PHARMACOLOGY OF COMMON ANTITHROMBOTICS OF COMMON... · PHARMACOLOGY OF COMMON ANTITHROMBOTICS KAMALES ARUMUGAM PRINCIPAL PHARMACIST ANTICOAGULATION WORKSHOP 19TH SEP 2014. INTRODUCTION

PHARMACOLOGY OF COMMON ANTITHROMBOTICS

KAMALES ARUMUGAM

PRINCIPAL PHARMACIST

ANTICOAGULATION WORKSHOP

19TH SEP 2014

INTRODUCTION

• Thrombus pathology

• Antiplatelet

• Anticoagulants

• HIT

• Switching Anticoagulants

• Fibrinolytics

THROMBI PATHOLOGY

ARTERIAL THROMBI VENOUS THROMBI

FORMATION Artery Vein; tend to fragment creating an embolus

INITIATION Spontaneously or mechanical rupture of atherosclerotic plaques

Venous stasis or vascular injury after surgery or trauma

COMPOSITION Mainly platelets, also contains fibrin & occasionally leukocytes & small amounts of coagulated erythrocytes

Fibrin & erythrocytes

KNOWN AS White thrombi Red thrombi

MANIFESTS AS MI, Unstable angina, Ischaemic stroke, Peripheralartery disease e.g. acute limb ischaemia

DVT, PE, AF related-thrombi

ANTITHROMBOTIC DRUGS

ANTIPLATELET DRUGS

ANTIPLATELET DRUGS

ANTIPLATELET DRUGS

• Aspirin

• P2Y12 inhibitors:– Clopidogrel

– Ticlopidine

– Prasugrel

– Ticagrelor

• Dipyridamole

• Glycoprotein IIb/IIIa inhibitors:– Abciximab

– Tirofiban

– Eptifibatide

• Antiplatelet drugs reduce mortality, risk of reinfarction & stroke

Thienopyridines

ASPIRIN

• MOA:

ASPIRIN

ASPIRIN (ASA)

PHARMACOKINETICS • Action: rapid, peak plasma levels in 20 min• Duration of action: 7-10 days• Clearance: rapid• Renal: caution in severe impairment; risk of bleeding & further

deterioration of renal function

INDICATIONS Acute MI, UA, Primary prevention of stroke & TIA, Secondary prevention of stroke, TIA & in IHD, Pain, Inflammation & fever

DOSE • Acute conditions: 150 – 300mg • Long term: 75 – 150mg daily

PRECAUTIONS • ASA & NSAID allergies & aspirin-sensitive asthma• Active peptic ulcer disease or other bleeding predispositions

COMMON ADVERSE EFFECTS

• GI side effects (2 – 4x higher with ASA use; dose related)• Asymptomatic blood loss• Increased bleeding time

PRACTICE POINTS • No evidence that EC products decrease GI bleeding risk• Patients with Hx of ASA-induced ulcer bleeding, clopidogrel

causes more recurrent ulcer bleeding than ASA combined with PPI

ADP P2Y12 RECEPTOR ANTAGONISTS

The active metabolites selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor (irreversibly) and the subsequent ADP-mediated

activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation

Clopidogrel, Ticlopidine, Prasugrel


CLOPIDOGREL (PLAVIX®)

PHARMACOKINETICS • Action: rapid, peak plasma levels in 45 min• Duration of action: 7-10 days• Metabolised extensively in the liver

INDICATIONS Prevention of vascular ischaemic evens in pts with symptomatic atherosclerosis, NSTEACS (with ASA), adjuvant to reperfusion for STEMI (with ASA), Prevention of thromboembolism after placement of stent

DOSE • Loading dose: 300 – 600mg • Long term: 75mg daily

PRECAUTIONS Combining clopidogrel with inhibitors of CYP2C19 or genetic lack of CYP2C19 activity may decrease clopidogrel'seffectiveness in reducing the risk of CV events (evidence is conflicting)

COMMON ADVERSE EFFECTS Diarrhoea, GI ulcers, dyspepsia, brusing, TTP (very rare)

PRACTICE POINTS Optimal duration of treatment in ACS & after placement of coronary stent is debated; longer treatment is recommended with a DES than with a BMS


TICLOPIDINE (TICLID®)

PHARMACOKINETICS • Action: peak plasma levels in 2 hours• Duration of action: 7-10 days• Metabolised extensively in the liver

INDICATIONS Secondary prevention of ischaemic stroke and TIA in patients intolerant of or unresponsive to other antiplatelet drugs

DOSE 250mg twice daily

PRECAUTIONS Hematologic adverse reactions, including neutropenia, thrombocytopenia, TTP, aplastic anemia, agranulocytosis, pancytopenia, and leukemia, including fatalities, have been reported; monitoring recommended; therapy discontinuation may be necessary


Diarrhoea, nausea, anorexia, vomiting, upper abdominal pain (tolerance may develop), mild-to-severe neutropenia

PRACTICE POINTS • Risk of neutropenia is greatest in the first 12 weeks of treatment; obtain FBC at baseline, then every 2 weeks for 4 months, then as indicated

• Stop ticlopidine if neutrophil count is <1.2x109/L or platelet count is <80x109/L; neutropenia is usually reversible on stopping ticlopidine


PRASUGREL (EFFIENT®)

PHARMACOKINETICS • Action: rapid, peak plasma levels in 30 mins• Duration of action: 7 – 9 days; 5 days (depending

loading/maintenance dose)• Hydrolysed in the intestine

INDICATIONS Prevention of atherothrombotic events (with ASA) in ACS (including STEMI and non-STEMI) to be managed with PCI

DOSE • Give with low-dose ASA (75–150 mg daily)• Initially 60 mg, then 10 mg once daily• >75 years or <60 kg: initially 60 mg, then 5 mg once daily

PRECAUTIONS • History of stroke or TIA—contraindicated due to an increased risk of bleeding and stroke in trials

• Asian ethnicity—may be at increased risk of bleeding


• Bleeding (may be severe and may cause anaemia)• Hypersensitivity reactions (cross-reactivity can occur with other

thienopyridines)

PRACTICE POINTS In UA/NSTEMI patients, where coronary angiography is performed within 48 hours after admission, the loading dose should only be given at the time of PCI


Selective and reversibly binding P2Y12 receptor antagonist that prevents ADP –mediated P2Y12 dependent platelet activation and aggregation


TICAGRELOR (BRILINTA®)

PHARMACOKINETICS • Action: rapid, peak plasma levels in 30 mins• Platelet function recovery 3-4 days after cessation• Metabolised in the liver by CYP3A4

INDICATIONS ACS (with aspirin)

DOSE • Give with low-dose ASA (75–150 mg daily)• Loading dose 180 mg, then 90 mg twice a day

PRECAUTIONS • Patients at risk of bradycardia (e.g. SSS without pacemaker, 2nd or 3rd-degree AV block) – asymptomatic ventricular pauses

• Asthma, COPD – ticagrelor may cause dyspnoea• Weight <60 kg – increases risk of bleeding• Hyperuricaemia – ticagrelor may increase uric acid concentration• Treatment with CYP3A4 strong inhibitors – contraindicated


Bleeding (may be severe & cause anaemia), dyspnoea, nausea, diarrhoea, non-cardiac chest pain, headache, raised uric acid concentration, raised creatinine concentration

PRACTICE POINTS 12-month study: ticagrelor+ASA more effective than clopidogrel+ASA in preventing CV events in patients with ACS:• Sig. reduction in MI & vascular death, but a non-sig. increase in stroke• Incidence total major bleeding similar, rate of major IC haemorrhage was

higher with ticagrelor• Risk–benefit of ticagrelor was less favourable with ASA doses >150mg daily

DIPYRIDAMOLE

It inhibits the uptake of adenosine into the platelet & erythrocytes stimulate platelet adenylate cyclase & increase levels of platelet cAMPprevent activation and

aggregation of platelet

DIPYRIDAMOLE

DIPYRIDAMOLE

PHARMACOKINETICS • Action: peak 2 – 3 hours (CR)• Extensively metabolized in the liver

INDICATIONS • Prevention of thromboembolism in patients with prosthetic heart valves (with warfarin)

• Secondary prevention of ischaemic stroke & TIA, including combination with ASA

• Cardiac stress testing (IV)

DOSE • Prevention of thromboembolism : PO 300 - 600mg daily in 3 -4 doses

• Secondary prevention of stroke & TIA: PO 200mg CR twice daily

PRECAUTIONS • Vasodilatory effect (used with caution in patients with severe CAD)• Beer’s Criteria (short-acting dipyridamole): Not recommended,

poorly tolerated & may cause orthostatic hypotension• Aortic stenosis – dipyridamole-induced vasodilation may increase

pressure gradient across aortic valve and worsen organ perfusion.• Unstable angina, recent MI – use with caution; vasodilation may

induce myocardial ischaemia.


Headache, diarrhoea, nausea, vomiting, hot flushes, hypotension, tachycardia

GLYCOPROTEIN IIb/IIIa INHIBITORS

Prevent binding of fibrinogen to platelet, by occupying glycoprotein IIb/IIIa receptor, thereby blocking platelet aggregation


ABCIXIMAB (REOPRO®)

PHARMACOKINETICS • Chimeric monoclonal antibody• Action: within 10 mins • Duration of action: Platelet function recovers over 48 hours• Remains in the circulation for ≥15 days in a platelet-bound state

INDICATIONS • PTCA and intracoronary stenting• Unstable angina refractory to treatment where PCI is planned

DOSE • PCI: IV bolus 250 mcg/kg before procedure, then 0.125mcg/kg/min for 12 hours

• Planned PCI in refractory unstable angina: Start 18–24 hours before intervention; IV bolus of 250 mcg/kg, followed by infusion of 10 mcg/min; stop 1 hour after intervention

PRECAUTIONS • Abciximab infusion within 30 days – increases risk & severity of thrombocytopenia

• Thrombocytopenia from previous abciximab – increases risk of recurrence


Bleeding, thrombocytopenia

PRACTICE POINTS Give low-dose ASA & heparin infusion with abciximabMonitor baseline PT, APTT, CrCl, platelet count, Hb & HCT; after starting, monitor Hb & HCT at 12 & 24 hrs, & platelet count at 2–4 hrs & 24 hrs


EPTIFIBATIDE (INTEGRILIN®)

PHARMACOKINETICS • Action: immediate• Duration of action: Return of platelet function 4 hours after stopping

continuous inf• Clearance: Renal

INDICATIONS • Unstable angina and non-STEMI in high-risk patients• Elective PCI with stenting

DOSE • PCI: IV bolus 180mcg/kg just before intervention, then 2nd bolus of 180mcg/kg 10 mins later. Start IV inf, 2mcg/kg/min, with first bolus until hospital DC or up to a max of 18–24 hrs post intervention

• UA, non-STEMI: IV bolus 180mcg/kg followed by 2mcg/kg/min IV inf for up to 72 hrs until initiation of CABG or DC from hospital. If PCI is performed during that time, continue inf for 20–24 hrs after intervention for an overall max duration of 96 hrs

PRECAUTIONS • Renal: Same bolus but reduce inf to 1mcg/kg/min• Hepatic: Avoid in patients with significant hepatic disease



PRACTICE POINTS • Give low-dose ASA and heparin infusion with eptifibatide• Monitor PT, APTT, CrCl, platelet, Hb & HCT before treatment; monitor Hb,

HCT and platelet within 6 hrs after start of treatment & at least once daily thereafter


TIROFIBAN (AGGRASTAT®)

PHARMACOKINETICS • Chimeric monoclonal antibody• Action: rapid, within 30 mins• Duration of action: Returns of platelet function within 8 hrs after

discontinuation• Clearance: Renal and biliary

INDICATIONS Unstable angina and non-STEMI in high-risk patients

DOSE IV 0.4mcg/kg/min for 30 minutes, followed by 0.1mcgkg/min for 48–108 hrs

PRECAUTIONS Renal: Reduce dose by 50% when CrCl <30 mL/min



PRACTICE POINTS • Give low-dose ASA and heparin infusion with tirofiban• Monitor PT, APTT, CrCl, platelet, Hb & HCT before treatment;

monitor Hb, HCT and platelet within 6 hrs after start of treatment & at least once daily thereafter

ANTICOAGULANTS

ANTICOAGULANTS

ANTICOAGULANTS – HISTORICAL DEVELOPMENT

1916 1924 1936 1940 1950s 20061970s 1976 1980s 1990s 2001

Oral

Injection

Spoiled sweet clover

Dicoumaroldiscovered

Warfarinclinical use

Warfarin / Vitamin Kmechanism

High / low doseWarfarin / INR

Warfarinclinical trials

Heparindiscovered

Heparinclinical use

Continous heparininfusion/

aPTT

LMWHdiscovered

LMWHclinical trials

Pentasaccharideclinical trials

Ximelagatranclinical trials

DabigatranRivaroxabanApixaban

AZD0837

ANTICOAGULANTS

• Heparins:– UFH

– Enoxaparin

– Tinzaparin

• Warfarin

• Direct Thrombin Inhibitors:– Dabigatran

– Bivalirudin

– Argatroban

– Lepirudin

– Melagatran

• Factor Xa Inhibitors:– Fondaparinux

– Rivaroxaban

– Apixaban

NA in Malaysia

HEPARIN (UFH)

When heparin sodium is combined with antithrombin III (heparin cofactor), thrombosis is blocked through inactivation of Factor Xa and inhibition of

prothrombin's conversion to thrombin (Factor IIa). This also prevents fibrin formation from fibrinogen during active thrombosis

HEPARINS

HEPARIN (UFH)

PHARMACOKINETICS • Action: immediate• Elimination T½: 1.5 hr (anticoagulation effect half-life)• Metabolised in the liver; inactive metabolic products are excreted

in the urine

INDICATIONS • Prevention of VTE & other thromboses in surgical and high-risk medical patients (including during procedures, eg haemodialysis)

• Treatment of VTE, ACS, peripheral arterial occlusion & disseminated intravascular coagulation (DIC)

DOSE Refer to PI/local protocols & indications for dose recommendations

PRECAUTIONS HIT


Thrombocytopenia, bleeding, HIT, increased liver transferases

PRACTICE POINTS • Unexpectedly high APTT may be due to blood sample being taken from same limb as heparin infusion

• Preferred over LMWH in severe renal impairment• Monitor APTT (6 hrs) after dose changes, platelet counts, HCT,

signs & symptoms of bleeding

LMWH

LMWH has greater capacity to potentiate factor Xa inhibition by antithrombinthan thrombin because, with a mean molecular weight of 4500–5000, at least

half of the LMWH chains are too short to bridge antithrombin to thrombin

LMWH

ENOXAPARIN (CLEXANE®)

PHARMACOKINETICS • Action: anti-Xa activity occurs 1 to 4 hours after injection Elimination T½: 4 – 5 hrs

• Metabolism: renal (40%) & hepatic

INDICATIONS • Prevention of VTE in surgical patients & in medical patients bedridden due to acute illness

• Treatment of venous thrombosis• Prevention of extracorporeal thrombosis during haemodialysis• Treatment of acute STEMI, non-STEMI and unstable angina• Treatment of PE

DOSE • Prophylaxis dose: 20-40 mg once daily• Treatment dose: 1mg/kg every 12 hrs• Adjusted by weight & CrCl (if <30ml/min use 50% dose)

PRECAUTIONS Caution in patients with renal impairment due to increased risk for bleeding; monitoring recommended (antifactor Xa)


Bleeding, bruising and pain at injection site, hyperkalaemia, mild reversible thrombocytopenia, increased aminotransferases

PRACTICE POINTS Consider heparin IV if an invasive procedure is anticipated as the anticoagulant effect diminishes more quickly after stopping

LMWH

TINZAPARIN (INNOHEP®)

PHARMACOKINETICS • Action: peak plasma activity being observed after 4 to 6 hours • Elimination T½: 1.5 hrs• Excreted in urine primarily unchanged drug

INDICATIONS • Treatment of DVT and PEPrevention of postoperative DVT in patients undergoing general and orthopaedic surgeryPrevention of extracorporeal thrombosis

DOSE • Prophylaxis dose: 75 anti Xa-units/kg/d or 3500 units/day• Treatment dose: 175 anti Xa-units/kg/d

PRECAUTIONS Caution in patients with renal or hepatic insufficiency; consider dose reduction


Erythema, increased LFTs, localised pain, injection site hematoma

COMPARISONS BETWEEN UFH & LMWH

ISSUES COMMENTS

Bleeding incidence similar for heparin and LMWHs

Protamine only partially effective in reversing effect of LMWHs

Renal impairment risk of severe bleeding is higher with LMWHs

Severe HIT lower with LMWHs; LMWHs should not be used as an alternative; cross-reactivity occurs in 90% of cases; incidence is even lower with danaparoid & it is used for treatment of HIT

Osteoporosis seems lower with LMWHs

General surgery (prevention) heparin & LMWHs have similar efficacy in preventing VTE

Orthopaedic surgery (prevention) LMWHs more effective than heparin or warfarin

DVT (treatment) LMWHs as effective as heparin in preventing recurrent thromboembolism and in reducing overall mortality

NSTEACS Enoxaparin appears to be slightly more effective than heparin in reducing the combined endpoint of death or MI but it increases the risk of major bleeding

VTE in cancer Long-term treatment with LMWHs (dalteparin) may be more effective than vitamin K antagonists

HIT

Digital Ischemia in a Patient with

Heparin-Induced Thrombocytopenia

HIT

HIT

• Occurs in <1% of patients with short-term use

• HIT should be suspected:

– Thrombocytopenia

– Thrombosis with thrombocytopenia

– Platelet count has fallen >50%

– Necrotic skin lesions at injection sites (heparin was started preceding 5-10 days)

• Diagnosis is initially made on clinical ground

– Assays with highest sensitivity and specificity may not be available & have slow turnaround time

1. Warkentin, TE, et al. Treatment and prevention of heparin-induced thrombocytopenia. ACCP Evidence-based clinical practice guidelines (8th edition) 2008;133 (6 Suppl): 340S..

HIT

• Delayed onset HIT has also occurred up to several weeks after stopping heparin

• May result in major ischaemic complications (eg stroke, limb ischaemia), bleeding or death

• Monitoring:– Early recognition is important

– Baseline platelet count is a MUST

– Daily platelet count starting from Day 1 in patients with history of past heparin exposure within 3 months (occurs earlier if patient has been recently (<100 days) exposed to heparin)

– Otherwise, start on Day 4

– Withhold heparin or LMWH if platelet count drops 30–50% below baseline and substitute alternative anticoagulant

HIT

• Treatment options:– Lepirudin, Argatroban (both FDA approved) or Bivalirudin (limited

data)

– Danaparoid (cross-reactivity 10%)

– Fondaparinux (weaker evidence)

• Warfarin alone should not be used– Risk of causing venous limb gangrene and/or skin necrosis

– Safe to be use when patient is adequately and stably anticoagulatedwith a drug that reduces thrombosis & when platelet count is > 150,000/microL

• Prophylactic platelet transfusions should not be administered for patient with HIT who do not have active bleeding

• If heparin-induced thrombocytopenia (HIT) is confirmed, future use of heparin or LMWH is contraindicated

WARFARIN

ELIMINATION T½ OF VIT-K DEPENDANT PROTEINS

PROTEIN T½ (hours)

Factor VII 4 – 6

Factor IX 24

Factor X 48 – 72

Factor II 60

Protein C 8

Protein S 30

Warfarin 40 (range 20 – 60)

LOADING DOSE VS MAINTENANCE DOSE

WARFARIN WARFARIN

PHARMACOKINETICS • Action: onset 24 hrs; peak 3 – 4 days; stabilised effect in 10 – 14 days (ave.12.5 days)

• Elimination T½: 20 – 60 hrs (mean 40hrs)• Metabolism: Hepatic (primarily via CYP2C9; minor pathway: CYP2C8, 2C18,

2C19, 1A2 & 3A4)

INDICATIONS • Prevention and treatment of VTE• Prevention of thromboembolism in patients with prosthetic heart valves• Prevention of stroke in patients with previous MI and increased embolic risk• Prevention of stroke in non-valvular AF

DOSE Follow local protocols & individualise according to TTR

PRECAUTIONS • Alcoholism—contraindicated• Compliance likely to be poor—avoid unless supervised administration • Protein C or protein S deficiency—increases risk of skin necrosis


Bleeding, skin necrosis (stop treatment), purple discolouration of toes, alopecia, fever, rash, nausea, vomiting, diarrhoea, hepatic dysfunction, allergic reactions, eg hypersensitivity

PRACTICE POINTS • Different brands are not bioequivalent and should not be interchanged• Many drugs interactions; monitor the INR when changing drug treatment• Consider use of a warning bracelet or necklace (Yayasan MedicAlert)• Advise patients of the intended duration of anticoagulation, and the potential

risks of stopping treatment without medical advice• Review the need for continued warfarin treatment regularly

DIRECT THROMBIN INHIBITORS

Reversibly inhibit both free and fibrin-bound thrombin, preventing conversion of fibrinogen to fibrin, preventing thrombus formation. Thrombin-induced platelet

aggregation is also inhibited

DIRECT THROMBIN INHIBITORS

DABIGATRAN (PRADAXA®)

PHARMACOKINETICS • Action: peak 0.5 – 2 hrs• Elimination T½: 12 – 17 hrs• Excretion: renal (primary); reduce dose in renal impairment

INDICATIONS • Prevention of VTE after elective total hip or knee replacement• Non-valvular AF or high risk of stroke or systemic embolism

DOSE • Prevention of VTE after knee/hip replacement: initially 110mg within 1–4 hrs after surgery, then 220mg once daily; CrCl 30–50 mL/min: 150 mg once daily

• Prevention of emboli in AF: 150mg BD; CrCl 30–50 mL/min & >75 yrs: 110mg BD

PRECAUTIONS • GI haemorrhage within previous 12 months – CI (more common than with warfarin in a clinical trial comparing their use in AF)

• Prosthetic heart valve – CI


Gastritis, dyspepsia, GI bleeding, oesophageal ulcers, increased liver enzymes & bilirubin

PRACTICE POINTS • Watch for drug interactions: verapamil, amiodarone, ketoconazole, • P-gp inhibitors, clarithromycin, dronedarone, etc. • Swallow capsule whole; oral bioavailability may be increased by 75 %

when the pellets are taken without capsule shell; increased risk of bleeding

SWITCHING ANTICOAGULANTS (DABIGATRAN)

SWITCHING RECOMMENDATIONS

From dabigatran to parenteral anticoagulant

• Prevention of VTE after knee/hip replacement: wait for 24 hours after the last dabigatran dose

• Prevention of emboli in AF: wait for 12 hours after the last dabigatran dose

From parenteral anticoagulant to dabigatran

• Start dabigatran within the 2 hours before the due time of the next dose of parenteral anticoagulant

From dabigatran to warfarin

• CrCl >50 mL/min: start warfarin 3 days before stopping dabigatran

• CrCl 30–50 mL/min: start warfarin 2 days before stopping dabigatran

• CrCl 15–30 mL/minute: start warfarin the day before stopping dabigatran

From warfarin to dabigatran

• Stop warfarin and start dabigatran when INR <2

FACTOR Xa INHIBITORS

Selectively inhibit factor Xa, blocking thrombin production, conversion of fibrinogen to fibrin, and thrombus development


FONDAPARINUX (ARIXTRA®)

PHARMACOKINETICS • Action: peak 3 hr• Elimination T½: 17 – 21 hr• Excretion: renal (primary); may need to reduce dose in renal impairment

INDICATIONS • Prevention of VTE in high-risk orthopaedic surgery (hip fracture, knee or hip replacement) and abdominal surgery

• Treatment of VTE• Treatment of high-risk unstable angina or non-STEMI (NSTEACS) if PCI is

not immediate

DOSE Prevention of VTE: 2.5mg SC once daily for 5–9 days; CrCl 30–50 mL/min, 1.5mg once dailyTreatment of VTE: <50 kg, 5mg SC once daily50–100 kg, 7.5mg SC once daily>100 kg, 10mg SC once daily>100 kg and CrCl 30–50 mL/minute, initial 10mg SC, then 7.5mg SC once dailyTreatment of high-risk NSTEACS: 2.5mg SC once daily

PRECAUTIONS Contraindicated when CrCl <30 mL/minute


Thrombocytopenia, allergy

PRACTICE POINTS NSTEACS additional dose of heparin must be given before an angiogram or PCI are performed


APIXABAN (ELIQUIS®)

PHARMACOKINETICS • Action: peak 3 – 4 hrs• Elimination T½: 12 hrs• Excretion: hepatic & renal (30%)

INDICATIONS • Prevention of VTE following elective hip or knee replacement• Non-valvular AF or high risk of stroke or systemic embolism

DOSE • Prevention of VTE after hip/knee replacement: 2.5mg BD• Prevention of emboli in AF: 5mg BD

PRECAUTIONS If at least 2 of: Weight <60 kg, age >80 years, SeCr>133 µmol/L, reducedose to 2.5mg BD


Nausea, thrombocytopenia, abnormal LFTs

PRACTICE POINTS Apixaban is not indicated for patients with hip fracture (no clinical trial data

SWITCHING ANTICOAGULANTS (APIXABAN)


From apixaban to parenteral anticoagulant (and vice versa)

• Start at time of the next scheduled dose

From apixaban to warfarin • Give warfarin with apixaban for 2 days, then check INR before the next apixaban dose. Continue both drugs until INR >2.

From warfarin to apixaban • Stop warfarin and start apixaban when INR <2


RIVAROXABAN (XARELTO®)

PHARMACOKINETICS • Action: peak 2 – 4 hrs• Elimination T½: 5 – 12 hrs• Excretion: Hepatic & renal (30%)

INDICATIONS • Prevention of VTE following elective hip or knee replacement• Treatment of acute VTE and prevention of subsequent VTE• Non-valvular AF or high risk of stroke or systemic embolism

DOSE Prevention of VTE after hip/knee replacement: 10mg once dailyTreatment of acute VTE & prevention of subsequent VTE: 15mg BD for 3 weeks, then 20 mg once dailyPrevention of emboli in AF: 20 mg once dailyCrCl 30–49 mL/minute: 15mg once daily

PRECAUTIONS Treatment with azoles (e.g. itraconazole) or HIV-PIs (e.g. ritonavir) CI


Peripheral oedema, itch, skin blisters, muscle spasm

PRACTICE POINTS • Rivaroxaban & warfarin given together affect the INR more than additively: INR will be misleadingly high (e.g. up to 12) if measured <24 hours after the previous rivaroxaban dose; vitamin K treatment or reduction in warfarin dose is not required

• INR is not a measure of rivaroxaban's anticoagulant effect

SWITCHING ANTICOAGULANTS (RIVAROXABAN)


From rivaroxaban to parenteral anticoagulant

• Give first dose of parenteral anticoagulant when the next rivaroxaban dose would have been due.

From rivaroxaban to warfarin • Limited data. Give warfarin with rivaroxaban until INR >2; use standard warfarin dose for the first 2 days, then adjust dose according to INR. While both drugs are being taken, check INR at least 24 hours after the previous rivaroxaban dose.

From parenteral anticoagulant to rivaroxaban

• Start rivaroxaban within the 2 hours before the due time of the next dose of parenteral anticoagulant or when an infusion is stopped.

From warfarin to rivaroxaban • Prevention of emboli in AF, stop warfarin and start rivaroxaban when INR <3

• Treatment of DVT, stop warfarin and start rivaroxabanwhen INR <2.5

FIBRINOLYTICS

FIBRINOLYTICS

FIBRINOLYTICS

Streptokinase binds plasminogen, which converts free plasminogen to plasmin. Alteplase, urokinase, recombinant urokinase (r-uk), reteplase and tenecteplase

cleave plasminogen to produce plasmin, which catalyses the breakdown of fibrin

FIBRINOLYTICS

• Non- fibrin specific

– Streptokinase (SK)

– Urokinase (UK)

• Fibrin-specific

– Alteplase (r-tPA)

– Tenecteplase

– Reteplase – NA in Malaysia

FIBRINOLYTICS

STREPTOKINASE (STREPTASE®)

PHARMACOKINETICS • Action: peak 20 mins• Elimination T½: 80 mins• Excretion: degraded to peptides & excreted renally

INDICATIONS Treatment of acute MI within 12 hours of onset, with persistent ST-segment elevation or recent left bundle-branch block

DOSE • Systemic: single dose of 1.5 million IU IV over 60 mins• Local intracoronary: bolus of 20,000 IU followed by a maintenance

infusion of 2,000 IU to 4,000 IU/min over 30 to 90 mins

PRECAUTIONS • Development of antibodies thus not if administered more than 5 days, particularly between 5 days and 12 months after initial treatment & effect reduced in patients with recent streptococcal infections

• CI in severe active bleeding disorders or disease states with an increased risk of bleeding


Hypotension, tachycardia, bradycardia (initial infusion), haemorrhage

PRACTICE POINTS Allergic reactions – pre-treat with Hydrocortisone 100mgActive heparinisation –neutralised with protamine sulphate APTT <2x normal control value before thrombolytic is started Warfarin treatment – the INR <1.3 before starting the streptokinase

FIBRINOLYTICS

UROKINASE

PHARMACOKINETICS • Action: rapid• Elimination T½: 10 – 20 mins• Excretion: Hepatic

INDICATIONS • Thrombosed IV cannulae, central venous catheters and haemodialysis shunts

• Peripheral arterial thromboembolism• DVT, PE

DOSE • Adjust individually depending on the clinical condition

PRECAUTIONS CI in severe active bleeding disorders or disease states with an increased risk of bleeding e.g. severe uncontrolled hypertension, severe hepatic disease, severe thrombocytopenia.


Bleeding, including bleeding at injection sites, intracerebral bleeding, internal bleeding (e.g. GI, genitourinary), transient hypotension

PRACTICE POINTS Stop heparin before giving urokinase; check APTT (should <2X the normal control value before beginning thrombolytic treatment & before reinstituting heparin

FIBRINOLYTICS

ALTEPLASE (ACTILYSE®)

PHARMACOKINETICS • Action: rapid• Elimination T½: 4 – 5 mins• Excretion: Hepatic

INDICATIONS • Acute STEMI• Massive pulmonary embolism• Acute ischaemic stroke

DOSE Adjust individually depending on the clinical condition

PRECAUTIONS Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase


Bleeding, including bleeding at injection sites, intracerebralbleeding, internal bleeding (e.g. GI, genitourinary), transient hypotension

PRACTICE POINTS • Avoid IM injections & other invasive procedures during thrombolytic treatment

• In case of severe bleeding not controlled by local pressure, stop infusion of thrombolytic; fibrinogen, platelets, coagulation factors, tranexamic acid may be useful (or protamine if heparin has been used)

FIBRINOLYTICS

TENECTEPLASE (METALYSE®)

PHARMACOKINETICS Action: rapidElimination T½: 90 – 130 minsExcretion: Hepatic

INDICATIONS Acute STEMI

DOSE Based on body weight, with a maximum dose of 10,000 units

PRECAUTIONS CI in severe active bleeding disorders or disease states with an increased risk of bleeding


Bleeding, including bleeding at injection sites, intracerebral bleeding, internal bleeding (eg GI, genitourinary), transient hypotension

PRACTICE POINTS • Avoid IM injections & other invasive procedures during thrombolytic treatment

• In case of severe bleeding not controlled by local pressure, stop infusion of thrombolytic; fibrinogen, platelets, coagulation factors, tranexamic acid may be useful (or protamine if heparin has been used)

SUMMARY

• The development of various anti-thrombotic agents has great impact in prevention & treatment of thrombosis-related diseases.

• Such agents markedly reduced death from heart attacks, the risk of stroke in people with atrial fibrillation and the risk of major stroke in patients with mini-strokes, pulmonary embolism etc.

• Emergence of new agents provides more options and convenience for patients in the future.

REFERENCES

1. Australian Medicines Hanbook 2014

2. Andrew D Blann et al. ABC of antithrombotic therapy. An overview of antithrombotic therapy. British Medical Journal 2001;325:762-5.

3. Patrono C et al. Antiplatelet drugs: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed). Chest.2008;118:1894-1909.

4. Jefrey l, Weitz, et al. New Antithrombotic Drugs. ACCP Evidence-based clinical practice guidelines (8th edition) 2008; 133:234S–256S

5. Warkentin, TE, et al. Treatment and prevention of heparin-induced thrombocytopenia. ACCP Evidence-based clinical practice guidelines (8th edition) 2008;133 (6 Suppl): 340S.

6. Ann K.Wittkowsky. New oral anticoagulants: a practical guide for clinicians. J ThrombThrombolysis. Published online: 04 November 2009

7. Zikria and Ansell. Oral anticoagulation with factor Xa and thrombin inhibitors: on the threshold of change. Current Opinion in Hematology 2009, 16: 347-356

8. electronic Medicines Compendium (eMC) [Internet database]. Stocks House, 9 North Street, Leatherhead, Surrey, England KT22 7AX. Updated periodically

9. Baskin, JL, et al. Thrombolytic therapy for central venous catheter occlusion. Haematologica May 201297:641-650;doi:10.3324/haematol.2011.050492

REFERENCES

10. Lawrence LK Leung. Anticoagulants other than heparin and warfarin. In: UpToDate, Mannucci P.M (Ed), UpToDate, Waltham, MA, 2012.

11. Thomas M.Hyers, M.D. Handbook of Antithrombotic Therapy. Fourth Edition.

12. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically

13. Koda-Kimble et al. Applied TherapeuticsThe Clinical Use of Drugs. 9th ed. Philadelphia: Lippincott-Raven; 2009: 15-1-34

14. Falk E, Fuster V, Shah P. Interrelationship between atherosclerosis and thrombosis. In: Verstraete M, Fuster V, Topol EJ. Cardiovascular thrombosis, 2nd ed. Philadelphia: Lippincott-Raven, 1998 pp 46-47

15. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug Information Handbook, 17th ed. Hudson, Ohio, Lexi-Comp, Inc.; 2008.

16. Spinler, SA, Dager, W. Overview of Heparin-Induced Thrombocytopenia. Am J Health Syst Pharm. 2003;60(20)

THANK YOU

Documents

PHARMACOLOGY OF COMMON ANTITHROMBOTICS OF COMMON... · PHARMACOLOGY OF COMMON ANTITHROMBOTICS KAMALES ARUMUGAM PRINCIPAL PHARMACIST ANTICOAGULATION WORKSHOP 19TH SEP 2014. INTRODUCTION