Pharmacology 12: Drugs used in Psychiatric Disease

Question 1

what is unipolar depression?

Answer 1

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.

Question 2

what is bipolar affective disorder?

Answer 2

characterised by depression and mania at different time in disease course, rarer than unipolar depression.

Question 3

why does therapeutic action of anti-depressants take several wks to occur?

Answer 3

changes in receptor expression and density
altered balance of various neurotransmitter systems
long term adaptive responses- altered gene expression and growth factors.

Question 4

noradrenaline and 5-HT as in what class of molecules?

Answer 4

monoamines

Question 5

4 different types of symptoms schizophrenia is assoc with?

Answer 5

+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

Question 6

how is schizophrenia thought to come about?

Answer 6

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.

Question 7

NTs thought to be reduced in depression?

Answer 7

5-HT and noradrenaline (monoamines)

Question 8

4 main dopamine pathways in the CNS?

Answer 8

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.

Question 9

why is it extremely important to understand the toxicities of anti-psychotic drugs?

Answer 9

some are highly toxic in OD, espec. tricyclic antidepresssants, and those prescribed them have a greater tendency to attempt suicide.

Question 10

3 core symptoms of depression?

Answer 10

low mood
decreased energy
anhedonia- inability to take pleasure in experiences which are normally enjoyable

2 of these must be present to diagnose depression

Question 11

symptoms of depression other than core symptoms?

Answer 11

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

Question 12

OTC preparation for mild depression, which has significant DDIs?

Answer 12

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.

Question 13

what is there an increased potential for during first few wks of pharmacological tment of depression?

Answer 13

anxiety
agitation
suicidal ideation

Question 14

1st line drugs for treating depression (moderate to severe)? mild should be treated with psychological therapy.

Answer 14

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

Question 15

which ADR has been reported more frequently in use of SSRIs in depression, than with other anti-depressants?

Answer 15

hyponatraemia- should be suspected if drowsiness, confusion or convulsions.

Question 16

how should patients taking anti-depressants be managed?

Answer 16

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.

Question 17

PKs of SSRIs?

Answer 17

almost completely absorbed from gut
long elimination t1/2s, so once daily dosing
metabolised in liver

Question 18

ADRs of SSRIs?

Answer 18

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

Question 19

examples of TCAs?

Answer 19

amitriptyline
imipramine
clomipramine
lofepramine

Question 20

PKs of TCAs?

Answer 20

Lipid soluble
Absorbed from gut
Long half lives
Metabolised in liver

Question 21

ADRs of TCAs?

Answer 21

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.

Question 22

example of drug used in psychiatric disease which lowers threshold for seizures?

Answer 22

TCAs e.g. amitriptyline

Question 23

factors involved in formulation of psychiatric disorders?

Answer 23

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.

Question 24

number of wks ptnt must have symptoms for before being diagnosed with depression?

Answer 24

> 2 wks

Question 25

3 theories for depression?

Answer 25

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.

Question 26

which drug classes are part of the monoamine uptake inhibitors?

Answer 26

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.

Question 27

how do SSRIs work?

Answer 27

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.

Question 28

why do SSRIs have a greater therapeutic index than TCAs and why is this important?

Answer 28

have a greater selectivity | important in depressed patient who may intentionally commit suicide by taking an OD

Question 29

important CVS ADRs of citalopram= a SSRI?

Answer 29

QT-interval prolongation, bradycardia, tachycardia, postural hypotension

Question 30

what are TCAs particularly useful for treating, other than depression?

Answer 30

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)

Question 31

how do TCAs act to treat depression?

Answer 31

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)

Question 32

what must be done with a patient who has overdosed on amitriptyline?

Answer 32

must be taken to resuscitation and CVS function must be monitored- ECG

Question 33

examples of pure non-selective monoamine uptake inhibitors (SNRIs)?

Answer 33

duloxetine | venlafaxine

Question 34

how do SNRIs work?

Answer 34

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.

Question 35

ADRs and toxicity with SNRIs?

Answer 35

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.

Question 36

define psychosis

Answer 36

a lack of contact with reality

Question 37

symptoms of paranoid schizophrenia?

Answer 37

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

Question 38

define a hallucination and delusion

Answer 38

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

Question 39

what is the dopamine hypothesis of schizophrenia?

Answer 39

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.

Question 40

which dopamine pathway do we wish to block in tment of schizophrenia and why?

Answer 40

the mesolimbic system= it's thought that hyperactivity of this is reponsible for the +ve symptoms e.g. hallucinations, delusions, disorganised speech.

Question 41

ADRs produced by D2 receptor blockage in nigrostriatal pathway in tment of schizophrenia?

Answer 41

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.

Question 42

ADRs with D2 receptor blockage in meso-cortical pathway?

Answer 42

enhanced -ve symptoms of schizophrenia and cognitive psychotic symptoms.

Question 43

ADRs with D2 receptor blockage in tuberoinfundibular pathway?

Answer 43

hyperprolactinemia (lactation-galactorrhoea, infertility, sexual dysfunction) **e.g. bromocriptine= dopamine agonist, so can be used to treat hyperprolactinaemia, which can help with infertility.

Question 44

NTs other than dopamine which schizophrenia is thought to be associated with?

Answer 44

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.

Question 45

action of all antipsychotics?

Answer 45

``` 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. ```

Question 46

examples of 1st generation/typical antipsychotics?

Answer 46

haloperidol | chlorpromazine

Question 47

examples of atypical antipsychotics?

Answer 47

risperidone olanzapine clozapine

Question 48

advantages of atypical antipsychotics?

Answer 48

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

Question 49

most severe ADR of typical antipsychotics?

Answer 49

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.

Question 50

what must be frequently monitored if given clozapine (atypical antipsychotic) for schizophrenia and why?

Answer 50

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.

Question 51

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?

Answer 51

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.

Question 52

example of antipsychotic most likely to cause hyperprolactinaemia?

Answer 52

risperidone this then can reduce libido, cause reduced fertility, reduced bone mineral density, galactorrhoea and breast enlargement.

Question 53

antipsychotics which commonly cause weight gain?

Answer 53

clozapine and olanzapine (both atypicals)

Question 54

how might neuroleptic malignant syndrome be treated?

Answer 54

``` bromocriptine= dopamine agonist, and syndrome has been cause by anti-psychotics= dopamine antagonists dantrolene= muscle relaxant, also used in malignant hyperthermia. ```

Question 55

ADRs of antipsychotics?

Answer 55

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 ```

Question 56

most efficacious antipsychotic?

Answer 56

clozapine (atypical)

Question 57

monitoring at start of therapy required for antipsychotics?

Answer 57

FBC Us and Es LFTs

Question 58

mechanism by which most of ADRs of typical antipsychotics takes place?

Answer 58

antagonism of D2 receptors in nigrostriatal pathway of basal ganglia, and pituitary gland.

Question 59

MOA of typical antipsychotics?

Answer 59

block D2 dopamine receptors in all of CNS dopaminergic pathways also anticholinergic effects, alphaadrenergic blockade and antihistamine effects

Question 60

why might a typical antipsychotic be used in an emergency, and which 1 might be used?

Answer 60

more sedating | haloperidol

Question 61

toxicity with typical antipsychotics?

Answer 61

CNS depression cardiac toxicity risk of sudden death with high dose

Question 62

characteristics of anxiety disorders?

Answer 62

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

Question 63

1st line tment of anxiety?

Answer 63

CBT

Question 64

drug tment of anxiety?

Answer 64

anti-depressants e.g. SSRIs, anxiolytics e.g BZDs- only indicated for ST RELIEF OF SEVERE ANXIETY, and occasionally antipsychotics.

Question 65

PKs of antipsychotics?

Answer 65

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.

Question 66

DDIs of antipsychotics?

Answer 66

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.

Question 67

how do BZDs act?

Answer 67

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

Question 68

examples of BZDs?

Answer 68

lorazepam | diazepam

Question 69

PKs of BZDs?

Answer 69

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

Question 70

ADRs of BZDs?

Answer 70

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

Question 71

BZD toxicity?

Answer 71

?cleft lip and palate if used in pregnancy If taken late in pregnancy may cause respiratory depression and feeding difficulties in baby

Question 72

what happens with BZD OD?

Answer 72

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.

Question 73

characteristics of mania?

Answer 73

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

Question 74

examples of mood stabilisers used to treat bipolar?

Answer 74

``` lithium sodium valproate carbamazepine lamotrigine- only effective for depression, = voltage-gated Na+ channel blockers antipsychotics ```

Question 75

theories of how lithium works?

Answer 75

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.

Question 76

PKs of lithium?

Answer 76

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

Question 77

what must be monitored during tment with lithium and why?

Answer 77

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

Question 78

uses of lithium?

Answer 78

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

Question 79

ADRs of lithium tment?

Answer 79

``` Memory problems- anterograde amnesia Thirst Polyuria Tremor Drowsiness Weight gain hair loss rashes hypothyroidism effect on kidneys- nephrotoxic ```

Question 80

DDIs of lithium?

Answer 80

NSAIDs- cause increased lithium reabsorption in PCT and elevation of its plasma conc to toxic levels

Question 81

why must lithium be stopped slowly?

Answer 81

stopping quickly causes rebound depression and mania

Question 82

toxic effects of lithium?

Answer 82

``` Need to monitor blood levels closely Vomiting Diarrhoea Coarse tremor Dysarthria Cognitive impairment Restlessness agitation ```

Question 83

Tment of lithium toxicity?

Answer 83

``` stop lithium supportive measures anticonvulsants increase fluid intake / IV Fluids etc haemodialysis may be necessary ```

Question 84

1st line pharmacological tment for dementia?

Answer 84

Acetyl Cholinesterase Inhibitors e.g. Donepezil Galantamine Rivastigmine but only give an extra yr of life before needing to go into a home

Question 85

what other drug tment can be used rather than AChesterase inhibitors in dementia tment?

Answer 85

NMDA antagonist- memantine

Question 86

what role does ACh normally play in brain which is reduced in Alzheimer's?

Answer 86

arousal memory attention mood

Question 87

important SEs of AChesterase inhibitors?

Answer 87

``` Nausea, vomiting, anorexia, diarrhoea Fatigue, insomnia, headache Bradycardia Worsening of COPD Gastric/duodenal ulcers ```

Question 88

what is memantine?

Answer 88

``` NMDA antagonist Licensed for moderate to severe dementia Usually well tolerated Common side effects include: hypertension, dyspnoea, headache, dizziness, drowsiness ```