CNS Pharmacology Flashcards
What is generalised anxiety?
Anxiety for no clear reason or focus, symptoms interfere with normal productive behaviour
Name two excitatory amino acids
Glutamate and aspartate
Name two inhibitory amino acids
GABA and glycine
What can receptors be determined by? (7 things)
Subunits Composition Pharmacology Time course Calcium permeability Distribution Neuronal function
What are the two main types of GABA receptors (based on their function)?
Ionotropic - NMDA, AMPA, Kainate and Delta (GABAa)
Metabotropic - GPCRs (GABAb)
What is the pathway for GRPI to activate PkC?
GQ increases -> PLC -> IP3 -> DAG -> PkC
What is the pathway for GRPII/III to activated potassium channels?
Gi/o decreases -> adenyl cyclase -> NaV -> activated potassium channels
What type of transmission does GABAa receptors mediate?
Fast inhibitory
GABAa receptors are selective to what ion?
Chloride
What is the agonist for the GABAa receptor at the orthosteric site?
Muscimol
What are the two antagonists for the GABAa receptor at the orthosteric site?
Bicuculline and pictrotoxin
What is the agonist for GABAa at the allosteric site?
Diazepam
What is the antagonist for GABAa at the allosteric site?
Flumazenil
What is the agonist for GABAb receptors?
Baclofen
What is the antagonist for GABAb receptors?
Phaclofen
What do GABAb receptors inhibit and what is the effect of this?
Voltage gated calcium channels = pre synaptic inhibition
What do GABAb receptors activate?
Potassium channels (GIRK) producing post synaptic inhibition
What is meant by constitutive activity?
Where the channels open in the absence of an agonist
What is betacarpaline?
An inverse agonist which stabilises the closed formation of channels, stopping occasional opening
What do allosteric binding sites do?
They modify the activity of a receptor to an agonist
In isolation they do not cause activation of the receptor eg they can not cause an overdose
What are the GABAa receptors targets for?
Sedatives, Anxioloytics, hypnotics, anti-convulsants, neurosteroids and some general anaesthetics
What are the subunits of the GABAa receptor?
2 alpha
2 beta
1 gamma or delta or epsilon
Where is the allosteric binding site in the GABAa receptors?
Between the alpha and gamma subunit
Which GABAa receptors are sensitive to benzodiazapine?
The gamma subunit must be present
Have to have alpha subunit of type 1, 2, 3 and 5 (4 and 6 are insensitive)
The difference is to one change in the amino acid sequence
Describe the experiment performed with mice which shows the effect of changing the alpha 2 subunit in the GABAa receptor
The wildtype mouse has normal alpha 2 subunit
The mutant mouse has mutated alpha 2 subunit (hist to threo)
In the light dark test:
1) Normally the mouse will hide in the dark box
2) Mice treated with diazapem will not hide
3) A knock-in mouse however does not show this effect and still hides
What are the physiological effects of benzodiazapine agonists (5 things?)
Sedation/anxioloytics Hypnosis Anterograde amnesia Anti-convulsants Reduction of muscle tone
What is hypnosis?
The latency of sleep onset increases, the duration of stage 2 (non-REM) sleep is increased and the duration of REM is decreased
Duration of slow wave sleep (associated with sleep walking and night terrors) is decreased
Which two drugs can cause anterograde amnesia?
Flunitrazepam and rohypnol
How do benzodiazapines increase the chloride currents across the membrane?
They can increase the frequency of channels opening
They can increase channel open time
They can decrease channel close time
They can increase channel conductance
What can drug half life be dependent on?
Renal function
Age
Microsomal enzyme induction
What is an active metabolite?
Results when a drug is metabolised by the body into a modified form which continues to produce effects in the body.
Usually these effects are similar to those of the parent drug but weaker, although they can still be significant
How man types of benziodiazapimes are there?
60
Why might zoipodem be prescribed?
Short half life
No active metabolites
Good for insomnia
Why might diazapam be prescribed?
Good for generalised anxiety
Long duration of action/ long half life
No heavy sedation
Produces active metabolites
What can be the adverse effects of benzodiazapine agaonists?
Sleepiness Impaired psychomotor function Amnesia Additive effects with other CNS depressants can be fatal in over dose Tolerance Misuse Physical dependence
What is tolerance?
Decreased responsiveness to a drug following continuous exposure
How can tolerance be overcome?
Increasing the dose
What is physical dependence characterised by?
Withdrawal symptoms eg Increased anxiety, Insomnia, CNS excitability and convulsions
Which drug is physical dependence more problematic with?
Triazolam - may cause day time anxiety when used to treat sleep disorders
What are the possible causes of epilepsy?
Head injury Local leisures Neoplasms in humans Infection Genetic
Describe grand-mal (generalised) seizures
Complete loss of control
Tonic - clonic like; rhythmic contraction and relaxation
Reticular formation controlling consciousness is lost
2 phases - 1) Rapid action potential firing and 2) Tonic-clonic seizures
Describe petit-mal (generalised) seizures
Absence of seizure type
Found in children
No fill contraction but they show on/off attention
Brain wave activity is distinct - rhythmic oscillations
Usually due to mutations in voltage gated calcium channels
What are partial seizures?
Not all brain regions are affected
The hypothalamus is affected - impact on the ANS so patients may show increased salivation and urination etc
Reticular formation is affected = loss of consciousness
Patients report a sensation before the seizure
Other changes may cause a seizure; blood glucose, pH change, stress and fatigue, flashing lights
What happens if neurons fill with too much calcium?
They die by apoptosis
What is status epilacticus?
A medical emergency where a generalised seizure has lasted longer then 2 minutes
What drug is given to stop a sezuire?
Diazapine
What are the 3 possible targets for anti-epileptic drugs?
1) Targeting GABAa receptors on the post-synaptic membrane
2) Stopping GABA uptake mechanisms
3) Inhibiting GABA metabolisms in the pre-synaptic neuron
Which ant-epileptic drugs increase GABA transmission?
Benzodiazapines eg clonazapem, clobazam and diazepam
Uptake inhibitors such as tiagabine
Metabolic inhibitors such as vigabitrin and valproate
What could be problems with using benzodiazapines to treat epilepsy?
Low therapeutic index, Sedation and complex pharmacokinetics
What can vigabitrin cause?
Depression
What type of cell has a role in regulating amino acid transimitter functions in the CNS?
Astrocytes
Which cell process makes glutamate?
The Krebs cycle
How is glutamate made?
In the Krebs cycle alpha-oxoglutarate -> glutamate -> glycine
Which enzyme converts glutamate to GABA?
Glutamic acid decarboxylase (GAD)
Neurons expressing GAD are what type of neurons?
Inhibitory as they can make GABA
Which drug increases levels of GAD and thus GABA?
Valproate
How is GABA broken down?
Broken down by 2 enzymes
1) GABA transaminase makes succinate semialdehyde
2) Succinate semialdehyde dehydrogenase then breaks down SS to make succinate which then enters the Krebs cycle
What are the epigentics related to valproate?
Methylation of DNA - scrunches up DNA to repress transription
Acetlyation of histones - DNA opens up for transcription factors to bind
Valproate inhibits the action of de-acetylase enzyme so transcription of enzymes such as GAD increases
Anti-epileptic drugs which target the excitatory synapse do what?
Block excitatory transmission at focus and limit the spread of epileptiform activity with use dependent sodium channels
They inhibit NaV responsible for action potentials
What are the three states that sodium channels can exist in?
1) Closed
2) Open (controlled by voltage)
3) Inactivated
Which state of NaV channels do anti-epileptic drugs stabilise?
The inactivated state - delayed return to the closed state, limiting the frequency of action potentials
The drugs only work on active channels
Which anti-epileptic drugs are used to stabilise the inactivated state of NaV channels?
Phenytoin
Carbamazepine
Lamotrigine
What could be the potential problems with using phenytoin?
Vertigo, ataxia, headaches, rashes
What could be the potential problems with using carbamazepine?
Microsomal enzyme induction, shouldn’t be combined with other drugs
What could the potential problems with using lamotrigine?
Nausea, dizziness, ataxia and rashes
Where are transient (T) voltage gated calcium channels highly expressed?
Raph nucleus
What is ethosuximide used to treat?
Absence seizures
What does GABA-pentin do?
Acts as a subunit of the calcium channels which regulates its trafficing to the membrane
Affects other voltage gated channels
Analgesic
What is levetiracetam?
Has a distinct drug target on synaptic vesicles (SV 2)
When associated with SV2 it impacts on loading vesicles with glutamate
pre-synaptic effect
What us unipolar depression?
Causes are reactive (75%) or endogenous (25%)
What is bipolar depression?
Manic depressive disorder, has a genetic link
What are some of the symptoms of depression?
Low mood (anodonia), Negative thoughts eg suicide, Pecimism, Irritability, Loss of interest in activities, Sleep disorders, Loss of appetite, Difficulty concentrating, Low self-esteem
How many people suffer from depression at some point in their lives in the USA?
1 in 6
What brain regions can be complicated in depression?
The singular cortex
Nucleus sucumbuns (part of the limbic system)`
Amygdala
Hippocampus
What has been observed in the nucleus sucumbuns
Increased activity with respect to trophic factor BDNF
Arises from input pathway (ventral tegmental area)
Receptors are TrkB
What is the amygdala important for?
Procesing fear responnses eg in response to a scar face
In the hippocampus a stress response causes a decrease in what?
BDNF signalling
How are peripheral hormones complicated in depression?
Effected metabolism eg gehrin and leptin
Effects centrally on the hippocampus
Shows why there is a link between depression and eating disorders
The adrenal gland - part of the HPA cortex responsible for release of adrenaline
What is postnatal depression and how can it affect children?
Occurs in mothers 6 weeks after birth
Causes the mother to neglect the child
Babies brainwaves can be altered if the mother is depressed so they are more likely to be depressed later in life
What three techniques can be used to make an animal depressed?
Forced swim test
Suspension from tail
Immobilisation
Which hormone is associated with depression?
cortisol (stress hormone)
What is the monoamine hypothesis?
Serotonin and or adrenaline
Drugs increasing levels of these have anti-depressant properties
Idea was depression simply reduced monoamines
What are the long term trophic effects of depression?
BDNF/TrkB has an effect on neurogenesis and synapse formation which is lowered in depression
Increased activation of glutamate receptors causes what?
Excess activation = neuronal apoptosis
Ketamine in low doses acts as what?
An anti-depressant (antagonist for NMDA receptors)
What is Iproniazid?
The first specific antidepressant
MAO inhibitor
What is reserpine?
Produces depression and parkinsonism, depletes stores of monamine transmitters
What are MAOIs?
Inhibit monoamine oxidases so neurotransimitters remain present
What are the three main classes of antidepressants?
1) Selective serotonin reuptake inhibitors
2) Classic tricyclic antidepressants
3) Monoamine oxidase inhibitors
What are SSRIs?
Block serotonin being taken up so receptors for serotonin are stimulated more
Highly specific to serotonin
Eg fluoxetine
What is an example of a classic tricylic antidepressant?
Imipramine
What is a tricylic antidepressant?
They are named after their chemical structure, which contains three rings of atoms
Inhibit the reuptake of serotonin and noradrenaline
Name two examples of MAOs
Phenylzine, moclobemide
What are the side effects of MAOs?
Increased sympathetic discharge in the periphary = hypertension
Which enzyme does MAO inhibit?
MAO type A
What are the side effects of MAOs?
Anticholinergic; dry mouth, blurred vision and constipation
Adrenergic; Alpha-adrenoreceptor blocked, postural hypertension
Histaminergic; H1 block, sedation
List examples of TCAs
Imipramine, Amitryptyline, clomipramine
Why are overdoses in TCAs dangerous?
Confusion, mania, cardiac dysrhythmia
What is fluexetine also known as?
Prozac
What are the two types of NA receptors in the somadendritic regions and what is their action on serotonin?
Alpha 1 - Increases 5HT
Alpha 2 = inhibits release of 5HT
Which receptor does Buspirone target?
5HT1A
Where are the most serotonin neurons found?
In the raphe nucleus
What is the precursor for 5HT?
Tryptophan
Name the main SSRI
Prozac
How does serotonin increase BDNF?
It works on cAMP = pKa activated = CREB (TF) = control of BDNF
How does lithium work to treat bipolar?
It permeates NaV channels - inhibits inositol )controls calcium signalling), AKT signalling and glycogen synthase kinase 3 signalling
Which antiepileptic drugs can also be used as mood stabilisers?
Carbamazepine, Valproate and Iamotrogine
What is the pathway to make noradrenaline?
Tyrosine = DOPA = dopamine = Noradrenaline = Adrenaline
Where is dopamine synthesised?
In vesicles
What is rebexitine?
A NARI (noradrenaline reuptake inhibitor) - not sufficient to treat depressionby itself
Which dopamine receptors are targeted to treat schizophrenia?
D2 and D4 (the even ones)
What are the four dopamine pathways in the CNS?
1) Nigrostatial pathway - fine motor control, lost in parkinsons
2) Mesocortical - pleasure-euphoria-reward system
3) Tuberhypophyseal pathway (prolactin = increased lactation)
4) Medullary chemoreceptor trigger zone = nausea and vomitting
Which dopamine pathway is targeted when treating scizophrenia?
The mesocortical pathway
What is the action of amphetamines?
Amphetamines stimulate secretion of DA and NA, inhibit MAO and metabolism of DA and NA, displace DA and NA from vesicles,
cause re-uptake transporters to work in reverse.
Activation of reward pathways, increased motor activity
What are trannsgenic mice lacking D1 insensitive to?
Cocaine and amphetamines
What are the side effects associated with chloropromazine and haloperidol (typical antipsychotics)?
Motor disturbances and prolactin secretion
What are phenothiazines?
Antipsychotic drugs which block the effect of dopamine eg chlorpromazine which is used to treat shcizophrenia
Give two examples of newer atypical anti psychotic drugs
Sulpiride
Clozapine
What is the action of most antipsychotic drugs?
They are antagonists for the D2 receptor which is inhibitory
This G protein-coupled receptor inhibits adenylyl cyclase activity
