Cardiopulm Flashcards
(420 cards)
1
Q
Drugs used for ischemic heart disease
A
Nitrates (nitrovasodilators)
Calcium channel blockers (non cardioactive and cardioactive)
Beta blockers
Ranolazine
2
Q
Name nitrates
A
Nitroglycerin
Isosorbide dinitrate
Isosorbide mononitrate
3
Q
Name calcium channel blockers
A
Non-cardioactive
Amlodipine
Nifedipine
Cardioactive
Dilitazem
Verapamil
4
Q
Name beta blockers
A
Propranolol
Nadolol
Metoprolol
Atenolol
5
Q
Ranolazine
A
Ok
6
Q
What is ischemic heart disease
A
Partial occlusion of coronary artery
7
Q
Classic angina (angina of effort, stable angina)
A
Occlusion of coronary arteries resulting from the formation of atherosclerotic plaque
- most common
- symptoms occur during exertion or stress
8
Q
Variant angina
A
Episodes of vasoconstriction of coronary arteries
Likely genetic
Symptoms at rest
Much less common than classics angina
9
Q
Angina
A
Imbalance between oxygen demand of the heart and oxygen supply via the coronary arteries
At rest oxygen demand=supply of oxygen through partially blocked artery
No symptoms
During exercise/stress
Oxygen demand> supply through partially blocked coronary artery
CHEST PAIN
10
Q
How reduce oxygen demand
A
Decrease cardiac work load
11
Q
How increase oxygen suppl
A
Increase blood flow through coronary arteries
12
Q
What are approaches to increase coronary blood flow
A
Coronary artery bypass grafting
Percutaneous transluminal coronary angioplasty (PTCA)
Atherectomy-tip of catheter shears off the plaque
-reoclusion
Stent-expandable tube used as scaffolding to keep vessel open
-drug elating stents (antiproliferative drugs)
Vasodilator
13
Q
Vasodilator to increase coronary blood flow
A
Useful in vasospastic (prinzmetal) angina
Relieves coronary spasm, restores blood flow to ischemic area, vasodilator
*spasm of proximal right coronary artery and its treatment with a vasodilator
14
Q
When are vasodilator not useful in treating angina
A
Atherosclerotic (classic ) angina
-coronary steal phenomenon-redistribution of blood to non ischemic areas-associated with the dilation of small arterioles (example-potent arteriolar vasodilator, such as DIPYRIDAMOLE)
15
Q
How reduce myocardial oxygen demand
A
HR, contractility, preload, afterload
Physic coronary flow
- isovolumetric contraction
- ejection
- diastole
16
Q
What drugs are used in chronic ischemic heart disease
A
Nitrates
Calcium channel blockers
Beta blockers
Ranolazine
17
Q
How is vasculature relaxed
A
Release of ENDOTHELIUM derived relaxing factor (EDRF) by Ach
Endothelium is necessary
Endogenous NOS makes NO, a vasorelaxing agent …NO and citrulline activate GC to make cGMP
18
Q
How are nitrates, NO donors
A
Organiz nitrates cause metabolic activation of NO (do do endothelial cells)
Outside cell then NO into cell
NO activates GC to turn GTP to cGMP In cell
GTP activates protein kinase G->myosin LC dephosphorylation->smooth muscle renalxation
PKG also opens K channels to allow K out and get hyperpolarization and reduced calcium entry
19
Q
What are the nitrovasodilators
A
Nitroglycerin
Isosorbide
Isosorbide mononitrate
20
Q
Pharmacokinetics of nitrovasodilators
A
Significant first pass metabolism-high nitrate reductase activity in the liver
-nitrate reductase activity in saturable
Bioavailability with oral route is low
Other routes that avoid first pass metabolism are used
Partially denigrated metabolites may still have activity and longer half lives
Isosorbide mononitrate is a poor substrate of nitrate reductase
-characterized by higher bioavailability
21
Q
MOA nitrates
A
Unknown enzymatic reaction releases NO (or other active metabolite)
-the role of mitochondrial aldehyde dehydrogenase 2 (ADH2)
Thiopental compounds are needed to release NO from nitrates
Vascular smooth muscle-NO dilate veins and (at much higher concentrations) large arteries
Sensitivity of vasculature to nitrate-induced vasodilationL
Veins>large arteries>small arteries and arterioles
-no “coronary steal” phenomenon
-inhibit platelet aggregation
22
Q
How do nitrates decrease myocardial oxygen demand
A
Relaxation of smooth msucle
- dilation of veins major effect)
- increased venous capacitance
- reduced ventricular preload
Dilation of arteries-higher concentrations off nitrates are needed, as compared to venous dilation
- may reduce afterload
- may dilate large pericardial coronary arteries
- there is no substantial increase inc ordinary blood flow into ischemic area in atherosclerotic angina
23
Q
What turns nitrate into NO
A
ADH2 thinks
24
Q
What does NO do
A
Vascular smooth muscle relaxation
25
How does NO help variant angina
Vascular smooth muscle relaxation->coronary artery dilation->coronary spasm relief
26
How do nitrates helps angina of effort
Vascular smooth muscle relaxation->venous dilation->reduced preload-> decreased O2 demand
27
Effects of NO beyond vasodilation
LDL oxidation
Superoxide radical
Smooth muscle cell proliferation
Platelet aggregation
Monocyte adhesion
28
Development of tolerance to nitrates
Depletion of thiol compounds
Increased generation of superoxide radicals
Reflex activation of sympathetic nervous system (tachycardia, decreased coronary blood supply)
Retention fo salt and water
-increased generation of superoxide radical depletes tissues of NO
29
What happens when NO joins superoxide
Becomes peroxynitrits or H2O2 and O2
30
Clinical use of nitrates
Short acting formulations are used to relieve the angina attack
Long acting preparations may be used to prevent attacks
31
Short acting nitrates
Nitroglycerin
Sublingual-10-30 min
Spray 10-30 min
Isosorbide dinitrate
Sublingual 30-60 min
Spray 90 min
32
Long acting nitrates
Nitroglycerin
Oral 4-8 hr
Ointment 3-6 hr
Patch 8-12 hr
Isosorbide dinitrate
Oral-4-6 hr
Isosorbide mononitrate
Oral 6-10 hr
33
Adverse effects of nitrates
HA (due to meningeal vasodilation; nitrates are contraindicated in intracranial pressure is elevated)
Orthostatic hypotension
Increased sympathetic discharge
- tachycardia
- increased cardiac contractility
Increased renal Na and H2O reabsorption
34
Drug interactions nitrate
ED meds (sildenafil, vardenadil, tadafil)
- inhibit cGMP PDE-5, increase cGMP
- minimal effects on hemodynamics when administered alone in men with coronary artery disease
- combination with nitrates causes severe increase in cGMP and a dramatic drop in BP
- acute MI have been reported
35
CGMP effect
Smooth muscle relaxation—-elective tissue and blood vessels
36
What calcium channel blockers are used in angina
Non cardioactive
- amlodipine (long t1/2=30-50 hr)
- nifedipine (short acting (t1/2=4 h)
- nicardipine (short acting t1/2 2-4 hours)
Cardioactive
- diltiazem
- verapamil
37
How do ca channel blockers work
Ca enters cells via voltage dependent ca channels to mediate smooth msucle contraction
Ca binds calmodulin which activates MLCK to cause MLC contraction with actin
38
What drug class causes most vasodilation
Amlodipine -dihydropyridine
39
What drug causes most decrease inc Adrian contractility
Verapamil-phenylalkylamina
Least is amlodipine
40
What drug causes most decrease in SA node
Verapamil and dilitiazem
41
What drug causes most decrease in conduction of AV node
Verapamil and diltiazen
Non amlodipine
42
How do calcium channel blockers decrease myocardial O2 demand (atherosclerotic angina)
Dilation of peripheral arterioles
- decrease PVR and afterload, decreased bp
- arterioles affected more than veins (less orthostatic hypotension)
- dihydropyridines are more potent vasodilator
Decreased cardiac contractility and HR (observed with cardioactive CCB)
43
How do calcium channel blockers increase blood supply (operates in variant angina)
Dilation of coronary arteries relieves local spasm
44
Major adverse effects of calcium channel blockers
Cardiac depression, cardiac arrest and acute heart failure (cardioactive)
Brady arrhythmias, atrioventricular block (cardioactive)
Short acting dihydropyridine CCB-vasodilation triggers reflec sympathetic activation
Nifedipine (immediate release) increases the risk of MI in patients with HTN-slow release and long acting dihydropyridines are better tolerated
45
Minor AE CCB
Flushing, headache, anorexia, dizzy
Peripheral edema
Constipation
46
Name beta blockers
Propranolol
Nadolol
Metoprolol
Atenolol
47
MOA beta blockers
Decreased myocardial oxygen demand
- decrease in HR leads to improved myocardial perfusion and reduced oxygen demand at rest and during exercise
- decrease inc interactivity
- decrease in bp leads t reduced afterload
48
AE beta blockers
Reduce cardiac output
Bronchoconstriction
Impaired glucose mobilization
Produce an favorable blood lipoprotein profile (increase VLDL and decrease HDL)
Sedation, depression
Withdrawal syndrome associated with sympathetic hyperresponsiveness
49
Contraindications beta blockers
```
Asthma
Peripheral vascular disease
Type I diabetics on insulin
Bradyarrhythmia and AV conduction abnormalities
Severe depression of cardiac function
```
50
Nitrates alone adverse effects
HR increase
| Contractility increase
51
AE beta blockers or calcium channel blockers
Increase end diastolic volume
Increase ejection time
52
Combined nitrates with beta blockers or calcium channel blockers
None of those bad side effects
Decrease HR
Decrease arterial pressure
Decrease or no change in end diastolic volume
No changecontractility
No change in ejection time
53
Ranolazine (new) 2006
Inhibits late Na current in cardiomyocytes
54
MOA ranolazine
Ischemic myocardium is often partially depolarized
Na channel inc ardiomyocytes is voltage gated
Late Na current is enhanced in ischemic myocardium and brings about Ca overload and depolarizer abnormalities
RANOLAXINE normalizes depolarization of cardiac myocytes and reduces mechanical dysfunction
- may reduce diastolic tension and compression of coronary vessel in diastole
- may reduce cardiac contractility and oxygen demand
55
Does ranolazine affect hr, coronary blood flow and peripheral hemodynamics
No
56
Clinical use of ranolazine
Stable angina which is refractory to standard medications
Decreases angina episodes and improves exercise tolerance in patients taking nitrates, or amlodipine, or atenolol
57
Approaches to treatment of variant angina
Prevention of episodes1
CCB are the first choice drugs
If CCB are contraindicated (low BP, bradycardia, AV block), long acting nitrates *
58
Approach to treat stable (atherosclerotic angina
Lipid lowering , lifestyle, immediate release nitrates (SL or spray), antiplatelet therapy (asprin)
BB or CCB or LA nitrate
Add CCB or BB
Low BO: LA nitrate or ranolazine
Consider triple therapy (BB +CCB+LA nitrate or ranolazine)
CABG surgery
59
What drug classes are used for lipid disorders
HMG-CoA reductase inhibitors (statins)
Niacin (nicotonic acid, vitamin B3)
Fabric acid derivatives (fibrates)
Bile acid sequestration (resins)
Cholesterol absorption inhibitors
New-
60
Name HMG-CoA reductase inhibitors (statins)
```
Atorvastatin
Fluvastatin
Lovastatin
Pitavastatin
Pravastastin
Rosuvastatin
Simvastatin
```
61
Name niacin
Niacin
62
Name fibrinic acid derivatives
Fenofibrate
| Gemfibrozil
63
Name bile acid sequestration
Cholestyramine
Cholesevelam
Colestipol
64
Name cholesterol absorption inhibitors
Ezetimibe
65
Name new treatments
Lomitapide
Mipomersen
Evolocumab, alirocumab
66
Dietary management of hyperlipidemia: when do
1at! Unless patient has evident coronary or peripheral vascular disease; patients with familial hypercholesterolemias always require drug therapy in addition to diet
67
How do dietary management
Total fat, cruise, and fructose increase vldl; alcohol can cause significant hypertriglyceridemia by increasing hepatic secretion of vldl; synthesis and secretion of vldl are increased by excess calories; during weight loss, LDL and VLDL levels may be much lower than can be maintained during neutral caloric balance (concluding that dietary changes suffice for lipid management can only be made after weight has stabilized for 1 month)
Generally dietary recommendations : limit total calories from fat 20-25% of daily intake, saturated fats to less than 8% of daily intake, cholesterol to less than 200 mg.day; reductions in serum cholesterol range from 10-20% adhering to these recommendations
68
Name HMG Coa reductase inhibitors
Statins
69
What are statins
Most effective agents in reducing LDL levels and best tolerated class of lipid lowering agents
70
Pharmacokinetics
Oral absorption varies from 40-75% with the exception of fluvastatin (almost completely absorbed; statin absorption enhanced bt food)
Big first pass metabolism
Plasma half lives range
Most excreted in bile
Metabolized by CYP3A4(lovastatin, simvastatin, atorvastatin)
Metabolized by CYP2C9 (fluvastatin and rosuvastatin )
Metabolized by 450 (pitavastastin ) limited
Pravastatin not CYP450@ metabolized
Pravastatin
71
MOA statins
Structural analogs of HMG-CoA (initial precursor of cholesterol) and inhibit MHG-CoA reductase, the rate limiting enzyme in cholesterol synthesis; inhibiting de node cholesterol synthesis depletes the intracellular supply of cholesterol, which causes the cell to increase the number of specific cell surface LDL receptors that can bind and internalize circulating LDLs; increased expression of surface LDL receptors reduced circulating LDL levels; can reduce LDL levels 20-55%
72
Potency statin
Atorvastatin=rosuvastatin>simvastatin>pitavastatin=lovastatin=pravastatin?fluvastatin
73
Therapeutic benefits statins
Plaque stabilization, improvement of coronary endothelial function, inhibitoin of platelet thrombus formation, and anti-inflammatory effects
Statins are effective in lowering plasma cholesterol levels in all types of hyperlipidemia; used alone or with resins, niacin or ezetimibe; and are primarily taken night (cholesterol synthesis occurs at night) except the longer acting atorvastatin, pitavastatin, rosuvastatin
74
Why statin taken at night
Cholesterol synthesis occurs at night
Except longer acting atorvastatin , pitavastatin, rosuvastatin
75
Liver AE statin
Elevations of serum aminotransferase activity (up to 3x normal in patients with liver disease or a history of alcohol abuse); levels decrease upon suspension of drug therapy
76
Muscle AE statin
Creatinine kinase activity levels may increase, particularly in patients who have a high level of physical activity; rhabdomyolysis (leading to myoglobinuria) can occur rarely and lead to renal injury; myopathy can occur with monotherapy; increased incidence of myopathy in Athens concomitantly taking statins and fibrates
77
Statins and war fin
Increase warfarin levels
78
Contraindications statins
Pregnant, Lactation or likely to become pregnant,
Liver disease or skeletal muscle myopathy
Kids restricted to those with homozygous familial hypercholestermia and some patients with heterozygous
Caution with other agents that inhibit , compete with or induce CYP 450 enzymes (except pravastatina Nd pitavastatin)
79
What does niacin do
Decrease TG, LDL, LP; increase HDL
80
Pharmacokinetics niacin
Converted to nicotinamide and is incorporated into NAD; well absorbed; distributed to mainly hepatic, renal, and adipose tissues extensive first pass metabolism; half life approximately 60 minutes (2x or 3x daily dosing)
81
MOA niacin
Inhibits the lipolysis of TG in adipose tissue (the primary producer of circulating FFA)
By reducing circulating FFA, the liver produces less VLDL and LDL levels decreased
Catabolic rate for HDL is decreased
Fibrinogen levels are reduced ant tissue plasminogen activator levels are increased
82
AE niacin
Intense cutaneous flush accompanied by an uncomfortable feeling of warmth that occurs after each dose when drug is started or when the dose is increased (asprin taken before niacin or once daily ibuprofen can mitigate the flushing, which is prostagladin mediated)
Pruritis, rash, dry skin or mucous membranes, acanthosis nigricans
Hepatotoxicity (monied liver enzymes0
83
Contraindications niacin
Hepatic disease or active peptic ulcer
Causation with DM-niacin induced insulin resistance, which can cause hyperglycemia —see acanthosis nigricans due to elevated insulin)
84
Niacin adipose tissue effect
Decrease hormone sensitive lipase->decreases plasma FFA
85
Liver niacin
Decreases apoA-i clearance which increases plasma HDL which increases cholesterol delivery-> increased excretion of cholesterol in bile
The decrease in FFA from adipose causes decrease in TG synthesis which decreases VLDL/LDL plasma -> decreases cholesterol delivery to peripheral cells
86
Peripheral cells niacin
Decrease in VLDL /LDL causes decrease cholesterol delivery which
Increased cholesterol removal causes increase HDL plasma which increases cholesterol delivery to liver which increase excretion of cholesterol in bile
87
Name fabric acid derivatives (fibrates)
Gemfibrozil
Fenofibrate
88
Pharmacokinetics fabric acid derivatives
Well absorbed when taken with a meal but less when taken on an empty stomach; gemfibrozil half life is 1.5 hours;
Fenofibrate half life is 20 hours
89
MOA fabric acid derivatives (fibrates)
Agonists for peroxisome proliferator-activated receptor alpha (PPARa), when activated, PPARa binds to DNA, regulating the expression of genes encoding proteins involved in lipoprotein structure and function (lipoprotein lipase, app A-I, app A-II expression is increased and apo C-III is decreased)
Major effect is increased oxidation of FA in liver and striated muscle
Increased lipolysis of TG via lipoprotein lipase while intracellular lipolysis in adipose tissue is decreased
VLDL levels decrease, LAL modestly decrease in most patients (LDL levels can increase as TG are reduced), HDL increase moderately
90
Why use fibrates
Management of hypertriglyceridemias where VLDL predominates, dysbetalipoproteinemia, and hyperTG that results from treatment with viral protease inhibitors
91
AE GI fibrocartilage acid derivatives
Mild GI disturbances are msot common and usually subside; increased the risk of cholelithiasis (due to an increase int he cholesterol content of bile) and should be used with caution in patients with biliary tract disease or in those at high risk (women, obese, native Americans
92
Fibrates and liver
Increased serum transaminases (3x normal)
93
Muscle fibrates
Myositis can occur (evaluate for muscle weakness and tenderness) myopathy and rhabdomyolysis have been reported (increased risk when fibrates and statins combined)
94
Fibrates anticoagulants
Fibrates May potentiation the actions of anticoagulants
95
Fibrates contraindications
Avoided in part it’s with hepatic or renal dysfunctional safely has not been established in pregnant or lactating women
96
How do fabric acid derivatives work
PPARa activation
97
What is PPARa activation cause
Increased apoAI, aIII synthesis in hepatocytes
(Increase HDL)
Decrease apoCIII synthesis in hepatocytes increase lipoprotein lipase expression in muscle vascular beds
(Decrease plasma TG)
Increase FA oxidation in hepatocytes
(Decrease plasma TG)
98
Name bile acid sequesterants (resins)
Colestipol, cholestyramine, colesevelam
99
Pharmacokinetics bile acid sequestrants
Large polymeric cationic exchange resins that are insoluble in water; neighbor absorbed nor metabolically altered by the intestine; totally excreted int he feces
100
MOA bile acid sequestrants
Positively changed compounds bind to negatively charged bile acids (metabolites of cholesterol) and increase bile acid excretion up to tenfold; increased excretion of bile acids enhance the conversion of cholesterol to bile acids int he liver via 7a-hydrocylation (normally controlled by negative feedback via bile acids) the decline in hepatic cholesterol stimulates an increase in hepatic LDL receptor, which enhances LDL clearance and lowers levels; however this effect is partially offset by enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase (therefore, combined use of statin substantially increases the effectiveness of resins)
101
Why use bile acid sequestrants
Bile acid sequestrants are used to treat patients with primary hypercholesterolemia (reduces LAL by 20%);
Monotherapy or in combination with niacin for treatment of Type II a and type IIb hyperlipidemia; use to relieve pruritus in patients who have bile salt accumulation
102
AE GI bile acid sequestrants
The most common, high doses impair the absorption of fat soluble vitamins ADEK
Impaired absorption of numerous drugs, including tetracycline, phenobarbital, digoxin, warfarin , pravastatin, fluvastatin, asprin and thiazide diuretics
103
How give resins
Additional meds given at least 1 hour before or at least 2 hours after
104
Contraindications bile acid sequestrants
Avoid or use with caution in patients with diverticulitis, preexisting bowel disease, or cholestasis
105
Name cholesterol absorption inhibitors
Ezetimibe
106
Pharmacokinetics ezetimibe
Highly water insoluble
Majority is excreted int he feces
22 hr half life
107
MOA ezetimibe
Selectively inhibits intestinal absorption of cholesterol and phytosterols
Thought to inhibit the transport protein NPC1L1
Effective even in the absence of dietary cholesterol due to inhibition of reabsorption of cholesterol excreted in bile
On average, ezetimibe lowers LDL by 18% and TG by 6% while raising HDL levels slightly 1.3%
108
Uses of cholesterol absorption inhibitors
Treat various causes of elevated cholesterol levels (hypercholesterlmia), homozygous familial hypercholesterolemia
Mixed hyperlipidemia I
109
AE ezetimibe
Avoid with bile acid sequesterants due to impaired ezetimibe absorption
110
List drugs that decrease LDL most to least
Statin>bile acid sequesterants>niacin>fibrates=cholesterol absorption inhibitor
111
List drug effect of HDL increase most to least
Niacin>fibrates>statins>bile acid sequesterants=choesltol absorption inhibitor
112
Effect of drugs on TG lowering most to least
Fibrates>niacin>statins>cholesterol absorption inhibitor>bile acid sequesterants
113
What is homozygous familial hypercholesterolemia
Mutations leading to dysfunctional LDL receptors incapable of taking up LDL fromt he bloodstream; reductase inhibitors rely on functional LDL receptors to achieve a LDL lowering effect and will not work in patients with homozygous familial hypercholestermia
114
Lomitapide MOA
Directly binds to an inhibits microsomes TG transverse protein MTP which is located in the lumen of the endoplasmic reticulum. MTP inhibiton prevents the assembly of apo-B containing lipoproteins in enterocytes and hepatocytes resulting in reduced production of chylomicrons and VLDL and subsequently reduces plasma LDL-C concentrations
115
CYP3A4 lomitapide
Substrate and inhibitor of CYP3A4, causing interactions with a number of drugs; most common AE effects are GI symptoms, increased liver aminotransferase levels, and hepatic fat accumulation (>250000$ a year)
116
MOA mipomersen
Antisense oligonucleotide that targets apolipoprotein B-100 mRNA and disrupts its function; ApoB-100 is the ligand that binds LDL to its receptor and is important for the transport and removal of atherogenic lipids; elevated levels of apoB, LDL-c and VLDL are associated with increased risk of atherosclerosis and cardiovascular diseases
117
AE mipomersen
Injection site reactions (SQ injection one time a week)
Flu like symptoms, HA, elevation of liver enzymes>3 times the upper limit of normal (discontinue if elevations persist or are accompanied by clinical symptoms, such as hepatic steatosis) 176,000 a year
118
Statin MOA
Inhibit HMG-CoA reductase
119
Effects statin
Reduce cholesterol synthesis and upregulate LDL receptors on hepatocytes+modest reduction in TG
120
Clinical statins
Atherosclerotic vascular disease (primary and secondary prevention) + acute coronary disease
121
PK statins
Oral 12-24 hours
122
Toxicity statin
Myopathy , hepatic dysregulation
123
Interactions statin
CYP dependent metabolism (3A4, 2C9) interacts with CYP inhibitors/competitors
124
Fibrates MOA
Peroxisome proliferator activated receptor alpha PPARa agonist
125
Effects fibrates
Decreases secretion of vldl, increases lipoprotein lipase activity, increase HDL
126
Clinical fibrates
HyperTG, low HDL
127
PK fibrates
Oral duration 3-24 hours
128
Toxicity fibrates
Myopathy, hepatic dysfunction
129
Bile acid sequesterants MOA
Binds bile acids in gut and prevents reabsorption and increases cholesterol catabolism and upregulated LDL receptors
130
Effects bile acid sequesterants
Decrease LDL
131
Clinical bile acid sequesterants
Elevated LDL, digitalis toxicity, pruritis
132
PK bile acid sequesterants
Take with meals not absorbed
133
Toxicity bile acid sequesterants
Constipation, bloating, interferes with absorption of some drugs and vitamins
134
Cholesterol absorption inhibitor MOA
Blocks sterol transporter NPC1L1 in intestine brush border
135
Effects cholesterol absorption inhibitors
Inhibits reabsorption of cholesterol excreted in bile and decreased LDL and phytosterols
136
Clinical cholesterol absorption inhibitor
Elevated LAL, phytosterols is
137
PK cholesterol absorption inhibitor
Oral 24 hours
138
Toxicity cholesterol absorption inhibitor
Low incidence of hepatic dysfunction, myositis
139
Niacin MOA
Decrease catabolism of apo AI and reduced VLDL secretion from liver
140
Effects niacin
Increases HDL and decreases LDL
141
Clinical niacin
Low HDL , elevated VLDL, elevated LDL in statin unresponsive or intolerant patients
142
PK niacin
Oral large doses
143
Niacin toxicity
Gastric irritation, flushing, low incidence of hepatic toxicity, may reduce glucose tolerance
144
PCSK9 humanized monoclonal antibodies MOA
Complexes PCSK9
145
Effects PCSK9 humanized monoclonal antibodies
Inhibits catabolism of LDL receptor
146
Clinical PCSK9 humanized monoclonal antibodies
Familial hypercholesterolemia not responsive to oral therapy
147
PK PSCK9 humanized monoclonal antibodies
Parenteral
148
Cost PCSK9
14,000 a year
149
Toxicity PCSK9 humanized monoclonal antibodies
Injection site reactions, nasopharyngitis, flu like, rarely myalgia, neurocognitice and ophthalmologist events
150
Drug classes used in thromboembolic disorders
Parenteral anticoagulants
Oral anticoagulants
Antiplatelet drugs
Thrombocytosis (fibrinolytic) drugs
151
Name parenteral anticoagulants
Indirect thrombin and factor Xa inhibitors
Direct thrombin inhibitors
152
Name indirect thrombin and factor Xa inhibitors
Unfractioned heparin
-heparin sodium
Low molecular weight heparin
- enoxaparin
- tinzaparin
- dalteparin
153
Name direct thrombin inhibitors
Lepirudin
Bivalirudin
Argatroban
154
What are oral anticoagulants
Coumadin anticoagulatnts
Direct oral anticoagulatnts
155
Name Coumadin anticoagulants
Warfarin
156
Name direct oral anticoagulatns
Factor Xa inhibitors
-rivaroxaban
-apixaban
—edoxaban
Direct thrombin inhibitor
-dabigatran
157
What are antiplatelet drugs
Inhibitors of thromboxane A2 synthesis
ADP receptor blockers
Platelet glycoproteins receptor blockers
Inhibitors of phosphodiesterases
158
Name inhibitors of thromboxane A2
Asprin
159
Name ADP receptor blockers
Clopidogrel
Prasugrel
Ticlopidine
Ticagrelor
160
Name platelet glycoproteins receptor blockers
Abciximab
Aptifibatide
Tirofiban
161
Inhibitors of phosphodiesterases
Dipyridamole
Cilostazol
162
What are thrombocytosis (fibrinolytic) drugs
Tissue type plasminogen activator drugs
Urokinase type plasminogen activator
Streptokinase
163
Name tissue type plasminogen activator drugs
Alteplase
Reteplase
Tenecteplase
164
Name urokinase type plasminogen activator
Urokinase
165
Name streptokinase preparations
Streptokinase
166
Blood clot
All clots involve both platelets and fibrin but the degree of involvement of platelet/fibrin in thrombus formation depends not he vascular location
167
White thrombus (platelet rich)
Forms in high pressure arteries and is the result of platelet binding to the damaged endothelium and aggregation with little involvement of fibrin
Pathological condition associated with white thrombi: local ischemia due to arterial occlusion (in coronary arteries: MIunstable angina)
168
Red thrombus (fibrin rich with trapped RBC)
Forms in low pressure veins and in heart; result of platelet binding and aggregation followed by formation of bulky fibrin tails in which red blood cells become enmeshed
Pathological conditions associated with red thrombi: pain and severe swelling, embolism and distal pathology (embolic stroke)
169
Anticoagulants
Regulate the function and synthesis of clotting factors
Used to prevent clots from forming in the venous system and heart (red thrombi)
170
Antiplatelet drugs
Inhibit platelet fruition
Primarily used to prevent clots from forming in the arteries (white thrombi)
171
Thrombocytosis
Destroy blood clots after they are formed
Re establish blood flow through vessels once clots have formed
172
How do antiplatelet drugs work
ADP
TXA2
5-HT increase
173
How do thrombolytics work
Fibrin?
174
How do anticoagulants work
Intrinsic and eextrinsic _>Xa turns prothrombin into thrombin
175
Indirect parenteral anticoagulants
Unfractionated heparin
-heparin sodium
Low molecular weight heparin
- enoxaparin
- tinzaparin
- dalteparin
Synthetic pentasaccharide
-fondaparinux
176
Direct thrombin inhibitos
Lepirudin
Bivalirudin
Argatroban
177
MOA indirect thrombin and FXa inhibitors
Indirect thrombin and FXa inhibitors-bind plasma serine protease inhibitor antithrombin III
Antithrombin III inhibits several clotting factor proteases, espicially thrombin (IIa), IXa, and Xa
In the absence of heparin, protease inhibition reactions are slow; heparin increases antithrombin III activity by 1000 fold
178
MOA HMW heparin
Inhibits the activity of both thrombin and factor Xa
179
MOA LMW heparin
Inhibitors factor Xa with little effect not hrombin
180
MOA fondaparinux
Inhibits factor Xa activity with no effect not hrombin
181
HMW vs LMW
Have practically equal efficiency in several thromboembolic conditions
LMW have increased bioavailability fromt he SC injection site and allow for less frequent injections and more predictable dosing
182
How is heparin given
Very hydrophilic, must be given IV or SC
183
What is heparin used to treat
Disorders secondary to red (fibrin rich) thrombi and reduce the risk of emboli
Protects against embolic stroke, pulmonary emboli
Administer to patients with DVT, atrial arrhythmias and other conditions that predispose towards red thrombi
Prevention of emboli during surgery or in hospitalized patients (reduce risk of emboli)
184
Heparin looks
Prevents clots from forming inc athletes
185
How monitor patients on heparin
Activated partial thrombophlebitis time (aPTT)
-measures the efficacy of the intrinsic (contact activation) pathway and a common pathways
- in order to activate the intrinsic pathway, phospholipids, activator(kaolin or silica) , and Ca are mixed with patients plasma
- evaluates serine protease factors (II, IX, X, XI, XII) affected by heparin
Anti-Xa assay
-designed to examine proteolytic activity of factor Xa
186
AE heparin
Bleeding
Heparin induced thrombocytopenia
-immunogenicity of the complex of heparin with platelet factor 4 (PF4)
187
What to look for in a patient on heparin
```
Thrombocytopenia (platelet removal by splenic macrophages)
and thrombosis (platelet aggregation)
```
188
HIT
A systemic hypercoagulable state
Characterized by venous and arterial thrombosis
Relate to the immune response to heparin
189
Treat HIT
To discontinue heparin and administer DTI
190
Contraindications heparin
Severe HTN
Active tuberculosis
Ulcers of GI tract
Patients with recent surgeries
191
How reverse heparin action
Protamine sulfate
192
Indirect factor Xa inhibitors
Fondaparinux
193
Fondaparinux
Synthetic pentasaccharide
194
MOA fondaparinux
Binds to antithrombin to indirectly inhibit factor Xa
- high affinity reversible binding to antithrombin III
- conformational change in the reactive loop greatly enhances antithrombin basal rate of factor Xa inactivation
- acts as an antithrombin III catalyst
195
How is fondaparinux unlike heparin
Does not inhibit thrombin activity
Rarely induces HIT
It’s action is not reversed by protamine sulfate
196
Clinical indications for heparin
Prevention of DVT
Treatment of acute DVT(in conjunction with warfain)
Treatment of pulmonary embolism
197
MOA direct thrombin inhibitors
Direct inhibitoin of the protease activity of thrombin
198
I valentines direct thrombin inhibitors (bind at both active site and substrate recognition site)
Lepirudin
Bivalirudin
199
Direct thrombin inhibitos that bind only at the thrombin active site
Argatroban
200
Lepirudin
Recombinant form of hirudin (which was originally purified from medicinal leeches)
Identical to natural hirudin except for substitution of leucine for isoleucine at the N terminal end of the molecule and the absence of a sulfate group on the tyrosinase at position 63
Irreversible inhibitor of thrombin
201
Bivalirudin
A synthetic, 20 aa peptide
Reversible inhibitor of thrombin
Also inhibits platelet aggregation
202
Argatroban
A small molecular weight inhibitor
Short acting drug-used intravenously
203
Clinical indications for direct thrombin inhibitors -parenteral
```
HIT
Coronary angioplasty (bivalirudin and argatroban)
```
204
AE direct thrombin inhibitors
Bleeding (should be used with caution as no antidote exists)
Repeated lepirudin use may cause anaphylactic reaction
205
Oral anticoagulatnts
Coumadin
-warfarin
```
Direct oral anticoagulants
-factor Xa inhibitors
—rivaroxaban
—apixaban
—edoxaban
```
Direct thrombin inhibitor
-dabigatran
206
Warfarin
Most commonly prescribed anticoagulatn in USA
207
MOA warfarin
Inhibits reactivation of vitamin K by inhibiting enzyme vitamin K episode reductase
Inhibits carboxylation of glutamate residues by GGCX in prothrombin and factors VII, IX, and X making them inactive
208
What proteins are affected by warfarin
Factor II
Hemostasis factors VII, IX, and X
Other proteins that function in apoptosis, bone ossification, extracellular matric formation
Carboxylation of glutamate residues is one of the common mechanisms of posttranslational modification of proteins
-converts hypofunction OA hemostatic factors into functional ones
209
Pharmacokinetics warfarin
Two stereoisomers: R and S
| S isomer is 3 to 5 fold more potent
210
R warfarin metabolization
CYP3A4
211
S warfarin metabolized
CYP2C9
212
OH derivatives are pumped out of hepatocytes by ABCB transporter into bile
Excreted with bile
213
How administer warfarin
Administer orally
| 100% bioavailability
214
Onset and half life of warfarin
12 hour onset delay
36 hour half life
215
99% of warfarin is bound to __
Plasma albumin (responsible for its small volume of distribution and a long half life)
216
Why do correct warfarin doses vary widely from patient to patient
Significant individual variability based on disease states and genetic make up
Multiple drug interactions
217
Clinical uses warfarin
Prevent thrombosis or prevent/treat thromboembolism
A fib
Prosthetic heart valves
218
AE warfarin
Teratogenic effect (bleeding disorder in fetus, abnormal bone formation)
Skin necrosis, infarction of breasts, intestines, extremities
Osteoporosis
Bleeding
219
Warfarin dose is titrations based on laboratory testing
PT-time to coagulation of plasma after the addition of a tissue factor (TF or factor III)-used for the evaluation of the extrinsic pathway
```
INR
.9-1.3 normal
.5 high chance of thrombosis
4-5-high chance of bleeding
2-3-range for patients on warfarin
```
220
PK warfarin
VKORC1 (vit K epoxied reductase complex subunit 1)-responsible for 30% variation in dose (low and high dose HaplotypE)
221
Who has high dose HaplotypE warfarin
African Americans, more resistant to warfarin
222
Who has low dose HaplotypE warfarin
Asian they are less resistant to warfarin
223
___-responsible for 10% variation in dose, mainly among Caucasian patients
CYP2C9
224
Warfarin drug interactions PK
CYP enzyme induction
CYP enzymes inhibiton
Reduced plasma protein binding
225
Pharmacodynamic warfarin interactions
Synergism with other antithrombotic drugs
Competitive antagonism (vit K)
Clotting factor concentration (diuretics)
226
Warfarin a disease states
Liver disease (reduced clotting factor synthesis)
Thyroid status
Warfarin and diet
227
What pharmacokinetics increase PT
Amiodarone
Cimetidine
Disulfiram
Metronidazole
Fluconazole
Phenylbutazone
Sulfinpyrazone
TMP-SMX
228
Pharmacodynamic increase PT
Asprin
Cephalosporins, third gen
Heparin
Hepatic disease hyperthyroidism
229
Pharmacokinetic decrease PT
Barbiturates
Cholestyramine
Rifampin
230
Pharmacodynamic decreased PT
Diuretics
Vit K
Hypothyroidism
231
Advantages of warfarin
Oral administration
Long duration of action
Drug clearance is independent of renal function
Reversal of action strategy has been developed
- vit k administration usually reverses warfarin action 12-24 hours
- if more rapid reversal is needed fresh frozen plasma or prothrombin complex concentrate are given
232
Warfarin drawbacks
Very high dosing variability, maintaining optimal drug concentration is difficult
This may lead to bleeding complications, such as intracranial hemorrhages
Requires INR monitoring
233
DOAC
Oral XA
Rivaroxaban
Apixaban
Edoxaban
Oral IIa
Dabigatran
Parenteral
XA
Fondaparinux LMWH
IIa
Argatroban
Bivalirudin
234
Clinical use of rivaroxaban, apixaban, edoxaban
Prevention of thromboembolism
Treat thromboembolism
Prevention of stroke in patients with atrial fib
235
Advantages rivaroxaban, apixaban, edoxaban
Given orally
Administered at fixed doses and do not require monitoring
Shown non inferiority compared with warfarin
Rapid onset of action as compared to warfain
236
Drawbacks rivaroxaban, apixaban, edoxaban
Excreted by kidneys; dose adjustment is needed in renal patients
237
Dabigatran
First oral DOAC approved by FDA
238
Clinical use dabigatran
To reduce the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation
Treatment of venous thromboembolism
239
Advantages dabigatran
Predictable pharmacokinetics and bioavailability
Fixed dosing and predictable anticoagulant action (no INR monitoring required)
Rapid onset and offset of action
No interaction with P450 metabolized drugs
Antidote approved
240
Antidote dabigatran
Idarucizumab-humanized antibody fragment that binds dabigatran with high affinity to prevent dabigatran inhibition of thrombin
241
Disadvantages dabigatran
80% renal excretion-may not be suitable in renal patients
242
Antidoes to HMV, LMW heparin
Protamine sulfate
243
Antidote to warfarin
Vitamin K, prothrombin complex concentrate
244
DOAC-FXa inhibitors antidote
Andexanet alfa
245
DOAC-DTI antidote
Idarucizumab
246
Heparin blood coagulation tests
APTT, anti Xa
247
Warfarin blood coagulation tests
PT-based (INR)
248
DOAC -FXa inhibitors blood coagulation tests
Anti-xa
249
DOAC -DTA blood coagulation tests
Diluted thrombin time (TT)
250
APTT
Intrinsic pathway
251
Anti Xa
Xa
252
Extrinsic pathway
PT
253
IIa
Diluted TT
254
Categories of antiplatelet drugs
Inhibitors of thromboxane A2
ADP receptor blockers
Platelet glycoprotein receptor blockers
Inhibitors of phosphodiesterase
255
Inhibitors of thromboxane A2 synthesis
Asprin
256
ADP receptor blockers
Clopidogrel
Prasugrel
Ticlopidine
Ticagrelor
257
Platelet glycoprotein receptor blockers
Abciximab
Eptifibatide
Tirofiban
258
Inhibitors of phosphodiesterases
Dipyridamole
| Cilostazol
259
MOA asprin
Inhibiton of cyclooxygenase
Decreased TXA2 production
260
Clinical use of asprin
Primary and secondary prevention of a heart attack and other vascular events (ischemic stroke, arterial thrombosis of the limbs resulting in intermittent claudication)
261
AE asprin
Peptic ulcer
| GI bleeding
262
MOA antiplatelet drugs
Blockers of ADP receptors
- inhibition of AC by a is relieved
- increased production of cAMP
Inhibitors of phosphodiesterase
- inhibition of cAMP degradation
- levels of cAMP in platelets are increased
263
Pharmacogenomics of clopidogrel
High variability of clopidogrel action
Related primary to metabolism by CYP2C19 isoenzymes
Nonfunctinal CYP2C19 allele is present in 50% Chinese, 34% african Americans, 25% caucasians, and 19% Mexican Americans
Cytochrome p450 status does not affect the use of other ADPKD receptor antagonists
264
Platelet glycoprotein (GP) IIb/IIIa is an integrins binding to extracellular ligand: fibrinogen, vitronectin, fibronectin, Von Willie Randolph factor
Ok
265
Platelet GP receptor antagonists
Target Arg-Glu-Asp (RGD) sequence
Prevent binding of ligand to the GP IIbIIIa receptor to inhibit platelet aggregation
266
GP Iib/IIIa antagonists work
GP Iib/IIIa receptors
267
What are the GP IIb/IIIa antagonists
Abciximab, tirofiban ,eptifibatide
268
Clinical use of antiplatelet drugs
Prevention of thrombosis in unstable angina and other acute coronary syndromes
Prevention of ischemic stroke and arterial thrombosis in peripheral vascular disease
In patients undergoing percutaneous coronary angioplasty and stunting
Inhibitors of phosphodiesterase are considered adjunct antiplatelet agents and used in combination with other antiplatelet agents or anticoagulatns
- dipyridamole with asprin to prevent cerebrovascular ischemia
- dipyridamole with warfarin in patients with prosthetic heart valves
- cilostazol is primarily used to treat intermittent claudication
269
MOA thrombolytics drugs
Activate endogenous fibrinolytic system by converting plasminogen into plasminogen
270
Plasminogen
Plasma zymogen that forms active enzyme upon cleavage of the peptide bond between arg-560 and val-561 by tPA or uPA
271
Plasmin
Activate serine protease that cleaves and degrades fibrin and other proteins (fibronectin, laminin, thrombospondin, vWF)
272
Types of fibrinolytic drugs (they alla ctivate plasminogen to plasmin)
Tissue type plasminogen activator (tPA)-endogenous protein that cleaves plasminogen, released by endothelium, needs fibrin as coactivator
Urokinase type plasminogen activator (urokinase, uPA)-endogenous protein , produced in kidneys; a human enzyme directly converting plasminogen to plasmin
Streptokinase-protein released by b-hemolytic streptococci, forms the complex with plasminogen, converts it into plasmin by non-proteolytic mechanism
273
TPA tissue type plasminogen activator drugs
Alteplase:recombinant human protein
Reteplase:recombinant modified human protein
Tenecteplase:recombinant mutated human protein
274
UPA urokinase type plasminogen activator
Urokinase
275
Streptokinase preparations
Streptokinase: purified from bacteria
276
Clinical uses thrombolytics (fibrinolytic) drugs
Acute ambolic/thrombotic stroke (within 3 h)
Acute MI
Pulmonary embolism
DVT
Ascending thrombophlebitis
277
Clot in cerebral artery-stroke
Treat with t-PA to break down the clot and open up artery
Most effective within 3 hours after embolic and thrombotic stroke
Can exacerbate the damage produced by hemorrhagic stroke
278
AE fibrinolytic drugs
Bleeding from the systemic fibrinogenolysis (streptokinase, urokinase)
Allergic reactions (streptokinase)
Systemic fibrinogenolysis with streptokinase and urokinase
279
Streptokinase, urokinase
Nonfibrin specific or less fibrin specific plasminogen activators
280
TPA
Fibrin specific plasminogen activators
281
Treat acute angina of classic angina
| Resting ekg is normal
Nitroglycerin
Normal HR normal BP sitting there and intermittent symptoms
And atorvastatin and asprin
282
How administer nitroglycerin for acute angina
Sublingual so bypass the first pass effect
Quick to heart where need it to exerting effect
283
Which body regulatory factor mimicked by nitroglycerin
NO (EDRF) comes from endothelial cells synthesized from arginine
284
What does NO increase
CGMP
285
MOA nitroglycerinwhich of the following treats angina
Forms free radical NO which in smooth muscle activates soluble GC->increase cGMP->dephosphorylation of myosin light chains and smooth msucle relaxation
286
Effects of nitroglycerin
Veins vasodilator
Reduced cardiac oxygen demand by decreasing preload
Modestly reduce afterload
Dilated coronary arteries/improves collateral flow
287
Clinical nitroglycerin
Acute angina pectoris or prevention
Acute decompensated heart failure (espicially when associated with acute MI)
Perioperative HTN (espicially during surgery)
Induction of intraoperative hypotension
288
Off label nitroglycerin
Intra anal treat anal fissure pain
Short term for GI and pulmonary arterial smooth muscle relaxation
289
Toxicities
Reflex tachycardia
Flushing
Hypotension , orthostatic hypotension
Peripheral edema
HA
N/v/xerostermia
Paresthesia, weakness,
Dyspnea, pharyngitis, rhinitis, diaphoresis
290
Direct consequence of nitroglycerin
Ok
Endothelial
291
Isosorbide mono and donate similar drugs with
Slower onset of action
292
Nifedipine MOA
Prototypical dihydropyridine CCB
Inhibits calcium ion channels or select voltage sensitive areas of vascular smooth muscle and myocardium during depolarization
293
Effects nifedipine
Cause relaxation of coronary vascular SM muscle->coronary vasodilation
Increases myocardial oxygen delivery in patients with vasospastic angina
Negative inotropy but less so than verapamil
Reduces vascular resistance, producing a reduction in arterial bp
Frequency independent not cardioactive
294
Clinical application nifedipine
Management of chronic stable or vasospastic angina
Treat HTN (sustained release products only)
First line for HTN
Non black without CKD
Black without CKD including those with diabetes, instead of an ACE or ARB
295
Off label nifedipine
HTN emergency of pregnancy
Preterm labor
Raynaud phenomenon
Pulmonary HTN
296
Pharmacokinetics nifedipine
Immediate and extended
Extensive hepatic metabolism via CYP34A
T1/2 2- 5hours increased by cirrhosis
Metabolites eliminated in urine
297
Toxicities nifedipine
Common-Flushing , peripheral edema
Dizzy, HA, nausea, heart burn.
Rare-Palpations and gingival hyperplasia
298
What if unstable and stable angina add after
Want drug exerts crease HR, myocardial contractility and wall tension
Dilitizam-decrease afterload, SA node,
But nadolol bc
299
Amlodipine
Limited to CAD and HT, but very widely used in part due to long HL 30-50 hours
300
Verapamil MOA
CCB non dihydropyridine
Inhibits Ca ion channels from entering the slow channels or select voltage sensitive areas of vascular smooth muscle and myocardium during depolarization
301
Effects verapamil
Produces relaxation of coronary vascular SM and coronary vasodilation
Increases myocardial oxygen delivery in patients with VASOSPASTIC angina
Slows AV
Decrease myocardial contractility, more negative inotropy than nifedipine or dilitazam
Frequency dependent
302
Clinical verapamil
IV: supraventricular tachycardia
Oral, treatment of
Primary HTN (CCB first line in JNC8)
Angina pectoris (vasospastic, chronic, stable, unstable)
Supraventricular tachycarrhythmia
303
Off label verapamil
Episodic migraine prevention , hypertrophic cardiomyopathy
304
Pharmacokinetics verampamil
Available as tablets with immediate and extended release as IV solution
Undergoes extensive hepatic metabolism via multiple YPs
Majority of metabolites are excreted in Irvine
T1/2 3-7 hours
305
Toxicities verapamil
Common-HA, gingival hyperplasia, constipation
Rare-peripheral edema, CHF, pulmonary HTN, AV block, flush rash, dyspepsia, flu like
306
Propranolol MOA
Nonselective competitive beta adrenergic blocker
Class II antiarrhythmic
Decrease camp
Block AC
307
Effects propranolol
Beta 1 block
Decreased HR, decreased myocardial contractility, decrease blood pressure, myocardial oxygen demand
Beta 2 block
Blunting of bronchodilator less vasodilation
308
What drug give instead b blocker if has asthma
Ok
| Metroprolol it is selective b1
309
Clinical propranolol
HTN
Angina pectoris
Pheochromocytoma
Essential tremor
Supraventricular arrhythmias
Ventricular tachycardia
Prevention of myocardial infarction
Migraine HA prophylaxis
310
Off label propranolol
Akathisia, antipsychotic induced performance anxiety
311
Pharmacokinetics propranolol
Given orally
25% reaches systemic circulation due to high first pass metabolism
Extended release formulation available
Also solutions for oral IV administration
312
Toxicities propranolol
Bronchospasm,dyspnea
Cold extremities
Bradycardia, AV conduction disturbance
CHF, cardiogenic shock, hypotension, syncope
Disrupted sleep with nightmares
Hyperglycemia or hypoglycemia, hyperkalemia, hyperlipidemia
Abdominal pain, diarrhea, constipation
Conjunctival decreased vision
313
What b blocker if cant sleep so tired
Atenolol
314
MOA atenolol
B1 selective
Antagonist
Little or no effect on B2 receptors except at high doses
Less CNS effect
315
Effects atenolol
B1 blocker
Decreased HR
Decreased myocardial contractility
Decreased blood pressure
Decreased myocardial oxygen demand
316
Clinical atenolol
Treatment of HTN, alone or in combination with other agents
Management of angina pectoris
Secondary prevention postmyocardial infarction
317
Vascular disease
Contraindication for b block decrease b2 mediated vasodilation and cold extremities
318
Off label atenolol
A fib
319
Pharmacokinetics atenolol
PO rapid but incomplete 50% absorption
Not lipophilic no cross BBB
T1/2 6-7 hours
Verampamil
Amlodipine-no reflex tachy
320
AE atenolol
Bradycardia persistent
2, 3 degree atrioventricular block
Cardiac failure, chest pain, hypotension
Cold extremities edema, raynaud
Confusion fatigue HA insomnia, lethargy nightmare
Constipated
IMPOTENCE
321
Metoprolol
Selective beta 1 blocker shorter HL than atenolol but available in extended release form; more lipid soluble so more likely to produce CNS effects
322
Bishop roll
Notable for having highest b 1 selectivity
323
Ranolazine MOA
Inhibits the late phase of the inward Na channel in ischemic cardiac myocytes during cardiac depolarization
Reducing intracellular sodium concentrations enhances calcium efflux via Na Ca exchange
Decreased intracellular calcium reduces ventricular tension and myocardial oxygen consumption
324
Effects ranolazine
Exerts antianginal and anti ischemic effects without changing hemodynamic parameters
Presumed to occur bc ranolazine facilitates myocardial relaxation
325
Clinical application ranolazine
Chronic angina
Stable ischemic heart disease
May be useful as substitute for beta blockers for relief of symptoms if initial treatment with beta blockers has unacceptable side effects, is ineffective, or contraindicated
May also be used in combination with beta blockers for relied of symptoms when initial treatment with beta blockers is not successful
326
Verampamil work on veins
No
327
Pharmacokinetics ranolazine
Administered as extended release tablets
Extensive hepatic metabolism CYP3A4major and 2D6minor ...so be aware of other drugs
1/2=7 hours
328
AE ranolazine
Bradycardia , hypotension , orthostatic hypotension, palpitation, peripheral edema
Prolonged QT interval (dose related), HA, dizziness, confusion, vertigo, syncope
Sweating , constipation, ab pain, anorexia, dyspepsia, nauseas, vomiting , xerostomia, hematuria, weakness, blurredvision, tinnitus, dyspnea
329
What is not associated with ad of verapamil
```
Constipation
Facial flushing
Gingival hyperplasia
Reflex tachycardia
Worsening of heart failrue
```
Reflex tachycardia
330
Coronary artery bypass
Often better option vs PCI when drug are inadequate
331
But start with non surgical. What causes imbalance
Decrease o
Increase demand
Decrease supply and increase demand
Unlike skeletal msucles cant stop and rest
332
What regions of the heart are more poorly perfused
Subendocardial regions
333
Decrease preload
Decrease intraventrucular pressure->increase subendocardial perfusion
334
When is the heart suckle perfused
Between beats,
| Decrease time for coronary perfusion
335
Patient no asthma or peripheral vascular disease, frequent predicable chest pain
Nitroglycerin patch-NO reflex stimulation of heart
Dilate veins not lower bp anymore potentiallly increase
Ranolazine -cause reflex tachycardia but drop BP
336
Amlodipine
Frequent predictable chest pain been taking atenolol for 15 years due to HTN . Addition of
337
Reflex tachycardia
CCB caused significant angina
Nifedipine
338
Least likely to be useful for variant angina
| Atenolol, dilitazem, nifedipine, nitroglycerin, verampamil
Ateolol
339
without affecting traditional indices of heart work such as heart rate bp and rate pressure product
Ranolazine -potentiation relaxation of heart
Block late Na current —late Na current goes into heart continuous influx of Na normally need between beets to drive Na Ca exchanger to bring Ca out of cells.calsium stays in cell and accumulates. When heart not relax as fast, squish capillaries and not get as good a flow
340
MOA unfractioned heparin
Prepared from lungs of cattle and intestines of pugs
Long polysaccharide chains with weight 300-30000
Pentasaccharide sequence found randomly along length that binds to/activates antithrombin III to inhibitic Xa and via formation of a ternary complex, thrombin
341
Effects heparin
Blocks generation of thrombin from prothrombin and also inactivated thrombin
Prevents formation of red clots
342
Clinical unfractioned heparin
Whenever there is a need for rapid onset anticoagulant effects including pulmonary embolism, stroke, DVT, disseminated intravascular coagulation acute MI
In preg bc doesn’t cross placenta
Extracorporeal circuits
343
Antidote heparin unfractioned
Protamine, many positive change bonds ironically with the negative charges of heparin
344
Pharmacokinetics heparin unfractioned
Partenterally
Highly negative
Can’t cross membranes
Binds nonspecificallyhighly variable plasma levels which require intensive monitoring via aPTT assay
He 1.5 hours
345
AE unfractioned heparin
Don’t give thrombocytopenia and uncontrollable bleeding, avoid during surgery or brain eye or spine procedures
Bleeding!!
Monitor bp , hr buried
Spinal or epidural hematoma can cause paralysis
HIT
-potentially fatal immune mediated disorder characterized by reduced platelet counts with a paradoxical increase in thrombotic events
346
MOA low molecular weight heparins
Heparin molecules of shorter length
Can’t form ternary complex with antithrombin III and thrombin that is need to inactivate this , but factor Xa is inhibitors
347
Effects low molecular weight heparin
Block Xa
Prevents red clots
348
Clinical low molecular weight heparin
Prevent DVT
Abdominal surgery or hip knee surgery
Treat DVT with or withou pulmonary embolism
Prevent ischemic complications
349
Pharmacokinetics low molecular weight heparin
Easier oral dosing is predictable
PREVENT DVT
Longer HL
350
AE low molecular weight heparin
Bleeding
HIT
Neurological injury in spinal puncture or spinal or epiduarla anesthesia
351
Fondaparinux MOA
Synthetic pentassachharide identical to antithrombin binding structure of heparin
Selectively inhibits Xa
352
Effects fondaparinux
Blocks coagulation by preventing conversion of prothrombin to thrombin
No effect on thrombin
More effective than enoxaparin but risk of bleeding
353
Clinical fondaparinux
Prevent DVT
Treat acute pulmonary embolism in conjunction with warfarin
Treat acute DVT with warfarin
354
Pharmacokinetics fondaparinux
SubQ
Predictable
HL17 hrs
Longer if renal impairment too long?
355
AE fondaparinux
Bleeding
Not reversible with protamine
No HIT
356
Bivalirudin MOA
Synthetic 20 aa peptide similar to hirudin directly blocks thrombin
357
Effects bivalirudin
Reversible inhibits coagulation
358
Clinical bivalirudin
With asprin for angioplasty
359
Pharmacokinetics bivalirudin
IV expensive
360
AE bivalirudin
Doesn’t require antithrombin and causes less bleeding
No antidote
361
Lepirudin
Recombinant form of leech hirudin that binds thrombin irreversibly no longer marketed
362
Argatroban MOA
Binds to catalytic site of thrombin
363
Argabatran clncial
Prophylaxis treatment of thrombosis in patients with HIT
364
How is efficacy of argatroban monitored
APTT
365
Pharmacokinetics argatroban
IV
| HL 45 min
366
AE argatroban
Hemorrhage
367
Warfain MOA
Vitamin K antagonist
368
Effects warfarin
Decrease production of biologically active forms of calcium dependent clotting factors II VII IX X
Protein C and S
369
Clinical warfarin
Prophylaxis thrombosis
Prevent venous thrombosis, thromboembolism with mechanical heart valves, prevent thrombosis in a fib, effects delayed so not for emergencies
370
Pharmacokinetics warfarin
Oral 100% available
Bile elimination
Slow onset
Slow offset
INR monitor
371
AE warfarin
Bleeding
Crosses placenta
Drug interactions
Liver disease
Cutaneous necrosis-protein c has a shorter half life than several othe clotting factors so warfarin administration can initially cause procoagulant state
Skin necrosis
372
Reverse warfarin
Bit K
| Fresh whole blood plasma concentrates
373
Rivaroxaban MOA
Direct inhibitor of activated factor X
374
Effects rivaroxaban
Directly inhibits the production of thrombin
375
Advantages of rivaroxaban over warfarin
```
Rapid onset
Fixed dose
Lower bleeding
Fewer drug interactions
No need for INR monitoring
```
376
Clinical rivaroxaban
Prevent DVT and pulmonary embolism
Prevent stroke with a fib
377
Antidote rivaroxaban
None
378
Pharmacokinetics rivaroxaban
Oral high bioavailability
379
AE rivaroxaban
Bleeding
- epidural hematoma
- intracranial bleed
- adrenal bleed
- GI bleed
Don’t five renal or hepatic impairment
No preg
Not combined with anticoagulatnts other
CYP34A
380
Dabigatran MOA
Reversible direct thrombin inhibitor
381
Effects dabigatran
Directly blocks thrombin
382
Advantages dabigatran over warfarin
Rapid onset
Don’t need monitor
Few drug interactions
Low risk bleeding
Same dose for all
383
Clinical dabigatran
Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
384
Contraindication dabigatran
Mechanical heart valves
385
AE dabigatran
Bleeding
Antidote idarucizumab
386
Asprin MOA
Irreversible inhibits cyclooxygenase
387
Effects asprin
Blocks formation TXA2
Persists for lifetime of platelet 5-9 days
388
Clinical asprin
TIA, chronic stable and unstable angina
MI prevention
Acute MI
Prevent restnosis after stent
389
AE asprin
Bleed
| Ulcer
390
MOA clopidogrel
Irreversible block of P2Y12 receptors on platelets
Prevents its Gi protein driven decrease in platelet cAMP
391
Effects clopidogrel
Prevent stenosis of coronary stents
Secondary prevention of MI and ischemic stroke
392
Pharmacokinetics clopidogrel
Prodrug
CYP2c19
Some variants cant activate it-Chinese
393
AE clopidogrel
Well tolerated
Bleeding
394
Prasugrel
Close relative to clopidogrel more effective with fewer drug interactions, but also causes major bleeding
395
Ticagrelor
Reversible P2Y12 blocker more effective but increase risk of hemorrhage stroke
396
Ticlopidine
Similar to clopidogrel removed from marked due to AE
397
Which needs cyp219 activation
Just clopidogrel move to others if issue
398
Abciximab MOA
Purified Fab fragment monoclonal antibody
399
Effects abciximab
Blocks final pathway of platelet aggregation
Inhibits aggregation caused by all factors
Most effective of antiplatelet drugs
400
Lingual abciximab
Acute coronary syndromes
| Percutaneous coronary intervention
401
Dipyridamole MOA
Unknown
402
Effects dipyridamole
Suppresses platelet aggregation
403
Clinical dipyridamole
Fixed dose with asprin for prevent recurrent ischemic stroke
404
AE dipyridamole
Bleeding
HA, dizzy
405
Cilostazol MOA
Type 3 phosphodiesterase inhibitors
Prolongs life of cAMP in platelets and cells
406
Effects cilostazol
Platelet aggregation inhibitor
Vasodilator
407
Clinical cilostazol
Intermittent claudication
408
Alteplase MOA
Purified glycoprotein of 537 aa
Human tpa sequence identical generated in Chinese hamster ovary cells by recombinant dna technology
409
Effects alteplase
Catalyze the conversion of clot bound plasminogen to plsmi
410
Clinical alteplase
Acute MI
Acute ischemic stroke
Acute massive pulmonary embolism
411
Pharmacokinetics alteplase
Large molecule parenteral
Short HL 5 min
412
AE alteplase
Bleeding
Intracranial hemorrhage
Destroying persisting clots
By degrading clotting factors, interferes with clot formation
413
Tenectaplase
Longer HL more effective for stroke
| Good for MI
414
Reteplase
Only MI HL 13-16 min
415
Contraindications alteplase
Intracranial hemorrhage
Cerebral vascular lesion
Ischemic stroke recently in months unless past 5 hours$
Aortic dissection
416
Urokinase MOA
Second physiologic plasminogen activator in urine
417
Effects urokinase
Major activator of fibrinolytic in fluid phase/extravascular compartment
418
Clinical urokinase
Pulmonary embolism
419
Pharmacokinetics urokinase
IV slowly
420
AE urokinase
Fatal hemorrhage
| Anaphylactic shock
