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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
Signs and symptoms of Cyanide toxicity
``` 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. ```
26
SNP treatment
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)
27
SNP treatment additional:
HYDROXOCOBALAMIN (cyanokit) | Binds to cyanide ions to form nontoxic cyanocobalamin which eliminated by the kidneys and allows body to use O2 again
28
Thiocyanate is cleared by the _____and half life is _____
kidneys | half life 3 days
29
SNP Clinical effects
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.
30
Vasodilators : SNP
Decreases Ventriular filling pressure | Increase SV
31
SNP may cause
increase plasma renin levels Activate RAAS (BP lowering goes way when titated off) ****REBOUND Hypertension (rare)
32
SNP can cause this phenomenon
Coronary Steal Phenomenon Give SNP --> steal blood and distribute globally even in areas you don't need in MI, bad, increased MI Size
33
Never give SNP
patient with hypotension related to MI | it causes SHUNTING OF BLOOD AWAY from ISCHEMIA areas to non-ischemic areas
34
****CEREBRAL effects of SNP ICP? Cerebral blood flow? Blood volume ?
Increased ICP | Increased cerebral blood flow and blood volume
35
How does SNP affect CPP
CPP = MAP- ICP | Decrease MP and increased ICP = decrease CPP
36
Other Clinical effects of SNP
Decreases PVR Decreased PaO2 Increased Intra pulmonary shunt
37
Clinical uses of SNP
``` Main areas 1.Induce controlled HTN during anesthesia, Maintain MAP 50-60 mmHg 2.Aortic surgery 3.HTN emergencies ```
38
Anesthesia precausion of SNP
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
39
ORGANIC NItrates | What is the active mediator?
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
3 organic nitrates example? which one use for anesthesia
Nitroglycerin Isosorbide dinitrate isosorbide 5 mononitrate
41
Issues with organic nitrates
Tolerance: repeated exposure to high doses of organic nitrates leads to a marked attenuation in the magnitude of their pharmacologic effects
42
*****Nitroglycerin
Potent venodilating agent NO EFFECT on dilation of arteries at LOW doses As the dose NTG is INCREASED
43
****With NTG, arterial vasodilation occurs at
100mcg/min IV | NOT mcg/KG
44
Onset of action of NTG
2-5 minutes
45
Les than 100mcg
only dilating veins
46
Drug of choice for HTN emergencies and active MI patient
NITROGLYCERIN
47
NTG CV effects
Decreased preload and afterload.
48
Routes of administration :
Multiple,
49
NTG mechanism of action
combines with SULFHYDRYL groups in vascular endothelim to create S-nitrosothiol compounds that increase the release of NO
50
NTG generates
NO and is direct NO "donor"
51
NTG requires enzymes to break down, unlike STP which does not require enzymes to work , therefore it takes
longer
52
NTG have _____bioavailability due to _____First pass heaptic effect from hepatic metabolism
LOW; large
53
Metabolism
by reductive hydrolysis int he liver | also undergoas extrahepatic metabolism in RBcs and vacular walls.
54
****NTG pharmacokinetics:
High Vd High clearance. INTER-individual variations in plasma concentration difficult to predict plasma levels
55
NTG pharmacokinetics comment on nitrate ions
Nitrate ions liberated during the metabolism of NTG can oxidize the ferrous ion in Hgb to the ferric state and produce METHEMOGLOBIN
56
Treatment of NTG toxicity?
Methylene blue 1-2mg/kg/IV
57
Methylene blue does what?
facilitate the conversion of methemoglobin to HEMOGLOBIN | rapid onset of action
58
NTG primarily
decreasing preload
59
Venodilation in NTG leads to : - Is myocardial contractility.
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
CV effects of NTG
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
Excessive decreased in diastolic pressure with NTG can:
evoke baroreceptor mediated REFLEX tachycardia and decreased coronary blood flow
62
Does NTG produce coronary steal
NO
63
NTG effects of organ systems
Decreased PVR | Decreased Pulmonary artery pressure and decreased PCWP
64
NTG effects of Cerebral vasculature
Can increase intracranial pressure in patients with decreased intracranial complaint.
65
Can be used to treat
SPARMS of sphincter of ODDI (relaxes the sphincter of ODDI)
66
NTG clinical uses
Controlled hypotension Treatment of spams of oddi sphincter acute HYPERTENSION in MI patients
67
NTG decreased preload
decrease pulm edema and PCWP
68
NTG adverse effects : DOUBLE H
HYPOTENSION | HEADACHES (worse with sublingual NTG)
69
Dangerous NTG adverse effects
METHOMOGLOBINEMIA (longer on it, the greater the risk)
70
Anesthesia considerations
decrease heparin effectiveness at HIGH doses. | NEED higher dose of heparin to maintain
71
Selective PDE 5 inhibitors
VIAGRA
72
***Never give organic nitrate vasodilators with
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
Right Ventricular MI never give NTG
those patients are dependent on PRELOAD.
74
An organic nitrate that acts as a vasodilator which effects both arteries and veins
Isosorbide nitrate
75
Pharmacokinetics
is metabolized by 2 metabolites that have longer half lives and these metabolites also act as NO donor.
76
Other peripheral vasodilators
Sildenafil (Viagra) Tadalafil (Cialis) - mean terminal half life up to 35 hours Vardenalfil Avanafil
77
Selective PDE5 inhibitors MOA
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
In patients with PAH, this can lead to
vasodilation of the pulmonary vascular bed to a lesser degree, vasodilation in the systemic circulation.
79
ACtion of PDE5 inhibitors in penile tissue
INCREASE BLOOD FLOW into the CORPUS CAVERNOSUM
80
PDE5 inhibitors these agents enhance the
effect of NO-mediated relaxation by inhibiting PDE5
81
SIde effects of PDE5 inhibitors
Headaches (most common) HYPOTENSION Flushing
82
Drugs interaction nitrates with selective PDE5 inhibitors
Contraindicated to give organic nitrates with PDE5 inhibitors due to the risk of SEVERE/EXTREME HYPOTENSION
83
Nitrates need a ________Before administering PDE5 inhibitors.
24-48 WASH OUT PERIOD
84
Fenoldopam is a
Benzazepine derivative agents that is selective POST synaptic dopamine 1 receptor agonists that is a RAPID ACTING VASODILATOR.
85
Agonism of dopamine 1 receptors leads to an
increase in cAMP in arterial vascular smooth muscle Decrease PVR and afterload increases renal perfusion , UO and SODIUM EXCRETION (diuresis and natriuresis)
86
Erectile dysfunction /PAH and NO
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
Now approved for the treatment of BPH
Cialis
88
Fenoldopam is a Which isomer is active? does it cross the BBB? MEtabolized by -->
racemic mixture S and R R- isomer responsible for the biological activity no CONJUGATION (not CYP 450) cannot be induced or inhibited.
89
Adverse effects of fenoldopam
headaches high dose, high adv effects May cause REFLEX TACHYCARDIA TOO MUCH of a decrease in afterload
90
Clinical uses of Fenoldopam
Short term tx of severe HTN | when rapid, but quickly reversible, emergency reduction of BP
91
Nesiritide is
recombinant human B-type Natriuretic peptide (rhBNP)
92
Nesiritide binds to
natriuretic peptide receptors A located in vascular SM and endothelial cells which stimulates guanylate cyclase to increase in cGMP
93
Nestiride clinical effects
``` Decrease preload Decrease afterload Decrease in PCWP Can cause reflex tachy (rare) Increase SV, and CI ```
94
Nestiride neurohormonal effects
Decreased secretion of NE, Aldosterone, Endothelin-1 POTENT NATRIURETIC effect Increase sodium excretion
95
Plasma half life of nestiride
15-20 mns | Monitor BP always

SRNAPharmacology I (29 decks)

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