Calcium channel blockers

• Dihydropyridine (DHPR) CCBs (nifedipine and amlodipine) primarily act on vascular smooth muscles.
  • Dihydropyridines = Dilate vessels.
• Nodihydropyridine CCBs (verapamil > diltiazem) primarily act on the heart.
  • Non-dihydropyridines = act on the Nodes and cardiac muscle

Feature	Skeletal Muscle	Cardiac Muscle	Smooth Muscle
Coupling	Mechanical (Voltage-gated)	Ca2+-Induced Ca2+ Release (CICR)	Chem/Elec-mechanical
Ca2+ Source	Intracellular Only (SR)	Extracellular + Intracellular	Extracellular + Intracellular
Ca2+ Sensor	Troponin C	Troponin C	Calmodulin (No Troponin)
Key Channel	RyR1 (physically linked to DHPR)	RyR2 (activated 2+ Ca2+ influx)	IP3 Receptor / Ca2+ Channels
Contraction	Tropomyosin movement	Tropomyosin movement	Myosin Phosphorylation (MLCK)
Relaxation	SERCA (Constitutive)	SERCA (Phospholamban reg.)	Myosin Phosphatase (MLCP)
Affected by CCBs?	NO DHPR acts only as a voltage sensor, not a channel.	YES: Non-Dihydropyridines (Verapamil, Diltiazem) target cardiac L-type channels to ↓ contractility/HR.	YES: Dihydropyridines (Amlodipine, Nifedipine) target vascular smooth muscle L-type channels to cause vasodilation.

Tip

• Skeletal muscle: opening of voltage-sensitive dihydropyridine receptors (DHPR) in the T tubules and the mechanically coupled ryanodine receptors (RYR) in the SR → SR releases Ca²⁺ into the sarcoplasm (buffered by calsequestrin) → increased intracellular Ca²⁺
  • CCBs can block an influx of extracellular calcium through DHPRs but cannot affect DHPR voltage-sensing capabilities or the resulting intracellular calcium release.
• Smooth muscle: stimulus opens L-type voltage-gated Ca²⁺ channels in the sarcolemma → influx of Ca²⁺ from the extracellular space into the smooth muscle cell (Ca²⁺ is also released from the SR, further increasing the intracellular concentration of Ca²⁺)
• Cardiac muscle: AP originating from the cardiac pacemaker cells → muscle cell depolarization that diffuses across the sarcolemma and into T-tubules → short, rapid influx of sodium; prolonged Ca²⁺ influx (via L-type Ca²⁺ channels) → Ca²⁺-induced Ca²⁺ release from the SR → increased intracellular Ca²⁺
• Therefore, both smooth muscle and cardiac muscle can be affected by CCBs because they rely on extracellular Ca²⁺ influx

Adverse effects

Dihydropyridines

• Effects due to vasodilation
  • Peripheral edema (esp. amlodipine): can be reduced by adding a renin-angiotensin system antagonist (ACEI or ARB).
    • Development of peripheral edema is related to preferential dilation of precapillary vessels (arteriolar dilation), which leads to increased capillary hydrostatic pressure and fluid extravasation into the interstitium.
    • ACEI/ARB can cause postcapillary venodilation and can normalize the increased capillary hydrostatic pressure, reducing the risk of peripheral edema in patients taking calcium channel blockers.
  • Headaches, dizziness
  • Facial flushing, feeling of warmth
  • Reflex tachycardia
• Gingival hyperplasia

Nondihydropyridines

• Reduced contractility
  • Verapamil decreases the amount of intracellular calcium available for excitation-contraction coupling within cardiac myocytes. This reduces myocardial contractility, which can be harmful in patients with impaired ventricular function.