What are the pharmacological treatment options for GAD?
SSRI or SNRI e.g. velafaxine, duloxetine
What are the pharmacological treatment options for acute stress reaction (ASR)?
BDZ; avoid >2wks due to increased development of PTSD
?Propanolol
What is the MoA of BDZs?
Potentiate GABAergic neurotransmission (inhibitory effect)
How would you describe a BDZ & what is the rationale?
Indicated in the ST relief (2-4wks only) of anxiety that is severe, disabling or causing unacceptable distress or in association with insomnia or ST-psychosomatic, organic or psychotic illness.
How should you prescribe SSRIs?
Starting doses from the lower end of the recommended range should be used to avoid initial agitation. The initial dose should be continued for 4-6 weeks.
If the patient does not show a robust response, the SSRI should be increased in one- to two-week incr
What are the adverse effects of SSRIs?
Sexual dysfunction, GI upset, insomnia and withdrawal on discontinuation. They can cause drug interactions, weight gain, and agitation and/or hyperactivation.
SE can interfere with QoL and medication adherence to these SE need to be recognised early.
What advice should be given upon starting an SSRI?
They don't start working immediately and onset of action is delayed. The duration of therapy is usually >6mths and those who experience a good response for GAD should continue the medication for at least 12mths.
Warn about common side effects.
What are the effects of an overdose of SRIs?
Less toxic than TCA & MAOIs
SNRIs have been associated with greater risk of significant toxicity and mortality in OD than SSRIs.
Serotonin syndrome
Most SSRI ingestion's develop minimal toxicity.
What is serotonin syndrome?
Autonomic instability, mental status change and increased neuromuscular tone. It is typically caused by combining 2 or more serotenergic agents. Traditionally caused by MAOIs, but SRIs now much more common.
How would you manage an antidepressant overdose?
ABCDE
Seizures usually respond to lorazepam or diazepam
Serotonin syndrome: supportive care, discontinuation of SRI and, if severe, a serotonin antagonist e.g. cyproheptadine.
QTc interval prolongation: serial ECGs to be certain the interval is not length
What is the prevalence of alcohol misuse?
23% of adults consume ethanol, in a hazardous way
3.6% of adults in England are alcohol dependent
5.2% (1 in 20) in HULL
How much of a problem is alcohol to the NHS?
40% patients admitted have alcohol use problem
Hospital admissions doubled in last 8yrs
I million p.a.
88% increase in liver disease 1993-2010
A decision is made to sedate the patient. What are the pharmacological agents available for this purpose?
BDZ are used to treat the psychomotor agitation most patients experience during withdrawal. Diazepam, lorazepam and chlordiazepoxide are used most frequently for alcohol withdrawal.
In general LA BDZs with active metabolites (e.g. diazepam) are preferred.
How would you manage a BDZ overdose?
General supportive care using ABCDE
How would you manage Wernicke's encephalopathy?
Use of IV thiamine (vit. B1)- usually in the form of Pabrinex
What are the features of BDZ withdrawal?
Tremors, anxiety, perceptual disturbances, dysphoria, psychosis and seizures.
The onset of withdrawal varies depending on the half-life. Symptoms may be delayed up to 3wks, but may appear as early as 24-48h after cessation of BDZs with short half-lives. T
How would you manage BDZ withdrawal?
BDZ withdrawal is treated with a BDZ that has a prolonged clinical affect, e.g. diazepam, given IV and titrated to effect.
The goal is to eliminate withdrawal symptoms without causing excessive sedation or respiratory depression.
Once symptoms are control
SSRI
citalopram, fluoxetine, paroxetine, sertraline
SNRI
duloxetine, venlafaxine
Selective noradrenaline reuptake inhibitors
reboxetine
Presynaptic alpha-2 blockers
mirtazapine
TCA
amitryptiline, imipramine, lofepramine
MAOI
phenelzine, tranylcypromine
Reversible inhibitors of monoamine oxidase A (RIMAs)
moclobemide
Melatonin receptor agonist and serotonin receptor antagonist
agomelatine
What is the first line treatment for moderate-severe depression?
SSRIs or SNRIs (better tolerated and safer in overdose than TCAs)
How should patients be monitored to assess the response to SSRIs?
Patient should be reviewed every 1-2 weeks at the start of antidepressant treatment. Treatment should be continued for at least 4 weeks (6 weeks in the elderly) before considering whether to switch antidepressant due to lack of efficacy. In cases of parti
What is the first line treatment for mild-moderate depression?
CBT
What are the main pharmacological choices for a person with mania?
The goal is remission; resolution of mood symptoms or improvement to the point where 1 or 2 symptoms of mild intensity persist.
The mainstay of treatments are lithium, anticonvulsants and antipsychotics used in combination (e.g. lithium + antipsychotic) o
Why use lithium?
Reduction in suicide risk due to mood stabilization
What are the contraindications for lithium use?
Lithium is CI in patient with:
Renal impairment
Sodium depletion
Dehydration
Significant CVD
What are the side effects of lithium?
Nausea and diarrhoea
CNS: tremor, giddiness, ataxia, dysarthria, mild cognitive impairment
Hypothyroidism -> interference with T4 synthesis (monitor thyroid every 6 months)
Reduced responsiveness to ADH, which can produce reversible nephrogenic diabetes i
How long should lithium be used for?
LT treatment of bipolar should continue for at least 2yrs from the last manic episode and up to 5yrs if the patient has risk factors for relapse.
An antidepressant may be required for coexisting depression, but should be avoided in those with rapid cyclin
How often should a patient be monitored to assess the response to lithium?
Samples should be taken 12 hours after the dose to achieve a serum-lithium concentration of 0.4-1 mmol/litre (lower end of the range for maintenance therapy and elderly patients).
A target serum-lithium concentration of 0.8-1 mmol/litre is recommended for
What are the non-pharmacological treatments for patients with bipolar?
ECT
What are the names of commonly used anticonvulsants?
Sodium valproate
Carbamazepine
Lamotrigine
What would be your pharmacological choices for managing a patient with psychosis?
Patients with psychosis at risk of harm to themselves or others may need to be hospitalized. A rapidly acting first-generation antipsychotic and/or a rapidly acting BDZ are suggested to sedate agitated, potentially violent patients with psychosis.
Antipsy
What factors should be taken into account when prescribing an antipsychotic?
Metabolic (including weight gain and DM)
EPSE (inclusing akathisia, dyskinesia and dystonia)
CV (including prolonged QT interval)
Hormonal (including increasing plasma PRL)
Other (including unpleasant subjective experiences)
Aripiprazole
D2 partial agonist; atypical antipsychotic
Atypical antipsychotics
D2 antagonist & 5HT2A antagonists
Risperidone
Olanzapine
Clozapine
Quetiapine
Aripiprazole
Side effects of atypical antipsychotics
weight gain (especially olanzapine and clozapine)
impaired glucose tolerance (T2DM)
dyslipidaemia
When should clozapine be prescribed?
Only when 2 other antipsychotics have failed
What are the side effects of clozapine?
Agranulocytosis and seizures
Hypersalivation
constipation
hypo/hypertension
weight gain
fever
nocturnal enuresis
Typical antipsychotics
Haloperidol (a butyrophenone)
Chlorpromazine (a phenothiazine)
Flupentixol (a thioxanthine)
Sulpiride (a substituted benzamide)
What are the side effects of typical antipsychotics?
EPSE (Parkinsonism, akathisia, dyskinesia)
hypotension
sexual dysfunction
breast swelling and tenderness
How often should a patient on antipsychotics be monitored to assess the response to treatment?
FBC, U&E, LFT is required at the start of therapy and the annually thereafter
Blood lipids and weight should be measured at baseline, at 3mths, and then yearly
Fasting blood glucose should be measured at baseline, at 4-6mths, and then yearly
Before initia
What non-pharmacological treatments are available for patients with schizophrenia?
Family therapy- patients and families should be educated about their illness, risks associated with psychosis (e.g. increased risk) and side effects of medication.
Caregivers should be advised to reduce environmental stimulation, not argue with delusional
What is apparent Volume of distribution (Vd)?
Vd is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma
What is the equation for Vd?
Amount of drug in the body/plasma concentration of the drug
Describe the compartment model of pharmacokinetics
The compartmental modeling of pharmacokinetics consists in describing the fate of a drug in the body, depicted as an entity divided into compartments. The drug leaves the site of administration (absorption) to enter a central compartment, from which it is
What is a two compartment model?
Drug is administered to and distributed from the central compartment. Usually, all the compartments are linked to the central compartment (mammillary model). This compartment encompasses the initial dilution volume, which is generally composed of plasma a
The final Vd of lithium (0.7-0.9 L/kg) approaches that of total body water.
This is a relatively small Vd and suggests predominant distribution in body water
After how long would you expect a drug to reach its steady state?
~5x the half-life of the drug
Lithium comes as standard and modified release formulations what might this mean for bioavailability and why?
Wide variations in bioavailability and thus care when moving from one formulation to another
How might you achieve a steady state concentration quicker?
Loading dose
In some situations, the steady state plasma concentration must be reached more rapidly. A higher dose can then be administered on treatment initiation, to compensate for accumulation
The volume Vd of digoxin is about 7.3L/kg. What does this suggests about its distribution?
That it is widely distributed outside the water compartment and is also protein bound or distributed by some other tissue type such as fat - in this case tissue binding in certain organs.
Digoxin has a large volume of distribution, due to its high affinit
Digoxin is predominantly excreted by the kidney so increasing the half life.
A reduced CrCl also alters the volume of distribution so that in patients with renal impairment the Vd is reduced.
What effects are these likely to have on its pharmacokinetics?
Delay in reaching steady state and an increase in the serum concentration for a given dose.
Most of the digoxin is eliminated unchanged by the kidneys. Renal clearance of digoxin exceeds the glomerular filtration rate of its free fraction, thus indicating
Digoxin is poorly absorbed from the gastro-intestinal tract, and dissolution time affects the overall bioavailability.
The two oral formulations of digoxin have different bioavailabilities:
Tablets F = 0.63
Liquid F = 0.75
Digoxin's oral bioavailability remains usually high (70%-80%), even though considerable metabolism of digoxin within the gastrointestinal tract may occur in some patients by hydrolysis in the acidic environment of the stomach or by digestion by intestinal
What is bioavailability?
Fraction of a dose of drug that is absorbed from its site of administration and reaches, in an unchanged form, the systemic circulation
How does codeine work as an analgesic?
Codeine is a prodrug and is metabolised to morphine- the active opiate, by CYP2D6
What are the implications of being a CYP2D6 ultra-rapid metaboliser?
CYP2D6 is highly polymorphic, with over 90 known allelic variants.
Subjects who are ultra-rapid metabolizers based upon CYP2D6 genotype have higher than expected morphine levels (an initial "overdose"), with more side effects and a shorter than expected d
Can you think of any other scenarios in which the pharmacogenetics of codeine and CYP2D6 may have an effect?
Breast feeding in a mother who is an ultra-rapid metabolism for CYP2D6
How has the NHS in the UK dealt with the issues of codeine and CYP2D6 genetic polymorphisms?
MHRA guidance
Drug Safety Update December 2012
Codeine isn't the only opiate potentially affected by this genetic polymorphism- can you list at least two others?
Hydrocodone, oxycodone, tramadol
Why might a person develop pancytopenia at a low comparative dose of azothioprine?
The enzyme thiopurine methyltransferase (TPMT) metabolises thiopurine drugs (azathioprine, mercaptopurine, tioguanine); the risk of myelosuppression is increased in patients with reduced activity of the enzyme, particularly for the few individuals in whom
What is the difference between pharmacogenetics and pharmacogenomics?
The term pharmacogenomics is often used interchangeably with pharmacogenetics. Although both terms relate to drug response based on genetic influences, pharmacogenetics focuses on single drug-gene interactions, while pharmacogenomics encompasses a more ge
Donepezil
AChE inhibitor
Rivastigmine
AChE inhibitor
Galantamine
AChE inhibitor
Memantine
non-competitive NMDA antagonist
Methylphenidate
NA-DA reuptake inhibitor
Atomoxetine
Noradrenaline reuptake inhibitor
Dexamfetamine
CNS stimulant; NA release and DA release at higher doses