Exam 2: Antiarrhythmics

Question 1

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

Answer 1

Rapid depolarization: Fast channels open, Na+ influx

Question 2

What happens during Phase 1? (Fast APs)

Answer 2

Na+ channels close

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

Question 3

What happens during Phase 2? (Fast APs)

Answer 3

Plateau: slow Ca++ channels open

slow influcx of Ca++

(still a little bit of K+ efflux)

Question 4

What happens during Phase 3? (Fast APs)

Answer 4

Repolarization: Ca++ channels close, K+ efflux

slow efflux of K+

Question 5

What happens during Phase 4? (Fast APs)

Answer 5

Return to RMP, -90mV

Question 6

When is the refractory period?

Answer 6

“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

Question 7

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

Answer 7

Question 8

Pacemaker Cells Phase 0

“Slow APs”

Answer 8

slower upstroke than in “fast” APs

critical firing threshold is -40 mV

(slower) Ca++ influx into cell

Question 9

Pacemaker Cells Phase 3

“Slow APs”

Answer 9

Repolarization (no plateau)

inactivation of Ca++ and Na+ channels

activation of K+ channels

Question 10

Pacemaker Cells Phase 4

“Slow APs”

Answer 10

Gradual depolarization

slow inward Na+ and Ca++ currents

Question 11

SA node (cardiac pacemaker) intrinsic rate

AVN intrinsic rate

Answer 11

SA Node = “70-80 bpm”

although NSR is technically 60-100 bpm

AVN = 40-60 bpm

AP conducts more slowly through the AVN

Question 12

arrhythmia classification

Answer 12

• 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

Question 13

Mechanisms of Arrhythmia Production (4)

Answer 13

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

2. 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

3. 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 2^nd pathway so you’ll get an accessory pathway – reentry rhythms

4. Conduction block – impulse fail to propagate in non-conducting tissue
   * D/t Damaged tissue, ischemia, fibrosis/scarring

Question 14

Factors Underlying Cardiac Arrhythmias

Answer 14

• 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?

Question 15

(Box 13-5) Causes of Intraop Rhythm Disturbances

(structural heart dz vs transient imbalance)

list a few from each

Answer 15

• 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

Question 16

Cardiac Arrhythmias: When do they require treatment?

Answer 16

• 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

Question 17

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

Answer 17

• 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)

Question 18

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

Answer 18

Most likely not

Question 19

Vaughan Williams Classification of Antiarrhythmic Drugs

Answer 19

• 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

Question 20

(Table) Classification of Antiarrhythmic Drugs

lists drug class and brands in each class

Answer 20

• 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

Question 21

Class I Agents, in general

Answer 21

• 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!!

Question 22

Class IA Agents

Answer 22

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)

Question 23

Procainamide

Answer 23

• 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)*

Question 24

Dysopyramide

Answer 24

• 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”*

Question 25

Class IC Agents

Answer 25

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)

Question 26

Flecainide

Answer 26

• 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!

Question 27

Propafenone (oral)

Answer 27

Class 1C

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

pro-pafenone, pro-torsades

Question 28

Class IB Agents

Answer 28

• 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)*

Question 29

Lidocaine

Answer 29

• 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 1^st 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

Question 30

Mexilitene (PO)

Answer 30

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 1^st-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)

Question 31

Phenytoin (Dilantin)

Answer 31

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!*

Question 32

Class II Agents

Answer 32

• 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”

Question 33

Propanolol

Answer 33

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

Question 34

Metoprolol

Answer 34

(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

Question 35

Esmolol

Answer 35

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

Question 36

Class III Agents

Answer 36

• 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

Question 37

Amiodarone

Answer 37

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

Question 38

Dronedarone (not much info)

Answer 38

• Class III drug
• lacks iodine, less lipophilic, less SEs

Question 39

Ibutilide & Dofetilide* (oral)

Answer 39

• 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

Question 40

Sotalol

Answer 40

• 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

Question 41

Class IV Agents

just what they do, drugs in this class

(uses will be another flashcard)

Answer 41

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

Question 42

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

Answer 42

• 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

Question 43

Look at this picture for the Ca++ Channel Blockers

Answer 43

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

Question 44

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

Answer 44

• 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, 2^nd 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

Question 45

Verapamil

Answer 45

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.*

Question 46

Diltiazem

Answer 46

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

Question 47

Nifedipine

Answer 47

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!

Question 48

Clevidipine

FYI - won’t be tested on this drug

Answer 48

• 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.

Question 49

Ca++ Channel Blockers:

SEs, Toxicity, Drug interactions

Answer 49

• 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

Question 50

OTHER Agents: list them

Answer 50

• Adenosine
• Digoxin
• Phenytoin
• Atropine
• Magnesium

Question 51

Adenosine

Answer 51

“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 1^st dose effective in ~60% cases
  • 2^nd 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!*

Question 52

Digoxin

Answer 52

“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

Question 53

Magnesium

Answer 53

“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.

Question 54

Atropine

Answer 54

“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

Question 55

Class I - II - III - IV channel blockers mnemonic

Answer 55

“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