1. Plants Used to Treat Heart Disease and Circulatory Problems

2. Cardiovascular Disease What is cardiovascular disease? US statistics Cost of cardiovascular disease

3. Common forms of cardiovascular disease The 61 million Americans with some form of cardiovascular disease including – coronary heart disease – stroke – congestive heart failure – high blood pressure – other conditions

4. Individual level risk factors for cardiovascular disease High Blood Pressure High Blood Cholesterol Tobacco Use Physical inactivity Poor nutrition Obesity Diabetes

5. Short list of plant-based compounds used in treatment Aspirin Digitoxin and digoxin Statin drugs Reserpine Dietary remedies – Red wine – Garlic – Flavinoids, isoflavones – Monounsaturated fats

6. Aspirin Suppresses prostaglandins by suppressing enzyme cyclooxygenase (COX) that leads to synthesis of prostaglandins One of prostaglandins is thromboxane which is produced in platelets in blood Aspirin halts thromboxane production - platelets become less sticky and less likely to plug up an artery - remarkably fast and can help survival during heart attack

7. Foxglove and heart disease Foxglove - Digitalis purpurea Extract called digitalis Folk medicine William Withering investigated this remedy from 1775-1785 - An Account of the Foxglove, and Some of Its Medical Uses, with Practical Remarks on Dropsy, and Other Diseases (1785)

8. Foxglove Digitalis purpurea Biennial in the Scrophulariaceae Leaves contain over 30 cardiac glycosides with digoxin and digitoxin the most significant

9. Digitoxin

10. Digoxin Sugars

11. Sugars in digitalis glycosides 2 molecules of digitose 1 molecule of 1-acetyl digitose 1 molecule of glucose Digitose

12. Digitalis purpurea and D. lanata Digitalis purpurea - both digitoxin and digoxin, with higher digitoxin levels Digitalis lanata (wooly foxglove) used for digoxin extraction

13. Mode of Action In medicinal doses, cardiac glycosides increase the strength of the contractions of heart and the force of the heart beat – prolongs the relaxation period – lowers the heart rate Increases cardiac output - more blood pumped Improved circulation, decreases edema, and increases kidney output Most effective treatment for congestive heart failure – NOT A CURE Toxic doses cause arrhythmias or even cardiac arrest – fine line between therapeutic and toxic dose

14. Action Both glycosides inhibit Na/K dependent membrane ATPase in the myocardial cells Intracellular calcium increases and contractile response is augmented Binding sites for digitalis glycosides on extracellular side of enzyme. Therapeutic levels of digitalis inhibit 10 to 30% of enzyme - toxic levels inhibit 50%

16. Digitalis glycosides and blood pressure Mixed data on effect of blood pressure Standard believe was that glycosides increased blood pressure – Rise in Na + and Ca ++ contents of vascular smooth muscle – This induced vasoconstriction However recent studies showed patients with lower blood pressure – especially during night

17. Use in geriatric patients About 13% of elderly use digitalis glycosides Almost 20% of patients in nursing homes Substantial risk of toxicity with 10 to 30% of hospitalized patients showing toxicity - and twofold increase in mortality Risk of toxicity increases with age – 80% of toxicity cases over 60 yrs - have more risk factors - mortality as high as 58% with digoxin

18. Digoxin vs Digitoxin Digitoxin was standard until 1970s In 1970s serum drug assay became available for digoxin and oral preparations became more standardized Also digoxin has shorter half-life in body These factors led physicians to believe digoxin was safer Digoxin one of most widely prescribed drugs today much more so than digitoxin

19. Differences in pharmacokinetics Digitoxin is more completely and predictably absorbed from the gastrointestinal tract Serum concentration not altered significantly by other medications or changes in renal or hepatic function Digitoxin also has a much longer elimination time (half life 5 to 7 days as opposed to digoxin which is 1 to 2 days)

20. Digitoxin Highly lipophilic Extensively bound to plasma proteins Mainly eliminated in urine and feces Does not accumulate during kidney dysfunction Bioavailabilty not reduced

21. Digoxin Less lipophilic Show lower protein binding Shorter half-life Mainly eliminated by kidney Accumulated quite rapidly in cases of insufficient kidney function In patients with toxic side effects, 70% had renal insufficiency

22. Differences in toxicity Prospective studies show – Digoxin toxicity rates 15 to 27% – Digitoxin toxicity rates 3 to 5.8% Recent study in Florida showed odds of toxicity three times greater for patients taking digoxin as opposed to digitoxin

23. Mortality rate at various serum digoxin concentrations