Calcium Channel Blockers

Question 1

What are the 3 classes of CCBs?

Answer 1

1. Phenylaklyamines
   
   • ​​Verapamil
2. Benzothiazepines
   
   • ​​Diltiazem
3. 1,4-Dihydropyridines
   
   • ​Nifedipine
   • Amlodipine

Question 2

Describe the CCB binding sites:

Answer 2

• **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

Question 3

Why do CCBs have a preference for cardiovasular cells?

Answer 3

• 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

Question 4

How do CCBs affect skeletal muscle?

Answer 4

• 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

Question 5

How do CCBs affect the nervous system?

Answer 5

• 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

Question 6

How do CCBs affect the heart?

Answer 6

• 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

Question 7

How do CCBs affect vascular smooth muscle?

Answer 7

• 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

Question 8

Selectivity of CCBs for Cardiac versus Arterial Muscle:

Answer 8

• Use-dependence vs. voltage-dependence
• phenylalkylamines (verapamil) & benzothiazepines (diltiazem) act preferentially on cardiac cells
• 1,4-dihydropyridines (nifedipine) act preferentially
  on arterial muscle cells

Question 9

Use-dependence:

Answer 9

• 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

Question 10

Voltage-dependence:

Answer 10

• 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

Question 11

Which CCB is used to treat angina?

Answer 11

• 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

Question 12

Which CCB is used to treat supraventricular arrythymias?

Answer 12

• 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

Question 13

Which CCB is used to treat HTN?

Answer 13

• 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

Question 14

Hemodynamic effects of CCBs:

Verapamil

• Peripheral Vasodilation:
• Coronary Vasodilation:
• Preload:
• Afterload:
• Contractility:
• Heart Rate:
• AV Conduction:

Answer 14

• Peripheral Vasodilatation: low
• Coronary Vasodilatation: intermediate
• Preload: none
• Afterload: intermediate
• Contractility: high
• Heart rate: high
• AV Conduction: high

Question 15

Hemodynamic effects of CCBs:

Diltiazem

• Peripheral Vasodilation:
• Coronary Vasodilation:
• Preload:
• Afterload:
• Contractility:
• Heart Rate:
• AV Conduction:

Answer 15

• Peripheral Vasodilation: low
• Coronary Vasodilation: intermediate
• Preload: none
• Afterload: intermediate
• Contractility: intermediate
• Heart Rate: high
• AV Conduction: intermediate

Question 16

Hemodynamic effects of CCBs:

Nifedipine & Amlodipine

• Peripheral Vasodilation:
• Coronary Vasodilation:
• Preload:
• Afterload:
• Contractility:
• Heart Rate:
• AV Conduction:

Answer 16

• 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

Question 17

Pharmacokinetics:

Absorption

Answer 17

• 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

Question 18

Pharmacokinetics:

Protein Binding

Answer 18

• Higher for the dihydropyridines

Question 19

Pharmacokinetics:

Half-life

Answer 19

• 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

Question 20

What are the vasodilator side effects caused by CCBs?

Answer 20

• Hypotension, headache, flushing and peripheral edema
• most commonly caused by the dihydropyridines
  
  • potent vasodilating action

Question 21

Constipation is the most common side effect of which CCB?

Answer 21

• verapamil
  
  • believed to relate to the high affinity of this drug for the L-type Ca²⁺ channels in gastrointestinal smooth muscle

Question 22

Which CCB can worsen congestive heart failure?

Answer 22

• verapamil may precipitate or exacerbate CHF symptoms in a small percentage of patients
  
  • negative inotropic effect

Question 23

Which CCB can cause an AV block?

Answer 23

• verampil
  
  • dampening effect on AV node conduction

Question 24

Diltiazem vs. Verapamil

Answer 24

• 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

Question 25

Long-acting Dihydropyridines:

Answer 25

• Dihydropyridines: powerful vasodilator action
• nifedipine demonstrates the highest frequency of such effects
  
  • less common with the sustained-release nifedipine
• amlodipine is better tolerated