Applied Neuropharmacology Flashcards
Describe the sequence of events in synaptic transmission.
- Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals.
- Na action potential invades terminal.
- Activates voltage gated Ca channels.
- Triggers Ca-dependent exocytosis of pre-packaged vesicles of transmitter.
- Transmitter diffuses across cleft and binds to inotropic and/or metabotropic receptors to evoke presynaptic response.
- Presynaptic autoreceptors inhibit further transmitter release
- Transmitter is (usually) inactivated by extracellular breakdown
- Or transmitter is (unusually) inactivated by extracellular breakdown.
- Transmitter is metabolised within cells
What receptor types are there in neurotransmitters?
Usually multiple receptor-types (both ionotropic and metabotropic) for each neurotransmitter
What is the difference between the synaptic transmission of ACh and most other transmitters?
ACh is inactivated by enzymatic breakdown in the synaptic cleft
Most other neurotransmitters are inactivated by high affinity uptake unto neurones and glia
How would blocking voltage gated Na channels effect synaptic transmission?
Reduce synaptic transmission
e.g. local anaesthetic
Blocks all action potentials so isn’t too useful
How would blocking voltage gated Ca channels effect synaptic transmission?
Reduce synaptic transmission
e.g. Those clever spider toxins
Would block all transmitter release, not too useful
How would blocking the release machinery effect synaptic transmission?
Reduce synaptic transmission
e.g. Botox
Would block all transmitter release, not too useful
How would blocking the postsynaptic receptors effect synaptic transmission?
Reduce synaptic transmission
e.g. Receptor antagonists
Competitive or non-competitive
(Selectivity helps)
How would increasing the breakdown of transmitter effect synaptic transmission?
Reduce synaptic transmission
How would increasing the uptake of transmitter effect synaptic transmission?
Reduce synaptic transmission
How would inhibiting synthesis and packaging of transmitter effect synaptic transmission?
Reduce synaptic transmission
Why is using an agonist to activate the postsynaptic receptors not so useful?
What is a better alternative?
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
How would blocking the breakdown of transmitter effect synaptic transmission?
Increase synaptic transmission
e.g. anticholinesterases on ACh
Why is it hard to design drugs to specifically target effects of a synaptic transmission?
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)
What is the limited range of neurotransmitters?
Acetycholine Monoamines Amino Acids Purines Neuropeptides NO
List the Monoamine neurotransmitters
Noradrenaline
Dopamine
Serotonin (5-HT)
Name the Amino Acid neurotransmitters
Glutamate
GABA
Glycine
Name the Purine neurotransmitters
ATP
Adenosine
Name the Neuropeptide neurotransmitters
Endorphins
CCK
Substance P
Why is NO a unique neurotransmitter?
NO isn’t packed up and released on Ca dependent exocytosis.
It is produced on demand as it is lipid soluble
Each neurotransmitter has 3 different attributes what are they?
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)
Dopamine effects what physiological functions?
Vomiting
Voluntary movement
Emotions
What is Parkinson’s disease?
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
What is the key enzyme in Dopamine synthesis which is lost in Parkinson’s disease?
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
Explain the difference in DA synthesis between the periphery and brain and the pharmacological significance of this
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
Explain dopamine receptors
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
How is dopamine broken down?
2 pathways (both breaking dopamine down to homovanillic acid)
MAO-B and COMT are the key enzymes in dopamine breakdown
List the dopaminergic drugs
DA precursor
-Levodopa (most effective)
DA agonists
- Bromocriptine, pergolide (considered old fashioned)
- Ropinirole
- Pramipexole
- Apomorphine
These drugs improve the symptoms of PD
What enzyme inhibitors can you use to treat PD?
Peripheral AAAD inhibitors
-Carbidopa, benserazide
MAOB inhibitors
-Selegiline
COMT inhibitors
-Entacapone
These drugs have no effect on synthetic dopamine agonists
What do enzyme inhibitors add to the treatment of PD?
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
Dopaminergic drugs have what effects?
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
What is dysathria?
Slurred speech
What effects will dopamine antagonists have?
Improve:
- Nausea
- Vomiting
- Psychosis
Worsen or cause:
- Parkonsin’s/ parkinsonism
- e.g. rigidity and bradykinesia in the limbs
Discuss vomiting and the blood brain barrier
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)
Describe domperidone
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)
Treatments may cause dyskinesia.
What is dyskinesia?
What may cause it?
Abnormal involuntary movements = AIMs
Dopaminergic drugs
-May cause dyskinesia
(e.g. chorea)
“too much movement”
DA antagonists
-May cause parkinsonism
“not enough movement”
What may happen with long term DA antagonist use?
What do you do about it?
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
What drugs are used for abnormal Noradrenaline?
Reuptake blockers
-e.g. tricyclic drugs are antidepressants
MOA inhibitors are antidepressants
What drugs are used for abnormal Serotonin; 5-HT?
Selective serotonin reuptake inhibitors (SSRIs) are antidepressants.
Triptans (selective 5-HT) used for the treatment of migraine
What drugs are used for abnormal GABA?
GABA agonists are anti-epilepsy drugs.
They also have anti-anxiety properties
