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The effects of digoxin and dopamine on the The effects of digoxin and dopamine on the oxygen consumption, lactate production and oxygen consumption, lactate production and haemodynamic performance of an isolated, haemodynamic performance of an isolated, perfused, working guinea-pig heart.perfused, working guinea-pig heart.
digoxin improves the haemodynamic digoxin improves the haemodynamic performance of the heart without altering its performance of the heart without altering its metabolism and therefore increases its metabolism and therefore increases its efficiency…. dopamine improves the efficiency…. dopamine improves the haemodynamic performance of the heart at the haemodynamic performance of the heart at the expense of increased aerobic and anaerobic expense of increased aerobic and anaerobic metabolism. metabolism.
Zannad E, Eur J Pharmacol (Zannad E, Eur J Pharmacol (1982 1982 ) Jul 9; ) Jul 9; 8181((22):):263-71263-71
Cardiovascular PharmacologyCardiovascular Pharmacology
Drugs and blood vesselsDrugs and blood vessels Drugs and the heartDrugs and the heart
Major clinical indications:Major clinical indications: HypertensionHypertension Angina pectorisAngina pectoris Cardiac failureCardiac failure AtherosclerosisAtherosclerosis Cardiac arrythmiasCardiac arrythmias
Drug action on Drug action on blood vesselsblood vessels
Prof John FinbergProf John Finberg
Pharmacology DepartmentPharmacology Department
Rappaport Faculty of MedicineRappaport Faculty of Medicine
Cardiovascular pharmacologyCardiovascular pharmacology
Control of intracellular calcium Control of intracellular calcium concentration is a major target in drug concentration is a major target in drug action on the CV systemaction on the CV system
Determination of contraction of vascular smooth muscle in vitro
Endothelium dependent and Endothelium dependent and independent vascular effectsindependent vascular effects
Blood vessel with endothelium
Blood vessel without endothelium
Endothelium dependent and Endothelium dependent and independent vascular effectsindependent vascular effects
Vascular smooth muscle cell
Endothelial cell
Lumen
Extracellular space
Endothelium-dependent Endothelium-dependent vasodilatorsvasodilators
AcetylcholineAcetylcholine
HistamineHistamine
EndothelinEndothelin
5-HT5-HT
BradykininBradykinin
Substance PSubstance P
Endothelial cell
Vascular smooth muscle cell
[Ca++]i
eNOS eNOSeNOS
L-Arg NO
Shear stress;Agonists, eg: ACh, BK, Hist, 5-HT, Substance P, ATP, ATII
GPCR
Endothelial cell
Vascular smooth muscle cell
Agonist, shear stress
NOS
NO
EDHF
Gap junctionHyper-polarisation
Direct agonist
contractionrelaxation
COX
PGI2
L-type voltage-gated channel
Ca++
SRCa++[Ca++] i
contraction
GPCR
agonist
IP3
P2X
ATP
Ligand-gated cationic channel
PLC
NA, AII, TP, ET1, 5-HT
Vascular smooth muscle cell direct contractants
SR
Ca++[Ca++] i
contraction
Ca++ Calmodulin
MLCK MLCK*
Myosin LC Myosin LC-P*
Actin-myosin crossbridges
MLCK = Myosin light chain kinaseMyosin LC = myosin light chains
Smooth muscle contraction mechanism
relaxation
MLCP MLCP*MLCP*
Myosin LC-P*Myosin LC-P* Myosin LC
MLCP = Myosin light chain phosphatase
Smooth muscle relaxation: NO
cGMP
GC GC*GC*
NO
GMPPDE
relaxation
MLCP MLCP*MLCP*
Myosin LC-P*Myosin LC-P* Myosin LC
MLCP = Myosin light chain phosphatase
Smooth muscle relaxation: agonists
cGMP
MLCK
cAMP
IP, 2
K+
ANP
GC GC*GC*
PGI2Adren
Vasodilators: Organic NitratesVasodilators: Organic Nitrates
Amyl nitrite: Brunton found it effective for Amyl nitrite: Brunton found it effective for anginaangina
Nitroglycerin: converted enzymatically and Nitroglycerin: converted enzymatically and non-enzymatically to NO; veins>arteriesnon-enzymatically to NO; veins>arteries
Sodium nitroprusside: converted directly Sodium nitroprusside: converted directly (non-enzymatically) to NO; (non-enzymatically) to NO;
veins = arteriesveins = arteries
Alfred Nobel 1833-1896
Discoverer of DYNAMITE (nitroglycerin + kieselguhr)
Suffered from angina pectoris but refused to take nitroglycerin
Sodium nitroprusside (SNP)
NO
Non-enzymatic
Organic nitrates R-NO2
Enzymatic + non-enzymaticThiols SH RSNO
R-SNO
Calcium channelsCalcium channels
1: 1: voltage-operatedvoltage-operated Blocked by dihydropyridines etcBlocked by dihydropyridines etc Opened by Ca++ agonist drugs eg BayK-8644Opened by Ca++ agonist drugs eg BayK-8644 Blockade shows use-dependenceBlockade shows use-dependence
2: 2: receptor-operatedreceptor-operated Opened by agonist eg ATP Opened by agonist eg ATP Incompletely blocked by BayK-8644Incompletely blocked by BayK-8644 Blockade does not show use-dependenceBlockade does not show use-dependence
Voltage dependent Ca2+ channels
1. L-type (long-conducting, cardiac,
smooth and striated muscle, neuronal)2. T-type (Transient)
3. N-type (neuronal)
4. P/Q-type (Cerebral Purkinje cell)
5. R-type (rat brain)
L-type calcium channel structureL-type calcium channel structure
Voltage gated calcium channelsVoltage gated calcium channels
αα1 subunits confer pharmacological 1 subunits confer pharmacological characteristicscharacteristics αα1S skeletal muscle1S skeletal muscle αα1C cardiac, smooth muscle, neuronal1C cardiac, smooth muscle, neuronal αα1D endocrine/neuronal1D endocrine/neuronal
αα1subunits have1subunits have II – – IV domains, each domain IV domains, each domain has S1-S6 segments with SS1 and SS2 short has S1-S6 segments with SS1 and SS2 short loopsloops
Calcium channel blockersCalcium channel blockers Phenylalkylamines, eg verapamilPhenylalkylamines, eg verapamil Dihydropyridines, eg nifedipineDihydropyridines, eg nifedipine Benzothiazines, eg diltiazemBenzothiazines, eg diltiazem
HeartHeart blood vessels blood vessels
Verapamil >Verapamil > diltiazem diltiazem > nifedipine> nifedipine
CaCa++++ channel blockade channel blockade
Channels cycle between resting, Channels cycle between resting, open, inactivatedopen, inactivated
Affinity for blocking drug depends on Affinity for blocking drug depends on statestate
Blockers show greatest affinity for Blockers show greatest affinity for inactivation stateinactivation state
L-type channels: sub-unit structure L-type channels: sub-unit structure and CCB binding sitesand CCB binding sites
D B
P
EndothelinsEndothelins
NOS
NO
COX
PGI2ETBET1
ETB
ETA
contraction
ET1
Bosentan: ETA,B antagonist: useful in pulmonary hypertension, but hepatotoxic
Neutral endopeptidase (NEP) Neutral endopeptidase (NEP) inhibitorsinhibitors
Actions of NEPs :Actions of NEPs : Metabolism of atrial natriuretic peptide (ANP),Metabolism of atrial natriuretic peptide (ANP), Metabolism of AMetabolism of AIIII Similar function to Endothelin converting enzyme (big Similar function to Endothelin converting enzyme (big
ET ET ET1) ET1)
NEP inhibitors increase ANP NEP inhibitors increase ANP vasodilation; vasodilation; reduce ET reduce ET vasodilation; can increase A vasodilation; can increase AII II vasoconstrictionvasoconstriction
Candoxatril, orally active NEPI, reduces BP but Candoxatril, orally active NEPI, reduces BP but unpredictable responseunpredictable response
Phosphodiesterase inhibitorsPhosphodiesterase inhibitors
Caffeine, aminophylline: general PDE-Caffeine, aminophylline: general PDE-II Amrinone, milrinone, PDE3-Amrinone, milrinone, PDE3-II, vasodilator , vasodilator
and positive inotropesand positive inotropes Sildenafil (Viagara): PDE5 cyclic GMP Sildenafil (Viagara): PDE5 cyclic GMP
inhibitor:inhibitor: Increases penile erection, affects color vision, Increases penile erection, affects color vision, Potential fatal combination with nitratesPotential fatal combination with nitrates
Ischemic heart diseaseIschemic heart disease
Cardiac work VO2
VO2 blood flow
Increased work increased demand for blood flow.
Demand cannot be met, so get anaerobic metabolism, increased
lactic acid production, and ischemic pain (angina pectoris)
Ischemic heart diseaseIschemic heart disease
In normal conditions, the increased coronary BF In normal conditions, the increased coronary BF in response to increased cardiac work is in response to increased cardiac work is mediated by NOmediated by NO
In coronary artery disease with plaque formation, In coronary artery disease with plaque formation, this mechanism is non-functionalthis mechanism is non-functional
As a result, direct vasodilator drugs, eg As a result, direct vasodilator drugs, eg dipyridamole, will not increase blood flow to dipyridamole, will not increase blood flow to ischemic area, but worsen the situation by ischemic area, but worsen the situation by causing “ischemic steal”causing “ischemic steal”
Stenosis of branchof coronary artery
Rang et al Pharmacology, 5th Edition, p280
“Ischemic steal”
Effect of nitrates
Angina pectorisAngina pectoris
Stable angina, treated with beta-blockers, Stable angina, treated with beta-blockers, Ca++ antagonists or nitratesCa++ antagonists or nitrates
Calcium antagonists, use verapamil type, Calcium antagonists, use verapamil type, reduce VOreduce VO2 2 during effortduring effort
variant angina, use vasodilator calcium variant angina, use vasodilator calcium blockers, eg nifedipine, amlodipine (long blockers, eg nifedipine, amlodipine (long acting)acting)
Additional treatments include aspirin, Additional treatments include aspirin, statins, dietstatins, diet
Pharmacological treatment of Pharmacological treatment of angina pectorisangina pectoris
Organic nitrates: NTG s/l, or isosorbide Organic nitrates: NTG s/l, or isosorbide dinitrate, isosorbide-5- mononitrate p.o. or dinitrate, isosorbide-5- mononitrate p.o. or s/ls/l
Therapeutic dose, reduce preload + Therapeutic dose, reduce preload + dilation of collateral vesselsdilation of collateral vessels
Excessive dose, reduces preload + Excessive dose, reduces preload + afterload afterload hypotension and tachycardia hypotension and tachycardia (detrimental)(detrimental)
Nitrates also reduce platelet aggregationNitrates also reduce platelet aggregation
Nitrates, side-effectsNitrates, side-effects
Relaxation of other smooth muscle, can relieve Relaxation of other smooth muscle, can relieve chest pain caused by esophageal spasmchest pain caused by esophageal spasm
Can potentiate or precipitate esophageal refluxCan potentiate or precipitate esophageal reflux Headache; tolerance developsHeadache; tolerance develops Tolerance to therapeutic effect minimised by Tolerance to therapeutic effect minimised by
intermittent dosing regimeintermittent dosing regime NBB: nitrates are contraindicated if patient is NBB: nitrates are contraindicated if patient is
taking phosphodiesterase inhibitor eg sildenafil taking phosphodiesterase inhibitor eg sildenafil (Viagra)!!(Viagra)!!
VasodilatorsVasodilators
NitratesNitrates Beta-adrenoceptor agonistsBeta-adrenoceptor agonists Alpha-1 adrenoceptor antagonistsAlpha-1 adrenoceptor antagonists Angiotensin antagonists (AT1 antagonists, ACE Angiotensin antagonists (AT1 antagonists, ACE
inhibitors)inhibitors) Calcium channel blockersCalcium channel blockers Potassium channel openersPotassium channel openers Endothelin antagonistsEndothelin antagonists PDE inhibitorsPDE inhibitors Hydralazine (mixed K+ opener and Ca++ antagonism)Hydralazine (mixed K+ opener and Ca++ antagonism)