01/22/16 Flashcards
1
Q
What is angina?
A
- Ankhon “strangling”, pectus “chest”
- Chest pain experienced as squeezing or pressure
- Also localized to shoulders, neck, jaw or back
- A symptom of coronary artery disease (CAD)
- Secondary artherosclerosis
2
Q
Types of Angina
A
- Stable
- Commons, follows predictable pattern
- Increase exercise, decrease with rest
- Unstable
- No pattern
- Not relieved by rest
- Precursor to heart attack, acute coronary syndrome
- Variant (or Prinzmetal;s)
- Rare
- Occurs at rest between midnight and early morning
3
Q
Coronary Arteries
A
- Branch off aorta
- Pass along outside surface of heart
- Supply myocardium
- Two main CA’s: left and right
- Branches penetrate cardiac muscle
4
Q
Schematic of Coronary Arteries
A
5
Q
Anatomy of an Artery
A
- composed of 3 distinct layers
- Adventitial
- Supporting layer
- Macrophages, monocytes, fibroblasts
- Medial
- Contractile layer
- Vascular smooth muscle cells
- Intima
- Inner layer adjacent to lumen
- Endothelium and elastic lamina
6
Q
Anatomy of an Artery (Figure)
A
7
Q
Anatomy of an Artery (Figure #2)
A
8
Q
Contraction of Vascular Smooth Muscle
A
- Contractile Galphaq-coupled GPCRs on vascular smooth muscle cells
- alpha1-adrenergic
- Angiotensin II type I
- Endothelin A
- 5-HT2 serotonin
- Kisspeptin 1R
- Activate myosin light chain kinase (MLCK)
- MLCK phosphorylates myosin
- Myosin binds actin
- Vessel contraction
9
Q
Contraction of Vascular Smooth Muscle (Figure)
A
10
Q
Nitric oxide production in endothelium
A
- Vasodilatory GPCRs on endothelium
- Bradykinin
- Angiotensin II type 2
- Endothelin B
- Muscarinic 1/3
- eNOS converts L-arginine + NADPH + O2→L-cirtulline + NO
- NO diffuses into adjacent smooth muscle cells
11
Q
NO production in endothelium (pathway figure)
A
12
Q
Nitric oxide stimulates vasodilation
A
- NO activates guanylyl cyclase→ ^cGMP
- Activates protein kinase G (PKG)
- PKG activates myosin light chain phosphtase
- Dephosphorylates myosin light chains
- PKG phosphorylates K+ channels
- ^K+ efflux
- hyperpolarization
- Vasodilation
13
Q
MLCP vs MLCK
A
14
Q
Coronary Artery Disease (CAD)
A
- Major cause of death world wide: “silent killer”
- Cummulative atheroma (i.e. plague) formation in CA’s
- Decrease lumenal diameter in CA’s
- Decrease O2/nutrient supply to myocardium
- Ischemia
- Myocardial infarction (MI)
- Rupture of atheroma
- MI and/or restenosis
- Leads to heart failure, arrthymia
15
Q
Atherosclerosis
A
- Thickening of artery wall to form “plaque” or “nodule”
- Chronic inflammatory response
- ROS/LpA2→LDL oxidation→monocytes/macrophages/T-Cells
- foam cells→”fatty streaks”
- atheroma: soft/yellow central layer, macrophages
- outer layer can be fibrous or calcified
16
Q
Virtual history of calcified nodule
A
17
Q
Treatment of Angina
A
- Decrease venous return/afterload:
- nitrovasodilators
- vascular selective Ca2+ channel blockers
- Decrease myocardial O2 demand:
- B-adrenergic receptor antagonists
- cardioselective Ca2+ channel blockers
- Treat CAD/atherosclerosis
- decrease cholesterol: statins
- prevent thrombi/clots: aspirin
- surgical procedures: stents/angioplasty
- lifestyle changes: exercise, diet, stop smoking
18
Q
Nitrovasodilators
A
- Amyl nitrate
- Nitroglycerin (Nitrostat, Trinipatch)
- Isosorbide mononitrate (Imdur, Ismo)
- Isosorbide dinitrate (Isordil)
19
Q
Nitrovasodilators: MOA
A
- denitrated by glutathione S-transferase in cells
- Release N2O
- Converted to nitric oxide
- Activated guanylyl cyclase
- Vasodilation
- Low doses→venodilation
- decrease venous return
- decrease cardiac workload/O2 demand
- High doses→arteriodilation
- decrease afterload
- decrease cardiac workload/O2 demand
20
Q
Nitrovasodilators: Clinical Uses
A
- Symptom relief of angina
- stable/unstable angina→decrease venous return→decrease cardiac output
- variant angina→relax coronary arteries→relieve coronary vasospasm
21
Q
Nitrovasodilators: Toxicity
A
- Severe vasodilation
- relax tachycardia
- orthostatic hypotension
- headache
- Tolerance with long-term use
- RAAS activity→aldosterone→Na+/H2O retention
- discontinued periodically (~8 hrs between doses)
22
Q
Nitrovasodilators: Formulations
A
23
Q
Phosphodiester type 5 inhibitors
A
- Sildenafil (Viagra)
- Vardenafil (Levitra)
- Tadalafil (Cialis)
24
Q
PDE5-Inhibitors: MOA
A
- Selectively inhibit PDE5
- Decrease cGMP breakdown
- Vasodilation
25
Q
PDE5-Inhibitors: Pharmacokinetics
A
- oral, sublingual
- rapid onset of action (minutes)
- long duration of action (hours)
26
Q
PDE5-Inhibitors: Clinical Uses
A
- Erectile dysfunction
- Angina
27
Q
PDE5-Inhibitors: Toxicity
A
- Vision problems
- Contraindicated with nitrovasodilators
- Excessive vasodilation
- Headache
- Dizziness
- Flushing
28
Q
Beta-adrenergic receptor anatgonists
A
- Propranolol (Inderal)
- Atenolol (Tenormin)
- Metoprolol (Lopressor)
29
Q
Beta-adrenergic receptor anatgonists: MOA
A
- Decrease cardiac output
- Decrease RAAS activity
- Decrease myocardial O2 demand
30
Q
Beta-adrenergic receptor anatgonists: Clinical uses
A
- Angina:
- Oral prophylactic
- Increase exercise tolerance
- duration ~6 hours
31
Q
Beta-adrenergic receptor anatgonists: Toxicity
A
- Contraindicated with bradycardia, asthma
- CNS sedation
32
Q
Cardioselective Ca2+ channel blockers
A
- Verapamil (Calan, Isoptin)
- Diltiazem (Cardiazem)
33
Q
Cardioselective Ca2+ channel blockers: MOA
A
- Inhibit voltage-gated L-type Ca2+ channels in cardiac myocytes
- decrease force and rate of cardiomyocyte contraction
- decrease cardiac output
34
Q
Cardioselective Ca2+ channel blockers: Toxicity
A
- Hypotension
- Excessive cardiac depression
- Constipation
35
Q
Vascular Selective Ca2+ channel blockers
A
- Dihydropyridines
- Nifedipine (Procardia)
- Amlodipine (Norvasc)
36
Q
Vascular Selective Ca2+ channel blockers: MOA
A
- Inhibit L-type Ca2+ channels on vascular smooth muscle cells
- Decrease arterial and venous contraction
- Decrease TPR
37
Q
Vascular Selective Ca2+ channel blockers: Toxicity
A
- Hypotension
- Flushing, dizziness
38
Q
Vascular Selective Ca2+ channel blockers: Clinical Use in Angina
A
- Oral prophylactic
- Effective for stable and unstable angina
- DDI at CYP450 3A4
39
Q
Ranolazine (Ranexa): MOA and Toxicity
A
- MOA
- late Na+ channel modulator (INa)→decrease Na+ influx in cardiomyocytes
- Decrease Ca2+ overload during ischemic event
- MARISA and CARISA clinical trials compared to other agents
- Decrease myocardial ischemia, time to exercise induced ischemic event
- Increase exercise tolerance>>beta blockers, vascular CCB or cardiac CCB
- late Na+ channel modulator (INa)→decrease Na+ influx in cardiomyocytes
- Toxicity
- Can prolong QT interval > Contraindicated in patients with long QT interval
- Constipation
- Flushing, dizziness
- CYP3A4, 2D6 substrate
40
Q
Nitroglycerin: Drug card
A
- Brand Name:
- Nitrostat
- MOA:
- Nitrovasodilator, nitric oxide donor
- Clinical uses:
- Angina
- acute coronary syndrome
- Toxicity
- tachycardia
- orthostatic hypotension
- headache
- Extra Info:
- Sublingual for acute angina: rapid onset (<1 min), short duration(~10-30 min)
- Oral for prophylactic: slow onset, longer duration (6-8hrs)
41
Q
Sildenafil: Drug Card
A
- Brand Name:
- Viagra
- MOA:
- PDE5 inhibitor
- Clincal Uses:
- Angina
- ED
- Toxicity:
- Tachycardia
- Hypotension
- Visual disturbances (yellow halos)
- Extra Info:
- Contraindicated with vasodilators
42
Q
Propranolol: Drug Card
A
- Brand Name:
- Inderal
- MOA:
- non-selective beta-adrenergic receptor antagonist
- Clinical Uses:
- Hypertension
- Congestive heart failure
- Angina
- Arrhythmias
- Toxicities:
- Bradycardia, atrioventricular block
- Bronchospasm
- CNS sedation
- Extra Info:
- Contraindicated in asthma
- Also used for performance anxiety and migraine
- Crosses blood brain barrier
43
Q
Metoprolol: Drug Card
A
- Brand Name:
- Lopressor
- MOA:
- selective beta1-adrenergic receptor antagonist
- Clinical Uses:
- Congestive heart failure
- Hypertension
- Toxicities:
- Bradycardia, atrioventricular block
- CNS sedation
- Extra Information:
- shown to reduce mortality in heart failure patients
- widely used for stage I/II HTN
44
Q
Verapamil: Drug Card
A
- Brand Name:
- Calan
- MOA:
- Cardioselective L-type Ca2+ channel blocker
- Clinical Uses:
- Hypertension
- Angina
- Arrhythmias
- Toxicities:
- Excessive cardiac depression
- Constipation
- Extra Information:
- Strong cardiac blocking effect
- weak vascular smooth muscle blocking effect
45
Q
Nifedipine: Drug Card
A
- Brand Name:
- Procardia
- MOA:
- Vascular selective L-type Ca2+ channel blocker
- Clinical Uses:
- Hypertension
- Angina
- Arrhythmias
- Toxicities:
- Hypotension
- Flushing
- Dizziness
- Extra Information:
- Strong vascular smooth muscle blocking effect
- Weak cardiac muscle blocking effect
46
Q
Ranolazine: Drug Card
A
- Brand Name:
- Ranexa
- MOA:
- late Na+ channel current modulator
- Clinical Uses:
- Chronic angina
- Toxicities:
- Constipation
- Dizziness
- Extra information:
- Avoid use in patients with long QT syndrome
- Numerous DDI’s due to CYP3A4, 2D6 metabolism
47
Q
A
