ANTICOAGULANTS, ANTIPLATELET DRUGS AND FIBRINOLYTIC AGENTS Flashcards
(29 cards)
1
Q
_____ – Arrest of blood loss from damaged vessels
- Platelet _____ and activation
- Blood _____ (_____ formation)
A
Hemostasis
adhesion
coagulation
fibrin
2
Q
thrombosis
- Inappropriate activation of haemostatic mechanisms
- -_____ thrombosis –associated with stasis of blood
- -_____ thrombosis –associated with atherosclerosis
A
Venous
arterial
3
Q
_____: A portion of thrombus may break away , travel as an embolus and lodge downstream, causing ischemia and infarction
A
embolus
4
Q
laboratory tests
- _____ – To assess the function of platelets
- -Normal 2-7 mins
- Platelet count (Platelet function test) – To quantify platelet function
- -Normal range: 150,000-450,000/µl
- Partial thromboplastin time (APTT) – To measure the speed of _____ pathway
- -Normal range: 25+- 10 seconds
- Prothrombin time – To measure the speed of _____ pathway
- -International normalized ratio (normal range 1.0)
A
Bleeding time
‘Intrinsic’
‘Extrinsic’
5
Q
laboratory tests
- Clotting time –
- -Normal _____ mins
- Factor VIII coagulant level in plasma (_____) < 50%
- Factor IX levels (_____)
- _____ ds – v WF antigen and Ristocetin cofactor (RcoF)
- -Normal value is 100% (Range is 50 -150%)
- -Levels of factor VIII parallels v WF
A
8-15
Hemophilia A
Hemophilia B
Von Willibrand’s
6
Q
drug therapy
- To promote _____
- To prevent or treat _____ or thromboembolism
A
hemostasis
thrombus
7
Q
defective hemostasis
-Deficiencies of clotting factors –
Hereditary –
-Classical hemophilia (lack of factor _____)
-Hemophilia B or Christmas disease caused by lack of factor _____ also called Christmas factor
-Missing factors can be supplied by giving _____ or concentrated preparations of factor VIII or factor IX
Acquired clotting defects –
- Liver disease,
- _____ deficiency,
- Excessive oral anticoagulant therapy –
- Require treatment with vitamin K
- Following excessive _____ therapy
- Difficulty in staunching hemorrhage following surgery or for menorrhagia
A
VIII IX fresh frozen plasma Vitamin K coagulation
8
Q
vitamin k
- _____ vitamin occurring naturally in plants
- Requires bile salts for absorption
- Essential for formation of factor_____, _____, _____, _____ as well as protein _____ and protein _____
- Acts as a cofactor for gamma-glutamyl carboxylase
- Enzyme is required for carboxylation of factors in the liver and also of protein C and S (natural anticoagulants)
- Activated by _____ in the _____
- Given orally or iv
- Synthetic preparation (Menadiol sodium phosphate)
A
Fat soluble II, VII, IX, X C S epoxide reductase liver
9
Q
clinical uses
- treatment and prevention of _____ resulting from the use of oral _____ like warfarin
- in babies to prevent hemorrhagic disease of new born
- in adults, for spruce, coeliac ds, steatorrhoea and obstructive jaundice
A
bleeding
anticoagulants
10
Q
THROMBOSIS AND VIRCHOW’S TRIAD
-Formation of _____ within the vasculature in the absence of _____
A
hemostatic plug
bleeding
11
Q
thrombosis Consequences – -Myocardial infarction, -Stroke, -DVT, -Pulmonary embolus
Drugs used to prevent or treat red thrombus are –
- _____ (Heparin and newer antithrombins)
- _____ (Warfarin and related compounds)
Drugs used for platelet-rich white thrombi are –
- Antiplatelet drugs (aspirin) and
- Fibrinolytic drugs
A
Injectable anticoagulants
Oral anticoagulants
12
Q
INJECTABLE ANTICOAGULANTS HEPARIN AND LMWHs
- Heparin - is present with histamine in mast cells
- Heparin fragments (LMWHs) are used increasingly in place of heparin
- MOA – Activate _____
- Antithrombin III inhibits _____, _____ and other serine proteases
- Thrombin is more sensitive to the inhibitory effect of heparin-antithrombin III complex as compared to factor X
- LMWHs increase the action of antithrombin III on _____ but not on _____
A
antithrombin III thrombin (II) factor Xa factor Xa thrombin
13
Q
ADMINISTRATION AND PHARMACOKINETICS
HEPARIN –
-Not absorbed from gut because of its charge and large size
-Given iv, sc (im injection can cause hematoma)
-Onset of action is _____ after iv injection but onset is delayed by 1 hour after _____
-Elimination T/2 is 40-90 minutes
-In emergencies- bolus dose is followed by continuous infusion
-The dosage is monitored with _____ and dosage is adjusted to achieve a value within (1.5 -2.5 times control)
A
immediate
sc inj
APTT
14
Q
unwanted effects
- Hemorrhage – Stop the therapy, if necessary give _____ iv. It is basic and forms an inactive complex with heparin
- _____ – Two types (Transitory early and Serious thrombocytopenia 2-14 days later)
- Thrombosis and DIC – Abs also bind to glycosaminoglycans on the surface of endothelial cells, leading to immune injury of the vessel wall
- _____ – With long term heparin (>6 months), seen usually during pregnancy
- Hypoaldosteronism – Consequent hyperkalemia
- Hypersensitivity reactions – Rare with heparin but more common with protamine sulfate
A
Protamine sulfate
Thrombocytopenia (HIT)
Osteoporosis
15
Q
HEPARIN INDUCED THROMBOCYTOPENIA(HIT)
- Suspect if recently treated with heparin
- Platelet counts decline within 5- 10 days in pt with no previous exposure to heparin
- Platelet activating abs recognizing multimolecular complexes bound to unfractionated heparin or LMWH
- Characteristics – Erythematous or necrotizing skin reactions at the site of injection or deep vein thrombosis, pulm emboli, stroke, MI
- Test – ELISA
- If confirmed, _____ is stopped immediately and treatment is started with _____
A
heparin
nonheparin anticoagulant
16
Q
LMWHs
- Given sc
- Longer elimination T/2 and is independent of _____
- Do not prolong _____
- Eliminated by _____ excretion
- As safe and effective as unfractionated heparin and more convenient to use
A
first order kinetics
APTT
renal
17
Q
ORAL ANTICOAGULANTS WARFARIN
- Mechanism – Inhibit the reduction of _____ to its active form (hydroquinone), therefore _____ of _____ acid residues in clotting factors _____, _____, _____, _____ does not occur
- Onset of action depends on the _____ of the factors
- -VII- T/2 is 6 hrs and is affected first and then IX, X, XI (24, 40, 60 hours)
A
vitamin K gamma carboxylation glutamic II, VII, IX, X elimination half life
18
Q
ADMINISTRATION AND PHARMACOKINETICS
- Warfarin is given orally
- Absorbed quickly and totally from GIT
- Has small _____ and binds strongly to plasma albumin
- Peak concentration is reached in one hour but the pharmacological effects set in 48 hours later
- The effect on PT starts at 12-16 hours and lasts for 4-5 days
- Warfarin is metabolized by P450 system
- Crosses _____ so is not given in pregnant pts (_____ in babies)
- Warfarin – 10 L/70kg, Digoxin – 500 L/70kg, Lidocaine – 120 L/70kg
A
volume of distribution
placenta
intracranial hemorrhage
19
Q
THERAPEUTIC CHALLENGES WITH WARFARIN
- Requires a careful balance between giving too little or too much
- Effects are seen only after 2 days
- Numerous drug interactions
- _____ is a must – _____ (Dose is adjusted to give an INR of 2-4)
- Duration of treatment varies- to prevent thromboembolism in _____ treatment is _____ term
A
Monitoring
INR
chronic atrial fibrillation
long
20
Q
FACTORS THAT POTENTIATE ORAL ANTICOAGULANTS
- _____ disease
- High _____ rate – Fever and thyrotoxicosis cause increased degradation of clotting factors
- Drugs that inhibit hepatic drug metabolism potentiate _____ –
- -Cimetidine, imipramine, co-trimoxazole, chloramphenicol, ciprofloxacin, metronidazole, amiodarone and azole antifungals
A
Liver
metabolic
warfarin
21
Q
FACTORS THAT POTENTIATE ORAL ANTICOAGULANTS
- Drugs that inhibit _____ function will increase the risk of bleeding –
- -NSAIDS, Aspirin, and antibiotics like moxalactam, carbenicillin
- Drugs that displace _____ from binding sites on _____ –
- -NSAIDs and Chloral hydrate
- Drugs that inhibit reduction of vitamin _____ – _____
- Drugs that decrease the availability of vitamin K – Broad spectrum antibiotics
A
platelet warfarin plasma albumin K cephalosporins
22
Q
FACTORS THAT LESSEN THE EFFECT OF ORAL ANTICOAGULANTS
- Physiological state/disease
- Conditions (_____) with increased coagulation factor synthesis
- _____ – Reduced degradation of coagulation factors
- Drugs –
- -Vitamin _____
- -Induce hepatic P450 enzymes – _____, _____, _____, _____)
- -Reduce absorption – _____
A
pregnancy Hypothyroidism K Rifampicin, Carbamazepine, Barbiturates, Griseofulvin cholestyramine
23
Q
UNWANTED EFFECTS
- Hemorrhage into bowel or brain
- Is teratogenic
- Necrosis of soft tissue (breast tissue, buttock) due to thrombosis in venules due to inhibition of biosynthesis of protein C
- Tt of overdose/increased INR –
- -Withhold _____
- -Administer _____, _____ or coagulation factor concentrates (for life threatening bleeding)
A
Warfarin,
Vit k
fresh plasma
24
Q
DIRECT THROMBIN INHIBITORS (DTIs)
- Directly inhibit thrombin to delay clotting
- Hirudin, the first parenteral DTI to be used, was isolated in the late 1800s from the medicinal leech,Hirudo medicinalis.
- Bivalent DTIs include Bivalirudin and Lepirudin, and bind both the active site (N-terminus) and the fibrinogen-binding exosite (C-terminus) of thrombin
- -_____ does not interact with HIT abs
A
Lepirudin
25
DIRECT THROMBIN INHIBITORS (DTIs)
- Univalent DTIs bind only the active site and include Argatroban and Dabigatran
- -Argatroban is not given in pts with _____(hepatic metabolism)
- -Dabigatran is contraindicated in _____ (renal excretion)
- These smaller molecules do not need monitoring, have a _____ therapeutic index and can be administered orally.
- Dabigatran is given _____, others are _____
- Uses – HIT, PCI in acute coronary syndrome, stroke prevention
```
hepatic dysfunction
renal failure
wide
orally
parenteral
```
26
LAB MONITORING OF DTIs
- _____(TDM) – is required
- -No reversal agents
- -Elevated levels carry the risk of life-threatening _____
- _____ (aPTT) –Measures the efficacy of both the intrinsic and the common coagulation pathways and is the method of choice in US.
Therapeutic drug monitoring
bleeding
Activated partial thromboplastin time
27
FACTOR Xa INHIBITORS
- Factor Xa is central to the propagation of coagulation.
- Activated Factor X, bound as part of the _____ complex on the surface of activated platelets, converts large amounts of _____ to _____, stimulating the so-called _____ .
prothrombinase
prothrombin
thrombin
‘thrombin burst’
28
INDIRECT FACTOR Xa INHIBITORS
- Fondaparinux – a synthetic indirect inhibitor of Factor Xa
- Potentiates the rate of _____ of Factor Xa by _____ and, unlike heparin, does not inactivate _____
- Does not inhibit Factor Xa bound in the prothrombinase complex; therefore, does not completely inhibit Factor Xa
- Administered _____, limiting long-term use
neutralization
antithrombin
thrombin
subcutaneously
29
DIRECT FACTOR Xa INHIBITORS
- Rivaroxaban, Apixaban and Edoxaban directly engage the active site of the Factor Xa molecule
- -Inhibit both _____ Factor Xa in plasma and Factor Xa attached to the _____
- -Administered _____
- Are ideal anticoagulants –
- -Oral administration
- -_____ regimens
- -_____ onset and offset of action
- -Predictable pharmacokinetics and pharmacodynamics
```
free
prothrombinase complex
orally
Fixed-dose
Rapid
```
