Applied Neuropharmacology

Question 1

Describe the sequence of events in synaptic transmission.

Answer 1

1. Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals.
2. Na action potential invades terminal.
3. Activates voltage gated Ca channels.
4. Triggers Ca-dependent exocytosis of pre-packaged vesicles of transmitter.
5. Transmitter diffuses across cleft and binds to inotropic and/or metabotropic receptors to evoke presynaptic response.
6. Presynaptic autoreceptors inhibit further transmitter release
7. Transmitter is (usually) inactivated by extracellular breakdown
8. Or transmitter is (unusually) inactivated by extracellular breakdown.
9. Transmitter is metabolised within cells

Question 2

What receptor types are there in neurotransmitters?

Answer 2

Usually multiple receptor-types (both ionotropic and metabotropic) for each neurotransmitter

Question 3

What is the difference between the synaptic transmission of ACh and most other transmitters?

Answer 3

ACh is inactivated by enzymatic breakdown in the synaptic cleft

Most other neurotransmitters are inactivated by high affinity uptake unto neurones and glia

Question 4

How would blocking voltage gated Na channels effect synaptic transmission?

Answer 4

Reduce synaptic transmission

e.g. local anaesthetic
Blocks all action potentials so isn’t too useful

Question 5

How would blocking voltage gated Ca channels effect synaptic transmission?

Answer 5

Reduce synaptic transmission

e.g. Those clever spider toxins
Would block all transmitter release, not too useful

Question 6

How would blocking the release machinery effect synaptic transmission?

Answer 6

Reduce synaptic transmission

e.g. Botox
Would block all transmitter release, not too useful

Question 7

How would blocking the postsynaptic receptors effect synaptic transmission?

Answer 7

Reduce synaptic transmission

e.g. Receptor antagonists
Competitive or non-competitive
(Selectivity helps)

Question 8

How would increasing the breakdown of transmitter effect synaptic transmission?

Answer 8

Reduce synaptic transmission

Question 9

How would increasing the uptake of transmitter effect synaptic transmission?

Answer 9

Reduce synaptic transmission

Question 10

How would inhibiting synthesis and packaging of transmitter effect synaptic transmission?

Answer 10

Reduce synaptic transmission

Question 11

Why is using an agonist to activate the postsynaptic receptors not so useful?
What is a better alternative?

Answer 11

Using an agonist to activate the postsynaptic receptors isn’t so useful because they get activated all the time (most of which is inappropriate)

Better to use an allosteric drug that doesn’t activate the receptor on its own, but potentiates the effects of the endogenous transmitter
e.g. benzodiazepines and barbiturates on GABA receptors

Question 12

How would blocking the breakdown of transmitter effect synaptic transmission?

Answer 12

Increase synaptic transmission

e.g. anticholinesterases on ACh

Question 13

Why is it hard to design drugs to specifically target effects of a synaptic transmission?

Answer 13

Most drugs are “dirty” drugs.
Wont just do one thing and will effect many different areas.

There is a limited range of neurotransmitters.

• So it should be no surprise that a single neurotransmitter has multiple functions in different regions
• Often in the brain and in the peripheral nervous system (separated by blood brain barrier)

Question 14

What is the limited range of neurotransmitters?

Answer 14

Acetycholine
Monoamines
Amino Acids
Purines
Neuropeptides
NO

Question 15

List the Monoamine neurotransmitters

Answer 15

Noradrenaline
Dopamine
Serotonin (5-HT)

Question 16

Name the Amino Acid neurotransmitters

Answer 16

Glutamate
GABA
Glycine

Question 17

Name the Purine neurotransmitters

Answer 17

ATP

Adenosine

Question 18

Name the Neuropeptide neurotransmitters

Answer 18

Endorphins
CCK
Substance P

Question 19

Why is NO a unique neurotransmitter?

Answer 19

NO isn’t packed up and released on Ca dependent exocytosis.

It is produced on demand as it is lipid soluble

Question 20

Each neurotransmitter has 3 different attributes what are they?

Answer 20

Its own anatomical distribution

Its own range of receptors it acts on

Its own range of functions in different regions (some separated by the blood brain barrier)

Question 21

Dopamine effects what physiological functions?

Answer 21

Vomiting
Voluntary movement
Emotions

Question 22

What is Parkinson’s disease?

Answer 22

Degeneration of Dopamine cells in the substantia nigra (nigrotriatal)

This causes a dopamine deficiency in the basal ganglia

Symptoms and signs:

• Tremour, Slowness, Stiffness, Stooped over posture
• Get gradually worse over time

Question 23

What is the key enzyme in Dopamine synthesis which is lost in Parkinson’s disease?

Answer 23

Tyrosine Hydroxylase
(converts tyrosine to DOPA)

Enzyme that converts DOPA to dopamine will still be abundant.
If you can get DOPA in you will get Dopamine produced

Question 24

Explain the difference in DA synthesis between the periphery and brain and the pharmacological significance of this

Answer 24

Tyrosine cannot be converted to DOPA in the brain

Tyrosine can be converted to Dopamine in the periphery

Dopamine cannot cross blood brain barrier but tyrosine and dopa can.

Dopa could be given but this would greatly increase peripheral Dopamine therefore enzyme for converting DOPA to dopamine is pharmacologically blocked

Question 25

Explain dopamine receptors

Answer 25

No ionotropic receptors (so dopamine cannot evoke fast EPSPs or IPSPs) 5 subtypes of metabotropic (i.e. g-protein coupled) receptor named D1-D5 Dopamine can produce many effects, and different effects in different brain regions, depending on which receptors are expressed So, in theory at least, a selective agonist or antagonist could produce a specific therapeutically useful effect

Question 26

How is dopamine broken down?

Answer 26

2 pathways (both breaking dopamine down to homovanillic acid) MAO-B and COMT are the key enzymes in dopamine breakdown

Question 27

List the dopaminergic drugs

Answer 27

DA precursor -Levodopa (most effective) DA agonists - Bromocriptine, pergolide (considered old fashioned) - Ropinirole - Pramipexole - Apomorphine These drugs improve the symptoms of PD

Question 28

What enzyme inhibitors can you use to treat PD?

Answer 28

Peripheral AAAD inhibitors -Carbidopa, benserazide MAOB inhibitors -Selegiline COMT inhibitors -Entacapone These drugs have no effect on synthetic dopamine agonists

Question 29

What do enzyme inhibitors add to the treatment of PD?

Answer 29

Peripheral AAAD inhibitors -Reduces peripheral side effects of levodopa and allows a greater proportion of the oral dose to reach the CNS Dopamine enzyme inhibitors -Reduce the metabolism of dopamine and so increase the effectiveness of levodopa

Question 30

Dopaminergic drugs have what effects?

Answer 30

Improve Parkinson's -e.g. rigidity and bradykinesia in the limbs Worsen or cause - Nausea - Vomiting - Psychosis Fail to help: - Midline features - e.g. dysathria, balance, cognition

Question 31

What is dysathria?

Answer 31

Slurred speech

Question 32

What effects will dopamine antagonists have?

Answer 32

Improve: - Nausea - Vomiting - Psychosis Worsen or cause: - Parkonsin's/ parkinsonism - e.g. rigidity and bradykinesia in the limbs

Question 33

Discuss vomiting and the blood brain barrier

Answer 33

Dopamine antagonist antiemetics will worsen PD and generally should not be used in people with PD. Area postrema (vomiting centre) in the medulla is functionally OUTSIDE BBB. if there was a DA antagonist that didn't cross the BBB that would be ok (There is: DOMPERIDONE)

Question 34

Describe domperidone

Answer 34

``` DA antagonist Anti-emetic Does not cross the BBB No antipsychotic properties Relatively safe to use in PD Has permitted the therapeutic use of apomorphine (which is a powerful emetic) ```

Question 35

Treatments may cause dyskinesia. What is dyskinesia? What may cause it?

Answer 35

Abnormal involuntary movements = AIMs Dopaminergic drugs -May cause dyskinesia (e.g. chorea) "too much movement" DA antagonists -May cause parkinsonism "not enough movement"

Question 36

What may happen with long term DA antagonist use? | What do you do about it?

Answer 36

Anti-emetics? NO -Chronic vomiting doesn't happen Antipsychotics? Yes -Often no alternative Often cause parkinsonism -e.g. receptor blockade in basal ganglia Sometimes cause dyskinesias: - Tardive dyskinesias (orofaciolingual) - ---Hard to explain: up regulation or increased sensitivity of certain DA receptors

Question 37

What drugs are used for abnormal Noradrenaline?

Answer 37

Reuptake blockers -e.g. tricyclic drugs are antidepressants MOA inhibitors are antidepressants

Question 38

What drugs are used for abnormal Serotonin; 5-HT?

Answer 38

Selective serotonin reuptake inhibitors (SSRIs) are antidepressants. Triptans (selective 5-HT) used for the treatment of migraine

Question 39

What drugs are used for abnormal GABA?

Answer 39

GABA agonists are anti-epilepsy drugs. | They also have anti-anxiety properties