Pharmacology 401 Exam 2 Material: Dr. Beavo

Front 1

Why does COX inhibition both promote and inhibit clotting?

Back 1

-Lowers Thromboxanes (induce clotting)
-Lowers Prostacyclins (prevent clotting)

Front 2

Warfarin:
-speed of onset? why?
-direct or indirect?

Back 2

-slow onset; inhibits formation of new coag factors --> must deplete current supply.

-indirect anticoagulant.

Front 3

Heparin
-speed of onset? why?
-direct or indirect?

Back 3

-FAST! binds ATIII and inhibits clotting cascade. Increases ATIII's affinity for thrombin --> less thrombin --> less clotting

-direct anticoagulant

Front 4

Abciximab (ReoPro)
MOA?

Back 4

Blocks the interaction between GpIIb/IIIa and fibrin/fibrinogen

Front 5

Dipyridamole (Aggrenox)
MOA?

Back 5

Antiplatelet.

Blocks the action of PDE. + cAMP, cGMP --> low Ca++ --> no shape change, no adhesion

Blocks platelet uptake of ADP

Front 6

LMW Heparins
MOA?

Back 6

Complexes w/Antithrombin III (AT-III)

Increases rate of thrombin:AT‐III complex formation ~1000x; degrade clotting factors, esp Xa.

Prevent conversion of prothrombin --> thrombin --> less amplification of clotting cascade.

Front 7

Clopidogrel (Plavix)
MOA?

Back 7

Platelet ADP receptor antagonist --> platelets no longer stimulated by ADP

Front 8

Aspirin
MOA?

Back 8

Anti-COX --> decreased production of Thromboxanes that stimulate platelet activation

Front 9

Warfarin (Coumadin)
MOA?

Back 9

Blocks recycling of vitamin K, which is necessary as a cofactor for synthesis of coagulation factors.

Front 10

Streptokinase
MOA?
Sefx?

Back 10

Complexes w/plasminogen --> now able to activate other plasminogen molecule

allergic rxns b/c bacterial

Front 11

What is the required time frame for administration of thrombolytic therapy?

Back 11

need to administer within 3h (max 3-6h) for any benefit.

--> 80% of pts who need it never get treatment :(

Front 12

Tissue Plasminogen Activator
MOA?
Sefx?

Back 12

Cleaves plasminogen to plasmin, which breaks up fibrin in clots

Made naturally by healthy endothelium; few sefx

Front 13

Urokinase
MOA?

Back 13

Proteolytically activates plasminogen directly

Front 14

Function of protein C?

Back 14

remove inhibition of tPA --> tPA induces Fibrinolysis

inactivates factor Va, VIIIa --> anticoagulant

Front 15

Why do we sometimes get rebound bleeding after warfarin withdrawal?

Back 15

Protein C is an anticoagulant and has most rapid turnover of serum proteases. Withdraw warfarin --> P.C comes back first --> bleeding.

Front 16

2 Functions of free thrombin?

Back 16

cleaves fibrinogen --> fibrin --> clot.

cleaves SIGNAL PEPTIDE from platelet thrombin receptor --> TETHERED LIGAND can bind --> - cAMP, + IP3 --> more adhesion.

Front 17

How does function of thrombin differ when bound to thrombomodulin?

Back 17

Bound to TM indicates healthy endothelium.

T cleaves protein C --> PC exerts anticoag effects

Front 18

How do platelets stick to the endothelium?

Back 18

GpIa binds collagen on endothelium

GpIb binds to Von Willebrand Factor on endothelium

Front 19

How do platelets stick to each other?

Back 19

GpIIb/IIIa binds fibrin, which polymerizes into a mesh over the clumped platelets.

Front 20

Role of Ca++ in platelet aggregation?

Back 20

increased [Ca++] in platelet cytosol --> GpIIb/IIIa modified to have higher affinity for fibrinogen --> encourages clotting.

Front 21

Inhibitors of TRH release from hypothalamus?

Back 21

Growth hormone
Glucocorticoids
Stress
Somatostatin
T3/T4

Front 22

Stimulators of TRH release?

Back 22

Estrogens
Low body temp
Low T3/T4

Front 23

MOA of Propylthiouracil?

Back 23

inhibit TPO (thyroid peroxidase) --> can't attach I to thyroglobulin

inhibits peripheral dehalogenases --> can't convert T4 to T3

Front 24

MOA of Methimazole?

Back 24

inhibit TPO (thyroid peroxidase) --> can't attach I to thyroglobulin

Front 25

Hormonal factors governing conversion of T4 to T3?

Back 25

beta-adrenergic stimulation --> increases conversion to T3

glucocorticoids --> DECREASE conversion to T3

Front 26

Metformin MOA?

Back 26

Increase AMP/ATP ratio in beta cell, inhibit GNG, increase glycolysis

Front 27

Thiazolidinediones
MOA?
Examples?

Back 27

PPAR-gamma transcription factor activators --> increase insulin sesitization

rosiglitazone, pioglitazone (-glitazones)

Front 28

GLP-1 mimetics
MOA?
Examples?

Back 28

slows stomach emptying, increases satiety, increases insulin secretion

Exenatide

Front 29

Sulfonylureas
MOA?
Examples?

Back 29

block K+ efflux channel on beta cell --> depolarize cell --> increased insulin secretion

tolbutamide, glipizide, etc. -ide

Front 30

DPP-IV Inhibitors?
MOA?
Examples?

Back 30

inhibit DPP-IV --> native GLP-1 not degraded, has more time to act

"gliptins"

Front 31

Meglitinides
MOA?
Examples?

Back 31

block K+ efflux channel on beta cell --> depolarize cell --> increased insulin secretion

repaglinide, nateglinide (-glinides)

Front 32

Alpha-glucosidase inhibitors
MOA?
Examples?

Back 32

Inhibit enzymatic hydrolysis of dietary sugars into glucose --> not absorbed.

acarbose

Front 33

What is insulin's major signaling pathway?

Back 33

80% of effects via PI3K pathway

involves scaffolding proteins IRS-1 and IRS-2

Front 34

What type of receptor is the insulin receptor? How does it activate MAP kinase cascade?

Back 34

Tyrosine Kinase

Phosphorylates IRS-1, which recruits Ras and catalyzes binding of GTP to activate Ras

Front 35

Why do we give Vitamin D3 rather than its active form?

Back 35

So body can choose what to do with it. (convert to 1,25-OH as necessary)

Front 36

Why do we give T4 rather than T3?

Back 36

So body can choose what to do with it. Convert to more active T3 if necessary; it doses itself

Front 37

PTH
What does it do?

Back 37

Increases Ca++:
↓ renal Ca++ excretion
+ renal PO4 excretion
+ bone resorption by osteoclasts
+ dietary Ca++ uptake in intestines

Front 38

Why is Vitamin D necessary for Ca++ balance?

Back 38

Increases synthesis of CALBINDIN which enables gut cells to transport Ca2+ across cell into ECF

Front 39

Bisphosphonates
MOA?
Examples?

Back 39

PPi analogs; chelate Ca++ --> taken up by osteoclast --> inhibits Farnesyl Pyrophosphate Synthase --> osteoclast can't localize proteins --> dies.

anything ending in "-dronate"

Front 40

Intermittent PTH
MOA?

Back 40

Forteo (Pfizer): Tx osteoporosis

short bursts of PTH stimulate osteoBlasts

Front 41

Rickets
Etiology?
Tx?

Back 41

Vitamin D deficiency --> no Ca++ uptake --> soft bones

Tx w/D3 supplementation

Front 42

Vitamin D resistant rickets
Etiol/Tx?

Back 42

Receptor or Vit D hydroxylase deficiency

Megadose w/D3 or try 1-OH-VitD if that doesn't work

Front 43

Sensipar
MOA?
Uses?

Back 43

Parathyroid Ca++ receptor sensitizer; mimics high level of serum Ca2+ --> less PTH --> less Ca++/VitD imbalance

Tx hyperparathyroidism in pts w/renal failure. (they have high serum PO4, low Ca++, thus high PTH)

Front 44

Relative potency 1,25-dihydroxycholecaficerol vs cholecalciferol?

Back 44

dihydroxy form is ~10,000x more potent

Front 45

How does PTH control VitD synthesis?

Back 45

PTH induces 1-hydroxylase --> increases active VitD

Thus low Ca++ increases VitD synth via PTH.

Front 46

Calcitonin
Where is it from?
What does it do?
Where does it act?

Back 46

From thyroid

ANTI-PTH: Decreases serum Ca++ if it's too high (tx hypercalcemia, vit D toxicity)

acts on intestine, kidney, bones

Front 47

Function of histamine?

Back 47

paracrine signaling molecule; mediates local anaphylactic reactions

Front 48

Where is histamine stored? How is it released?

Back 48

Pre-formed granules in mast cells

Released via exocytosis of granules. PLC/IP3/Ca++ signaling as a result of FcRI receptor crosslinking on mast cell surface.

Front 49

How is mast cell histamine secretion regulated on a chemical level?

Back 49

Negative feedback: Histamine binds H2 receptor
OR Epinephrine binds beta-2 adrenergic receptor (Epi-Pen)

--> ++ increased cAMP --> decrease histamine release.

Front 50

H1 receptor
Function?
Location?

Back 50

+ smooth muscle contraction, capillary permeability, edema,

located in resp tract, skin, mucous membranes

Front 51

H2 receptor
Function?
Location?

Back 51

increase gastric HCl secretion, inhibit mast cell histamine release (neg feedback)

in stomach parietal cells; on surface of mast cells

Front 52

1st gen Antihistamines
MOA?

Back 52

nonselectively block histamine receptors --> many sefx; drowsiness when they cross BBB

Front 53

Factors that stimulate HCl release in the stomach?

Back 53

-Acetylcholine (directly to parietal cell or via ECL cell/histamine)
-Gastrin (directly to parietal cell or via ECL cell/histamine)
-Histamine from ECL cells

Front 54

What cells secrete histamine in the stomach?
Stimuli?

Back 54

ECL cells (Enterochromaffin-Like Cells; a specialized mast cell)

Gastrin from G cell
Acetylcholine from vagus nerve

Front 55

How does Histamine stimulate HCl release from parietal cells?

Back 55

+ intracellular cAMP --> more H+/K+ ATPase pumps are recruited to lumenal membrane --> increased H+ secretion.

Front 56

MOA of PPI's?

Back 56

covalently modify H+/K+ ATPase ("proton pump") --> it is out of commission until you make more of them.

Needs high H+ to work.

Front 57

Effect of PTH on kidney WRT vitamin D?

Back 57

Increases conversion of vit D to active metabolites.

Front 58

Average daily flux of Ca++ through body?

Back 58

~200mg

Front 59

What is B-48 and where does it bind?

Back 59

Surface ligand on chylomicron/chylomicron remnant

Binds E-Receptor on liver

Front 60

What is E and where does it bind?

Back 60

Surface ligand on chylomicron/chylomicron remnant

Binds chylomicron remnant receptor (E receptor) on liver

Front 61

What is B-100 and where is it located? What does it do?

Back 61

Apolipoprotein on surface of LDL particle.

Binds LDL receptor on liver --> LDL taken up and out of bloodstream.

OR when oxidized, binds SR-B1 scavenger receptor on foam cell --> incorporated into atherosclerotic plaque :(

Front 62

What is SR-B1? Where is it located and what does it do?

Back 62

Scavenger Receptor

On liver + Steroidogenic tissues; enables uptake of HDL particles.

Front 63

CETP
Function?
Location?

Back 63

Cholesterol Ester Transfer Protein

xfer CE from HDL <--> other Lipoproteins

Front 64

Nicotinic acid (Niacin)
MOA?
Effects/sefx?

Back 64

Nicotinic acid binds GPCR --> inhibit adenylyl cyclase --> inhibit lipolysis

(-) TAG, FFA, LDL, VLDL
(+) HDL

anti-insulin, hyperuricemic sefx, flushing (take aspirin)

Front 65

Fibrates
MOA?
Effects/sefx?

Back 65

binds PPAR-alpha --> stimulates FA oxidation, increases LPL

(-) TG's, LDL, VLDL, TC
(small +) HDL

Front 66

Statins
MOA?
Effects/sefx?

Back 66

inhibit HMG-coA Reductase --> no cholesterol synthesis

(-) LDL....but takes a few years to see benefit

Sefx = rhabdomyolysis

Front 67

CETP Inhibitors
MOA
Effects/sefx?

Back 67

block CETP mediated xfer of cholesterol from HDL to other lipoproteins

(+) HDL--dramatic increase!
caveat: may increase risk for MI?

Front 68

Bile Acid Resins
MOA?
Effects/sefx?

Back 68

Anion exchange resins that bind bile so it can't be re-absorbed/recycled --> cholesterol in bile gets eliminated in feces

(-) TC, LDL

Not absorbed --> no toxicities

Front 69

Sterols/Ezetimibe
MOA?
Effects/sefx?

Back 69

blocks uptake of dietary cholesterol in gut (via NPC1L1)

(-) LDL
(+) HDL, very small increase

Front 70

Probucol
MOA?

Back 70

acts as antioxidant to prevent oxidation of B-100 --> maximize LDL uptake by liver.

(if LDL has oxidized B-100 it binds SR-B1 instead of LDL-R)