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
PDE5-Inhibitors: Pharmacokinetics
* oral, sublingual
* rapid onset of action (minutes)
* long duration of action (hours)
26
PDE5-Inhibitors: Clinical Uses
* Erectile dysfunction
* Angina
27
PDE5-Inhibitors: Toxicity
* Vision problems
* Contraindicated with nitrovasodilators
* Excessive vasodilation
* Headache
* Dizziness
* Flushing
28
Beta-adrenergic receptor anatgonists
* **Propranolol (Inderal)**
* Atenolol (Tenormin)
* **Metoprolol (Lopressor)**
29
Beta-adrenergic receptor anatgonists: MOA
* Decrease cardiac output
* Decrease RAAS activity
* Decrease myocardial O2 demand
30
Beta-adrenergic receptor anatgonists: Clinical uses
* Angina:
* Oral prophylactic
* Increase exercise tolerance
* duration ~6 hours
31
Beta-adrenergic receptor anatgonists: Toxicity
* Contraindicated with bradycardia, asthma
* CNS sedation
32
Cardioselective Ca2+ channel blockers
* **Verapamil (Calan, Isoptin)**
* Diltiazem (Cardiazem)
33
Cardioselective Ca2+ channel blockers: MOA
* Inhibit voltage-gated L-type Ca2+ channels in cardiac myocytes
* decrease force and rate of cardiomyocyte contraction
* decrease cardiac output
34
Cardioselective Ca2+ channel blockers: Toxicity
* Hypotension
* Excessive cardiac depression
* Constipation
35
Vascular Selective Ca2+ channel blockers
* Dihydropyridines
* **Nifedipine (Procardia)**
* Amlodipine (Norvasc)
36
Vascular Selective Ca2+ channel blockers: MOA
* Inhibit L-type Ca2+ channels on vascular smooth muscle cells
* Decrease arterial and venous contraction
* Decrease TPR
37
Vascular Selective Ca2+ channel blockers: Toxicity
* Hypotension
* Flushing, dizziness
38
Vascular Selective Ca2+ channel blockers: Clinical Use in Angina
* Oral prophylactic
* Effective for stable and unstable angina
* DDI at CYP450 3A4
39
Ranolazine (Ranexa): MOA and Toxicity
* 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
* Toxicity
* Can prolong QT interval \> Contraindicated in patients with long QT interval
* Constipation
* Flushing, dizziness
* CYP3A4, 2D6 substrate
40
Nitroglycerin: Drug card
* 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
Sildenafil: Drug Card
* Brand Name:
* Viagra
* MOA:
* PDE5 inhibitor
* Clincal Uses:
* Angina
* ED
* Toxicity:
* Tachycardia
* Hypotension
* Visual disturbances (yellow halos)
* Extra Info:
* Contraindicated with vasodilators
42
Propranolol: Drug Card
* 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
Metoprolol: Drug Card
* 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
Verapamil: Drug Card
* 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
Nifedipine: Drug Card
* 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
Ranolazine: Drug Card
* 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
