Exam 4 Flashcards
1
Q
type of angina characterized by lumen that is narrowed by plaque, inappropriate vasoconstriction, less than normal blood flow that could be fine at rest but noticeable with exercise
A
stable angina
2
Q
type of angina characterized by a ruptured plaque, platelet aggregation, thrombus formation, unopposed vasoconstriction, pain even at rest
A
unstable angina
3
Q
type of angina characterized by no overt plaques, intense vasospasm with pain that comes and goes
A
variant angina
4
Q
age, gender, family history of premature this, hypercholesterolemia, hypertension, smoking, type II diabetes, sedentary lifestyle, obesity, and more
A
risk factors for coronary artery disease (CAD)
5
Q
what are the main determinants of myocardial oxygen demand?
A
heart rate, contractility, afterload, preload
6
Q
what is the main determinant of myocardial oxygen supply?
A
coronary blood flow (greater demand necessitates greater flow)
7
Q
this class of drugs delivers nitric oxide to vessels: nitrate compound is denitrated by mitochondrial aldehyde dehydrogenase (mtALDH, higher concentration of mtALDH in veins so more NO in veins) which forms nitric oxide (NO), this increases cGMP which decreases calcium levels inside cells so less contraction of vessels leading to relaxation of vascular smooth muscle cells (veins more than arteries)
A
organic nitrates mechanism of action
8
Q
class of drugs whose primary action is venodilation which decreases preload (greatest effect in veins because mtALDH mostly found in veins), coronary artery dilation, some arteriolar dilation (decreased afterload), net result is decreased myocardial oxygen demand with increased oxygen supply in some situations
A
physiological effects of organic nitrates
9
Q
hepatic glutathione-organic nitrate reductase converts these drugs into inactive metabolites, high first pass metabolism, high capacity, limited oral bioavailability (sublingual forms have rapid onset but shorter duration, oral/transdermal forms have slower onset but longer duration)
A
metabolism of organic nitrates
10
Q
what is the use of sublingual organic nitrates like sublingual nitroglycerine or isosorbide dintrate?
A
to relieve acute angina
11
Q
what is the use of oral/dermal organic nitrates like nitroglycerin ointment, nitroglycerin dermal patches, oral isosorbide dinitrate?
A
for prophylaxis of angina
12
Q
continuous exposure of these drugs leads to tachyphylaxis (rapid development of tolerance) because following repeated/prolonged use these drugs oxidize mtALDH and decrease its activity (longer the enzyme is exposed to drug less able to remove NO from drug)
A
limitations of organic nitrates
13
Q
- side effects of these drugs include orthostatic hypotension, tachycardia, throbbing headache, dizziness, flushing of skin
- contraindications include PDE5 inhibitors for erectile dysfunction (combo use leads to hypotension, SNS activation and increased MVO2)
A
side effects/contraindications of organic nitrates
14
Q
what are organic nitrates mainly used for (what types of angina)?
A
stable and variant angina, somewhat helpful in unstable
15
Q
what is the main effect of calcium channel blockers?
A
decrease intracellular calcium
16
Q
primary physiological effects: decreased heart rate, contractility, conduction velocity all for decreased oxygen demand
A
physiological effects of cardioprotective calcium channel blockers (diltiazem, verapamil)
17
Q
primary physiological effects: decreased afterload for decreased oxygen demand, but if decrease BP too fast there will be an increase in SNS activity leading to an increase in oxygen demand
A
physiological effects of dihydropyridine calcium channel blockers (nifedipine, amlodipine, felodipine)
18
Q
nifedipine XL, amlodipine, felodipine are more (slowly/quickly) absorbed for (less/more) tachycardia
A
slowly, less
19
Q
- decrease myocardial oxygen consumption due to decreased contractility and heart rate, relaxation of coronary smooth muscle cells
- net effects: decreased oxygen demand and vasospasms
- main uses: variant and stable angina
- toxicity/side effects: bradycardia, heart block, dizziness, edema, flushing, constipation
A
diltiazem and verapamil calcium channel blockers
20
Q
- physiological effects: reduces myocardial oxygen consumption through decreased force of contraction and heart rate (decreased oxygen demand), slightly increases coronary flow to ischemia areas (due to increased perfusion time of ventricles leading to slight increase in oxygen supply, not consistent)
- net effects: decreased myocardial oxygen consumption and slight increase in coronary blood flow
A
beta blockers (selective and nonselective)
21
Q
why are nonselective beta blockers contraindicated/cautious use in variant angina?
A
if block beta 2 receptors the alpha 1 receptor activity will be unchecked because usually there is a balance between beta 2 and alpha 1 leading to more vasoconstriction
21
Q
toxicity/side effects: bradycardia, heart failure, low exercise tolerance, rebound effect due to more beta 1 receptors (increase angina if abruptly stop), bronchospasm with nonselective, CNS effects with lipophilic nonselective (fatigue, depression, nightmares)
A
toxicity and side effects of beta blockers
21
Q
what are the main uses of beta blockers in angina?
A
stable and unstable angina
22
Q
this drug blocks the late Na+ current during the cardiac action potential (this current is increased during ischemia), increased late Na+ current results in increased intracellular Na+ which causes increased intracellular Ca2+, increased Ca2+ results in increased contractility and increased oxygen demand — this drug BLOCKS all that, reduces calcium overload which decreases ventricular stiffness, diastolic wall tension, cardiac contractility (these changes reduce myocardial oxygen consumption)
A
ranolazine
23
unstable angina (acute coronary syndromes), atrial fibrillation, pulmonary embolism, deep vein thrombosis, heart failure, stroke, different procedures
uses of anticoagulants
24
which takes longer, the intrinsic pathway (activated partial thromboplastin time aPTT) or extrinsic pathway (prothrombin time PT)?
intrinsic
25
what is the enzyme that converts prothrombin (II) to thrombin (IIa)?
Xa (prothrombin activator)
26
what is the enzyme that converts fibrinogen to fibrin?
IIa (thrombin)
27
heterogeneous mixture of sulfated glycosaminoglycans, naturally occuring in mast cells, have both unfractionated and low molecular weight, not orally active (must be given IV or SC), active site is the pentasaccharide (five sugar) sequence
heparins
28
MOA: circulating antithrombin (produced by liver) has a low affinity to bind and inactivate Xa and IIa, this drug binds to circulating antithrombin and increases its affinity for IIa and Xa (1000x), the complex of this drug-antithrombin-FIIa/FXa are rapidly removed by liver (suicide inhibition)
heparins
29
are low molecular weight heparins better at inhibiting Xa or IIa?
Xa
30
this heparin is just the pentasaccharide fragment, SC injection, eliminated unchanged in the urine so contraindicated in patients with low creatinine clearance, effect lasts days after discontinuing drug (no antidote at this time), less likely to induce thrombocytopenia
fondaparinux
31
- side effects: bleeding (dose related), heparin induced thrombocytopenia, osteoporosis (long term use, relatively rare)
- contraindications: active bleeding, coagulopathies (hemophilia, significant thrombocytopenia), hypersensitivity to pork or beef products, severe hypertension, intracranial hemorrhage
unfractionated heparin
32
what is needed as a cofactor for inhibition by heparins?
antithrombin
33
these drugs do not need antithrombin as a cofactor for inhibition, work as direct FXa inhibitors (DOACs)
direct FXa inhibitors - rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Sazaysa)
34
- reversal agent for FXa inhibitors
- MOA: recombinant modified human factor Xa decoy, higher affinity to the FXa inhibitor than natural FXa
andexanet alfa (AndexXa)
35
- direct oral competitive thrombin (FIIa) inhibitor, approved for prevention of emboli with Afib, VTE, hip/knee replacements
- doesn't require monitoring
- absolute oral bioavailability 3-7%, rapid absorption
- prodrug rapidly converted to active drug by esterase-catalyzed hydrolysis in plasma and liver
- elimination: half-life 12-17 hours, 80% renally eliminated (renal adjustments)
dabigatran (Pradaxa)
36
reversal agent for dabigatran (Pradaxa), bolus dosing (x2) reverses anticoagulation in minutes, low rate of thrombotic events, mAB antibody against Pradaxa
Idarucizumab (Praxbind)
37
- MOA: antagonist of vitamin K (actually an inhibitor of vitamin K epoxide reductase) --> vitamin K needed in synthesis of FUNCTIONAL clotting factors like FII, FVII, FIX, FX
- results in a 30-50% decrease in functional clotting factors, time to reach full effect is 3-5 days because already have some clotting factors circulating (only inhibiting synthesis), duration of action after stopping is several days because liver needs time to synthesize new clotting factors, 100% bioavailability
- extensively metabolized by CYP2C9 (genetic polymorphisms render patients more or less sensitive to effects of warfarin
- drug interactions: 99% bound to plasma proteins, dietary vitamin K interaction, drug inhibitors or inducers of CYP enzymes, long plasma half life about 36 hours, results in variable patient response and therapy requires INR (international normalized ratio) monitoring
- toxicity: bleeding (correct with vitamin K administration if time allows, if need rapid reversal do blood transfusion/fresh frozen plasma/concentrate of human factors also available)
- contraindications: pregnancy, preexisting bleeding
warfarin (Coumadin)
38
what type of drugs prevent platelet activation/aggregation and the mechanisms of this differ between classes (A, B, C)
antiplatelet drugs
39
- MOA: IRREVERSIBLY acetylates and inhibits cyclooxygenase (COX) enzyme in platelets
- effect: decreased TXA2 resulting in decreased platelet activation and adhesion
- once COX enzyme is acetylated the platelet is out of commission because platelets have no nuclei so no regeneration of COX-1 --> rationale for 81 mg/day dose
aspirin
40
inhibits ADP-dependent activation/aggregation of platelets by blocking ADP receptor (P2Y12) on platelets
antiplatelet drugs: ADP antagonists --> irreversible (ticlopidine, clopidogrel, prasugrel), reversible (ticagrelor)
41
- MOA: irreversible P2Y12 inhibitor, prodrug requiring conversion to active metabolite
- loading dose needed
- metabolism: complex with two CYP450 steps, poor metabolizers have reduced activation, significant drug interactions with CYP2C19 inhibitors
- contraindications: active bleeding history, history of intracranial hemorrhage, severe liver disease, poor CYP2C19 metabolizer status
- advantages: extensive clinical experience, cost effective, once daily dosing
- disadvantages: variable response, genetic variations affect efficacy, many drug interactions
clopidogrel (Plavix)
42
- MOA: irreversible P2Y12 inhibitor, prodrug requiring conversion to active metabolite
- loading dose needed
- metabolism: single step CYp activation, less affected by genetic variations and more efficient conversion to active form, fewer drug interactions
- contraindications: active bleeding history, history of stroke/TIA, severe liver disease, patients older than 75 (relative), patients weighing less than 60kg (relative)
- advantages: more predictable response with less genetic variability
- disadvantages: higher bleeding risk, limited use in elderly/low weight patients
prasugrel (Effient)
43
- MOA: reversible direct-acting P2Y212 inhibitor, not a prodrug
- loading dose needed then BID dosing
- metabolism: direct acting so no activation needed, metabolized by CYP3A4, strong CYP3A4 inhibitors or inducers affect levels
- contraindications: active bleeding, history of intracranial hemorrhage, severe liver disease, concomitant strong CYP3A4 inducers/inhibitors
- advantages: reversible binding, no activation required, rapid onset/offset
- disadvantages: twice daily dosing, higher cost
ticagrelor (Brilinta)
44
these drugs all block FUNCTIONAL fibrinogen receptors on ACTIVATED platelets
IIb/IIIa receptor antagonists - abciximab, eptifibatide, tirofiban
45
- monoclonal antibody against fibrinogen receptor
- non-competitive inhibition
- half life 8-12 hours
- slow reversibility
abciximab (Reopro)
46
- synthetic peptide of part of fibrinogen, derived from rattlesnake venom, blocks fibrinogen from binding to activated platelets
- competitive inhibition
- half life 2.5 hours
- quick reversibility
eptifibatide (Integrilin)
47
- synthetic non-peptide that blocks fibrinogen from binding to activated platelets
- competitive inhibition
- half life 2 hours
- quick reversibility
tirofiban (Aggrastat)
48
- reversal agent for ADP and IIb/IIIa antagonists (off label use)
- platelet function gradually returns to baseline values over 5-9 days after discontinuation of ADP or IIb/IIIa antagonists
- thought to increase platelet aggression but MOA not fully understood
- for rapid reversal give platelet concentration
desmopressin (Nocdurna)
49
- agents used to degrade (lyse) existing fibrin clots, developed because many patients enter the healthcare system after clot formation has occurred
- used to dissolve existing fibrin clots by converting circulating plasminogen (inactive) to plasmin, all effectively degrade fibrin clots but mechanisms differ slightly
- side effects: bleeding, allergic reactions
- contraindications/warnings: recent bleeding (ulcers, trauma, etc), recent surgery/invasive procedures, severe hypertension, history of stroke
fibrinolytic agents - streptokinase (Streptase, Kabikinase), alteplase recombinant tPA (Activase), Tenecteplase (TNKase)
50
- produced by streptococci bacteria (not active), binds to plasminogen and forms an active enzyme complex (60 minute infusion), enzyme complex (drug + plasminogen) catalyzes conversion of plasminogen to active plasmin
- non-fibrin specific, more systemic effect and higher bleeding risk, lower cost option
streptokinase (Streptase, Kabikinase)
51
- direct copy of natural tPA, 90 minute infusion
- drug binds fibrin first, then complex binds plasminogen forming triad (fibrin specificity)
alteplase (Activase)
52
- modified tPA
- amino acid substitutions at three sites for decreased plasma clearance, longer half life, increased fibrin specificity
- less than one minute infusion
- drug binds fibrin first then complex binds plasminogen forming triad (fibrin specificity)
tenecteplase (TNKase)
53
statin therapy that achieves at least a 50% reduction in LDL cholesterol, rosuvastatin 20-40 mg, atorvastatin 80 mg
high intensity
54
statin therapy that achieves 30-49% reduction in LDL cholesterol, atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg
moderate intensity
55
statin therapy that achieves less than 30% reduction in LDL cholesterol unless contraindicated, simvastatin 10 mg, pravastatin 10-20 mg, lovastatin 20 mg
low intensity
56
what is the rate limiting step in the synthesis of cholesterol?
HMG CoA reductase
57
goal of cholesterol lowering therapy is to decrease _______ in plasma
LDLs
58
- MOA: reversible competitive inhibitors of HMG CoA reductase activity
- all have high first pass extraction in liver, most of the absorbed dose excreted in bile
- look like the intermediate mevalonic acid
- effects: decrease cholesterol synthesis in liver, decrease plasma VLDL and LDL concentration, increase LDL receptor number on hepatocytes for increased removal of LDLs from plasma
- usually taken at bedtime because synthesis of cholesterol is increased then so therapy more effective at decreasing LDLs (EXCEPT for atorvastatin and rosuvastatin because longer half life so doesn't have to be taken at night)
- side effects: well tolerated, myalgias, increased liver transaminase, rhabdomyolysis (muscle inflammation and pain), renal failure
- drug interactions: metabolism by CYP3A4/CYP2C9, effects of classic CYP inducers/inhibitors, liver dysfunction
- contraindications: pregnancy
HMG CoA reductase inhibitors (statins) - atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin
59
- MOA: positively charged at GI pH, bile salts/acids are negatively charged, drugs bind to cholesterol containing bile acids/salts secreted into the intestine by the liver (stays in intestine so increased excretion), reduces enterohepatic recirculation of cholesterol
- decrease reabsorption of bile acids/salts so increased bile/cholesterol excretion in feces, increased hepatic LDL receptor expression (decreased LDLs in plasma), increased hepatic cholesterol synthesis which tempers therapeutic effect
- take with meals because that is when bile will be present in intestine
- side effects: NONE --> these drugs don't get absorbed systemically through GI tract, stay in intestine and excreted in feces
- local effects: bloating, abdominal discomfort, constipation, compliance issues
- drug interactions: binds other anionic drugs/compounds, dose other drugs 1 hour before or 3 hours after these
bile acid binding resins/bile acid sequestrants - cholestyramine (Questran), colestipol (Colestid)
60
- MOA: inhibits absorption of cholesterol at brush border, inhibits a cholesterol transporter NPC1L1 located in brush border of intestinal epithelia, does NOT affect absorption of vitamin A, D, E, warfarin, OCs, etc, reduced delivery of intestinal cholesterol to the liver stimulates expression of hepatic LDL receptors which enhances LDL clearance from the plasma
- once a day dosing of 10 mg with/without food
- adverse effects: rare allergic reactions, otherwise well tolerated
- generally used in combination with statins
cholesterol absorption inhibitors - ezetimibe (Zetia)
61
- MOA: inhibits free fatty acid mobilization from adipose tissue leading to decreased substrate for VLDL synthesis in liver which leads to reduced LDLs, increases lipoprotein lipase activity which promotes clearance of chylomicrons and VLDL triglycerides, decreased HDL clearance so more HDLs
- water soluble vitamin B3, first hypolipidemic agent
- effects: decreases LDLs, increases HDLs, decreases TGs
- side effects: intense cutaneous flushing, GI irritations, hepatic dysfunction, hyperglycemia
- often used as adjunct therapy to raise HDLs, available OTC
- contraindications/cautions: liver dysfunction, peptic ulcers, diabetic patients, pregnancy
niacin ER (Niaspan)
62
- MOA: stimulates the PPAR alpha (peroxisome proliferator activated receptor)
- decreases VLDL synthesis
- relatively inefficient decrease in LDLs but effective in patients with hypertriglyceridemia
- side effects: gallstones, GI irritation, GI/hepatic tumors
- contraindications/cautions: patients on anticoagulant therapy (increases effect), patients with hepatic or renal dysfunction
fibric acid derivatives - gemfibrozil (Lopid), Clofibrate (TriCor)
63
- fully humanized monoclonal antibodies that work by inactivating PCSK9
- increase number of surface hepatocyte LDL receptors
- can be injected once every 2 or 4 weeks
- recommended as add on therapy if cholesterol not at target with statin and ezetimibe therapy
PCSK9 inhibitors - evolocumab (Repatha), alirocumab (Praluent)
64
- small interfering RNA fragments that inhibit the production of PCSK9 protein
- just twice yearly injections
- monoclonal antibody
Leqvio (inclisiran)
65
any deviation from normal heartbeat pattern, bradycardia, tachycardia, asynchronous, all can reduce cardiac output and some can cause death
cardiac arrhythmias
66
which node is the pacemaker?
SA node
67
which node has a delay so the blood can fill the ventricles before contraction/pump?
AV node
68
what phase is rapid depolarization and what happens to ions?
phase 0, Na+ inward in muscle and Ca2+ inward in nodes
69
what phase is early repolarization and what happens to ions?
phase 1, K+ outward in muscle
70
what phase is the plateau and what happens to ions?
phase 2, Ca2+ in and K+ out in muscle
71
what phase is repolarization and what happens to ions?
phase 3, K+ out and Ca2+ in for both muscle and nodes
72
what phase is resting potential and what happens to ions?
phase 4, balanced ions in muscle, nodes are leaky to cations going in
73
decrease automaticity (ability of cardiomyocytes to depolarize spontaneously), increase action potential duration (heart can't beat more than once at a time), prolong effective refractory period, decrease AP conduction velocity --> most act by altering ion fluxes within tissues in the heart
antiarrhythmic drug therapy
74
portion of action potential cycle where another action potential cannot be initiated no matter how strong the stimulus, increasing this can reduce occurence of certain arrhythmias
effective refractory period
75
portion of the action potential where a strong stimulus can initiate another action potential, increasing this can reduce occurence of certain arrhythmias
relative refractory period
76
- causes of arrhythmia is often unknown and can be associated with other factors like electrolyte imbalances, hypoxia due to ischemia, drug interactions, acute or chronic illnesses
- patient to patient variability in response to drug therapy
- multiple actions of most drugs
- narrow therapeutic index of most drugs and some drugs can precipitate lethal arrhythmias in some patients
- empirical dosing/use --> educated guess and check
difficulties with antiarrhythmic drug therapy
77
what are class I antiarrhythmic drugs?
Na+ channel blockers, rate dependent function
78
what are class II antiarrhythmic drugs?
beta adrenergic receptor blockers
79
what are class III antiarrhythmic drugs?
K+ channel blockers
80
what are class IV antiarrhythmic drugs?
Ca2+ channel blockers
81
- moderate potency Na+ blockers, slows the upstroke of the action potential, decreases conduction velocity, increases action potential duration, increases refractoriness
- broad spectrum uses: atrial and ventricular arrhythmias
- drugs preferentially target rapidly depolarizing tissue more than normal tissue which has efficacy in slowing tachycardias
- prolonged repolarization for increased refractory period which has efficacy in stopping reentrant arrhythmias
class IA antiarrhythmics - procainamide (Procanbid), quinidine (Cardioquin, Quinora), disopyramide (Norpace)
82
- low potency Na+ blockers
- have their highest affinity for Na+ channels in ischemic cells (acidosis, altered RMP)
- decreased phase 0 slope and slow conduction
- decreases automaticity
- shortens action potential duration
- used in ventricular arrhythmias, ineffective on atrial tissue
- highly lipophilic and use-dependent blockade, decreases ventricular tachycardia or fibrillation after cardioversion
class IB antiarrhythmics - lidocaine
83
- high potency Na+ blockers
- decrease phase 0 upstroke and action potential conduction velocity
- in atrial cells at fast rates and AV node can increase action potential duration and refractoriness
- no change in ventricular action potential duration, decreases conduction velocity of action potential
- used in supraventricular (above the ventricles) arrhythmias
- increase action potential duration disproportionately more in atria at fast rates, marked depressive effects on cardiac function, must be used with discretion
- increased mortality in patients recovering from MI
class IC antiarrhythmics - flecainide (Tambocor), propafenone (Rythmol)
84
- provoke or increase arrhythmias
- exacerbate congestive heart failure
- can induce heart block between atria and ventricles
- hypotension
- GI distress
- sedation, tremor, dizziness, blurred vision
- nausea/vomiting
side effects of class I antiarrhythmics
85
- beta blockers
- increase A-V refractoriness
- decrease conduction velocity
- increase action potential duration (atria, nodal tissue)
- indications: atrial and ventricular tachycardia
- decrease in mortality after MI
- side effects: cardiovascular (bradycardia, HF, low exercise tolerance), rebound effect (increased receptor number with long term blockage), bronchospasms (nonselective), sedation (lipophilic nonselective), metabolic effects (increased triglycerides, blunted recovery from hypoglycemia)
class II antiarrhythmics - propranolol (Inderal), sotalol (Betapace), esmolol (Brevibloc, beta 1 selective)
86
- blocks K+ channels
- increases repolarization time and action potential duration
- indications: most arrhythmias (atrial and ventricular)
- highly lipophilic, concentrates in tissues so very long half life, slightly decreases mortality after MI
- side effects: hypotension and decreased left ventricle contractility, muscle weakness, liver dysfunction, hypo/hyperthyroidism (due to iodines on molecule), hallucinations, nightmares, depression, peripheral neuropathy, headache, ataxia, tremors, pulmonary fibrosis
class III antiarrhythmics - amiodarone (Pacerone, Cordarone), dronedarone (Multaq), dofetilide (Tikosyn)
87
- calcium channel blockers
- blocks L-type calcium channels, decreases slope of phase 4 primarily (decrease automaticity), decrease HR, decrease A-V conduction
- indications: atrial tachycardia/fibrillation and AV node arrhythmias
- do not reduce mortality after MI
- dihydropyridines are ineffective
- side effects (mostly with concomitant therapy): hypotension, sinus bradycardia, heart block, decreased cardiac contractility, constipation, peripheral edema, extensively metabolized in liver so cautious use in patients with hepatic dysfunction
class IV antiarrhythmics - verapamil (Calan), diltiazem (Cardizem)
