ASPIRIN
www.propofology.com
Dr. David Lyness
@Gas_Craic
acetylsalicylic acid
http://ceaccp.oxfordjournals.org/content/7/5/157.full.pdf+html
Wikipedia Aspirin - Molecular Image & Pharmacokinetics
Single Dose Aspirin for Acute Analgesia - Trial - http://www.ncbi.nlm.nih.gov/pubmed/10796855
Aspirin and clopidogrel act synergistically.
Secondary prevention with aspirin reduces mortality by up to 30% in high-risk groups.
Withdrawal of aspirin in patients with coronary artery disease is associated with a 2–4x increase in risk of death and MI.
Over 10% of episodes of ACS in the perioperative period are precipitated by pre-operative cessation of aspirin.
There is no ‘antidote’ to aspirin and clopidogrel whilst they remain in the blood - you would need to give lots of platelets
Patients with stents are at high risk of thrombotic events if their therapy is changed, especially in the first
3 months after insertion.
USED AS AN ANALGESIC, ANTIPYRETIC & ANTI-INFLAMMATORY DRUG
ALSO USED TO PREVENT PLATELET AGGREGATION ACUTELY & IN SECONDARY PREVENTION
Aspirin is a weak acid with a pKa of 3.5.
It is absorbed in the blood through the cells lining the stomach.
Highly charged molecules pass through this lining slowly, but neutral molecules pass through the lining more quickly.
The pH of the stomach is about 1.5 and the pH of the small intestine is about 6.
Since this is a simple weak acid, when you are 1 pH unit below the pKa it will be fully protonated and have no charge (COOH). At 1 pH unit above the pKa you will be fully protonated, and will be in the COO- charged form. The pH of the stomach is so low that aspirin will be fully protonated, neutral and will pass quickly through the lining. The pH of the small intestine is much higher, so the aspirin will be in the COO- charged form and will not pass through the lining.
LOADING AWESOME
- Antiplatelet activity = IRREVERSIBLY BLOCKS the activity of COX-1 enzyme for the life of the platelet.
- COX-1 causes production of thromboxane A2, a potent vasoconstrictor and stimulator of platelet aggregation
- Thromboxane A2 is derived from arachidonic acid - a key inflammatory intermediate and vasodilator.
- Aspirin is 50–100x more effective against COX 1 than COX 2 (inflammation)
- This is why larger doses are required to achieve anti-inflammatory effects.
- Rapidly absorbed in the stomach and has a half-life of 15 – 20 min - the long lasting effects happen in this time!
- Rapidly absorbed in the stomach and has a half-life of 15 – 20 min - the long lasting effects happen in this time!
- Platelet turnover is 10% per day = after aspirin is stopped, plt function will normalise in 7–10 days (new Plts formed)
A single dose of 100 mg leads to a 98% reduction in thromboxane B2 (breakdown product of thromboxane A2) within 1h of ingestion, and abnormalities of platelet aggregation can be measured up to 10 days after ingestion.
Clopidogrel = Prodrug = Thienopyridine. Reduces platelet aggregation by the selective, irreversible inhibition of the P2Y12 ADP receptor on the platelet surface (one of three ADP receptors). Has no direct effects on the metabolism of arachidonic acid.
About 50–80% is plasma protein bound and the rest remains in the active, ionized state; protein binding is concentration-dependent.
The volume of distribution is 0.1–0.2 l/kg. Acidosis increases the Vd because of enhancement of tissue penetration of salicylate.
Undergoes 80% gluconuride metabolism in the liver to 2 esters and some of it is hydroxylated.
When larger doses are considered, there is a switch from first to zero-order kinetics as metabolic pathways become saturated.
In long term aspirin therapy, meta-analysis has shown aspirin:
1. Reduces vascular death by 15%
2. Reduces non-fatal vascular events [non-fatal myocardial infarction (MI) or stroke] by 30% in high-risk patients
It is common practice to load patients with 300mg of Aspirin + Clopidogrel in addition to a LMWH such as Enoxaparin in acute MI or thrombotic stroke.
Analgesic and antipyretic doses of aspirin vary widely - some OTC boxes quoting 900mg be given for such effects.
One trial of single-dose aspirin for acute pain found significant benefit of aspirin over placebo for aspirin 600/650 mg, 1000 mg and 1200 mg.
2p / 300mg tablet OTC
It is unlikely you will get much more anti-platelet effect above
a single ~100mg dose - it can work faster however (acute situations)
