10 Calcium Channel Blockers Flashcards
What provides the activator Ca2+ required for contraction of cardiac muscle cells and contributes to the upstroke of the AP in the SA and AV nodes of the heart?
Long-lasting (L-type) Ca2+ channels
Blockers reduce cardiac automaticity and AV nodal conduction and potentially vasodilation depending on affinity to vascular Ca2+ channels
What are the three main classes of Calcium Channel Blockers?
Phenylalkylamines
– verapamil
Benzothiazepines
– diltiazem
1,4-Dihydropyridines
- nifedipine
- amlodipine
Why are Ca2+ Channel Blockers generally used to treat?
- angina pectoris
- hypertension
- tx of supraventricular arrhythmias
Ca2+ channel binding that are use-dependent binding, target what type of cells?
Cardiac Cells
- Diltiazem
- Verapamil
The activity of a CCB in a particular tissue is affected by the location of the binding site on the channel protein, and the frequency of channel opening. The verapamil and diltiazem binding sites are deep within the channel, and access to these sites is increased when the channel opens with high frequency. Thus, the rapidly firing of action potentials in the myocardium and the SA and AV node promote binding of these CCBs, which exert particularly effective block in the myocardium and in cardiac conducting cells.
Ca2+ channel binding that are voltage-dependent binding, target what type of cells?
Smooth muscle
- Nifedipine
The binding site for the dihydropyridine CCBs (nifedipine, amlodipine) is on the outside surface of the channel protein, and these drugs bind to the depolarized state of the channel with extremely high affinity. Because the resting membrane potential of vascular smooth muscle cells is more depolarized (≅ -65 mV), the dihydropyridine drugs bind preferentially to vascular smooth muscle to induce vasodilation.
What is the mechanism of action of Ca2+ channel binders?
- Inc the time that Ca2+ channels are non-conducting
- relaxation of the arterial smooth muscle (reduction in afterload)»_space;> venous (preload)
What types of Ca2+ channels mediate neurotransmitter release in neurons?
N-type and P-type
Neurons express L-type Ca2+ channels, but Ca2+ influx through N-type and P-type Ca2+ channels primarily mediates neurotransmitter release. Thus, the CCBs have little effect on neurotransmitter release and few CNS side effects.
Why is skeletal muscle relatively insensitive to Ca2+ Channel binders?
The lack of effect of CCBs on skeletal muscle tone is primarily due to the fact that CCBs do not affect the release of intracellular Ca2+ channel that mediates skeletal muscle contraction.
Further- more, skeletal muscle primarily expresses a different isoform of the L-type Ca2+ channel that is
relatively insensitive to CCB block compared to the cardiac and vascular variants of the channel.
What do vascular smooth muscle cells rely on for excitability and contraction?
L-type Ca2+ channels
Most VSMCs do not generate action potentials, but show graded membrane potential changes in response to neurotransmitters. As the VSMCs depolarize, the voltage-gated L-type Ca2+ channels open and Ca2+ influx activates the contractile proteins to mediate a graded contraction.
What CCB can be used to treat angina and why?
Diltiazem
The beneficial effect is reduced cardiac workload, because diltiazem decreases the SA node firing rate (i.e., lowers heart rate if high) and reduces cardiac afterload by causing peripheral vasodilation.
Additionally, diltiazem is a potential dilator of coronary arteries permitting increased blood flow to the myocardium to prevent or ameliorate ischemia.
The dihydropyridines (nifedipine and amlodipine) are also used, since as coronary vasodilators, they produce reductions in myocardial oxygen demand and in arterial pressure.
What CCB can be used to treat supraventricular arrhythmias and why?
Diltiazem or verapamil are useful because these drugs reduce the firing rate of the SA node and reduce conduction through the AV node. The latter is helpful in reducing ventricular response rates if the atria is firing too fast (atrial flutter or fibrillation). Verapamil and diltiazem are indicated for heart rate control in patients with supraventricular tachycardia.
What CCB can be used to treat hypertension?
Often a dihydropyridine (nifedipine, amlodipine) is used because of their potent vasodilator action. The reduced blood pressure, however, may trigger reflex tachycardia and can increase the workload of the heart. A beta blocking drug (i.e., propranolol) is often administered in conjunction with the dihydropyridines to prevent reflex tachycardia. Nifedipine and other dihydropyridine drugs are contraindicated in patients with tachyarrhythmias.
Oral absorption of CCBs?
All greats than 90%: Verapamil Diltiazem Nifedipine Amlodipine
Which CCBs do not undergo extensive first-pass metabolism?
Bioavailability:
- Verapamil: 10-35%
- *Diltiazem: 41-67%
- *Nifedipine: 45-86%
- *Amlodipine: 64-90%
Which CCB has the longest half-life?
Verapamil: 2.8-6.3 hrs Diltiazem: 3.5-7 hrs Nifedipine: 1.9-5.8 hrs **Amlodipine: 30-50 hrs - slow release dihydropyridines cause less reflex tachycardia
