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PHRM 844 Module #2 > Vasodilators > Flashcards

Vasodilators Flashcards

1
Q

Vasodilators

A

cyclic GMP modulators: organic nitrates/nitrites, PDE inhibitors, natriuretic peptide
K+ channel agonists
enodthelin receptor antagonists
PGI2 analogs - IP receptor agonists

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2
Q

Vasodilators that regulate membrane potential (reducing voltage-gated Ca2+ channel activity)

A

K+ channel agonists/openers

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3
Q

K+ channel agonists/openers

A

increasing K+ channel opening relaxes vascular smooth muscle
K+ flux sets the membrane potential
The longer K+ channels are open, the closer the membrane potential is to the K+ equilibrium potential
The closer the membrane potential is to the K+ equilibrium potential, the harder it is to depolarize the membrane enough to open Voltage-Gated Ca2+ Channels

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4
Q

K+ channel agonists/openers: minoxidil

A

prodrug
Activated in vivo by sulfotransferase 1A1
Used with loop diuretics and beta blockers
Very potent vasodilator- effective in severe, drug resistant forms of hypertension.
cAMP PDE inhibition may contribute to its efficacy
open class of K+ channels to help maintain (-) resting membrane potential; inhibits depolarization, inhibits Ca2+ influx through voltage-gated Ca2+ channels
Given orally (or topically to promote hair growth) - hypertrichosis

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5
Q

K+ channel agonists/openers: diazoxide

A

Used intravenously to treat acute hypertension
Very potent vasodilator- effective in severe, drug resistant forms of hypertension.
props open K ATP channels in vasculature, stabilize membrane potential and causes vasodilation
Inhibits release of insulin from pancreatic b-cells
Used orally for hypoglycemia secondary to hyperinsulinemia

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6
Q

K+ channel agonists/openers: adenosine

A

Binds to A1 receptor - a GPCR; doesn’t directly bind to K+ channels like the others
Increases conductance of a K+ channel - hyperpolarization and relaxation
Given IV- coronary stress test
Also- supraventricular arrhythmias

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7
Q

Hyperpolarization of vascular smooth muscle by adenosine

A

Gbeta,gamma binds and activates GIRK (G-protein activated inwardly rectifying K+ channel) - conducts K+ efflux & membrane hyperpolarization
activation of A1R causes activation of G protein, Gbeta,gamma binding to GIRK opens the channel, causes hyperpolarization of cardiac + vasculature smooth muscle

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8
Q

Drugs that stimulate nitric oxide production

A

organic nitrates
organic nitrites
indirect effect on vascular smooth muscle

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9
Q

Nitric oxide-cyclic GMP pathway

A

nitric oxide synthase –> isoforms: nNOS, iNOS, eNOS; in the vascular endothelium activated by Ca2+-CAM; produces NO from arginine
NOS in vascular endothelium and NO diffuses to vascular smooth muscle
eNOS is found in the endothelial cells of the vasculature.
NO was referred to as EDRF (endothelial derived relaxing factor)
Guanylate Cyclase in found in the vascular smooth muscle.
Exogenously applied NO can directly relax smooth muscle.
Nitric Oxide binds to heme iron prosthetic group in Guanylate Cyclase, stimulating production of cGMP and activating protein kinase G (cGKI)

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10
Q

How does protein kinase G relax smooth muscle

A

activation of protein kinase G causes phosphorylation of Cav1.2 and when phosphorylated, inhibits Ca2+ influx
(Cav1.2) - Inhibition of L-type Ca2+ channels; inhibits Ca2+ influx into smooth muscle cells
(BKCa) - Stimulation of Ca2+ -activated K+ channels; helps hyperpolarize membrane potential, inhibits Ca2+ influx into smooth muscle cells
(Myosin Phosphatase 1) - Decreased MLC phosphorylation; dephosphorylate myosin light chain
(Phospholamban - phosphorylated by protein kinase G) - Enhanced Ca2+ uptake in to ER; decrease amount of Ca2+ available to stimulate contraction via activation of myosin light chain kinase

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11
Q

Acetylcholine relaxes smooth muscle via

A

NO

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12
Q

Organic nitrates

A

Non-selective vasodilators - dilate veins + arteries
Breakdown to Nitric Oxide (Bioactivation)
Don’t require functional endothelium
Acute or chronic administration

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13
Q

Organic nitrates/nitrites

A

amylnitrite - inhalation
glyceryl trinitrate
pentaerythritol tetranitrate
isosorbide dinitrate - good oral bioavailability
isosorbide mononitrate - good oral bioavailability
nitroprusside - IV

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14
Q

PK of organic ntirates

A

Oral bioavailability: least - glyceryl trinitrate then isosorbide dinitrate, then isosorbide mononitrate
Half life: shortest - glyceryl trinitrate then isosorbide dinitrate, then isosorbide mononitrate
Given sublingually in treatment of acute attacks of angina
Given orally or transdermally for prolonged prophylaxis
Tolerance occurs with continuous administration

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15
Q

Pharmacogenetics of glycerol trinitrate

A

Glu 504 Lys polymorphism in ALDH-2
Glu 504 is 10X more efficient in metabolizing GTN
30-50% of Asian population has at least one Lys 504 allele
Likely accounts for the lack of efficacy of GTN in a large percentage of the Asian population
The Lys 504 allele also accounts for alcohol intolerance, as acetaldehyde metabolism is also reduced.

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16
Q

Differences in activation of glyceryl trinitrate (GTN) and isosorbide dinitrate/isosorbide mononitrate (ISMN/ISDN)

A

bioactivation is ALDH-2 independent for ISMN/ISDN but it required for GTN
possible activators: CYPs, xanthine oxidase, glithathione-S-transferase, cytosolic-ALDH
no clear 1 pathway for bioactivation

17
Q

Mechanisms of cell damage initiated by hyperglycemia

A

AGE precursor methylglyoxal inhibits vasorelaxation stimulated by acetylcholine/Nitric Oxide
methylglyoxal can react with arginine to form MG-H1 and this moeity cannot be converted to NO

18
Q

Sodium nitroprusside (SNP)

A

Given IV for acute management of hypertensive crisis and severe decompensated heart failure
Dilates veins and arterioles
Metabolized in erythrocytes to
NO*, 4 CN-, and cyanmethemoglobin (limits duration of treatment) - generating cyanide, very rapidly generates NO –> rapid effect on dilating vein + arterioles
CN- can inhibit oxidative metabolism- lactic acid accumulation.
CN- converted to less toxic SCN- by rhodanase, excreted via kidney
Sodium thiosulfate or hydroxocobalamin may be used for detoxification

19
Q

Organic nitrates: hydralazine

A

Doesn’t generate NO via bioactivation
Dilates arterioles preferentially
Mechanism not clear, appears to interfere with release of Ca2+ from the ER - reduce Ca2+ available to drive contraction
May also prevent oxidation of NO.
Can induce a Lupus-like syndrome
Given orally or IV
Combined with ISDN in BiDil:
Antioxidant activity potentiates vasodilatory activity of ISDN. BiDil decreases mortality in African Americans with CHF.

20
Q

Human type B natriuretic peptide (BNP)

A

Elevates NO levels through a diff pathway
Synthesized and secreted from heart muscle in response to increased blood volume.
Given IV in acutely decompensated HF
Binds to and activates membrane-bound guanylate cyclase (diff enzyme from the NO one, this is membrane bound and part of a receptor; NO one is soluble and has a heme center) in vascular smooth muscle and endothelial cells.

21
Q

Natriuretic peptide - membrane bound GC

A

ANP binds to natriuretic, binding of peptide to receptor activates intracellular guanylate cyclic domain, get an increase in cGMP –> decrease in amount of Ca2+ available to drive contraction –> vasodilatory effect

22
Q

Sacubitril

A

Inhibitor of neprilysin (a protease) - inhibits breakdown of natriuretic peptides
Combined with ARB valsartan (Entresto) ARNI Oral; BID
Pro-drug activated by esterases
Prevents breakdown of BNP, enhancing it’s action. (and angiotensin II and bradykinin - elevated levels (valsartan helps decrease these elevated levels))!
Not used with ACE inhibitors
Used to treat heart failure (both HFrEF and HFpEF)

23
Q

Drugs that inhibit the breakdown of cGMP/AMP: phosphodiesterase inhibitors

A

PDE3 (cAMP): amrinone, milrinone
PDE5 (cGMP): dipyridamole, sildenafil
cleave cGMP to GNP
bind in active site of phosphodiesterases and inhibit their ability to break down diff cyclic nucleotides

24
Q

cAMP phosphodiesterase inhibitors

A

amrinone/milrinone:
Given intravenously
Direct positive inotropic effect on myocardium Minimal chronotropic effect
Direct vasodilatory effect on vascular smooth muscle Used mainly in CHF (acute treatment) - not used chronically

25
Q

cGMP phosphodiesterase inhibitors

A

sildenafil:
Sildenafil is a potent and specific inhibitor of cGMP PDE 5.
10 fold selectivity of PDE 5 over inhibition of PDE 6 (retina)
Bluish vision
4000 fold selectivity of PDE 5 over inhibition of PDE 3 (CV)
lack of systemic vasodilation
Effect of Sildenafil (Viagra) on blood flow in the penis: PDE 5 is predominant in the corpus cavernosum. PDE 6 in retina is also weakly inhibited.

26
Q

Selective PDE 5 inhibitors

A

tadalafil (cialis): More selective for PDE 5 than Viagra; Longer duration of action than Viagra or Levitra
vardenafil (levitra): Shorter time to onset than Viagra; More selective for PDE5 than Viagra
sildenafil
regulation of contraction of smooth muscle within corpus cavernosum

27
Q

Selective PDE 5 inhibitors contraindications

A

any PDE5 inhibitor with organic nitrates
Why? - cGMP is an inhibitor of PDE 3
Precipitous drop in blood pressure- both drugs increase accumulation of cGMP.
Besides stimulating guanylyl cyclase, cGMP also inhibits PDE3, potentially increasing cAMP levels in VSM cells.
cGMP and cAMP both stimulate vasodilation via distinct mechanisms.

28
Q

Vasodilators used in pulmonary arterial hypertension (PAH)

A

vasoconstrictor antagonists

29
Q

Endothelin signaling

A

increased in PAH (constriction of arteries in lungs)
want to inhibit ET-1 activation: ET-1 increases Ca2+ - ETa and ETb cause vasoconstriction and proliferation of pulmonary arteries
ET-1 also have ETb that leads to activation of guanyl cyclase - NO and PGI2 get into vascular smooth muscle and increase cGMP and cAMP to cause vasodilation and antiproliferation

30
Q

Vasoconstrictor antagonists: bosetan and macitentan

A

Bosentan (Tracleer) and Macitentan (Opsumit) Specific, low MW
Endothelin receptor antagonists
Block both ETa (VSM) and ETb (VSM + Endothel) receptors

31
Q

Vasoconstrictor antagonists: ambrisentan

A

Ambrisentan (Letairis)
Blocks only ETa receptors
Approved for Pulmonary Arterial Hypertension Contraindicated in pregnancy (class); hepatotoxicity (Bosentan)
**Only available to females through special programs

32
Q

Prostacyclin analogs

A

Relax pulmonary vascular SM
PGI2 (epoprostenol; t1/2 3-5 min); IV
Treprostinil (Remodulin; t1/2~4 hrs); Oral, IV
Iloprost (Ventavis ; t1/2~ 30 min); Inhalation
Selexipag (Uptravi; t1/2 6-13 hrs); Oral
Used to treat pulmonary arterial hypertension

33
Q

Allosteric activator of sGC

A

Riociguat (Adempas) for Pulmonary Hypertension
Potentiates the effect of NO*
Stimulates sGC activity allosterically
Increases cGMP concentration in VSM
Not combined with nitrates or PDE5 inhibitors ( bc also increase cGMP levels )
Contraindicated in pregnancy
Risk of hemorrhage
Substrate for P-gp, CYP1A1, 3A
**Only available to females through special programs

34
Q

Selective PDE 5 inhibitors

A

PDE5 is expressed in vascular smooth muscle of the lungs.
Viagra (sildenifil) and Cialis (Tadalafil) are both indicated for treatment of pulmonary arterial hypertension.
Both are thought to enhance the vasodilatory effect of NO*.

35
Q

Know the selectivity of the vasodilators (i.e. do they dilate veins, arteries, or both?).

A

organic nitrates: non-selective vasodilators, dilate veins + arteries
cAMP/cGMP phosphodiesterase inhibitors: ?????
K+ channel openers: arteries

36
Q

Identify phosphodiesterase inhibitors with selectivity for cAMP vs. cGMP phosphodoesteases by name and structure.

A

Selective for cAMP: amrinone, milrinone (PDE3)
selective for cGMP: dipyridamole, sildenafil (PDE5)

37
Q

Differentiate the structure and activity of hydralazine from the organic nitrates/nitrites.

A

Nitrates are NO donors; hydralazine is a an antioxidant through the reduction of NO consumption

38
Q

Differentiate the action of adenosine on K+ channels from that of minoxidil and diazoxide.

A

adenosine doesn’t directly bind to K+ channels like minoxidil and diazoxide do
instead it works by binding to A1 receptor-a GPCR

PHRM 844 Module #2 (23 decks)

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