Acute Coronary Syndrome

• ACUTE CORONARY SYNDROMES

  • a group of disorders characterised by severe chest pain radiating to left arm and jaw
  • not relieved by rest- lasts more than a few minutes
  • three main categories

  1. Unstable angina
  2. NSTEMI: non ST elevated myocardial infarction
  3. STEMI: ST elevated myocardial infarction

  • all involve cardiac ischaemia and may involve tissue damage
  • all caused by coronary artery thrombosis
• TREATMENT FOR ACS

  • for pain (opioids)
  • reduce cardiac workload/ improve blood supply (beta blockers/ GTN)
  • prevent further thrombosis (aspirin/ tricagrelor/ clopidogrel/ herapins/ atorvastatin)
  • repercussion (PCl/ CABG)
• THROMBOSIS

  • Thrombus:

  1. fibrin framework
  2. traps platlets, other blood cells
  3. attached to vessel walls (impede blood flow, reduce perfusion of tissues, can cause heart attack)

  • venous thrombosis (coagulation has a major role)
  • arterial thrombosis (platelet aggregation and coagulation)
  • many influence approach on drug use
• EMBOLISM

  • Embolus

  1. fragment or whole thrombus reattached from vessel wall
  2. travels through vessels
  3. blocks small vessels in pulmonary, cardiac, CNS circulation

  *pulmonary embolism

  *myocardial inferaction

  *stroke

  *limb infraction
• • aim of drug intervention: inhibit thrombus formation, without preventing normal haemostasis
  • targeting for modifying thrombosis process includes:

  1. modifying coagulation (most successful in venous thrombosis)
  2. modifying platelet aggregation (important in arterial thrombosis)
  3. modifying clot, thrombus breakdown (after prophylaxis fails)

  • primary and secondary prevention:

  1. prevents heart attacks
  2. prevents strokes
  3. reduce damage after heart attack/ stroke (fibrinolysis only)
  4. in patients with atrial fibrillation
  5. after heart valve replacement surgery
• HERAPIN

  • present in liver, lungs, mast cells
  • family of sulphated mucopolysaccharides
  • repeating groups with high -ve charge (essential for activity)
  • THROMBIN is a proteolytic enzyme that converts fibrinogen (soluble) to fibrin

  1. active thrombin is produced by cleavage of prothrombin by factor Xa
  2. factor Xa is produced from factor X (inactive) by both Factor IXa and factor VIIa

  • action of herapin:

  1. inhibits action of thrombin, factors Xa, IXa
  2. requires presence of antithrombin III, an endogenous protease inhibitors
  3. normally ATIII opposes coagulation `
• HERAPIN cont.

  • Herapin increases the rate (1000 fold) of formation of anti-thrombin III-thrombin complex

  *Herapin needs to bind to both ATIII and factor IIa (thrombin)

  • Other actions of herapin include:

  1. reduces platelet aggregation through inhibition of thrombin
  2. reduce platelet numbers (involves anti-platelet antibodies)
  3. influence lipid metabolism (removes lipids from plasma)

  • Clinical uses of herapin:

  1. venous thrombosis/ embolism
  2. used immediately after heart attack/ stroke
  3. reduces risk of DVT after orthopaedic surgery
  4. LMV herapins now preferred
• PROBLEMS WITH HEPARINS

  1. poorly absorbed from oral administration
  2. can cause allergic reactions
  3. dose needs to be individualised to the patient
  4. may need monitoring
  5. risk of haemorrhage
• WARFARIN

  • Oral anticoafulants
  • Used in:

  1. venous thrombosis-embolism
  2. prevention of stroke in patients with atria fibrillation; heart valve replacement

  • related in structure to Vit K
  • Antagonise Vit K role in formation of various clotting factors

  1. factors II (prothrombin), VII, IX, X
  2. prevents γ-carboxylation of precursors
  3. precursors inactive in promoting coagulation
• PROBLEMS WITH WARFARIN INCLUDE

  1. slow onset (pre-existing factors need to be depleted)
  2. activity by vIT k
  3. Warfarin exists as R, S isomers (s 5x more potent)
  4. risk of haemorrhage
  5. teratogenic
  6. drug interactions through:

  *enzyme induction by other drugs

  *enzyme inhibition by other drugs

  *displacement from protein binding
• DIRECT ACTING ANTICOAGULANTS

  • direct inhibitors of thrombin (e.g. dabigatran)
  • inhibitors of factor Xa (e.g. rivaroxaban)
  • easier to use than warfarin as it doesn't require monitoring
  • USES: prevent stroke in patients with atrial fibrillation + DVT
• PLATELET ADHESION, ACTIVATION AND AGGREGATION

  • Platlets are derived from megakaryocytes (bone marrow cells)

  1. fragments of cytoplasm (no nucleus)

  PLATELET AGGREGATION/ ACTIVATION

  • stimuli include: ADP/ TxA2/ THROMBIN
  • TxA2 synthesised from arachidonic acid by cyclo-oxygenase (COX)
  • Platelets synthesise TxA2 when activated
  • TxA2 is released from platelets

  1. increases levels of active glycoproteins IIb/ IIa receptors

  • other platelets activate and a chain begins
  • the platelets become cross-linked by fibrinogen
  • prostacyclin release from the endothelium inhibits aggregation
• ANTIPLATELET DRUGS

  • ASPIRIN irreversibly blocks playlet COX enzyme, reducing TxA2 synthesis

  1. low doses of aspirin used to avoid reducing enzyme in endothelium (source go prostacyclin)
  2. aspirin alters balance between platelet TxA2 and endothelial prostacyclin (PGI2)`

  • ASPIRIN unwanted effects

  1. extended bleeding time
  2. indigestion
  3. allergy (rare)
  4. may provoke asthma attacks
  5. Reye's syndrome (liver + brain damage)
• Antiplatelet drugs

  Modulate expression of glycoprotein IIb/IIa receptors
• Clopidogrel

  Inhibits glycoprotein IIb/IIa receptor expression on platelets by blocking the ADP receptor irreversibly
• Ticagrelor

  Allosterically inhibits the ADP receptor
• Unwanted effects of Clopidogrel + Ticagrelor

  • Extended bleeding time
  • GI tract problems
  • Headaches/dizziness
  • Gout (ticagrelor)
  • Breathlessness (ticagrelor)
• Clopidogrel + Ticagrelor

  Raise cAMP levels, prevent aggregation
• Unwanted effects of Dipyridamole

  • Muscle pains
  • GI tract problems
  • Headache/dizziness
  • Flushing/feeling hot (vasodilator)
  • Can precipitate/worsen angina
• THROMBOLYTIC DRUGS ('CLOT BUSTERS')

  PCI:

  1. rapid
  2. relatively safe
  3. requires specialist centre

  THROMBOLYSIS:

  1. very rapid
  2. relatively risky
  3. requires little equipment