BT PO 1.120 Pharmacology of anticoagulant drugs

One winter’s day in 1933, a young farmer named Ed Carlson drove 200 miles in a blizzard, to the biochemistry building at the University of Wisconsin with a dead cow, a bucket of un-clotted blood and a truckload of old sweet clover. He carried the bucket of blood into the only office that was open, and pleaded with the researcher, one Karl Link, to help him with his dying cattle.

So begins a wonderful story of scientific discovery, Vitamin K, newborn haemorrhagic disease, and of course rat poison (years later, Link was recuperating from tuberculosis in a facility with a rat problem and he got to thinking…) with the eventual development of a drug that has saved countless lives from stroke and DVT over the last 60 years.

Prof Karl Link was known for his fine dress sense

I once by chance sat next to a professor of medical history from Wisconsin in a restaurant in New York. He didn’t know any of this. I gave him a short tutorial …

More clinically, although many consider warfarin’s days to be numbered, there are a lot of patients out there who will be on it for years to come, and there’s a fair chance that in the middle of the night, if the anaesthetist does not know how to correctly manage a patient on warfarin, then nobody else in theatre will be able to either.

T/F 3mg intravenous Vitamin K will bring the INR down to 1.4 in 90% of patients within 12 hours

T/F Macrolide administration to a patient on warfarin will invariably make the INR increase to dangerously high levels

T/F Acute increases in the dose of warfarin can cause catastrophic skin necrosis

T/F Reversal of warfarin with Prothrombinex works in 5 minutes but costs 500 times as much as Vitamin K

T/F A raised INR due to hepatic liver disease does not imply the same degree of coagulopathy as the same INR caused by warfarin

References:

Peck & Hill has the basic facts on warfarin & reversal.

Australian reversal protocols here: An update of consensus guidelines for warfarin reversal. The Medical Journal of Australia, 198(4), 198–199.2013, Tran, H. A., et al

For those of you with oodles of time, you can read more of the history online here, or here, or in Wardrop & Keeling (2008) – The story of the discovery of heparin and warfarin. British Journal of Haematology, 141(6), 757–763.

And for the true Karl Link enthusiast, here is a home movie film of him visiting the Wisconsin Alumni Research Foundation, complete with his dog and some ears of corn.


BT_PO 1.119 Describe the mode of action of protamine and potential adverse reactions

Unless you’re doing a cardiac term you won’t have much contact with this drug. However much badness can result from the intemperate use of this drug (even worse if you’ve forgotten to give the heparin in the first place!) so you need to know about it. Most of the important points are covered in the statements below and again I used Goodman and Gilman because I’ve recently bought self a copy. (Also used Stoelting cos there wasn’t much in G&G…annoying)

T/F  Protamine is a polypeptide drug derived from fish sperm and is positively charged

T/F  Protamine should be given slowly to reduce the risk of anaphylaxis

T/F  to antagonise unfractionated heparin the dose is approximately 1mg Protamine per 100 units of heparin

T/F  Protamine doesn’t antagonise LMWH at all

T/F  paradoxically, Protamine can cause an anticoagulant effect itself

T/F Protamine is cleared more rapidly than heparin and this accounts for the ‘heparin rebound’ effect

T/F Protamine is contraindicated in individuals with a seafood allergy

Bleedy McBleedster

BT_PO 1.121

Describe methods to reverse the effect of warfarin

BT_PO 1.120

Describe the pharmacology of warfarin and other anticoagulant drugs

The metabolic clearance of warfarin is inhibited by amiodarone. TRUE/FALSE

Third generation cephalosporins reduce the anticoagulant effect of warfarin. TRUE/FALSE

Intravenous vitamin K should return the prothrombin time to a normal range within 1 hour. TRUE/FALSE

Skin necrosis is a side effect of warfarin therapy. TRUE/FALSE

Warfarin can be reversed with recombinant factor VIIa TRUE/FALSE

Heparin

BT_PO 1.118 Describe the pharmacology of heparin and low molecular weight heparins including their side-effects

T/F All modern drugs now are produced by recombinant DNA technology.

Bull
Actually Heparin is still made from mammalian sources. Beginning in the 1940s heparin was manufactured from bovine lung and pig intestinal mucosa. Because of the BSE crisis, bovine heparin was voluntarily removed. This meant that most of the world’s supply of heparin came from pigs intestines from slaughterhouses in China.

In 2007 there was a crisis in which heparin was adulterated, which illustrated the problem of relying on a single source for a drug. There is now a suggestion that bovine heparin should be re-introduced into clinical practice.

 

 

T/F Both fractionated and unfractionated heparin require anti-thrombin as a cofactor

T/F Heparin exhibits a 4 fold variation in sensitivity and 3 fold variation in its rate of metabolism between patients

T/F The half life of heparin is 1-2 hours and varies directly with the total dose

T/F Heparin induced thrombocytopaenia is the result of a non-specific immune reaction

T/F Heparin is cleared from the circulation by hepatic mechanisms alone