anticoagulation drugs Flashcards
- contact activation in – pathway
- tissue factor in – pathway
-Essentially the Coagulation Cascade describes the iterative conversion of — plasma fibrinogen to — fibrin by a series of carefully regulated — events.
-The fibrin formed makes ‘—” or—, which trap – cells, to: - — a damaged blood vessel,
- prevent —
-and prevent — invasion.
-The cascade has 2 different “start points”:
1- —-charged surfaces-exposed on damaged tissue activates —
2- — released from Damaged blood vessels, activates —
-The final 3 steps in the cascade are targets for —
(1) Factor X activates (2)— (aka —) which converts (3)— to —
intrinsic
extrinsic
soluble
insoluble
enzymatic events
strings or fibres
blood cells
seal
blood loos
microb invasion
-ve charged
Factor XII
tissue factor
factor VII
drug action
thrombin
aka factor ii
fibrinogen to fibrin
disorder of haemostasis can be:
1- too little coagulation:
- acquired disorders as — deficiency , — disease , — loss as immune thrombocytopenia
- inherited ( genetic ) disorder as —- for factor — or — for factor —- , and —- disease as well as abnormal — function
- induced disorder is the — demand of coagulation system as caused by severe wounds or platelt loss
2- too much coagulation:
Venous:
-Prolonged— eg after surgery or long-haul flights
-Due to presence of — eg cardiac valve
-Atrial Fibrillation
-Due to — deficiency of regulatory factors eg
Factor V Leiden (30%);
Protein C,S (5%);
Antithrombin III(2-3%)
Lupus anticoagulant
Pregnancy
Smoking, obesity, age
Cancer
DVT Deep vein Thrombosis
VTE Venous Thromboembolism
DIC Disseminated Intravascular coagulation
-Arterial
ASCVD (Atherosclerotic cardiovascular disease)
Atrial Fibrillation / cardiac Arrhythmias / or the presence of artificial surfaces eg cardiac valve
Myocardial Infarction; Stable / unstable Angina
Acute Coronary Syndromes
vitamin k , liver disease and platelt loss
haemophilia A for factor VIII
haemophilia B for factor IX
von willebrand disease
platelt fucntion
excessive
stasis
artificial surface
genetic
1- Excessive clotting in intact intact — :
Deep Vein Thrombosis
-Primarily caused by — action of —
2- Excessive clotting in intact — :
Angina,
Myocardial Infarction
Thrombotic Stroke
Peripheral arterial disease
-Primarily caused by — — activation
veins
excessive
coagulation
artries
excessive
platelt activation
treating disorders of excessive clotting:
- Venous Coagulation: Anticoagulant drugs:
1-Oral Anti-coagulants — (— antagonist)
2-Parenteral Anti-coagulants — (acts as an –)
3- — Oral Anti-Coagulant Drugs Dabigitran,Rivaroxiban, Apixiban
To — already-formed clots, we can also use Thrombolytic drugs
Tissue Plasminogen Activator (tPA) / Streptokinase
-Arterial Thrombosis:
Antiplatelet /Anti-thrombotic drugs: 4 different types
- —
- — Receptor Antagonists eg Clopidogrel
- — antagonists eg Abciximab
- Platelet – Inhibitor eg Dipyridamole
warfirn
vitamin k
heparin
anti thrombin
new
dissolves
aspirin
ADP
intergin
platelt signalling
— is essential for blood clotting
- whole blood in Glass tube @37oC so the blood clots in —
whole blood drawn into vaccutainer containing anti-coagulant (—) so it —
* add Ca++ + Tissue Factor (also called — ; obtained from —) so the blood clots in — by prothrombin time of PT , quick test one stage prothrombin time accelerated clotting time
calicum
5-11 min
citrate
doesnt clot
thromboplastin
animals
12-14 sec
-Calcium ions (Ca++) play a major role in the tight regulation of —
-Most anti-coagulant reagents, used to maintain blood in fluid form for laboratory testing, act by — in blood samples
-Ca++ enables complete — of several coagulation factors via the – charged residues on some — Factors (II,VII, IX & X).
-Negatively charged residues on coagulation proteins are often —
-Ca++ ‘bridges’ the binding of the —charged — factors to —-charged — (PL-) that are found on the surface of activated – / damaged –
coagulation
Chelating Calcium
activation
-ve charged residue
coagulation factors
vitamin k dependent
-ve charged coagulation to -ve charged phospholipid
activated platelets or damaged endothelium
role of vitamin k:
-All Coagulation Factors are synthesised in the —
-Factors II, VII, IX, X, Protein C and Protein S-all contain clusters of — amino acids in their protein sequences
-A – enzyme called gamma(g)-glutamyl carboxylase — modifies critical coagulation factors
-This enzyme adds a —-charged — group to the clusters of already —-charged — residues to generate:
Gamma-carboxy-Glutamic Acid (GLA)
-GLA residues serve as—-affinity binding sites for –
Vitamin K is an essential— for this reaction
liver
glutamic acid
hepatic
post transolatioally
-ve charged y-carboxyl group
-ve charged glutamic acid
high
ca++
catalyst
-Vitamin K is synthesized by – in mammalian – or is obtained in diet from rich —
-Vitamin K is required for the necessary – of — residues on F II, VII, IX and X in the— to yield — in the liver.
-GLA residues serve as – affinity binding sites for —
Vitamin K deficiency:
Bruising , — disease of the newborn
Can be caused by Antibiotic –
Alcoholic — disease
bacteria
gut
rich green veg
modification
glutamate
liver
gamma carboxy Glutamate residues (GLA)
high
ca++
hameorrahgic
antibiotic overdose
liver
— is a vitamin k antagonist which inhibits — and prevents correct – of factors II VII, IX and X, rendering them useless as it also affects — and —
-Its effects are not seen until — after — (= time taken to — endogenous stores)
-Effects last — (= time taken to — correctly synthesized the GLA-modified Factors II, VII, IX and X)
warfarin
coagulation cascade
synthesis
protein c and s
24-48 hours
ingestion
deplete
4-5 days
regenerate
-Whereas Vitamin K enables the – modification of Coagulation Factors II, VII, IX and X, Warfarin — this reaction by preventing vitamin K —
-Normally, anenzymecalled— , enables Vitamin K recycling through an — /— biochemical cycle
- Warfarin — this enzyme
Warfarin is therefore a Vitamin K — agent
-Warfarin is prescribed to people with an increased tendency for — or as—(prevention of further episodes) in those individuals that have previously formed a –
-Is safe for—term use (except in—)
-Often used in patients with — in veins or arteries
While warfarin is one of several drugs popularly referred to as a “—;” this is a misnomer, since it does not affect the —of blood.
Atrial fibrillation
Heart failure
Stroke
Deep vein thrombosis
Pulmonary embolism
Prosthetic heart valve
Acute coronary syndrome
GLA
blocks
recycling
vitamin K epoxide reductase
oxidation/reduction
inhibits
depleting
venous thrombosis
2ndary prophylaxis
blood clot
long
preggo
artificial graft
blood thinners
viscosity
coagulation test 1 PT:
The prothrombin time (PT) is equivalent to the time required for the — of the coagulation cascade to operate:
A prolonged or shortened prothrombin time indicates a – of – processes
1- prothrombin time PT:
is measured in ‘— ’
But can vary greatly from hospital to hospital due to
Source of — , — of thromboplastin, — , — , –
time is —
2- prothrombin ratio PR which is a better measure which is —- over — and it takes —-
3- international normalised ratio INR which is even better measure
is the PR which is obtained using the — international reference— (Tissue Factor) preparation. This is usually a – recombinant protein produced by – protocols and it takes —
extrinsic pathway (TF)
disorder
clotting
seconds
thromboplastin, storage , temp , humidity , equipement
12-14 seconds
PT of patient sample in seconds/ PT of normal pooled plasma in seconds
0.8-1.2
primary
thromboplastin
human
genetic engineering
0.8-1.2
causes of prolonged PT:
1- — Disease (since all coagulation Factors are synthesized in the in the — )
2- — deficiency (since its required for the correct synthesis of Factors II, VII, IX and X in the liver)
3- — Treatment
4- A specific (genetic) deficiency of, or inhibition of, Factors VII, X, II (prothrombin), V, or Fibrinogen (Tissue Factor Pathway)
Other Illness eg
Sepsis / Disseminated intravascular coagulation; depletes coagulation factors
The infrequent antiphospholipid antibodies (aPLs) (lupus anticoagulant phenomenon) with anti-prothrombin activity.
Note:
-Treatment withheparindoes not normally prolong the PT (Due to the addition of heparin-neutralizing materials to the PT reagent)
Oral direct thrombin and factor Xa inhibitors cause prolongation of PT.
liver
liver
vitamin k
warfarin
challenges to warfarin treatment:
-Warfarin use is challenging because its therapeutic range is – and – is affected by many factors including — variation in — , – interactions, and — .
-ie it has a – Therapeutic Index
-So its use must be carefully & regularly monitored – in Warfarin Clinics
-Many drug interactions exist:
Metabolised — (antibiotics; alcohol, antipsychotic drugs, antiplatelet agents)
which basically: — anticoagulant effect
Rifampicin,
carbamazepine
alcohol
Plasma—-bound (salicylates, penicillin, sulphonamides, clofibrate & phenytoin) which basically: — anticoagulant effect
NSAIDs
Amiodarone
Food, alcohol & drugs
Foods which contains large Qs of vitamin K include rich green vegetables
- — ; so not to be used in –
narrow
dosing
genetic variation in CYT P450s
drug interaction and diet
low
hepatically
decreased
protein bound
increased
teratogenic
preggo
warfarin must be –
Patient counselled re side effects; drug interactions, pregnancy
Must attend warfarin clinic – /— for PT / INR assessment of clotting rates
to assess coagulation—
to guide— adjustments to optimize the time in the — which is a surrogate for clinical outcomes.
monitored
weekly / monthly
function
dose
therapeutic range (TTR),
adverse effects of warfarin:
- increases — risk –a problem with all anticoagulant drugs
- Contraindicated in – due to teratogenesis and / or bleeding in fetus
- Skin —*: A rare but serious complication resulting from treatment with warfarin
Note: patients complain about long-term use of Warfarin due to the multiple ways it interferes with their Quality of Life:
Need for regular trips to warfarin clinic
Need to restrict diet
Need to take care when prescribed other drugs or using OTC remedies
*In warfarin’s initial stages of action, inhibition o — & — is — than inhibition of the othercoagulation factors.
-The – the initial dose of vitamin K-antagonist, the more pronounced these differences are.
-This coagulation factor imbalance leads to— activation of coagulation, resulting in a — state and—-
-The blood clots interrupt the blood supply to the skin, causing—-.
- — is an innate anticoagulant, and as warfarin further decreases Protein C levels, it can lead to massive — with — and— of limbs.
The sites of occurrence of such thrombi are indicated -
bleeding
preggo
necrosis
protein c and factor VII
stronger
larger
paradoxical
hyperocoaguable state and thrombosis
necrosis
protein c
thrombosis w necrosis and gangrene
-Warfarin (and coumarin) iscontraindicated in — , as it passes through the— barrier and may cause — in the foetus;
-warfarin use during pregnancy is commonly associated with spontaneous abortion, stillbirth,neonatal death, andpreterm birth
-Warfarin (and coumarins) are also—, that is, they cause —; the incidence of birth defects in infants exposed to warfarinin uteroappears to be around 5%, although higher figures (up to 30%) have been reported
-Usually, in patients who need anti-coagulants, warfarin is avoided in the —-, and a— molecular weight—such asenoxaparinis substituted.
-With heparin, risk of maternal haemorrhage and other complications are still increased, but heparins do not cross the — barrier, so do not cause —
Note: newer Direct Oral Anticoagulant (DOAC) drugs also have a role here
pregnancy
placental barrier
bleeding
tetratogen
birth defects
first trimester
low
heparin
placental
birth defects
summary of warfarin:
-Warfarin (coumarins), (unlike heparin; see later), is an — bioavailable drug
Is therefore more acceptable for regular treatment of patients with coagulation / clotting disorders than heparins
-It inhibits the correct — of Factors II, VII, IX and X, in the—
-Warfarin has a – therapeutic index
-Must be — routinely to ensure TTR > –
-Like other anti-coagulant drugs, — is a major side effect.
-Patients need to be counselled re potential for drug &food interactions
-Contraindicated in —
orally
synthesis
liver
low
monitored >65%
bleeding
pregnancy
what activates thrombosis:
- — endothelium :
-Released — or
-Activates — cascade - which generates —
-Thrombin (generated by the coagulation cascade)
-Converts — to— and Activates –
-Exposed Collagen: Binds plasma —
and Platelets —
- —
damaged
tissue factor
thrombin
fribongen
polymeric fibrin
platelets
vWf
adhere
stasis
what inhibits thrombosis:
- — Endothelium
- Intact endothelium expresses the following molecules on its surface:
–> — proteoglycans which binds & activates —
—> – which inhibits — pathway
-Intact endothelium produces — of platelet activation (— &— )
-Blood plasma contains high levels of —
-Blood plasma contains —
intact
heparin
ATIII
thrombudulin
intrinsic
inhibitors ( NO and PGI2)
Antithrombin III (ATIII)
TFPI
naturalising occurring heparan:
- Heparan is a – , — (of variable length)found — in all — tissues
-It is stored in granules of — and—.
- It has the — , —charge densityof any knownbiological molecule (arising from specific penta-saccharide sequences)
-Heparan sulfate proteoglycan(HSPG) is synthesised by — and expressed at the surface of — cells
-It is a —- associated —in which HS chains are attached in close proximity to cell surface.
-Endogenous heparin and heparin-binding proteins have a variety of —, —, and— effects, which are still incompletely understood
linear polyscarides
naturally in all animal tissues
mast cells and basophils
highest -ve charge
endothelial cells
intact
membrane associated
proteoglycan
anticoagulant, anti inflammatory , and antiangiogenic effects
heparin - regulates coagulation via ATIII:
-Anti-Thrombin III (ATIII) is a — protein
-On its own, it is a – inhibitor of — (Factor —) (and also Factor –)
-Heparan + ATIII complex = more — inhibitor of Thrombin and Factor Xa (potency is enhanced by >— fold)
Therefore heparan, on surface of – cells— coagulation
-The rate of antithrombin-thrombin inactivation increases by — to 1 million foldin the presence of — and physiological levels of —
or
- — on the surface of intact endothelial surfaces enhances the inhibitory potency of AT III
plasma protein
weak
thrombin
factor lla and factor xa
more potent
>10,000
endothelial cells
regulates
10,000
heparin and calcium
HS
therpautic heparin:
-More than 100 years ago, a medical student at Johns Hopkins University found a way to extract “an anticoagulant substance” from a dog liver. This substance prolonged the time required for plasma to clotex vivo.
-The extract, was named heparin, as it was derived from —( —) tissue.
discovered byJay McLeanandWilliam
-It remains one of the most important— drugs in current clinical use.
liver ( hepatic )
anticoagulant
pharmaceutical heparin comes in – forms
-Pharmaceutical-grade heparin is derived from the — tissue of animals that have been slaughtered for meat such as pigs & cattle.
-There is no one— structure for heparin.
-However, all heparins contain the specific— sequence that binds and activates —
-Heparin is rich in – charge
1-Unfractionated heparin(UFH) :
It has a mixture of — length— ; mean length is — saccharide units (15,000 da)
Has a — half-life in the circulation (—hours)
1-Low-molecular-weight heparin(LMWH)
is heparin that has beenfractionatedto sequester molecules with – molecular weight but — density of the critical pentasacharide. (15 saccharide units; 5000Da)
its pharmacodynamics are more —
Its half life is – (– hours)
3-Synthetic products (eg Fondaparinux)
consists only of the minimal — Only
3
mucosal tissue
unique
pentascaride
Anti-Thrombin III (ATIII)
-ve
different length of polysacrides
45
short
1-2 hours
low
high density
more predictable
increased ( 5-4)
heparin sulphate (HS ) polysaccharides
1- unfrationated heparin ( UFH ) :
- — or –
- — onset of action and clearance, allowing more finely tuned — when needed (eg, for surgical procedures or bleeding)
-Needs to be monitored using the – test
-OK in —
-Disadv: Heparin-Induced — (HIT)
2- low molecular weight heparin LMWH :
-Enoxaparin, Tinzaparin
- — only
-predictable — ; therefore does not normally require routine —
-Its half life is — ( —)
- — in renal failure
Disadv: Heparin-induced Thrombocytopenia- though – than UFH
3- synthetic products:
-Fondaparinux
-Suitable for use in — (object to the animal source of the of UFH / LMWHs)
-However, its renal excretion precludes its use in patients with –
IV or Sub Q
rapid
titiration
aPTT
renal failure
Heparin-Induced Thrombocytopenia (HIT)
SubQ only
pharmodynamics
monitoring
increased ( 5-4 hours)
contradicted
less
vegans
renal dysfunctions
( info: Baseline testing, prior to administration of heparin should be performed: (PT, aPTT, a complete blood count (CBC)- with platelet count. Bleeding history should be obtained).
