Applied Neuropharmacology

Question 1

Describe the general sequence of events that occur during

synaptic transmission

Answer 1

Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals

Na+ action potential invades terminal

Activates voltage gated Ca2+-channels

Triggers Ca2+-dependent exocytosis of pre-packaged vesicles of transmitter (ie Ca2+ comes in and vesicle lets neurotransmitters out

Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response

Presynaptic autoreceptors inhibit further transmitter release

Transmitter is (usually) inactivated by uptake into glia or neurones

Or transmitter is (unusually) inactivated by extracellular breakdown - Ach inactivated by enzymatic breakdown

Transmitter is metabolised within cells

Question 2

how could you block synaptic transmission? (7)

Answer 2

Block the voltage gated Na+ channels – eg local anaesthetics, would block all action potentials, not too useful.

Block the voltage gated Ca2+ channels – eg those clever spider toxins, would block all transmitter release, not too useful.

Block the release machinery, eg botox, would block all transmitter release, not too useful.

Block the postsynaptic receptors, eg receptor antagonists, competitive or non-competitive. Selectivity helps. Lots of examples of that.

Activate those presynaptic inhibitory receptors.

Inhibit synthesis and packaging of transmitter.

Or if you need to potentiate the action of a transmitter, what would you do?

Question 3

How could you increase synaptic transmission

Answer 3

Increase synthesis by flooding the cells with the appropriate precursors.

Potentiate effects of transmitter on receptor (eg increase channel open time)

Block breakdown of transmitter

block uptake of transmitter

Question 4

List some common neurotransmitters

Answer 4

Ach

Monoamines:-

• NA
• Dopamine
• Serotonin

Amino acids:-

• Glutamate
• GABA
• Glycine

Purines:-

• ATP
• Adenosine

Neuropeptides:-

• CCK
• Endorphins
• Substance P

Nitric Oxide

Question 5

Neurotransmitters often act in the brain and in the PNS which is separated by what?

Answer 5

the blood brain barrier

Question 6

What happens with Parkinson’s disease

Answer 6

Degeneration of dopamine cells in the substantia nigra

also a dopamine deficiency in the basal ganglia

Question 7

Which physiological functions is dopamine involved with?

Answer 7

voluntary movement
emotions/reward
vomiting

Question 8

Where is dopamine found in the brain?

Answer 8

brain stem
basal ganglia
limbic system and frontal cortex

Question 9

Dopamine synthesis

Answer 9

Glycine - alanine -others Tyrosine - DOPA - Dopamine

Question 10

How is dopamine synthesis modulated in vivo?

Answer 10

can pharmacologically block the conversion of DOPA to Dopamine

Tyrosine can be lost through degeneration so that it doesn’t turn into DOPA

Question 11

There are no ionotropic dopamine receptors - what does this mean?

Answer 11

so dopamine cannot evoke fast EPSPs or IPSPs

Question 12

What are the key enzymes involved in dopamine breakdown?

Answer 12

MAO-B - selegiline, rasagiline

COMT - entacapone, opicapone

Question 13

Symptoms associated with parkinson’s disease

Answer 13

stiffness
slow movements
change in posture
tremor

Question 14

Dopaminergic drugs

Answer 14

precursor - Levodopa (L’DOPA) - its supplementation can increase dopamine levels in the body

agonists:-
Ergots - Bromocriptine, perfolide

Non-Ergots - ropinirole, pramipexole
Apomorphine

These drugs improve some symptoms of PD

Question 15

How do peripheral Aromatic L-amino acid decarboxylase (AAAD) inhibitors work

Answer 15

they inhibit the synthesis of dopamine by the AAAD enzyme

decrease peripheral side-effects of levodopa and allows a greater
proportion of the oral dose to reach the CNS

Question 16

Give 2 examples of peripheral AAAD inhibitors

Answer 16

carbidopa

benserazide

Question 17

How do MAOB and COMT inhibitors work?

Answer 17

decrease metabolism of dopamine and so increase effectiveness of levodopa

Question 18

Dopaminergic drug pros and cons

Answer 18

pros - improve some motor features of Parkinson’s - limb rigidity and bradykinesia (slow movement), tremor

cons - worsen or cause nausea, vomiting, psychosis, impulsivity/abnormal behaviour

Question 19

What do dopaminergic drugs fail to help? (3)

Answer 19

dysathria - speech articulation
balance
cognition

Question 20

Dopamine antagonists (block dopamine receptors) pros and cons

Answer 20

improve nausea, vomiting, psychosis

worsen or cause Parkinsonism

Question 21

what is Parkinsonism?

Answer 21

a clinical syndrome characterised by tremor, bradykinesia (slow!), rigidity, and postural instability. It is found in Parkinson’s disease

Question 22

what type of drug should generally not be used in people with Parkinson’s disease

Answer 22

dopamine antagonist antiemetics (anti-sickness) as these worsen parkinson’s disease

Question 23

what is the area postrema and where is it found?

Answer 23

vomiting centre

functionally found outside the BBB

Question 24

Name a Dopamine antagonist that does not cross the BBB

Answer 24

domperidone

Question 25

What is domperidone?

Answer 25

an anti-emetic that doesn’t cross the BBB

has no antipsychotic properties

relatively safe to use in Parkinson’s disease

Question 26

What is dyskinesias

Answer 26

abnormal involuntary movements

Question 27

which type of drug may cause dyskinesias?

Answer 27

dopaminergic drugs (too much movement)

Question 28

GABA agonists are what type of drugs?

Answer 28

anti-epilepsy drugs

also anti-anxiety