Beta Blockers (Dawes) Flashcards
What are the 7 indicators for Beta Blockers?
- Hypertension
- Angina
- Heart failure
- Arrhythmias (AF, atrial flutter, SVT)
- (most beta-blockers are used in rate control- not to treat rhythm) only used to slow down rate in hope to minimize damage of tachycardia)
- Thyrotoxicosis
- Reduce conversion of T4 to T3 (more potent)
- Symptom relief only
- Migraine prophylaxis
- Anxiety
What are the mechanism of action of Beta Blockers?
Adrenergic Receptors
Note that beta blockers have the ability to block bronchodilation, which has increased risk of asthma flare-ups
Beta-blockers block b-adrenergic receptor pathways
- Chronic beta-blockade can lead to the attenuation of mitogen-activated kinases associated with beta-receptors.
- In response to long-term beta-blockade, more beta receptors are produced on post-synaptic membrane to try and overcome blockade.
Mechanism Of Action
b-blockers antagonise b-adrenoreceptors. Most b-blockers block b1 and b2 receptors (not really any b3 blockers)
It has varying selectivity:
- b1>>>b2 includes metoprolol, atenolol, celiprolol,esmolol etc.
- b1=b2 includes propranolol, nadolol
Mixed antagonists (a and b blocker) include labetalol, carvedilol.
What drugs have greater affinity for B1 than B2 receptors?
Metoprolol
Atenolol
Celiprolol
Where are B1 and B2 receptors found?
What do they do?
B1
- Heart (causes tachycardia, increased contractility
- Kidneys
- Adipocytes
B2
- Blood vesses (dilatation)
- Bronchi (relaxation)
What are the pharmacological differences between the different types of Beta Blockers?
1) Selectivity (b1 vs b2)
2) Solubility (water/hydrophilic vs lipid/lipophiic)
3) Elimination (renal vs liver)
- Water soluble mainly eliminated in the kidneys
- Lipid soluble mainly metabolized in the liver, can also cross BBB
4) Half-life (variable)
- Water soluble have long half-life
- Lipid soluble have shorter half-life (absorbed rapidly, rapid metabolism by liver)
5) Additional properties/mechanisms
- a-adrenergic blocking properties
- Antioxidant / NO enhancing
- Intrinsic sympathomimetic activity (ISA)
6) Inverse agonism (metoprolol>carvedilol)
7) Receptor upregulation (↓ carvedilol)
Briefly describe the pharmacokinetics of 3 commonly used Beta Blockers
- Metoprolol
- b1 blocker
- Lipid soluble, hepatic metabolism
- Atenolol
- b1 blocker
- Polar (water soluble), renal excretion
- Propranolol
- b1 and b2 blocker
- Lipid soluble, hepatic metabolism
Describe the Pharmacokinetics of Beta Blockers
Pharmacokinetics
Absorption
- Well-absorbed orally
- Sustained release preparations, some IV preparations
Distribution
- Variable lipophilicity
-
Propranolol, metoprolol has high lipophilicity.
- Extensive rapid gut absorption
- Pre-systemic metabolism (gut wall and liver); high protein binding
- Can cross BBB
-
Atenolol, sotalol has low lipophilicity (high hydrophilic)
- Renal excretion
- Longer half-life
-
Propranolol, metoprolol has high lipophilicity.
- Half-life of 2-5 hours
Summary
One exception to conventional pharmacokinetics is esmolol
- Requires IV infusion because of extremely short half-life (few minutes), as it is eliminated by blood esterase
- Used in intensive care in people with very high BP emergencies (allows us to titrate dosage quickly to find effective dose)
Describe the CVS pharmacodynatmics (effects) of Beta blockers?
1) Lowering BP (mechanism unclear)
- Reduce cardiac output (decrease HR, decrease cardiac work)
- Reset baroreceptors
- Renin inhibition (because renin is under beta-agonist control)
- Central actions (reduce sympathetic activity)
- Presynaptic actions
- b blockers® reduce norepinephrine release
- Decreases TPR
2) Negative chronotropic (reduce heart rate)
- SA node effects
- AV node transmission
3) Inotropic effects
-
Negative (acute/short term)
- If patient presents with acute heart failure, giving beta-blocker can worsen symptoms since decreased inotropy can decrease perfusion further
- Instead, stabilize patient with diuretics, then slowly introduce beta-blocker after a week or so
- Positive (chronic/long term)
Describe pharamcodynamics of Beta Blockers in
1) Respiratory system
2) Eye
3) Metabolic system
4) Thyrotoxicosis
5) Migrane
Respiratory
- b2 receptor antagonism
- Contraindicated in asthmatics
Eye
- Reduce aqueous humour production
- Given topically to reduce pressure in eye, e.g. in people with glaucoma
Metabolic
- Decreases glycogenolysis (b2), important in people with diabetes (not contraindication)
- In diabetic hypoglycaemia, bodies breakdown glycogen (glycogenolysis) to increase glucose
- Beta-blocker can prolong hypoglycaemia and mask diabetic hypoglycaemia
Thyrotoxicosis (Hyperthyroidism)
- Negatively chronotropic
- Decreases conversion of T4 to T3, therefore reducing symptoms of hyperthyroidism
Migraine
- Particularly lipophilic drugs since they can cross the BBB (unknown central mechanism)
- Chronically improving migraine
What are some adverse effects of Beta-Blockers?
Beta-Blockers Adverse Effects
- In respiratory system, it causes asthma exacerbation
- In CVS, it causes
- hypotension,
- bradycardia,
- acute CCF exacerbation (negative inotrope),
- promote vasospasm
- Fatigue, impotence, nightmares
- Mask hypoglycaemia
- Drug withdrawal
- Be careful with chronic beta-blockers users, need to titrate it down
- Long term use causes increase expression of beta receptors on post-synaptic membrane, sudden stoppage can cause marked tachycardia, hence nasty angina attack (withdrawal symptom).
What are the drug interactions with Beta Blockers?
- Verapamil
- (contraindication, marked negative chronotropic effect (both drugs are potent, negatively chronotropic))
- Verapamil is a calcium channel blocker
- (contraindication, marked negative chronotropic effect (both drugs are potent, negatively chronotropic))
- Diltiazem
- (caution, but acceptable as diltiazem has a milder effect)
- Diltiazem is a calcium channel blocker.
- (caution, but acceptable as diltiazem has a milder effect)
- Other BP lowering drugs
- Antidiabetic drugs (hypoglycaemia awareness)
Describe the indicators for Beta-Blockers
Angina
- It includes metoprolol CR (23.75-190mg/day), atenolol (25-100mg/day)
- Reduce heart rate and cardiac work, improve symptoms
Post MI
- Decreases arrhythmias (there is sympathetic surge post-MI, blockade can reduce risk of arrhythmia)
- Decreases ventricular rupture
- Increases cardiac remodelling (increased ejection fraction)
Heart Failure (Chronic)
- Heart failure patients are almost always on ACE inhibitor and b-blocker.
- These b-blockers are primarily indicated for reduced ejection fraction heart failure (equally effective, despite different mechanisms):
- Carvedilol (mixed b antagonist/a antagonist/antioxidant) (3.125mg bd®50mg bd)
- Metoprolol (b1 selective) (23.75mg od®190mg od)
- Bisoprolol (b1 selective) (1.25mg od®10mg od)
Hypertension
- It includes atenolol, metoprolol.
- Mechanism of reducing BP is unclear (2nd/3rd line therapy for hypertension).
Thyrotoxicosis
- It includes propranolol.
- Mechanism is by blocking T4 ® T3 conversion. Improves tachycardia, tremor, agitation.
Migraine
- It includes propranolol.
- Mechanism is via action on central b1 receptors?
Describe the Beta receptor ratios in damaged hearts
Ratio of b2- anda1-Adrenergic Receptors in Damaged Heart
- In damaged heart, b1 receptor population in post-synaptic membrane falls, and ratio of receptors shifts, so there is increased relative proportion of b2- and a1-receptors.
- It is suggested that chronic beta blockade leads to increased b-receptor population to normal, which improves outcome (increased survival).
What are the mechanism of action of beta blockers in HEART FAILURE
Mechanism Of Beta Blockers In Heart Failure
- Decreased cardiac sympathetic tone (¯HR, diastolic filling, ¯O2 consumption)
- Upregulation of beta receptors
- Modulation of post-receptor inhibitory proteins
- Attenuate apoptosis
- Improve baroreceptor function
- Improve LV remodelling
40 year old man with new onset angina, hyperlipidaemia, childhood asthma, and hypertension
Pulse 80bpm, BP 160/80mmHg.
How would you treat this man?
Treatment include:
- Not beta-blocker due to childhood asthma (don’t want exacerbation)
- A good medication would be diltiazem (control heart rate, BP, and reduce cardiac work)
