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12. Pharmacology > B blockers > Flashcards

B blockers Flashcards

1
Q

Types of B R and site of action

A

B1 adrenoreceptor: HEART MUSCLE
B2 adrenoreceptor: BRONCHIAL AND VASCULAR SMOOTH MUSCLE
B3 adrenoreceptor: ENDOTHELIAL

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2
Q

B1: types of R

A
  • Receptor: on sarcolemma
    o Coupled to G protein:
     Gs → adenylyl cyclase →cAMP → prot kin A activation → Pi of Ca protein → Ca2+ channel opening →↑ rate of myocardial contraction
  • ↑ATPase activity
  • ↑activation of troponin C → ↑ contraction force = positive INOTROPE
  • Pi of phospholamban → ↑ rate of Ca2+ uptake by SR = positive LUSITROPE
  • ↑ SA node PM rate = positive CHRONOTROPE
  • ↑ conduction speed = positive DROMOTROPE
     Gi: interrupted by G inhibitory protein
  • Vagal activation → muscarinic stimulation
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3
Q

B1: effect of blocker depends on

A

o Absorption
o Binding ability
o Generation of metabolites
o Extend of inhibition of B-R

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4
Q

Secondary effects of B blockade

A

o Rapid relaxation: ↑ Ca2+ uptake and rapid ↓ in cytosolic [Ca2+]
o ↓HR and force of contraction: ↑cAMP → ↑ Pi of troponin-I → shorter interaction of actin and myosin
o ↓ myocardial O2 consumption: switch to O2 conserving glucose (vs O2-wasting FAs)
o ↑# of B-R (sustained tx): can explain improved systolic fct

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5
Q

B2 receptors

A
  • Receptors: 20-25% of myocardial B-R
    o Upregulation in HF
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6
Q

Effect of B2

A

hypotension + vasodilation

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7
Q

Effect of B3

A

mediated vasodilation induced by NO

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8
Q

What is B turnoff mechanism

A
  • B-R stimulation → activation of B-adrenergic R kinase (B-ARK) or G prot-coupled R kinase 2 (GRK2)
    o Pi of R →B-arrestin recruitment → desensitization of stimulated R = uncoupling from Gs and internalization
    o If sustained → lysosomal destruction → downregulation of R density
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9
Q

Turn off mechanism exacerbated by

A

o CHF: ↑ cisculating catecholamines
o Iatrogenic: B agonists (Dobutamine)
 Tachyphylaxis = progressive loss/↓ therapeutic efficacy

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10
Q

1st generation non-selective agents: drugs

A

Propanolol, sotalol, carteolol, nadolol, penbutolol

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11
Q

1st generation non-selective agents: effect

A
  • Block ALL receptors (B1 + B2)
  • Similar effect on cardiovascular system to B1 selective agents
    o >marked pulmonary and peripheral effects
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12
Q

2nd generation cardio selective agents: drugs

A

Atenolol, acebutolol, betaxolol, bisoprolol, metoprolol

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13
Q

2nd generation cardio selective agents: action

A
  • Selective for B1-R
    o ↑ selectivity at higher doses
    o Bisoprolol = most selective
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14
Q

2nd generation cardio selective agents: cardiovascular effects

A

bradycardia, negative inotropy, vasodilation
o ↓ bronchospasm
o Few peripheral effects

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15
Q

3rd generation vasodilatory agents: drugs

A

Vasodilatory nonselective: labetalol, carvedilol, pindolol
Vasodilatory selective: nebivolol

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16
Q

3rd generation vasodilatory agents: effect/action

A
  • Direct vasodilation via NO
  • A adrenergic blockade
  • B2 intrinsic sympathomimetic activity
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17
Q

Goal of B blocker

A

counter interact adrenergic stimulation
o ↓ myocardial O2 demand: from bradycardia and ↓ contractility

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18
Q

Cardiovascular effect of B blockade

A

negative
o Chronotrope → SA node
o Dromotrope → AV node
o Inotrope → myocardial contractility

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19
Q

Effect on coronary flow

A
  • Coronary flow and myocardial perfusion
    o B-mediated coronary vasodilation
     cAMP formation
     ↓ [Ca2+] levels in vascular SM cell
    o Β-blockade: ↓HR → ↑diastolic filling time → ↑diastolic filling perfusion
     Overcome ↓B-stimulation
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20
Q

Effect on systemic circulation

A

o ↓CO: initial ↓ = 20%
 Compensatory ↑SVR → remain unchanged
 MAP will ↓ after 1-2 days 2nd to ↓HR and CO

o Hypotensive effects
 Inhibition of B-R on terminal neurons → facilitate NE release → ↓ adrenergic mediated vasoconstriction.
 CNS effect: ↓ adrenergic outflow
 ↓ RAAS activity: ↓B-R mediated renin release

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21
Q

Best B blocker for patients w/ concomitant respiratory dz

A

cardio selective B1 for bronchospasms
o Non selective tend to cause ↑ pulmonary complications

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22
Q

Best B blocker for patients w/ concomitant cardiovascular dz

A

o Hypertension/angina: not 1st choice medication
o Sick sinus syndrome: pure B blockade dangerous
o Raynaud phenomenon: avoid propranolol with vasoconstrictive effects
o Peripheral vascular disease: B-blocker contraindicated

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23
Q

Side effects

A

o Smooth muscle spasm: bronchospasm, cold extremities
o Exaggeration of cardiac therapeutic actions: bradycardia, heart block, negative inotrope
o CNS penetration: insomnia, depression
 Only for liposoluble B blockers with high brain penetration → propranolol
o Metabolic side effects
o Fatigue: unclear mechanism

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24
Q

Cardiac CI

A

o Absolute
 Severe bradycardia, high degree heart block
 Cardiogenic shock
 LV failure
o Relative: angina, other agents suppressing AV/SA nodes

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25
Pulmonary CI
o Absolute: severe asthma/bronchospasm o Relative: mild asthma, bronchospasm, lower airway dz
26
CNS CI
o Absolute: severe depression o Relative: hallucinations, highly lipid soluble agent
27
Peripheral vascular CI
o Absolute: active dz (gangrene, skin necrosis) o Relative: cold extremities, absent pulse, Raynaud
28
Other CI
* Diabetes mellitus: relative → insulin requiring diabetes (B-blockers may ↑ blood sugar) * Renal failure: relative → avoid medications eliminated by kidneys * Liver failure: relative → avoid medications metabolized by liver * Pregnancy: relative → can depress vital signs in neonates, uterine vasoconstriction * Hyperlipidemia: relative → unfavorable effect on blood lipid profile o ↑ Triglyceride and ↓HDL-cholesterol
29
Overdose: c/s
Bradycardia
30
Overdose: tx
→ responsive to atropine o Glucagon: theory, should ↑cAMP o PDEi: amrinone, milrinone  ↑[cAMP] o Dobutamine: positive inotrope
31
Duration of action esmolol
shortest ½ life (9min) → need CRI for effect
32
Duration of action propanolol
½ life 3h  Chronic administration: hepatic saturation → longer ½ life
33
If higher dose given
o Higher dose of any → longer biologic effects
34
Active metabolite propanolol
4-hydroxypropanolol Highly protein bound
35
Metabolism: general
primarily liver or kidney o 1st pass hepatic metabolism → liposoluble compounds  ↓dose inliver dz or low output states  Penetrate brain barrier
36
Metabolism: propanolol
100% liver  Lipophilic, least water soluble
37
Metabolism atenolol and sotalol
100% kidney  Hydrophilic, least liposoluble  Low brain penetration
38
Drug interaction
o ↑ plasma levels of lidocaine o Paroxetine ↑ plasma levels → inhibition of metabolism (CYP2D6)
39
Esmolol: MOA
Selective B1
40
Esmolol: indications
Periop SVT Non compensatory sinus tach Emergency hypertension Unstable angina
41
Esmolol: pharmacoK
Ultra short acting
42
Atenolol: MOA
selective B1
43
Atenolol: indications
Angina Post infarction Hypertension Arrhythmias SAS, PS HCM
44
Atenolol: pharmacoK
Poorly liposoluble Excreted primarily kidneys Long plasma ½ life
45
Bisoprolol: MOA
Highly selective B1
46
Bisoprolol: indications
Hypertension only
47
Metoprolol: MOA
Selective B1
48
Metoprolol: pharmacoK
Moderate liposoluble Hepatic metabolism
49
Nebivolol: MOA
Highly cardio selective Peripheral vasodilation
50
Nebivolol: pharmacoK
Highly liposoluble Metabolism: 50% hepatic, 50% renal
51
Nebivolol: other effects
Reverse endothelial dysfct ↑ insulin sensitivity
52
Bisoprolol: pharmacoK
Mildly liposoluble Metabolism: 50% hepatic, 50% renal
53
Acebutolol: MOA
Selective B1
54
Acebutolol: pharmacoK
Poorly liposoluble Metabolism: 20% hepatic, 80% renal
55
Acebutolol: other effect
Intrinsic sympathomimetic activity
56
Betaxolol: MOA
selective B1
57
Betaxolol: pharmacoK
Moderate liposoluble Metabolism: hepatic
58
Celiprolol: MOA
selective B1
59
Propanolol: MOA
Nonselective Block B1 and B2
60
Propanolol: indication
Angina Acute/post myocardial infarction Hypertension Arrhythmias Tetralogy of Fallot Sinus tach, SVT, VA HCM Hypertension HyperT4 Pheochromocytoma
61
Propanolol: pharmacoK
Liposoluble Extensive 1st pass hepatic metabolism Short plasma ½ life
62
Carvedilol: MOA
Nonselective B blocker A1 Antioxidant
63
Carvedilol: indication
Hypertension CHF Post myocardial infarction LV dysfct
64
Carvedilol: pharmacoK
Mildly liposoluble Hepatic metabolism
65
Carvedilol: other effects
Formation of NO Stimulation of B-arrestin MAP kinase A-R
66
Sotalol: MOA
Nonselective Class III anti arrhythmic
67
Sotalol: pharmacoK
Water soluble Excreted by kidneys
68
Sotalol: indications
Ventricular arrhythmias Afib/flutter
69
Timolol: MOA
Nonselective
70
Timolol: indications
Post infarct protection
71
Timolol: pharmacoK
Mildly liposoluble Metabolism: 80% hepatic, 20% renal
72
Nadolol: MOA
Non selective
73
Nadolol: pharmacoK
Poorly liposoluble Renal metabolism
74
Labetalol: MOA
Non selective
75
Labetalol: pharmacoK
Highly liposoluble Hepatic metabolism mostly, some renal
76
Pindolol: MOA
Non selective
77
Pindolol: pharmacoK
Mildly liposoluble Metabolism: 60% hepatic, 40% renal
78
Pindolol: other effect
Intrinsic sympathomimetic activity
79
Carteolol: pharmacoK
Poorly liposoluble Metabolism: renal
80
Carteolol: other effects
Intrinsic sympathomimetic activity
81
Oxprenolol: pharmacoK
Highly liposoluble
82
Penbutolol: pharmacoK
Highly liposoluble Hepatic metabolism
83
Penbutolol: other effects
Intrinsic sympathomimetic activity
84
Clinical uses of B blockers
Myocardial ischemia (angina pectoris) Hypertension Arrhythmias Heart failure Other cardiac indications * HOCM * Catecholaminergic polymorphic Vtach o Help prevent exercise induced Vtach * Mitral stenosis o ↑ diastolic filling o Improve exercise tolerance * MV prolapse o If 2nd arrhythmias * Dissecting aneurysm * Marfan syndrome o Against Ao dilation * Vasovagal syncope o Control episodic adrenergic reflex * Tetralogy of Fallot * Congenital QT prolongation syndrome o If underlying mutation affects K+ channels modulated outward currents * Postural tachycardia syndrome
85
Non cardiac indications
* Stroke * Vascular, non cardiac surgery: ↓ perioperative death from cardiac causes/infarction in high risk patients * Thyrotoxicosis * Anxiety states * Glaucoma * Migraine * Esophageal varices
86
Why BB w/: myocardial ischemia
* ↑ myocardial O2 demand and inadequate coronary vasodilation * B-blockade o ↓HR → ↓O2 demand o ↓afterload o ↑diastolic filling time o ↓contractility o ↓O2 wasting
87
Benefits of BB w/ myocardial ischemia
o Hu: ↓ mortality by 25-40% o ↓ventricular arrhythmia and reinfarction
88
Indications for hypertension
* No longer recommended for systemic hypertension o Better outcome w amlodipine o ↓ SVR: from sustained ↓CO, ↓PVR and ↓ renin release * Indications o HFwih hypertension o Post myocardial infarction hypertension o High coronary risk o Diabetes
89
Anti arrhythmics effects
* Multiple anti arrhythmic effects o Anti-ischemic effects o Membrane stabilizing effects → inhibit phase 0 o Limit If current o AP prolongation (class III) o Counter interact arrhythmogenic effect of catecholamine excess  ↓cAMP and ↓Ca2+ → triggered arrhythmias * Useful for SVTs and VAs: o Inhibit initial atrial ectopic beats o Slow AV node conduction → ↓ ventricular response
90
Mechanism proposed to help w/ HF
o Improve B-adrenergic signaling o Self-regulation o Hyperphosphorylation hypothesis o Bradycardia o Protection from catecholamine myocyte toxicity o Antiarrhythmic effects Antiapoptosis o Renin-Angiotensin inhibition
91
How to apply B blockers in HF
o Stable systolic HF o Slowly titrate up  Watch for adverse side effects  Never stop abruptly: risk of ischemia/infarction o Hu: ↓ mortality in 1/3 of patients  Every 5bpm ↓in HR → 18% ↓risk of death o No studies in animals o No studies for diastolic HF
92
How BB improve B adrenergic signaling
 ↓GRK2 expression → ↓ internalization of B-R * ↑ adenylyl cyclase activity → improve contractility  Upregulation of B2-R may have inhibitory effects * Excessive formation of Gi and hyperPi SR * Role of B2-R in HF not fully understood
93
BB self regulation mechanism
 Potent/rapid physiologic switch-off feedback * Mute B-adrenergic stimulation → avoid perpetuated activation * Activation of GRK2 → B-arrestin → internalization o ↓activation of adenylyl cyclase o Change from Gs to Gi * B arrestin signaling → counter balancing protective path o Protective ERK/MAP kinase pathway
94
Hyperphosphorylation hypothesis
 Excess adrenergic stim → hyperPi of Ca2+ release channels on SR (RyR) * Defective function of RyR → Ca2+ leak → [Ca2+] overload * Ca2+ pump regulating uptake of Ca2+ into SR is downregulated * → ↑ and ↓ of cytosolic [Ca2+] → poor relaxation/contraction  B-blockade would reverse this effect
95
how bradycardis from BB is beneficial for heart
 Improve coronary artery blood flow  ↓myocardial O2 demand  ↓ Xtra matrix collagen  Improve LV EF
96
Effects of catecholamines on myocytes
o Protection from catecholamine myocyte toxicity  CHF → B-stimulation → ↑ circulating catecholamines * Membrane damage * Promote sub destruction

12. Pharmacology (10 decks)

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