section iii circulation system. overview of cardiovascular diseases §common cardiac diseases...

Section IIISection IIICirculation systemCirculation system

Overview of Cardiovascular DiseasesOverview of Cardiovascular DiseasesCommon Cardiac DiseasesCommon Cardiac Diseases Abnormal contractilityAbnormal contractility ：： Heart failuresHeart failures Abnormal rhythmsAbnormal rhythms ：： ArrhythmiasArrhythmias Abnormal blood supplyAbnormal blood supply ：： Ischemic heart diseasesIschemic heart diseases Myocardial disordersMyocardial disorders

Common vascular diseasesCommon vascular diseases Abnormal systematic resistanceAbnormal systematic resistance ：： HypertensionHypertension Dysfunction of coronary vesselsDysfunction of coronary vessels ：： Coronary vascular diseasesCoronary vascular diseases Dysfunction of cerebral vesselsDysfunction of cerebral vessels ：： Cerebral ischemia, hemorrhageCerebral ischemia, hemorrhage

Dysfunction of pulmonary vesselsDysfunction of pulmonary vessels ：： Pulmonary hypertensionPulmonary hypertension Dysfunction of peripheral vessels: Dysfunction of peripheral vessels: PPeripheral vascular disordereripheral vascular disorder

ArteriosclerosisArteriosclerosis

Overview of Cardiovascular DrugsOverview of Cardiovascular Drugs

Classification based on target organs/tissuesClassification based on target organs/tissues HeartHeart ：： Heart failures, arrhythmias, cardiac ischemia, oveHeart failures, arrhythmias, cardiac ischemia, ove

r-load of the heartr-load of the heart VesselsVessels ：： Vasodilatation, vasoconstriction, arteriosclerosisVasodilatation, vasoconstriction, arteriosclerosis

Classification based on the mechanismsClassification based on the mechanisms Ion channelsIon channels ：： CaCa2+2+, Na, Na++, K, K+ + channelschannels ReceptorsReceptors ：： Adrenoreceptors, ATAdrenoreceptors, AT11 receptors, receptors, etc.etc.

EnzymesEnzymes ：： ACEI, NaACEI, Na++-K-K++-ATPase, HMG-CoA reductase-ATPase, HMG-CoA reductase OthersOthers ：： DiureticsDiuretics

Chapter 6Chapter 6 Cardiovascular DrugsCardiovascular Drugs

Part 1Part 1 Drugs affecting ion Drugs affecting ion channels in CVSchannels in CVS

Modes of solute transmembrane transportModes of solute transmembrane transport

ion channelion channel

A.A. General properties of ion channels in CVS General properties of ion channels in CVS

Properties of ion channelsProperties of ion channels

PermeationPermeationSelectivitySelectivityGating Gating voltage-gatedvoltage-gated chemically gated: chemically gated: ligand-gatedligand-gated phospharylation-gatedphospharylation-gated

mechanosensitive mechanosensitive nongated background / leak channelsnongated background / leak channels

Ion Ion transmemtransmembranebrane

transporttransport

Gating mechanisms Gating mechanisms of ion channelsof ion channels

Chemically gatedChemically gated

Ligand-gatedLigand-gated

Chemically gatedChemically gated

Phospharylation-Phospharylation-gated:gated: G protein / sG protein / second massagersecond massagers

Voltage-gatedVoltage-gated

MechanosensitiveMechanosensitive


Voltage-gated ion channelsVoltage-gated ion channels

NaNa++ channels channels

CaCa2+2+ channels channels

KK++ channels channels

Structure of Structure of -subunit-subunit

General structure General structure of ion channelsof ion channels

voltage sensorvoltage sensorfilterfilter

NaNa++ Channels ChannelsKK++ Channels Channels

CaCa2+2+ Channels Channels


Functional regulation of Functional regulation of voltage-gated ion channelsvoltage-gated ion channels

Activation (open)Activation (open)

Inactivation (close)Inactivation (close)

Gating modes of Gating modes of ion channelsion channels

Ligand-gated ion channelsLigand-gated ion channels

G protein/cyclic nucleotide-gated ion channelsG protein/cyclic nucleotide-gated ion channels

subunit of G proteinsubunit of G protein

cyclic AMPcyclic AMP

B.B. Drugs affecting ion channels in CVS Drugs affecting ion channels in CVS

Calcium channel blockersCalcium channel blockers

1. 1. Intracellular free CaIntracellular free Ca2+2+

(1) Ca(1) Ca2+2+ inward flow inward flow Voltage-gatedVoltage-gated ：： L, L, T,T, N, P, Q, R typesN, P, Q, R types Chemically gated: NMDA receptorChemically gated: NMDA receptor

(2) Release of stored Ca(2) Release of stored Ca2+2+

IPIP33 receptor receptor

Calcium channelsCalcium channels

BoxBox Voltage-gated calcium channelsVoltage-gated calcium channels

L-type calcium channelsL-type calcium channels Activated at Activated at －－ 10 mV, inactivated at 10 mV, inactivated at －－ 6060 ～－～－ 90 mV; 90 mV; Long lasting opening;Long lasting opening; Distributed in myocardial and vascular tissuesDistributed in myocardial and vascular tissues

T-type calcium channelsT-type calcium channels Activated at Activated at －－ 70 mV, inactivated at 70 mV, inactivated at －－ 100100 ～－～－ 60 mV;60 mV; Transient opening;Transient opening; Distributed mainly in heart conduction system (S-A node), artDistributed mainly in heart conduction system (S-A node), art

erial walls, erial walls, etc.etc.

2. 2. Structures and functions of voltage-gated Structures and functions of voltage-gated calcium channelscalcium channels

5 subunits: 5 subunits: 11, , 22, , , , , , 1 1 subunit is a more important structuresubunit is a more important structure

4 domains, 6TM in each domain4 domains, 6TM in each domain S4:S4: voltage sensor, voltage sensor, ，， S6:S6: site of drug binding site of drug binding

B.B. Calcium channel blockersCalcium channel blockers

verapamilverapamil

dihydropyridinesdihydropyridines

Binding sites of antagonists on L-type calcium channelsBinding sites of antagonists on L-type calcium channels

3. 3. Classification of calcium channel blockersClassification of calcium channel blockers Calcium channel blockers:Calcium channel blockers: The drugs which selectively act The drugs which selectively act

on voltage-gated calcium channels and block influx of Caon voltage-gated calcium channels and block influx of Ca2+2+

Selective calcium channel blockersSelective calcium channel blockers Dihydropyridines Dihydropyridines (( 二氢吡啶类二氢吡啶类 ):): nifedipine nifedipine 硝苯地平硝苯地平

nimoldipine nimoldipine 尼莫地平尼莫地平 amlodipine amlodipine 氨氯地平氨氯地平 PhenPhen

ylalkylamines ylalkylamines (( 苯烷胺类苯烷胺类 ):): verapamil verapamil 维拉帕米维拉帕米 Benzothiazepines Benzothiazepines (( 苯硫卓类苯硫卓类 ):): diltiazem diltiazem 地尔硫卓地尔硫卓

Non-selective calcium channel blockersNon-selective calcium channel blockers


艹艹艹艹

N

NO2

H3C

H

CH3

H3COOC COOCH3H

CH(CH3)2

CH3O

CH3O

CH3

CH2CH2NCH2CH2CH2CCN

OCH3

OCH3

OCH3

S

N

H

H

OCH2CH2N(CH3)2

OCOCH3

Verapamil Verapamil 维拉帕米维拉帕米

Nifedipine Nifedipine 硝苯地平硝苯地平 Diltiazem Diltiazem 地尔硫卓地尔硫卓艹艹

4. 4. Pharmacological effectsPharmacological effects

(1) Cardiac effects (1) Cardiac effects

A.A. Negative inotropic effect Negative inotropic effect ：： excitation-contracexcitation-contraction discoupling tion discoupling

B.B. Negative chronotropic and slowing conducti Negative chronotropic and slowing conducti

on action:on action: phase 4 of spontaneous depolarization aphase 4 of spontaneous depolarization and phase 0 of depolarization of slow response autonomind phase 0 of depolarization of slow response autonomic cells c cells

C.C. Protective effect on cardiac ischemia Protective effect on cardiac ischemia


(2) Effects on smooth muscles (2) Effects on smooth muscles

A.A. Vascular smooth muscle: Vascular smooth muscle: relaxing the arterial smooth muscles, especially relaxing the arterial smooth muscles, especially

coronary artery coronary artery

B.B. Others Others ：： smooth muscle of bronchus, gastrointestinal tract, smooth muscle of bronchus, gastrointestinal tract,

urine tract, uterusurine tract, uterus


Mechanism of calcium channel Mechanism of calcium channel blockerblocker on on myocardial and vascular smooth musclemyocardial and vascular smooth muscle

(3) (3) Anti-atherosclerosisAnti-atherosclerosis AlleviatinAlleviating Cag Ca2+2+ overload overload Inhibiting proliferation of smooth muscle cells and proteiInhibiting proliferation of smooth muscle cells and protei

n production of arterial matrixn production of arterial matrix Inhibiting lipid peroxidationInhibiting lipid peroxidation

Decreasing cholesterol levelDecreasing cholesterol level

(4) Hemodynamic effects(4) Hemodynamic effects Improving membrane stability of erythrocytesImproving membrane stability of erythrocytes Inhibiting platelet aggregationInhibiting platelet aggregation


(5) Others(5) Others

Kidney: Kidney: increasing the blood flow of increasing the blood flow of kidneykidney

Endocrine: Endocrine: inhibiting the release of inhibiting the release of ACTH, TSH, insulin, ACTH, TSH, insulin, etc.etc.


5. 5. Action modes Action modes

(1) actions on different functional states(1) actions on different functional states

Activated: Activated: verapamilverapamil Inactivated: Inactivated: diltiazemdiltiazem Resting: Resting: nifedipinenifedipine

(2) Open frequency-dependency(2) Open frequency-dependency

Frequency-dependent: Frequency-dependent: verapamil, diltiazemverapamil, diltiazem Frequency-independent:Frequency-independent: nifedipinenifedipine


6. 6. Clinical usesClinical uses

(1) Angina pectoris(1) Angina pectoris

Variant angina:Variant angina: nifedipinenifedipine Stable angina:Stable angina: verapamil, diltiazemUnstable angina:Unstable angina: verapamil, diltiazem, nifedipine + receptor blockers


(2) Arrhythmias(2) Arrhythmias

supraventricular tachycardiasupraventricular tachycardia

arrhythmias induced by triggered activitarrhythmias induced by triggered activity following after-depolarization y following after-depolarization

－－ verapamil, diltiazemverapamil, diltiazem


(3) Hypertension(3) Hypertension

nifedipine; nifedipine; verapamil, diltiazemverapamil, diltiazemComplicated withComplicated with coronary heart disease, mycoronary heart disease, my

ocardial ischemia, peripheral vascular diseaseocardial ischemia, peripheral vascular diseases, bronchial asthma, chronic obstructive pulms, bronchial asthma, chronic obstructive pulmonary diseases, onary diseases, etc.etc.


(4) Cerebrovascular diseases (4) Cerebrovascular diseases

transient ischemic attack, transient ischemic attack,

cerebral thrombosis,cerebral thrombosis,

subarachnoid hemorrhage subarachnoid hemorrhage

(5) Others(5) Others

peripheral vascular spasmodic disease,peripheral vascular spasmodic disease,

arteriosclerosisarteriosclerosis

etc.etc.


7. 7. Adverse effectsAdverse effects peripheral edema: peripheral edema: nifedipine > verapamil > diltiaznifedipine > verapamil > diltiaz

emem

symptoms of sympathetic excitation (heart rate insymptoms of sympathetic excitation (heart rate increase): crease): nifedipinenifedipine

reduced heart rate: reduced heart rate: verapamil, diltiazemverapamil, diltiazem

hypotension: hypotension: nifedipinenifedipine

ContraindicationsContraindications ：： hypotension (hypotension (nifedipinenifedipine); ); severe heart failure, sinus bradycardia, atrioventric severe heart failure, sinus bradycardia, atrioventricular block (ular block (verapamil, diltiazemverapamil, diltiazem))


8. 8. Special agentsSpecial agents

Nifedipine Nifedipine 硝苯地平硝苯地平

N

NO2

H3C

H

CH3

H3COOC COOCH3H


(1) Pharmacological effects(1) Pharmacological effects Vessels:Vessels: vasodilatation, hypotension, increase of cardiac outputvasodilatation, hypotension, increase of cardiac output Heart:Heart: reflex increase of heart rate, weak direct inhibiting reflex increase of heart rate, weak direct inhibiting

effectseffects

(2) Clinical uses(2) Clinical uses Angina pectoris; hypertension; peripheral vascular diseases;Angina pectoris; hypertension; peripheral vascular diseases;

etc.etc. Slow releasing forms:Slow releasing forms: adverse effects adverse effects ; action duration ; action duration

(3) Adverse effects(3) Adverse effects Hypotension; tachycardia; edema; headache, flushing,Hypotension; tachycardia; edema; headache, flushing, etc.etc.


Nimodipine Nimodipine 尼莫地平尼莫地平

HCOCH2CH2OCH3(CH3)2CHOC

CH3

H

H3C

NO2

NO O

Selectively acting on cerebral vasculatureSelectively acting on cerebral vasculature


Verapamil Verapamil 维拉帕米维拉帕米

CH(CH3)2

CH3O

CH3O

CH3

CH2CH2NCH2CH2CH2CCN

OCH3

OCH3

Potent efficacy on the heart, and weak on the vesselsPotent efficacy on the heart, and weak on the vessels


Diltiazem Diltiazem 地尔硫卓地尔硫卓

OCH3

S

N

H

H

OCH2CH2N(CH3)2

OCOCH3

Potent efficacy on the heart and the vesselsPotent efficacy on the heart and the vessels

B.B. Calcium channel blockersCalcium channel blockers艹艹


Potassium channel modulatorsPotassium channel modulatorsPotassium channel blockersPotassium channel blockers

Sulfonylureas:Sulfonylureas: for treatment of diabetes for treatment of diabetes

Drugs under researchDrugs under research

Potassium channel openersPotassium channel openers

nicorandil (nicorandil ( 尼可地尔尼可地尔 ), pinacidil (), pinacidil ( 吡那地尔吡那地尔 ), cromakalim), cromakalim (( 克罗卡林克罗卡林 ))

Effects are similar to calcium channel blockersEffects are similar to calcium channel blockers


Sodium channel blockersSodium channel blockers

Local anestheticsLocal anesthetics

Antiarrythmic drugs Antiarrythmic drugs (class I)(class I)

section iii circulation system. overview of cardiovascular diseases §common cardiac diseases...

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