Transcript Agents to Treat Hypertension

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
http://www.beauregard.org/bldpress.htm
• 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
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 Category
Systolic
(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?
• Affects 1 billion people worldwide
• Affects 65 million Americans age 6+
• 30% of people with hypertension don’t
know they have it
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%
(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:
http://www.physicaltherapy.ca/cardio/Hypertension1.html
– 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 inhibitors
Thiazide 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 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)
http://www.szgdocent.org/resource/rr/c-viper.htm
• 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
ACE
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu → Asp-Arg-Val-Tyr-Ile-His-Pro-Phe + His-Leu
Angiotensin I
Angiotensin II
• The reaction produces angiotensin II, an
octapeptide
• ACE is membrane-bound and could not be
isolated for study
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
[2]
• 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
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
http://en.wikipedia.org/wiki/Enalapril
• 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
Dicarboxyl-containing
ACE-Inhibitors
• Lisinopril
– Active molecule
– Lysine analogue of
enalaprilat
– Characterized by:
• Slow, variable, & incomplete
absorption (30%- not
reduced by food)
http://www.medsafe.govt.nz/profs/Datasheet/p/prinzidepic1.gif
– 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.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%)
http://www.drugs.com/pdr/images/10/04044002.jpg
• 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.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
http://www.geocities.com/lubolahchev/Moexipril.html
• 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.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
http://www.beauregard.org/bldpress.htm
• 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 ACEInhibitors
• 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
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.