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BB1 > Neuropharmacology > Flashcards

Neuropharmacology Flashcards

1
Q

What are the two types of factors that determine the success of a pharmacological treatment?

A
  • Primary issues – related directly to the disease and its pathology
    o Understanding of the pathophysiology of the disease
    o Choice of the correct treatment target
  • Secondary issues – related directly to the therapeutic regime chosen (e.g. type of drug, mode of administration)
    o Ensure that drugs reach the target
    o Minimise the adverse effects
    o Manage any drug-resistance
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2
Q

How is current neuroscience moving from a neurone-centric approach?

A
  • Note: current neuroscience research is moving from a neurone-centric approach, to the recognition of the importance of the non-neuronal cells (glia)
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3
Q

What is a therapeutic target? What would be the ideal case for a neurological target? Why is this often not the case?

A
  • A target in therapeutics is a well-defined entity (e.g. a receptor, an enzyme…)
  • Ideal case: a disease would be clearly associated with a specific CNS region and a well-defined cellular target within that region – but most neurological disease has a much higher level of complexity and involves intricate brain networks
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4
Q

How are chemical synapses involved in treatment targets?

A

See diagram in lecture notes

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5
Q

What are important questions to consider when treating a disease affecting the CNS?

A
  • Is it possible to identify the CNS structure associated with a specific disease?
  • What is the best target for a disease, and is it one or more targets?
  • Can we make drugs to affect that target?
  • Will the drugs reach the target?
  • Do patients always respond to treatment?
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6
Q

What are 4 examples of disease affecting the central nervous system?

A

Parkinson’s Disease
Depression
Schizophrenia
Addiction

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7
Q

What are the symptoms of Parkinson’s disease and Parkinsonism? What is the cause of this, and which monoamine deficits are associated with it? How are the two conditions different?

A
  • Tremor, rigidity and slow movement
  • Slurred speech, affected gait
  • Irreversible disease progression
  • Loss of a specific group of cells in the brain (in the substantia nigra) which produce dopamine
  • Deficit in dopamine
  • Note: parkinsonism (seen often in boxers) is a state that reproduces many characteristics of Parkinson’s disease

See synapse diagram in lecture notes

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8
Q

What is dopamine and how is it synthesised?

A
  • Dopamine is a monoamine neurotransmitter

See diagram in notes for biosynthesis

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9
Q

What are the treatment options for Parkinson’s? What might the problems with these be?

A
  • Examples:
  • Provide the deficient neurotransmitter: dopamine
  • Provide dopamine precursors: L-Dopa
  • But neither can reach the brain after peripheral administration!!
  • Dopamine cannot reach the brain
  • Systemic oral administration of L-Dopa leads to conversion into dopamine outside the brain - and this can trigger intense vomiting, triggered by peripheral formation of dopamine
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10
Q

What is the solution to the problems with treating Parkinson’s with L-Dopa?

A
  • Provide L-Dopa combined with an inhibitor of the enzyme L-aromatic
  • amino acid decarboxylase, WHICH DOES NOT HAVE
    ACCESS TO THE BRAIN, therefore L-Dopa is converted into dopamine ONLY IN THE BRAIN
  • Another solution is to stimulate the dopamine receptors directly with dopamine receptor agonists
  • (Agonist = a compound that stimulates directly receptors)

See equation in notes

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11
Q

What are the symptoms of schizophrenia? Which monoamine is increased? What type of pathology is it?

A
  • Significant cognitive disruption
  • Hallucinations, delusions
  • Paranoid behaviour
  • Disruption of social contact
  • Withdrawal from family and friends
  • Hyperactivity in the ventral striatum
  • Increased release of dopamine
  • But note that other structures are also affected.
    o It is a diffuse pathology.

See synapse diagram in notes

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12
Q

What are the treatment options for schizophrenia?

A
  • Example:
  • Provide dopamine receptor antagonists (antipsychotic or neuroleptic drugs)
  • Antipsychotic drugs block dopamine receptors – BUT THEY ALSO BLOCK OTHER RECEPTORS…
  • Lack of specificity of a drug causes inevitably adverse (side) effects
  • Example: the antipsychotic drug thioridazine acts on a variety of receptors

See pie chart in notes

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13
Q

What are the adverse effects of antipsychotic drugs?

A
  • Extrapyramidal effects (e.g. parkinsonism)
  • Rise in prolactin (breast enlargement, amenorrhoea)
  • Weight gain
  • General - allergic and toxic reactions
  • Anticholinergic (antimuscarinic) effects
  • Postural hypotension
  • And no way to avoid these adverse effects – they are part of the lack of specificity of the antipsychotic drugs. The drugs bind to many targets, which causes the emergence of adverse effects.
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14
Q

What are the symptoms and causes of depression? Which monoamine deficits are involved?

A
  • Low mood
  • Lack of energy
  • Disrupted sleep
  • Loss of interest
  • Tiredness
  • Dysfunction in the activity of monoamine systems in the brain
  • Insufficient level of serotonin and noradrenaline
  • Extensive innervation of the forebrain by serotonin and noradrenaline neurones

See synapse diagram in notes

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15
Q

What are the treatment options for depression?

A
  • Examples:
  • Increase monoaminergic transmission through various mechanisms (e.g. inhibitors of transport/reuptake of monoamines, such as the tricyclic antidepressants or the selective serotonin reuptake inhibitors…)
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16
Q

What are the tricyclic antidepressants? What are their adverse effects?

A
  • Inhibit reuptake (transport) of monoamines such as serotonin or noradrenaline
  • BUT ALSO:
    o Have affinity for histamine H1receptors, muscarinic cholinergic receptors, α1 and α2 adrenoceptors…
  • THEREFORE…
    o Adverse effects: dry mouth, blurred vision, constipation, urinary retention, fatigue, sedation, weight gain, postural hypotension, dizziness, loss of libido
  • And also, there is resistance to antidepressant treatment in many patients…
17
Q

What are the major practical challenges in therapeutics?

A
  • How to balance efficacy vs. adverse consequences and manage adverse effects
18
Q

What are the adverse effects of antidepressants?

A 
o	Dry mouth
o	Blurred vision
o	Constipation
o	Urinary retention 
o	Fatigue
o	Sedation
o	Weight gain
o	Postural hypotension
o	Dizziness
o	Loss of libido
19
Q

What are the adverse effects of antipsychotic drugs?

A

o Extrapyramidal effects (e.g. parkinsonism)
o Rise in prolactin (breast enlargement, amenorrhoea)
o Weight gain
o Allergic and toxic reactions
o Anticholinergic effects
o Postural hypotension

20
Q

What is the solution to adverse effects of drugs?

A
  • Solution: reduce the dose or switch to a different drug…
21
Q

When might a condition become resistant to treatment? What is an example of a cause of this?

A
  • The resistance to treatment may be apparent immediately after the onset of the treatment or it can develop after a period of treatment
  • Example of cause of resistance: genetic variations in drug transporters
22
Q

What might be the benefit of microchip-based personalised medicine?

A
  • The emergence of microchip-based personalised medicine may enable us in future to predict efficacy before prescribing a particular drug
23
Q

What are examples of addiction? How might it develop? How is it treated? Is there a single drug target?

A
  • Abuse of cocaine, ecstasy, heroin, ketamine, alcohol, nicotine
  • Gradual onset – drug use becomes the dominant activity
  • Treatment must relieve withdrawal symptoms
  • Single drug target ? NO!

See synapse diagram in notes

24
Q

What are the treatment options for addiction? Give examples.

A 
-	Provide a drug substitute?
o	Methadone for heroin substitution
-	Provide a vaccine?
o	Antibodies against cocaine
-	Decrease some of the toxicity associated with addiction?
o	Nicotine replacement therapy – patches
-	Aversion therapy?
-	Induce nausea/sickness  upon alcohol consumption – block metabolism of alcohol with the drug disulfiram
25
Q

What are the main treatment challenges in diseases of the CNS?

A
  • Define the most relevant treatment target
  • Increase the specificity of action of drugs, so that adverse effects are avoided
  • Improve the prediction of response to treatment
  • Develop drugs which can reach the CNS
26
Q

What does effectiveness of treatment imply successful passage of drugs across?

A
  • Effectiveness the blood-brain barrier (BBB)

- Drug solubility in lipids – essential for crossing membranes

27
Q

Why might drug targets in the CNS never be reached? What are examples of transporters that cause this effect? Which drugs are substrates of these transporters? What is the normal action of these transporters?

A
  • Drug targets in the CNS may be never reached because intrinsic or acquired overexpression of multidrug transporters at the BBB restricts the brain uptake of drugs
  • Example of such transporters: the ABC family = ATP-binding cassette transporters
  • Many drugs with effects on the central nervous system are substrates of these transporters, e.g. antiepileptic drugs
  • BBB and BCSB provide very effective barriers to the free diffusion of many hydrophilic drugs into the brain, allow lipid soluble to cross. However certain lipophilic substance, in this case AEDs, also act as substrates for ABCs (ATP-binding cassette transporters).
  • ABCs normal action is to restrict the entry of potentially toxic lipophilic substance entry to the brain.
28
Q

The detection of which substance in brain tissue is implicated in drug resistance and drug efflux from where? What is the solution for this and what are examples of such drugs?

A
  • Detection in brain tissue of P-glycoprotein – a drug transporter of the ABC family, implicated in drug resistance and drug efflux back from the endothelium into the blood
  • The solution would be the block of the expression/activity of such transporters
    o Examples of inhibitors of ABC transporters: verapamil, cyclosporine A

See diagram in notes

29
Q

What are mechanisms of drug resistance in epilepsy?

A
  • Drug transporter changes are just one example of mechanism underlying the resistance of patients to treatment in neurological disease - note the multiple potential causes of treatment resistance in epilepsy

See diagram in notes for other causes

30
Q

Summarise key issues discussed in the lecture

A
  • Examples of drug targets
  • Importance of the blood-brain barrier
  • Side-effects of treatment and their impact
  • The concept of treatment resistance
31
Q

What is the main takeaway of this lecture?

A
  • We need a better understanding of the brain (normal and in disease)
  • and better understanding of the significant inter-individual variability
  • in order to better treat CNS disease in the 21st century
  • Fundamental questions remain in neuroscience: why does the brain age so strikingly differently in different individuals?

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