorporation into chylomicrons
• Reduce flux of cholesterol from intestines to liver
• Reduce flux of cholesterol to VLDL
o Lowers plasma LDL-C ( increased expression of LDL receptors)
• Pharmacokinetics
o Oral administration
o Rapid glucoronidation to active metabolite
o Half life: 22 hours
• Adverse effects
o Generally well tolerated
o Bile acid sequestrants inhibits absorption of ezetimibe
Use:
o Primary hypercholesterolemia
o Combined with statins (Simvastatin + Ezetimibe)
• Statin inhibits cholesterol biosynthesis
• Ezetimibe inhibits intestinal cholesterol absorption
• Increased risk of myopathy in combo
Omega-3 Fatty Acid
o Combo of eicosapenaenoic acid (EPA) and docosahexanenoic acid (DHA)
o Mechanism: Possible: inhibition of acyl CoA diacylglycerol acyltransferase, increase hepatic beta-oxidation, reduction of hepatic synthesis of TG or increase in plasma LPL activity
o Pharmacokinetics: oral administration
o Adverse effects: Fish allergies, may increase LDL, may increase liver enzymes, monitor INR ( prolonged bleeding time)
o Use: adjuvant to diet therapy in tx of hypertriclyeridemia
Proprotein convertase subtilisin/kexin 9 (PCSK9)
• Mechanism: mediator of hepatic LDL receptor degradation
o Decreases steady state level of expression of LDL receptor on hepatocyte
o Autocatalytic cleavage in ER followed by secretion into plasma→ binds on LDLr
o LDLd/PCSK9 complex gets internalized→ degradation→ prevents recycling
• PCSK9 inhibitors
o REGN727
o AMG 145
o PCSK9 antibody
Microsomal triglyceride transfer protein (MTP)
• Mechanism: MTP is important in hepatic assembly of plasma lipoproteins (mediates transfer of TG to VDLP)
o Reduces plasma LDL-C concentration
• Lopitamide o Directly binds to MTP o Oral administration o Primarily hepatic metabolism (CYP3A4) o Side effects: GI sxs, hepatotoxicity o Use: adjunct to dietary therapy and other lipid lowering tx to reduce LDL-C, total cholesterol, apoB, nonHDL-C in pts with homozygous familial Hypercholesterolemia
Apolipoprotein B-100 (apoB-100)
• Mechanism: ApoB100 is important component of LDL-C and VLDL
• Mipomersen: antisense oligonucleotide that targets apoB100 mRNA→ disrupts function
o Hybridizes within the coding region of apoB100 mRNA and activates RNAse→ degradation
o Pharmacokinetics
• Once/ week subcutaneous injection
• Lipid lower effects persisted for up to 3 mo after last dose
o Adverse effects: injection site reactions, flu-like sxs, headache, elevation of liver enzymes
o Use: FDA approved as orphan drug
o First in class tx for homozygous familial hypercholesterolemia
o Adjunct to dietary therapy and other lipid lowering tx to reduce LDL-C, total cholesterol, ApoB1000, non-HDL-C ptx w/ familial hypercholesterolemia
Nitrates
Nitroglycerin
Isosorbide dinitrate
Isosorbide mononitrate
Nitroglycerin
Acute therapy
Mechanism: enzymatically denitrated in smooth muscle.
Free nitrate converted in NO–> activates guanylyl cyclase increase GMP
causes vasodilation (decrease pre-load).
Kinetics: low bioavailability. Inactivated in liver. Administered sublingually.
Adverse: Due to CV actions ( headache, hypotension, reflex tachycardia)
Isosorbide dinitrate
Chronic therapy
Mechanism: causes vasodilation
Kinetics: 25% orally bioavailable
Longer DOA
Metabolized by liver to biologically active form
Can develop tolerance (reverses rapidly)
Adverse: Due to CV actions ( headache, hypotension, reflex tachycardia)
Isosorbide mononitrate
Chronic therapy Mechanism: vasodilation Kinetics: no 1st past metabolism Half life: 5 hours Can develop tolerance (reverses rapidly) Adverse: Due to CV actions ( headache, hypotension, reflex tachycardia)
BETA adrenergic receptor blockers
Propranolol Timolol Metoprolol Atenolol Carvedilol
Beta Blocker Propranolol Timolol Metoprolol Atenolol Carvedilol
• Mechanism: anti-anginal by reducing oxygen demand (decrease force of ventricular contraction and heart rate due to blockade of effects of endogenous B1 receptors)
o Not useful for angina cases due exclusively to vasospasm
o Decrease oxygen demand (decrease HR, contractility, blood pressure)
o Small increase in oxygen supply to ischemia areas (increase time in diastole)
o Decrease in cardiac output→ increase in preload → increased wall tension)
• Adverse effects:
o Avoid in patients with obstructive airway disease, acutely decompensated heart failure
o Contraindicated in pts with marked bradycardia or certain types of heart block
o Use with caution in pts with insulin treated diabetes (mask tachycardia)
o Side effects: fatigue, sexual dysfunction
Calcium Channel Blocker
Nifedipine
Amlodipine
Verapamil
Diltiazem
