Antiplatelets

1. Antiplatelets and Fibrinolytics
NUR 652-Pharmacologic
Applications in Primary Care
Mikael D. Jones, Pharm.D., BCPS

2. Introduction
• Antiplatelet agents are used both prophylactically
and acutely in the setting of ACS to inhibit platelet
activation and/or aggregation
• 4 main classes of antiplatelet drugs:
– Cyclooxygenase (COX-1) Inhibitors
• ASA is prototype and only one used
– Phosphodiesterase (PDE) inhibitors
• dipyridamole is prototype
– ADP receptor antagonists
• clopidogrel, prasugrel, ticagrelor
– GPIIb/IIIa receptor inhibitors
• Abciximab, eptifibatide, tirofiban

4. Wh ite HD. Am J C ar diol. 1 99 7; 80 (4 A): 2B- 10 B.
Mechanism of action for platelet activation

5. TxA2
Receptor
AA
PGH2
TXA2
COX-1
aspirin
Clopidogrel, Prasugrel, Ticagrelor
Eptifibatide and Abciximab

6. Antiplatelet Drugs
Endothelium
Arachidonic Acid
Cyclooxygenase
(COX-1)
cyclic endoperoxides
prostacyclin synthase
Prostacyclin
(PGI2)
Platelet
IP receptor
adenylyl cyclase
á cAMP
AMP
Phosphodiesterase
(PDE)
phospholipase A2
Arachidonic Acid
COX-1
cyclic endoperoxides
thromboxane synthase
thromboxane A2
(TXA2)
Platelet
activation
Platelet
inhibition
stimulus

7. Aspirin
• Mechanism of Action:
– Irreversibly blocks cyclooxygenase (COX-1)
activity by acetylating the enzyme
– Prevents the conversion of arachidonic acid to
TXA2 in platelets
• TXA2 promotes platelet aggregation and
vasoconstriction
– Platelet-induced TXA2 synthesis is blocked
for the life of the platelet (7-10 days)

8. Aspirin
• Mechanism of Action:
– COX-1 inhibition also prevents the
formation of PGI2 in vascular endothelium
• PGI2 promotes vasodilation and inhibits platelet
aggregation
• endothelium can regenerate COX-1 restoring
PGI2 production within hours
– net result is that aspirin preferentially
inhibits TXA2 rather than PGI2, favoring
vasodilation and inhibition of platelet
aggregation
– Aspirin does not inhibit platelet adherence

9. Aspirin
• Indications:
– UA/NQWMI
– Prevention of MI
– H/O thrombotic stroke or transient ischemic
attacks (TIAs)
– Alternative to warfarin to prevent thrombosis in
certain populations of patients with atrial fibrillation
– Intermittent claudication
– Antipyretic, analgesic and anti-inflammatory
– Chemoprevention of colon cancer
– Kawasaki’s Disease

10. Aspirin
• Dosing of aspirin:
– Recommended dose varies depending on
indication
– Antiplatelet doses range from 81-325
mg/day
• usual dose for ACS, acute MI, etc is 325 mg
given immediately upon symptoms
• prophylactic dose ranges from 81 - 325 mg
daily
• higher doses may decrease effectiveness due
to decreased ability to regenerate PGI2

11. Aspirin
• Dosing of aspirin:
– 325 mg daily for chemoprevention
– Higher doses used for anti-inflammatory,
analgesic and antipyretic indications

12. Aspirin
• Adverse effects of ASA occur in
response to PG and TX inhibition and
are dose-dependent:
– GI effects (due to PGE2 inhibition)
• abdominal pain
• heartburn
• nausea
• GI ulceration and bleeding
– enteric coated products and buffered
products may decrease GI symptoms

13. Aspirin
• Adverse effects of ASA occur in
response to PG and TX inhibition and
are dose-dependent:
– Bleeding (due to inhibition of TXA2)
• d/c 7 days prior to elective surgery
– Renal dysfunction (due to inhibition of renal
PGs)
• progressive dysfunction with chronic use
– Exacerbation of asthma (due to shifting of
AA metabolism to lipoxygenase pathway)
• increases LT formation which are known
inflammatory mediators in asthma

14. Aspirin
• Other adverse effects:
– tinnitus, headache, dizziness, confusion,
hearing loss and metabolic acidosis due to
salicylate toxicity
– hypersensitivity reactions ranging from
rash to angioedema to anaphylaxis
– Reye syndrome
• do not administer to children under the age of
16
– Avoid during pregnancy (esp. during 3rd
trimester)
• prolonged labor, increased risk for antepartum
and postpartum hemorrhage

15. Aspirin
• Drug interactions:
– NSAIDs: increased risk for bleeding
– warfarin: increased risk for bleeding
– other antiplatelets: increased risk for
bleeding
– plasma protein binding displacement
interactions:
• variable depending on specific medications
taken concurrently
– valproic acid
– tolazamide
– tolbutamide

16. Dipyridamole (Persantine)
• Mechanism of Action:
– inhibits cyclic nucleotide phosphodiesterase
(PDE) which causes cAMP breakdown
• results in increased cAMP and inhibition of
platelet aggregation
• increased cAMP also results in vasodilation
– blocks adenosine uptake into cells
• A2 receptors stimulate platelet adenylate cyclase
and inhibit platelet activation

17. Dipyridamole (Persantine)
• Clinical use:
– adjunct to coumarin anticoagulants
(warfarin) in patients with prosthetic heart
valves who cannot take aspirin
– cardiac stress testing
• use for this indication declining as adenosine is
being used

18. Dipyridamole (Persantine)
• Usual dose:
– 75-100 mg four times daily (PO)
• Adverse effects:
– exacerbation of angina following IV
administration during stress testing
– hypotension (IV)
– GI upset (PO)
– dizziness (PO)

19. Dipyridamole (Persantine)
• Drug interactions:
– increased risk for bleeding when given in
combination with ASA and other antiplatelets
or anticoagulants
– theophylline
• patients on theophylline may require higher
doses of dipyridamole during stress testing (hold
theo for 36 hours prior to test)

20. Dipyridamole/ASA combination
(Aggrenox)
• Aggrenox is combination of 25 mg aspirin and
200 mg dipyridamole in a sustained release
formulation to be taken twice daily
• Approved for use to reduce the risk of stroke in
patients with TIAs or with history of thrombotic
stroke
• Adverse effects and drug interactions are a
combination of those seen with ASA and
dipyridamole individually

21. Cilostazol (Pletal)
• A quinolinone derivative
• MOA:
– inhibits cellular phosphodiesterase, particularly
phosphodiesterase III (PDE III) leading to
increased levels of cAMP
• cAMP causes vasodilation and inhibition of platelet
aggregation
• Clinical use:
– Indicated to reduce symptoms of intermittent
claudication (increases walking distance)

22. Cilostazol (Pletal)
• Contraindications:
– CHF of any severity (other oral
phosphodiesterase inhibitors have
been shown to increase mortality in
patients with CHF
– hypersensitivity to any components
of the product

23. Cilostazol (Pletal)
• Drug Interactions:
– Cilostazol could have pharmacokinetic
interactions because of effects of other
drugs on its metabolism by CYP3A4 (eg,
erythromycin, ketoconazole) or CYP2C19
(eg, omeprazole)
– Platelet function inhibitors: Cilostazol
could have pharmacodynamic
interactions with other platelet function
inhibitors including aspirin, ticlodipine or
clopidrogel

24. Cilostazol (Pletal)
• Usual dose:
– 100mg PO BID 1/2 hour before, or
two hours after meals
– decrease to 50mg PO BID if given
concurrently with CYP inhibitors

25. Cilostazol (Pletal)
• Adverse Effects:
– headache
– diarrhea
– palpitations
– CHF has been reported with other
PDE III inhibitors; contraindicated
for use in patients with CHF

26. ADP Antagonists
(Thienopyridines)
• Clopidogrel, Prasugrel, Ticagrelor
• MOA:
- inhibit platelet aggregation by inhibiting ADP-
induced platelet fibrinogen binding (this links
platelets together to form aggregates or
“plugs”)
- Clopidogrel and Prasugrel are irreversible
inhibitors
- Ticagrelor is reversible
- Antiplatelet effect takes 24-48 hours to
develop ; Loading dose employed

27. ADP Antagonists
(Thienopyridines)
• Dosing of Plavix:
– Loading Doses are used to decrease the time to maximal
platelet inhibition
• 75 mg po QD takes 7 days for maximal effect
• 300mg po X1 before PCI takes 6-10 hours for maximal effect
• 600mg po x1 before PCI takes 2 hours for maximal
– Maintenance Dose
• 75 mg po qd
– requires transformation by the liver
– following oral administration, the time to peak concentration is
about 2 hours
– the effect of clopidogrel continues for several days after
discontinuing the drug

28. ADP Antagonists
(Thienopyridines)
• Adverse effects:
– both can cause GI upset, diarrhea and rash
• Drug Interactions:
– CYP 2C19 inhibitors may decrease
effectiveness because decreased conversion
to active metabolite

29. ADP Antagonists
(Thienopyridines)
• Contraindications:
– Plavix:
• known hypersensitivity
• active pathological bleeding such as peptic ulcer or
intracranial hemorrhage

30. ADP Antagonists
(Thienopyridines)
• Prasugrel (Effient™)
– NewerADP antagonist
– FDA indications
• Reduces rate of thrombotic cardiovascular events
(eg, stent thrombosis) in patients with unstable
angina, non-ST-segment elevation MI, or ST-
elevation MI (STEMI) managed with percutaneous
coronary intervention (PCI)

31. ADP Antagonists
(Thienopyridines)
• Prasugrel (Effient™)
– Dosing
• Loading Dose 60mg
• Maintenance Dose 10mg (in combination with
Aspirin 81-325mg/day)
– Adverse effects similar to other
Thienopyridines
• Bleeding risks may be higher for certain patient
populations (see warnings)

32. ADP Antagonists
(Thienopyridines)
• Prasugrel (Effient™)
– Contraindications
• Peptic Ulcer disease
• Intracranial hemmorrahge
• TIA/Stroke
– Warnings
• Bleeding risk increased in patients ≥75, <60kg,
recent CABG or other surgical procedure,
concomitant use of Warfarin, NSAIDS
• D/c ≥7 days before CABG and avoid in patients
with probable need for CABG

33. ADP Antagonists
(Thienopyridines)
• Ticagrelor (Brilinta™)
– Newest ADP antagonist
– FDA indications
• ACS (with aspirin)-Reduces risk of cv death, MI,
stroke and stent thrombosis
– Dosing
• Loading Dose 180mg
• Maintenance Dose 90mg BID (in combination with
Aspirin 81mg/day)
– Do not use a higher dose of aspirin as it reduces
effectiveness

34. ADP Antagonists
(Thienopyridines)
• Ticagrelor (Brilinta™)
– Drug Interactions
• Avoid with strong CYP 3A4 inhibitors
– Adverse effects
• Bleeding
• Bradycardia, dyspnea, gynecomastia in men

35. ADP Antagonists
(Thienopyridines)
• Ticagrelor (Brilinta™)
– Contraindications
• Peptic Ulcer disease
• Intracranial hemmorrahge
• Severe hepatic impairment
– Warnings
• ↑Risk of bleeding in patients with advanced age,
invasive procedures, and use of medications that
increase bleeding risk and moderate hepatic
impairment.
• stopped five days before surgery if possible. B

36. GPIIb/IIIa Inhibitors
• Includes the agents tirofiban (Aggrastat) and
eptifibatide (Integrilin)
• both are antagonists of the platelet glycoprotein (GP)
IIb/IIIa receptor - the major platelet surface receptor
involved in platelet aggregation
• both inhibit ex vivo platelet aggregation in a dose-
and concentration-dependent manner
• to be effective, > 90% of these receptors have to be blocked
• Potent antithrombotic effects and has been shown to
decrease mortality and reinfarction

37. GPIIb/IIIa Inhibitors
• Clinical Use:
– Indicated for use in acute coronary syndrome,
including patients who are to be managed
medically and those undergoing percutaneous
coronary intervention (PCI)
• PCI (balloon angioplasty or stent placement) is
associated with acute and late (3-6 month) occlusion
• acute occlusion is reduced by antiplatelet agents started
before the procedure and heparin during and after the
procedure
• late stenosis does not improve with antiplatelet agents
(may improve with new drug eluting stents)

38. GPIIb/IIIa Inhibitors
• Clinical Use:
– Used as adjunct to PCI for the prevention
of acute cardiac ischemic complication in
patients that are high risk for abrupt
closure of the treated coronary artery
– Patients with UA/MSTEMI not responding
to medical therapy when PCI is planned
within 24 hours

39. GPIIb/IIIa Inhibitors
• Clinical Use:
– Integrilin has broadest indications for use:
• Elective, urgent or emergency PCI
• Patients with UA/NQMI who are medically
managed and those undergoing PCI
– Aggrastat is not used in elective, urgent or
emergency PCI
• Higher doses are being studied to see if this
improves efficacy

40. GPIIb/IIIa Inhibitors
• Dosing of Aggrastat:
– Loading infusion rate (0.4 mg/kg/min for 30
min.) followed by maintenance infusion
rate (0.1 mg/kg/min)
– Larger margin of safety than Reopro
• Reversible platelet aggregation due to short
half-life (2 hours)
• Platelet function is restored toward baseline
(<50% inhibition) within 4 hours after infusion.
– Used in combination with aspirin and
heparin

41. GPIIb/IIIa Inhibitors
• Dosing of Integrilin
– Bolus and constant infusion rate based on
indication and patient characteristics
• weight, serum creatinine
• see protocol
– Reversible following cessation of infusion
(half-life 2.5 hour)
– originally intended for use with ASA &
heparin
• Reevaluation of the PURSUIT Trial (March 2001)
suggests that monotherapy with eptifibatide is
reasonable (although most everyone continues to
receive combination therapy)

42. GPIIb/IIIa Inhibitors
• Adverse Reactions:
– High incidence of bleeding
– thrombocytopenia (less than with Reopro)

43. Abciximab (Reopro)
• MOA:
– Fab fragment of a human-murine
monoclonal antibody that binds to the
platelet glycoprotein (GP) IIb/IIIa receptor
leading to inhibition of platelet aggregation

44. Abciximab (Reopro)
• Clinical Use:
– Used as an adjunct to percutaneous transluminal
angioplasty (PCTA) for the prevention of acute
cardiac ischemic complications in patients at high
risk for abrupt closure of the treated coronary
vessel
– Patients with UA/NQMI not responding to medical
therapy when PCI is planned within 24 hours
– Abciximab use in patients with UA or NQWMI not
undergoing PCI shows no significant benefit
(GUSTO trial)

45. Abciximab (Reopro)
• Dosing:
– Low margin of safety
• long half-life affects platelet function for 12-24
hours after infusion
• no antidote for over-dose
– abciximab is used with aspirin and heparin
– usual dose is 0.25 mg/kg via I.V. bolus
given 10-60 minutes before the start of
PCI, followed by continuous infusion (10
mcg/min) for 12 hours

46. Abciximab (Reopro)
• Adverse Reactions:
– Bleeding
– Formation of antibodies occurs in up to
6.5% of patients; percentage increases
with repeated use
– Anaphylaxis has NOT been reported
– Severe thrombocytopenia occurs with
repeat exposure

47. Fibrinolytics

48. Introduction
• Physiological fibrinolysis/thrombolysis:
– Fibrin clots are dissolved endogenously by
the action of plasmin, a proteolytic enzyme
formed by the cleavage of the plasma protein
plasminogen
– Plasminogen is activated endogenously by
tissue plasminogen activator (tPA) which is
released from endothelial cells
– tPA binds preferentially to the plasminogen
bound to fibrin and activates it with less effect
on circulating plasminogen

49. Introduction
• Fibrinolytic drugs, sometimes called “clot
busters” are used to dissolve fibrin clots
whenever the presence of a clot causes
imminent danger to the patient
– Acute treatment of myocardial infarction is the
primary indication for these agents
– Also used in the setting of thrombotic stroke,
PE and for catheter patency
• The earlier the drug is given to dissolve
the blockage in the vessel, the better the
patient prognosis

50. Introduction
• Best outcome occurs with drug
administration within one hour of onset
• Protocols allow administration of the
fibrinolytic agent up to six hours from the
onset of MI
• Risk of hemorrhage with these drugs is
great, even more than with antiplatelet and
anticoagulant agents

51. Introduction
• Available fibrinolytic drugs include:
–streptokinase (Kabikinase, Streptase)
–anistreplase (anisoylated streptokinase
activator complex; APSAC; Eminase)
–urokinase (Abbokinase)
–tissue plasminogen activator (tPA;
alteplase, Activase)
–reteplase (Retevase)

52. Streptokinase
• (Kabikinase, Streptase):
– enzyme derived from beta hemolytic streptococcus
– forms a complex with plasminogen via 1:1 stable,
noncovalent binding to induce a conformational
change that exposes the active site of plasminogen
leading to its activation
– administered by IV infusion, intracoronary infusion
and into occluded cannulae
– available as powder for injection; dosed in
international units

53. Streptokinase
• Indications:
– acute evolving transmural MI, DVT, arterial
embolism and occluded AV cannulae
• Adverse effects:
– Allergic reactions including bronchospasm,
breathing difficulty, itching, rash, flushing
– Hemorrhage
• Least expensive of the treatment
alternatives

54. Anistreplase
• A complex of streptokinase and
plasminogen with the catalytic center of
the complex blocked by an anisoyl group
• deacylation of the complex occurs in vivo ;
half-life of fibrinolytic activity is
approximately 94 minutes compared to 23
minutes for streptokinase alone
• administered by IV injection over 2-5
minutes in a dose of 30 units

55. Anistreplase
• Indications:
– indicated for management of acute
myocardial infarction
• Adverse effects:
– hemorrhage

56. Urokinase
• Acts directly on plasminogen to
enzymatically activate it to plasmin
• administered similarly to streptokinase
• protein is of human origin from urine or
kidney cell cultures
• not as antigenic as streptokinase
• considerably more expensive than
streptokinase

57. Urokinase
• Indications:
– PE
– coronary artery thrombosis
– IV catheter clearance
• Adverse effects
– hemorrhage
– allergic reactions

58. Tissue plasminogen activator
• genetically engineered version of human
tPA
• 100-fold more potent at activating
plasminogen bound to fibrin than
circulating plasminogen
• should limit the risk of widespread
fibrinolysis and hemorrhage
• cleared by hepatic metabolism with a half-
life of 5-10 minutes

59. Tissue plasminogen activator
• Indications:
– indicated for acute MI
– more recently approved for treatment of acute
ischemic stroke within 3 hours of onset of
symptoms
• Adverse effects:
– hemorrhage

60. tPA-absolute contraindications
• > 3 hours onset of sxs
(stroke indication)
• Sustained BO
>185/100
• Hx of intracranial
neoplasm, AVM,
Aneurysm, or
intracranial
hemorrhage
• Active internal
bleeding
• Gl bleeding with/in 21
days
• Recent MI
• Major surgery w/in 14
days

61. tPA-absolute contraindications
• Platelets <100,000
• Glucose <50 or >400
• Elevated aPTT or PT/INR
• Prior stroke w/in 90 days
• Prior Head traum w/in 90 days

62. Reteplase
• recombinant fibrinolytic agent
• advantage over tPA is the dosing regimen
• two injections of 10 units injected over a
two minute period with the second
injection 30 minutes after the first are
given rather than continuous IV infusion
with tPA
• cost is similar between the two

63. Tenecteplase (TNKase)
• Fibrinolytic agent indicated for acute MI
• Dosing
– Advatange over tPa
– Single bolus over 5 seconds
– Dose dependent upon weight
• Max 50mg
• <60kg give 30mg
• Add 5mg for every 10kg (max 50mg)
• Contraindications, ADRs, costs the same as
other agents

64. Aminocaproic acid (Amicar)
• fibrinolytic antagonist
• inhibits plasminogen activator substances
• used to treat excessive bleeding due to
hyperfibrinolysis
• can be given orally or IV
• dosing regimen is 5 grams to start and 1-
1.25 grams hourly; continue for up to 8
hours or until bleeding is controlled