Calcium Channel BlockersCalcium Channel Blockers

Zheng Zhang

Department of Pharmacology

School of Pharmaceutical Sciences

Central South University

A class of drugs that act by interfering with the A class of drugs that act by interfering with the

activity of Caactivity of Ca2+2+ channels on membrane, blocking channels on membrane, blocking

CaCa2+2+ influx, and decreasing the cytoplasmic levels influx, and decreasing the cytoplasmic levels

of Caof Ca2+2+

Calcium channel blockersCalcium channel blockers

(Calcium antagonist)(Calcium antagonist)

Physiological roles of CaPhysiological roles of Ca2+2+

Vascular smooth muscle tone maintenanceVascular smooth muscle tone maintenance

Myocardial contractionMyocardial contraction

Maintenance of cardiac automaticity and Maintenance of cardiac automaticity and

propagation propagation

Miscellaneous : cell proliferation, gland excretion, Miscellaneous : cell proliferation, gland excretion,

cellular migration, release of transmitters, blood cellular migration, release of transmitters, blood

coagulation.coagulation.

Sources of intracellular free calciumSources of intracellular free calcium

Calcium enflux through calcium channels Calcium enflux through calcium channels

Calcium release from the sarco- or Calcium release from the sarco- or

endoplasmic reticulum and mitochondriaendoplasmic reticulum and mitochondria

Classification of Classification of calciumcalcium channels channels

1.1. Voltage-dependent CaVoltage-dependent Ca2+2+ channel (VDCC) channel (VDCC) Opened during depolarization Opened during depolarization Six subtypes: T, L, N, P, Q, RSix subtypes: T, L, N, P, Q, R

2.2. Receptor-operated CaReceptor-operated Ca2+2+ channel (ROC): channel (ROC): Controlled by agonist, e.g. catecholamines Controlled by agonist, e.g. catecholamines

Insensitive to membrane depolarizationInsensitive to membrane depolarization

L-type calcium channel and mechanism L-type calcium channel and mechanism

of drug actionof drug action

1. L-type calcium channel1. L-type calcium channel

Components and structureComponents and structure Five subunits: Five subunits: 1, 1, 2, 2, , , , and , and Functional subunit: Functional subunit: 11

Channel structure and Channel structure and 1 subunit1 subunit

Menbrane

Outside

Inside

DHP: Dihydropyridine; PAA: Phenylalkylamines

2. Channel status and drug action2. Channel status and drug action

O

I R[Ca2+]i = Ca n p

[Ca2+]i: total calcium influx

Ca: single channel calcium influx

n: number of channels

p: probability of opening

+

Calcium channel blockers

II. Pharmacological actionsII. Pharmacological actions

1. Negative inotropic effect1. Negative inotropic effect

Decrease slow calcium influx during phase 2Decrease slow calcium influx during phase 2

contractility contractility

A. Heart:A. Heart:

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)B. Vascular smooth muscle cells (VSMCs)

1.1. Relax VSMCs and reduce BP, arterioles are more Relax VSMCs and reduce BP, arterioles are more

sensitive than veinssensitive than veins

2.2. Most potent in dilation the coronary arterialMost potent in dilation the coronary arterial

treatment for variant anginatreatment for variant angina

3.3. Nimodipine and Nicardipine are particularly selective for Nimodipine and Nicardipine are particularly selective for

cerebral blood vesselscerebral blood vessels

C. Other smooth muscle cellsC. Other smooth muscle cells

Relax bronchiolar, uterine and gastrointestinal SMCs

Selectivity of calcium blockers toward heart Selectivity of calcium blockers toward heart

and vasculatureand vasculature

Verapamil Verapamil heart heart vascular SMC vascular SMC

Nifedipine Nifedipine heart heart vascular SMC vascular SMC

Diltiazem Diltiazem heart heart vascular SMC vascular SMC

Blood pressure baroreceptor sense

sympathetic activity contractility and heart

rate

Reflex increase in heart rate

Nifedipine > Diltiazem > VerapamilNifedipine > 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 (房扑 ) and fibrillation (房颤 )

Atriaventricular node (房室结 )

conduction ventricular rate

Ventricular tachycardia (室性心动过速 )

Caused by coronary spasm

No effect on other ventricular arrhythmia

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

1. Not affect cardiac output 2. Dilate renal vessels water and salt

excretion without water and salt retention3. Uric acid excretion 4. Decrease risk of shock5. Prevent and reverse cardiovascular

hypertrophy or remodeling

4. Myocardium infarction4. Myocardium infarction

Ischemia Ischemia membrane stability membrane stability , depolarization , depolarization

calcium influx , overload

activation of ATP consuming enzymes

energy tores susceptibility to damage

+

Calcium overload during MI:

energy stores

Ischemia

5. Congestive heart failure5. Congestive heart failure Therapeutic use is controversialTherapeutic use is controversial

Indications: CHF accompanied by angina or Indications: CHF accompanied by angina or

hypertensionhypertension

Efficacy in ventricular diastolic dysfunction > Efficacy in ventricular diastolic dysfunction >

ventricular systolic dysfunction ventricular systolic dysfunction

6. Hypertrophic myocardiopathy

Contraindications: left heart failure, sick sinus

syndrome, atrioventricular block

7. Atherosclerosis (AS, 7. Atherosclerosis (AS, 动脉粥样硬化动脉粥样硬化 ) )

Prevent or attenuate the Prevent or attenuate the

development of ASdevelopment of AS

Decrease CaDecrease Ca2+2+ in cytoplasm in cytoplasm

Inhibit platelet aggregationInhibit platelet aggregation

Dilate vasculatureDilate vasculature

Inhibit proliferation (Inhibit proliferation ( 增殖增殖 ) of vascular SMC) of vascular SMC

8. Vascular disease8. Vascular disease Cerebral vascular spasm and cerebral ischemia Cerebral vascular spasm and cerebral ischemia

((脑血管痉挛和脑缺血脑血管痉挛和脑缺血 ))

Subarachnoid hemorrhage (Subarachnoid hemorrhage ( 朱网膜下腔出血朱网膜下腔出血 ))

Primary pulmonary hypertensionPrimary pulmonary hypertension

Peripheral vascular disease: Raynaud’s Peripheral vascular disease: Raynaud’s

phenomenon (phenomenon ( 雷诺病雷诺病 ))

IV. PharmacokineticsIV. 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

Headache, Headache,

fatigue (fatigue ( 乏力乏力 ),),

heart-throb (heart-throb ( 心悸心悸 ),),

constipation (constipation ( 便秘便秘 ), ),

anklebone (anklebone ( 踝关节踝关节 ) edema) edema

V. Adverse reactionV. Adverse reaction

Cardiac inhibition Cardiac inhibition

VI. Classification of CCBsVI. Classification of CCBs

1.1. Phenyalkylamines (Phenyalkylamines ( 苯烷胺类苯烷胺类 ): ): e.g. e.g.

Verapamil (Verapamil ( 维拉帕米维拉帕米 ), and Anipamil (), and Anipamil ( 阿尼帕阿尼帕米米 ))

2.2. Dihydropyridines (Dihydropyridines ( 二氢吡啶类二氢吡啶类 ): ): Nifedipine Nifedipine

(( 硝苯地平硝苯地平 ), Nomodipine (), Nomodipine ( 尼莫地平尼莫地平 ), ),

Nicardipine (Nicardipine ( 尼卡地平尼卡地平 ), Felodipine (), Felodipine ( 非洛地非洛地平平 ), Amlodipine (), Amlodipine ( 氨氯地平氨氯地平 ))

3.3. Benzothiazepines (Benzothiazepines ( 地尔硫 类地尔硫 类 ): ): e.g. e.g.

Diltiazem (Diltiazem ( 地尔硫 卓 地尔硫 卓 ))

卓卓

A. Actions

1. Vasodilation ( 扩张血管 ) Peripheral and lung resistant vessel beds Coronary artery

Nifedipine (Nifedipine ( 硝苯地平硝苯地平 ))

2. Heart: positive inotropic ( 正性肌力 ) effect

Reflex sympathetic activity Reflex sympathetic activity myocardium myocardium

contractility contractility

B. Therapeutics uses

1.1. HypertensionHypertension

2.2. Variant anginaVariant angina

3.3. Heart failure:Heart failure: acute left ventricular acute left ventricular

failure caused by ischemia or failure caused by ischemia or

hypertensionhypertension

4.4. Others:Others: pulmonary hypertension pulmonary hypertension

(( 肺动脉高压肺动脉高压 ), Raynaud’s disease ), Raynaud’s disease

(( 雷诺病雷诺病 ))

C. Adverse reactions ：Headache, hypotension, flush, peripheral Headache, hypotension, flush, peripheral

edema, tachycardiaedema, tachycardia

D. ContraindicationsD. Contraindications

Be Cautious in HF and unstable angina

Nitrendipine (Nitrendipine ( 尼群地平尼群地平 ))

Vasodilation activity 6-fold higher than Vasodilation activity 6-fold higher than

nifedipinenifedipine Inhibit secretion of aldosterone (Inhibit secretion of aldosterone ( 醛固酮醛固酮 )) Long-acting, tLong-acting, t1/21/2 = 7 ~ 8 hours = 7 ~ 8 hours Therapeutic use: hypertension and anginaTherapeutic use: hypertension and angina

Nisodipine ( 尼索地平 )

The strongest CCBThe strongest CCB Highly selective for coronary arteryHighly selective for coronary artery Rapidly absorbed with low bioavailabilityRapidly absorbed with low bioavailability Therapeutic use: hypertension and anginaTherapeutic use: hypertension and angina

Nicardipine

Selective for cerebral vessels and coronary Selective for cerebral vessels and coronary

arteryartery Inhibits phosphodiesterase (Inhibits phosphodiesterase ( 磷酸二酯酶磷酸二酯酶 )) Therapeutic use: hypertension, angina, Therapeutic use: hypertension, angina,

cerebral vasospasm and ischemiacerebral vasospasm and ischemia

Nimodipine

Highly selective for cerebral vesselsHighly selective for cerebral vessels Preserves and promotes memoryPreserves and promotes memory Therapeutic use: cerebral vasospasm and Therapeutic use: cerebral vasospasm and

ischemia, subarachnoid hemorrhageischemia, subarachnoid hemorrhage

Amlodipine

Slow but Slow but long acting, tlong acting, t1/21/2 = 35 ~ 50 hours = 35 ~ 50 hours

Bioavailability: 60% ~ 65%Bioavailability: 60% ~ 65% Therapeutic use: hypertension and anginaTherapeutic use: hypertension and angina

Verapamil (Isoptin)Verapamil (Isoptin)

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

A. Actions ：

B. Therapeutics usesB. Therapeutics uses

1.1. Supraventricular tachycardiaSupraventricular tachycardia

2.2. Angia (variant)Angia (variant)

3.3. HypertensionHypertension

4.4. Hypertrophic myocardiopathyHypertrophic myocardiopathy

C. Adverse reaction

1. Constipation, flush, headache, itch

2. Large doses: atrioventricular blockade

3. Most serious: hypotension (i.v)

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

Diltiazem

B. Therapeutics uses

1.1. Supraventricular tachycardiaSupraventricular tachycardia

2.2. Variant angina and angina of effort Variant angina and angina of effort

3.3. HypertensionHypertension

4.4. Hypertrophic myocardiopathyHypertrophic myocardiopathy

C. Adverse reaction

Rash, constipation, headache, flushing, dizziness, Rash, constipation, headache, flushing, dizziness, angioneurotic edemaangioneurotic edema

D. D. ContraindicationsContraindications

The same as verapamilThe same as verapamil