Calcium Channel Blockers Flashcards
1
Q
What are the 3 classes of CCBs?
A
-
Phenylaklyamines
- Verapamil
-
Benzothiazepines
- Diltiazem
-
1,4-Dihydropyridines
- Nifedipine
- Amlodipine
2
Q
Describe the CCB binding sites:
A
- **L-type Ca2+ channel **
- CCBs interact with a specific domain
- allosteric relatioship
- each site influences the gating mechanism of the L-type Ca2+ channel
- only one class is generally prescribed at a time to avoid unpredictable effects
3
Q
Why do CCBs have a preference for cardiovasular cells?
A
-
voltage-sensitive
- binding site for each class of CCB
- Therapeutic activity usually limited primarily to cardiac and vascular smooth muscle cells
- Have only low affinity for other types of voltage-gated Ca2+ channels including:
- neuronal (N-type) and Purkinje (P-type) Ca2+ channels found in the nervous system
- Do not affect Ca2+ mobilization from intracellular stores
4
Q
How do CCBs affect skeletal muscle?
A
- skeletal muscle is relatively insensitive to CCBs
- CCBs do not affect the release of intracellular Ca2+ channel that mediates skeletal muscle contraction
- skeletal muscle primarily expresses a different isoform of the L-type Ca2+ channel that is relatively insensitive to CCB block
5
Q
How do CCBs affect the nervous system?
A
-
Ca2+ influx through N-type (neuronal-type) and P-type (Purkinjetype) Ca2+ channels primarily mediates neurotransmitter release
- CCBs have little effect on neurotransmitter release
- few CNS side effects
6
Q
How do CCBs affect the heart?
A
- All cardiac cells densely express L-type Ca2+ channels
- action potential in the sinoatrial (SA) and atrioventricular (AV) node depends on Ca2+ channels
- required for contraction of atrial and ventricular muscle cells
7
Q
How do CCBs affect vascular smooth muscle?
A
- Vascular smooth muscle cells (VSMCs) rely solely on L-type Ca2+ channels for excitability and contraction
-
No action potential:
- graded membrane potential changes
- circulating factors
- voltage-gated L-type Ca2+ channels open and Ca2+ influx activates
- mediates graded contraction
8
Q
Selectivity of CCBs for Cardiac versus Arterial Muscle:
A
- Use-dependence vs. voltage-dependence
- phenylalkylamines (verapamil) & benzothiazepines (diltiazem) act preferentially on cardiac cells
-
1,4-dihydropyridines (nifedipine) act preferentially
on arterial muscle cells
9
Q
Use-dependence:
A
- Activity of CCBs affected by:
- location of the binding site on the channel protein
- frequency of channel opening
-
verapamil and diltiazem:
- binding sites are deep within the channel
- access to these sites is increased when the channel opens with high frequency
- rapidly firing of action potentials in the myocardium and the SA and AV node promote binding of these CCBs
- exert effective block in the myocardium and in cardiac conducting cells
- cause vasodilation in vascular smooth muscle
10
Q
Voltage-dependence:
A
- Binding site for the dihydropyridine CCBs (nifedipine, amlodipine) is on the outside surface of the channel protein
- bind to the depolarized state of the channel with extremely high affinity
- bind preferentially to vascular smooth muscle to induce vasodilation
-
dihydropyridines act mostly on arteries
- significantly reduce cardiac afterload not cardiac preload
11
Q
Which CCB is used to treat angina?
A
-
Diltiazem:
- reduces cardiac workload
- decreases the SA node firing rate (i.e., lowers heart rate if high)
- reduces cardiac afterload by causing peripheral vasodilation
- diltiazem is a potential dilator of coronary arteries
12
Q
Which CCB is used to treat supraventricular arrythymias?
A
-
diltiazem or verapamil:
- reduce the firing rate of the SA node and reduce conduction through the AV node
- verapamil: helpful in reducing ventricular response rates if the atria is firing too fast
- used to treat supraventricular arrythymias
13
Q
Which CCB is used to treat HTN?
A
- Often a dihydropyridine ⇒ potent vasodilator action
-
may trigger reflex tachycardia
- particularly for short-acting dihydropyridine
- 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
14
Q
Hemodynamic effects of CCBs:
Verapamil
- Peripheral Vasodilation:
- Coronary Vasodilation:
- Preload:
- Afterload:
- Contractility:
- Heart Rate:
- AV Conduction:
A
- Peripheral Vasodilatation: low
- Coronary Vasodilatation: intermediate
- Preload: none
- Afterload: intermediate
- Contractility: high
- Heart rate: high
- AV Conduction: high
15
Q
Hemodynamic effects of CCBs:
Diltiazem
- Peripheral Vasodilation:
- Coronary Vasodilation:
- Preload:
- Afterload:
- Contractility:
- Heart Rate:
- AV Conduction:
A
- Peripheral Vasodilation: low
- Coronary Vasodilation: intermediate
- Preload: none
- Afterload: intermediate
- Contractility: intermediate
- Heart Rate: high
- AV Conduction: intermediate
16
Q
Hemodynamic effects of CCBs:
Nifedipine & Amlodipine
- Peripheral Vasodilation:
- Coronary Vasodilation:
- Preload:
- Afterload:
- Contractility:
- Heart Rate:
- AV Conduction:
A
- Peripheral Vasodilation: intermediate
- Coronary Vasodilation: high
- Preload: none
- Afterload: high
- Contractility: low (increase/decrease*)
- Heart Rate: low/none
- Av Conduction: none
*LV function may decrease with concurrent beta
blocker use; otherwise it increases due to reflex
sympathetic stimulation
17
Q
Pharmacokinetics:
Absorption
A
-
well absorbed after oral administration
- distinctions in oral bioavailability ⇒ differences in first-pass metabolism
- wide variations in plasma levels
- marked differences between the oral and intravenous doses
18
Q
Pharmacokinetics:
Protein Binding
A
- Higher for the dihydropyridines
19
Q
Pharmacokinetics:
Half-life
A
- relatively short except for amlodipine
- approximately 3 to 6 hours
- extended-release formulas allow for once or twice a day administration
-
only amlodipine has a half-life consistent with once-daily administration
- slow release of dihydropyridines reduces reflex tachycardia
20
Q
What are the vasodilator side effects caused by CCBs?
A
- Hypotension, headache, flushing and peripheral edema
- most commonly caused by the dihydropyridines
- potent vasodilating action
21
Q
Constipation is the most common side effect of which CCB?
A
-
verapamil
- believed to relate to the high affinity of this drug for the L-type Ca2+ channels in gastrointestinal smooth muscle
22
Q
Which CCB can worsen congestive heart failure?
A
-
verapamil may precipitate or exacerbate CHF symptoms in a small percentage of patients
- negative inotropic effect
23
Q
Which CCB can cause an AV block?
A
-
verampil
- dampening effect on AV node conduction
24
Q
Diltiazem vs. Verapamil
A
-
Diltiazem:
- similar but less potent cardiac effects than verapamil
- less dramatic peripheral vasodilatation than nifedipine
- best tolerated of the original CCBs
-
AV conduction disturbances and heart block may occur with diltiazem
- risk is lower than in patients receiving verapamil
25
Q
Long-acting Dihydropyridines:
A
- Dihydropyridines: powerful vasodilator action
- nifedipine demonstrates the highest frequency of such effects
- less common with the sustained-release nifedipine
- amlodipine is better tolerated
