Drugs Flashcards
Switching from citalopram, escitalopram, sertraline, or paroxetine to another SSRI
the first SSRI should be withdrawn* before the alternative SSRI is started
Switching from fluoxetine to another SSRI
withdraw then leave a gap of 4-7 days (as it has a long half-life) before starting a low-dose of the alternative SSRI
Switching from a SSRI to a tricyclic antidepressant (TCA)
cross-tapering is recommend (the current drug dose is reduced slowly, whilst the dose of the new drug is increased slowly)
- an exceptions is fluoxetine which should be withdrawn prior to TCAs being started
Switching from citalopram, escitalopram, sertraline, or paroxetine to venlafaxine
cross-taper cautiously.
Start venlafaxine 37.5 mg daily and increase very slowly
Switching from fluoxetine to venlafaxine
withdraw and then start venlafaxine at 37.5 mg each day and increase very slowly
Contraindications to SSRIs
Poorly controlled epilepsy; SSRIs should not be used if the patient enters a manic phase
Caution in children and adolescents
Most suitable SSRI for patients with a history of heart disease?
Sertraline
SSRI side effects
Side effects:
QT prolongation (citalopram)
GI disturbance
Gastric ulcers
headache,
tiredness,
insomina,
suicidal ideation (young people - use flouxitine) nausea,
loss libido,
hyponatremia (elderly),
SIADH
Seritonin syndrome: neuromuscular excitation, hyperreflexia, myoclonus, rigidity, autonomic nervous system, excitation, hyperthermia, sweating, altered mental state, confusion more likely in combination with amphetamines, ecstacy
How should patients take SSRIs?
Once a day
PO
Take in morning or at night depending on side effects
6 months of remission before stopping
Starts to work 4-6 weeks
May feel worse for first two weeks
Mechanism of action SSRIs
Action - seritonin reuptake inhibitor - prolongs seritonin time in brain - more circulating
Indications for SSRIs
Depressive illness
Panic disorder
PTSD
Social anxiety
Pre-Menstrual syndrome
TCA side effects
Tricyclic anti-depressants are a second line medication for depression. They are strongly associated
with anti-cholinergic activity. Consequently, the common side effects include:
Urinary retention
Drowsiness
Blurred vision
Constipation
Dry mouth
lengthening of QT interval
Tricyclic antidepressants - cautions and contraindications
• Contraindicated in those with previous heart disease
• Can exacerbate schizophrenia
• May exacerbate long QT syndrome
• Use with caution in pregnancy and breastfeeding
- May alter blood sugar in T1 and T2 diabetes mellitus
- May precipitate urinary retention, so avoid in men with enlarged prostates
- Uses the Cytochrome P450 metabolic pathway, so avoid in those on other CP450 medications or
those with liver damage
What metabolic pathway do TCAs use?
Cytochrome P450 metabolic pathwa
Therefore avoid in those on other CP450 medications or those with liver damage
In which patients are SNRIs contraindicated?
Patients with a history of heart disease and HTN
What SSRI should be avoided in post natal depression?
Fluoxetine
How is amitriptyline taken?
50-150mg in daily divided doses PO
How long dose amity take to work as an antidepressant
Patients may start to feel better after 1-2 weeks but takes 4-6 weeks to have full affect
For how long should amitriptyline be taken for antidepressant affects before stopping
6 months remission before stopping
What should be monitored in pts taking high dose amitriptyline
ECG monitoring - e.g. 150mg of amitriptyline (100mg in over 65s)
TCA indications
Migraine prophylaxis
Neuropathic pain
Depressive illness
Panic disorders
OCD
PTSD
GAD
Stopping antidepressants
After 6 months remission
Reduce dose gradually over a 4 week period
Side effects of antipsychotics
EPSEs: Parkinsonism, akathisia, dystonia, dyskinesia (less likely in atypical)
Hyoerprolactinaemia: sexual dysfunction, increased risk of osteoperosis, amennorrhoea in women, galactorrhoea (less likely in atypical)
Metabolic: weight gain, T2DM risk, hyperlipidaemia, metabolic syndrome risk
Neurological: seizures, neuroleptic malignant syndrome
Anticholinergic: tachycardia, blurred vision, dry mouth, constipation, urinary retention
How do atypical antipsychotics differ from typical antipsychotics
Atypical antipsychotics are more selective in their dopamine blockade and also block serotonin 5-HT2 receptors.
They are less likely to causes EPSEs and hyperprolactinaemia,
What advantage does aripiprazole have other other atypical antipsychotics
Aripiprazole is a partial dopamine agonist and so is less likely to cause EPSEs than the others.
Monitoring and serious side effect of clozapine
However, patients on clozapine require regular blood tests to check their neutrophil levels as clozapine can cause agranulocytosis, which is potentially life-threatening.
Theories as to mechanism of action of lithium as a mood stabiliser
interferes with inositol triphosphate formation
interferes with cAMP formation
Lithium: indications
Prophylactically in bipolar disorder
An adjunct in refractory depression
Pharmacokinetics and pharmacodynamics of lithium
PK
Narrow therapeutic range
Long plasma half life
PD
Excreted primarily by kidneys
Adverse affects of lithium
nausea/vomiting, diarrhoea
fine tremor
nephrotoxicity: polyuria, secondary to nephrogenic diabetes insipidus
thyroid enlargement, may lead to hypothyroidism
ECG: T wave flattening/inversion
weight gain
idiopathic intracranial hypertension
leucocytosis
hyperparathyroidism and resultant hypercalcaemia
When checking lithium levels, the sample should be taken how many hours post-dose
12
After starting lithium levels should be performed when (until concentrations are stable)?
Weekly
And after each dose change (1 week later and then weekly)
Until concentrations are stable
Once stable, every 3 months
Once established how often should lithium levels be checked
Every 3 months
Monitoring of lithium
Levels: weekly when dose changed or levels not stable (12 hours post dose!)
Thyroid function - 6 months
Renal function: U&Es and calcium - 6 months
What should patients on lithium be issued with?
Information booklet
Alert card
Record book
Management of lithium toxicity
The management of lithium toxicity is largely supportive and requires specialist input.
Stop lithium
Maintaining electrolyte balance, monitoring renal function and seizure control are the main aims.
IV fluid therapy and alkalisation of the urine are beneficial and enhance excretion of the drug.
Benzodiazepines may be used to treat agitation and seizures in lithium toxicity.
Haemodialysis can be required if the renal function is poor.
How to explain how lithium works to a patient
“Lithium works by changing the way your brain processes signals to help stabilise your mood.”
Mechanism of action unknown – does all sorts of things in the brain, notably lowering noradrenaline release and increasing serotonin synthesis
How should patients take lithium
Swallow with plenty of water
Encourage to take at night
Patient must take medication at same time every day
Do not stop suddenly or change dose without speaking to a doctor
Do not take double dose if missed, just take next dose as normal
Carry lithium record book at all times in case of emergency
Common side effects of lithium which are usually mild and self resolving
Increased thirst
Increased volume and frequency of urination
Tiredness
Weight gain
Fine tremor
Patients taking lithium should seek urgent medical attention if they experience what symptoms
Confusion
Drowsiness
Problems with vision
Loss of appetite
Difficulty speaking
Seizures
Excessive thirst and urination
LITHIUM - lithium side effects and complications
Lethargy
Insipidus (diabetes)
Tremor
Hypothyroidism
Insides (gastrointestinal)
Urine (increased)
Metallic taste
Why should NSAIDs be avoided alongside lithiu,
Can increase serum level of lithium
How to reduce risk of lithium toxicity
Taking dose at same time every day
Regularly attending blood monitoring
Lithium in pregnancy
Lithium associated birth defects generally occur within the first trimester of pregnancy when the fetal organs are developing
Lithium has been shown to increase the risk of fetal heart defects
Lithium is able to pass into the baby’s circulation through breastmilk and breastfeeding should therefore be avoided
Advise the patient that they should use a reliable method of contraception such as a subdermal implant or intrauterine system (IUS) to prevent accidental pregnancy whilst taking lithium.
What risk is increased when starting antidepressants in people under 30 with GAD?
Suicidal ideation and self harm
Monitor weekly for first month
Use of benzodiazepines in anxiety disorders?
Benzodiazapines should not be prescribed for more than 10 days due to risk of dependency and
sedation. Use only to overcome symptoms so severe they obstruct initiation of more appropriate psychological treatment
Diazepam preferred due to longer half life (less risk of withdrawal symptoms with neurotic symptoms, neurological symptoms like ataxia, paraesthesia, hyperacusis and other major symptoms such as hallucinations, psychosis and epilepsy)
Use of Busipirone (5HT1A¬ agonist) in anxiety disorders
Busipirone (5HT1A¬ agonist) is suitable for short term management
Delayed onset of action
Diminished efficacy in previous benzo users
Side effects: dizziness, headache and nausea
Minimal sedation
Which specific ECG change can be associated with haloperidol use?
Prolongation of the QT interval has been associated with haloperidol use, which can increase the risk of ventricular tachyarrhythmia and sudden death. It is therefore recommended that ECG measurements are taken after dose changes of haloperidol, as well as annually.
Typical/ first gen antipsychotics: mechanism of action
Dopamine D2 receptor antagonists, blocking dopaminergic transmission in the mesolimbic pathways
Which receptors do atypical antispychtoics work on?
Act on a variety of receptors (D2, D3, D4, 5-HT)
Typical vs atypical antipsychotics - which is more associated with metabolic effects?
Atypical
Common atypical/second generation antipsychotics
Clozapine
Risperidone
Olanzapine
Common typical antipsychotics
Haloperidol
Chlopromazine
Typical antipsychotics: EPSEs?
Parkinsonism
acute dystonia
sustained muscle contraction (e.g. torticollis, oculogyric crisis)
may be managed with procyclidine
akathisia (severe restlessness)
tardive dyskinesia (late onset of choreoathetoid movements, abnormal, involuntary, may occur in 40% of patients, may be irreversible, most common is chewing and pouting of jaw)
Side effects on typical antispychtoics
antimuscarinic: dry mouth, blurred vision, urinary retention, constipation
sedation, weight gain
raised prolactin
may result in galactorrhoea
due to inhibition of the dopaminergic tuberoinfundibular pathway
impaired glucose tolerance
neuroleptic malignant syndrome: pyrexia, muscle stiffness
reduced seizure threshold (greater with atypicals)
prolonged QT interval (particularly haloperidol)
Elderly patients:
increased risk of stroke
increased risk of venous thromboembolism
EPSEs (parkinsonism, acute dystonia, akathisia (severe restlessness), tardive dyskinesia)
How can acute dystonia be managed?
Administer IM or IV anticholinergics – first line is procyclidine
Continue for 1 to 2 days after dystonia and consider long-term prophylactic
What is acute dystonia?
sustained muscle contraction (e.g. torticollis, oculogyric crisis)
Often paniful, producing twisted abnormal postures
Most common: neck, tongue, jaw, oculogyric crisis (neck arached eyes rolled back)
What is tardive dyskinesia?
late onset of choreoathetoid movements, abnormal, involuntary
may occur in 40% of patients taking typical antispychotics
may be irreversible
most common is chewing and pouting of jaw
Side effects related to all antispychotics?
Sedation
Hyperprolactinaemia
Sexual dysfunction
Cardiac Arrhythmias
Reduction of seizure threshold
Increased risk of stroke death in the elderly (when used in demenatia-related psychosis)
Increased risk of stroke in the elderly
Metabolic/main side effects of second generation/atypical antipsychotics
Weight gain
Worsening glycaemic control
Dyslipidaemia
Hyperprolactinaemia (both first and second gen)
Which second generation antipsychotic is associated with low WCC?
clozapine is associated with agranulocytosis
Examples of atypical/second generation antipsychotics?
clozapine
olanzapine: higher risk of dyslipidemia and obesity
risperidone
quetiapine
amisulpride
aripiprazole: generally good side-effect profile,
particularly for prolactin elevation
When can use of Clozapine be considered?
Clozapine should be introduced if schizophrenia is not controlled despite the sequential use of two or more antipsychotic drugs (one of which should be a second-generation antipsychotic drug), each for at least 6–8 weeks.
Clozapine particular adverse effects
agranulocytosis (1%), neutropaenia (3%)
reduced seizure threshold - can induce seizures in up to 3% of patients
constipation (potentially fatal bowel obstruction) - GI hypo-mobility
myocarditis: a baseline ECG should be taken before starting treatment
hypersalivation
hypothyroidism
Changes to what lifestyle factor may require dose adjustment of clozapine?
Dose adjustment of clozapine might be necessary if smoking is started or stopped during treatment.
The monitoring requires for patients taking antipsychotic medication are extensive. This is on top of the clinical follow-up that such patients clearly require. The BNF advises what monitoring when initiating therapy?
Also annually:
Full blood count (FBC) (initially weekly for clozapine)
Urea and electrolytes (U&E)
Liver function tests (LFT)
CVS risk assessment
Also at 3 months and then annually:
Weight
Lipids
Also at 6 months and then annually:
Fasting blood glucose
Prolactin
Carefully when titrating dosage:
Blood pressure
Basline:
ECG
The monitoring requires for patients taking antipsychotic medication are extensive. This is on top of the clinical follow-up that such patients clearly require. The BNF advises what monitoring annually
Full blood count (FBC) (initially weekly for clozapine)
Urea and electrolytes (U&E)
Liver function tests (LFT)
Lipids
Weight
Fasting blood glucose
Prolactin
CVS risk assessment
The monitoring requires for patients taking antipsychotic medication are extensive. This is on top of the clinical follow-up that such patients clearly require. The BNF advises what monitoring after 3 months of therapy?
Weight
Lipids
And then annually
The monitoring requires for patients taking antipsychotic medication are extensive. This is on top of the clinical follow-up that such patients clearly require. The BNF advises what monitoring after 3 months of therapy?
Fasting blood glucose
Prolactin
And the annually
Mirtazapine used to be classed as a NaSSA (Noradrenergic and Specific Serotonergic Antidepressant) but is now a class of its own - what is the mechanism of action?
Mirtazapine is an antidepressant that works by blocking alpha2-adrenergic receptors, which increases the release of neurotransmitters.
Acts as a 5HT-2 and 5HT-3 antagonist
What makes mirtazapine useful in the elderly
Mirtazapine has fewer side effects and interactions than many other antidepressants and so is useful in older people who may be affected more or be taking other medications.
Two side effects of mirtazapine, sedation and an increased appetite, can be beneficial in older people that are suffering from insomnia and poor appetite.
When should patients on mirtazapine be advised to take it?
In the evening, due to sedating affects
Monoamine oxidase inhibitors - mechanism of action
Inhibition in metabolism of serotonin and noradrenaline
(serotonin and noradrenaline are metabolised by monoamine oxidase in the presynaptic cell)
Examples of non-selective monoamine oxidase inhibitors?
tranylcypromine
phenelzine
What might MAOIs be used to treat and why are the not used often?
used in the treatment of atypical depression (e.g. hyperphagia) and other psychiatric disorders
not used frequently due to side-effects
Significant adverse effects/interactions with MAOIs
hypertensive reactions with tyramine containing foods e.g. cheese, pickled herring, Bovril, Oxo, Marmite, broad beans
anticholinergic effects:
Drowsiness or sedation.
Blurred vision.
Dizziness.
Urinary retention.
Confusion or delirium.
Hallucinations.
Dry mouth.
Which SSRI is used post MI?
sertraline is useful post myocardial infarction as there is more evidence for its safe use in this situation than other antidepressants
Significant in that MI has a particularly increased risk of developing depression
SSRIs should be used with caution in children and adolescents.What is the drug of choice when an antidepressant is indicated?
Fluoxetine
What might need to be prescribed to patients on SSRis who are also taking NSAIDs
there is an increased risk of gastrointestinal bleeding in patients taking SSRIs. A proton pump inhibitor should be prescribed if a patient is also taking a NSAID
Which SSRIs have a higher propensity for drug interactions
fluoxetine and paroxetine
In what condition MUST SSRIs be ommited
Mania
Which SSRIs are associated with QT interval changes and what cautions are implicated by this?
it advised that citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with:
congenital long QT syndrome;
known pre-existing QT interval prolongation; or in combination with other medicines that prolong the QT interval
the maximum daily dose is now 40 mg for adults; 20 mg for patients older than 65 years; and 20 mg for those with hepatic impairment
Main potential interactions with SSRIs?
NSAIDs: NICE guidelines advise ‘do not normally offer SSRIs’, but if given co-prescribe a proton pump inhibitor
warfarin / heparin: NICE guidelines recommend avoiding SSRIs and considering mirtazapine
aspirin: see above
triptans - increased risk of serotonin syndrome
monoamine oxidase inhibitors (MAOIs) - increased risk of serotonin syndrome
What should be considered as an alternative to SSRIs in patients also taking warfarin/heparin
mirtazapine
When should review of patients initiating SSRIs take place?
Following the initiation of antidepressant therapy patients should normally be reviewed by a doctor after 2 weeks.
For patients under the age of 25 years or at increased risk of suicide should be reviewed after 1 week
When stopping a SSRI the dose should be gradually reduced over a 4 week period with the exception of which drug - for which this is not necessary
Fluoxetine
Which SSRI has a higher incidence of discontinuation symptoms.
Paroxetine (short half life)
SSRI discontinuation symptoms
increased mood change
restlessness
difficulty sleeping
unsteadiness
sweating
gastrointestinal symptoms: pain, cramping,
diarrhoea, vomiting
paraesthesia
shaking
adgitation
headaches
clonus
irritability
SSRIs and pregnancy
- 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
What are SNRIs and what are they used to treat?
Serotonin and noradrenaline reuptake inhibitor (SNRI’s) are a class of relatively new antidepressants
They are used to treat major depressive disorders, generalised anxiety disorder, social anxiety disorder and panic disorder and menopausal symptoms.
SNRI mechanism of action
Inhibiting the reuptake increases the concentrations of serotonin and noradrenaline in the synaptic cleft leading to the effects.
Common examples of SNRIs
venlafaxine
duloxetine
Severity of TCA overdose by drug
lofepramine has a lower incidence of toxicity in overdose
amitriptyline and dosulepin (dothiepin) are considered the most dangerous in overdose
Which TCAs considered ‘more sedative’?
Amitriptyline
Clomipramine
Dosulepin
Trazodone (technically a tricylic related antidepressant)
Which TCAs considered ‘less sedative’?
Imipramine
Lofepramine
Nortriptyline
For what general purposes are benzodiazepines used?
sedation
hypnotic
anxiolytic
anticonvulsant
muscle relaxant
How do benzodiazepines work?
Benzodiazepines enhance the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by increasing the frequency of chloride channels.
Patients commonly develop a tolerance and dependence to benzodiazepines and care should therefore be exercised on prescribing these drugs. The Committee on Safety of Medicines advises that benzodiazepines are only prescribed for how long?
a short period of time (2-4 weeks)
The BNF gives what advice on how to withdraw a benzodiazepine?
The dose should be withdrawn in steps of about 1/8 (range 1/10 to 1/4) of the daily dose every fortnight.
A suggested protocol for patients experiencing difficulty is given:
switch patients to the equivalent dose of diazepam
reduce dose of diazepam every 2-3 weeks in steps of 2 or 2.5 mg
time needed for withdrawal can vary from 4 weeks to a year or more
Symptoms of withdrawal from benzodiazepine?
If patients withdraw too quickly from benzodiazepines they may experience benzodiazepine withdrawal syndrome, a condition very similar to alcohol withdrawal syndrome. This may occur up to 3 weeks after stopping a long-acting drug. Features include:
insomnia
irritability
anxiety
tremor
loss of appetite
tinnitus
perspiration
perceptual disturbances
seizures
What psychiatric drugs enhance the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) what is their action
GABAa drugs
benzodiazipines increase the frequency of chloride channels
barbiturates increase the duration of chloride channel opening
Barbidurates increase duration & Frendodiazepines increase frequency
There is good evidence for the efficacy of hypnotic drugs in short-term insomnia. However, there are many adverse effects such as what?
daytime sedation
poor motor coordination
cognitive impairment
related concerns about accidents and injuries
In addition, tolerance to the hypnotic effects of benzodiazepines may be rapid (within a few days or weeks of regular use).
What are Z drugs?
Z drugs have similar effects to benzodiazepines but are different structurally.
They act on the α2-subunit of the GABA receptor.
What are the 3 groups of Z drugs
Imidazopyridines: e.g. zolpidem
Cyclopyrrolones: e.g. zopiclone
Pyrazolopyrimidines: e.g. zaleplon
On which receptors does methamphetamine act?
Methamphetamine acts at TAAR1 (Trace Amine-Associated Receptor 1) receptors.
On which receptors does cocaine act?
Cocaine acts at dopamine receptors.
What do cocaine and methamphetamine have in common?
Both are stimulants
Both, in low doses, produce a feeling of increased concentration and focus.
Both increase the available amount of dopamine in the brain, producing the associated pleasurable effects of the drugs.
What is serotonin syndrome?
Serotonin syndrome (SS) is a potentially life-threatening disorder that is characterised by altered mental status (i.e. confusion), autonomic hyperactivity, and neuromuscular abnormalities (e.g. rigidity, clonus, hyperreflexia).
Why does serotonin syndrome occur?
It is due to increased serotonergic activity in the central nervous system (CNS) that can be induced by a range of medications that increase serotonergic transmission by altering the neurotransmitter serotonin.
Most common medication implicated in serotonin syndrome?
SSRI
What is serotonin and what are its functions?
Serotonin is a monoamine neurotransmitter that is derived from the amino acid tryptophan. It has important functions in the CNS and peripheral nervous system (PNS):
CNS: modulates thermoregulation, behaviour, and attention
PNS: regulates GI motility, vasoconstriction, bronchoconstriction, and uterine contraction
Other: promotes platelet aggregation (thus, combined use with anti-platelets can increase bleeding risk)
Serotonin syndrome: causative agents that cause an increased release of serotonin
Amphetamines
MDMA (ecstasy)
Cocaine
Serotonin syndrome: causative agents that cause a reduced uptake of serotonin
SSRIs
SNRIs
MDMA
Tricycle antidepressants
Serotonin modulators
Serotonin syndrome: causative agents that inhibit serotonin metabolism
Monoamine oxidase inhibitors
Serotonin syndrome: causative agents that are serotonin receptor agonists
Buspirone
Triptans
Serotonin syndrome: causative agent that increases sensitivity of serotonin receptor
Lithium
Symptoms of serotonin syndrome
Altered mental status: may present as anxiety, restlessness, disorientation, or agitation
Sweating
Fever
Vomiting
Diarrhoea
Signs of serotonin syndrome
Dilated pupils
Flushed skin, diaphoresis
Tachycardia, hypertension
Hyperthermia (>38.0º)
Hyperreflexia
Clonus: repeated, rhythmic contractions
Myoclonus: sudden jerky or spastic contraction
Rigidity
Bilateral upgoing plantars (Babinski sign)
Hunter criteria
Hunter criteria
SS can be diagnosed in a patient taking a serotonergic agent (e.g. SSRI) and presents with one of the following features:
- Spontaneous clonus
- Inducible/ocular clonus and agitation or diaphoresis
- Tremor and hyperreflexia
- Hyperthermia, hypertonia, and ocular/inducible clonus
Serotonin syndrome - investigations
Investigations are useful to determine the severity of SS and to exclude alternative causes.
Bedside: ECG, cardiac monitoring (particularly if profound autonomic symptoms), blood glucose, urine dip
Bloods: full blood count, urea & electrolytes, LFTs, coagulation, blood cultures (if febrile), creatine kinase, and blood gas. Patients may have features of neutrophilia, acute kidney injury, or elevated CK levels.
Severe cases of SS can lead to rhabdomyolysis (i.e. skeletal muscle necrosis).
Imaging: cerebral imaging (i.e. CT/MRI) may be needed in patients with new-onset altered mental status to exclude an alternative cause. A chest x-ray is usually needed as part of a septic screen if patients are febrile.
Special: a lumbar puncture may be needed to exclude an intracerebral infection or investigate for an alternative cause of confusion (e.g. autoimmune encephalopathy).
Differentials for SS
Neuroleptic malignant syndrome
Malignant hyperthermia
Recreational drug use
What is malignant hyperthermia
a rare genetic disorder characterised by hyperthermia, muscle rigidity, and dysautonomia in the setting of exposure to certain anaesthetic agents (e.g. succinylcholine) or vigorous exercise.
General management of SS
The management of SS largely depends on the severity of symptoms.
In mild cases, patients may be observed for 4-6 hours and then discharged.
In severe cases, patients may need organ support in intensive care.
Serotonin antagonists can be given in severe cases although evidence for their use is incomplete.
Serotonin syndrome - supportive management
The serotonergic agent should be stopped and patients should be monitored in the appropriate setting.
Cardiac monitoring is usually required due to dysautonomia.
Patients should be monitored and specific complications treated (e.g. electrolyte imbalance, acute kidney injury, rhabdomyolysis).
In severe cases, patients may require organ support (e.g. intubation & ventilation, haemofiltration) and admission to intensive care.
Specific interventions that are helpful:
include intravenous fluids to maintain euvolaemic state,
antipyretics and cooling blankets for hyperthermia,
specific antihypertensive agents for profound hypertension,
benzodiazepines as necessary for agitation.
In severe hyperthermia (>41º), antipyretics are unlikely to work as the increased body temperature is due to muscular activity not altered hypothalamic regulation. Therefore, sedation, paralysis, and tracheal intubation are usually required.
Medical therapy for serotonin syndrome
If supportive measures including the use of benzodiazepines fail to improve vital signs or agitation, patients can be considered for serotonin antagonists (e.g. Cyproheptadine).
Cyproheptadine is a histamine receptor antagonist with action against serotonin receptors.
Serotonin syndrome - follow up
SS usually resolves within 24 hours of stopping the serotonergic medication.
Patients will mild symptoms who recover quickly may only need observation for 4-6 hours.
Advice should always be sought from ‘Toxbase’ or a toxicologist if in doubt. This is particularly important in patients where an overdose has been taken.
It is important to avoid co-prescription of multiple serotonergic agents to prevent the development of SS.
Serotonin syndrome - complications
Cardiac arrest
Cardiac arrhythmias
Acute kidney injury
Rhabdomyolysis
Disseminated intravascular coagulation
Seizures
Respiratory failure
Venous thromboembolism
What is neuroleptic malignant syndrome?
Neuroleptic malignant syndrome (NMS), is a rare, life-threatening disorder that is associated with the use of antipsychotic drugs (previously known as neuroleptic medications) but the exact cause is unknown.
What is neuroleptic malignant syndrome characterised by?
Altered mental status (i.e. confusion)
Fever
Muscular rigidity
Dysautonomia (i.e. autonomic instability).
What causes NMS
The exact cause of NMS remains unknown.
The condition is associated with the use of antipsychotics, but predominantly potent first-generation or ‘typical’ antipsychotics that are dopamine (D2) receptor antagonists.
This includes haloperidol and fluphenazine.
Rarely, other drugs with central dopamine antagonism can cause NMS (e.g. metoclopramide).
Pathogenesis of neuroleptic malignant syndrome
It is suspected that central blockade of dopamine in the hypothalamus leads to hyperthermia and dysautonomia.
Blockade of other central pathways can give rise to movement disorders (e.g. tremor, rigidity) that are well recognised side-effects even in the absence of NMS.
Alternatively, there may be direct toxic effects of these drugs on peripheral muscle or disruption of the sympathetic nervous system.
A genetic predisposition has also been suggested.
When does NMS occur in relation to the initiation of anti-psychotic therapy
NMS will typically occur within the first two weeks of starting an antipsychotic.
However, it can occur after a single dose or after many years of using the medication.
NMS following cessation of causative agent
The majority of episodes will resolve within two weeks of stopping the drug, although patients may require a prolonged period of supportive management and mortality can be up to 20%.
Risk factors for NMS
Higher antipsychotic doses
High-potency antipsychotics
Concomitant drug use (e.g. lithium)
Depot formulations (i.e. long-acting)
Acute medical illness (e.g. trauma,
infection)
Acute catatonia (state or immobility)
Previous NMS
NMS - clinical features
ALTERED MENTAL STATUS: often presents with agitation and delirium.
CATONIA: May progress to severe encephalopathy and coma.
RIDGIDITY felt as a generalised increase in tone and may be severe.
Other motor abnormalities can be present.
FEVER (>38º): less pronounced with second-generation antipsychotics.
May be >40º.
DYSAUTONOMIA: describes abnormalities in the autonomic nervous system.
Thus, often termed ‘autonomic instability’. Leads to tachycardia, labile blood pressure, profuse sweating (i.e. diaphoresis) and/or arrhythmias.
NMS - differentials
Serotonin syndrome: similar presentation to NMS in association with selective serotonin reuptake inhibitor (SSRI) drug use. Characterised by nausea, vomiting, diarrhoea, shivering, hyperreflexia, myoclonus, and ataxia.
Malignant hyperthermia: a rare genetic disorder characterised by hyperthermia, muscle rigidity, and dysautonomia in the setting of exposure to certain anaesthetic agents (e.g. succinylcholine) or vigorous exercise.
Recreational drug use: both use of MDMA (i.e. ecstasy) and cocaine have been associated with an NMS-like syndrome.
Supportive management of NMS
The antipsychotic drug should be stopped and patients should be monitored in the appropriate setting.
Cardiac monitoring is usually required due to dysautonomia.
Patients should be monitored and specific complications treated (e.g. electrolyte imbalance, acute kidney injury, rhabdomyolysis).
In severe cases, patients may require organ support (e.g. intubation & ventilation, haemofiltration) and admission to intensive care.
Specific interventions that are helpful include intravenous fluids to maintain euvolaemic state, antipyretics and cooling blankets for hyperthermia, antihypertensive agents (e.g. clonidine) for profound hypertension and benzodiazepines as necessary for agitation.
Medical therapy of NMS
The use of specific medical therapies in NMS is controversial due to inconsistent evidence. In moderate to severe cases, dantrolene or bromocriptine may be used alongside supportive measures.
Dantrolene: ryanodine receptor antagonist (causes skeletal muscle relaxation). Helps treat hyperthermia and rigidity.
Bromocriptine: dopamine agonist. Prescribed to restore ‘dopaminergic tone’.
NMS - complications
Mortality from NMS ranges from 5-20% depending on the patient population studied.
NMS may be life-threatening and a number of severe complications can develop:
Cardiac arrest
Cardiac arrhythmias
Acute kidney injury
Rhabdomyolysis
Disseminated intravascular coagulation
Seizures
Respiratory failure
Venous thromboembolism
Signs and symptoms of lithium toxicity
ataxia
COARSE tremor
confusion
nystagmus
nausea and vomiting
seizures
Coarse tremor
impaired coordination
dysarthria
Arrhythmias
Visual disturbance
Why should flumazenil be used with caution in ?benzo overdose?
Flumazenil is a benzodiazepine antagonist and can be used in the treatment of benzodiazepine overdose. However, it is not commonly used since there are several risks associated with this medication. Firstly, in benzodiazepine-dependent patients it can precipitate seizures and so should be avoided. It is also often avoided if there is a possibility of a mixed overdose since the benzodiazepine may actually be inhibiting some of the harmful effects of the other drugs that have been taken and flumazenil can reverse this protective effect, precipitating features such as seizures and cardiac arrhythmias from the other drugs.
What common side effects may occur on initiation of SSRIs might be countered by judicious use of benzodiazepines?
Restlessness and agitation
What should be monitored in doses of Venlafaxine above 225mgs?
Caution with higher doses in heart disease – monitor blood pressure at doses above 225mgs.
SNRIs have a similar side effect profile to SSRIs, but have a greater potential for which side effects specifically?
sedation
nausea
sexual dysfunction
Histamine receptor side effects
Dry mouth
Drowsiness
Dizziness
Nausea and vomiting
Muscarinic (Ach) receptor side effects
Dry mouth, difficulty swallowing, thirst
Difficulty urinating, urinary retention
Hot and flushed skin. Dry skin
Adrenergic/Noradrenergic receptor side effects
Sweating
Tremor
Headaches
Nausea
Dizziness
Side effects of SSRIs that are more likely to persist after initiation of therapy?
Weight changes (usually loss, can be gain)
Sexual dysfunction - arousal, orgasm
Why does chemically treating depression have a risk of suicidal ideation compared to other antidepressants?
Energy and volition may improve before outlook on life improves as depression treated - therefore may be motivated to action thoughts of ‘not wanting to be here’
How do SNRIs act differently to SSRI’s
Act in the same way as SSRI’s (increase serotonin activity by reducing the presynaptic reuptake of serotonin after release) but also bind to noradrenaline reuptake receptors
Why does fluoxetine have a particularly high risk of serotonin syndrome compared to other SRRIs
Long half life
Why does paroxetine have a particularly high risk of discontinuation syndrome?
Short half life
What non-psychiatric therapeutic affect to SNRIs have an evidence base for?
Treatment of neuropathic pain
Why does mirtazapine cause sedation, even at low doses?
Strong H1 (histamine) receptor activity (antagonist) - occupying most receptors even at low doses
SSRIs vs TCAs advantages vs disadvantages
SSRIs - tolerated better
TCA - QTc prolongation, higher risk in toxicity in overdose
TCAs - do not cause insomnia as SSRIs do and have a sedative affect - can help with sleep
SSRIs - more likely to cause GI upset and nausea
SSRIs- less CVS side effects
TCA - less likely to cause sexual dysfunction
Disadvantages of the use of MAOIs such as moclobamide
Inhibit enzyme that breaks down tyramine - potential for tyramine reaction leading to hypertensive crisis - avoid cheese, pickled meats, wine and other tyramine products
Potential significant and dangerous interaction with other drugs
If changing to another antidepressant a washout period of up to 6 week is required
What type of drug is moclobamide?
Reversable MAOI
How do MAOIs work to treat atypical depression
Monoamine oxidase inhibitors – MAOI – A (work more on serotonin) and MAOI – B (work more on dopamine). All can potentially increase adrenaline.
Vortioxetine advantages
Multiple different affects on serotonergic activity - differs according to receptor
Well tolerated – most common side effect is nausea (but less severe than Venlafaxine)
Evidence for improvement in difficult to treat cognitive symptoms
Increasing the dose vs switching antidepressant
If an antidepressant is going to work there will usually be an effect within the first 3 weeks, but wait 4 weeks before making a final decision.
For depression: if an antidepressant has absolutely no benefit at a typical dose it’s not worth increasing the dose – switch. If partial benefit increase the dose.
For anxiety (especially OCD): consider increasing dose if no initial benefit.
If an antidepressant has significant side-effects these may get better in a couple of weeks but if they cause a big problem for the patient – switch.
Considerations when choosing an antidepressant
What has been used before?
Was it effective and/or tolerated?
Are there particular symptoms or comorbidities you may want to address: Weight loss/Insomnia/Neuropathic pain
In new cases with no previous treatment start with an SSRI unless there is major weight loss or major sleep difficulty – in which case consider Mirtazapine, or comorbid neuropathic pain, in which case consider and SNRI
In most cases start with an SSRI, if no effect switch to a different SSRI, if no effect switch to SNRI Venlafaxine or Mirtazapine
Patient ICE
How do antidepressants improve mood other than on a biological level
Encourages changes feeding into a sense of well being, creates habit, motivates routine
The value at which QTc becomes prolongates
Men 450ms
Women 470ms
How do antipsychotics (neuroleptics) work and how do they cause unwanted side effects
All current antipsychotics reduce level of dopamine activity at D2 receptors.
Target dopaminergic pathways in the brain are mesocortical and mesolimbic
Unwanted effects come from action at nigrostriatal (movement) and tuberoinfundibular (hypothalamic-pituitary-adrenal axis)
All antipsychotics have potential for sedation, extrapyramidal side-effects and weight gain
All antipsychotics can cause acute dystonia, including oculogyric crisis
Pros and cons of aripiprazole compared to other SGAs/atypicals
Less effective
Better side effect profiles
D2 partial agonist (not antagonist)
Why are LFTs performed baseline and yearly for patients taking antipsychotics
NASH and hepitatis risk
Differences in action of typical vs atypical antispychotics
Typical tend to bind more to muscarinic and histaminic receptors
Atypical tend to have more serotonergic activity.
Rare but serious side effect of antipsychotics
NMS (neuroleptic malignant syndrome): Rare, life threatening reaction to antipsychotics
Fever, confusuion, muscle rigidity, sweating, autonomic instablity
May cause death: rhabdomyolysis, renal failure, seziures
Risks: young men, high doses, antispychtoic naive, high potency dopamine antagonists (typicals)
Mgx: emergency ref to A&E, stop antipsychtoics, give benzodiazepine for acute behavioural distrubance, reduce temp (cooing blankets), O2 if needed, rhabdomyolysis - fluid and sodium bicarbonate (alkalise urine), relax muscles - 1st line dantrolene or lorazepam, second line bromocriptine
Muscle relaxants used in NMS
1st line:
Dantrolene ( ryanodine receptor antagonist, also helps with hyperthermia)
Lorazepam (benzodiazepine, also helps with acute behavioural disturbance
2nd line: Bromocriptine (dopamine agonist, restores ‘dopaminergic tone’
Why are anticholinergics sometimes used alongside antipsychotics
Relative decrease of dopamine relative to acetylcholine in nigrostriatal pathway due to antipsychotics
Anti-cholinergics antagonise the acetylcholine receptors to reduce EPSEs
How is clozapine initiated and monitored differently to other antipsychotics
Dose titrated slowly upward over two weeks and vital signs monitored due to potential dysregulation
Close monitoring of FBC: weekly for first 18 weeks, then fortnightly for up to a year, then monthly
Management of agranulocytosis during clozapine therapy
Stop clozapine
Stop any other potentially marrow supressing drugs - e.g. soddium valproate
Avoid other antipsychotics for 2 weeks if possible, if not aripiprazole has less potential for bone marrow supression
Contact Consultant Haematologist as an emergency
Avoid sources of infection. Consider prophylactic broad-spectrum antibiotics
Sometimes lithium is used to increased WCC and neutrophil count
Granulocyte colony-stimulating factor (G-CSF) has been used
What is clozapine less likely to cause than other antipsychotics
NMS
Less potent D2 receptor antagonist
What is akathisia
A movement disorder causing a feeling of restlessness and an inability to stay still.
What are the following examples of?
Beta-blockers
Benzodiazepines
Pregabalin
Antidepressants
Anxiolytics (anti anxiety)
Mechanism of action of benzodiazepines
Bind to GABA receptors to potentiate the effect of GABA and therefore reduce the excitability of neurones.
Therefore they are positive allosteric modulators of GABA receptor
What anxiolytic might cause paradoxical disinhibition and how is this managed?
Benzodiazepines - increased dosage should address this
Pregabalin indications
Used in anxiety, neuropathic pain and epilepsy
Pregabalin mechanism of action
Binds to voltage gated calcium channels on neurones
Reduces neuronal activity (i.e. is a CNS depressant)
Pregabalin - concerns and adverse affects
Causes sedation and can cause weight gain
Less potential for misuse and dependence (and tolerance) than benzodiazepines – but still misused – nickname “Budweisers”
What drugs are used as hypnotics
Benzodiazepines:
Temazepam, Lormatazepam, Nitrazepam
Nonbenzodiazepines:
Act in a very similar way (positive allosteric modulators) but are structurally different to benzodiazepines
Also called Z drugs
Zopiclone, Zolpidem
Groups of mood stabilisers
Lithium
Anticonvulsants
Second Generation (Atypical) Antipsychotics
Potential concerns with hypnotics and how they are prescribed to avoid this
Significant potential for misuse, dependence, rebound insomnia.
Use for up to 6 weeks
Use for only two weeks and take for only 5 out of 7 days each week to reduce potential for tolerance (ideally not two days in a row)
Lithium indications
Bipolar disorder
Also used to augment antidepressants
Long term effects of lithium
Hypothyroidism - usually reversable and can prescribe levothyroxine
Renal impairment - usually reversable and occurs most above therapeutic dose
Lithium affect on self harm/suicide
Significant evidence that lithium reduces suicide – and it has a licence for reduction of self-harm
Lithium: coarse vs fine tremor
Fine tremor - side effect
Coarse tremor - toxicity
Special considerations for lithium in hot climates
Not excreted by sweat
Patients will need to drink plenty of water to ensure blood levels do not become too high leading to toxicity
Drugs that have dangerous interactions with lithium
NSAIDS
Loop diuretics
ACE inhibitors
Common anticonvulsants used to stabalise mood in bipolar
Sodium valproate
Carbamazepine
Lamotrigine
Considerations when starting sodium valproate
avoid in women of child bearing age due to teratogenicity. Check LFTs before and soon after starting
Why is lamotrigine prescribed gradually?
potential for Stevens Johnson Syndrome
Why are stimulants thought to improve ADHD symptoms
Theory that ascending reticular activating system under fires
Stimulants increase activity at ARS - hedonic tone
What drug might be suitable for patients with a history of substance abuse/addiction with ADHD?
Atomoxetine: noradrenaline re-uptake inhibitor
What are the dangers of rapid tranquillisation?
Loss of consciousness
Airway obstruction
Respiratory depression
Hypertension
Cardiac
EPSE
Development of what during an episode of NMS significantly increases mortality?
If AKI develops during an episode of NMS this can increase mortality significantly.
NMS signs on examination and bloods
Lead-pipe type muscular rigidity
Hyperthermia (above 38degrees)
Tachycardia
Hypotension/Hypertension – Fluctuating BP usually.
Incontinence.
CK elevated.
U&Es may show metabolic disturbance (due to AKI or acidosis).
Bone profile may show hypercalcaemia.
FBC may show leucocytosis.
LFTs may be deranged and LDH raised.
ABG may show metabolic acidosis.
Advantages of Paliperidone
- Paliperidone is a depot version of Risperidone.
- Paliperidone does not require oral medication (Risperidone) to be taken during initiation, so is a good choice in a patient who is currently refusing all oral medications.
- It is initiated through loading doses of IM injections (Day 1 and Day 8 of treatment, then monthly thereafter).
-If a patient remains stable for at least four months on the monthly dose of IM Paliperidone, they can instead be given a formulation which only requires administration every 3 months.
Weight neutral antipsychotic
Aripiprazole
Why might a depot of Zuclopenthixol Decanoate cause falls
Parkinsonism:shuffling gate
What is the biggest cause of death due to clozapine
Constipation
Safe antipsychotic to prescribe in patients with significant cardiac history
Aripiprazole - doesn’t cause QTc prolongation
What receptors do SSRIs act on
5-HT
Stages of lithium toxicity
What analgesia is not routinely prescribed for patients on lithium and why?
NSAIDs, as they may increase the concentration of lithium
Drugs used to treat mania
Lithium or sodium valproate
Atypical antipsychotic e.g. Olanzapine or quetiapine
What mood stablasier isn’t used To treat mania
Lamotrigine - used to treat bipolar depression
What mood stabilised is not a management option for resistant depression
Sodium valproate
Why should patinets taking lamotrigine be advised to see their doctor immediately is they develop a rash
Stevens-Johnson syndrome & toxic epidermal necrolysis are rare side effects with Lamotrigine, which can be used sometimes for treatment resistant depression. Patients are advised to see their doctor immediately if they develop a rash
What drug may be used to treat moderate/severe tradvive dyskinesia resulting from antipsychotic use
Tetrabenazine may be used to treat moderate/severe tardive dyskinesia
Illicit use of methylphenidate
Methylphenidate, more commonly known as ‘Ritalin’, is a stimulant prescription drug usually
used in the treatment of Attention Deficit Hyperactivity Disorder. However, it has potential for
illicit abuse and can be found among student populations who believe it improves their
concentration and focus. This woman presents with insomnia, restlessness, increased
temperature, increased blood pressure and increased heart rate, all likely to be caused by the
illicit use of Methylphenidate
What component of diet should stay the same once iniatied on lithium therapy
Salt
Missed clozapine dose
If doses are missed for more than 2 consecutive days (48 hours), you will need to restart their clozapine slowly (like when they first started on it). This restart of treatment needs to be under the direction of a Psychiatrist. This is because when you start Clozapine after a break of >48 hours, it can make side effects worse, such as blood pressure changes, drowsiness and dizziness. If there is a gap in treatment of 3 days (72 hours) then you may also require more frequent blood tests for a short period.
A long history of anti-psychotic use can cause akathisia, what is this?
Akathisia is a sense of inner restlessness and inability to keep still
What psychiatric drug can precipitate a benign leucocytosis
Benign leucocytosis is a relatively common finding associated with various drugs, most commonly corticosteroids, lithium and beta-blockers. Together with an unremarkable examination, safety netting for infective or malignant signs, and continuing the normal monitoring schedule is most appropriate in this case
Pupil related side effect of TCAs
Mydriasis (pupil dilation)
TCAS (side effects of tricyclic antidepressants)
Thrombocytopaenia
Cardiac (arrhythmias, MI, stroke, postural hypotension)
Anticholinergic (tachycardia, urinary retention, dry mouth, blurry vision, constipation) - Cant see, cant pee cant spit, cant sh*t
Seizures
What is the most appropriate drug to prescribe to prevent alcohol withdrawal symptoms?
CHLORDIAZEPOXIDE
first-line: long-acting benzodiazepines e.g. chlordiazepoxide or diazepam. Lorazepam may be preferable in patients with hepatic
Which drug has the most tolerable side effect profile of the atypical antispsychotics, particularly for prolactin elevation?
Aripiprazole
What parameter should be monitored after commencing venlafaxine
It can cause an increase in blood pressure and heart rate.
It is contraindicated in patients with uncontrolled hypertension.
Hence,
regular blood pressure monitoring is required.
The first-line treatment for a manic episode in bipolar affective disorder is an antipsychotic. What are the antipsychotics most commonly used in the treatment of manic episodes or mixed episodes in bipolar affective disorder?
quetiapine,
olanzapine,
risperidone
haloperidol.
What TCA do nice recommend for OCD if SSRI and SNRI fail or not suitable
clomipramine
What anti hypertensive may be a good option to prescribe to a patient taking lithium
Atenolol
antipsychotics may cause disruption of which pathway leading to osteoporosis
tuberoinfundibular pathway
