Applied Neuropharmacology

Question 1

Describe a synaptic transmission - Ca2+ dependant exocytosis

Answer 1

Synthesis and packing of neurotransmitter in presynaptic terminals
Na action potential reaches terminal
Activates voltage gated Ca channels which triggers the exocytosis of pre-packaged vesicles of transmitter

Question 2

Describe synapse transmission after Ca dependant exocytosis

Answer 2

Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
Presynaptic auto receptors inhibit further transmitter release
Transmitter inactivated by uptake into glia or neurons
Transmitter metabolised within cells

Question 3

What are some ways which there can be pharmacological manipulation to reduce synaptic transmission?

Answer 3

Block voltage gated Na channels
Inhibit synthesis an packaging of neurotransmitter
Activate presynaptic inhibitory receptors
Block postsynaptic responses
Block voltage gated Ca channels
Increase breakdown of neurotransmitter
Block release machinery
Increase uptake of transmitter

Question 4

What is an example of a pharmacological agent which blocks voltage gated Na channels?

Answer 4

Local anaesthetic

Question 5

What is an example of a pharmacological agent which blocks release machinery?

Answer 5

Botulinum

Question 6

What are some pharmacological manipulations to potentiate synaptic transmission?

Answer 6

Block uptake of transmission - SSRI
Block breakdown of transmitter - anti-cholinesterase
Potentiate effects of transmitter on receptor
Activate postsynaptic receptors with an agonist
Increase synthesis and packaging of neurotransmitter

Question 7

What are some neurotransmitters?

Answer 7

Acetylcholine
Monoamines - NA, dopamine, serotonin
Amino acids - glutamate, GABA, Glycine
Purine - ATP and adenosine
Neuropeptides - endorphins, CCK, Substance P
NO

Question 8

Does neurotransmitters have one or multiple functions?

Answer 8

Multiple as minimal range of neurotransmitters
Often have function in brain and PNS separated by BBB

Question 9

What does each neurotransmitter have?

Answer 9

Own anatomical distribution, own range of receptors it acts on, and own range of function in different regions

Question 10

Where is the anatomical distribution of dopamine in the brain?

Answer 10

Brainstem
Basal ganglia
Limbic region and frontal cortex

Question 11

What are the physiological effects of dopamine?

Answer 11

Voluntary movement
Emotions and reward
Vomiting
Acts on tubero-infundibular pathway

Question 12

What is Parkinson’s disease?

Answer 12

Degeneration of DA cells in the SN
Dopamine deficiency in basal ganglia

Question 13

How is dopamine synthesised?

Answer 13

From glycine - tyrosine - DOPA to dopamine

Question 14

How can DA synthesis be modulated in vivo?

Answer 14

Can give injection of DOPA to increase DA but has side effects in periphery
This increases DA in BBB
Need to pharmacologically block AAAD so dopamine isn’t increased in periphery and stops unwanted side effects

Question 15

Describe dopamine receptors

Answer 15

No ionotropic receptors
5 subtypes of metabotropic receptors D1-5
Depending on which receptors - different effects and regions of brain effected

Question 16

What are the key enzymes in dopamine metabolic breakdown?

Answer 16

Monoamine oxidase B - MAO-B
catechol-O-methyltransferase - COMT

Question 17

What is dopamine metabolised into?

Answer 17

Homovanillic acid

Question 18

What are the symptoms of Parkinson’s disease?

Answer 18

Stiffness, slow movements, change in posture and tremor

Question 19

What is a DA precursor drug?

Answer 19

Levodopa

Question 20

What are some DA agonist drugs?

Answer 20

Ergots - no loner used, bromocriptine
Non-ergots - ropinirole, pramipexole, rotigotine
Apomorphine

Question 21

What are some enzyme inhibitors used for PD?

Answer 21

Peripheral AAAD inhibitors - carbidopa, benserazide
MOAB inhibitors - selegiline, rasagiline, safinamide
COMT inhibitors - entacapone, opicapone

Question 22

What is the function of peripheral AAAD inhibitors?

Answer 22

Decrease peripheral side effects of levodopa and slows greater proportion of oral dose to reach the CNS

Question 23

What is the function of MOAB and COMT inhibitors?

Answer 23

Decreases metabolism of dopamine and increases effectiveness of levodopa

Question 24

What is given with levadopa?

Answer 24

Carbidopa or Benserazide to decrease peripheral side effects
COMT inhibitor to decrease DA metabolism

Question 25

What can worsen or be caused by dopaminergic drugs?

Answer 25

Nausea, vomiting, psychosis, impulsivity/ abnormal behaviours

Question 26

What does dopaminergic drugs help improve?

Answer 26

Some motor features of PD
Limb rigidity, bradykinesia and tremor

Question 27

What does dopaminergic drugs fail to help in PD?

Answer 27

Midline features
Dysarthria, balance and cognition

Question 28

What does dopamine antagonists improve and worsen?

Answer 28

Improves nausea, vomiting, and psychosis
Worsens parkinsonism

Question 29

Describe DA antagonists antiemetics and vomiting

Answer 29

Worsens PD and should not be given
The vomiting centre in medulla is outside the BBB - need a DA antagonist that dosen’t cross the BBB - domperidone

Question 30

What is domperidone?

Answer 30

DA antagonist, anti-emetic, does not cross BBB, no antipsychotic properties and relatively safe in PD
Has permitted therapeutic use of apomorphine
Risk is QT prolongation

Question 31

What is dyskinesia?

Answer 31

Abnormal involuntary movements
Dopaminergic drugs may cause this but DA antagonists may cause PD

Question 32

What are some long term effects of DA antagonist use?

Answer 32

Antipsychotics/ anti-dizziness
Often cause PD as receptor blockage at basal ganglia
Dyskinesia