Med Chem Spring Lec 5

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Treatment of Heart Failure – Nonglycosidic Positive Inotropic Drugs

Nonglycosidic positive inotropic drugs can be divided into two main classes, what are they?

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those that act via stimulating the synthesis of cyclic adenosine monophosphate (cAMP), such as adrenergic and dopaminergic agonists; and those that inhibit the hydrolysis of cAMP, such as phosphodiesterase 3 (PDE3) inhibitors.

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PDE3 Inhibitors affect what? What does this increase? What does it promote?

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a GPCR and increase intracellular cAMP, promoting cardiac muscle contraction but vasodilation of vascular smooth muscle.

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_____ is the drug of choice from among the currently available PDE3 inhibitors

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Milrinone

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Milrinone is the drug of choice from among the currently available PDE3 inhibitors because why?

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because of its greater selectivity for PDE3, shorter half-life (30–60 min), and fewer side effects

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The well-known catecholamines norepinephrine and epinephrine are potent what?

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nonselective adrenergic receptor agonists.

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Because the actions of these agents are not limited to the myocardial
β1-receptors they produce what?

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undesirable positive chronotropic effects, exacerbating arrhythmias, and also cause vasoconstriction.

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______ is a β1-adrenergic agonist on the myocardium with beneficial effects, the composite of a variety of actions on the heart and the peripheral vasculature.

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Dobutamine

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Dobutamine is active only by

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the intravenous route because of its rapid first-pass metabolism via COMT (catechal-O-methyl transferase).

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____ is the chronic disease affecting the coronary arteries, which supply oxygenated blood from the left ventricle to all heart tissues, including the ventricles them-elves.

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Angina pectoris

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When the lumen of the coronary artery becomes restricted, it becomes less efficient in doing what? What does this do to the heart?

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supplying blood and oxygen to the heart, and the heart is said to be ischemic (oxygen deficient).

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______ is the primary symptom of ischemic heart disease and is characterized by a sudden, severe pain originating in the chest.

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Angina

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Antianginal drugs act to alleviate and prevent what?

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anginal attacks

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Antianginal drugs act to alleviate and prevent anginal attacks by altering what?

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the oxygen supply/oxygen demand ratio to the cardiac muscle or dilating the coronary vessels.

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Three classes of drugs are found to be very efficient in this regard, although via different mechanisms. These include what?

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organic nitrates, calcium channel blockers and β-adrenergic blockers

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The vasodilating effect of organic nitrates on the veins leads to what?

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pooling of the blood in the veins and decreased venous return to the heart (decreased preload),

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The vasodilating effect of organic nitrates on the veins leads to pooling of the blood in the veins and decreased venous return to the heart (decreased preload), how does this differ from the vasodialation of the coronary arterioles?

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whereas vasodilation of the coronary arterioles decreases the resistance of the peripheral tissues(decreasedafterload).

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What are 5 members of Antianginal Drugs – Nitrates, Nitrites
?

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amyl nitrite (amyl nitrite inhalant USP),
nitroglycerin,
isosorbidedinitrate, erythrityltetranitrate, and pentaerythritoltetranitrate.

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Five members of this class are in clinical use today: amyl nitrite (amyl nitrite inhalant USP), nitroglycerin, isosorbidedinitrate, erythrityltetranitrate, and pentaerythritoltetranitrate. Two additional organic nitrates are what?

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tenitramine and propatylnitrate, are currently available in Europe.

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What is the proper names of nitroglycerin and amyl nitrite?

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Nitroglycerin vs. glyceryltrinitrate. Amyl nitrite vs. an isoamyl nitrite.

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Common names vs proper names: Nitroglycerin vs. glyceryltrinitrate. Amyl nitrite vs. an isoamyl nitrite.

The small lipophilic ester character makes them what? When are they hydrolyzed?

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volatile and they are hydrolyze in the presence of moisture.

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The lipophilic nature of these esters, however, makes these agents very efficient in emergency treatment of what?

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anginal episodes as a result of their rapid absorption through biomembranes.

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The organic nitrates are pharmacological sources of ___ ___ for the body

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nitric oxide

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Other drugs – ___ __ ___– require some metabolism to free the NO from their chemical structures.

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he nitric oxide donors

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Molsidomine is an oral NO donor known as a ______?

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sydnoneimine,

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Molsidomine is an oral NO donor known as a sydnoneimine is what kind of compound? What is it soluble in?

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a mesionic compound that is soluble in both water and organic solvents.

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Molsidomine is enzymatically metabolized by __ ___ to its active metabolite?

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liver esterases

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What is Molsidomine active metabolite?

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linsodimine,

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Molsidomine is enzymatically metabolized by liver esterases to its active metabolite, linsodimine, which is spontaneously converted in the blood into what?

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nitrosometabolite SIN-1A.

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Molecular oxygen is required to release NO from what?

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SIN-1A

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_______ has a slower onset and longer duration of action than conventional nitrates

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Molsidomine

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Molsidomine has a slower onset and longer duration of action than conventional nitrates because of the relatively slow rate of conversion to what?

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linsodimine

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Nitric oxide acts as a ___ ___

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cellular messenger

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Nitric oxide acts as a cellular messenger, leading to activation of soluble

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guanylatecyclase

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Nitric oxide acts as a cellular messenger, leading to activation of soluble guanylatecyclase to release ___ and ___

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cGMP and vasodilation

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___ ___are specialized myocardial fibers that conduct an electrical stimulus or impulse that enables the heart to contract in a coordinated fashion.

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Purkinje fibers

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The resting cell has a membrane potential of approximately ___

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-90 mV,

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The resting cell has a membrane potential of approximately -90 mV, with the inside of the cell being electronegative relative to the outside of the cell. This is termed the ___ ____

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transmembrane resting potential.

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On excitation, what does the transmembrane potential so?

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reverses, and the inside of the membrane rapidly becomes positive with respect to the outside.

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On recovery from excitation (repolarization), the __ _____is restored.

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resting potential

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What does phase zero represent?

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represents depolarization and reversal of the transmembrane potential,

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Phases 1–3 represent what?

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different stages of repolarization,

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Phase 4 represents what?

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the resting potential.

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Purkinje fibers “wire” the heart for what>

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for electrical impulses,

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Purkinje fibers “wire” the heart for electrical impulses, allowing the heart to do what?

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to beat in a coordinated fashion.

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Purkinje fibers “wire” the heart for electrical impulses, allowing the heart to beat in a coordinated fashion. The electrical potentials are the result of a coordinated sequence of what?

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ion movements in and out of these cells.

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_____ initially enters the cell, followed by a ___ ____, and finally, a ____ _____returns the cell to its resting state

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Sodium

calcium influx

potassium efflux

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. Several antiarrhythmic agents exert their effects by altering __ ___?

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ion fluxes

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class IA moa? What is its primary sites of action? What are drug examples?

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Na channel blockade
slows Phase O depolarization

Atrial and ventricular tissue

Quinidines
Procainamide

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Class IB moa? What is its primary sites of action?

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Na channel blockade
shorten Phase 3 repolarization

Ventricular tissue

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Class IC moa? What is its primary sites of action?

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Na channel blockade
markedly slows Phase O depolarization

Ventricular tissue

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class II MOA? Primary sites of ACtion?

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blocks symaptheticβ-adrenergic receptors
slows Phase 4 repolarization

SA node
AV node

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Class III MOA? Primary sites of ACtion?

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K channel blockade
prolongs Phase 3 repolarization

Atrial and ventricular tissue

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Class IV MOA? Primary sites of ACtion?

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Ca channel blockade
slows Phase 4 repolarization

SA node
AV node

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Quinidines are metabolized to the what forms?

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des-methyl and hydroxylated-vinyl forms,

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Quinidines are metabolized to the des-methyl and hydroxylated-vinyl forms, which are only about __as active as parent compound

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1/3

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______ produces significant though short-lived antiarrhythmic effects along with considerable central nervous system toxicity.

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Procaine

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Moreover, procaine is not active orally because of why?

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ITs short duration

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Moreover, procaine is not active orally because of its short duration of action caused by both what?

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chemical and plasma esterase hydrolysis.

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Moreover, procaine is not active orally because of its short duration of action caused by both chemical and plasma esterase hydrolysis. A logical modification of this molecule was the isosteric replacement of the ester with an amide group. This produced orally active ____

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procainamide,

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Lidocaine normally is reserved for the treatment of what?

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ventricular arrhythmias.

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What are two orally bioavailable derivatives of Lidocaine.

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Tocainamide and Mexilitine

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_____ was originally used as an antiepileptic, but CV side-effects were also found to be effective in the treatment of arrhythmias.

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Phentoin

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Phentoin w as originally used as an antiepileptic, but CV side-effects were also found to be effective in the treatment of arrhythmias. The cyclic 5-membered hydantoin ring makes the drug what?

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poorly soluble, slow to absorb, and resistant to metabolism.

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Flecainideand Encainide act as what?

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as Type 1C antiarrhythmics

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_____ is a local anesthetic that is structurally similar and has Type 1C activity

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Propafenone

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is a phenothiazene analogue that exhibits a persitent Type 1C effect,

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Moricizine

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Class II are inhibitors of what?

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depolarization by the depression of adrenergically enhanced calcium influx through a β-receptor blockade.

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Inhibitors of repolarization, they cause an extended refractory period (Phase 4), by blocking what?

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potassium channels.

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Inhibitors of repolarization, they cause an extended refractory period (Phase 4), by blocking potassium channels. _______ was the first drug used with this effect, although hypotension could be a severe side effect.

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Bretyliumtosylate

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____ and ____ are essentially Sotalol derivatives that lack β-adrerenergic blocking activity.

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Ibutilide and Dofetilide

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____ acts as a ClassI-IV antiarrhymic and has a unique mechanism of action involving alteration of the lipid membrane in which ion channels an receptors are located.

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Amiodarone

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What are Class IA examples

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procaine

procainamide

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What are 4 class IB examples

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Lidocaine, tocainide, Mexiletine, phenytoin

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What are 4 class IC examples

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flecainide, encainide, propafenone, Moricizine

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What are 2 class II examples

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propranolol

sotalol