Cardiology Test 3- Lapinsky Anti-coagulation/anti-platelet agents

coagulation: the process by which blood changes from a liquid to a ___ to form a blood clot

gel

coagulation potentially results in ____ (ie the stopping of blood loss from a damaged blood vessel)

hemostasis

___ ____ (aka thrombocytes): one component of blood whose function is to react to bleeding from injury to a blood vessel by clumping together, thus initiating the formation of a blood clot

blood platelets

___ ___ ___: distinct proteins within the blood of a patient that help form blood clots to stop bleeding when an injury occurs

blood clotting factors

blood clot forms when aggregated blood platelets and RBCs form a "plug" that is held together by a mesh of cross-linked ____

fibrin

drugs that prevent clot formation include ___ and ___

anticoagulants, antiplatelets

removal of existing clot

-works by the drug dissolving the clot, and includes ____

fibrinolytics

basic steps in hemostasis:

1) vessel injury

2) vessel spasm

3) platelets adhere to injury site and aggregate to form plug (primary hemostasis)

4) insoluble __ strands form and coagulate to hold the blood clot together (secondary hemostasis)

fibrin

seondary hemostasis

1) platelets and damaged cells release ___ ___

factor Xa

seondary hemostasis

1) platelets and damaged cells release factor Xa

2) which then forms _____ _____

prothrombin activator

prothrombin activator= factor ___ + factor ___ + ____

Xa, Va, Ca

seondary hemostasis

1) platelets and damaged cells release factor Xa

2) which then forms prothrombin activator

3) then, prothrombin activator converts ___ to ___

prothrombin, thrombin

seondary hemostasis

1) platelets and damaged cells release factor Xa

2) which then forms prothrombin activator

3) then, prothrombin activator converts prothrombin to thrombin

4) then, thrombin converts ___ to ____

fibrinogen, fibrin

Primary hemostasis: ___ ___ aggregate to the site of an injured blood vessel and form a "plug"

blood platelets

while primary hemostasis is occuring, ___ hemostasis can begin

secondary

secondary hemostasis (aka ___ ____)

blood coagulation

secondary hemostasis: blood clotting factors get _____ activated by an active blood clotting factor to form ___

proteolytically, fibrin

the blood clotting cascade is so complex because:

1) the body needs to ___ the response tightly (blood clotting must happen only when needed)

control

the blood clotting cascade is so complex because:

2) the body needs to ___ the signal (it is a chain reaction)

amplify

the blood clotting cascade is so complex because:

3) the body needs to build in ____ (a back up system). If one of the two pathway fails, blood clotting can still occur through the other.

redundancy

the blood clotting cascade is so complex because:

4) the body needs to ___ with other body systems (inflammation, the immune system, wound healing)

integrate

In sum, the blood clotting cascade is so complex because it needs to be __, powerful, and safe

precise

____ pathway: All the factors needed are already present in the blood

___ pathway: needs factors outside of blood

intrinsic, extrinsic

Extrinsic and Intrinsic pathways merge on ___ ___

factor x

anti-coagulation drug targets

1) "direct" or "indirect" ___ ___ inhibitors

2) "direct" ____ inhibition

factor Xa, thrombin

drug targets

Factor Xa= "___ ___" of secondary hemostasis

Thrombin= "__ ___" of secondary hemostasis

volume knob, power plug

drug targets

Factor Xa= is ___ (earlier) in blood clotting cascade

Thrombin= is ___ step in blood clotting cascade

upstream, final

drug targets

Factor Xa= causes _______ thrombin formation

Thrombin= blockage of _____ thrombin activity

decreased, all

drug targets

Factor Xa= ___ procoagulation mechanism

Thrombin=___ procoagulation mechanisms

1, 4

drug targets

Factor Xa= ____ fibrin formation

Thrombin= fibrin formation completely ____

decreased, blocked

Vitamin K is required for human body to make what 4 blood clotting factors?

factor II, factor VII, factor IX, factor X

Vitamin K is responsible for "_____"

carboxylation

Vitamin K is responsible for "carboxylation"--adding additional CO2- groups to ___ ___ residues within the notes blood clotting factors to create a binding site for Ca+2

glutamic acid

Inhibiting the function of Vitamin K ____ the synthesis of mature/functionally active vitamin K dependent blood clotting factors (factor II, factor VII, factor IX, factor X)

prevents

Inhibiting the function of Vitamin K prevents the synthesis of mature/functionally active vitamin K dependent blood clotting factors.

This is the MOA of ____!!

warfarin

Vitamin K is an ____ for warfarin toxicity

antidote

Warfarin is a ____ inhibitor

VKORC1

VKORC1 converts inactive oxidized vitamin K → ___ ___ vitamin K

active reduced

by inhibiting VKORC1, warfarin _____ the vitamin K in its inactive oxidized form, so it cannot form mature/active vitamin K dependent blood clotting factors

traps

__-___ _____: enzyme that adds CO2 to Glu residues within clotting factors

gamma-glutamyl carboxylase

Without the active, reduced form of Vitamin K, the liver cannot produce mature/active vitamin K dependent blood clotting factors OR the natural anticoagulant proteins: protein __ and protein __

C, S

Warfarin has a ___ anti-coagulant effect of 4-5 days

delayed

Warfarin has a delayed anti-coagulant effect of 4-5 days because it takes time for the body to inactivate any ____ vitamin K dependent blood clotting factors from the blood circulation!!!

prexisting

Warfarin has high ___ ___ binding, mainly to albumin

plasma protein

Warfarin has high plasma protein binding, mainly to albumin, which is why the drug is a significant source of plasma-protein drug displacement ____ with other drugs !!

interactions

Warfarin is hepatically inactivated by CYP1A2, CYP3A4, and ___ (major!)

CYP2C9

Elimination half life of warfarin is __ hours (long)

36

Since the elimination half life of warfarin is long, the anticoagulation effects can last up to __ days after drug discontinuation !! (for body to re-establish normal levels of vitamin K dependent blood clotting factors)

5

there can be genetic polymorphisms in ____, which slow the natural inactivation metabolism of warfarin and lead to increased risk of bleeding

CYP2C9

there can be genetic polymorphisms in _____, which dictate how well warfarin binds to VKORC1, and can therefore require dosing adjustments

VKORC1

CYP2C9 polymorphisms = predict __ of warfarin

VKORC1 polymorphisms= predict __ ___ of warfarin

safety, clinical efficacy

take home message: genetic testing can help optimize __ and decrease ___ ___

dosing, bleeding risk

Warfarin is a notorious red flag drug with a _____ therapeutic index

narrow

therapeutic index= ___ dose/ ___ dose

toxic, effective

a higher therapeutic index means increased _____

safety

Warfarin has a narrow therapeutic index. Small dose changes can lead to LARGE shifts in ___

INR

INR (international normalized ratio): measures how ____ it takes blood to clot compared to normal

long

HIGH INR

-____ blood clotting time

-____ bleeding risk

increased, increased

LOW INR

-____ blood clotting time

-____ bleeding risk

decreased, decreased

Warfarin has drug interactions with CYP ____ (like azole antifungals)

inhibitors

What happens when azole antifungals (CYP inhibitors) interact with Warfarin?

-_____ warfarin inactivation metabolism

decreased

What happens when azole antifungals (CYP inhibitors) interact with Warfarin?

-____ INR, so increased ____

increased, bleeding

Warfarin has drug interactions with CYP ____ (like Rifampin)

inducers

What happens when Rifampin (CYP inducer) interact with Warfarin?

-_____ warfarin inactivation metabolism

increased

What happens when Rifampin (CYP inducer) interact with Warfarin?

-____ INR, so increased ____

decreased, clotting

Warfarin has drug interactions with other drugs that are highly ___ ___ bound (like Phenytoin)

plasma protein

What happens when Phenytoin interact with Warfarin?

-Warfarin is ___ from albumin, so there is ___ free warfarin

displaced, increased

Warfarin has drug interactions with drugs that suppress ____ ____ (like antibiotics)

gut flora

What happens when antibiotics (gut flora suppression) interact with Warfarin?

-there is ___ bacteria that can synthesize vitamin K

decreased

What happens when antibiotics (gut flora suppression) interact with Warfarin?

-____ INR, so increased ____

increased, bleeding

Warfarin has drug interactions with drugs that cause additive ___-___ effects (like NSAIDs and SSRIs)

anti-platelets

What happens when NSAIDS+SSRIs (additive anti-platelet effect) interact with Warfarin?

-decreased platelet function to ____

-increased ____

aggregate, bleeding

when NSAIDS+SSRIs (additive anti-platelet effect) interact with Warfarin, there is increased bleeding even if the __ is normal !!

INR

Warfarin has drug interactions with ___ ___ supplements (from the diet/green tea)

vitamin k

What happens when vitamin K supplements interact with Warfarin?

-_____ synthesis of vitamin K dependent blood clotting factors

increased

What happens when vitamin K supplements interact with Warfarin?

-____ INR, so increased ___

decreased, clotting

warfarin's effect can also be impacted by ____ status and interactions with ___ (like ginkgo, garlic, etc.)

thyroid, herbals

Heparin is a naturally occurring anti-coagulant that is a highly ___ glycosaminoglycan (ie a polysaccharide) that can be extracted from porcine intestinal mucosa or bovine lung tissue

sulfated

There is a specific pentasaccharide sequence on heparin that is responsible for recognizing and binding to ____-___ ____ as the drug target

anti-thrombin III

Heparin features repeated disaccharide units of iduronic or glucuronic acid plus glucosamine with ____ sulfation

variable

heparin has a ____ negative charge (as compared to warfarin which has a single negative charge)

strong

heparin is a ___ sized polymer (as compared to warfarin which is a small polymer)

large

heparin is highly _____ (as compared to warfarin which has a balance of H2O/lipid solubility)

polar

heparin is administered ___ (IV or SC)

parenterally

heparin has a __ onset and offset of action, so it is useful in acute settings

rapid

heparin is an "___" anticoagulant. It acts as a catalyst that dramatically accelerates the natural inhibitory activity of ____

indirect, ATIII

Heparin MOA

step 1- the specific pentasaccharide sequence on heparin binds to ___ with high affinity

ATIII

Heparin binding causes a ___ change in ATIII

conformational

Heparin MOA

step 2- enhanced ____ of certain blood clotting factors by ATIII

inactivation

Key concept= How much each blood clotting factor is inhibited by ATIII depends on Heparin's ___ ____

chain length

The inactivation ratio for factor Xa: thrombin with unfractionated heparin (UFH) is __:___

1, 1

unfractionated heparin (UFH) has the longest chain that can form a "___ ___" to inactivate both factor Xa: thrombin in a ratio of 1:1

molecular bridge

Since unfractionated heparin (UFH) has the longest chain that can inactivate both factor Xa: thrombin in a ratio of 1:1, it has the ___ risk of uncontrolled bleeding

highest

low molecular weight heparins (LMWHs) (like enoxaparin and dalteparin) are depolymerized ____ of UFH via enzymatic or chemical cleavage

fragments

unlike UFH, the low molecular weight heparins (LMWHs) have a chain length that is too ___ to bind to thrombin

short

The inactivation ratio for factor Xa: thrombin with low molecular weight heparins (LMWHs) is __-__:___

2-4:1

low molecular weight heparins (LMWHs) inactivation ratio for factor Xa: thrombin is 2-4:1. Thus it has preferential indirect inhibition of __ ___

factor Xa

Fondaparinux is a synthetic _____ identical to the ATIII binding sequence of heparin

pentasaccharide

The inactivation ratio for factor Xa: thrombin with Fondaparinux is __:___

>100, 1

The inactivation ratio for factor Xa: thrombin with Fondaparinux is >100:1. Thus, Fondaparinux is a selective inhibitor of ___ ___

factor xa