Pharmacological Treatment

Question 1

General information about antipsychotics

Answer 1

-Side effects; extra-pyramidal, worsened by high doses and long periods of treatment
-Clozapine showed less EPSEs and therefore classed as atypical/ second generation
-Antipsychotics divided into first and second generation (typical and atypical)

Question 2

Common first generation antipsychotics

Answer 2

-Chlorpromazine
-Haloperidol
-Sulpiride
-Flupentixol (Depixol)
-Zuclopenthixol (Clopixol)

Question 3

Common second generation antipsychotics

Answer 3

-Clozapine
-Olanzapine
-Quetiapine
-Risperidone
-Aripiprazole

Question 4

Mechanism of action of antipsychotics

Answer 4

-The primary mechanism for all antipsychotics (with the exception of clozapine) is dopamine D2 receptor antagonism in the mesolimbic pathway
-Most second generation antipsychotics also block serotonin receptors (5-HT2)
-This blockage of dopamine receptors occurs throughout the brain leading to diverse side-effects – there is also blockade of muscarinic, histaminergic and alpha adrenergic receptors (just like TCAs)

Question 5

Indications of antipsychotics

Answer 5

-Schizophrenia, schizoaffective disorder and delusional disorders
-Depression or mania with psychosis
-Prophylaxis in bipolar disorder
-Psychotic episodes secondary to a medical condition or psychoactive substance use
-Delirium
-Behavioural disturbance in dementia
-Severe agitation, anxiety and violent or impulsive behaviour
-Tics (Tourette syndrome)
-Nausea and vomiting
-Intractable hiccups and pruritus

Question 6

Side effects of antipsychotics

Answer 6

-Dopamine receptor antagonism leads to:
=Worsening of negative and cognitive symptoms of schizophrenia
=EPSEs (motor symptoms that arise from dysfunction of the striatum of basal ganglia)
=Hyperprolactinaemia (galactorrhoea, infertility and sexual dysfunction)

-Anticholinergic effects lead to dry mouth, constipation, urinary retention and blurred vision

-Alpha-adrenergic blockade leads to postural hypotension

-Histaminergic blockade causes sedation and weight gain
=Metabolic syndrome is more common with second generation drugs

-Increased risk of cardiac arrhythmias and sudden death due to QTc prolongation

-Photosensitivity, rashes, lowered seizure threshold, hepatotoxicity and agranulocytosis

Question 7

Extrapyramidal side effects of antipsychotics

Answer 7

1. Acute dystonia = involuntary sustained muscular contractions/ spasms
   =Occur within 72 hours of starting treatment. Treat with procyclidine.
2. Akathisia = feeling of inner restlessness and muscular discomfort
   =Occurs within days to weeks of starting treatment. Treat with propranolol or benzos.
3. Parkinsonism = muscular rigidity, bradykinesia and resting tremor
   =Occur within a month of commencing treatment. Treat with procyclidine.
4. Tardive dyskinesia = Rhythmic, involuntary movements (chewing, grimacing)
   =Common in patients on long-term treatment. Treat by withdrawing drug and avoid anticholinergics as they worsen symptoms

Question 8

Overview of neuroleptic malignant syndrome

Answer 8

-Condition with insidious onset, characterised by triad of:
=Neuromuscular abnormalities – severe lead pipe rigidity
=Altered consciousness
=Autonomic dysfunction – hyperthermia, tachycardia, sweating and labile blood pressure

-Usually occurring within 4-11 days of initiation or dose increase
-Bloods show elevated creatinine kinase, white cells and LFTs with metabolic acidosis

-Treat by discontinuing the drug, active cooling, fluids and consider ICU admission

Question 9

Overview of clozapine

Answer 9

-Considered the only true “atypical” antipsychotic due to its distinct receptor binding pattern and effectiveness in 2/3 of treatment-resistant cases
-Its use is limited for patients with treatment-resistant schizophrenia due to the potentially life-threatening risk for bone marrow suppression with agranulocytosis (0.8% of patients)
=FBC should be monitored before and weekly then monthly throughout treatment, and patients warned to contact their GP if they develop a sore throat
=With monitoring, fatalities from agranulocytosis are very rate (<1 in 5000 patients)
-There is also additional cardiac risk associated with clozapine (myocarditis and cardiomyopathy) and it is commonly implicated in severe constipation and bowel obstruction

Question 10

Contraindications to antipsychotics

Answer 10

-Parkinson disease or Lewy Body dementia can be exacerbated by antipsychotics
-Patients with known arrhythmias or family history of sudden death should have QTc monitored closely before and during treatment

Question 11

Monitoring of antipsychotics

Answer 11

-Pulse and BP at 12 weeks at year year then annually
-Fasting blood glucose or HbA1c, and blood lipid levels at 12 weeks, at 1 year and then annually
-Adherence
-Overall physical health
-Weight, weekly for the first 6 weeks, then at 12 weeks, at 1 year and then annually (plotted on a chart)
-Waist circumference annually (plotted on chart)
-Response to treatment, including changes in symptoms and behaviour
-Side effects of treatment, taking into account overlap between certain side effects and clinical features of schizophrenia (for example, the overlap between akathisia and agitation or anxiety) and impact on functioning
-The emergence of movement disorders
-ECG should be monitored at initiation and throughout treatment especially in those with a cardiac history or risk factors

Question 12

What is rapid tranquilisation?

Answer 12

-When medication is used to manage severe psychomotor agitation or aggressive behaviour that hasn’t been defused using simple environmental or behavioural interventions
-Severe agitation or aggressive behaviour may arise in patients with psychosis, mania, dementia, delirium and substance use intoxication or withdrawal
-Where possible, attempts should initially be made to safely de-escalate the situation without the use of medications

Question 13

How is rapid tranquilisation given?

Answer 13

1. Accepting oral medication
   -Oral lorazepam 1-2 mg (0.5mg in older adults)
   -If psychotic context or ineffective: consider in addition oral antipsychotic but aim to avoid combining antipsychotics
2. Refusing oral medication, significant risk to self or others
   -IM lorazepam 1-2 mg (0.5mg in older adults)
   -If psychotic context or ineffective: consider in addition AM antipsychotic (haloperidol 5mg and/or promethazine 50mg)

=Repeat as required every 45-60 minutes, consider IV tranquilisation in exceptional circumstances only.
=Review legal status: if IM given under common law patient requires assessment for detention, review by senior doctor at least daily

Question 14

Interventions occurring simultaneously to rapid tranquilisation

Answer 14

-Environmental interventions
=Create calm environment (turn off TV radio, remove other patients to another room
=Remove objects used as weapons
=Get hep from trained staff

-Behavioural interventions
=Talk slowly and softly
=Never turn back
=Between exit and patient
=Eye contact for rapport/ threatening
=Innocuous questions about sleeping and eating useful distraction
=Allow patient to verbalise feelings but cut short if anger is escalating
=Restraint may be necessary with removal to safer secluded area

Question 15

Precautions for rapid tranquilisation

Answer 15

-If parenteral benzodiazepines are given, flumazenil must be available (in case of benzodiazepine toxicity)
-If haloperidol is given, procyclidine must be available (in case of acute dystonias)
-After parenteral rapid tranquilisation, frequently observe temperature, pulse, RR, hydration and level of consciousness until patient ambulatory
= The patient appears asleep or sedated
=Patient has recently taken recreational drugs or alcohol
=BNF maximum doses for medication have been exceeded
=Patient has a pre-existing physical health problem
=Patient has experienced any harm as a result of the intervention
-Detention under the Mental Health Act must be considered if rapid tranquilisation is required for an informal patient

Question 16

What is Psychological Therapy?

Answer 16

The interaction between a therapist and a patient which aims to impact beneficial changes in the patient’s thoughts, feelings and behaviours

Question 17

What is CBT?

Answer 17

-A psychological therapy aimed at challenging automatic thoughts and dysfunctional assumptions which can affect the relationship between an individuals thoughts, feeling and behaviours

Question 18

What are automatic thoughts?

Answer 18

Thoughts which involuntarily enter an individuals mind in response to specific situations (e.g. “they don’t like me”, “I’m an idiot”)

Question 19

What are dysfunctional assumptions?

Answer 19

Faulty rules that individuals live by that underlie what automatic thoughts occur. If a rule broken the result is psychological stress (e.g. “if I don’t win then I am useless”, “if I disappoint someone then I am a horrible person”, “if I tell people how I feel then I am weak”)

Question 20

NICE recommendations for CBT

Answer 20

-Anxiety Disorders (including Panic Attacks and Post-Traumatic Stress Disorder)
-Depression
-Obsessive Compulsive Disorder (OCD)
-Schizophrenia and related psychoses
-Bipolar Disorder
-Eating Disorders
-There is also good evidence that CBT is helpful in treating many other conditions, including: chronic fatigue, chronic pain, medically unexplained symptoms, sleep problems, and anger management

Question 21

CBT structure

Answer 21

-Modalities = self-directed (books, DVDs, interactive websites, apps, internet based forums/discussion groups) or in-person (group or individual)
-Time limited – 12-24 sessions
-Goal oriented
-Focus is on present problems (not concerned with how problems developed or unconscious factors)
-Strongly collaborative therapeutic relationship
-Involves patients doing ‘homework assignments’
-Patient encouraged to keep a diary of automatic thoughts, which helps to identify their thinking style

Question 22

Therapeutic factors of CBT

Answer 22

-Client factors
=Personal strengths
=Social supports

-Therapist-client relationship factors (therapeutic alliance)
=Empathy
=Acceptance
=Warmth

-Client’s expectance of change

Question 23

Prognosis of CBT

Answer 23

-A recent systematic review and meta-analysis in the British Journal of Psychiatry (2017) found that the standardised mean difference in scores on the Hamilton Rating Scale for Depression in randomised controlled trials (RCTs) between CBT and pill placebo was 0.22 (95% CI 0.42 to0.02).
-This gives a number needed to treat (NNT) = 12 which compares favourably with antidepressant RCTs where the NNT = 9.
-There is a strong pill placebo effect in the treatment of depression with improvement in 30-50% across studies, but the reported benefits of CBT and antidepressants in depression are significantly above the placebo response.
-Hence, it is worth treating depression! (and both psychological &pharmacological interventions can be effective)

Question 24

What is psychological therapy?

Answer 24

The interaction between a therapist and a patient which aims to impact beneficial changes in the patient’s thoughts, feelings and behaviours

Question 25

Main psychological treatments for depression

Answer 25

CBT, mindfulness-based cognitive therapy, interpersonal therapy, psychodynamic therapy, group therapy

Question 26

Main psychological treatments of anxiety disorders

Answer 26

CBT, mindfulness-based cognitive behavioural therapy, exposure and response prevention (for OCD), systematic desensitisation (for phobias)

Question 27

Main psychological treatments for PTSD

Answer 27

CBT, eye movement desensitisation and reprocessing (EMDR) therapy

Question 28

Main psychological treatments for schizophrenia

Answer 28

CBT, family therapy

Question 29

Main psychological treatments for eating disorders

Answer 29

CBT, focused psychodynamic psychotherapy, interpersonal therapy, family therapy

Question 30

Main psychological treatments for Emotionally unstable personality disorder

Answer 30

Dialectical behaviour therapy, mentalisation-based therapy, psychodynamic therapy, CBT, cognitive analytic therapy, therapeutic communities

Question 31

Main psychological treatments for alcohol dependence

Answer 31

CBT, group therapy, motivational interviewing

Question 32

Describe counselling and supportive psychotherapy

Answer 32

-Indications
=Minor mental health or interpersonal difficulties
=Stressful life experiences (i.e. grief counselling for bereavement)

-Characteristics
=Usually brief, focussing on specific issues
=May be unstructured or include education, explanation and advice

-Person-centred counselling
=Therapist role = empathic and reflective
=Patients discover their own insights

-Problem-solving counselling
=Therapist role = more directive, focused
=Patient actively assisted in finding solutions

Question 33

Psychoanalytic vs psychodynamic psychotherapy

Answer 33

Psychoanalysis = patient sees therapist several times a week, time frame not specified, patient lying on couch, therapist out of view, rarely provided by NHS due to time and resource intensive nature, still practiced in private sector

Psychodynamic psychotherapy = once weekly, 50mins per session, sitting face-to-face, interactive, individual or group sessions, duration of months-years depending on individual need and response

Question 34

Assumptions of psychodynamic psychotherapy

Answer 34

-Basic assumptions:
=Unconscious thoughts, feelings and fantasies give rise to distressing symptoms
=These process are kept unconscious by defence mechanisms

-Unconscious = a thought, feeling or fantasy which is inaccessible to the conscious mind but affects behaviour and emotions

-Defence mechanism = a method of suppressing distressing thoughts, feelings or fantasies which are employed when anxiety-producing aspects of the self threaten to break through to the conscious mind

Question 35

Aims of psychodynamic psychotherapy

Answer 35

-Aims:
=To facilitate conscious recognition of symptom-causing unconscious processes
=To facilitate understanding of unconscious processes in context of a safe, caring relationship

-Modern psychodynamic psychotherapy relies on the analysis of transference and counter-transference:
=Transference = theoretical process by which a patient transfers feelings or attitudes experienced in an earlier significant relationship onto the therapist
=Counter-transference = the feelings that are evoked in the therapist, which can indicate to the therapist how a patient is feeling and subsequently help them empathise

Question 36

Describe graded exposure therapy

Answer 36

-Indicated for phobias and posttraumatic stress disorder
-Hierarchy of increasingly ‘threatening’ situations (e.g. spider in room next door= spider in same room = spider near patient = spider in patient’s hand)
-Step wise treatment – patients only move on to next step when anxiety relief achieved for current step

Question 37

Describe exposure with response prevention

Answer 37

-Indicated for obsessive-compulsive disorder
-Patients encouraged to resist carrying out compulsions until urge diminishes
-Step wise increase to more severe compulsion-evoking situations

Question 38

Describe relaxation psychological therapy

Answer 38

-Indicated for anxiety
-Progressive relaxation of muscle groups, breathing exercises, visualising relaxing images and situations

Question 39

Describe Interpersonal therapy

Answer 39

-Assumption that problems in social functioning and interpersonal relationships are significant factors in the development of mental illness and also consequences of mental illness
-Aims to enable patients to evaluate their social interactions and improve interpersonal skills, focuses on current problems, not their origins, brief (12-16 sessions)

Question 40

Describe group therapy

Answer 40

-Possible for many treatment modalities (supportive to CBT to psychodynamic approaches)
-Once weekly hourly meetings with 1-2 therapists and 5-10 patients, duration of months (CBT)to years (psychodynamic)
-Safe social setting, allows recognition that patients are ‘not alone’ in having their particular problems

Question 41

Describe family therapy

Answer 41

-Therapy that treats the family as a whole, not individually focused
-Aims to improve communication and conflict resolution and subsequently a patient’s symptoms

Question 42

Overview of SSRIs

Answer 42

-Selective Serotonin Reuptake Inhibitors (SSRIs)
-Examples: fluoxetine, sertraline, paroxetine, citalopram
-MoA: selective presynaptic blockade of serotonin reuptake pumps
-Indications: first-line for depression, anxiety disorders and OCD
-Side-effects:
=Common = GI disturbance, increased risk of GI bleeding, loss of appetite, insomnia, sweating and sexual dysfunction, hyponatraemia
=Importantly there can be increased agitation and anxiety during initiation of treatment that increases the risk of suicide – patients must be counselled for this
-Contraindications: mania, poorly controlled epilepsy and citalopram use in long QTc, interactions with NSAID (PPI), warfarin or heparin (use mirtazapine), triptans
-Reviewed after 2 weeks/ under 30 and increased risk of suicide 1 week, continue until at least 6 months after remissions to reduce risk of relapse, gradually reduced over 4 weeks

Question 43

Overview of SNRIs

Answer 43

-Serotonin and noradrenaline reuptake inhibitors (SNRIs)
-Examples: venlafaxine, duloxetine
-MoA: presynaptic blockade of noradrenaline and serotonin reuptake pumps (also dopamine at high doses)
-Indications: depression, anxiety disorders, OCD (not usually first line)
-Side-effects:
=Similar to SSRIs but more severe.
=More toxic in overdose (but less so than tricyclics).
=Discontinuation symptoms common.
-Contraindications: mania, uncontrolled hypertension, high risk of arrhythmia

Question 44

Overview of NaSSA

Answer 44

-Noradrenergic and specific serotonergic antidepressant
-Examples: mirtazapine
-MoA: increases release of noradrenaline and serotonin from presynaptic neurons(via presynaptic alpha-2 receptor blockade)
-Indication: depression where sedation or increased oral intake is desirable/ depression where avoiding sexual side effects is important
-Side-effects:
=Very commonly increased appetite/weight gain, sedation, headache and dry mouth
=Less commonly, postural hypotension, tremor and peripheral oedema
-Contraindications: mania, age under 18 years

Question 45

Overview of TCAs

Answer 45

-Tricyclic Antidepressants
-Examples: amitriptyline, clomipramine, lofepramine
-MoA: presynaptic blockade of noradrenaline, serotonin reuptake pumps. Also block muscarinic, histaminergic and alpha-adrenergic receptors (side effects)
-Indications: depression, anxiety disorders, OCD (clomipramine) (not first line) Also chronic pain, nocturnal enuresis and narcolepsy
-Side-effects: sedation, weight gain, anticholinergic effects, (dry mouth, urinary retention, blurred vision and constipation), postural hypotension, cardiotoxicity (prolonged QTc, heart block, arrhythmias = dangerous in OD)
-Contraindications: mania, recent MI, arrhythmias, and high risk of overdose

Question 46

Choice of TCA

Answer 46

low-dose amitriptyline is commonly used in the management of neuropathic pain and the prophylaxis of headache (both tension and migraine)
lofepramine has a lower incidence of toxicity in overdose
amitriptyline and dosulepin (dothiepin) are considered the most dangerous in overdose

Question 47

Overview of MAOIS

Answer 47

-Monoamine Oxidase Inhibitors
-Examples: phenelzine, moclobemide
-MoA: non-selective inhibition of monoamine oxidase A and B (most irreversible inhibition, but moclobemide reversible)
-Indication: Depression (esp. atypical), anxiety disorders (generally 3rd line) Also used in Parkinson disease and migraine prophylaxis
-Side-effects:
=Risk of hypertensive crisis if patient ingests tyramine-rich foods (e.g. cheese, beer) or takes certain other medications (e.g. decongestants containing ephedrine or L-dopa)
=Also postural hypotension and anticholinergic effects similar to TCAs
-Contraindications: mania, cerebrovascular disease and phaeochromocytoma

Question 48

Describe Discontinuation Syndrome

Answer 48

-The abrupt withdrawal of any antidepressant can result in discontinuation syndrome
-Symptoms include GI disturbance (pain, cramping, diarrhoea, vomiting), agitation/restlessness, dizziness/unsteadiness, headache, tremor/paraesthesia and insomnia, sweating
-For this reason, all antidepressants (apart from the longer half-life SSRI, fluoxetine) should be gradually tapered down before stopping

Question 49

Describe Serotonin Syndrome

Answer 49

-Acute onset condition occurring usually after one or two doses of a new serotonergic medication (commonly concurrent use of SSRI and MAOI)

-Characterised by triad of:
=Neuromuscular abnormalities (myoclonus/clonus, hyperreflexia, tremor, muscular rigidity)!!!!
=Altered consciousness
=Autonomic dysfunction (hyperthermia, sweating, tachycardia, labile BP)

-Bloods show elevated creatinine kinase, WCC and ALT with a metabolic acidosis
-Management: discontinue the medication, cool the patient, manage hydration with fluids and consider need for ICU (plus cyproheptadine in more severe cases)
-Avoid by careful swapping of antidepressants: see NICE CKS (March 2020)

Question 50

Serotonin syndrome vs neuroleptic malignant syndrome

Answer 50

-Serotonin: hyperreflexia and clonus (serotonin excess)
NMS: lead pipe rigidity (dopamine blockade)

Question 51

Choice of antidepressant

Answer 51

-NICE recommends any SSRI as first line for mod-severe depression
-Factors which influence choice of 1st or 2nd line antidepressant:
=Previous good response
=Side-effects
=Comorbid physical health problems
=Comorbid mental health problems
=Risk for overdose
=Atypical depression

Question 52

What happens when an antidepressant doesn’t work?

Answer 52

-Is the medication being taken appropriately?
=Confirm concordance, duration of treatment (at least 4 weeks),minimum therapeutic dose

-Reassess the diagnosis
=Substance use? Personality disorder? Ongoing psychosocial stressor?

-Consider talking therapy

-Consider changing the medication
=Increase the dose
=Change to another SSRI (e.g. fluoxetine to sertraline)
=Change class (e.g. sertraline to venlafaxine or mirtazapine)
=Treatment resistant options (d/w secondary care)

-Consider ECT

Question 53

What are mood stabilisers?

Answer 53

-Mood stabilisers are used as prophylaxis against future mood episodes(depression or elation). They can also be used to treat acute hypo/mania anddepressive episodes.
-Antimanic agents aim to treat acute mania. Substantial overlap with mood stabilisers but different first line, second line agents.

-Three types of mood stabiliser:
=Lithium (1st line for prophylaxis)
=Some antipsychotics (quetiapine, olanzapine) (1st line for mania, 2nd line for prophylaxis)
=Some anticonvulsants (sodium valproate, lamotrigine, carbamazepine) (2nd or 3rd line)

Question 54

Overview of Lithium

Answer 54

MoA: lithium modulates neurotransmitter levels through influencing activation of second messenger systems and subsequent gene expression

-Indications:
=Prophylaxis against bipolar affective disorder relapse (1st line)
=Acute mania (if already taking, or add in as 3rd line augmentation agent)
=Treatment-resistant depression

-Side-effects:
=Thirst, polydipsia, polyuria (if severe: nephrogenic diabetes insipidus)
=Impaired renal function (benign for most)
=Hypothyroidism and hyperparathyroidism
=Precipitates/worsens skin problems (e.g. psoriasis); Weight gain and oedema; Concentration and memory problems; Tremor; Cardiac conduction alterations (T wave inversion, QRS broadening)

-Contraindications: cardiac conduction abnormalities/arrhythmias, untreated hypothyroidism

Question 55

Describe lithium toxicity

Answer 55

-Lithium has a narrow therapeutic index
=0.4-0.8 mmol/L in depression
=0.6-1.0 mmol/L in treatment of mania and as prophylaxis for bipolar disorder

-Toxicity defined as >1.5 mmol/L
=At these levels there is nausea and vomiting, coarse tremor, ataxia and muscle weakness
=>2 mmol/L is dangerously toxic: presents with nystagmus, dysarthria, hyperactive tendon reflexes, oliguria, hypotension, impaired consciousness, seizures and coma

-Lithium is excreted mostly by the kidneys – if kidney function is poor (e.g. older adult, dehydration) then levels of lithium will be higher
-Drug interactions: thiazide diuretics, NSAIDs, ACE inhibitors can increase lithium levels via effects on kidneys
-Brand of lithium: different preparations different bioavalabilities

Question 56

Describe Lithium monitoring

Answer 56

-Investigations should be carried out prior to initiation of therapy:
=FBC, U+Es
=Calcium and TFTs
=ECG for those with known cardiac disease or risk factors
=Pregnancy test if indicated (risk of teratogenicity)

-Lithium levels should be taken weekly until a therapeutic level has been maintained for a two-week period
=They are then done 3-monthly for the first year, and then every 6 months thereafter

-Renal function, calcium and thyroid function should be checked at least every6 months along with weight/BMI

Question 57

MoA of anticonvulsants

Answer 57

-Examples: Valproate, lamotrigine, carbamazepine
-Mechanism of action: inhibition of voltage-gated sodium channels and enhancement of GABA-ergic neurotransmission

Question 58

Overview of Sodium valproate

Answer 58

-Indications: prophylaxis of bipolar disorder (2nd line), acute mania (3rd line),epilepsy
-Side-effects: high teratogenicity, nausea, ankle swelling, hair loss, tremor, raised LFTs and haematological abnormalities, sedation and dizziness
-Contraindications: woman of child bearing potential*, active liver disease, history of drug-induced hepatic dysfunction *unless severe disease, no other alternative, and on a pregnancy prevention plan
-Monitoring:
=Baseline FBC, LFTs and BMI
=At 6 months then yearly: FBC, LFT, PT and BMI

Question 59

Overview of Lamotrigine

Answer 59

-Indications: prophylaxis of depressive episodes in bipolar disorder (3rd line),epilepsy

-Side-effects: nausea, headache, aggression/irritability, sedation and dizziness,
=Rarely it is associated with Stevens-Johnson syndrome, usually within the first 8weeks of use – stop immediately if there are signs of a rash

-Contraindications: previous rash on lamotrigine

Question 60

Overview of Carbamazepine

Answer 60

-Indications: prophylaxis of bipolar disorder (3rd line), epilepsy

-Side-effects: CYP enzyme induction with multiple drug: drug interactions, vision problems, hyponatraemia, raised LFTs and haematological abnormalities, ataxia, drowsiness and fatigue
-Contraindications: AV conduction abnormalities, bone-marrow suppression

-Monitoring:
=Baseline FBC, U+Es, LFTs and ECG
=FBC and LFTs can be checked up to fortnightly during dose titration(manufacturers recommend but BNF doesn’t). Useful to check if pt unwell

Question 61

Examples of anxiolytic, hypnotic, and sedative drugs

Answer 61

-Anxiolytic drug: one that reduces anxiety
-Hypnotic drug: one that induces sleep
-Sedative drug: a drug with both above properties (old term: tranquillizer)
=All of these drugs have significant abuse potential and can cause dependence
=Their effects are increased by alcohol

-Benzodiazepines are sedative, whereas Z-drugs (zopiclone, zolpidem and zaleplon) are hypnotic
-Other sedative drugs: sedating antidepressants, sedating antipsychotics, and pregabalin.
-Other anxiolytics (non-sedative): SSRIs, SNRIs and buspirone.
-Other hypnotics: sedating antihistamines, low dose trazodone & melatonin

Question 62

Overview of Benzodiazepines

Answer 62

-Examples: diazepam, lorazepam, midazolam, chlordiazepoxide
-Effects: anxiolytic, muscle relaxant, anticonvulsant, hypnotic
-Mechanism of action: potentiate GABA (main inhibitory neurotransmitter), act as GABAA-positive allosteric modulators (PAMs): increasing the affinity of the GABAA receptor complex for GABA and chloride ion flow into the cell, hyperpolarising post-synaptic membranes and reducing neuronal excitability
-Indications: insomnia (short-term use); anxiety disorders (short-term use); alcohol withdrawal (chlordiazepoxide / diazepam); sedation / rapid tranquillization for acute behaviour disturbance, mania or psychosis; akathisia (restlessness associated with antipsychotics); epilepsy prophylaxis, treatment of status epilepticus; management of muscle spasm
-Contraindications: Acute pulmonary insufficiency; marked neuromuscular respiratory weakness; sleep apnoea syndrome; unstable myasthenia gravis
-Notable side-effects: sedation, fatigue, weakness, depression, dizziness, loss of coordination (ataxia), slurred speech, memory problems (dose dependent), confusion, agitation.

Question 63

Overview of Z-drugs (hypnotic)

Answer 63

-Examples: zopiclone, zolpidem and zaleplon
-Effects: hypnotic
-Mechanism of action: like benzodiazepines, they potentiate the action of GABA by acting as GABAA-PAMs but bind selectively to a subtype of the benzodiazepine receptor, the alpha1 isoform, reducing neuronal excitability, particularly in sleep centres in the brain.
-Indications: Insomnia (short-term use only)
-Contraindications: Marked neuromuscular respiratory weakness; myasthenia gravis; respiratory failure; severe sleep apnoea syndrome
-Notable side-effects: sedation, dizziness, loss of coordination (ataxia), memory problems(dose dependent), agitation. Less commonly: dry mouth, bad taste (bitter / metallic), change in appetite, constipation, blurred vision, headache, hallucinations

Question 64

Cautions related to use of benzodiazepines and Z drugs

Answer 64

-Risk of dependence with prolonged use
=There is a significant abuse potential and caution is needed in prescribing, particularly to vulnerable patients e.g. those with a history of alcohol or recreational drug misuse.

-Drowsiness, ataxia and reduced coordination
=Patients should be warned about dangers of driving and operating machinery
=This predisposes to falls in the elderly – use with great caution

-Respiratory depression
=Use with caution in chronic respiratory problems (e.g. COPD, sleep apnoea)
=Flumazenil is a benzodiazepine receptor antagonist that can reverse the effects of benzodiazepines and z drugs in case of toxicity

-Alcohol, opiates, tricyclics, antihistamines and other sedatives (includingantipsychotics) can all enhance the effects of sedative drugs

Question 65

NICE guidelines for benzodiazepines for alcohol detox

Answer 65

-Medication for assisted withdrawal is done with a standard protocol either as an outpatient or inpatient.
-This usually involves a fixed dose regimen of chlordiazepoxide or diazepam unless there is liver impairment, when lorazepam is preferred due to its limited liver metabolism.
-The initial dose of medication depends on the severity of alcohol dependence and/or regular daily level of alcohol consumption.
-The dose of the benzodiazepine is gradually reduced over 7–10 days to avoid alcohol withdrawal symptoms

Question 66

The Goldilocks hypnotic principle

Answer 66

The ideal hypnotic has a half–life that is not too long and not too short.

-Hypnotics with medium / long half-lives of 10-30 hours (or more)
=e.g. diazepam, temazepam, most tricyclic antidepressants, mirtazapine, most sedating antipsychotics
=Good for sleep maintenance but produce “hangover effects” the next day: e.g. sedation, memory problems, increased risk of falls

-Hypnotics with very short half-lives of 1-3 hours
=e.g. zaleplon, zolpidem, midazolam, melatonin
=Good for initial insomnia but may wear off too soon and cause loss of sleep maintenance

-Hypnotics with ”just right” half-lives of around 6 hours
=e.g. zopiclone, zolpidem CR*, low dose trazodone, melatonin MR**
=Have a rapid onset of action and plasma levels remain high enough only for the duration of a normal night’s sleep

Question 67

What does management of alcohol and recreational drug dependence involve?

Answer 67

1. Harm-reduction of continued use
2. Physical detoxification (if symptoms of a withdrawal syndrome are present)
3. Maintenance of abstinence (if the patient wishes to do so)

Pharmacological interventions at each stage
1. Substitute prescribing
2. Management of withdrawal
3. Aversive and anti-craving/ anti-reward agents

Question 68

Describe the role of substitute prescribing

Answer 68

-Indications:
=To acutely reduce or prevent withdrawal symptoms when detox is planned
=To stabilize drug intake and reduce secondary harm
=To begin the process of changing drug-taking behaviour
=To provide an incentive to continue contact with services and facilitate ongoing treatment

-Should only be considered:
=There is objective evidence of dependence
=Patient appears realistically motivated to change
=There is no reason to believe the patient will not cooperate
=Monitoring services are available

Only considered when:
-Objective evidence of dependence
-Patient appears realistically motivated to chnage
-No reason to believe patient will not cooperate
-Monitoring services available

Question 69

Contraindications and cautions of methadone and buprenorphine

Answer 69

-Contraindications:
=any cause of acute respiratory depression
=head injury
=raised ICP
=risk of paralytic ileus,
=phaeochromocytoma
n.b. may cause QT prolongation –increased risk if pre-existing cardiac conduction problems or on other QT prolonging medications

-Cautions
=disorders affecting respiratory function (asthma, COPD, myasthenia gravis)
= epilepsy
=hypotension
=hypothyroidism
=adrenocortical insufficiency
=IBD
=obstructive bowel disorders
=disorders of bladder outflow (prostatic hypertrophy, urethral stenosis)

Question 70

Overview of methadone

Answer 70

-Mechanism: long acting mu opioid receptor agonist
-Side effects: opioid (constipation, sedation, euphoria, nausea, QTc prolongation above 100mg/day)
-Overdose risk: prolonged action increases risk of other depressants used on top
-Precipitated withdrawal does not occur
-Supervised consumption to prevent diversion
-NO ceiling effects
-10-40mg starting daily dose
-60-120mL maintenance daily dose

Question 71

Overview of buprenorphine

Answer 71

-Long acting mu opioid receptor partial agonist
-Side effects: less sedating, less euphoric than methadone
-Lower overdose risk as partial agonist
-A few days withdrawal syndrome
-Precipitated withdrawal can occur if taken by a person with opioid dependency and circulating opioids
-Supervised consumption or combination with naloxone (opioid antagonist which is inactive if taken orally but blocks receptors if injected)
-Ceiling effects: cannot satisfy very strong cravings as partial agonist (less suitable for people using large amounts of heroin)
-4-8mh starting dose
-12-16mg maintenance daily dose

Question 72

Consideration of alcohol withdrawal

Answer 72

-For the majority of patients, an outpatient or community-based detoxification will be safe and effective.
-Contraindications to detoxification in the community include severe dependence, a history of withdrawal seizures or delirium tremens, an unsupportive home environment, significant physical or psychiatric comorbidity, advanced age, pregnancy, or a previous failed community detoxification. In these cases, inpatient detoxification is advised.
-Unplanned, short notice detoxification should only be undertaken if absolutely necessary(e.g. if a patient has to be an inpatient for another reason).
-In general, detoxification works best when it is planned in advance to allow the perpetuating factors for dependence to be addressed alongside detoxification.
-Medication may not be necessary if the patient has been drinking less than 15 units/day(men) or 10 units/day (women) and has no current or previous withdrawal symptoms

Question 73

Treatment of alcohol withdrawal

Answer 73

-In order to relieve severe symptoms and reduce the risk for developing seizures or delirium tremens, a drug with similar neurochemical effects to alcohol is prescribed, usually a long-acting benzodiazepine (e.g. chlordiazepoxide, diazepam or lorazepam which is short acting).
-Initially, high doses are given, which are gradually reduced over 5–7 days.
-Because of the high-risk of precipitating Wernicke encephalopathy (brain damage due to thiamine deficiency), thiamine is given prophylactically to those undergoing alcohol withdrawal.
=If they are well-nourished and otherwise physically well, oral supplements are recommended.
=However, parenteral thiamine (Pabrinex) is needed if there is any suspicion of the onset of Wernicke, or if they are acutely physically unwell for any reason, if they are admitted to hospital, if they are malnourished, or have decompensated liver disease

Question 74

Overview of Disulfiram (Antabuse)

Answer 74

-Indications: an aversive adjunct in the treatment of alcohol dependence
-Mode of action: blocks the aldehyde dehydrogenase enzyme, causing an accumulation of acetaldehyde if alcohol is consumed. This causes unpleasant symptoms of anxiety, flushing, palpitations, headache and nausea very soon after alcohol consumption.
-Side effects: bad breath, drowsiness, fatigue, liver damage, nausea &vomiting, reduced libido, skin reactions, psychiatric symptoms (depression, mania, paranoia, psychosis)
-Contraindications: patients with heart failure, stroke or coronary heart disease, hypertension, severe liver disease, cognitive impairment, psychosis, personality disorder, suicide risk.
-Cautions: continued use of alcohol (!), avoid in porphyrias, diabetes, epilepsy, respiratory disease.

Question 75

Overview of Acamprosate (Campral)

Answer 75

-Indications: Maintenance of abstinence in alcohol-dependent patients
-Mode of action: enhances GABA transmission and inhibits glutamate transmission via NMDA receptors and appears to reduce the likelihood of relapse after detoxification by reducing craving. It is safe to use while drinking.
-Side effects: abdominal pain, diarrhoea, flatulence, nausea, sexual dysfunction, skin reactions, vomiting
-Contraindications: no specific contraindications
-Cautions: continued alcohol abuse (risk of treatment failure)

Question 76

Overview of Naltrexone (Nalorex)/ Nalmefene (Selincro)

Answer 76

-Indications: reduction of alcohol consumption in patients with alcohol dependence who have a high drinking risk without physical withdrawal symptoms and who do not need immediate detoxification
-Mode of action: block opioid receptors, appear to both reduce cravings for alcohol and when taken in conjunction with normal drinking, reduce the pleasant effect of alcohol, therefore decreasing the desire to drink and the amount consumed.
-Side effects: decreased appetite, dry mouth, nausea, vomiting, loss of weight, sleep problems, tiredness, malaise, poor concentration, confusion, dizziness, drowsiness, headache, tremor, restlessness, altered sensations, sweats, muscle spasms, reduced libido, palpitations, tachycardia, and rarely dissociation and hallucinations
-Contraindications: recent history of acute alcohol withdrawal syndrome, recent or current opioid use.
-Cautions: avoid prolonged treatment (over 1 year), care in those with history of seizures(even alcohol withdrawal seizures), may exacerbate underlying psychiatric illness.

Question 77

Overview of Acetyl Cholinesterase Inhibitors

Answer 77

-Indications: Donepezil, rivastigmine and galantamine, are recommended by NICE (2018) for patients with mild (MMSE 21-26) to moderate (MMSE10-20) Alzheimer dementia.
-Mode of action: the precise mechanism has not been fully determined but these compounds all cause specific, non-competitive, reversible inhibition of acetylcholinesterase (AChE), leading to an accumulation of acetyl choline acetyl cholinesterase (AChE), leading to an accumulation of acetylcholine(ACh). Galantamine is also an allosteric modulator of nicotinic acetyl choline receptors (nAChRs) increasing their response to ACh (i.e. dual action)
-Side effects: The most common adverse events are diarrhoea, muscle cramps, fatigue, nausea, vomiting, anorexia and insomnia. Most adverse events are mild, transient, and relate to dose changes.
-Contraindications: no specific contraindications
-Cautions: asthma, COPD, sick sinus syndrome (and other conduction abnormalities), susceptibility to peptic ulcers, epilepsy

Question 78

Overview of Memantine

Answer 78

-Indications: Memantine, is recommended by NICE (2018) for those with moderate (MMSE 10-20) Alzheimer dementia who are intolerant of or have a contraindication to cholinesterase inhibitors, or with severe (MMSE less than10) Alzheimer dementia.
-Mode of action: N-methyl-d-aspartate (NMDA) receptor antagonist, thought to reduce excitotoxic damage by blocking NMDA receptors and preventing to reduce excitotoxic damage by blocking NMDA receptors and preventing the influx of calcium.
-Side effects: Dizziness, headache, diarrhoea, constipation; rarely confusion, allergic skin reactions.
-Contraindications: no specific contraindications
-Cautions: history of seizures, cardiovascular disease, liver disease, renal impairment

Question 79

NICE guidelines for dementia drugs

Answer 79

-Commencing treatment
=On the advice of either a secondary care medical specialist (psychiatry, old age medicine, neurology)
=Or by another healthcare professional (e.g. GP or advanced nurse practitioner) with special expertise in diagnosis and treatment of Alzheimer dementia
-Length or treatment
=Only while it has a worthwhile effect on cognitive, global, functional, or behavioural symptoms

Question 80

Treatment in other dementia related conditions

Answer 80

-Mild cognitive impairment (MCI) - AChEIs and memantine are not recommended (except in preventative clinical research).
-Vascular dementia – AChEIs and memantine are not recommended. The cornerstone of treatment is preventing further strokes by ensuring vascular risk factors are optimally managed.
-Mixed Alzheimer/vascular dementia - AChEIs and memantine can be prescribed
-Lewy body dementias - AChEIs are recommended. Rivastigmine has the most evidence of benefit in both Lewy body dementia and dementia associated with Parkinson disease (esp. non-cognitive symptoms leading to distress or challenging behaviour).
-Frontotemporal dementias - AChEIs and memantine can worsen behavioural abnormalities and are not usually recommended

Question 81

Discontinuation symptoms (SSRI)

Answer 81

-Increased mood change
-Restlessness
-Difficulty sleeping
-Unsteadiness
-Sweating
-Gastrointestinal symptoms: pain, cramping, diarrhoea, vomiting
-Paraesthesia

Question 82

SSRI in pregnancy

Answer 82

-BNF says to weigh up benefits and risk when deciding whether to use in pregnancy.
- Use during the first trimester gives a small increased risk of congenital heart defects
- Use during the third trimester can result in persistent pulmonary hypertension of the newborn
- Paroxetine has an increased risk of congenital malformations, particularly in the first trimester