Neuropharmacology Flashcards
what are the factors that determine the success of a pharmacological treatment
primary issues
secondary issues
what are primary issues
Primary issues these are related directly to the disease and its pathology
give examples of primary issues
Understanding of the pathophysiology of the disease – understanding the history of the disease
Choice of the correct treatment target
what are secondary issues
Secondary issues these related directly to the therapeutic regime
give some examples of secondary issues
Ensure that drugs reach the target
Minimise the adverse effects
Manage any potential drug-resistance
what is the ideal case for treatment and why can that not happen
- 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
what are the types of targets for drugs
- receptor or enzyme
what are the symptoms of Parkinson’s
Tremor, rigidity and slow movement
Slurred speech, affected gait
Irreversible disease progression
what is the difference between Parkinson’s disease and Parkinsonism
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
what causes parkinsons disease
- Loss of a specific group of cells in the brain (substantia nigra) which produce dopamine
- Deficit in dopamine
How do you treat parkinsons
Provide the deficient neurotransmitter: dopamine
Provide dopamine precursors: L-Dopa
How do you make dopamine
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
what does the inhibitor of the L-aromatic amino acid decarboxylase do
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
what happens if you are given an oral administration of L dopa
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
what is the solution to L dopa and dopamine not being able to get to the blood Brian barrier
- 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
what are the symptoms of schizophrenia
Significant cognitive disruption Hallucinations, delusions Paranoid behaviour Disruption of social contact Withdrawal from family and friends
what is the cause of schizophrenia
Hyperactivity in the ventral striatum
Increased release of dopamine
what are the treatments of schizophrenia
- dopamine receptor antagonists - antipsychotics of neuroleptic drugs
what is the downside of neuroleptic drugs
Neuroleptic drugs block dopamine receptors –
BUT THEY ALSO BLOCK OTHER RECEPTORS…
- therefore there lack of specificity causes side effects
what are the adverse effects of antipsychotic drugs
Rise in prolactin (breast enlargement, amenorrhoea)
Weight gain
General - allergic and toxic reactions
Anticholinergic (antimuscarinic) effects
Postural hypotension
what are the symptoms of depression
Low mood Lack of energy Disrupted sleep Loss of interest Tiredness
what is the cause of depression
Dysfunction in the activity of monoamine systems in the brain
Insufficient level of serotonin and noradrenaline
(monoamine theory)
what are the treatment for depression
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)
what do tricyclics do
Inhibit reuptake (transport) of monoamines such as serotonin or noradrenaline
BUT ALSO:
Have affinity for histamine H1receptors, muscarinic cholinergic receptors, α1 and α2 adrenoceptors…
what are the adverse effects of tricyclics
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
what is the solutions to adverse effects of drugs
reduce the dose or switch to a different drug
why do we have resistance to treatment
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
when can resistance to treatment develop
The resistance to treatment may be apparent immediately
after the onset of the treatment or it can develop after a
period of treatment
describe how addiction occurs
Gradual onset – drug use becomes the dominant activity
what must treatment do for addiction
Help addict overcome symtpoms
Help relieve withdrawl symptoms
what does
- Ectasy do
- heroin do
- nicotine do
- ketamine do
- cocaine do
in terms of drug receptor interaction
Ecstasy increases release of monoamines
Heroin = Mu opioid receptor agonist
Nicotine = nicotinic cholinergic receptor agonist
Ketamine = glutamate receptor antagonist
Cocaine inhibits uptake
of monoamines
what are the treatment options for addiction
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
effectiveness of treatment implies…
successful passage of drugs across the blood-brain barrier
- Drug solubility in lipids – essential for crossing membranes
why may drug targets in the CNS never be reached
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
How do you manage drug resistance
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
what are inhibitors of ABC transporters
verapamil
cyclosporine A
