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Angeli - N929 Pharmacology > Exam 2: Antiarrhythmics > Flashcards

Exam 2: Antiarrhythmics Flashcards

1
Q

What happens during Phase 0? (fast APs - CMs)

A

Rapid depolarization: Fast channels open, Na+ influx

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2
Q

What happens during Phase 1? (Fast APs)

A

Na+ channels close

(little bit of K+ efflux, but this isn’t their main phase)

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3
Q

What happens during Phase 2? (Fast APs)

A

Plateau: slow Ca++ channels open

slow influcx of Ca++

(still a little bit of K+ efflux)

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4
Q

What happens during Phase 3? (Fast APs)

A

Repolarization: Ca++ channels close, K+ efflux

slow efflux of K+

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5
Q

What happens during Phase 4? (Fast APs)

A

Return to RMP, -90mV

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6
Q

When is the refractory period?

A

“period in which no new AP can be regenerated”

phase 1-3 are absolute refractory period, but phase 3 starts the relative refratory period when you could have another AP

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7
Q

Picture of Phases of Fast AP (cardiomyocytes) with Antiarrhythmic Drug Classes on it

A
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8
Q

Pacemaker Cells Phase 0

“Slow APs”

A

slower upstroke than in “fast” APs

critical firing threshold is -40 mV

(slower) Ca++ influx into cell

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9
Q

Pacemaker Cells Phase 3

“Slow APs”

A

Repolarization (no plateau)

inactivation of Ca++ and Na+ channels

activation of K+ channels

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10
Q

Pacemaker Cells Phase 4

“Slow APs”

A

Gradual depolarization

slow inward Na+ and Ca++ currents

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11
Q

SA node (cardiac pacemaker) intrinsic rate

AVN intrinsic rate

A

SA Node = “70-80 bpm”

although NSR is technically 60-100 bpm

AVN = 40-60 bpm

AP conducts more slowly through the AVN

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12
Q

arrhythmia classification

A
  • Site of origin of abnormality (atrial/ junctional / ventricular)
    • Complexes on ECG (narrow/broad)
      • Broad complexes either originate in the ventricles, or originate from the atria but there’s aberrant conduction through the ventricle (LBBB/RBBB)
    • Heart rhythm (regular/irregular)
    • Heart rate is increased or decreased
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13
Q

Mechanisms of Arrhythmia Production (4)

A
  1. Altered automaticity - latent pacemaker cells take over the SA nodes role; escape beats
  • Decreased automaticity – SB
  • Increased automaticity – ST
  • SAN rate decreases that are excessive, that might cause the other cardiac cells to reach threshold before those, and become ectopic PPM cells
  • Abnormal PPM activity can occur if you have overactive catecholamine activity – strong SNS discharges (ex: pain)
  • Ectopic foci can arise in atrial, nodal, purkinje or ventricular muscle
  1. Delayed after-depolarization - normal action potential of cardiac cell triggers a train of abnormal depolarizations
  • Main cause ^Ca++ starts an inward current, and starts an abnormal train of APs
  • R on T phenomena
  1. Re-entry - refractory tissue reactivated repeatedly and rapidly due to unidirectional block, which causes abnormal continuous circuit
  • Defects in impulse conduction
  • Ex: WPW
  • Normally when 2 paths meet they die out, but in this case there’s no 2nd pathway so you’ll get an accessory pathway – reentry rhythms
  1. Conduction block – impulse fail to propagate in non-conducting tissue
    * D/t Damaged tissue, ischemia, fibrosis/scarring
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14
Q

Factors Underlying Cardiac Arrhythmias

A
  • Arterial hypoxemia
  • Electrolyte imbalance
  • Acid-base abnormalities
  • Myocardial ischemia
  • Altered sympathetic nervous system activity
  • Bradycardia
  • Administration of certain drugs
  • Enlargement of a failing ventricle
  • Ex: did we give them Demerol, which can increase the HR? Have they had an MI and there’s dead, unconducting tissue that’s causing this?
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15
Q

(Box 13-5) Causes of Intraop Rhythm Disturbances

(structural heart dz vs transient imbalance)

list a few from each

A
  • Structural Heart Disease
    • CAD
    • MI
    • Valvular and congenital heart disease
    • Cardiomyopathy
    • Sick sinus syndrome or prolonged QT interval syndrome
    • WPW – Wolff-Parkinson-White
    • HD 2/2 systemic disease (eg. uremia, DM)
    • SB
    • AVN heart block
  • Transient Imbalance
    • Stress: electrolyte/metabolic imbalance
    • Largyngoscopy, hypoxia, hypercarbia
    • Device malfunction, microshock
    • Dx or therapeutic intervention (PPM, AICD)
    • Surgical stimulation
    • CVADs
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16
Q

Cardiac Arrhythmias: When do they require treatment?

A
  • They cannot be corrected by the removing the precipitating cause – always try to do this first!
    • Ex: peds, if anesthesia is light, can see some ectopy!
    • ^CO2 → ectopy!
    • Ex: after MI, the prophylactic use of ventricular antiarrhythmic agents increased mortality bc of pro-arrhythmic effects!
  • Hemodynamic stability is compromised
  • The disturbance predisposes to more serious cardiac arrhythmias or co-morbidities
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17
Q

Non-pharmacological treatment (we don’t usually do any of these, but it’s good to know)

A
  • Acute
    • Vagal maneuvers/Valsalva/cardiac massage/cardiac sinus pressure/carotid massage
    • Cardioversion
  • Prophylaxis
    • Radiofrequency catheter ablation – used to tx SVTs
    • Implantable defibrillator – for ventricular tachycardias, usually paired with AV sequential pacing
  • Pacing (external, temporary, permanent)
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18
Q

If your pt has a new arrhythmia do you proceed iwth the surgery?

A

Most likely not

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19
Q

Vaughan Williams Classification of Antiarrhythmic Drugs

A
  • Class I: Sodium channel blockers
    • Affect phase 0
  • Class II: Beta adrenergic blockers
    • Affect phase 4
  • Class III: Potassium channel blockers
    • Work during phase 3, to extend the refractory pd
    • “Class 3 work during phase 3 – K+”
  • Class IV: Calcium channel blockers
    • Work during phase 2
  • Class V: Unclassified drugs
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20
Q

(Table) Classification of Antiarrhythmic Drugs

lists drug class and brands in each class

A
  • I. Depression of phase 0 depolarization (block Na+ channels)
    • Drug: –
  • IA. Moderate depression and prolonged repolarization
    • Drug: Quinidine, procainamide, disopyramide
  • IB. Weak depression and shortened repolarization
    • Drug: Lidocaine, mexilitene, phenytoin, tocainamide
  • IC. Strong depression with little effect on repolarization
    • Drug: flecainide, propafenone, moricizine
    • All the I’s work on phase 0
  • II. B-adrenergic blocking effects
    • Drug: esmolol, propranolol, metoprolol, timolol, pindolol, atenolol, avebutolol, nadolol, carvediolol
  • III. Prolongs repolarization (blocks K+ channels)
    • Drug: Amiodarone, bretylium, sotalol, ibutilide, dofetilide (Tikosyn)
  • IV. Ca++ channel-blocking effects
    • Drug: verapamil, diltiazem
  • Other
    • Drug: Adenosine, adenosine triphosphate, digoxin, atropine
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21
Q

Class I Agents, in general

A
  • Categorized by how quickly they dissociate from the receptor/channel (?)
  • Block sodium channels which depresses Phase 0 in depolarization of the cardiac action potential with resultant decreases in action potential propagation (decrease in depolarization rate) and slowing of conduction velocity
  • Used to treat SVT, AF, and WPW (reentry rhythms)
  • ~ inhibits AP propagation
  • “Membrane-stabilizing agents”
  • These agents bind most strongly when the channels are open or inactivated, less strongly when they are in the resting state
  • Bind to the sites on alpha subunits, inhibiting AP propagation

IA are the only ones that lengthen the repolarization period!!

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22
Q

Class IA Agents

A

how quickly they dissociate from blocking the Na+ channel

  • Slow conduction velocity and pacemaker rate
  • Intermediate Na+ channel blocker (intermediate dissociation)
  • Direct depressant effects on the SA and AV node
  • Decreased depolarization rate (phase 0)
  • Prolonged repolarization (bc they block the K+ channels to some degree, but not as much as Class III) – although they might have multiple actions, we’re concerned with their primary MOA, which is how they’re classified
  • Increased AP duration
  • Used for Atrial and Ventricular Arrhythmias
  • Eliminated by hepatic metabolism
  • (implicated in reversible lupus like syndrome)
  • A lot of these aren’t used anymore, have been replaced by Class IC drugs
  • ↑ AP duration,**↓ automaticity, ↑ QT duration, ↓ depolarization rate and conduction velocity
  • Drugs in this class: Quinidine (prototype), Procainamide, Disopyramide (Norpace)
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23
Q

Procainamide

A
  • Procainamide (Trade: Pronestyl, Procan) - ACLS
  • Class IA
  • Used in the treatment of ventricular tachyarrhythmias (less effective with atrial)
  • Dose: Loading 100 mg IV every 5 minutes until rate controlled (max 15 mg/kg); then infusion 2-6 mg/min
  • Side effects:
    • Myocardial depression leading to hypotension
    • Syndrome that resembles lupus erythematous
  • Have to check blood levels for this drug – goal 4-8 mcg/mL
  • 15% protein-bound
  • T1/2 – 2 hrs

  • Pro-cain, pro-cent (100 mg), a-mide (q5), pro CHF, pro SLE”*
  • Procainamide = ventricular only*
  • (as opposed to di-sopyramide, A and V, DIE of CHF)*
24
Q

Dysopyramide

A
  • Disopyramide (Trade: Norpace)
    • Suppresses atrial and ventricular tachyarrhythmias
    • Oral agent
    • Has significant myocardial depressant effects and can precipitate congestive heart failure and hypotension
  • Di-sopyramide = 2, both atrial and ventricular (as opposed to procainamide)*
  • “Die-sopyramide of CHF”*
25
Q

Class IC Agents

A

also block Na+ channels, but dissociate very slowly

  • Slow Na+ channel blocker (slow dissociation), so does not vary much during the cardiac cycle
  • Potent decrease of depolarization rate phase 0 and decreased conduction rate, with increased AP
    • But don’t have much effect on AP and the effective refractory pd in ventricular CMs
    • But do shorten the AP on the cells in the Purkinje fibers
    • This difference in effect on different types of cardiac cells may contribute to their pro-arrhythmic effects
  • Markedly inhibit conduction through the His-Purkinje system
  • Good for PVCs, better for atrial arrhythmias (WPW)
  • Suppress the SA Node
  • Drugs in this class: Flecainide (Prototype), Propafenone (PO)

Think B-A-C (B has the least effect on Na+ channels, and C has the MOST)

26
Q

Flecainide

A
  • Flecainide - Class IC Prototype
    • Is a fluorinated LA analog of procainamide (????)
    • Delays conduction in the bypass tracts – so good for reentry rhythms
    • Main use was for prophylaxis in pAfib
    • Effective in the treatment of suppressing ventricular PVCs and ventricular tachycardia; also atrial tachyarrhythmia’s; Wolff-Parkinson-White syndrome (reentry rhythm)
    • Oral agent
    • Has pro-arrhythmic side effects***
      • Used to be used ventricular ectopic beats – no longer recommend – higher incidence of sudden death associated with VF if the pt had an MI

Rhyme Time: Flecainide, good for WPW, caused VF in post-MI’s!

27
Q

Propafenone (oral)

A

Class 1C

  • Suppression of ventricular and atrial tachyarrhythmias
  • Oral agent
  • Has pro-arrhythmic side effects*** – torsades, VF

pro-pafenone, pro-torsades

28
Q

Class IB Agents

A
  • Fast Na+ channel blocker (fast dissociation)
    • Binds to the open channels, dissociates quickly. It dissociates in time for the next AP, but premature beats are what will be aborted
  • Alters the action potential by inhibiting sodium ion influx via rapidly binding to and blocking sodium channels (fast)
  • Produces little effect on maximum velocity depolarization rate, but shortens repolarization → ↓ AP duration and shortens refractory period
  • Decreases automaticity
  • Also binds to cells that are deplorized, such as in ischemia/diseased – suppresses Na+ channel in that tissue as well (other classes of drugs don’t do that)
  • Drugs in this class: Lidocaine, Mexilitine (PO), Phenytoin (Dilantin)
  • “IB - I BE fast (dissociates quickly), I B(ind) to ischemic cells (used on MI patients)”*
  • IB - lido IV, mexili-tene, pheny-T, only V (ventricular)*
  • ALSO QPC, LMP (lettuce mayo pickles)*
29
Q

Lidocaine

A
  • Lidocaine* - Class IB Prototype
    • Used as LA, induction – blunt laryngeal reflexes
    • Used in the treatment of ventricular arrhythmias
      • Is no longer recommended for preventing ventricular fibrillation after acute MI (Stoelting, 5th ed. p. 523)
      • Changed that recommendation bc they found ↑ mortality d/t bradyarrhythmias and asystole
    • Particularly effective in suppression reentry rhythms: ventricular tachycardia, fibrillation, PVCs
      • Raises VF threshold (what does that mean), delays rate of spontaneous phase 4 depolarization (**↓ the gradual decrease in K+ ion permeability that normally occurs during that phase)
      • Not effective for SVT
    • Pharmacokinetics:
      • Dose: 1-1.5 mg/kg IV, infusion 1-4 mg/min (max dose 3 mg/kg)
        • Only used IV bc extensive 1st pass metabolism PO
      • 50% protein binding
      • Hepatic metabolism – think of CYP 450!!
        • Active metabolite, which prolongs elimination half-time.
        • Metabolism may be impaired by drugs such as cimetidine (Tagamet) and propanolol (inhibitors), or physiologic altering conditions such CHF, acute MI, liver dysfunctioin, GA; or can be induced by drugs like barbiturates, phenytoin (Dilantin), or rifampin (CYP 450 inducers)
      • 10% renal elimination
    • Not a pro-arrhythmic, dissociates so quickly!!
    • Adverse effects: (toxicity) hypotension, bradycardia, seizures, CNS depression, drowsiness, dizziness, lightheadedness, tinnitus, confusion, apnea, myocardial depression, sinus arrest, heart block, ventilatory depression, cardiac arrest and can augment preexisting neuromuscular blockade
30
Q

Mexilitene (PO)

A

Class IB

  • Chronic suppression of ventricular cardiac tachyarrhythmias
  • If you have a pt on mexilitene, make sure you get cardiac clearance for them to have surgery!
  • 150-200 mg q8hrs PO
  • Similar to lidocaine, has an amine side group that helps it avoid the 1st-pass hepatic metabolism
  • Also can be used for neuropathic pain

Like the PO lidocaine, other IB agent

(MPL - mayo pickles lettuce, mexilitene, pheny-t/phenytoin, lidocaine)

31
Q

Phenytoin (Dilantin)

A

Class IB

  • Effects resemble Lidocaine
  • Class IB agent
  • Used in suppression of ventricular arrhythmias associated with digitalis toxicity
  • Can also be used other ventricular tachycardias or torsades de pointes (but would realistically reach for Lido before this)
  • Given IV (can precipitate in D5W; mix in NS)
  • Can cause pain or thrombosis when given in peripheral IV
  • Dose: 1.5 mg/kg IV every 5 min (so think dose ≅ Lido) up to 10-15 mg/kg
    • Causes severe hypotension if given rapidly! “Pheny-to, give it slow!”
  • Therapeutic blood levels 10-18 mcg/mL
  • Metabolized by liver
  • Excreted in urine
  • Elimination ½ time @24 hours
  • Adverse effects: CNS disturbances, partially inhibits insulin secretion, bone marrow depression, nausea, also associated with Stevens Johnson syndrome
    • Toxicity = CNS disturbances, vertigo, slurred speech
  • Pheny-T (IB).*
  • Pheny-to, give it slow, don’t mix it with D5W doe, works for 20-foe (T1/2 24 hrs), fucks up your bone mar-row, and your insulin - WHOA! And Verti-go!*
32
Q

Class II Agents

A
  • Class II drugs - Beta-adrenergic antagonists (AKA B-blockers). Depress spontaneous phase 4 depolarization resulting in SA node discharge decrease
    • Slows rate of depolarization – slow HR – IN NODAL TISSUE
    • Blocks the B-ARs, doesn’t block the Ca++ channels for phase 4 depolarization.
  • These are drugs that are used to stop arrhythmias d/t excessive circulating catecholamines, or excessive SNS stimulation.
  • Drug-induced slowing of heart rate with resulting decreases in myocardial oxygen requirements is desirable in patients with CAD
  • Slow speed of conduction of cardiac impulses through atrial tissues and AV node resulting in prolongation of the P-R interval on ECG, increased duration of the action potential in atria
  • Decreased automaticity
  • Used to treat SVT, atrial and ventricular arrhythmias
  • Used to suppress and treat ventricular dysrhythmias during MI and reperfusion
    • Also decrease mortality in ppl who have had a recent MI – decrease tachyarrhythmias that can occur after MI
  • To treat tachyarrhythmias secondary to digoxin toxicity, and SVT (atrial fibrillation or flutter).
    • Prevents catecholamine binding to beta receptors
    • Slowing of heart rate
    • Decrease myocardial oxygen requirements (good for CAD/MI patients)
    • Decrease rate of atrial contraction in aflutter (said afib but the atria isn’t contracting during afib)
  • ​Drugs in this class: Propanolol, metoprolol, esmolol, all the -olols

“B-AR (blocker), longer P-R”

33
Q

Propanolol

A

Prototype Class I Agent

  • Prototype
  • Beta-adrenergic antagonist (nonselective) – not good for asthma d/t bronchoconstriction
  • Used to prevent reoccurrence of tachyarrhythmias, both supraventricular and ventricular precipitated by sympathetic stimulation
  • Onset: 2-5 minutes
  • Peak effect 10-15 minutes, duration 3-4 hours
  • Elimination half-time 2-4 hours
  • Cardiac effects: decreased HR, contractility, CO; increased PVR, coronary vascular resistance; however, oxygen demand lowered, ↓ inotropy, ↓ chronotropy
34
Q

Metoprolol

A

(More on this in the other cardiac lecture)

Class I Agent

  • Beta-adrenergic antagonist (selective B1)
    • Remember that this doesn’t mean that they are *exclusive* for B1, just more selective for it
  • Dose: Dose 5 mg IV over 5 minutes; max dose 15 mg over 20 min.
  • Onset: 2.5 min.
  • Duration: Half-life 3-4 hours
  • Metabolized by liver
  • Can be used in mild CHF
35
Q

Esmolol

A

Class I Agent

  • Beta-adrenergic antagonist (selective B1)
  • Dose: 0.5 mg/kg IV bolus over 1 min, then 50-300 mcg/kg/min
  • Duration <10 minutes
  • Affects HR without decreasing BP significantly in small doses
  • Metabolism: hydrolyzed by plasma esterases ≠ PChE

es-molol, (plasma) es-terase

36
Q

Class III Agents

A
  • Class III Agents – K+ ion channel blockers
    • Class III drugs block potassium ion channels resulting in prolongation of cardiac depolarization and increasing action potential duration, and lengthening repolarization.
      • Don’t need to know inward/outward rectifier stuff
      • Just know that they work on Phase III, and extend repolarization and AP
      • ALSO work on Na+, Ca++ channels, and noncompetitively block alpha and beta ARs!
      • Lots of actions! Just know that it 1) extends Phase III, 2) extends repolarization/refractory period, and 3) decreases the membrane excitability of all myocardial cells
  • ​​Decrease the proportion of the cardiac cycle during which myocardial cells are excitable and thus susceptible to a triggering event
  • Used to treat supraventricular and ventricular arrhythmias
  • Can prolong QT interval and develop torsades → most Class III drugs are proarrhythmic
  • Prophylaxis in cardiac surgery patients r/t high incidence of Afib
  • Preventative therapy in patients who have survived sudden cardiac death who are not candidates for ICD
  • Control rhythm in Afib
  • Drugs in this class: Amiodarone, Dronedarone, Sotatol, Ibutilide, Dofetilide
37
Q

Amiodarone

A

Class III prototype

  • also has Class I, II, and IV antiarrhythmic properties
  • Potassium/ sodium/ calcium channel blocker (Class IV drug during Phase 2), alpha- and beta- adrenergic antagonist
  • Used for prophylaxis or acute treatment in the treatment of atrial and ventricular arrhythmias (refractory SVT, refractory VT/ VF, AF)
  • 1st line drug VT/ VF when resistant to electrical defibrillation
    • One of the most effective drugs in preventing ventricular arrhythmias in CHF pts, and also used prophylactic/acute tx of atrial OR ventricular arrhythmias
  • Good for post-MI/abnormal heart tissue, pts who have irritable heart tissue
  • Dose: Bolus 150-300 mg IV over 2-5 minutes, up to 5 mg/kg, then 1 mg/hr x 6 hrs, then 0.5 mg/hr x 18 hrs
  • Prolonged elimination half-life (29 days)
  • Hepatic metabolism, active metabolite
  • Biliary/ intestinal excretion
  • Therapeutic plasma level 1.0-3.5 ug/mL
  • Extensive protein binding 96%
  • Large volume of distribution
  • CVAD preferred, phlebitis if given through PIV
  • Monitor K+, susceptible to TDP, lengthening the refractory pd so much
  • ↓ incidence of afib post-cardiac surgery (given preop)
  • Adverse Effects of Amio – esp if high doses or long time of use
    • Pulmonary toxicity – acute or chronic onset → fibrosis!!
      • Think it’s d/t free oxygen radicals in the lungs
    • Pulmonary edema
    • ARDS
    • Photosensitive rashes
    • Grey/blue discoloration of skin
    • Thyroid abnormalities 2% - amio contains iodine, so pts can develop hypo/hyperthyroidism
    • Corneal deposits
    • CNS/GI disturbance
    • Pro-arrhythmic effects (torsades de pointes)
    • Heart block l Hypotension
    • Sleep disturbances
    • Abnormal LFT 20%
    • Inhibits hepatic CYP P450 – prolonged effect of other CYP 450 metab drugs (coumadin, dig) and muscle relaxants may last longer also
38
Q

Dronedarone (not much info)

A
  • Class III drug
  • lacks iodine, less lipophilic, less SEs
39
Q

Ibutilide & Dofetilide* (oral)

A
  • Class III Antiarrhythmic
  • Used for conversion of Afib or Aflutter to NSR
  • Used for the maintenance of sinus rhythm after Afib or conversion of Afib to sinus
  • Proarrhythmic, prolongs QT interval
40
Q

Sotalol

A
  • Class II and Class III Antiarrhythmic Drug
  • Beta-adrenergic antagonist (nonselective) and potassium channel blocker
    • So combo Class II and III, and also B1 and B2 nonselective
  • Used to treat severe sustained ventricular tachycardia and ventricular fibrillation; to prevent reoccurrence of tachyarrhythmias, especially Aflutter and AF
  • Side effects: prolonged QT interval, bradycardia, myocardial depression, fatigue, dyspnea, AV block
  • Caution in patients with asthma
  • Excreted in urine
  • Phase III – extend refractory pd, TDP risk
41
Q

Class IV Agents

just what they do, drugs in this class

(uses will be another flashcard)

A

Ca++ Channel Blockers

  • Calcium ion channel present in:
    • Cell membranes of skeletal muscle
    • Vascular smooth muscle
    • Cardiac muscle
    • Mesenteric muscle
    • Neurons
    • Glandular cells
    • Ca++ is the universal messenger in most of our cells
  • There are many different types (L, N, T)
    • We’re focusing on L-type channels
    • Has 5 subunits (Alpha-1,2 beta, etc)
      • We’re interested in the alpha 1 subunit – center of the channel, and is the main pathway for Ca++ entry into the cell
      • So when drugs bind to the L-type channel, they’re ↓ing the entry of Ca++ into the cell!
  • Calcium channel blockers bind to the receptor on voltage-gated calcium ions maintaining the channels in an inactive or closed state
  • Selectively interfere with inward calcium ion movement across myocardial and vascular smooth muscle cells.
  • Classified based on structure:
    • Phenyl-alkyl-amines - AV node (Verapamil)
      • “verapa-phenyl-alkyl-amines”
    • Benzothiazepines - AV node (Diltiazem)
      • “benzo = diazepam. benzo-thiazepines = diltiazem”
    • 1,4-dihydropyridines - arterial beds (Nifedopine)
  • Drugs in this class: Verapamil, Diltiazem, Nifedipine
42
Q

Class IV - Ca++ Channel Blocker uses (+ a little bit more of what they do)

A
  • Vascular
    • Angina
    • Systemic hypertension
    • Pulmonary hypertension
      • as opposed to vasopressin, which is a potent vasoconstrictor, but DILATES renal afferent arteriole, cerebral and pulmonary vasculature
    • Cerebral arterial spasm (ex: post-bleed)
    • Raynaud’s disease
    • Migraine
    • All good at dilating Coronary Arteries - ↓s contractility of VSMC
      • Complementary to nitrates since working through a different pathway
  • Non-vascular
    • Bronchial asthma
    • Esophageal spasm
    • Dysmenorrhea
    • Premature labor (prevention of)
  • Block slow calcium channels
    • *primary site AV node
    • Block slow calcium channels, which decreases conduction through SA and AV node and shortens Phase 2 (the plateau) of the action potential in ventricular myocytes
      • AP decreased
      • Impair impulse propagation in nodal tissue
      • Also ↓ spontaneous phase 4 depol in nodal tissue
    • Contractility/chronotropy of the heart decreases
43
Q

Look at this picture for the Ca++ Channel Blockers

A
  • Verapamil - Blocks the binding site, right in the center
  • Nefedipine – modulates the binding site in smooth muscle
44
Q

Ca++ Channel blockers MOA, effects, what do they treat

A
  • Remember that it’s Class IV
  • Mechanism of action:
    • Calcium channel has several subtypes
      • L, T, N, P channels
    • The L type channel is important in determining vascular tone and cardiac contractility
    • Decreased Ca+ keeps intracellular Ca+ low
  • Effects:
    • Decreased contractility
    • Decreased HR
    • Decreased activity of SA node
    • Decreased rate of conduction of impulses via AV node
    • Vascular smooth muscle relaxation: ↓ SVR & BP (arterial > venous)
    • → ultimately decreases workload of the heart and decreased O2 demand (good for angina or CAD, 2nd line tx for UA)
  • Used in the treatment of SVT and ventricular rate control in Afib and Aflutter
    • Good for reentrant tachycardias whose main pathway is the AVN
    • VSMC is also modulated by Ca++ → VSMC relaxation → vasodilation → ↓ BP!
  • Used to prevent reoccurrence of SVT
  • Not used in ventricular arrhythmias
  • Calcium channel blockers
    • Verapamil* – Class IV Prototype
    • Diltiazem *
  • Ultimately shorten phase 2, shorten AP -↓* *HR,* *↓* *activity in SA node, dilate Cas (↓ SVR, ↓ BP)

Calci-um, only atri-um

45
Q

Verapamil

A

Class IV

  • Blocks the binding site, right in the center - Verapa-MIDDLE
  • Synthetic Derivative of papaverine
  • Its levoisomer is specific for the slow calcium channel
  • Primary site of action is the AV node
    • Depresses the AV node
    • Negative chronotropic effect on SA node
    • Negative inotropic effect on myocardial muscle
    • Moderate vasodilation on coronary as well as systemic arteries (does this, but not as well as some of the other agents *prescribed for this issue* - primarily used as an antiarrhythmic)
  • Clinical uses
    • SVT
    • Vasospastic Angina pectoris
    • HTN
    • Hypertrophic cardiomyopathy
    • Maternal and fetal tachydysrhythmias
    • Premature onset of labor
  • Pharmacokinetics- Verapamil
    • Highly protein bound – 87-98% (presence of other agents such as lidocaine, diazepam, propranolol ↑its activity)
    • Orally almost completely absorbed with extensive hepatic first pass metabolism and almost none of the drug appears unchanged in the urine.
    • Oral Peaks in 30-45 minutes, IV 15 minutes
    • E ½ t is 6-12hrs
      • Active metabolite: norverapamil
    • Dose 2.5-10 mg IV over 1-3 minutes (max dose 20 mg)
    • Continuous infusion 5 ug/kg/minute
    • Do not use IV verapamil with ß- blocker (heart block)
    • T1/2 6-8 hours
    • Hepatic metabolism, with active metabolite
    • Excreted in the urine, and bile
    • Side effects: myocardial depression, hypotension, constipation, bradycardia, nausea, prolongs effects of neuromuscular blockers, and can impair antagonism of blockade also (can impair reversal?)
    • Verapamil and diltiazem can also have LA activity, and can ↑ r/f LA toxicity if giving regional anesthesia
    • Myocardial depression/hypovolemic, can give 1g Ca Gluconate before administration of verapamil to decrease the amount of hypotension
  • (Bit of a stretch) - AV-erapamil (AVN primary site of action, mostly used as an antiarrhythmic), still … does all of the things that Ca-Channel blockers do (neg chronotropy, neg inotropy, vasodilate coronaries/systemic arteries)*
  • Verapamil-LABOR. idk i feel like it’s unique and she’s gonna ask about it.*
46
Q

Diltiazem

A

Class IV

  • Benzothiazepines derivative
  • Binds at alpha subunit of the L-type Ca++ channel
  • Principle site of action is the AV node
    • 1st line treatment for SVTs
    • HTN
    • Intermediate potency between verapamil and nifedipine
    • Minimal CV depressant effects
  • Clinical Uses – Similar to verapamil
    • SVT
    • Vasospastic Angina pectoris
    • HTN
    • Hypertrophic cardiomyopathy
    • Maternal and fetal tachydysrhythmias
  • PO or IV
  • Dose is 0.25-0.35mg/kg over 2 minutes can repeat in 15 minutes
    • IV infusion 10mg/h
  • Pharmacokinetics-Diltiazem
    • Oral onset is 15 minutes and peaks in 30 minutes
    • 70-80% protein bound/excreted in the bile and urine (inactive metab)
    • E ½ t is 4-6 hours
    • Liver disease may require a decreased dose
  • PD – mixed cardiac and vascular effects, this is why it’s also used for HTN
  • SEs
    • Myocardial depression
    • Hypotension
    • Constipation
    • bradycardia
47
Q

Nifedipine

A

Class IV

  • Dihydropyridine derivative
  • Clinical uses
    • Angina pectoris
  • Primary site of action is peripheral arterioles
    • Coronary and peripheral vasodilator properties > verapamil
    • Little to no effect on SA or AV node
    • ↓ SVR, BP (main use)
    • Reflex tachycardia
    • Can produce myocardial depression in pts with LV dysfunction or on beta blockers
  • Pharmacokinetics
    • IV, oral or sublingual
    • Oral – effects in 20 minutes/peaks 60-90 minutes
    • 90% Protein Bound/hepatic metabolism/ excreted in the urine

E ½ t is 3-7hrs

Ni-fed up with your BP, CP!

48
Q

Clevidipine

FYI - won’t be tested on this drug

A
  • Dihydropyridine
  • Potent vasodilator
  • Broken down by plasma esterases
  • 4-6 mg/hr IV (normal dose), start at 1-2 mg/hr and titrate up to 32 mg/hr
  • Duke using this. Not on exam.
49
Q

Ca++ Channel Blockers:

SEs, Toxicity, Drug interactions

A
  • Side effects
    • Cancer!! If taking them for a prolonged pd of time. WTF.
    • Cardiac problems - heart blocks, esp if on B-blockers already
    • Bleeding = Prolonged, interfere with plt fn
    • GI = constipation
  • Drug Interactions:
    • Can potentiate the Myocardial depression and vasodilation from Inhalational agents
    • Can potentiate Neuromuscular blockers
    • Verapamil and Beta blockers = heart block
    • Verapamil-increases risk of Local anesthetic toxicity
    • Verapamil + dantrolene = (can cause) hyperkalemia due to slowing of inward movement of K+ ions can result in cardiac collapse
    • CCB interact with calcium mediated Platelet function
    • Digoxin: CCBs can increase the plasma concentration of digoxin by decreasing its plasma clearance
    • H2 antagonists
      • ranitidine and cimetidine alter hepatic enzyme activity and thus could increase plasma levels of CCB
  • Toxicity of CCB – may be reversed with IV administration of calcium or dopamine
  • Side effects:
    • vertigo
    • headache
    • flushing
    • hypotension
    • paresthesias
    • muscle weakness
    • Can induce renal dysfunction**
    • coronary vasospasm with abrupt discontinuation** - need to be slowly discontinued
50
Q

OTHER Agents: list them

A
  • Adenosine
  • Digoxin
  • Phenytoin
  • Atropine
  • Magnesium
51
Q

Adenosine

A

“Other” category

used for SVT

  • Replaced verapamil for tx of SVT
  • Binds to A1 purine nucleotide receptors (activates adenosine receptors to open K+ channels and increase K+ currents) - ↑ K+ conductance, shortens AP
  • Slows AV nodal conduction – ME: how does increasing the conductance slow down AVN conductance? I thought it would repolarize quicker and then be ready for the next beat. But maybe bc K+ is coming out quickly, then the whole process is shortened
    • Stops the arrhythmia from occurring
    • Creates a hyperpolarization of nodal cells → decreases the excitability of AVN cells
  • Used for acute Rx only
  • Used for termination of SVT/ diagnosis of VT
  • Produced endogenously, has effects on nerve tissue, cardiac muscle, plts, “and breathing”
  • Dose 6mg IV, rapid bolus
    • Give over ~1 second
    • Large AC or CVAD, flush immediately
  • Repeated if necessary after 3 minutes, 6-12 mg IV at that time
    • Usually 1st dose effective in ~60% cases
    • 2nd dose effective ~90% cases
  • T1/2 < 10 seconds
  • Eliminated by plasma and vascular endothelial cell enzymes
    • Enzymes in RBCs. Is taken up by nucleic transporter cells located in the surface of vascular endothelium
  • Side effects: excessive AV or SA nodal inhibition, facial flushing, headache, dyspnea, chest discomfort, nausea, bronchospasm
    • Contraindicated in asthma, heart block (bc it slows the AV conduction so much)
    • Feel “impending doom”

Youtube:

  • aden-osine → ↓ aden-ylyl cyclase → ↓ cAMP*
  • Also ↑ K+ efflux – transient heart block in AVN!*
52
Q

Digoxin

A

“Other” category

  • Cardiac glycoside
  • Increases vagal activity, thus decreasing activity of SA node and prolongs conduction of impulses thru the AV node
  • Decreases HR, preload and afterload
  • Slows AV conduction by increasing AV node refractory period
  • Positive inotrope- used to treat CHF
    • We never give this in the OR
    • Therapeutic range is very narrow
  • Binds the Na-K-ATPase pump, and slows the extrusion of Ca++ (Na-Ca++ exchange) → positive inotropy
    • ↓ ventricular preload, afterload, wall tension and O2 consumption in the failing heart
    • ↓ HR
    • ↑ inotropy
  • Used for the management of atrial fibrillation or flutter (controls ventricular rate), especially with impaired heart function
  • Dose: 0.5-1 mg in divided doses over 12-24 hrs
  • Onset of action 30-60 minutes
  • T1/2 36 hours
  • Narrow therapeutic index
  • Therapeutic levels 0.5-1.2 ng/mL
  • Weak protein binding
  • 90% Excreted by kidneys
  • Reduce dose in elderly/renal impairment
  • Adverse effects (think of slowing of the AVN)
    • Arrhythmias, heart block, anorexia, nausea, diarrhea, confusion, agitation
    • potentiated by hypokalemia and hypomagnesaemia
    • Toxicity treatment
      • Phenytoin for ventricular arrhythmias
      • Pacing
      • Atropine
53
Q

Magnesium

A

“Other” category

  • Works at sodium, potassium and calcium channels
  • Can be used with Very good for torsades de pointes
  • Dose 1 Gm IV over 20 minutes; can be repeated.
54
Q

Atropine

A

“Other” category

  • Muscarinic receptor antagonist/anticholinergic
  • Unstable bradyarrhythmias
  • 0.4 – 1.0 mg and repeat as necessary
  • Metabolized by the liver
  • Onset <1 minute
  • DOA 30-60 minutes
  • Caution using <0.4 mg → paradoxical response of intense bradycardia
55
Q

Class I - II - III - IV channel blockers mnemonic

A

“Some block potassium channels”

Class I - SOME - SOdium channel blocker

Class II - BLOCK - B-blocker

Class III - POTASSIUM - Potassium channel blockers

Class IV - CHANNELS - Ca++ channel blockers

Angeli - N929 Pharmacology (12 decks)

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