Quiz 1 Pharm

Question 1

HMG CoA Reductase Inhibitors

Answer 1

Atorvastatin Lovastatin Simvastatin Statin

Question 2

HMG CoA Reductase Inhibitors;
Atorvastatin 
Lovastatin 
Simvastatin 
Statin

Mechanism

Answer 2

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

Question 3

Niacin (Nicotinic Acid)

Answer 3

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

Question 4

Bile-Acid Binding Resin

Cholestyramine

Answer 4

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

Question 5

Fibric acids/fibrates
PPAR Activators
Gemfibrozil
Fenofibrate

Answer 5

• 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

Question 6

Ezetimibe

Answer 6

• 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

Question 7

Omega-3 Fatty Acid

Answer 7

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

Question 8

Proprotein convertase subtilisin/kexin 9 (PCSK9)

Answer 8

• 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

Question 9

Microsomal triglyceride transfer protein (MTP)

Answer 9

• 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

Question 10

Apolipoprotein B-100 (apoB-100)

Answer 10

• 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

Question 11

Nitrates

Answer 11

Nitroglycerin
Isosorbide dinitrate
Isosorbide mononitrate

Question 12

Nitroglycerin

Answer 12

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)

Question 13

Isosorbide dinitrate

Answer 13

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)

Question 14

Isosorbide mononitrate

Answer 14

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)

Question 15

BETA adrenergic receptor blockers

Answer 15

Propranolol
Timolol 
Metoprolol 
Atenolol 
Carvedilol

Question 16

Beta Blocker
Propranolol
Timolol 
Metoprolol 
Atenolol 
Carvedilol

Answer 16

• 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

Question 17

Calcium Channel Blocker

Answer 17

Nifedipine
Amlodipine
Verapamil
Diltiazem

Question 18

Nifedipine

Answer 18

• Mechanism: antagonize voltage gated L type calcium channels
• Dihdropyridines
o Potent vasodilators
o Relieve ischemia by
• Decreasing oxygen demand: vasodilation→ decreases afterload→ reduces wall stress
• Increasing oxygen supply: coronary vasodilation
o Potent agents for relief of vasospasms
o Nifedipine, amlodipine

Question 19

Amlodipine

Answer 19

• Mechanism: antagonize voltage gated L type calcium channels
• Dihdropyridines
o Potent vasodilators
o Relieve ischemia by
• Decreasing oxygen demand: vasodilation→ decreases afterload→ reduces wall stress
• Increasing oxygen supply: coronary vasodilation
o Potent agents for relief of vasospasms

Question 20

Verapamil

Answer 20

• Mechanism: antagonize voltage gated L type calcium channels
o Vasodilators
o Relieve ischemia by decreasing oxygen demand by reducing force of contracting and heart rate
o Verapamil, diltiazem
o Adverse effects: headache, flushing, decrease contractility (V,D), bradycardia V,D), constipation (V)

Question 21

Diltiazem

Answer 21

• Mechanism: antagonize voltage gated L type calcium channels
o Vasodilators
o Relieve ischemia by decreasing oxygen demand by reducing force of contracting and heart rate
o Verapamil, diltiazem
o Adverse effects: headache, flushing, decrease contractility (V,D), bradycardia V,D), edema (N,D),

Question 22

Pharmacological stress test agents

Answer 22

Dobutamine

Adenosine

Question 23

Dobutamine

Answer 23

Stress testing

Increase contractility to stimulate exercise

Question 24

Adenosine

Answer 24

Stress testing
Cause arterial dilation. Normal arteries will dilate in response to adenosine but diseased cells will not be able to dilate as much

Question 25

Antiplatelet drugs

Answer 25

Aspirin Dipyridamole Ticlopidine Clopidogrel Prasugrel Ticagrelor Abciximab Eptifibatide

Question 26

Aspirin

Answer 26

o Mechanism: Inhibits platelet aggregation by irreversibly acetylating cyclooxygenase→ blocks prostaglandin metabolism and TXA2 synthesis (potent stimulator of platelet aggregation) o Kinetics: absorbed in GI tract. Half life of 20 min. • Platelets lack nuclei so permanent effect on COX-1 • Platelet turnover is 10% per day. Takes 10 days for renewal of platelet population o Adverse: Bleeding and GI irritation (higher doses→ higher side effects) o Use in pts with CVD • Used in pts with UA, Acute MI, history of MI (reduces incidence of future fatal and non-fatal coronary events) • Used in pts with chronic stable angina w/o hx of MI • Used in pts who have had a minor stroke or TIA (reduces rate of future stroke) • Used in pts who have undergone coronary artery bypass surgery (decrease chance of graft occlusion) o Recommendations: low dose ASA for pts with clinical manifestations of coronary artery disease • Older than 50 with atherosclerosis risk factor (elevated LDL, reduced HDL, smoker, HTN, Diabetes, lack of PA)

Question 27

Dipyridamole

Answer 27

o Pts who cannot tolerate ASA o Mechanism unclear—inhibits platelet aggregation • Increase platelet cAMP (block phosphodiesterase, block cellular uptake and destruction of adenosine) • Given along, drug has no proven cardiac benefits o Use: coronary vasodilation, angina prophylaxis o Toxicity: Nausea, headache, flushing, hypotension, abdominal pain

Question 28

Ticlopidine

Answer 28

Mechanism: Inhibit ADP-mediated activation of platelets (Irreversible) Side effect: associated with Severe neutropenia and thrombotic thrombocytopenic purpura

Question 29

Clopidogrel

Answer 29

Mechanism: Inhibit ADP-mediated activation of platelets (Irreversible) Use: UA/NSTEMI ( w/ASA), STEMI, MI, stroke, PAD Adverse: metabolized by CYP2C19 • Co-administration of omeprazole is a concern (PPI inhibits CYP2C19)

Question 30

Prasugrel

Answer 30

Mechanism: Inhibit ADP-mediated activation of platelets (Irreversible) Use: reduce rate of thrombotic CV events (stent thrombosis) Adverse: metabolized by CYP3A4 and CYP2B6 • Higher potency and more rapid onset (efficient generation of metabolite) • Higher and more consistent rate of platelet inhibition

Question 31

Ticagrelor

Answer 31

Mechanism: Inhibit ADP-mediated activation of platelets o Reversible: Ticagrelor Side effect: cause dyspnea Use: (w/ASA) for secondary thrombotic events in pts with UA, STEMI, NSTEMI

Question 32

Abciximab

Answer 32

* Mechanism: Chimeric human mouse monoclonal antibody that blocks access of fibrinogen, vWF and other adhesive molecules (prevent fibrinogen binding) * Non-competitive * Kinetics: IV administration. Slow clearance * Use: Pts undergoing PCI. Used in combo with ASA and Heparin (LMWH). Also use with tPA for thrombolysis * Adverse: Bleeding

Question 33

Eptifibatide

Answer 33

* Mechanism: Synthetic peptide antagonist that prevents fibrinogen cross-linking of platelets * Binds specifically to GP IIb/IIIA * Kinetics: IV administration. Renal clearance. Effect is reversible and platelet aggregation response returns to normal within 4-8 hrs * Use: pts undergoing PCI, UA, MI (often with LMWH) * Prevent coronary thrombosis in persons with UA or non-STEMI * Prevent thrombosis in pts having coronary angioplasty or stent plascement for STEMI

Question 34

Anticoagulant drugs

Answer 34

``` Heparin (UFH) Low molecular weight heparins (LMWH) Enoxaparin Dalteparin Bivalirudin Fondaparinux Dabigatran Rivaroxaban ```

Question 35

Heparin (UFH)

Answer 35

o Mechanism: no intrinsic anticoagulant activity. Binds anti-thrombin→ change in AT that accelerates interaction with Xa • Xa required for activation of prothrombin→ thrombin • Anti-thrombin inactivates Xa • Binds to both Thrombin and anti-thrombin→ decreases thrombin and Xa levels o Kinetics: Not absorbed. IV administration o Adverse: bleeding esp. those who are undergoing PCI. Risk of HIT. o Use: recurrent or persistent chest pain, AMI, +serum marker and dynamic ECG

Question 36

Low molecular weight heparins (LMWH) Enoxaparin Dalteparin

Answer 36

o Mechanism: greater capacity to potentiate factor Xa inhibition by AT (can’t bridge AT to thrombin) o Kinetics: not absorbed. Given parenterally. Half life 4-6 hours. Renal clearance (renal impairment) o Adverse: Incidence of bleeding is less in pts treated with LWMH. Also lower incidence of thrombocytopenia o Use: initial management of UA or AMI.

Question 37

Bivalirudin

Answer 37

• Mechanism: Direct thrombin inhibitor that occupies catalytic site of thrombin (phe-pro-arg-pro). Thrombin can regain function by cleaving Arg-Pro bond. • Kinetics: IV and excreted by kidneys. Half life of 25 minutes • Adverse: use w/ caution in pts with renal failure • Use: alternative to heparin in pts undergoing angioplasty or cardiopulmonary bypass surgery o Inhibits independently of anti-thrombin o Acts on circulating and clot bound thrombin o No thrombocytopenia o Unstable angina patients undergoing percutaneous coronary intervention o Major adverse effect is bleeding o Free thrombin vs. fibrin bound thrombin • Thrombin bound to fibrin in a thrombus is enzymatically active and protected from inactivation by AT • Fibrin-bound thrombin can locally activate platelets and trigger coagulation → thrombus growth • Heparin only inactivates circulating thrombin • Direct thrombin inhibitors inactivate free and fibrin bound

Question 38

Fondaparinux

Answer 38

o Mechanism: Direct factor Xa inhibitor (binds AT that increases ability of AT to inactivate XA) o Kinetics: SubQ injection. Excreted in urine ( do not use in pts with renal failure) o Adverse: less likely to trigger heparin induce thrombocytopenia o Use: Treatment of ACS: UA, STEMI, NSTEMI

Question 39

Dabigatran

Answer 39

o Mechanism: Direct thrombin inhibitor that inhibits both free and fibrin bound thrombin o Kinetics: oral o Use: long term anti-coagulation

Question 40

Rivaroxaban

Answer 40

o Mechanism: direct Xa inhibitor o Kinetics: oral o Use: long term anti-coagulation

Question 41

Alteplase

Answer 41

• Alteplase (tPA) o Mechanism: transforms inactive precursor plasminogen into active protease plasmin→ lyses fibrin clots o Kinetics: about 80% cleared from plasma within 10 min of infusion o Adverse effects: minor bleeding. Risks for intracranial bleed: older age, HTN, low body weight o Use: Thrombolytic therapy reduces mortality and limits infarct size in pts with AMI associated with ST elevation or LBBB • Needs to be administered ASAP ideally within 30 min of presentation o Systemic lytic state (interfere with coagulation in general circulation) o Contraindications: 30% of pts may be unsuited for thrombolytics o Active peptic ulcer, recent stroke, recovering from recent surgery

Question 42

HMG-CoA reductase inhibitor Pharmacokinetics Lovastatin Simvastatin Pravastatin Atoravastatin

Answer 42

o First pass hepatic uptake of all statins o All HMG coA reduce inhibits preferentially effect liver o Lovastatin and Simvastatin administered as inactive lactone • Lactone prodrug is hydrolyzed to beta-hydroxy acid • Simvastatin: T1/2: 12 hours o Pravastatin, atorvastatin administered as active, open ring form • Atorvastatin: T1/2: 20 hours o Atoravastatin, simvastatin, lovastatin metabolized by CYP3A4

Question 43

HMG-CoA reductase inhibitor: adverse effects

Answer 43

o Minor: GI sxs o Major: myopathy and rhabdomyolysis • Intense myalgia (arms/thighs), CK increase • Myopathy risks increase with gemfibrozil (inhibits uptake of active forms of statins) • Simva +Niacin associated w/ increase risk of myopathy in Chinese population o CYP3A4 contraindications: macrolides, azoles, protease inhibitors, grapefruit juice

Question 44

Use of Statins

Answer 44

o First line therapy for patients who are at risk for MI due to hypercholesterolemia • Statins are effective in almost all patients with high LDL-C • Exception in pts with familial hypercholesterolemia