Term
| What is the most common type of arrhythmia? |
|
Definition
|
|
Term
| Normal path of heart conduction system? |
|
Definition
SA node (upper right atrium)
AV node (AV Junction)
His bundle (AV Junction)
Purkinje Fibers (Ventricles, septum)
Ventricular Muscle |
|
|
Term
| Where is the heart innervated by the SNS/PNS? |
|
Definition
At the SA node
-Adrenergic and cholinergic nerve terminals very dense
-Control speed and strength of contraction |
|
|
Term
| Which is worse, flutter or fibrillation? |
|
Definition
Fibrillation (can count the beats per minute)
Flutter (~250 bpm)
(tachycardia ~100 bpm) |
|
|
Term
| Activation of sympathetic nerve terminals in heart cause what? What are the NT and receptors? |
|
Definition
Positive chronotropic response
Beta-1-adrenergic receptors get activated by NE/Epi |
|
|
Term
| If contraction started at the top of the heart what would this result in? |
|
Definition
| It would be an arrhythmia and would cause poor contraction of the heart and blood would not pump efficiently (decreased BP) |
|
|
Term
| What are the two primary parts of the AV junction? |
|
Definition
|
|
Term
| How does the ECG pattern differ when the AV node becomes the initiator of the signal (failure of the SA node)? |
|
Definition
40-60 bpm (slower)
No P wave (no atrial contraction) |
|
|
Term
| T or F: velocity of electrical impulses (conductivity) varies through different parts of the heart? |
|
Definition
T:
Slowest thru AV node
Fastest thru Purkinje fibers and ventricular myocytes |
|
|
Term
| What controls conduction velocity within the heart? |
|
Definition
Types of channels in the tissue
(measured by times between ECG peaks) |
|
|
Term
|
Definition
Capacity of certain cardiac cells to function as pacemakers
-Spontaneous generation of electrical impulses that spread throughout heart |
|
|
Term
| If automaticity of SA node is depressed what can happen? |
|
Definition
Cells outside the SA node (atria, AV junction, or ventricles) can act as independent pacemakers
this occurs with failure of SA node |
|
|
Term
| What is 'sick sinus syndrome?' |
|
Definition
Severe depression of sinus node function
Dizziness/syncope can occur from excessive bradycardia |
|
|
Term
| What is abnormally increased automaticity? |
|
Definition
Occurs outside of the SA node (the usual pacemaker) when other cells become the pacemaker of the heart (ectopic)
-Results in ventricular premature beats (not a consistent arrhythmia - maybe just 1-2 times daily)
-Rapid run of ectopic beats results in an abnormal tachycardia |
|
|
Term
| What determines cardiac electrical activity? |
|
Definition
|
|
Term
| Ways a channel can change from 'open' to 'closed' conformation |
|
Definition
1. Tail-end clogs up pore
2. Pore squeezes together (more slowly than the tail blockade) |
|
|
Term
| Why are the insides of cells typically more negative than the extracellular space? |
|
Definition
Proteins - amino acids
(ion pumps) |
|
|
Term
| What are the changes in cell membrane potential the result of? |
|
Definition
flow of positively charged ions
-from the extracellular space (thru ion channels)
-between adjoining cells through gap junctions (critical for the spread of signals from cell to cell in heart) |
|
|
Term
| Where are gap junctions located on cells (in heart)? Where are ion channels located? |
|
Definition
Gap junctions: ends of cells (structure of cells facilitates their propagation in this manner)
Ion channels: sides/middle of cells |
|
|
Term
| What protein can be found facilitating the gap junction signalling? |
|
Definition
Connexons
(considered to be a potential future-drug target) |
|
|
Term
| How are ion channels selective for specific ions? |
|
Definition
1. charges: channel might be positive (selective for Cl-)
2. Level of charge (Ca2+ vs Na/K)
3. Shape of ions are different (especially in water) - applies to Na and K |
|
|
Term
| Membrane voltage determines what for a channel? |
|
Definition
Membrane voltage determines the FRACTION OF TIME that the channel allows ions to permeate
If the probability of a channel being open is voltage dependent, activation (time in the open state) will increase with membrane depolarization |
|
|
Term
| T or F: there are anti-arrhythmics that target chloride channels? |
|
Definition
|
|
Term
| T or F: energy is required to move ions through a channel |
|
Definition
| F - energy is not required to flow through a channel (gradient is already created - which might have required energy) |
|
|
Term
| What occurs during depolarization? |
|
Definition
Positively charged ions (Na and Ca) flow into cell
-intracellular potential decreases
-inside of cell becomes less negative (charge approaches zero)
Specific ion channels and pumps return these ions to their resting pre-depolarized concentrations within and outside of the cell (must be completed within 1 sec for normal heart beat) |
|
|
Term
| How is the resting potential restored? |
|
Definition
1. Na/K ATPase pump: energy dependent; 3 Na ions out and 2 K ions in
2. Ca gradient is restored by Na/Ca exchanger (NCX) - driven by the Na gradient that is established |
|
|
Term
| Describe Phase 4 of the AP |
|
Definition
Resting membrane potential (diastole)
~90 mV in myocytes
-Gradient established by [1] pumps (Na/K ATPase pump) and [2] fixed anionic charges in the cell (proteins)
Na channels are CLOSED (Na's electrical and concentration gradients direct flow into resting cells)
K channels are OPEN at negative potentials (MAJOR CONTRIBUTOR TO THE RESTING POTENTIAL) |
|
|
Term
| What is the major contributor ion to the resting membrane potential? |
|
Definition
|
|
Term
| Describe Phase 0 of the AP |
|
Definition
Rapid depolarization
-Stimulation of cardiac cells
-Depolarization stimulus must exceed threshold potential (~70 mV)
-More intense stimuli will not produce larger APs (all or none)
-KEY: sudden increase in membrane conductance to Na
-Slope determined by the max rate of depolarization (Vmax) - faster=more vertical
-fast Na channels open and K channels close |
|
|
Term
| What must sense a change in voltage to propagate an action potential? |
|
Definition
| Ion channels (to know whether to open/close) |
|
|
Term
| Which is faster, Na channel activation or deactivation? |
|
Definition
Activation of the channel proceeds faster than inactivation can occur
-Na flows through its channel ~1 msec (while both gates are open simultaneously) |
|
|
Term
| What are the two gates of the sodium channel? |
|
Definition
m (activation) gate: opened by a stimulus (change in charge); fast
-closed at resting state
h (inactivation) gate: closed by a stimulus; slow
-open at resting state
-cant sense a change in voltage like m gate |
|
|
Term
| When does the Na channel return to resting state (leave inactivation phase)? |
|
Definition
When membrane potential reaches ~60 mV (becomes significantly negative again)
-m gate closes FAST
-h gate opens slowly |
|
|
Term
| When is a cell termed 'refactory?' |
|
Definition
Until the h gate reopens (leaves the inactivated state) the cell is termed refractory - can not be depolarized
-The cell will be insensitive to stimulus (regardless of intensity) |
|
|
Term
|
Definition
Early Rapid Repolarization
-Rapid and transient
-Reached ~0 mV (early notch)
Na channels are inactivated, but there is outward movement of Na via the Na/Ca exchanger operating in reverse mode
Transient outward K current (Kto): turns off quickly (like Na channels) |
|
|
Term
|
Definition
Exchange of 3 Na per 1 Ca with direction being based on Na gradient
-In cell membranes
-Diastole: (at rest) Ca out/Na in
-Systole: (depolarization) Ca in/Na out |
|
|
Term
|
Definition
Plateau Phase
Results from competition between ions:
OUTWARD current:
-K+ (via delayed rectifier currents) and Cl-
INWARD current:
-Ca (L-type channels)
Na being exchanged for internal Ca |
|
|
Term
|
Definition
Final Rapid Repolarization
-Inactivation of L-type Ca channel (decrease in intracellular movement of positive charges)
-Increased activation of repolarizing K currents (delayed-rectifier K currents)- blocking specific delayed-rectifier current causes AEs of K channel blockers
membrane potential gets restored |
|
|
Term
| Node APs dont have which Phase? |
|
Definition
| Phase 2 (or 1) because they don't contract (think that Ca causes the contraction and phase 2 has only Ca movement) |
|
|
Term
| T or F: the AP at a node is not as negative as that in a myocyte |
|
Definition
|
|
Term
| Potassium movement at rest |
|
Definition
K channels have an open conformation at rest (allows K to leave cell - potassium leak)
-this creates the negative potential at rest |
|
|
Term
| What two phases of cardiac AP are the delayed-rectifier K currents activated? |
|
Definition
|
|
Term
| What will happen if a drug blocked the delayed-rectifier K channels? |
|
Definition
| resting potential will be achieved more slowly |
|
|
Term
| Which phase is associated with maximum diastolic potential? |
|
Definition
Phase 4 (when the cell will be most negative)
-Na channels are inactivated |
|
|
Term
| what is the pacemaker current like during phase 4 (aka only in nodes)? |
|
Definition
Slow inward current carried by Na ions (aka iNa slow)
inward movement of Ca via transient followed by L-type Ca channels) |
|
|
Term
| Name 3 ways the rate of pacemaker discharge can be slowed? |
|
Definition
1. Increasing max diastolic potential (making cell more negative)
2. Decreasing slope of Phase 4 (more of a flat line means it will take it longer for cell to reach threshold)
3. Change in threshold potential (make it more positive so it will take more stimuli to reach it) |
|
|
Term
| What causes nodal cells to reach depolarization? |
|
Definition
NOT Na
Inward Ca current is responsible for Phase 0 (L-type Ca channels |
|
|
Term
| What is the primary cause of an AP in the node? |
|
Definition
Calcium inward movement (L-type channels)
-This is Na in the muscle cells |
|
|
Term
| Would it be a good idea to have a drug try to target T-type Ca channels? |
|
Definition
It is a possible future drug target (but hasnt been done yet)
Dont forget that most of the 'better' anti-arrhythmics actually target several different channels, not just a select one |
|
|
Term
| Where are T-type Ca channels located? |
|
Definition
|
|
Term
| If want to inhibit a nodal arrhythmia, what drug might be a good choice to use? |
|
Definition
| CCB since will block L-type Ca channels (what triggers APs in nodes) |
|
|
Term
| After a cell has depolarized, when can the cell depolarize again at the very soonest? |
|
Definition
Mid- to late Phase 3
The stimulus intensity will need to be increased in order to reach threshold |
|
|
Term
| What is the effective refractory period? |
|
Definition
| The interval between phase 0 and the time when a premature stimulus can NOT generate a propagated AP |
|
|
Term
| What are some ways that the effective refractory period can be prolonged? |
|
Definition
1. Increasing the duration of the AP (longer time to begin the refractory period)
2. Slowing rate of recovery of Na channel from inactivation |
|
|
Term
| How are APs that are generated late in phase 3 different from a regular AP? |
|
Definition
There is often insufficient Na influx to result in a self-sustaining AP - may produce a change in potential, but not transmit an AP
BUT, if enough stimuli to create an AP the AP will have a slower upstroke in Phase 0 and may be weaker |
|
|
Term
| What is the relative refractory period and when is it? |
|
Definition
It is the time when most of the Na channels are back in the resting state in Phase 3
The further into Phase 3, the more Na channels will be in the resting state
-If adequate stimuli, a normal AP can result early (ex: arrhythmia) |
|
|
Term
| What are two things that can determine conduction velocity (aka speed of transmission of signal from cell to cell) and 3 things that can adversely affect conduction velocity (based on the 2 determinants)? |
|
Definition
1. The magnitude of the excitatory current
2. Intercellular current flow is increased by gap junctions
Adversely affected by:
1. Decrease in strength of the excitatory stimulus (or partially depolarized resting membrane potential)
2. Decreased membrane receptiveness (Drugs blocking Na)
3. Increased resistance to axial current flow (decrease in gap junctions) |
|
|
Term
| The initiation of a heart beat is governed by ____________. |
|
Definition
| Automaticity (note: it is not the SA node always, but it is the usual pacemaker) |
|
|
Term
| The rate of firing of APs in the heart depends on what two things? |
|
Definition
1. Type of cell
2. Extracellular environment |
|
|
Term
| T or F: mild arrhythmias often require treatment. |
|
Definition
| T - because they may lead to potentially lethal arrhythmias (premature ventricular contraction may trigger ventricular fibrillation) |
|
|
Term
The majority of people with arrhythmias got it how?
What are some other general causes of arrhythmias? |
|
Definition
They had an acute MI (~80%)
Ischemia, hypoxia, scarred/diseased cardiac tissue, over-stretching of cardiac fibers (HF) |
|
|
Term
| Arrhythmias are depolarizations that deviate from normal. What are 3 ways it can deviate from normal? |
|
Definition
1. Abnormal site of origin
2. Abnormal rate/regularity of timing
3. Abnormal conduction of impulse |
|
|
Term
| What are some potential MOAs for arrhythmia formation due to disturbances of impulse formation? |
|
Definition
1. Shortened duration of the AP or duration of the diastolic interval (Phase 4) (tachyarrhythmia)
2. Lengthening duration of the AP or duration of the diastolic interval (bradyarrhthmia)
3. Changes in determinants of pacemaker rate:
-Maximum diastolic membrane potential
-Slope of phase 4 depolarization (influences time to threshold)
-Threshold potential |
|
|
Term
| Potential MOA of bradyarrhythmia? |
|
Definition
Vagal stimulation (Ach) lowers pacemaker rate by making the maximum diastolic potential more negative (~100 mV)
-This reduces the slope of phase 4 depolarization |
|
|
Term
| Potential MOA of tacyarrhythmia? |
|
Definition
| Beta receptor activation - accelerate pacemaker rate by increasing slope of phase 4 |
|
|
Term
| What is an "after-depolarization?" |
|
Definition
Depolarization that interrupts:
Phase 3: (early after-depolarization)
Phase 4: (delayed after-depolarization)
Develop during or after a normally evoked AP
Referred to as "triggered" automaticity because they require a normal AP for their initiation
-If it reaches threshold, a secondary triggered beat will occur |
|
|
Term
| How do delayed after-depolarizations occur? |
|
Definition
-Caused by high intracellular Ca
-Worsened by fast heart rates
-Responsible for arrhythmias caused by excessive NE/Epi stimulation |
|
|
Term
| Why are early after-depolarizations bad? |
|
Definition
-Contribute to the development of long QT-related arrhythmias
-Worsened by slow heart rate |
|
|
Term
|
Definition
Disturbances of impulse conduction
Abnormality of conduction - depressed conduction
Classified based on location
-AV block
-Bundle branch block (bundle of His)
Causes atrial contractions to not match up with ventricular contractions |
|
|
Term
| What are the three conditions that must be present for re-entry of cardiac signal to occur (aka heart block)? |
|
Definition
1. Obstacle: (physiologic or anatomic) to normal conduction
-establishes a circuit around which the re-entrant wavefront can propagate
2. Unidirectional block exists in the circuit (ex: the conduction stops in one direction, but continues in the opposite direction of usual conduction)
3. Conduction time is long enough to allow for retrograde impulse to not enter refractory tissue as it travels around the obstacle (because already depolarized) |
|
|
Term
| What can cause bradycardia |
|
Definition
1. Aging (max discharge rate of SA node, decreases with age) - sinus bradycardia is a major cause of fatigue, weakness, and syncope
2. Meds: CCB, beta-blockers
3. Abnormal impulse transmission - AV block |
|
|
Term
| What are the kinds of AV Block? |
|
Definition
First degree AV Block: delayed conduction
Second degree AV Block: conduction with occasional lack of AV conduction
-Has two Types (I and II)
Third degree AV Block: compete block - no communication between atria and ventricles |
|
|
Term
| What is the worst kind of AV Block? |
|
Definition
| Third degree (total block) |
|
|
Term
| Describe first degree AV block and how it can occur? |
|
Definition
Delayed transmission (not complete block)
Impulses will get to ventricles, but will just take longer than normal to get there
-Most commonly in AV node (not bundle of His)
medications (esp: beta-blockers and CCBs) can slow AV conduction |
|
|
Term
| Differentiate between the two types of 2nd Degree AV block |
|
Definition
Conduction with occasional lack of AV conduction
Type I: (more common) localized in the AV node
-less serious than block at a lower level
-with conduction loss in the AV node, the discharge rate of the His bundle is sufficient to prevent death
Type II: (more serious) intermittent block in the His bundle |
|
|
Term
| What are mechanisms of tachycardia? |
|
Definition
Enhanced automaticity
-Paroxysmal sinus tachycardia (in SA Node)
-Junctional or His bundle tachycardia |
|
|
Term
| What does the QT interval represent? |
|
Definition
| time during which ventricular depolarizaton and repolarization occurs (repolarization is longer) |
|
|
Term
| T or F: any condition or drug that prolongs or delays ventricular repolarization will probably prolong the QT-interval |
|
Definition
T
Ex: drugs (Class IA and III anti-arrhythmics), severe bradycardia, hypokalemia |
|
|
Term
| Why is the repolarization of the atria not evident on an ECG? |
|
Definition
| The QRS wave covers it up (it is present, just masked) |
|
|
Term
|
Definition
It is sometimes present on an ECG and is part of ventricular repolarization
-not really relevant to drugs |
|
|
Term
| Why is prolongation of the QT-interval significant? |
|
Definition
Can allow for spontaneous depolarization of Purkinje cells during repolarization (aka early after-depolarizations)
-Pro-arrhythmic condition
-Can lead to development of polymorphic ventricular tachycardia (Torsades)
-Risk will increase as HR decreases |
|
|
Term
| T or F: the risk of QT prolongation with increase with decreased HR? |
|
Definition
|
|
Term
| What are four common mechanisms used in drugs to combat arrhythmias? |
|
Definition
1. Na channel blockade
2. SNS blockade
3. Prolongation of the effective refractory period (increased duration of AP with K channel blockers)
4. Calcium channel blockade |
|
|
Term
| MOA of Sodium channel blockade for arrhythmias? |
|
Definition
Results in a decreased slope of Phase 0 b/c of decreased Na influx (only affects muscles, not nodes)
-Increased in threshold for excitability (slows automaticity)
-Prolongs rate of recovery of the Na channel leading to increase in the refractoriness of the cell (reduces automaticity) |
|
|
Term
| What types of arrhythmias are Na channel blockers used for? |
|
Definition
Disorders of impulse formation
-Decreased automaticity produced
-Effective in treating arrhythmias resulting from delayed and early after-depolarizations
Disorders of impulse propagation
-Increases refractory state of the Na channel (can stop the re-entrant wave b/c deters depolarization) |
|
|
Term
| MOA of K+ channel blockers for arrhythmias? |
|
Definition
K determines the resting potential and the repolarization rate
SO: will increase AP duration by slowing repolarization (Phase 3) and increases refractory time (slows down how quickly tissue will regain ability to fire an AP) |
|
|
Term
| What types of arrhythmias are K channel blockers used for? |
|
Definition
Re-entry arrhythmias - by increasing refractoriness and inhibiting impulse propagation
(Some K blockers also block Na channels)
NOTE: prolonging the AP can increase early after-depolarization induced arrhythmias |
|
|
Term
| Which types of anti-arrhythmics are more prone to be pro-arrhythmic? |
|
Definition
| Drugs that are more specific for just one type of channel |
|
|
Term
| MOA of CCBs for arrhythmias? |
|
Definition
Primarily affects slow response tissue (ex: SA node and AV node)
-Decreases Ca influx during Phase 4 (decreases automaticity)
-Increases inactivated state of the Ca channel (increasing refractory time of AV node) |
|
|
Term
| What type of arrhythmias are CCBs good for? |
|
Definition
| Re-entrant arrhythmias involving the AV node (ex: AV block: 1st, 2nd type I, 3rd degree) |
|
|
Term
| T or F: CCBs are relatively safe in terms of not stimulating extra arrhythmias? |
|
Definition
|
|
Term
| MOA of beta-blockers being sued for arrhythmias? |
|
Definition
Beta adrenergic activation of the SA node is decreased
Decreases:
1. magnitude of depolarizing Ca current
2. magnitude or repolarizing K current
3. rate and pacemaker current
4. delayed after-depolarizations |
|
|
Term
| T or F: anti-arrhythmics may have selectivity for disease tissue? |
|
Definition
T:
Decreased automaticity of ectopic pacemakers more than SA node
Reduced conduction and excitability (increased refractory period to a greater extent in depolarized tissue compared to normal tissue) |
|
|
Term
| T or F: some anti-arrhythmics have increased affinity for channels in the activated or inactivated state? |
|
Definition
T - some might have lower affinity for channels in the resting state (ex: will be targeting Phases 0 or 2 [Na or K/Ca activation])
-This helps to target tissue that is excessively stimulated tat is common in arrhythmias |
|
|
Term
| Where in the heart are channels most susceptible to drug blockade (anti-arrhythmics)? |
|
Definition
Ventricular channels - because there are the most channels activated per unit time
-Specifically during ventricular tachycardia |
|
|
Term
| During a loss of resting potential what happens to resting membrane potential? |
|
Definition
It is less negative - there will be many inactive channels during rest
This may affect your drug choice |
|
|
Term
| How does recovery from block depend on the state of the channels (in arrhythmias)? |
|
Definition
Channels in NORMAL cells that become blocked will rapidly lose drug during the resting portion of the cycle
Channels that are chronically depolarized where the membrane potential is more positive than -70 mV will recover from block more slowly |
|
|
Term
| Where in the heart does abnormal automaticity occur? |
|
Definition
|
|
Term
| What are some different mechanisms that drugs can slow automatic rhythms? |
|
Definition
1. Reducing the slope of phase 4 by vagal stimulation
-Inhibits iCa and iNa(slow)
-Activation of iK (stabilizes membrane potential during Phase 4)
2. Increase AP threshold (making more positive)
3. Increase max diastolic potential (making more negative at rest)
4. Increase AP duration (prolonged repolarization phase) |
|
|
Term
| What are the Four Main Classes of Anti-arrhythmics? |
|
Definition
Class I: Sodium channel blocers (3 subclasses)
Class II: Beta-blockers
Class III: prolongation of AP duration and effective refractory period (Primarily K channel blockers)
Class IV: CCBs |
|
|
Term
| What two factors determines how the Class I anti-arrhythmics are divided in to different subclasses? |
|
Definition
1. Effects on AP duration (DURATION)
2. Kinetics of interaction with Na channels (determines their ability to slow conduction) (SPEED) |
|
|
Term
| What are the effects of the different Class I anti-arrhythmics on the ventricular AP? |
|
Definition
Class IA:
-Moderate Na-channel blockade
-Increased effective refractory period (Phase 3)
Class IB
-Weak Na-channel blockade
-Decreased effective refractory period
Class IC:
-Strong Na-channel blockade
-No change in effective refractory period |
|
|
Term
| If an anti-arrhythmic changes conduction velocity, what phase of the AP is being affected? |
|
Definition
|
|
Term
| What are some examples of Class IA anti-arrhythmics? |
|
Definition
Quinidine
Disopyramide
Procainamide |
|
|
Term
| MOA of classIA anti-arrhythmics? |
|
Definition
Moderate Na block causes mild reduction of Vmax (slows conduction)
Lengthens duration of AP, prolongs repolarization by blocking K channels |
|
|
Term
| What are potential toxic issues associated with Class IA anti-arrhythmics? |
|
Definition
QT prolongation and torsades
This is an issue with any drug that will cause QT prolongation |
|
|
Term
| Disopyramide has two MOAs, what are they? |
|
Definition
Class IA anti-arrhythmic (intermediate Na channel binding; lengthen duration of AP)
Muscarinic receptor blocker (atropine-like effects ->tachycardia) |
|
|
Term
| What Class IA antiarrhythmic is no longer on the market as oral formulation? |
|
Definition
| Procainamide - injection only |
|
|
Term
| Examples of Class IB anti-arrhythmics? |
|
Definition
|
|
Term
| MOA of Class IB anti-arrhythmics? |
|
Definition
Rapid kinetics of Na-channel binding - so makes it a weak blocker
-effects only occur in depolarized (ischemic) tissue (open or inactivated Na channels) which is why it is best for tachyventricular arrhythmias
Blocks late (phase 2-3) Na current (shortens AP) |
|
|
Term
| Lidocaine use as antiarrhythmic |
|
Definition
Class 1B
Low toxicity, high degree of effectiveness in arrhythmias associated with MI (decreases ventricular fibrillation)
-Decreases automaticity, increases threshold
Because of big first past metabolism by liver only IV |
|
|
Term
| Mexiletine compared to lidocaine |
|
Definition
| Mexiletine is available PO because decreased first-pass metabolism |
|
|
Term
| MOA of Class IC anti-arrhythmics? |
|
Definition
Slow time constant for recovery (potent block of Na channels) - slows conduction in normal tissue
-Increases QRS interval (because makes slope of Phase 0 flatter)
-Increases threshold, decreases automaticity (so do IB) - need more firing because this is acting against it |
|
|
Term
| Examples of Class IC Anti-arrhythmics |
|
Definition
Flecainide
Propafenone (Rythmol) |
|
|
Term
| T or F: the incidence of pro-arrhythmia is low in the absence of structural heart disease |
|
Definition
| T - Class IC can be used in the absence of structural defects because will illicit effect on normal heart tissue |
|
|
Term
| Flecainide: class and use |
|
Definition
Class IC anti-arrhythmics
Effective for suppressing premature ventricular contractions
-Dont use in ischemic heart disease - increased mortality |
|
|
Term
| What does R represent on the ECG? |
|
Definition
|
|
Term
| What drugs are classified as Class II anti-arrhythmics? |
|
Definition
Beta blockers
Specifically indicated:
-Sotalol (Betapace)
-Propranolol (Inderal)
-Esmolol (Brevibloc)
Can use selective or non-selective beta-blocker for arrhythmia, but dont want any with intrinsic sympathomimetic activity |
|
|
Term
| MOA of Class II anti-arrhythmics? |
|
Definition
Reduce sympathetic effects
-decreases sinus rate
-decreases conduction velocity (esp. in AV node)
-blocks re-entry mechanisms (inhibits aberrant pacemaker activity) |
|
|
Term
| Where are beta-adrenergic receptors in the heart? |
|
Definition
Cardiac nodal tissue
Conducting system
Contracting myocytes
Both beta-1 and beta-2 are present, but more beta-1 |
|
|
Term
| In nodal tissue, what NT primarily binds to the beta receptors? |
|
Definition
|
|
Term
| Sympathetic activation effects on the heart? |
|
Definition
1. increase SA node automaticity: increased pacemaker current and rate
2. Increases conduction velocity (especially in the AV node)
3. Increases aberrant pacemaker activity (produces ectopic foci) |
|
|
Term
| What tissue of the heart is most greatly affected by beta blockers? |
|
Definition
Nodal tissue
Thus, efficacy for suppressing ventricular ectopic depolarizations is less than with Class I agents (because more or a focus on nodal tissue) |
|
|
Term
| Clinical uses of beta-blockers |
|
Definition
1. terminate re-entrant arrhythmias involving AV node
2. control ventricular response rate in A.fib or flutter
3. treatment of Torsades, especially when triggered by emotional stress (decreases early after-depolarization activity from excessive NE/Epi surges)
Best for arrhythmias originating before the ventricles, better if AV node |
|
|
Term
| Heartbeat with fibrillation versus flutter |
|
Definition
Fib: dont really have a heartbeat
Flutter: ~200-250 beats/min |
|
|
Term
|
Definition
Class II anti-arrhythmic
Selective beta-1 blocker (no intrinsic activity)
IV only (continuous infusion)
Metabolized by erythrocyte esterases (in blood not liver)
ultra-short half-life
Use: rapid control of the ventricular rate during atrial flutter or fibrillation |
|
|
Term
| What is the MOA of Amiodarone? What is its class? |
|
Definition
Class III anti-arrhythmic
Multiple pharmacological effects
-Blocks Na channels in the inactivated state (decreases Phase 0 upstroke)
-Blocks K currents in Phase 3 (prolongs AP duration)
-Structural analog of thyroid hormone
-Very lipid soluble - disrupts multiple ion channels
ALSO:
-Alpha and Beta adrenergic effects-->decreased TPR (hypotension, especially with IV) |
|
|
Term
| How is amiodarone supplied? |
|
Definition
|
|
Term
| Which is more pro-arrhythmic: amiodarone or Class I drugs? |
|
Definition
|
|
Term
| What are some clinical uses of amiodarone? |
|
Definition
PO:
-recurrent ventricular tachycardia or fibrillation
-maintain sinus rhythm in patients with atrial fibrillation
IV
-acute termination of ventricular tachycardia or fibrillation |
|
|
Term
| T or F: amiodarone is difficult to dose |
|
Definition
|
|
Term
| What is the most serious ADR seen with amiodarone? |
|
Definition
Pulmonary fibrosis
-especially with high-dose chronic therapy (up to 15%)
-May be rapidly progressing and fatal
-Increased risk of pneumonia in patients with underlying lung disease |
|
|
Term
|
Definition
Pulmonary fibrosis
Corneal micro-deposits leading to optic neuropathy/neuritis and visual impairment
Liver dysfunction (~15%)
Neuropathy/Muscle weakness
Photosensitivity due to skin deposits (25%) - gray-blue discoloration of sun exposed skin
Thyroid dysfunction: alters TH conversion; hypo/hyperthyroidism
Most people will get an ADR (~75%, 25% will D/C) |
|
|
Term
|
Definition
VERY lipid soluble - concentrates in tissue
half-life with chronic therapy ~2 months
Onset of activity is delayed (PO drug-loading regimens require several weeks) - high dose at first then decrease |
|
|
Term
| Precautions with amiodarone? |
|
Definition
Monitor for pulmonary toxicity
Use with caution in patients with underlying pulmonary or thyroid disease |
|
|
Term
| Drug interactions with amiodarone |
|
Definition
CYP 2C9, 2D6, 3A3/4
-can increase levels of DIGOXIN, other anti-arrhythmics, WARFARIN (decreases dose up to 50%)
Additive with other drugs that prolong QT interval: phenothiazines, TCA, FQ
Other drugs that slow AV conduction (increases risk of AV block): CCBs, beta-blockers, digoxin |
|
|
Term
| What are the Class III anti-arrhythmics? |
|
Definition
Amiodarone
Dronedarone (Multaq)
Sotalol
Ibutilide (Covert)
Dofetilide (Tikosyn) |
|
|
Term
| How does dronedarone compare to amiodarone? |
|
Definition
Safer and more tolerable, but not as effective at maintaining sinus rhythm
-stronger anti-adrenergic effects than amiodarone (limits use in heart failure)
Structure:
-No iodine (decreased ADR related to thyroid)
-Polar groups - less lipophilic, shorter half-life, decreased tissue accumulation |
|
|
Term
|
Definition
Blocks:
Multiple K currents
Fast Na current
L-type Ca current
stronger anti-adrenergic effects than amiodarone (limited use in HF) |
|
|
Term
| What are some drug interactions with dronedarone? |
|
Definition
| Inactivated by CYP3A4 - increased levels with inhibitors (antifungals, macrolides, antibiotics) |
|
|
Term
| While dronedarone is safer than amiodarone in general, what type of patient should you caution in (more than if you were using amiodarone)? |
|
Definition
| Heart failure patients, because increased anti-adrenergic effects |
|
|
Term
|
Definition
Sotalol
-Class 2 and 3
Non-selective beta-blocker
BUT its primary anti-arrhythmic effects are blocking K channels during Phase 3 repolarization
Enatiomers matter:
d-enantiomer: only Class III effects (slows repolarization)
l-enantiomer: both Class II and III effects depending on dose!
-II: occur at 25 mg/day
-III: only occur >160 mg/day
No intrinsic sympathomimetic activity (ISA)
No effect on conduction velocity in fast-response tissue (myocytes) |
|
|
Term
| Which anti-arrhythmic has been classified in two Classes? |
|
Definition
|
|
Term
|
Definition
Atrial fibrillation and flutter
Ventricular tachycardia (but trials show that amiodarone is more effective than sotalol at maintaining sinus rhythm during A.fib) |
|
|
Term
| What is an ADR of sotalol? |
|
Definition
may cause early after-depolarizations
-increased torsades de pointes (especially with hypokalemia) |
|
|
Term
|
Definition
Good PO absorption, but better on empty stomach
half-life ~12 hours
eliminated in urine unchanged: must adjust dose for renal insufficiency |
|
|
Term
| Contraindications of sotalol |
|
Definition
-Asthma
-2nd/3rd degree heart block (unless paced)
-Congenital or acquired QT syndrome
-Creatinine clearance <40 ml/min (for A.fib - absolute) |
|
|
Term
|
Definition
Must initiate in setting with ECG monitoring
-check baseline QT interval - if QT >450msec at baseline, would not likely use sotalol
Initial dose based on renal function
CrCl >60: 80 mg BID
CrCl 40-60: 80 mg QD
CrCl <40: DO NOT GIVE (CI)
Recheck QT 2-4 hours after dose - if QT >500 msec, D/C drug |
|
|
Term
| Drug interactions with sotalol |
|
Definition
Concurrent drugs that also prolong QT interval
Beta blocekrs, CCBs = additive effects on AV conduction |
|
|
Term
| What is atherosclerosis and why is it bad? |
|
Definition
Accumulation of cholesterol, macrophages, lipoproteins, and collagen in the intima of arteries
(atheromatous plaque)
Leads to the occlusion of the lumen and risk of rupture, leading to complete blockage
Responsible for ~40.6% of ALL deaths |
|
|
Term
| What is the leading cause of atherosclerosis? |
|
Definition
|
|
Term
| What are three classes of liporoteins? |
|
Definition
VLDL:
-TG rich
-10-15% of serum cholesterol
-precursor of LDL
LDL: (includes IDL)
-70% of serum cholesterol
-associated with formation of plaques
HDL:
-up to 40% of serum cholesterol
-inversely related with CHD (b/c carrying cholesterol back to liver) |
|
|
Term
| What do lipoprotein particles contain? |
|
Definition
-Lipid core of TG and cholesterol esters
-Outer monolayer of phospholipid, cholesterol, and apolipoproteins
-The apoproteins specify receptor interaction and class (receptors are unique to certain tissues where the particles are supposed to dump contents):
1. ApoA - HDL
2. ApoB - LDL
3. ApoB,C,E - VLDL |
|
|
Term
| Order of processing of lipoproteins |
|
Definition
Chylomicrons in intestine from dietary fat (contains apo-B48); distributes to all tissues
Reprocessed in liver to VLDL-->IDL-->LDL (as lipids are removed in tissues)
HDL carries lipid and cholesterol back to liver from peripheral tissue |
|
|
Term
| Which lipoproteins are high in protein? |
|
Definition
|
|
Term
| What happens to the cholesterol esters in HDL? |
|
Definition
1. Can be taken up by liver by SR-B1 receptor (then cholesterol eliminated via bile)
2. Transferred back to VLDL via:
-Cholesterol ester transfer protein (CETP)
-Lecithin-cholesterol acyl-transferase (LCAT)
**Attempting to make drug targets for these, but none yet - want to decrease levels of these because dont want cholesterol going back out into circulation |
|
|
Term
|
Definition
Lp(a)
LDL/VLDL particle in which ApoB is linked to apo(a) glycoprotein
High levels (>50 mg/dl) are associated with atherosclerosis and CVD, but the actual function of Lp(a) is unknown (may promote clotting b/c looks like plasminogen)
-often found in kidney disease
Typically 3x higher in blacks |
|
|
Term
| What drug can lower Lp(a)? |
|
Definition
only Niacin (~30% decrease)
Treatment is recommended only if patient is at risk of CVD and has levels of >50mg/dl (>80th percentile) |
|
|
Term
| What does a null mutation in ApoC do? |
|
Definition
Less ApoC (~50% decrease) is cardioprotective
-null mutation seen in Amish
-lower TG, LDL and higher HDL
Mutation results in a premature termination of translation and loss of protein |
|
|
Term
| What is ApoC and is it good or bad? |
|
Definition
Secreted by the liver and intestine
-Presence impairs hepatic uptake of LDL and VLDL and increases HDL uptake
-Increases monocyte adhesion to vascular cells, promotes inflammation
-Associated with increased CVD risk |
|
|
Term
| What drug can lower ApoC? |
|
Definition
|
|
Term
| What are some characterizations of hyperlipidemia disorders? |
|
Definition
1. Hypercholesterolemia: high total serum cholesterol
2. Hypertriglyceridemia: high total serum TG (>33% of population has TG>150)
3. Mixed Hyperlipidemia: high serum cholesterol and TGs
4. Atherogenic dyslipidemia: high TG, small dense LDL particles, and low HDL |
|
|
Term
| What are some types of primary hyperlipidemia? |
|
Definition
1. Defective LDL receptor: cant take up lipid from circulation (many possible causes: may be b/c failure to express, failure to bind, failure to process that the lipid is binding) (1:500)
2. Defective apoB100 lipoprotein: LDL doesnt bind LDL receptor (1:1000)
3. PCSK9 mutations: involved in LDL receptor expression (autosomal dominant) (1:2500) |
|
|
Term
| Heterozygous vs Homozygous FH due to defective LDL receptor |
|
Definition
-Heterozygous FH most common - <25% activity (CVD as early as 30 yo)
-Homozygous FH - atherosclerosis in kids |
|
|
Term
| How high are cholesterol and LDL in patients with familial hyperlipidemia? |
|
Definition
Cholesterol >300 mg/dl
LDL >220 mg/dl |
|
|
Term
| What are some common causes of secondary hyperlipidemia? |
|
Definition
TG>cholesterol; low HDL-C: Diabetes
TG>cholesterol
Alcohol
Nephrotic syndrome
Contraceptive/Estrogen use
Glucocorticoid excess
Cholesterol>TG
Hypothyroidism
obstructive liver disease |
|
|
Term
| What is considered desirable vs high for total cholesterol? |
|
Definition
|
|
Term
| What is considered desirable vs low for HDL? |
|
Definition
|
|
Term
| What is considered desirable vs high for LDL? |
|
Definition
Ideal: <100
-for very high risk patients: <70
High: >160 |
|
|
Term
| What is considered desirable vs high for total TG? |
|
Definition
|
|
Term
| What is the normal turnover of cholesterol daily? |
|
Definition
~1 g/day
600 mg in feces
400 mg in bile acids
100 mg in skin/steroid hormone synthesis |
|
|
Term
| How much cholesterol is from endogenous synthesis? |
|
Definition
50-75% (700-900 mg/daily)
-25% made in liver (but virtually all cells are capable of making cholesterol)
All cholesterol in neural tissues is synthesized in situ (cant cross BBB) |
|
|
Term
| What types of food does dietary cholesterol come from? |
|
Definition
Animal products
-meet, eggs, seafood, high-fat dairy
Plants and fungi make alternative sterols (sitosterol, ergosterol) |
|
|
Term
| A 10% reduction in LDL will correspond to a ____% reduction in CHD. |
|
Definition
|
|
Term
| A 10% increase in HDL will correspond to a ____% reduction in CHD. |
|
Definition
|
|
Term
| T or F: with hyperlipidemia, it is important to determine which lipids are high in order to determine what drug to use? |
|
Definition
|
|
Term
| T or F: we are concerned with hyperlipidemia because of the formation of plaques cause occlusion of the blood vessels |
|
Definition
| F - we are concerned with the plaques because they will rip away from the vessel wall and cause a clot to form |
|
|
Term
| What dietary modifications should be considered for someone with hyperlipidemia? |
|
Definition
Total fat <35% of total calories
-SATURATED FAT <7%** MOST IMP!
Cholesterol<200mg/d if HLD (<300mg/d if normal)
Carbs ~50% of total cal
Dietary fiber: 20-30g/d
2 g/d of plant sterols (compete with uptake)
Can decrease LDL by 20-30% |
|
|
Term
| Besides diet, what other lifestyle modifications can be implemented to decrease lipids |
|
Definition
Exercise
Weight reduction
Smoking cessation (+ will decrease BP)
Give lifestyle changes 3-6months before drug therapy |
|
|
Term
| T or F: with hyperlipidemia, once a drug is started, the patient will be on it for life. |
|
Definition
|
|
Term
| What are some types of hyperlipidemic meds? |
|
Definition
1. HMG CoA Reductase Inhibitors: statins
2. Resin/Bile Acid sequestrants
3. Niacin
4. Fibrates
5. Selective cholesterol uptake inhibitors |
|
|
Term
| MOA of HMG-CoA reductase inhibitors? |
|
Definition
Block the principle regulating step of cholesterol synthesis
-3rd step (generation of mevalonate)
Inhibition:
-increases LDL receptor (increases LDL uptake)
-decreases cholesterol synthesis and lipoprotein secretion from liver |
|
|
Term
| What is the most effective drug at decreasing LDL cholesterol? |
|
Definition
Statins
~20-40% reduction with standard dose, 60% at max dose (Rosuvastatin and atorvastatin yield greater reductions- more potent) |
|
|
Term
| Doubling the dose of a statin decreases LDL-C by ________. |
|
Definition
Lowers LDL by 6%
This is good to know since can help determine how much a dose should be increased to cause a certain decrease in LDL |
|
|
Term
| How long will it take to see the full effect of a given statin dose? |
|
Definition
| 7-10 days for max effect to be achieved |
|
|
Term
| Do statins affect HDL or TG? |
|
Definition
Yes!
HDL: increase of 5-8% (and if has low HDL can increase up to 20%)
TG: decrease TG up to 45% if >250 and 25% if <250 mg/dl |
|
|
Term
| Why do statins have limited effectiveness in familial hypercholesterolemia? |
|
Definition
B/c most of these patients have loss of function of LDL receptor, which is a main target of these drugs
-so can only decrease synthesis in these patients |
|
|
Term
| Besides direct effect on LDL, HDL, and TG, what are some other potential benefits of statins? |
|
Definition
Pleiotropic effects
1. anti-inflammatory: decrease CRP independent of LDL lowering (JUPITER TRIAL)
2. Improved endothelial function: increase NO release (may be independent of LDL lowering)
3. May stabilize atheromas:
-Inhibit monocyte infiltration
-Inhibit proliferation of smooth muscle (including tumor growth) |
|
|
Term
| T or F: half of all MIs occur in patients with normal/low cholesterol. |
|
Definition
|
|
Term
|
Definition
BIG study of patients with LDL cholesterol <130 (boarderline risk) and CRP>2 mg/L (high)
Decreased 2 year incidence of MI and stroke by 50%
~4% of the population are like those studied
Caused broadening of Crestor indication to include people at low-moderate risk of heart disease with high CRP or other risk factors, but with normal cholesterol
BUT, not recommended (yet) to test CRP as a screening tool for heart disease |
|
|
Term
| CRP varies among races, which population has the highest average level? |
|
Definition
| African Americans (then Hispanics) |
|
|
Term
| OVERALL: What is CRPs role in determining risk of heart disease/need to go on a statin? |
|
Definition
Inflammatory marker
-JUPITER trial showed that statin will decrease heart disease in patients with high CRP
BUT going on a statin will decrease the risk of CVD events regardless of CRP level (even if cholesterol is normal) |
|
|
Term
|
Definition
1. Myopathy
2. Hepatotoxicity (dose-related) reversible (monitor liver enzymes at 3,6,12 months)
3. Cognitive loss: no objective evidence (yet), but 2nd most common complaint
4. Increased risk of developing diabetes and cataracts (but still low risk)
-Risk of cataracts is greatest in diabetes
5. Fatigue (esp on exertion) women>men
6. Peripheral neuropathy, sexual dysfunction, fall indication of hyperthyroidism (Low TSH levels and normal T4/T3) |
|
|
Term
| Risks of statins outweigh benefits in those over _______ years of age? |
|
Definition
| 70 years old - dont use statin |
|
|
Term
| Myopathy can lead to_________. |
|
Definition
|
|
Term
| Who is at an increased risk of myopathy with statin use? |
|
Definition
Elderly
Hepatic or renal dysfunction
Disease (esp. DM)
Other drugs that can cause rhabdo or that will interact with statins |
|
|
Term
| What statin drug interactions can increase the risk of myopathy? |
|
Definition
CYP3A4 substrates (most common)
-Fibrates (gemfibrozil -38%), cyclosporine, digoxin, warfarin, macrolides, azoles, niacin, HIV protease inhibitors
Gemfibrozil - 2nd issue - completes for uptake into liver (doubles plasma concentration of statin (not an issue with fenofibrate)
**Only use 25% of statin max dose when combined with one of the above drugs |
|
|
Term
| What are symptoms of rhabdomyolysis? |
|
Definition
-intense muscle pain usually in arms and thighs first
-weakness
-fatigue
-myoglobinuria can lead to renal failure
-serum creatine kinase levels are typically elevated 10-fold
-can occur at anytime (not just at beginning) |
|
|
Term
| T or F: if myopathy occurs, statins should be discontinued |
|
Definition
T!
And all other drugs that may be contributing |
|
|
Term
| What genetic variation is associated with statin-myopathy risk? |
|
Definition
SLCO1B1
Homozygous in the variant (CC) are 20x higher risk of myopathy b/c lower activity resulting in decreased statin uptake by liver
-Genetic testing is available for this variant |
|
|
Term
| Possible ways statins may cause myopathy? |
|
Definition
1. Blocking isoprenoid synthesis (most notably CoQ10) needed for ETC
2. Preventing prenylation of regulatory proteins: (Rho, Rac, Ras) needed to suppress apoptosis
3. Preventing selenocysteine tRNA synthesis: prenylation eeded for functional tRNA synthesis (need selenium)
4. Reducing muscle cholesterol levels: can cause lipid storage myopathy; cholesterol needed to stabilize membranes
5. Autoimmune sensitization to HMG-CoA reductase |
|
|
Term
| Treatment/Prevention options of statin-related myopathy? |
|
Definition
CoQ10 supplements (120-600 mg/d) - may not be helpful
Exercise
L-carnitine supplementation |
|
|
Term
| T or F: the FDA recommends limiting the 80 mg dose of simvastatin to only patients who have had no myopathy with simvastatin therapy over last 12 months |
|
Definition
|
|
Term
|
Definition
Absorption: 30-85%; extensive first pass (5-30% F)
-uptake by organic anion transporters (OATB1B1, SLCO1B1)
Simvastatin and Lovastatin must be activated by liver (from lactone)
Several are CYP3A4 substrates
-Pravastatin is NOT metabolized
-Fluvastatin is CTP2C9 substrate too
half-life: ~1-4 hr (Lipitor and Crestor =20 hr) |
|
|
Term
| Dosing and use of statins |
|
Definition
Starting doses are designed to lower LDL by 20-30% (QD)
-40 mg Pravastatin; 10-20 mg atorvastatin
Cholesterol synthesis is diurnal (max at night) - so take in evening! |
|
|
Term
| T or F: statins can be used in pregnancy |
|
Definition
|
|
Term
| Hydrophilic statins are less likely to cross skeletal muscle membranes and less likely to cause ADRs. Which statins fit into this category? |
|
Definition
| Rosuvastatin(Crestor) and Pravastatin |
|
|
Term
| Statins that do NOT have active metabolites are less likely to cause ADRs. Which statins fit into this category? |
|
Definition
Pitavastatin (Livalo)
Pravastatin
Fluvastatin (Lescol) |
|
|
Term
| Many statins are 3A4 substrates, which can contribute to risk of ADRs. Which statins are NOT substrates for 3A4? |
|
Definition
Rosuvastatin
Pravastatin
Fluvastatin
(Pitavastatin is only slight) |
|
|
Term
| What two things should be checked before beginning a statin? |
|
Definition
1. Thyroid status (hypothyroidism = increased risk of myopathy)
2. Baseline creatine kinase (CK) |
|
|
Term
| What two statins may allow for alternate daily dosing? |
|
Definition
| Rosuvastatin and atorvastatin (longer half-life = 20 hr) |
|
|
Term
| What are the oldest and safest hypolipidemics? |
|
Definition
|
|
Term
| What are some bile acid sequestrants? |
|
Definition
Cholestyramine
Colestipol
Colesevelam (Welchol) |
|
|
Term
| MOA of bile acid sequestrants? |
|
Definition
Highly positively charged polymers that act as anion-exchange resins
Bind negatively charged bile acids and promote their elimination in feces
(Nonsoluble and can be absorbed)
KEY: loss of bile acids stimulate cholesterol uptake into liver from blood |
|
|
Term
| What is the preferred drug for cholesterol in kids and women who are pregnant? |
|
Definition
|
|
Term
| Bile acid sequestrant's role in hyperlipidemia? |
|
Definition
-Kids (11-20)
-Pregnancy
-second-line behind statins
-add-on therapy to statins |
|
|
Term
| How much bile acid is usually recycled? |
|
Definition
|
|
Term
| When bile acids are lost and not recycled, what occurs? |
|
Definition
1. Hepatic cholesterol synthesis is increased
2. LDL receptor expression increases
3. Bile acid synthesis from cholesterol increases
4. Serum cholesterol levels fall
TG synthesis is also often increased (BAD) |
|
|
Term
| Addition of _______ substantially increases the effectiveness of a bile acid sequestrant by _____ |
|
Definition
| a statin increases the effectiveness by blocking cholesterol synthesis (which is usually stimulated with BAS) |
|
|
Term
| T or F: the higher the dose of a bile acid sequestrant, the greater then decrease in cholesterol. |
|
Definition
T, dose determines effectiveness
Max effect in 1-2 weeks |
|
|
Term
| Dosage forms of bile acid sequestrants? |
|
Definition
Powders - mix with water and drink as a slurry (gritty - less so if refrigerated)
Capsule (Colesvelam [Welchol])
Tablet (Colestipol)
**Take pills with plenty of water |
|
|
Term
| Dosing of bile acid sequestrants? |
|
Definition
| 4-5 g BID immediately before meals |
|
|
Term
| ADRs of bile acid sequestrants? |
|
Definition
Common: bloating, dyspepsia, constipation (less with colesevelam)
Raises TG oftentimes in patients
Interfere with absorption of many drugs (diuretics, digoxin, beta-blockers, STATINS) -must take them at least 1 hour before or 3-4 hr after BAS
Rare: hyperchloremic acidosis (b/c Cl salt) |
|
|
Term
| Contraindication of bile acid sequestrants |
|
Definition
|
|
Term
| What drugs can be combined with bile acid sequestrants? |
|
Definition
Statins (space though so can get absorbed)
Niacin
Very effective at lowering LDL |
|
|
Term
| What is the best agent for increasing HDL? |
|
Definition
Niacin (~30-40% increase)
-best effect in patients with NORMAL HDL levels |
|
|
Term
| T or F: Low HDL levels (<50) are an independent risk factor for CVD? |
|
Definition
|
|
Term
|
Definition
Best for increasing HDL
-Lowers TG (35-45%) - max effect in 1 wk
-Lowers LDL (20-30%) - max effect in 3-6wks
-Lowers Lp(a) (indep risk factor for CVD) |
|
|
Term
| What limits the dose of niacin |
|
Definition
ADRs:
flushing and dyspepsia |
|
|
Term
| MOA of niacin for hyperlipidemia |
|
Definition
1. inhibits lipolysis of TGs in adipose tissue
-Down regulated hormone-sensitive lipase
-Decreases release of free fatty acids into blood -->decreases hepatic TG synthesis and VLDL secretion-->Lower LDL secretion
2. Decreases cholesterol ester transfer protein (CETP) activity [which usually transfers cholesterol from HDL to LDL/VLDL (so higher HDL levels)]
3. Stimulates cholesterol export from macrophages (good for atheroma prevention) |
|
|
Term
|
Definition
1. Flushing and pruritis on upper body/face (prostaglandin mediated PGE-2)
2. Dry skin (moisturize!)
3. Re-aggravate PUD
4. Hepatotoxic - most serious concern
-less with Niaspan (more common with >2g/d of sustained release OTC preparations)
5. Aggravate insulin resistance in DM (long-term risk of new-onset DM is low) ->hyperglycemia/insulin resistance resolves after 3-6 mo
6. Aggravate gout |
|
|
Term
| How to lessen flushing with Niacin |
|
Definition
-give ASA before to lessen
-most common with hot drinks/EtOH
-usually stops after 2-3 weeks at stable dose, but if skip a dose can return
-less common if take with meals |
|
|
Term
| How can hepatotoxicity present? |
|
Definition
Elevated serum ALT, hyperglycemia
Flu-like sx: fatigue, weakness
Decline in LDL of 50% |
|
|
Term
| T or F: niacin can be used in pregnancy to lower cholesterol |
|
Definition
F! (Cat C)
The doses are higher than normal and cause birth defects in animals |
|
|
Term
| What is the max daily dose of Niacin? |
|
Definition
1.5-2 g/day
Higher doses can cause hepatotoxicity |
|
|
Term
| What is the only form of niacin approved for dyslipidemia? |
|
Definition
| Niaspan (least likely to cause hepatotoxicity) |
|
|
Term
|
Definition
1qHS
Start with 500 mg for first month
Titrate up to 2 gm/d max
ASA 30 min prior can decrease flushing |
|
|
Term
| Which gene is associated with higher HDL levels? |
|
Definition
LIPG Asn 396Ser
higher HDL, but did not have a significant decrease in risk of MI |
|
|
Term
| T or F: Niaspan improves HDL levels (and TGs) but there is no evidence that it lessens CVD event risk? |
|
Definition
| T - while low HDL is an independent risk factor for CVD, it is unsure of whether or not raising HDL with meds will better the morbidity/mortality in these patients. |
|
|
Term
| What are some examples of fibrates? |
|
Definition
Gemfibrozil (Lopid)
Fenofibrate (Tricor, Antara, Trilipix) |
|
|
Term
|
Definition
PPAR-alpha agonists (primarily in brown adipose and liver)
-promotes oxidation of fatty acids and TGs
-Increases lipoprotein lipase expression (enhances clearance of TG rich lipoproteins (VLDL)
-Decreased production of apoC (increases VLDL clearance)
-HDL increases by increase in apoA expression |
|
|
Term
| What is the preferred fibrate to use with statins? |
|
Definition
| Fenofibrate, because gemfibrozil blocks (competes with) the uptake of statins |
|
|
Term
| What is the drug of choice in hypertriglyceridemia? |
|
Definition
|
|
Term
| What drugs for hyperlipidemia are often used in diabetics? |
|
Definition
|
|
Term
| What is type IV hyperlipidemia? |
|
Definition
| elevated VLDL (dysbetalipoproteinemia) |
|
|
Term
| What are some types of hypertriglyceridemia? |
|
Definition
Type IV hyperlipidemia (high VLDL)
Severe hyperTG (>400)
Chylomicronemia |
|
|
Term
| What lipoprotein are fibrates not very good at fixing, and actually might worsen? |
|
Definition
LDL - has seen to increase LDL in some cases if there is any change at all
-Combine with a statin to provent |
|
|
Term
| T or F: Fibrates reduce fatal and non-fatal CV events. |
|
Definition
T - by 34%
BUT no effect on total mortality in 5 yr period - only real improvement/prevention seen in patients with hyperTG and low LDL |
|
|
Term
| Dosing and administration of fibrates? |
|
Definition
Well absorbed when TAKEN WITH A MEAL
QD or BID
highly protein bound (albumin)
half-life: 1 hr (gemfib) 20 hr (fenofib)
Renally excreted (CI in renal failure) |
|
|
Term
|
Definition
WELL TOLERATED
-GI effects
-Rash, myalgia, fatigue
-Potentiate PO anticoagulants (displaecment from ALB) - may need to decrease dose of anticoagulant
-MYOPATHY with STATINS (esp Gemfib) - competes with liver uptake
-increased bile stone formation (esp with old/off market one) |
|
|
Term
| T or F: fibrates can be used in kids. |
|
Definition
|
|
Term
| T or F: fibrates can be used during pregnancy. |
|
Definition
| F - teratogenic in animals (Cat C) |
|
|
Term
|
Definition
(Zetia) Cholesterol uptake blocker
Prevents cholesterol absorption by blocking NPC1L1 sterol uptake transporter
-Does NOT affect TG absorption |
|
|
Term
|
Definition
Decreases cholesterol content of chylomicrons (remnant chylomicrons are very atherogenic)
Decrease in cholesterol to liver stimulates:
-increased LDL receptor expression (decreases serum cholesterol)
-increased cholesterol synthsis
-Lowers LDL by 18% (equal to low-dose statin) BUT increases more atherogenic LDL particles than normally present |
|
|
Term
| Ezetimibe's effect on LDL |
|
Definition
Does lower LDL by 18% but seems to alter LDL-subclass profile to a more ATHEROGENIC distribution ->increased small dense LDL particles
BAD |
|
|
Term
| What else is taken up by the same transporter that ezetimibe blocks? |
|
Definition
plant sterols (which are good)
Addition of 2-3 g/day of plant sterols will decrease LDL by 6-15% (by competing with cholesterol uptake) |
|
|
Term
|
Definition
|
|
Term
|
Definition
moderate F
-undergoes enterohepatic recirculation (glucouronidates in instestine)
LONG HALF-LIFE (20-30 hr)
Bile acid sequestrants bind to ezetimibe - DO NOT COMBO |
|
|
Term
| Ezetimibe is most effective when __________? |
|
Definition
Combined with a statin
Ex: Vytorin (with simvastatin)
Good to lower LDL even more (up to 60%)
and decrease dose of statin (less hepatotoxicity and myotoxicity) |
|
|
Term
| The addition of ezetimibe to sivastatin provided no added benefit in preventing/reducing carotid artery intima media thickening (aka atherosclerosis) even though lowered LDL. What are some possible explanations? |
|
Definition
1. Lowering LDL isnt enought to decrease atherosclerosis
2. Intima media thickness is not a good indicator of atheroma progression
3. Bad sample population (familial hypercholesterolemia only studied, max intimal reductions may already have been achieved, study too short) |
|
|
Term
| Which is better in combination with a statin: niacin or ezetimibe? |
|
Definition
| Niacin (better at decreasing carotid intima media thickness) but remember still not better at decreasing CV events |
|
|
Term
| CETP Inhibitors are currently being studied for hyperlipidemia, but there was a major ADR with one that stopped trials, what was it? |
|
Definition
| Increased aldosterone and BP which led to death due to CV events |
|
|
Term
| Anacetrapib - what is it? |
|
Definition
New drug in development that is a CETP inhibitor that lacks off-target stimulation of aldosterone
-Decreased LDL by 38% and increased HDL by 138% |
|
|
Term
| T or F: raising HDL when inflammation is present (aka high CRP) may be pro-atherogenic |
|
Definition
| T - this makes the CETP inhibitors that are being studied controversial. |
|
|
Term
|
Definition
2nd generation antisense drug that reduces synthesis of ApoB 100 (also decreases Lp(a))
-Prinicpal lipoprotein component of LDL
-Weekly SQ
-ONLY FOR SEVERE DISEASE
-Decreases LDL and TG in patients intolerant to statins
-ADRs is BIG ISSUE: elevated liver enzymes, flu-like symptoms (~90%), hepatotoxicity, NASH (54%)
-Big variation in response (10-70% decrease in LDL) |
|
|
Term
|
Definition
PCSK - protease that seems to regulate LDL receptor levels
-Drug in development to lower PCSK in patients with familial hypercholesterolemia |
|
|
Term
|
Definition
microsomal TG transfer protein (MTP) inhibitor
-Blocks absorption of dietary TGs and cholesterol and assembly into lipoproteins
-Approved for homozygous FH and FC (chylomicronemia) - lowers LDL ~40
GI ADR may limit use |
|
|
Term
| What types of drugs are currently being investigated for the treatment of hyperlipidemia? |
|
Definition
1. antisense drugs to target CRP
2. inducer of ApoA1 synthesis
3. antibody to PCSK9
4. second generation antisense drut to ApoB 100
5. CETP inhibitors |
|
|
Term
| What is the main target of fish oil? |
|
Definition
|
|
Term
| Which anti--arrhythmics are capable of decreasing automaticity? |
|
Definition
|
|
Term
| Class and MOA of Ibutilide |
|
Definition
Class III (aka Covert)
Prolongs AP (blocks outward K)
+ (Unique among class III) increases influx of Na during phase 3 thru slow inward Na channels (doesn't affect Phase 0) |
|
|
Term
| Clinical uses of ibutilide |
|
Definition
Rapidly convert patients with A.fib/flutter of recent onset to normal sinus rhythm
-Works best in combination with electrical caridoversion |
|
|
Term
| Drugs that broaden the QT interval are associated with causing what ADR? |
|
Definition
| Early after-depolarization arrhythmias |
|
|
Term
| ADR common to all anti-arrhythmics? |
|
Definition
|
|
Term
| Dosing a PK of ibutilide? |
|
Definition
Half-life ~6hr
1 mg over 10 min (IV ONLY) [1/2 of conversions will occur during infusion]
*Can repeat once if patient no covered within 10 min |
|
|
Term
| Drug interactions with ibutilide? |
|
Definition
1. Class I or other anti-arrhythmics (increased risk of ventricular tachycardia and torsades)
2. Drugs that prolong QT interval:
Phenothiazines, TCAs, FQ |
|
|
Term
| What is the most specific drug in in Class III? |
|
Definition
Dofetilide (Tikosyn)
-Specific for outward K current |
|
|
Term
| MOA and class of dofetilide? |
|
Definition
Class III
-Specific blocker of outward K current
Delays Phase 3 repolarization, prolongs AP
(No effect on Na, Ca, adrenergic receptors, hemodynamics [CO and TPR]) |
|
|
Term
| What are the primary clinical uses of Dofetilide? |
|
Definition
Anti-arrhythmic
-restore normal sinus rhythm during A.fib or flutter
-maintain normal sinus rhythm following conversion (electric shock) by other means |
|
|
Term
| What are contraindications to dofetilide? |
|
Definition
-Torsades de pointes
-QT prolongation (>450msec)
-RENAL IMPAIRMENT (can use but caution)- not recommended to use in patients with other drugs that may compete for renal secretion via cationic transporter (triamterene, metformin, amiloride)
-HR<50 (bradycardia)
-Concurrent use of drugs that prolong QT interval |
|
|
Term
| Which anti-arrhythmic is only available thru a REMS program, why? |
|
Definition
Dofetilide (tikosyn)
Because it is so specific
Must be started with ECG monitoring |
|
|
Term
| What are some ADRs seen with Dofetilide? |
|
Definition
Torsades
Increases QT directly related to plasma concentrations (drug dosage is based on creatinine clearance) |
|
|
Term
| What are the Class IV anti-arrhythmics? |
|
Definition
Calcium Channel Blockers (block L-type only)
Results in slowed conduction and increased refractory period in Ca-dependent tissues (SA and AV nodes) |
|
|
Term
| What are the two primary Class IV anti-arrhythmics? |
|
Definition
Verapamil
Diltiazem
**Dihydropyridine CCBs are NOT effective anti-arrhythmics (b/c act in periphery) |
|
|
Term
| MOA of all Class IV anti-arrhythmics |
|
Definition
Depress the slope of diastolic depolarization (prolongs AP by not opposing K)
causes Vmax of Phase 0 in NODES to be delayed |
|
|
Term
| What are some clinical uses for the Class IV anti-arrhythmics? |
|
Definition
1. re-entrant supraventricular tachycardia involving the AV node (b/c CCB good at controlling the AP here)
2. Control ventricular response rate in A.fib or flutter (although it will rarely convert them)
GOOD at controlling the ventricles response to issues in atria/nodes |
|
|
Term
| What are the cardiac effects of Class IV anti-arrhythmics? |
|
Definition
1. Reduce magnitude of Ca current into cardiac cells
2. Decreases rate of recovery of the Ca channel (increases refractory period)
3. Decreases conduction velocity through AV node
*As frequency of stimulation is increased, the blockade of the channel is increased |
|
|
Term
| Which class of anti-arrhythmics is generally the 'safest'? |
|
Definition
|
|
Term
| What are the ADRs for Class IV anti-arrhythmics? |
|
Definition
AV block
Cardiac depression
Bradycardia |
|
|
Term
| Drug interactions with CCBs? |
|
Definition
DIGOXIN - levels of dig can be increased (results in conduction disturbances)
Ca supplements
Beta-blockers - produce similar effects (lead to bradycardia) |
|
|
Term
| What is adenosine and what type of arrhythmia is it used for? |
|
Definition
| Nucleoside used in the acute treatment of Re-entrant supraventricular tachycardia |
|
|
Term
|
Definition
Affects AV > SA node
Activates Ach-sensitive outward K current (hyperpolarization of membrane during phase 3-> increases AV node refractory period)
Inhibition of Ca current by decreasing cAMP (slows conduction of Ca-dependent APs-> decreases slope of phase 4 and 0) |
|
|
Term
| What is the DOC for rapid conversion of paroxysmal supraventricular tachycardia to sinus rhythm? |
|
Definition
Adenosine (Adenocard)
Few ADRs and high efficacy
(Does not covert A.fib, A.flutter, V.tachycardia) |
|
|
Term
|
Definition
usually short-lived and self-limiting (b/c short half-life =10sec)
Flushing
SOB |
|
|
Term
| What is the only contraindication for Adenosine use? |
|
Definition
|
|
Term
| Drug interactions with adenosine? |
|
Definition
Theophylline and caffeine = competitive antagonism at adenosine receptor (overcome by higher doses of Adenosine)
Dipyridamole (antiplatelet) may enhance effect of adenosine b/c blocks nucleoside transporter (aka cant clear) - decrease dose of adenosin |
|
|
Term
| Magnesium Sulfate for anti-arrhythmias? |
|
Definition
IV ONLY
Unknown MOA
Used in digoxin-induced arrhythmias, Torsades, and acute MI
(used in normal/low Mg patients) |
|
|
Term
|
Definition
Used to control ventricular rate during chronic A.fib
Decreasing use (better potency and larger therapeutic windows with other drugs)
-Previously sued for conversion, but delayed onset of action (hours) after IV dosing makes it not ideal
-doesnt seem to work when issue with exercise induced arrhythmias(?) |
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