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94 Cards in this Set
- Front
- Back
Major groups of drugs for the treatment of CV disorders
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Adrenergic Blockers: (Angina, hypertension, HF, arrhythmias ACE inhibitors: hypertension, HF Nitrates: angina +Inotropic agents: HF Others: diuretics, antithrombotics etc Antiarrhythmic agents |
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Positive Inotropic Agents
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force heart contraction - can actually accelerate the disease state but make the symptoms better |
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What is Angina
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Anginais broadly defined as an imbalance between oxygen supply to oxygendemand in the heart. - due to atherosclerosis in the coronary vasculature, vasospasms of coronary artery or both |
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symptoms of angina
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severe ischemia results in pain describes as heavy an crushing |
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Type of angina
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-Generally caused by advanced coronaryatherosclerosis. 2. Vasospastic angina (aka varied angina or Prinxmetal's angina) --> caused by spasms 3. Unstable angina: caused by formation of platelet thrombi in coronary vessels |
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General approaches for the management of Ischemic Heart Disease
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1.Correction of lifestyle 2.Specific pharmacological approaches 3.Revascularization: PTCA (or PCI), CABG 4.Gene therapy (still consideredexperimental) |
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PCI (balloon angioplasty)
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you put in a balloon inside the coronaryartery and then inflated. When theballoon is removed, stent is left in place. The problem is that plaques can developon the side of the stent and inside the stent. There is a move to implant stants thathave drugs attached to them to prevent the accumulation of plaque |
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Major determinants of myocardial Oxygen demand
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1. Wall stress -intraventricular pressure -intraventricular volume -wall thickness 2. Heart Rate 3. Contractile Force |
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Major determinants of coronary blood flow
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1. Coronary resistance -neural factors (large epicardial vessels) -intrinsic factors (resistance vessels) 2. Extravascular factors -systole: negligible coronaryblood flow -diastole: maximum coronary blood flow |
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Preload
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Theamount of blood in the left ventricle at the endof diastole (end diastolic volume, EDV). This is, in part, controlledby the amount of blood returning to the heart (venous return). the circulation.Can be reduced by drugs which dilate the venous side of |
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Afterload
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Determinedby the mean arterial pressure andcan be reduced by drugs which dilate thearterial side fthe circulation. |
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Reflex responses to Vasodilation
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Many drugs are used as dilators – thereis a reflex mechanism that comes into play. Anything which reduced blood pressure will trigger these reflexes. Consequences of decrease in renalperfusion. Renin is also under the control ofsympathetic --- kidneys sense decrease in renal perfusion and trigger increasein renin release but also by the direct innervation by sympathetic system |
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general approaches to treat angina with drugs
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-dilate coronary arteries (increase o2 supply) -decreased HR and/or contractility ( decreased O2 demand) -Decrease after load -Decrease preload -for Unstable Angina also antithromotic medications |
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Major Drug Groups used to treat ANgina
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1.Drugs which inhibit myocardial O2demand Nitrates Beta adrenergic receptorblockers Calcium channel blockers 2.Drugs which increase coronary flow CCBs Nitrates 3.Antithrombotic agents Aspirin Glycoprotein IIb/IIIaantagonists |
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Nitrates
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-undergo rapid hepatic biotransformation by glutathione-dependent organic nitrate reductase -route of administration depends on the type of angina. For predictable angina, taken as a relief, for unpredictable ones; taken as a preventative |
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Cardiovascular effects of Nitrates
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1. direct vasodilation --> redistribution of blood flow to ischemic regions of the endocardium 2. dilation or arterioles leading to a reduction in afterload 3. dilation of veins --> dec. preload (%wise greater than afterload) 4. Antiplatelet effect: |
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Mechanism of Action of nitrates
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On top of thesmooth musclethereis a layer of cells called endothelial cells. In non-disease state, they protect the bloodvessels by generating nitric oxide. Thereare 3 nitric oxide synthases. Nitricoxide produced, enters vessel and all is good. People with heart disease almost always have damaged endothelial layeror completely removed. So in thosepatients those vessels do not have nitric oxide produced. Nitrates come to the rescue because theybecome de-nitratedandrelease nitric oxide in the cell. SO ina way it is replacing the endothelial cells. |
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Mechanism of Action of nitrates
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Calcium activates this enxyme LMCK– this kinase phosphorylates protein myosin light-chain(contractile protein) – it can interact with actin to cause contraction. One of the functions of cGMP isto dephosphorylate myosine lightchain –contraction cannot occur and the blood vessel is allowed to relax. cGMP can be broken down by a family ofenzymes “ “ - you don’t want cGMParound all the time. Sildenafil works by inhibiting phosphodiesterasebecause now cGMPcannot be broken down and you have the same effect as nitrates. Patients who are being treated with nitrates,can have powerful additive effects if they are given viagra. Contraindicated drugs. |
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Calcium Channel Blockers for the treatment of Angina
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1.Benzene acetonitriles (verapamil) 2.Dihydropyridines (nifedipine) 3.Benzothiazepines (diltiazem) |
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Calcium Channel Blockers for the treatment of Angina
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Irrespective of structure, all CCBs blockCa2+ entryby blocking the slow inward calcium channel(ISI). However, selectivity towards cardiac vsvascular tissues varies Verapamil > Diltiazem > Nifedipine |
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Site of Action of CCBs
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AV node (Decrease conduction) Cardiac myocytes (decrease afterload & O2 demand) Coronary arteries (increase vasodilation and O2 supply) Veins: (minimal venodilation) Arterioles: (inc. vasodilation, dec. afterload and O2 demand) |
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Effectiveness of CCBs in treating Angina
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VASOSPASTIC ANGINA: All are effective in reducing coronaryconstriction via a direct dilating influence. Improvement generally seen in>90% ofpatients with a large %age showing complete eliminationof anginalepisodes. STABLE ANGINA: All are effective: mechanism due to areduction in oxygen demand via: 1.Decreased afterload 2.Decreased heart rate 3.Decrease contractile force Unstable Angina: somewhat |
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Pure Dilator alone
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Beta Adrenergic Receptor Blockers for the treatment of Angina
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Use of these drugs (egpropranolol) based solely on anti-sympathetic nervous systemeffects. |
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Mechanism by which Beta blockers work (used on the demand side of the equation) reduce cardiac function |
1.Decreased heart rate (negative chronotropic effect) resulting in increasedend-diastolic volume (EDV*) 2.Decreased contractile force (negativeinotropic effect) 3.Decreased blood pressure |
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Beta Blockers
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-also anti-hypertensors by unknown mechanism -have to be careful. If you slow heart down, spends more time in diastole, and more time for right ventricle to fill up --> increased EDV -->increased O2 demand. So just beta blockers on their own is not desirable |
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Combination therapy for the treatment of angina: Beta blocker + nifedipine (CCB)
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-Nifedipine decreases afterload -Beta Blocker prevents reflex sympathetic cardio-stimulation -Result: reduction in O2 demand |
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Combination therapy for the treatment of angina: Beta blocker + nitrate
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-Nitrate attenuates increased EDV produced by Beta blocker -Beta blocker prevents reflex sympathetic cardiostimulation -Result: added efficacy |
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Combination therapy for the treatment of angina: CCB + nitrate
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Combined decrease of both preload andafterload; however this combination can causeexcessive vasodilation and thus reflex cardiostimulation |
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Combination therapy for the treatment of angina: Beta blocker + CCB + Nitrate
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used in patients refractory to any other combination |
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3 major patterns of LV hypertrophy
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ConcentricLVH: pressure load leads to growth in cardiomyocytethickness Eccentric LVH: volume load produces myocyte lengthening Post MI LVH: stretched and dilated infarcted tissueincreases the left-ventricular volume with acombined volume and pressure load on thenon-infarcted zonesFibrosiscontributes to all three patterns |
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Physiological Hypertrophy is an adaptive response to Growth signals
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General approaches for the management of HF
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Pharmacological Surgical |
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Surgical treatment of HF
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Heart transplant (only curative approach) Leftventricular assist devices (LVADs) Skeletalmyoplasty(limited improvement) Ventricularreconstruction (experimental) Celltransplantation (experimental) |
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Drugs used for the treatment of HF
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2. Preload/afterload reducers 3. Beta adrenoreceptor blockers |
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2. Preload/afterload reducers
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genereally forchronic heart failure, not ideal. Theseare used mostly for acute heart failure. Anything with a pril is an ace inhibitor. They are widely used. Angiotension 2receptors have been introduced because ace inhibitors have this chronic coughas side effect |
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Positive Inotropic agents
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-digitalis glycosides -catecholamines -xanthine derivatives |
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Beta adrenoreceptor blockers
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carvedilol For a long time they were contraindicatedbecause they thought the conditioned would be worse Beta blockers may actually promotehealing of the heart |
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ACE inhibitors for treatment of HF
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In a study they NYHA class 2 and three patients They compared the effect of aceinhibitors and antagonist AT1 Both drugs reduced BP identically and yetthe patient receiving the ACE inhibitor much better. That proved that the effect of ACE inhibitormust be working by some other mechanism other than vasodilation Sudden cardiac death is important. Take home message is that ACE inhibitors mustbe doing something else instead of vasodilation. |
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Mechanism of Action of ACE inhibitors or AT1 antagonist in HF
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1. Vasodilating/afterload reduction Angiotensin II: potent vasoconstrictor stimulatessympathetic nervous systemincreases aldosterone production 2.Preventionof myocardial hypertrophy and remodelling |
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Mechanism of Positive Inotrope such as DIgitalis
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1. Inhibition of Sodium-Potassium pump --> reduced Ca2+ removal via Na-Ca exchange or reverse mode Ca influx via Na-Ca exchange --> Increase intracellular Ca2+ levels --> Positive Inotropic effect |
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Other Inotropic agents
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-Phosphodiesterase Inhibitors (amrinone, milrinone) -- inhibit PDE 3 to prevent cAMP breakdown |
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Problems with + Inotropic Agents
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1.Potential for toxicity (all,calcium-dependent) 2.Narrow therapeutic index (especiallyglycosides) 3.Increase cardiac work/oxygen demand 4.Low K (diuretic use) increases toxicity(glycosides only) 5.Although inotropes can improve quality of life, recentevidence suggests possible increased mortality |
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Beta Arenergic Blockers for Heart Failure
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mild to moderate CHF -6 months follow up -dose dependent improvement in LVfunction -73% reduction in mortality -60% reduction in hospitalization rate |
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B-Blocker Treatment in HF
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Effects: -increase injection fraction -improve symptoms -decrease hospitalization -decrease heart transplantation -slows progression of HF and decreases mortality |
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B-Blocker Mechannism
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-decrease heart rate -improve diastolic filling -up regulation of B-adrenoreceptors |
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Propranolol
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-not a specific B-blocker - blocks both Beta1 and 2. Patients with asthma shouldn't take it. |
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Improving Survival in CHF
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From: (diuretic + digoxin) to (diuretic + digoxin + ACE-1) + (diuretic + digoxin + ACE-1 + B-Blocker) + (diuretic + digoxin + ACE-1 + B-Blocker + Candesartan) |
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Potential future treatment for HF
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antioxidants endothelin receptor antagonis cytokine receptor antagonist alternative medicines (traditional Chinese such as ginseng) gene therapy (direct molecular targeting) cell transplant therapy |
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Hypertension facts
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-prevalence varies with age, sex, race -usually asymptomatic -diagnosis based on repeated measurements of elevated bp -Approx. 90% unknown cause but generally associated with genetic inheritance, psychological stress, lifestyle |
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Classification of Hypertension
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systolic/diastolic Pressure <120/80 Normal 120-135/80-89 Pre-hypertension >140/90 hypertension 140-159/90-99 stage 1 >160/100 Stage 2 Decision to treat the middle grey area dependent on other risks |
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Hypertension: general
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Guidelines for treating hypertension
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1.Relief of stress 2. Dietary management (eglow dietary Na) 3. Regular exercise 4. Weightreduction (if needed) 5. Control of risk factors contributing to development of atherosclerosis |
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High Na+ intake increases risk of hypertension-related complications |
Govt recommended intake of Na 2000mg/day Doctors recommend 1500mg/day can of soup has over 500mg alone |
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Redcution of averge dietary sodium from 3500 mg/day to 1700
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5 million fewer physician visits for hypertension 1/2 billion savings in healthcare spendings 13% reduction is CVD |
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Goals of Ant hypertension therapy |
•To optimally reduce cardiovascular riskby reducing the blood pressure to specified targets. –This usually requires two or more drugs and lifestyle changes –The systolic target is moredifficult to achieve however controlling systolic blood pressure is asimportant if not more important than controlling diastolic blood pressure |
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Principle of hypertensive therapy
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hence all hypertensive drugs must act either by reducing CO or the peripheral vascular resistance |
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When to use pharmacological treatment for hypertension
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-If bp is higher than 130/80 and patient has diabetes and/or Chronic kidney disease |
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Targets for Antihypertensive therapy
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*B-receptors of the heart: Propranolol and other B-blockers *alpha-receptors of vessels: Prazosin and other a1-blockers *Vascular smooth muscle: hydralazine, minoxidil, diazoxide, Verapamil and other CCBs, Fenoldopam *Sympathetic ganglia: trimethaphan *Kidney tubules: thiazides *Vasomotor centre (brain): methyldopa, clonidine, Guanbenz, Guanfacine *Angiotensin receptor of vessels: losartan and other AT1 blockers *Kidneys: ACE inhibitors |
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4 primary anatomical Targets for blood pressure control
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2. capacitance vessels* 3. heart* 4. kidneys *not a major target |
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Summary of site of Action of different classes of antihypertensive drugs
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(Not used much, lots of side effects) Directly acting vasodilatators: AT1 receptorantagonists (``sartans`) α1 receptor antagonists (egprazosin) Calcium channel blockers (egnifedipine) Other vasodilatators (eg hydralazine,minoxidil) Drugs acting on the kidneys Diuretics βreceptor blockers Drugs acting on therenin-angiotensin system ACEinhibitors AT1 receptorantagonists Directinhibitors of renin (Aliskerin)
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Aliskerin
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Aliskiren –direct target renin àassociated with toxicity àcautionary warnings By blocking an upstream effector likerenin has a lot of other side effects Its still available but not widelyused. This drug came out 4-5 years ago |
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CCBs for hypertension
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Major effect of calcium channel blockersis to dilate coronary arteries – some calcium channel blockers also have someadditional affects à mildaldosteroneffect, mild diuretic Nifedipine –half life 7-8 hours is still considered a short acting Major function – reduction in pressure –reduction in afterload Beta blockers – propranolol first durg used– nonspecific – crosses BBB easily. Somestudies suggest that its centrally acting. Newer Beta blockers have less effect on CNS, and are specific and havebetter effect than propranolol. So thisidea that propranolol is acting centrally may not be true. Beta blockers reduce heart function and thatshould reduce blood pressure. But thereare studies that show that depressed cardiac function does not necessarily leadto decreased BP. When you give beta blockers for a longtime, nerve endings reduce norepeinepherinrelease. This may be the mechanism, sothis is why it takes time for reduction in bp. Reason why doctors don’t perscribe betablockers -Lateeffect -Unknownmechanism -Otherside effects |
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CCBs for hypertension
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Calcium channel blockers (CCBs = calciumantagonists) act largely by peripheral arterial dilation, with a lesserdiuretic effect. They also evoke counterregulatory mechanisms, dependent on stimulation ofrenin and formation of angiotensin, as well as on reflex release ofnorepinephrine. Such acute adrenergic stimulation with short-acting nifedipine(N) may precipitate myocardial ischemia in the presence of coronary disease .Currently only long-acting CCBs are used in the treatment of hypertension. Theinhibition of aldosterone release obviates overall fluid retention. D = diltiazem;SVR = systemic vascular resistance; V = verapamil. |
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Beta Blockers
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Proposed antihypertensivemechanisms of beta-blockade. An early fall in heart rate (HR), stroke volume(SV), and cardiac output (CO) does not lead to a corresponding fall in bloodpressure because of baroreflex-mediated increased peripheral &alpha-adrenergic vasoconstriction, with a rise in systemic vascular resistance.Within a few days beta-blockade of prejunctional receptors on the terminal neuron withconsequent inhibition of release of norepinephrine (NE), which may explain whythe SVR falls to normal. The blood pressure now falls. In the case of vasodilatory beta-blockers, with addedalpha-blockade, there is an early decrease in SVR and a rapid fall in BP
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Diuretics |
Diuretics are widely used to treatHypertension and also for HF for the same reasons The major effect is the loss of sodium –they act on the sodium regulatory systems in the nephron – wherever sodiumgoes, water follows. Lose sodium à losewater , lower blood volume à lowpressure When Renin is activated then you getangiotensin 2 upregulation. So combination diuretics and ACE inhibitorswork well because the ACE inhibitors stop these reflexes to loss of sodium |
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Diuretics
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If you take diuretics chronically, theblood volume comes back to normal and yet the hypertension is reduced. There is a disoacciationbetween blood volume and hypertension. Why is that? Nobody knows. SO itsnot a simple reduction in blood volume. There has got to be some other mechanism |
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Diuretcs
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•The primary class (first line of choice)of diuretics used for the treatment of hypertension are the Thiazide Diureticswhereas others (eg Loop Diuretics or K+ sparingdiuretics) are less frequently prescribed although under some circumstancesthese may be advantageous over thiazides. |
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Site of Diuretic Action in the Nephron
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Thiazide diuretics: Primarily byblocking an electroneutral Na-Cl cotransporter (NCC) in DCT producing moderate natriuresis. Additional vasodilatation likelycontributes to Antihypertensive effects Loop diuretics: Primarily by inhibiting the Na-K-Cl cotransporter in TAL K+-sparing diuretics/aldosterone antagonists: Primarily by decreasing Natransport through epithelial Na channels (ENaC).Since Na transport is coupled to Ksecretion, a K- sparing diuresis results |
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Combination therapy for hypertension
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-ACE inhibitor + Calcium channelblocker (CCB) -ACEinhibitor + thiazide diuretic -Angiotensinreceptor blocker (ARB) + thiazide diuretic -ARB + CCB -Beta adrenergic receptor blocker+ thiazide diuretic A number of these combined medicationsare available as singletablet/capsule |
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Cardiac Arrhythmias
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Can occur in anyone, even with anyonewith a normal heart. Very verycomplex and can be caused by different mechanisms Every single arrhythmic agent actuallyhas the ability to induce arrhythmia so they can be quite risk because theytarget some key ions channels in cardiac cell itself |
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Action Potential in Different regions of Heart
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Currents Underlying the Ventricular Action POtential
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Were only looking at the middle figure Two component of action potential -rapid depolarization -and then repolarization At RMP – heart rate is at - 90 mV Rapid sodium entry (phase 0) increasepositive Now there is a rapid transient curve(potassium curve) What is happening here is that thesepotassium curve is an outward current Calcium curve is an inward curent The only thing preventing Pottasiumgoing out and calcium getting in determines the plateouphase Depening onthe membrane potential the two above are activated or inactivated. Calcium current is turned off as MEMBRANEpotential reaches critical levels Potassium is still going out and thisbrings the membrane potential to normal level àrepolarization When calcium current is inactivated(coming in) the otassiumcontinues to go out leading to a more negative inside. So the characteristics of these actionpotential are important to know how these antiarhymathetics work During the plateuphase, the heart can not be stimulated again ( refractory period) In arrhythmia, if you can prolong the plateouphase, that is desirable |
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Effective Refractory Period
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Period comprising phases 0,1, 2, and partof phase 3 that a new action potential cannot be initiated (also referred to asthe absolute refractory period or ARP). Modulation (prolongation) of ERP represents the target for a number ofantiarrhythmic agents. |
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2 general mechanisms of Arrhythmias
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1.Disturbances of impulse formation(triggered automaticity) 2.Disturbances of impulse conduction(reentry) |
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Triggered automaticity
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Early afterdepolarization: due to leakage of Ca2+ and cardiac cell cannot be re-excited Delayed afterdepolarization: probably due to abnormal release of calcium inside the cell |
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Reentry as a mechanism for Arrhythmias
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If you block a pathway, this pathway can gobackwards (rentry) If it is a bidirectional block, it getsstuck, so it has to be unidirectional block |
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Classes of Antiarrhythmic agents
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Class I Na+ channel blockers which increase ERP byprolonging sodiumchannel inactivation.Subdivided into class IA (moderate blockers, quinidine), IB (rapid blockers, eg lidocaine) and IC (potent blockers, egflecainide) -odium channel blockers can be used – toprolong the plateouphase so that the cell in heart cannot be rexcited. When you use them in the heart they canbecome very dangerous because it can lead to death. Class II Beta adrenergic blockers. Decrease tonic sympathetic stimulation. Useful for the treatment of SNS-dependent supraventricular and ventriculararrhythmias (egatenolol, metoprolol). |
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Classes of Antiarrhythmic agents
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Class III K+ channel blockers which increase ERP bydecreasing the magnitude of repolarizing currents during phase 2 of the actionpotential. Useful for reentry-dependentarrhythmias (egamiodarone).
Class IV Ca2+ channel blockers targeting pacemakercell action potentials. Useful for treating arrhythmias involving reentry in AVnode (egverapamil, diltiazem). |
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Classes of Antiarrhythmic agents
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Classes of Antiarrhythmic agents
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