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SRNAPharmacology I > Peripheral VASODILATORS > Flashcards

Peripheral VASODILATORS Flashcards

1
Q

Peripheral vasodilators most frequent clinical uses

A

Treat HTN crisis and pulmonary HTN
produced CONTROLLED HYPOTENSION during anesthesia to REDUCE BLOOD LOSS
Facilitation of vessel surgery

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2
Q

Nitric Oxide (NO) pathway is a _______substance
Produced by?
synthesized in ________from the amino acid ______- by
_______________
catalyzes oxidation of ______To produce _______and ______
also called___________

A

NO is a gaseous substance
produced by endothelial cells and other cells
synthesized from L-arginine AA using Nitric oxide synthetase
Catalyzes oxidation of L-arginine to produce L-citrulline and NO
NO is also called EDFR (Endothelium derived relaxing factors.

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3
Q

NO MOA

Broken down by?

A

Endothelial cells diffuse into smooth muscle where it binds to and activate guanylate cyclase which is an enzyme that dephopsphorylate GTP to cGMP and increases cGMP concentration
cGMP, which act as 2nd messenger, then induces smooth muscle relaxation via multiple mechanism
Broken down by PHOSPHODIESTERASES

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4
Q

NO CV effects

A

Decrease PVR
decrease SVR
Inhibit platelet aggregation, role in inflammatory system and platelet activity

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5
Q

***NO pathway and bleeding risk

A

**Drugs that work through NO pathway DO NOT INCREASE bleeding risk

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6
Q

Endogenous NO act as a

A

neurotransmitter in the brain, spinal cord and PNS
Releases in response to NMDA glutamate receptors
Modulating anesthetic effect

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7
Q

**NO Anesthesia mechanism

A

***The main interest of NO in ANESTHEISA is its role as a VASODILATOR

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8
Q

Sodium Nitroprusside (SNP)

A

Direct acting MIXED and VENOUS vasodilator that produces nonselective relaxation of peripheral arterial and venous vascular smooth muscle
DECREASES Preload and afterload, and BP

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9
Q

SNP is very potent almost in____________ chemical structure

A

50% cyanide

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10
Q

Onset of SNP

A

Immediate (seconds)

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11
Q

Duration of action of SNP

A

1-2 min

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12
Q

SNP usually required

A

Direct artery pressure monitoring.

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13
Q

SNP is vasodilator agents that acts by

A

releasing NO
Direct NO donor
and NO is the active mediator.

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14
Q

SNP MOA

A

NO carries out the CV effect

Increases cGMP –> Vascular smooth muscle relaxation leading to vasodilation

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15
Q

SNP interact and binds to

A

-oxyhemoglobin to form METHEMOGLOBIN an unstable nitroprusside radical
-This unstable nitroprusside radical then dissociate rapidly to relase (5) cyanide ions AND nitric oxide
-CANNOT BE inhbitired or reduced
The

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16
Q

Amount of cyanide ions is

A

dose dependent.

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17
Q

Sodium nitroprusside must be p

A

protect from light –> bluish color complete degradation

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18
Q

SNP products of the nitroprusside /hemoglobin reaction are-

A

(1) Cyanide ions: CN ions reacts with methemoglobin to form cyanmethemoglobulin, which is NON-toxic
(4) the other 4 cyanide ions: The majority of the CN ions produced during the biotransformation of nitroprusside go to liver and are converted by enzyme RHODANASE , which uses THIOSULFATE (cofactor) as a sulfur donor to form THIOCYANATE -THYOCYONATE is then Excreted by Kidneys

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19
Q

What is the main route of elimination of CN - ions :

A

via the conversion to THIOCYANATE

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20
Q

ONLY excreted via kidneys

A

SNP

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21
Q

Free cyanide ions that are not otherwise removed can bind to

A

the CYTOCHROME OXIDASE complex in cells preventing the cell from being able to use Oxygen and can cause toxicity

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22
Q

**Toxicity of SNP

A

Methemoglobinemia
Thiocyanate toxicity
Cyanide toxicity

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23
Q

The recommended dose of SNP is up to

A

10mcg/kg/min results in cyanide formation at a far greater rate than humans rate of detoxification

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24
Q

Even though SNP is excreted by kidneys cyanide removal required 3 things

A

Adequate liver function
Adequate renal function
adequate bioavailability of thiosulfate

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25
Q

Signs and symptoms of Cyanide toxicity

A 
headache dizziness, (CNS)
Tachycardia, mydriasis, 
APNEA
****increased mixed venous PO2 = decreased PaO2 (due to paralysis of cytochrome oxidase and the inability of tissues to use O2)
(body cannot use o2)
***SMELL OF ALMONDS on breath
Metabolic acidosis due to ANAEROBIC metabolism 
LA > 8 , cyanide > 40 mM dangerous.
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26
Q

SNP treatment

A

Administer 100% O2
Adequate hydration

**Amyl nitrite (Converts Hgb to methemoglobin, which reacts with free cyanide to form CYANMETHEMOGLOBIN (non-toxic)
***Sodium nitrite (same mechanisms ) 5mg/kg IV over 2-4 mins
Sodium thiosulfate, (cofactor needed by liver to convert cyanide to thiocyanide)

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27
Q

SNP treatment additional:

A

HYDROXOCOBALAMIN (cyanokit)

Binds to cyanide ions to form nontoxic cyanocobalamin which eliminated by the kidneys and allows body to use O2 again

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28
Q

Thiocyanate is cleared by the _____and half life is _____

A

kidneys

half life 3 days

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29
Q

SNP Clinical effects

A

Hypotension
Decreased preload and afterload
Dilation of coronary arteries.
***Baroreceptor-mediated reflex response to the SNP induced decreases in systemic BP manifested as Tachycardia and increased myocardial contractility.

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30
Q

Vasodilators : SNP

A

Decreases Ventriular filling pressure

Increase SV

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31
Q

SNP may cause

A

increase plasma renin levels
Activate RAAS (BP lowering goes way when titated off)
**REBOUND Hypertension (rare)

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32
Q

SNP can cause this phenomenon

A

Coronary Steal Phenomenon
Give SNP –> steal blood and distribute globally even in areas you don’t need
in MI, bad, increased MI Size

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33
Q

Never give SNP

A

patient with hypotension related to MI

it causes SHUNTING OF BLOOD AWAY from ISCHEMIA areas to non-ischemic areas

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34
Q

**CEREBRAL effects of SNP
ICP?
Cerebral blood flow?
Blood volume ?

A

Increased ICP

Increased cerebral blood flow and blood volume

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35
Q

How does SNP affect CPP

A

CPP = MAP- ICP

Decrease MP and increased ICP = decrease CPP

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36
Q

Other Clinical effects of SNP

A

Decreases PVR
Decreased PaO2
Increased Intra pulmonary shunt

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37
Q

Clinical uses of SNP

A 
Main areas 
1.Induce controlled HTN during anesthesia, 
Maintain MAP 50-60 mmHg
2.Aortic surgery
3.HTN emergencies
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38
Q

Anesthesia precausion of SNP

A

patietn’s capacity to compensate for anemia and Hypovolemia may be diminished
if possible, pre existing anemia and hypovolemia should be corrected

Hypotensive anesthetics technique may also cause abnormalities of the pulmonary ventilation/perfusion ration, pt intolerant these abnormalities may required HIGHER fraction of O2

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39
Q

ORGANIC NItrates

What is the active mediator?

A

These agents are PRODRUGS are sources of NO. All organic nitrates must be metabolized to generate gaseous NO and it is NO that is the active mediator?

40
Q

3 organic nitrates example? which one use for anesthesia

A

Nitroglycerin
Isosorbide dinitrate
isosorbide 5 mononitrate

41
Q

Issues with organic nitrates

A

Tolerance: repeated exposure to high doses of organic nitrates leads to a marked attenuation in the magnitude of their pharmacologic effects

42
Q

*****Nitroglycerin

A

Potent venodilating agent NO EFFECT on dilation of arteries at LOW doses
As the dose NTG is INCREASED

43
Q

**With NTG, arterial vasodilation occurs at

A

100mcg/min IV

NOT mcg/KG

44
Q

Onset of action of NTG

A

2-5 minutes

45
Q

Les than 100mcg

A

only dilating veins

46
Q

Drug of choice for HTN emergencies and active MI patient

A

NITROGLYCERIN

47
Q

NTG CV effects

A

Decreased preload and afterload.

48
Q

Routes of administration :

A

Multiple,

49
Q

NTG mechanism of action

A

combines with SULFHYDRYL groups in vascular endothelim to create S-nitrosothiol compounds that increase the release of NO

50
Q

NTG generates

A

NO and is direct NO “donor”

51
Q

NTG requires enzymes to break down, unlike STP which does not require enzymes to work , therefore it takes

A

longer

52
Q

NTG have _____bioavailability due to _____First pass heaptic effect from hepatic metabolism

A

LOW; large

53
Q

Metabolism

A

by reductive hydrolysis int he liver

also undergoas extrahepatic metabolism in RBcs and vacular walls.

54
Q

**NTG pharmacokinetics:

A

High Vd
High clearance.
INTER-individual variations in plasma concentration difficult to predict plasma levels

55
Q

NTG pharmacokinetics comment on nitrate ions

A

Nitrate ions liberated during the metabolism of NTG can oxidize the ferrous ion in Hgb to the ferric state and produce METHEMOGLOBIN

56
Q

Treatment of NTG toxicity?

A

Methylene blue 1-2mg/kg/IV

57
Q

Methylene blue does what?

A

facilitate the conversion of methemoglobin to HEMOGLOBIN

rapid onset of action

58
Q

NTG primarily

A

decreasing preload

59
Q

Venodilation in NTG leads to :

  • Is myocardial contractility.
A

decrease preload, which stretch on the myocardium (decrease myocardial wall tension)
Right and left END diastolic pressure (filling pressure ) decreased
Decreased RAP, and decreased CO
Myocardial contractility is TYPICALL UNAFFECTED

60
Q

CV effects of NTG

A

Coronary vasodilation (through multiple mechanisms)
GOOD for MI patients, increased blood supply to the coronary arteries, increasing coronary blood flow to ischemic area.
NO CORONARY STEAL with this drug.

61
Q

Excessive decreased in diastolic pressure with NTG can:

A

evoke baroreceptor mediated REFLEX tachycardia and decreased coronary blood flow

62
Q

Does NTG produce coronary steal

A

NO

63
Q

NTG effects of organ systems

A

Decreased PVR

Decreased Pulmonary artery pressure and decreased PCWP

64
Q

NTG effects of Cerebral vasculature

A

Can increase intracranial pressure in patients with decreased intracranial complaint.

65
Q

Can be used to treat

A

SPARMS of sphincter of ODDI (relaxes the sphincter of ODDI)

66
Q

NTG clinical uses

A

Controlled hypotension
Treatment of spams of oddi sphincter
acute HYPERTENSION in MI patients

67
Q

NTG decreased preload

A

decrease pulm edema and PCWP

68
Q

NTG adverse effects : DOUBLE H

A

HYPOTENSION

HEADACHES (worse with sublingual NTG)

69
Q

Dangerous NTG adverse effects

A

METHOMOGLOBINEMIA (longer on it, the greater the risk)

70
Q

Anesthesia considerations

A

decrease heparin effectiveness at HIGH doses.

NEED higher dose of heparin to maintain

71
Q

Selective PDE 5 inhibitors

A

VIAGRA

72
Q

***Never give organic nitrate vasodilators with

A

selective PDE5 inhibitors due to additive hypotensive effects. in the presence of PDE5 inhibitor . organic nitrates cause profound increases in cGMP and can produce dramatic reductions in BP leading to EXTREME hypotension

73
Q

Right Ventricular MI never give NTG

A

those patients are dependent on PRELOAD.

74
Q

An organic nitrate that acts as a vasodilator which effects both arteries and veins

A

Isosorbide nitrate

75
Q

Pharmacokinetics

A

is metabolized by 2 metabolites that have longer half lives and these metabolites also act as NO donor.

76
Q

Other peripheral vasodilators

A

Sildenafil (Viagra)
Tadalafil (Cialis) - mean terminal half life up to 35 hours
Vardenalfil
Avanafil

77
Q

Selective PDE5 inhibitors MOA

A

Inhibit cGMP specific PHOSPHODIESTERASE type 5 enzyme in the smooth muscle of the pulmonary vasculature and corpus CAVERNOSUM, where PDE5 is responsible for degradation of cGMP
- This PDE-5 inhibition increases the concentration of cGMP within pulmonary vasculature and corpus cavernosum smooth muscle cells resulting in SM relaxation

78
Q

In patients with PAH, this can lead to

A

vasodilation of the pulmonary vascular bed to a lesser degree, vasodilation in the systemic circulation.

79
Q

ACtion of PDE5 inhibitors in penile tissue

A

INCREASE BLOOD FLOW into the CORPUS CAVERNOSUM

80
Q

PDE5 inhibitors these agents enhance the

A

effect of NO-mediated relaxation by inhibiting PDE5

81
Q

SIde effects of PDE5 inhibitors

A

Headaches (most common)
HYPOTENSION
Flushing

82
Q

Drugs interaction nitrates with selective PDE5 inhibitors

A

Contraindicated to give organic nitrates with PDE5 inhibitors due to the risk of SEVERE/EXTREME HYPOTENSION

83
Q

Nitrates need a ________Before administering PDE5 inhibitors.

A

24-48 WASH OUT PERIOD

84
Q

Fenoldopam is a

A

Benzazepine derivative agents that is selective POST synaptic dopamine 1 receptor agonists that is a RAPID ACTING VASODILATOR.

85
Q

Agonism of dopamine 1 receptors leads to an

A

increase in cAMP in arterial vascular smooth muscle
Decrease PVR and afterload
increases renal perfusion , UO and SODIUM EXCRETION (diuresis and natriuresis)

86
Q

Erectile dysfunction /PAH and NO

A

stimulates the formation of cGMP, increases cGMP levels which leads to relaxation of SM in:

  • CORPUS CAVENOSUM leading to erection
  • pulmonary vascular bed leading to vasodilation
87
Q

Now approved for the treatment of BPH

A

Cialis

88
Q

Fenoldopam is a
Which isomer is active?
does it cross the BBB?
MEtabolized by –>

A

racemic mixture S and R
R- isomer responsible for the biological activity
no
CONJUGATION (not CYP 450) cannot be induced or inhibited.

89
Q

Adverse effects of fenoldopam

A

headaches
high dose, high adv effects
May cause REFLEX TACHYCARDIA
TOO MUCH of a decrease in afterload

90
Q

Clinical uses of Fenoldopam

A

Short term tx of severe HTN

when rapid, but quickly reversible, emergency reduction of BP

91
Q

Nesiritide is

A

recombinant human B-type Natriuretic peptide (rhBNP)

92
Q

Nesiritide binds to

A

natriuretic peptide receptors A located in vascular SM and endothelial cells which stimulates guanylate cyclase to increase in cGMP

93
Q

Nestiride clinical effects

A 
Decrease preload
Decrease afterload
Decrease in PCWP
Can cause reflex tachy (rare)
Increase SV, and CI
94
Q

Nestiride neurohormonal effects

A

Decreased secretion of NE, Aldosterone, Endothelin-1
POTENT NATRIURETIC effect
Increase sodium excretion

95
Q

Plasma half life of nestiride

A

15-20 mns

Monitor BP always

SRNAPharmacology I (29 decks)

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