Pharmacology of the nervous system

Question 1

When thinking about individual drugs what are the 3 main things to think about?

Answer 1

1. What is the target for the drug?
2. Where is the effect produced or where is the target (more precise the better)?
3. What is the response produced when the drug interacts with the target.

Question 2

In the case of Heroin, what is the response produced?

Answer 2

• Think about why people take it?
  
  • Analgesia
  • Cough suppression
  • Euphoria
• Therefore, the response can be different based on what you are trying to achieve.

Question 3

In the case of Heroin, where would the effect be produced?

Answer 3

• For analgesia:
  
  • Different parts of the brain but Peri-aqueductal grey region is significant.
• For cough suppression:
  
  • Solitary nucleus
• For Euphoria:
  
  • The ventral tegmental area

Question 4

In the case of Heroin, what is the target or what is it binding to?

Answer 4

• Opioid receptor
  
  • Recognises opioid endogenous and exogenous compounds
  • Exogenous include:
    
    • Heroin
    • Morphine
  • Endogenous include:
    
    • Endorphins

Question 5

How can side effects be produced?

Answer 5

Side effects can be produced by drug action:

• On other targets in the same tissue or other tissues
• On the same target in other tissues
• Dependent on the dose of drug administrated.
  
  • Off-target effects tend to kick in as the dose increases.

Question 6

What is the relevance of the figure below for the pramipexole side effects?

Answer 6

• There are 4 dopaminergic pathways in the brain so you may get side effects as other pathways may also be impacted by dopamine receptor agonists.
• Pramipexole can act on dopamine receptors (same target) but in different tissues yielding unwanted side effects.
• For example, acting on the dopamine receptors in the gut may lead to a degree of constipation.

Question 7

What are the characteristics of the ‘safest’ drugs?

Answer 7

• The safest drugs have a large difference between the dose required to induce the desired effect and the dose required to induce side effects/adverse effects.
• Increasing dose decreases selectivity as drug effects are dose-related.

Question 8

What are the 4 main classes of drugs target?

Answer 8

Over 99% of drug effects are produced by interaction with one of these targets:

• Enzymes
• Ion channels
• Receptors
• Transport proteins

Question 9

What are the 4 most commonly prescribed drugs (both locally and globally)?

Answer 9

Not all CNS drugs, some act peripherally:

• Atorvastatin
• Amlodipine
• Salbutamol
• Citalopram

Question 10

What does atorvastatin target and what effects does it have?

Answer 10

• Acts on enzymes
• Statins are the most commonly prescribed drugs in the UK.
• Atorvastatin acts on an enzyme called HMG co a reductase by inhibiting it.

Question 11

What does amlodipine target and what effects does it have?

Answer 11

• Act on ion channels
• Acts on calcium channels and is useful for hypertension.
• Blocking the ion channel causes a certain amount of vasodilation reducing BP.

Question 12

What does salbutamol target and what effects does it have?

Answer 12

• act on receptors
• Present in blue (Ventolin) inhalers for asthma
• Bind to beta two adrenergic receptors in the lung and stimulates a response.
• Bronchodilator

Question 13

What does citalopram target and what effects does it have?

Answer 13

• Acts on transport proteins
• Antidepressant
• Selective Serotonin Reuptake Inhibitor (blocks SSR).

Question 14

What effect can drug acting on targets bring about?

Answer 14

• Enhanced activation - stimulate an effect
• Prevent activation - block an effect from being produced.

Question 15

What characteristic is required for a drug to be a really effective therapeutic agent?

Answer 15

• It must show a high degree of selectivity to a drug target.
• In designing drugs, ideally, you would want to design a drug that would only fit into one target

Question 16

Consider 3 central nervous system neurotransmitters: Dopamine, Noradrenaline and Serotonin. Are there structural similarities?

Answer 16

• They have differences but they are pretty similar overall
• The consequence of this is that to a certain degree they are going to fit in same sort of locks.

Question 17

Why might selectivity be more important for drugs than endogenous compounds like dopamine?

Answer 17

• Endogenous compounds like neurotransmitters are specifically delivered to their drug targets.
  
  • They are released into relevant synapses where they can affect a drug target
  • Dopamine is found in vesicles in nerve terminals of dopaminergic pathways (in dopaminergic nerves) to act on dopamine receptors.
  • Noradrenaline released by a noradrenaline producing nerve to act on adrenergic receptors.
  • Serotonin released by serotonergic nerves very close to serotonin receptors.
• Exogenous drugs largely taken orally need to get into the body, then into the bloodstream and then be distributed to the relevant tissue to cause an effect.
  
  • Problem is it can get into any tissue and if the drug is similar to an endogenous compound that acts on a different drug target then it may cause side effects.

Question 18

What is a side effect?

Answer 18

• An effect produced by the drug that is secondary to the intended effect.
• They can be off-target effects or on-target effects.

Question 19

What is an adverse effect?

Answer 19

It is a side effect that has negative health consequences.

Question 20

What will increasing doses of pramipexole achieve in terms of off-target effects?

Answer 20

• No effect at a really low dose
• Increasing dose slowly at a certain point, the therapeutic effect will kick in
• It is a domain receptor agonist and is most similar to dopamine so at a relatively low dose it will have dopamine like effects.
• But as you increase the dose, some serotonergic side effect kicking in
• Eventually, other side effects like noradrenaline side effects will kick in.
• This is because although Pramipexole is not very similar to serotonin and noradrenaline, it is similar enough to activate some receptors at a high dose.

Question 21

Session review

Answer 21