תל השומר ' נה מוחמד פנימית ד'מחאג

• Overview

• indications

• Available drugs

• Special usage

• Side effect

• Contraindications

• Drug interactions

Anti platelets

• Platelets, "thrombocytes", are blood cells whose function (along with the

coagulation factors) is to stop bleeding.

• Platelets have no nucleus: they are fragments of cytoplasm which are derived

from the megakaryocytes[2] of the bone marrow,

• The ratio of platelets to red blood cells in a healthy adult is 1:10 to 1:20.

• The main function is to contribute to hemostasis:

1. adhesion :platelets attach to substances outside the interrupted endothelium:

2. activation, they change shape, turn on receptors and secrete chemical

messengers

3. Aggregation: they connect to each other through receptor bridges:.

• Formation of this platelet plug (primary hemostasis)

• fibrin deposition and linking (secondary hemostasis).

Overview

White clot vs red clot

Thromboxane A2 inhibitors

• Amplifies the initial signal of the platelets activation

• Produced from the arachidonic acid by COX enzymes

• Platelets express only COX 1 .

• Aspirin and non selective COX inhibitors are preferred

• causes platelets to change shape, release their granules,

and aggregate

• interfere with platelet aggregation in vitro prolong the bleeding time in vivo.

Cardiopirin ® , Cartia ® , Micropirin ®, Tevapirin®

aspirin

• aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme

cyclooxygenase.

Indications : Ischemic Stroke, Angina Pectoris , Thromboembolic Stroke(CABG): (PTCA): For carotid endarterectomy, Kawasaki vasculitis prophylaxis ;secondary prevention

Dosage:

1. The FDA has approved the use of 325 mg/d for primary prophylaxis of myocardial infarction.

1. Maintenance and secondary prevention - 75-100 mg daily.

Side effects: mainly gastrointestinal side effects

• Large doses of salicylate, a metabolite of aspirin, cause temporary tinnitus

• Reye's syndrome, a rare but severe illness ‘acute encephalopathy and fatty liver, can occur when children or adolescents are given aspirin for a fever or other illnesses or infections

• FDA recommends ,should not be given to under the age of 12

Contraindications

• people who are allergic to ibuprofen or naproxen,or who have salicylate

intolerance

• caution should be exercised in those with asthma or NSAID-precipitated

bronchospasm.

• peptic ulcers, or gastritis ,stomach

• Patients with hemophilia or other bleeding tendencies

• Aspirin is known to cause hemolytic anemia in people who have the

genetic disease glucose-6-phosphate dehydrogenase deficiency,

particularly in large doses and depending on the severity of the disease.

• People with kidney disease, hyperuricemia, or gout should not take aspirin

because it inhibits the kidneys' ability to excrete uric acid.

Primary prevention Vs secondary prevention

ESC Expert Consensus Document

Expert Consensus Document on the Use of Antiplatelet Agents

European Heart Journal (2004) 25, 166–181

cAMP and cGMP targeted drugs

Mechanism of Action• Non-nitrate coronary vasodilator in high doses over short time therapy • Inhibition adenosine uptake inhibiting platelet reactivity

• Phosphodiesterase inhibition increased cAMP in platelet reduced aggregation

• Inhibition of Thromboxane A2 formation

Dipyridamole [® Cardoxin forte ® Aggrenox]

1. Pharmacokinetics : Peak : 2-2.5 hr Duration of action: 6 hr Protein Bound: 99% Excretion: Feces

Dialyzable: No metab.: Liver 2. Effect can take 2-3 weeks. Short t ½ 3-4 times a day

1. Dosage : 75mg-100mg PO qhr 6 ; net dose 225mg-450mg per day

2. Side effects : >10% Chest pain (20%) Angina exacerbation, IV (19.7%) Abnormal ECG (15.9%) Headache.

1. Contraindication : use with caution in case of other vasodialators e.g.[diprophylline , PDE5 inhibitors

,theophylline]. Category: B enters breast milk

1. In over dose :a) aminophylline which reverses its hemodynamic effects (vasodilation)b) 99% protein affinity dialysis is not likely to be of benefit.

• Clinical use :1. Vasodilation in healthy and stenoted arties . 2. Dipyridamole is an indirect vasodilator increased adenosine levels

3. thus it can be used in Myocardial Perfusion SPECT.

4. Less efficient as monotherapy . In combo with aspirin [ Aggrenox ]

ADP receptor antagonistsThienopyridine

• ADP is stored in dense bodies inside blood platelets and is released upon platelet

activation.

• ADP receptors found on platelets (P2Y1, P2Y12, and P2X1), which leads to platelet

activation.

1. P2Y1 :initiate platelet aggregation and shape change

2. P2Y12 :amplify the response to ADP

Irreversibly blocking the ADP receptor on plateletsThe antithrombotic effects of clopidogrel are dose-dependent;

within 5 hours after an oral loading dose of 300 mg, 80% of platelet activity will be inhibited.

Indications :

1. Prior to PCI or prior to fibrinolysis

2. After stent imblantaion

3. After CABG

4. Patients who cant tolerate aspirin

Dosage:1. 1. Loading dose of 600mg , previous dose 300mg

2. The maintenance dose of clopidogrel is 75 mg/d, which achieves maximum platelet

inhibition.

3. “ CURRENT study “ – better prognosis with 150mg maintenance dose

4. Maintenance dose for 1 year

5. The duration effect is 7–10 days

Adverse effects 1. ticlopidine include nausea, dyspepsia, and diarrhea in up to 20% of patients,

hemorrhage in 5%, and, most seriously, leukopenia in 1% [ within first 3 months]2. Major bleeding

Clopidogrel ® Plavix ; Ticlopidine ® Ticlid

Clopidogrel's use in ACS was evaluated in CURE (2001), CLARITY-TIMI

28 (2005),[1] and ARMYDA-2 (2005),[2] and remains the standard of care in ACS

INTERPRETATION: • In patients undergoing PCI for acute coronary syndromes, a 7-day double-

dose clopidogrel regimen was associated with a reduction in cardiovascular

events and stent thrombosis compared with the standard dose.

• Efficacy and safety did not differ between high-dose and low-dose aspirin.

• A double-dose clopidogrel regimen can be considered for all patients with

acute coronary syndromes treated with an early invasive strategy and

intended early PCI

Prasugrel ® Effient

• more rapid antiplatelet effect compared with clopidogrel owing to its faster metabolic

activation.

• prasugrel is a prodrug activated by CYP3A4, CYP2B6

• Pharmacology:• Start within15 min after a 60-mg loading dose

• maximal plasma concentration at 30 min.

• Indications :• like other anti platelets drugs [ ACS , prior to PCI ,STEMI,NSTEMI ]

• Gold standard drug in STEMI

• Contraindications : A. age >75

B. weight <60kg

C. Hemorrhagic events history mainly CNS , TIA ,CVA

• Dosage:1) loading dose of 60mg > 600mg of Plavix

2) Maintenance dose of 10mg for 9 months > 75mg of plavix

TRITON-TIMI 38

• Safety : Significant increase in serious bleeding

(32% increase)

• In ischemia guided strategy prasugrel has no superiority

• As first line therapy prior to PCI prasugrel < clopidogrel.

• Patients with stents prasugrel > clopidogrel

Ticagrelor ®(Brilinta)

• non-thienopyridine,direct selective reversible antagonist of the P2Y12 receptor.• Brilinta> Plavix

• Pharmacology:• No metabolic activation required

• noncompetitive allosteric antagonism • It is rapidly absorbed in the small intestine

• plasma half-life is approximately 6–8 .

• Contraindication : unlike prasugrel [ age , weight ]

• Side effects: 10-15% dyspnea due to increased bradykinin , 1st AV block

• Interactions : increases levels of lomitapide [treatment of familial hypercholesterolemia]

• Elimination Ticagrelor is eliminated in the feces, with less than 1% found in the urine, suggesting that renal dose adjustment is not necessary.

• Dosage:• Twice daily due to short t1/2.

• Loading dose of 180 mg PO (two 90mg tablets)

• Maintenance dose 90 mg every 12 hr for mean 9 months

• Brilinta 180mg>Plavix 600mg – according to PLATO study

PLATOn-=18,000

Compared to clopidogrel, ticagrelor significantly reduced the rate of CV death, MI, or stroke without an increase in the rate of overall major bleeding

glycoprotein 2b3a receptor antagonist

Abciximab ®ReoPro

• Chimeric monoclonal antibody; prevents binding of fibrinogen, vWF to glycoprotein IIb/IIIa receptor sites on platelets

Pharmacokinetics

• Half-life: 30 min Onset: 10 min Peak time: ~30 min (platelet inhibition)

• Duration: 72 hr Platelet binding: Remains bound for 15 days

Indications :Adjunct to PCIA. Prevention of cardiac ischemic complications in patients undergoing PCI

B. Indicated for prevention of cardiac complications in patients with unstable angina with

PCI planned within 24 hr

dosage• 0.25 mg/kg IV bolus over at least 1 min, 10-60 min before start of PCI, THEN

• 0.125 mcg/kg/min IV continuous infusion for 12 hr;

• > infusion rate of 10 mcg/min

Adverse Effects >10%

Bleeding, minor (70-82%) Bleeding, major (17-21%) Hypotension (14-21%)

Contraindications

Active major bleeding, thrombocytopenia, CVA (within 2 years) Peptic ulcer ;Recent surgery; trauma,

increased bleeding with Oral anticoagulant use within 7 days

abciximab is not beneficial as first-line medical treatment in patients admitted with ACS

(®Tirofiban) Aggrastat- (® Eptifabetite) Integrilin

Small molecules that Blocks binding of fibrinogen and vWb factor to IIb/IIIa receptors

Favored above ReoPro , cheaper , safer , shorter t1/2

Indications :• to reduce the rate of thrombotic cardiovascular in patients with(NSTE-ACS)• Prior/during PCI

Pharmacology : Half-life: 2 hr ; Duration: 4 hr

Excretion: Urine (65%); feces (25%) Dialyzable: Yes

Adverse Effects >10% Bleeding, minor (11%)

Contraindications : bleeding ; thrombocytopenia ;trauma ; renal impairment ClCr<30

ESC Expert Consensus Document

Expert Consensus Document on the

Use of Antiplatelet Agents

European Heart Journal (2004) 25, 166–181

Quick summary

1. Recommendation and

guidelines

2. STEMI VS NSTEMI

3. PRIMARY prevention

4. Secondary prevention

5. CONTRAINDICATIONS

Canadian Journal of Cardiology 29 (2013) 1334e1345

European Heart Journal (2014) 35, 2383–2431

doi:10.1093/eurheartj/ehu282

November 2013 NICE clinical guideline 94 guidance.nice.org.uk/cg94

• PCI and high-risk ACS, DAPT treatment is recommended for 1 year irrespective of stent type.

• In NSTEMI Brilinta > Prasugrel ® Effient In STEMI Prasugrel ® Effient > Brilinta

• Brilinta > ® Effient if : age >75 , weight <60kg , [previous TIA ]***

• Combo with aspirin 75mg-81mg* is favored

• Aspirin is COX1 inhibitor - GI complications In secondary prevention – risk Vs benefit

• Plavix is favored if prasugrel or Ticagrelor aren’t tolerated .

• Prasugrel and Plavix = indirect irreversible

• Ticagrelor = direct reversible

Before surgery :

1. Plavix or Ticagrelor at least 5 days

2. Prasugrel should least 7-10 days

3. Abciximab [ ReoPro] at least 10-12hr

4. (®Tirofiban) Aggrastat- (® Eptifabetite) Integrilin at least 4hr

NSTEMI

• Ticagrelor 90 mg X2 day > clopidogrel 75 mg daily for 12yr in patients with moderate to

high risk as defined in PLATOstudy http://www.nejm.org/doi/full/10.1056/NEJMoa0904327

• prasugrel 10 mg daily > clopidogrel 75mg daily for 12 months in patients with

NSTEMI after PCI (Strong Recommendation, High-Quality Evidence).

• We recommend avoiding prasugrel in patients with previous TIA or stroke or in

patients who are not treated with PCI

• Patients in whom clopidogrel is to be used, a higher maintenance dose of 150 mg daily

be considered for the first 6 days in patients with NSTEMI treated with PCI

• Ticagrelor > prasugrel in PCI, CABG, or medical therapy alone,

• whereas prasugrel should be used only in patients undergoing PCI.

• In patients 75 years of age or older or weight 60 kg, when available, prasugrel 5 mg daily could

be considered.

STEMI

• prasugrel 10 mg daily or Ticagrelor 90 mg X 2 day for 12 months in combo with 75 mg

aspirin after primary PCI

Not tolerable

clopidogrel 75 mg daily day for 12 months

maintenance dose of 150 mg daily for the first 6 days is favored

Thanks Docs