| What are drugs used in treating or preventing dysfunctions of blood? | Anticoagulants (Heparine, LMWH, vitamin K antagonists)
Platelet Aggregation Inhibitors (Aspirin, Clopidogrel, Dipyridamol, Abciximab)
Thrombolytic Agents (Streptokinase, Urokinase...) |
| What are mechanisms of actions of anticoagulant drugs? | Either inhibit action of coagulation factors (thrombin inhibitors like heparin and related agents)
Or interfere w/synthesis of coagulation factors (vitamin K antagonists such as warfarin) |
| What is heparin? | Heparin occurs naturally as a macromolecule complexed with histamine in mast cells
Heparin standard is an injectable, rapidly acting anticoagulant that is often used acutely to interfere with the formation of thrombin.
-Unfractionated heparin is a mixture of straight-chain, anionic Glycosaminoglycans (Glycosamin + uronique acid) with a wide range of molecular weights
It is strongly acidic because of the presence of sulfate and carboxylic acid groups |
| What is LMWH? | Low-molecular-weight forms of heparin (LMWHs) can also act as anticoagulants which led to the isolation of enoxaparin (Lovenox <6000) the first LMWH.
The LMWHs are heterogeneous compounds (one-third 1/3 the size of unfractionated heparin) produced by the chemical or enzymatic depolymerization of unfractionated heparin.
Because they are free of some of the drawbacks associated with the polymer, they are replacing the use of heparin in many clinical situations |
| What is the mechanism of action of heparin and LMWH? | Heparin acts at a number of molecular targets, but its anticoagulant effect is a consequence of binding
to antithrombin III (pentasaccharide sequence of heparin), with the subsequent rapid inactivation of
coagulation factors. Heparin serves as a true catalyst (cofacteur), allowing antithrombin III to rapidly
combine with and inhibit circulating thrombin and Factor Xa.
LMWHs complex with antithrombin III and inactivate Factor Xa but do not bind as avidly to thrombin.
**AT III: Antithrombin III is an α-globulin. It inhibits serine proteases, including several of the clotting factors most importantly, thrombin (Factor IIa) and Factor Xa |
| How are pharmacokinetics of heparin? | Occurs w/in minutes of IV admin or 1-2 hours after SC (heparin) but anti-factor Xa takes 4 hours after SC (LMWH)
Binds to plasma proteins neutralizing its effect so some are resistant to them, taken up by monocyte/macrophage system.
Inactive metabolites and heparin parents are excreted into the urine renal insufficiency prolongs half life
Half life apprx 1.5 hours heparin, LMWH 3-7 hours
Neither of them crosses the placenta |
| What are therapeutic uses of heparin? | Tx acute DVT and PE, Prophylactic to prevent postop venous thrombosis and those in acute phase MI.
Extracorporeal devices (dialysis machine) to prevent thrombosis.
AG of choice for pregnant women as they don't cross placenta due to large size and negative charge.
Don't require same intense monitoring as heparin makes them useful for both inpatient and outpatient therapy |
| What are adverse effects of heparin? | Hemorrhage (should have careful monitoring, manage by ceasing admin or treating w/protamine sulfate (perfusion))
Hypersensitivity (obtained from porcine sources and may be antigenic, possible effects include chills, fever, urticaria, and anaphylactic shock)
Thrombocytopenia (serious condition, type I common mild decrease in platelet number due to non immuno mechanisms, occurs first 4-5 days and not serious
Type II immunoallergic mechanism cause platelet aggregation and release) |
| What are contraindications of heparin? | Hypersensitivity, Bleeding disorders, having or have had recent surgery of the brain or eye |
| What are other PRL AGs? | ✓ Argatroban is a synthetic parenteral anticoagulant that is derived from l-arginine.
✓ It is a direct thrombin inhibitor.
✓ Argatroban is used for the prophylaxis or treatment of venous thromboembolism in patients with HIT, and it is also approved for use during Percutaneous coronary interventions (PCI) in patients who have or are at risk for developing HIT.
✓ Argatroban is metabolized in the liver and has a half-life of about 39 to 51 minutes.
Monitoring includes aPTT, hemoglobin, and hematocrit.
✓ Because Argatroban is metabolized in the liver, it may be used in patients with renal dysfunction, but it should be used cautiously in patients with hepatic impairment.
✓ As with other anticoagulants, the major side effect is bleeding. |
| What are oral form AGs? | Dabigatran (prodrug of active moiety, oral direct thrombin inhibitor, inhibits free thrombin and clot-bound.
alternative thromboprophylaxis in orthopedic surgery.
Rivaroxaban and Apixaban (Oral Xa Inhibitors, both bind to active site prevent ability to convert prothrombin to thrombin, used to prevent stroke in A fib) |
| What is mechanism of action of vitamin K antagonists? | Several of the protein coagulation factors (including Factors II, VII, IX, and X) require vitamin K as a cofactor for their synthesis by the liver.
These factors undergo vitamin K–dependent posttranslational modification, whereby a number of their glutamic acid residues are carboxyated to form γ-carboxyglutamic acid residues
Warfarin treatment results in the production of clotting factors with diminished activity (10%– 40% of normal). Unlike heparin, the anticoagulant effects of warfarin are not observed until 8 to 12 hours after drug administration, but peak effects may be delayed for 72 to 96 hours |
| How are pharmacokinetics of vitamin K antagonists? | Warfarin rapidly absorbed PO, 99% bound to albumin prevents diffusion to CSF, urine and breast milk but can be displaced by other drugs and lead to elevated activity.
Readily crosses placenta, half life 40 hours, metabolism by CYP450 conjugated and excreted in urine and stool |
| What are therapeutic uses of warfarin? | ✓ Prevent the progression or recurrence of acute DVT or PE after initial heparin treatment.
✓ Prevention of venous thromboembolism during orthopaedic surgery.
✓ Prophylactically, used in patients with acute myocardial infarction, or chronic atrial fibrillation |
| What are adverse effects of warfarin? | Bleeding disorders: The principal adverse reaction caused by warfarin treatment is hemorrhage. Therefore, it is important to frequently monitor (INR) and adjust the anticoagulant effect.
Minor bleeding may be treated by withdrawal of the drug and administration of oral vitamin K;
Severe bleeding requires that greater doses of the vitamin K be given intravenously. Whole blood, frozen plasma, or plasma concentrates of the blood factors may also be employed to arrest hemorrhage. |
| What are drug interactions and contraindications of warfarin? | Drug Interactions
Warfarin has numerous drug interactions that may potentiate or attenuate its anticoagulant effect.
Contraindications
Warfarin should never be used during pregnancy, because it is teratogenic and can cause abortion as well as birth defects |
| What are platelet aggregation inhibitors? | ✓ COX-1 inhibitors
✓ ADP receptors antagonists
✓ GPIIbIIIa receptors antagonists |
| What are COX inhibitors (Aspirin)? | Aspirin inhibits thromboxane A2 synthesis from arachidonic acid in platelets by irreversible acetylation of a serine residue on the active site of COX-1, thereby irreversibly inactivating the enzyme.
The inhibitory effect is rapid and the resulting suppression of platelet aggregation last for the life of the platelet, which is approximately 7 to 10 days.
Aspirin is the only antiplatelet agent that irreversibly inhibits platelet function. |
| What are therapeutic uses of aspirin? | Aspirin is used in the prophylactic treatment of transient cerebral ischemia, to reduce the incidence of recurrent MI, and to decrease mortality in the setting of primary and secondary prevention of MI.
Complete inactivation of platelets occurs with 75 mg of aspirin given daily.
The recommended dose of aspirin ranges from 50 to 325 mg daily |
| How are pharmacokinetics of aspirin? | When given orally, aspirin is absorbed by passive diffusion and quickly hydrolyzed to salicylic acid in the liver.
Salicylic acid is further metabolized in the liver, and some is excreted unchanged in the urine.
The half-life of aspirin ranges from 15 to 20 minutes and for salicylic acid is 3 to 12 hours. |
| What are adverse effects of aspirin? | Bleeding time is prolonged by aspirin treatment, causing complications that include anincreased incidence of gastrointestinal (GI) bleeding, especially at higher doses of the drug |
| What are ADP inhibitors? | Ticlopidine, Clopidogrel, prasugrel, and ticagrelor are P2Y12 ADP receptor inhibitors that also block platelet aggregation but by a mechanism different from that of aspirin
The maximum inhibition of platelet aggregation is achieved in 1 to 3 hours with ticagrelor, 2 to 4 hours with prasugrel, 3 to 4 days with ticlopidine, and 3 to 5 days with Clopidogrel
When treatment is suspended, the platelet system requires time to recover |
| What are therapeutic uses of ADP inhibitors? | Clopidogrel is approved for
✓ prevention of atherosclerotic events in patients with a recent MI or stroke
and in those with established peripheral arterial disease.
✓ prophylaxis of thrombotic events in acute coronary syndromes
✓ used to prevent thrombotic events associated with percutaneous coronary intervention (PCI) with or without coronary stenting. |
| How are pharmacokinetics of ADP inhibitors? | Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on its active metabolite, which is produced via metabolism by CYP 2C19.
Genetic polymorphism of CYP 2C19 leads to a reduced clinical response in patients who are “poor metabolizers” of clopidogrel. Tests are currently available to identify poor metabolizers. |
| What are adverse effects of ADP inhibitors? | These agents can cause prolonged bleeding for which there is no antidote.
Clopidogrel causes fewer adverse reactions, and the incidence of neutropenia is lower then Ticlopidine |
| What is dipyridamole? | ✓ increases intracellular levels of cAMP by inhibiting phosphodiesterase, resulting in decreased thromboxane A2 synthesis
✓ a coronary vasodilator, is employed prophylactically to treat angina pectoris.
✓ is usually given in combination with aspirin or warfarin; it is ineffective when used alone.
✓ Dipyridamole commonly causes headache and can lead to orthostatic hypotension.
✓ Old product |
| What are GP IIB/IIIa receptor antagonists? | Abciximab (monoclonal Ab forms complex, given IV blockes fibrinogen conversion to fibrin.
Used alongside aspirin or heparin for prevention of coronary ischemic complications, approved for pt w/unstable angina.
Adverse effect bleeding |
| What are thrombolytic drugs? | Acute thromboembolic disease in selected patients may be treated by the administration of agents that activate the conversion of plasminogen to plasmin, a serine protease that hydrolyzes fibrin and, thus, dissolves clots.
Streptokinase, one of the first agents to be approved, causes a systemic fibrinolytic state that can lead to bleeding problems.
Alteplase acts more locally on the thrombotic fibrin to produce fibrinolysis.
Urokinase is produced naturally in human kidneys and directly converts plasminogen into active plasmin.
Thrombolytic drugs may lyse both normal and pathologic thrombi |
| What are therapeutic uses of thrombolytics? | Originally used for the treatment of DVT and serious PE,
thrombolytic drugs are now being used less frequently
for these conditions.
Their tendency to cause bleeding has also limited their
use in treating acute peripheral arterial thrombosis or
MI. |
| What are adverse effects of thrombolytics? | The thrombolytic agents do not distinguish between
the fibrin of an unwanted thrombus and the fibrin of a
beneficial hemostatic plug.
Thus, hemorrhage is a major side effect.
For example, a previously unsuspected lesion, such as a
gastric ulcer, may hemorrhage following injection of a
thrombolytic agent |
| What is alteplase? | formerly known as tissue plasminogen activator or tPA is a serine protease originally derived from cultured human melanoma cells. It is now obtained as a product of recombinant DNA technology.
Reteplase is a genetically engineered, smaller derivative of recombinant tPA.
Alteplase has a low affinity for free plasminogen in the plasma, but it rapidly activates plasminogen that is bound to fibrin in a thrombus or a hemostatic plug.
Thus, alteplase is said to be “fibrin selective” at low doses.
Alteplase is approved for the treatment of MI, massive PE, and acute ischemic stroke.
Alteplase has a very short half-life (5 to 30 minutes), and therefore, 10% of the total dose is injected intravenously as a bolus and the remaining drug is administered over 60 minutes |
