Calcium Channel Blockers

  1. Calcium channel blockers - can do 3 things:
    And are of three groups:
    • 1. vasodilation
    • 2. -'ve chonotropic effect
    • 3. -'ve inotropic effect

    • Groups:
    • 1,4 dyhydrophyridine - NIFEPIDINE
    • phenylalkylamine - VERAPAMIL
    • benzothiazepine - DILTIAZEM
  2. Calcium channels
    Fast response
    Slow response
    • Fast response: characteristic of working atrial and ventricular fibers and His-Purkinje fibers
    • Ca2+ influx mediates phase 2 (plateau phase) of the AP

    • Slow Response: Characteristic of SA and AV nodes
    • Ca2+ influx mediates phase 0 depolarization

    • L&T channels function in E-C coupling in cardiac and smooth muscle cells.
    • NPQ and R channels are responsible for neuronal Ca2+ influx in response to depolarization
  3. L- channel
    • Slow/long-lasting
    • Activation threshold - 50 mV (relatively high)
    • responsivle for Ca2_ influx required for contraction in cardiac and smooth muscle
    • Mediates phase 0 of slow response and phase 2 of fast response of cardiac action potential and contributes to phase 4
    • Blocked by organic Ca2+ antagonists (1,4 dihydropyridines, phenylalkylamines, benzothiazepines)
  4. T-channel
    • transient calcium channel
    • Activation theshold is -70 mV
    • fast channel - relative to L channel, still slow relative to Na+ channel
    • Contributes to phase 4 depolarization
    • Insensitive to organic Ca2+ antagonists
  5. L-channel subunit - most important
    • alpha 1, 2, beta, gamma, delta
    • most important - alpha-1 - because it forms the pore and has the binding sites for Ca2+ antagonists
    • distinct binding sites are allosterically linked
  6. Ca2+ antagonist dependence on channel state
    • Verapamil and diltiazem: require an open channel to gain access to binding sistes (they are more polar)
    • Dihydropyridines e.g. nifedipine may gain access to the inactivated state of the channel through the membrane (more hydrophobic)
  7. Verapamil and Diltiazem
    • Favored in rapidly firing tissues in which channels tend to be in the open state (use-dependence/frequency-dependence)
    • Vascular/cardiac selectivity of Verapamil: 1.3
    • Vascular/cardiac selectivity of Diltiazem: 0.3
  8. Dihydropyridines
    vascular/cardiac selectivities
    • dihydropyridines favored in partially depolarized tissue such as vascular smooth muscle
    • "voltage-dependence"
  9. Nifedipine: vascular effects
    • Blockade of Ca2+ influx into vascular smooth muscle produces relaxation/vasodilation mostly in arterial and arteriolar smooth muscke (venous smooth muscle relatively unaffected)
    • Reduces peripheral resistance
    • Reduces arterial BP
    • Most postent vasodilator of the Ca-channel antagonists
  10. Nifedipine: Cardiac effects
    • arterial/arteriolar vasodilation decreases cardiac afterload
    • preload-relatively unaffected
    • IMPORTANT: able to block V-dependent Ca2+ channels in the heart (would predict -'ve inotropic and -'ve chronotropic effects)
    • BUT: due to high vascular/cardiac sensitivity of nifedipine, the decrease in arterial BP achieved at therapeutic doses elicits sympathetic reflexes to increase heart rate and contractility
    • SO: direct -'ve inotropic and -'ve chronotropic effects require doses higher than those required for peripheral vasodilation

    Net effect: modest increase in cardiac output
  11. Verapamil: Vascular and Cardiac effects
    • Vascular effects:
    • Arterial and arteriolar vasodilation - less effect on venous smooth muscle
    • Decreases arterial BP due to a drop in peripheral resistance

    • Cardiac effects:
    • Increased afterload
    • Decreased magnitutde of Ca2+ current, prolongs recovery period
    • SA rate decreased
    • AV conduction slowed
    • At doses producing vasodilation, Verapamil has significant direct negative inotropic and chronotropic effects. There are couteracted to some extent by reflex xympathetic activation
  12. Diltiazem
    • Vascular and cardiac effects similar to Verapamil (somewhat less -'ve inotropy)
    • As with Verapamil, direct negative inotropic and chronotropic effects tend to be offset by sympathetic reflex activation producing variability in heart rate and contractility.
  13. Effects of:
    ON Coronary Vasodilation
    • Nifedipine - very increased
    • Verapamil - increased
    • Diltiazem - increased
  14. Effects of:
    ON Coronary blood flow
    • Nifedipine - very increased
    • Verapamil - increased
    • Diltiazem - increased
  15. Effects of:
    ON peripheral vasodilation
    • Nifedipine - very increased
    • Verapamil - increased
    • Diltiazem - slightly increased
  16. Effects of:
    ON HR
    • Nifedipine - quite increased
    • Verapamil - slightly decreased
    • Diltiazem - slightly decreased
  17. Effects of:
    ON Cardiac Contractility
    • Nifedipine - No effect or slightly increased
    • Verapami l- No effect or slightly decreased
    • Diltiazem - No effect or slightly decreased
  18. Effects of:
    ON AV node conduction and ERP (effective refractory period)
    • Nifedipine - no effect
    • Verapamil and Diltiazem: decreased AV node conduction and increased ERP
  19. Therapeutic uses of Calcium Channel Blockers
    • Angina pectoris - exertional (Chronic stable, Typical):
    • Decrease oxygen demand by
    • Decreased afterload
    • decreased HR or contractility
    • increased O2 supply from coronary artery vasodilation

    • Vasospastic (Variant, Atypical) Angina:
    • relax vasospasm

    • Unstable (preinfarction) Angina:
    • helpful if underlying mechanism is vasospasm (often used with nitroglycerin)

    HTN: direct effect of arterial relaxation and drop in peripheral resistance

    • Supraventricular Cardiac Arrhythmias: Decrease SA node pacemaker rate in AV node - conduction velocity is decreased and ERP is increased. (control ventricular rate in atrial fivrillation and flutter and used in reentrant tachycardias w/AV node involvement)
    • NOTE: nifedipine - NOT indicated b/c of high potential for reflex tachycardia
  20. Common adverse side effects of Ca2+ channel blockers
    • Due to excessive vasodilation: dizziness, hypotension, headache, flushing, constipation, nausea
    • Peripheral and pulmonary edema
    • These effects tend to abate with time
  21. Serious Adverse Effects of Ca2+ blockers
    • Bradycardia, AV block, Heart failure, cardiac arrest
    • Aggravation of myocardial ischemia with nifedipine:
    • 1. excessive hypotension may lead to decreased coronary perfusion pressure
    • 2. Dilation of arterioles in non-obstructed (non-ischemic) areas increases flow, while ischemic areas, being maximally dilated, receive no increase in flow. --CORONARY STEAL
    • 3. There is increased oxygen demand due to reflex tachycardia
  22. Contraindications of Ca2+ channel blockers
    • treatment with Verapamil or Diltiazem (particularly IV or in combination with B-adrenergic blockade is contraindicated in patients with:
    • Hypotension
    • Severe left ventricular dysfunction
    • Sick sins syndrome
    • Second or Third degree AV block
    • In case of Verapamil, patients with an accessory bypass tract
  23. Drug interactions of Ca2+ channel blockers
    • Verapamil or diltiazem - increase serum digoxin concentration - causes excessive slowing of ventricular rate in atrial fibrillation
    • Combination with B-adrenergic receptor blockers may lead to: bradycardia, heart block, or heart failure.
    • The three classes with Quinidine may lead to excessive hypotension
Card Set
Calcium Channel Blockers
Calcium Channel blockers