Cardiovascular drugs Flashcards
BP =
CO x TPR
A pipe problem insinuates what type of issue with BP?
TPR
A pump problem implies what type of issue with BP?
CO
If your BP was low due to poor TPR, what drug class would be the best remedy?
Vasopressors
If your BP was low due to poor CO, what drug class would you use to remedy the problem?
Inotropes
By what means do inotropes increase CO to increase BP?
They improve contractility.
By what means do vasopressors increase TPR (SVR) to increase BP?
They increase vascular tone.
How does vasodilation affect cardiac filling pressures?
Vasodilation decreases cardiac filling pressures.
How does cardiac failure affect filling pressures?
Cardiac failure increases filling pressures.
By what means does spinal/epidural anesthesia cause hypotension?
They wipe out the SVR.
If your patient is undergoing an AAA and their CVP doubles during surgery, what do you suspect?
The heart is failing, and the CVP is likely increasing due to some kind of backup in flow.
How would spinal/epidural administration affect CVP?
Spinals and epidurals decrease SVR, which decreases cardiac filling pressures (therefore manifesting as a decrease in CVP).
How does calcium aid in causing muscular contraction in the heart?
Ca++ binds to troponin-C, a protein that sits on the surface of tropomyosin. Once troponin is bound, there is a conformational shift that allows the removal of tropomyosin from the actin surface. Once actin is exposed, myosin can bind to it. This is called cross-bridge cycling.
Where is intracellular Ca++ stored?
In the sarcoplasmic reticulum
The sarcoplasmic reticulum is in contact with the cell membrane via:
T-tubules
What spurs Ca++ release from the SR?
Electrical signals enter the SR from the cell membrane via T-tubules, exciting the SR and spurring the release of Ca++ into the cell. Ca++ release is a positive feedback loop in that the initial release of Ca++ encourages further release of Ca++ within the cell.
How does intracellular Ca++ reenter the SR to be stored?
Via nonvoltage-dependent Ca++ channels called ryanodine receptors
What are ryanodine receptors?
Nonvoltage-dependent Ca++ channels on the surface of the SR that regulate the reentry of Ca++ into the SR
When does relaxation of the cardiac tissue occur?
Relaxation takes place when Ca++ is pumped back into the SR via ATPase
What enzymes allow Ca++ to be pumped back into the SR through ryanodine receptors?
ATPase
Ca++ is not only pumped back into the SR after contraction; it is also pumped out of the cell. What mechanism is responsible?
Ca++ is pumped out of the cell via Na+/K+ ATPase and Na+/Ca++ exchange
What two processes remove Ca++ to the extracellular space?
First, Na+ is pumped into the cell via Na+/K+/ATPase pump. Then Ca++ is pumped out of the cell along with Na+ via Na+/Ca++ exchange.
What defines inotropy?
The quantity of intracellular Ca++
The maximum amount of tension the heart can develop
What term relates to the maximal amount of tension the heart can develop?
Inotropy
What term relates to the quantity of Ca++ within the cardiac cell?
Inotropy
What term relates to the rate of Ca++ delivery?
Chronotropy
What term relates to the rate of contraction?
Chronotropy
What is chronotropy?
The rate of contraction defined by the rate of Ca++ delivery
What is lusitropy?
The rate of muscle relaxation defined by the removal of intracellular Ca++
What term relates to the removal of intraceullar Ca++?
Lusitropy
What term relates to the rate of muscle relaxation?
Lusitropy
What determines the rate of contraction?
The rate of Ca++ delivery
What determines the rate of relaxation?
The rate of intracellular Ca++ removal
What determines the maximal tension that can develop in the heart?
Quantity of intracellular Ca++
What molecule is an important second messenger in muscle contraction?
cAMP
How will an increase in cyclic AMP affect muscle contractility?
It will increase intracellular Ca++ release, which increases contractility.
What role does cyclic AMP play in contractility?
cAMP is a second messenger that spurs SR to release Ca++.
What receptors are known as “effectors of SNS”?
Adrenergic receptors
Medications that work by activating adrenergic receptors are known as:
sympathomimetics
What effect is mediated by alpha 1 receptors?
Vasoconstriction
Alpha 1 receptors mediate what effect?
Vasoconstriction
What class of adrenergic receptors are involved in vasoconstriction?
Alpha adrenergic receptors
Which alpha adrenergic receptors are involved in inhibition of presynaptic NE release?
Alpha 2 receptor
Effects of alpha 2 receptor activation include
Vasoconstriction
Inhibition of presynaptic NE release
T/F: alpha 1 adrenergic receptor activation inhibits presynaptic release of NE.
False; alpha 2 action
T/F: alpha 2 adrenergic receptors are strictly involved in vasoconstriction.
False; alpha 2 receptor activation causes vasoconstriction, but it also causes inhibition of NE release.
Effects of beta 1 receptor activation?
Increased myocardial chronotropy + inotropy
What class of adrenergic receptors increase myocardial inotropy when activated?
Beta receptors
Activatation of B1 receptors causes:
Increased myocardial chronotropy + inotropy
Activation of which beta receptor causes increase in myocardial chronotropy?
B1 receptor
Which type of adrenergic receptor is involved in vasodilation in vessels and lungs?
B2
B2 causes vasodilation in:
vessels and lungs
T/F: alpha2 receptors cause vasodilation.
False; alpha2 receptors causes vasoconstriction. B2 receptors cause vasodilation in vessels and lungs.
What type of beta receptor acts strictly on the heart?
B1 receptors
What does it mean to say that B1 receptor activation increases myocardial chronotropy and inotropy?
It increases HR + contractility of the heart.
If you wanted to fix a “pump” problem, you would adminster a drug that worked on which variety of adrenergic receptor?
Beta
If you wanted to fix a “pipe” problem, you would adminsiter a drug that worked on which variety of adrenergic receptor?
Alpha
T/F: both B1 and B2 serve to increase HR.
True.
What types of drugs activate alpha and beta adrenergic receptors?
Sympathomimetics
T/F: All clinically used catecholamines work via adrenergic receptors and are therefore sympathomimetics.
True
Are catecholamines sympathomimetics?
All of the catecholamines that we use in the clinical setting are sympathomimetics.
What two structures make up a catecholamine?
Catechol ring + ethylamine tail
Ethylamine + catechol =
Catecholamine
T/F: catecholamines are made up of an ethylamine ring and a catechol tail.
False: catechol ring and ethylamine tail
The ethylamine tail of a catecholamine has wait nitrous molecule attached to it?
NH2
T/F: All catetcholamines are endogenous.
False; some catecholamines are synthetic.
Are catecholamines endogenous or synthetic?
Both.
Are all sympathomimetics catecholamines?
No, but for our purposes, all catecholamines are sympathomimetics.
Name some examples of endogenous catecholamines:
Norepi, epi, dopamine
Name some examples of synthetic catecholamines:
Isoproteronol
Dobutamine
All catecholamines work via what type of receptor?
Adrenergic receptor
Mechanism of action of beta agonists?
Beta agonists bind to beta receptors on the cell membrane, stimulating adenylyl cyclase. Activated adenylyl cyclase then converts ATP to additional cAMP, enhancing Ca++ release from the SR and increasing contractility.
By what means do beta agonists increase contractility (inotropy) in the heart?
Beta agonists bind to beta receptors, activating adenylyl cyclase and triggering synthesis of cAMP from ATP. Increased concentrations of cAMP encourages higher amounts of Ca++ release from SR, increasing contractility.
What is the primary method of activating beta receptors?
Catecholamines
What catecholamines act as beta agonists?
Epi, norepi, dobutamine, and isoproteronol
T/F: epinephrine is the most clinically effective beta agonist.
False; no B-agonist has been proven to be more effective than another.
T/F: epinephrine activates alpha and beta receptors equally.
True.
What must you keep in mind when choosing to treat with catecholamines.
Each catecholamine will effect alpha and beta adrenergic receptors differently, so you must decide which effects you want and which you must avoid.
What is an appropriate rate for a norepi drip?
1-20 mcg/min
What is an appropriate rate for a dopamine drip?
2-20 mcg/kg/min
What is an appropriate rate for an epinephrine drip?
1-20 mcg/min
What is an appropriate rate for a dobutamine drip?
2-10 mcg/kg/min
What is an appropriate rate for an isoproterenol drip?
1-5 mcg/min
Which catecholamine drips are weight dependent?
Dobutamine
Dopamine
1-20 mcg/min
Epi or norepi
2-20 mcg/kg/min
Dopamine
2-10 mcg/kg/min
Dobutamine
1-5 mcg/min
Isoproterenol
Which catecholamine is a strong non-selective beta agonist with no effects on alpha?
Isoproterenol
Does isoproterenol have greater affinity for B1 or B2 receptors?
Equally strong affinity for both
Isoproterenol only works on what type of adrenergic receptors?
Beta
Based on receptor activation, what type of drug is norepi?
A vasopressor and an inotrope
Is norepi a stronger vasopressor or a stronger inotrope?
A stronger vasopressor
Which catecholamine has no B2 effects, meaning it does not cause vasodilation in the lungs or vessels?
Norepi
Which catecholamine has an equally strong effect on beta 1, beta 2, and alpha 1 receptors?
Epi
Which inotropes also have vasopressive effects? Which is stronger in that regard?
Dopamine + dobutamine; dopamine is a stronger vasopressor than dobutamine
Name some adverse effects of norepinephrine.
Norepi acts on B1 and A1 receptors. Its strong effects on A1 receptors can increase SVR so much that CO decreases.
Which catecholamine is the agent of choice in anaphylaxis?
Epi
Which catecholamine is prone to causing arrythmias?
Epi
T/F: norepi is arrhythmogenic.
False; epi is arrhythmogenic.
Which catecholamine is largely indirectly acting?
Dopamine: mild inotrope and moderate vasopressor
Which catecholamine is prone to causing moderate tachycardia?
Dobutamine
Dobutamine may cause:
moderate tachycardia
Which catecholamine is prone to causing severe tachycardia, arrhythmias, and decreased SVR?
Isoproteronol. It is a strong beta agonist, which may increase HR to the point of arrhythmia and decreased SVR.
Adverse effects of isoproteronol:
Severe tachycardia
Arrhythmias
Decreased SVR
What do phosphodiesterases do?
They break down cyclic nucleotides like cAMP and cGMP.
T/F: phosphodiesterases only break down cAMP.
False; break down cGMP as well
What are cyclic nucelotides?
Second messengers that activate protein kinases and open ion channels.
What do cyclic nucleotides open? What do they activate?
Open ion channels
Activate protein kinases
If cyclic nucleotides activate protein kinases and open ion channels, what do phosphodiesterases do?
They break down cyclic nucleotides and therefore prevent the activation of protein kinases to open ion channels.
How many PDE families are known?
11
T/F: PDE families include a vast number of cell types.
True.
Name three common PDE III inhibitors.
Amrinone
Milrinone
Enoximone
What type of drug is amrinone?
PDE III inhibitor
What type of drug is milrinone?
PDE III inhibitor
What type of drug is enoximone?
PDE III inhibitor
Enoximone is a:
PDE III inhibitor
Milrinone is a:
PDE III inhibitor
Amrinone is a:
PDE III inhibitor
Loading dose of amrinone?
Infusion rate?
Duration?
LD: 1 mg/kg
IR: 2-10 mcg/kg/min
Duration: 2 hours
Loading dose of milrinone?
Infusion rate?
Duration?
LD: 0.05 mg/kg
IR: 0.5 mcg/kg/min
Duration: 30 minutes
Loading does of enoximone?
Infusion rate?
Duration?
LD: 0.5 mg/kg
IR: 10 mcg/kg/min
Duration: 1 hour
Which PDE III inhibitor is excreted by the liver?
Enoximone
Enoximone is excreted by the
liver.
Where do Ca++ sensitizers work?
Work on the interaction of troponin and Ca++ or the response of the myofilaments to Ca++ binding
What is the major benefit to using Ca++ sensitizers instead of catecholamines or PDE inhibitors?
Ca++ sensitizers do not increase intracellular Ca++ levels, so they are less arrythmogenic and do not increase O2 consumption.
PDE family 1 is found where? What do they regulate?
They are found in smooth muscle cells, likely regulating proliferation in vascular tissue.
Which family is found in smooth muscle cells? What is its action there?
PDE 1
Likely regulates proliferation in vascular tissue
PDE family 3 is found where?
Type A is found in CV system and platelets.
Type B is found in liver/adipose and may be activated by insulin.
Which PDE family is of most interest for this topic?
PDE 3, Type A
Where is Type A PDE 3 family found?
CV system + platelets
Where are PDE 4 found?
In inflammatory cells
Which PDE family may play a role in COPD and arthritis?
PDE 4
What is the most prominent family of PDE? Where are they found?
PDE 5; found in the penis
T/F: PDE inhibitors work synergistically with B agonists.
True
T/F PDE inhibitors work synergistically with B antagonists.
False; work synergistically with B agonists
Effects of PDE inhibitors in cardiac myocytes?
They inhibit the breakdown of cAMP, which increases cAMP concentrations to increase Ca++ release to incrase contractility.
T/F: PDE inhibitors have effects both in cardiac myocytes and in vascular tissue.
True
What are the effects of PDE inhibitors in vascular tissue?
Increase cyclic nucleotides to cause smooth muscle relaxation
They decrease PA pressures and decrease SVR
PDE inhibitors are known as
inodilators because of their inotropic effects in the heart and their vasodilator effects in vascular tissue
Effect of PDE inhibitors on PA pressures?
Decrease PA pressures
What class of drug is effective in management of pulmonary hypertension?
PDE inhibitors
What effects do PDE inhibitors have on SVR
Increased cyclic AMP in vascular tissue causes smooth muscle relaxation and decreases SVR
T/F: PDE inhibitors have a strictly inotropic effect.
False
By what PDE family do PDE inhibitors cause vasodilation?
PDE 3
Conventional inotropes are known as:
Ca++ mobilizers
T/F: Ca++ sensitizers increase O2 consumption.
False; they do not increase the amount of Ca++ in the cell, so they do not add any work to the cell
What are the benefits to the fact that Ca++ sensitizers do not increase Ca++ levels in the cell?
Less arrhythmogenic
Do not increase O2 consumption
Any drug that ends in “-endan” is a:
Ca++ sensitizer
Name two Ca++ sensitizers.
Pimobendan
Levosimendan
Which Ca++ sensitizer is used as a longterm treatment for CHF?
Pimobendan
Pimobendan is used as a long term treatment for
CHF
T/F: Levosimendan increases troponin-C affinity to Ca++.
False; it does nothing to affect affinity of Ca++ to Troponin C; instead, it binds to Troponin C to stabilize the troponin/Ca++ conformational change
How does Levosimendan aid in contractility?
It binds to troponin in a Ca++-dependent manner and stabilizes the troponin/Ca++ conformational change
How do Ca++ levels affect action of levosimendan?
The more Ca++ present, the more stabilizing activity of levosimendan.
Which increases O2 consumption more, milrinone or levosimendan.
Levosimendan does nothing to increase Ca++ levels in the cell, so it does not increase O2 consumption as much as milrinone, a PDE III inhibitor.
What is the overall goal of vasopressors?
To increase SVR
Two groups of vasopressors?
Non-catecholamines
Catecholamines
Within the vasopressor realm, what are the two kinds of non-catecholamines?
Sympathomimetics
Non-sympathomimetics
T/F: cAMP is an important second messenger for alpha receptors within the vasculature.
F; cAMP is only significant in myocardial activity.
What is the second messenger for alpha receptors on vasculature?
IP3-DAG pathway
By what means does A1 receptor activation increase intracellular Ca++ concentration? What is the effect?
Activation triggers the IP3-DAG pathway, which increases Ca++ concentration and causes smooth muscle relaxation.
A1 receptors are present where?
On systemic and pulmonary vasculature
A1 receptors are present on what vasculature?
Systemic and pulmonary
What catecholamine has the most prominent affects on A1 receptors?
Norepi
Which catecholamine has greater effects on A1 receptors, dopamine or epi?
They have equal effects
Which catecholamine has no effect on alpha 1 receptors?
Isopropenterol
Name two non-catecholamine sympathomimetics:
Phenylephrine
Methoxamine
What type of drug is phenylephrine?
Pure, direct acting a agonist
Is phenylephrine a catecholamine?
No, it is a non-catecholamine
IV bolus of phenylephrine?
Time of onset?
Duration?
Infusion rate?
Bolus: 1-2 mcg/kg
Onset: 30 s
Duration: 2-3 minutes
IR: 25 - 100 mcg/min
Is the phenylephrine drip rate weight-dependent?
No, it is 25-100 mcg/min.
What type of drug is methoxamine?
Pure, direct acting A agonist
T/F: methoxamine is a catecholamine.
False; it is a non-catecholamine.
Bolus of methoxamine?
Onset?
Duration?
Bolus: 5-10 mg
Onset: 1 minute
Duration: 5-10 minutes
Which is longer acting, phenylephrine or methoxamine?
Methoxamine
What type of drug is ephedrine?
An indirect acting alpha agonist
A non-catecholamine sympathomimetic
Which non-catecholamine sympathomimetic causes NE release from neurons?
Ephedrine
Issue with chronic use of ephedrine?
Ephedrine prevents the reuptake of NE into neurons via granules yet perpetuates the release of NE from neurons. Therefore, NE stores are eventually depleted.
T/F: ephedrine has no beta activity.
False; it has very little beta activity, but it does have beta activity.
What inactivates ephedrine in the liver?
MAO in liver inhibits ephedrine.
What inactivates ephedrine in the liver?
MAO
What population group may experience prolonged effects of ephedrine? Why?
Those who are on MAO inhibitors (anti-depressants) because MAO inactivates ephedrine in the liver; without that inactivation step, expect a prolonged effect.
How is ephedrine excreted?
40% is excreted unchanged in the urine
What percentage of ephedrine is excreted unchanged in the urine?
40%
Ephedrine is contraindicated in what patient population?
Those on MAO inhibitors, a type of antidepressant.
Prolonged effect of ephedrine could deplete NE stores.
What type of drug is vasopressin?
A non-sympathomimetic vasopressor
T/F: vasopressin has strong alpha adrenergic activity.
False; it works on V recepors
Does vasopressin utilize alpha receptors?
No
Name a drug that is a non-sympathomimetic vasopressor.
Vasopressin
By what means does vasopressin cause vasoconstriction?
Activation of V1 receptors
Which drug acts on V1 receptors? What is the action of V1 receptors?
Vasopressin
V1 receptors release Ca++ to cause SM contraction
Second messenger in vasopressin mechanism of action?
DAG-IP3
What types of drugs utilize DAG-IP3 as a second messenger?
Those that work on alpha receptors and v-receptors.
Where are V1 receptors located? V2? V3?
V1: vascular smooth muscle
V2: kidneys
V3: CNS
Where are V2 receptors located? Their activation results in?
Located in the kidney.
Activation results in increased water permeability and dilatation of renal endothelium
Activation of what V receptor results in increased water retention and dilalation of renal endothelium?
V2 receptors
Activation of what V receptor results in increased ACTH release?
V3
Where are V3 receptors located?
Pitutarity gland (CNS)
T/F: the principle role of vasopressin is regulation of vascular tone.
False; more important effects in V3 and V2 receptors than in V1 receptors.
Physiological level of vasopressin the body:
5-10 pmol/L
What disorder can cause vasopressin levels to double or triple in the body?
Onset of sepsis
Affect of onset of sepsis on vasopressin levels?
Doubles/triples
What happens to vasopressin levels as sepsis continues (no longer onset phase)?
Vasopressin levels decrease dramatically to 1/3 of normal levels.
What is a proper infusion rate to replace vasopressin the event of prolonged sepsis or CPB?
4-6 units/hr infusions
When might you give your patient a vasopressin drip of 4-6 units/hr?
In the event of prolonged sepsis or CPB
Where are alpha receptors located?
In periphery and in lungs
Vasopressin causes intense vasoconstriction. What are some risks that comes with that?
Myocardial ischemia
Decreased CO
Mesenteric ischemia
Digital necrosis
Why might vasopressin be beneficial in the case of pulmonary HTN?
Its effects are less severe in pulmonary vasculature because V receptors are not in the lungs
What may you give if your patient’s MAP is below 50 mmHg and they are on a norepi drip of greater than 35 mcg/min?
Methylene blue
Methylene blue may treat what problem associated w/ high rates of norepi infusion?
Refractory vasodilation
Why does a norepi infusion cause refractory vasodilation?
It has strong alpha effects
T/F: methlyene blue may be administered in the event that your patient has very low MAPs with a high infusion rate of norepi, but only as a rescue measure.
True.
Why is methylene blue effective in the treatment of refractory vasodilation?
NO activates guanylate cyclase to increase levels of cGMP in the body and cause smooth muscle relaxation. Methylene blue inhibits guanylate cyclase, preventing the proliferation of cyclic nucelotides.
Methylene blue inhibits:
guanylate cyclase
Guanylate cyclase is inhibited by:
Methylene blue
To treat refractory vasodilation, what bolus dose of methylene blue should you give?
Over what amount of time?
Bolus: 1.5 - 2 mg/kg
Give over 10-60 minutes.
Methylene blue adminsitration causes minimal side effects at what dose limit?
<2 mg/ kg
What are mild side effects you may see in your patient upon administration of methylene blue?
Transient decrease in SpO2 monitoring
Mild skin and urine discoloration
High doses of methylene blue may cause:
hyperbilirubinemia + hemolytic anemia
What population should never receive methylene blue? Why?
Patients on SSRIs shouldn’t receive methylene blue because it may cause serotonin syndrome.
What symptoms define serotonin syndrome?
Hypotension
Tachycardia
Hyperthermia
Your 24 yo patient presents with BP 65/40, HR 100, 92 SpO2, and a rash. What do you suspect? How should you treat it?
Anaphylaxis
Treat with epinephrine.
High CVP indicate what issue, pump or pipe?
High CVP indicates that the heart isn’t pumping like it should. Give a beta agonist to remedy.
