Pschopharmacology Flashcards
Classification of treatments
- Chemical
- e.g. drugs, medicines, immunotherapy
- Electrical stimulation
- e.g. ECT, neurostimulation
- Structural rearrangement
- e.g. surgery, deep brain stimulation, psychosurgery
- Talking (psycho) therapies
- e.g. CBT, exposure therapy
Classification of psychiatric drugs
Based on chemical structure
- Every drug has unique structure
- Not useful for clinical decision making, more for data and synthesis
Based on what illnesses they treat
- Easy for doctors to choose a drug based on diagnosis
- Some drugs may work in different disorders
- Many psychiatric disorders have multiple symptoms, and one medicine may not treat them all
Based on pharmacology
- E.g. instead of antipsychotic, dopamine blocker
- E.g. instead of antidepressant, serotonin / noradrenaline / dopamine enhancer
- E.g. instead of hypnotic or anxiolytic, GABA enhancer
GABA receptors
GABA-A - ion channel which spans nerve membrane
- benzodiazepines, alcohol, anaesthetics, and barbiturates enhance GABA
Is the major inhibitory neurotransmitter in the cns so when activated it conducts cl- causing hyperpolarization
GABA-B - G protein coupled receptor
- GHB binds with a low affinity via GIRK CHANNELS,when activated causes k+ extrusion so hyperpoloarization. Weak agonist propoerty of GHK seen centrally only not in spinal chord as has no affinity there for BDZ or alcohol
Chemical treatments in psychiatry
Work on one (occasionally two) of the following systems:
- Receptors
- Neurotransmitter reuptakes sites
- Ion channels
- Enzymes
Targets are in the brain, but can affect systems elsewhere in the body - particularly in the liver if the target is an enzyme
Most neurotransmitters reuptaken into neurones via transporters, some limit further release of neurotransmitter, some broken down enzymatically.
Enzyme targeting medicines
- Monoamine oxidase Inhibitors for treatment of depression and anxiety
- Acetylcholinesterase inhibitors for dementia
- Lithium as a mood stabiliser (blocks glycogen synthase kinase, to prevent cyclical dysregulation seen in bipolar disorder)generally drug treatments block enzyme activity
Receptor targeting medicines
- Receptor blockers (antagonists)
- Dopamine receptor blockers for schizophrenia
- Serotonin receptor subtype blockers for depression
- Histamine receptor blockers for sleep
Antagonists block endogenous agonist binding to the receptor - Receptor stimulators (agonists)
- Benzodiazepines for sleep (enhances GABA)
- Guanfacine for ADHD (enhances noradrenaline)
Agonists mimic the endogenous agonist, stimulating the receptor
Reuptake site targeting medicines
Many psych drugs block reuptake site so increase neurotransmitters concentration in synapse to enhance post sympathetic receptors activity - Citalopram (serotonin reuptake inhibitor - SRI) for depression and anxiety
- Desipramine (noradrenaline reuptake inhibitor - NRI) for depression
- Methylphenidate (dopamine reuptake inhibitor - DRI) for ADHD
- Some medicines switch the reuptake site direction to enhance
release of neurotransmitters
- e.g. amfetamine for ADHD (releases dopamine and noradrenaline, and blocks reuptake)
Most neurotransmitters are recovered and recycled via reuptake sites
Seratonin neurotransmitter system 5-HT
- 5HT neurones begin in the midbrain, and extend to the hippocampus
- Serotonin is released, which then works on serotonin receptors on the post synapse
- There are 15 separate genes which encode for serotonin receptors, which control a variety of functions, including:
- Cognition
- Mood
- Temperature control
- Carbon dioxide regulation
Some, such as 5HT1a, are inhibitory, but most are excitatory.
The coupling to G proteins or ion channels determine if inhibitory or excitatory - Serotonin is reuptaken at reuptake channels in the synaptic and axon membrane
- This process is blocked by SRIs
- Serotonin may also act on presynaptic receptors to inhibit neurone firing and further serotonin release - homeostatic regulation
Ion channel targeting medicines:
blocks channels to reduce neuronal excitability)
- Sodium channel blockers
- Sodium valproate for epilepsy and to stabilise mood
- Carbamazepine for epilepsy and to stabilise mood
- Calcium channel blockers
- Gabapentin for epilepsy and anxiety
- Pregabalin for epilepsy and anxiety
Fast acting Neurotransmitters (on-off switch)
- Excitatory ⇒ glutamate, 80% of all neurons in pyramidal cells
- Inhibitory ⇒ GABA, 15% of interneurones
- Roles in core processes involved with memory, movement, vision etc
Slow acting Neurotransmitters (modulators)
- Dopamine, serotonin, noradrenaline, acetylcholine
- Endorphins and other peptides
- Roles in emotions, drives and motivations, attention, and valence of memories
Glutamate
- Causes epilepsy when in excess, may be treated with the blocker Perampanel
- Found in high levels in alcoholism, may be treated with the blockers Acamprosate or Ketamine
GABA
Causes anxiety when deficient may be treated with enhancer benzodiazepines
5-HT
Deficiency of 5-HT results in Depression or anxiety, which may be treated with serotonin enhancers such as SRIs or MAOIs
Dopamine
Excess dopamine is associated with psychosis, which may be treated with dopamine receptor blockers.
The idea for using these blockers as a treatment for dopamine came from amfetamine psychosis amongst cyclists
Noradrenaline
Excess noradrenaline may be found in patients who have nightmares, particularly in PTSD or REM behaviour disorder. These may be treated with blockers, such as Prazosin
Acetylcholine
Deficiency of Acetylcholine is strongly associated with dementia, and may be treated with acetylcholine esterase enzyme blockers
Drug treatments for depression
MAOI
TCA
SSRI
SNRI
NRI
DRI
Melatonin agonists
Multimodal drugs
Receptor antagonist
MAOI
- Phenelzine
- Moclobemide
TCA
- Clomipramine
- Imipramine
- Amitriptyline
SSRI
- Paroxetine
- Fluoxetine
- Sertraline
- Fluvoxamine
- Citalopram
- Escitalopram
Receptor antagonist
- Mirtazapine
- Trazodone
- Mianserin
SNRI
- Venlafaxine
- Milnacipran
- Duloxetine
- Desvenlafaxine
NRI
Reboxetine
DRI
Bupropion
Melatonin agonist
Agomelatine
Multimodal drugs
- Vilazodone - USA - SSRI - 5-HT1a agonist
- Vortioxetine - SSRI + numerous other 5-HT receptor effects
Partial agonists
Lower max efficacy, so more safe, especially in overdose
In states of high neurotransmitters or excess agonists then the partial agonists can act as an antagonist
Examples:
- Buprenorphine → replaces heroin
- Aripiprazole → used to keep dopamine above the levels that haloperidol would bring it down to, allows patients to feel normal with less motor side effects
- Varenicline → replaces nicotine in smoking cessation by blocking the nicotine receptor, so effects of smoking aren’t felt
Inverse agonists
Opposite effects to agonists
Reverse the effects of agonists at receptors
(Basically bind to the same receptor but cause an opposite effect)
Histamine inverse agonists may be useful for ADHD as they keep you awake
GABA inverse agonists can help dementia symptoms by increasing cognition?
Receptor subtypes
There are five subunits of GABA receptors, with numerous possibilities, but three are most common
a1b2y2 - most common, located in cortex and helps with sleep
a3b3y2 - second most common, in the limbic system and helps with relaxation
a2b3y2 - third most common, in the limbic system and helps with relaxation
Pyramidal cells
Pyramidal cells aggregate information from other cells, and are gated in their response by GABA receptors
Allosteric modulation
GABA-A receptor has a benzodiazepine binding site, alcohol binding and a binding site for barbiturates
- These sites are targets for different drugs and natural substances
- They act at allosteric sites to enhance the action of GABA, which causes sedation, calming, and anti-epileptic effects
- Neurosteroids act on the GABA system, and are regulated by things such as pregnancy or periods, this is why some women may have epilepsy only at certain times of their menstrual cycle
- GABA binds at the orthosteric site, inhibiting the neuron and effectively calming the brain
Drug selectivity
Most drugs = highly selective
E.g. Haloperidol acts on the D2 receptor, and has mild action on the alpha 1 receptor but is unlikely to have therapeutic effects
- Adverse effects of haloperidol are therefore due to dopamine receptor blocking (extrapyramidal side effects)
Some drugs are less selective
E.g. Clozapine acts on D2 receptor, H1 receptor, Alpha 2 receptor, Alpha 1 receptor, 5-HT1A receptor, M1-4 receptor, and the 5-HT2 receptor with a mix of therapeutic and non therapeutic effects
- lots of adverse effects due to off target effects, such as weight gain and metabolic syndrome
Citalopram effects Only the serotonin transporter, meanwhile Amitriptyline effects the serotonin and noradrenaline transporters, H1, 5HT2, M1-4n and alpha-1 receptors
Treatment of alochol depenedence via GABAb
GABAB agonists e.g. Baclofen attenuate many of the positive reinforcing aspects of reward
Baclofen safe when given in combination with intoxicating doses of alcohol and has minimal abuse liability.
GABAB receptor agonism therefore has the potential to treat all aspects of alcohol dependence which include:
Alleviating acute withdrawal
Initiating and maintaining abstinence
Reducing craving and craving-related relapse
Since GHB works in a similar manner to Baclofen it may be worth considering as an alternative therapy to Baclofen in the treatment of alcohol dependence.
Alprazolam
eg xanax
GABA
it is a benzodiazepine receptor agonist (non selective GABA A receptor positive allosteric modulator)
treats generalised anxiety disorder,panic disorder,short term treatment of anxiety and alcohol withdrawal
Baclofen
GABA
is a agonist
used in spacticity
decreases alcohol craving in alcohol dependant patients
Neurone auto receptor
Usually inhibitory
Activated by neurotransmitters
Inhibit calcium influx
Reduce neurotransmitter release
Switch of firing of terminal
How does the seratonin system prevent the release of too much seratonin
Serotonin release acts on presynaptic autoreceptors to inhibit further NT release through negative feedback
How many post synaptic serotonin receptors are there in the brain and what are the 2 main ones?
14 of them
- 5HT1A- is an inhibitory receptor which dampens activity in the neurones it’s in to reduce anxiety and depression
- 5HT2- psychedelic drugs work on this to have hallucinogenic effects. Might be involved in schizophrenia and is involved in eating + regulation of sleep
