Stroke Drugs Flashcards
Stroke
a syndrome of rapid onset of cerebral deficit (usually focal) lasting more than 24 hours or leading to death, with no apparent cause other than a vascular one.
Typically hemiplegic.
transient ischaemic attack (TIA)
Symptoms similar to stroke but short-lived;(few min to 24 hrs). Complete recovery within a day or so.
Thromboembolic infarction
85%
Blockage - Cerebral Infarction
Cerebral, cerebellar & subarachnoid haemorrhage
15%
Damage/Bleed; Intracranial Haemorrhage
Fibrinolysis [Thrombolysis]
Whenever coagulation cascade activated, so is fibrinolytic system
Plasmin: body’s own “clot-buster” degrades fibrin. Trypsin-like substance (protease), formed locally…
…from plasminogen which is deposited on fibrin strands as the clot forms.
NB: Part of healing process: clots dissolve once the repair has been made
Plasminogen is activated by plasminogen activators which diffuse into thrombus: convert plasminogen → plasmin
NB (2) These actions localised to the clot; any plasmin that escapes into the circulation is inactivated by plasmin inhibitors
Alteplase(& other r-tPAs):
recombinant HUMAN proteins, so non-antigenic.
Given intravenously in specialist stroke units (bleeding risk)
Short-acting.
UK: only Alteplase currently licensed for use in acute ischaemic stroke
Major 1995 study shows tPA effective only if given within the first 3 hours of the ischaemic event.
But: Must confirm ISCHAEMIC event before giving tPA using brain imaging (CT or MRI scan)
So… suspected ischaemic stroke & likely candidate for tPA must be spotted, & imaged, FAST - ‘Door to scan time’
FAST (Face Arms Speech Time)
• Facial Weakness: Can the person smile?
Has their mouth or eyelid drooped?
• Arm Weakness: Can the person raise both arms?
• Speech problems: Can the person speak clearly and understand what you say?
• Time to call 999.
Targets for modifying thrombosis process?
Modify coagulation most successful in venous thrombosis Modify platelet aggregation important in arterial thrombosis Modify clot, thrombus breakdown after prophylaxis fails
Antiplatelet Drugs & Ischaemic Stroke
Mechanism 1
Mechanism 1: inhibit platelet aggregation & thrombus formation by preventing GPIIa/IIIb receptor expression.
Aspirin (acetylsalicylic acid): non steroidal anti-inflammatory drug (NSAIDS)
→ Inhibits cyclo-oxygenase (COX1).
→ Prevents thromboxane formation
Dipyridamole
→ Inhibits thromboxane synthase
→ Prevents thromboxane formation
Dipyridamole often used in conjunction with Aspirin
Clopidogrel (& similar agents) → antagonize actions of ADP at purinergic (ADP) receptors
Antiplatelet Drugs & Ischaemic Stroke Mechanism 2
Mechanism 2: preventing GPIIa/IIIb receptor interaction
Abciximab: Ab to GPIIb/IIIa receptors: prevents linking of platelets to fibres
Aspirin
Aspirin – works acutely so given early, certainly in first 24 hrs (300 mg).
Typically given for 2 wks
Then ‘Antiplatelet regime’ established
e.g. aspirin + dipyridamole, or clopidogrel
Choice of drug(s) depends on guidelines, what patient tolerates
The Clotting Cascade
Clotting factors: family of proteins that circulate in blood
When blood contacts damaged tissue or exposed collagen, the “clotting cascade” is triggered
Initiated by activation of factors VIII or XII
These then activate another clotting factor, and so on
Activation of Prothrombin (factor II) is a critical step:
thrombin converts fibrinogen into fibrin
Fibrin: insoluble, stable, traps platelets. Clot formation
Heparin
Heparin (intravenous administration), activates (one of) body’s own anti-clotting molecules, antithrombin III.
Works IMMEDIATELY
Two forms of Heparin:
the original unfractionated heparin;
low molecular weight heparins i.e. heparin fragments (more predictable)
Warfarin
Warfarin (a coumarin) – acts on the liver to inhibit the enzyme Vitamin K reductase.
Enzyme uses Vitamin K to ‘final assemble’ clotting factors II, VII, IX and X.
Warfarin similar in structure to Vitamin K
- action (gradually) diminishing concs. of clotting factors
- eventually body not being able to make as much fibrin
- orally active
