Antiplatelet

Prajogo Wibowo
 ASPIRIN
• Acetylsalicylic acid, ASA
Mechanism of Action:
• aspirin (acetylsalicylic acid) acetylates a serine
residue in the active sites for both COX-1 &
COX-2, which irreversibly inhibits these
enzymes
• Low doses of aspirin selectively inhibit COX-1. The
effect on platelet COX-1 activity is permanent for the
lifetime of the platelet, since platelets lack DNA and
cannot synthesize new enzyme. This enables the use of
low dose aspirin as a selective antiplatelet drug
• At higher doses, aspirin inhibits both isoforms of COX.
• The combination of COX-1 & (at higher doses) COX-2
inhibition are the molecular basis for aspirin's
analgesic, antipyretic & anti-inflammatory effects.
Indications:
• Anti-inflammatory. Aspirin interferes with the chemical mediators
of the kallikrein system, thus inhibiting granulocyte adherence to
damaged vasculature, stabilizing lysosomes, and inhibiting the
chemotaxis of PMN leukocytes and macrophages.
• Analgesia. Aspirin is effective in reducing pain of mild to moderate
intensity through its effects on inflammation and probably because
it inhibits pain stimuli at a subcortical (central) site. It is not
effective for severe visceral pain.
• Antipyretic. Aspirin reduces elevated body temperature (but it has
little effect on body temperature in normal healthy patients). This
effect is probably mediated by both COX inhibition in the CNS and
inhibition of IL-1 (which is released by macrophages during
episodes of inflammation).
• Antiplatelet Effects. Single low doses of aspirin (81 mg daily)
produce a slightly prolonged bleeding time, which doubles if
administration is continued for a week. The change is due to
irreversible inhibition of platelet COX-1, so that aspirin's
antiplatelet effect lasts 8-10 days (the life of the platelet).
• MI Prophylaxis: Aspirin is indicated to reduce the risk of death
and/or nonfatal myocardial infarction in patients with a previous
infarction or unstable angina pectoris.
• Transient Ischemic Attacks: Aspirin is indicated for reducing the risk
of recurrent transient ischemic attacks (TIAs) or stroke in men who
have transient ischemia of the brain due to fibrin emboli. There is
currently no evidence that aspirin is effective in reducing TIAs in
women, or is of benefit in the treatment of completed strokes in
men or women.
Contraindications:
• Hypersensitivity to NSAIDs or history of bleeding
disorders, such as GI bleeding or hemophilia
• Not recommended during pregnancy, but may be
valuable in treating preeclampsia-eclampsia.
• Children and teenagers should not use this
medicine for chicken pox or flu symptoms before
a doctor is consulted about Reye's syndrome, a
rare but serious illness reported to be associated
with aspirin.
Pharmacokinetics:
• Aspirin is rapidly hydrolyzed primarily in the liver to
salicylic acid, which is conjugated with glycine (forming
salicyluric acid) and glucuronic acid and excreted
largely in the urine
• As a result of rapid hydrolysis, plasma concentrations
of aspirin are always low and rarely exceed 20 mcg/ml
at ordinary therapeutic doses
• The peak salicylate level for uncoated aspirin occurs in
about 2 hours; however with enteric coated aspirin
tablets this is delayed.
• The plasma half-life for aspirin is approximately 15
minutes; that for salicylate lengthens as the dose
increases:
• Doses of 300 to 650 mg have a half-life of 3.1 to 3.2
hours
• Doses of 1 gram have a half-life of 5 hours and with 2
grams it is increased to about 9 hours
• Salicylates are excreted mainly by the kidney. Studies in
man indicate that salicylate is excreted in the urine as
free salicylic acid (10%), salicyluric acid (75%), salicylic
phenolic (10%) and acyl (5%) glucuronides and gentisic
acid (<1%).
Side Effects:
• Aspirin may trigger asthmatic symptoms in some
patients
• Other expected side effects are dose-dependent
– With therapeutic doses:
• gastric upset, gastric and duodenal ulcers are the most
common side effects
– With higher doses:
• “salicylism” can occur - vomiting, tinnitus, decreased
hearing, vertigo (reversible)
– With very large doses:
• Hyperpnea (increased depth & rate of respiration) through a direct effect on
the medulla resulting in a respiratory alkalosis
• Body temperature may be elevated due to uncoupling of oxidative
phosphorylation, potentially resulting in severe hyperthermia (Olson, 2009).
– At progressively higher and potentially fatal doses (300 to 500
mg/kg)(or 20-35 full strength 325 mg tablets):
• Respiratory alkalosis combined with a severe metabolic acidosis (due to
salicylate accumulation & compensatory responses to respiratory alkalosis)
develop
• Potassium moves from the intracellular space to the extracellular space
• Excretion of hydrogen ions produces acidic urine along with the depletion of
sodium bicarbonate and potassium
• Seizures, coma, pulmonary edema & cardiovascular collapse can occur
• Death is caused by CNS failure & CV collapse.
 CLOPIDOGREL
Mechanism of Action:
• Clopidogrel is a prodrug that must be
metabolized by CYP 2C19 to be effective
• Its active metabolite irreversibly blocks the
ADP receptor on platelets, thereby reducing
platelet aggregation
• It has no effect on prostaglandin metabolism
(unlike aspirin)
Indications:
• Recent MI, acute coronary syndrome, stroke or
established peripheral artery disease, after coronary
stenting (to reduce the risk of restenosis)
• Secondary prevention after an MI for those who are
allergic to aspirin
Contraindications:
• Patients with intracranial hemorrhage, peptic ulcers or
other active bleeding disorders
• Use with caution in patients with recent trauma or
surgery due to risk of bleeding. Caution is needed in
patients with liver impairment.
Side Effects:
• Serious Bleeding!
• Thrombotic thrombocytopenic purpura (a
blood disorder that causes blood clots to form
in small blood vessels around the body,
resulting in a low platelet count or
thrombocytopenia)
Drug Interactions:
• Use of other antiplatelet or anticoagulants may
increase the risk of bleeding
Notes:
• Monitor the platelet count with a baseline CBC &
repeat every 6 months
• Ticlodipine is another drug with the same
mechanism of action. However it causes
leukopenia in ~1% of patients, requiring regular
monitoring of blood counts. This is why
clopidogrel has replaced its use in clinical practice