Last edited: 9/25/2021

1. ANTI-PLATELET MEDICATIONS
Anti-platelet Medications | Mechanism of Action, Medical Editor: Abigail S. Xu, RPh
Indications, Adverse Reactions, Contraindications

OUTLINE
(A) TXA2 SYNTHESIS INHIBITORS
I) MECHANISM OF ACTION
II) INDICATIONS
III) ADVERSE DRUG REACTIONS (ADRS)
IV) CONTRAINDICATIONS
V) REVIEW QUESTIONS
VI) REFERENCES

I) MECHANISM OF ACTION

Hemostasis Overview

Endothelial Cells
● line the inner portion of blood vessels
● release chemicals such as PGI2 and Nitric Oxide (NO) Figure 2. TXA2 Synthesis
that inactivate platelets to keep blood antithrombotic
● damaged vessel lining → ↓PGI2 and NO → ↓inhibition of TXA2 Roles
platelet → ↑platelet that attach to endothelial lining ● Activate Gq pathway → activate Phospholipase C (PLC)
→ break down PIP2 into IP3 and DAG
von Willebrand Factor (vWF)
Inositol Triphosphate (IP3)
● proteins that attach to the exposed collagen following o Binds to endoplasmic reticulum-like network and
endothelial damage stimulate protein channel to shuttle out Ca2+
● made by endothelial cells and platelets o Shuttled out Ca2+ stimulates degranulation →
release of ADP, 5HT, Ca2+, TXA2 → ↑platelet
Glycoprotein Ib (GPIb) aggregation
● binds platelet to VWF Diacylglycerol (DAG)
o activate Protein Kinase C (PKC) → stimulate GP
Delta/ Dense granules
IIb/IIIa → stabilize platelet plug
● release platelet aggregation agents that call other
platelets to the injured site Drug that Inhibits TXA2 Synthesis
o Serotonin (5HT) Aspirin (ASA)
o ADP
o Ca2+ ● irreversibly inhibits cyclooxygenase (COX) 1 and 2 that
o Thromboxane A2 (TXA2) are responsible for the conversion of arachidonic acid to
PGG2, ultimately leading to decrease in TXA2 production
Glycoprotein IIb/IIIa (GP IIb/IIIa) → ↓platelet aggregation & ↓stability of platelet plug
● protein complex on the surface of platelets [Trevor, Katzung, & (B) ADP RECEPTOR INHIBITORS
Kruidering-Hall, 2015]
● when activated, aggregates platelets by binding to fibrin ADP Roles
[Trevor, Katzung, & Kruidering-Hall, 2015]
a. bind to P2Y12 receptor on platelet surface → activate
Gi pathway → inhibit adenylate cyclase (AC) →↓ATP
→↓cAMP → ↓PKA → ↓phosphorylation of VASP into
inactive form → ↑active VASP → ↑stimulation of GP
IIb/IIIa → ↑platelet plug stability

Adenylate cyclase
o responsible for the conversion of ATP into cyclic
AMP (cAMP); cAMP will then activate protein
kinase A (PKA) that will phosphorylate active
vasodilator stimulatory protein (VASP) into the
inactive VASP-P
VASP (active)
o stimulate GP IIb/IIIa → ↑platelet plug stability

Figure 1. Summary of Thrombus Formation and Mechanism of b. bind to P2Y12 receptor on platelet surface → activate
Action of Antiplatelet Medications Gq pathway → activate Phospholipase C (PLC) →
[Trevor, Katzung, & Kruidering-Hall, 2015, p. 281, Fig. 34-3] break down PIP2 into IP3 and DAG (see discussion on
Gq in TXA2)

anti-platelet medications CARDIOVASCULAR PHARMACOLOGY: Note #1. 1 of 4

Drugs that block ADP receptor Potency of drugs (Most potent to least potent)
● block P2Y12 receptor leading to inhibition of Gi and Gq Abciximab
pathways, ultimately leading to decreased platelet o only give to high-risk patients
aggregation and inhibition of GPIIb/IIIa o not commonly given since GPIIb/IIIa Inhibitors has the
● Thienopyridine Derivatives highest bleeding risk
o Converted in the liver to active metabolites that Prasugrel
irreversibly inhibit ADP receptor [Trevor, Katzung, & Kruidering- o black box warning for bleeding
Ticagrelor
Hall, 2015]
o Clopidogrel (Plavix) o commonly used
o Prasugrel (Effient) Clopidogrel
o Ticlopidine – not commonly used anymore due to o commonly used
adverse drug reactions (ADRs) o has risk of Thrombotic Thrombocytopenic Purpura
(TPP)
● Non-thienopyridine o some individuals may be poor metabolizers due to
o Does not require activation and reversibly inhibit ADP CYP2C19 mutation
receptor [Trevor, Katzung, & Kruidering-Hall, 2015] Aspirin
o Ticagrelor (Brilinta) o Least bleeding risk
(C) GPIIB/IIIA INHIBITORS Usual drug combos used in Percutaneous Coronary
● Inhibit GP IIb/IIIa interaction → ↓stability of platelet plug Intervention (PCI)
o Abciximab o Long-term/ Post-PCI: ASA + Clopidogrel
o Pre-PCI: ASA + Ticagrelor
o Tirofiban
o High-Risk Patients Pre-PCI: ASA + Abciximab
o Eptifibatide

(D) PHOSPHODIESTERASE-3 (PDE-3) INHIBITORS (B) CEREBROVASCULAR ACCIDENTS (CVA)

● Inhibit PDE-3 (enzyme that breaks down cAMP) ● Blood clots in brain, stroke
o ↓cAMP breakdown → ↑cAMP → ↑PKA → ● ASA + Clopidogrel (given 3-4.5 hours post-CVA)
↑phosphorylation of VASP →↓VASP active →
Important!
inhibition of GPIIb/IIIa During first 3-4.5 hours of CVA
o Cilostazol o give tPA (tissue plasminogen activator)
o Dipyridamole
(C) CAROTID ARTERY STENTING (PRE AND POST)
Other Mechanism and Use of PDE-3 Inhibitors
● Drug Combination: ASA + Clopidogrel
● cause smooth muscle relaxation → dilate blood vessel →
↑ blood flow (D) CORONARY ARTERY DISEASE PROPHYLAXIS
● Use: Peripheral Artery Disease
● ASA can prevent another MI or CVA
● Mechanism:
o Normal Physiology (E) GIANT CELL ARTERITIS
 In smooth muscles, adenosine binds to its
● Inflammation of temporal arteries (vasculitis) increases
receptor and activate Gs → activates AC, which
risk of developing clots that can block the temporal artery
converts ATP to cAMP → activate PKA →
branches, such as ophthalmic artery and arteries that
phosphorylate myosin light chain kinase (MLCK)
supply muscles for mastication, leading to pain in
to its inactivated form MLCK-P → no smooth
temples, vision loss, or jaw claudication
muscle contraction
● Drug: ASA
o Cilostazol and Dipyridamole
 inhibit PDE-3 → ↓ cAMP breakdown → ↑ cAMP → (F) PERIPHERAL ARTERY DISEASE (PAD)
↑PKA →↑phosphorylation of MLCK → inhibition of
● Plaques or clots in the vessels of the leg occlude blood
smooth muscle contraction → smooth muscle
flow to the surrounding muscles leading to development
relaxation → blood vessel dilation
of ulcers, gangrene, or claudication due to decreased
II) INDICATIONS oxygen supply
● Drug Combination: ASA + Cilostazol
(A) ACUTE CORONARY SYNDROME (ACS)
(G) PROPHYLAXIS OF COLORECTAL CANCER
● Thrombus or blockade in the myocardial blood vessels (LYNCH SYNDROME)
● Types of ACS
● ASA decrease risk of Colorectal cancer (especially Lynch
Unstable Angina
Syndrome)
Non-ST Elevated Myocardial Infarction (NSTEMI)
● Lynch Syndrome: tumors that form in different parts of
ST Elevated Myocardial Infarction (STEMI)
body (colorectal, endometrial, ovarian, renal, pancreatic)
Drug Combinations for ACS
(H) STRESS TEST
● ASA + Clopidogrel/ Prasugrel/ Ticagrelor/
● Assessment of myocardial perfusion in CAD is usually
*Abciximab (*only for high-risk patients)
done by exercise-induced stress test. If the patient
cannot exercise, Dipyridamole can be used.
High-risk patients ● Dipyridamole dilates myocardial vessels to see perfusion
o >75 y/o via imaging techniques. Dipyridamole increases blood
o Diabetic flow of normal vessels, but stenotic vessels are not
o ST segment deviations
dilated.
o ↑↑Troponin
o Left Ventricular Ejection Fraction (LVEF) <40% Important Dosage to Remember:
o Pulmonary Edema ASA
o ACS: 325mg ASA chewed then swallowed
o CAD Prophylaxis: 80mg ASA/ day
Clopidogrel
o Loading dose of 300 mg, then 75mg/day

2 of 4 CARDIOVASCULAR PHARMACOLOGY: Note #1. . anti-platelet medications

 III) ADVERSE DRUG REACTIONS (ADRS) ● If Salicylates (i.e., ASA) are given to patient:
o Salicylates get metabolized by enzymes in the hepatic
(A) BLEEDING mitochondria, producing metabolites that inhibit β-
oxidation, leading to ↓Acetyl-CoA → ↓NADH and
Anterior Epistaxis – nosebleed
FADH2 → ↓ATP production
Gingival bleeding – bleeding in gums
Bleeding indications on skin ● Viral infections:
a. Petechiae – pinpoint hemorrhage on skin o Viruses increase metabolism of salicylates →
b. Purpura – larger pinpoint hemorrhaging ↑salicylate metabolites → ↑ inhibition of β-oxidation →
c. Ecchymosis – large bruising → → ↓ATP → ↓cell function → cell death
Hematemesis- vomiting blood ● Detoxification in Liver
Melena – upper GI bleed – dark or black feces o Amino Acids can be degraded in the liver, forming
Hematochezia – lower GI bleed – red stool ammonia (NH3) as a product.
Excessive Vaginal/Uterine Bleeding o NH3 is then metabolized and excreted via the Urea
cycle in the hepatic mitochondria.
Monitoring patients o If there is liver failure (i.e., due to giving salicylates
● Look for signs of bleeding (physical exam) during viral infections), the liver would not be able to
● CBC to check for anemia metabolize ammonia via the Urea cycle.
● Hemoccult to check for GI bleed  ↑ NH3 in blood → NH3 into CNS → NH3 converts
glutamate into glutamine in the astrocytes →
(B) THROMBOTIC THROMBOCYTOPENIC PURPURA astrocytes become osmotically active → swelling
(TTP) → Encephalopathy
● Syndrome characterized by formation of small thrombi, Signs and Symptoms of Encephalopathy
platelet consumption and thrombocytopenia [Trevor, Katzung, & o Vomiting
Kruidering-Hall, 2015] o Fatigue
● Associated with Ticlopidine and Clopidogrel use o Seizures
o Coma
Mechanism: o Delirium
● Normal Physiology: VWF monomers fuse together
Reye Syndrome Triad
forming multimers. Multimers can be broken down again
into monomers via ADAMS T13 enzyme. ● <19y/o, febrile (possibly due to viral infection)
● Effect of Anti-platelets (i.e., Ticlopidine and Clopidogrel) ● Liver Damage (↑AST/ALT)
o ↓ ADAMS T13 level → ↑VWF multimers → platelets ● Signs of Encephalopathy
will stick to the multimers → ↑clots and ↓platelets
Remember:
(since they are consumed in the formation of clots) Aspirin increases the risk for Reye’s syndrome, so giving
Conditions or Medications that ↓ADAMS T13 ASA to <19y/o febrile patients is contraindicated.
o Antiplatelet medications (Ticlopidine, Clopidogrel)
o Lupus
o Chemotherapy (Gemcitabine, Cyclosporine) (B) THROMBOCYTOPENIA
Signs and Symptoms of TTP (“FAT-RN”) ● Low platelet count (<100,000)
● Fever (> 100.4 ⁰F) ● Contraindicated especially in GPIIb/IIIa inhibitors i.e.,
● Hemolytic Anemia due to breakdown of RBC Abciximab
o ↑LDH, ↑Bilirubin, ↓Haptoglobin (C) UNCONTROLLED BLOOD PRESSURE/
● Thrombocytopenia ↓platelets AORTIC DISSECTION
● Renal damage ● High BP can tear tunica intima of blood vessels → aortic
o Basic Metabolic Panel (BMP) ↑Creatinine, ↑BUN dissection → ↑ bleeding risk
● Neurological Damage
(D) BLEEDING
o Headache
o Confusion ● GI bleed, perforated peptic ulcer
● Subarachnoid hemorrhage
Treatment of TTP
(E) TRAUMA/ SURGERY
● Plasmapheresis: clean blood by removing different
substances V) REVIEW QUESTIONS
● Steroids to ↓inflammatory response
● Rituximab Which of the following is a GP IIb/IIIa inhibitor?
a. Clopidogrel
IV) CONTRAINDICATIONS b. Aspirin
c. Ticlopidine
(A) <19Y/O + FEVER d. Abciximab
RISK OF DEVELOPING REYE SYNDROME
● Never give ASA Which drug can be used in cardiac stress test?
Mechanism: a. Tirofiban
b. Dipyridamole
● Normal Physiology: c. Prasugrel
o Hepatic mitochondria break down free fatty acids into d. Eptifibatide
acetyl-CoA via β-oxidation. Acetyl-CoA goes into the
Krebs Cycle forming NADH and FADH2 that
stimulates the electron transport chain (ETC) to make What is the mechanism of action of Aspirin?
ATP. a. Inhibits PDE-3
b. Blocks P2Y12 receptor
c. Inhibits COX-1 and COX-2
d. Inhibit GP IIb/IIIa

anti-platelet medications CARDIOVASCULAR PHARMACOLOGY: Note #1. 3 of 4

 What enzyme metabolizes Clopidogrel?
a. CYP2C19
b. ADAMS T13
c. PDE-3
d. Adenylyl cyclase

What is given to patients suffering from CVA during

the first 3 to 4.5 hours?
a. Aspirin
b. Clopidogrel
c. tPA
d. Ticlopidine
Which enzyme is responsible for the conversion of
ATP into cAMP?
a. Phospholipase C
b. Adenylate Cyclase
c. PDE-3
d. Protein Kinase A

Which drug is contraindicated in children with fever

since it increases the risk of developing Reye’s
syndrome?
a. Clopidogrel
b. Paracetamol
c. Aspirin
d. Tylenol

Which of the following is given only in high-risk ACS

patients?
a. Aspirin
b. Clopidogrel
c. Abciximab
d. Cilostazol

Loading dose of Clopidogrel

a. 325 mg
b. 300 mg
c. 80 mg
d. 75 mg

Which can be used for Peripheral Artery Disease?

a. Cilostazol
b. Abciximab
c. Tirofiban
d. Clopidogrel

CHECK YOUR ANSWERS

VI) REFERENCES
● Trevor, A., Katzung, B., & Kruidering-Hall, M. (2015). Katzung &
Trevor’s Pharmacology Examination & Board Review. McGraw Hill
Education

4 of 4 CARDIOVASCULAR PHARMACOLOGY: Note #1. . anti-platelet medications