04.22 - IHD Pharm (Ostrom) Flashcards
What determines myocardial demand?
HR, Contractility, Wall tension (afterload)
2 Main CV effects of Nitrates
(1) Venodilation reduces Preload; (2) Coronary Vasodilation
2 major non-dihydropyridine CCB’s, and which is better
Verapamil > Diltiazem
2 mechanisms of Ranolazine
Late sodium current inhibitor; Partial FA oxidase inhibitor –> Increase glucose oxidation and efficiency of O2 utilization in heart
2 Non-Dihydro CCB’s
Verapamil, Diltiazem
3 Widespread Uses of CCB’s
Angina, HTN, Supraventricular Arrhythmias
5 Dihydro CCB’s
Nifedipine, Nicardipine, Isradipine, Felodipine, Amlodipine
Absolute Contraindication for Nitrates
PDE inhibitors
Action of Ca2+ in cardiac muscle cell
Binding to Troponin C reduces inhibition of actin-myosin cross-bridges
Action of Ca2+ in smooth muscle cell
Binding to Calmodulin activates MLCK, which phosphorylates myosin and triggers contraction
Adverse Effects of Nitrates
Hypotension, Headache, Drug Rash
Adverse reactions with Ranolazine
Dizziness, headache, constipation, nausea (4-6%)
AE’s caused by all CCB’s
Hypotension, Peripheral Edema
AE’s of DHP CCB’s
Excessive Vasodilation, GI, Per Edema, Coronary Steal
AE’s of Verapamil, Diltiazem
Bradycardia, Asystole, AV Block; Constipation; CHF
All patients with CHD should receive
Aspirin
Another source of concern for CCB’s
may increase cancer risk (not shown in ALLHAT)
Are CCB’s good at treating HTN
One study says yes, other no
Best choice for oral anti-HTN in patient with Prinzmetal’s would be
DHP CCB
Cardiac cells rely on L-type Ca channels for
Contraction (contractile cells) and Upstroke of AP in Nodal Cells
CCB’s act on what type of Ca channels
L-Type
CCB’s are highly effect for relief of symptoms in
Exertional and Vasospastic Angina
CCB’s in patients with CAD
fail to consistently reduce reinfarction or CAD mortality; Imparied LV function
Chemical class of Diltiazem
Benzothiazepines
Chemical class of Verapamil
Phenylalkylamines
Con to Ranolazine
Cost; Will not relieve acute angina attacks
Conclusion: When should CCB’s be used
Unable to tolerate BB’s; Or add-on for angina uncontrolled by BB + nitrate
Contraindications for All CCB’s
Hypotension, Advance HF
Contraindications for Non-DHP CCB’s only
Sinus Bradycardia, AV conduction defects (also Hypotension, Advance HF)
DHP =
Vasodilation = Baroreceptor Reflex
Direct effects of Non-Di CCB’s predominate to
Reduce Heart Work: HR, Contractility, Slowed AV conduction
Do BB’s prevent vasospasm?
No
Drug of choice in Angina overall
Beta blockers
Effect of Nitrates on BP and HR
BP unchanged or slight decrease, HR unchanged or slight increase
Effect of Nitrates on Coronary Arteries
Vasodilate, Prevents or reverses coronary vasospasm
Effect of Nitrates on Pulmonary Vascular Resistance and CO
PVR decreased, CO reduced slightly
Effects of Nitrate Venodilation
Decreased Preload –> Reduces wall stress and MvO2, Subendocardial blood flow increased
For Exertional Angina, use BB why?
Reduces HR, contractility
For Unstable Angina, use BB’s with
Nitrates, ASA, and Heparin
For Vasospastic Angina, use BB why?
DON’T
How do CCB’s effect CV function w/out significant side effects
Specific for L-type Ca Channels
How do CYP inducers affect Verapamil, Diltiazem
Reduce their levels
How do Di CCB’s reduce MvO2
Vasodilation = Reduced afterload
How do Non-Di CCB’s reduce MvO2
Reduce heart work (demand)
How does increased Diastole affect coronary perfusion?
Increases
Indications of Ranolazine
Chronic, stable agina in combo with Amlodapine, BB, or Nitrates
Major Contraindications of Ranolazine
Digoxin (conc. increases); CYP; Long QT
Mechanisms of Tolerance to Nitrates
Volume Expansion, Neurohumoral Activation, Depletion of Tissue Cysteine Stores
MOA of Milrinone
PDE4 inhibitor
Most common side effects of DHP’s are due to
Vasodilation
Most common ventricular dysfunction
Heart Failure
Notable pharmacokinetics for CCB’s
Extensive First-Pass metab; CYP3A4; Short plasma half-life; Bolus effect
Pharmacodynamic interactions with Verapamil, Diltiazem
BB’s increase risk of Nodal Block
Primary drug class of choice for most types of angina
Nitrates
Problem with Di CCB’s
Reflex cardiac stimulation: HR, Contractility
Properties of L-Type Ca Channels
V-dep, Large Conductance, Slow inactivation
Rationale for combining BB with CCBs (Di)
Prevent coronary vasospasm, reduce systemic vascular resistance
Rationale for combining BB with Nitrates:
Reduces LVEDP, LV Volume, Dilates coronary arteries
Situations favoring Di CCB
With BB for Coronary Vasodilation, reduced afterload; Sinus brady, Nodal block; Valvular insufficiency
Special effect of non-Di CCB’s on coronary arteries
Coronary Vasodilation: Prevents or reverses Vasospasm
Special feature of lipophilic BB’s
Can reduce afterload thru CNS effects
Vascular specificity of CCBs
Induce relaxation of arterial SM but not Venous (reduce afterload, not preload)
What does voltage-dep binding of Nifedipine select for smooth muscle ca channels?
SM voltage less variable
What is target of nitrates?
*–> NO –> GC –> Increase cGMP
What type of Ca channels mediate NT release in neurons
N- and P-type
When should Renolazine be used:
Increase exercise tolerance and time to onset of angina; Adjunct when refractory to other tx’s
When would Non-Di CCB’s be indicated
Pt can’t use BB: Asthma/COPD, Insuline-dep DM, PVD
Which anti-anginal(s) doesn’t vasodilate coronaries?
BB
Which anti-anginal(s) doesn’t reduce HR
Nitrates, Dihydro CCBs
Which anti-anginal(s) reduce afterload?
All
Which anti-anginal(s) reduce preload?
Nitrates
Which CCB causes constipation
Verapamil
Which CCB class binds in use-dependent way
Non-DHP
Which CCB class binds in voltage-dependent way
DHP
Which CCB class is a selective vasodilator
Dihydro –> Can cause reflex
Which CCB class needs to be used with Beta blocker
Dihydropyridine to prevent reflex cardiac stimulation
Which CCB worsens CHF
Verapamil
Which CCB’s are CYP3A4 substrates
Verapamil, Diltiazem
Which CCB’s slow the recovery of the L-type channel?
Verapamin, Diltiazem (non-dihydro)
Which class of CCB’s affect AV node conduction
Non-Di CCB’s slow
Which is preferred, Di or Non-Di CCB’s?
Dihydropyridine, unless patient can’t tolerate BB
Which of the following decrease CHD events: BBs, Nitrates, CCBs
BBs do, Nitrates don’t, CCBs are variable
Why do Nitrates cause Headache
Vasodilation of Meningeal arteries
Worst choice of oral anti-HTN in patient with Prinzmetal’s
Beta Blocker
