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

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

Measuring Blood Pressure Measured with: –Stethoscope –Sphygmomanometer (blood pressure cuff) Having your blood pressure measured is the only way to test for hypertension

Classifying Blood Pressure by Readings Blood Pressure Category Systolic (mm Hg) Diastolic (mm Hg) Normal<120<80 Prehypertension High: Stage High: Stage 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 GenderPrevalence 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 GenderDeath 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

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

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 diuretics Thiazide diuretic + ACE inhibitor ACE inhibitorsThiazide diuretic + ARB Angiotensin II receptor blockers Thiazide diuretic + Beta blocker Beta blockers Thiazide 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 mellitusACE Inhibitors, ARBs, Diuretics, Beta Blockers, Calcium Channel Blockers Heart failureDiuretics, Beta Blockers, ACE Inhibitors, ARBs, spironolactone Heart attackBeta Blockers, ACE Inhibitors, spironolactone Isolated systolic hypertension (elevated systolic only) Diuretics, certain Long-acting Calcium Channel Blockers Kidney DiseaseACE Inhibitors, ARBs Recurrent Stroke PreventionDiuretics, 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

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 IAngiotensin 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]

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

Dicarboxyl-containing ACE-Inhibitors Enalapril –Prodrug, activated in vivo to enalaprilat C 2 H 5 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

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

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

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

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

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

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

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

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, Patrick, Graham L. An Introduction to Medicinal Chemistry. 3 ed. New York: Oxford University Press, Online Sources: For more detailed citations, please see accompanying paper.