4 Drugs & Stroke Flashcards
Lecture Outline
Definitions & Overview
Early Pathology of Ischaemic Insult
Fibrinolytic Agents
Mechanisms of Action, The Treatment of Stroke
Anti-Platelet Drugs
Mechanisms of Action, Relevance to Stroke
Anti-Coagulant Agents
Mechanisms of Action, The Treatment of Stroke
Prevention of Stroke
Definitions & The Clinical Problem
Stroke
Lay definition: “weakness, either permanent or transient on one side, often with loss of speech”.
Clinical: “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.
‘Mini-stroke’ or transient ischaemic attack (TIA) Symptoms similar to stroke but short-lived;(few min to 24 hrs). Complete recovery within a day or so.
Definitions & The Clinical Problem
Mortality: 9-12% of UK deaths; 3rd most common cause
Death rate following stroke c. 25%; more common in men than women; more deadly in women?
~900,000 stroke victims in the UK; 1.2 million bed days per year; 5-20% in-hospital mortality
But: good news – UK incidence fell by 30% from 1999-2008
Morbidity: V substantial. For survivors, 50% show incomplete recovery; 50% need some daily assistance.
Costs: rehab, long-term care, nursing, lost productivity etc
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 (why is this useful?)
Drugs and Fibrinolysis [Thrombolysis]
Activation of Plasminogen
“Clot busters” improve outcome; but associated w risk of intracerebral haemorrhage…
Modern ones are ‘recombinant tissue plasminogen activators’ or ‘r-tPAs’ e.g.
Alteplase® (& other r-tPAs): recombinant HUMAN proteins, so non-antigenic.
Given intravenously in specialist stroke units (bleeding risk)
Short-acting.
Drugs and Fibrinolysis [Thrombolysis]
UK: only Alteplase currently licensed for use in acute ischaemic stroke
Snag: 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 (How?)
Ans: brain imaging (CT or MRI scan)
So… suspected ischaemic stroke & likely candidate for tPA must be spotted, & imaged, FAST - ‘Door to scan time’
Spotting strokes quickly
FAST (Face Arms Speech Time) test:
quick recognition of key symptoms of a TIA or stroke.
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? (last year’s lecture)
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: 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®
Antiplatelet Drugs & Ischaemic Stroke
Mechanism 1: preventing GPIIa/IIIb receptor expression
Clopidogrel (& similar agents) → antagonize actions of ADP at
purinergic (ADP) receptors
Mechanism 2: preventing GPIIa/IIIb receptor interaction
Abciximab: Ab to GPIIb/IIIa receptors: prevents linking of platelets to fibres
Downsides of aspirin? (think NSAIDs)
Anti-platelet drugs in ischaemic stroke /TIA
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
Anti-Coagulant Drugs & The Clotting Cascade
Mechanism 1; Activation of antithrombin
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)
Anti-Coagulant Drugs & The Clotting Cascade
Mechanism 2; inhibition of vitamin K reductase:
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
Anti-Coagulant Drugs & The Clotting Cascade
Mechanism 2; inhibition of vitamin K reductase:
“Warfarin is a pain to use”
International Normalised Ratio’: How much slower is clotting time compared to normal
Warfarin takes days to act (or reverse)
V. complex metabolism in body SO;
Dose MUST be adjusted individually – MONITORING via INR
[Warfarin] in blood (& clotting) will CHANGE with LOTS of things e.g.
- diet, drinking, acute illness etc etc.
Warfarin INTERACTS with many other drugs (prescrptn & OTC)
Source of many ‘drug-related adverse effects’
