Applied Neuropharmacology Flashcards
Describe the sequence of events in synaptic transmission?
step one synaptic transmission?
Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals
step two synaptic transmission?
Na+ action potential reaches terminal
step three synaptic transmission?
Activates voltage gated Ca2+ channels
step four synaptic transmission?
Triggers Ca2+-dependent exocytosis of pre-packaged vesicles of transmitter
step five synaptic transmission?
Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
step six synaptic tranmission?
Presynaptic autoreceptors inhibit further transmitter release
step seven synaptic transmission?
Transmitter is (usually) inactivated by uptake into glia or neurons
step eight synaptic transmission?
transmitter is metabolised within cells
What are the different receptor types for neurotransmitters?
Ionotropic (respond to ligand binding)
Metabotropic (acts through a second messenger. It may be located at the surface of the cell or in vesicles)
Is acetylcholine uptaked into glia/neural cells or is it inactivated by breakdown?
Inactivated by enzymatic breakdown in the synaptic cleft
What are some methods of pharmacological manipulation to reduce synaptic transmission?
what are examples of blocking Na+ voltage gated channels?
local anaesthetics, lidocaine
what are examples of blocking Ca+ voltage gated channels?
black widow spider venom
What are some methods of pharmacological manipulation to increase synaptic transmission?
what is a pharmacological management which blocks breakdown of transmitter?
anti-cholinesterases
what is a pharmacological management which blocks uptake of transmitter
SSRIs
what is an example of pharmalogical manipulation that increases synthesis and packaging of neurotransmitter?
e.g. by increasing availability of precursors
What are examples of different neurotransmitters?
Acetylcholine
Monoamines
Noradrenaline
Dopamine
Serotonin (5-HT)
Amino acids
Glutamate
GABA
Glycine
Purines
ATP
Adenosine
Neuropeptides
Endorphins
CCK
Substance P
NO
what are examples of monoamines?
Noradrenaline
Dopamine
Serotonin (5-HT)
what are examples of amino acids?
Glutamate
GABA
Glycine
What are examples of purines that act as neurotransmitters?
ATP
Adenosine
What are examples of neuropeptides that act as neurotransmitters?
Endorphins
CCK
Substance P
A limited range of neurotransmitters means what in terms of function?
a single neurotransmitter has multiple functions in different regions
Often in the brain and in the peripheral nervous system – separated by the blood-brain barrier
What things about neurotransmitters are unique?
Each neurotransmitter has:
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)
What is the anatomical distribution of dopamine?
Brain stem
Basal ganglia
Limbic system and frontal cortex
What physiological functions are affected by dopamine?
Voluntary movement
Emotions/reward
Vomiting
What four pathways does dopamine act in?
mesocortical pathway
nigrostriatal pathway
tubero-infundibular pathway
mesolimbic pathway
What is the mesolimbic pathway?
Projects VTA to nucleus accumbens and other limbic structures
What does overactivity of the mesolimbic pathway lead to?
Schizophrenia and hallucinations
What is the mesocortical pathway?
projects to frontal cortex
The mesolimbic pathway has a role in what?
Role in reward and addiction
The mesocortical pathway has a role in what?
Involved in executive function
What does the tubero-infudibular pathway do?
inhibits prolactin
What is PD caused by?
Degeneration of DA cells in the SN (nigrostriatal)
DA deficiency in the basal ganglia
How does PD impact dopamine?
Caused by degeneration of DA cells in the nigrostriatal so causes dopamine deficiency in the basal ganglia
Describe the synthesis of dopamine?
How can dopamine synthesis be modulated in vivo?
Pharmacologically block the conversion of DOPA to dopamine in the periphery, so DOPA crosses the blood brain barrier into the brain and is converted to dopamine there
Are any dopamine receptors ionotropic?
No ionotropic receptors (so dopamine cannot evoke fast EPSPs or IPSPs)
What class of receptors are dopamine receptors?
Metabotropic (ie g-protein coupled)
How many different subtypes of metabotropic dopamine receptors are there?
5 subtypes named D1 - D5
Dopamine can produce many different effects, and different effects in different brain regions. What does this depend on?
which receptors are expressed
What protein are dopamine receptors coupled to?
D1 and D5
What dopamine receptors inhibite adenylate cyclase?
D2, D3 and D4
What are key enzymes in the breakdown of dopamine?
Monoamine oxidase B (MAO-B)
Catechol-O-methyltransferase (COMT)
What is dopamine ultimately broken down into?
homovanillic acid
What are symptoms of PD?
Stiffness, slow movements, change in posture, tremor
What are examples of dopaminergic drugs?
DA precursor
Levodopa
DA agonists
Ergots:
Bromocriptine, pergolide, cabergoline
No longer used: 5-HT(2B) stimulation → fibrosis
Non-ergots
ropinirole, pramipexole, rotigotine
Apomorphine
These drugs improve some symptoms of PD
Why are dopaminergic drugs used in the treatment of PD?
ease symptoms
what is an example of a DA precursor?
Levodopa
what are exampes of DA agonists?
Ergots:
Bromocriptine, pergolide, cabergoline
No longer used: 5-HT(2B) stimulation → fibrosis
Non-ergots
ropinirole, pramipexole, rotigotine
What are some enzyme inhibitors used for preserve dopamine levels?
Peripheral AAAD inhibitors
Such as carbidopa and benserazide
Decreases peripheral side effects of levodopa and allows greater proportion of oral dose to reach CNS
MAOB inhibitors
Such as selegiline, rasagiline and safinamide
COMT inhibitors
Such as entacapone and opicapone
Decreases metabolism of dopamine and increased effectiveness of levodopa
Peripheral AAAD inhibitors examples?
carbidopa and benserazide
effect of Peripheral AAAD inhibitors?
Decreases peripheral side effects of levodopa and allows greater proportion of oral dose to reach CNS
examples of MAOB inhibitors?
Such as selegiline, rasagiline and safinamide
examples of COMT?
Such as entacapone and opicapone
effect of COMT?
Decreases metabolism of dopamine and increased effectiveness of levodopa
what do enzyme inhibitors have no effect on?
synthetic dopamine agonists
Drug treatment of PD targets what?
Dopaminergic neurons
What are some possible side effects of dopaminergic drugs?
Worsen or cause
Nausea
Vomiting
Psychosis
Impulsivity/abnormal behaviours
Dopaminergic drugs improve what?
Some motor features of Parkinson’s
e.g. limb rigidity & bradykinesia, tremor
what do Dopaminergic drugs fail to help?
“Midline” features
eg dysathria, balance, cognition.
what do dopmaine antagonists improve?
Nausea
Vomiting
Psychosis
what can dopamine antagonists worsen or cause?
Parkinsonism
How can antagonitsts that do not cross the blood brain barrier improve vomiting?
Area postrema (vomiting centre) is in the medullar and functionally outside the blood brain barrier
What is the vomiting centre called?
Area postrema
What drug is used to treat vomiting in PD patients?
Domperiodne
DA antagonist
Anti-emetic
Does not cross blood brain barrier
No antipsychotic properties
Relatively safe to use in PD
Has permitted the therapeutic use of apomorphine (which is a powerful emetic)
What is dyskinesias?
Abnormal involuntary movements
Which of DA agonists and DA antagonists cause dyskinesias?
What can long term DA antagonist use lead to?
GABA agonists are used to treat what?
Anti-epilepsy drug
Also have anti-anxiety properties
Serotonin is used to treat what?
Selective serotonin reuptake inhibitors (SSRIs) are antidepressants
Triptans (selective 5HT agonists) used for the treatment of migraine
Noradrenaline is used to treat what?
Reuptake blockers such as tricyclic drugs are antidepressants
MAO inhibitors are antidepressants
