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74 Cards in this Set
- Front
- Back
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What are Calcium Channels?
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They are cell membrane proteins that, when open, allow calcium to pass through the cell membrane along a concentration gradient.
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What are the two varieties of calcium channels?
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Ligand Activated
Voltage Activated |
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How is a ligand calcium channel activated?
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It is activated when a ligand binds to the channel.
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How is a voltage activated calcium channel activated?
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It is activated in response to electrical depolarization.
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What are the five types of voltage activated calcium channels? Which one is targeted by the CCB on the market?
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L, T, N, P/Q, and R
The L-type channel is the one targeted by CCBs on the market. |
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Where do the L-type voltage-sensitive calcium channels mediate the entry of extracellular calcium?
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Smooth Muscles
Cardiac Muscles Sinoatrial (SA) and Atrioventricular (AV) Nodal Cells |
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What does an increase in calcium trigger?
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It triggers contraction in smooth muscle and cardiac myoctes.
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What does depolarization in SA and AV nodes depend largely on?
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It depends on the influx of calcium through L-type calcium channels.
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What does the inhibition of calcium channel function by CCB lead to?
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It leads to smooth muscle relaxation and negative inotropic and chronotropic effects in the heart.
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What do all CCB relax?
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Aterial Smooth Muscle
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Do CCB have any effect on Venous beds or cardiac preload?
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CCB have lesser effects on venous beds and no significant effect on cardiac preload.
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Name the six steps in the Method of Action in Vascular Smooth Muscle.
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1. Channel opens in response to depolarization of the membrane.
2. Extracellular calcium moves into the cell. 3. Intracellular calcium is released. 4. Enhance binding of calcium to calmodulin. 5. Myosin light-chain kinase activated. 6. Phosphorylation of the myosin light chain leads to the contraction of smooth muscle. |
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Name the four steps in the Method of Action in Cardiac Myocytes.
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1. Calcium binds to troponin.
2. Relieves the inhibitory effect on the contractile apparatus. 3. Permits actin and myosin interaction. 4. Leads to contraction. |
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What inotropic effects does a calcium channel blockade have?
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Negative
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What determines whether a CCB will have negative chronotropic effects?
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Depends on whether or not the agent delays the recovery of the L-type channel.
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CCB - Absorption
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Nearly complete but most have significant first-pass effect
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CCB - Distribution
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Generally have high protein binding (70-98%)
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CCB - Metabolism
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Majority by CYP3A4
Drug interaction and dose adjustment |
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CCB - Elimination
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Elimination half-life varies widely from 1.3-64 hours
Have various formulations available |
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What are the two types of calcium channel blockers?
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Non-Dihydropyridines (non-DHPs)
Dihydropyridines (DHPs) |
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Name two Non-Dihydropyridine medications.
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Benzothiazepines - Diltiazem
Phenylalkylamines - Verapamil |
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Name eight Dihydropyridine medications.
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Amlodipine, Clevidipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nisoldipine, Nimodipine
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Where does the CCB bind on the L-type calcium channel?
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alpha-1 subunit
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How do Non-Dihydropyridines affect the heart?
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1. Reduction of heart rate by reducing firing of the SA node (negative chronotropic effect).
2. Slows conduction through AV nodes (negative dromotropic effect). 3. reduces cardiac oxygen requirements by reducing the force of cardiac contraction (negative inotropic effect). |
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How do Non-Dihydropyridines affect Vascular Smooth Muscle (arteries)?
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1. Increase coronary blood flow
2. Reduction in afterload due to arterial relaxation. 3. Non-DHPs have no effect on venous tone or preload |
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How do Non-Dihydropyridines affect Blood Pressure?
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Reduction of blood pressure due to lower heart rate, lessened cardiac contractility, and decreased afterload
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How do Dihydropyridines affect Vascular Smooth Muscle (arteries)?
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1. Reduction in afterload due to arterial relaxation.
2. Increase in coronary blood flow. 3. DHPs have no effect on venous tone or preload. |
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How to Dihydropyridines affect Blood Pressure?
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Reduction of blood pressure doe to decreased afterload
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Which CCBs have more pronounced effects on Blood Pressure reduction and Vascular Smooth Muscle relaxation?
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DHPs have more pronounced effects than non-DHPs on BP reduction and vascular smooth muscle relaxation.
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How are DHPs and non-DHPs the same?
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Both:
1. Relax arterial smooth muscle 2. Decrease coronary vascular resistance which increases coronary blood flow |
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How do non-DHPs differ from DHPs?
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Non-DHPs:
1. Have more direct chronotropic, dromotropic, and inotropic effect 2. Reflex tachycardia is canceled by the negative chronotropic effect |
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How do DHPs differ from non-DHPs?
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DHPs:
1. Are more potent vaodilators 2. Some might elicit sympathetic reflexes causing tachycardia and positive inotropy (overcome the negative inotropic effect, if any) |
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How do Diltiazem and Verapamil differ (both are non-DHPs)?
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Verapamil has more suppression of cardiac contractility than Diltiazem.
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What can CCBs with short half-lives cause?
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1. Rapid change in blood pressure and repeated reflex tachycardia (sympathetic reflex)
2. May enhance the risk of adverse cardiac events. |
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What is the benefit of CCBs with long half-lives?
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Less reflex tachycardia, dizziness, and flushing
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True/False: Most CCBs on the market have long half-lives or are sold in extended release formulations.
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TRUE
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What are the approved indications of Non-DHPs?
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Angina
Hypertension Supraventricular tachycardia |
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How do Non-DHPs help angina?
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1. Decrease oxygen deman due to decreased force of contraction and reduction in heart rate and afterload.
2. Increase coronary blood flow 3. Favorable for variant angina |
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How do Non-DHPs help hypertension?
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reduction of blood pressure due to lower heart rate, lessened cardiac contractility, and decreased afterload.
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How do Non-DHPs help supraventricular tachycardia?
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Reduce ventricular rate by slowing conduction through the AV node
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What are the approved indications for DHPs?
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Angina
Hypertension |
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How do DHPs help in Angina?
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1. Decrease peripheral vascular resistance
2. Increase coronary blood flow 3. Favorable for variant angina |
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Which anti-anginal DHPs are more selective for coronary blood vessels?
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Amlodipine
Nifedipine Nicardipine |
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Hoe do DHPs help in hypertension?
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Almost entirely by vasodilation
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Name the half-life, formulation, and indication(s) for Amlodipine.
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Half-Life - 30-50 hours
Formulation - Immediate Release Indications - Hypertension and Angina |
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Name the half-life, formulation and indication(s) for Clevidipine.
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Half-Life - 1-15 minutes
Formulation - IV Indication - Hypertension |
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Name the half-life, formulation, and indication(s) for Nimodipine.
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Half-Life - 9 hours
Formulation - Immediate Release and IV Indication - Cerebrovascular disorders |
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Name three facts about Nimodipine.
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1. High lipid solubility (cross BBB)
2. Effective in inhibiting cerebral vasospasm 3. Improves patient's neurological outcomes associated with subarachnoid hemorrhage |
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Name two facts about Clevidipine.
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1. Metabolized by plasma esterases (not CYP3A4)
2. Indicated for lowering Blood Pressure when oral agents cannot be given |
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Name three differences between DHPs and Non-DHPs.
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1. DHPs are more potent vasodilators than non-DHPs
2. DHPs do NOT have antiarrhythmic effects 3. Non-DHPs (Verapamil and Diltiazem) have higher levels of recommendation in treating angina than DHPs in several guidelines |
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Name four other indications for CCB.
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1. Migraine Prophylaxis
2. Reynaud's Syndrome 3. Cerebral Ischemia 4. Subarachnoid Hemorrhage |
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What are four contraindications for Non-DHPs?
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1. Advanced heart block
2, Hypotension 3. Severe aortic Stenosis 4. Cardiogenic shock |
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Why are non-DHPs contraindicated in Advanced heart block?
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Non-DHPs slow AV node conduction and may exacerbate existing heart block
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Why are non-DHPs contraindicated in Hypotension?
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Non-DHPs decrease blood pressure and thus produce greater hypotension
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Why are non-DHPs contraindicated in severe aortic stenosis?
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The vasodilation effect of non-DHPs will lower cardiac output and further reduce the oxygen supply to the heart
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Why are non-DHPs contraindicated in cardiogenic shock?
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Non-DHPs would further reduce the heart rate and blood pressure
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What are the four contraindications for DHPs?
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1. Severe Aortic Stenosis (narrowing of aortic valve opening)
2. Hypotension 3. Cardiogenic Shock 4. Unstable angina or recent MI |
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Why are DHPs contraindicated in unstable angina or recent MIs?
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The immediate release formulations with short half-lives are what's contraindicated.
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What are three relative contraindications?
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1. Heart Failure - Negative inotropic activity can exacerbate CHF
2. Liver Failure - They are predominantly metabolized via the liver 3. GERD - Reduce lower esophageal sphincter contraction and may exacerbate GERD |
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What are the Adverse Events of Non-DHPs?
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1. SA and AV node effects - First degree AV block, bradycardia, exacerbation of CHF or pulmonary edema
2. GI effects - Nausea, vomiting, diarrhea, anorexia, and constipation (greatest with Verapamil) 3. Peripheral Vasodilation - flushing, headache, hypotension, peripheral edema, and dizziness 4. Uncommon: elevations of liver enzyme, CNS effects (fatigue, nervousness, drowsiness, depression, insomnia, and confusion), gingival hyperplasia, skin reactions, and urinary retention |
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What are the Adverse Events of DHPs?
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1. Peripheral vasodilation (peripheral edema, dyspnea, wheezing, flushing, headache, hypotension, and dizziness)
2. GI Effects 3. Uncommon: CNS effects, skin reactions, and gingival hyperplasia (Nifedipine is worse than Diltiazem or Verapamil) |
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How do anesthetics have drug interactions with Non-DHPs?
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Depress cardiac contractility and conductivity
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How does amiodarone have a drug interaction with Non-DHPs?
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Slows heart rate
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How do beta-blockers have drug interactions with Non-DHPs?
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1. Beta-Blocker + Non-DHP CCB increase risk for heart block and excessive negative inotropic effects
2. For BP reduction, consider a Beta-Blocker and DHP |
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How does Digoxin have drug interactions with Non-DHPs?
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1. Digoxin increases intracellular calcium and slows AV conduction
2. Risk of heart block with combination 3. Verapamil also inhibits the P-glycoprotein drug transporter and thus increases digoxin levels |
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Which five drugs do Non-DHPs reduce the metabolism of via CYP3A4 inhibition?
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May increase levels of:
1. Amiodarone 2. Cyclosporine 3. Statins: Lovastatin and Simvastatin 4. Tacrolimus 5. Theophylline |
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Which drug do Non-DHPs prevent from converting to its active form?
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Prednisone because it prevents the conversion to prednisolone which is the active form.
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Which four substances inhibit CYP3A4 and will therefore increase diltiazem and verapamil levels?
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1. Protease inhibitors
2. Azole antifungals 3. SSRIs 4. Grapefruit juice |
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What will Rifampin do to Non-DHPs?
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Rifampin is a CYP3A4 inducer, so it may decrease diltiazem or verapamil levels
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Which three drugs do DHPs reduce metabolism of by CYP3A4 inhibition?
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1. Simvastatin
2. Cyclosporine 3. Clopidogrel |
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What three substances may increase DHP levels due to inhibition of CYP3A4?
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1. Azole antifungals
2. Protease inhibitors 3. Grapefruit juice |
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What effect would Rifampin have on DHP levels?
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Rifampin is a CYP3A4 inducer, so it may decrease DHP levels.
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Given Vasodilation, Suppression of cardiac contractility, Suppression of automaticity, and suppression of condiction, which three will Non-DHPs affect significantly with no/minimal effects from DHPs?
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1 Suppression of Cardiac Contractility
2. Suppression of automaticity 3. Suppression of conduction |
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Given Vasodilation, Suppression of Cardiac Contractility, Suppression of Automaticity, and Suppression of AV Node, which category will DHPs predominate in over Non-DHPs?
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Vasodilation
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