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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
Q

Pulmonary CI

A

o Absolute: severe asthma/bronchospasm
o Relative: mild asthma, bronchospasm, lower airway dz

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26
Q

CNS CI

A

o Absolute: severe depression
o Relative: hallucinations, highly lipid soluble agent

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27
Q

Peripheral vascular CI

A

o Absolute: active dz (gangrene, skin necrosis)
o Relative: cold extremities, absent pulse, Raynaud

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28
Q

Other CI

A
  • 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
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29
Q

Overdose: c/s

A

Bradycardia

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30
Q

Overdose: tx

A

→ responsive to atropine
o Glucagon: theory, should ↑cAMP
o PDEi: amrinone, milrinone
 ↑[cAMP]
o Dobutamine: positive inotrope

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31
Q

Duration of action esmolol

A

shortest ½ life (9min) → need CRI for effect

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32
Q

Duration of action propanolol

A

½ life 3h
 Chronic administration: hepatic saturation → longer ½ life

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33
Q

If higher dose given

A

o Higher dose of any → longer biologic effects

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34
Q

Active metabolite propanolol

A

4-hydroxypropanolol

Highly protein bound

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35
Q

Metabolism: general

A

primarily liver or kidney
o 1st pass hepatic metabolism → liposoluble compounds
 ↓dose inliver dz or low output states
 Penetrate brain barrier

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36
Q

Metabolism: propanolol

A

100% liver
 Lipophilic, least water soluble

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37
Q

Metabolism atenolol and sotalol

A

100% kidney
 Hydrophilic, least liposoluble
 Low brain penetration

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38
Q

Drug interaction

A

o ↑ plasma levels of lidocaine
o Paroxetine ↑ plasma levels → inhibition of metabolism (CYP2D6)

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39
Q

Esmolol: MOA

A

Selective B1

40
Q

Esmolol: indications

A

Periop SVT
Non compensatory sinus tach
Emergency hypertension
Unstable angina

41
Q

Esmolol: pharmacoK

A

Ultra short acting

42
Q

Atenolol: MOA

A

selective B1

43
Q

Atenolol: indications

A

Angina
Post infarction
Hypertension
Arrhythmias
SAS, PS
HCM

44
Q

Atenolol: pharmacoK

A

Poorly liposoluble
Excreted primarily kidneys
Long plasma ½ life

45
Q

Bisoprolol: MOA

A

Highly selective B1

46
Q

Bisoprolol: indications

A

Hypertension only

47
Q

Metoprolol: MOA

A

Selective B1

48
Q

Metoprolol: pharmacoK

A

Moderate liposoluble
Hepatic metabolism

49
Q

Nebivolol: MOA

A

Highly cardio selective
Peripheral vasodilation

50
Q

Nebivolol: pharmacoK

A

Highly liposoluble
Metabolism: 50% hepatic, 50% renal

51
Q

Nebivolol: other effects

A

Reverse endothelial dysfct
↑ insulin sensitivity

52
Q

Bisoprolol: pharmacoK

A

Mildly liposoluble
Metabolism: 50% hepatic, 50% renal

53
Q

Acebutolol: MOA

A

Selective B1

54
Q

Acebutolol: pharmacoK

A

Poorly liposoluble
Metabolism: 20% hepatic, 80% renal

55
Q

Acebutolol: other effect

A

Intrinsic sympathomimetic activity

56
Q

Betaxolol: MOA

A

selective B1

57
Q

Betaxolol: pharmacoK

A

Moderate liposoluble
Metabolism: hepatic

58
Q

Celiprolol: MOA

A

selective B1

59
Q

Propanolol: MOA

A

Nonselective
Block B1 and B2

60
Q

Propanolol: indication

A

Angina
Acute/post myocardial infarction
Hypertension
Arrhythmias
Tetralogy of Fallot
Sinus tach, SVT, VA
HCM
Hypertension
HyperT4
Pheochromocytoma

61
Q

Propanolol: pharmacoK

A

Liposoluble
Extensive 1st pass hepatic metabolism
Short plasma ½ life

62
Q

Carvedilol: MOA

A

Nonselective B blocker
A1
Antioxidant

63
Q

Carvedilol: indication

A

Hypertension
CHF
Post myocardial infarction
LV dysfct

64
Q

Carvedilol: pharmacoK

A

Mildly liposoluble
Hepatic metabolism

65
Q

Carvedilol: other effects

A

Formation of NO
Stimulation of B-arrestin MAP kinase
A-R

66
Q

Sotalol: MOA

A

Nonselective
Class III anti arrhythmic

67
Q

Sotalol: pharmacoK

A

Water soluble
Excreted by kidneys

68
Q

Sotalol: indications

A

Ventricular arrhythmias
Afib/flutter

69
Q

Timolol: MOA

A

Nonselective

70
Q

Timolol: indications

A

Post infarct protection

71
Q

Timolol: pharmacoK

A

Mildly liposoluble
Metabolism: 80% hepatic, 20% renal

72
Q

Nadolol: MOA

A

Non selective

73
Q

Nadolol: pharmacoK

A

Poorly liposoluble
Renal metabolism

74
Q

Labetalol: MOA

A

Non selective

75
Q

Labetalol: pharmacoK

A

Highly liposoluble
Hepatic metabolism mostly, some renal

76
Q

Pindolol: MOA

A

Non selective

77
Q

Pindolol: pharmacoK

A

Mildly liposoluble
Metabolism: 60% hepatic, 40% renal

78
Q

Pindolol: other effect

A

Intrinsic sympathomimetic activity

79
Q

Carteolol: pharmacoK

A

Poorly liposoluble
Metabolism: renal

80
Q

Carteolol: other effects

A

Intrinsic sympathomimetic activity

81
Q

Oxprenolol: pharmacoK

A

Highly liposoluble

82
Q

Penbutolol: pharmacoK

A

Highly liposoluble
Hepatic metabolism

83
Q

Penbutolol: other effects

A

Intrinsic sympathomimetic activity

84
Q

Clinical uses of B blockers

A

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
Q

Non cardiac indications

A
  • Stroke
  • Vascular, non cardiac surgery: ↓ perioperative death from cardiac causes/infarction in high risk patients
  • Thyrotoxicosis
  • Anxiety states
  • Glaucoma
  • Migraine
  • Esophageal varices
86
Q

Why BB w/: myocardial ischemia

A
  • ↑ 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
Q

Benefits of BB w/ myocardial ischemia

A

o Hu: ↓ mortality by 25-40%
o ↓ventricular arrhythmia and reinfarction

88
Q

Indications for hypertension

A
  • 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
Q

Anti arrhythmics effects

A
  • 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
Q

Mechanism proposed to help w/ HF

A

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
Q

How to apply B blockers in HF

A

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
Q

How BB improve B adrenergic signaling

A

 ↓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
Q

BB self regulation mechanism

A

 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
Q

Hyperphosphorylation hypothesis

A

 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
Q

how bradycardis from BB is beneficial for heart

A

 Improve coronary artery blood flow
 ↓myocardial O2 demand
 ↓ Xtra matrix collagen
 Improve LV EF

96
Q

Effects of catecholamines on myocytes

A

o Protection from catecholamine myocyte toxicity
 CHF → B-stimulation → ↑ circulating catecholamines
* Membrane damage
* Promote sub destruction

12. Pharmacology (10 decks)

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