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.
define psychosis
a lack of contact with reality
symptoms of paranoid schizophrenia?
Disturbances of thinking
Hallucinations, usually auditory- external voice in ear like someone sat next to them.
Delusions
Unusual speech- thought disorder
Behavioural changes
Lack of insight
Negative symptoms e.g. asoical and amotivated
define a hallucination and delusion
Hallucination- a perception in the absence of an external stimulus-auditory, olfactory, visual, gustatory, tactile.
Delusion- a fixed false belief that it out of keeping with someone’s culture or religious beliefs
what is the dopamine hypothesis of schizophrenia?
schizophrenia is the result of increased and dysregulated levels of dopamine neurotransmission in the brain.
Amphetamine causes symptoms very similar to positive
symptoms of schizophrenia e.g. delusions, hallucinations and disorganised speech, but amphetamine does not cause negative symptoms e.g. avolition- decrease in initiation of goal-directed behaviour.
Dopamine antagonists are the best treatment for schizophrenia (antipsychotics).
Some evidence of increased dopamine function in schizophrenics
BUT
Dopamine antagonists do not treat negative symptoms
Changes in dopamine function may be a response to long
term drug treatment.
which dopamine pathway do we wish to block in tment of schizophrenia and why?
the mesolimbic system= it’s thought that hyperactivity of this is reponsible for the +ve symptoms e.g. hallucinations, delusions, disorganised speech.
ADRs produced by D2 receptor blockage in nigrostriatal pathway in tment of schizophrenia?
extrapyramidal SEs e.g. slowness, stiffness, and tremor. and tardive dyskinesia= basal ganglia disorder that results in involuntary movements of face, lips and tongue, often seen as involuntary chewing movements accompanied by smacking of the lips and tongue. Thought to result from a hypersensitivity to dopamine and its agonists.
ADRs with D2 receptor blockage in meso-cortical pathway?
enhanced -ve symptoms of schizophrenia and cognitive psychotic symptoms.
ADRs with D2 receptor blockage in tuberoinfundibular pathway?
hyperprolactinemia (lactation-galactorrhoea, infertility, sexual dysfunction)
**e.g. bromocriptine= dopamine agonist, so can be used to treat hyperprolactinaemia, which can help with infertility.
NTs other than dopamine which schizophrenia is thought to be associated with?
5-HT- has been implicated in a number of behaviours disturbed in schizophrenia (e.g. perception,
attention, mood, aggression, sexual drive, appetite,
motor behaviour, sleep)
Many of the most effective antipsychotic drugs are
antagonists at 5HT-2A receptors. (Clozapine)
Precursors of 5HT (e.g. tryptophan) exacerbate
schizophrenia
glutamae- main excitatory neurotransmitter in the
brain. Phencyclidine (PCP: angel dust: non-competitive antagonist at NMDA-type glutamate receptors) induces symptoms very similar to schizophrenia.
Post-mortem studies have shown
• increased cortical glutamate receptors
• increased binding of glutamate receptor ligands in cortex, basal ganglia and hippocampal formation.
action of all antipsychotics?
Sedation- within hours Tranquilisation- within hours Antipsychotic-several days or weeks Activating effect within weeks- negative symptoms (probably not the typicals) Production of extrapyramidal side effects- hours or days. Much less with the atypical antipsychotics e.g. risperidone and clozapine.
examples of 1st generation/typical antipsychotics?
haloperidol
chlorpromazine
examples of atypical antipsychotics?
risperidone
olanzapine
clozapine
advantages of atypical antipsychotics?
less extrapyramidal side effects e.g. rigidity and slowness of movement, so more acceptable to patient
some once daily dosage
different preps e.g. dissolvable
differing SE profiles can be matched to ptnt characteristics
most severe ADR of typical antipsychotics?
neuroleptic malignant syndrome= characterised by catatonia, stupor, fever, and AN instability- fluctuating temp, BP and pulse.
symptoms thought in part to be due to antipsychotic actions on dopaminergic systems in the hypothalamus= essential for body’s ability to control temp.
what must be frequently monitored if given clozapine (atypical antipsychotic) for schizophrenia and why?
white blood cell counts and close follow up as risk of agranulocytosis= almost no granulocytes= mainly refers to neutrophils, but also include eosinophils, basophils and mast cells= INFECTION RISK- may present with sudden fever, rigors and sore throat.
other than the EP symptoms which may be experienced with antipsychotics e.g. rigidity and tardive dyskinesia, what is 1 of the main causes of non-adherence?
drug induced sexual dysfunction
Reduced dopamine transmission and hyperprolactinaemia decrease libido; antimuscarinic effects can cause disorders of arousal; and alpha1-adrenoceptor antagonists are associated with erection and ejaculation problems in men. Risperidone (atypical) and haloperidol (typical) commonly cause sexual dysfunction. If sexual dysfunction is thought to be antipsychotic-induced, dose reduction or switching medication should be considered.
example of antipsychotic most likely to cause hyperprolactinaemia?
risperidone
this then can reduce libido, cause reduced fertility, reduced bone mineral density, galactorrhoea and breast enlargement.
antipsychotics which commonly cause weight gain?
clozapine and olanzapine (both atypicals)
how might neuroleptic malignant syndrome be treated?
bromocriptine= dopamine agonist, and syndrome has been cause by anti-psychotics= dopamine antagonists dantrolene= muscle relaxant, also used in malignant hyperthermia.
ADRs of antipsychotics?
EP symptoms= parkinsonian e.g. bradykinesia, resting tremor and rigidity
dystonia= abnormal face and body movements, and dyskinesia= unintended, involuntary and uncontrollable movments.
akathisia= restlessness
tardive dyskinesia= may be irreversible on withdrawing therapy and tment usually ineffective.
hyperprolactinaemia sexual dysfunction weight gain- satiety centre affected in arcuate nucleus in hypothalamus hyperglycaemia and diabetes CVS effects e.g. tachycardia, hypotension, QT interval prolonged e.g. with haloperidol. neuroleptic malignant syndrome hypersalivation with clozapine drowsiness purplish pigmentation
most efficacious antipsychotic?
clozapine (atypical)
monitoring at start of therapy required for antipsychotics?
FBC
Us and Es
LFTs
mechanism by which most of ADRs of typical antipsychotics takes place?
antagonism of D2 receptors in nigrostriatal pathway of basal ganglia, and pituitary gland.
MOA of typical antipsychotics?
block D2 dopamine receptors in all of CNS dopaminergic pathways
also anticholinergic effects, alphaadrenergic
blockade and antihistamine effects
why might a typical antipsychotic be used in an emergency, and which 1 might be used?
more sedating
haloperidol
toxicity with typical antipsychotics?
CNS depression
cardiac toxicity
risk of sudden death with high dose
characteristics of anxiety disorders?
fear out of proportion to situation
avoidance
fear of dying, going crazy
Physical symptoms – light headedness, shortness of breath, hot and cold flushes, nausea, palpitations, numbness, pins and needles
1st line tment of anxiety?
CBT
drug tment of anxiety?
anti-depressants e.g. SSRIs, anxiolytics e.g BZDs- only indicated for ST RELIEF OF SEVERE ANXIETY, and occasionally antipsychotics.
PKs of antipsychotics?
highly lipophilic, metabolism in liver and high binding to plasma proteins and 1st pass met.
oral therapy typically for chronic use, may give IM to treat acutely psychotic ptnt who may be danger to themselves and others.
kinetics not strictly 1st order, but t1/2s of typicals usuallt 1 day, do once daily dosing regimen.
haloperidol may be given as decanoate ester= depot, given IM and slowly hydrolysed and released, highly lipophilic. long-acting, can be given every 3-4 wks, dso useful for non-compliant ptnts.
DDIs of antipsychotics?
drugs used in Parkinson’s disease- their action is inhibited, causing worsening of parkinsonian symptoms
BZDs- their sedative effects are potentiated, as are sedative effects of centrally active anti-histamines.
how do BZDs act?
high-affinity, highly selctive drugs, bind to GABA A receptors at an allosteric binding site to enhance GABAergic neurotransmission- increase frequency of Cl- ion channel opening in presence of low GABA.
only bind to BDZ receptor of which there are 2 main groups- high and low affinity
High affinity group- important in anxiolytic, hypnotic and anticonvulsant effects of BDZs
Inhibitory effects in brain
examples of BZDs?
lorazepam
diazepam
PKs of BZDs?
Bioavailability following oral admin. good, almost
complete- maximum concentrations 30-90 minutes, highly lipophilic so rapid and complete absorption, and CNS diffusion rapid.
metabolism via CYP450 in liver
Renal excretion
Long t1/2
plasma protein bound but don’t compete with other plasma protein bound drugs
ADRs of BZDs?
tolerance and dependence- so tment withdrawl can cause SEs e.g. insomnia, agitation and anxiety, so give for no longer than 10 days.
Common- drowsiness, dizziness, psychomotor impairment
Occasional- dry mouth, blurred vision, gastrointestinal upset, ataxia, headache, reduced blood pressure
Rare- amnesia, restlessness, rash
BZD toxicity?
?cleft lip and palate if used in
pregnancy
If taken late in pregnancy may cause respiratory depression and feeding difficulties in baby
what happens with BZD OD?
resp depression
can give IV flumazenil= an antagonist/partial inverse agonist at BDZ receptors may be useful in reversing effects, but t1/2 shorter than BZDs so wears off 1st.
characteristics of mania?
Feeling unusually excited, happy, optimistic or
feeling irritable
Overactive
Poor concentration and short attention span
Poor sleep
Rapid speech, jump from one idea to another
Poor judgement (overspending)
Increased interest in sex
Psychotic symptoms- hallucinations, grandiose
delusions
examples of mood stabilisers used to treat bipolar?
lithium sodium valproate carbamazepine lamotrigine- only effective for depression, = voltage-gated Na+ channel blockers antipsychotics
theories of how lithium works?
Electrolytes and channels- may compete with
magnesium and calcium ions
Neurotransmitters - Li increases 5HT, chronic Li
may reduce 5-HT receptor sites
Second messenger systems- lithium attenuates
the effects of certain neurotransmitters on their
receptors without altering receptor density.
PKs of lithium?
Renal excretion
Slow release preparations can be given once daily
Lithium levels need to be monitored(at least 3
monthly) and taken 12 hours after last oral dose –
narrow therapeutic window
Need check renal function, and thyroid function
before starting and every 6 months
what must be monitored during tment with lithium and why?
thyroid function every 6mnths as can cause hypothyroidism
and renal function every 6 mnths- as eliminated via kidneys and very nephrotoxic, can cause nephrogenic DI
uses of lithium?
Prophylaxis of Mania and Depression in bipolar
disorder
Augmentation of antidepressants in unipolar
depression
Good evidence for reducing suicidality
Of all mood stabilisers Lithium has the best evidence
ADRs of lithium tment?
Memory problems- anterograde amnesia Thirst Polyuria Tremor Drowsiness Weight gain hair loss rashes hypothyroidism effect on kidneys- nephrotoxic
DDIs of lithium?
NSAIDs- cause increased lithium reabsorption in PCT and elevation of its plasma conc to toxic levels
why must lithium be stopped slowly?
stopping quickly causes rebound depression and mania
toxic effects of lithium?
Need to monitor blood levels closely Vomiting Diarrhoea Coarse tremor Dysarthria Cognitive impairment Restlessness agitation
Tment of lithium toxicity?
stop lithium supportive measures anticonvulsants increase fluid intake / IV Fluids etc haemodialysis may be necessary
1st line pharmacological tment for dementia?
Acetyl Cholinesterase Inhibitors e.g.
Donepezil
Galantamine
Rivastigmine
but only give an extra yr of life before needing to go into a home
what other drug tment can be used rather than AChesterase inhibitors in dementia tment?
NMDA antagonist- memantine
what role does ACh normally play in brain which is reduced in Alzheimer’s?
arousal
memory
attention
mood
important SEs of AChesterase inhibitors?
Nausea, vomiting, anorexia, diarrhoea Fatigue, insomnia, headache Bradycardia Worsening of COPD Gastric/duodenal ulcers
what is memantine?
NMDA antagonist Licensed for moderate to severe dementia Usually well tolerated Common side effects include: hypertension, dyspnoea, headache, dizziness, drowsiness
