Pathophysiology, Pharmacology and Pharmacotherapy of Coronary Artery Disease Flashcards

Question

Cardiovascular risk factor reduction goals and strategies

Answer 1

risk factor: dyslipidemia, HTN, DM, smoking, weight management, physical activity

Answer 2

treatment goal: >50 % reduction in LDL preferred treatment: Lifestyle modifications; Low (< 7%) saturated fat, Low (<200 mg/dL) C; Moderate-High Intensity Statins

Answer 3

treatment goal: BP < 130/80 mmHg preferred treatment: Lifestyle modifications; Therapy based on compelling indications with b- blockers, ACEIs, ARBs + others as necessary

Answer 4

treatment goal: HbA1c < 7 % preferred treatment: Individualize to reach goal T2DM with ASCVD: SGLT2 or GLP-1

Answer 5

treatment goal: Complete Smoking Cessation/Exposure preferred treatment: Systematic strategy, pharmacotherapy

Answer 6

treatment goal: BMI 18.5-24.9; Waist circumference (40 men, 35 women); Wt loss 5-10 % initially preferred treatment: Diet/lifestyle counseling, printed educational materials and encourage

Answer 7

treatment goal: 30-60 min mod intensity activity 5-7 days/wk; Cardiac Rehab/Supervised preferred treatment: Brisk walking, swimming, cycling; Increased daily activities

Answer 8

* Influenza vaccination * Alcohol consumption * Exposure to air pollution * Management of psychological factors

Answer 9

* Anti-platelet therapy * Statin therapy: See dyslipidemia lectures * RAS Inhibitors: ACE inhibitor/ARB therapy * Colchicine? (may decrease CV risk) * Beta-blockers

Answer 10

* Acetylation and irreversible inactivation of platelet COX-1 * Antiplatelet activity: Blocking TXA2 synthesis: Interferes with platelet aggregation; Prolongs bleeding time; Blocks arterial thrombi formation

Answer 11

COX-1 promotes clotting: aspirin --> TXA2 --> increases platelet aggregation + vasoconstriction --> aspirin prevents platelet aggregation COX-2 has protective anti-coagulative effect: coxibs --> prostacyclin, PGI2 --> inhibits platelet aggregation + vasodilation --> higher thrombotic risk want to maximize COX-1 inhibition and minimize COX-2 inhibition; high dose aspirin also blocks COX-2, why we use low dose aspirin

Answer 12

aspirin: loading dose - 162-325 mg P2Y12 inhibitors: Clopidogrel (Plavix): loading dose - 300-600 mg; Prasugrel (Effient): loading dose - 60 mg; Ticagrelor (Brilinta): loading dose 180 mg; Cangrelor (Kengreal)

Answer 13

Beneficial (low dose): Irreversibly inhibits COX-1, blocking the formation of TXA2 (potent platelet aggregant and vasoconstrictor) Detrimental (higher dose): Inhibits COX-2, blocking formation of PGI2 (opposite of above) take aspirin tab during MI --> prevent thrombus from progressing, can't take EC, not fast enough EC protects against gastric distress (only dissolves in SI) ASA decreases platelet aggregation; low dose - reduces risk of future CV events

Answer 14

Selectively inhibit adenosine diphosphate induced platelet aggregation with no direct effect on TXA2

Answer 15

* Gastrointestinal: bleeding * Hematologic: bleeding (intracranial and extracranial) * Hypersensitivity * Major bleeding: 2-3 % in year 1

Answer 16

clopidogrel prasugrel ticagrelor

Answer 17

CYP dependent; conversion to active

Answer 18

less CYP dependent; conversion to active

Answer 19

direct acting

Answer 20

block P2Y12 receptor; no more ADP stimulated mechanism

Answer 21

* Clopidogrel: Bleeding, Diarrhea, Rash; ~1% increase in major bleeding when added to ASA * Prasugrel: Bleeding, Diarrhea, Rash; ~0.6% increase (Absolute risk) in major bleeding/ 0.5% increase in life-threatening bleeding (vs. clopidogrel) * Ticagrelor: Bleeding, bradycardia, heart block, dyspnea

Answer 22

* 1. CCD: No history of stent implantation * 2. CCD: Elective PCI + Stent: Bare metal stent (BMS).....Seldom Used; Drug eluting stent (DES) - drug in stent that's released to provide more protection * 3. CCD and CABG: PCI/Stent then CABG; CABG

Answer 23

AKA: secondary prevention * SAPT (Single-Antiplatelet Therapy): ALL patients with a history of CCD should receive ASA 75- 100 mg/day indefinitely (preference for 81 mg); Absolute contraindications or significant intolerance - clopidogrel 75 mg/day * DAPT (Dual-Antiplatelet Therapy)?: “Certain high-risk patients” (i.e pt who continues to have events) may receive both *all pts with chronic coronary disease should recieve aspirin for life

Answer 24

ASA + P2Y12 inhibitor

Answer 25

stent expands at site, becomes part of vessel wall in coronary artery; area becomes endothelialized, cells surround stent and leave vessel open intracoronary artery stents: * Bare Metal Stents: Uncommonly used - BMS and durable polymer BMS * Drug Eluting Stents - 1st Generation: Sirolimus, Paclitaxel; 2nd Generation: Everolimus, Zotarolimus (anti-proliferative interrupt, portion of cell cycle prevents rapid inflammation around cell site); 3rd Generation (Biosorbable polymer): Biolimus, Sirolimus, Everolimus

Answer 26

* Before procedure: ASA and P2Y12 inhibitor loading dose * After procedure: low risk bleeding - DAPT: min 6 mo, SAPT: indefinitely; high risk of bleeding/overt bleeding - DAPT: 1-3 mo; SAPT: P2Y12 inhibitor until 12 mo; SAPT: indefinitely * New recommendations do not distinguish between choice of P2Y12 inhibitor agents: Clopidogrel 75 mg daily; Prasugrel 10 mg daily; Ticagrelor 90 mg BID * DAPT: ASA + P2Y12 inhibitor * SAPT: ASA 81 mg preference

Answer 27

* CABG: DAPT: ASA 81 mg/day + Clopidogrel 75 mg/day; SAPT: ASA Indefinitely; Clopidogrel may be reasonable for 12 months; There is some controversy regarding the need for DAPT

Answer 28

100 risk of cerebral hemorrhage + stroke are higher

Answer 29

* Used in almost all pts with coronary disease * Stabilize plaque, improved ET function, inhibition of VSM cell growth, decreased macrophage migration, and ?anti-ox properties, Do not improve symptomatic ischemia (don't decrease angina, decrease risk of CV events) * ↓ CV events in high-risk patients w/w LV dysfxn; Benefit maybe lower in lower risk patients * Should be considered in all patients with CCD: Especially patients with LVEF <40%, HTN, DM or CKD; Ramipril 10 mg/day (HOPE) and Perindopril 8 mg/day (EUROPA) studied * ARBs in those who are intolerant (cough/AE) to ACEIs: Telmisartan 80 mg daily (ONTARGET) studied * Combination therapy (ACEI + ARB) NOT recommended

Answer 30

* Reduces inflammation, likely via reduction in IL-1b and IL-18 * Indicated for reducing the risks of myocardial infarction, stroke, coronary revascularization, and cardiovascular deaths in adults with established ASCVD or multiple risk factors * Role: ?High risk with elevated hsCRP (>2) (C reactive protein anti-inflammatory marker) * CYP3A and P-gp substrate: caution with strong inhibitors * Contraindicated in severe renal and hepatic disease approved for tx of chronic coronary disease

Answer 31

* Increase myocardial oxygen supply: Dilation of coronary arteries (reduce vasospasm), collateral blood flow, prolong diastole; How do we deal with fixed stenosis or thrombus? * Decrease myocardial oxygen demand: Heart rate; Myocardial contractility; Intramyocardial wall tension * Systolic blood pressure (afterload) * Left-ventricular end-diastolic volume (preload)

Answer 32

organic nitrates

Answer 33

* Mechanism of Action: Nitric oxide donors/releasers; Activation of guanylate cyclase * Activity: Marked venodilation (decreased preload) - dilate veins before heart, decrease blood flow to heart; Less arteriole dilation, coronary and peripheral; Inhibition of platelet aggregation (minor) * NTG = GTN (glyceryl trinitrate)

Answer 34

NO produced in endothelial cells; NO accompanies vascular smooth muscle cells how NO leads to SMC relaxation: increases cGMP

Answer 35

clinical effects: increased myocardial O2 supply - Endothelium-dependent vasodilation...dilates epicardial arteries and coronary collateral vessels; decreased myocardial O2 demand - Venous vasodilation causes reduced preload and decreased LV volume no effect on the natural history of the disease (just treat symptoms)

Answer 36

nitroglycerin tabs, nitroglycerin spray, nitroglycerin powder packets, nitroglycerin buccal tabs, ISDN chewable tabs, ISDN SL tabs

Answer 37

* Selection of agents: Spray vs. tablets * Patient information: Storage; Administration

Answer 38

patient experiences chest pain/discomfort --> take ONE nitroglycerin dose SL --> unimproved/worsening 5 min after taking one tab --> call 911 and take another tab); can take up to 3 tabs before the paramedics arrive

Answer 39

tabs: Keep in original dark glass container...No plastic Rx container; no safety cap; cotton plug removal; Place under tongue, do not swallow tab; Do not store in bathroom or humid locations spray: Spray under tongue, do not inhale; do not shake both: Keep on person at all times; Need for Rx refills 6 mo tabs ~3 yr spray; Reinforce technique for administration: sit, time frame, etc.; preventative use instructions; 911 procedure

Answer 40

* Adverse effects: Headache (throbbing or pulsating sensation); Hypotension, dizziness, lightheadedness and facial flushing; Reflex tachycardia (BP is reduced --> release catacholamines --> increase HR, this could lead to reflex ischemia) * APAP use * Extreme caution with PDEI (potential risk of hypotension) * Monitoring Parameters

Answer 41

sildenafil; riociguat; alpha blockers - risk of hypotension * Vasodilatory effects of nitrates may be substantially enhanced (25 mmHg drop in SBP)....fatal events have been observed * All package labeling states the PDEIs for ED are contraindicated * Duration of time to avoid PDEI’s within nitrates - avanafil: 12 hr; sildenafil and vardenafil: 24 hr; tadalafil: 48 hr

Answer 42

* SL NTG tablets (0.15-0.6 mg) or SL spray delivers (0.4 mg/spray) should be utilized in all patients: Products may also be useful for the prevention of angina, when taken just prior to the initiation of exertion or some other event which precipitates angina.

Answer 43

beta blockers, calcium channel blockers, nitrates

Answer 44

beta blockers block catecholamines from generating an increase in HR, contractility, and conduction velocity beta2 AR receptors: epinephrine, isoproterenol, albuterol - block Gs-R --> increase cAMP --> relaxation

Answer 45

* Mechanism of Action: competitive, reversible inhibitors of beta- adrenergic stimulation by catecholamines * Desired effects on myocardial oxygen demand: Reduce HR (mainly during sympathetic stimulation); Reduce myocardial contractility; Reduce arterial BP (afterload) * Undesired effect on myocardial oxygen demand: Reduce HR → Increase diastolic filling time → Increase LVEDV → Increase Preload (negates some of the benefits) * Effect on myocardial oxygen supply? - blood flow through coronary artery increases during diastole * Associated with reduced ventricular arrhythmias and remodeling

Answer 46

atenolol, metoprolol at low doses, beta1 is predominant receptor blocked, otherwise considered non-selective at higher doses want cardioselective in pts with asthma @ low dose

Answer 47

propranolol, carvedilol

Answer 48

pindolol, acebutolol not a lot of rationale use with angina; contraindicated in post-MI pts

Answer 49

propranolol, carvedilol

Answer 50

atenolol, bisoprolol

Answer 51

* Cardiac: sinus bradycardia, sinus arrest, AV block, reduced LVEF * Others: bronchoconstriction, fatigue, depression, nightmares, sexual dysfunction, exercise intolerance, intensification of insulin-induced hypoglycemia and peripheral vascular complication. * β-blocker withdrawal syndrome

Answer 52

* Initiate at lowest dose and titrate to symptom reduction * Goal Heart Rate: Rest: 50-60 BPM; Exercise * < 100 BPM * 75 % of HR that typically causes angina * Painful episodes: NTG use

Answer 53

* Cardiac: Decrease influx of trigger Ca2+ in myocytes; Decreased chronotropy in nodal cells; Inotropy in myocytes * Vascular: vasodilation all block L-type Ca2+ channel --> blocks effects of Ca2+, block contraction

Answer 54

verapamil, diltiazem (1:1) --> balanced effect on myocardium + vasculature nifedipine, amlodipine (10:1), felodipine, isradipine, nicardipine (100:1) --> much stronger affinity effect on vasodilation

Answer 55

Dihydropyridines (potent vasodilators): Hypotension, flushing, headache and dizziness Peripheral edema, likely related to arteriolar vasodilation Reduced myocardial contractility (DHPs?) Reflex adrenergic activation Non-Dihydropyridines: Reduced myocardial contractility (V>D) AV/SA nodal conduction disturbances: bradycardia and atrioventricular block (V>D) Hypotension, flushing, headache and dizziness Constipation (V>D) verapamil + diltiazem contraindicated in HF - potent inducers of inotropy

Answer 56

* Initiate at lowest dose and titrate to symptom reduction * Painful episodes: NTG use * Monitoring parameters: DHP - edema, BP; Non-DHP - just like beta-blockers; HR 50-60 @ rest and <100 while exercising

Answer 57

* ↓ response in the presence of continuously or frequently administered nitrates. * Not an all-or-none process * Examples: 24-hour applications of transdermal NTG; Continuous infusions of IV NTG; ISDN administered four times daily * Prevention of nitrate tolerance: Nitrate free period of at least 10-12 hours; Biopharmaceutics and PK contribute to the amount of time required to be dosage-free

Answer 58

* Reversible (hours) in absence of drug * ALDH2 inactivation in mitochondria * ISMN and ISDN also elicit tolerance but via a slower, less understood process. GTN activated by aldehyde dehydrogenase to become inactive

Answer 59

NTG patch ISDN tabs ISMN tabs ISMN SR tabs

Answer 60

once daily on for 12-14 hrs off for 10-12 hrs on: 7am off 7-9 pm

Answer 61

2-3 times/day 8 am, 12 pm, 4 pm 10 mg TID (8,12,4)

Answer 62

2 times/day 7 hours apart 8 am and 3 pm 20 mg twice daily (8am and 3pm)

Answer 63

once daily 8 am 30 mg once daily

Answer 64

* Discussion of nitrate free interval * Patches: Apply the patch between elbows and knees Apply the patch to clean, dry, hairless (or nearly free) skin that is not irritated, scarred, burned, broken, or calloused. Choose a different area each day. You may shower while you are wearing a NTG skin patch. Do not cut the patch (won't release at zero order rate) Wash hands before and after

Answer 65

* Do not rub or massage ointment * Do not cover the area

Answer 66

* Initiate at lowest dose and titrate to symptom reduction * Painful episodes: NTG use * Adverse effects: BP reduction; trying to avoid relfex tachycardia * Monitoring parameters

Answer 67

DHP + nitrates are primary problem agents with reflex tachycardia

Answer 68

ischemia --> decrease O2 + ATP supply and decrease LV function --> increase Na+ --> increase Ca2+ --> increase myofilament activation --> increase LVEDP/LV wall tension, increase O2 + ATP consumption --> decrease microcirculation ranolazine prevents the increase in Na+ (inhibits INa,late)

Answer 69

* MOA: Inhibition of late inward Na+ current in ischemic myocytes, ↓ intracellular Na+ --> ↓ Ca2+ influx * DOES NOT affect HR, BP, inotropy, or perfusion like traditional anti-ischemic agents

Answer 70

* Doesn't affect BP, may have advantage in pts with low BP * Product: Ranexa 500 mg ER tablets: Titration from 500 BID to 1000 BID over 1-2 weeks * US Indication: treatment of chronic angina * EMA: add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies * Combination therapy: Add to CCBs, beta-blockers, or nitrates when inadequate response to monotherapy * Monotherapy only when BP/HR too low with first-line agents

Answer 71

* Metabolized via CYP3A4 (70-85%) and CYP2D6 (10-15%); Substrate for P-gp * Prone to drug-interactions: Should not be used with strong 3A inhibitors (KTZ, ITZ, PIs clarithromycin) or inducers (CBZ, RIF, St John’s wort, etc.); Limit dose (500 BID) with moderate inhibitors (Dilt, Ver, ERY AND FLZ) *Ranolazine inhibits CYP3A and or P-gp * Adverse effects: Constipation, nausea, dizziness and headache; Dose-related increase in QT-interval; should not be used with other drugs that prolong the QT interval

Answer 72

* When to initiate therapy is dependent on each individual patient (symptoms, other conditions, etc.) * Three drug classes can be used first-line: ß-blockers, calcium channel blockers, and nitrates * Selection of an initial drug should be based upon the patient characteristics and concomitant conditions

Answer 73

* ß-blockers should be selected as initial therapy in patients without contraindications: Compelling indications: Stable HF, History of MI; Especially useful in... Atrial Fib, high resting HR, migraine headaches; Avoid in...vasospastic/Prinzmetal’s angina, conduction disturbances (SA nodal block/AV nodal block in absence of pace maker) * Contraindications: Bradycardia (HR < 50); High degree AV block or sick sinus syndrome (with no pacemaker)

Answer 74

* Non-DHP CCBs preferred, instead of ß-blockers if..: Contraindications to ß-blockers; Unacceptable side effects to ß-blockers; Potentially useful in... chronic lung diseases, HTN, DM, and peripheral vascular disease * Contraindications: Non-DHPs: HFrEF, Bradycardia (HR < 50); High degree AV block or sick sinus syndrome (with no pacemaker); DHPs: HFrEF (except amlodipine and felodipine)

Answer 75

* Monotherapy with long-acting nitrates can be challenging due to nitrate free period and tolerance. THUS, preferred as...: Combination with ß-blockers/non-DHPs (to blunt nitrate induced increase in HR); Short acting PRN nitrates to relieve discomfort or prevent ischemia before exertion * Cautions: HOCM, severe aortic stenosis, PDI use

Answer 76

prior ACS/MI (non-ISA) heart failure/LVD sinus tachycardia; SV tachycardia; A fib ventricular arrhythmias migraines hyperthyroidism

Answer 77

HTN bradycardia/AV block diabetes PVD/raynaud's severe asthma/COPD prinzmetal's angina

Answer 78

HTN sinus tachycardia; SV tachycardia; A fib diabetes PVD/raynaud's severe asthma/COPD prinzmetal's angina

Answer 79

bradycarida/AV block sick sinus syndrome heart failure decompensation severe depression severe asthma/COPD

Answer 80

bradycardia/AV block sick sinus syndrome (non-DHPs) heart failure severe hypertrophic obstructive CM severe aortic stenosis

Answer 81

ED with PDE5 severe hypertrophic obstructive CM severe aortic stenosis

Answer 82

combo therapy: * Nitrates and ß-blockers * Nitrates and non DHP-CCBs * DHP CCB and ß-blockers: also cause reflex tachycardia but beta-blockers block that effect) * ß-blockers and non-DHP CCBs : Generally, should be avoided (b/c of HR lowering) * Triple therapy: ß-blockers, Nitrates and CCBs * Ranolazine: Ideal role is unclear: Combination with other agents when not effective; BP/HR “too low” to add other agents

Answer 83

* Postmenopausal HRT * Antioxidants (Vit C, E, Beta- carotene) * Homocysteine/Folic acid, Vit B6 or B12 * Herbal supplements (garlic, Coenzyme Q10, selenium, chromium) * NSAIDS/COX-2 inhibitors * Rosiglitazone * ?Chelation therapy

Answer 84

ASA is irreversible bind, compete w/ ASA @ COX-1 site, may decrease benefits in pts w/ CV disease all other NSAIDs do this in a competitive concentration dependent manner can go away when stopping use

Answer 85

* Patients and clinicians should share decision-making of the personal benefit–risk balance: Potential GI, CV and renal impacts * Define the desired or needed therapeutic benefits * Consider the non-pharmacological and pharmacological options available to help to achieve these benefits: When considering NSAIDs, identify the patient’s cardiovascular, gastrointestinal, renal and other physiological risks that are potentially vulnerable to NSAID-associated adverse effects; Review existing medications and the potential effect of adding NSAID therapy * Prioritize non-pharmacological approaches and instigate them first, if possible: Set a date to review their effectiveness, keep a patient pain/effect diary

Answer 86

*Use should be viewed as a temporary adjunct to non-pharmacological measures *Use lowest dose for shortest time, single dose likely minimal impact *Keep a patient pain/effect diary *Select ibuprofen or naproxen as first alternatives (with gastroprotection - maybe PPI, used for shortest amount of time possible)— both have an effective analgesic dose range within the lower end of cardiovascular thrombotic risk estimates, and gastrointestinal risks can be offset to some extent with gastroprotection *Celecoxib doses up to 200 mg per day have similar cardiovascular risk estimates but seem to have poorer analgesic effects; at doses >200 mg per day, the cardiovascular thrombotic risk escalates * Avoid diclofenac * Take the ASA at least 2 hours prior to NSAID - gives ASA chance to acetylate that platelet COX, NSAID can't compete with it * Adjunctive APAP may minimize NSAID needs * Within 1 week, review the benefits of NSAID use and the patient’s diary record and check for AEs, aiming to down-titrate or cease the NSAID use while adjusting or up-titrating non-pharm measures * Plan for ongoing support, prioritizing non-pharm measures to optimize the patient’s wellness, function and fitness, and to minimize the need for pharmacological measures * If unsuccessful, consider referral to a multidisciplinary pain team for assistance

Answer 87

Prinzmetal’s angina; Vasospastic Angina Variant Angina * Ischemia/angina usually occurs at rest, not precipitated by physical exertion or emotional stress * Associated with ECG ST-segment elevation * Ischemic episodes occur most frequently in the early morning hours * Not necessarily associated with atherosclerosis.

Answer 88

*Acute treatment (ie SL NTG,etc.) * Chronic treatment: Calcium channel blockers; Nitrates; ß-blockers: NO!; Combination therapy