Pharmacology 12: Drugs used in Psychiatric Disease Flashcards
what is unipolar depression?
mood swing always in same direction
majority due to external triggers e.g. difficult life events (reactive depression.)
but 25% have endogenous depression= no such relationship with life events, this is often familial.
what is bipolar affective disorder?
characterised by depression and mania at different time in disease course, rarer than unipolar depression.
why does therapeutic action of anti-depressants take several wks to occur?
changes in receptor expression and density
altered balance of various neurotransmitter systems
long term adaptive responses- altered gene expression and growth factors.
noradrenaline and 5-HT as in what class of molecules?
monoamines
4 different types of symptoms schizophrenia is assoc with?
+ve e.g. hallucinations, delusions, thought disorders, abnormal behaviour
-ve e.g. blunted affect, social withdrawal, poverty of thought and speech
cognitive e.g. selective attention, poor memory, reduced abstract thought
affective e.g. anxiety and depression
how is schizophrenia thought to come about?
underlying genetic predisposition, with strong familial component. Then appears that multiple environemental insults e.g. maternal gestational hypertenson increase brain dysfunction. Repeated insults lead to phenotypical expression of schizophrenia.
chronic, often leading to significant neurodegenerative disease.
NTs thought to be reduced in depression?
5-HT and noradrenaline (monoamines)
4 main dopamine pathways in the CNS?
nigrostriatal pathways
meso-limbic pathways= important in emotional response and behaviour, and connect hippocampal and amygdala areas.
meso-cortical pathways= important in arousal and mood
tubero-hypophyseal system= small pathways in hypothalamus and pituitary.
why is it extremely important to understand the toxicities of anti-psychotic drugs?
some are highly toxic in OD, espec. tricyclic antidepresssants, and those prescribed them have a greater tendency to attempt suicide.
3 core symptoms of depression?
low mood
decreased energy
anhedonia- inability to take pleasure in experiences which are normally enjoyable
2 of these must be present to diagnose depression
symptoms of depression other than core symptoms?
sleep disturbances e.g. early morning wakening decreased appetite physical aches and pains irritability suicidal thoughts or acts, self harm feelings of hopelessness and helplessness reduced libido reduced concentration psychotic symptoms
OTC preparation for mild depression, which has significant DDIs?
St John’s Wort
CYP450 inducer, so increases metabolism of drugs which are metabolised by this system e.g. COCP, statins, warfarin, and so reduce their therapeutic effects in the body.
other inducers: PCBRAS= phenytoin, carbamazeine, barbiturates, rifampicin, alcohol- LT high intake, sulfonylureas and St john’s wort.
what is there an increased potential for during first few wks of pharmacological tment of depression?
anxiety
agitation
suicidal ideation
1st line drugs for treating depression (moderate to severe)? mild should be treated with psychological therapy.
SSRIs= selective serotonin reuptake inhibitors, as better tolerated and safe in OD than other antidepressants
e.g. citalopram= most selective, fluoxetine, sertraline, paroxetine=most potent reputake inhibitor
which ADR has been reported more frequently in use of SSRIs in depression, than with other anti-depressants?
hyponatraemia- should be suspected if drowsiness, confusion or convulsions.
how should patients taking anti-depressants be managed?
Should monitor for suicidal thoughts, hostility and self-harm at start of tment or if doese chnaged.
Patients should be reviewed every 1–2 weeks at the start of antidepressant treatment. Treatment should be continued for at least 4 weeks (6 weeks in the elderly) before considering whether to switch antidepressant due to lack of efficacy. In cases of partial response, continue for a further 2–4 weeks (elderly patients may take longer to respond).
Following remission, antidepressant treatment should be continued at the same dose for at least 6 months (about 12 months in the elderly), or for at least 12 months in patients receiving treatment for generalised anxiety disorder (as the likelihood of relapse is high). Patients with a history of recurrent depression should receive maintenance treatment for at least 2 years.
PKs of SSRIs?
almost completely absorbed from gut
long elimination t1/2s, so once daily dosing
metabolised in liver
ADRs of SSRIs?
common= GI disturbances e.g. diarrhoea, nausea, anorexia rare= precipitation of mania, increased suicidal ideation- can give ptnt the motivation and energy they need whilst still feeling low, extra-pyramidal syndromes, dyskinesias and tremor
tend to be time-limited= 1-2 wks, and then pass.
reasonably safe in OD if taken on own
examples of TCAs?
amitriptyline
imipramine
clomipramine
lofepramine
PKs of TCAs?
Lipid soluble
Absorbed from gut
Long half lives
Metabolised in liver
ADRs of TCAs?
CNS- sedation and impairment of psychomotor
performance, lowering of seizure threshold
Autonomic nervous system, reduction in glandular
secretions, eye accommodation block
CVS- tachycardia, postural hypotension, impair
myocardial contractility, sudden cardiac death as cause arrhythmias and heart block.
GI-constipation
more likely to cause death if OD in suicide attempt, cardiovascular and epileptogenic effects are dangerous in overdosage.
example of drug used in psychiatric disease which lowers threshold for seizures?
TCAs e.g. amitriptyline
factors involved in formulation of psychiatric disorders?
Genetic vulnerability to the expression of the disease
Life events (divorce, bereavement)
Individuals personality, coping skills, social support
Other environmental influences e.g. viruses, toxins,
other diseases
BIOPSYCHOSOCIAL MODEL: bio, psycho and social factors, and these can be predisposing, precipitating and perpetuating e.g. gentic suscept, taking cannabis and lack of social support respectively.
number of wks ptnt must have symptoms for before being diagnosed with depression?
> 2 wks
3 theories for depression?
1= monoamine hypothesis= depression due to a deficiency of monoamine NTs- NA and 5-HT, therefore
certain drugs that depleted these could
induce depression- e.g. Reserpine – mixed evidence
E.g.Monoamine oxidase inhibitors( MAOIs) block the
enzyme monoamine oxidase from destroying
neurotransmitters.
2= NT receptor hypothesis= An abnormality in the receptors for monoamine transmission leads to
depression, depletion of neurotransmitter causes
compensatory up regulation of post
synaptic receptors- some post mortem
evidence.
but no clear evidence for these, and increasing evidence that these systems don’t respond normally despite normal levels of monoamines and their receptors.
3= - The Monoamine Hypothesis of gene expression
Deficiency in molecular functioning, hypothesised problem within the molecular events distal to the
receptor.
which drug classes are part of the monoamine uptake inhibitors?
non-selective and selective NA and 5-HT re-uptake inhibitors
non-selective= those with additional actions e.g. TCAs, and SNRIs= serotonin NA reuptake inhibitors.
how do SSRIs work?
block the 5-HT NT re-uptake pump on the pre-synaptic membrane, increasing 5-HT levels in EC space so increased 5-HT receptor activation and enhance postsynaptic responses.
at higher doses, may lose selectivity and also bind to NA transporters.
why do SSRIs have a greater therapeutic index than TCAs and why is this important?
have a greater selectivity
important in depressed patient who may intentionally commit suicide by taking an OD
important CVS ADRs of citalopram= a SSRI?
QT-interval prolongation, bradycardia, tachycardia, postural hypotension
what are TCAs particularly useful for treating, other than depression?
treating chronic pain syndromes e.g. neuropathic pain, used at lower doses than those needed to produce anti-depressant effects
used to treat migraine headaches, other somatic pain disorders and chronic fatigue syndrome (ME- myalgic encephalopathy)
how do TCAs act to treat depression?
inhibit reuptake of both 5-HT and NA from EC space by blocking their reuptake transporters.
also have other effects= Muscarinic cholinoceptor blockade- reduced cholinergic neurotransmission (anticholinergic effect), and alpha 1-adrenoceptor blockade- suppression of noradrenergic neurotransmission (sympatholytic effect)
what must be done with a patient who has overdosed on amitriptyline?
must be taken to resuscitation and CVS function must be monitored- ECG
examples of pure non-selective monoamine uptake inhibitors (SNRIs)?
duloxetine
venlafaxine
how do SNRIs work?
block 5-HT and NA reuptake transporters in a concentration-dependent manner, so at low concentrations, increases EC 5-HT levels but at higher concentrations, also increases EC NA levels.
ADRs and toxicity with SNRIs?
same as for SSRIs e.g. GI ADRs like diarrhoea and anorexia, also sleep disturbance, increased BP, dry
mouth, hyponatraemia
Relatively short t1/2 therefore may
be a withdrawal syndrome on discontinuation.
