nullPharmacologyPharmacologyDrugs that Affect the Cardiovascular SystemTopicsTopicsElectrophysiology
Vaughn-Williams classification
Antihypertensives
Hemostatic agentsCardiac FunctionCardiac FunctionDependent upon
Adequate amounts of ATP
Adequate amounts of Ca++
Coordinated electrical stimulusAdequate Amounts of ATPAdequate Amounts of ATPNeeded to:
Maintain electrochemical gradients
Propagate action potentials
Power muscle contractionAdequate Amounts of CalciumAdequate Amounts of CalciumCalcium is ‘glue’ that links electrical and mechanical events.Coordinated Electrical StimulationCoordinated Electrical StimulationHeart capable of automaticity
Two types of myocardial tissue
Contractile
Conductive
Impulses travel through ‘action potential superhighway’.A.P. SuperHighwayA.P. SuperHighwaySinoatrial node
Atrioventricular node
Bundle of His
Bundle Branches
Fascicles
Purkinje NetworkElectrophysiologyElectrophysiologyTwo types of action potentials
Fast potentials
Found in contractile tissue
Slow potentials
Found in SA, AV node tissuesFast PotentialFast Potential-80-60-40-200+20RMP
-80 to 90 mVPhase 1Phase 2Phase 3Phase 4controlled by Na+
channels = “fast channels”Fast PotentialFast PotentialPhase 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 PotentialCardiac Conduction CycleCardiac Conduction CycleSlow PotentialSlow Potential-80-60-40-200Phase 4Phase 3dependent upon Ca++ channels = “slow channels”Slow PotentialSlow PotentialSelf-depolarizing
Responsible for automaticity
Phase 4 depolarization
‘slow sodium-calcium channels’
‘leaky’ to sodium
Phase 3 repolarization
K+ effluxCardiac Pacemaker DominanceCardiac Pacemaker DominanceIntrinsic firing rates:
SA = 60 – 100
AV = 45 – 60
Purkinje = 15 - 45Cardiac PacemakersCardiac PacemakersSA is primary
Faster depolarization rate
Faster Ca++ ‘leak’
Others are ‘backups’
Graduated depolarization rate
Graduated Ca++ leak ratePotential TermsPotential TermsAPDERPRRPrelative
refractory
periodeffective refractory periodaction potential durationDysrhythmia GenerationDysrhythmia GenerationAbnormal genesis
Imbalance of ANS stimuli
Pathologic phase 4 depolarization
Ectopic fociDysrhythmia GenerationDysrhythmia GenerationAbnormal conduction
Analogies:
One way valve
Buggies stuck in muddy roadsReentrant CircuitsReentrant CircuitsWarning!Warning!All antidysrhythmics have arrythmogenic properties
In other words, they all can CAUSE dysrhythmias too!AHA Recommendation ClassificationsAHA Recommendation ClassificationsDescribes weight of supporting evidence NOT mechanism
Class I
Class IIa
Class IIb
Indeterminant
Class IIIView AHA definitionsVaughn-Williams ClassificationVaughn-Williams ClassificationClass 1
Ia
Ib
Ic
Class II
Class III
Class IV
MiscDescription of mechanism NOT evidenceClass I: Sodium Channel BlockersClass I: Sodium Channel BlockersDecrease 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 dysrhythmiasClass Ia AgentsClass Ia AgentsSlow conduction through ventricles
Decrease repolarization rate
Widen QRS and QT intervals
May promote Torsades des Pointes!PDQ:
procainamide (Pronestyl®)
disopyramide (Norpace®)
qunidine
(Quinidex®)Class Ib AgentsClass Ib AgentsSlow conduction through ventricles
Increase rate of repolarization
Reduce automaticity
Effective for ectopic foci
May have other usesLTMD:
lidocaine (Xylocaine®)
tocainide (Tonocard®)
mexiletine (Mexitil®)
phenytoin (Dilantin®)Class Ic AgentsClass Ic AgentsSlow conduction through ventricles, atria & conduction system
Decrease repolarization rate
Decrease contractility
Rare last chance drugflecainide (Tambocor®)
propafenone (Rythmol®)Class II: Beta BlockersClass II: Beta BlockersBeta1 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 tachycardiasClass II: Beta BlockersClass II: Beta Blockerspropranolol (Inderal®)
acebutolol (Sectral®)
esmolol (Brevibloc®)Class III: Potassium Channel BlockersClass III: Potassium Channel BlockersDecreases 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 hypotensionClass IV: Calcium Channel BlockersClass IV: Calcium Channel BlockersSimilar effect as ß blockers
Decrease SA/AV automaticity
Decrease AV conductivity
Useful in breaking reentrant circuit
Prime side effect: hypotension & bradycardiaverapamil (Calan®)
diltiazem (Cardizem®)
Note: nifedipine doesn’t work on heartMisc. AgentsMisc. Agentsadenosine (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)Misc. AgentsMisc. AgentsCardiac Glycocides
digoxin (Lanoxin®)
Inhibits NaKATP pump
Increases intracellular Ca++
via Na+-Ca++ exchange pump
Increases contractility
Decreases AV conduction velocityPharmacologyPharmacologyAntihypertensivesAntihypertensive ClassesAntihypertensive Classesdiuretics
beta blockers
angiotensin-converting enzyme (ACE) inhibitors
calcium channel blockers
vasodilatorsBlood Pressure = CO X PVRBlood Pressure = CO X PVRCardiac Output = SV x HR
PVR = AfterloadBP = CO x PVRBP = CO x PVRKey:CCB = calcium channel blockers
CA Adrenergics = central-acting adrenergics
ACEi’s = angiotensin-converting enzyme inhibitorsnullBP = CO x PVRPeripheral Sympathetic
Receptors
alpha beta
1. alpha blockers 2. beta blockersLocal Acting
1. Peripheral-Acting AdrenergicsAlpha1 BlockersAlpha1 BlockersStimulate alpha1 receptors -> hypertension
Block alpha1 receptors -> hypotensiondoxazosin (Cardura®)
prazosin (Minipress®)
terazosin (Hytrin®)
Central Acting AdrenergicsCentral Acting AdrenergicsStimulate alpha2 receptors
inhibit alpha1 stimulation
hypotensionclonidine (Catapress®)
methyldopa (Aldomet®)
Peripheral Acting AdrenergicsPeripheral Acting Adrenergicsreserpine (Serpalan®)
inhibits the release of NE
diminishes NE stores
leads to hypotension
Prominent side effect of depression
also diminishes seratoninAdrenergic Side EffectsAdrenergic Side EffectsCommon
dry mouth, drowsiness, sedation & constipation
orthostatic hypotension
Less common
headache, sleep disturbances, nausea, rash & palpitationsACE Inhibitors Angiotensin I
ACE
Angiotensin II
1. potent vasoconstrictor
- increases BP
2. stimulates Aldosterone
- Na+ & H2O
reabsorbtion
ACE Inhibitors .RAASRenin-Angiotensin Aldosterone SystemRenin-Angiotensin Aldosterone SystemAngiotensin II = vasoconstrictor
Constricts blood vessels & increases BP
Increases SVR or afterload
ACE-I blocks these effects decreasing SVR & afterloadACE InhibitorsACE InhibitorsAldosterone secreted from adrenal glands cause sodium & water reabsorption
Increase blood volume
Increase preload
ACE-I blocks this and decreases preloadAngiotensin Converting Enzyme InhibitorsAngiotensin Converting Enzyme Inhibitorscaptopril (Capoten®)
enalapril (Vasotec®)
lisinopril (Prinivil® & Zestril®)
quinapril (Accupril®)
ramipril (Altace®)
benazepril (Lotensin®)
fosinopril (Monopril®)Calcium Channel BlockersCalcium Channel BlockersUsed for:
Angina
Tachycardias
HypertensionCCB Site of ActionCCB Site of Actiondiltiazem & verapamilnifedipine
(and other
dihydropyridines)CCB ActionCCB Actiondiltiazem & verapamil
decrease automaticity & conduction in SA & AV nodes
decrease myocardial contractility
decreased smooth muscle tone
decreased PVR
nifedipine
decreased smooth muscle tone
decreased PVRSide Effects of CCBsSide Effects of CCBsCardiovascular
hypotension, palpitations & tachycardia
Gastrointestinal
constipation & nausea
Other
rash, flushing & peripheral edemaCalcium Channel BlockersCalcium Channel Blockersdiltiazem (Cardizem®)
verapamil (Calan®, Isoptin®)
nifedipine (Procardia®, Adalat®)Diuretic Site of ActionDiuretic Site of Action.loop of Henleproximal
tubuleDistal
tubuleCollecting
duct
MechanismMechanismWater 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 !
Side Effects of DiureticsSide Effects of Diureticselectrolyte losses [Na+ & K+ ]
fluid losses [dehydration]
myalgia
N/V/D
dizziness
hyperglycemiaDiureticsDiureticsThiazides:
chlorothiazide (Diuril®) & hydrochlorothiazide (HCTZ®, HydroDIURIL®)
Loop Diuretics
furosemide (Lasix®), bumetanide (Bumex®)
Potassium Sparing Diuretics
spironolactone (Aldactone®)Mechanism of VasodilatorsMechanism of VasodilatorsDirectly relaxes arteriole smooth muscle
Decrease SVR = decrease afterload Side Effects of VasodilatorsSide Effects of Vasodilatorshydralazine (Apresoline®)
Reflex tachycardia
sodium nitroprusside (Nipride®)
Cyanide toxicity in renal failure
CNS toxicity = agitation, hallucinations, etc.VasodilatorsVasodilatorsdiazoxide [Hyperstat®]
hydralazine [Apresoline®]
minoxidil [Loniten®]
sodium Nitroprusside [Nipride®]PharmacologyPharmacologyDrugs Affecting HemostasisHemostasisHemostasisReproduce figure 11-9, page 359 Sherwood Platelet AdhesionPlatelet AdhesionCoagulation CascadeCoagulation CascadeReproduce following components of cascade:
Prothrombin -> thrombin
Fibrinogen -> fibrin
Plasminogen -> plasminPlatelet InhibitorsPlatelet InhibitorsInhibit the aggregation of platelets
Indicated in progressing MI, TIA/CVA
Side Effects: uncontrolled bleeding
No effect on existing thrombi Aspirin AspirinInhibits COX
Arachidonic acid (COX) -> TXA2 ( aggregation)GP IIB/IIIA InhibitorsGP IIB/IIIA InhibitorsGP IIb/IIIa
InhibitorsFibrinogenGP IIb/IIIa
ReceptorGP IIB/IIIA InhibitorsGP IIB/IIIA Inhibitorsabciximab (ReoPro®)
eptifibitide (Integrilin®)
tirofiban (Aggrastat®)AnticoagulantsAnticoagulantsInterrupt clotting cascade at various points
No effect on platelets
Heparin & LMW Heparin (Lovenox®)
warfarin (Coumadin®)HeparinHeparinEndogenous
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 aloneHeparinHeparinMeasured 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. warfarin (Coumadin®)warfarin (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 factorsThrombolyticsThrombolyticsDirectly break up clots
Promote natural thrombolysis
Enhance activation of plasminogen
‘Time is Muscle’streptokinase (Streptase®)
alteplase (tPA®, Activase®)
anistreplase (Eminase®)
reteplase (Retevase®)
tenecteplase (TNKase®)Occlusion MechanismOcclusion MechanismtPA MechanismtPA MechanismCholesterol MetabolismCholesterol MetabolismCholesterol 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 mechanismLipoproteinsLipoproteinsLipids 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 circulationWhy We Fear CholesterolWhy We Fear CholesterolRisk 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 decreasedWhy We Fear CholesterolWhy We Fear CholesterolPlaque cap can rupture
Collagen exposed
Clotting cascade activated
Platelet adhesion
Thrombus formation
Embolus formation possible
Occlusion causes ischemiaLipid DepositionLipid DepositionThrombus FormationThrombus FormationPlatelet AdhesionPlatelet AdhesionEmbolus FormationEmbolus FormationOcclusion Causes InfarctionOcclusion Causes InfarctionAntihyperlipidemic AgentsAntihyperlipidemic AgentsGoal: 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®)
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