Clinical psychopharmacology Flashcards
Manfred Joshua Sakel
(therapy, year)
Insulin Coma Therapy for schizophrenia
1934
Ladislas Meduna
(therapy, year)
Convulsive Therapy for schizophrenia (using camphor and metrazol)
1934
Egas Moniz
(therapy, year)
Frontal leucotomy for schizophrenia and depression
1935
Cerletti and Bini
(therapy, year)
Introduced electroconvulsive therapy (ECT) for schizophrenia
1938
Erik Jacobsen + Jens Hald
(drug, year)
Invented Disulfiram in 1948
Initially it was developed as an anthelmintic, then later its use in alcohol dependency was recognised.
John Cade
(drug, year)
Discovered the antimanic effects of Lithium
1949
Frank Berger
(drug, year)
Invented Meprobamate in the 1940s
This was hailed as the first ‘tranquiliser’ in 1954
Paul Charpentier
(drug, year)
Invented Chlorpromazine
1950
Jean Delay + Pierre Deniker
(drug, year)
First used Chlorpromazine to treat psychosis
1952
Who coined the term ‘neuroleptic’
Pierre Deniker with reference to the drug Chlorpromazine, which he first used to treat psychosis in 1952 with Jean Delay
Mahlon Kline
(drug, year)
Isolated Reserpine from the rauwolfia plant in India
1954
Reserpine was prescribed more frequently than chlorpromazine in the 1950s, but its use decreased as it caused akathisia
Roland Kuhn
(drug, year)
Discovered the antidepressant effects of Imipramine - the first tricyclic antidepressant
1955
Paul Janssen (drug, year)
Invented Haloperidol
1958
Leo Sternbach
(drug, year)
Invented chlordiazepoxide (librium) - the first benzodiazepine
1955
Mahlon Kline
(antidepressant, year)
Iproniazid
- the first antidepressant
1957
(The antidepressant effects of isoniazid, an MAOI, had been noted in the 1950s while being used to treat tuberculosis. Iproniazid was invented in 1957 and used effectively to treat depression, but was later withdrawn due to its hepatotoxicity)
John Kane
(drug, year)
Introduced Clozapine into clinical practice for treatment-resistant schizophrenia
1988
======================================================
Clozapine had been invented in 1958 by Fritz Hunziker
Arvid Carlssen
(drug, year)
Synthesised Zimeldine - the first SSRI - in the late 1970s/early 1980s.
This was withdrawn due to it causing hypersensitivity syndrome and demyelinating disease.
Blackwell
(key discovery, year)
First described the ‘cheese reaction’ seen in MAOI-associated hypertension
1963
Who coined the term ‘antidepressant’?
Max Lurie 1953
- with reference to Isoniazid
SSRIs - common adverse effects (5)
GI effects (nausea, D+V, constipation)
Increased risk of GI bleeding
Dizziness
Sexual dysfunction
Hyponatraemia
Which SSRI is preferred in the elderly?
Citalopram - associated with lower risk of drug interactions
Which SSRI is preferred post-MI?
Sertraline
Which SSRI is preferred in children/adolescents?
Fluoxetine
Tricyclic antidepressants - subdivision (2) + difference in mechanisms
1st gen - Tertiary amines
- boost serotonin and noradrenaline.
2nd gen - Secondary amines
- lower side effect profile and act primarily on noradrenaline.
Tricyclic antidepressants - tertiary amines (8)
Amitriptyline
Lofepramine
Imipramine
Clomipramine
Dosulepin (Dothiepin)
Doxepin
Trimipramine
Butriptyline
Tricyclic antidepressants - secondary amines (4)
Protriptyline
Amoxapine
Nortriptyline
Desipramine
‘PAND’
Tricyclic antidepressants - common side effects (5)
drowsiness
dry mouth
blurred vision
constipation
urinary retention
Monoamine Oxidase Inhibitors (MAOI) - subdivision (2)
Irreversible MAOIs (traditional) - ‘PIT’
- Phenelzine
- Isocarboxazid
- Tranylcypromine
Reversible MAOIs
- Moclobemide
(aka RIMA - Reversible Inhibitor of Monoamine oxidase type A)
- less likely to cause cheese reaction than the traditional MAOIs
Serotonin-Noradrenaline Reuptake Inhibitors, SNRI (3)
Venlafaxine
Duloxetine
Milnacipran
Noradrenaline Reuptake Inhibitors, NARI (2)
Reboxetine
Atomoxetine
Dopamine Reuptake Inhibitor, DARI (1)
Bupropion
Serotonin Antagonist and Reuptake Inhibitor, SARI (1)
Trazodone
Noradrenergic and Specific Serotonergic Antagonists, NaSSA (2)
Mirtazepine
Mianserin
Chlorpromazine, Promazine
(structural classification)
Phenothiazine (aliphatic side chain)
Thioridazine, Pipothiazine
(structural classification)
Phenothiazine (piperidine side chain)
Trifluoperazine, Fluphenazine
(structural classification)
Phenothiazine (piperizine side chain)
Haloperidol, Benperidol, Droperidol
(structural classification)
Butyrophenone
Flupenthixol, Zuclupenthixol
(structural classification)
Thioxanthene
Pimozide
(structural classification)
Diphenylbutylpiperidine
Clozapine
(structural classification)
Dibenzodiazepine
Risperidone (structural classification)
Benzoxasole
Olanzapine (structural classification)
Thienobenzodiazepine
Quetiapine (structural classification)
Dibenzothiazepine
Sulpride, Amisulpride (structural classification)
Substituted benzamide
Aripiprazole (structural classification)
Arylpiperidylindole (quinolone)
Tricyclic antidepressant considered least toxic in overdose
Lofepramine
Tricyclic antidepressants considered most toxic in overdose (2)
Amitriptylline
Dosulepin
Clozapine - indications
NICE guidelines recommend the use of clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs.
They stipulated that at least one of the drugs should be a non-clozapine second-generation antipsychotic.
Clozapine (levels)
The average clozapine dose in the UK is 450 mg/day.
A ‘therapeutic range’ has not been established. It is generally accepted that a level of 350 µg/L is necessary to achieve a therapeutic response.
Levels greater than 500 µg/L should be treated with caution as there is a risk of seizures.
Lower doses may be required in non-smokers, the elderly, females, and in patients using enzyme inhibitors (e.g. SSRI’s). Treatment should of course be guided by clinical response (treat the patient not the level).
Clozapine - common side effects (8)
Drowsiness/ sedation
Dizziness
Insomnia
Salivation
Nausea + Vomiting
Dyspepsia
Weight gain
Constipation
Clozapine - adverse effects (10)
Agranulocytosis
Myocarditis
Seizures
Severe orthostatic hypotension with or without syncope
Increased mortality in elderly patients with dementia related psychosis
Colitis
Pancreatitis
Thrombocytopenia
Thromboembolism
Insulin resistance and diabetes mellitus
==========================================
(Approx 33 percent developed diabetes mellitus over a ten year period (Henderson, 2005)) The BNF advices caution in the following circumstances: prostatic hypertrophy susceptibility to angle-closure glaucoma adult over 60 years
Clozapine - agranulocytosis
(prevalence, timing, rechallenge)
Agranulocyotosis occurs in 1-2% of patients on clozapine
It is more common in the first 18 weeks of treatment
One-third of patients who stop clozapine due to neutropenia or agranulocytosis will develop a blood dyscrasia on rechallenge.
In most cases, the second reaction will occur more rapidly, be more severe, and will last longer than the first
Clozapine - agranulocytosis (treatment)
Lithium has been shown to independently raise the white cell count and has been used in this way successfully in combination with clozapine. Use of this combination can enable patients to continue on treatment when they develop neutropenia.
Having said that there are case reports suggesting that the combined use of lithium and clozapine can result in toxicity and so this combination must be used with caution.
Clozapine - augmentation (favoured drugs)
Sulpride and amisulpride are the favoured antipsychotics for augmentation with clozapine as their selectivity for D2 dopamine blockade compliments clozapine (which lacks high potency dopamine blockade).
Lamotrigine has the best evidence of the mood stabilisers to support its use as an augmentation strategy.
Atypical antipsychotics available in depot form (3)
Olanzapine
Aripiprazole
Risperidone - Risperdal Consta or Paliperidone
‘OAR’
Lithium (therapeutic index)
0.4 - 1.2 mmol/L
Lithium - side effects (10)
Drowsiness
Dry mouth
Polyuria
Polydipsia
Metallic taste
Muscle weakness
GI - Nausea + Diarrhoea
Weight gain
Fine tremor
Worsening of psoriasis
Lithium - long-term adverse effects (4)
Hypothyroidism
Irreversible nephrogenic diabetes insipidus
Reduced GFR (chronic kidney disease)
Hyperparathyroidism
Drugs that increase lithium levels (3)
NSAIDs/COX-2 inhibitors
ACE inhibitors
Thiazide diuretics
====================================
NB: Loop diuretics (furosemide) generally have no effect on lithium levels
Lithium
- teratogenic effect
- risk
- increased risk from general population
Cardiac (Ebstein’s) anomalies
The risk of Ebstein’s in women taking lithium is 1 in 1000
(which is 20 times the normal level).
Carbamazepine (mechanism of action)
binds to sodium channels increases their refractory period
Carbamazepine - adverse effects (8)
P450 enzyme inducer
dizziness and ataxia
drowsiness
headache
visual disturbances (especially diplopia)
Steven-Johnson syndrome
leucopenia and agranulocytosis
syndrome of inappropriate ADH secretion (hyponatraemia)
Carbamazepine (teratogenic effect)
Fingernail hypoplasia, craniofacial defects
Valproate (mechanism of action)
GABA agonist
NMDA antagonist
Valproate - forms (3, + indications)
1 - Semi-sodium valproate (Depakote) (licensed for acute mania associated with bipolar disorder)
2 - Valproic acid (licensed for acute mania associated with bipolar disorder)
3 - Sodium valproate (licensed for epilepsy)
[Note that the BNF 61 is not consistent with the Maudsley Guidelines 10th Edition which suggest valproic acid is not licensed for acute mania.]
Valproate (teratogenic effect)
Spina bifida, hypospadias
Valproate - key adverse effects (4)
Tiredness
Significant weight gain (30-50% of patients)
Tremor (up to 25% of patients)
Hair loss (5% to 10% of patients, with curly regrowth once valproate is stopped)
Topiramate (mechanism of action)
GABA agonist
NMDA antagonist
Na channel stabiliser
Topiramate (use)
Refractory or rapid cycling bipolar affective disorder where lithium plus valproate has been ineffective
Phenytoin (mechanism of action)
binds to sodium channels increasing their refractory period
Phenytoin (teratogenic effects - 4)
Craniofacial defects
limb defects
cerebrovascular defects
mental retardation
Phenytoin (chronic adverse effects - 7)
gingival hyperplasia (secondary to increased expression of platelet derived growth factor, PDGF)
hirsutism
coarsening of facial features
drowsiness
megaloblastic anaemia (2ndary to altered folate metabolism) peripheral neuropathy osteomalacia (enhanced vitamin D metabolism)
lymphadenopathy
dyskinesia
Benzodiazepines (mechanism of action)
Potentiation of the GABA inhibitory effect on the CNS by increasing the number and frequency of chloride channel opening
Benzodiazepines (pharmacokinetics)
- absorbed well following oral administration
- they show high plasma protein binding (95% for diazepam)
- mainly metabolised in the liver
- they tend to be highly lipophilic and rapidly cross the blood brain barrier and placental barrier
Diazepam (half-life)
20-100 hours
Clonazepam (half-life)
18-50 hours
Chlordiazepoxide (half-life)
5-30 hours
Nitrazepam (half-life)
15-38 hours
Temazepam (half-life)
8-22 hours
Lorazepam (half-life)
10-20 hours
Alprazolam (half-life)
10-15 hours
Oxzazepam (half-life)
6-10 hours
Zopiclone (half-life)
5-6 hours
Zolpidem (half-life)
2 hours
(SPMM states 1-3 hours)
Zaleplon (half-life)
2 hours
(SPMM states 1 hour)
Buspirone (mechanism of action)
5HT1A partial agonist
Licensed for the short-term management of anxiety
Who coined the term ‘placebo effect’?
Henry K. Beecher (1955)
Active placebo (definition)
a drug which has its own inherent effects but none for the condition for which it is being given.
e.g. the use of atropine as the control drug in trials of antidepressants.
Factors that increase placebo response
- Injections > oral
- brighter coloured tablets
- larger tablets
- status of the treating professional
- branded > unbranded
Placebo response - pattern analyses
Pattern analyses have shown that the improvement as a result of placebo in depression tends to be abrupt, occurs early in treatment and is less likely to persist, whereas improvement in response to antidepressants tends to be gradual, occurs later and is more likely to persist.
Placebo sag (essence)
a situation where the placebo effect is diminished (attenuated) with repeated use
Placebo response rate (%) in - depression - schizophrenia
Depression - 60%
Schizophrenia - 30%
Drug approval process (5 steps)
Animal studies
Phase 1 clinical trials - safety
Phase 2 clinical trials - effectiveness
Phase 3 clinical trials - superiority
Phase 4 clinical trials - post-marketing surveillance
… clinical trials involve only a small number of healthy people (possibly as few as 15-20). The focus is to evaluate the drugs safety, determine a safe dosage range, and identify side effects.
Phase 1
In … clinical trials the drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
Phase 2
In … trials the drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments (or placebos), and collect information that will allow the experimental drug or treatment to be used safely.
Phase 3
are done after the drug has been granted a license. They gather further information on the drug in areas not addressed in the previous trials (e.g. Safety in pregnancy) and also to find other potential uses for the drug.
Phase 4 (post-marketing trials)
Pharmacokinetics - core components (4)
Absorption
Distribution
Metabolism
Elimination
‘ADME’
Absorption (definition)
The process by which a drug enters the bloodstream
What route of administration yields the fastest absorption?
Inhalation
Bioavailability (definition)
the fraction of an administered dose of a drug that reaches the systemic circulation in an unchanged form
(by definition, when a medication is administered intravenously, its bioavailability is 100%)
Distribution (definition + two key factors)
the reversible transfer of a drug from one location to another within the body
2 important factors affecting this are:
- tissue perfusion
- drug lipophilicity
Metabolism (definition)
the biotransformation of compounds into new compounds, in order that they are made more water-soluble and can be more easily excreted from the body
Elimination (definition)
how a drug is removed from the body, whether unaltered or in the form of its metabolites
First-pass metabolism (aka, definition)
aka prehepatic/presystemic metabolism
the intestinal and hepatic degradation or alteration of a drug or substance taken by mouth, after absorption, that removes some of the active substance from the blood before it enters the general circulation
Plasma half-life (definition)
the time taken to eliminate 50% of the absorbed dose of a drug from a person’s plasma
Biological half-life (definition)
the time taken for a drug to lose half of its pharmacologic activity
Clearance (definition)
the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time period
[aka renal clearance or renal plasma clearance where referring specifically to the kidneys]
Blood brain barrier (definition, key facts)
a barrier separating the circulating blood flow in the human body from the extracellular fluid in the brain.
- it consists of capillary endothelial cells tightly packed together
- lipid soluble molecules pass through relatively easily whereas water soluble ones do not
- Large molecules do not pass through the easily
- Molecules that are highly charged struggle to pass through
- The permeability of the BBB increases when it is inflamed
- Nasally administered drugs can theoretically bypass the BBB
- At several areas the BBB is fenestrated to allow neurosecretory products to enter the blood
- Posterior pituitary
- Area postrema
Cytochrome P450 system (essence)
- an evolved mechanism that deals with exogenous toxins and is therefore essential in the metabolism of drugs
- comprises about fifty separate enzymes
- the enzymes are located on the endoplastic reticulum of cells and are mainly found in the liver and small intestine
Which Cytochrome P450 enzyme is involved in the metabolism of clozapine?
CYP1A2
Grapefruit juice
(interaction with the Cytochrome P450 system, drugs affected)
Inhibits CYP3A4
Increases levels of:
- carbamazepine
- benzos: diazepam, nitrazepam
- neuroleptics: aripiprazole, quetiapine
- antidepressants: sertraline, trazodone
Inhibits CYP1A2
Increases levels of:
- clozapine
Caffeine
(interaction with the Cytochrome P450 system, drugs affected)
Inhibits CYP1A2
Increases levels of:
- clozapine
Tobacco
(interaction with the Cytochrome P450 system, drugs affected)
Induces CYP1A2
Reduces levels of:
- clozapine
- olanzapine
- fluvoxamine
Steady state (essence)
This refers to the situation where the intake of a drug is at the same overall rate as its elimination from the body, so that there is no net change in the amount of drug in the person’s system.
It is usually reached after 4-5 times the half-life of the drug has elapsed after commencement of regular dosing.
First-order kinetics
(aka, essence)
aka Linear kinetics
elimination of the drug takes place at a rate proportional to the plasma concentration
- a constant fraction of the drug is eliminated per unit time, but the actual amount of drug eliminated per unit time varies (reduces with plasma concentration)
- drugs that follow linear kinetics have a fixed half-life
- most drugs undergo linear kinetics
Zero-order kinetics
(aka, essence)
aka non-linear kinetics
elimination of the drug take place at a constant rate, regardless of the plasma concentration
- the fraction of the drug eliminated per unit time varies, but the actual amount of drug eliminated per unit time stays the same
- drugs that follow non-linear kinetics do not have a fixed half-life (the half-life will be longer at the beginning and get shorter as the total amount of drug in the body decreases)
Pharmacokinetic changes with increasing age
(distribution)
More fat, less water
- lipid-soluble drugs are more widely distributed, therefore decreased plasma levels
- water-soluble drugs are less well-distributed, therefore increased plasma levels
Less albumin
- greater unbound free fraction (increased amounts of active drug)
Pharmacokinetic changes with increasing age (metabolism)
Reduced liver activity -> reduced first-pass metabolism
Pharmacokinetic changes with increasing age (elimination)
More fat, less water
- half-life of lipid-soluble drugs is increased
Which cytochrome P450 enzyme displays the most phenotypic variation?
CYP2D6
Frequency of CYP2D6 poor metabolisers across ethnic groups
Asian < Caucasian < African American
Which ethnic groups have the highest proportions of CYP2D6 ultrarapid metabolisers?
Middle Eastern and North African
Pharmacokinetic changes in pregnancy (distribution, excretion)
D - increased water and fat content leads to dilution and hence lower plasma levels of drug
E - increased blood flow leads to increased renal clearance of many drugs
Benzodiazepines are metabolised in the liver by which Cytochrome P450 enzyme
CYP3A4
Drugs that have been removed from the UK market due to their effect on the QTc interval (2)
thioridazine
droperidol
Kinetic homogeneity (essence)
An assumption made in therapeutic drug monitoring that plasma drug concentration is roughly equal to the concentration at the site of action.
Therapeutic Index (definition)
TD50: ED50
The ratio of the median toxic dose (TD50) and the median effective dose of a drug (ED50)
Therapeutic Window (definition)
The difference between the minimum effective concentration and the minimum toxic concentration of a drug
Psychiatric drugs with narrow therapeutic index (3)
Carbamazepine
Lithium
Phenytoin
Diazepam (active metabolite)
Desmethyldiazepam
Dothiepin (active metabolite)
Dothiepinsulfoxide
Fluoxetine (half-life)
(active metabolite + half-life)
Fluoxetine half-life - 4-6 days
Fluoxetine’s active metabolite is norfluoxetine
- has a similar activity on 5-HT reuptake
- half-life of 4-16 days
Imipramine (active metabolite)
Desimipramine
Risperidone (active metabolite)
9-Hydroxyrisperidone
Amitriptyline (active metabolite)
Nortriptyline
Codeine (active metabolite)
Morphine
Amisulpride
(mechanism of action, profile)
D2/D3 selective antagonist
cause substantial increase in prolactin
less likely to produce EPSEs
lack sedative and anticholinergic properties
low affinity selective antagonist of ‘D2 like’ receptors (D2=D3>D4) - little affinity for D1 like receptors (D1 and D5) or non dopaminergic receptors (serotonin, histamine, adrenergic, and cholinergic)
Aripiprazole
(mechanism of action, profile)
D2 partial agonist
5HT1A partial agonist
5HT2A antagonist
activating profile
prodopaminergic SEs - insomnia, nausea, vomiting
less likely to cause weight gain
Arsenapine
(mechanism of action, profile)
D2 antagonist
5HT2A antagonist
alpha-2 adrenoceptor antagonist
requires sublingual administration in UK
licensed for mania but no schizophrenia
Chlorpromazine
(mechanism of action, profile)
D2 antagonist
alpha-1 adrenoceptor antagonist -> hypotension
H1 antagonist -> sedating
muscarinic acetylcholin receptor antagonist -> dry mouth, urinary difficulties, constipation
Clozapine
(mechanism of action)
D2 antagonist (weak)
D4 antagonist
5HT2 antagonist (high affinity)
5HT6 antagonist
H1 antagonist
Alpha-1 antagonist
Muscarinic cholinergic receptor antagonist
Lurasidone
(mechanism of action, profile)
D2 antagonist (potent)
5-HT2 antagonist (potent)
Binds only weakly to H1 and and alpha-1 receptors, therefore less sedation, weight gain, and orthostatic hypotension
Olanzapine
(mechanism of action, profile)
High 5HT2/D2 blocking ratio
Potent D4 and 5HT6 blockade
Significant anticholinergic and H1-antagonism, therefore strongly sedating
Quetiapine
(mechanism of action, profile)
D2 antagonist (weak)
5-HT2 antagonist (weak)
H1 antagonist and anticholinergic
Highly sedating
Risperidone
(mechanism of action, profile)
D2 antagonist (potent)
5-HT2 antagonist (potent)
alpha-1 antagonist
mild sedation and hypotension
in higher therapeutic doses can lead to EPSEs and hyperprolactinaemia similar to typicals
Sulpiride
(mechanism of action, profile)
Selective D2 antagonism
causes substantial increase in prolactin
less likely to produce EPSEs
lack sedative and anticholinergic properties
Ziprasidone
(mechanism of action, profile)
D2 antagonist
5HT2 antagonist
5HT1a agonist
Noradrenaline reuptake inhibitor
Not licensed in UK
QT interval prolongation
Agomelatine
(mechanism of action)
Melatonergic receptor agonist (MT1 and MT2)
5-HT2C antagonist
Bupropion
(mechanism of action, profile)
Norepinephrine-dopamine reuptake inhibitor (NDRI)
Nicotinic acetylcholine receptor antagonist
Used in smoking cessation and depression
=====================================
Class - Aminoketone
Increases seizure risk and is contraindicated in seizure disorders
Buspirone
(mechanism of action, profile)
5HT1A partial agonist
Effective in generalised anxiety disorder but not panic disorder.
Unlike benzodiazepines, the anxiolytic effects take several days to develop.
Citalopram
(mechanism of action, profile)
Selective Serotonin Re-uptake Inhibitor (SSRI)
Associated with QT interval prolongation
Clomipramine
(mechanism of action, profile)
5HT reuptake inhibitor (most potent of the tricyclics)
Its metabolite desmethylclomipramine is an effective noradrenaline reuptake inhibitor
Only tricyclic effective in OCD
Duloxetine
(mechanism of action)
Serotonin and noradrenaline reuptake inhibitor (SNRI)
Mirtazapine
(mechanism of action, profile)
Noradrenaline and serotonin specific antidepressant (NaSSa)
5HT2 antagonist
5HT3 antagonist
H1 antagonist
alpha 1 and alpha 2 antagonist
muscarinic antagonist (moderate)
Sedating profile
Venlafaxine
(mechanism of action, profile)
Serotonin and noradrenaline reuptake inhibitor (SNRI)
- potent 5HT reuptake inhibition
- noradrenaline reuptake inhibition only apparent at higher doses
- negligible affinity for other receptors, therefore lacks sedative and anticholinergic properties*
Reboxetine
(mechanism of action, profile)
Selective Noradrenaline Re-uptake Inhibitor (NARI)
No clinically significant effects on other receptors
St John’s Wort
(mechanism of action, profile)
Weak MAOI
Weak SNRI
(also considered by some to be a weak SSRI)
Trazodone
(mechanism of action, profile)
SARI (Serotonin antagonist and reuptake inhibitor)
5HT2 antagonism
5HT reuptake inhibition (weak)
alpha-1 antagonism
Distinct sedating profile
Moclobemide
(mechanism of action, profile)
Reversible inhibitor of monoamine oxidase type A
No tyramine reaction, making it advantages compared with conventional MAOIs. However, therapeutic efficacy not well established.
Donepezil
Rivastigmine
Galantamine
(mechanism of action)
Reversible acetylcholinesterase inhibitor (all)
Rivastigmine is additionally a butyrylcholinesterase inhibitor
Galantamine is additionally a nicotinic acetylcholine receptor agonist
Memantine
(mechanism of action)
NMDA (glutamate) receptor antagonist
Valproate
(mechanism of action, profile)
Unknown. However, according to MRCPsych mentor:
GABA agonist
NMDA antagonist
Gabapentin
(mechanism of action, profile)
Mechanism unclear - known to inhibit voltage activated calcium channels but it is not clear if this is how it exerts its therapeutic effect
- Sedating*
- Not licensed for the treatment of mood disorders*
Topiramate
(mechanism of action)
GABA agonist
NMDA antagonist
Na channel stabiliser
Carbamazepine
(mechanism of action)
Stabilises Na channels
Phenytoin
(mechanism of action)
Stabilises Na channels
Lamotrigine
(mechanism of action, profile)
Blocks voltage-dependent sodium channels
Reduces excitatory neurotransmitter release - esp. glutamate
- not licensed in UK for mood disorders.*
- some evidence of benefit in bipolar depression, but not mania*
Pregabalin
(mechanism of action, profile)
Inhibition of the alpha-2-delta subunit of voltage-gated calcium channels in the central nervous system
licensed for generalised anxiety disorder and neuropathic pain
Benzodiazepines
(mechanism of action)
Facilitate GABA transmission by acting as agonists on the omega site within the GABA-A complex
(all are agonists except clonazepam which is a partial agonist)
They therefore facilitate inhibitory neurotransmission via chloride ions - they increase the frequency and duration (not number) of chloride channel openings
Z-drugs
(mechanism of action)
GABA-A agonists
(but act on different parts of the GABA-A complex to benzodiazepines)
Ketamine
(mechanism of action)
NMDA antagonist
Phencyclidine
NMDA antagonist
Lofexedine
(mechanism of action, use)
(presynpatic) Alpha 2 adrenoceptor agonist
historically used to treat high blood pressure, but more commonly used to help with the physical symptoms of opioid withdrawal
Clonidine
(mechanism of action, uses)
(presynaptic) Alpha 2 adrenoceptor agonist
Hypertension
Prevention of recurrent migraine,
Prevention of vascular headache,
Menopausal symptoms, particularly flushing and vasomotor conditions
Buprenorphine
(mechanism of action, use)
Partial agonist at the mu-opioid receptor
Adjunct in the treatment of opioid dependence
Naloxone
(mechanism of action)
Short-acting mu opioid antagonist
Methadone
(mechanism of action, use)
Mu opioid receptor agonist
Adjunct in treatment of opioid dependence
Longer acting than heroin
Atomoxetine
(mechanism of action, use)
Noradrenaline reuptake inhibitor (NARI)
used in ADHD
Varenicline
(mechanism of action, use)
selective nicotine-receptor partial agonist.
used in smoking cessation
Disulfiram
(mechanism of action, use)
Irreversibly inhibits aldehyde dehydrogenase
Adjunct in the treatment of alcohol dependence
Acamprosate
(mechanism of action, use)
Metabotropic glutamate receptor antagonist
GABA-A agonist
a synthetic taurine analogue
Maintenance of abstinence in alcohol-dependent patients
Selegiline
(mechanism of action, use)
selective, irreversible inhibition of monoamine oxidase type B
(also inhibits MAO-A at higher doses)
Parkinson’s disease
Drugs that inhibit tricyclic antidepressant metabolism (6)
Phenothiazines
SSRI: fluoxetine, paroxetine
Disulfiram
Methylphenidate
Quinidine
Cimetidine
Drugs that induce tricyclic antidepressant metabolism (5)
Smoking
Phenytoin
Carbamazepine
Contraceptive pill
Barbiturates
Tricyclics and Phenothiazines - interaction
Mutual inhibition of metabolism
-> increase in levels of both antipsychotic and TCA
Tricyclics and warfarin - interaction
TCAs increase warfarin levels - high risk of bleeding
Tricyclics and clonidine - interaction
TCAs reduce clonidine levels - risk of hypertensive crisis
Tricyclics and MAOIs - interaction
Synergistic serotonergic enhancement (especially with clomipramine)
-> increased risk of serotonin syndrome
TCAs reduce tyramine entry via monoamine reuptake channels
-> lower risk of cheese reaction
Fluoxetine and Paroxetine - pharmacokinetics
Both are capable of inhibiting their own clearance at clinically relevant doses
- they therefore have nonlinear pharmacokinetics
- changes in dose can produce proportionately large changes in plasma level
Most selective SSRI
Citalopram
(and escitalopram)
Citalopram
- half-life
- interactions
33 hours
Not a potent inhibitor of most cytochrome enzymes
Escitalopram
- half-life
- interactions
30 hours
Not a potent inhibitor of most cytochrome enzymes
Fluoxetine
- half-life
- interactions
4-6 days
Inhibits CYP2D6, CYP3A4.
Increases levels of some antipsychotics, some benzodiazepines, carbamazepine, ciclosporin, phenytoin, tricyclics
Never use with MAOIs
Avoid selegiline and St John’s Wort
Fluvoxamine
- half-life
- interactions
17-22 hours
Inhibits CYP1A2/2C9/3A4.
Increases levels of some benzodiazepines, carbamazepine, ciclosporin, phenytoin, some tricyclics, methadone, olanzapine, clozapine, propanolol, theophylline, warfarin
Paroxetine
- half-life
- notable side effects
- interactions
24 hours
antimuscarinic effects and sedation more common
Potent inhibitor of CYP2D6/3A4.
Increases levels of some antipsychotics and tricyclics
Never use with MAOIs. Avoid St John’s Wort
Sertraline
- half-life
- interactions
26 hours
Inhibits CYP2D6.
Increases levels of some antipsychotics and tricyclics
Avoid St John’s Wort
irreversible MAOIs
- how long to wait after stopping before starting drugs with potential interactions
2 weeks
MAOI - combinations
The combination of MAOIs and TCAs, appears safe if both treatments are initiated in low doses simultaneously and are gradually increased together.
The combination of MAOIs and SSRIs (or clomipramine) is generally contraindicated, because it can cause potentially fatal reactions such as serotonin syndrome.
Lithium (pharmacokinetics)
- absorption
- distribution
- metabolism
- elimination
rapidly absorbed following oral administration
does not bind to plasma proteins
it is not metabolised so does not have an active metabolite
it is almost exclusively excreted by the kidneys unchanged
========================
Blood samples for lithium should be taken 12 hours post dose (for people prescribed a single daily dose).
Lithium - monitoring
Lithium blood level should ‘normally’ be checked every 3 months
Thyroid and renal function should be checked every 6 months
Adverse drug reactions
- type A
- type B
Type A (pharmacological) can be predicted from the pharmacology of the drug involved. They are dose dependent and so are reversible on withdrawal of the drug.
Type B reactions (idiosyncratic) cannot be predicted from the known pharmacology of the drug. Type B reactions include allergic reactions.
=======================
Type A accounts for 80% of all ADRs
Antidopaminergic side effects (8)
Galactorrhoea, gynecomastia,
menstrual disturbance,
lowered sperm count,
reduced libido,
Parkinsonism,
dystonia,
akathisia,
tardive dyskinesia
Anticholinergic (central M1) side effects (2)
Memory impairment,
confusion
Anticholinergic (peripheral M1) side effects (7)
Dry mouth,
blurred vision,
glaucoma,
tachycardia,
urinary retention,
constipation,
ataxia
Histaminergic H1 side effects (2)
Weight gain,
sedation
Adrenergic alpha 1 antagonism side effects (4)
Orthostatic hypotension,
sedation,
sexual dysfunction,
priapism
Antipsychotics recommended in hepatic impairment (3)
Haloperidol
Amisulpride
Sulpiride
Antidepressants recommended in hepatic impairment (3)
Imipramine
Paroxetine
Citalopram
Mood stabilisers recommended in hepatic impairment (1)
Lithium
Sedatives recommended in hepatic impairment (4)
Lorazepam
Oxazepam
Temazepam
Zopliclone 3.75mg (with care)
Receptors implicated in weight gain (2)
Histamine H1 antagonism
Serotonin 5-HT2C antagonism
CNS side effects like anxiety and agitation in the initial few weeks of treatment with SSRIs are proposed to be due to —
(receptors, location)
Over stimulation of 5HT2 receptors in the limbic system
Clozapine-related hypersalivation
- suggested mechanisms (3)
muscarinic M4 agonism
adrenergic alpha 2 antagonism
inhibition of the swallowing reflex
Which SSRI is present in high concentrations in breast milk?
Fluoxetine
Tetrabenazine
- use
Licensed in UK for treatment of moderate to severe tardive dyskinesia
Terazosin
- mechanism
- use
alpha 1 adrenoceptor antagonist
effective in reducing excessive sweating caused by antidepressant treatment, especially venlafaxine and SSRIs
Psychostimulants
(Dexamfetamine, Methylphenidate)
- common side effects (3)
appetite suppression
sleep disturbance
abdominal pain
Psychostimulants
(Dexamfetamine, Methylphenidate)
- uncommon side effects (6)
weight loss
restricted growth
headache
worsening of tics
behavioural rebound
significantly raised blood pressure
QTc prolongation
- cardiac risk factors (6)
Long QT syndrome
Bradycardia
Ischaemic heart disease
Myocarditis
Myocardial infarction
Left ventricular hypertrophy
QTc prolongation
- metabolic risk factors (3)
Hypokalaemia
Hypomagnesaemia
Hypocalcaemia
QTc prolongation
- risk factors (other) - 5
Extreme physical exertion
Stress or shock
Anorexia nervosa
Extremes of age (old or young)
Female gender
Non-psychotropic drugs causing QTc prolongation
- antibiotics (2)
- antiarrthythmics (2)
- antimalarials (2)
- Others (3)
Antibiotics
- Ampicillin
- Erythromycin
Antiarrthythmics
- Amiodarone
- Sotalol
Antimalarials
- Chloroquine
- Quinine
Others
- Methadone
- Tamoxifen
- Amantadine
QTc interval (men)
- normal
- borderline
- prolonged
normal <440
borderline 440-450
prolonged >450
QTc interval (women)
- normal
- borderline
- prolonged
normal <440
borderline 440-460
prolonged >460
QTc interval
<440ms (men)
<470ms (women)
(Recommended action)
No action required unless T-wave morphology
QTc interval:
>440ms (men)
>470ms (women)
(recommended action)
Consider reducing dose
or switching to drug of lower QTc effect,
repeat ECG and refer to cardiology
QTc interval:
>500ms (men and women)
(recommended action)
Stop causative drug,
switch to drug of lower effect
refer to cardiology
Antipsychotics with high effect on QTc interval (2)
Haloperidol
Pimozide
Antipsychotics with moderate effect on QTc interval (4)
Quetiapine
Chlorpromazine
Zotepine
Ziprasidone
Antipsychotics with low effect on QTc interval (4)
Amisulpride
Clozapine
Olanzapine
Risperidone
Antipsychotics with no effect on QTc interval (2)
Aripiprazole
Paliperidone
Adverse drug reactions
- Type A
- Type B
Type A (pharmacological) reactions can be predicted from the pharmacology of the drug involved. They are dose dependent and so are reversible on withdrawal of the drug.
Type B (idiosyncratic) reactions cannot be predicted from the known pharmacology of the drug. Type B reactions include allergic reactions.
====================================
Type A account for up to 80% of all ARDs.
Affinity
(definition)
how avidly the drug binds to the receptor
Potency
(definition)
the concentration or dose of a drug required to produce 50% of the drug’s maximal effect.
Potency depends on both the affinity of a drug for its receptor, and the efficiency with which drug-receptor interaction is coupled to response
Efficacy
(aka, definition)
also referred to as ‘intrinsic activity’
the ability of the drug to elicit a response when it binds to the receptor
EPSEs (4)
Parkinsonism - characterized by the triad of tremor, rigidity (lead pipe or cogwheel), and bradykinesia
Akathisia - a subjective sense of restlessness, along with such objective evidence of restlessness as pacing or rocking
Dystonias - prolonged and unintentional muscular contractions of voluntary or involuntary muscles
Tardive dyskinesia - involuntary, repetitive body movements. This may include grimacing, sticking out the tongue, or smacking the lips
‘PAD-T’
EPSEs - Dystonia
- prevalence
- more common in (3)
- time taken to develop
- treatments (4)
10%
More common in:
- young males
- neuroleptic-naive
- high potency drugs (e.g. haloperidol)
develops within minutes or hours of starting antipsychotics
Treatments:
- anticholinergic drugs
- switch antipsychotic
- botulinum toxin
- rTMS
EPSEs - Dystonia
- examples (5)
Torticollis - cervical muscles spasms, resulting in a twisted posturing of the neck.
Trismus - contraction of the jaw musculature and can result in lockjaw.
Opisthotonus - arched posturing of the head, trunk, and extremities.
Laryngeal dystonia - difficulty in breathing
Oculogyric crises - involuntary contraction of one or more of the extraocular muscles, which may result in a fixed gaze with diplopia
EPSEs - Parkinsonism
- prevalence
- more common in (2)
- time taken to develop
- treatments (2)
20%
more common in
- elderly females
- those with pre-existing neuro damage (e.g. stroke)
Days to weeks after antipsychotic started or dose increased
Treatments
- reduce dose/switch
- anticholinergic drugs
EPSEs - Akathisia
- prevalence
- time taken to develop
- treatments (8)
25%
Hours to weeks
Treatments:
- reduce dose/switch
- propranolol
- clonazepam
- mirtazepine
- trazodone
- mianserin
- cyproheptadine
- diphenhydramine
EPSEs - Tardive dyskinesia
- prevalence
- more common in (3)
- time taken to develop
- treatments (3)
5% of patients per year of antipsychotic exposure
More common in
- elderly women
- those with affective illness
- those who have had EPSE early on in treatment
develops over months to years
Treatments
- stop anticholinergic
- reduce dose/switch to an atypical (clozapine/quetiapine)
- tetrabenazine
Antidepressants - alternative routes of administration
- liquid (1)
- patch (1)
liquid - Fluoxetine
patch - Selegeline
Antidepressants available as IV preparations (4)
Citalopram
Mirtazepine
Amitriptyline
Clomipramine
SIADH
- risk factors (9)
Hyponatraemia caused by SIADH is associated with both antidepressants and antipsychotics
Being elderly
Being female
Being a smoker
Having medical co-morbidity
Polypharmacy
Low body weight
Low baseline sodium concentration
Reduced renal function
Warm weather
Absorption
- where does it occur?
- Absorption by oral administration occurs primarily in the small bowel
- Absorption of many slow or sustained release drugs occurs in the large bowel.
- There is poor absorption in the acidic stomach but conversely good absorption in the alkaline jejunum, ileum, colon and rectum.
Serotonin syndrome
- cause
- onset
- clinical presentation
excess serotonergic activity in the CNS
most frequent cause of severe reaction is the co-administration of an MAOI with an SSRI
typically acute and rapidly progressive, following shortly after one or two doses of the offending medication.
clinical triad:
- neuromuscular abnormalities
- clonus
- hyperreflexia
- muscular rigidity
- altered mental state
- autonomic dysfunction
- hyperthermia
Neuroleptic malignant syndrome (NMS)
- cause
- onset
- presentation
almost exclusively caused by antipsychotics (but is also associated with antidepressants and lithium).
Rapid and large dose increases often trigger it, along with rapid dose reductions, and abrupt withdrawal of anticholinergics.
typically develops within 2 weeks of initial treatment but may occur at any time the drug is being taken.
Presentation
- hyperthermia
- muscle rigidity -> rhabdomyolysis, elevated CPK
- altered consciousness
Serotonin syndrome vs Neuroleptic malignant syndrome
- commonalities
- differences
Common features include alteration in consciousness, sweating, autonomic instability, hyperthermia, and elevated CPK levels.
Serotonin syndrome typically has an acute onset (within 24 hours of drug administration), whereas that of NMS is more insidious (typically taking up to 2 weeks to appear).
Nocturnal enuresis in children
- licensed antidepressants (3)
Amitriptyline
Imipramine
Nortriptyline
Phobic and obsessional states
- licensed antidepressants (1)
Clomipramine
Adjunctive treatment of cataplexy associated with narcolepsy
- licensed antidepressants (1)
Clomipramine
[Cataplexy - ‘C’ for ‘Clomipramine’]
Panic disorder and agoraphobia
- licensed antidepressants (5)
Citalopram
Escitalopram
Sertraline
Paroxetine
Venlafaxine
Social anxiety / phobia
- licensed antidepressants (5)
Escitalopram
Paroxetine
Sertraline
Moclobemide
Venlafaxine
Generalised anxiety disorder
- licensed antidepressants (4)
Escitalopram
Paroxetine
Duloxetine
Venlafaxine
OCD
- licensed antidepressants (5)
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Bulimia nervosa
- licensed antidepressants (1)
Fluoxetine
PTSD
- licensed antidepressants (2)
Paroxetine
Sertraline
Modafinil
- class
- properties
- uses
psychostimulant
enhances wakefulness, attention, and vigilance. It is similar to amphetamines apart from that it tends to lack the euphoric effects, does not seem to be associated with dependence or tolerance, and does not tend to precipitate psychosis.
licensed for:
- narcolepsy
- obstructive sleep apnea
- chronic shift work
- also suggested as an adjunctive treatment for depression (in the Maudsley).
More recently it has also been used as a ‘smart drug’ in the hope that it will boost normal cognitive functioning.
Schizophrenia (Duration of treatment)
Inform the service user that there is a high risk of relapse if they stop medication in the next 1-2 years.
(NICE guidelines)
Cannabis (heavy use)
- Length of time detectable in urine
14-28 days
Cannabis (single use)
- Length of time detectable in urine
3 days
Phencyclidine
- Length of time detectable in urine
8 days
Methadone
- Length of time detectable in urine
3 days
Morphine
- Length of time detectable in urine
3 days
Benzodiazepine
- Length of time detectable in urine
3 days
Heroin
- Length of time detectable in urine
3 days
Cocaine
- Length of time detectable in urine
1-3 days
Amphetamine
- Length of time detectable in urine
1-3 days
LSD
Length of time detectable in urine
1-3 days
Codeine
Length of time detectable in urine
2 days
Alcohol
Length of time detectable in urine
12 hours
What proportion of people prescribed Clozapine experience silarrhoea?
31% of patients using clozapine develop hypersalivation (silarrhoea)
Suboxone
- constituents
Suboxone is a combination of four parts buprenorphine to one part naloxone.
The latter is added to prevent addicts from injecting the tablets, as this was common when addicts were given pure buprenorphine tablets. Because it contains naloxone it is likely to produce intense withdrawal symptoms if injected, this does not occur when the tablet is swallowed as naloxone is not absorbed by the gut.
Subutex
- active ingredient
buprenorphine
Time to steady state:
Amisulpride
Clozapine
Quetiapine
Risperidone (oral)
Tricyclics
Valproate
2-3 days
Time to steady state:
Lithium
4-5 days
Time to steady state:
Aripiprazole
14-16 days
Time to steady state:
Carbamazapine
14 days
Time to steady state:
Olanzapine
7 days
Time to steady state:
Risperidone (depot)
6-8 weeks
Time to steady state
Paliperidone (depot)
2 months
Clozapine - neutropenia
- risk factors (3)
Race - Afro-Caribbean 77% increase in risk
Age - risk decreases as age increases
Low baseline white cell count
Clozapine - agranulocytosis
- definition
- risk factors (2)
absolute neutrophil count (ANC) of less than 0.5 * 10^9/L
Ethnicity - Asians are 2.4 times more likely than Caucasians to develop agranulocytosis on clozapine
Age - risk increases with age
Tardive dyskinesia
- risk factors (7)
Advancing age
Female
Ethnicity - higher rates in African Americans
Affective disorder
1st gen > 2nd antipsychotics
Mental retardation
Substance abuse
Drugs unsuitable for compliance aids e.g. dosette box (8)
Sodium valproate
Zopiclone
Venlafaxine
Topiramate
Methylphenidate
Mirtazapine
Olanzapine
Amisulpride
Aripiprazole
CYP2D6 is inactive in —% of white people, and —% of Asians
(i.e. they are poor metabolisers)
CYP2D6 is inactive in 6-10% of white people, and 2% of Asians.
