Pharmacology of neurotransmitters Flashcards
What are the main types of inhibitory and stimulatory neurotransmitters in the CNS?
STIMULATORY
glutamate
INHIBITORY
GABA
Why is brain pharmacology complicated?
one neurotransmitter has multiple has effects
with many pathways that are interconnected
this is also why drugs modulating CNS pharma are complex and numerous
(unlike peripheral pharmacology)
What are the association between dopamine and disease?
PARKINSON’S DISEASE
reduced dopamine
PSYCHOSIS, SCHIZOPHRENIA
increased dopamine
What is the association between serotonin and disease?
DEPRESSION reduced serotonin (5-HT)
What is the association between GABA and disease?
SEDATION, ANXIETY
increased GABA
What are the main features of a neurotransmitter?
- synthesised in neurons
- stored in vesicles and secreted from neurons
- identity of action: stimulate neurons/receptors should be the same effect as applying NT
- receptors for NT: use of agonists or antagonists
- termination of response: uptake transporters or enzymes
What are the different types of neurotransmitters in the CNS?
AMINO ACIDS
fast mechanism
excitatory, inhibitory
AMINES
slower response than AAs
more involved with modulation of the excitation/inhibition response rather than binary response
NEUROTROPHIC AGENTS
not technically NTs
work in conjunction with NTs to modulate their effects
sometimes these are also secreted from other non-neural cells e.g. immune cells
What are the AMINO ACID types of neurotransmitters in the CNS?
EXCITATORY
glutamate
aspartate
INHIBITORY
GABA
glycine
What is GABA?
-> key inhibitory NT
= gamma-amino-butyric -acid
What are the AMINE types of neurotransmitters in the CNS?
- dopamine
- serotonin (5-HT)
What are types of neurotrophic agents active in the CNS?
- Substance P
- calcitonin-gene related peptide (CGRP)
- vasoactive intestinal peptide (VIP)
- brain-derived neurotrophic factor (BDNF)
released from neurones + other cell types
can act at pre- or post-synaptic sites (do not conform to normal NT rules)
The synthesis of which 2 NTs are interconnected?
glutamate + GABA
this means that changes in glutamate will potentially affect GABA function too
How is glutamate made?
(= NT)
- converted from glutamine released from glial cells, which then enter the neurones
- made from glucose via the Krebs cycle
(so if increased rate of Krebs cycle, increase ate of glutamate synthesis)
How is GABA made?
From glutamate
via glutamic acid decarboxylase (enzyme is required in GABAergic neurons)
What is glutamate?
major EXCITATORY NT in CNS
distributed through the CNS
Binds to:
1) ligand-gated ion channel receptors (fast)
e. g. AMPA, NMDA and kainate
- > binding causes Na+/Ca2+ influx and membrane depolarisation and AP firing
2) GPCR: mGlu (slower response)
both will induce AP firing in subsequent neuron via binding at the post-synaptic membrane
How is glutamate involved in learning and memory?
SYNAPTIC PLASTICITY is the basis for learning/memory
high frequency stimulation of neurons, enhances the synaptic activity
Glutamate -> NMDA -> Ca2+ influx -> synapse function modulated -> basis for learning and memory (hippocampus)
What is glutamate excitotoxicity?
Glutamate is toxic when overexpressed to abundant in the synapses
Removed quickly (glutamate uptake transporters) into glial cells or converted into glutamine in astrocytes
Stroke: ischaemia -> cell death -> necrotic release of glutamate -> hyper-stimulation -> glial cell toxicity
What is the pharma potential of glutamate?
interesting for neurodegeneration
but may have huge side effects
What is ketamine?
non-competitive block/inhibitor of NDMA receptors
(blocks effects of glutamate binding)
- anaesthesia
- recreational
What is GABA?
major INHIBITORY NT in CNS
mainly found in interneurones
Binds to:
1) ligand gated: GABA-A
2) GPCR: GABA-B
What proportion of CNS is GABAergic?
30% of all synapses are GABAergic
What is the purpose of having inhibitory interneurones in the CNS?
provides distinction between different types of excitation
does this by breaking down neural info into levels of excitation (relative to inhibitory signals)
How does GABA-A signalling work?
binds to ligand-gated ion channels
Causes Cl- influx: results in hyperpolarisation -> termination of AP (inhibition)
How does GABA-B signalling work?
binds to GPCRs
causes opening of K+ channels and therefore closes Ca2+ channels
-> hyperpolarisation -> termination of AP (inhibition)
How does glycine NT work?
inhibitory NT, important in the spinal cord
binds to a ligand-gated receptor/ion channel: causes Cl- influx -> hyperpolarisation -> AP termination
What are the effects of inhibitory NT binding at the pre-synaptic terminal?
reduced release of excitatory NTs
How do benzodiazepines work?
increased activity go GABA-A receptors (agonist)
increased Cl- influx (channel activity increases)
- used for sedation, anxiety
How do barbiturates work?
similar mechanism to benzodiazepines (GABA-A agonist, increased Cl- flux -> hyperpolarisation -> inhibition of AP)
not used as much due to toxic effects
How does strychnine world?
glycine receptor antagonist
reduced Cl- activity (Cl- influx) -> reduced effect of glycine -> reduced inhibitory transmission -> (indirectly more excitatory transmission)
SE include: muscle spasm, asphyxiation (very toxic)
How does tetanus toxin work?
= glycine receptor antagonist
reduced glycine release -> less inhibitory transmission -> (indirectly more excitatory transmission)
effects: muscle spasms, lock-jaw
What are the associations between dopamine and disease?
PSYCHOTIC DISORDERS
increased dopamine
PARKINSON'S DISEASE reduced dopamine (neurons)
ADDICTION
changes to dopamine levels
Where does dopamine work in the CNS?
Projections of dopaminergic neurons in CORPUS STRIATUM.
These neurons travel to:
- PRL (anterior pituitary)
- motor cortex (cerebellum)
- addiction, reward, dependence (temporal lobe)
What does dopamine bind to?
5 known dopamine receptors: D1-D5
All GPCRs
How is dopamine synthesised?
FROM L-TYR
tyrosine -> DOPA
-> tyr hydroxylase (rate-limiting step)
DOPA -> dopamine
-> DOPA decarboxylase (DCC)
How is dopamine broken down?
2 pathways:
- Monoamine oxidase (MAO)
- catechol-O-methyltransferase (COMT)
How may dopamine levels be increased pharmacologically?
- increase synthesis from L-Tyr
- reduce catabolism (MAOi or COMTi)
Why is it insufficient to prescribe oral dopamine on its own (Levodopa) for Parkinson’s disease?
oral DOPA will undergo first pass metabolism in the liver
and will be converted to dopamine peripherally and catabolised before reaching the brain
Can’t just increase the dose, because then you will just see the peripheral effects as side effects
What is oral dopamine usually prescribed with for Parkinson’s disease?
- Peripheral DDC inhibitor (Cardidopa), does not cross BBB
this means that DOPA will only be converted to dopamine in the brain - COMT inhibitor (entacapone)
prevents dopamine metabolism (systemically)
Why do only a 1/3rd of PD’s patients have improvements after 5 yr?
whilst oral DOPA + DDCi + COMTi is effective (80% pt improvement)
this effect reduces over time
(thought to be due to build up of tolerance and high circulating dopamine altering how neurons work- plasticity)
side effects: dyskinesia, mood changes, fluctuation in clinical state (bad-to-good-to-bad)
N+V, anorexia, hypotension
Which dopamine agonists are used for Parkinson’s Rx?
BROMOCRIPTINE (D1/D2 selective) often first-line Rx few motor adverse effects not as effective as L-DOPA SE: excessive vomiting, sleepiness (somnolence)
ROPINIROLE (D2/3 selective) newer drug less side effects evidence for changing behaviour: may stimulate reward system (temporal lobe) e.g. gambling, sexual disinhibition
What is somnolence?
sleeping for an excessively long period of type
different to hypersomnia
What are MAO-B inhibitors?
used to Rx Parkinson’s disease
e.g. SELEGILINE
MAO-B specific to CNS (not in periphery)
therefore blocking MAO-B does not cause cheese reaction
Levedopa + selegiline combo is better than levodopa alone (for Sx relief and prolonging life)
What is a cheese reaction?
HYPERACUTE HYPERTENSION (hypertensive crisis)
cheese/chocolate contain high [TYRAMINE] which gets exchanged for NA in sympathetic nerves
causes hyperstimuatopn of a1 receptors and hypertensive crisis
normally tyramine is catabolised by MAO, but if there are MAOi on board, the tyramine will accumulate
Why are dopamine antagonists used?
strong correlation between increased [dopamine] and psychosis/schizophrenia
What is haloperidol?
typical anti-psychotic drug, selective D2 receptor antagonist
Significant SE (extra-pyramidal):
- acute dystonia (PD-like)
- akathisia (restlessness)
- tardive dyskinesia (pointless random movements, difficult to reverse)
- Hyper-PRL reaction (gynaecomastia and weight gain since no negative feedback)
How does Olanzapine work?
Atypical anti-psychotics
D2 and 5-HT2 receptor antagonist
less extrapyramidal effects
can cause metabolic issues: weight gain, DM, lipid profile changes
What are extra-pyramidal effects?
usually in dopamine modulation
- acute dystonia (PD-like)
- akathisia (restlessness)
- tardive dyskinesia (pointless random movements, difficult to reverse)
- Hyper-PRL reaction (gynaecomastia and weight gain since no negative feedback)
Why do anti-psychotic drugs often have compliance issues?
often many side effects
and take a long time to take effect
What is the solution? Depot administration?
What is serotonin?
NT: strong link to mood disorders (depression, anxiety)
14 5-HT receptors (13 GPCRs, 1 ligand-gated)
5-HT3 binds to ligand-gated ion channel (MoA for Endansentron)
Where are serotoninergic neurons located?
originate in the midbrain but travel into multiple parts of the cortexes (many effects)
multiple functions: behaviour, mood, sleep, feeding
also linked to endogenous analgesia pathway in descending spinal cord
What is stress-induced analgesia?
Descending pathways of spinal cord capable fo inhibiting pain signals entering the spinal cord due to 5-HT signalling (there is sensing of pain, but no transmission to the brain means there is no interpretation of pain)
e.g. in trauma
How is serotonin synthesised?
From TRYPTOPHAN (essential dietary AA)
tryptophan -> 5-hydroxytryptophan
(tryptophanhydroxylase)
5-hydroxytryptophan -> 5-HT
(5-hydroxytryptophan decarboxylase)
How is serotonin signal catabolised?
taken up from cleft into the presynaptic terminal (uptake transporter)
5-HT not degraded directly in synaptic cleft
broken down by MAO in presynaptic terminal
What are the associations between serotonin (5-HT) and disease?
MOOD (AFFECTIVE) DISORDERS
reduced 5-HT
How do SSRIs work?
anti-depressants
= selective serotonin re-uptake inhibitors
e.g. fluoxetine
reduces 5-HT reuptake into pre-synaptic terminals (increases the [5-HT] in the synapse)
used to treat moderate-severe depression, panic disorder, OCD
safer in OD
How do tricyclic anti-depressants work?
e.g. amitryptyline
used to Rx moderate-severe depression, neuropathic pain (low doses)
works by: 5-HT and NA reuptake inhibitor
What other drugs target the 5-HT system?
MAO INHIBITORS e.g. phenelzine anti-depressants can trigger cheese reaction not used that much
SUMATRIPTAN
5-HT1B/D agonist
vasoconstriction
Rx for migraine
BUSPIRONE
5-HT1A agonist
Rx anxiety
ONDANSENTRON
5-HT3 agonist
Anti-emetic
ATYPICAL ANTI-PSYCHOTICS
e.g. olanzipine
also blocs 5-HT2 receptors
How are 5-HT agonists used to treat neuropathic pain?
utilises the stress-induced analgesia mechanism
increases 5-HT signalling in descending pathway of spinal cord
therefore blocks sensory pain signals the brain
no interpretation
reduced pain
(used at lower doses for this application)
