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CV Flashcards

1
Q

Chylomicrons

A

formed by enterocytes, deliver dietary triglycerides to tissues

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2
Q

Chylomicron remnants

A

product of chylomicron metabolism, carry dietary cholesterol to liver

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3
Q

VLDL

A

made by liver, deliver endogenous triglycerides to tissues

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4
Q

IDL

A

products of VLDL metabolism, return endogenous lipids to liver or are converted to LDL, also called VLDL remnants

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5
Q

LDL

A

products of VLDL/IDL metabolism, deliver cholesterol to tissues

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6
Q

HDL

A

reverse cholesterol transport (take cholesterol from tissues to liver)

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7
Q

Lp(a)

A

modified LDL, uncertain function

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8
Q

ApoB100

A

Found on: VLDL, IDL, LDL
Synthesized in liver
Ligand for the LDL receptor
Only one ApoB per lipoprotein so measurement of ApoB100 is a marker of the # of VLDL, IDL and LDL present

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9
Q

ApoB48

A

Found on: CM
Truncated form of ApoB100 (result of gene editing)
Synthesized in enterocytes
Does not bind the LDL receptor
Can be measured as a marker of the # of chylomicrons and chylomicron remnants

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10
Q

ApoCII

A

Found on: HDL, CM, VLDL, IDL
Activates lipoprotein lipase, is exchanged between lipoproteins
Synthesized by the liver
Other ApoCs exist - ApoCIII inhibits lipoprotein lipase, conflicting info about ApoC1 function

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11
Q

ApoE

A

Found on: CM remnants, VLDL, IDL, HDL
Synthesized by the liver (and in some neural tissue)
Ligand for LDL receptor and LDL-receptor related protein
May stimulate hepatic triglyceride lipase and believed to have anti-inflammatory properties in the brain

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12
Q

ApoA1

A

Found on: HDL

activates LCAT and binds to SRB1

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13
Q

Apo(a)

A

Found on: lipoprotein (a)
Synthesized by the liver, unknown function
Forms a disulfide bond with ApoB100 to form Lp(a)

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14
Q

Pancreatic lipase

A

secreted by: pancreas cleaves dietary TG to a monoacylglycerol and 2 FFAs

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15
Q

Lipoprotein lipase (LPL)

A
  • highly expressed by muscle and adipose tissue. -Secreted and anchored to endothelium by proteoglycan chains so it lines vessels supplying those tissues.
  • Completely cleaves TG that are carried on lipoproteins. -Its expression is stimulated by insulin.
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16
Q

Hormone sensitive lipase (HSL)

A

-Expressed within adipocytes and crucial for lipolysis in the fasted state. –Completely cleaves TRG. —Stimulated by glucagon, epinephrine and cortisol. Inhibited by insulin.

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17
Q

Hepatic lipase (HL, HTGL)

A
  • secreted by: liver
  • remains bound on cell surface but can be released into bloodstream
  • release and activation not well understood
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18
Q

LDLR

A
  • Recognizes both ApoB100 and ApoE (but not ApoB48, sometimes called the B100/E receptor)
  • Expression is regulated by intracellular cholesterol concentration
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19
Q

LRP

A
  • Less specific – binds lipoproteins as well as many other ligands including proteases, bacterial toxins, etc)
  • Highly expressed in liver, brain, placenta
  • Its expression is not regulated by cholesterol concentration
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20
Q

Scavenger receptors (SR-B1, SR-A1, SR-A2)

A
  • Bind many different types of ligands
  • SR-B1 binds HDL
  • SR-A1 and SR-A2 are highly expressed by macrophages and have high affinity for oxidized LDL
  • Expression is not regulated by cholesterol concentration
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21
Q

NPC1L1

A

Niemann-Pick C1-Like protein imports cholesterol; some de novo synthesis of cholesterol also occurs in enterocytes

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22
Q

MGAT and DGAT

A

Catalyzes addition of activated fatty acids to MG then DG in enterocytes

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23
Q

MTTP

A

microsomal triglyceride transfer protein cotranslationally adds TG and CE to ApoB48 (cotranslational lipidation)

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24
Q

Lipoproteins are composed of…

A
  • Core rich in TG and CE

- outer surface of phospholipids, free cholesterol, and apoprotein/apolipoproteins

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25
Q

Apoprotein function

A

crucial for regulating interactions of lipoproteins with metabolizing enzymes and cellular receptors

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26
Q

CM maturation and metabolism

A
  • HDL transfers its ApoE and ApoCII (mature CM)
  • LPL activated by ApoCII, cleaving TG
  • glycerol goes to liver, FAs enter cells for storage or energy
  • CM now CM remnants
  • CM remnants taken up by liver (mediated by receptor that recognizes ApoE)
  • CM remnants degraded, resulting in release of amino acids, fatty acids, and cholesterol
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27
Q

ACAT and LCAT

A

Add fatty acids to free cholesterol to make CE (ACAT in enterocytes, LCAT in HDL)

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28
Q

G3-P synthesis

A
  • G3-P is the starting material for TG synthesis in adipose and liver
  • G3-P can be made from DHAP (liver and adipose) or glycerol (liver)
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29
Q

What happens to TG levels in patient with insulin resistance or low insulin?

A
  • LPL is low (since insulin isn’t there to stimulate it)

- Increased TG levels in blood since they’re not getting cleaved in CM

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30
Q

VLDL Metabolism

A
  • VLDL mature when they receive ApoE and ApoCII from HDL
  • VLDL TG are cleaved by LPL to provide fatty acids for use or storage
  • VLDL become IDL as their TG are removed
  • Some IDL are taken up by the liver in a receptor mediated process (mainly LDL receptor mediated)
  • The remaining IDL become LDL when they lose additional TG and return ApoE and ApoCII to HDL
  • VLDL /IDL/LDL can also transfer some of their TG to HDL in exchange for CE
  • Some LDL travel to peripheral tissues where they are taken up to provide cholesterol for things such as membrane and steroid synthesis
  • The remaining LDL are taken up by the liver
  • Excess LDL may be oxidized and taken up by arterial wall macrophages (initiate atherosclerosis)
  • LDL can also become Lp(a) when apo(a) forms a covalent bond with ApoB100. Lp(a) are also taken up by macrophages thus promoting atherosclerosis
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31
Q

What enzyme removes TG from IDL to form LDL?

A

Hepatic lipase

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32
Q

What enzyme catalyzes exchange of TG on VLDL/IDL/LDL for CE on HDL?

A

cholesterol ester transfer protein

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33
Q

Where is CETP made and where does it circulate?

A

Liver; circulates in plasma bound to HDL; transfers CE to ApoB100 containing lipoproteins and TG to HDL

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34
Q

Regulation of LDL uptake

A

-IDL and LDL can enter cells through the LDL receptor, the LDL receptor-related protein (LRP) and scavenger (SR family) receptors but the high affinity LDL receptor is considered to be the cholesterol “gatekeeper” in the liver
-Oxidized LDL are recognized by scavenger receptors which are highly expressed on macrophages
-Endocytosis occurs upon binding and lipoprotein contents are degraded as described for chylomicrons
-Free cholesterol suppresses expression of the LDL receptor but not the LRP or scavenger receptors
Because of this, you can get a lot of lipid accumulating in macrophages
-Proprotein convertase subtilisin kexin type 9 (PCSK9) binds to the LDL-R and promotes its degradation within the liver

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35
Q

What transporter does free cholsterol use to enter HDL?

A

ATP binding cassette family

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36
Q

HDL reverse cholesterol transport

A
  • HDL contribute ApoCII and ApoE to chylomicrons and VLDL
  • They also pick up more cholesterol from cells as they circulate – including from arterial wall macrophages. The cholesterol is esterified by LCAT
  • HDL donate CE to VLDL/IDL/LDL in exchange for TRG in the process catalyzed by CETP as described earlier
  • They can also be taken up by the liver through scavenger receptors
  • The net result is delivery of peripheral cholesterol back to the liver on IDL/LDL and HDL.
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37
Q

What enzyme breaks down TG in the fasted state?

A

Hormone sensitive lipase

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38
Q

Beta 1 location; GPCR, signaling; action

A

Heart, kidneys; Galphas, cAMP; increase CO, renin release

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39
Q

Beta 2 location; GPCR, signaling; action

A

airway, blood vessels; Galphas, cAMP; smooth muscle relaxation, vasodilation

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40
Q

Alpha 1 location; GPCR, signaling; action

A

blood vessels; Galphaq, PLC; vasoconstriction

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41
Q

Alpha 2 location; GPCR, signaling; action

A

presynaptic neurons; Galphai, cAMP; inhibit NE or ACh release

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42
Q

M2 location; GPCR, signaling; action

A

heart; Galphai, cAMP; decrease HR

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43
Q

M3 location; GPCR, signaling; action

A

airway, endothelial cells; Galphaq, PLC; smooth muscle constriction, vasodilation

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44
Q

Autoreceptors

A

Alpha 2; inhibitory

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45
Q

Heteroreceptors

A

Beta 2; excitatory

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46
Q

M2 receptor pathway (cardiac myocytes)

A

Decrease cAMP»decrease PKA»dephosphorylation

Open K channels»hyperpolarization»less firing

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47
Q

M3 receptor pathway (endothelial cells)

A

Activate PLC»increase DAG»increase PKC»increase phosphorylation»increase altering activity of enzymes and receptors
Activate PLC»increase IP3»increase Ca»increase Ca/calmodulin»increase NO synthesis»vasodilation

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48
Q

Beta 1 (cardiac myocytes)

A

Adenylyl cyclase on»increase cAMP»increase PKA»increase Ca»increase contractility

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49
Q

Beta 2 (smooth muscle cells)

A

Adenylyl cyclase on»increase cAMP»(-) myosin light chain kinase»decrease phosphorylation of smooth muscle myosin»vasodilation

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50
Q

Alpha 1 (smooth muscle cells)

A

Activate PLC»increase DAG»increase PKC» increase phosphorylation»increase altering activity of enzymes and receptors
Activate PLC»increase IP3»increase calcium»increase Ca/calmodulin»increase myosin kinase

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51
Q

Alpha 2 (smooth muscle cells)

A

Inactivate adenylyl cyclase»decrease cAMP»(+) myosin light chain kinase» increase phosphorylation of smooth muscle myosin»vasoconstriction

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52
Q

Monckeberg medial (calcific) sclerosis

A

Calcifications in muscular artery walls, typically involves internal elastic lamina, age >50 years, lumen unaffected, usually not clinically significant

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53
Q

Arteriolosclerosis

A

Small arteries and arterioles, may cause downstream ischemia, hypertension

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54
Q

Hyaline arteriolosclerosis

A

Homogenous, pink hyaline thickening with associated luminal narrowing

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55
Q

Cause of hyaline arteriolosclerosis

A

Increased smooth muscle cell matrix synthesis in response to hemodynamic stress
Leakage of plasma protein across injured endothelial cells

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56
Q

Hyperplastic arteriolosclerosis

A
  • Concentric, laminated (onion-skin) thickening of the walls with luminal narrowing
  • associated with severe hypertension
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57
Q

Nonmodifiable risk factors for atherosclerosis

A

Genetic abnormalities, family history, increasing age, male

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58
Q

Modifiable risk factors for atherosclerosis

A

Hyperlipidemia, hypertension, cigarettes, diabetes, inflammation

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59
Q

Most important independent risk factor for athersclerosis

A

Family history/genetics

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60
Q

Most common cause of left ventricular hypertrophy

A

Hypertension

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61
Q

Causes hypercholesterolemia

A

Diabetes, hypothyroidism

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62
Q

Independent marker for risk of MI, stroke, PAD, sudden cardiac death

A

C-reactive protein

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63
Q

Response to injury hypothesis

A

Chronic inflammatory and healing response of arterial wall to endothelial injury; progression occurs through endothelial cells, smooth muscle cells, lipoproteins, monocyte-derived macrophages, T lymphocytes

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64
Q

Sequence of progression of atherosclerosis

A
  1. endothelial injury and dysfunction
  2. Accumulation of lipoproteins (mainly LDL) in vessel wall
  3. monocyte adhesion to endothelium
  4. platelet adhesion
  5. factor release from platelets, macrophages, and vascular walls
  6. smooth muscle proliferation, ECM production, recruitment of T cells
  7. lipid accumulation
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65
Q

What does endothelial injury and dysfunction do?

A

Causes increased vascular permeability, leukocyte adhesion, and thrombosis

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66
Q

What do monocytes do when they adhere to endothelium?

A

Migrate into intima, transform into macrophages and foam cells

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67
Q

What does factor release from platelets, macrophages, and vascular walls do?

A

Induces smooth muscle cell recruitment

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68
Q

Causes of dysfunction in endothelium

A
  • Hemodynamic disturbances
    - Plaques tend to occur at sites of altered flow - ostia of exiting vessels, branches, posterior aorta
  • Hypercholesterolemia
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69
Q

Hyperlipidemia mechanism in atherosclerosis

A
  • Lipoproteins accumulate within the intima
    • Aggregate or are oxidized by free radicals
    • Modified LDL cannot be completely degraded
    • Accumulates in macrophages, results in foam cells
70
Q

Mechanism of foam cells in injury

A
  • Toxic to endothelial cells, smooth muscle cells and macrophages
  • Stimulates release of cytokines, growth factors and chemokines that further recruit and activate macrophages – vicious cycle
71
Q

Other pathogenesis of atherosclerosis

A
  • Inflammation
  • Infection
  • Smooth muscle proliferation and matrix synthesis
72
Q

Inflammation pathogenesis of atherosclerosis

A
  • Possibly triggered by accumulation of cholesterol crystals and free fatty acids in macrophages
    • Inflammasome activation, produce pro-inflammatory cytokine IL-1
    • Cytokines and chemokines recruit and activate more inflammatory cells
    • Chronic inflammatory reaction in vessel wall activates endothelial and smooth muscle cells, contributes to atherosclerosis
73
Q

Smooth muscle proliferation and matrix synthesis pathogenesis of atherosclerosis

A
  • Convert a fatty streak into a mature atheroma, contribute to growth of atherosclerotic lesions
  • More inflammation may breakdown the ECM → unstable plaque
74
Q

Gross fatty streaks are…

A

Flat yellow spots that may join to form streaks

75
Q

Microscopic fatty streaks are…

A

Lipid-filled foamy macrophages

76
Q

Do fatty streaks cause flow problems?

A

No; only when they develop into plaques

77
Q

Gross atherosclerotic plaque

A
  • White-yellow and encroach on the lumen
  • Red-brown if superimposed thrombus over ulcerated plaques
  • Patchy, rarely circumferential
  • Varying sizes and stages of development is normal
78
Q

Why are plaques patchy?

A

Likely because of hemodynamics

79
Q

Most extensively involved areas of plaques in descending order

A
  • Lower abdominal aorta
  • Coronary arteries
  • Popliteal arteries
  • Internal carotid arteries
  • Circle of Willis
80
Q

Microscopic athersclerotic plaque

A
  • Three components:
    • Smooth muscle cells, macrophages, and T-cells
    • Extracellular matrix, including collagen, elastic fibers and proteoglycans
    • Intracellular and extracellular lipids
  • Typically fibrous cap of smooth muscle and dense collagen
  • Shoulder area with macrophages, T cells and smooth muscle
  • Deep is a necrotic core, with lipid (cholesterol and cholesterol esters), foam cells, fibrin, thrombus, debris
  • Neovascularization at periphery
81
Q

Vessels involved in atherosclerotic plaques

A

Large elastic (aorta, carotid, iliac) and large and medium-sized muscular (coronary, popliteal) arteries

82
Q

Complications in vessels of plaques

A
  • Acute occlusion
  • Chronic narrowing of the vessel lumen
  • Aneurysm formation
  • Embolism
83
Q

Critical stenosis

A

Stenosis that causes ischemia; generally 70% in coronaries

84
Q

70% narrowing in coronaries can cause…

A
  • Can result in exertional chest pain (stable angina)
  • Sudden cardiac death
  • Chronic ischemic heart disease
85
Q

70% narrowing elsewhere can cause…

A
  • Mesenteric occlusion and bowel ischemia
  • Ischemic encephalopathy
  • Intermittent claudication
86
Q

Categories of plaque changes

A
  • Rupture/fissuring – exposes thrombogenic plaque constituents
  • Erosion/ulceration – exposes thrombogenic subendothelial basement membrane to blood
  • Hemorrhage into the atheroma – expands its volume
87
Q

Acute changes in plaques are influenced by…

A
  • Intrinsic factors – plaque structure and composition
  • “Vulnerable” plaques – thin fibrous caps, large lipid cores, greater inflammation
  • Extrinsic factors
  • adrenergic stimulation
  • emotional distress
88
Q

Additional complications of atherosclerosis

A
  • Atheroembolism
    • Rupture can discharge necrotic debris into the bloodstream, producing microemboli
  • Aneurysm formation
    • Pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness and potential rupture
89
Q

Lumen can also be compromised by vasoconstriction, stimulated by…

A
  • Adrenergic agonists
  • Platelet contents
  • Endothelial cell dysfunction
  • Mediators from vascular cells
90
Q

Atherogenesis

A
  • Begins early in life – possibly in fetal life or shortly after birth
  • Typical atherosclerotic lesion forms over 20-30 years – initially clinically insignificant
    • Exception – homozygous familial hypercholesterolemia
91
Q

3 stages of plaque life

A
  • Initiation and formation
  • Adaptation
  • Clinical
92
Q

Chylomicrons composition

A

TG»>phospholipid>CE>FC/protein

93
Q

VLDL composition

A

TG>CE/phospholipid>protein>FC

94
Q

LDL composition

A

CE>phospholipid/protein>TG/FC

95
Q

HDL composition

A

protein>phospholipid>CE>TG/FC

96
Q

Familial hypercholesterolemia

A
  • Due to a mutation in the gene encoding LDL receptor
  • Results in loss of feedback control, with elevated levels of cholesterol
    • Cannot bind or clear LDL from circulation
    • Also have increased LDL synthesis
  • Autosomal dominant, one of the most frequently occurring Mendelian disorders
  • Over 900 mutations have been identified
  • Familial hypercholesterolemia is present in 3-6% of survivors of MI
97
Q

Dysbetalipoproteinemia

A
  • Apolipoprotein E is present on chylomicrons, chylomicron remnants, VLDL and IDL
  • Binds to LDL receptor, helps clear these from circulation
  • Three common electrophoretic isoforms – E3 (most common), E4, and E2
  • Different phenotypes have variability in metabolism - approximately 20% of variation in serum cholesterol is attributed to this polymorphism
98
Q

Lipoprotein

A
  • LDL-like particle, glycoprotein apo (a) is linked to apoB-100 by a disulfide bond
  • Function and atherogenic properties are not well understood, but
  • High levels are associated with increased risk of atherosclerosis
  • Levels are heritable
  • Levels are not altered by most cholesterol lowering drugs
99
Q

Familial hypercholesterolemia heterozygotes

A
  • 1/500
  • 50% of normal high-affinity LDLR
  • 2-3x cholesterol elevation; LDL-C>220
  • tendinous xanthomas, premature atherosclerosis
100
Q

Familial hypercholesterolemia homozygotes

A
  • 1/1 mil
  • 5-6x cholesterol elevation; LDL-C>400
  • skin xanthomas, atherosclerosis, MIs before 20
  • if untreated, premature death secondary to MI
101
Q

Most common homozygous form of dysbetalipoproteinemia

A

ApoE2 (E2/E2); has much lower affinity for LDLR so lipoproteins accumulate in blood

102
Q

Lipid panel

A
  • Typically will give values for total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG)
  • Usually directly measures TC, HDL-C, and TG
103
Q

How is LDL-C calculated?

A

Friedewald formula; LDL-C = TG - HDL-C - VLDL-C

104
Q

What are the 2 assumptions of the Friedewald formula?

A
  • All TG is carried by VLDL – no chylomicrons present
    • Explains, for the most part, why fasting specimen is recommended for LDL-C value
  • TG/cholesterol ratio is invariant – changes as TG level increases
    • Explains, for the most part, why it is not accurate with high TG levels (generally about 400 mg/dL)
105
Q

Hypoxia

A

deficiency of oxygen

106
Q

Ischemia

A
  • Most common type of cell injury in clinical medicine
  • Results from hypoxia due to reduced blood flow
  • Compromises delivery of substrates for glycolysis – get compromised aerobic and anaerobic metabolism
  • Causes more rapid tissue injury than hypoxia alone
107
Q

Infart

A
  • Ischemic necrosis caused by occlusion of either the arterial supply or venous drainage
  • Coagulative necrosis develops distal to it
108
Q

IHD

A
  • Imbalance between supply (perfusion) and demand (for oxygenated blood)
  • Also reduces availability of nutrients and removal of metabolic wastes
  • Ischemia is less well tolerated than just hypoxia, such as with anemia, lung disease, etc
  • Vast majority (>90%) of cases due to reduced flow from atherosclerotic coronary arteries
    • IHD frequently called coronary artery disease (CAD)
  • Typically a long period (decades) of silent progression before onset of symptoms – due to atherosclerosis
109
Q

Additional causes of IHD

A
  • Emboli, myocardial vessel inflammation, or vascular spasm

- Increased demand may make some occlusion symptomatic – tachycardia, hypoxemia, systemic hypotension

110
Q

Clinical syndromes of IHD

A
  • Angina pectoris (“chest pain”)
    • Ischemia is not severe enough to cause infarction, but symptoms portend infarction risk
  • Myocardial Infarction
    • Ischemia causes frank cardiac necrosis
  • Chronic ischemic heart disease with heart failure
  • Sudden Cardiac Death
111
Q

Angina pectoris

A
  • Paroxysmal and usually recurrent attacks of substernal or precordial chest discomfort
  • Caused by transient myocardial ischemia that is insufficient to induce myocyte necrosis
  • Three overlapping patterns
  • Some are silent (no symptoms), particularly in geriatric population and those with diabetic neuropathy
112
Q

Stable (typical) angina

A
  • Most common form, caused by imbalance between coronary perfusion relative to myocardial demand
    • May be secondary to physical activity, emotional excitement, or psychological stress
  • Typically described as a deep, poorly localized pressure, squeezing or burning sensation; unusually as pain
  • Usually relieved with rest or drugs such as vasodilators or calcium channel blockers
113
Q

Prinzmetal variant angina

A
  • Uncommon form of episodic ischemia, caused by coronary artery spasm
  • May have underlying atherosclerosis, but unrelated to activity
  • Generally responds to vasodilators
114
Q

Unstable or crescendo angina

A
  • Pattern of increasingly frequent, prolonged (> 20 min), or severe angina or chest discomfort described as frank pain
  • Precipitated by progressively lower levels of activity or at rest
  • Typically caused by disruption of an atherosclerotic plaque with partial thrombosis, and possibly embolization and/or vasospasm
  • Approximately half have evidence of myocardial necrosis
  • MI may be imminent
115
Q

Alpha 1 adrenoreceptors

A
  • present on the postsynaptic membrane of the effector organs
    • Coupled with Gq and initiates reactions through activation of phospholipase C&raquo_space;↑IP3&raquo_space;↑Ca2+» Contraction
116
Q

Alpha 2 adrenoreceptors

A
  • present on presynaptic nerve endings, β cell of pancreas, on vascular smooth muscle
    • Coupled with Gi and inhibits AC and decreases cAMP signaling
117
Q

Alpha 1 locations and effects

A

Aorta, coronary a. - vasoconstriction

118
Q

Alpha 2 locations and effects

A

inhibitory receptor of SNS; brain - modulate dopamine transmission

119
Q

When do alpha 2 receptors cause vasoconstriction

A

Only when agonists are given locally or in high oral doses

120
Q

Beta 1 receptor locations

A
  • Heart
  • Kidney (juxtaglomerular cells)
  • Presynaptic adrenergic/cholinergic nerve terminals
  • Adipose tissue
121
Q

Beta 2 receptor locations

A
  • Vascular smooth muscle (arterioles; EXCEPT skin and cerebral)
  • Bronchiole smooth muscle
  • Liver
122
Q

Beta sympathomimetics

A

1: increases contractility and stimulation of SA node»increase CO
2: decrease TPR by vasodilation

123
Q

Alpha selective direct agonists

A

Phenylephrine - 1

Clonidine - 2

124
Q

Beta selective direct agonists

A

Dobutamine - 1
Albuterol - 2
Isoproterenol - non
Dopamine - non

125
Q

Non-selective direct agonists

A

Epi
NE
Ephedrine
Pseudoephedrine

126
Q

Indirect agonists

A

Amphetamine

Cocaine

127
Q

Non-selective alpha-antagonists

A

Phenoxybenzamine

Phentolamine

128
Q

Selective alpha-antagonists

A

Prazosin - 1
Terazosin - 1
Doxazosin - 1

129
Q

Beta-antagonists

A 
Acebutolol
Esmolol
Metoprolol
Pindolol
Propranolol
Carvedilol
130
Q

Phenylephrine

A
  • Synthetic drug favors α1 over α2
    • Marked vasoconstriction
      • Increases peripheral arterial resistance and decreases venous capacitance
  • Clinical usage:
    • Nasal congestion
    • Hypotension/shock
  • Causes mydriasis
131
Q

Clonidine

A
  • Treatment systemic hypertension (2nd line therapy)
    • Decreases HR and reduces TPR&raquo_space;decreased CO
      • Will see a brief RISE in BP followed by prolonged hypotension when given parenterally
    • Reduces arterial pressure, decreases RENAL vascular resistance and maintains renal blood flow
  • Very lipid soluble (enters CNS)
    • Well absorbed orally & widely distributed
    • Targets cardiac centers in CNS
  • Typical administration: oral or transdermal
  • α2:α1specificity ratio is 200:1
132
Q

Dobutamine

A
  • Beta 1
  • now known to have actions at alphas
  • clinical usage
    • heart failure»severe cardiac decompensation
    • cardiac stress testing
133
Q

Albuterol

A
  • Beta 2
  • relaxes bronchial smooth muscle with little effect on HR
  • Clinical usage
    • bronchospasm and COPD
134
Q

Isoproterenol

A
  • Positive chronotropic and inotropic actions&raquo_space; increasing cardiac output (β1)
  • Potent vasodilator (β2)
    • Fall in diastolic blood pressure; systolic remains same or rises slightly
    • Lowers peripheral mean arterial pressure
  • Clinical
    • mild or transient episodes of heart block that don’t require shock or pacemaker therapy
135
Q

Dopamine

A
  • Low doses activate D1 in renal and vascular beds&raquo_space; local vasodilatation, renal blood flow and glomerular filtration&raquo_space; diuresis
  • Mid doses activate cardiac β1-receptors (direct and indirect)&raquo_space; increased heart rate, cardiac contractility and stroke volume&raquo_space; increased CO
  • Higher doses activate systemic α-receptors&raquo_space; vasoconstriction&raquo_space; increased systemic resistance
    • May mimic actions of epinephrine
  • Clinical Usage: Adjunct in the treatment of shock that persists after adequate fluid volume replacement
    • MI, open heart surgery, renal failure, cardiac decompensation
136
Q

Epinephrine

A
  • Potent cardiac stimulant and vasoconstrictor
    • Leads to increased SV, HR, and CO
      • β1-receptors induce positive inotropic and chronotropic actions
        • Acts directly on myocardium and SA node
      • α1-receptors cause vasoconstriction in vascular beds&raquo_space; predominates at high doses
    • Activates β2-receptors in skeletal muscle blood vessels and liver&raquo_space; dilation
      • Vasculature β2-receptors are more sensitive than α –receptors&raquo_space; can decrease diastolic pressure
137
Q

Epinephrine clinical

A

ACLS (asystole or pulseless arrest), bradycardia, acute bronchospasm, local vasoconstriction (surgery), anaphylaxis

138
Q

Norepinephrine

A

-Less effective that epi @ alpha receptors
-Little beta 2 effect
-CV effects: increase TPR, diastolic, and systolic BP (baroreceptor reflex reduces HR)
Clinical: shock or severe hypotension

139
Q

Ephedrine

A
  • High oral bioavailability and long duration of action (hours)
  • Releases tissue stores of NE&raquo_space; a & b-adrenergic stimulation
    • Activation of β receptors (early asthma treatment)
  • Causes mild stimulation of CNS/improves athletic performance
140
Q

Pseudoephedrine

A
  • Used to treat nasal, sinus, and Eustachian tube congestion
    • Stimulates a-adrenergic receptors of respiratory mucosa causing vasoconstriction
    • Stimulates b-adrenergic receptors causing bronchial relaxation, increased heart rate and contractility
  • Precursor to methamphetamine&raquo_space; ↓OTC availability
141
Q

Amphetamine

A
  • Acts as both an norepinephrine transporter (NET) substrate and a reuptake blocker, eliciting reverse transport and blocking normal uptake, thereby increasing NE levels in and beyond the synaptic cleft
  • CNS&raquo_space; stimulant&raquo_space; Narcolepsy, ADHD
  • Periphery&raquo_space; ↓reuptake of NE and release of stored catecholamines
142
Q

Cocaine

A
  • Blocks the norepinephrine transporter (NET)
    • Required for cellular uptake of norepinephrine
      • Norepinephrine accumulates in the synaptic cleft to stimulate a & b adrenoceptors
143
Q

Sympathomimetic toxicity

A
  • Examples: Cocaine, amphetamines, etc.
  • Mental status: hyperalert, agitation, hallucinations, paranoia
  • Pupils: mydriasis
  • Vital signs: tachycardia, hypertension, hyperthermia, widened pulse pressure, tachypnea, hyperpnea
  • Other manifestations: diaphoresis, tremors, hyperreflexia, seizures
144
Q

Which alpha antagonist isn’t competitive?

A

Phenoxybenzamine

145
Q

Phenoxybenzamine

A
  • Slightly more selective to α1
  • Noncompetitive
  • May also block the reuptake of norepinephrine
  • Absorbed well after oral administration but bioavailability is low
    • Can enter CNS
  • Attenuates vasoconstriction and reduces BP
146
Q

Phentolamine

A
  • Competitive block at α1 and α2

- Effects similar to phenoxybenzamine

147
Q

Clinical usage of phenoxybenzamine

A
  • Pheochromocytoma - tumor of adrenal medulla or sympathetic ganglia
    • tumor secretes catecholamines (NE, epi)
  • can add beta antagonist after the fact to have unopposed alpha vasoconstriction first
148
Q

Clinical usage of alpha 1-adrenergic antagonists

A
  • Primary hypertension
    • Lower peripheral vascular resistance
  • BPH
    • helps with urinary continence by relaxing smooth muscle in bladder neck, prostate capsule, and prostatic urethra
149
Q

Adverse effects of alpha 1-adrenergic antagonists

A
  • orthostatic hypotension
  • dizziness, headache
  • miosis
  • nasal congestion
  • urination
150
Q

How does specificty move with higher doses?

A

DIMINISHES

151
Q

Pharmacokinetic properties of beta-adrenergic receptor antagonists

A
  • Well absorbed PO
  • t1/2 - 3-10 hours (EXCEPT esmolol ~10-20 minutes)
  • typically metabolized in liver (poor metabolizers have higher plasma concentrations)
152
Q

Propranolol

A
  • Prototypical β-blocking drug
  • Undergoes extensive first-pass metabolism
    • Bioavailability is low
    • Amount reaching circulation varies among individuals
  • Very lipid soluble; crosses BBB
  • Also formulated as sustained release
153
Q

Metoprolol

A
  • β1-selective (modest)
    • Safer for patients who experience bronchoconstriction after propranolol
  • Undergoes CYP2D6 metabolism
    • Poor metabolizers exhibit 3x-10x higher plasma concentrations after administration of metoprolol than extensive metabolizers
  • Available in sustained release tablets
154
Q

Esmolol (IV)

A
  • Ultra-short acting β1-adrenergic antagonist
    • Gets metabolized by esterases in red blood cells
    • Peak effect occurs within 6-10 min
    • Block lasts ~20 min post-infusion
  • CV Clinical usage: supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, and perioperative hypertension
155
Q

Pindolol and Acebutolol

A
  • Partial β-agonists with intrinsic sympathetic activity (ISA)
    • Pindolol is a non-selective β-blocker
    • Acebutolol β1-blocker
    • Exhibit low level agonist activity while acting as a receptor site antagonist
  • CV Clinical usage: hypertension and angina
    • Good for patients that exhibit bradycardia
      • ISA activity prevents severe bradycardia from occurring
156
Q

ISA

A
  • β-blockers with ISA cause mild peripheral vasodilation without reducing cardiac output (e.g., pindolol, acebutolol)
    • They act as partial agonists
      - Interact with β receptors to cause measurable agonist response while blocking the greater agonist effects of endogenous catecholamines at the same time
      - Provide low-grade β stimulation at rest but act as typical β blockers when sympathetic activity is high
  • β-blockers without ISA lower blood pressure by decreasing cardiac output and inhibiting renin release and central sympathetic outflow
  • ISA’s are beneficial for bradyarrhythmias or peripheral vascular disease, but can potentially be used for hypertension
157
Q

Carvedilol

A
  • Non-selective β-adrenergic receptor antagonist & α1-receptor antagonist
    • Stronger ability to antagonize catecholamines at β-receptor
  • Antioxidant properties
    • Contributes to clinical benefit in chronic heart failure
  • Racemic mixture with stereoselective metabolism: (R)-carvedilol
158
Q

Beta antagonists clinical

A
  • Hypertension: β-adrenergic receptor antagonists with clinical indication
  • Heart failure: following MI, long-term use improves symptoms, reduces hospitalization, and enhances survival
  • Ischemic Heart Disease: reduce anginal episodes and improve exercise tolerance
  • Cardiac arrhythmias: supraventricular and ventricular show benefit after treatment with β receptor antagonists
  • Hyperthyroidism symptoms with propranolol
159
Q

Beta antagonists

A
  • Depresses myocardial contractility and excitability
  • Heart failure&raquo_space; Causes cardiac decompensation
  • Severe hypotension
  • Bradycardia
  • AV block
  • Fatigue/exercise intolerance
  • Erectile dysfunction
160
Q

Clinical considerations of beta-adrenergic antagonists

A
  • Generally avoided in patients with:
    • Asthma
    • Nodal dysfunction (sinoatrial or atrioventricular)
      • In combination with other drugs that inhibit AV conduction (EX: verapamil)
    • Diabetes (better treated with ACE inhibitors)
  • β-adrenergic receptor blockers WITHOUT ISA:
    • Increase triglycerides in plasma (EX: propranolol)
    • Lower HDL cholesterol
    • β-adrenergic receptor blockers WITH ISA have little effect on blood lipids
  • SHOULD NEVER BE ABRUPTLY STOPPED (taper 2 wks)
    • To avoid acute tachycardia, hypertension, and/or ischemia
161
Q

Beta-blocker overdose

A

-Bradycardia, hypotension most common

162
Q

HMG-CoA reductase inhibitors

A

Drugs: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin
MOA: block HMG-CoA reductase to increase LDLR expression
Lipid profile: Lower LDL, some TG, increase HDL some
Clinical:
Adverse effects: elevated serum aminotransferase activity, myalgia, myositis/myopathy, rhabdomyolysis, increased risk of diabetes
Contraindications: liver disease, pregnant, breast-feeding, or women who will become pregnant, children
Route:

163
Q

Bile acid binding resins

A

Drugs: colestipol, cholestyramine, colesevelam
MOA: bind to bile acids to prevent their reabsorption»increase excretion of bile»increase liver bile acid synthesis»greater demand for liver cholesterol
Lipid profile: decrease LDL some
Clinical:
Adverse effects: constipation, bloating, steatorrhea, impaired absorption of ADEK, impaired absorption of certain drugs
Contraindications: homozygous LDLR deficiency, diverticulitis
Route: drink mix, tablet, suspension

164
Q

Cholesterol absorption inhibitor

A

Drug: ezetimibe
MOA: blocks NPC1L1 to inhibit cholesterol absorption»more LDLR by liver
Lipid profile: lower LDL some
Clinical: homozygous FH with statin
Adverse effects: myopathy when taken with statin
Contraindications:
Route:

165
Q

Niacin

A

Drug: Niacin
MOA: inhibit DGAT and to prevent VLDL secretion; inhibit hormone sensitive lipase
Lipid profile: increase HDL
Clinical: FH not achieving target LDL reduction with other drugs, may be useful in Lp(a)
Adverse effects: flushing, nausea and abdominal discomfort, elevated aminotransferase levels, acanthosis nigricans, hyperglycemia, hyperuricemia, macular edema
Contraindications: peptic ulcer, liver disease
Route:

166
Q

Fibrates

A

Drugs: gemfibrozil, fenofibrate
MOA: peroxisome proliferator activated receptor alpha agonists»upregulate LPL, ApoA1, ApoA2 and down-regulate ApoCIII; stimulate beta-oxidation
Lipid profile: decrease TG
Clinical: hypertriglyceridemia
Adverse effects: GI, myopathy, high levels of aminotransferases, decreased WBC or hematocrit, rhabdo, cholesterol gallstones
Contraindications: hepatic or renal dysfunction, biliary disease; drug interactions: potentiate anticoagulants, myopathy with statin
Route:

167
Q

Omega 3 FA

A 
Drugs: lovaza, epanova
MOA: 
Lipid profile: lower TG some
Clinical: hypertriglyceridemia
Adverse effects: belching, taste alteration, vomiting, constipation, pruritis, rash, increased aminotransferases, increased LDL, prolongation of bleeding, hypersensitivity
Contraindications: fish allergy
Route:
168
Q

PCSK9 inhibitors

A

Drugs: alirocumab, evolocumab
MOA: bind PCSK9 and prevent it from binding LDLR (prevents lysosomal degradation) allows more LDLR on surface of liver so more LDL into hepatocytes
Lipid profile: lower LDL
Clinical: FH or clinical atherosclerotic disease
Adverse effects: hypersensitivity, injection site reaction
Contraindications:
Route: injection

169
Q

Mipomersen

A

MOA: antisense oligonucleotide binds to Apo100 mRNA, prevents ApoB100 synthesis
Lipid profile: LDL
Clinical: homozygous familial hypercholesterolemia
Adverse effects: injection site reaction, flu-like symptoms, hepatotoxicity
Contraindications:
Route: injection

170
Q

Lomitapide

A

MOA: MTTP inhibitor»decreased CM and VLDL synthesis
Lipid profile: LDL
Clinical: homozygous familial hypercholesterolemia
Adverse effects: GI disturbances, hepatotoxicity, embryotoxicity
Contraindications:
Route:

CV (3 decks)

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