Coronary Artery Disease/Lipid Lowering Drugs/Angina Drugs/Anticoagulants Flashcards
• As CAD progresses > certain drugs begin to show up when you begin to have heart damage
○ Antilipemic - cholesterol lowers and high BP meds
§ Can be prescribed ____ on > prevent damage
○ Thrombolytics - lyses a ____
§ Used during an occlusive stroke/MI
§ Given ____
○ Anticoagulants
§ Affect components of clotting cascade
○ Antianginal
§ ____ angina - people go out into the cold/walking up a hill > chest tightness - some occlusion of the coronaries
○ Antiarrhythmics
§ Some damage to the haerrt > causing abnormal beats
§ ____ is no longer controlling the heart
○ CHF agents
§ Used when the heart is ____ > chunk of cardiac tissue is not pumping efficiently
§ Retaining water and sodium
early clot IV exertional/stable SA node damaged
Coronary Arteries
Blockage of this one sometimes called “the ____r”
widow maker
• Aortic stenosis
○ ____ deposits
○ Valve gets stiff > not getting enough blood to the brain
○ Can thread stents through the ____ artery, and replace the whole aortic valve ____
calcium
femoral
non-invasively
Coronary artery ultrastructure
• \_\_\_\_ - feed the coronaries
vaso vasorum
Hypothesis: etiology of atherosclerosis
• Plaque formation in coronaries ○ People have \_\_\_\_ (bad chol) that get picked up by macrophages and beocme engulfed ○ The macrophages burst, the lipids are modified > sticky and stick to the \_\_\_\_ ○ Calcium and platelets come > development of a plaque • In order to have a heart attack > do not need to have complete occlusion > some plaques > \_\_\_\_ (occluding ~30%) > bursts > injury and platelets and clotting factors come in and then a \_\_\_\_ occlusion > thrombus formation • Good genes > plaques do not progress as much ○ \_\_\_\_predisposition
LDL coronaries fibrous cap complete genetic
Atherosclerosis: basic mechanism
• LDL carries cholesterol and related chemicals to the BV ○ Lipoprotein • Foam cells and macrophages try to degrade > spits out and now it's a form that can readily bind to \_\_\_\_ (can bind to other vessels too) • Also a growth of \_\_\_\_
coronaries
smooth muscle cells
Types and degrees of coronary atherosclerosis
* 40-60% of coronary blocked > can be \_\_\_\_ unless they push themselves * The purple is Ca++ * Formation of lumens that may form after the heart attack, but permanent \_\_\_\_ tissue death
asymptomatic
irreversible
Early atherosclerosis
• Early atherosclerosis
○ A ____ cap is present > won’t set off the clotting cascade
• Late atherosclerosis ○ The cap is now \_\_\_\_ > if ruptures can result in pathologic plaque • Pathologic plaque ○ Do not need complete blockage of the vessel; if thin fibrous cap > breaks, and the body tries to heal it with platelets and \_\_\_\_ ○ Give patient thrombolytics > \_\_\_\_ drugs > if not in there soon enough > \_\_\_\_ damage ○ Can also get a \_\_\_\_
larger thinner clotting factors IV irreversible baby aspirin
Evolution of obstructive atherosclerotic plaque
• Disruption of plaque > \_\_\_\_
clotting cascade
Vulnerable Plaque Concept:
• What makes plaques vulnerable to breaking and setting off the cascade
○ ____ excess > vasoconstrictor, causes water and sodium retention, stimulates the CNS; also balances the things that accelerate water/sodium excretion and vasodilators
§ ACE inhibitors (-pril)
□ Have ____ effects; block metabolism
§ -sartans > block the ____
□ No bradykinin effects, only blocks the receptor
• Band of fibrous tissue covering the coronary plaque gets thin and ruptures and end up with a heart attack
ATII
bradykinin
receptors
Not all plaques are created equal
• The plaque not only bulges into the lumen and it bulges out ○ Thin cap: ruptures • Bottom: thick cap, will not \_\_\_\_ and will not result in the clotting cascade ○ If gets too turbulent > can still start the clotting cascade • \_\_\_\_ plays a role in thinning the cap
rupture
smoking
Evolution of myocardial infarcation
• Occlusion in the LAD ○ Cardiac muscle will \_\_\_\_ ○ End up with \_\_\_\_ (or death)
die
CHF
• Irreversible injury can start quickly
○ ____ hours
• If thrombolytic administration > the sooner the better
○ Under an ____ is best
1/2 to 4 hours
hour
Antihyperlipidemic Agents
• Can be prescribed throughout the cause of \_\_\_\_ ○ If try to lower cholesterol and doesn't work > you go on these ○ End in \_\_\_\_ § \_\_\_\_ inhibitors § Inhibit rate-limiting step of \_\_\_\_ synthesis § Big effect in lowering \_\_\_\_, and a little effect in raising HDL (you want to do this - \_\_\_\_ is the best in raising HDL; taking 1-4 grams of it per day; not well tolerated)
CAD -statin HMG CoA reductase LDL niacin
Lipoprotein Particle Size
• Biggest particle: \_\_\_\_ ○ Eat a steak, take a blood sample > oily patches around the blood ○ Can get processed down further • As density increase, diameter \_\_\_\_ • Lower everything except HDL ○ HDL picks up cholesterol, and takes it into the \_\_\_\_ (into bile and out of body)
chylomicrons
decrease
liver
Relative amounts of protein, triglyceride and cholesterol in lipoproteins
• Chylomicrons ○ Little \_\_\_\_, a lot of \_\_\_\_ and little chole • LDL ○ Medium \_\_\_\_, low in TF, and most in \_\_\_\_ • HDL ○ Most \_\_\_\_, not as much chol as LDL, and little \_\_\_\_
protein TG protein chol protein TG
Therapeutic HMG-coA reductase inhibitors
• -statins ○ People say that everyone should take them; well-tolerated and good benefits, but still new things coming out about them ○ Been looked at for \_\_\_\_ § Are people with more cardio problems prone to ALZ? § Poor blood flow to \_\_\_\_ > more likely to get tissue damage • Lovastatin ○ \_\_\_\_ one on the market ○ Only data they had - lowered LDL by 20-35%, raised HDL by 5-7%, lowered TG ○ Well-\_\_\_\_ • Simvastatin ○ People with bad lipid profiles were having fewer \_\_\_\_ events • Pravastain, fluvastatin ○ Difference in \_\_\_\_ ○ Differences in how processed in body § All go through \_\_\_\_> chances of interactions, but some have more chance of interaction
• Rosuvastatin ○ Is the most \_\_\_\_, and have a \_\_\_\_ ceiling effect > a better job of reducing bad cholesterol and TG ○ May have more \_\_\_\_ • Atorvastatin ○ \_\_\_\_ selling drug in the US
alzheimer's brain first tolerated cardio potency cyto P450 powerful higher side effects #1/#2
Cholesterol synthesis
• \_\_\_\_ is the first precursor to HMG CoA • HMG CoA goes to \_\_\_\_ via reductase ○ A step before the synthesis of cholesterol ○ They all work the same way
acetate
mevalonate
Relative potency: HMG CoA reductase inhibitors
• After people have been on the drugs for 3-6 mo • \_\_\_\_ mg daily ○ Too weak to give just 10 mg daily ○ Major effect: \_\_\_\_ § Normal LDL may be between \_\_\_\_ § LDL/HDL ratio - would like it to be under a \_\_\_\_ ○ Modest effect on raising HDL cholesterol ○ Better effect on lowering TG • If you up the dose you get more action ○ More side effects however ○ Rhabdomylysis § \_\_\_\_ destruction § Muscle aching § If gets bad enough > breakdown products in the \_\_\_\_ > acute renal failure
10 LDL 100-130 2 skeletal muscle kidney tubule
Statins: mechanism
• ApoB 100; ApoE ○ Part of proteins on \_\_\_\_ and cholesterol, and also the carriers of TG
LDL
Additional Effects of Statins: • Improve \_\_\_\_ function – enhances SMC NO synthesis • Improve plaque stability • reduces \_\_\_\_ • reduces macrophage secretion of MMPs • Reduce \_\_\_\_and cholesterol uptake by macrophages • Reduce platelet aggregation • Reduce \_\_\_\_ levels
• Enhance NO synthesis ○ Mild \_\_\_\_ effect ○ Not like NG, but still something ○ Not getting \_\_\_\_ from these! ○ Local enhancement • Plaque stability ○ Do not want it to \_\_\_\_ • Reduce platelet aggregation ○ Take \_\_\_\_; more selective • CRP ○ C-reactive protein ○ \_\_\_\_
endothelial cell plaque inflammation lipoprotein oxidation systemic CRP vasodilator postural hypotension rupture aspirin inflammatory marker
Adverse Effects of Statins:
• ____ – 1-3% (increease ____)
• ____ – 1.5% - 5.0% (____ fatigue)
• ____ toxicity – 1% (difficulty ____)
• Liver inflammation (1-3%) ○ First couple of months > by six months take a blood sample ○ When liver enzymes increase > sign of liver damage/inflammation • Myopathy ○ Doesn't all go to rhabdo - but the muscles begin to ache > off the drugs • CNS toxicity ○ Being studied for ALZ; know that it's getting into the brain
hepatotoxicity ALT myopathy myalgia CNS concentrating
Additional Interactions of Statins:
• Significant first pass ____ of all statins
- atorvastatin, pravastatin, rosuvastatin taken up via ____. Blockade of OATP2 by other agents (I.e., ____) will increaes levels of these statins
• Metabolism by CYP3A4
- ____, lovastatin, ____ primarily metabolized by
CYP3A4
- ____, fluvastatin, ____ not extensively metabolized
by CYP3A4
• Inhibitors of CYP3A4
- macrolide antibiotics (____)
- ____ (itraconazole, fluconazole, chlortrimazole) - cyclosporine
- ____ (antidepressant)
- HIV protease inhibitors
- ____• Organic anion transporter
○ Pump that pumps drug from blood into the small intestine
○ Gemfibrozil (not a -statin)
§ Placed on this if patient’s livers are so bad in order to get an ____ effect
§ Pumps -statins into small intestine > more likely to get isde effects
• Macrolide antibiotics
○ Not good for ____ in the oral cavity
○ Allergic to penicillin > also for amoxicillin
§ Reach for clindamycin now
• Azole antifungals
○ Tie up the primary metabolic pathway of warfarin > increase the level > ____ in brain/GI tract
• Cyclosporine
○ Immunosuppressant
○ Raises blood levels of -statins
• HIV protease inhibitors
• Grapefruit juice
hepatic uptake
organic anion transporter 2
gemfibrozil
atorvastatin
simvastatin
pravastatin
rosuvastatin
erythromycin
azole antifungals
nefazodone
grapefruit juic
additive
anaerobes
bleeds
Single dose simvastatin (Zocor®) pharmacokinetics following 3 glasses water or grapefruit juice per day.
• Increased incidence of people consuming grapefruit juice and on -statins > \_\_\_\_ and rhabdomyolysis ○ Typical grapefruit juice consumption (not gallons) ○ Worse because multiple dosing with a -statin • By drinking grapefruit juice > increase -statin levels by \_\_\_\_ ○ Evidence based interaction
muscle aches
5 fold
Other agents:
Fibric acid derivatives:
•____
•gemfibrozil
Mechanism:
increase lipolysis of ____ via lipoprotein lipase in adipose tissue – decrease plasma ____ – increase ____ – modest in decrease ____
• Gemfibrozil ○ Causes lipids to be chewed up > end result: intermediate lipoproteins go to LDL (VLDL go down), modest increase in HDL and a decrease in LDL ○ Fibric acid derivative (fibro) ○ Will seen it the most that's not a -statin
clofibrate TG VLDL HDL LDL
Other agents:
Nicotinic Acid (Niacin): •decreases VLDL and LDL via reduced liver secretion of \_\_\_\_; can increase \_\_\_\_ as much as 15-30%
Bile Acid Sequestrants
•____
•colestipol
Mechanism: binds bile salts in ____ and prevents reabsorption of fats – lowers ____
Probucol: ____ - reduces LDL modestly but also ____ HDL
• Niacin ○ Biggest effect on HDL ○ Yang of the -statins • BAS ○ \_\_\_\_; very "sandy" ○ Mix with orange juice and drink as quickly as possible ○ Ionic \_\_\_\_ ○ Tie up cholesterol and TGs in the gut so they don't get \_\_\_\_ ○ Not a lot of systemic absorption; stays local ○ \_\_\_\_ is hard • Probucol ○ Do not need to know about it ○ Reduces HDL, not used anymore
VLDL HDL cholestyramine jejunum and ileum LDL lipohylic antioxidant reduces
powdery
resin
absorbed
compliance
Niaspan®
• ____ niacin
• Absorption, ____ hours (niacin 30-60 min)
• T1/2ß; ____ min; nicotinamide 8 hours
• Primary adverse effects: ▫ \_\_\_\_(warmth, redness, itching, tingling) ▫ Diarrhea ▫ \_\_\_\_ ▫ Vomiting ▫ Increased \_\_\_\_ ▫ Pruritus
• Comes on slower but lasts longer • [???] • Flushing reaction ○ [???] ○ Involves a \_\_\_\_ component
extended release 4-5 20-45 flushing nausea cough prostaglandin
Niaspan
• Groups started with high LDL (185-190) ○ Mevacor for 4 weeks ○ Niaspan for 28 weeks ○ Group got the combo § Dose escalated the drugs § Most of LDL reduction is on the -statin § Niaspan gets rid of a little LDL □ Better dose response; for mevacor on 20 mg you cannot push it much higher § When combine both drugs > \_\_\_\_ effect □ This comnination reduces \_\_\_\_r events over a statin alone § Look at HDL elevation: niaspan □ The longer they're on it, the higher the dose > the more you get; but if you get \_\_\_\_g per day it's hard to take
additive
cardiovascular
2
Niaspan
AIM-HIGH (____: Impact on Global Health Outcomes)
- Hypothesis: ↓LDL + ↑HDL improves therapeutic outcome over ↓LDL alone
- Zocor [simvastatin] + placebo vs Zocor + Niaspan
- 32 month follow-up.
• End Points: Composite end point of ____ death, nonfatal MI,
ischemic stroke, hospitalization for non-ST segment elevation acute coronary syndrome, or symptom-driven coronary or cerebral revascularization
Results
• Study terminated 18 months early: almost no chance Niaspan
would prove ____.
• Additional small increase in ____ in high-dose niacin users – 28/1,718, Niaspan, vs 12 /1,696 placebo ; not clear if difference was coincidence; previous studies have shown no stroke risk from niacin.”
• AIM-HIGH ○ People that go on the combo will have fewer CV events than zocor alone § Zocor and niaspan § More HDL rise, and greater LDL drop ○ Terminated 18 mo early > the combination showed no benefit • Package insert says that there isn't evidence that it reduces \_\_\_\_ events
atherothrombosis intervention in metabolic syndrome with low HDL/HIGH triglycerides CHD beneficial strokes CV
And one more….
ezetimibe (Zetia®)
inhibits a specific transport process in ____, which take up cholesterol from the lumen. The putative transport protein is ____. In wild-type mice, ezetimibe inhibits cholesterol absorption by about 70%; in NPC1L1 knockout mice, cholesterol absorption is 86% lower than in wild-type mice, and ezetimibe has no effect on cholesterol absorption
Simvastatin = Vytorin Reduces \_\_\_\_-cholesterol by approximately 45—60% vs 33—49% LDL reduction with simvastatin monotherapy (10—80 mg/day) or 18% LDL reduction with ezetimibe monotherapy (10 mg/day)
• Vytorin ○ Combo of zocor and ezetimide ○ Ezetimide ties up a \_\_\_\_ that pumps lipids from the small intestine back into the blood stream • Ezetimide by itself: reduces LDL by 18% • Zocor by itself: reduces LDL by 33-49% ○ Combine both: additive effect > \_\_\_\_% reduction ○ Why the FDA will not accept surrogate markers anymore > have to show the benefit
jejunal enterocytes NPC1L1 LDL transport pump 45-60
• Compared vytorin to simvastatin alone (zocor)
○ Looked at plaque buildup on carotid arteries > won’t cause an MI but will lead to an ____
○ No ____ to the combo
○ Sales of this drug dropped by 50%
occlusive stroke
advantage
• Did the combo compared to simvastatin alone prevent more heart attack, strokes, etc.?
○ ____% reduction compared to simvastatin alone
• You would have to expose to 20 people to this combination compared to 20 others who got simvastatin, to get one in combo group where you prevented a bad event
○ Here, it’s an acceptable number to treat - the results of this event is really ____ (stroke/MI)
5-6
bad
Omega-3 Fatty Acid Ethyl Esters
5, 8, 11, 14 eicosatetraenoic acid (____)
8, 11, 14, 17 eicosatetranoic acid (____)
* Consuming these is good for you * Many different types, but the ones that have most benefit are the \_\_\_\_ for the heart
n-6
n-3
omega-3
• DHA and EPA ○ Seem to be most involved in cardiac health ○ May increase \_\_\_\_ and lower LDL ○ In \_\_\_\_ fatty fish § Salmon and tuna ○ Breast milk contains a lot of \_\_\_\_ • Omega 6 ○ Good for the \_\_\_\_
HDL
cold-water
omega-3
skin
Omega-3 Fatty Acid Ethyl Ester
Lovaza®
Adjunct to diet therapy in the treatment of ____ (≥500 mg/dL)
Possible mechanisms include:
• inhibition of ____;
• increased hepatic beta-oxidation;
• reduction in the ____ of triglycerides;
• increase in plasma lipoprotein lipase activity.
• \_\_\_\_ omega-3 • Indication for people with hereditary hypertriglyceridemia ○ Just as bad as LDL cholesterol • Normal TG level: 70-150 mg/dL ○ These people are over 500 ○ Having heart attacks at \_\_\_\_ • May be on this and a statin • \_\_\_\_ drug, not that palatable
hypertriglycerdemia acyl CoA: 1,2 diacylglycerol acyltrasnferase hepatic synthesis concentrated mid-20s prescription
Angina
(fr. Gk anchone strangling, fr. anchein to strangle)
Mechanism: imbalance between oxygen supply and demand
Varieties:
• ____
• Prinzmetal (variant)
• ____
• Prinzmetal ○ Small % of people with angina symptoms ○ Coronary arteries go into \_\_\_\_ ○ Drugs that work the best on this: \_\_\_\_ channel blockers • In an acute attack > \_\_\_\_ ○ All the other drugs > used \_\_\_\_ (prevent attacks) • Unstable ○ On the bridge of having a heart attack § While sittinf down ○ Getting occlusion for a brief couple of seconds
chronic/stable/exertional unstable vasospasm Ca++ sublingual NG prophylactically
Triggers of angina: The 4 E’s: • \_\_\_\_ • Exertion • \_\_\_\_ to cold • Emotion
Also:
• ____
eating
exposure
smoking
Agents:
• Nitrates ○ All derivatives of \_\_\_\_ ○ Work by being nitric oxide (NO) donors § Stimulates cGMP pathway and produces vasodilation throughout the \_\_\_\_ (not just the coronaries) ○ Extremely \_\_\_\_ ○ Acute attack: § Sublingual NG □ In BS in 3-4 minutes § Amyl nitrite □ \_\_\_\_ under the tongue; rarely used today ○ Isorbide dinitrate and pent § \_\_\_\_, and transdermal delivery □ Longer to get into the BS § Taken \_\_\_\_ to prevent attacks
NG body hypotensive spray pills chronically
Other agents:
b-blockers
calcium antagonist
• Used \_\_\_\_, and can be used in other CV diseases ○ Which can be used for other things? § Propranolol can be used in \_\_\_\_, or in the CHF; used in people with \_\_\_\_ disorders (blocks B2 receptors) □ Prop vs meto: ® Look at local anesthetics ® Meto is cardioselective (\_\_\_\_ receptors) ® Prop blocks both \_\_\_\_ receptors ◊ In an asthmatic > potential death due to asthmatic attack ○ Nifedipine § \_\_\_\_ channel blocker used in hypertension, sometimes in CHF § All the -pines (amlodipine) are pure vasodilators □ The other two (borapamil and diltizem) > not only vasodilate but they can bind to Ca++ channel in \_\_\_\_ > decrease HR and contraction force (just like beta blockers) > decrease \_\_\_\_ demand > less likely to get an angina attack § All the Ca++ blockers can cause \_\_\_\_
prophylactically hypertension migraine B1 B1 and B2 Ca++ heart myocardial oxygen gingival hyperplasia
Mechanisms
* NO stimulates \_\_\_\_ > vascular relaxation * B2 agonists (not good in angina attack) hit smooth muscle on \_\_\_\_ > stimulate cAMP pathway > \_\_\_\_ (good in treating asthmatic attacks) * Slightly diff \_\_\_\_ on each type of smooth muscle
cGMP
bronchial tree
bronchodilation
receptor
Nitrates
Adverse Responses
• ____, reflex tachycardia, methemoglobinemia
• ____, dizziness, weakness (associated with postural
hypotension
• Interaction with ____ nhibitors used for MED (sildenafil, tadalafil, vardenafil) – SEVERE ____
Calcium Antagonists
• ____, reflex tachycardia with nifedipine, amlodipine
• Dizziness, headache, nausea
• ____
b-Blockers
• ____
• Hypotension
• Blockade of pulmonary ____ receptors (propranolol and not metoprolol)
• Bradycardia (may require pacemaker)
• Prolonged ____, widened ____ (interaction with verapamil)
• Delay recovery from insulin-induced hypoglycemia
• ____, depression, fatigue, sleep disturbances
• Nitrates AE ○ Any vasodilator can do reflex tachycardia (bad for angina attack) - dose them up slowly ○ Strong oxidizing drugs - push the dose > \_\_\_\_ > Fe2+ to Fe3+ > doesn't carry oxygen well > various shades of blue § Benzocaine and prilocaine can also do this in an overdose (locals that are strong oxidizing drugs) • Ca++ antagonists ○ Reflex tachycardia more likely with the \_\_\_\_; the others have direct slowing action on heart so less likely • Beta-blockers ○ Drugs get into the CNS § Feel very tired
hypotension
headache
PDE-5
hypotension
hypotension
gingival hyperplasia
CHF B2 AV conduction QRS seizures
methemoglobemia
-pines
Mechanopharmacological Therapy
Coronary Stent
• Balloon in ____ artery > expand > stick a stent in there
• Re-stenosis ○ The \_\_\_\_ grows into the stent and occludes the smooth muscle
coronary
smooth muscle
Pathology of Restenosis after Vascular Injury
• Before stents > balloon angioplasty > stick a catheter and expand the lumen of the coronary > elastic recoil ○ The stent prevents \_\_\_\_ • Rheological factors [???] • Localized \_\_\_\_ where tissue starts growing into the stent ○ SMC gets activated and grow into the stent
elastic recoil
inflammation
Sirolimus (rapamycin)
- ____ product
- Source = streptomyces ____
- ____ stable molecule
- MW=914
- Highly ____ (log P>4.0)
- Potent antiproliferative & immunosuppressive agent
- Whole Blood t 1/2 = ____
- Unique mechanism of action• Drug-loaded stents
○ CYPHER stent
• Slowly release drug from stent in localized area
○ Tiny amounts; hardly any gets into systemic circulation
• Rapamycin
○ Potent anti-proliferative and immunosuppressive agent
○ Used in patients with ____
○ Also seen in ____ studies
fermentation hygroscopicus small lipophilic 60 hours organ transplants CART-T
Sirolimus (rapamycin)
* Affect cell cycle and hits mTOR > arrests growth from \_\_\_\_ (doesn't affect \_\_\_\_ directly) * End result sirolimus hits the \_\_\_\_ receptor
G1 to S
mitosis
mTOR
Paclitaxel
• Most other stents have derivatives of rapamycin
• Other stents have paclitaxel slowly released
○ Major drug in ____
○ When given high systemic doses > kills cells > ____
○ When tiny bits leach out of stent > arrests ____, doesn’t kill cells
breast cancer
apoptosis
cell growth
Currently Available Drug-Eluting Stents
•Cypherâ (sirolimus) •Endeavorâ (zotarolimus) •Promusâ (everolimus)
•Taxusâ (paclitaxel)
•Xience VÔ (everolimus)
* Four of them are derivatives of \_\_\_\_ * One has \_\_\_\_
sirulimus
paclitaxel
Mechanopharmacology of a CYPHER Stent
• 5-10years out, ____ does occur.
restenosis
• Fibrinolytics can only be given ____
IV
Definitions: \_\_\_\_ - intravascular clot \_\_\_\_ - prevent formation of a thrombus \_\_\_\_ - prevent platelet aggregation \_\_\_\_ - dissolve pre-formed thrombus
thrombus
anticoagulant
antithrombotic
fibrinolytic
Mechanisms of Blood Coagulation
Blood coagulation refers to the process of forming a clot to stop bleeding. Coagulation is a complicated subject and is greatly simplified here for the student’s understanding.
To stop bleeding, the body relies on the interaction of three processes:
Primary hemostasis involves the first two processes.
- Vasoconstriction. ____ is the body’s first response to injury in the vascular wall. When injury occurs, vessel walls constrict, causing reduced blood flow to the site of injury.
- Platelet plug. Platelets aggregate to the site of the
injury. They stick together acting as a “____.” Platelets also activate the process which causes a fibrin clot to form, known as ____.• First thing that occurs: vasoconstrictive process; then platelets start aggregating and stick to each other
○ Sticking to each other > not enough to form a ____
vasoconstriction
plug
secondary hemostasis
clot
Secondary hemostasis.
3. ____ alone are not enough to secure the damage in the vessel wall. A clot must form at the site of injury. The formation of a clot depends upon several substances called ____. These factors are designated by roman numerals I through XIII. These factors activate each other in what as known as the clotting cascade. The end result of this cascade is that ____n, a soluble plasma protein, is cleaved into ____, a nonsoluble plasma protein. The fibrin proteins stick together forming a clot.
The clotting cascade occurs through two separate pathways that interact, the intrinsic and the extrinsic pathway.
Extrinsic Pathway
The extrinsic pathway is activated by external trauma that causes blood to escape from the vascular system. This pathway is ____ than the intrinsic pathway. It involves factor ____.
Intrinsic Pathway
The intrinsic pathway is activated by trauma inside the vascular system, and is activated by ____, exposed endothelium, chemicals, or collagen. This pathway is ____ than the extrinsic pathway, but more important. It involves factors ____I.
Common Pathway
Both pathways meet and finish the pathway of clot production in what is known as the common pathway. The common pathway involves factors ____.
• In addition to platelets, there's a clotting cascade: ○ Extrinsic § Mainly involves factor VII § Some crosstalk between pathways § Blood getting out of the BV that interacts with other tissue that turns it on ○ Intrinsic § Factors that are in the blood
platelets
clotting factors
fibrinogen
fibrin
quicker
VII
platelets
slower
XII, XI, IX, VIII
I, II, V and X
Blood Clotting Cascade
PT (12-14 sec) +thromboplastin
aPTT (26-33 sec) Kaolin substrate, phospholipid
• Intrinsic pathway ○ Steps are \_\_\_\_ dependent, and \_\_\_\_ dependent • Extrinsic pathway (darker gray) ○ A lot \_\_\_\_ ○ Can stop bleeding on it's own quicker • Crosstalk between both • Major final steps: pro-thrombin to \_\_\_\_; catalyst for fibrinogen to fibrin (thereby forming the clot) ○ Drugs that inhibit platelets, or inhibit factors in the clotting cascade
Ca++
vitamin K
shorter
thrombin
Thrombosis - Cellular Response
Vascular injury
>
Platelet aggregation/Tissue binding Factors: 1) \_\_\_\_ 2) fibrinogen 3) mediators (\_\_\_\_, TXA2, \_\_\_\_, ADP)
>
Fibrin formation/RBC binding
• [???] • 5-HT > serotonin > causes platelets to aggregate (but no nucleus, so they get serotonin from sucking it up from the \_\_\_\_) ○ SSRIs > mild \_\_\_\_ effects - may have additive effects if take it with \_\_\_\_ • ADP receptors on platelet > when stimulated > activated, and more likely to \_\_\_\_ together
collagen thrombin 5-HT stream antiplatelet NSAIDs stick
Thrombosis and Antithrombotic Approaches
• Crosstalk between platelet activating system and the clotting cascade ○ PAR § Proteolytic activating receptor □ Thrombin can also activate \_\_\_\_, not just the fibrin formation step ○ P2Y § Type of \_\_\_\_ receptor § Activated by ADP, and activates platelets that bind to each other > \_\_\_\_ > form bridges that hold the platelets together • Anticoagulants act on \_\_\_\_ • Antithrombotics ○ Hit \_\_\_\_, hit ADP receptors or the \_\_\_\_ receptors ○ These are not as powerful as the \_\_\_\_
platelets ADP IIb/IIIA factors thromboxane IIb/IIIA anticoagulants
Arachidonic Acid Pathway
• Doses of aspirin that are used for cardioprotection/occlusive stroke protein > ____mg per day; analgesic dose of aspirin is 3000-4000mg per day
○ Do not give for someone at risk of bleeding stroke
○ Take TXA2 out, and don’t affect PGI2
§ Prostaglandins involved in ____, and thromboxanes in platelets are ____ and stimualte platelty aggregation
§ PGI2, product of endo cells > ____ and inhibits plate aggrgeation
§ If equally knock both out > it’s a wash
§ Difference histo between endo and platelets:
□ No ____ on platelets, endothelial cells have a nucleus > can regenerate ____ readily
81-325 cytoprotectants vasoconstrictive vasodilator nucleus cyclooxygenase
Differences between molecules
- Thromboxane A2
- Localization = ____
- Stimulates platelet ____
- ____
• Prostacyclin (PGI2) • Localization =
____ cells
• Inhibits platelet ____
• ____
Platelets lack nucleus. Cannot regenerate ____ when aspirin irreversibly binds. Also low dose aspirin selective for blocking COX-1 in ____ over COX-2 in endothelium.
Endothelial cells have nucleus and can ____ COX within a couple of hours, plus COX is predominantly ____.
• Aspirin irreversibly binds cyclooxygenase (whether it's 1 or 2), but the endo cells can regenerate
platelets aggregation vasoconstrictive endothelial aggregation vasodilatory COX platelets regenerate COX2
