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Psychopharmacology lecture notes
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Notes Psychopharmacology lecturesHeleen de Kruijff
Specificiteit: in hoeverre een stof specifiek in zijn werking is, als receptoren op veel meer
organen zitten, waardoor je meer bijwerkingen kan krijgen.
Selectiviteit: in hoeverre een stof selectief is om aan een bepaalde receptor te binden of dat
het aan veel receptoren bindt.
Lecture 1: introduction
April 21th 2020
Part 2: psychopharmacology in bird’s eye view
A drug or pharmacon = an administered substance that influences physiological processes.
- Sometimes these substances are present in the body already, supplement.
- You don’t call it a pharmacon if it is (primarily) a nutrient.
Psychoactive substances = influence processes in the brain and hence behaviour, cognition
and affect.
They can be used in a therapeutic way or recreational.
Pharmacology = studies the influence of substances on biological processes.
Psychopharmacology = focusses on their effects on behaviour, cognition and affect, including
the mechanisms in the brain.
Interest because of clinical applications and development of future applications.
Pharmacokinetics = how does a substance move through the body?
- Is it being degraded? Travels it easily through blood or fat etc.?
- About how medication is metabolised in different people.
Pharmacodynamics = to what receptors does the substance bind and what effect does the
substance have on the receptor?
- What does it do to the body once it is in there?
In psychopharmacology this means: interactions with neurotransmitters.
Part 3: neurotransmitters
Make sure you get this basis for the rest. It is discussed in the book in chapters 2 till 4 as
well.
Neurotransmission basics:
- Neurons: send signals
- Action potential: synapse at the end of an axon is activated.
- Transmitter is released in the synaptic cleft.
- First it has to be synthesised or generated.
- After release there is some degradation to end the action potential.
- Receptors are complex protein chains.
,What is the most typical receptor? A. presynaptic B. postsynaptic C. autoreceptor
- Answer is B. They are the most abundant. Reactions depend on these receptors.
What is not a drug target to influence the functioning of neurons? A. receptor activation B.
metabolite excretion C. reuptake blockade D. enzyme modulation E. all of the above are
possible targets.
- Answer is B. the way metabolites are excreted from the body is typically not a way
drugs influence bodily processes.
- Metabolites are the parts in which a molecule is being dissembles before it is being
excreted. Most of the time they don’t have a psychoactive effect anymore.
Activation of receptors:
- Two types: directly coupled or indirectly coupled via second messengers.
- Intra- and extracellular space is divided by a membrane.
- Potential difference between in- and outside (resting potential is around -70mV)
- Neurotransmitters act on neurons via receptors
- Effect = EPSP or IPSP, a small change with respect to the resting potential that can
add up to the threshold for an action potential.
o EPSP decrease potential differences towards 0 which increases the chances
of an action potential being generated.
o IPSP increase potential differences.
Chemical messengers in the synapse: nutrient amino-acid neurotransmitter vesicle
formation release of neurotransmitters into the synaptic cleft.
Neurotransmitters act very specifically or more general:
- Only < 1% of the neurons uses NE, DA, 5-HT
- More frequent (around 50%) = GABA and Glu
- Some synapses use too abundant receptors like GABA and Glu, which doesn’t allow
drug targets to be very specific and drugs influence way more of the brain than you
want.
- Sometimes there is a big chance of side effects with more abundant receptors.
Where do these neurotransmitters come from?
- Precursors are substances that are needed to construct neurotransmitters from
- For monoamines (single amine group, NH2)
o Catecholamines: DA (dopamine), NE (norepinephrine), E (epinephrine)
Needed precursor is tyrosine
Is an essential amino acid, (= get into your body through food).
Tyrosine dopa DA NE E
o Indolamines: 5-HT
Needed precursor is tryptophan
- Amino acids have glucose as a precursor. Glutamate and GABA are examples for
amino acids.
- For Ach the precursor is choline/lecithin
- For peptides like oxytocin and endorphins you need amino acids as precursors.
o Longer chains of proteins.
,Types of receptor (based on location on the cell):
1. Presynaptic auto-receptor
- Is present on its own neuron.
- Has a feedback role, when there is enough of
the neurotransmitter the transmission will be ended.
2. Auto-receptors on other locations on the cell.
3. Post-synaptic, axo-dendritic (most known)
- axo-dendritic: neurons that are activated by an
axon-dendrite binding.
4. heteroreceptor (presynaptic)
- React to input of another neuron.
- Modulates the synapse from another neuron.
Activation of these receptors can have very different implications.
Most important form of communication is synaptic axo-dendritic. Other forms of
neurotransmission:
- Phenomenon of retrograde transmission (cannabinoid system)
- Post synaptic neuron released endo-cannabinoids that activate pre-synaptic
receptors and so end neurotransmission.
- Non-synaptic diffusion: no transmission between pre- and post-synaptic connections.
Receptors on other parts of the neuron can be activated, because the
neurotransmitter flows away from the releasing neuron.
- Neuromodulators: they don’t influence receptors directly, they modify them. When
neurotransmitters bind the properties are different. For example benzodiazepines.
- Neurohormones: released in the blood. HPA-axis for example. More distance
possible.
In the table you see the most important
neurotransmitters, see that most have different
subtypes of receptors. For example serotonin has
18 types divided in families.
After the release of neurotransmitters, this starts
neurotransmission. This needs to be ended as well.
There are different ways to do so. Sometimes they
are being degraded directly or being taken back in
the cell and degraded in the cell itself.
- ACh is degraded extracellular and then
taken back into the cell.
- Serotonin is being taken back into the cell and broken down inside.
- Peptides are typically degraded outside of the cell.
- 95% of catecholamines are taken back inside before degradation. But there is 5% that
will be degraded in the PFC extracellular via COMT. Interesting for mental disorders.
This way you know what you do with a drug is more specifically to this part.
- Amino-acids are being degraded in the cell. Glu is a pre-cursor for GABA.
, Localisation: NE and 5-HT are originated in the LC (NE) and raphe nuclei (5-HT)
- Relatively few cells, but may be influential projections to the entire cortex.
Points of engagement around the synapse by drugs:
- Amount of transmitter:
o Synthesis (modify the presence precursor or the activity of enzymes)
o Uptake of transmitter in and release from vesicles.
- Blocking or modulating receptors (pre/post synaptic)
- Ending influence through:
o Reuptake blocking (very often used for psychoactive drugs)
o Degradation (extra/intracellular)
Part 4: background
Start of this field was mostly through serendipity, by accident things were discovered.
Nowadays more hypothesis based research, discovering drugs after stating hypothesis.
Registration is a prerequisite for prescription.
- NL: college ter beoordeling van geneesmiddelen
- Registration based on research into efficacy and safety of a drug.
- To be admitted there have to be a lot of steps taken:
o Preclinical phases: being done in all kinds of laboratory animals.
Efficacy: at least likely that it has some sort of effect, prediction not
always possible.
Administration: in what way can a drug being administered (most
often tested via injections), orally it does not always reach the brain
(degradation in gastro-intestinal system or not able to cross the blood-
brain barrier)
Safety: what are the side effects and how serious are these? Need to
be tolerable. Also when administered systematically (in entire body).
Therapeutic index = relation between letal dose (LD) and
effective dose (ED) = LD/ED higher is better, because you
want the difference to be large.
Drug interactions need to be charted.
Toxicity (harmful effects): expected and unexpected effects.
Also determine TD50 (toxic dose, 50 = 50% will show side
effects).
Animal research is now also done in cell culture, so you do not have to
test on animals as much.
Patent will be requested for when there is an effect found. After this
request they try to get it on the market asap. Research on modes of
administration etcetera.
o Clinical trials (in humans):
Phase 1: test if non-toxic, tolerable on small groups of people. Is it safe
for human use?
Phase 2: limited efficacy studies, does it show the wanted effect in
patients? Also a cost/benefit consideration is made.
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