Transcript Cardiovascular Agents

Cardiovascular Agents
Michael Perez
Cardiovascular Disease
These are various
and have
innumerable
amounts of
treatments and
drugs used in
treatment
Focus on
hypertension and
angina (chest pain.)
Hypertension and
angina
Both of these can be caused by
constriction of the blood vessels in the
body, or simply by an increase in blood
flow in a vessel that isn’t dilated
completely. This of course causes
hypertension directly (high blood
pressure) and leads to chest pains if
these vessels deliver blood to the heart.
Nitric Oxide
Discovered in the early 1980’s.
A molecule that acts as a hormone by
being formed in response to a signal,
causing the smooth muscles
surrounding blood vessels to relax.
Causes blood pressure to go down
Mechanism of action not completely
understood
NO Synthesis in Body
Nitric oxide is formed by the oxidation of larginine via an enzyme called nitric oxide
synthase.
The NOS enzyme uses NADPH and oxygen
as cosubstrates


The NOS enzyme catalyzes a five-electron
oxidation of Argenine to NO and L-citrullline using
NADH as the source of electrons.
NOS produces NO in response to increased
calcium ion concentrations.
NOS
The enzyme is divided
into reductase and
oxygenase domains
with the central part of
the protein containing
a consensus
sequence for
calcium/calmodulin
binding.
Mechanism of Synthesis
Simpler Reaction
Possible NO Mechanism
This is not definitive, but is considered the
most likely way NO works:


target protein for nitric oxide is guanylyl cyclase,
enzyme that generates cyclic GMP from GTP by
causing a conformational change in guanylyl
cyclase by binding to the allosteric site on the
enzyme.
Cyclic GMP causes cylic GMP dependent kinase
to become activated, which phosphorylates
myosin light-chain kinase, making it inactive. This
renders it unable to interact with calcium ions that
bind to calmodulin and prevents phosphorylation
of myosin that interacts with actin to cause the
contraction of smooth muscle.
Nitro-vasodilator Drugs
These are metabolized into NO in the body
by an unknown reactions.
Ascanio Sobrero in Turin, Italy, first
discovered nitroglycerine in 1847. Sobrero
noticed that strong headaches were a direct
result of small quantites of agent placed on
the tongue.
Constantin Hering in 1849 tested
nitroglycerine on volunteers. Hering believed
that nitroglycerine might be used to relieve
headaches through the notion that “like cures
like.”
Nitroglycerine
In 1867 William Murrell
first used nitroglycerine
to treat angina.
In 1977, Ferid Murad
discovered the release
of nitric oxide from
nitroglycerine, causing
vascular smooth muscle
to dilate.
Sodium Nitroprusside
Nitroprusside consists of iron and cyanide
groups.
When liberation of cyanide takes place, the
drug is metabolized in the mitochondria.
Cyanide doesn’t cause toxic effects because
it is converted to thiocyanate. The kidney
later excretes thiocyanate.
Sodium nitroprusside is used for the
treatment of hypertensive emergencies, and
is given intravenously. Most frequently given
early in the treatment of acute heart failure.
Side Effects and
Downfalls
Patients have shown
resistance to nitroglycerine
and other vasodilators, like
amyl nitrate, after long
periods of use.
Thiocyanate accumulation
occurs, more often in
patients with kidney
problems after prolonged
nitroprusside infusion
causing nausea,
disorientation, psychosis
and muscle spasms.
Calcium Channel
Antagonists
These drugs have become the alternative as
of late to nitro-vasodilators in treating
hypertension and angina.
These act in much the same way, only they
directly block calcium from being released by
cells that later binds to calmodulin, preventing
phosphorylation of myosin that interacts with
actin to cause smooth muscle contraction.
Drugs and their receptor
target
Antagonists target the voltagedependent L-type calcium channels that
release the calcium ions responsible for
cardiac and smooth muscle contraction.
Bind the calcium channel and prevent it
from releasing calcium ions.
Dihydropyrdines
Nifedipine
Selective for smooth
vascular muscle over
cardiac muscle and
quick results
Short acting
Some instances of
heart attacks and
mortality
Different group of
dihydropyridines have
longer effects
DHP Structure
Chemical structure requirement for
these 1, 4-DHP agents to be active as
antagonists:

First, an aromatic ring is placed at the top
of the general nifedipine structure, which is
attached to the C-4 position.

Optimal to have the phenyl ring substituted at
the ortho-postion by an electron withdrawing
substituent. Studies have shown that a bulky
substituent at this position is favorable.
Modifications for
Antagonsim
X-ray diffraction
revealed that the DHP
has boat type
conformation with a
distortion at the c-4
postion and affects the
antagonistic nature
greatly
Ester groups in the C-3
and C-5 positions also
increase antagonist
activity
Conformational
Representation of DHP
L-Type Calcium Channel
Here is the transmembrane receptor
and the binding sites of different
antagonists are shown.
Diphenylalkylamines
Verapamil is most
common
Acts at different site
of L-type channel
Equally selective for
cardiac and vascular
smooth muscle

Risk of undesirable
myocardial
depression
Potential Drug
Improvements
Mibefradil

A tetralol derivative has been developed
from rougly 500 derivatives of verapamil.
This drug showed selectivity between
vascular and cardiac tissues during assay
screening and some clinical studies using
a guinea pig heart. Still in trials.