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Pharmacology -- Test #3 > Organic Nitrates and Vasodilators > Flashcards

Organic Nitrates and Vasodilators Flashcards

1
Q

Two main types of vasodilators presented in the lecture

A

Cyclic GMP modulators

K+ Channel Agonists

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2
Q

Three types of cyclic GMP modulators

A

Organic Nitrates/Nitrites
PDE Inhibitors
Vasoactive Peptides

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3
Q

How is Nitric Oxide made?

A

Conversion of L-Arginine into L-citruline+NO by Nitric Oxide synthase

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4
Q

Three isoforms of Nitric Oxide Synthase

A

nNOS (Neuronal)
iNOS (Inducible)
eNOS (Endothelial)

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5
Q

How is eNOA activated?

A

Ca-CAM

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6
Q

How does endothelial NOS influence skeletal muscle?

A

the NO diffuses out to the vascular smooth muscle

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7
Q

How does NO lead to protein Kinase G

A

NO binds heme prosthetic group of Guanylate Cyclase, stimulating the production of cGMP and activating protein kinase G.

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8
Q

How does cGMP activation influence cell activity?

A

It dephosphorylates Myosin LC, causing muscle relaxation

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9
Q

Where is eNOS? where is Guanylate Cyclase?

A

eNOS – Endothelial cells of vasculature

GC – Vascular smooth muscle

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10
Q

Four ways that Protein Kinase G relaxes smooth muscle

A
  1. Inhibition of L-type Ca Channels
  2. Stimulation of Ca activated K Channels
  3. Decreases MLC P-ation
  4. Enhanced Ca uptake into the ER
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11
Q

In an experiment, phenylephrine is applied to a normal vascular tissue sample, then acetylcholine afterward. What do you see?

A

Phenylephrine causes increase in tension that is released by acetylcholine

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12
Q

In an experiment, phenylephrine is applied to a vascular tissue sample with no endothelium, then acetylcholine afterward. What do you see?

A

Phenylephrine still increases tension, but acetylchoine can no longer release it

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13
Q

In an experiment, phenylephrine is applied to a normal vascular tissue sample soaked in L-NMMA, then acetylcholine afterward. What do you see?

A

Same as without L-NMMA EXCEPT the drop following acetylcholine exposure is smaller
(NMMA is a competitive inhibitor of NOsynthase)

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14
Q

In an experiment, first hemoglobin, then phenylephrine is applied to a normal vascular tissue sample, then acetylcholine afterward. What do you see?

A

Contraction, but no relaxation

NO complexes with the heme iron

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15
Q

Three important given organic nitrates

A 
Glycerol trinitrate (GTN)
Isosorbide dinitrate (ISDN)
Isosorbide mononitrate (5-ISMN)
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16
Q

Of the three given organic nitrates, rank from most to least half life and bioavailablily

A

5-ISMN, ISN

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17
Q

How are nitrates typically given in acute angina patients?

A

Sublingually

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18
Q

Risk of continuous administration of nitrates?

A

Tolerance

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19
Q

What do Organic Nitrates vasodilate?

A

Both Veins and Arteries

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20
Q

What happens to Organic nitrates after you take them?

A

They are broken down to NO by aldehyde dehydrogenase

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21
Q

Important nitrite listed?

A

Amylnitrite
Liquid – Inhaled Drug
“Poppers”

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22
Q

Molecularly speaking, how does GTN tolerance happen?

A

GTN requires use of ALDH2 to generate the active thionitrate intermediate. ALDH2 is regenerated by oxidizing reduced lipoic acid. Eventually, theres not enough reduced lipoic acid sitting around, so ALDH2 isn’t remade, so the active form of ALDH2 isn’t made.

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23
Q

Mutation that might make GTN ineffective?

A

Glu 504 Lys polymorphism

24
Q

Difference between GTN, ISMN, and ISDN activation?

A

Very similar

GTN and ISDN look like they both use mitochondrial and cytoplasmic ROS, which ISMN only used cytoplasmic

25
Q

Three important types of Prostacyclin analogs

A

PGI2 (epoprostenol)
Treprostinil
Iloprost

26
Q

Which prostacyclin analog has the longest half life? shortest?

A

Longest – Treprostinil (Remodulin) at 4 hours

Shortest – PGI2 at 3-5 minutes

27
Q

What are prostacyclin analogs used for?

A

Treatment of pulmonary arterial hypertension

28
Q

What is Hydralizine?

A

An organic nitrate that dilates arterioles preferentially

Appears to interfere with Ca release from theER

29
Q

Hydralizine associated risks (2)

A
  1. Can induce a lupus-like syndrome

2. when combined with ISDN, increased likelihood of mortality in African Americans with CHF

30
Q

Indications for Sodium Nitroprusside?

A

Given IV for acute management of HYPERTENISVE CRISIS and SEVERE DECOMPENSATED HEART FAILURE

31
Q

Sodium Nitroprusside works on…

A

Veins and Arterioles

32
Q

How does Sodium Nitroprusside work?

A

Metabolized in RBCs to NO and Cyanide

This is why it can only be given acutely

33
Q

CN can be converted to SCN by….

A

Rhodanase

34
Q

What is Riociguat? How does it work?

A

An allosteric activator of GC used to treat Pulmonary HTN.
1) Potentiates NO activity
2) Stimulates GC allosterically
Overall – Increased cGMP concentration in vascular SM

35
Q

Who should never get Riociguat?

A

Folks taking nitrates, PDE5 inhibitors

Pregnant Women

36
Q

Riociguat is a substrate for…

A

P-gp, CYP1A1, 3A

37
Q

What is the alternative mechanism of NO that may play a role?

A

Covalent modification of proteins by a nitrosyl transfer

Contributes to tolerance and endothelial dysfxn

38
Q

Phosphodiesterase 3 inhibitors

A

(In)Amrinone

Milrinone

39
Q

What do Phosphodiesterase 3 inhibitors do

A

make cAMP last longer

40
Q

List phosphodiesterase 5 inhibitors

A

Dipyridamole

Sildenafil

41
Q

What do Phosphodiesterase 5 inhibitors do

A

Make cGMP last longer

42
Q

Important details for cAMP Phosphodiesterase inhibitors

A

Given IV
Direct positive inotropic effect on myocardium
Direct vasodilatory effect on vascular smooth muscle

43
Q

cAMP Phosphodiesterase inhibitors are given in treatment of…

A

CHF (acute treatment)

44
Q

Common name for Sildenafil

A

Viagra

45
Q

Name three selective PDE 5 inhibitors

A

Tadalafil (Cialis)
Vardenafil (Levitra)
Sildenafil (Viagra)

46
Q

Why is there blueish vision for some folks with PDE5 inhibitors

A

also can activate some PDE6 in the retina

47
Q

Compare Levitra and Viagra

A

Shorter time to onset than Viagra

More selective for PDE5

48
Q

Compare Cialis and Viagra

A

More selective for PDE5 than Viagra

Longer duration of action than Viagra or Levitra

49
Q

What is Natrecor?

A

A Human type B natriuretic Peptide analog used to treat acutely decompensated HF

50
Q

How does Natrecor work?

A

Synthesized and secreted from heart muscle in response to increased blood volume.
Binds to/activates membrane bound guanylate cyclase in vascular smooth muscle and endothelial cells

51
Q

Describe how the vasodilators influence cell channels.

A

Vasodilators use camp->PKA or cGMP->PKG to promote potassium channel opening. This allows the membrane potential to approach the K potential, making it harder to depolarize and open up the Voltage gated Ca channels.

52
Q

Classic examples of a K+ Channel Agonist

A

Minoxidil

Diazoxide

53
Q

Why give Minoxidil?

A

Given with loop diuretics + beta blockers for HTN

Given topically to promote hair growth

54
Q

Why give Diazoxide?

A

Used IV to treat acute, severe/drug resistant HTN

Also given for hypoglycemia secondary to hyperinsulinemia

55
Q

What does Adenosine do?

A

Binds to A1 receptor a GPCR
Increases the conductance of the K+ channel
Given for CORONARY STRESS TEST

56
Q

How does adenosine dilate vessels?

A

Adenosine Receptor (A1) is activated and turns on the GIRK channel to conduct K+ efflux, causing membrane hyperpolarization

Pharmacology -- Test #3 (13 decks)

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