PRO DRUGS:
OLMESARTAN MEDOXOMIL
Kelsey Davis, Courtney Getchell, Robert Kolar
Introduction
We will be covering the topic of prodrugs, specifically
a hypertension medication Olmesartan.
1)
An introduction to prodrugs and what they are
used for.
2)
How Olmesartan works and is distributed.
3)
Benefits and Risks.
What Is A Prodrug?


Simply, a prodrug is the precursor of the active
form of a drug.
In more complex terms, a prodrug is an inactive
form of a drug, but once administered, it undergoes
a conversion by metabolic processes to become the
active, pharmacological agent.
Why Design & Prescribe Prodrugs?

Prodrugs are designed to improve UNDESIRABLE and
CHALLENGING properties of drugs such as:



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Prodrugs ENHANCE the ADAME properties of the drugs. Especially:



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Formulation
Delivery
Toxicity
Absorption
Distribution
Metabolism
Excretion
And, Prodrugs are designed with greater selectivity for a particular
target. This improves the effect of the drug and also contributes to
decreasing the risk of unwanted tissue and organ toxicity.
Prevalence of Prodrugs in Medicine


Surprisingly, prodrugs are found in numerous types
of medications.
The beginning of the 21st century marked
breakthroughs in the development of prodrugs.
 Since
2008, at least 33% of small-molecular-weight
drugs have been prepared as prodrugs.
 Currently, 10% of all marked medicines are classified
as prodrugs.
Structure of a Prodrug

Generally, a prodrug is comprised of three key components:
The promoiety, the parent molecule, and the spacer.




The promoiety is a molecule used to mask the active group of the
drug by bonding to the parent molecule.
The parent molecule is the component that is released from the
promoiety once it is inside the body and contains the active form
of the drug.
The spacer is a synthetic handle used to attach the drug and the
promoiety, especially in the case of steric hindrance.
In some cases, a double prodrug may be prepared. This
consists of a second promoiety attached to the first
promoiety linked to the parent drug.

These promoieties are usually different and require different
methods of hydrolysis.
Prodrug Structures
Single Prodrug
Spacer
Double Prodrug
Bioactivation of a Prodrug


Once administered the body, prodrugs can be
converted to the active form by chemical reactions of
metabolic processes or more commonly by enzymemediated processes.
The enzymes involved in bioactivation largely include:

Esterases


hydrolyze esters into two components: an acid and an alcohol.
Cytochrome P450 Enzymes
perform an oxidation reaction of an R-group, converting it to an
alcohol
 In terms of prodrug activation, these Cytochrome P450 enzymes
oxidize the prodrug, resulting in the production of a metabolite, or
the active parent drug.

General Mechanism of a Prodrug
1.
2.
3.
4.
5.
The prodrug, containing its parent
molecule and promoiety, is
administered to the body.
It remains in that form while in the
extracellular fluids and while crossing
barriers to reach its target.
Once at the site of action, conversion
of the prodrug will take place either
by chemical or enzymatic reactions.
The prodrug is disassembled into its
parent molecule (active drug) and the
promoiety.
The parent molecule releases the
active drug particles and the
promoiety leaves the cell or tissue and
is excreted.
Bioactivation: Olmesartan Medoxomil


Due to the nature of prodrugs, they must be
bioactivated to be useful.
Olmesartan Medoxomil is converted to its active
form in the intestines when it is absorbed.
 During
absorption, ester hydrolysis activates olmesartan
medoxomil to the active form olmesartan
Ester Hydrolysis
• Utilizing enzyme activity, olmesartan medoxomil is converted to olmesartan by
addition of water and release of carbon dioxide and diacetyl.
• There is an addition of an OH group where the diacetyl is taken off . This is seen
with most CYP activity and is useful for helping the body excrete the toxin.
Absorption


Using suspension of the tablet in a formula solution
or tablets produce the same effect.
Taking olmasartan medoxomil with food does not
change the effective dose of olmasartan.
In the Blood Stream



After being hydrolized by ester hydrolysis,
Olmesartan is not metabolized any further.
Blood concentration levels stay at a steady 26%
Within 1-2 hours, the concentration of olmasartan in
the blood is at its peak.
Distribution

Olmasartan binds effectively to blood plasma
protein, but does not penetrate red blood cells.
 This


allows for effective transport throughout the body
Travelling through the body, it stays in the blood
stream and targets smooth muscle angiotensin
receptors.
Olmasartan poorly penetrates the blood brain
barrier, if at all.
Regulation of Blood Pressure
Baroreceptors sense increased arterial
pressure (case of high blood pressure)
2.
Increased action potentials sent to the
vasomotor system in the medulla via the
glossopharyngeal nerve
3.
Signal inhibits the vasoconstriction center
(sympathetic) and excites vasodilation
(vagal parasympathetic) centers sends
message using ACh as neurotransmitter
along the vagus nerve
4.
Results in reduced heart rate, cardiac
output, contractile strength, and
peripheral resistance, which contribute to
lowering blood pressure
* Opposite stimulation and inhibition occurs
when blood pressure is lowered, sympathetic
system uses norepinephrine as a
neurotransmitter instead of ACh
1.
The Role of Angiotensin



Angiotensinogen is released in liver, converted to angiotensin I by Renin from the
kidneys, and then converted to angiotensin II by angiotensin converting enzyme
(ACE) originating from the lungs and kidneys.
Angiotensin II increases heart rate via SNS stimulation and also increases water
retention via ADH and aldosterone. This leads to increased blood pressure.
Renin is released to enable the Renin-Angiotensin System (RAS) during low
arterial pressure conditions2
Hypertension




Sustained high blood pressure
(>140/90)
Increased chance of heart disease,
coronary artery disease, renal
failure, and stroke
Caused by increased peripheral
resistance
 Disruption of sympathetic nervous
system and/or the reninangiotensin-aldosterone system
Increased risk through obesity,
smoking, high sodium diet,
sedentary lifestyle, stress, and
genetic propensity
Hypertension and Angiotensin


Parasympathetic effects of baroreceptors are diminished
during hypertension because they specialize in short-term
regulation
Hypertension affects kidney function by restricting renal
blood flow and preventing regular resorption
Excess salt retention increased RAS activation
 Renin is released--> Angiotensin I forms and is then converted to
Angiotensin II
 Binds to receptor, increasing heart rate and aldosterone release
 Excess fluid retention from ADH and aldosterone
 Fluid balance returns to normal, but arterial pressure rises via
increased sympathetic stimulation and fluid retention

Olmesartan Mechanism of Action



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Angiotensin II is formed by ACE and then binds to AT1 receptors in vascular
smooth muscle
Olmesartan blocks this receptor (and AT2 to a lesser extent)
Prevent binding of angiotensin II, and therefore its vasoconstriction action is
inhibited lower blood pressure
Aldosterone release is not stimulated by angiotensin II decreased water
retention reduced blood volume
Other effects of Olmesartan

Negative feedback of
angiotensin II on renin
production is inhibited



Renin and angiotensin II level
remain high
This has no major effect, as the
receptors are blocked
Contrary to ACE inhibitors,
angiotensin receptor blockers
do not inhibit the conversion
of bradykinin to inactive
kinins

Bradykinin induces
vasodilation and respiratory
constriction (inflammatory
peptide)
Pharmokinetics

Follows linear pharmokinetics for
single doses <320mg and
multiple doses of 80 mg




The dosage declines at a constant
rate
Half life independent from
concentration
Clearance independent of dose
Olmesartan has a plasma
clearance of 1.3 L per hour and
a renal clearance of 0.6 L per
hour11


Clearance= Volume of distribution
* K (elimination constant)
Rate of removal from plasma and
kidneys
Excretion



After converted to its active
form, no further metabolism
occurs to Olmesartan
Two phase elimination with a
half-life of 13 hours in the
second phase
35% to 50% is resorbed from
urine, and the rest is excreted
via the biliary system (feces)
Benefits

Activation by our own metabolism allows for an inactive
drug with little risks to be administered.
Damaging effects can be seen from active drugs being
ingested, such as ibuprofen and its tendency to cause ulcers
when used heavily
 Use of our bodies metabolism allows the detoxifying effects
to be lessened, allowing for higher levels of bioavailable
drug.


Olmesartan can be administered at an 80mg dose
which is double the dosage point where there is no
increased effect and not be dangerous.

It also can be administered effectively at low doses,
approximately 2.5mg
Benefits Continued

Excretion of Olmesartan is slow enough to allow a
40mg dose to be 90% effective at 24 hours after
ingestion.
 Once
daily administration is sufficient to provide 24
hours of medication effect
 It only takes 1-2 hours for peak availability
Risks


Renal impaired patients cannot excrete Olmesartan
readily and can see tripled blood serum levels
after multiple doses.
Use in pregnancy and infants younger than a year
old show signs of abnormal kidney growth and high
morbidity due to RAAS pathway being blocked.
 This
is associated with all renin-angiotensin system
drugs
Side Effects

Common side effects of Benicar include dizziness,
bronchitis, back pain, headache, flu-like symptoms,
hematuria, and sinusitis.
Sources
1.
"Benicar (Olmesartan Medoxomil) Drug Information: Clinical Pharmacology - Prescribing Information at RxList." RxList. 27 June 2014. Web. 24 Apr. 2015. .
2.
Huttunen, K.M., Raunio, H., and Rautio, J. Prodrugs---from Serendipity to Rational Design. Pharmacological Reviews. 2011; 63: 750-771.
3.
4.
5.
6.
7.
8.
9.
10.
Klabunde R. Arterial Baroreceptors. Cardiovascular Physiology Concepts. April 24, 2014. http://www.cvphysiology.com/Blood%20Pressure/BP012.htm. Accessed
April 18, 2015.
Paul M, Mehr A, Kretz R. Physiology of Local Renin-Angiotensin Systems. Physiological Reviews. July 2006;86(3):747-803.
Whelton PK, He J, Appel LJ, et al. Primary Prevention of Hypertension: Clinical and Public Health Advisory From the National High Blood Pressure Education
Program. JAMA. 2002;288(15):1882-1888. doi:10.1001/jama.288.15.1882.
Navar LG. Counterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic Hypertension. Journal of Applied Physiology.
2010;109(6):1998-2000. doi:10.1152/japplphysiol.00182.2010a.
Head G. Baroreflexes and cardiovascular regulation in hypertension. Journal of Cardiovascular Pharmacology. 1995;26(2):S7-16.
Kobori H, Nangaku M, Navar L, Nishiyama A. The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease.
Pharmacological Reviews. September 2007;59(3):251-287.
Navar LG. Counterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic Hypertension. Journal of Applied Physiology.
2010;109(6):1998-2000. doi:10.1152/japplphysiol.00182.2010a.
Klabunde R. Arterial Baroreceptors. Cardiovascular Physiology Concepts. April 24, 2014. http://www.cvphysiology.com/Blood%20Pressure/BP012.htm. Accessed
April 18, 2015.
11.
Paul M, Mehr A, Kretz R. Physiology of Local Renin-Angiotensin Systems. Physiological Reviews. July 2006;86(3):747-803.
12.
Prodrug. (n.d.) Dorland's Medical Dictionary for Health Consumers. 2007. Web. 20 Apr. 2015.
13.
"Promoiety." Promoiety. ProZ.com. 15 Apr. 2011. Web. 17 Apr. 2015
14.
15.
16.
17.
Ratain MJ, Plunkett WK Jr. Principles of Pharmacokinetics. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition.
Hamilton (ON): BC Decker; 2003.
Head G. Baroreflexes and cardiovascular regulation in hypertension. Journal of Cardiovascular Pharmacology. 1995;26(2):S7-16.
Kobori H, Nangaku M, Navar L, Nishiyama A. The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease.
Pharmacological Reviews. September 2007;59(3):251-287.
Yang, Y., Aloysius, H., Inoyama, D., Chen, Y., and Hu, L. Enzyme-mediated hydrolytic activation of prodrugs. Acta Pharmaceutica Sinica B. 2011; 1(3): 143-159.