Adverse Drug Reactions Flashcards
Define tolerance
The need to use increased doses of a drug to maintain a clinical effect.
What can lead to tolerance of a drug?
Down-regulation
Up-regulation
Reduced responsitivity without alterations in receptor numbers
What is down-regulation?
Decreased sensitivity of target receptors due to decreased numbers due to agonists
What is up-regulation?
Increase in numbers of receptors due to antagonists
What is cross-tolerance?
When drugs with similar pharmacological actions can lead to tolerance of the other drug
What is reverse tolerance?
When sensitivity to a drug effect increases over time.
Give an e.g. of downregulation which leads to a therapeutic effect.
When SSRIs are used, the 5HT1A autoreceptors in somatodendritic zones undergo down-regulation secondary to increased serotonin availability when reuptake is blocked; this leads to increase in serotonergic tone of neurons.
Define withdrawl
When drugs are administered for reasonable period of time, physiological adaptation develops which on withdrawl of drug can get disturbed and leads to withdrawl symptoms.
What type of drug leads to withdrawl symptoms?
Abrupt withdrawl of treatment for an agent with short eliminatino half-life
Which has longer half-life; methadone or heroin?
Methadone
Why does methadone lead to less withdrawl than heroin?
Methadone has a longer half-life
Why does Paroxetine lead to withdrawl?
It has anticholinergic properties; withdrawl causes rebound symptoms
Paroxetine inhibitis its own metabolism via CYP2D6, so withdrawl leads to loss of inhibition, excessive paroxetine breakdown, sudden steep drop in levels and then withdrawl symptoms.
Why does Fluoxetine produce fewer withdrawl symptoms?
Its active metabolite, norfluoxetine, has a long half-life
What is the advice of benzodiazepine reducing regime?
10% dose reduction every 2 weeks.
Why must you wait 72 hours before prescribing naltrexone for an opioid detoxified patient?
Prescribing an antagonist can precipitate withdrawl symptoms.
Which cause more withdrawl; full or partial agonists?
Full
What kinetics do sustained release formulations affect?
Absorption kinetics
Do depot or oral preparations have more withdrawl potential?
Oral
Does XL or plan preparation of a drug lead to more withdrawl symptoms?
Neither; both same
Which receptors cause side effect of agitation?
Alpha 2 blockade
5HT2A/2C stimulation
DRI
Which receptors cause side effect of akathisia?
D2 blockade
5HT2A stimulation
Which receptors cause side effect of delirium?
Antimuscarinic
Which receptors cause side effect of EPSE?
D2 blockade reduces with 5HT2A antagonism
Which receptors cause side effect of hyperthermia?
Antimuscarinic action
In serotonin syndrome may be due to 5HT2A/2C.
Which receptors cause side effect of insomnia?
Alpha 1 stimulation
5HT2A stimulation
Which receptors cause side effect of amnesia?
Anticholinergic effect
GABAa stimulation
Which receptors cause side effect of hyperprolactinaemia?
D2 blockade
5HT1A stimulation
Which receptors cause side effect of disrupted slow wave sleep?
Slow wave sleep is maintained by 5HT2A inhibition; hence 5HT2A stimulation disrupts this.
Which receptors cause side effect of sweating?
Cholinergic effect
Increases with noradrenaline reuptake inhibition
Which receptors cause side effect of postural hypotension?
Alpha 1 antagonism
Which receptors cause side effect of appetite loss?
5HT2A stimulation
Which receptors cause side effect of increased appetite?
Antihistamine
Which receptors cause side effect of GI discomfort/nausea?
5HT3 stimulation
Which receptors cause side effect of weight gain?
Antihistamine
5HT2C antagonism
Symptoms of anticholinergic effects?
Blurred vision Delirium Constipation Tachycardia Dry secretions Decreased sweating Urinary retention Hyperthermia
What conditions do anticholinergics increase risk of?
Narrow-angle glaucoma
Photophobia due to mydriasis
Which receptors cause side effect of anorgasmia?
Alpha 1 antagonism
5HT2A/C stimulation
Which receptors cause side effect of retrograde ejaculation?
Alpha 1 block
Anticholinergic
Antihistamine
Which receptors cause side effect of tardive dyskinesia?
Supersensitivity of dopamine receptors which develops due to prolonged therapy with dopamine blocking drugs
Which receptors cause side effect of impotence?
Alpha 2 blockade
5HT2A/C stimulation
Which receptors cause side effect of priapism?
Alpha 1 blockade
Which receptors cause side effect of obsessions?
5HT1D stimuation
Which receptors cause reduced OCD?
5HT1A/2A
Which receptors cause side effect of pathological gambling?
Habituation of dopamine receptors on repeated use of dopamine agonists, leading to dopamine dysregulation syndrome
Which drugs cause insulin resistance?
Valproate
Olanzapine
Which polymorphism leads to weight gain?
Drugs with strong 5HT2C affinity used on patients with specific variant of polymorphism of 5HT2C receptor promotor regions
What types of antipsychotics cause weight gain more than others?
Low-potency produce more weight gain than high potency.
Give examples of EPSE
Acute dystonia Akathisia Parkinsonism Tarde dyskinesia Dystonia Perioral tremor
Which type of antipsychotics lead to EPSEs?
High potency
Which EPSEs are due to late SEs and chronic use of antipsychotics?
Tardive dyskinesia
Dystonia
Perioral tremor
What causes hyperprolactinaemia?
Blocking of D2 receptors on anterior pituitary mammotrophic cells that normally are tonically inhibited by dopamine produced in hypothalamic arcuate nucleus.
Which antipsychotics induce Parkinsonism?
Trifluoperazine Chlorpromazine Raclopride Haloperidol Fluphenazine Risperidone
Why do some antipsychotics cause Parkinsonism?
They bind more tightly than the endogenous ligand dopamine to D2
Which drugs are less likely to cause Parkinsonism and why?
Anticholinergics
Quetiapine
Clozapine
Bind more loosely to D2 than dopamine
Difference between tightly bound and loosely bound antipsychotic drugs
Loosely bound:
Weaker potency, so need higher doses to be clinically effective but can be titrated faster.
Less chance of EPSEs
Which type of antipsychotics are more likely to lead to relapse?
Loosely bound antipsychotics as may dissociate from D2 receptor rapidly
When is drug-induced Parkinsonism seen?
Within 90 days of treatment
Which characteristic of Parkinsons is not seen in its drug-induced form?
Pill-rolling tremor
Coarse tremor seen instead
Who are at high risk of Parkinsonism from antipsychotics?
Elderly
Female
At what D2 receptor occupancy by antipsychotics leads to EPSE?
Higher than 80%
Why are atypical antipsychotics thought to have a lower chance of causing EPSEs?
Anticholinergic
HT2A antagonism
Less avidity of bindng i.e. hit and run profile (clozapine, quetiapine)
What can you use to treat drug-induced Parkinsonism?
Anticholinergics for up to 6 weeks
Why must anticholinergics used to treat drug-induced Parkinsonism be withdrawn after 4-6 weeks?
Tolerance can develop for EPSEs
Longer use of anticholinergics increases risk of Tardive Dyskinesia
What are dystonias?
Brief or prolonged contractions of specific groups of muscles
Give e.g. of dystonias
Oculogyric crises Tongue protrusion Trismus Torticolis Blepharospasm
When in the course of treatment do dystonias occur?
Early
Who is more likely to get dystonias?
Young men starting high-dose of high potency medications, especially IM.
What can be used to treat dystonias?
Reassurance
Anticholinergics
What causes akathisia?
Higher D2 occupancy in striatum
Symptoms of Akathisia?
Inability to relax
Pacing
Rocking with alternation of sitting and standing
What drugs can cause akathisia?
Neuroleptics
Antidepressants
Sympathomimetics
Treatment for Akathisia?
Dose reduction
Changing drug
Adding beta blocker/anticholinergic drug/benzo/cryoheptadine
Risk factors for Tardive Dyskinesia
Female
Elderly
Diabetes
Previous brain damage
Affective illness rather than pure psychosis
Children
Learning difficulties
Afro-carribean
Long-term co-precription of anticholinergics
Frequent drug holidays - will lead to high dose prescription with each relapse
When does tardive dyskinesia occur?
At least 6 months, often 1-2 years of treatment.
What is tardive dyskinesia?
Abnormal, involuntary, irregular choreaoathetotic movements of muscles of head, limbs and trunk.
Most common type of tardive dyskinesia?
Perioral movements
What exacerbates Tardive dyskinesia?
Stress
Absent on sleep
What is particularly striking in Tardive Dyskinesia patients?
Absence of insight
Treatment of Tardive Dyskinesia?
Spontaneously resolve - unlikely in elderly. Clozapine Dose reduction Withdrawl of drug Switch to atypicals Add clonazepam
When can neuroleptic malignant syndrome occur?
Anytime during treatment
Symptoms of NMS?
Extreme hyperthermia Severe muscular rigidity Confusion Autonomic fluctuations (BP, HR) Akinetic/mute
Blood test values of NMS
High WCC, CK, LFTs, plasma myoglobin
Myoglobinuria
Onset of NMS?
24-72 hours
How long does NMS last if untreated?
10-14 days
When is NMS more common?
Young men
After agitation
Using high potency drugs, especially rapid tranq
Dopaminergic drugs on withdrawl
Mechanism underlying NMS?
Dopamine blockade or hypothalamic sympathetic dysregulation
Mortality rate of NMS?
20-30% if untreated
Higher if depot used
Management of NMS?
Fluid replacement & prevent renal failure secondary to myoglobinuria
Prevent aspiration pneumonia
Stop antipsychotic
Which drugs can be used to treat NMS?
Dantrolene
Bromocriptine
Amantadine
What antipsychotics need to be considered after NMS occurs?
Low potency or atypical
How many patients on clozapine develop agrunulocytosis?
1 in 100
When is risk of agrunulocytosis at maximum on clozapine?
Between 4-18 weeks
Main SE of clozapine related to dose?
Salivation Sedation Weight gain Fatigue Lowering of seizure threshold
Which SE of clozapine are not dose realted?
Arganulocytosis
Myocarditis
What happens if yellow result occurs on someone on clozapine?
Monitoring frequency must increase until green signal obtained
Which drug may precipitate clozapine-associated neutropenia?
Paroxetine
Effect of increased dopaminergic transmission on sexual function?
Enhances sexual arousal
Penile erection
Effect of hyperprolactinaemia on women?
Amenorrhoea
Reduced sexual desire
Hirsutism
How do antipsychotics lead to reduced sexual function?
Reduce dopamine transmission
Inducing hyperprolactinaemia
Which drugs cause ejaculatory problems?
Neuroleptics
Which drugs are linked to priapism?
Risperidone Chlorpromazine Clozapine Olanzapine Thioridazine Trazodone
Is priapism drug-dependent or duration-dependent?
Neither
What can priapism lead to if untreated?
Permanent impotance
What is used to treat sexual dysfunction in men due to hyperprolactinaemia?
Bromocriptine
How does Bromocriptine work?
Dopamine agonist
What drugs lower seizure threshold?
Low potency antipsychotics
Dose-dependent
Which antipsyshotic is the most sedating?
Chlorpromazine - due to H1 antihistamine
Which drugs are more likely to cause anticholinergic syndrome; high or low potency drugs?
Low
Impact of neuroleptics on cardiac function?
Reduce cardiac contractility
Increase circulating catecholamines
Prolong atrial and ventricular conduction time
Which drugs are more cardio-toxiac; low or high potency?
Low potency
ECG changes with neuroleptics?
QT and PR prolongation
Blunting of T waves
ST depression
Which psychiatric medications can cause Torsades de Pointes?
Thioridazine
Droperidol
What leads to antipsychotic related sudden death?
Cardiac arrhythmias
Seizures
Asphyixation
Malignant hyperthermia
Which types of drugs cause postual drop?
Low potency drugs
Skin side effects on antipsychotics?
Allergic dermatitis and photosensitivity on low-potency drugs.
What is the skin SE of Chlorpromazine?
Blue-gray discoloration in areas exposed to light - reversible.
Which eye condition is a known SE of Thioridazone?
Irreversible retinal pigmentation if used >1000mg a day
Early symptom: nocturnal confusion due to difficulty with night vision.
Effect of Chlorpromazine on eyesight?
Pigmentation of anterior lens and posterior cornea; white-brown stellate granular deposits.
Benign.
Which antipsychotic can lead to cholestatic jaundice?
Chlorpromazine
When does drug-induced obstructive jaundice occur?
First month of treatment
What is associated with drug-induced jaundice?
Rash
Eosinophilia
Treatment for drug-induced jaundice?
Immediately stop antipsychotic
Avoid rechallenge
Signs of Haloperidol OD on EEG?
Diffuse slowing and low voltage
Which typical antipsychotic is safest in an OD?q
Haloperidol isone
What mediates QTc?
Blockade of rapid component of delayed rectifier potassium current responsible for repolarisation of cardiac Purkinje cells and myocardial cells.
How do drugs cause prolonged QTc?
Bind to delayed rectifier K+ channgel and thereby decrease outward movement of K+
Which antipsychotics have greater risk of causing prolonged QTc?
Droperidol
Pimozide
Sertindole
Thioridazine
What are the symptoms of inadvertent intravascular injection event/postinjection delirium sedation syndrome?
Sedation Confusion Dizziness Dysarthria Somnolence
When does inadvertent intravascular injection event/postinjection delirium sedation syndrome occur?
20min - 3 hours after injection of olanzapine pamoate (long-acting depot)
Treatment for inadvertent intravascular injection event/postinjection delirium sedation syndrome?
Supportive medical care; symptoms alleviate within 3-72 hours
What is inadvertent intravascular injection event/postinjection delirium sedation syndrome linked to?
Accidental punctures of vessel or injects into capillary bed leaking
What is Metabolic syndrome composed of?
Obesity Dyslipidaemia Glucose intolerance Insulin resistance HTN
WHO criteria for metabolic syndrome
Insulin resistance and /or impaired fasting glucose and/or impaired glucose tolerance and two or more of the following:
Waist-hip ratio >0.9 (mean), >0.85 (women) or BMI 30
Triglyceride level 1.7 or high-density lipoprotein M0.9 (men) or <1 (women)
BP 140/90 or treated HTN
Microalbuminuria
Prevalence of Diabetes on schizophrenics?
Twice as prevalent than in general population
Drugs that are most linked with metabolic syndrome/
Olanzapine Clozapine Quetiapine Risperidone Aripiprazole (worst at top)
Which gender have higher risk of metabolic syndrome if schizophrenic?
Females
What type of study was the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness)?
Double-blind pragmatic RCT
What drugs were looked at in CATIE?
Olanzapine Quetiapine Risperidone Ziprasidone Perphenazine
Which antipsychotic has lowest discontinuation rate?
Olanzapine
What type of study was CUtLASS (Cost utility of latest antipsychotic drugs in schizophrenia study)?
Unblinded RCT comparing first-generation and second-generation antipsychotics
Which 2nd-generation antipsychotics were used in CUtLASS?
Amsulpride Olanzapine Quetiapine Risperidone Clozapine (in second phase)
Outcome of CUtLASS?
Those on 1st generation antipsychotics did relatively better.
Advantage of clozapine in symptom improvement over 1 year and patients preferred it.
Long-term SE of Lithium
Hypothyroidism
Irreversible nephrogenic diabetes insipidus
Reduced GFR (chronic kidney disease)
Hyperparathyroidism
Which diuretic has no effect on Lithium levels?
Loop diuretics
What score is used to assess severity of Lithium toxicity
AMDISEN 0 - no signs 1 - mild 2 - moderate 3 - severe
Which antipsychotic is best to treat negative symptoms?
Amisulpride
Which SSRIs cause prolonged QTc?
Citalopram
Which TCA is the most selective inhibitor of serotonin?
Clomipramine
Which TCA is the most selective inhibitor of noradrenaline?
Desipramine
Which TCAs have the least anticholinergic activity?
Amoxapine
Nortriptyline
Desipramine
Maprotiline
Which TCAs have the most antihistaminic activity?
Doxepin
Which TCA is associated with weight gain
Amitriptyline
Cardiac SE of TCAs?
QT prolongation
Tachycardia
Flattened T waves
Depressed ST segment
Effect of TCAs on overdose?
Cardiac arrhythmias
Anticholinergic delirium
May occur 3-4 days after due to long half-life
Treatment for TCA overdose?
Lavage
QRS monitoring
No antidose
Symptoms of anticholinergic delirium?
Confusion Visual hallucinations Hyperpyrexia Loss of visual accommodation Peripheral vasodilatation Drying of mucous membranes
Which TCA can cause hyperprolactinaemia?
Amoxapine
SEs of all TCAs?
SIADH Hyponatraemia Fine rapid tremor Dysarthria Precipitate angle closure glaucoma
What happens if TCAs are reduced too quickly?
Cholinergic rebound
What is the best way to reduce TCAs?
Reduce 25-50mg per 2-3 days
When can discontinuation reaction occur with TCAs?
48 hours - 2 weeks after
Mechanism of serotonin syndrome
Excessive serotonergic transmission in brain. Most CNS symptoms due to 5HT 2A stimulation
Features of serotonin syndrome
Diarrhoea Myoclonus Diaphoresis Hyperactive reflexes Ataxia Hypomania/labile mood Disorientation
Which drugs are high risk of serotonin syndrome?
Combination of SSRI with MAOI/RIMA/Serotonergic TCAs/SNRI/Lithium/L-tryptophan
Combination of TCA and MAOI
Combining any of the above with Tramadol, pethidine, meperidine
Oxazolidionine antibacterial linezoloid
Tetrabenazine
Entacapone
Selegiline
What is oxazolidinone antibacterial linezolid?
Reversible non-selective MAOI
What is Tetrabenazine?
Acts via dopamine and serotonin depletion at nerve endings
What is entacapone?
COMT inhibitor
Treatment of serotonin syndrome?
Stop agent
Correct vital signs
Benzos
5HT2A antagonists
Name some 5HT2A antagonists that can be used in the treatment of serotonin syndrome
Cyproheptadine
Atypical antipsychotics
Chlorpromazine
Why do SSRIs cause anorexia when starting, then weight gain late during therapy?
Desensitization and down-regulation of receptors.
What is fluoxetine associated with in particular?
Change in duration of menstrual period
Effect of SSRIs on platelets?
Thrombasthenia - functional impairment of platelet aggregation
Impact of Thrombasthenia?
Easy bruising
Prolonged bleeding
(in those with gastric ulcers or bleeding diathesis)