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294 Cards in this Set
- Front
- Back
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myocardial ischemia - definition
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imbalance between oxygen supply and myocardial oxygen demand in the heart
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causes of SUPPLY ischemia
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low coronary blood flow
hypoxia |
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causes of DEMAND ischemia
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high myocardial oxygen demand
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3 primary determinants of myocardial oxygen demand
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HR
myocardial contractility wall stress or tension (preload & afterload) |
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3 secondary determinants of myocardial oxygen demand
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electrical activity
basal cellular metabolism fatty acid uptake |
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5 biochemical consequences of myocardial ischemia
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aerobic to anaerobic shift
decrease ATP increase ADP decrease creatinine phosphate increase lactic acid increase intracellular calcium |
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5 functional consequences of myocardial ischemia
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decreased ventricular relaxation
decreased ventricular contraction increased filling pressures ECG abnormalities chest pain |
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agina pectoris
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chest pain caused by myocardial ischemia
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myocardial stunning
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a BRIEF period of myocardial ischemia causing a PROLONGED impairment of myocardial dysfunction with a gradual return to normal function
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myocardial hibernation
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a reduction in myocardial contractility (and therefore oxygen consumption) to match a reduced oxygen supply
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myocardial hibernation predicts a good functional response to...
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restoration of cardiac blood supply
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Can stunned or hibernating myocardial ischemia be identified non-invasively?
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yes
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where does myocardial necrosis occur first?
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subendocardium
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progression of myocardial necross from subendocardium to subepidcardium takes place over what time period?
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4-6 hours
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myocardial infarction - definition
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death of cardiac cells due to myocardial ischemia
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5 other conditions caused by myocardial ischemia (besides MI)
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silent ischemia
chronic stable angina (coronary atherosclerosis) variant angina (coronary vasospasm) unstable angina (non-occlusive coronary thrombus) myocardial infarction (occlusive coronary thrombus) |
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2 clinical conditions comprising acute coronary syndrome
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unstable angina (non-occlusive coronary thrombus)
myocardial infarction (occlusive coronary thrombus) |
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symptoms of MI
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chest pain
SOB wk/dz syncope ECG changes (S-T segment) cardiac proteins in blood decreased systolic BP arrthythmias anxiety CV collapse/death |
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treatment phases for myocardial ischemia
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primary prevention
angina acute MI secondary prevention (after MI) |
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The choice of drug therapy for myocardial ischemia depends on the phase of myocardial ischemia why?
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because the mechanisms causing ischemia are not identidcal in the different phases
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2 biggest prevention factors of myocardial ischemia
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decreased hypercholesterolemia
drug therapy |
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6 other prevention factors of myocardial ischemia
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decrease cigarette smoking
decrease HTN control DM decrease obesity increase physical activity decrease EtOH consumption |
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6 drug classes to treat dyslipidemia
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bile-acid binding resins
statins chl absorption inhibitors fibrates niacin (nicotinic acid) fish oils |
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2 drug names of bil=acid binding resins
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cholestryamine
colestipol |
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molecular mechanisms of bile-acid binders
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bind bile acids, causing their excretion in stool & increasing hepatic bile-acid synthesis
ergo, hepatic chl content declines, stimulating the production of LDL receptors more LDL extracted from blood |
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integrated response to bile-acid bind resins
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decrease LDL
increase TGs increase HDL |
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therapeutic use of bile-acid binding resins
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adjunctive therapty in pts w/ severe hypercholesterolemia due to increased LDL
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adverse effects of bile-acid binding resins
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bloating
dyspepsia ocnstipation |
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effect of bile-acid binding resins is partially offset by...
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increased synthesis of cholesterol
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6 drug names for statins
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atorvastatin
fluvastatin lovastatin pravastatin rosuvastatin simvastatin |
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molecular mechanisms of statins
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statins inhibit hepatic HMG-CoA reductase
thus reducing chl synthesis resulting in increased expression of the LDL receptor on hepatocytes |
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integrated response to statins
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decreased LDL
decreased TGs increased HDL |
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therapeutic use of statins
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primary & secondary prevention of coronary artery disease
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adverse effects of statins
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myopathy
hepatotoxicity |
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drug name for chl absorption blockers
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Ezetimibe
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molecular mechanisms of chl absorption blockers
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inhibits a specific transport process in the jejunum
putative transport protein is NPC1L1 reduced chl uptake --> increased hepatic synthesis and increased expression of LDL receptors on hepatocytes |
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integrated response to chl absorption blockers
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decreased LDL
decreased TGs increased HDL |
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therapeutic use of chl absorption blockers
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adjunctive therapy with statins
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adverse effects to chl absoprtion blockers
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rare allergic reactions
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why should ezetimibe not be administered with bile acid binding resins?
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bile acid binding resins inhibit absorption of ezetimibe
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molecular mechanisms of niacin
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inhibits lipolysis of TGs by hormone-sensitive lipase in adipose tissue, reducing transport of FFA to liver
thus reducing hepatic TG synthesis also reduces TG synthesis by inhibiting esterification of FFA in liver VLDL synthesis is decreased raises HDL-C levels by decreaseing clearnace of apoA-I in HDL |
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integrated response to niacin
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decreased LDL
decreased TG increased HDL |
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therapeutic use of niacin
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hypertriglyceremia
elevated LDL-C good in patients with hyperTG and low HDL-C levels |
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adverse effects of niacin
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flushing
hepatotoxicity insulin-resistance gout GI |
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concurrent use of niacin with what increases risk of myopathy?
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statins
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safest niacin preparation
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sustained-release niacin (Niaspan)
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Fibrates - names of drugs
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fenofibrate
gemfibrozil clofibrate |
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molecular mechanisms of fibrates
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bind to PPAR-alpha
reduces TGs by causing: - stimulation of FA oxidation, - increased lipoprotein lipase synthesis - reduced expression of apoC-III increases in HDL-C due to PPAR-alpha simulation of apoA-I & II expression |
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integrated response to fibrates
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decreased LDL
decreased TGs increased HDL |
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thereapeutic use of fibrates
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severe hyperTG
high TGs & low HDL-C levels associated w/ metabolic syndrome (DM II) |
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adverse effects of fibrates
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GI
urticaria hair loss |
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concurrent use of fibrates with what drug increases risk of myopathy?
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statins
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classic presentation of angina pectoris
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retrosternal chest discomfort, rather than frank pain
usually described as pressure, heaviness, squeezing, burning or choking sensation |
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stable angina
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precipitated by exertion, eating, exposure to cold, or emotional stress
lasts for 1-5 min relieved by rest or nitroglycerin |
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variant angina
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occurs at rest, often at night
much more common in smokers |
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T/F: chest pain lasting a few seconds is likely to be angina pectoris
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False
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slient ischemia
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ambulatory ECG monitoring has shown to be common
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drugs to treat stable and variant angina
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nitrates
calcium channel blockers beta-adrenergic blockers |
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nitrates - drug names
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NITRATES:
nitroglycerin isosorbide dinitrate isosorbide 5-mononitrate |
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molecular mechanisms of nitrates
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nitrates enter cells, release NO
NO --> GC --> cGMP in vascular muscle --> vasorelaxation in platelets, aggregation inhibited |
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integrated response to nitrates
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NITRATES:
decreased systemic venous contraction decreased systemic arterial contraction --> decreased myocardial O2 decreased large coronary artery contraction --> increase myocardial O2 supply demand |
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therapeutic use of nitrates
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sublingual or i.v. to terminate angina episodes
oral, patch, ointment prophylactically |
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adverse effects of nitrates
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NITRATES:
HA flushing hypotension |
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Major problem with nitrates
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tolerance
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How is tolerance for nitrates minimized
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intermittent therapy
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What class of drugs enhance and prolong nitrate actions? How?
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Sildenafil and other ED drugs
by blockign cGMP metabolism |
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beta-adrenergic blockers - drug names
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BETA BLOCKERS
atenolol metoprolol nadolol propanolol |
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molecular mechanisms of beta blockers
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competitively block actions of neuronally released and circulating catecholamines on beta adrenergic receptors
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integrated response to beta blockers
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BETA BLOCKERS
decrease HR & contractility decrease arterial BP --> decrease myocardial O2 demand increase coronary flow by increasing time in diastole --> in crease myocardial O2 supply |
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therapeutic use for beta blockers
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BETA BLOCKERS
orally for chronic prophylaxis of stable angina unpredictable effects in variant angina |
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adverse effects of beta blockers
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cardiac effects
bronchoconstriction lethargy fatigue mental dpression nightmares hypoglycemia |
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abrupt withdrawal of beta blockers can precipitate what?
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angina attacks
other ischemic symptoms |
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drug names of calcium channel blockers
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mifedipine/SR
nicardipine amlodipine nisoldipine dilitazem/SR verapamil/SR |
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molecular mechanisms of Ca2+ channel blockers
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non-competetively inhibit the movement of Ca2_ ions thru voltage sensitive L-type membrane Ca2+ channels (all)
slow channel recovery time |
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integrated response to Ca2+ channel blockers
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decreased HR & contractility
decreased systemic arterial contraction (all) decreased coronary artery contraction |
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therapeutic use of Ca2+ channel blockers
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Ca2+ channel blockers:
orally for chronic prophylaxis of stable or variant angina |
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adverse effects of Ca2+ channel blockers
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Ca2+ channel blockers:
HA dizziness flushing hypotension leg edema constipation N/V |
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What drug class should Ca2+ channel blockers not be combined with?
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beta blockers
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Ranolazine molecular mechanisms
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blocks "late" Na+ current
thus preventing intracellular Na+ & Ca2_ concentration caused by ischemia also partly inhibits FAOx --> increased utilization of glucose for energy by the heart |
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integrated response to Ranolazine
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ranolazine:
does not significantly affect BP or HR increases exercise tolerance and decreases anginal attacks |
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Ranolazine therapeutic use
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orally for chronic prophylaxis of stable angina alone or incombination iwth nitrates, beta-blockers or Ca2+ channel blockers
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adverse effects of Ranolazine
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Ranolazine:
Dz HA constipation nausea |
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Are efficacy and tolerability of Ranolzine affected by old age and comorbid conditions?
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no
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Ivabradine
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new drug therapy for chronic stable angina
decrease HR by blocking pacemaker current |
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nicorandil
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new drug therapy for chronic stable angina
coronary dilation by opening ATP sensitive K+ channels |
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trimetazidine
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new drug therapy for chronic stable angina
mitochondrial 3-ketoacyl CoA thiolase inhibitor shifts ischemic myocardium from FA to carb use |
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Perhexilene
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new drug therapy for chronic stable angina
mitochondrial carnitine-palmitoyl-transferase inhibitor shifts ischemic myocardium from FA to carb use |
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NSTEMI, aka:
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unstable angina
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symptoms of unstable angina
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unstable angina:
angina at rest > 20 min more intense pain than usual angina pain occuring with steadily increasing freq/severity |
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most common cause of unstable angina
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plaque rupture or erosion
with superimposed nonocclusive thrombus |
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ASA molecular mechanisms
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permanently acetylates COX 1
blocking synthesis of TxA2 by platelet reduced release of TxA2 --> decreased aggregation effect lasts 7-10 days |
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integrated response to ASA
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> 50% reduction at risk of death or MI
benefits obserable w/in first day of tx |
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therapeutic use of ASA
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oral dosing
low doses preferable |
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adverse effects of ASA
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risk of bleeding
allergic response in some patients |
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ADP inhibitors - drug names
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clopidogrel
ticlopidine |
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molecular mechanisms of ADP inhibitors
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inhibit binding of ADP to its receptor on platelets
decreaseing platelet aggregation and subsequent activation |
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integrated response to ADP inhibitors
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ADP inhibitors:
20-35% reduction in risk of death or MI early initiation of tx --> improved outcomes |
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ADP inhibitors - adverse effects
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neutropenia
TTP GI bleeding |
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drug names of GP IIb/IIa receptor inhibitors
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abciximab
eptifibatide tirofiban |
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molecular mechanisms of GP IIb/IIa receptor inhibitors
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prevent fibirinogen mediated cross-linkage of paltelts thru GP IIb/IIa receptors on platelets
thus decreasing aggregation |
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integrated response to GP IIb/IIa receptor inhibitors
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reduction in risk of death or MI
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therapeutic use of GP IIb/IIa receptor inhibitors
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given i.v.
v. short duration of action used w/ aspirin & heparin |
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adverse effects to GP IIb/IIa receptor inhibitors
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thrombocytopenia
bleeding |
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when are GP IIb/IIa receptor inhibitors more effective?
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when used prior to percutaneous coronary interventions
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3 anti-platelet drug types
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GP IIb/IIa receptor inhibitors
ASA ADP inhibitors |
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heparins
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unfractionated heparin
low MW heparins enoxaparin |
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molecular mechanisms of heparin
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heparin catalyzes inhibition of various coagulation proteases by antithrombin
antithrombin inhibits coagulation factors of the intrinsic and common pathways: thrombin Xa IXa |
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LMWH acts mainly on...
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factor Xa
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integrated response to heparin
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reduction in death or MI when combined with ASA in pts with unstable angina
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therapeutic use of heparin
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given i.v.
LMWH is given s.c. |
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benefits of LMWH over heparin
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more reliable absorption and plasma half-life than heparin
less risk of thrombocytopenia |
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adverse effects of heparin
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bleeding
thrombocytopenia |
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mechanism behind heparin resistance
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differences in concentrations of heparin-binding proteins in plasma
or b/c of accelerated clearance of the drug |
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fondaparinux molecular mechanisms
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FONDAPARINUX:
synthetic, sulfated pentasaccharide that binds to antithrombin and causes selective inhibition of factor Xa |
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integrated response to fondaparinux
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efficacy in reducing death or MI in ACS similar to heparins
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therapeutic use of fondaparinux
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specificity and selectivity of fonaparinux, combined with its long half-life and 100% bioavailability (s.c.)
allows once-daily anticoagulation w/o need for monitoring activated clotting time |
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adverse effects of fondaparinux
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FONDAPARINUX:
bleeding (but less than w/ heparin) |
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direct thrombin inhibitors - drug names
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lepirudin
bivalirudin argatroban |
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molecular mechanisms of direct thrombin inhibitors
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bind to catalytic site of thrombin and prevent substrate access
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integrated response to direct thombin inhibitors
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produce stable level of anticoagulation, but not yet proven to be beneficial in unstable angina
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administration of direct thrombin inhibitors
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i.v.
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adverse effects of direct thrombin inhibitors
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bleeding
unlikely to cuase thrombocytopenia |
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drug classes in acute drug tx of MI
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fibrinolytics
analgesics renin-angiotensin inhibitors ASA nitates beta blockers antiplatelet drugs anticoagulants |
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fibrinolytics - drug names
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FIBRINOLYTICS:
alteplase reteplase tenecteplase |
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fibrinolytics - molecular mechanisms
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binds to fibrin & activates bound plaminogen much more rapidly than it activates circulating plasminogen
this prevents systemic formation of plasmin and induction of a systemic lytics state |
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integrated response to fibrinolytics
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recanalizes thrombotic occlusion and restores coronary flow
reudces infarct size improves myocardial function & survival over short & long term |
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therapeutic use of fibrinolytics
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i.v.
benefit greatest w/ early administration (< 2 hours after symptoms begin) |
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adverse effects to fibrinolytics
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bleeding
stroke (esp when coadministered w/ heparin) |
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analgesics - drug names
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morphine
meperidine pentazocine |
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molecular mechanisms of analgesics
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stimulate mu-type opioid receptors in the brain & SC
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integrated response to analgesics
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reduction of pain, anxiety, restlessness and autonomic activity
decreased venous & arterial contraction all of these effects decrease cardiac O2 demand |
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therapeutic use for analgeiscs
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admin i.v. until pain relieved or eveident toxicity occurs
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adverse effects of analgesics
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hypotension
depression of respiration vomiting |
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2 types of renin angiotensin inhibitors
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ACE inhibitors
angiotensin receptor blockers |
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ACE inhibitors - names
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enalapril
lisinopril |
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angiotensin receptor blockers - names
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valsartan
candesartan losartan |
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renin angiotensin inhibitors - molecular mechanisms
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block angiotensin formation by inhibiting ACE
block access of angiotensin to the AT-1 type tissue receptor (ARB) |
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integrated resposne to renin angiotensin inhibitors
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decreased venous and arterial contraction
decreased sympathetic activity increased renal Na+/H2O excretion reduce ventricular remodeling - 2* prevention |
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theraepeutic use of renin angiotensin inhibitors
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administered after initiation of ASA, beta blckers and reperfusion therapy (w/in 24 hours of event)
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adverse effects to renin angiotensin inhibitors
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hypotension
cough (ACE-I) angioedema (ACE-I, rare) |
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6 drugs used in 2* prevention of MI
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beta blockers
ASA antiplatelet drugs renin angiotensin inhibitors lipid-lowering drugs oral anticoagulants |
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oral anticoagulants
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warfarin
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oral anticoagulants - molecular mehcanisms
|
block synthesis of reduced form of Vitamin K (KH2) that is necessary for synthesis of factors II, VII, IX and X
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integrated response
|
decreased growth of existing thrombi
prevent development of new thrombi |
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therapeutic use of oral anticoagulatnats
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onset of optimal anticoagulant effect requires several days
intensity of response monitored using prothrombin time (PT) |
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adverse effects
|
bleeding (5-7%)
skin necrosis many drug interactions |
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intensity of warfarin effect influenced by...
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dietary vitamin K (inverse relationship)
liver disease increases anticoagulant action of warfarin |
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1* hemodynamic event in heart failure
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impaired cardiac contractility
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imparied cardiac contractility, aka:
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myocardial failure
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heart failure, aka:
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systolic dysfunction
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4 causes of decreased contractility
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myocardial ischemia
cardiomyopathies valvular disease advanced age |
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5 symptoms of heart failure
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fatigue
exercise intolerance exertional dyspnea pulmonary systemic edema |
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3 causes of dyspnea
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increased ventilatory rate
diminished lung compliance underperfusion of respiratory muscle |
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sudden worsening of the symptoms of heart failure
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acute decompensation
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8 RFs for heart failure
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age
sex (men > women) ethnicity (Afr-Am > White) FMHx chronic alcohol abuse CAD HTN smoking obesity |
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systolic dysfunction is usually accompanied by
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ventricular dilation
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systolic dysfunction causes a decrease in ____ and an increase in _____, which results in _____
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Systolid cysfunction casues a decrease in stroke volume and an increase in ventricular end-diastolic volume, which results in a smaller ejection fraction (EF).
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Ejection Fraction =
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EF = stroke volume / end diastolic volume
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immediate physiological response to myocardial failure
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ventricular dilation (Frank -Starling mechanism)
neurohormonal activation |
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long-term physiological response to myocardial failure
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myocardial remodeling
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major phamacological strategy in treating heart failure is
|
to moderate neurohumoral activation
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neurohormonal activation (RAS, SNS) causes:
|
increased HR
decreased Na+ excretion increased venous tone increased arterial tone hypertrophy arrhythmias |
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4 hormone levels raised in response to neurohormonal activation following decreased myocardial contractility
|
aldosterone
ANP, BNP vasopressin endothlin |
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increased venous tone causes...
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increased pre-load
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increased arterial tone causes ...
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increased afterload
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increased HR causes...
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increased myocardial oxygen demand
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ventricular dilation caused by decreased myocardial contractility causes...
|
increased wall stress
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Diastolic dysfunction, aka:
|
heart failure with preserved EF
|
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Diastolic dysfunction
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impaired ventricular filling caused by
hypertrophied, stiffened ventricles or by slowed ventricular relaxation |
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ventricular hypertrophy is most often a consequence of
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chronic hypertension
|
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which is more challenging to treat, diastolic or systolic dysfunction?
|
diastolic
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which therapy prolongs survival more than any other therapy in treating heart failure?
|
cardiac transplantation
|
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2 phases of heart failure therapy
|
(1) chronic stable heart failure:
goals - to minimize symptoms, improve functional capacity, slow progression, decrease hospitalizations and prolong survival (2) acutely decompensated heart failure: goals - to stabilize pt, restore organ perfusion, reduce cardiac filling pressures and return patient to chronic therapy |
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drug classes used to treat chronic heart failure (systolic dysfunction)
|
diuretics
nitrates direct arterial vasodilators (hydralazine) digoxin RAS inhibitors beta blockers aldosterone antagonists natriuretic peptides |
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drugs used to treat acutely decompensated heart failure
|
diuretics
nitrates Ca2+ Channel blockers beta blockers phosphodiesterase inhibitors nesiritide (natriuretic peptide) |
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loop diuretics - molecular mechanisms
|
inhibit reversibly the Na+/K+/2Cl- cotransporter on luminal membrane of epithelial cells of thick ascending limb of loop of Henle
|
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integrated response to loop diuretics
|
increase renal excretion of Na+, H2), K+, Ca2+, Mg 2+, Cl-, H+
relax systemic veins (increase venous capacitance) both actions decrease preload (decrease cardiac energy needs) |
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therapeutic use of loop diuretics
|
no proven effect on survival
used for chronic heart failure (oral) used for acute decomp (i.v.) |
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adverse effects of loop diuretics
|
volume depletion
K+ depletion metabolic alkalosis |
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overcome resistance to diuretic effect of loop diuretics in HF patients by...
|
higher dose
or adding thiazide |
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loop diuretics are often used in conjucntion with...
|
patossium-sparing diuretic (to prevent K+ loss)
|
|
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actions of loop diureitcs are potentiated by what drug class?
|
renin-angiotensin inhibitors
|
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thiazide diuretics - molecular mechanisms
|
reversibly inhibits the Na+/Cl- cotransporter on luminal membrane of the distal convoluted tubule
|
|
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integrated response of thiazide diuretics
|
increased renal excretion of Na+, H2O, K+, Mg2+, Cl-, H+
decreased Ca2+ excretion lower efficacy than loop diuretics |
|
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therapeutic use of thiazide diuretics
|
no proven effect on survival
used only for chronic stable heart failure (oral) |
|
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adverse effects
|
volume depletion
K+ depletion increase uric acid levels increase glucose levels |
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thiazide diuretics are often used in conjuction with...
|
K+ - sparing diuretic
|
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potassium sparing diuretics - molecular mechanisms
|
blcok luminal epithelial cell Na+ chennels in late distal tubule and collecting ducts
|
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integrated response to K+ - sparing diuretics
|
increased renal exretion of Na+, H2), Cl-
decreased exretion of Ca2+, K+, Mg2+, H+ very low efficacy alone |
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|
terapeutic use
|
no proven effect on survival
used with loop and/or thiazide diuretics to prevent K+ loss |
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adverse effects of K+ - sparing diuretics
|
hyperkalemia
GI |
|
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aldosterone antagonists - molecular mechanisms
|
block epression of luminal epithelial cell Na+ channels in the late distal tubuel and collecting ducts
competitive antagonist of the aldosterone receptor in kidney and other tissues (heart) |
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Aldosterone antagonists - integrated response
|
increased renal exretion of Na+, H2O, Cl-
decreased excretion of Ca2+, K_, Mg2+, H+ low efficacy alone inhibit ventricular remodeling, thus slowing prevention of heart failure |
|
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therapeutic use of aldosterone antagonists
|
proven to prolong survival when added to std treatments for severe, chronic HF
effect appears to be independent of diuretic action of drug |
|
|
adverse effects of aldosterone antagonists
|
hyperkalemia
gynecomastia and impotence menstrual irregularities |
|
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renin angiotensin inhibitors - molecular mechanisms
|
block angiotensin formation by inhibiting ACE1
block access of angiotensin to the AT-1 type tissue receptor (ARB) |
|
|
integrated response to renin angiotensin inhibitors
|
decreased venous and arterial contraction
decreased SNS increased renal Na+/H2) exretion reduce ventricular remodeling |
|
|
therapeutic use of renin angiotensin inhibitors
|
proven to improve survival
mainstay of current tx of systolic dysfunction |
|
|
adverse effects of renin angiotensin inhibitors
|
hypotension
cough (ACE1) angioedema (ACE1, rare) |
|
|
Is it beneficial to compine ACE1 and ARB to treat HF?
|
no
|
|
|
beta blockers - molecular mechanisms
|
competitively blcok actions of neuronally released and circulaing catecholamines on beta blockers
|
|
|
integrated response to beta blockers
|
oral use starting with very low doses
sympatoms may worsen initially proven to prolong survival only for use in chronic heart failure |
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adverse effects of beta blockers
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cardiac effects
bronchoconstriction lethargy fatigue mental depression nightmares hypoglycemia |
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beta blockers should be used with caution in patients with...
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cardiac conduction disorders
obstructive lung disease |
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abrupt withdrawal of beta blockers can precipitate
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angina attacks
other ischemic symptoms |
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integrated response direct arterial vasodilators
|
decreased arteriolar contracton -->
decreased afterload --> decreased cardiac oxygen consumption |
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therapeutic use of direct arterial vasodilators (hydrazaline)
|
proven to prolong survial when used with isosorbide dinitrate for chronic HF
most visodilators don't improve survival |
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adverse effets of direct arterial vasodilators
|
HA
dz tachycardia edema |
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nitrates - molecular mechanisms
|
nitrates enter cells and release NO
ativates soluble GC to produce cGMP causses vasorelaxation |
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integrated response to nitrates
|
decrease systemic venous contracton (decrease preload)
decrease systemic arterial contraction (decrease afterload) both effects decrease filling pressures, which decreases pulmonary and systemic edema also decreases cardiac work |
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therapeutic use of nitrates
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i.v. or sublingual for acute decomp
oral for chronic stable angina no proven effect on survival alone |
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adverse effects of nitrates
|
HA
flushing hypotension |
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Digoxin - molec. mechs.
|
binds to alpha subunit of Na/K-ATPase
inhibits Na+ transport out of cell resulting increased concentration reduces activity of Na+-Ca2+ exchanger that extrudes intracellular Ca2+ during myocyte repolarization this decrease exchanger activity --> increase in intracell. Ca2_ and therefore an increase in myocyte contractility also decreases SNS & increases PNS |
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Digoxin integrated response
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increased CO
decreased filling pressures improved exercise tolerance decreased edema |
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therapeutic use of digoxin
|
v. low TI
careful monitoring req'd use now restricted to severe HF or pt w/ A-Fib no effect on survival |
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adverse effects of digoxin
|
anorexia
N/V blurred vision arrhythmias |
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beta agonists - molec. mechs
|
activate beta-receptors in heart to increase cardiac contratility
DA also activates DA receptors in kidney to increase renal blood flow at higher doeses, stimulates alpha receptors |
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integrated response to beta agonists
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increase CO
decrease filling pressures |
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therapeutic use of beta agonists
|
use is restricted to actute decompensated HF
decreases symptoms, maintains circulatory stability no effect on survival |
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adverse effects of beta agonists
|
tachycardia
arrhythmias |
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phosphdiesterase inhibitors - molec. mechs.
|
inhibit phsophdiesterase type IIIa (assoc. w/ SR for cardiac myocytes and vasc. smooth. mm.)
--> increased cAMP in SR --> incrased intracell. Ca2+ |
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integrated response to phosphdiesterase inhibitors
|
increase cardiac contractility and rate of relaxation
decreased venous, arterial contraction increase CO; decrease filling pressures decreased pulm. arteral contraction |
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therapeutic use of phosphodiesterase inhibitors
|
use restricted to actue decomp
decreases symptoms maintains circulatory stability no effect on survival |
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adverse effects of phosphodiesterase inhibitors
|
hypotension
arrthythmias |
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nesiritide molec. mechs
|
recombinant form of human BNP
|
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integrated response to nesiritide
|
decrease venous, arterial contracton
increase CO; decrease filling pressures |
|
|
therapeutic use of nesiritide
|
restricted to acute decomp
decrease symptoms, maintians circulatory stability no effect on survival |
|
|
adverse effects of nesiritide
|
hypotension
increased plasma creatinine may increase risk of mortality and renal insufficiency |
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drugs used to treat chronic diastolic dysfunction
|
diuretics
renin agniotensin inhibitors beta blockers nitrates |
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treatment strategy for diastolic dysfunction
|
decrease preload (diuretics or nitrates) --> decrease filling pressure --> decrease cardiac wall stress 00> decreas cardiac work, edema
|
|
|
problem with diastolic dysfunction treatment
|
in diastolic dysfunction, CO depends on high filling pressure
excessive reduction in filling pressure --> decreased CO |
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what diastolic dysfunction treatment is proven to prolong survival?
|
none
|
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6 new targets for drug therapy of heart failure
|
growth & remodeling
suppression of apoptosis Ca2+ uptake into SR Ca2+ entry energy metabolism contractile efficiency |
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current tx of arrhythmias is centered on...
|
surgical and device-based therapies
|
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4 cardiac electrical properties
|
excitability
automaticity conductivity refractoriness |
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cardiac excitability
|
inversely proportional to the strength of an electrical impulse required to cause cardiac contraction
|
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cardiac automaticity
|
ability of cardiac cell to spontaneously depolarize (i.e.: exhibit pacemaker properties)
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cardiac conductivity
|
proportional to the velocity at which an electrical impulse travels in the heart
|
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cardiac refractoriness
|
proportional to the time require for a cardiac fiber to regain the ability to conduct a second electrical impulse after a first
|
|
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symptoms of arrhythmias
|
palpitations
light-headedness dyspnea sweating angina vague chest discomfort |
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severe ventricular arrhythmias compromise ____ and thus are more likely to be ____
|
compromise the pumping efficiency of the heart
more likely to be symptomatic |
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A-fib promotes ______ in ______, increasing the risk of _____
|
A-fib prmotes thrombus formtion in the atrial appendages, increasing the risk of embolic stroke
|
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|
ventricular fibrillation is...
|
an acute, life-threatening emergency
|
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|
arrhythmias are classified according to which two things?
|
site or origin
heart rate |
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tachycardic arrhythmias
|
flutter
fibrillation |
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bracycaric arrhythmias
|
block
|
|
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3 abnormalities of impulse conduction
|
re-entry
conduction block bypass tracts |
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main adverse effect of all anti-arrhythmic drugs
|
induction of arrhythmias
|
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Class Ia drugs for tachyarrhythmias
|
Block Na+ and K+ channels
|
|
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Class Ia drugs for tachyarrhythmias - integrated response
|
decreased conduction
increased refractoriness decreased automaticity increased QRS increased QT |
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therapeutic use of class IA drugs for tachyarrhythmias
|
wide-spectrum
|
|
|
Class IA drugs are _____ antagonists
|
muscarinic
|
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Class IB drugs for tachyarrhythmias - molec mech
|
block Na+ channels, usu. when HR high or in ischemic or damaged tissue
|
|
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integrated response to Class IB drugs for tachyarrhythmias
|
decreased conduction
decresed automaticity decreased QT |
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therapeutic use for class IB drugs
|
effective against ventricular tachyarrhythmias caused by reentry or ectopic automaticity
useful against digoxin-induced tachyarrhythmias and i pt w/ long QT syndrome |
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class IC drugs for tachyarrhythmias - molec mechs
|
block Na_ channels (slow onset and offset)
|
|
|
integrated response to Class IC drugs
|
decreased conduction
decreased automaticity increased QRS |
|
|
therapeutic use of class IC drugs
|
serious ventricular arrhythmias caused by reentry
atrial flutter A-fib AV nodal reentry tachycardia |
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Class II for tachyarrhythmias - molec mechs
|
block beta receptors
|
|
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Class III drugs for arrhythmia - integrated response
|
increase refractoriness
decrease automaticity increase QT decrease PR |
|
|
therapeutic use of Class III Drugs
|
effective against supraventricular and ventricular arrhythmias caused by reentry or ectopic automaticity
used to terminate A-fib good for treating arrhythmias in pt w/ heart failure |
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class IV drugs - molec mechs
|
block L-type Ca2+ channels
|
|
|
class IV drugs - integrated response
|
decreased AV conduction
decreased automaticity increased PR |
|
|
therapeutic use of class IV drugs
|
AV nodal reentry tachycardia
ventricular rate control in A-fib |
|
|
digoxin use for arrhythmias
|
decrease AV conduction
increase PR |
|
|
therapeutic use of digoxin for arrhythmias
|
ventricular rate control in patients with heart failure and A-fib
|
|
|
Adenosine molec mechs for tx of arrhythmias
|
increase K+ channel opening
decrease intracellular cAMP levels by inhibition of AC |
|
|
Adenosine integrated response
|
decrease AV conduction
increase PR decrease sinus node rate |
|
|
2 "HTN" diseases not associated with elevated systemic arterial BP
|
pulmonary HTN
portal HTN |
|
|
RFs for essential HTN
|
obesity
FMHx high salt intake race sedentary lifestyle excessive EtOH intake |
|
|
mean arterial pressure (MAP) =
|
MAP = CO x TPR
|
|
|
TPR is determined primarily by the ...
|
diameter of arterial blood vessels
|
|
|
drug classes used to treat HTN
|
diuretics
beta blockers calcium channel blocker ACE inhibitors/AngII receptor blockers |
|
|
first choice of initial drug in most cases of essential HTN
|
thiazide diuretics
|
|
|
thiazide diuretics - molec mechs
|
reversibly inhibits the Na+/Cli cotransporter on the luminal membrane of the distal convoluted tubule
|
|
|
integrated response of thiazide diuretics for HTN
|
increased renal excretion of Na+, H2O, K+, Mg2+, Cl-, H+
decreases Ca2+ activates RAS |
|
|
therapeutic use of thiazide diuretics for HTN
|
wide use as initial monotherapy
black and elderly pts often respond beter dietary salt restriction potentiates response |
|
|
adverse effects of thiazide diuretics
|
hypokalemia
Mg2+ loss increased uric acid & glucose levels |
|
|
integrated response to renin angiotensin inhibitors
|
decrease actions of angiotensin II
decrease venous and arterial contraction decrease SNS increase renal Na+/H2O decrease TPR |
|
|
therapeutic use of renin angiotensin inhibitors
|
somewhat less effective in Blacks and elderly
stronly potentiated by addition of diuretic provide excellent protection against nephropathy (esp. DM), CAD, HF |
|
|
What is the benefit to combining ACEi and ARB to treat HTN?
|
there isn't one
|
|
|
2nd generation renin angiotensin inhibitors (Aliskiren) - molec mechs
|
block angiotensin I and II formation by inhibiting the enzymatic activity of renin
|
|
|
integrated response to Aliskiren (renin/ang inhibitor)
|
same as first gen. renin angiotensin inhibitors
|
|
|
therapeutic use of Aliskiren
|
somewhat less effective in Blacks
strongly potentiated by add'n of diuretic produce additive effects when combined with ACEi or ARB efficacy equivalent to ACEi and ARB |
|
|
adverse effects to Aliskiren
|
diarrhea
allergic reaction counterindicated by pregnancy |
|
|
Alpha blockers - molec mechs
|
block alpha1-adrenergic receptors
|
|
|
integrated response to alpha blockers
|
decrease arterial and venous contractile response to NE & Epi
decrease TPR |
|
|
alpha blockers - therapeutic use
|
tolerance is a problem
monotherapy for BPH part of polytherapy for resistant HTN |
|
|
adverse effects of alpha blockers
|
hypotension
dz HA cause strong fluid retention - should be used with diuretic |
|
|
centrally acting sympatholytics - molec mechs
|
acxtivate alpha2-adrenergic receptors in the brainstem
|
|
|
integrated response to centrally acting sympatholytics
|
decrease SNS
decrease CO and TPR |
|
|
therapeutic use of centrally acting sympatholytics
|
limited to resistant HTN
|
|
|
adverse effects of centrally acting sympatholytics
|
sedation
drymouth bradycardia |
|
|
integrated response to direct arterial vasodilators (HTN)
|
decrease arteriolar contraction --> decreased TPR
strongly activate SNS and RAS cause renal Na+ retention |
