Cardiaovascular Drugs.ppt
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Transcript of Cardiaovascular Drugs.ppt
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PharmacologyPharmacologyPharmacologyPharmacology
Drugs that Affect the Cardiovascular System
Drugs that Affect the Cardiovascular System
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TopicsTopicsTopicsTopics
• Electrophysiology
• Vaughn-Williams classification
• Antihypertensives
• Hemostatic agents
• Electrophysiology
• Vaughn-Williams classification
• Antihypertensives
• Hemostatic agents
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Cardiac FunctionCardiac FunctionCardiac FunctionCardiac Function
• Dependent upon– Adequate amounts of ATP– Adequate amounts of Ca++
– Coordinated electrical stimulus
• Dependent upon– Adequate amounts of ATP– Adequate amounts of Ca++
– Coordinated electrical stimulus
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Adequate Amounts of ATPAdequate Amounts of ATPAdequate Amounts of ATPAdequate Amounts of ATP
• Needed to:– Maintain electrochemical gradients– Propagate action potentials– Power muscle contraction
• Needed to:– Maintain electrochemical gradients– Propagate action potentials– Power muscle contraction
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Adequate Amounts of CalciumAdequate Amounts of CalciumAdequate Amounts of CalciumAdequate Amounts of Calcium
• Calcium is ‘glue’ that links electrical and mechanical events.
• Calcium is ‘glue’ that links electrical and mechanical events.
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Coordinated Electrical Coordinated Electrical StimulationStimulationCoordinated Electrical Coordinated Electrical StimulationStimulation• Heart capable of automaticity
• Two types of myocardial tissue– Contractile– Conductive
• Impulses travel through ‘action potential superhighway’.
• Heart capable of automaticity
• Two types of myocardial tissue– Contractile– Conductive
• Impulses travel through ‘action potential superhighway’.
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A.P. SuperHighwayA.P. SuperHighwayA.P. SuperHighwayA.P. SuperHighway
• Sinoatrial node• Atrioventricular
node• Bundle of His• Bundle Branches
– Fascicles
• Purkinje Network
• Sinoatrial node• Atrioventricular
node• Bundle of His• Bundle Branches
– Fascicles
• Purkinje Network
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ElectrophysiologyElectrophysiologyElectrophysiologyElectrophysiology
• Two types of action potentials– Fast potentials
• Found in contractile tissue
– Slow potentials• Found in SA, AV node tissues
• Two types of action potentials– Fast potentials
• Found in contractile tissue
– Slow potentials• Found in SA, AV node tissues
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Fast PotentialFast PotentialFast PotentialFast Potential
-80
-60
-40
-20
0
+20
RMP-80 to 90 mV
Phase 1
Phase 2
Phase 3
Phase 4
controlled by Na+
channels = “fast channels”
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Fast PotentialFast PotentialFast PotentialFast Potential
• Phase 0: Na+ influx “fast sodium channels”
• Phase 1: K + efflux
• Phase 2: (Plateau) K + efflux – AND Ca + + influx
• Phase 3: K+ efflux
• Phase 4: Resting Membrane Potential
• Phase 0: Na+ influx “fast sodium channels”
• Phase 1: K + efflux
• Phase 2: (Plateau) K + efflux – AND Ca + + influx
• Phase 3: K+ efflux
• Phase 4: Resting Membrane Potential
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Cardiac Conduction CycleCardiac Conduction CycleCardiac Conduction CycleCardiac Conduction Cycle
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Slow PotentialSlow PotentialSlow PotentialSlow Potential
-80
-60
-40
-20
0
Phase 4 Phase 3
dependent upon Ca++ channels = “slow channels”
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Slow PotentialSlow PotentialSlow PotentialSlow Potential
• Self-depolarizing– Responsible for automaticity
• Phase 4 depolarization– ‘slow sodium-calcium channels’– ‘leaky’ to sodium
• Phase 3 repolarization– K+ efflux
• Self-depolarizing– Responsible for automaticity
• Phase 4 depolarization– ‘slow sodium-calcium channels’– ‘leaky’ to sodium
• Phase 3 repolarization– K+ efflux
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Cardiac Pacemaker Cardiac Pacemaker DominanceDominanceCardiac Pacemaker Cardiac Pacemaker DominanceDominance• Intrinsic firing rates:
– SA = 60 – 100 – AV = 45 – 60– Purkinje = 15 - 45
• Intrinsic firing rates:– SA = 60 – 100 – AV = 45 – 60– Purkinje = 15 - 45
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Cardiac PacemakersCardiac PacemakersCardiac PacemakersCardiac Pacemakers
• SA is primary– Faster depolarization rate
• Faster Ca++ ‘leak’
• Others are ‘backups’– Graduated depolarization rate
• Graduated Ca++ leak rate
• SA is primary– Faster depolarization rate
• Faster Ca++ ‘leak’
• Others are ‘backups’– Graduated depolarization rate
• Graduated Ca++ leak rate
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Potential TermsPotential TermsPotential TermsPotential Terms
APD
ERP
RRP relative refractoryperiod
effective refractory period
action potential duration
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Dysrhythmia GenerationDysrhythmia GenerationDysrhythmia GenerationDysrhythmia Generation
• Abnormal genesis– Imbalance of ANS stimuli– Pathologic phase 4 depolarization
• Ectopic foci
• Abnormal genesis– Imbalance of ANS stimuli– Pathologic phase 4 depolarization
• Ectopic foci
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Dysrhythmia GenerationDysrhythmia GenerationDysrhythmia GenerationDysrhythmia Generation
• Abnormal conduction
• Analogies:– One way valve
– Buggies stuck in muddy roads
• Abnormal conduction
• Analogies:– One way valve
– Buggies stuck in muddy roads
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Reentrant CircuitsReentrant CircuitsReentrant CircuitsReentrant Circuits
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Warning!Warning!Warning!Warning!
• All antidysrhythmics have arrythmogenic properties
• In other words, they all can CAUSE dysrhythmias too!
• All antidysrhythmics have arrythmogenic properties
• In other words, they all can CAUSE dysrhythmias too!
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AHA Recommendation AHA Recommendation ClassificationsClassificationsAHA Recommendation AHA Recommendation ClassificationsClassifications• Describes weight of
supporting evidence NOT mechanism
• Class I• Class IIa• Class IIb • Indeterminant• Class III
• Describes weight of supporting evidence NOT mechanism
• Class I• Class IIa• Class IIb • Indeterminant• Class III
• View AHA definitions• View AHA definitions
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Vaughn-Williams Vaughn-Williams ClassificationClassificationVaughn-Williams Vaughn-Williams ClassificationClassification• Class 1
– Ia– Ib– Ic
• Class II• Class III• Class IV• Misc
• Class 1– Ia– Ib– Ic
• Class II• Class III• Class IV• Misc
• Description of mechanism NOT evidence
• Description of mechanism NOT evidence
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Class I: Sodium Channel Class I: Sodium Channel BlockersBlockersClass I: Sodium Channel Class I: Sodium Channel BlockersBlockers• Decrease Na+ movement in phases 0 and 4
• Decreases rate of propagation (conduction) via tissue with fast potential (Purkinje)– Ignores those with slow potential (SA/AV)
• Indications: ventricular dysrhythmias
• Decrease Na+ movement in phases 0 and 4
• Decreases rate of propagation (conduction) via tissue with fast potential (Purkinje)– Ignores those with slow potential (SA/AV)
• Indications: ventricular dysrhythmias
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Class Ia AgentsClass Ia AgentsClass Ia AgentsClass Ia Agents
• Slow conduction through ventricles
• Decrease repolarization rate– Widen QRS and QT
intervals• May promote Torsades
des Pointes!
• Slow conduction through ventricles
• Decrease repolarization rate– Widen QRS and QT
intervals• May promote Torsades
des Pointes!
• PDQ:– procainamide
(Pronestyl®)
– disopyramide (Norpace®)
– qunidine
– (Quinidex®)
• PDQ:– procainamide
(Pronestyl®)
– disopyramide (Norpace®)
– qunidine
– (Quinidex®)
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Class Ib AgentsClass Ib AgentsClass Ib AgentsClass Ib Agents
• Slow conduction through ventricles
• Increase rate of repolarization
• Reduce automaticity– Effective for ectopic
foci
• May have other uses
• Slow conduction through ventricles
• Increase rate of repolarization
• Reduce automaticity– Effective for ectopic
foci
• May have other uses
• LTMD:– lidocaine (Xylocaine®)
– tocainide (Tonocard®)
– mexiletine (Mexitil®)
– phenytoin (Dilantin®)
• LTMD:– lidocaine (Xylocaine®)
– tocainide (Tonocard®)
– mexiletine (Mexitil®)
– phenytoin (Dilantin®)
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Class Ic AgentsClass Ic AgentsClass Ic AgentsClass Ic Agents
• Slow conduction through ventricles, atria & conduction system
• Decrease repolarization rate
• Decrease contractility• Rare last chance drug
• Slow conduction through ventricles, atria & conduction system
• Decrease repolarization rate
• Decrease contractility• Rare last chance drug
• flecainide (Tambocor®)
• propafenone (Rythmol®)
• flecainide (Tambocor®)
• propafenone (Rythmol®)
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Class II: Beta BlockersClass II: Beta BlockersClass II: Beta BlockersClass II: Beta Blockers
• Beta1 receptors in heart attached to Ca++ channels– Gradual Ca++ influx responsible for
automaticity
• Beta1 blockade decreases Ca++ influx– Effects similar to Class IV (Ca++ channel
blockers)
• Limited # approved for tachycardias
• Beta1 receptors in heart attached to Ca++ channels– Gradual Ca++ influx responsible for
automaticity
• Beta1 blockade decreases Ca++ influx– Effects similar to Class IV (Ca++ channel
blockers)
• Limited # approved for tachycardias
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Class II: Beta BlockersClass II: Beta BlockersClass II: Beta BlockersClass II: Beta Blockers
• propranolol (Inderal®)
• acebutolol (Sectral®)
• esmolol (Brevibloc®)
• propranolol (Inderal®)
• acebutolol (Sectral®)
• esmolol (Brevibloc®)
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Class III: Potassium Channel Class III: Potassium Channel BlockersBlockersClass III: Potassium Channel Class III: Potassium Channel BlockersBlockers• Decreases K+ efflux during repolarization• Prolongs repolarization• Extends effective refractory period• Prototype: bretyllium tosylate (Bretylol®)
– Initial norepi discharge may cause temporary hypertension/tachycardia
– Subsequent norepi depletion may cause hypotension
• Decreases K+ efflux during repolarization• Prolongs repolarization• Extends effective refractory period• Prototype: bretyllium tosylate (Bretylol®)
– Initial norepi discharge may cause temporary hypertension/tachycardia
– Subsequent norepi depletion may cause hypotension
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Class IV: Calcium Channel Class IV: Calcium Channel BlockersBlockersClass IV: Calcium Channel Class IV: Calcium Channel BlockersBlockers• Similar effect as ß
blockers
• Decrease SA/AV automaticity
• Decrease AV conductivity
• Useful in breaking reentrant circuit
• Prime side effect: hypotension & bradycardia
• Similar effect as ß blockers
• Decrease SA/AV automaticity
• Decrease AV conductivity
• Useful in breaking reentrant circuit
• Prime side effect: hypotension & bradycardia
• verapamil (Calan®)• diltiazem (Cardizem®)
• Note: nifedipine doesn’t work on heart
• verapamil (Calan®)• diltiazem (Cardizem®)
• Note: nifedipine doesn’t work on heart
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Misc. AgentsMisc. AgentsMisc. AgentsMisc. Agents
• adenosine (Adenocard®)– Decreases Ca++ influx & increases K+ efflux via
2nd messenger pathway• Hyperpolarization of membrane
• Decreased conduction velocity via slow potentials
• No effect on fast potentials
• Profound side effects possible (but short-lived)
• adenosine (Adenocard®)– Decreases Ca++ influx & increases K+ efflux via
2nd messenger pathway• Hyperpolarization of membrane
• Decreased conduction velocity via slow potentials
• No effect on fast potentials
• Profound side effects possible (but short-lived)
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Misc. AgentsMisc. AgentsMisc. AgentsMisc. Agents
• Cardiac Glycocides
• digoxin (Lanoxin®)– Inhibits NaKATP pump– Increases intracellular Ca++
• via Na+-Ca++ exchange pump
– Increases contractility– Decreases AV conduction velocity
• Cardiac Glycocides
• digoxin (Lanoxin®)– Inhibits NaKATP pump– Increases intracellular Ca++
• via Na+-Ca++ exchange pump
– Increases contractility– Decreases AV conduction velocity
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PharmacologyPharmacologyPharmacologyPharmacology
AntihypertensivesAntihypertensives
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Antihypertensive ClassesAntihypertensive ClassesAntihypertensive ClassesAntihypertensive Classes
• diuretics
• beta blockers
• angiotensin-converting enzyme (ACE) inhibitors
• calcium channel blockers
• vasodilators
• diuretics
• beta blockers
• angiotensin-converting enzyme (ACE) inhibitors
• calcium channel blockers
• vasodilators
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Blood Pressure = CO X PVRBlood Pressure = CO X PVRBlood Pressure = CO X PVRBlood Pressure = CO X PVR
• Cardiac Output = SV x HR
• PVR = Afterload
• Cardiac Output = SV x HR
• PVR = Afterload
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BP = CO x PVRBP = CO x PVRBP = CO x PVRBP = CO x PVR
Key:
CCB = calcium channel blockers
CA Adrenergics = central-acting adrenergics
ACEi’s = angiotensin-converting enzyme inhibitors
cardiac factors circulating volume
heart rate
contractility
1. Beta Blockers2. CCB’s3. C.A. Adrenergics
salt
aldosterone
ACEi’s
Diuretics
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BP = CO x PVR
Hormones
1. vasodilators2. ACEI’s3. CCB’s
Central Nervous System
1. CA Adrenergics
Peripheral SympatheticReceptors
alpha beta
1. alpha blockers 2. beta blockers
Local Acting1. Peripheral-Acting Adrenergics
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AlphaAlpha11 Blockers BlockersAlphaAlpha11 Blockers Blockers
Stimulate alpha1 receptors -> hypertension
Block alpha1 receptors -> hypotension
Stimulate alpha1 receptors -> hypertension
Block alpha1 receptors -> hypotension
• doxazosin (Cardura®)
• prazosin (Minipress®)
• terazosin (Hytrin®)
• doxazosin (Cardura®)
• prazosin (Minipress®)
• terazosin (Hytrin®)
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Central Acting AdrenergicsCentral Acting AdrenergicsCentral Acting AdrenergicsCentral Acting Adrenergics
• Stimulate alpha2 receptors – inhibit alpha1 stimulation
• hypotension
• Stimulate alpha2 receptors – inhibit alpha1 stimulation
• hypotension
• clonidine (Catapress®)
• methyldopa (Aldomet®)
• clonidine (Catapress®)
• methyldopa (Aldomet®)
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Peripheral Acting AdrenergicsPeripheral Acting AdrenergicsPeripheral Acting AdrenergicsPeripheral Acting Adrenergics
• reserpine (Serpalan®)
• inhibits the release of NE
• diminishes NE stores
• leads to hypotension
• Prominent side effect of depression– also diminishes seratonin
• reserpine (Serpalan®)
• inhibits the release of NE
• diminishes NE stores
• leads to hypotension
• Prominent side effect of depression– also diminishes seratonin
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Adrenergic Side EffectsAdrenergic Side EffectsAdrenergic Side EffectsAdrenergic Side Effects
• Common– dry mouth, drowsiness, sedation & constipation– orthostatic hypotension
• Less common– headache, sleep disturbances, nausea, rash &
palpitations
• Common– dry mouth, drowsiness, sedation & constipation– orthostatic hypotension
• Less common– headache, sleep disturbances, nausea, rash &
palpitations
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Angiotensin I
ACE
Angiotensin II
1. potent vasoconstrictor
- increases BP
2. stimulates Aldosterone
- Na+ & H2O
reabsorbtion
ACE Inhibitors ACE Inhibitors ACE Inhibitors ACE Inhibitors .
RAAS
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Renin-Angiotensin Renin-Angiotensin Aldosterone SystemAldosterone SystemRenin-Angiotensin Renin-Angiotensin Aldosterone SystemAldosterone System• Angiotensin II = vasoconstrictor• Constricts blood vessels & increases BP• Increases SVR or afterload• ACE-I blocks these effects decreasing SVR &
afterload
• Angiotensin II = vasoconstrictor• Constricts blood vessels & increases BP• Increases SVR or afterload• ACE-I blocks these effects decreasing SVR &
afterload
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ACE InhibitorsACE InhibitorsACE InhibitorsACE Inhibitors
• Aldosterone secreted from adrenal glands
cause sodium & water reabsorption
• Increase blood volume
• Increase preload
• ACE-I blocks this and decreases preload
• Aldosterone secreted from adrenal glands
cause sodium & water reabsorption
• Increase blood volume
• Increase preload
• ACE-I blocks this and decreases preload
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Angiotensin Converting Angiotensin Converting Enzyme InhibitorsEnzyme InhibitorsAngiotensin Converting Angiotensin Converting Enzyme InhibitorsEnzyme Inhibitors• captopril (Capoten®)
• enalapril (Vasotec®)
• lisinopril (Prinivil® & Zestril®)
• quinapril (Accupril®)
• ramipril (Altace®)
• benazepril (Lotensin®)
• fosinopril (Monopril®)
• captopril (Capoten®)
• enalapril (Vasotec®)
• lisinopril (Prinivil® & Zestril®)
• quinapril (Accupril®)
• ramipril (Altace®)
• benazepril (Lotensin®)
• fosinopril (Monopril®)
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Calcium Channel BlockersCalcium Channel BlockersCalcium Channel BlockersCalcium Channel Blockers
• Used for:
• Angina
• Tachycardias
• Hypertension
• Used for:
• Angina
• Tachycardias
• Hypertension
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CCB Site of ActionCCB Site of ActionCCB Site of ActionCCB Site of Action
diltiazem & verapamil
nifedipine (and otherdihydropyridines)
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CCB ActionCCB ActionCCB ActionCCB Action
• diltiazem & verapamil
• decrease automaticity & conduction in SA & AV nodes
• decrease myocardial contractility
• decreased smooth muscle tone
• decreased PVR
• nifedipine
• decreased smooth muscle tone
• decreased PVR
• diltiazem & verapamil
• decrease automaticity & conduction in SA & AV nodes
• decrease myocardial contractility
• decreased smooth muscle tone
• decreased PVR
• nifedipine
• decreased smooth muscle tone
• decreased PVR
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Side Effects of CCBsSide Effects of CCBsSide Effects of CCBsSide Effects of CCBs
• Cardiovascular
• hypotension, palpitations & tachycardia
• Gastrointestinal
• constipation & nausea
• Other
• rash, flushing & peripheral edema
• Cardiovascular
• hypotension, palpitations & tachycardia
• Gastrointestinal
• constipation & nausea
• Other
• rash, flushing & peripheral edema
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Calcium Channel BlockersCalcium Channel BlockersCalcium Channel BlockersCalcium Channel Blockers
• diltiazem (Cardizem®)
• verapamil (Calan®, Isoptin®)
• nifedipine (Procardia®, Adalat®)
• diltiazem (Cardizem®)
• verapamil (Calan®, Isoptin®)
• nifedipine (Procardia®, Adalat®)
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Diuretic Site of ActionDiuretic Site of ActionDiuretic Site of ActionDiuretic Site of Action
.
loop of Henle
proximaltubule
Distal tubule
Collecting duct
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MechanismMechanismMechanismMechanism
• Water follows Na+
• 20-25% of all Na+ is reabsorbed into the blood
stream in the loop of Henle
• 5-10% in distal tubule & 3% in collecting ducts
• If it can not be absorbed it is excreted with the
urine
Blood volume = preload !
• Water follows Na+
• 20-25% of all Na+ is reabsorbed into the blood
stream in the loop of Henle
• 5-10% in distal tubule & 3% in collecting ducts
• If it can not be absorbed it is excreted with the
urine
Blood volume = preload !
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Side Effects of DiureticsSide Effects of DiureticsSide Effects of DiureticsSide Effects of Diuretics
• electrolyte losses [Na+ & K+ ]
• fluid losses [dehydration]
• myalgia
• N/V/D
• dizziness
• hyperglycemia
• electrolyte losses [Na+ & K+ ]
• fluid losses [dehydration]
• myalgia
• N/V/D
• dizziness
• hyperglycemia
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DiureticsDiureticsDiureticsDiuretics
• Thiazides:
• chlorothiazide (Diuril®) & hydrochlorothiazide
(HCTZ®, HydroDIURIL®)
• Loop Diuretics
• furosemide (Lasix®), bumetanide (Bumex®)
• Potassium Sparing Diuretics
• spironolactone (Aldactone®)
• Thiazides:
• chlorothiazide (Diuril®) & hydrochlorothiazide
(HCTZ®, HydroDIURIL®)
• Loop Diuretics
• furosemide (Lasix®), bumetanide (Bumex®)
• Potassium Sparing Diuretics
• spironolactone (Aldactone®)
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Mechanism of VasodilatorsMechanism of VasodilatorsMechanism of VasodilatorsMechanism of Vasodilators
• Directly relaxes arteriole smooth muscle
• Decrease SVR = decrease afterload
• Directly relaxes arteriole smooth muscle
• Decrease SVR = decrease afterload
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Side Effects of VasodilatorsSide Effects of VasodilatorsSide Effects of VasodilatorsSide Effects of Vasodilators
• hydralazine (Apresoline®)– Reflex tachycardia
• sodium nitroprusside (Nipride®)– Cyanide toxicity in renal failure– CNS toxicity = agitation, hallucinations, etc.
• hydralazine (Apresoline®)– Reflex tachycardia
• sodium nitroprusside (Nipride®)– Cyanide toxicity in renal failure– CNS toxicity = agitation, hallucinations, etc.
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VasodilatorsVasodilatorsVasodilatorsVasodilators
• diazoxide [Hyperstat®]
• hydralazine [Apresoline®]
• minoxidil [Loniten®]
• sodium Nitroprusside [Nipride®]
• diazoxide [Hyperstat®]
• hydralazine [Apresoline®]
• minoxidil [Loniten®]
• sodium Nitroprusside [Nipride®]
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PharmacologyPharmacologyPharmacologyPharmacology
Drugs Affecting HemostasisDrugs Affecting Hemostasis
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HemostasisHemostasisHemostasisHemostasis
• Reproduce figure 11-9, page 359 Sherwood • Reproduce figure 11-9, page 359 Sherwood
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Platelet AdhesionPlatelet AdhesionPlatelet AdhesionPlatelet Adhesion
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Coagulation CascadeCoagulation CascadeCoagulation CascadeCoagulation Cascade
• Reproduce following components of cascade:– Prothrombin -> thrombin
• Fibrinogen -> fibrin
– Plasminogen -> plasmin
• Reproduce following components of cascade:– Prothrombin -> thrombin
• Fibrinogen -> fibrin
– Plasminogen -> plasmin
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Platelet InhibitorsPlatelet InhibitorsPlatelet InhibitorsPlatelet Inhibitors
• Inhibit the aggregation of platelets
• Indicated in progressing MI, TIA/CVA
• Side Effects: uncontrolled bleeding
• No effect on existing thrombi
• Inhibit the aggregation of platelets
• Indicated in progressing MI, TIA/CVA
• Side Effects: uncontrolled bleeding
• No effect on existing thrombi
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AspirinAspirin AspirinAspirin
– Inhibits COX• Arachidonic acid (COX) -> TXA2 ( aggregation)
– Inhibits COX• Arachidonic acid (COX) -> TXA2 ( aggregation)
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GP IIB/IIIA InhibitorsGP IIB/IIIA InhibitorsGP IIB/IIIA InhibitorsGP IIB/IIIA Inhibitors
GP GP IIIIb/b/IIIIIIaaInhibitorsInhibitors
Fibrinogen
GP GP IIIIb/b/IIIIIIaaReceptorReceptor
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GP IIB/IIIA InhibitorsGP IIB/IIIA InhibitorsGP IIB/IIIA InhibitorsGP IIB/IIIA Inhibitors
• abciximab (ReoPro®)
• eptifibitide (Integrilin®)
• tirofiban (Aggrastat®)
• abciximab (ReoPro®)
• eptifibitide (Integrilin®)
• tirofiban (Aggrastat®)
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AnticoagulantsAnticoagulantsAnticoagulantsAnticoagulants
• Interrupt clotting cascade at various points– No effect on platelets
• Heparin & LMW Heparin (Lovenox®)
• warfarin (Coumadin®)
• Interrupt clotting cascade at various points– No effect on platelets
• Heparin & LMW Heparin (Lovenox®)
• warfarin (Coumadin®)
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HeparinHeparinHeparinHeparin
• Endogenous– Released from mast cells/basophils
• Binds with antithrombin III• Antithrombin III binds with and inactivates excess
thrombin to regionalize clotting activity.– Most thrombin (80-95%) captured in fibrin mesh.
• Antithrombin-heparin complex 1000X as effective as antithrombin III alone
• Endogenous– Released from mast cells/basophils
• Binds with antithrombin III• Antithrombin III binds with and inactivates excess
thrombin to regionalize clotting activity.– Most thrombin (80-95%) captured in fibrin mesh.
• Antithrombin-heparin complex 1000X as effective as antithrombin III alone
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HeparinHeparinHeparinHeparin
• Measured in Units, not milligrams
• Indications:– MI, PE, DVT, ischemic CVA
• Antidote for heparin OD: protamine.– MOA: heparin is strongly negatively charged.
Protamine is strongly positively charged.
• Measured in Units, not milligrams
• Indications:– MI, PE, DVT, ischemic CVA
• Antidote for heparin OD: protamine.– MOA: heparin is strongly negatively charged.
Protamine is strongly positively charged.
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warfarin (Coumadinwarfarin (Coumadin®®))warfarin (Coumadinwarfarin (Coumadin®®))
• Factors II, VII, IX and X all vitamin K dependent enzymes
• Warfarin competes with vitamin K in the synthesis of these enzymes.
• Depletes the reserves of clotting factors.
• Delayed onset (~12 hours) due to existing factors
• Factors II, VII, IX and X all vitamin K dependent enzymes
• Warfarin competes with vitamin K in the synthesis of these enzymes.
• Depletes the reserves of clotting factors.
• Delayed onset (~12 hours) due to existing factors
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ThrombolyticsThrombolyticsThrombolyticsThrombolytics
• Directly break up clots– Promote natural
thrombolysis
• Enhance activation of plasminogen
• ‘Time is Muscle’
• Directly break up clots– Promote natural
thrombolysis
• Enhance activation of plasminogen
• ‘Time is Muscle’
• streptokinase (Streptase®)
• alteplase (tPA®, Activase®)
• anistreplase (Eminase®)• reteplase (Retevase®)• tenecteplase (TNKase®)
• streptokinase (Streptase®)
• alteplase (tPA®, Activase®)
• anistreplase (Eminase®)• reteplase (Retevase®)• tenecteplase (TNKase®)
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Occlusion MechanismOcclusion MechanismOcclusion MechanismOcclusion Mechanism
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tPA MechanismtPA MechanismtPA MechanismtPA Mechanism
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Cholesterol MetabolismCholesterol MetabolismCholesterol MetabolismCholesterol Metabolism
• Cholesterol important component in membranes and as hormone precursor
• Synthesized in liver– Hydroxymethylglutaryl coenzyme A reductase– (HMG CoA reductase) dependant
• Stored in tissues for latter use• Insoluble in plasma (a type of lipid)
– Must have transport mechanism
• Cholesterol important component in membranes and as hormone precursor
• Synthesized in liver– Hydroxymethylglutaryl coenzyme A reductase– (HMG CoA reductase) dependant
• Stored in tissues for latter use• Insoluble in plasma (a type of lipid)
– Must have transport mechanism
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LipoproteinsLipoproteinsLipoproteinsLipoproteins
• Lipids are surrounded by protein coat to ‘hide’ hydrophobic fatty core.
• Lipoproteins described by density– VLDL, LDL, IDL, HDL, VHDL
• LDL contain most cholesterol in body– Transport cholesterol from liver to tissues for use
(“Bad”)
• HDL move cholesterol back to liver– “Good” b/c remove cholesterol from circulation
• Lipids are surrounded by protein coat to ‘hide’ hydrophobic fatty core.
• Lipoproteins described by density– VLDL, LDL, IDL, HDL, VHDL
• LDL contain most cholesterol in body– Transport cholesterol from liver to tissues for use
(“Bad”)
• HDL move cholesterol back to liver– “Good” b/c remove cholesterol from circulation
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Why We Fear CholesterolWhy We Fear CholesterolWhy We Fear CholesterolWhy We Fear Cholesterol
• Risk of CAD linked to LDL levels• LDLs are deposited under endothelial surface and
oxidized where they:– Attracts monocytes -> macrophages
– Macrophages engulf oxidized LDL• Vacuolation into ‘foam cells’
– Foam cells protrude against intimal lining• Eventually a tough cap is formed
– Vascular diameter & blood flow decreased
• Risk of CAD linked to LDL levels• LDLs are deposited under endothelial surface and
oxidized where they:– Attracts monocytes -> macrophages
– Macrophages engulf oxidized LDL• Vacuolation into ‘foam cells’
– Foam cells protrude against intimal lining• Eventually a tough cap is formed
– Vascular diameter & blood flow decreased
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Why We Fear CholesterolWhy We Fear CholesterolWhy We Fear CholesterolWhy We Fear Cholesterol
• Plaque cap can rupture
• Collagen exposed
• Clotting cascade activated
• Platelet adhesion
• Thrombus formation
• Embolus formation possible
• Occlusion causes ischemia
• Plaque cap can rupture
• Collagen exposed
• Clotting cascade activated
• Platelet adhesion
• Thrombus formation
• Embolus formation possible
• Occlusion causes ischemia
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Lipid DepositionLipid DepositionLipid DepositionLipid Deposition
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Thrombus FormationThrombus FormationThrombus FormationThrombus Formation
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Platelet AdhesionPlatelet AdhesionPlatelet AdhesionPlatelet Adhesion
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Embolus FormationEmbolus FormationEmbolus FormationEmbolus Formation
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Occlusion Causes InfarctionOcclusion Causes InfarctionOcclusion Causes InfarctionOcclusion Causes Infarction
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Antihyperlipidemic AgentsAntihyperlipidemic AgentsAntihyperlipidemic AgentsAntihyperlipidemic Agents
• Goal: Decrease LDL– Inhibition of LDL
synthesis
– Increase LDL receptors in liver
• Target: < 200 mg/dl• Statins are HMG
CoA reductase inhibitors
• Goal: Decrease LDL– Inhibition of LDL
synthesis
– Increase LDL receptors in liver
• Target: < 200 mg/dl• Statins are HMG
CoA reductase inhibitors
• lovastatin (Mevacor®)• pravastatin (Pravachol®)• simvastatin (Zocor®)• atorvastatin (Lipitor®)
• lovastatin (Mevacor®)• pravastatin (Pravachol®)• simvastatin (Zocor®)• atorvastatin (Lipitor®)