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Pharmacotherapy II > Hypertension Hockerman Exam 3 > Flashcards

Hypertension Hockerman Exam 3 Flashcards

1
Q

Why is the Ca gradient so high across cellular membranes?

A

Calcium is a second messenger so small changes have big effects.

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2
Q

What ion gradient is the basis for the resting membrane potential?

A

Potassium–leak channels allow the RMP to be the same as the equilibrium potential of potassium.

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3
Q

What is the basis for potassium channel selectivity for potassium?

A

The loops of the channel are spaced precisely to bind K better than H2O, stripping the hydration off the ion and allowing it to pass through.

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4
Q

What is the most important calcium channel in cardiac and smooth muscle?

A

Cav 1.2–trigger for vasoconstriction.

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5
Q

What is the basis for voltage gating in the calcium channel?

A

It has extra helixes that have a cluster of (+) amino acids internally–when RMP negative, pulls helixes downward into cell. Depolarization allows outer helix to move out of the way so inner helixes are free to open.

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6
Q

What are the two basic uses for calcium channel blockers?

A

Block of calcium channels in vascular smooth muscle (vasodilation in HTN and angina) and block of channels in cardiac muscle and SA/AV node (antiarrhythmic–if frequency dependent).

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7
Q

What muscle cells depend on extracellular calcium for contraction?

A

Smooth muscle and cardiac muscle–calcium coming in is amplified by release from intracellular stores.

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8
Q

How does increased calcium-calmodulin cause contraction in vascular smooth muscle?

A

It activates myosin LC kinase, which phosphorylates myocin LC to the active form which can cause contraction.

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9
Q

How does beta-adrenergic stimulation increase calcium influx?

A

It makes calcium channels open at more (-) voltages, increasing heart rate and contractility (impact on AV node)

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10
Q

What protein does calcium bind to in cardiac muscle that causes contraction?

A

Troponin. Troponin-calcium displaces tropomyosin allowing contraction. Similar to skeletal muscle, but IS dependent on extracellular calcium.

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11
Q

Why does skeletal muscle not rely on extracellular calcium for contraction?

A

There is a direct link between the voltage-gated calcium channel and RYR1, which causes release of calcium from the SR when the calcium channel changes conformation.

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12
Q

Name features of a dihydropyridine CCB.

A

Dihydropyridine ring attached to ring with a nitrogen attached to a proton (required) and ester linked side chains.

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13
Q

What dihydropyridine CCB is remarkably short acting, used for IV infusion only, and contains soy and egg allergens?

A

Clevidipine (Cleviprex)

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14
Q

Name members of the dihydropyridine CCBs.

A

Amlodipine, felodipine, nifedipine, isradipine, clevidipine, nisoldipine, nimodipine, nicardipine.

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15
Q

What are the characteristics of a dihydropyridine calcium channel blockade?

A

Voltage dependence (stronger affinity at depolarized RMP), tonic block/not frequency dependent (can bind to closed channel)

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16
Q

What tissues are DHPs selective for? Why?

A

Smooth muscle, especially in coronary arteries and vascular smooth muscle. This is because smooth muscle has a more positive RMP than cardiac muscle.

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17
Q

What DHP is unique in a slower onset, longer duration of action, and less reflex tachycardia?

A

Amlodipine

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18
Q

What DHP may uniquely depress cardiac function due to less tissue selectivity?

A

Nifedipine–avoid fast releasing nifedipine! (reflex tachycardia)

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19
Q

Why are DHPs efficaceous in angina?

A

they reduce oxygen demand in the heart.

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20
Q

What DHP is selective for cerebral arteries and is used in subarachnoid hemorrhage?

A

Nimodipine

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21
Q

What kind of CCB is verapamil and what kind of block does it exhibit?

A

Phenylalkylamine CCB; shows characteristic frequency dependence (only blocks open channel), minimal tonic block.

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22
Q

Compare the activity of verapamil to the DHP CCBs.

A

Verapamil causes less potent vasodilation but larger impact on the heart–slows HR and force of contraction, blunting reflex tachycardia.

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23
Q

What are the characteristics of diltiazem blockade?

A

Some tonic (closed channel) block and some frequency dependence (two different sites?)

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24
Q

How does the activity of diltiazem compare to verapamil and the DHPs?

A

Less potent vasodilation than either DHPs or verapamil, more initial reflex tachycardia than verapamil, some efficacy in arrhythmias unlike DHPs.

25
Q

What side effect are all CCBs prone to?

A

Edema!

26
Q

What side effects are more unique to the DHPs out of the CCBs?

A

Facial flushing, tachycardia, headaches

27
Q

What side effect is unique and a major adherence barrier in verapamil?

A

Constipation– >20%. Peristalsis significantly slowed.

28
Q

Which is active to cause constriction–myosin LC kinase or phosphorylated myosin LC kinase?

A

UNphosphorylated myosin LC kinase–phosphorylated is inactive and causes relaxation.

29
Q

Which is active to cause constriction–myosin LC or phosphorylated myosin LC?

A

PHOSphorylated myosin LC causes contraction–prevent this by phosphorylating myosin LC kinase.

30
Q

What are the four endogenous peptide vasoconstrictors?

A

Angiotensin, vasopressin, endothelin (elevated in PAH), urotensin (elevated in diabetics)

31
Q

How do endogenous peptide vasoconstrictors cause vasoconstriction?

A

Various cytokines, hormones, and sheer stress inhibit or activate production of endothelin 1. This then binds to receptors on vascular endothelium at the ETbeta (leads to NO production) and vascular smooth muscle at ETalpha (leads to pronounced vasoconstriction)–Net effect vasoconstriction

32
Q

What two vasoconstrictor antagonists block both ETa and ETb?

A

Bosentan (Tracleer) and macitentan (Opsumit)

33
Q

What vasoconstrictor antagonist blocks only ETa receptors and is approved for pulmonary arterial hypertension?

A

Ambrisentan

34
Q

What population should never receive a vasoconstrictor antagonist?

A

Pregnant women

35
Q

What are clinical uses of vasoconstrictors?

A

Treatment of shock (anaphylactic, brain trauma, hemorrhagic), adjunct to anesthesia to reduce clearance and systemic exposure, chronic orthostatic hypotension

36
Q

Name three types of cGMP modulating vasodilators

A

Organic nitrates, PDE inhibitors, vasoactive peptides

37
Q

What second messenger activates nitric oxide synthase?

A

Calcium-calmodulin

38
Q

Where is NO produced? Where does it act?

A

It is produced in the vascular endothelium and diffuses into the vascular smooth muscle where it acts.

39
Q

How does NO cause vasodilation?

A

NO binds to guanylate cyclase, stimulating production of cGMP, which activates PKG. PKG relaxes smooth muscle by inhibiting Cav 1.2 channels, stimulating calcium channels to hyperpolarize the cell, decreasing myosin LC phosphorylation, and increasing calcium uptake into the ER.

40
Q

How do organic nitrates like glyceryl trinitrate, isosorbide di- and mono-nitrate, amylnitrite, and nitroprusside work?

A

They break down to nitric oxide which is a vasodilator–does not need functional endothelium to work.

41
Q

What is a big drawback of the organic nitrates? How does this occur?

A

Tolerance develops quickly after continuous administration. This happens because the ALDH2 which is required for activation of nitrates cannot be regenerated with continuous administration. After it is used up, activation of the organic nitrate will stop, stopping NO production

42
Q

What polymorphism is responsible for both the organic nitrate lack of efficacy and alcohol intolerance in asian populations?

A

Lys 504 instead of Glu 504–dramatically lower efficacy.

43
Q

What are the commercially available forms of prostacyclin and what condition are they used to treat?

A

Epoprostenol IV, treprostinil PO/IV, iloprost inh. Used for PAH.

44
Q

What vessels does hydralazine preferentially dilate? What autoimmune condition can it induce?

A

Preferentially dilates arterioles; can induce lupus-like syndrome.

45
Q

How is hydralazine used in practice?

A

Often combined with isosorbide dinitrate–potentiates vasodilatory activity. Combination decreases mortality with AA pts with CHF. Used for refractory HTN.

46
Q

Why should you use sodium nitroprusside with caution?

A

The abundance of cyanide groups can lead to cyanide toxicity. Detoxify with sodium thiosulfate or hydroxocobalmin. However, it can be used for HTN crisis and severe decompensated HF.

47
Q

What is riociguate used for and what are the risks?

A

Used for PAH because it potentiates the effect of NO to increase cGMP concentration. Risk of hemorrhage, teratogenic.

48
Q

What is the alternate mechanism of action for NO?

A

Covalent modification of proteins after bonding to glutathione.

49
Q

How do PDE inhibitors cause vasodilation?

A

By preventing breakdown of cAMP, they lead to increased MLCK phosphorylation and relaxation. PDE5 inhibitors act in the corpus cavernosum selectively.

50
Q

How are PDE3 inhibitors amrinone and milrinone given? Do they affect the rate or strength of heart contraction more?

A

Given IV–increase contractility but not heart rate. Vasodilatory, used in CHF acutely.

51
Q

What second messenger do PDE5 inhibitors affect?

A

cGMP

52
Q

Do PDE5 inhibitors (sildenafil, dipyridamole, tadalafil, vardenafil) cause vasodilation?

A

No–4000 fold selectivity for PDE5/PDE3

53
Q

How do PDE5 inhibitors sometimes cause bluish vision?

A

Inhibition of PDE6 in the retina

54
Q

What PDE5 inhibitor is the least selective?

A

Viagra (sildanefil)

55
Q

What natriuretic peptide analog is given IV in acutely decompensated HF to cause vasodilation through membrane bound guanylate cyclase?

A

Natrecor (nesiritide)

56
Q

How does minoxidil cause vasodilation? What is its big side effect?

A

After bioactivation by sulfotransferase, it opens potassium channels, causing hyperpolarization that makes it harder for calcium channels to open. Can cause hair growth (hypertrichosis).

57
Q

What is an additional use for diazoxide, a potent potassium channel agonist?

A

Inhibits release of insulin from pancreatic beta cells–can be used orally for hypoglycemia secondary to hyperinsulinemia.

58
Q

What is a use for adenosine and how does it work?

A

It is used for coronary stress tests. Through a1 GPCR, it increases conductance of potassium channel, causing hyperpolarization.

Pharmacotherapy II (15 decks)

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