drugs used for PAD and DVT Flashcards
What are the Parenteral anticoagulants that are indirect thrombin/Xa inhibitors
Unfractionated/high molecular heparin
low molecular weight heparins:
-enoxaparin, dalteparin, tinzaparin
synthetic pentasccharides:
-fondaparinux
what are the paraenteral anticoagulants that are direct thrombin inhibitors
Bivalirudin
argatroban
what are the oral anticoagulant?
Coumarin derivative
Warfarin
what are the direct oral anticoagulant factor Xa inhibitors
rivaroxaban
apixaban
endoxaban
what are the direct oral anticoagulant thrombin inhibitors
dabigatran
what are the oral antiplatelet phosphodiesterase inhibitor?
dipyridamole, cilostazol
difference between a red clot and white clot
red clot is fibrin rich with trapped RBC
- atrial fibrillation to stroke
- DVT
- PE
White clot: platelet rich
-damaged endothelium ruptured atherosclerotic plaques that lead to unstable angina, myocardial infarction
what are some PAD complications?
Critical limb ischemia:
- sores that dont heal that lead to infection, tissue death (gangrene)
- may need amputation
Stroke and Heart attack
what is the best way for PAD prevention?
HEalthy lifestyle
- quit smoking
- keep diabetes under control
- exercise
- low cholesterol
- heat healthy foods and maintain a healthy weight
Medications to treat PAD
•
Cholesterol-lowering medications… e.g., statins (see “Drugs to Treat Hyperlipidemia”)
–
goal is LDL < 100 mg/dL
•
High blood pressure medications, if needed… (see “Drugs to Treat Hypertension and HTN Urgency/Emergency”)
–
goal is < 130/80 mm Hg
•
Control blood sugar levels if diabetic…
–
e.g., metformin for T2DM (drugs will be discussed in EN RE II, Med 218)
•
Prevent arterial blood clots (see “Drugs to Treat Cardiac Arrhythmias/ACS/Stable Angina”)
–
antiplatelet drugs: e.g., aspirin, clopidogrel… avoid concurrent gingko biloba (↑bleeding risk)
–
locally-infused clot buster drugs if occlusion from clot due to plaque rupture
•
Symptom-relief medications.
–
cilostazol
–
pentoxifylline, well-tolerated but less efficacious alternative
cilostazol MOA, effects and Clinical applications
MOA: type 3 phosphodiesterase inhibitor that prolongs life of cAMP on platelets and cells
Effects: Platelet aggregation inhibitor
-vasodilator
Clinical applications:
-intermittent claudication
Pharmacokinetics, toxicities and BB warning ciostazol
Pharmacokinetics:
- oral tablet 2x a day
- metabolized by CYP3A4
toxicities:
- headache
- diarrhea
- palpitations
- dizziness
- peripheral edema
BB warning: -contraindicated in patients with heart failure, use is asssociated with decreased survival of class III and class IV patients
what are the surgical treatment of PAD
Balloon or laser angioplasty stent
atherectomy
symptoms of an affected leg with DVT
swelling
pain and cramping in the calf
-red/discolored skin
-warmth
lead to PE
DVT risk factors
•
genetic blood-clotting disorder –e.g., factor V Leiden, mutation ↑prothrombin
•
prolonged bed rest, such as during a long hospital stay, or paralysis –calf muscles don’t help blood circulate
•
injury or surgical damage to veins
•
pregnancy
•
overweight or obese
•
oral contraceptives or hormone replacement therapy –estrogen ↑synthesis of clotting factors
•
smoking affects blood clotting and circulation
•
cancer –
•
vein compression by tumor, unusual blood flow patterns in tumor
•
hypercoagulable state due to secretions –e.g., tissue factor, ADP, thrombin, thrombogenic tumor exosomesdue to surface expression of phosphatidylserine
•
heart failure–low cardiac output means sluggish flow
•
inflammatory bowel disease–2-3x higher risk due to hypercoagulable state from altered expression of various proteins, exact etiology uncertain
•
family history
•
age… risk increases if age > 60 yrs
•
sitting for long periods of time, such as when driving or flying
DVT prevention
Avoid sitting still
-dont cross legs
Make lifestyle changes:
- lose weight if overweight
- quit smoking
Exercise
Drug options for treatment of DVT
Anticoagulants
Clot busters
Non-pharmacologic treatment of DVT
Compression socks
Stents
Vena cava filter
what drugs block white clot formation
antiplatelet drugs
what drugs block red clots formation
Anticoagulant drugs block thrombin activation/fibrin formation
what drugs destroy formed clots?
thrombolytic drugs
MOA effects and Clinical applications of heparin unfracetionated
MOA: made from lungs of cattle and pigs and lots can vary
- long polysaccharide chain
- pentasaccharide sequence found randomly that binds antithrombin III and inhibits factor Xa
effects:
- blocks generation of thrombin
- inactivates thrombin
- prevents red clots
Clinical applications:
-rapid onset anticoagulant effects
(PE, stroke, DVT, DIC, acute MI)
-used in pregnancy and doesn’t cross placenta
-used in catheters extracorporeal circuits
antidote: Protamine (positive charges)
Pharmacokinetics and toxicites
Pharma:
- parenterally (IV or SC) since it is negatively charged
- binds nonspecifically
- variable plasma levels so must monitor aPTT assay (1.5-2)
- half life 1.5 hrs can vary
Toxicities:
- contraindicted in thrombocytopenia and uncontrolled bleeding
- avoid in surgery
- heparin induced thrombocytopenia (reduced platelet and thrombotic events)
MOA, effects, and Clinical applications of Enoxaparin
MOA: LMW heparin
-cant form tertnary complex with antithrombin III and thrombin but factor Xa is inhibited
effects:
- selectively blocks factor Xa
- prevents red clots
- little effect on thrombin
Clinical applications:
- prevent DVT, after surgery
- treatment of DVT +/- PE
- prevent ischemic complications
- safe in pregnancy
Pharmacokinetics and toxicites of enoxaprin?
Pharm:
- easier to use than unfrac hep since dosing is predictable
- first choice treatment and prevention of DVT
- longer half lives
Toxicites:
- bleeding is a major adverse effect
- protamine is the antidote
- Heparin induced toxicity
- can cause severe neurological injuries in spinal punctures
what are the characteristics of delteparin, and tinazeparin?
similar to enoxaparin with similar indications
MOA, effects, Clinical applications of Fondaparinux
MOA: synthetic pentasaccharide identical to antithrombin binding structure of heparin
-short length it is selectively inhibits factor Xa without affecting thrombin
Effects:
- blocks coagulation by preventing conversion of prothrombin to thrombin
- no effect on thrombin
- more effective than enoxaparn but has increased risk for bleeding
Clinical applications:
- prevents DVT
- treatment of acute PE and DVT in conjunction of warfarin
Pharmacokinetics and toxicites of fondaparinux
Pharm:
- administer subQ as a fixed dose
- predictable pharmacokinetics
- long half life
Toxicities:
- bleeding is biggest concern
- not reversible with protamine
- does not cause heparin induced thrombocytopenia
MOA, effects, CLinical applications of Bivalirudin
MOA: synthetic 20 aa peptide similar to hirudin (anticoagulant of leeches)
directly blocks thrombin
effects:
-reversibly inhibits thrombin blocks both catalytic site and substrate binding site of thrombin
Clinical applications:
-can be given in combination with aspirin to patients undergoing coronary angioplasty
Pharmacokinetics and Toxicites of Bivalirudin
Pharm:
- must be given IV like heparin
- expensive
TOxicites:
- doesn’t require antithrombin and causes less bleeding
- but no antidote
- anaphylaxis with repeated use
what is desirudin?
recombinant form of Hirudin and is no longer available in U.S.
MOA, effects, and clinical applications of argatroban?
MOA: small molecular weight thrombin inhibitor that directly binds to catalytic site of thrombin similar to hirudin analogs
-does not bind to substrate binding site as well
effects:
- reduces development of new thrombosis
- permits restoration of platelet counts in those with HIT
Clinical applications:
- Prophylaxis and treatment of thrombosis in patients with HIT
- efficacy of treatment is monitored by aPTT
Pharmacokinetics and toxicites of argatroban
Pharmaco: given IV and has a short half life
Toxicities:
-risk for hemorrhage
MOA, effects, and clinical applications of warfarin
MOA: vitamin K antagonist
-oldest oral anticoagulant
effects:
-decreases production of biologically active forms of calcium dependant factors II, VII, IX, and X and protein C and S
Clinical applications:
- used for long term prophylaxis of thrombosis
- prevent DVT, PE, Thrombosis via afib
- prevent thromboembolism of mechanical heart valves
- not useful in emergencies since effects are delayed
Pharmacokinetics, toxicites and contraindications of warfarin?
Pharm:
- orally active
- eliminated by liver in bile
- slow onset
- slow offset
- monitored with prothrombin time (INR) (2-3)
- Monitored frequently whenever a drug is added or subtracted
Contraindicted:
-patients with high risk of bleeding or surgery of the brain, eye, or spinal cord
Toxicites:
- bleeding
- reversed by administering vitamin K, FFP
- liver disease is a risk
drugs can increase the effects
- promote bleeding
- decrease effects as well
two proteins that are first seen lost in the administration of warfarin
Factor VII
Protein C
what is Cutaneous Necrosis?
Protein c has a shorter half life than several other clotting factors that warfarin administration can initially cause a pro coagulant state
MOA, Effects, and Clinical applications of rivaroxban?
MOA: direct inhibitor of activated factor X
Effects :
- directly inhibits the production of thrombin
- rapid onset
- fixed dosage
- lower bleeding risk
- fewer drug interactions
- no need for INR monitoring
Clinical applications:
-prevent DVT and PE, and stroke with a nonvalvular a fib
no antidote but maybe andexanet alfa
Pharmacokinetics and toxicites of rivaroxban
Pharm:
- administered orally as a high bioavailabillity
- half life 5-9 hrs
Toxicites:
- bleeding
- epidural hematoma, intercranial, adrenal, GI bleeding
- avoided in patients with significant renal or hepatic impairment
- appears safe in pregnancy
- not combined with other anticoagulants interacts with CYP34A
what are other drugs similar to rivaroxaban?
apixaban, and edoxaban
MOA, effects, and clinical applications of dabigatran
MOA: reversible direct thrombin inhibitor
Effects:
- directly blocks thrombin
- rapid onset
- no need to monitor
- few drug interactions
- lower risk of bleeding
- same dose is used for all patients
Clinical applications:
- prevention of stroke and systemic embolism in patients with nonvalvular atrial fib
- contraindication for therapy of those with mechanical heart valves
Pharmacokinetics and toxicities of dabigatran:
Pharmacokinetics:
- pills are unstable and must be kept in bottle
- eliminated by kidney with half life of 13 hrs
- given orally be taken with or without food
Toxicites:
- Bleeding is the major concern
- antidote recently approved (idarucizumb)
- compete for p-GP transporter
how to monitor Heparins?
aPTT, anti-Xa
how to monitor warfarin
PT-based (INR)
how to monitor DOAC-factor Xa inhibitors
anti-Xa
how to monitor DOAC- direct thrombin inhibitor
Diluted thrombin time (TT)
Non fractionated and LMW heparin antidote?
Protamine sulfate due to high + charge
Warfarin antidote?
Vitamin K, prothrombin complex concentrate
DOAC factor Xa inhibitors antidote
andexanet alfa
DOAC direct thrombin inhibitors antidote
idarucizumab
