Anti-platelet medications
Strategies and Targets
1. COX - 1 Aspirin
2. Increase cAMP, in turn increases PKA and intracellular
calcium which inhibits platelet activation
Phosphodiesterase inhibitors + Prostacyclin agonists
3. Inhibition of the ADP dependent pathway through
P1Y12 receptor inhibition Clopidogrel, Prasugrel
4. Prevent fibrinogen binding to GpIIb-IIIa GPIIb-IIIa
receptor
5. Inhibition of thrombin related platelet activation
Inhibition of PAR-1
PHARMACOLOGICAL AGENTS PHARMACODYNAMICS PHARM
Mechanism of action: Irreversible inhibition of COX-1 enzyme mainly in platelets by
covalently binding a serine residue to the enzyme active site
Administration
Indirect properties of aspirin:
Oral: 75 to
Reduction of inflammatory cytokines
Reduction of oxygen radicals
Duration of pl
Reduction of growth factors
Permanen
lifespan)
COX INHIBITORS Acetylsalicylic acid - Aspirin Why is aspirin only given in low doses?
Higher dosage also results in COX-2 inhibition (in other cells other than platelets)
Elimination ha
which decreases both TXA2 and prostacyclin (anti-platelet agents).
15-20 min
When we administer higher dose we loose sensitivity to COX-1 inhibition, meaning
that if we only want anti-platelet effect there is no need for a higher dose.
What about other NSAIDs?
With other NSAIDs the platelet inhibition is not permanent so they are not used as
anti-platelets.
Mechanism of action - Dipyridamol: Inhibition of PDE3 and PDE5 leading to
decreased cAMP degradation. Increased levels of cAMP lead to PKA activation and
decreased intracellular calcium which in turn inhibits platelet activation.
Dipyridamole by itself has only weak antiplatelet effects Administered in
combination with aspirin (secondary long-term prevention of stroke and TIA)
Mechanism of action - Cilostazol: selective inhibition of PDE3A (a subtype of PDE3)
PDE inhibitors
Dipyridamol PDE inhib
ad
PDE INHIBITORS AND Cilostazol
PROSTACYCLIN ANALOG Prostacycl
Prostacyclin analog ad
Iloprost Mechanism of action - Iloprost: activation of adenylate cyclase to increase intra-
platelet cAMP level.
Mechanism of action: They all lead to inhibition of the P1Y12 ADP receptor.
Clopidogrel and prasugrel are both irreversible antagonists of P1Y12.
Clopidogrel requires 2 sequential reactions for activation, this involves several CYP
enzymes which increases the potential for drug-drug interactions
Clopidogrel vs Prasugrel
Prasugrel is more efficiently metabolized inhibits platelet aggregation faster,
more consistently and to a higher degree than Clopidogrel;
Clopidogrel requires a loading dose to achieve maximal antiplatelet effect
rapidly;
Prasugrel causes much fewer drug-drug interactions than clopidogrel,
Prasugrel shows lower inter-individual variability in response to its antiplatelet
activity;
There are 4: Prasugrel is associated with a significantly increased incidence of major adverse
Clopidogrel - Irreversibile bleeding events.
antagonist, prodrug
Prasugrel - Ticagrelor (cyclopentyl-triazolopyrimidine):
Clopidog
ADP RECERPTOR Thienopyridines; prodrug Competitive antagonist at the P2Y12- ADP receptor;
ticagrelor a
PATHWAY INHIBITORS Ticagrelor -Direct acting Does not require metabolic activation;
Cangrelor o
nucleoside; nucleotide Faster, more potent and more predictable antiplatelet effect than Clopidogrel
but slightly less potent than prasugrel;
derivatives
Adverse effects: bleeding (major), dyspnea and bradycardia.
Cangrelor - active drug;
reversible antagonists
Cangrelor (ATP analog):
Reversible inhibitor of the platelet P2Y12- ADP receptor;
Rapid onset of action (steady state= 30 min);
Elimination half-time= 9 min;
Platelet activity rapidly returns to its normal state within 60 min after interruption
, Targets:
Anti-coagulants
AT III
Thrombin (Factor IIa)
Factor Xa
Vitamin K dependent coagulation fac
PHARMACOLOGICAL SIDE EFFECTS +
PHARMACODYNAMICS PHARMACOKINETICS INDICATIONS ANTIDOT
AGENTS CONTRAINDICATIONS
Mechanism of action: Heparins binds to ATIII
working as a catalyzer in the inactivation of factor
Xa and thrombin
Side effects
UFH IIa = Xa (IX, XI, XII)
Bleeding / Hemorrhage
LMWH Xa > IIa UFH:
Heparin-induced
Higher inter-individual availability
thrombocytopenia
IV and subcutaneous Clinical uses
Unfractioned heparin (UFH) Osteoporosis
administration Prophylaxis of
Hypoaldosteronism
Reduced bioavailability thromboembolic diseases
HEPARINS Low molecular weight heparin Higher binding to plasma proteins
(hyperkalaemia)
(venous
Hypersensitivity reactions
(INDIRECT (LMWH) Binding to cell surfaces
(protamine)
thromboembolism);
Protamine Sulfate (M
Reviparin UFH Treatment of deep vein
UFH)
THROMBIN Enoxaparin Monitoring required with aPPT LMWH:
Contraindications:
thrombosis and
Dalteparin sodium Low cost and long history of clinical use Stable and predictable PK pulmonary embolism;
INHIBITORS) Nadroparin calcium Unpredictable anticoagulant effect Subcutaneous administration
Active bleeding, Hemophilia and
Treatment of unstable
Thrombocytopenia;
No renal failure restriction Longer half-life angina and acute
Severe Hypertension;
Reversible Better bioavailability myocardial infarction
Severe hepatic and renal disease;
Lower binding to plasma proteins
Ulcerative lesions in GI tract
LMWH Reduced binding to cell surfaces
Intracranial hemorrhage, recent
Monitoring not required
surgery and brain Metastasis
High cost
Weight-base dosing and renal failure
restrictions
Questionable reversibility
Mechanism of action: Binding to AT III and
inducing the conformational change required for
binding to factor Xa and inactivating it.
Chemically synthetic pentasaccharide
Indirect inhibitor of Xa PK profile:
SELECTIVE Fondaparinux
No effect on thrombin Bioavailability - 100% First selective Factor Xa
No antidote
Clearance - renal Major adverse effects: Inhibitor approved for
FACTOR Xa (Ultra low molecular weight
Half-life - longest out of the Severe bleeding prevention and treatment of
(Protamine sulfate d
heparin) work)
INHIBITOR heparins. Depends on renal deep vein thrombosis
clearance
Mechanism of Action: inhibit thrombin directly and
independently from anti-thrombin by binding to its
active catalytic site and/or its exosite.
Bivalirudin: bivalent agent (catalytic site and
Bivalirudin - clearance: Kidney, Liver,
exosite 1) reversible inhibition;
non-organ
Lepirudin: bivalent agent (catalytic site and
exosite 1) irreversible inhibition;
Argatroban - clearance: Liver
Argatroban: univalent agent (catalytic site)
reversible inhibition.
Pharmacokinetics of Dabigatran:
Dabigatran: univalent agent (catalytic site)
Predictable PK profile;
Lepirudin reversible inhibition. Oral administration
DIRECT Bivalirudin
Allows a fixed-dose regimen;
No need for monitoring; Only Dabigatran has
THROMBIN Argatroban Afinity for thrombin: Lepirudin > bivalirudin >
Half-life 12 hours;
Bleeding Dabigatran is a DOAC
(Idarucizuma
Dabigatran argatroban
INHIBITORS Primarily eliminated via the kidney;
Not metabolized by CYP P450
enzymes;
Drug-drug interactions: Dabigatran
is a substrate of P-glycoprotein
(drugs that also use p-
glycoprotein: digoxin, rivaroxaban,
others)
Mechanism of action: Competitive inhibition of
the vitamin K epoxide reductase component 1
(VKORC1). This leads to a decrease in activation of
vitamin K dependent coagulation factors (II, VII, IX, Pharmacokinetics
Adverse effects
X) as well as protein C and S. Rapidly and completely absorbed
Bleeding/Hemorrhage (bowel or
after oral administration;
brain);
Delayed action: 18-24 h ( (i.e., for 3 to 4 factor Bioavailability: 100%;
Teratogenic effects;
VII half-lives); Small distribution volume; Clinical uses:
Osteoporosis and abnormal bone
High plasma protein binding Primary and secondary
formation;
Onset of action depends on elimination half-lives capacity: 99% (albumin) high prevention of venous
Skin necrosis;
of the Vitamin K-dependent clotting factors: potential of Adverse effects - thromboembolism;
Nausea, vomiting, diarrhea and
Factor II (Prothrombin): 60 h; especially NSAIDs Prevention of systemic
hepatotoxicity;
Factor VII (Proconvertin): 6 h; Peak concentration occurs within embolism in patients
Cholesterol micro-embolization
Factor IX (Stuart factor): 24 h; 60-90 min after administration with prosthetic heart
syndrome (“Purple toe In case of bleeding:
Factor X (Antihemophilic factor B): 40 h. Long elimination half-life: 36-40 valves;
VITAMIN K h (high variability);
syndrome”).
Prevention of stroke,
Withdrawal of the
Warfarin Administration of
Hydroxylated by cytochrome recurrent infarction and
ANTAGONISTS P450 system and eliminated in
Absolute contraindications
death in patients with
+ Fresh frozen pla
Large esophageal varices; PPBS fraction
urine; Potential for drug-drug acute myocardial
Significant thrombocytopenia;
interactions infarction;
Acute clinically significant bleed;
Crosses placenta and appears in Prophylaxis of genetic
Strategies and Targets
1. COX - 1 Aspirin
2. Increase cAMP, in turn increases PKA and intracellular
calcium which inhibits platelet activation
Phosphodiesterase inhibitors + Prostacyclin agonists
3. Inhibition of the ADP dependent pathway through
P1Y12 receptor inhibition Clopidogrel, Prasugrel
4. Prevent fibrinogen binding to GpIIb-IIIa GPIIb-IIIa
receptor
5. Inhibition of thrombin related platelet activation
Inhibition of PAR-1
PHARMACOLOGICAL AGENTS PHARMACODYNAMICS PHARM
Mechanism of action: Irreversible inhibition of COX-1 enzyme mainly in platelets by
covalently binding a serine residue to the enzyme active site
Administration
Indirect properties of aspirin:
Oral: 75 to
Reduction of inflammatory cytokines
Reduction of oxygen radicals
Duration of pl
Reduction of growth factors
Permanen
lifespan)
COX INHIBITORS Acetylsalicylic acid - Aspirin Why is aspirin only given in low doses?
Higher dosage also results in COX-2 inhibition (in other cells other than platelets)
Elimination ha
which decreases both TXA2 and prostacyclin (anti-platelet agents).
15-20 min
When we administer higher dose we loose sensitivity to COX-1 inhibition, meaning
that if we only want anti-platelet effect there is no need for a higher dose.
What about other NSAIDs?
With other NSAIDs the platelet inhibition is not permanent so they are not used as
anti-platelets.
Mechanism of action - Dipyridamol: Inhibition of PDE3 and PDE5 leading to
decreased cAMP degradation. Increased levels of cAMP lead to PKA activation and
decreased intracellular calcium which in turn inhibits platelet activation.
Dipyridamole by itself has only weak antiplatelet effects Administered in
combination with aspirin (secondary long-term prevention of stroke and TIA)
Mechanism of action - Cilostazol: selective inhibition of PDE3A (a subtype of PDE3)
PDE inhibitors
Dipyridamol PDE inhib
ad
PDE INHIBITORS AND Cilostazol
PROSTACYCLIN ANALOG Prostacycl
Prostacyclin analog ad
Iloprost Mechanism of action - Iloprost: activation of adenylate cyclase to increase intra-
platelet cAMP level.
Mechanism of action: They all lead to inhibition of the P1Y12 ADP receptor.
Clopidogrel and prasugrel are both irreversible antagonists of P1Y12.
Clopidogrel requires 2 sequential reactions for activation, this involves several CYP
enzymes which increases the potential for drug-drug interactions
Clopidogrel vs Prasugrel
Prasugrel is more efficiently metabolized inhibits platelet aggregation faster,
more consistently and to a higher degree than Clopidogrel;
Clopidogrel requires a loading dose to achieve maximal antiplatelet effect
rapidly;
Prasugrel causes much fewer drug-drug interactions than clopidogrel,
Prasugrel shows lower inter-individual variability in response to its antiplatelet
activity;
There are 4: Prasugrel is associated with a significantly increased incidence of major adverse
Clopidogrel - Irreversibile bleeding events.
antagonist, prodrug
Prasugrel - Ticagrelor (cyclopentyl-triazolopyrimidine):
Clopidog
ADP RECERPTOR Thienopyridines; prodrug Competitive antagonist at the P2Y12- ADP receptor;
ticagrelor a
PATHWAY INHIBITORS Ticagrelor -Direct acting Does not require metabolic activation;
Cangrelor o
nucleoside; nucleotide Faster, more potent and more predictable antiplatelet effect than Clopidogrel
but slightly less potent than prasugrel;
derivatives
Adverse effects: bleeding (major), dyspnea and bradycardia.
Cangrelor - active drug;
reversible antagonists
Cangrelor (ATP analog):
Reversible inhibitor of the platelet P2Y12- ADP receptor;
Rapid onset of action (steady state= 30 min);
Elimination half-time= 9 min;
Platelet activity rapidly returns to its normal state within 60 min after interruption
, Targets:
Anti-coagulants
AT III
Thrombin (Factor IIa)
Factor Xa
Vitamin K dependent coagulation fac
PHARMACOLOGICAL SIDE EFFECTS +
PHARMACODYNAMICS PHARMACOKINETICS INDICATIONS ANTIDOT
AGENTS CONTRAINDICATIONS
Mechanism of action: Heparins binds to ATIII
working as a catalyzer in the inactivation of factor
Xa and thrombin
Side effects
UFH IIa = Xa (IX, XI, XII)
Bleeding / Hemorrhage
LMWH Xa > IIa UFH:
Heparin-induced
Higher inter-individual availability
thrombocytopenia
IV and subcutaneous Clinical uses
Unfractioned heparin (UFH) Osteoporosis
administration Prophylaxis of
Hypoaldosteronism
Reduced bioavailability thromboembolic diseases
HEPARINS Low molecular weight heparin Higher binding to plasma proteins
(hyperkalaemia)
(venous
Hypersensitivity reactions
(INDIRECT (LMWH) Binding to cell surfaces
(protamine)
thromboembolism);
Protamine Sulfate (M
Reviparin UFH Treatment of deep vein
UFH)
THROMBIN Enoxaparin Monitoring required with aPPT LMWH:
Contraindications:
thrombosis and
Dalteparin sodium Low cost and long history of clinical use Stable and predictable PK pulmonary embolism;
INHIBITORS) Nadroparin calcium Unpredictable anticoagulant effect Subcutaneous administration
Active bleeding, Hemophilia and
Treatment of unstable
Thrombocytopenia;
No renal failure restriction Longer half-life angina and acute
Severe Hypertension;
Reversible Better bioavailability myocardial infarction
Severe hepatic and renal disease;
Lower binding to plasma proteins
Ulcerative lesions in GI tract
LMWH Reduced binding to cell surfaces
Intracranial hemorrhage, recent
Monitoring not required
surgery and brain Metastasis
High cost
Weight-base dosing and renal failure
restrictions
Questionable reversibility
Mechanism of action: Binding to AT III and
inducing the conformational change required for
binding to factor Xa and inactivating it.
Chemically synthetic pentasaccharide
Indirect inhibitor of Xa PK profile:
SELECTIVE Fondaparinux
No effect on thrombin Bioavailability - 100% First selective Factor Xa
No antidote
Clearance - renal Major adverse effects: Inhibitor approved for
FACTOR Xa (Ultra low molecular weight
Half-life - longest out of the Severe bleeding prevention and treatment of
(Protamine sulfate d
heparin) work)
INHIBITOR heparins. Depends on renal deep vein thrombosis
clearance
Mechanism of Action: inhibit thrombin directly and
independently from anti-thrombin by binding to its
active catalytic site and/or its exosite.
Bivalirudin: bivalent agent (catalytic site and
Bivalirudin - clearance: Kidney, Liver,
exosite 1) reversible inhibition;
non-organ
Lepirudin: bivalent agent (catalytic site and
exosite 1) irreversible inhibition;
Argatroban - clearance: Liver
Argatroban: univalent agent (catalytic site)
reversible inhibition.
Pharmacokinetics of Dabigatran:
Dabigatran: univalent agent (catalytic site)
Predictable PK profile;
Lepirudin reversible inhibition. Oral administration
DIRECT Bivalirudin
Allows a fixed-dose regimen;
No need for monitoring; Only Dabigatran has
THROMBIN Argatroban Afinity for thrombin: Lepirudin > bivalirudin >
Half-life 12 hours;
Bleeding Dabigatran is a DOAC
(Idarucizuma
Dabigatran argatroban
INHIBITORS Primarily eliminated via the kidney;
Not metabolized by CYP P450
enzymes;
Drug-drug interactions: Dabigatran
is a substrate of P-glycoprotein
(drugs that also use p-
glycoprotein: digoxin, rivaroxaban,
others)
Mechanism of action: Competitive inhibition of
the vitamin K epoxide reductase component 1
(VKORC1). This leads to a decrease in activation of
vitamin K dependent coagulation factors (II, VII, IX, Pharmacokinetics
Adverse effects
X) as well as protein C and S. Rapidly and completely absorbed
Bleeding/Hemorrhage (bowel or
after oral administration;
brain);
Delayed action: 18-24 h ( (i.e., for 3 to 4 factor Bioavailability: 100%;
Teratogenic effects;
VII half-lives); Small distribution volume; Clinical uses:
Osteoporosis and abnormal bone
High plasma protein binding Primary and secondary
formation;
Onset of action depends on elimination half-lives capacity: 99% (albumin) high prevention of venous
Skin necrosis;
of the Vitamin K-dependent clotting factors: potential of Adverse effects - thromboembolism;
Nausea, vomiting, diarrhea and
Factor II (Prothrombin): 60 h; especially NSAIDs Prevention of systemic
hepatotoxicity;
Factor VII (Proconvertin): 6 h; Peak concentration occurs within embolism in patients
Cholesterol micro-embolization
Factor IX (Stuart factor): 24 h; 60-90 min after administration with prosthetic heart
syndrome (“Purple toe In case of bleeding:
Factor X (Antihemophilic factor B): 40 h. Long elimination half-life: 36-40 valves;
VITAMIN K h (high variability);
syndrome”).
Prevention of stroke,
Withdrawal of the
Warfarin Administration of
Hydroxylated by cytochrome recurrent infarction and
ANTAGONISTS P450 system and eliminated in
Absolute contraindications
death in patients with
+ Fresh frozen pla
Large esophageal varices; PPBS fraction
urine; Potential for drug-drug acute myocardial
Significant thrombocytopenia;
interactions infarction;
Acute clinically significant bleed;
Crosses placenta and appears in Prophylaxis of genetic
