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Pharmacology > Anticoagulants > Flashcards

Anticoagulants Flashcards

1
Q

Heparin (unfractionated) Mechanism of Action

A

Catalyze anthithrombin inhibition by changing shape of several coagulation proteases
AT suicide susbtrate for number of different activated coagulation factors especially thrombin and Xa (iXa, XIa, XIIa)–> activated collation factor attacks specific Arg-Ser peptide bond in the reactive site of AT and becomes trapped and a inactivated
1000 fold increase in reaction rate in the presence of heparin–> serve a catalytic template for which AT and activated coagulation factor can bind (conformational change in AT making reactive site more accessible to proteases)

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2
Q

Heparin uses and Absorption and Metabolism

A

Prevent further clot formation and prevent further extension of the clot
Does not affect synthesis of clotting factors and doesn’t lyse clot
Heparin sodium- sulfate groups replaced by sodium but four sulfate groups on D-glucosamines not replaced (critical for anticoagulant activity)
Not absorbed orally because very large and negatively charged (immediate onset in IV)
Half-life dependent on dose and cleared and degraded by reticuloendothelial system (monocytes and macrophages) and liver
Does not cross placenta so used in pregnancy

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3
Q

How to know if Heparin is working

A

Blood sample collected with citrate to inactivate Ca and prevent clotting then add negatively charged phospholipids (should clot in 26-33 sec)
Called activated partial thromboplastin time (aPTT)- intrinsic and common pathway
Heparin increases time to 1.5 to 2.5 times normal

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4
Q

Heparin Uses

A

Acute Venous thromboembolism or Pulmonary Embolism - bolus injection followed by IV infusion (1.8 to 2.5 times normal) and also administer warfarin
Initial management of unstable angina or acute MI
Coronary angioplasty or stent replacement
Cardiopulmonary bypass- very high dose/ aPTT increased indefinitely
Prophylactic Heparin for prevention of venous thrombosis- subq admin with low dose so no effect on a PTT
In vitro case- hemodialysis, blood samples drawn for lab, maintain patency of in dwelling arterial catheters
Drug of choice in pregnancy

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5
Q

Adverse Reactions in Heparin

A

Bleeding and hemorrhage
Heparin Induced Thrombocytopenia- platelet counts decreased by 50% from normal and more incidence in women (Ig antibodies against platelet factor 4 and and complex activates platelets by binding to Fcgamma2a receptors on platelet which causes platelet aggregation release of PF4, and thrombin generation and fall in platelet number)
Discontinue immediately and give LMWH

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6
Q

Contraindication

A

Active bleeding
Severe uncontrolled hypertension
Recent surgery of eye, brain, spinal cord

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7
Q

Low Molecular weight Heparin

A

End apart and Dalteparin
Fragments of standard MW Heparins- 15 monosaccharid units
Inhibit Factor Xa but not thrombin- eventually inhibit thrombin
Administer Subq and longer half life than heparin
Parenteral Administration and absorbed more uniformally
Renal elimination- risk with renal disease

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8
Q

LMWH Adverse Effects and Contraindications

A

Less risk of bleeding compared to heparin
Lower risk of thrombocytopenia compared to heparin
Contraindications: active bleeding, severe uncontrolled hypertension, recent surgery of eye brain, spinal cord, renal impairment

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9
Q

LMWH Treatment

A

Acute DVT
Prophylaxis of DVT
Hip replacemnt surgery during and following hospitalization
Acute unstable angina and MI

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10
Q

Parenterally Administered Anticoagulants

A

DIrect Thrombin Inhibitors (lepirudin and Bivalirudin)

Selective Factor Xa Inhibitor (Fondaparinux)

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11
Q

Lepirudin and Bivalirudin

A

Direct Thrombin Inhibitors- bind to thrombin active site and bind 1:1 complex (catalytic site and exosite 1) so can’t activate fibrinogen to fibrin
Hirudin is the polypeptide derived from leech and then recombinant forms to drugs
IV administration
Renal excretion
Adverse effect is hemorrhage
Contraindications: active bleeding, severe uncontrolled hypertension, recent surgery of eye, brain and spinal cord
THerapeutic use: alternative to heparin so used if had heparin induced thrombocytopenia

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12
Q

Fondaparinux

A

Selective Factor Xa inhibitor-
Subq
Renal excretion
Adverse effect: hemorrhage
Contraindication: uncontrolled hypertension, surgery of brain, eye and spinal cord, hemorrhage
Therapeutic use: prevention of DVT in surgery, treatment of acute PE, treatment of acute DVT without PE

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13
Q

Protamine Sulfate (Heparin antagonist)

A

Low MW and positively charged compound (from fish sperm)
Chemical antagonist- high affinity for negative molecules and binds 1:1 and form inactive complex
Adverse effects: weak anticoagulant properties in high doses or when used alone, anaphylactic reactions (fish hypersensitivity or previous exposure to insulin products because of protamine), severe pulmonary hypertension
Therapeutic use: heparin overdose with acute bleeding that can’t be controlled by stopping heparin, reverse heparin in cardiopulmonary bypass

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14
Q

Oral Anticoagulant

A

Warfarin
Dabigatran
Rivaroxaban

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15
Q

Warfarin Structure

A

Physical Properties: fat soluble derivative of 4-hydroxycoumarin, structural analog of Vitamin K (synthesized by gut bacteria and dietary sources)
Structure: 3 types of Warfarin- racemic mixture (S and R), S-warfarin (active form), R-warfarin
Racemic mixture is give to patients

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16
Q

Warfarin Mechanism of Action

A

Vitamin K antagonist
Functional zymogen (clotting factors) activated in liver and is carboxylated
Need reduced form of vitamin K for carboxylation and then Vitamin K is oxidized and then needs to be reduced again by Vitamin K reductase
Warfarin blocks Vitamin K reductase so don’t have active Vitamin K and don’t have active clotting factor- competitive inhibition
Different CYP450s for different types

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17
Q

How to measure if Warfarin is working

A

Measure prothrombin time (PT)
Blood collect with citrate to inactivate Ca and prevent clotting
Add thromboplastin- saline extract that contains tissue factor and phospholipids and clots in 12 to 14 seconds)
Variability in thromboplastin so now measure International Normalized Ratio (INR) to see ratio of patient to standard method (normal is between 0.8 and 1.2)
With warfarin INR= 2-3

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18
Q

Warfarin Therapeutic effects

A

Takes several hours to day
May take a day to get to the appropriate concentration but 48 hours to get to INR therapeutic effect- takes time for active clotting factors circulating to break down before coagulation is inhibited because not making new clotting factors (depends on half life of each clotting factor)

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19
Q

Absorption and metabolism Warfarin

A

Oral administration of racemic mixture
Highly bound to plasma proteins
Inactivated by CYP enzymes (CYP 2C9 for S warfarin)

20
Q

Warfarin Adverse Reactions and Contraindications

A

Hemorrhage major adverse reaction
Contraindication: hemorrhage, surgery of eye, brain and spinal cord, uncontrolled hypertension
CYP2C9 polymorphism to increase bleeding, genetic variation in vit K epoxide reductase complex protein, pregnancy (bone metabolism/ Vit K dependent) and liver, kidney disease and Vit K deficiency

21
Q

Rare Adverse Reactions with Warfarin

A

Purple toe Syndrome- reversible, sometimes painful, blue-tinged coloration of plantar surfaces and sides of this that blanches with pressure and fades with elevation of legs (3-8 weeks after initial therapy)
Skin necrosis/gangrene- appearance of skin lesion 3-10 days after treatment is initiated, lesion characterized by widespread thrombosis of micro vascualture, relationship to C deficiency

22
Q

Reversal of Warfarin

A

Related to risk of hemorrhage (if minor stop the drug)
INR>5- Vit K administer but time delay for effectiveness
Immediate reversal- transfusion with fresh frozen plasma

23
Q

Drug/Food Interactions with Warfarin

A

Cause poor control of anti-coagulation
Increase risk of bleeding
May decrease effectiveness
Food: Increase INR (cranberries, alcohol, vitamin E supplement ) and decrease INR to cause drug to not work ( green vegetables, green tea, soy beans, Vit K supplement)

24
Q

Therapeutic uses of Warfarin

A

Long term treatment of venous thromboembolism disease
Prophylaxis against thromboembolism in atrial fibrillation
Prophylaxis against thromboembolism in patients with prosthetic heart valve
Prophylaxis against thromboembolism in patients with dilated cardiomyopathy
Takes time to work so if needed immediately then give LMWH then warfarin= bridging effect

25
Q

Genetics and Warfarin

A

CYP2c9 *2 and *3 have decreased activity- warfarin not inactivated so need less
Several VKORC1 variants- produce less so need less warfarin and more VKORC1 so use more warfarin

26
Q

Dabigatran

A

Pro-drug
MOA: interact with active site of thrombin
Potent, reversible, competitive direct thrombin inhibitor
Inhibits fibrin bound (can get access to active site still so better inhibitor) and free thrombin- thrombin bound to fibrin within a thrombus remains enzymatic ally active and protected from inactivation by antithrombin and fibrin bound thrombin locally activates platelets and trigger coagulation and cause thrombus to grow
Monitoring: none because little effect on PT and INR
Pharmacokinetics: oral administration with rapid onset and short half life, not substrate for CYP 450, excreted by kidney
Adverse Effects: risk of bleeding (less than observed with warfarin but no antidote) and GI upset (more with warfarin)
Contraindication : Renal impairment, advanced liver disease, Valvular heart disease (bioprosthetic heart valve)
Drug interactions: substrate of P-glycoprotein efflux transporter (back to GI from blood)
Rifampin (P-GP inducer) can reduce plasma concentration of Dabigatran
Verapamil (P-GP inhibitor) so increase plasma concentration
Therapeutic uses: no valvular atrial fibrillation at risk for stroke or system embolism and prophylaxis with knee or high replacement

27
Q

Rivaroxaban

A

Direct Factor Xa inhibitor
Xa- Site of amplification of thrombin generation and activated by both intrinsic and extrinsic pathway
Inhibition decreases amplified generation of thrombin without affecting existing levels (remaining thrombin ensure primary hemostasis)
Affect both clot bound Factor Xa (unlike heparin) and non clot bound
Oral administration with rapid onset of action and longer duration
Metabolism: CYP450 in hepatic and CYP independent metabolism (drug interactions)
Dual mode of elimination: metabolic degrade in liver and the other in urine
Adverse effects : bleeding, and drug interactions (CYP 3A4 inhibitor and inducer and P glycoprotein inducer and inhibitors)
Monitoring: Certain subsets
Therapeutic uses: Patient with no valvular atrial fibrillation at risk for stork or systemic embolism and prophylaxis in patients with knee and hip replacement

28
Q

NOACS with Warfarin

A

Disadvantage: severe chronic kidney disease do not use, more expensive, no specific antidote, limited availability of monitoring
Advantage: rapid onset and offset, limited hepatic metabolism and fewer drug and food interactions , wide therapeutic window, fewer adverse effects, lower risk of intracranial hemorrhage

29
Q

Activation of plasminogen to plasmin

A

Needed for fibrinolysis
Endogenous: t-Pa and Prourokinase
Exogenous: Ateplase (recombinant t-PA) and Tenecteplase (recombinant t-PA)

30
Q

Alteplase

A

Recombinant DNA technology
Activates bound plasminogen to plasma and more specific to fibrin clot
Very short half life- IV infusion
Act on bound plasminogen

31
Q

Tenecteplase

A 
DNA recombinant technology 
Longer half life 
Single bolus administration 
Resistant to inhibition by PAI- 1
T-PA activate plasminogen to plasmin- fibrin specificity
32
Q

Complications of Thrombolytics therapy

A

Hemorrhage - Systemic lytic state (disseminated intravascular coagulation DIC where blood clots form throughout blood vessels and increases clotting uses up late lots and clotting factors in blood which causes life threatening bleeding)
Less risk of bleeding when used for acute MI versus Pulmonary Embolism or DVT (due to dose and duration of therapy)
More bleeding complication if with heparin or aspiring

33
Q

Therapeutic Implications of Thrombolytics

A

Acute MI
Treatment of Pulmonary embolism/DVT. ( Ateplase)
Stroke (Ateplase)

34
Q

Aminocaproic Acid

A

Inhibitor of Fibrinolysis
Lysis analog that binds to lysine binding sites on plasminogen and plasmin and block binding of fibrin with plasmin- reverse states associeated with fibrinolysis

35
Q

Anti platelets Drugs

A 
Aspirin 
Dipyridamole
Ticlopidine
Clopidogrel
Prasugrel
Ticagrelor 
Abciximab
Eptifibatide
36
Q

Receptors

A

GPIb/GPIa/IIa- glycoprotein receptor proteins that bind collage, VWF, and cause platelets to adhere to subendothelium
GP2b/3a- glycoprotein receptor that binds fibrinogen
P

37
Q

Low Dose Aspirin

A

Irreversible acetylated COX 1 in platelet (no COX 2 in platelet)
Lock production of thromboxane
Platelets lack nuclei so permanent effect of aspiring
Endothelial cells produce prostacyclin which inhibits aggregation so block COX 1 which will inhibit aggregation
Therapeutic use: MI prophylaxis, preeclampsyia prophylaxis, unstable angina/acute coronary syndrome, stroke prophylaxis, acute phase or ischemic stroke, alone or in combination with Thrombolytics in acute MI

38
Q

Dipyridamole

A

Vasodilatory and inhibitor of platelet aggregation
Mechanism: inhibitor of phosphodiesterase (PDE3 and PDE5) and increase cAMP to inhibit platelet aggregation
Adverse effect: headache, GI upset,
Therapeutic use: prophylaxis in prosthetic heart valves and in combination with aspirin for prevention of secondary MI or TIA

39
Q

Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor

A

Mechanism: act through P2Y1 and P2Y12 receptors to inhibit ADP induced platelet aggregation
Irreversible binding except Ticagrelor
If patient requires and is taking Clopidogrel, the waiting period is necessary to prevent platelet function to return normal— reversible is better for surgery

40
Q

Anti platelet Drugs

A

Pharmacokinetics: oral drugs and some are metabolized with P450 (Clopidogrel and Ticlopidine prodrugs metabolized by Cyp2C19)
Adverse effect: bleeding all drugs, dyspnea with Ticagrelor, Ticlopidine- neutropenia)

41
Q

Drug Interactions

A

Aspiring and Clopidogrel and complain of GI irritation

Omeprazole and also substrate for CYP 2C19 so competition and get less active metabolite of Clopidogrel

42
Q

Abciximab and Eptifibatide

A

GbIIb/ IIIa antagonist

IV preparation

43
Q

Abciximab

A

Fab fragment of other chimeric human monoclonal antibody
Prevent binding of fibrinogen, vW factor, and other adhesive molecules
Steric hindrance and blocks access of molecules to receptor
Non-competitive and not a direct interaction with binding site
Pharmacokinetics: quick onset of action but delayed clearance but effective up to 7 days
Clinical use: patients undergoing precutaneous coronary intervention including angioplasty or stent placement and in combination with aspirin and heparin and use with alteplase for Thrombolytics

44
Q

Eptifibatide

A

Cyclic heptane pride
Derivative of disintegrates
Competitive reversible inhibitor
Contains enough a KGD (Lys- Gly-Asp) sequence motif that binds specifically to GP IIb-IIIa receptor on platelet surface and blocks binding of fibrinogen activated platelets
Pharmacokinetics: quick onset, quick offset and renal clearance
Clinical use: patients with unstable angina, MI, patients undergoing precutaneous coronary intervention (PCI) including angioplast or stent placement

45
Q

Adverse Effects

A

Bleeding, Thrombocytopenia, Hypotension, Bradycardia

Eptifibatide- causation in patients with renal disease because renal clearance

46
Q

Heparin

A

Heterogenous mixture of sulfated polysaccharides
Heparan sulfate
Highly negatively charged
Commercial sources- porcine intestine and heterogeneity in commercial prep composition

Pharmacology (12 decks)

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