B.1 Flashcards
Drugs influencing blood coagulation I: Antiplatelet agents, Fibrinolytic drugs, Drugs inhibiting bleeding
- Antiplatelets: Acetylsalicylic acid, Clopidogrel, Prasygrel, Ticagrelor, Abciximab
- Fibrinolytic: Alteplase, Reteplase
- Drugs inhibiting bleeding: Fibrin foam, Vitamin K, Epsilon-amino-caproic acid, Epinephrine
Acetylsalicylic acid (Aspirin)
MOA: Prevents platelet aggregation,
Irreversibly inactivates COX-1 preventing conversion of arachidonic acid to TXA2 or PGI2 (→alters the balance btw TXA2 and PGI2 in the platelet/vascular endothelium axis in favor of PGI2);
Pharmacokintics: p.o administration, metabolized in the liver (to Salicylic acid) and excreted in urine (increased if urine is alkalinised),
T1/2 of Aspirin- 15-20min,
T1/2 of Salicylic acid- 3-12h;
IND: prophylaxis of arterial thromboembolism events, inhibition of platelet aggregation in case of unstable angina, MI, cerebrovascular circulatory disorders (→saturating dose - 250-500mg - in acute cases, then low dose - 100mg/day), also used to treat pain and fever, inflammation;
SEs: GI bleeding (bc the cytoprotective action of PGs is decreased), bronchospasms (in some individuals), Toxic doses cause respiratory alkalosis followed by acidosis, bleeding time↑, in children risk of Reye’s syndrome; Drug interactions: its effect increases by anticoagulants and thrombolytic drugs
Clopidogrel
MOA: irreversible, non-competitive P2Y12-R antagonist (inhibit ADP binding to P2Y12→ inhibit activation of GP IIb/IIIa→ no platelet aggregation),
prevents platelet activation;
IND: Cardio- and cerebrovascular circulatory disorders (alternatives of Aspirin/used in combo), Prevention of atherosclerotic events in patients with a recent MI/stroke and in those with peripheral arterial disease, also prophylaxis of thrombotic events in acute coronary syndrome, used to prevent thrombotic events associated with PCIs with/ w/o coronary stenting; Pharmacokinetics: max. inhibition of platelet aggregation is achieved in 3-5days,
P.O adm. (requires loading dose for quicker antiplatelet effect),
↑plasma protein binding, prodrug!→Hepatic metabolism to active drug by CYP2C19, eliminated by feces/urine;
SEs: bleeding, GIT discomfort, rashes, neutropenia (rare), TTP;
Drug-interactions: CYP2C19 inhibitors inhibit the conversion of clopidogrel to active drug in the liver; Contra-IND: pregnancy, lactation
Prasugrel
MOA: irreversible P2Y12-R antagonist (same mechanism as Clopidogrel),
prevents platelet activation;
IND: Cardio- and cerebrovascular circulatory disorders, decrease thrombotic cardiovascular events in patients with acute coronary syndromes (→unstable angina, NSTEMI, STEMI managed with PCIs);
Pharmacokinetics: max. inhibition of platelet aggregation is achieved in 2-4h, P.O adm. (requires loading dose as well), ↑plasma protein binding, Hepatic metabolism by P-450 system, eliminated by feces/urine;
SEs: prolonged bleeding, TTP, ;
Contra-IND: Pregnancy, lactation
Ticagrelor
MOA: reversible, non-competitive P2Y12-R ant. (same mechanism as Clopidogrel), prevents platelet activation;
IND: In combination with Aspirin (→Ticagrelor p.o prophylaxis of arterial thromboembolism events); Pharmacokinetics: max. inhibition of platelet aggregation is achieved in 1-3h, P.O adm., bile excretion;
SEs: prolonged bleeding, rarely- leuko and thrombocytopenia;
Conta-IND: pregnancy, lactation
Abciximab
MOA: irreversible, chimeric mAb inhibiting Glycoprotein (GP) IIb/IIIa receptor complex
(→it blocks the binding of fibrinogen and vWf→platelet aggregation is inhibited), binds to endothelial cells and vitronectin-Rs;
IND: Primarily PCIs, prevents restenosis and reinfarction, adjuncts to PCI for prevention of cardiac ischemic complications,
also approved in patients with unstable angina not responding to conventional therapy when PCI is planned within 24h;
Pharmacokinetics; i.v. adm.→given by i.v bolus following i.v infusion (with heparin and aspirin),
T1/2-30min, has biological effect of 18-24h (DOA), metabolism unknown!;
SEs: bleeding, thrombocytopenia, hypotension, bradycardia, nausea, vomiting
Alteplase
MOA: recombinant tPA
(→Directly converts plasminogen to plasmin→fibrin degradation, lysing the clot);
Pharmacokinetics: T1/2- 40min, adm. by i.v or infusion; IND: PE (MUST prove it’s a PE first!→ perform enhanced chest CT, then do risk vs. benefit assessment), Ischemic stroke (1st do MRI/CT to check if it’s ischemic or hemorrhagic stroke!), MI (definitive treatment PCI!→ if symptoms of MI strated less than 12h ago + the closest PCI lab is more than 2h away→use fibrinolytics);
SEs: hemorrhage;
Contra-IND: RELEVANT FOR PE!!→
-Absolut: patients w/intracranial bleeding, known malignancies or intracranial malformations, active bleeding anywhere (EXCEPT- menstural bleed), if there was hemorrhagic/ischemic stroke in the past 3 months. -Relative: HTN (>180/110mmHg), surgery in the past month, >75yo, pregnancy, INR>1.7;
Benefit: During ALS, if the patient is hemodynamically unstable due to the PE, serious respiratory failure (hypoxemia w/ hypocapnia), certain symptoms of RV failure, large proximal DVT;
Ischemic stroke considerations: do 2 types of MRI
(→ DWI and PWI/FLAIR and check if they match or not→ in case of mismatch you can use fibrinolytics),
if symptoms started <3h ago its worth to give the drug, if more than 3h then there are more risks for example reperfusion injury
Extra: Inactivated in circulation by PAI-1.
ROA: IV
Reteplase
MOA: recombinant tPA
(→Directly converts plasminogen to plasmin→fibrin degradation, lysing the clot);
Pharmacokinetics: T1/2- 40min, adm. by i.v or infusion; IND: PE (MUST prove it’s a PE first!→ perform enhanced chest CT, then do risk vs. benefit assessment), Ischemic stroke (1st do MRI/CT to check if it’s ischemic or hemorrhagic stroke!), MI (definitive treatment PCI!→ if symptoms of MI strated less than 12h ago + the closest PCI lab is more than 2h away→use fibrinolytics);
Contra-IND: GI-bleeding history, recent surgery, severe trauma in the last 10 days.
SEs: hemorrhage;
Extra: has longer T1/2 and faster onset of action. Inactivated in circulation by PAI-1.
ROA: IV
Vitamin K
MOA: post-ribosomal modification of F-II, VII, IX, X and protein C.
Also it’s an antagonist of oral anticoagulants;
Kinetics: its action starts only after 6h, becoming complete after 1 day.
ROA- i.v or p.o (i.v. dosing should be very slow→ rapid infusion - risk of dyspnea, chest pain, may be fatal in extreme cases).
Has 3 forms:
-Vit. K1 (in diet),
-2 (synthesized by bacteria in gut flora),
-3 (synthetic form);
IND: coumarin overdose- INR: 5-7< (not until there is no bleeding), all newborns (especially preterm), severe hepatic failure, malabsorption, prolonged parenteral feeding, intestinal flora impairment
S.Es: thrombosis
ROA: IV, oral
Extra: IV administration must be slow- rapid infusion may cause dyspnea, chest pain, death
Epsilon-aminocaproic acid
MOA: inhibits plasminogen activation→prevents fibrinolysis (→keeping the clot alive for longer time); Pharmacokinetics: i.v mainly or locally (for specific IND→check extra);
IND: to reduce hemorrhage following dental extraction or prostatectomy, for menorrhagia, epistaxis, hereditary angioedema, thrombolytic overdose;
SEs: GIT disturbances, rarely HST skin reactions, disturbed color vision, intravascular thrombosis, crosses the placenta.
ROA: oral, parenteral
Epinephrine
MOA: vasoconstrictor (α,β agonist), local hemostatic agent;
IND: effective in controlling mucosal bleeding across large surface areas within the operative field, given with lidocain in local anesthesia;
SEs: HTN, intracranial bleeding, tachycardia, arrhythmias
Fibrin-foam
MOA: local hemostatic agent, mimics the final steps of the blood coagulation cascade, forming a stable fibrin clot that assists hemostasis and wound healing; Content: human fibrinogen and humanor bovine-derived thrombin;
IND: surgeries (→cardiac, vascular, reconstructive plastic, oral and maxillofacial), urologic applications (e.g. renal injuries)
Injury of vessel wall
- Vasospasm
- Platelet activation, adhesion and aggregation (white thrombus)
- Coagulation of blood- red thrombus
- Fibrinolysis (clot lysis)
- Cell proliferation, repair mechanisms
Antiplatelet properties of the endothelium
overing the highly thrombogenic basement membrane
* Undamaged endothelium does not bind platelets
* PGI2 and NO from uninjured endothelium inhibit platelet adhesion
* ADPase counteracts the platelet aggregating effect of ADP
Anticoagulant properties of the endothelium
Heparin-like molecules: activation of AT III (which inactivates proteases)
* Thrombomodulin: changes specificity of thrombin (activates protein c, which inactivates FVa and FVIIIa)
* Production of t-PA: activates a fibrinolysis through the conversion of plasminogen to plasmin
