Drugs acting on the central nervous system

Question 1

Local anaesthetic (such as lidocaine) act by ?

Answer 1

Blocking conduction along never fibres

Question 2

What does blocked voltage-gated Na+ ion channels prevent ?

Answer 2

Action potentials

Question 3

Generally, small fibres (e.g. Aδ and C fibres) are?

Answer 3

Blocked more easily than larger ones

Question 4

So, pain conduction is blocked before ?

Answer 4

Other sensory pathways - e.g. touch (Aβ fibres) or motor (Aα fibres)

Question 5

What is anxiety ?

Answer 5

Normal response to threatening situations such as:

• Defensive behaviours
• Arousal and alertness
• Negative emotions

Question 6

Anxiety disorders occur when ?

Answer 6

These reactions are produced without a specific stimulus

Question 7

What are Anxiolytics ?

Answer 7

Drugs used to treat anxiety (worry and fear)

Question 8

What are Hypnotics ?

Answer 8

Drugs used to treat insomnia (being unable to sleep)

Question 9

Many drugs have ?

Answer 9

Both effects

Question 10

Many anxiolytic drugs were first developed to treat other conditions such as ?

Answer 10

• Depression
• Epilepsy
• Schizophrenia

Question 11

What drugs are used to treat anxiety ?

Answer 11

1. Benzodiazepines - most commonly used
   - For short-term (2-4 weeks) relief of anxiety and insomnia that is severe, disabling or causing the patient extreme distress
2. Antidepressants
   - SSRIs, SNRIs, tricyclic antidepressants (TCAs), MAO inhibitors
3. Buspirone
4. Anti-epileptic drugs
5. Antipsychotic drugs (used to treat schizophrenia)
6. β-adrenoreceptor antagonists (e.g. propanolol)
   - Treat the symptoms associated with anxiety, e.g. tremor, sweating, palpitation, etc.

Question 12

What is the mechanism of action of benzodiazepines?

Answer 12

1. Binds to GABAa receptor anf increase their affinity for GABA
2. Effects:
   - Reduction of anxiety
   - Sleep
   - Anticonvulsant
   - Amnesia

Question 13

Where does Benzodiazepines bind at ?

Answer 13

An allosteric site at interface between α and γ subunits

Question 14

What is Flumazenil ?

Answer 14

It is a competitive antagonist of BDZ

- Used to treat overdose

Question 15

What is β- carboline ?

Answer 15

This is an inverse agonist

• Causes increased anxiety
• Stabilises inactive form of GABA receptor and decreases affinity for GABA

Question 16

What happens when Benzodiazepines is used as hypnotics ?

Answer 16

Short acting benzodiazepines (midazolam, lorazepam) - less ‘hangover’ effects (do not feel sleepy/drowsy the next morning)

Question 17

Why should it not be used for long periods ?

Answer 17

(2 to 4 weeks only for severe anxiety and insomnia) due to tolerance and dependence

Question 18

What are some other hypnotics ?

Answer 18

1. Zaleplon, zolpidem, zopiclone
   - Known as the ‘z’- drugs
   - Bind to GABAa receptor similar to benzodiazepines (but not benzodiazepines structurally)
   - Specific for α1 subunit - no anxiolytic activity
2. Chlormethiazole
   - Binds to GABAa receptor at a different site to benzodiazepines
3. Melatonin receptor agonists, e.g. melatonin
   - Involved in setting diurnal (day/night) rhythm
4. Antihistamines (1st generation), e.g. promethazine
   - Develop for hay fever, but can cause drowsiness

Question 19

According to the monoamine theory of depression, drugs that ?

Answer 19

Drugs that increase serotonin or noradrenaline transmission enhanced mood

Question 20

Explain the serotonin (5HT) signalling in neurones ?

Answer 20

• 5-HT synthesised with nerve terminal and released into the synaptic cleft upon depolarisation
• 5-HT is recovered into presynaptic nerve terminal by 5-HT reuptake transporter for degradation
• Selective Serotonin Reuptake Inhibitors (SSRIs) thus increases synaptic levels of serotonin
• MAO also degrades 5-HT
• Presynaptic 5-HT1D receptor acts as an autoreceptor to provide negative feedback on 5-HT release

Question 21

Where is Noradrenaline synthesised ?

Answer 21

In the nerve termini and released into synaptic cleft upon depolarisation

Question 22

What is on the presynaptic nerve termini and what does it do ?

Answer 22

There is NA reuptake transporter on the presynaptic nerve termini transporting NA back to the presynaptic neurons for degradation by enzymes such as monoamine oxidase (MAO)

Question 23

What does presynaptic α2-adrenoceptors act as and what does it provide?

Answer 23

Presynaptic α2-adrenoceptors act as autoreceptors to provide negative feedback on NA release

Question 24

What is the basis of action of the antihypertensives clonidine and methyldpopa?

Answer 24

α2-agonists that cause sympathetic inhibition - lowers blood pressure

Question 25

What are drugs acting indirectly on noradrenergic pathways ?

Answer 25

Sympathomimetics

Question 26

What are sympathomimetic amines structurally similar to ?

Answer 26

Noradrenaline

Question 27

What does Amphetamine produce ?

Answer 27

Strong stimulation (also release 5-HT and dopamine in brain)

Question 28

What is Ephedrine used as?

Answer 28

Decongestant (in colds)

Question 29

What do Monoamine oxidase inhibitors ?

Answer 29

Inhibit monoamine oxidases and therefore increase levels of neurotransmitters (e.g. NA, 5-HT) in neurons

Question 30

What are the two forms of MAOs ? and what do they break down ?

Answer 30

Type A and Type B - Type A preferably breaks down NA and 5-HT - Both Type A and B breaks down Dopamine and Tyramine

Question 31

Give example of MAO irreversible inhibitors ?

Answer 31

- Isocarboxazid, phenelzine, tranylcypromine - Bind to the enzyme covalently - Non-selective for type A and B MAO

Question 32

Give example of MAO reversible, selective inhibitors ?

Answer 32

- Moclobemide - Selective for MAO- A (NA and 5-HT specific) - (MAO-B inhibitors, e.g. Selegilline are used as an adjunct in the treatment of Parkinson's disease)

Question 33

What are the side effects of MAOIs ?

Answer 33

1. Hypotension 2. Increased appetite and weight gain 3. Insomnia 4. 'Cheese reaction' - Cheese and other fermented food rich in tyramine - Normally metabolised by MAOs in gut and liver - With MAOIs, tyramine enters the bloodstream - Displaces NA in nerve terminals causing sympathomimetic effect - Causes acute hypertension

Question 34

Why are Selective Serotonin Reuptake Inhibitors (SSRIs) currently the most commonly prescribed (first-line drig treatment) ?

Answer 34

- Fewer side-effects than MAOIs or TCAs - Safer in overdose (some risk of cardiac arrhythmia) However, relatively more expensive

Question 35

What does Fluoxetine and paroxetine inhibit ?

Answer 35

CYP2D6 - should not be used with TCAs

Question 36

What are some other examples of SSRIs ?

Answer 36

Citalopram, escitalopram, sertraline, fluvoxamine

Question 37

What is Parkinson's disease ?

Answer 37

1. Progressive neurodegenerative disease characterised by: 4 main symptoms: - Tremor - Muscle rigidity - Bradykinesia (reduction in voluntary movement) - Postural instability

Question 38

What do some other symptoms include ?

Answer 38

- Sleep, sensory and autonomic disturbances | - Cognitive impairment

Question 39

What are the possible causes of Parkinson's disease ?

Answer 39

1. Genetic and environmental factors - Mutation in a gene coding for a synaptic protein called α-Synuclein has been implicated - Toxin MPTP and chronic systemic exposure to pesticides can cause Parkinson-like symptoms 2. Drug-induced (known as 'Parkinsonism' - Affects 10-15% of patients using dopamine receptor antagonists (e.g. antipsychotics) - Drugs implicated in induing Parkinson-like symptoms include: - Antiemetics - Antipsychotics - SSRIs, lithium, cinnarizine, valproate

Question 40

What is the Pathogenesis of PD ?

Answer 40

- Loss of dopaminergic neurons in basal ganglia, especially substantia nigra and nigrostriatal pathway - PD becomes clinically significant when ~80% of the dopaminergic neurons in substantia nigra is lost (there is a ~5% year latency period)

Question 41

What is the pharmacological treatment of PD ?

Answer 41

1. Disease progression can be rapid particularly in early onset (young patients) PD 2. All agents used only to treat symptoms, do not reverse or stop the progression of the disease - Dopamine Precursor; Levodopa - Dopamine receptor antagonists - Monoamine oxidase B (MAO-B) inhibitors - Catechol-O-methyltransferase (COMT) inhibitors - Anticholinergics (antimuscarinics)

Question 42

Explain Levodopa (L-dopa)?

Answer 42

- Most effective treatment - Dopamine (DA) cannot cross BBB, so ineffective given orally or IV - Levodopa (L-dopa) is the precursor of DA, absorbed well from GI tract and actively transported across the BBB (the brain's natural source of DA) - However, 99% of L-dopa is metabolised peripherally to DA by dopa decarboxylase, contributing to side effects (e.g. nausea & vomiting, postural hypotension)

Question 43

Explain DOPA decarboxylase inhibitors ?

Answer 43

1. L-dopa given with inhibitors of dopa dearboxylase, cabidopa or benserazide - Prevent L-dopa decarboxylation in periphery - Cannot cross BBB, so L-dopa can be converted to DA only within the brain - Reduces levodopa dose needed by 10 fold, and reduces side-effects

Question 44

L-dopa + carbidopa =

Answer 44

Co-careldopa (Sinemet)

Question 45

L-dopa + benserazide =

Answer 45

Co-beneldopa (Madopar)

Question 46

Explain the relationship between CBD and Parkinson's ?

Answer 46

A significant increase in well-being & quality of life was observed in Parkinson's patients with the use of CBD