Cardiovascular Agents (5)

7/31/2019 Cardiovascular Agents (5)

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Cardiovascular Agents

Michael Perez


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Cardiovascular Disease

These are variousand haveinnumerableamounts of treatments anddrugs used intreatmentFocus onhypertension andangina (chest pain.)


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Hypertension and

anginaBoth of these can be caused byconstriction of the blood vessels in thebody, or simply by an increase in bloodflow in a vessel that isnt dilatedcompletely. This of course causes

hypertension directly (high bloodpressure) and leads to chest pains if these vessels deliver blood to the heart.


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Nitric Oxide

Discovered in the early 1980s. A molecule that acts as a hormone bybeing formed in response to a signal,causing the smooth musclessurrounding blood vessels to relax.

Causes blood pressure to go downMechanism of action not completelyunderstood


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NO Synthesis in Body

Nitric oxide is formed by the oxidation of l-arginine via an enzyme called nitric oxidesynthase.The NOS enzyme uses NADPH and oxygenas cosubstrates

The NOS enzyme catalyzes a five-electronoxidation of Argenine to NO and L-citrullline usingNADH as the source of electrons.NOS produces NO in response to increasedcalcium ion concentrations.


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NOS

The enzyme is dividedinto reductase andoxygenase domainswith the central part of

the protein containinga consensus sequencefor calcium/calmodulinbinding.


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Mechanism of Synthesis


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Simpler Reaction


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Possible NO MechanismThis is not definitive, but is considered themost likely way NO works:

target protein for nitric oxide is guanylyl cyclase,enzyme that generates cyclic GMP from GTP bycausing a conformational change in guanylylcyclase by binding to the allosteric site on theenzyme.Cyclic GMP causes cylic GMP dependent kinase tobecome activated, which phosphorylates myosinlight-chain kinase, making it inactive. This rendersit unable to interact with calcium ions that bind tocalmodulin and prevents phosphorylation of myosinthat interacts with actin to cause the contraction of

smooth muscle.


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Nitro-vasodilator DrugsThese are metabolized into NO in the body byan unknown reactions.

Ascanio Sobrero in Turin, Italy, firstdiscovered nitroglycerine in 1847. Sobreronoticed that strong headaches were a directresult of small quantites of agent placed onthe tongue.Constantin Hering in 1849 testednitroglycerine on volunteers. Hering believedthat nitroglycerine might be used to relieveheadaches through the notion that like cureslike.


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Nitroglycerine

In 1867 William Murrellfirst used nitroglycerineto treat angina.In 1977, Ferid Muraddiscovered the releaseof nitric oxide fromnitroglycerine, causingvascular smooth muscleto dilate.
http://en.wikipedia.org/wiki/Image:1%2C2%2C3-Tris-nitrooxy-propane.png


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Sodium Nitroprusside

Nitroprusside consists of iron and cyanidegroups.

When liberation of cyanide takes place, thedrug is metabolized in the mitochondria.Cyanide doesnt cause toxic effects becauseit is converted to thiocyanate. The kidneylater excretes thiocyanate.Sodium nitroprusside is used for thetreatment of hypertensive emergencies, andis given intravenously. Most frequently givenearly in the treatment of acute heart failure.


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Side Effects and

DownfallsPatients have shownresistance to nitroglycerineand other vasodilators, like

amyl nitrate, after longperiods of use.Thiocyanate accumulationoccurs, more often inpatients with kidneyproblems after prolongednitroprusside infusioncausing nausea,disorientation, psychosisand muscle spasms.


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Calcium Channel

AntagonistsThese drugs have become the alternative asof late to nitro-vasodilators in treating

hypertension and angina.These act in much the same way, only theydirectly block calcium from being released bycells that later binds to calmodulin, preventingphosphorylation of myosin that interacts withactin to cause smooth muscle contraction.


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Drugs and their receptor

target Antagonists target the voltage-dependent L-type calcium channels thatrelease the calcium ions responsible for cardiac and smooth muscle contraction.Bind the calcium channel and prevent it

from releasing calcium ions.


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Dihydropyrdines

NifedipineSelective for smoothvascular muscle over cardiac muscle andquick resultsShort actingSome instances of heart

attacks and mortalityDifferent group of dihydropyridines havelonger effects


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DHP Structure

Chemical structure requirement for these 1, 4-DHP agents to be active as

antagonists:First, an aromatic ring is placed at the topof the general nifedipine structure, which isattached to the C-4 position.

Optimal to have the phenyl ring substituted atthe ortho-postion by an electron withdrawingsubstituent. Studies have shown that a bulkysubstituent at this position is favorable.


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Modifications for

AntagonsimX-ray diffractionrevealed that the DHPhas boat type

conformation with adistortion at the c-4postion and affects theantagonistic naturegreatly

Ester groups in the C-3and C-5 positions alsoincrease antagonistactivity


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Conformational

Representation of DHP


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L-Type Calcium ChannelHere is the transmembrane receptor and the binding sites of differentantagonists are shown.


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Diphenylalkylamines

Verapamil is mostcommon

Acts at different siteof L-type channelEqually selective for cardiac and vascular

smooth muscleRisk of undesirablemyocardialdepression


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Potential Drug

ImprovementsMibefradil

A tetralol derivative has been developed

from rougly 500 derivatives of verapamil.This drug showed selectivity betweenvascular and cardiac tissues during assayscreening and some clinical studies using aguinea pig heart. Still in trials.

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Cardiovascular Agents (5)