Neuropharmacology

Question 1

what are the factors that determine the success of a pharmacological treatment

Answer 1

primary issues

secondary issues

Question 2

what are primary issues

Answer 2

Primary issues these are related directly to the disease and its pathology

Question 3

give examples of primary issues

Answer 3

Understanding of the pathophysiology of the disease – understanding the history of the disease

Choice of the correct treatment target

Question 4

what are secondary issues

Answer 4

Secondary issues these related directly to the therapeutic regime

Question 5

give some examples of secondary issues

Answer 5

Ensure that drugs reach the target

Minimise the adverse effects

Manage any potential drug-resistance

Question 6

what is the ideal case for treatment and why can that not happen

Answer 6

• a disease would be clearly associated with a specific CNS region
  and a well-defined cellular target
  – but most neurological disease has a much
  higher level of complexity and involves interconnected circuits

Question 7

what are the types of targets for drugs

Answer 7

• receptor or enzyme

Question 8

what are the symptoms of Parkinson’s

Answer 8

Tremor, rigidity and slow movement

Slurred speech, affected gait

Irreversible disease progression

Question 9

what is the difference between Parkinson’s disease and Parkinsonism

Answer 9

Parkinsons disease – it tends to emerge spontaneously, they don’t have a particular cause and just occur as you age

Parkinsoanism – seen in boxers – and reproduces characteristics of Parkinson’s disease

Question 10

what causes parkinsons disease

Answer 10

• Loss of a specific group of cells in the brain (substantia nigra) which produce dopamine
• Deficit in dopamine

Question 11

How do you treat parkinsons

Answer 11

Provide the deficient neurotransmitter: dopamine

Provide dopamine precursors: L-Dopa

Question 12

How do you make dopamine

Answer 12

Dopamine is made from L- tyrosine, then made to L-dopa which is converted to dopamine, the final step is catalyzed by L-arotmatic amino acid decarboxylase

Question 13

what does the inhibitor of the L-aromatic amino acid decarboxylase do

Answer 13

Can administer L dopa with an inhibitor of the enzyme L-arotmatic amino acid decarboxylase but the inhibitor cannot cross the BBB, give L dopa with the inhibitor and this allows you to protect L dopa and convert it only when it gets into the brain and convert it to dopamine

Question 14

what happens if you are given an oral administration of L dopa

Answer 14

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

Question 15

what is the solution to L dopa and dopamine not being able to get to the blood Brian barrier

Answer 15

• 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

Question 16

what are the symptoms of schizophrenia

Answer 16

Significant cognitive disruption
Hallucinations, delusions
Paranoid behaviour
Disruption of social contact
Withdrawal from family and friends

Question 17

what is the cause of schizophrenia

Answer 17

Hyperactivity in the ventral striatum

Increased release of dopamine

Question 18

what are the treatments of schizophrenia

Answer 18

• dopamine receptor antagonists - antipsychotics of neuroleptic drugs

Question 19

what is the downside of neuroleptic drugs

Answer 19

Neuroleptic drugs block dopamine receptors –
BUT THEY ALSO BLOCK OTHER RECEPTORS…
- therefore there lack of specificity causes side effects

Question 20

what are the adverse effects of antipsychotic drugs

Answer 20

Rise in prolactin (breast enlargement, amenorrhoea)
Weight gain

General - allergic and toxic reactions

Anticholinergic (antimuscarinic) effects

Postural hypotension

Question 21

what are the symptoms of depression

Answer 21

Low mood
Lack of energy
Disrupted sleep
Loss of interest
Tiredness

Question 22

what is the cause of depression

Answer 22

Dysfunction in the activity of monoamine systems in the brain
Insufficient level of serotonin and noradrenaline
(monoamine theory)

Question 23

what are the treatment for depression

Answer 23

Increase monoaminergic transmission
(e.g. inhibitors of transport/reuptake of monoamines, such as the tricyclic antidepressants or the selective serotonin reuptake inhibitors…)
(blocks the uptake and maintains the neurotransmitter for longer in the synaptic cleft)

Question 24

what do tricyclics do

Answer 24

Inhibit reuptake (transport) of monoamines such as serotonin or noradrenaline

BUT ALSO:
Have affinity for histamine H1receptors, muscarinic cholinergic receptors, α1 and α2 adrenoceptors…

Question 25

what are the adverse effects of tricyclics

Answer 25

dry mouth, blurred vision, constipation, urinary retention, fatigue, sedation, weight gain, postural hypotension, dizziness, loss of libido
- there is also resistance to treatment in many patients

Question 26

what is the solutions to adverse effects of drugs

Answer 26

reduce the dose or switch to a different drug

Question 27

why do we have resistance to treatment

Answer 27

Body has drug transporter systems which excrete the drug
If you have a high expression of these drug transporters this may have an impact on how the patient will respond to the drug

Question 28

when can resistance to treatment develop

Answer 28

The resistance to treatment may be apparent immediately
after the onset of the treatment or it can develop after a
period of treatment

Question 29

describe how addiction occurs

Answer 29

Gradual onset – drug use becomes the dominant activity

Question 30

what must treatment do for addiction

Answer 30

Help addict overcome symtpoms

Help relieve withdrawl symptoms

Question 31

what does

• Ectasy do
• heroin do
• nicotine do
• ketamine do
• cocaine do

in terms of drug receptor interaction

Answer 31

Ecstasy increases release of monoamines

Heroin = Mu opioid receptor agonist

Nicotine = nicotinic cholinergic receptor agonist

Ketamine = glutamate receptor antagonist

Cocaine inhibits uptake
of monoamines

Question 32

what are the treatment options for addiction

Answer 32

Provide a drug substitute?
Methadone for heroin substitution

Provide a vaccine?
Antibodies against cocaine

Decrease some of the toxicity associated with addiction?
Nicotine replacement therapy – patches

Aversion therapy?
Induce nausea/sickness upon alcohol consumption – block
metabolism of alcohol with disulfiram

Question 33

effectiveness of treatment implies…

Answer 33

successful passage of drugs across the blood-brain barrier

- Drug solubility in lipids – essential for crossing membranes

Question 34

why may drug targets in the CNS never be reached

Answer 34

Drug targets in the CNS may be never reached because intrinsic or acquired overexpression of multidrug transporters at the BBB restricts 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

Question 35

How do you manage drug resistance

Answer 35

Detection in brain tissue of P-glycoprotein – a drug transporter
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
Examples of inhibitors of ABC transporters: verapamil, cyclosporine A

Question 36

what are inhibitors of ABC transporters

Answer 36

verapamil

cyclosporine A