Calcium Channel Blockers

Zheng Zhang
Department of Pharmacology
School of Pharmaceutical Sciences
Central South University

Calcium channel blockers

(Calcium antagonist)
A class of drugs that act by interfering with the
activity of Ca2+ channels on membrane, blocking
Ca2+ influx, and decreasing the cytoplasmic levels
of Ca2+

Physiological roles of Ca2+

Vascular smooth muscle tone maintenance

Myocardial contraction

Maintenance of cardiac automaticity and

propagation

Miscellaneous : cell proliferation, gland excretion,

cellular migration, release of transmitters, blood
coagulation.

Sources of intracellular free calcium

Calcium enflux through calcium channels

Calcium release from the sarco- or

endoplasmic reticulum and mitochondria

Classification of calcium channels

Voltage-dependent Ca2+ channel (VDCC)

Opened during depolarization

1.

Six subtypes: T, L, N, P, Q, R

Receptor-operated Ca2+ channel (ROC):

Controlled by agonist, e.g. catecholamines

Insensitive to membrane depolarization

2.

L-type calcium channel and mechanism

of drug action

1. L-type calcium channel

Components and structure

Five subunits: 1, 2, , , and
Functional subunit: 1

Channel structure and 1 subunit

Outside
Menbrane
Inside
DHP: Dihydropyridine; PAA: Phenylalkylamines

2. Channel status and drug action

Calcium channel
blockers

O
+

[Ca2+]i = Ca n p

[Ca2+]i: total calcium influx

Ca: single channel calcium influx
n: number of channels
p: probability of opening

II. Pharmacological actions

A. Heart:
1. Negative inotropic effect
Decrease slow calcium influx during phase 2
contractility
2. Negative chronotropic and negative conductive
action
Slow Ca2+ influx in sinoatrial node
automaticity
Slow Ca2+ influx in atrioventricular node
conduction velocity

B. Vascular smooth muscle cells (VSMCs)

1.

Relax VSMCs and reduce BP, arterioles are more

sensitive than veins

2.

Most potent in dilation the coronary arterial

3.

treatment for variant angina

Nimodipine and Nicardipine are particularly selective for

cerebral blood vessels

C. Other smooth muscle cells

Relax bronchiolar, uterine and gastrointestinal

SMCs

Selectivity of calcium blockers toward heart

and vasculature

Verapamil

heart vascular SMC

Nifedipine

heart vascular SMC

Diltiazem

heart vascular SMC

Reflex increase in heart rate

Blood pressure baroreceptor sense
sympathetic activity contractility and
heart rate

Nifedipine > Diltiazem > Verapamil

III. Therapeutic uses

1. Angina

Variant angina: dilate coronary artery,

first-line
Angina of effort: BP , afterload,
oxygen demand

2. Supraventricular arhythmia
Supraventricular tachycardia

Verapamil is the first-selected agent

Supraventricular tachycardia caused by

reentry
Verapamil is the first-selected agent

Sinus rhythm recovered in 80% patients

Use-dependence: channels being used

frequently are more susceptible to block

 Atrial flutter ( ) and fibrillation ( )

Atriaventricular node ( )
conduction ventricular rate

Ventricular tachycardia ( )

Caused by coronary spasm

No effect on other ventricular arrhythmia

3. Hypertension ( )
Efficacy correlates with baseline BP
No effect in normotensives
Advantages:

1. Not affect cardiac output

2. Dilate renal vessels water and salt
excretion without water and salt retention
3. Uric acid excretion
4. Decrease risk of shock
5. Prevent and reverse cardiovascular
hypertrophy or remodeling

4. Myocardium infarction
Calcium overload during MI:
Ischemia membrane stability , depolarization

calcium influx , overload

activation of ATP consuming enzymes

energy
tores
energy
stores
susceptibility to damage

Ischemia

5. Congestive heart failure

Therapeutic use is controversial

Indications: CHF accompanied by angina or

hypertension

Efficacy in ventricular diastolic dysfunction >

ventricular systolic dysfunction

6. Hypertrophic myocardiopathy
Contraindications: left heart failure, sick sinus
syndrome, atrioventricular block

7. Atherosclerosis (AS,
) Prevent or attenuate the
development of AS
Decrease Ca2+ in cytoplasm
Inhibit platelet aggregation
Dilate vasculature
Inhibit proliferation ( ) of vascular SMC

8. Vascular disease

Cerebral vascular spasm and cerebral ischemia

( )

Subarachnoid hemorrhage ( )

Primary pulmonary hypertension

Peripheral vascular disease: Raynauds

phenomenon ( )

IV. Pharmacokinetics
Easily absorbed after oral intake ( > 90%)
Extensive first pass elimination
Metabolism in liver by cytochrome P450s

(CYP3A4)
Most have short half-lives (t1/2=3~8 h)
Be cautious in hepatic dysfunction

V. Adverse reaction
Headache,
fatigue ( ),
heart-throb ( ),
constipation ( ),
anklebone ( ) edema

Cardiac inhibition

VI. Classification of CCBs

1.

Phenyalkylamines ( ): e.g.
Verapamil ( ), and Anipamil (
)

2.

Dihydropyridines ( ): Nifedipine
( ), Nomodipine ( ),
Nicardipine ( ), Felodipine (
), Amlodipine ( )

Benzothiazepines ( ): e.g.
Diltiazem ( )

3.

Nifedipine ( )
A. Actions
1. Vasodilation ( )
Peripheral and lung resistant vessel beds
Coronary artery
2. Heart: positive inotropic ( ) effect
Reflex sympathetic activity myocardium
contractility

B. Therapeutics uses
1.
2.
3.

Hypertension
Variant angina
Heart failure: acute left ventricular
failure caused by ischemia or
hypertension
4. Others: pulmonary hypertension
( ), Raynauds disease
( )

C. Adverse reactions
Headache, hypotension, flush, peripheral
edema, tachycardia

D. Contraindications
Be Cautious in HF and unstable angina

Nitrendipine ( )

Vasodilation activity 6-fold higher than

nifedipine
Inhibit secretion of aldosterone ( )
Long-acting, t1/2 = 7 ~ 8 hours
Therapeutic use: hypertension and angina

Nisodipine ( )

The strongest CCB

Highly selective for coronary artery
Rapidly absorbed with low bioavailability
Therapeutic use: hypertension and angina

Nicardipine
Selective for cerebral vessels and coronary
artery
Inhibits phosphodiesterase ( )
Therapeutic use: hypertension, angina,
cerebral vasospasm and ischemia

Nimodipine

Highly selective for cerebral vessels

Preserves and promotes memory
Therapeutic use: cerebral vasospasm and
ischemia, subarachnoid hemorrhage

Amlodipine
Slow but long acting, t1/2 = 35 ~ 50 hours
Bioavailability: 60% ~ 65%
Therapeutic use: hypertension and angina

Verapamil (Isoptin)
A. Actions
Negative inotropic effect
Blocks calcium channel; activates phosphodiesterase;
inhibits the function of systolic proteins
Negative chronotropic effect
P-R interval dose dependent
Vasodilation
Resistant vessels and coronary artery
Reflex sympathetic activity is mild

B. Therapeutics uses
1.
2.
3.
4.

Supraventricular tachycardia
Angia (variant)
Hypertension
Hypertrophic myocardiopathy

C. Adverse reaction
1. Constipation, flush, headache, itch
2. Large doses: atrioventricular blockade
3. Most serious: hypotension (i.v)

Diltiazem
A.

Actions

1.

Negative inotropic effect

2.

Negative chronotropic effect

3.

Vasodilation of coronary artery and its branches,

and peripheral resistant vessels

4.

Ameliorates myocardial metabolism and protects

the function of mitochondria

B. Therapeutics uses
1.
2.
3.
4.

Supraventricular tachycardia
Variant angina and angina of effort
Hypertension
Hypertrophic myocardiopathy

C. Adverse reaction
Rash, constipation, headache, flushing, dizziness,
angioneurotic edema
D.
Contraindications
The same as verapamil