Agents to Treat Hypertension:
Angiotensin-Converting Enzyme (ACE) Inhibitors
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
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
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
Classifying Blood Pressure by Readings
Blood Pressure CategorySystolic (mm Hg)
Diastolic (mm Hg)
Normal <120 <80
Prehypertension 120-139 80-89
High: Stage 1 140-159 90-99
High: Stage 2 160 + 100 +
• 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
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
Risk Factors
• 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
Who is Affected by Hypertension?
Race and Gender Prevalence
White Female 19.3%
White Male 24.4%
African-American Female 34.2%
African-American Male 35.0%
Hispanic Female 22.0%
Hispanic Male 25.2%
Race and Gender Death Rate
White Males 14.4%
African-American Males 49.6%
White Females 13.7%
African-American Females 40.5%
• 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)
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
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
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
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
Drug Therapies
Stage 1 Hypertension
Stage 2 Hypertension
Thiazide diureticsThiazide diuretic + ACE
inhibitor
ACE inhibitors Thiazide diuretic + ARB
Angiotensin II receptor blockers
Thiazide diuretic + Beta blocker
Beta blockersThiazide diuretic +
Calcium channel blocker
Calcium channel blockers
Combination therapies
Drug Therapies
Options for Individualizing Antihypertensive Drug Therapy
If you have hypertension and the following:
Then your doctor may prescribe one of the following:
Diabetes mellitus ACE Inhibitors, ARBs, Diuretics, Beta Blockers, Calcium Channel Blockers
Heart failure Diuretics, Beta Blockers, ACE Inhibitors, ARBs, spironolactone
Heart attack Beta Blockers, ACE Inhibitors, spironolactone
Isolated systolic hypertension (elevated systolic only)
Diuretics, certain Long-acting Calcium Channel Blockers
Kidney Disease ACE Inhibitors, ARBs
Recurrent Stroke Prevention Diuretics, ACE Inhibitors
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
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
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]
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]
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]
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]
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]
ACE-Inhibitors
[1]
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
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
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
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
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
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
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
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
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
SourcesPrint 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.org4. www.healthatoz.com5. www.americanheart.org6. www.drugdigest.org7. http://www.beauregard.org/bldpress.htm8. http://www.everybody.co.nz/page-3f71418a-d1e1-43d7-9ac0-fdcb4a79a3e3.aspx9. http://www.merck.com/media/mmhe2/figures/fg022_2.gif10. http://member.rivernet.com.au/balehirs/drHt2.jpg11. http://www.physicaltherapy.ca/cardio/Hypertension1.html12. http://www.szgdocent.org/resource/rr/c-viper.htm13. http://home.caregroup.org/clinical/altmed/interactions/Drugs/Captopril.htm14. http://en.wikipedia.org/wiki/Enalapril15. http://www.medsafe.govt.nz/profs/Datasheet/p/prinzidepic1.gif16. http://www.alchemchina.com/products/apis_b.files/Benazepril.gif17. http://www.drugs.com/pdr/images/10/04044002.jpg18. http://www.medicinescomplete.com/mc/clarke/current/images/clk1438c001.gif19. http://www.smspharma.com/images/ramipril_img.gif20. http://www.geocities.com/lubolahchev/Moexipril.html21. http://www.fortunecity.com/roswell/spells/260/c9900109.gif22. http://en.wikipedia.org/wiki/Monopril23. http://www.beauregard.org/bldpress.htm24. http://www.cbi.cnptia.embrapa.br/~jorgehf/index2.html
For more detailed citations, please see accompanying paper.
