Cardio-Pharm I- Antidysrhythmic Agents I Flashcards
The ability for a cell to respond to an external electrical stimulus (usually in the form of an action potential):
excitability
The ability for a cell or region of cells to initiate an action potential:
automaticity
The ability of a cell or region of cells to receive and/or transmit an action potential:
conductivity
The ability to alter the rate of electrical conduction
dromotropism
The inability of a cell to receive and transmit an action potential:
refractoriness
What is the action potential duration (APD)?
Phase 0 to the next phase 0
What is the effective refractory period (ERP)? or absolute refractory period
phase 0 to about the middle of phase 3 - cell cannot be stimulated by an external force.
Why is the slope in phase 4 not flat like a non-nodal action potential?
As Ca2+ comes into the cell in phase 4, the resting potential tends to depolarize.
When phase 4 reaches the threshold, it depolarizes automatically
Which ions cause the rapid depolarization in nodal and non-nodal action potential in phase 0?
Non-nodal - Na+
Nodal - Ca+2
Phase 3 of both nodal and non-nodal action potentials are both due to what movement of what ion?
K+ leaving the cell
Na+ channel blockers (type I anti-dysrhythmic) will affect which type of rhythm?
conduction rhythm
What type of cardiac action potential will be affected by Ca2+ channel blockers (type 4 anti-dysrhythmic)?
nodal action potentials (SA and AV node) - affect nodal dysrhythmia
What do we call anything above or at the level of the AV node?
supraventricular
Supraventricular dysrythmias affect which part of the heart?
mainly the AV and SA node (primarily treated with drugs that affect phase 0)
Ventricular dysrythmias are mainly treated with which group of drugs?
Drugs that affect mainly Na+ and K+ (phase 0 and phase 3)
The sympathetic nervous system affects which parts of cardiac functionality?
SA node • Atria • AV node • His-Purkinje • Ventricle
The parasympathetic nervous system affects which parts of cardiac functionality?
• SA node • Atria • AV node
What are the 2 major categories of dysrhythmias?
supraventricular and ventricular
What does it mean to have a regular vs irregular rhythm?
Regular means that there is a one to one ratio between atrial and ventriclar contraction (QRS complex to every P wave)
What are the consequences of dysrhthmia when it comes to compromise of mechanical performance?
decreased efficiency = decreased SV = decreased CO
What are the consequences of dysrhthmia when it comes to Prodysrhythmic/Dysrhythmogenic?
it can progress to something worse - conversion of v. tachycardia to v. fibrillation
What are the consequences of dysrhthmia when it comes to thrombogenesis?
• atrial flutter & fibrillation contribute to increased stroke incidence
Increased PR interval
First degree AV node block
Not all P waves pass
2nd degree heart block
no P/QRS relationship
3rd degree heart block
Class Ia antidysrhythmics (Na+ channel blockers):
quinidine, procainamide, disopyramide
Class Ib (Na+ channel blockers) anytidysrhytmics:
lidocaine, phenytoin
Class Ic (Na+ channel blockers) antidysrythmics:
flecainide
Class II antidysrythmic:
propanolol
Class III antidysrhytnmics:
amiodarone, sotalol, ibutilide
Class IV antidysrhythmics:
verapamil, diltiazem
Class V antidysrhymics (misc. group):
adenosine, digoxin, atropine
What type of tissue deals with this type of action potential?
Non-nodal tissue where phase 0 depolarization is due to Na+ influx
What type of tissue deals with this type of action potential?
• Nodal tissue where phase 0 depolarization is due to Ca+2 influx
What does it mean when the ERP/APD ratio is increased?
It decreases exciteability (Na+ channel blockers)
Class I Agents – General
Block voltage-sensitive Na+ channels to varying degrees in tissues of the heart • tend to slow VMAX (phase ) • reduce/increase automaticity, delay conduction, prolong ERP • ERP/APD ratio increased/decreased • useful in varying degrees for dysrhythmia and/or digitalis or MI-induced dysrhythmia
conductile; 0; reduce; increased; ventricular
What is the overall effect in Class I antidysrhythmics?
a decrease in ventricular exciteability
Class Ia Agents can block Na+, K+, and Ca2+ channels: what are the effects of each of these channels?
‘Moderate’ binding to Na+ channels • moderate effects on phase 0 depolarization
K+ channel blockade • delayed phase 3 repolarization • prolonged QRS and QT
Ca+2 channel blocking effect at high doses • depressed phase 2 and nodal phase 0
Can class Ia agents be used for supraventricular and ventricular dysrhythmia?
yes
Class Ib agents work mainly with what type of ion channel and what it is the effect?
‘Weak’ binding to Na+ channels
• weak effect on phase 0 depolarization due to rapid ‘on-off’ receptor kinetics
this is unique MOA actually increases exciteability as demonstrated in the figure
Which class and subtype of antidysrhythmics work good in use in digitalis and MI-induced dysrhythmia?
Class Ib agents: lidocaine, phenytoin
What are the effects of Class Ic antidysrhythmics agents and why are they used less often?
‘Strongest’ binding to Na+ channels
• slow ‘on-off’ kinetics with marked effects on phase 0 depolarization (can be completely blocked)
lengthened QRS and APD, QT unchanged
• lengthened PR (depressed AV nodal conduction)
(very potent, can stop heart, only used in certain cases)
Class II agents are mainly compromised of :
β-adrenergic antagonists
β-receptors are G-protein-coupled to Ca+2 channels and therefore class II antidysrhythmic agents will effect primarily on which type of action potential?
nodal phase 0 depolarization
Though mainly B-blockers, Class II antidysrhythmic agents also have effects on:
SA nodal automaticity (phase 4) depression,
AV nodal conduction,
decreased ventricular contractility
Class II agents are mainly used for which type of dysrhymia?
supraventricular dysryhtmia
Class III agents mainly have effects on which ion channels?
K+
Though class III agents mainly effect K+ channels, they also have effects on Ca2+, Na+ as well as (direct or indirect)
B-receptors
The action of Class III agents on K+ channels have what effect on action potential?
prolong phase 3 repolarization; ↑QT
Which class of agents are also useful for ventricular re-entry/fibrillatory dysrhythmia?
Class III agents
Class IV agents, in general, act directly on which type of ion channel?
Ca+2 channel antagonists (direct calcium channel blockers) - hence mainly work on depressed SA nodal automaticity, AV nodal conduction
Because Class II and IV agents work on all Ca2+ channels, their use can depress SA nodal automaticity and AV nodal conduction, however Ca2+ channels are all over the ventricular muscle as well and these agents can also:
decrease ventricular contractility (Class II and IV agents)
Quinidine, Ia
- bark alkaloid, d-isomer of quinine
- Use: and dysrhythmia due to effects on nodal (↓automaticity) and non-nodal tissue (↑QRS and ↑)
- PK: extensive protein binding and active metabolites results in rather long t½
- dosage adjustment required in dysfunction and elderly with reduced renal function
cinchona; supraventricular/ventricular; QT; plasma; renal
How do we resolve long QT syndrome produced by drugs?
treat with other drugs
quinidine, Ia (cont.)
- Therapeutic Use: • atrial flutter and , paroxysmal tachycardia (PAT), Paroxysmal tachycardia (PSVT), etc. • tachycardia
- Adverse Effects ( discontinue use):
- nausea, vomiting, diarrhea
- (tinnitis, hearing loss, blurred vision)
- due to α-adrenergic blocking effect
- dysrhythmogenicity ( due to drug induced increases in QT interval)
fibrillation; atrial; supraventricular; ventricular; 33%; cinchonism;
hypotension; torsades de pointes
What is this pathology when you have longer and longer prolongation of QT interval?
Tordades de pointes (twisted points)
How do you treat torsades de pointes?
Treatment usually involves the application of parenteral MgSO4
procainamide, Ia
similar pharmacology and use as
- procainamide has no ester linkage, ∴ little CNS access
- PK: metabolism depends on hepatic activity and renal function
- of procainamide excreted unchanged in urine
- rapid-acetylators: t½=2.5-3hrs • slow-acetylators: t½>5hrs (30-40% of patients)
quinidine; N-acetyltransferase; 70%
procainamide, Ia (cont.)
- Adverse Effects:
- slow-acetylators develop an upon chronic use (reversible on discontinuation)
- GI nausea and vomiting are very common
- decreased renal function may be
• mental confusion and
SLE-like syndrome; prodysrhythmic; torsade de pointes
SLE-like syndrome can be cause by which type Ia antidysrhyhmic and what are the symptoms?
procainamide
arthralgia, pericarditis, fever, weakness, skin lesions, lymphadenopathy, anemia and hepatomegaly
Which antidysrythmic inhibits reentry mechanisms in ventricular tissue which suppresses spontaneous ventricular depolarizations and has preferential action on ischemic tissue with excellent use in post-MI or digoxin-induced tachycardia?
lidocaine, Ib
Lidocaine, Ib, is unique in that it may actually lengthen/shorten the ERP and APD within the His-Purkinje system, which would increase in exciteabilty in normal concuction pathways
lengthen
Though lidocaine can increase/decrease ERP which increases/decreases exciteability in normal tissue, it can actually go into necrotic cells and increase/depress conduction (prolong ERP) which increases/decreases exciteability.
decrease
increase
depress
decreases
Which antidysrhythmic inhibits reentry mechanisms in ventricular tissue, intitially suppressing spontaneous ventricular depolarizations
lidocaine, Ib
Lidocaine, lb, is administered by which method only and how is it metabolized?
IV administration and extensive hepatic metabolism into active metabolites, no excretion of unchanged drug
Which antidysrhythmic has a potent Na+ channel blockade (slow on-off kinetics) whcih markedly depresses cardiac conduction?
flecainide, Ic -hence not used clinically often
Flecainide, Ic, because of its potency is only used to treat?
refractory life-threatening ectopic ventricular dysrhythmia
by prolonging phase 0 and widening QRS
Propranolol is which type of antidysrhythmic?
Class II, competitive, β-receptor antagonists- indirect Ca2+ channel blocker as well
What are 3 other Class II antidysrhythmics other than propranolol and which receptors to they work on?
esmolol (β1, β2), metoprolol (β1), acebutolol (β1)
Which antidysrhythmic competes with adrenergic transmitters for binding at sympathetic sites in SA and AV nodes, atrial, and ventricular tissue?
Class II, propranolol
Propranolol, II, being an indirect Ca2+ blocker has effect on phase in nodal or dysrhythmia, but also can have an effect on cardiac in ventriclar tissue.
0
supraventricular
contractility
The overall effect of propranolol, II, is ? It also ↓conduction in atria, AV node, ventricles; ↓SA/AV nodal automaticity
↓HR/CO (↑ERP)
Propranolol, II, is excellent in the use for which pathologies?
atrial flutter & fibrillation, PAT, and digoxin-induced dysrhythmia
propranolol, II
- PK: for sustained treatment of dysrhythmia
- extensive first-pass metabolism = bioavailability
- IV dosage provides immediate effects
- wide distribution to , placenta, breast milk, etc.
PO
25%
BBB
Propranolol, II
- Adverse Effects:
- , asystole (heart completely stops, AV node completely blocked)
- with non-selective antagonists
- withdrawal effect due to receptor up-regulation
hypotension
bronchospasm
rebound
Always consider IV administration of antidysrhythmics as low/high dose.
high, and always monitor
Amiodarone, Class III
- like other class III agents, alters flux during phase 3, ∴↑ and ↑APD
- utility in refractory dysrhythmia • purported less/more prodysrhythmic potential
K+
ERP
ventricular
less
amiodarone, III
PK: and IV availability
• t½=1-2 months (extensive distribution with s/s levels in 1-5 months, ∴ aggressive loading doses) • slow hepatic de-ethylation to active metabolite, N-desethyl-amiodarone (DEA)
PO
amiodarone, Class III
- Adverse Effects: ( incidence rate in chronic oral administration)
- GI nausea and vomiting
- toxicity (10-17%, pneumonitis/ARDS)
- may elevate enzymes
- (micro-deposition in the eye)
- disorders/tumors (iodinated benzofuran chemical structural is similar to thyroxine)
75%
pulmonary
liver
photosensitivity
thyroid
ibutilide, dofetilide, etc., III
equate with which drug?
amiodarone
What happens to the PR interval with the use of Class II and Class IV agents that block Ca2+ in AV node?
Increased PR interval
Verapamil, IV are what kind of ion blocker? And it is useful in the tx of what?
Ca2+, useful in tx of supraventricular tachycardia (also can use diltiazem), angina and hypertension (at higher dose)
Which type of Ca2+ channels are primarily affected by verapamil, IV?
“slow” inward Ca+2 channels in nodal tissue
What affect does verapamil, IV, have on ventricular dysrhythmia?
ventricular dysrhythmia unaffected (no ventricular Na+ conduction effect)
What are the overall effects of verapamil, IV?
↓HR (↓SA automaticity), ↑PR, ↓AV conduction
• cardiac depression (↓ ventricular contractility and ↓HR result in ↓SV and ↓CO)
IV verapamil, IV is used for ?
PO verapamil, is used for?
IV for rapid conversion of SVT
PO for maintenance of recurrent SVT
Verapamil, IV is highly which means it sticks around for a while in CNS, placental and breast milk access.
lipophillic
Hemodialysis is ineffective with which antidysrhythmic?
verapamil
Which drug is more useful than digoxin for rate control in atrial fib since Ca+2 channel blockade in AV node persists during sympathetic stimulation?
verapamil, IV
verapamil ADEs:
GI constipation
- hypotension
- exacerbate CHF
- AV heart block in combination with β-blockers
- male sexual dysfunction
Verapamil, IV, can also be used as a to lower BP due to extended use. (works on all Ca2+ channel blockers)
antihypertensive
Why are we concerned about possible GI constipation ADEs with antidysryhtmics?
Possible chance of bearing down due to valsalva maneuver consequences
Adenosine is considered in what class of antidysrhythmics?
Class V or “other”
What Class V antidysrhythmic is a purin nucleoside and useful for conversion of reentrant SVT (PAT, PSVT and WPW) to NSR and is comparable to verapamil?
adenosine, administered as large rapid acting bolus
Adenosine works on which type of receptor to produce complete AV nodal block (temporarily stopping the heart)?
Subtype A1 receptors in AV nodal tissue (not to be confused with a1 receptors)
What is the overall effect of adenosine, IV, on AV nodal subtype A1 receptors?
AV nodal hyperpolarization due to adenosine-stimulated opening of membrane K+ channels
• produces complete AV nodal block
Adenosine, IV, is very susceptible to acid degradation which results in a very short ? It also has rapid plasma metabolism in which case needs to be administered where?
half-life, 10- 15 seconds
clsoe to the heart in bolus form, not IV
Adenosine is used for a action, hopefully the AV nodal conduction will return to NSR
conversion
