Anticoagulants, Antiplatelets, Fibrinolytic drugs, anemia agents and bleeding disorders (A 16/17/18/19) Flashcards
indirect thrombin inhibitor
Heparin (HMW)
(enoxaparin) dalteparin, (tinzaparin) (LMW) factor X and IX
Fondaparinux,
(Danaparoid)
factor X
Warfarin (coumarin anticoagulant)
Acenocumarol
Phenprocumon
factor VII IX X C S II
antidote for heparin
not on the list
Protamine sulfate
more potent for UFH than LMWH
not for Fondaparinux and Danaparoid
- Basic peptide (positively-charged), binds to acidic UFH (negatively- charged) to reverse its action
- Only partially reverses the effects of LMW heparins and does not affect the action of fondaparinux
- Parenteral administration
- Reverse excessive anticlotting activity of unfractionated heparin
antidote for warfarin
not on the list
ciraparantag
oral direct factor X inhibitor
Rivaroxaban
(Apixaban)
(endoxaban)
direct thrombin inhibitor
(Hirudin) Bivalirudin (Argatroban) (Melagatran) (Lepirudin)
antidote for direct factor Xa inhibitor
not on the list
Adexanet alpha
oral direct thrombin inhibitor
Dabigatran-etexilate (mesylate)
Antidote oral direct thrombin inhibitor
not on the list
Idarucizumab
Fibrinolytic agents
(Streptokinase)
Alteplase,
Reteplase,
(Tenecteplase)
Antiplatelet action:
Aspirin - Cox inhibitor: thromboxane A2
ADP-P2Y12-Receptor blocker: Clodiprogel (Ticlopidine) Prasugrel (Cangrelor)
Glycoprotein IIb/IIIa:
Abciximab
Eptifibatide
(Tirofiban)
Additional:
(Dipyridamole) (inhibits adenosine uptake + cGMP phosphodiesterase)
cilostazol:
PDE3 inhibitor
Ticagrelor????????????
Anticoagulants
inhibit the formation of fibrin clots
Heparin LMW heparin Fondaparinux Warfarin Bivalirudin Dabigatran-etexilate Rivaroxaban
Unfractionated heparin (UFH)
Binds reversibly to antithrombin III (AT-III) → accelerates the rate at which AT-III inactivates coagulation enzymes – thrombin (factor IIa) and factor Xa → heparin-ATIII complex can also inactivate factors IX, ((XI, XII and plasmin - not really mentioned in book))
*Acts on preformed blood elements – provides anticoagulant effect immediately following
administration
• Antithrombin III is a serpine (serin protease inhibitor), inactivating
thrombin and factor Xa (ratio 1:1) (and IXa)
- Acidic polysaccharide polymer (obtained from animal sources)
- IV, subcutaneous
• bad absorption - only parenteral use (i.v. or s.c.)
• after s.c. adiministration: UFH about 30%, but uncertain bioavailability
• UFH - binding to endothel, macrophages, plasma proteins → at the beginning of the treatment these binding sites must be
saturated first, it also complicates its elimination - do not cross placenta!!!
- Activity monitored via aPTT (1,5-2,5 times prolonged compared with control value)
• UFH - 60-90 min half-life
Indication:
- Acute and rapid anticoagulation (intensive) → DVT, pulmonary embolism, acute MI
- Disseminated intravascular coagulation (DIC)
- Drug of choice for extracorporeal circulation (UFH)
• treatment of deep venous thrombosis, acute pulmonary emboli,
arterial embolies
• prophylaxis of postoperative venous thromboses and recurrent
thromboembolism
• myocardial infarction (after or without thrombolysis), unstable angina
• anticoagulant therapy during pregnancy
• extracorporal circulation
- Side effects:
- bleeding
- (protamine as reversal agent; mainly for unfractionated heparin),
- heparin-induced thrombocytopenia (HIT),
- osteoporosis (with chronic use)
- Heparin-induced thrombocytopenia (HIT) → antibody mediated thrombocyte aggregation, paradoxically hypercoagulable state with thromboembolic risk
(IgG complex with heparin and PF-4)
• rarely: hair loss, allergic reactions, mild transaminase elevation,
high doses - impaired aldosterone synthesis,
osteoporosis may be associated with long-term (3-6 months) therapy
• most side effects are less frequent when LMWH is used
• heparin induced thrombocytopenia (HIT)
type I - 5-10% - reversible, transient (usually in the first 4 days)
type II - 0,5-3% - very dangerous (20-30% lethal), antibodymediated thrombocyte aggregation paradoxically
thromboembolic complications
Low-molecular weight heparin (LMWH)
(- Enoxaparin)
- Dalteparin
Binds reversibly to antithrombin III (AT-III) → accelerates the rate at which AT-III inactivates coagulation enzymes – thrombin (factor IIa) and factor Xa → heparin-ATIII complex can also inactivate factors IX, ((XI, XII and plasmin - not really mentioned in book))
*Acts on preformed blood elements – provides anticoagulant effect immediately following administration
Heparin chains shorter than 18
monosaccharid units (LMWH) inactivate
preferentially factor Xa (compared with
thrombin the ratio is 2-4:1)
less effect on thrombin, more factor X
- Acidic polysaccharide polymer (obtained from animal sources)
- More selective for factor Xa inhibition (milder effect on thrombin)
• bad absorption - only parenteral use (i.v. or s.c.)
• after s.c. adiministration: LMWH stable and high (>90%) bioavailability
- Higher bioavailability
- equal efficacy
- Longer duration of action
- Renal metabolism (consider dose adjustment in renal impairment)
• LMWH - limited binding toendothel, macrophages, plasma proteins - more
predictible dose-effect relation and elimination
- do not cross placenta!!!
• LMWH - longer (2-4 h) half-life
- aPTT is not prolonged by LMWHs, their effect can not be monitored by aPTT, but usually it is not needed due to the more predictible pharmacokinetics (except renal failure - anti-Xa assay)
- Acute and rapid anticoagulation (intensive) → DVT, pulmonary embolism, acute MI
- Disseminated intravascular coagulation (DIC)
- Drug of choice when anticoagulant therapy is required
during pregnancy (LMWH) - different LMWH preparations are not the same (composition, pharmacokinetics etc.)
- similar indications as by natural heparin, in massive embolism natural heparin is used
- Side effects:
- bleeding
- (protamine as reversal agent; mainly for unfractionated heparin),
- heparin-induced thrombocytopenia (HIT),
- osteoporosis (with chronic use)
- Heparin-induced thrombocytopenia (HIT) → antibody mediated thrombocyte aggregation, paradoxically hypercoagulable state with thromboembolic risk
(IgG complex with heparin and PF-4)
• rarely: hair loss, allergic reactions, mild transaminase elevation,
high doses - impaired aldosterone synthesis,
osteoporosis may be associated with long-term (3-6 months) therapy
• most side effects are less frequent when LMWH is used
(• enoxaparin, certoparin, dalteparin, ardeparin, nadroparin)
Fondaparinux
Binds reversibly to antithrombin III (AT-III) → accelerates the rate at which AT-III inactivates coagulation enzymes – thrombin (factor IIa) and factor Xa → heparin-ATIII complex can also inactivate factors IX, ((XI, XII and plasmin - not really mentioned in book))
*Acts on preformed blood elements – provides anticoagulant effect immediately following administration
- just factor X activity (book) synthetic that bind antithrombin
- Synthetic drug (contains the biologically active pentasaccharide present in heparin)
- More selective for factor Xa inhibition (milder effect on thrombin)
- Subcutaneous
indication and side effect?
• synthetic pentasaccharid, analogue of the antithrombin III
binding subunits of heparin
• the „lowest molecular weight heparin”
• inactivates only factor Xa
• only parenteral use, s.c. - 100% bioavailability, half-life 15-17h
• deep venous thrombosis can be its major indication, does not
cause HIT type II., but may cause bleeding and can not be
reversed by protamin
• longer acting analogue: idraparinux - one s.c. inj./week
Warfarin
Coumarin anticoagulants
Inhibit vitamin K epoxide reductase (VKOR) → prevent post-translational γ-carboxylation of coagulation factors:
• complete synthesis of several
clotting factors (factors II, VII, IX, X
and protein C) in the liver includes
a final gamma-carboxylation on glutamate
residues (necessary to Ca2+ binding
and so binding to phospholipids)
• gamma-carboxylation is coupled with the
oxidation of reduced vitamin K
(hydroquinone form) to epoxide form
• cumarins block the the vitamin K
epoxide reductase and so the
transformation of the vitamin back to
its hydroquinone form functionally
inactive clotting factors are synthetized
• delay (8-12 hours) in the anticoagulant effect
• their action can be antagonized by vitamin K (with several hours delay)
II, VII, IX, X, protein C
4-hydroxy-cumarin derivatives - differences only in potency and duration of action
→ reduced coagulation activity
*Warfarin also interfere with the synthesis of anti-coagulation factors: (same mechanism as the other factors??- according to book)
– protein C and protein S
**No effect on pre-formed factors (complete therapeutic effect is achieved only after 2-3 days) → may require “heparin bridge”
kinetics:
- Lipid soluble
- Oral (bioavailability ↑)
- Highly bound to plasma proteins (Vd ↓)
- Metabolised by hepatic CYP-450 enzymes (warfarin concentration may be affected by inducing/inhibiting agents)
- Narrow therapeutic index; dose should be closely-monitored and
corrected using PT assay !!!!(expressed as INR)
- Normal INR value (non-anticoagulant patient) < 1.1
- Therapeutically accepted INR 2-3 (PT)
Pharmacokinetics
• good absorption (almost 100%) oral anticoagulants
• 90-99% albumin binding in plasma
• crossing the placenta, with the exception of warfarin presence
in breast milk
• metabolism in liver (major step is glucuronid conjugation)
• excretion mainly with the urine, in part with the bile
• half-life - individual variations
acenocoumarol 9-24h
warfarin 25-60h (usually around 40h)
(phenprocoumon 130-160h)
indications:
- Chronic anticoagulation – thrombi, emboli, post-MI, heart valve damage, atrial arrhythmias
• continuation of heparin therapy, prophilactic use to prevent thromboembolism
Contraindications:
pregnancy, nursing women, active bleeding,
incerased risk of dangerous bleeding
- Side effects:
- bleeding,
- skin necrosis (initially, low protein C induces hypercoagulable state – superficial tissue necrosis),
- drug interactions,
- teratogenic (fetal bleeding, bone defects)
Toxicity
• bleeding (minor bleeding 10-20%, major bleeding <5%, lethal
<1%), dramatically increased risk if INR>4
• malformations, death of the fetus (pregnancy is
contraindication!)
• necrosis of the subcutaneous tissue (and the skin) - rare - might affect the breast, fatty tissue, intestine, extremities
- possible reason - inhibition of protein C will be prominent at first - in the first week potentially increased risk of local thromboembolism
• additional rare adverse effects: allergic reactions, gastrointestinal symptoms, alopecia, purple toe syndrome
• reversal of the action - vitamin K1 (slow onset of action), in more severe cases fresh-frozen plasma, factor concentrates
Interactions:
• K-vitamin concentration in the blood - dependent on diet, intestinal
bacterial flora
• pharmacokinetic interactions
• at the absorption - inhibition by antacids, cholestyramin
• at the albumin binding - several drugs (e.g. NSAIDs) - clinical
importance is limited
• at the metabolism
• enzyme inhibitors: phenylbutazone, sulfinpyrazone,
metronidazole, fluconazole, sulfonamides, amiodaron,
disulfiram, cimetidine
• enzyme inducers: barbiturates, rifampin, carbamazepine,
phenytoin, griseofulvin
• pharmacodynamic interactions
• increased anticoagulation: heparin, aspirin, liver disease,
hyperthyreoidism, certain cephalosporins with N-methylthiotetrazol substitution (e.g. cefamandol, cefoperazone)
• decreased coagulation: vitamin K, hypothyreoidism, strong diuretic therapy, corticosteroids
Resistance to cumarin
• rare, due to mutation of vitamin K epoxid reductase
Cumarin sensitivity
• genetic polymorphism of the cumarin metabolizing enzyme (CYP2C9) - decreased activity
~ 10% (caucasians 10-20%, afro-americans, asians <5%)
Bivalirudin
Direct-acting thrombin inhibitor
- Peptide drug (medicinal leeches derivative)
- Parenteral
- Anticoagulation in patients with heparin-induced thrombocytopenia (HIT)
- In combination with aspirin
→ during percutaneous coronary intervention (PCI)
- synthetic hirudin-like compound (direct thrombin inhibitor)
- more rapid onset and shorter duration of action than that of hirudin
- only i.v. use - percutaneous coronary angioplasty
- elimination is mostly independent from kidney
monitoring its action: aPTT (it should be 1,5-3x higher than the
control)
• adverse effects: bleeding
• no antidote
(Dabigatran and Argatroban) are also direct acting thrombin inhibitors
(Argatroban):
- Parenteral
- Anticoagulation in patients with heparin-induced thrombocytopenia (HIT)
Rivaroxaban
Direct-acting factor Xa inhibitors
NOAC → novel oral anticoagulants (dabigatran is also considered under the group)
- Oral
- Rapid onset of action
- Shorter half-life than warfarin
- Do not require monitoring by PT or aPTT
- Prevention of venous-thromboembolism following knee or hip surgery
- Prevention of embolic stroke in patients with atrial fibrillation
- orally active
- direct factor Xa-inhibitors, 2x/d
• Indications: prophylaxis of deep vein thrombosis and pulmonary embolism in
patients undergoing knee or hip replacement surgery; reduce the risk of stroke and
systemic embolism in patients with nonvalvular atrial fibrillation; acute and chronic
treatment of deep venous thrombosis and pulmonary embolism
• potential antidotes:
- adexanet-alfa (recombinant analogue of factor Xa) – only Xa-inhibitors
- ciraparantag – Xa-inhibitors, dabigatran, heparin
(Apixaban):
- Prevention of embolic stroke in patients with atrial fibrillation
Dabigatran-etexilate
Direct-acting thrombin inhibitors
-ORAL
NOAC → novel oral anticoagulants
- Does not require monitoring by PT or aPTT
- Atrial fibrillation (chronic therapy as alternative to warfarin)
Thrombolytic/Fibrinolytic agents (lyse existing thrombi)
Tissue plasminogen activator (t-PA):
Direct conversion of plasminogen into plasmin
Alteplase
Reteplase
Forms a complex with plasminogen → rapid conversion of plasminogen to plasmin
(Streptokinase)
