Anticoagulants and thrombolytic Flashcards
Which of the following drugs does not interact with warfarin?
A. Loop diuretics
B. Cephalosporins
C. Phenobarbitone
D. Benzodiazepines
D
Explanation
[Drugs that decrease INR]
Decrease due to changes in pharmacodynamics:
- Vitamin k (increase synthesis in clotting factors)
- Diuretics (increase synthesis in clotting factors)
- Hereditary resistance to clotting factors
- Hypothyroidism (decrease turnover rate of clotting factors)
Decrease due to changes in pharmacokinetics:
- Barbiturates (increase metabolism)
- Rifampicin (increase metabolism)
- Cholestyramine (decrease gut absorption of warfarin)
[Drugs that increase INR]
Increase due to changes in pharmacodynamics:
- Aspirin (increase turnover of clotting factors and platelets)
- Third gen cephalosporins (eliminate bacteria that produce Vit K)
- Heparin
- Hyperthyroidism
Increase due to changes in pharmacokinetics:
-Amiodarone, cimetidine, disulfiram, metronidazole, fluconazole and Bactrim (decrease metabolism)
Which if the following clotting factor proteases does Heparin not inhibit?
A. IIa
B. Xa
C. Va
D. IXa
C
Explanation
Heparin is a heterogenous mixture of sulphated mucopolysaccarides extracted from porcine or bovine intestine. It must be given IV or in the cleaxane form, subcutaneously. Protamine sulphate neutralizes heparin directly. Heparin is of animal origin and should be used with caution in patients with allergy. Increased loss of hair and transient alopecia has been reported. Long term heparin is associated with osteoporosis and spontaneous fractures. Mineral corticoid deficiency is also associated with long term heparin usage. Heparin accelerates antithrombin protease inhibitory reaction against clotting factors IIa, IXa, and Xa by forming equimolar stable complexes with them
Note: from a source https://www.ahajournals.org/doi/full/10.1161/hq0701.093686: Mechanism of action and pharmacology of unfractionated Heparin- Heparin is a sulfated polysaccharide with a molecular weight range of 3000 to 30 000 Da (mean, 15 000 Da). It produces its major anticoagulant effect by inactivating thrombin and activated factor X (factor Xa) through an antithrombin (AT)-dependent mechanism. Heparin binds to AT through a high-affinity pentasaccharide, which is present on about a third of heparin molecules. For inhibition of thrombin, heparin must bind to both the coagulation enzyme and AT, whereas binding to the enzyme is not required for inhibition of factor Xa. Molecules of heparin with fewer than 18 saccharides lack the chain length to bridge between thrombin and AT and therefore are unable to inhibit thrombin. In contrast, very small heparin fragments containing the pentasaccharide sequence inhibit factor Xa via AT. By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of platelets and of factors V and VIII.
The majority of sources I have looked into do not mention Heparin as an inhibitor of Factor V
In the current textbook it states that Warfarin should never be administered during pregnancy.
Note: warfarin has place in pregnancy albeit a small one. Women who have prosthetic heart valves and are at high risk of thromboembolism. Counselling and considerations (a team approach) need to be made regarding risk vs benefit. The recommendation would be to use LMWH in the first trimester and warfarin in the second and third trimester until week 36 of pregnancy.
For the purposes of the exam, follow the statement: Warfarin should never be administered during pregnancy.
LMWH is favoured over UFH during pregnancy; LMWH does not cross the placenta and has several advantages over UFH: It has a more predictable attainment of therapeutic levels of anticoagulation, appears to have less effect on bone, and is associated with less bleeding and thrombocytopenia
Extra:
Under normal circumstances, antithrombin III (ATIII) inactivates thrombin (factor IIa) and factor Xa. This process occurs at a slow rate. Administered heparin binds reversibly to ATIII and leads to almost instantaneous inactivation of factors IIa and Xa The heparin-ATIII complex can also inactivate factors IX, XI, XII and plasmin. The mechanism of action of heparin is ATIII-dependent. It acts mainly by accelerating the rate of the neutralization of certain activated coagulation factors by antithrombin, but other mechanisms may also be involved. The antithrombotic effect of heparin is well correlated to the inhibition of factor Xa. Heparin is not a thrombolytic or fibrinolytic. It prevents progression of existing clots by inhibiting further clotting. The lysis of existing clots relies on endogenous thrombolytics.
Which statment is not true of warfarin?
A. It is 99% protein bound
B. Half life is 6 hours
C. It has 100% bioavailability
D. It affects the function of vit K
B
Explanation
Warfarin is generally administered as the sodium salt and has 100% oral bioavailability. Warfarin’s half-life is 36hrs. Over 99% of racemic warfarin is bound to plasma albumin, which may contribute to its small volume of distribution (the albumin space), its long half-life in plasma -36hrs, and the lack of urinary excretion of unchanged drug.
Warfarin decreases blood coagulation by inhibiting vitamin K epoxidereducatse that recycles oxidised vitamin K1 to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII. Warfarin does not antagonize the action of vitamin K, but rather effects vitamin K recycling, depleting active vitamin K. Thus, the pharmacologic action may always be reversed by administrating new vitamin K
Which of the following statements regarding streptokinase is true?
A. It is synthesised by the human kidney
B. It activates the plasminogen that is bound to fibrin
C. It is a complex lipopolysaccharide.
D. It binds to the endogenous plasminogen
D
Explanation
Streptokinase is a protein (but not an enzyme in itself) synthesized by streptococci. It combines with the proactivator plasminogen.
The kidney synthesizes urokinase.
tPA preferentially activates plasminogen that is bound to fibrin
Note:
Streptokinase forms a complex with endogenous plasminogen; the plasminogen in this complex undergoes a conformational change that allows it to rapidly convert free plasminogen into plasmin. Unlike the forms of t-PA, streptokinase does not show selectivity for fibrin-bound plasminogen
Heparin induced mild thrombocytopenia is caused by?
A. Platelet aggregation.
B. Anti-platelet antibodies
C. Release of lipoprotein lipase
D. Thrombosis
A
Explanation
Heparin induced thrombocytopenia is transient and occurs 5-14 days after therapy. It may occur sooner if the patient is already sensitised to heparin. HIT occurs in 5% of patients receiving heparin. A smaller subset of patients may develop an antibody-mediated cause of thrombocytopenia that is associated with thrombosis. In this instance, the heparin-induced antibody is directed against the heparin platelet factor 4 complex. These antigen-antibody complexes bind to the Fc receptor on adjacent platelets, causing aggregation and paradoxical thromboembolism. The risk of HIT is lowered but not eliminated by the use of LMWH preparations. Once severe HIT occurs it will be exacerbated by the use of LMWH as well and must be avoided. Treatment involves cessation of the heparin and the use of other NON-heparin based anticoagulants must be started
Note: In the pathology TB it sattes
HIT has two types:
T1:Mild HIT occurring rapidly after initiation of heparin therapy. Caused by heparin induced aggregation of platelets. often resolves despite continuation of treatment. Is of little clinical importance
T2: Severe, life threatening HIT occurring between 5-14 days (sooner if previously sensitised) of unfractionated heparin, mediated by antibodies to heparin and platelet factor 4
Regarding warfarin, which of the following statements is correct?
A. It has a half life of 6 hours
B. It is 75% protein bound
C. It is broken down in the GIT
D. It decreases thromboplastins
D
Explanation
Warfarin has a bioavailability of 100%. Over 99% of warfarin is bound to plasma albumin, which may contribute to its small volume of distribution, its long half-life of 36hrs and it lack of urinary excretion of unchanged drug. The traditional term “thromboplastin” refers to a phospholipid-protein extract of tissue (usually lung, brain, or placenta) that contains both the tissue factor and phospholipid necessary to promote activation of factor X by factor VII. Warfarin’s anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of the four vitamin K dependant clotting factors- 2, 7, 9, 10.
Note: warfarin has an 8-12hr delayed onset of action. Doses >0.75mg/kg of warfarin do not hasten the anticoagulant effect of warfarin further
Which of the following drugs does not increase the action of warfarin?
A. Amiodarone
B. Phenobarbitone
C. Metronidazole
D. Disulfiram
B
Explanation
[Drugs that decrease INR]
Decrease due to changes in pharmacodynamics:
- Vitamin k (increase synthesis in clotting factors)
- Diuretics (increase synthesis in clotting factors)
- Hereditary resistance to clotting factors
- Hypothyroidism (decrease turnover rate of clotting factors)
Decrease due to changes in pharmacokinetics:
- Barbiturates (increase metabolism)
- Rifampicin (increase metabolism)
- Cholestyramine (decrease gut absorption of warfarin)
[Drugs that increase INR]
Increase due to changes in pharmacodynamics:
- Aspirin (increase turnover of clotting factors and platelets)
- Third gen cephalosporins (eliminate bacteria that produce Vit K)
- Heparin
- Hyperthyroidism
Increase due to changes in pharmacokinetics:
-Amiodarone, cimetidine, disulfiram, metronidazole, fluconazole and Bactrim (decrease metabolism)
In which condition is Low molecular weight heparin levels in plasma not necessary to measure?
A Renal insufficiency
B Obesity
C Liver insufficiency
D Pregnancy
C
Explanation
Weight based dosing of LMWH results in predictable pharmacokinetics and plasma levels in patients with normal renal function. Therefore, LMWH levels are not generally measured except in the setting of renal insufficiency, obesity and pregnancy.
Note: The effects of LMWHs cannot be acceptably measured using the partial thromboplastin time (PTT) or activated clotting time (ACT) tests. Rather, LMWH therapy is monitored by the anti-factor Xa assay, measuring anti-factor Xa activity rather than a clotting time.
What drug does not affect the metabolism of warfarin?
A. Rifampicin
B. Benzodiazepines
C. Phenobarbiton
D. Cimetidine
B
Explanation
[Drugs that decrease INR]
Decrease due to changes in pharmacodynamics:
- Vitamin k (increase synthesis in clotting factors)
- Diuretics (increase synthesis in clotting factors)
- Hereditary resistance to clotting factors
- Hypothyroidism (decrease turnover rate of clotting factors)
Decrease due to changes in pharmacokinetics:
- Barbiturates (increase metabolism)
- Rifampicin (increase metabolism)
- Cholestyramine (decrease gut absorption of warfarin)
[Drugs that increase INR]
Increase due to changes in pharmacodynamics:
- Aspirin (increase turnover of clotting factors and platelets)
- Third gen cephalosporins (eliminate bacteria that produce Vit K)
- Heparin
- Hyperthyroidism
Increase due to changes in pharmacokinetics:
-Amiodarone, cimetidine, disulfiram, metronidazole, fluconazole and Bactrim (decrease metabolism)
Which statement is correct regarding fibrinolytics?
A. Aminocaproic acid is an inhibitor of fibrinolysis
B. TIMI trial shows that GI haemorrhage is the most common adverse effect
C. Streptokinase is a human product
D. Gastrointestinal bleed within the previous 12 months is a contraindication
A
Explanation
Streptokinase is a streptococcal bacterial protein.
A GIT bleed in the last 2-4 weeks or an active peptic ulcer is a contraindication to fibrinolysis.
TIMI trial showed that haemorrhagic stroke is the most common side effect.
Urokinase is a cheap human enzyme.
REMEMBER: tranexamic acid an analog of aminocaproic acid is an inhibitor of fibrinolysis. It competitively inhibits plasminogen activation. It is administered orally with a 15mg/kg loading dose followed by 30mg/kg every 6hrs. An IVI preparation is also available. 1000mg infusion over about 5min
Regarding fibrinolytics, select the correct answer.
A. Urokinase is a human product
B. tPA does not occur naturally
C. All thrombolytics act to convert active plasminogen to plasmin.
D APSAC lack the streptococcal antigen
A
Explanation
Fibrinolytics act by converting inactive plasminogen to plasmin. Plasmin itself cannot be used because naturally occurring inhibitors in plasma prevent its effects. Plasmin formed inside a thrombus by these activators are protected form plasma antiplasmins, which allow it to lyse the thrombus from within.
Urokinase is a human enzyme synthesized by the kidney. APSAC- anisoylated plasminogen streptokinase activator complex- consists of a complex of purified human plasminogen and bacterial streptokinase that has been acylated to protect the enzyme’s active site. tPA occurs on the endothelial cells of vessels.
REMEMBER: tranexamic acid an analog of aminocaproic acid is an inhibitor of fibrinolysis. It competitively inhibits plasminogen activation. It is administered orally with a 15mg/kg loading dose followed by 30mg/kg every 6hrs. An IVI preparation is also available. 1000mg infusion over about 5min
Anistreplase is antigenic and promotes antibody formation
Fibrinolytics is the correct description of the drugs, but the term thrombolytic is sometimes used
If a patient is on warfarin, which of the following drugs cause an increased INR?
A. Rifampicin
B. Cholestyramine
C. Amiodorone
D. Barbituates
C
Explanation
[Drugs that decrease INR]
Decrease due to changes in pharmacodynamics:
- Vitamin k (increase synthesis in clotting factors)
- Diuretics (increase synthesis in clotting factors)
- Hereditary resistance to clotting factors
- Hypothyroidism (decrease turnover rate of clotting factors)
Decrease due to changes in pharmacokinetics:
- Barbiturates (increase metabolism)
- Rifampicin (increase metabolism)
- Cholestyramine (decrease gut absorption of warfarin)
[Drugs that increase INR]
Increase due to changes in pharmacodynamics:
- Aspirin (increase turnover of clotting factors and platelets)
- Third gen cephalosporins (eliminate bacteria that produce Vit K)
- Heparin
- Hyperthyroidism
Increase due to changes in pharmacokinetics:
-Amiodarone, cimetidine, disulfiram, metronidazole, fluconazole and Bactrim (decrease metabolism)
Regarding heparin, which of the following statements is correct?
A. It may cause alopecia
B. Protamine is a competitive antagonist of heparin
C. LMW fractions have more effect on thrombin than HMW fractions
D. It inhibits antithrombin III
A
Explanation
LMW heparin inhibits activated factor X but has less effect on antithrombin - and on the coagulation in general - than HMW heparin. Heparin’s biological activity is dependant upon the plasma potease inhibitor antithrombin III. In the presence of heparin the antithrombin-clotting factor complex (which inhibits clot formation) is accelerated 1000 fold. Heparin accelerates this antithrombin protease inhibitory reaction against clotting factors IIa, IXa, and Xa by forming equimolar stable complexes with them Protamin binds to heparin and forms a complexes devoid of anticoagulant activity
Which of the following statements regarding ticlopidine is correct?
A. It has no GI side effects
B. Leukopenia is a common side effect
C. It reduces platelet aggregation by the irreversible inhibition of the ADP-receptor
D. It inhibits prostaglandin metabolism
C
Explanation
Ticlopidine, unlike aspirin, has no effect on prostaglandin metabolism.
GIT symptoms do occur: 20% may suffer dyspepsia, nausea and diarrhea. 5% GIT haemorrhage.
Only 1% of patients develop leucopenia. TTP may also occur.
Which of the following fibrinolytics can be given as a PUSH BOLUS?
A. Tenecteplase
B. Alteplase
C. Streptokinase
D. Anistreplase
A
Explanation
Streptokinase: Loading dose and infusion
Urokinase: Loading dose and infusion
Alteplase: Infusion
Tenecteplase: Push bolus
Anistreplase: Single bolus over 3-5min
