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  3. Universiteit Utrecht (UU)
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  5. Psychopharmacology (201700081)

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Samenvatting alle hoorcolleges Psychopharmacology ()
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Volledige en uitgebreide samenvatting (met afbeeldingen) van alle hoorcolleges, gegeven bij het vak 'Psychopharmacology' aan de UU.

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  • 15 september 2022
  • 56
  • 2020/2021
  • College aantekeningen
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Voorbeeld van de inhoud

Hoorcolleges Psychopharmacology

HC 1: introduction to psychopharmacology
Pharmacology studies the influence of substances on biological processes (living beings).
→ Psychopharmacology focuses on their effects on behaviour, cognition and affect, incl.
their mechanisms in the brain.

Pharmacokinetics ‘How does a substance move through the body?’
- This topic is covered in the Principles lecture

To be distinguished from Pharmacodynamics:
- To what receptors does the substance bind?
- What effect does the substance have on the receptor?
In psychopharmacology this means: interactions with neurotransmitters.

Neurotransmission
- Neurons
- Action potential
- Synapse
- Transmitter
a. synthesis
b. release
c. degradation
- Receptor (here the drug can have different kinds of effects)

The most typical receptor is a postsynaptic receptor.
Question: What is not a drug target to influence the functioning of neurons?
1. Receptor activation
2. Metabolite excretion
3. Reuptake blockade
4. Enzyme modulation
5. All of the above are possible targets

Frequency of neurotransmitters
Specific Neurotransmitters: total number of neurons (~100.000.000.000, 100 billion)
There are relatively few number of neurons (<1%):
- E.g. NE, DA, 5-HT
- Relatively specific targets for drugs!
Frequent (~50% of synapses):
- GABA, Glu
- also: endocannabinoid receptor in many synapses
Even though implicated in disorders / effects of compounds
- GABA: alcohol, sedatives, anxiolytics
- Glu, NMDA: epilepsy, Huntington, aids dementia, schizophrenia
→ Problem with specificity of drug targets


Specific Neurotransmitters: Where from?


1

,→ Precursors (Een precursor of uitgangsstof is een chemische stof die tijdens een reactie in
een andere stof wordt omgezet. De precursor dient als voorloper voor een bepaald eindproduct,
vaak de stof van interesse).
- Monoamines (single amine group, NH2)
a. Catecholamines: DA, NE, E
- Precursor: tyrosine → L-DOPA → DOPA → NE (noradrenaline)→
Epinephrine (adrenaline)
b. Indolamines: 5-HT
- Precursor: tryptophan
- Amino Acids
a. Glu, GABA
- Precursor: glucose
- ACh:
a. Precursor: choline/lecithine
- Peptides: oxytocine, endorphins
a. Precursor: amino acids

Neurotransmission: Types of Receptor
(based on location on cell)
- Post-synaptic, axo-dendritic (3)
a. Most typical type
- Presynaptic:
a. Autoreceptors
- Detects release of NT from own neuron (1) or groups of neurons (2)
- Hetero Receptor (4)
a. Modulates synaps: presynaptische neuron die reageert op de input van een
ander neuron en dan de synaps van een ander neuron moduleert

Specific Neurotransmitters (NT): Whereto? Ending NT activity
- Combinations of degradation (metabolism) in synapse and reuptake within the cell.
For example:
a. ACh: degradation by extracellular enzyme AChE (then reuptake)
b. 5-HT: reuptake (and intracellular degradation)
c. Peptides (proteins, amino acid chains): degradation (degradation into smaller
peptides, then diffusion)

From serendipity
- First insights from folklore (e.g., alcohol)
- Later developments often coincidence
- E.g., the discovery of penicillin
To hypothesis based research
- Research programs in pharmaceutical industry and universities for targeted drug
discovery

What are hypotheses based on?
1. Basic knowledge ‘preclinical research’, e.g. about:
- How neurotransmitter levels are de- or increased
- Which brain cells/regions are involved in a brain function


2

, - Which kinds of substances may affect a neurotransmitter
- Which kinds of substances may affect a certain type of brain cell
- What are potential beneficial and side effects of a substance
2. Clinical knowledge ‘clinical research’, e.g. about:
- Which brain functions are involved in a psychiatric disorder
- Which brain cells/regions are involved in a psychiatric disorder
- What is known about levels of neurotransmitters in a disorder
- Different subtypes if a disorder that may require different treatment

Hypotheses based research
→ Starts with knowledge from the literature
What is known about a (clinical) phenomenon?
- Which neurotransmitter (NT) may affect this function?
- Which substances (medicines) may affect this NT?
- What patient characteristics may influence whether a certain approach will work (and
for a given patient)?
- Is the substance prone to side effects / toxicity / addiction?
- Do the beneficial effects outweigh the side effects?
→ What is not known and would be important to find out?

When can a new substance be prescribed?
→ New compounds must be admitted by a regulatory board.
- NL: College ter Beoordeling van Geneesmiddelen (CBG)
- Europe: Europe Medicine Agency (EMA)
- US: Food & Drug Administration (FDA)
Registration for medications based on research into:
1. Efficacy
2. Safety

Registration
→ To be admitted by CBG / EMA / FDA
- Preclinical phases (animal research precedes administration in humans):
1. Efficacy
2. Administration
3. Safety
- Clinical trials (in humans):
a. Phase 1: non-toxic, tolerable
b. Phase 2: limited efficacy studies
c. Phase 3: large, multi-center
studies

Registration: Drug safety
Therapeutic index = relation between the toxic dose (TD) and
t.o.v. effective dose: TD50 / ED50

TD50 / ED50 → this should be a large effect. The greater
the distance between the 2 doses, the better



3

, Besides the therapeutic index, you also look at:
1. drug interactions
2. toxicity (harmful effects)
- expected effects: often temporary
- unexpected effects: e.g., allergies
→ Look at your patients, if they are suicidal, you should not give them a whole
bottle of very effective pills, because there might be a chance they kill
themselves.

Timeframe introduction new medication
1. Preclinical phase
- productie (er wordt een molecuul samengesteld)
- dit wordt getest op werkzaamheid
- test voor toedieningsvormen
- preklinisch onderzoek op dieren
2. Aanvraag: To be admitted by CBG / EMA / FDA
3. Clinical trials in humans
- phase 1: Is the substance safe? In the first phase researchers test whether
human subjects (most often healthy volunteers) tolerate the substance.
- phase 2: Does it work? If the substance is sufficiently safe, sick people take
the place of the healthy. Aim is now to test whether the substance really
works against the disease. Most often this phase starts with a small number
of patients who take the new drug.
- phase 3: Does it work, and is it better than other existing drugs? When the
results in phase 2 are good, larger trials start with a larger number of patients.
In this phase, the new drug is first tested against a placebo and then against
existing treatments.
4. Precede registration (approved). Drug is now approved and on the market. Now,
side-effects and optimal doses will come to light. Even after a drug has been
registered, research continues. This is mostly focussed on side effects in the long
term, or the optimal treatment duration. But often the medicine is tested for its effects
on other diseases as well. Phase 4 is important because major side effects usually
do not come to light until this phase (example: rimonabant)

What’s in a name?
- Chemical name/ formula N-Methyl-gamma-(4-
(trifluoromethyl)phenoxy)benzenepropanamine
- Codename: LY110140
- Generic name, easier to communicate: fluoxetine
- Brand name (®)
a. Patent holder: ‘Prozac’ (Eli-Lilly)
b. After the patent expires, it is also sold under the generic name

Drugs VS. medicines
Related to their purpose: a medicine aims to cure, a drug does not necessarily have the
purpose.
- Hence: all medicines are drugs, whereas not all drugs are medicines
- And medication? Defined as the process of treating an illness with medicine.


4

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