Medicines delivered to the lungs Flashcards

1
Q

What were the natural starting point for drugs such as salbutamol, dobutamine and xamoterol?

A

Natural neurotransmitters such as noradrenaline and adrenaline

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2
Q

What are adrenergic receptors?

A

G protein receptors

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3
Q

Where does the serine residue interact with in a catecholamine?

A

Phenolic group via hydrogen bonding

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4
Q

Where does the aromatic ring of the Phe-290 (phenylalanine) react?

A

Catechol ring via van der waal interactions

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5
Q

Where does the aspartic residue act on the catecholamine?

A

Protonated nitrogen by ionic bonding

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6
Q

Define what a catecholamine is?

A

Any class of aromatic amines that include a number of neurotransmitters such as noradrenaline and dopamine

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7
Q

Explain what the activation of beta 2 receptor agonists resulted in?

A
  1. Bronchial relaxation in the lungs where there are many beta 2 receptors
  2. Dilation of the airways
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8
Q

Explain the action of adrenaline on the airways and why it was replaced with isoprenaline?

A
  1. Adrenaline is only short acting and isn’t selective on Beta 2 receptors
  2. It activated many different beta receptors which led to many side effects and cardiovascular effects
  3. Isoetherine is more selective on the beta 2 receptors so is used as an anti-asthmatic
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9
Q

Explain how isoprenaline was more selective to beta receptors compared to alpha receptors and how they made compounds more selective in the future?

A
  1. Large bulky N alkyl substituent
  2. No selectivity differences between different types of Beta receptors
  3. Introducing alkyl substituents to the side chain made the compounds more selective to beta receptors
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10
Q

In order to prevent COMT from turning molecules into inactive ethers, what was done about the molecules? What was the end result?

A
  1. Meta-phenol group was replaced with a group that could selectively bind to the receptor, but couldn’t be metabolised
  2. Production of Salbutamol by changing the meta-phenol group to a hydroxyethyl group
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11
Q

What is chiral switching?

A
  1. When a patented racemic drug is reaching the end of its patent
  2. Companies then form the pure enantiomer that is proven to work better than the racemic form
  3. Example: Salbutamol (R) is 68 more times active then (S) form
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12
Q

Describe N-alkylation in terms of salbutamol?

A
  1. Salbutamol has a bulky N-t-butyl group (NH- C- (CH3)3)
  2. The bulkier the N- alkyl substituent meant loss of potency at alpha receptor (increased potency at beta receptor)
  3. Bulky arylalkyl group can fit into a Beta adrenoceptor with a “hydrophobic pocket”
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13
Q

What is salmefamol compared to salbutamol?

A

Has a Bulky N-arylalkyl is 1.5 times more potent than salbutamol and has longer duration of activity (6 hours)

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14
Q

How was salmeterol produced and how does it compare to salbutamol?

A
  1. Nocturnal asthma was a problem that occurred around 4am which needed to be solved
  2. A more lipophilic drug would bind more strongly to the tissue and act for a longer period of time
  3. This was done by increase the length of the N- substituent with a further hydrocarbon chain and aromatic ring
  4. Twice the potency of salbutamol and an extended action of 12 hours
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15
Q

How is an anti-asthmatic drug reduced in terms of life time?

A
  1. Most anti-asthmatic drugs are inhaled in the form of an inhaler to reduce the number of side effects in the body
  2. However, it’s life time is reduced when a lot of it is swallowed and absorbed into the blood supply by the gastrointestinal tract
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16
Q

What is the problem with an anti-asthmatic drug such as Cromakalim?

A

It has useful anti-asthmatic properties and is potent/stable but is easily metabolised in the blood stream to cause cardiovascular problems

17
Q

Describe the synthesis of salbutamol?

A
Step 1 – Friedel Craft acylation (Aspirin)
Step 2 – Esterification
Step 3 – Bromination
Step 4 – Nucleophilic substitution
Step 5 – Reduction
Step 6 - Hydrogenation (salbutamol)