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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
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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
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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)
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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
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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
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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)
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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
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Dihydropyridines
vascular/cardiac selectivities
- dihydropyridines favored in partially depolarized tissue such as vascular smooth muscle
- "voltage-dependence"
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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
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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
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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
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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.
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Effects of:
Nifedipine
Verapamil
Diltiazem
ON Coronary Vasodilation
- Nifedipine - very increased
- Verapamil - increased
- Diltiazem - increased
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Effects of:
Nifedipine
Verapamil
Diltiazem
ON Coronary blood flow
- Nifedipine - very increased
- Verapamil - increased
- Diltiazem - increased
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Effects of:
Nifedipine
Verapamil
Diltiazem
ON peripheral vasodilation
- Nifedipine - very increased
- Verapamil - increased
- Diltiazem - slightly increased
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Effects of:
Nifedipine
Verapamil
Diltiazem
ON HR
- Nifedipine - quite increased
- Verapamil - slightly decreased
- Diltiazem - slightly decreased
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Effects of:
Nifedipine
Verapamil
Diltiazem
ON Cardiac Contractility
- Nifedipine - No effect or slightly increased
- Verapami l- No effect or slightly decreased
- Diltiazem - No effect or slightly decreased
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Effects of:
Nifedipine
Verapamil
Diltiazem
ON AV node conduction and ERP (effective refractory period)
- Nifedipine - no effect
- Verapamil and Diltiazem: decreased AV node conduction and increased ERP
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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
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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
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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
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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
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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
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