BETA ADRENERGIC RECEPTOR ANTAGONISTS Flashcards
What are the 4 Non-selective (first generation) beta adrenergic receptor antagonists?
Nadolol
Propranolol
Timolol
Sotalol
4 B-1 selective Antagonists (Second Gen)
Atenolol
Bisoprolol
Esmolol
Metroprolol
2 Non-selective 3rd generation Beta antagonists
Carvedilol
Labetalol
Name 1 B1-selective (3rd gen.) antagonist
Nebivolol
B1-receptor locations and what they affect
2 organs of interest
Heart
* Rate
* Contractility
* Automaticity
* Conduction velocity
Kidney (juxtaglomerular cells)
* Renin release
B-2 receptor locations and functions
3 organs of interest
Lung
* Bronchorelaxation
Skeletal muscle
* Vasodilation
* Glycogenolysis
Liver
* Glycogenolysis
* Gluconeogenesis
Identify some pharmacological properties of Beta receptor antagonists
Absorption (exceptions) / Distribution / Metabolism (exception)
Well absorbed after oral administration
Bioavailability is limited to varying degrees due to first-pass
metabolism
* Except for sotalol
Rapidly distributed and have large volumes of distribution
Most β antagonists have half-lives in the range of 3-10
hours
* Esmolol is a major exception, 10 min half-life
Primary mechanisms of action of B-antagonists
Specifically block β adrenergic receptors
Differ in their relative affinities for β1 and β2 receptors
None are absolutely specific for β1 receptors
* Selectivity is dose-related
Identify some secondary (variable) mechanisms of action. (when do they inhibit activation of B receptors, and when do they activate them).
Agonist / ISA / what can they help prevent
Secondary mechanisms (variable)
* Partial agonists as well
- Also referred as intrinsic sympathomimetic activity (ISA)
- Inhibit the activation of β receptors in the presence of high catecholamine concentrations
– but moderately activate the receptors in absence of endogenous agonists
* May help prevent profound bradycardia or negative inotropy
* Clinical significance is unclear
Identify additional secondary mechanisms of action
anesthetic / what do they block / CV effects
Local anesthetic or membrane-stabilizing activity
Block α1 receptors (labetalol, carvedilol)
Additional cardiovascular effects (third generation β blockers)
* Vasodilator (nebivolol, carteolol)
* Antioxidant (carvedilol)
B-adrenergic antagonists effects on the cardiovascular system. (HR, contractility, automaticity and conduction)
When are effects most evident?
Decreases most sympatheticallysupported cardiac functions
* Heart rate, contractility, automaticity and conduction
Depends on activity of sympathetic nervous system
* Modest effect when tonic stimulation is low
* Cardiovascular effects are most evident with exercise
- Attenuates expected rise in heart rate and contractility
B antagnoist effects on BP, Cardiac Output, short term / long term effect on total peripheral resistance (TPR).
effect on presynaptic norepinephrine release / renin
Lowers blood pressure in patients with hypertension
* Generally do not lower blood pressure in normotensive patients
Mechanisms not fully understood
* Decreased CO
- Acute compensatory increase in TPR
- Reduction in TPR with long-term use
Block presynaptic β2 receptors that enhance NE release
Reduced β1-stimulation of renin release from juxtaglomerular cells
Additional vascular effects (e.g. vasodilation)
B antagonist effects on the eye
- Reduce intraocular pressure
- Decreased aqueous humor
- Useful for patients with chronic open-angle glaucoma
Adverse effects on the CV-system
heart failure / Heart rhythm / Vascular / discontinuation / exercise
May cause or exacerbate heart failure
* Yet, extensive clinical evidence demonstrates that β blockers prolong the lives of heart failure patients
Bradyarrhythmias
* Particularly in patients taking other drugs that impair sinus or AV node function
Exacerbate peripheral vascular disease
* Raynaud’s phenomenon
Abrupt discontinuation
* Exacerbates angina
* Increased risk of sudden death
Exercise intolerance
Adverse effects on pulmonary system
receptor / asthma / COPD / less likely / ischemic heart disease
Block β2 receptors in bronchial smooth muscle
* Little effect in normal individuals
* In patients with asthma or COPD, can cause life-threatening bronchoconstriction
Less likely with β1-selective antagonists or β antagonists with Intrinsic sympathomimetic activity
* Should still be used with great caution in patients with bronchospastic diseases
* Patients with COPD may tolerate β1- selective blockers
- Benefits for patients with concomitant ischemic heart disease may outweigh the risks
Adverse effects on CNS
- Fatigue
- Sleep disturbances (insomnia, nightmares)
- Depression
- No clear correlation with the incidence of CNS effects and
lipophilicity
Adverse Metabolic Effects
which ones less likely to affect metabolism?
Delays recovery from hypoglycemia
* β2-mediated effects of catecholamine on gluconeogenesis and glycogenolysis
* β1-selective antagonists are less likely to delay recovery from hypoglycemia
Blunts the perception of symptoms of hypoglycemia
* Tremor, tachycardia, nervousness
Propranolol (first gen. non-selective prototype) mechanism of action.
receptors / onset / bioavailability
- Competitive, reversible antagonist of β1 and β2 receptors
- Rapid and completely absorbed
- Substantial first pass metabolism causes variable bioavailability
PROPRANOLOL clinical uses
BP / heart /
Hypertension
Angina pectoris
Cardiac arrhythmias
Myocardial infarction
Pheochromocytoma
-As an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine- secreting tumors
Migraine prophylaxis
Essential tremor
PROPRANOLOL Adverse effects
Cardiovascular:
* Bradycardia
* Hypotension
* Acute heart failure
Other:
* Bronchospasm
* Blunt recognition of hypoglycemia
* Fatigue
Abrupt withdrawal symptoms
TIMOLOL (non-selective 1st Gen) mechanism of action / therapeutic use
Competitive, reversible antagonist of β1 and β2 receptors
Major therapeutic use
* Glaucoma
- Decreases aqueous humor formation
- Also available orally and used similarly as propranolol
METOPROLOL (B1 2nd gen) mechanism of action
Competitive, reversible antagonist of β1 receptors
* Cardioselective
At low doses, is more selective for β1 receptor (10 fold)
METOPROLOL Clinical Uses
- Hypertension
- Angina
- Acute myocardial infarction
- Congestive heart failure
METOPROLOL: Adverse Effects
Some overlap with propranolol, especially with cardiovascular effects:
* Bradycardia
* Hypotension
* Acute heart failure
* Fatigue
Less risk of bronchoconstriction or metabolic effects
* Mediated by β2 receptors
ESMOLOL: Mechanism of action / half-life / metabolism / route / and clinical uses
Moderately selective β1 receptor antagonist
Ultra-short acting
* t1/2 = ~8 min
Cleaved by esterases in the plasma
Administered intravenously and is used when β blockade of
short duration is desired
* Intraoperative and postoperative tachycardia and/or hypertension
* Sinus tachycardia
* Supraventricular tachycardia and atrial fibrillation/flutter
Labetalol: Mechanism of action / clinical uses
Competitive, reversible antagonist of α1 and both β receptors
Used to treat:
* Hypertension
* Hypertensive emergencies (IV administration)
Nebivolol: Mechanism of action / vascular effects / clinical uses
Highly selective β1 receptor antagonist
Also stimulates NO-mediated vasodilation
Used to treat:
* Hypertension
Carvedilol: Mechanism of action / inflammation / clinical uses
Competitive, reversible antagonist of α1 and both β receptors
Also has antioxidant and anti- inflammatory properties
Blocks L-type calcium channels at higher doses
Used to treat:
* Heart failure with reduced ejection fraction
* Hypertension
* Reduces mortality in patients after myocardial infarction
Efficacy of BETA
ADRENERGIC RECEPTOR
ANTAGONISTS treating hypertension
first line therapy? /
Effective and well-tolerated
No longer a first-line therapy, particularly in patients over
age 60 years
* May be associated with inferior protection against stroke risk (particularly among smokers)
Beta blockers without ISA are preferred in patients with
angina or a history of myocardial infarction
How do BETA ADRENERGIC RECEPTOR ANTAGONISTS help treat Ischemic Heart Disease?
cardiac work / O2 / angina / exercise / MI / indicated during…
Blockade of cardiac β receptors results in:
* Decreased cardiac work
* Reduction in oxygen demand
Reduces the frequency of angina episodes
Improves exercise tolerance in many patients with angina
Prolongs survival of patients who have had a myocardial infarction
* Timolol, propranolol, metoprolol
Strongly indicated in the acute phase of myocardial infarction
* To reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable
* Should use a β antagonist without ISA (Intrinsic sympathomimetic activity)
CLINICAL USE OF BETA ADRENERGIC RECEPTOR ANTAGONISTS for Cardiac arrhythmias
AFIB / AV-node / ectopic beats / esmolol / sotalol
Effective in the treatment of both supraventricular and ventricular arrhythmias
Slows ventricular response rates to atrial flutter and fibrillation
* Increases atrioventricular nodal refractory period
Can also reduce ventricular ectopic beats, especially if precipitated by catecholamines
Esmolol is useful against acute perioperative arrhythmias
* Short duration of action
Sotalol has antiarrhythmic effects involving ion channel blockade
CLINICAL USE OF BETA ADRENERGIC RECEPTOR ANTAGONISTS in Heart failure
Effective in reducing mortality in patients with chronic
heart failure
* Metoprolol, bisoprolol, carvedilol
Mechanisms are uncertain
* Beneficial effects on myocardial remodeling
* Decreases the risk of sudden death
CLINICAL USE OF BETA
ADRENERGIC RECEPTOR
ANTAGONISTS in Glaucoma
pressure / topical administration / adverse effects
Reduces intraocular pressure
* Reduced production of aqueous humor by the ciliary body
Open-angle glaucoma
* Comparable efficacy to epinephrine or pilocarpine
* Better tolerated
Beta blockers that lack local anesthetic properties are suitable for local use in the eye
Topical administration:
* Timolol
* Local daily dose applied is small compared to common systemic doses
* Still, may be absorbed from the eye and cause serious adverse effects in the heart and airways
CLINICAL USE OF BETA
ADRENERGIC RECEPTOR
ANTAGONISTS in Hyperthyroidism
Beta blockers ameliorate the symptoms of hyperthyroidism
that are caused by increased beta-adrenergic tone
* These include palpitations, tachycardia, tremulousness, anxiety, and heat intolerance
Should be given to most hyperthyroid patients who do not
have a contraindication to their use
CLINICAL USE OF BETA
ADRENERGIC RECEPTOR
ANTAGONISTS for Migraines
preventative / effective / maybe effective
Preventative treatment
* Reduces the frequency and intensity
- Established as effective
- Propranolol, metoprolol, timolol
Probably effective
* Atenolol, nadolol
CLINICAL USE OF BETA ADRENERGIC RECEPTOR ANTAGONISTS for Essential Tremors
Sympathetic activity may
enhance skeletal muscle tremor
* Propranolol
CLINICAL USE OF BETA
ADRENERGIC RECEPTOR
ANTAGONISTS for performance anxiety
- Reduction of the somatic
manifestations of anxiety - Propranolol
B1-selective antagonists are preferable in patients with:
- Bronchospasm
- Diabetes
- Peripheral vascular disease
- Raynaud’s phenomenon
- Third generation β antagonists may offer therapeutic advantages
