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Cardiology M2 > 11 10 2014 Hematological agents > Flashcards

11 10 2014 Hematological agents Flashcards

1
Q

Aspirin Mechanism

Why do you not want to give a high dose of Aspirin?

Why is aspirin not a complete anti-thormbotic agent?

A

irreversible acetylation of COX-1 (essential enzyme for TXA2 production)

Depending on dose it usually inhibits platelet COX-1 (higher doses can inhibit Cox-1 in endothelial cells – which you don’t really want because it will impaired Prostaglandin production – they are antagonists of TXA2)

Only inhibits thrombosis via COX-1… other mechanisms of thrombosis are not affected (ex ADP)

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2
Q

Clinical uses of Aspirin

A pro to using Aspiring

However… what should it not be used as?

A
  1. prophylaxis (325mg/day)
  2. Unstable Angina
  3. acute myocardial infarction
  4. History of myocardial infarction
    * prevention of secondary events

Reduces incidence of future fatal and nonfatal coronary events.

HOWEVER, it is not clear if it should be used as PRIMARY prevention

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3
Q

Adverse effects of Aspirin

A
  • GI bleed
  • increased risk of hemorhagic stroke
  • increased incidence of peptic ulcer disease
  • may also exaggerate gout symptoms (since it is excreted by kidney it competes with uric acid)
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4
Q

Clopidogrel (Plavix)
Prasugrel ( Eficient)
Ticlopidine

Type of drug?
Mechanism?

A

Thienopyridiens

Irreversibly inhibit the binding of ADP to its receptor on platelets – inhibits GPIIb/IIIa activation

= inhibits platelet aggregation!

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5
Q

When do you use clopidogrel (Plavix) or Prasugrel (Eficient)

A

Patients who have had a previous:
MI
Stroke
Peripheral vascular disease

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6
Q

Sideeffects of clopidogrel and Prasugrel

A downfall to using these drugs incase someone needs surgery for acute coronary syndrome?

A

Bleeding, dyspepsia (indigestion), diarrhea

Rare:
Severe neutropenia and thrombotic thrombocytopenic purport (which is why ticlopidine is limited)

Irreversible platelet inhibitors: ned to wait a period of several days to allow platelet function to return in order to prevent preoperative bleeding complications

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7
Q

Pharmacokinetics of clopidogrel and prasugrel

A

prodrugs
Metabolized by CYP 450

  • prasugrel is metabolized quicker
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8
Q

mechanism of Abciximab, eptifibataide, and tirofiban?

What are they used commonly for?

A

Reversible Glycoprotein IIB/ IIIA receptor antagonists

_bind to receptor and prevent them from being activated when platelet binds to vWF.

Prevents binding of fibrin
= prevents formation of 3D platelet plug

USE:
improve outcomes of patients undergoing percutaneous coronary interventions and in high-risk acute coronary syndromes

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9
Q

Abciximab – exact structure/form

What is approved for?

A

monoclonal antibody directed against GPIIB/IIIA complex.

Approved for coronary angioplasty and acute coronary syndrome (ACS)

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10
Q

Eptifibatide – exact structure/ form

A

synthetic peptide of the detail chain of fibrinogen
– mediates binding of fibrinogen to the receptor

  • drug occupies receptor and inhibits binding of fibrin
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11
Q

Tirofiban – exact structure/ form

A

non-peptide analog of the main recognition sequence of GPIIb/ IIIa receptors

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12
Q

Pharmacokinetics of Glycoprotein IIb/IIIa receptor antagonists?

A

all must be administered through IV

Abciximab has a short plasma half life so it can be reversed by discontinuing drug.

Other two have a longer half life and may continue to inactive transfused platelets even after discontinuation

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13
Q

dipyridamole

A

given to patients intolerable of aspirins but it is not as effective as aspirin

Platelet Inhibitor
- inhibits phosphodiesterase PDE5 – increase cAMP and blocks platelet response to ADP

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14
Q

Unfractionated Heparin

mechanism?

A

Specific from blocking thrombin

-associates with anti-thrombin in circulation
recall that anti-thrombin (AT) naturally inhibits action of thrombin (clotting factor)

  • reduces thrombin’s ability to make fibrin
  • AT- heparin inactivates factor 10
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15
Q

How is UFH administered and when should you use Unfractionated heparin

A

parenterally – taken other than ingestion.
- not absorbed by GI tract

use when:

  1. unstable angina and NSTEMI
  2. acute MI after fibrinolytic therapy or extensive wall motion abnormality present
  3. Pulmonary embolism or deep venous thrombosis
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16
Q

What are side effects of heparin?

How can you treat an overdose of UFH?

A

bleeding and heparin induced thrombocytopenia (HIT)

Protamine Sulfate: forms a stable complex

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17
Q

Heparin induced thrombocytopenia (HIT)

A

Dangerous form:

  • immune mediated condition due to Heparin-platelet complex.
  • causes bleeding and thrombosis (paradoxically) – results in platelet activation, aggregation and clot production
  • platelet falls drastically and is not dependent on the dose

Immediate cessation of heparin

If patient has HIT do not give them UFH or Low molecular weight heparins

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18
Q

Some pharmacokinetics of UFH

  • half-life
  • bioavailability?
  • monitor?
  • bind to plasma proteins?
A

short half-life
bioavailability varies on individual
need to check aPTT or Anti-Xa
Highly bound to plasma proteins

19
Q

Low molecular weight Heparins (LMWH):

names – 3 drugs

A

Enoxaparin, Dalteparin Tinzaparin

  • the “parins”
20
Q

Mechanism of LMWH?

A

preferentially inactivates factor 10a (need larger molecule to inactivate thrombin)

21
Q

Advantages of LMWH over UFH?

A
  1. inhibition of platelet-bound factor Xa: more prominent anticoagulant effect
  2. less binding to plasma proteins and endothelial cells = more predictable bioavailability and longer half-life
  3. fewer bleeding complications
  4. Lower incidence of immune-mediated HIT

Has a longer half life
Can be administered subcutaneously– injection once or twice a day without frequent blood monitoring
excreted by kidneys

22
Q

LMWH is effective for what?

A
  • Preventing deep venous thrombosis during post-operative period
  • treatment of acute venous thromboembolic disease and acute coronary syndromes.
23
Q

When should UFH be given instead of LMWH

A
  • prevention of venous thrombosis

- Treatment of angina

24
Q

Fondaparinux (Arixtra)

  • What it is and what it targets?
  • clinical uses?
A

synthetic pentasaccharide that specifically inhibits factor Xa
synthetic factor Xa inhibitor

  • prevention of venous thormboembolism following surfer; initial treatment of DVT and Pulmonary embolism
25
Q

Advantage of Fondaparinux

A

Both UFH and LMWH bind to platelet factor 4 = HIT
* Fondaparinux does not bind to platelet factor 4
= NO Heparin Induced Thromocytopenia!!!
* does not require monitoring by aPTT

26
Q

Mechanism of Fondaparinux

A

binds to AT3 ( antithrombin 3) with high affinity = greatly increases AT’s ability to inactivate factor 10a

27
Q

Clinical use of Fondaparinux

A
  1. used for post-operative prevention of thromoemblism : hip fracture, hip replacement, total knee replacement, major abdominal surgery.
  2. Initial treatment for DVT and pulmonary embolism
28
Q

Contraindications to using Heparin?

A
  • hypersensitivity to the drug
  • Actively bleeding
  • genetic bleeding disorders ( Hemophila)
29
Q

Who are the direct thrombin inhibitors?

A

Hirudin, Lepirudin, Bivalirudin, argatroban

30
Q

Mechanism of direct thrombin inhibitors?

- advantage over heparin?

A

They bind directly to thrombin. Benefit over Heparin is that Heparin - AT complex can only bind circulating thrombin and not thrombin already in clot.

Since Direct thrombin inhibitors don’t rely on AT, they inhibit both circulating and clot-bound thrombin.

Do not cause thrombocytopenia and can be used in HIT patients

31
Q

Hirudin

A

Directly inhibits thrombin
recombinant form of desirudin – 65 amino acid protein isolated from medical leeches (hirudo medicinal is)

Most potent known inhibitor of thrombin

Does not cause thrombocytopenia.

Approved for:
prevention of deep vein thrombosis after elective hip arthroplasty

32
Q

Bivalriudin

A

synthetic peptide – directly inhibits thrombin
Short half life (25 min)
20% renal clearance
Inhibits platelet activation
FDA approved for use in coronary angioplasty

33
Q

Argatroban

A

small synthetic derivative of arginine
- directly inhibits thrombin

First and ONLY ANTICOAGULANT INDICATED FOR BOTH PROPHYLAXIS AND HIT

34
Q

Warfin

Pharmacokinetics

A

Indirect anti-coagulant.

Plasma concentration peaks about 2-8 hr afar an oral dose

99% bound to plasma proteins (albumin)
- Half-life in plasma is 25-60 hrs

Extent of coagulation has to be measured via prothrombin time ( extrinsic ) PT.

35
Q

Mechanism of Warfin

A

blocks VKORC1 : Vitamin K reductase

inhibits biosynthesis of vitamin K depdent zymogens: Factors 2, 7, 9, 10 and Protein C/S

36
Q

Adverse effects of warfin

A

-1. bleeding
If bleeding arises during Warfin treatment, it can be reversed within hours with the addition of vitamin K. OR MORE QUICKLY WITH PLATELET TRANSFUSION

  1. Birth defects and abortion – contraindicated during pregnancy
  2. Skin necrosis
37
Q

Dabigatran

A

Thrombin inhibitor
New direct oral anticoagulant

Reversible direct competative inhibitor of thrombin activity

38
Q

Dabigatran pharmacokinetics and adverse effects:

A

prodrug
Low oral bioavailability
Renally cleared

Adverse effects: bleeding, GI disturbances

39
Q

Rivaroxaban

Mechanism
Pharmacokinetics
Adverse effects?

A

Direct inhibitor of Factor X – direct anticoagulant

Oral bioavailability increases with food
Clearance: 70% liver via CYP3A4

Bleeding

40
Q

tPA and urokinase pharmacology (pharmacology of firinolytic drugs

A

rapidly lyse thrombi by catalyzing the formation of plasmin from plasminogen.

41
Q

Alteplase

A

human tPA manufactured by recombinant technology

42
Q

contradictions to treatment with tPA

A 
Absolute constraints:
prior intercranial hemorrhage
Ischemic stroke (3 months)
Suspected aortic dissection
Active bleeding
Significant closed head trauma

Relative constraints
uncontrolled hypertension
Traumatic or prolonged CPR or major surgery within 3 weeks

43
Q

Aminocaprioc acid:

what is it?
Pharmacokinetics?
Clinical uses?
Adverse effects?

A

Fibrinolytic inhibitor
- synthetic inhibitor of fibrinoylsis

Orally or parenterally
Binds plasmin and plasminogen and interferes with function

clinical uses:

  • Adjunct therapy to hemophilia
  • bleeding from Fibrinolytic therapy
  • postsurgical gastrointestinal bleeding and bladder
  • Hemorrhage secondary to radiation
Adverse effects:
Intravascular thrombosis from inhibition of plasminogen. 
Hypotension
Myopathy
Abdominal discomfort
Diarrhea
nasal stuffiness

Cardiology M2 (25 decks)

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