Neuropharmacology: Treatment of Disease Flashcards
(40 cards)
What is the basic pathology of PD? Neurotransmitter lost, site of neurodegeneration, Pathways affected in the brain
PD is the result of dopaminergic signalling via the nigrostriatal pathway.
this is due neurodegeneration occurring in the substantia nigra. (70-80% when symptoms are observed.
The loss of this signalling results in depleted dopaminergic projections to the striatum and a lack of dopamine mediated motor drive via the direct pathway from the striatum to the thalamus.
outline both the direct and indirect pathway and explain how PD alters their regulation?
Direct:
Striatum—–internal segment of Globus palidus——Thalamus++++++Prefrontal cortex/motor cortex e.t.c.
As you can see the striatum dis-inhibits the thalamus to drive movement.
Normally dopamine input from the substantia nigra acts on D1 receptors to excite this pathway, hence its loss in PD leads to a loss of this motor drive.
Indirect:
Striatum——External segment of Globus pallidus——-Sub thlamic nuclei+++++++globus pallidus internal segment——Thalamus+++++++ Prefrontal cortex/motor cortex e.t.c.
Here the striatum dis-inhibits the subthalamic nuclei which then drives the inhibition of the thalamus via the excitation of the globus pallidus internal segment. Pathway usually inhibits unwanted movement.
Normally the substantia nigra inhibits this pathway via release dopamine onto D2 receptor in the striatum. Hence its loss in PD means the this pathways activity is increased.
Key to notice is that the substantia nigra is clearly key to modulate these pathways to drive movement, so likely wanted movement, hence it is this voluntary movement we lose in PD.
What are 5 main symptoms of PD: Try to explain the cause of each?
Akinesia: Struggle with voluntary movements, due to a loss of the motor drive from the substantia nigra
Rigidity of muscles: Muscles have a tesned tone with increased resistance in limb movement (cog like joint movement)
Resting tremor: At REST the patient tremors, usually starting in the hands on one side and soon spreading through the body on both sides. This is the result of a loss of dopaminergic inhibition of intrinsic excitatory cholinergic synapses in the striatum.
Anxiety, depression, loss of executive function (decreased attention): possibly related to lack of dopamine signalling throughout other pathways mesolimbic which drives reward), and increased globus pallidus inhibition of the thalamus which project to prefrontal cortex which is related to executive function.
Shuffling walk: loss of voluntary movement again.
Dementia later on.
Name 3 established causes of PD
Age: The risk is greatly increased with age.
EO however:
Genetics: Mutations linked to the Parkin protein have been linked to EO PD
Drug that inhibit dopamine release (reserpine) or block dopamine receptors (chloropromazine)
Ischemia: hemorrhage and stroke related neuronal death often can occur around the basal ganglia.
What is the relationship between insecticides,MPTP and PD?
Both MPTP and Insecticides have been related to PD via neurotoxic action on mitochondria
Increased PD in agricultural areas has been related to insecticides inhibition of mitochondrial oxidation resulting in neuronal death in the substantia nigra. E.g Rhotenone caused PD like symptoms is animals.
MPTP is involved in the manufacturing of heroin. Its uptake into the basal ganglia results in its breakdown by Monoamine oxidase-B to form MPP+. This prevents mitochondrial oxidation resulting in neuronal death. this is a helpful tool for creating PD models, and brought to mind an idea that toxic dopamine metabolites did this aswell.
4 main dopamine pathways?
Nigrostriatal, Mesolimbic, Mesocortical, Chemoreceptor trigger zone
Parkinson can be treated by increasing the available dopamine: Outline 2 ways this can be achieved and include the issues with each treatment?
Levodopa: L-dopa is a precursor of dopamine. (converted by L dopa-decarboxylase
So L-dopa can be given to increase the available Dopamine and relieve symptoms (mainly akinesia and rigidity)
Issues: requires surviving dopaminergic neurons for successful conversion. hence it has diminishing rewards as the disease progresses
Will require co-application with a L-dopa decarboxylase inhibitor (Carbidopa, cannot cross BBB) this prevents conversion to dopamine in the periphery – systemic effects, also dopamine cannot cross BBB so this increases the action of levodopa.
Observed to cause on/off effect, symptoms can be worsened and then disappear.
MAO-B inhibitor: Selegine
MAO-B breaks down dopamine and so this is given to prevent that and extend its action in the striatum. this is often given along side L-dopa.
Issues: Still requires active dopaminergic neurons.
Selegine can be converted to amphetamine, causing anxiety. (Instead Rasagline can be given, very good as also shown to slow disease progression.)
Parkinsons can be treated by directly stimulating the dopamine receptors: Outline a classic treatment and discuss the advantages if this treatment in comparison to levodopa?
Classically a D2 agonist like Bromocriptine will be given with a D2 antagonist like Domperidone (to prevent systemic effects.
This does not require active dopaminergic neurons to work and therefore does not suffer from diminishing returns.
Alternative Parkinson treatment (Not L-Dopa, Agonists or MAO-B inhibitors)
Atropine: An ACh antagonist which can be given to help with the resting tremor.
Amantadine: This is an antiviral drug that was found to increase dopamine release and reduce glutamate NMDA signalling which is related to excitotoxic neurodegeneration.
Deep brain stimulation: derived dopamine release in the basal ganglia.
Transplants or grafts of dopaminergic cells from adrenal mudulla or foetal mescenphalic area. however neurodegeneration does still occur around the path.
3 main causes of Schizophrenia
Increased 5HT signalling: This has been shown by the ability of Hallucinogens like LSD activating their receptors.
Truncated Glutamate signalling: (Not really targeted for treatment due to widespread important action of NMDA)
There is reduced signaling specifically via the NMDA receptor. shown by the ability of antagonists like PHENYCYCLIDINE to cause both negative and positive symptoms.
Altered Dopamine signalling:
Hyperactivity in the mesolimbic pathway associated with positive symptoms. (mesolimbic pathway is associted with psychosis, this is also why amphetamines have been shown to trigger psychosis.)
Hypo activity in the mesocortical pathway is associated with the reward pathway, hence hypo activity here is unsurprisingly causing flattened personality and lack of psycho motor drives.
3 positive and 3 negative symptoms of schizophrenia
Positive: Hallucinations (Auditory) Delusions Catatonia (rigid immobility) Disorganized thought patterns
Negative:
Blunted personality
Lower drive (psycho-motor drive)
poverty of speech (alogia)
Discuss the use of typical neurleptics to treat schizophrenia
Typical neurleptics target the Dopamine theory of schizophrenia.
Dopamine antagonists, with an increased affinity for D2 are used to target the hyperactivity in the Mesolimbic pathway
They also antagonise muscharinic receptors (Thought to help with Parkinsonism and Alpha1 adrenoceptors causing hypo-tension.
Also antagonize H1 receptors to have a sedative affect
E.g Haloperidol (but very strong D2 affinity causing terrible Extra pyramidal side effects.
Chlorpromazine is more appropriate.
main issues:
Also inhibits function of other dopaminergic neurons. inhibition of D2 in basal ganglia results in pseudo Parkinsonism. (Terrible EPS like dystonia which is repetitive unwanted movements)
ONLY treats the positive symptoms
Causes long term Tardive dyskinesia (unwanted movements
Amenhorea and thus impotency in men
Discuss the use of atypical neurleptics to treat schizophrenia
Atypical target the role of enhanced serotonin signalling.
they antagonize excitatory 5HT2A/2C receptors, to reduce psychosis, whilst agonizing Inhibitory 5HT1A receptors to increase dopamine release in the frontal lobe.
they also antagonize muscharin and alpha 1 adrenoceptors to help with Parkinsonism and causing hypotention respectively.
an Example is Clozapine
MAJOR benefit is this treats both positive and negative symptoms.
Major issues.
Can increase fat increasing risk of diabetes and CHD
Agranulocytosis: a reduction in white blood cell count.
Give an example of a new 3rd nludephsiological and bGen neurleptic
Aripiprazole: This drug is a partial agonist of D2 receptors, as well as a weak agonist of serotonin receptors.
This is not a complete block so causes a lot less EPS
A partial agonist simply reduces the output.
Still only for Positive symptoms but much more appealing to the patient.
Outline Depression? include psychological and physical symptoms
Depression is a common affective disorder (mood disorder)
Psychological symptoms: anhedonia (cant experience pleasure), depressed mood, lack of motivation, suicidal thought, poor concentration.
Biological: fatigue, loss of appetite, sleep disturbance, aches and pains.
what are the two distinct forms of depression?
Depression can be uni-polar, 1 way always downwards mood change.
or
Bipolar: low points in mood are also matched by periods of mania
outline the Mono amine theory of depression?
This essentially states that a functional deficit in mono amines (NA and 5HT) causes depression, hyperactivity is related to mania.
What other release is associated with depression?
Corticotrophin releasing hormone is also found to be increased in depressed individuals and causes animals to mimic depressed symptoms. This drug causes the release of ACTH from the anterior pituitary causing the adrenal cortex to release cortisol into the blood.
Outline the 2 main treatments of uni polar depression and more option
Thymeleptics: re-elevate mood (prevent mono-amine re uptake)
Tricyclics-block NA re-uptake (mainly) but is non selective (imipramine, desipramine). (issues: effect is not instant, side effects like sedation due to H1 antag, and issues with motor coordination, hypertension due to alpha 1 inhibition.)
SSRIs: block 5HT reuptake selectively e.g Citalopram or fluoxetine. goof as selective so less side effects and is safer in overdose. however can cause tremors or a a loss of libido.
NRIs and SNRIs: selectively block Na re-uptake (Maprotiline) and 5HT and NA respectively (Venlafaxine and Mirtazapine) SNRIs also act as antagonists of alpha 2 receptors to prevent presynaptic inhibtion of release (Issues: much reduced side effects all round)
Thymeretics: boost psycho-motor drive (prevent metabolism of mono-amine).
Inhibits MAO-A (don’t touch MAO-B, will have no effect)
either can irreversibly (Clorgyline) or reversibly (Pirlindalole). (Issues: also effcet MAO-A in PNS, this breakdown is key to breaking down tyramine to prevent it entering the systemic blood. causes hypetension and tachycardia due to triggering NA release by replacing it in vesicles. ( so cant take with foods like cheese)
ECT: electrical pulses to treat depression,works at a high efficacy.
Rolipram: this is a phosphodiesterase inhibitor: this leads to cAMP increase and therefore protein kinase A increase resulting in increased NA release. .
What are anxiolytics and hypnotics?
These are drugs used to treat anxiety, stress or induce sleep.
What are the main targets of hynotics and anxiolytics?
GABA A, NA and 5HT.
Examples of anxiolytics and Hypnotics targeting NA?
They tend to use Beta blockers. Drugs like propanolol will bind beta 2 receptors on the heart and reduce the rate and force of the heart beat , resulting in a reduced BP and reduced levels of stress.
Examples of anxiolytics and Hypnotics targeting 5HT?
Buspirone is the main example. It is a partial agonist selective for the inhibitor 5HT 1 a receptor. This works in 2 stages. usually the 5ht is released causing inhibition n the post-synaptic membrane va the 5ht1a receptors at the same time as inhibiting its own secretion by autoreceptor role on the pre-synaptic membrane.
First stage it will compete to bind the receptor, reducing the inhibition.
second stage the pre-synaptic membrane become desensitized to 5HT ad therefore there is more 5ht release causing more post-synaptic inhibition, treating the anxiety. influence is in the thalami and limbic areas
Examples of anxiolytics and Hypnotics targeting GABA?
The main anxiolytic are benzodiazepines. These bind to alosteric sites on GABA A receptors and increase the influx of chloride to inhibit the post-synaptic membrane. examples are: Diazepam, (this is a anxiolytic and anti-convulsive, its good as it has an active metabolite Nordiazepam)
Zolpidum and zopiclone will also act allosteric sites to increase the inward current of chloride. these have very short-half lives lending them more to the function of hypnotics
there are also the old school barbiturates. AMYLOBARBITONE which directly binds to the channel and opens it . this drug is used to hep with insomnia. however the confusion it causes is dangerous as double dosing can lead to death,
there are new 3rd gen drugs like Beta carbolines which are reverse agonist binding the allosteric site to cause channels closure, and flumazenil, which is a antagonist of the gaba a receptor. (targets alosteric site as well.
Note flumazenil can be used to counter the effect of benzodiazepine overdose.
These all can cause confusion, muscle weakness, amnesia, drowsiness, tolerance builds so issues with dependence and these show withdrawal symptoms.
