B blockers Flashcards
Types of B R and site of action
B1 adrenoreceptor: HEART MUSCLE
B2 adrenoreceptor: BRONCHIAL AND VASCULAR SMOOTH MUSCLE
B3 adrenoreceptor: ENDOTHELIAL
B1: types of R
- 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
B1: effect of blocker depends on
o Absorption
o Binding ability
o Generation of metabolites
o Extend of inhibition of B-R
Secondary effects of B blockade
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
B2 receptors
- Receptors: 20-25% of myocardial B-R
o Upregulation in HF
Effect of B2
hypotension + vasodilation
Effect of B3
mediated vasodilation induced by NO
What is B turnoff mechanism
- 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
Turn off mechanism exacerbated by
o CHF: ↑ cisculating catecholamines
o Iatrogenic: B agonists (Dobutamine)
Tachyphylaxis = progressive loss/↓ therapeutic efficacy
1st generation non-selective agents: drugs
Propanolol, sotalol, carteolol, nadolol, penbutolol
1st generation non-selective agents: effect
- Block ALL receptors (B1 + B2)
- Similar effect on cardiovascular system to B1 selective agents
o >marked pulmonary and peripheral effects
2nd generation cardio selective agents: drugs
Atenolol, acebutolol, betaxolol, bisoprolol, metoprolol
2nd generation cardio selective agents: action
- Selective for B1-R
o ↑ selectivity at higher doses
o Bisoprolol = most selective
2nd generation cardio selective agents: cardiovascular effects
bradycardia, negative inotropy, vasodilation
o ↓ bronchospasm
o Few peripheral effects
3rd generation vasodilatory agents: drugs
Vasodilatory nonselective: labetalol, carvedilol, pindolol
Vasodilatory selective: nebivolol
3rd generation vasodilatory agents: effect/action
- Direct vasodilation via NO
- A adrenergic blockade
- B2 intrinsic sympathomimetic activity
Goal of B blocker
counter interact adrenergic stimulation
o ↓ myocardial O2 demand: from bradycardia and ↓ contractility
Cardiovascular effect of B blockade
negative
o Chronotrope → SA node
o Dromotrope → AV node
o Inotrope → myocardial contractility
Effect on coronary flow
- 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
Effect on systemic circulation
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
Best B blocker for patients w/ concomitant respiratory dz
cardio selective B1 for bronchospasms
o Non selective tend to cause ↑ pulmonary complications
Best B blocker for patients w/ concomitant cardiovascular dz
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
Side effects
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
Cardiac CI
o Absolute
Severe bradycardia, high degree heart block
Cardiogenic shock
LV failure
o Relative: angina, other agents suppressing AV/SA nodes
Pulmonary CI
o Absolute: severe asthma/bronchospasm
o Relative: mild asthma, bronchospasm, lower airway dz
CNS CI
o Absolute: severe depression
o Relative: hallucinations, highly lipid soluble agent
Peripheral vascular CI
o Absolute: active dz (gangrene, skin necrosis)
o Relative: cold extremities, absent pulse, Raynaud
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
Overdose: c/s
Bradycardia
Overdose: tx
→ responsive to atropine
o Glucagon: theory, should ↑cAMP
o PDEi: amrinone, milrinone
↑[cAMP]
o Dobutamine: positive inotrope
Duration of action esmolol
shortest ½ life (9min) → need CRI for effect
Duration of action propanolol
½ life 3h
Chronic administration: hepatic saturation → longer ½ life
If higher dose given
o Higher dose of any → longer biologic effects
Active metabolite propanolol
4-hydroxypropanolol
Highly protein bound
Metabolism: general
primarily liver or kidney
o 1st pass hepatic metabolism → liposoluble compounds
↓dose inliver dz or low output states
Penetrate brain barrier
Metabolism: propanolol
100% liver
Lipophilic, least water soluble
Metabolism atenolol and sotalol
100% kidney
Hydrophilic, least liposoluble
Low brain penetration
Drug interaction
o ↑ plasma levels of lidocaine
o Paroxetine ↑ plasma levels → inhibition of metabolism (CYP2D6)
Esmolol: MOA
Selective B1
Esmolol: indications
Periop SVT
Non compensatory sinus tach
Emergency hypertension
Unstable angina
Esmolol: pharmacoK
Ultra short acting
Atenolol: MOA
selective B1
Atenolol: indications
Angina
Post infarction
Hypertension
Arrhythmias
SAS, PS
HCM
Atenolol: pharmacoK
Poorly liposoluble
Excreted primarily kidneys
Long plasma ½ life
Bisoprolol: MOA
Highly selective B1
Bisoprolol: indications
Hypertension only
Metoprolol: MOA
Selective B1
Metoprolol: pharmacoK
Moderate liposoluble
Hepatic metabolism
Nebivolol: MOA
Highly cardio selective
Peripheral vasodilation
Nebivolol: pharmacoK
Highly liposoluble
Metabolism: 50% hepatic, 50% renal
Nebivolol: other effects
Reverse endothelial dysfct
↑ insulin sensitivity
Bisoprolol: pharmacoK
Mildly liposoluble
Metabolism: 50% hepatic, 50% renal
Acebutolol: MOA
Selective B1
Acebutolol: pharmacoK
Poorly liposoluble
Metabolism: 20% hepatic, 80% renal
Acebutolol: other effect
Intrinsic sympathomimetic activity
Betaxolol: MOA
selective B1
Betaxolol: pharmacoK
Moderate liposoluble
Metabolism: hepatic
Celiprolol: MOA
selective B1
Propanolol: MOA
Nonselective
Block B1 and B2
Propanolol: indication
Angina
Acute/post myocardial infarction
Hypertension
Arrhythmias
Tetralogy of Fallot
Sinus tach, SVT, VA
HCM
Hypertension
HyperT4
Pheochromocytoma
Propanolol: pharmacoK
Liposoluble
Extensive 1st pass hepatic metabolism
Short plasma ½ life
Carvedilol: MOA
Nonselective B blocker
A1
Antioxidant
Carvedilol: indication
Hypertension
CHF
Post myocardial infarction
LV dysfct
Carvedilol: pharmacoK
Mildly liposoluble
Hepatic metabolism
Carvedilol: other effects
Formation of NO
Stimulation of B-arrestin MAP kinase
A-R
Sotalol: MOA
Nonselective
Class III anti arrhythmic
Sotalol: pharmacoK
Water soluble
Excreted by kidneys
Sotalol: indications
Ventricular arrhythmias
Afib/flutter
Timolol: MOA
Nonselective
Timolol: indications
Post infarct protection
Timolol: pharmacoK
Mildly liposoluble
Metabolism: 80% hepatic, 20% renal
Nadolol: MOA
Non selective
Nadolol: pharmacoK
Poorly liposoluble
Renal metabolism
Labetalol: MOA
Non selective
Labetalol: pharmacoK
Highly liposoluble
Hepatic metabolism mostly, some renal
Pindolol: MOA
Non selective
Pindolol: pharmacoK
Mildly liposoluble
Metabolism: 60% hepatic, 40% renal
Pindolol: other effect
Intrinsic sympathomimetic activity
Carteolol: pharmacoK
Poorly liposoluble
Metabolism: renal
Carteolol: other effects
Intrinsic sympathomimetic activity
Oxprenolol: pharmacoK
Highly liposoluble
Penbutolol: pharmacoK
Highly liposoluble
Hepatic metabolism
Penbutolol: other effects
Intrinsic sympathomimetic activity
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
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
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
Benefits of BB w/ myocardial ischemia
o Hu: ↓ mortality by 25-40%
o ↓ventricular arrhythmia and reinfarction
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
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
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
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
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
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
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
how bradycardis from BB is beneficial for heart
Improve coronary artery blood flow
↓myocardial O2 demand
↓ Xtra matrix collagen
Improve LV EF
Effects of catecholamines on myocytes
o Protection from catecholamine myocyte toxicity
CHF → B-stimulation → ↑ circulating catecholamines
* Membrane damage
* Promote sub destruction
