FAFP2 Pharmaceutical care II Seminar: Cardiovascular system II. - anticoagulants Pharmacist's role in providing pharmaceutical care to patients with anticoagulants Patients with warfarin Patients with new oral anticoagulants (NOACs) 1. 4. 2020 PharmDr. Bc. Dana Mazánková, Ph.D. mazankovad@vfu.cz ANTICOAGULANT TREATMENT • Warfarin • Low Molecular Weight Heparins (LMWHs) • New Oral AntiCoagulants - NOACs ▫ Dabigatran ▫ Rivaroxaban ▫ Apixaban Warfarin • vitamin K antagonist • anticoagulant effect by decreasing of activity of: protrombin, factors VII, IX, X • racemic mixture of 2 enantiomers: ▫ S-warfarin is 2-5 times more potent then R-warfarin Warfarin pharmacokinetic • immediate and complete absorption from GI tract - oral administration • nearly completely bound to plasma proteins (albumin): 99 % • the maximum plasma concentration: til 90 min. • T1/2: 34 - 45 h. • anticoagulant effect begins: til 60 h. ▫ → latency of warfarin effect • anticoagulant effect persists: 72 h. ▫ → long persisting effect after warfarin withdrawals • liver metabolism : til 120 h. • S- and R-warfarin are metabolized differently in the liver: ▫ S is metabolized primarily by CYP 2C9 ▫ R is metabolized by CYP 1A2, CYP 2C19, CYP 3A4 Warfarin indications Myocardial infarction Pulmonary embolism Trombophilia Deep vein trombosis Prevention of thromboembolism in atrial fibrillation Thromboembolic stroke prophylaxis Pharmacist's role in providing pharmaceutical care to patients with warfarin Warfarin side effects Any signs of an allergic reaction to warfarin: • urticaria, difficult breathing, swelling of your face, lips, tongue, or throat Warfarin increases patient's risk of bleeding, any signs of bleeding: • petechia • unusual headache, feeling very weak or dizzy • swelling (edema), pain • bleeding gums, nosebleeds • bleeding from needle injections that will not stop • heavy menstrual periods or abnormal vaginal bleeding • blood in your urine, bloody or tarry stools • coughing up blood or vomit that looks like coffee grounds Group of patients with increased risk of bleeding • high BP or serious heart disease • kidney disease • cancer or low blood cell counts • an accident or surgery • stomach bleeding, intestines bleeding • a stroke • age of 65 or older Side effects always consult your doctor or pharmacist. Recommend seeking emergency help if patient have any bleeding that will not stop! Teratogenity • warfarin readily crosses placenta • information for women patients: If you are not pregnant, use effective birth control to prevent pregnancy while taking warfarin and for at least 1 month after your last dose. Tell your doctor right if you become pregnant. Breast-feeding a baby • it is not known whether warfarin passes into breast milk Dosage of warfarin • take warfarin at the same time every day, with or without food – once a day, in the morning • never take a double dose • initial dose: 2 to 5 mg orally once a day • maintenance dose: 2 to 10 mg orally once a day • dosage should not be the same in various days • necessity of daily dose oscillates individually Missing a dose of warfarin • information for patients ▫ take the missed dose as soon as you remember  if you usually take warfarin in the morning and forget to take it at your normal time, take it as soon as you remember and continue as normal  If you forget to take your dose of warfarin in the evening but remember before midnight on the same day, take the missed dose ▫ skip the missed dose if it is almost time for your next scheduled dose Color coding of warfarin tablets - US - in the United States, manufacturers of both brand and generic warfarin have agreed to make each strength a consistent color Helpful Mnemonics: „Please Let Granny Brown Bring Peaches To Your Wedding“ Warfarin overdosing • immediate warfarin withdrawal • carbo medicinalis • elimination of warfarin effect : ▫ concentrate of protrombin complex ▫ warfarin antidote: vitamin K (phytomenadiol) Factors influencing stability of anticoagulant therapy I. Patient's compliance II. Warfarin interactions III. Non-pharmacological influence I. Patient's compliance • adherence to terms of INR monitorig ▫ beginning of warfarin treatment: INR control 2 – 3x a week ▫ ongoing warfarin treatment: INR control once a 4 - 6 weeks ▫ long-term ongoing warfarin treatment: INR control once a 12 weeks INR monitoring INR values: - healthy person who is not taking a blood thinner: INR 0,8 – 1,2 - people taking blood thinners: INR 2 – 3 Information for patient: If your value of INR is too high, it may increase your risk for uncontrollable bleeding. If your value of INR is too low may put you at risk for a blood clot or stroke. Quality of INR control - efficacy of warfarin is limitedy by quality of INR control: - multiple food and drug interactions - variable pharmacodynamic / pharmacokinetic - narrow therapeutic window (INR 2 – 3) - regular monitoring and dose adjustement • proper drug using ▫ patient receive „warfarin / anticoagulant alert card“ ▫ right instruction for warfarin using (from physician, from pharmacist) • adherence to diet limitation • inform also other physicians, that patient use warfarin • avoid cutting yourself while taking anticoagulant medication because of the risk of excessive bleeding • take care when shaving and brushing your teeth • wear protective clothing when gardening, sewing or playing contact sports • use insect repellent to avoid insect bites • because of the risk of bleeding, dose of warfarin may need to be lowered or stopped a few days before having an operation or dental work • BEWARE: random using of other various drugs • BEWARE: alcohol exccess II. Warfarin interactions • S-warfarin metabolized primarily by CYP 2C9 • R-warfarin metabolized primarily by CYP 3A4, CYP 1A2, CYP 2C19 • aspect of isomer effectiveness: high-risk are drugs from group of inhibitors CYP 2C9 • aspect of high of plasmatic concentration: higher plasmatic concentrations have R-warfarin Drug – drug interactions Drugs, that can increase anticoagulant effect or risk of bleeding: • Amiodaron • Cimetidine • Levothyroxine • Omeprazole (PPI) • Laxatives (senna concentrates) • Phenytoin • Quinidine • Quinine • Ibuprofen Anticoagulant effect Safe pharmacotherapy in patients with warfarin Analgetic drugs • metamizol • paracetamol • opiates • tramadol • in the case of necessity of NSAIDs: diclofenac ▫ pantoprazol Antipyretic drugs • metamizol • paracetamol Antibiotics • azitromycin, spiramycin • penicillins • cefalosporins • ciprofloxacin, ofloxacin • nitrofurantoin Proton pump inhibitors (PPI) • pantoprazol III. Non-pharmacological influence Herbal drugs and other aspects, that can increase anticoagulant effect or risk of bleeding • alcohol exccess • Koenzym Q10 • Herbal products ▫ Chamomilla recutita ▫ Allium sativum - garlic ▫ Ginkgo biloba ▫ Panax ginseng ▫ Salvia oficinalis ▫ cranberry • Fever • Inappetence, malnutrition • Diarrhea • Hyperthyreosis • Liver insuficience III. Non-pharmacological influence Herbal drugs and other aspects, that can decrease anticoagulant effect or risk of blood clot • foods that are rich in vit. K • Smoking • Herbal products • Hypericum perforatum • Thea sinensis • Hyporthyreosis Low Molecular Weight Heparins (LMWHs) • predictable level of anticoagulation • monitoring: routine measurement of anti‐Xa levels is not indicated ▫ except in the setting of: 1. renal failure 2. obesity 3. gravidity 4. children therapy LMWH indication Venous Thromboembolism (deep vein thrombosis) Deep vein thrombosis prophylaxis Switching from warfarin Anticoagulant treatment in gravidity LMWH side effects • Increased bleeding • antidotum: ▫ Protamin ▫ Recombinant factor VII a • Heparin induced trombocytopeny After beginning with LMWH therapy always control of blood count!!! LMWH subcutaneous self-application Apixaban Edoxaban New Oral AntiCoagulants - NOACs Direct trombin inhibitor (DTIs) - dabigatran (Pradaxa tbl) - twice daily Oral direct factor Xa inhibitors (Anti-Xa inhibitors ) - rivaroxaban (Xarelto) - once daily - apixaban (Eliquis) - twice daily - edoxaban (Lixiana tbl) - once daily NOACs indication Stroke prevention in atrial fibrillation Venous Thromboembolism (deep vein thrombosis) Prevention of VTE (deep vein thrombosis) after total hipp or knee replacement surgery Pharmacological properties of NOACs Drug Dabigatran Rivaroxaban Apixaban Edoxaban Mechanism Direct thrombin inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor Direct factor Xa inh. Pro-drug Yes No No No Bioavailability, % 6% 66% without food up to 100% with food 50% 62% Half-life, h 12–17 h 5–9 h (young) 12 h 9–11 h 11–13 h (elderly) Time to maximum plasma concentration 0.5–2 2–4 h 1–4 h 1–2 h Renal excretion 80% 35% 25% 50% Liver metabolism No Yes Yes Minimal Gastrointestinal tolerability Dyspepsia No problem No problem No problem Absorption with food No effect +39% more No effect 6–22% more Intake with food? No Mandatory No No official recommendation Dosing Twice daily Once daily Twice daily Once daily NOACs - pros - oral tablets - uses of fixed-dosing - wider therapeutic window - absence od drug interactions - vs. apixaban - no laboratory monitoring - rapid onset of action NOACs - cons - miss a dose – risk of clot - no agent for anti-Xa inhibitors - reservations in patients with kidney disease - high cost - Patient Alert Cards