Anti-Ischemic Medications Flashcards
1
Q
Myocardial Ischemia
- Definition
- Two types
A
- Definition
- When metabolic requirements of the myocyte exceed available supply of oxygen
- Two types
- Supply side ischemia
- Demand side ischemia
2
Q
Supply Side Ischemia
- Definition
- Affected by two factors
A
- Definition
- When myocardial oxygen supply doesn’t meet myocardial oxygen demand
- Affected by two factors
- Oxygen carrying capacity of blood
- Coronary blood flow volume
3
Q
Supply Side Ischemia: Oxygen Carrying Capacity
- Determined by two factors
- Oxygen supply
- Hemoblogin content of the circulatory system
- Normal circumstances
A
- Determined by two factors
- Oxygen supply
- Environmental factors: changes in altitude or inhaled FiO2
- Intrinsic factors: underlying lung disease due to emphysema or pneumonia
- Hemoglobin content of the circulatory system
- Influenced by conditions like anemia or alterations in oxygen binding capacity of hemoglobin
- Seen w/ hemoglobinopathies like sickle cell disease or methemoglobinemia
- Oxygen supply
- Normal circumstances
- Oxygen carrying capacity remains constant
- Myocardial oxygen extraction is nearly max at rest
- Acute changes in myocardial oxygen supply occur primarily through changes in coronary blood flow volume
4
Q
Supply Side Ischemia: Coronary Blood Flow Volume
- Modulated through changes in…
- Max during…
- Increases as…
A
- Modulated through changes in…
- Coronary artery perfusion pressure (directly)
- Extrinsic compressive forces on the coronary artery (indirectly)
- Intrinsic coronary artery resistance (indirectly)
- Max during…
- Ventricular diastole when extrinsic compressive forces exerted on the coronary vessels by LV systolic contraction are minimized
- Increases as…
- Intrinsic vascular resistance decreases
5
Q
Supply Side Ischemia: Coronary Flow Reserve
- Regulates…
- Modulated by…
- 3 levels of vessel resistance in the coronary vasculature
- Normal circumstances
A
- Regulates…
- Intrinsic coronary vascular resistance
- Modulated by…
- Changes in arteriolar smooth muscle tone via regulation of Ca2_ channel activity
- 3 levels of vessel resistance in the coronary vasculature
- R1: epicardial conductance
- R2: precapillary arterioles
- R3: microcirculation / capillary beds
- Normal circumstances
- Autoregulation of intrinsic vascular resistance occurs primarily in R2 & R3 vessels
- Vasodilitation occurs in response to metabolic stress / myocardial ischemia due to mycoardial supply-demand mismatch
6
Q
Supply Side Ischemia: Nitric Oxide
- Regulates…
- Life cycle
- Treatment options
A
- Regulates…
- Coronary blood flow in R2 vessels
- NO: arteriolar & venodilator
- Production of NO (endothelium-derived relaxing factor, EDRF) secondarily activates myogenic & endothelium dependent vasodilatation
- Life cycle
- Activation of endothelial NO synthetase (eNOS)
- NO produced by intact endothelium from L-arginine
- Diffuses across endothelium
- Coverts GTP to cGMP via guanylate cyclase
- Decreases cytosolic Ca2_ concentration
- Triggers smooth muscle relaxation, vasodilation, & increased myocardial blood suply
- Treatment options
- NO may treat supply side ischemia
7
Q
Demand Side Ischemia
- Definition
- Altered by changes in…
A
- Definition
- When myocardial oxygen demand exceeds myocardial oxygen supply
- Altered by changes in…
- Heart rate
- Myocardial contractility
- Myocardial wall stress
8
Q
Demand Side Ischemia: Heart Rate
- Double product
- Relationship
- Treatment options
A
- Double product
- Myocardial oxygen demand / consumption = HR & systemic BP
- Relationship
- Linear relationship b/n HR & myocardial oxygen uptake
- Physicla stressors –> increase HR –> increase myocardial oxygen consumption
- Treatment options
- Attenuation of this chronotropic response w/ anti-adrenergic agents (ex. beta-blockers) can help treat myocardial ischemia
9
Q
Demand Side Ischemia: Myocardial Contractility
- Peripheral oxygen requirements
- Cardiac output
- Stroke volume
- Myofibril contractility is regulated by changes in..
- Myocyte excitation-contraction coupling
- Beta adrenergic system
- Ca2+ channel & beta-adrenergic receptor antagonists
A
- Peripheral oxygen requirements
- Increase w/ exercise
- Trigger events that lead to increased cardiac output to meet demands of peripheral metabolism
- Cardiac output
- CO = HR & SV
- Stroke volume
- Modulated by changes in myofibril contractility
- Myofibril contractility is regulated by changes in…
- Loading conditions of the heart
- Sympathetic tone
- Myocyte excitation-contraction coupling
- Transmembrane Ca2+ influx into the myocyte via L-type Ca2+ channels
- Ca2+-induced Ca2+ channel release: activated ryanodine receptors trigger a larger efflux of Ca2+ from the SR
- Surge in intracellular Ca2+ binds troponin-C
- Troponin-C inhibits troponin-I to expose active sites on thin actin
- Intercalation of thick myosin heads w/ subsequen myofibril contraction
- Increased cytosolic Ca2+ –> increased myocardial contractility –> increased metabolic activity & oxygen demand
- Beta adrenergic system
- Beta-1 adrenergic receptor stimulation
- Activation of Gs protein
- Activation of adenylate cyclase
- cAMP production
- Activation of L-type Ca2+ channels
- Ca2+-induced Ca2+ channel release from the SR
- Increased myocardial contractility & oxygen consumption
- Ca2+ channel & beta-adrenergic receptor antagonists
- Inhibit the myocyte excitation-contraction coupling response & the beta adrenergic system
- Treat MI
10
Q
Demand Side Ischemia: Wall Stress
- LaPlace’s Law
- Relationships
- Pharmacological manipulation
A
- LaPlace’s Law
- Myocardial wall stress = (P * R) / 2h
- Myocardial wall stress varies directly w/ LV pressure (P) & radius (R)
- Myocardial wall stress varies indirectly w/ myocardial wall thickness (h)
- Relationships
- Decrease LV pressure & radius + increase LV wall thickness –> reduce wall stress & myocardial oxygen consumptoin
- Alter LV pressure, radius, & wall thickeness by changing preload & afterload
- Pharmacological manipulation
- Manipulating LV pressure, radius, & wall thickness can manage demand side ischemia & chronic coronray artery ischemia
11
Q
3 Major Categories of Anti-Ischemic Medications
A
- Nitrates
- Beta adrenergic receptor antagonists
- Calcium channel antagonists
12
Q
Nitrates: Mechanism of Action
- Nitrate conversion
- Net effects of nitrates in managing coronray artery disease
- Supply
- Coronary blood flow: vascular resistance
- Coronary blood flow: extrinsic vompression
- Diastolic perfusion time
- Collateral circulation
- Demand
- Heart rate
- Contractility
- Wall tension: preload
- Wall tension: afterload
- Supply
- Dosages
- Lower dosages
- Higher dosages
- Other
A
- Nitrate conversion
- Mitochondrial aldehyde dehydrogenase converts exogenous nitrates to NO using sulfhydryl group cofactors
- Net effects of nitrates in managing coronray artery disease
- Supply
- Coronary blood flow: vascular resistance: ↓↓↓
- Coronary blood flow: extrinsic vompression: ↓↓
- Diastolic perfusion time: 0 or ↓
- Collateral circulation: ↑
- Demand
- Heart rate: 0 or ↑
- Contractility: 0 or ↑
- Wall tension: preload: ↓↓↓
- Wall tension: afterload: ↓
- Supply
- Dosages
- Lower dosages
- Venodilation –> decreased preload, myocardial wall tension, & myocardial oxygen demand
- Higher dosages
- Arterial vasodilation –> increased myocardial blood supply
- Other
- Recruitment of collateral vessels –> increased myocardial blood supply from non-ischemic to ischemic territories
- Lower dosages
13
Q
Nitrates: Short vs. Long Acting
- Short acting nitrates
- Administration
- Absorption
- Onset & duration
- Prophylactic use
- Long acting nitrates
- Administration
- Isosorbide dinitrate (oral)
- Isosorbide mononitrate (oral)
A
- Short acting nitrates
- Administration
- Mucosal absorption: sublingual tablets or oral spray
- Transdermal absorption: nitroglycerin ointment
- Absorption
- Bypasses enteral absorption
- Avoids first pass metabolism in the liver
- Provides rapid, transient delivery of meds directly into the bloodstream within minutes
- Onset & duration
- Brief onset allows treatment of acute angina
- Brief duration deactivates the drug by hepatic metabolism within 30-60 minutes
- Prophylactic use
- Used prior to activities that can trigger angina
- Can improve exercise tolerance for 30-40 minutes
- Administration
- Long acting nitrates
- Administration
- Oral forms
- Sustained release transdermal patch
- Isosorbide dinitrate (oral)
- Enteral absorption –> rapid first pass hepatic metabolism
- Variable drug bioavailability
- Renally excreted
- Dosed 2x/day
- Isosorbide mononitrate (oral)
- Doesn’t undergo significant first-pass hepatic metabolism
- Greater bioavailability
- Dosed 1x/day
- Administration
14
Q
Nitrates: Side Effects
- Nitrate tolerance (tachyphylaxis)
- Definition
- Prevented by…
- Other side effects
A
- Nitrate tolerance (tachyphylaxis)
- Definition
- In patients taking chronic long acting nitrates, drug effect becomes less potent over time
- Prevented by…
- Adjusting the nitrate dosing interval to provide a 10-12 hour nitrate free interval (at night) to allow for resensitization
- Removing time released transdermal nitroglycerin patches at night & reapplying them in the morning
- Definition
- Other side effects
- Headache & flushing (common)
- Related to vasodilation of meningeal & cutaneous blood vessels
- Hypotension
- From venous & arterial dilation in the presence of intravascular volume depletion
- Hypoxemia (uncommon)
- Inhibition of vasoconstriction in regions of pulmonary hypoventilation –> ventilation/perfusion mismatch
- Tissue hypoxia (rare)
- In patients w/ methemoglobinemia
- Hypotension w/ phosphodiesterase inhibitors
- Phosphodiesterase inhibitors (ex. sildenafil) are contraindicated
- Headache & flushing (common)
15
Q
Beta-Adrenoreceptor Antagonists (Beta-Blockers): Types of Adrenoreceptors
- Beta-adrenoreceptor antagonists
- Beta-1 receptors
- Location
- Effects
- Treatment
- Beta-2 receptors
- Location
- Effects
- Side effects
- Alpha receptors
- Location
- Effects
A
- Beta-adrenoreceptor antagonists
- Exert their effect on the CV system through competitive inhibition of effects of endogenous catecholamines
- Beta-1 receptors
- Location
- Found in myocardium & specialixed conduction tissue
- Effects
- Increase myocyte contractility
- Accelerate SA node depolarization
- Accelerate His-Purkinje system conduction
- Treatment
- Treat ischemic heart disease by decreasing chronotropic & myocardial contractile responses during physcial stress (ex. exercise)
- Location
- Beta-2 receptors
- Location
- Found in peripheral & coronary circulation & in pulmonary bronchioles
- Effects
- Promote dilation of peripheral vasculature
- Promote relaxation of pulmonary bronciholes
- Side effects
- Claudication in patients w/ peripheral vascular disease
- Coronary vasospasm in patients w/ vasospastic (Prinzmetal’s) angina
- Bronchospasm in patients w/ reactive airway disease (ex. asthma)
- Location
- Alpha receptors
- Location
- Found in peripheral circulation
- Effects
- Trigger peripheral vasoconstriction
- Promote vasodilation –> decrease afterload
- Location