Page 634 - Basic _ Clinical Pharmacology ( PDFDrive )

620 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

aggregate (see Chapter 18). Drugs that antagonize this pathway purpura has been reported. Because of its superior adverse effect
interfere with platelet aggregation in vitro and prolong the bleed- profile and dosing requirements, clopidogrel is frequently preferred
ing time in vivo. Aspirin is the prototype of this class of drugs. over ticlopidine. The antithrombotic effects of clopidogrel are dose-
As described in Chapter 18, aspirin inhibits the synthesis of dependent; within 5 hours after an oral loading dose of 300 mg,
thromboxane A by irreversible acetylation of the enzyme cyclo- 80% of platelet activity will be inhibited. The maintenance dosage
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oxygenase. Other salicylates and nonsteroidal anti-inflammatory of clopidogrel is 75 mg/d, which achieves maximum platelet inhibi-
drugs also inhibit cyclooxygenase but have a shorter duration of tion. The duration of the antiplatelet effect is 7–10 days. Clopido-
inhibitory action because they cannot acetylate cyclooxygenase; grel is a prodrug that requires activation via the cytochrome P450
that is, their action is reversible. enzyme isoform CYP2C19. Depending on the single nucleotide
In 2014, following a review of the available data, the FDA polymorphism (SNP) inheritance pattern in CYP2C19, individuals
reversed course and concluded that aspirin for primary prophylaxis may be poor metabolizers of clopidogrel, and these patients may
(patients without a history of myocardial infarction or stroke) be at increased risk of cardiovascular events due to inadequate
was not supported by the available data but did carry significant drug effect. The FDA has recommended CYP2C19 genotyping to
bleeding risk. In contrast, meta-analysis of many published trials identify such patients and advises prescribers to consider alterna-
of aspirin and other antiplatelet agents have demonstrated the util- tive therapies in poor metabolizers (see Chapter 5). However, more
ity of aspirin in the secondary prevention of vascular events among recent studies have questioned the impact of CYP2C19 metabolizer
patients with a history of vascular events. status on outcomes. Drugs that impair CYP2C19 function, such as
omeprazole, should be used with caution.
Prasugrel, similar to clopidogrel, is approved for patients with
THIENOPYRIDINES: TICLOPIDINE, acute coronary syndromes. The drug is given orally as a 60-mg
CLOPIDOGREL, & PRASUGREL loading dose and then 10 mg/d in combination with aspirin
as outlined for clopidogrel. The Trial to assess Improvement in
Ticlopidine, clopidogrel, and prasugrel reduce platelet aggregation Therapeutic Outcomes by Optimizing Platelet Inhibition with
by inhibiting the ADP pathway of platelets. These drugs irrevers- Prasugrel (TRITON-TIMI38) compared prasugrel with clopi-
ibly block the ADP P2Y receptor on platelets. Unlike aspirin, dogrel in a randomized, double-blind trial with aspirin and other
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these drugs have no effect on prostaglandin metabolism. Use of standard therapies managed with percutaneous coronary inter-
ticlopidine, clopidogrel, or prasugrel to prevent thrombosis is now ventions. This trial showed a reduction in the primary composite
considered standard practice in patients undergoing placement of cardiovascular endpoint (cardiovascular death, nonfatal stroke, or
a coronary stent. As the indications and adverse effects of these nonfatal myocardial infarction) for prasugrel in comparison with
drugs are different, they will be considered individually. clopidogrel. However, the major and minor bleeding risk was
Ticlopidine is approved for prevention of stroke in patients with increased with prasugrel. Prasugrel is contraindicated in patients
a history of a transient ischemic attack (TIA) or thrombotic stroke, with history of TIA or stroke because of increased bleeding risk.
and in combination with aspirin for prevention of coronary stent In contrast to clopidogrel, cytochrome P450 genotype status is not
thrombosis. Adverse effects of ticlopidine include nausea, dyspepsia, an important factor in prasugrel pharmacology.
and diarrhea in up to 20% of patients, hemorrhage in 5%, and, Ticagrelor is a newer type of ADP inhibitor (cyclopentyl triazo-
most seriously, leukopenia in 1%. The leukopenia is detected by lopyrimidine) and is also approved for oral use in combination with
regular monitoring of the white blood cell count during the first aspirin in patients with acute coronary syndromes. Cangrelor is a
3 months of treatment. Development of thrombotic thrombo- parenteral P2Y inhibitor approved for IV use in coronary interven-
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cytopenic purpura has also been associated with the ingestion of tions in patients without previous ADP P2Y inhibitor therapy.
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ticlopidine. The dosage of ticlopidine is 250 mg twice daily orally.
Because of the significant side effect profile, the use of ticlopidine Aspirin & Clopidogrel Resistance
for stroke prevention should be restricted to those who are intoler-
ant of or have failed aspirin therapy. Dosages of ticlopidine less than The reported incidence of resistance to these drugs varies greatly,
500 mg/d may be efficacious with fewer adverse effects. from less than 5% to 75%. In part this variation reflects the
Clopidogrel is approved for patients with unstable angina or definition of resistance (recurrent thrombosis while on antiplatelet
non-ST-elevation acute myocardial infarction (NSTEMI) in com- therapy versus in vitro testing), methods by which drug response
bination with aspirin; for patients with ST-elevation myocardial is measured, and patient compliance. Several methods for testing
infarction (STEMI); or recent myocardial infarction, stroke, or aspirin and clopidogrel resistance in vitro are now FDA-approved.
established peripheral arterial disease. For NSTEMI, the dosage However, the measures of drug resistance vary considerably by
is a 300-mg loading dose orally followed by 75 mg daily of clopi- testing method. These tests may be useful in selected patients to
dogrel, with a daily aspirin dosage of 75–325 mg. For patients assess compliance or identify patients at increased risk of recur-
with STEMI, the dosage is 75 mg daily of clopidogrel orally, in rent thrombotic events. However, their utility in routine clinical
association with aspirin as above; and for recent myocardial infarc- decision-making outside of clinical trials remains controversial.
tion, stroke, or peripheral vascular disease, the dosage is 75 mg/d. A recent randomized prospective trial found no benefit over
Clopidogrel has fewer adverse effects than ticlopidine and is standard therapy when information obtained from monitoring
rarely associated with neutropenia. Thrombotic thrombocytopenic antiplatelet drug effect was used to alter therapy.