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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
A.A. General properties of ion channels in CVS General properties of ion channels in CVS
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
A.A. General properties of ion channels in CVS General properties of ion channels in CVS
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
B.B. Calcium channel blockersCalcium 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
B.B. Calcium channel blockersCalcium channel blockers
(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
B.B. Calcium channel blockersCalcium channel blockers
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
B.B. Calcium channel blockersCalcium channel blockers
(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.
B.B. Calcium channel blockersCalcium channel blockers
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
B.B. Calcium channel blockersCalcium channel blockers
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
B.B. Calcium channel blockersCalcium channel 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
B.B. Calcium channel blockersCalcium channel blockers
(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.
B.B. Calcium channel blockersCalcium channel blockers
(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.
B.B. Calcium channel blockersCalcium channel blockers
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))
B.B. Calcium channel blockersCalcium channel blockers
8. 8. Special agentsSpecial agents
Nifedipine Nifedipine 硝苯地平硝苯地平
N
NO2
H3C
H
CH3
H3COOC COOCH3H
B.B. Calcium channel blockersCalcium channel blockers
(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.
B.B. Calcium channel blockersCalcium channel blockers
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
B.B. Calcium channel blockersCalcium channel blockers
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
B.B. Calcium channel blockersCalcium channel blockers
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
B.B. Calcium channel blockersCalcium channel blockers
B.B. Drugs affecting ion channels in CVS Drugs affecting ion channels in CVS
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
B.B. Drugs affecting ion channels in CVS Drugs affecting ion channels in CVS
Sodium channel blockersSodium channel blockers
Local anestheticsLocal anesthetics
Antiarrythmic drugs Antiarrythmic drugs (class I)(class I)