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Pharmacology: Cardio > Nitrates > Flashcards

Nitrates Flashcards

1
Q

What are organic nitrates?

A

Prodrugs that are sources/donors of NO

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2
Q

How does NO lead to vasodilation?

A
  • NO activates the soluble isoform of guanylyl cyclase, thereby increasing intracellular
    levels of cGMP
  • In turn, cGMP promotes the dephosphorylation of the myosin light chain ( myosin-LC-PO4) and the reduction of cytosolic Ca2+ (both cGMP dependent PKG activation)and leads to the relaxation of smooth muscle cells in a broad range of tissues
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3
Q

.

A

/

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4
Q

Explain the formation of NO in the body

A
  • Made possible by three isoforms of NOS (eNOS, iNOS, nNOS)
  • They are calcium dependent and oxidize L-arginine to from NO and L-citrulline as a byproduct
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5
Q

What are organic nitrates derived from?

A

Organic polyol esters of nitric acid

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6
Q

What are organic nitrites derived from?

A

Organic esters of nitrous acid

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7
Q

Nitrate esters vs nitritie esters vs nitro chemical bond characteristics

A

Nitrate esters (—C—O—NO2) and nitrite esters (—C—O—NO) are characterized by a sequence of carbonoxygen- nitrogen, whereas nitro compounds possess carbon-nitrogen bonds (C—NO2)

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8
Q

./

A

/.

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9
Q

Is nitroglycerin a nitro compound?

A
  • No, it is erroneously called nitroglycerin, however, this nomenclature is both widespread and official
  • It’s true name should be glyceryl trinitrate (nitroglycerin)
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10
Q

What does the term nitrovasodilators refer to?

A

A term for both organic nitrates and nitrites

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11
Q

What is the established mechanism of activation and action of nitroglycerin?

A

Include a nonenzymatic reaction with l-cysteine, formation of nitrite and NO by ALDH2 (Aldehyde dehydrogenase 2, mitochondrial enzyme), activation of soluble guanylyl cyclase, and generation of cGMP

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12
Q

Which organic nitrates are available for clinical use?

A
  • Nitroglycerin (glyceryl trinitrate)
  • Isosorbide dinitrate (ISDN)
  • Isosorbide-5-mononitrate (ISMN)
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13
Q

Bioactivation of ISDN and ISMN

A

ALDH2 independent, suggesting the involvement of other enzymes, such as CYPs, xanthine oxidoreductase, and cytosolic ALDH isoforms

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14
Q

Which race is nitroglycerin not so effective?

A

Individuals of Asian origin carry an inactive ALDH2 variant and do not respond adequately to GTN but do respond to ISDN

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15
Q

How does activation of PKG affect Ca+2 levels in cells?

A

Decreases cytosolic Ca+2 levels by:
- Increasing SER uptake of Ca+2
- Increasing efflux of Ca+2
- Increase in Ca+2 activated K+ channel activity

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16
Q

Action of NO on soluble cGMP is elicited through what?

A

Seems to be elicited in substantial part by S-nitrosothiol

17
Q

What can organic nitrates be divided into?

A

High potency nitrates (GTN, PETN) and low potency nitrates (ISDN, ISMN)

18
Q

What is reduced phosphorylation of myosin light chain kinase a result of in the presence of increased cGMP?

A

Reduced phosphorylation of myosin light chain is the result of decreased myosin light-chain kinase activity and increased myosin light-chain phosphatase activity

19
Q

Hemodynamic effects of nitrovasodilators

A
  • Promote relaxation of vascular smooth muscle leading to dilation of blood vessels
  • GTN dilates large blood vessels (>200-μm diameter) more potently than small vessels. explaining why low doses of GTN preferentially dilate veins and conductance arteries and leave the tone of the small-to-medium arterioles (that regulate resistance) unaffected
  • At low-to-medium doses, preferential venodilation increases venous capacitance which decreases venous return, leading to a fall in left and right ventricular chamber size and end-diastolic pressures, reduced wall stress, and thereby reduced cardiac O2 demand
  • An additional benefit of reducing preload is
    that it increases the pressure gradient for perfusion across the ventricular wall, which favors subendocardial perfusion
  • Pulmonary vascular resistance and cardiac output are slightly reduced
  • Doses of GTN that do not alter systemic arterial pressure may still produce arteriolar dilation in the face and neck, resulting in a facial flush, or dilation of meningeal arterial vessels, causing headache.
  • Higher doses of organic nitrates cause further venous pooling and may decrease arteriolar resistance as well, thereby decreasing systolic and diastolic blood pressure
  • Nitrovasodilators preferentially decrease preload by dilating venous capacitance vessels
  • The decrease in afterload is generally small and mainly
    observed at higher doses.
20
Q

Side effect oh high doses of organic nitrates

A
  • Higher doses of organic nitrates cause further venous pooling and may decrease arteriolar resistance as well, thereby decreasing systolic and diastolic blood pressure and causing pallor, weakness, dizziness,
    and activation of compensatory sympathetic reflexes
  • This can happen to such an extent that coronary flow is compromised, and the sympathetic increase in myocardial O2 demand overrides the beneficial action of the nitrovasodilators, leading to ischemia
  • In addition, sublingual nitroglycerin administration may produce bradycardia and hypotension, probably owing to activation of the Bezold-Jarisch reflex
  • In patients with autonomic dysfunction and an inability to increase sympathetic outflow (multiple-system atrophy and pure autonomic failure are the most common forms, much less commonly seen in the autonomic dysfunction associated with diabetes), the fall in blood pressure consequent to the venodilation produced by nitrates cannot be compensated which may reduce arterial pressure and coronary perfusion pressure significantly, producing potentially life-threatening hypotension and even aggravating angina.
21
Q

What are non-hemodynamic effects of organic nitrates?

A
  • Platelets: Decreases aggregation and thrombus formation
  • Neutrophils: Decreases cell adhesion and chemotaxis in acute inflammation, modulation of microvascular permeability
  • Endothelial cells: Protection against post-ischemic endothelial dysfunction
  • The nitrovasodilators also relax smooth muscles of the
    bronchial tract, the gallbladder, biliary ducts, and sphincter of Oddi and
    the GI tract
22
Q

Mechanism of antianginal efficacy of organic nitrate is attributed to what?

A
  • The major antianginal effect of nitrovasodilators is mediated by preload reduction rather than coronary artery dilation
  • When GTN is injected directly into the coronary circulation of patients with CAD, anginal attacks (induced by electrical pacing) are not aborted even when coronary blood flow is increased. In contrast, sublingual administration of GTN does relieve anginal pain in the same patients
  • This interpretation is supported by studies in exercising patients showing that angina occurs at the same value of the triple product (Aortic pressure × Heart rate × Ejection time (the time interval from aortic valve opening to aortic valve closure), which is roughly proportional to
    myocardial consumption of O2) with or without nitroglycerin. - Thus, the beneficial effect of nitroglycerin has to result from reduced cardiac O2
    demand rather than an increase in the delivery of O2 to ischemic regions of myocardium. - However, these results do not preclude the possibility that a favorable redistribution of blood flow to ischemic subendocardial
    myocardium may contribute to relief of pain in a typical anginal attack, and they do not preclude the possibility that direct coronary vasodilation may be the major effect of nitroglycerin in situations where vasospasm
    compromises myocardial blood flow.
23
Q

What is ventricular wall tension affected by?

A
  • Preload and afterload
  • Increasing end-diastolic volume augments the ventricular wall tension
24
Q

What is afterload?

A

Amount of pressure that the heart needs to exert to eject the blood during ventricular contraction

25
Q

What is afterload associated to?

A
  • In the absence of aortic valvular disease, afterload is related to peripheral resistance
  • Decreasing peripheral arteriolar resistance reduces afterload and thus myocardial work and O2 consumption
  • The distensibility of the large conductance arteries such as the aorta may play an additional role

Pharmacology: Cardio (3 decks)

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