Beta Blockers

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  • Created by: LBCW0502
  • Created on: 21-01-19 18:36
What is a beta blocker?
A substance that blocks (antagonises) beta receptors throughout the body. Abundant and widely distributed. Affect many organ systems and are used in many disease states
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Beta blockers interact with which type of receptors?
GCRPs (mechanism)
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Beta blockers are used for which treatments?
Angina pectoris (chest pain - lack of oxygen to the heart). Arrhythmias (irregular heart rhythms). Heart attack. Heart failure. Hypertension (high BP)
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Beta blockers are used as a prophylaxis to reduce to risk of what?
Protects the heart in people who have coronary artery disease. Reduces risk of stroke. protective prior to non-cardiac surgery in persons at high risk of complications
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Describe features of the effectiveness of beta blockers (1)
Generally work by affecting the response to some nerve impulses. B1 receptors are responsible for HR and strength of heart beat/force of contraction. B2 receptors responsible for function of smooth muscles (control autonomic body functions)
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Describe features of the effectiveness of beta blockers (2)
Want more selective b1 and b2 blockers (to reduce side effects)
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Who discovered the first beta blocker?
Sir James Black
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Outline the biosynthesis of noradrenaline and adrenaline
L-tyrosine - (tyrosine hydroxylase) - levodopa - (dopa decarboxylase) - dopamine - (dopamine beta hydroxylase) - noradrenaline - (N-methyltransferase) - adrenaline (in adrenal medulla)
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Which two enzymes are used to metabolise adrenaline?
MAO (forms aldehyde which is unstable and is converted to COOH group) and COMT (adds methoxy group to structure) - makes structure more water soluble to be excreted
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Describe features of the design strategy for beta blockers (1)
Propranolol modified by replacing methyl group with isopropyl group to make it bulkier. Formation of isoprenaline (not effective as beta blocker, it is a selective beta agonist)
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Describe features of the design strategy for beta blockers (2)
OH replaced with Cl (bulkier) to form dichloropisoprenaline (partial agonist and toxic)
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Describe features of the design strategy for beta blockers (3)
Aromatic ring added to DCI to form pronethalol (partial agonist but also blocked receptors)
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Describe features of the design strategy for beta blockers (4)
Introduce oxygen to structure – formation of propranolol (antagonist but not selective). Propranolol structure is the pharmacophore for beta blockers
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Describe features of propranolol
First successful beta blocker developed. Non-selective. Treatment for hypertension. S isomer 100 x more active than R isomer. Control tachycardia tremor associated with anxiety. Migraine prophylaxis. CI (asthma, bronchitis, block b2 receptors)
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Outline the synthesis of propranolol (1)
Phenol (pKa ~ 10) add NaOH (remove proton), add epichlorohydrin (alkyl halide), Sn2 reaction to remove Cl atom (two different Sn2 reaction pathways), add amine (reacts with epoxide) to produce beta blocker
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Outline the synthesis of propranolol (2)
Make different beta blockers by using different amines. Epichlorohydrin – very toxic. Mixture of two enantiomers (chiral carbon in epichlorohydrin)
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Outline the synthesis of propranolol (3)
Either separate R/S enantiomers or use different (chiral) epichlorohydrin
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What are the key components of a beta blocker chemical structure?
Naphthalene can be replaced by heteroaromatic groups. Ether acts as H-bond acceptor. Alcohol needed for H bonding. Must have secondary amine. Ionised for receptor interaction. Isopropyl group directs beta blocker activity
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Give other examples of non-selective beta blockers
Nadalol (remove aromaticity), pindolol (heterocycles), timolol (aryls)
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Describe features of second generation beta blockers (1)
Propranolol act on b1 and b2 adrenoceptors. Antagonism of b2 receptors constricts airways. Propranolol cannot be used in asthmatic patients. Second generation beta blockers are designed to be b1 selective
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Describe features of second generation beta blockers (2)
Must be para-substituted on the aromatic ring (fit in receptor). Extra H bonding interaction takes place. Not possible with b2 adrenoceptors
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Give examples of b1 selective beta blockers (para-substitution)
Atenolol, acebutolol, metoprolol, betaxolol, bisoprolol, esmolol
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What is the log P for propranolol?
2.2 (facilitate transfer across BBB, CNS side effects, make compound more hydrophilic)
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What are the log D values for atenolol, betaxolol and bisprolol?
-1.80, 0.31, -0.06
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Describe features of bisoprolol (1)
Both lipid and water soluble properties, prime candidate over other beta blockers, decreased CNS effects (doesn't pass BBB). t1/2 of 10-12 hrs (nearly complete absorption into blood when ingested)
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Describe features of bisoprolol (2)
b1 selective (heart and kidneys), minimise effects of non-selective beta blockers, bisoprolol suitable for cardiac events (b1 - cardiospecific)
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What are the clinical effects of beta blockers?
Alleviate angina (justified). Lower BP (unexpected). Hypertension now main area of use
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How is propranolol metabolised?
Glucuronidation. CYP450 (OH added to aromatic ring). MAO (amine and methyl group replaced with OH and COOH)
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Describe features of cardioselective beta blockers
Blocks cardiac b1 receptors without blocking vascular b1 (cardioselective). No effect on bronchial b1 receptors (important for asthmatics)
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What are the properties of beta blockers? (1)
Cardioselectivity (only block b1 receptors). Non-cardioselective beta blockers block both b1 and b2 receptors. Some beta blockers are partial agonists at beta receptors
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What are the properties of beta blockers? (2)
High lipid solubility (short t1/2, high brain penetration). Low lipid solubility (long t1/2, low brain penetration)
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Describe features of glaucoma (1)
Each normal eye produces 2 mL of water/min (metabolism and ion influx, 70 mL in course of life time). In efflux of ion inefficient pressure builds up, normally 10-10 mmHg can raise to 70 mmHg
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Describe features of glaucoma (2)
Timolol is very efficient at reducing this pressure, low log P value < 0.5, less side effects
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Describe drug treatments for anxiety
Penetrate BBB, CNS side effects, antagonists for 5HT receptors. Pindolol and propranolol (particularly active). Assist in coping with stress, relax muscles etc.
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Beta blockers interact with which type of receptors?

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GCRPs (mechanism)

Card 3

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Beta blockers are used for which treatments?

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Card 4

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Beta blockers are used as a prophylaxis to reduce to risk of what?

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Card 5

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Describe features of the effectiveness of beta blockers (1)

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