Vasodilators Flashcards
Most frequent clinical uses of Peripheral Vasodilator?
1) Tx of hypertensive crisis and pulmonary HTN
2) Produce controlled hypotension spring anesthesia to reduce blood loss
3) Fascilatation of vessel surgery
4) Acute decompensated HF mgmt
5) Ichemic heart disease i.e. ACS and chest pain
*Hows is NO produced in our bodies
1) NO is produced by vascular endothelial cells and various other tissues of the body
2) Endogenous NO is synthesized from L-Argenine by the enzyme Nitric Oxide Synthase (NOS)
3) NOS enzyme catalyzes the oxidation of L-Argenine to produce L-citruline and NO
*Nitric Oxide is also known by what other name?
Endothelium-derived Relaxing Factor (EDRF)
Explain the steps of how NO moves from Endothelial cells to Smooth muscle cells and cause dilation?
1) NO produced by endothelial cells»_space;> diffuses into smooth muscle cells»_space;> NO binds and activates soluble guanylate cyclase»_space;> Guanylate cyclase dephosphorylates into GTP and cGMP»_space;> cGMP (2nd Msgr) induces smooth muscle relaxation
How is cGMP metabolized
It is broken down by phosphodiesterase, which convert cGMP to guanosine monophosphate (GMP)
Cardiovascular Effects of NO
1) Vasodilation
2) ↓ pulmonary vascular resistance
Pulmonary Effects of NO
- Bronchodilation, improves ventilation-perfusion matching
Effects of NO on Platelets
1) Inhibits platelets activation, aggregation, and adhesion to the vascular endothelium
Does NO prolong bleeding time
No
Anti-inflammatory Effects of NO
1) NO has a role in modulation of inflammation, host defenses and immunologic function
2) Inhibits leukocyte adhesion to vascular endothelium
Anti-Proliferative Effects of NO
Inhibits smooth muscle hyperplasia
Nervous System Effects of NO
1) Endogenous NO is a neurotransmitter in the brain, spinal cord, and PNS
2) NO released in response to stimulation of excitatory (NMDA) glutamate receptor
3) NO is involved in anti-nociceptive and in modulating anesthetics effects
4) Various peripheral nerves are known to synthesize and release NO i.e. nerves to myenteric plexus and penile tissue
What is the main use for NO in Anesthesia?
As a vasodilator
Sodium Nitroprusside (Nipride) MOA
- Direct-acting non-selective mixed arterial and venous smooth muscle dilator
- 44% cyanide by weight
Sodium Nitroprusside (Nipride) onset duration and 1 1/2
1) Onset - immediate (seconds)
2) Duration - 1 to 2 mins
3) T 1/2 - ~ 2mins
Which 2 equipment is needed when administering Sodium Nitroprusside (Nipride)?
1) IV Pump
2) A-line
*Sodium Nitroprusside (Nipride) MOA
1) SNP is a vasodilator that releases NO when broken down (* known as a “direct NO donor)
2) NO then follows its normal pathway to producing smooth muscle vasodilation
Sodium Nitroprusside (Nipride) Metabolism
1) SNP interacts with oxyhemoglobin to form methemoglobin and an unstable nitroprusside radical
* 2) This unstable radical then dissociates rapidly to release 5 cyanide ions AND NO /? (which occurs via a non-enzymatic process)
3) The amount of cyanide and NO generated depends on the dose of SNP administered
What is the effect of light on SNP
SNP decomposes when exposed to light
What does it indicate if a solution of SNP is bluish in color
It indicated almost complete degradation and breakdown to cyanide
What are the products of Nitroprusside/hemoglobin reaction?
1) 1 Cyanide ion - reacts with methemoglobin to form cyanmethemoglon which is non-toxic.
2) 4 cyanide ions - converted in the liver to thiocyanate by rhodanse, which uses thiosulfate to do so.
3) Thiocyanate is then excreted by the kidneys
What happens if cyanide is not removed by either binding to methemoglobin or by being converted to thiocyanate?
Free cyanide ions that are not removed can bind to cytochrome complex in cell walls and cause toxicity.
Effect of hypothermia on cyanide metabolism?
1) Nonezymatic release - not inhibited by hypothermia except during cardiopulmonary bypass
2) Enzymatic conversion to thiocynate - delayed by hypothermia
3 Toxicities the could result from SNP
1) Methemoglobinemia
2) Thiocynate toxicity
3) Cyanide toxicity (most toxic
Sodium Nitroprusside (Nipride) Cyanide toxicity levels
1) SNP infusions up to 2mcg/kg/min eliminated by liver without causing cyanide toxicity
2) SNP infusions > 2mcg/kg/min result in does-dependent accumulation of cyanide and ↑ risk of toxicity
What happens if free cyanide radicals bind to and inactivate cytochrome oxidase?
This leads to anoxia, aerobic metabolism and lactic acidosis
*The removal of cyanide ion depends on which 3 physiological requirements?
1) Adequate liver function
2) Adequaterenal function
3) Adequate bioavailability of thiosulfate
Signs and Symptoms of Cyanide toxicity
1) Headache, dizziness, tachypnea/hyperapnea 1)early, tachycardia, N/V, mydriasis, bradypnea/apnea (late)
2) ↑ mixed venous PO2 = PaO2 due to paralysis of cytochrome oxidase and the inability to tissues to use O2
3) Venous hyperemia with bright red blood
4) Smell of almonds on breath
5) Metabolic acidosis due to anaerobic metabolism
6) Cardiovascular collapse
7) CNS dysfunction
CNS dysfunction due to cyanide toxicity sysmptoms
1) Mental status changes i.e. confusion and disorientation
2) seizures
3) encephalopathy
4) coma
5) irreversible focal neurological damage
Sodium Nitroprusside (Nipride) Cyanide toxicity Tx
1) 100% O2, hydration, CV support and seizure mgmt
2) Amyl nitrate
3) Sodium nitrate (5mg/kg IV over 2 to 4 mins)
4) Sodium thiosulfate (150 to 200 mg/kg IV over 15 mins
5) Hydroxocobalamin (aka Cyanokit)
What is the MOA of the following SNP cyanide toxicity Tx:
1) Amyl nitrate
2) Sodium nitrate (5mg/kg IV over 2 to 4 mins)
3) Sodium thiosulfate (150 to 200 mg/kg IV over 15 mins
4) Hydroxocobalamin (aka CYANOKIT)
1) Amyl nitrate - converts Hgb to methemoglobin, which reacts with cyanide to form cyanomethemoglobin
2) Sodium nitrate - Converts Hgb to methemoglobin, which reacts with cyanide to
form cyanmethemoglobin
3) Sodium thiosulfate - acts as a source of sulfur groups, which are needed for the conversion of cyanide to thiocyanate
4) Hydroxocobalamin - Binds to cyanide to form nontoxic cyanocobalamin which is
eliminated by the kidneys and allows the body to use O2 again
Thiocyanate Toxicity Characteristics
1) Cleared via the kidneys
2) 100x less toxic than cyanide
3) Is dialyzable
4) Thiocyanate toxicity onset is slower than cyanide toxicity
Cardiovascular Clinical Effects of Sodium Nitroprusside
1) Hypotension (⇓ SVR)
2) ⇓ preload and ⇓ afterload
3) Dilation of coronary arteries
4) Baroreceptor-mediated reflex responses to the SNP-induced decreases in systemic BP manifest as tachycardia and increased myocardial contractility
5) Reduces cardiac filling pressures (⇓ right atrial and ventricular pressures)
6) May cause coronary steal!
7) ⇑ plasma renin
8) ⇑ plasma concentrations of of catecholamines can occur
Sodium Nitroprusside (Nipride®) Coronary Steal Phenomenon
- SNP ↑ the area of damage associated with a MI due to coronary steal
- Coronary steal due to coronary perfusion pressure and associate coronary blood flow leading to possible myocardial ischemia
You should never use SNP in which type of PT
A PT with an acute I or after an acute MI
*Cerebral Effects of SNP
1) SNP ↑ cerebral blood flow and blood volume, which can * ↑ ICP
2) Cerebral steal
The potential of increasing ICP by SNP is not present in which situation?
if SNP is administered after the dura has been surgically opened
How is Cerebral Perfusion Pressure (CPP) calculated?
CPP = MAP - ICP
How does SNP affect CPP?
↓ MAP - ↑ ICP = ↓CPP
SNP should be avoided in PTs with which cerebral conditions?
1) ↓ Intracranial compliance
2) High ICP
3) Carotid stenosis
Cerebral Steal Phenomenon
When non-ischemic blood vessels in the brain dilate and steal blood from the already insufficiently supplied ischemic vessels.
Sodium Nitroprusside (Nipride®) Clinical Effects on Platelet Function
1) Inhibits/decreases platelet aggregation and may result in
increased bleeding time
2) Clinical bleeding has not been observed with SNP postoperatively
Sodium Nitroprusside (Nipride®) Clinical Effects on Pulmonary Fxn
– Decreases pulmonary vascular resistance and decreases PaO2 – Increases intrapulmonary shunting
Sodium Nitroprusside (Nipride®) Clinical Uses
1) Induce controlled hypotension during anesthesia to reduce bleeding (maintain MAP 50-60 mmHg)
2) Aortic Surgery
3) Hypertensive emergencies
4) ↓ BP in cardiac surgery
5) Tx of acute decompensated HF
Purpose of using SNP during Aortic surgery?
SNP attenuates proximal hypertension associated with cross-clamping the aorta
How can SNP use during Aortic Surgery lead to spinal cord ischemia?
SNP may aggrevate hypotension distal to the clamp
3 uses of SNP during Cardiac surgery
1) ↓ BP
2) Valve rep. tx for pulmonary htn
3) Admin. of SNP during warming phase of cardiopulmonary bypass surgery improves blood flow and heat to peripheral tissue
How does SNP affect the patient under anesthesia?
- When SNP is used for control hypotension during anesthesia, their capacity to compensate for anemia and hypovolemia is diminished.
- Pre-existing anemia and hypovolemia should be corrected prior to administration
What are Organic Nitrates
- aka Nitrodilators are Prodrugs that are metabolized to the active metabolite of NO
1) Nitroglycerin (NTG)
2) Isosorbide Dinitrite (ISDN)
3) Isosorbide-5-Mononitrate (ISMN)
Tolerance to Organic Nitrates
- Repeated exposure to high doses leads to tolerance
- Tolerance can occur in 24-48 hrs of continuous IV NTG
What is the most effect approach to limit the the development of Tolerance to Organic Nitrates?
Introduce a “Nitrate or Drug Free Interval” of 8 to 12 hrs each day.
Nitroglycerin MOA
- Potent Venodilator with no effect on arteries
- Generates NO and is a direct NO donor
MOA by which NTG donates NO and MOA by which it generates NO
1) Donates - NTG combines with sufhydryl groups in vascular endothelium to create S-nitrosothiol compounds that increase the release of NO.
2) NTG undergo an enzymatic biotransformation requiring the presence of thio-containing compounds to generate NO
Nitroglycerin onset, duration, and dosing range
1) Onset - 2 to 5 mins
2) Duration - 5 to 10 mins
3) Dose - 5 to 100 mcg/min IV (up to 200mcg/min in Tx of ADHF) and 0.3 mg SL q5mins x3 doses
4) At doses > 100mcg/min IV, arteriole vasodilation occurs
Undesirable effects of NTG in PTs with compromised cerebral and renal perfusion?
1) ↓ Preload and ↓ CO
Routes of NTG administration
1) Sublingual (SL) - peak plasma levels ~ 5mins
2) IV CI
3) Oral
4) Buccal
5) Transdermal (patch and ointment)
NTG plasma concentrations are affected by _______ ?
The route of administration
Nitroglycerin Pharmacokinetics
1) Low bioavailability bco large 1st pass effect
2) Metabolized by reductive hydrolysis in liver and also metabolized by RBCs and vascular walls
There are multiple nitrate and nitrite metabolites formed from the metabolism of NTG, What are those metabolites broken down to?
Glycerol and CO2
NTG t 1/2
1 to 3 mins
*What is the Tx for Methemoglonemia? How does it work?
- Methylene blue 1 to 2 mg/kg IV over mins
- MB facilitates the conversion of methemoglobin to hemoglobin
Whats the signifance in doses of NTG <100 mcg/min and doses > 100mcg/min?
1) < 100 mcg/min dilate veins
2) Doses > 100 mcg/min dilate arterioles
Nitroglycerin Effects on Organ Systems
1) ↓ BP, preload, SVR, ↓ filling pressures, ↓ PCWP
2) Reflex tachycardia
3) Coronary dilation
4) Relaxation of sphincter of Oddi
5) ↓ Esophageal tone
6) Inhibits platelet function
*Nitroglycerin Clinical Uses
• Controlled hypotension *• Treatment of sphincter of Oddi Spasm • Angina pectoris • Coronary vasospasm • Acute coronary syndromes (ACS) • Acute decompensated heart failure (ADHF) – Subset II or IV • Acute hypertension
2% Nitro paste lasts how long?
Offers protection for 4 to 8 hrs
*NTG Adverse Effects
- 1) Methemoglobinemia
2) Hypotension (most common) and headache
3) N/V
4) Flushing and Rash
5) Reflex Tachycardia and weakness
NTG Drug-Drug interaction
1) ⇓ heparin effectiveness at HIGH doses
2) Additive hypotensive effects with PDE5 inhibitors]3)
Why should caution be taken when administering NTG to PTs with RV infarction?
These PTs are preload dependent
NTG is not recommended for PTs with which conditions? why?
1) Hypertrophic obstructive cardiomyopathy
2) Severe aortic stenosis
* Both of these conditions require maintenance of preload to keep coronary perfusion going
Isosorbide Dinitrate (ISDN) MOA (oral drug)
- Vasodilator with effects on BOTH arteries and veins (⇓ afterload and ⇓ preload)
Isosorbide Dinitrate (ISDN) Metabolism
- Undergoes extensive first pass metabolism
- Metabolized to 2 metabolite that have longer half-lives and also act as NO donors
What are the 2 active metabolites of ISDN
1) Isosorbide-2-mononitrate
2) Isosorbide-5-mononitrate (the more active metabolite)
Isosorbide-5-Mononitrate (ISMN) Characteristics
oral drug
1) An active metabolite of ISDN
2) Vasodilates both veins and arteries
3) 100% Bioavailability
4) Max plasma conc. achieved in 30 to 60 mins
5) Not subject to 1st pass metabolism
How does NO help with Erectile dysfunction and Pulmonary. HTN?
1) NO stimulates formation of cGMP which leads to Smooth muscle relaxation leads to dilation of vessels in corpus cavernous leading to an erection
2) NO stimulates formation of cGMP which leads to Smooth muscle relaxation leads to dilation of vessels in pulmonary vascular beds which ↓ pressure
How can the effects of NO be enhanced when treating erectile dysfunction and pulmonary HTN?
cGMP can be enhanced via inhibition of cGMP-specific PDE5 which is primarily found in the corpus cavernosum and the pulmonary vasculature.
Selective PDE5 Inhibitor Agents on the Market
1) Sildenafil (Viagra®, Revatio®)
2) Tadalafil (Cialis®, Adcirca®)
– Has a mean terminal half-life of up to ~35 hours (LONG!)Cialis® is now approved for use in treatment of BPH
3) Vardenafil (Levitra®, Staxyn®)
4) Avanafil (Stendra®)
Selective PDE5 Inhibitors MOA
1) Inhibits cGMP-specific PDE5 enzyme in smooth muscle of corpus cavernosum and the pulmonary vasculature.
2) These agents enhance the effect of NO-mediated relaxation by inhibiting PDE5
Selective PDE5 Inhibitors Side Effects
1) Headache (most common), 2) Flushing
3) Nasopharyngitis
4) dyspepsia
5) Hypotension
Fenoldopam (Corlopam®) MOA
1) A benzazepine derivative agent that is a selective post- synaptic dopamine-1 receptor agonist that is a rapid-acting vasodilator.
2) Agonism of dopamine-1 receptors leads to an increase in cAMP in arterial vascular smooth muscle
3) Vasodilates coronary, renal, mesenteric and peripheral arteries (⇓ PVR, ⇓ afterload)
4) Increases renal perfusion, urine output and sodium excretion (diuresis and natriuesis effects)
Fenoldopam (Corlopam®) Characteristics
1) Racemic mixture with R-isomer responsible for the biological activity
2) T 1/2 - 5 mins
3) Max response -15 mins
4) Duration - 30 to 60 mins
5) Doesn’t cross BBB
6) Metabolism - via liver
Fenoldopam (Corlopam®) Side Effects
1) Headache - #1 most common adverse effect
2) Hypotension - dose-dependent
3) Nausea
4) Flushing (cutaneous dilation)
5) Reflex tachycardia - dose-dependent
6) Increase in intraocular pressure - dose-dependent • 6) ST-T abnormalities - primarily T-wave inversion
Fenoldopam (Corlopam®) Clinical Uses
Short term treatment (up to 48 hours) of severe HTN when rapid, but quickly reversible, emergency reduction of blood pressure is indicated. May be discontinued abruptly or tapered gradually i.e. PT in hypertensive emergency with impaired renal function
Use caution when administering Fenoldopam to PTs with which disorder?
Intraocular hypertension
Nesiritide (Natrecor®) MOA
1) A recombinant human B-type NP
2) binds to the NP receptor A (NPR-A) located on vascular smooth muscle and endothelial cells which stimulates guanylate cyclase leading to increases in cGMP concentrations
Nesiritide (Natrecor®) Hemodynamic Effects
1) Dose-dependent arterial vasodilation which ⇓ systemic vascular
resistance (⇓ afterload)
2) Dose-dependent venous vasodilation which ⇓ preload resulting
in ⇓ right & left ventricular filling pressures
3 ) Dose-dependent ⇓ in PCWP
4) Minimal changes in heart rate
5) ⇑ stroke volume, ⇑ cardiac index
6) Improvement in dyspnea
*Nesiritide (Natrecor®) Adverse Reactions
- 1) Hypotension (the most common and the dose-limiting side effect)
2) Headache
3) Nausea
4) Worsening renal function
