Mod 4 Anticoagulation Flashcards
hemostasis involves pathways what what
bring about a cessation of bleeding
in clot formation there are intrinsic and extreins pathways that converge where and do what
these pathways converge on the step where prothrombin factor II is converted to thrombin factor IIa by factor Xa
thrombin then acts on fibrinogen to produce fibring
this is monomeric fibring that then becomes cross linked to form the clot
red clots result when
result when red blood cells become trapped in the fibrin mesh
these usually occur on the venous side of the circulation and can result in thromboembolism
drugs taht act on red clot part of the pathway care called what
anticoagulants
what does warfarin do
inhibits the syntheiss of prothrombin by inhibting the formation of active vitamin K
what does unfractionated hpring do
inhibtis btoh the activation of prothrombin by factor Xa and the activity of thrombin
low molecular weight fractionated heprins are more selective in inhibting what
factor Xa
what is an example of selective Xa inhibtior
xarelto (rivaroxoban) and thomin inhibitors sich as dabatran (pradaxa)
drugs that prevent platelet aggregation do what
prolong the bleeding time
without platelet aggregation what happens
no plug is formed and the bleeing time is prolonged
platelets for what kind of clot
white clot that is typically found on the arterial side and can lead to embolism
drugs taht inhibit platlet aggregation include
aspirin and clopidogrel
what does aspirin do
inhibtis cycooygenase enzyme thus inhibiting the production fo thromboxi AII
what does clopidogrel do
inhibits the binding of ADP to its receptor site on platelets thus inhibiting platelet activation
unfractionated heprin is a mixture of what
acid mucoolysaccharide
since unfractionated heprin is unfractuonated what can the molecular weight be
can range anywhere from 2000-30000 daltons
what is the mechanism of action of heprin
antithrombin III (naturally occuring protein found in blood) binds to rhombin producing an inactive complex and this process normally occurs slowly
when heprin binds to antithrombin, it causes a 1000 fold incraese in teh rate of the reaction
once the heprin antithrombin thrombin complex is fomred, heprin can dissocated and bind to other antithrombin proteins causing more complexes to be formed
what is one advantage of heprin to warfarin
it acts immediately
heprin is normally given intravenously
sometimes given subcutaneously
never given IM becuase of the risk of hematoma formation
what is the pharmacology of unfractionated heprin
ufh inhibits factors IIa (thrombin) and Xa
what are the therapeutic uses of heprin
dvt prophalaxis and treatmetn
embolism prophylax and treatment pulmonary
percutantoes coronary intervetntion, blod transfusions, dialysis
what are the side effects of heprin
bleeding - avoid bleeding diathesis/uncontrolled bleeding
thrombocytopenia
what is the antidote for heprin
protamie sulfate
how does protamine sulfate work
excessive bleeding with unfractionated heprin can be treated with protamine sulfate that binfs to heprin and prvents heprin from binding to antithombin
what is thrombocytopenia
most serious side effect of unfractionated heprin
results from a drop in platelets
if this occurs then heprin treatment must immediately be stopped
what is the molecular weight of low molecular weight heprins
2000 to 6000 daltons
waht si the advantage of using low molecular weight heprin
no monitoring and less side effects - less likely to cause thrombocytopenia
the uses are the same as UF heprin
what is an example of a low molecualr weight heprin
enoxaparin
this is more Xa selective thatn inbiiting thormbin
what is the action of warfarin
acts to prevent the formation of active clottings factors 7 9 10 and 2 (protrombin)
inhibits the syntheiss of vitamin k dependent clotting facotors
formation of the clotting factors is dependent on what
dependent on the presense of vitamin k
what is the mechanism of action of warfain
vitamin k epoxide reductase is an enyme that converts oxidized inactive vitamin K to reduced active vitamin K
vitamin k serves as a cofactor in the synthesis of the clotting factors such as prothrombin
inhibit virtamin k epoxide reductase
as a result there is no vitamin k available to use for the synthesis of clotting factors
what is the therapeutic use of warfain
dvt prophhylaxis and treatment
embolism prophylaxis and treatment
atrial fibrilation - prophylaxis of systemic embolism
why is afib concering for thromboembolism
results in the pooling of blood in the atria and can result in the developemnt of thromboembolism
this can cause embolism of cerebral vesles and stroke
warfarin prior to and following afib treatment
what are side effects of warfarin
bleeding
contraindicated in pregnancy
what is the antidote for warfarin
vitamin k1
can warfarin be used in pregnancy
causes fetal malformation
striculy contraindicated
category x
what are considerations for warfarin use
oral bioavailabilty - can be oral and good for outpt use
dalyaed onset of action so must overlap with heprin
must monitor prothrombin time (pt)
warfain undergores microsomal metabolism (cyp 2c9)
cyp 2c9 inhibitors will prolong the warfarin pt time
why must warfarin be overlapped with heprin
clotting cascade proteins have long half life of 4-6 hours for factor 7 up to 60 ohurs for protrhombin
so even if you inhibit the synthesis of new clotting factors with warfain, you still have clotting facotrs that are already present in the blood
as a result onet of warfarin actin can be delayed for days for even weeks
improtant when starting warfarin to overlap therapy with heparin
what are food and drug interactions with warfarin taht increaes the activity of warfarin and why
most nsaids
cimetidne (macrolides and azoles)
these drugs inhibit cytochrome p450 enzumes thus preventing warfarin metabolism this increaseing the activity of warfarin
what are food and drug interactins with warfarin that decrease the activity of warfarin and why
phenobarbital
bile acid resins
vitamin k foods
induce cyp405 enzymes increasing warfarin metabolism reducing warfarin activity
need to incrase dose of warfarin if take cyp450 inducler
what is the action of dabigatran
direct thrombin inhibitor
what is the action of rivaroxaban
factor xa inhibitor
what are dabigatran and rivaroxaban uses
commonily used in prolypaxis treatment of a fib
now replacing warfarin in treatment of DVT and pulmonary embolism long term therapy
dpes pt time need to be monitored with rivaroxaban dabigatran
prothrombin time does not need to be obtained
what are considerations with dabigatran and rivaroxaban
bleeding major concern
do not require pt monitoring
faster onset of action than warfarin
limited drug to drug interaction compared iwth warfarin
what is the mechanism of action of aspirin and clopidogrel
inhibits platelet aggregation or prevents platelet activation
platelets have thormboxane a2 receptors on their surface and adp receptors what happens when thromboxin A two binds
binding of the thromboxin AII to the thromboxane receptor or adp to its receptor initiates platelet activation that leads to aggregation
the flbrinogen recetpor on platelets is called waht and what does it do
glycoprotein 2b3a receptor which recognizes fibrinogen on tohe platelets
stimulation by thromboxin a2 or adp causes waht
a cross linking of the platelets resulting in platelet aggregation
what does aspirin do
inhibits the cyclooxygenase 1 (cox1) enzyme and inhibits the formation of thrombozin A2
this inhibition if irreversable
what does clopidogrel do
inhibits the binding of adp to adp receptor and inhibits platelet aggregation
what are therapeudic uses fo aspirina nd clopidogrel
acture coronoary syndrome such as mi or unstable angina
adjunct to percutaneous coronary intervention
prophylaxis of transient ischemic attacks
why are aspirin and clopidogrel mandatory after mi
if it requires percutaenous cornonary intervention such as angioplasty or stenting
goal to prevent new clot formation in colonary arteries
what are the side effects/considerations of aspirin and clopidogrel
gi in aspirin
clopodogrel is a produg which requires the activatio of cyp450 enzymes - requires hepatic metabolism
blood disorders (thrombotic thrombocytopenia, purpura, agranulocytosis
hemostasis is controleld by what
coagulation cascase and platlet aggredation
coagulation cascade results in the formation of what
fibrin clot
fibrin clot can be inhibtiied by what
anticoagulatns such as warfarin/heprin/noas such as riveroxiban and dabigatron
effect of antiogoaulation is monitored in vitro and manifests as
pt time in warfarin
platelet aggregatioon results in the formation of
platelet plug
platelet plug can be inhibtied by
antithormbotics like cox inhibitors and adp r antagonists
the effect of antithombotics manifests as
increased bleedig time
what is the antidote of warfarin
viatmin k1
what ios the antidote of heprin
protamine so4
when blood levels of lipids are elevated what can this lead to
lead to development of coronary artery disease
what is the biochemistry of lipoprotein
lipoproteins have an inner hydrophobic core with cholesterol esterase and triglycerides
there are different ratios of cholesterols and triglycerides in lipoprotiens
there is also an outer hydrophillic coat with phospholipiids unsterifed cholesterole (free) and apolipoproteins
what are apolipoproteins
are a key part of the lipoprotein
they rovide structure activate enzymes and serve as ligands ofr receptors
waht is the ligand for the LDL recepotr
apob100
what is the rate limiting step in cholesterol synthesis
hdm coa reductase enzyme is the rate limiting step in cholesterol synthesis
hdm coa reductase results in waht
leads to teh production of VLDL that are secreted by the hepatocytes into the blood stream
what is the composition of VLDL
triglyceride rich
about 80% cholesterol
one VLDL is in the blood what happens q
they are acted upon by lipoprotein lipase
these lipases revmoe the rriglycerisdes rseulting the for thefmatio fo free fatty acids
what do free fatty acids do
along with glucose are used as an energy source for the body
what is the structure of LDL
cholesterol rich protein
triclyceride poor
carry 60-70% of palsma cholesterol
arise from metabolism of vldl remant
how is cholesterol delivered throughout the body
LDL binds to the LDL receptor and becomes internalized
what is cholesterol used by cells for
used by cells for making biological membranes, in steroid formation , in myelin formation and for bile salts
ldl can be deposited in teh intimal space of arteries such as
coronary arteries
LDL is removed by what
removed by ldl receptors in teh liver or peripheral tissues or deposeited into intimal space of coronary, carotid or peripharla arteries
HDl is involed in what
reverse cholesterol transport which takes excess cholestroll and returns it to the hapatocytes
this is how we remove choleserol from the body
HDL possesses waht kind of effects
posesses anti aterogentic effects
when there is an incraese in LDL cholesterol then waht
there is a greater risk for cad
when we decrease LDL then what
we decrease the risk fo coronary artery diease
when LDL is deposited in the intimal space, what happens
ldl becomes oxidized leading to the formation fo atherscleroti cplaque
this initiates an inflammatory cascade
what are risk factors for dyslipidemia
hypertension, smoking, diabetes, stress and genetic factors
what is the goal of therapy for dyslipidemia
goal for therapy are to improve lipiprotein profules and reduce palque formation and stabilize existing plaques
like to reduce 20% of ldl during treatment
what are examples of drugs for dyslipidemia
statins
niacin
fibrates
bile acid sequestrants
cholesterol absorption inhibitors
what are examples of statins
atorvastatin (lipitor) and pravastatin (pravachol)w
what is the pharmacology of statins
stains inhibit hmg coa reductase thus inhibtiiign the early rate limiting step in cholesterol biosynthesis
decrease in hepatic vldl and plasma ldl and will cause an increase in teh expression of ldl receptors
with an incraese in ldl receptors there is more ldl taken up into hepatocytes and less blood cholesterol
overall waht do stains do
inhibt hmg coa resuctase
reduce choleserol synthesis
decrease plasma ldl levels (20-25%)
increaed expression fo ldl receptors
small change in hdl and triglyceride?
what are side effects of statins
liver toxicity initially
rhabdomyolysis msucle pain and weakness
insulin resistance - incrase a1c
contra indiceted in pregnacy
what are statins contraindicated in oregnacy
inhibit cholesterol synthesis which is required for fetal developent
what is the pharacolgy of niacin
vit b3
decreaes vldl secretion from hepatocytes this reduced blood ldl
reduced triglycerides 35-40%
reduced plasma ldl levels (20-30%0
increases plasma hdl levels (30-40%)
what are the two forms of niacin
crystalline niacin
systained release niacin
wahta are side ffects of crystalized niacin
flusing and itching
this is prostaglandin mediated so treat with aspirin
what are side effects of niacin in sustained release form
hepatotoxicity so have to monitor liver function annually
why is niacin contraindicated in pregnancy
teratogeinc effects
what arre examples of the fibrates
clofibrate and gemfibrozil
what is the pharmacolgoy of fibrates
these drugs bind to peroxosome proliferator activated receptors (PPAR)
this causes increased expression of ldl receptors
leads to modest decrase in ldl and decrease in triglycerides
what are ppars
nuclear receptors that stimulate the transcription of specific genes following ligand binding
what are the side effects of fibrates
rhabdomyalysis especially when given with statins
what is an example of bile acid sequesterants
cholestyramine
what is the pharmacology of bile acid sequestrants
bile acid sequensterants become retained in the lumen of the gut
in the gut they bind to bile acids and prevent to absorptin
this stimulates the coversoin of cholesterol to bile acids in the liver and thus a decrease in cholesetrol synthesis
this leads to compensatory increase in ldl receptor expression
decrase in plasma ldl levels
since bile acid sequenterants decrese choleserol levels there can be a conpensatory increase in hmg coa reductase
this is situation where statin that inhbits hmg coa reductase might be coadminsitered
what are the side effects of bile acid sequesterants
potential increase of hmg coa reductase expression and stimualte cholestol synthesis so combine with statin therapy
constipation and bloating
what is an example of cholesterol absorption inhibitor
ezetimibe (zetia)
what is the pharmacology of cholesterol absorption inhibitors ezetimibe
resuced cholesrol absorpiton (inhibit intestinal absorpiton of choelsterol)
reduces ldl levls plasma and leads to a compensatory increase in hepatic LDL receptor expression do increased liver ldl
little to no effect on triglycerides and hdl
why would you combine ezetimbine witih statin
further decrease ldl levels
both decrease in cholesterol absoption
stain prevents compensatory increase in cholesterol in liver from hmg coa reductase upregualtion
side effect of zetia
side effect from combo w statin
