Agents to Treat Hypertension:

1. Agents to Treat Hypertension: Angiotensin-Converting Enzyme (ACE) Inhibitors

2. What is Hypertension? • A serious disease affecting 1 in 3 adults in the United States • More commonly known as High Blood Pressure • Occurs when blood is forced through the heart and arteries under excessive pressure http://www.beauregard.org/bldpress.htm

3. What is Blood Pressure? • Blood pressure readings have two components: • Systolic pressure • Heart muscles contracted • Diastolic pressure • Heart muscles relaxed • With hypertension: • Arteries narrow thereby increasing pressure • Fluid volume in arteries increases which can increase pressure http://www.everybody.co.nz/page-3f71418a-d1e1-43d7-9ac0-fdcb4a79a3e3.aspx

4. Measuring Blood Pressure • Measured with: • Stethoscope • Sphygmomanometer (blood pressure cuff) • Having your blood pressure measured is the only way to test for hypertension http://www.merck.com/media/mmhe2/figures/fg022_2.gif

5. Classifying Blood Pressure by Readings • High Blood Pressure = Elevated systolic pressure and/or elevated diastolic pressure • The highest reading dictates classification • Elevated readings must occur on multiple occasions to be diagnosed

6. Classifying Hypertension by Causes • Primary or Essential Hypertension • 90-95% of hypertension cases • Causes are unknown, but linked to risk factors • Secondary Hypertension • 5-10% of hypertension cases • Caused by disease states • Some causes include: kidney disease, atherosclerosis, hormone imbalances, pregnancy, and some medications

7. Controllable Alcohol use Excess sodium Lack of exercise Stress Smoking Obesity due to inactivity/overeating Medications Uncontrollable Age Race Gender Family history Medical condition Obesity due to medical condition Medications Risk Factors

8. Who is Affected by Hypertension? • Affects 1 billion people worldwide • Affects 65 million Americans age 6+ • 30% of people with hypertension don’t know they have it (Death rates per 100,000 people)

9. Why Should I Care? • Hypertension can elevate your risk for: • Stroke • Blood clots • Bleeding • Heart attacks • Heart enlargement • Heart failure • Kidney failure • Atherosclerosis http://member.rivernet.com.au/balehirs/drHt2.jpg

10. Treatment Options for Hypertension • Prevention is the best treatment strategy • The goal of treatment: • Lower blood pressure to prevent associated complications • Typically <140/90 mmHg http://www.physicaltherapy.ca/cardio/Hypertension1.html

11. Treatment Options for Hypertension • Normal blood pressure cases: • Prevent hypertension • Reduction of controllable risk factors • Prehypertension cases: • Reduction of controllable risk factors • Careful monitoring • Stage 1 & Stage 2 hypertension cases: • Reduction of controllable risk factors • Close monitoring • Drug therapies

12. Available Drug Therapies • Drug therapies available: • ACE (angiotensin-converting enzyme) inhibitors • Alpha blockers • Alpha-2-agonists • Angiotensin II receptor blockers • Beta blockers • Calcium channel blockers • Combined alpha and beta blockers • Combined ACE inhibitors and diuretics • Diuretics

13. Drug Therapies

14. Drug Therapies

15. History Highlights: ACE-Inhibitors • Discovered in 1960’s • Venom of pit vipers intensified the response to bradykinin, a vasodilator • Response was caused by peptides that inhibited kininase II, an enzyme that inactivated bradykinin • Later found that kininase II = ACE (angiotensin-converting enzyme) • First Drug- Teprotide • Nonapeptide that lowered blood pressure caused by primary hypertension • Not orally active http://www.szgdocent.org/resource/rr/c-viper.htm

16. ACE-Inhibitors • ACE is a zinc metalloproteinase • It catalyses the hydrolysis of a dipeptide fragment, His-Leu, from a decapeptide, angiotensin Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu → Asp-Arg-Val-Tyr-Ile-His-Pro-Phe + His-Leu • The reaction produces angiotensin II, an octapeptide • ACE is membrane-bound and could not be isolated for study ACE Angiotensin I Angiotensin II

17. Carboxypeptidase • Carboxypeptidase is a zinc metalloproteinase that could be isolated • Carboxypeptidase splits a terminal amino acid from a peptide chain • In the presence of L-benzylsuccinic acid the reaction is inhibited [2]

18. Carboxypeptidase • Key features of the carboxypeptidase active site: • Charged arginine • Forms an ionic bond with the terminal carboxylic acid • Zinc ion • Binds to carbonyl of terminal peptide • S1’ pocket • Allows for the side chain of the terminal amino acid [2]

19. L-Benzylsuccinic Acid • Inhibits carboxypeptidase • Key features: • Benzyl group to fill the S1’ pocket • Carboxylate anion for ionic interactions with arginine • Second carboxylate to act as a ligand for the zinc ion • Lack of a peptide bonds prevents it from being hydrolyzed and removed from the active site [2]

20. ACE-Inhibitors • From the carboxypeptidase it was assumed that the ACE active site had: • Arginine • Zinc ion • S pockets • Inhibitor used = Succinyl proline • Proline is located on the terminus of teprotide • Distance between the dipeptide and peptide were thought to be greater than the distance between the amino acid and peptide chain • Analogous to benzylsuccinic acid [2]

21. ACE-Inhibitors • Next developments increased binding affinity • Captopril • Methyl group to fill S1’ • Thiol added to interact with zinc • Enalaprilat • Glutarylproline replaced succinyl proline to better fit the S1 pocket • Lisinopril • Similar to enalaprilat with a aminobutyl substitutent replacing methyl substitutent [2] [2]

22. ACE-Inhibitors [1]

23. Sulfhydryl-containing ACE-Inhibitors • Captopril • Active compound • 75% bioavailability, which can be reduced by food • Take 1 hour prior to food consumption • Eliminated in the urine • Captopril, captopril disulfide dimmers, and captopril-cysteine disulfide http://home.caregroup.org/clinical/altmed/interactions/Drugs/Captopril.htm

24. Dicarboxyl-containing ACE-Inhibitors • Enalapril • Prodrug, activated in vivo to enalaprilat • C2H5 group is hydrolyzed by esterases in the liver • Eliminated by the kidneys • Enalapril and enalaprilat • Bioavailability of 60%, not reduced by food • Enalaprilat • Active dicarboxylic acid • Not orally stable • IV administration only http://en.wikipedia.org/wiki/Enalapril http://en.wikipedia.org/wiki/Enalapril

25. Dicarboxyl-containing ACE-Inhibitors • Lisinopril • Active molecule • Lysine analogue of enalaprilat • Characterized by: • Slow, variable, & incomplete absorption (30%- not reduced by food) • Eliminated intact by the kidneys • Benazepril • Prodrug, activated to be benazeprilat • Eliminated by kidney and liver via urine and bile • High potency in vitro with a low uptake, 37%- can be reduced when food is present http://www.medsafe.govt.nz/profs/Datasheet/p/prinzidepic1.gif http://www.alchemchina.com/products/apis_b.files/Benazepril.gif

26. Dicarboxyl-containing ACE-Inhibitors • Trandolapril • Prodrug, activated to trandolaprilat • Active form has 70% bioavailability, slowed by food • Eliminated in urine (33%) and feces (66%) • Quinapril • Prodrug, activated to quinaprilat • 60% absorption, slowed by food • Two half-lives in the body • Initial ~2 hours • Prolonged ~25 hours • Due strong binding with tissue ACE http://www.drugs.com/pdr/images/10/04044002.jpg http://www.medicinescomplete.com/mc/clarke/current/images/clk1438c001.gif

27. Dicarboxyl-containing ACE-Inhibitors • Ramipril • Prodrug, active form ramiprilat • Created via cleavage of ester moiety • Rapidly absorbed, slowed by food • Triphasic elimination half-life: • Initial 2-4 hours • Extensive tissue distribution • Intermediate 9-18 hours • Clearance of free ramiprilat from plasma • Terminal 50+ hours • Dissociation from tissue ACE http://www.smspharma.com/images/ramipril_img.gif

28. Dicarboxyl-containing ACE-Inhibitors • Moexipril • Prodrug, active form is moexiprilat • 13% bioavailability for moexiprilat due to incomplete absorption of moexipril • Take 1 hour prior to food consumption • Perindopril • Prodrug, active form is perindoprilat • 75% bioavailability for the prodrug • 35% bioavailability for the active form, reduced in the presence of food • Eliminated by the kidneys http://www.geocities.com/lubolahchev/Moexipril.html http://www.fortunecity.com/roswell/spells/260/c9900109.gif

29. Phosphorous-containing ACE-Inhibitors • Fosinopril • Prodrug converted to fosinoprilat • Slow absorption, slowed further by food • 36% uptake • Eliminated by kidneys and liver • Dual elimination allows for use despite the presence of renal disease http://en.wikipedia.org/wiki/Monopril

30. Side Effects of ACE-Inhibitors • Hypotension with the first dose • Dry cough 5-20% of people • Hyperkalemia (High K+ levels) • Acute renal failure • Fetopathic effects in pregnant women • Skin rash • Dysgeusia, loss of taste http://www.beauregard.org/bldpress.htm

31. The Future of ACE-Inhibitors • In 2003 X-ray crystallography revealed the structure of ACE joined with lisinopril. • Indicated that the arginine is actually a lysine residue • Possibility of new inhibitors with greater binding capabilities and greater selectivity http://www.cbi.cnptia.embrapa.br/~jorgehf/index2.html

32. Sources Print Sources: 1. Brunton, Laurence L., John S. Lazo, and Keith L. Parker, eds. The Pharmacological Basis of Therapeutics. 11 ed. New York: McGraw-Hill, 2006. 2. Patrick, Graham L. An Introduction to Medicinal Chemistry. 3 ed. New York: Oxford University Press, 2005. Online Sources: 3. www.aurorahealthcare.org 4. www.healthatoz.com 5. www.americanheart.org 6. www.drugdigest.org 7. http://www.beauregard.org/bldpress.htm 8. http://www.everybody.co.nz/page-3f71418a-d1e1-43d7-9ac0-fdcb4a79a3e3.aspx 9. http://www.merck.com/media/mmhe2/figures/fg022_2.gif 10. http://member.rivernet.com.au/balehirs/drHt2.jpg 11. http://www.physicaltherapy.ca/cardio/Hypertension1.html 12. http://www.szgdocent.org/resource/rr/c-viper.htm 13. http://home.caregroup.org/clinical/altmed/interactions/Drugs/Captopril.htm 14. http://en.wikipedia.org/wiki/Enalapril 15. http://www.medsafe.govt.nz/profs/Datasheet/p/prinzidepic1.gif 16. http://www.alchemchina.com/products/apis_b.files/Benazepril.gif 17. http://www.drugs.com/pdr/images/10/04044002.jpg 18. http://www.medicinescomplete.com/mc/clarke/current/images/clk1438c001.gif 19. http://www.smspharma.com/images/ramipril_img.gif 20. http://www.geocities.com/lubolahchev/Moexipril.html 21. http://www.fortunecity.com/roswell/spells/260/c9900109.gif 22. http://en.wikipedia.org/wiki/Monopril 23. http://www.beauregard.org/bldpress.htm 24. http://www.cbi.cnptia.embrapa.br/~jorgehf/index2.html For more detailed citations, please see accompanying paper.