Antidepressants Flashcards
What is psychosis?
can be SPLIT into SCHIZOPHRENIA and the AFFECTIVE DISORDERS (mania and depression)
What are the emotional and biological symptoms of depression?
EMOTIONAL SYMTPOMS:
- misery, apathy
- pessimism
- low self-esteem
- loss of motivation
- anhedonia
BIOLOGICAL SYMPTOMS:
- slowing of thought and action
- loss of libido, loss of appetite
- sleep disturbance
What are the features of unipolar depression (/depressive disorder)?
- Mood swings are in same direction
- Relatively late onset (adulthood)
- Unipolar depression can be split into reactive depression (75%) and endogenous depression (25%)
Reactive depression: depression in response to stressful life events, that is non-familial
Endogenous depression: depression that is unrelated to external stresses, with a familial pattern
What are the features of bipolar depression (/manic depression)?
- Oscillating depression and mania (hyper-excitability with symptoms opposite to depression)
- This is less common than unipolar depression, and tends to have an early adult onset
- There is a strong hereditary tendency
What are the treatments for unipolar and bipolar depression?
uni polar: drug treatment (same for reactive and endogenous depression)
bipolar : lithium
What is the monoamine theory of depression?
Noradrenaline & 5-HT are the two monoamines involved in this hypothesis
The changes in NA and 5-HT that we see are rapid – there is a rapid onset
However, the clinical effect can take weeks, before we see the optimal action of the drug
There is a dissociation in between the neurochemical change and the antidepressant effect
- In response to many antidepressant drugs, we see a down-regulation: α2, β, 5HT receptors - often correlates in a more timely fashion with the onset of clinical drug effectiveness
It may be these changes therefore, that are responsible for the clinical drug effects
What are TCAs?
tri-cyclic anti-depressant
e.g amitriptyline
- two main chemical groups: the dibenzazepines and dibenzcycloheptenes
- TCAs are three-ringed structures
- All are neuronal monoamine re-uptake inhibitors
- prevent reuptake of NA and 5-HT much more so than dopamine -> potentiate the action of these monoamines for much longer
*delayed down-regulation of b-adrenoceptors and 5HT2 receptors
What are the pharmacokinetic factors of TCAs?
- Rapid oral absorption – all TCAs are given orally and absorbed orally
- Highly plasma protein bound (90 – 95% of TCAs are PPB)
- Hepatic metabolism - this generates active metabolites (weaker) -> then undergo renal excretion (as glucuronide conjugates)
- Plasma t1/2 (10-20 hours) – relatively long half life, so can be given once a day (long duration of action)
What are the unwanted effects of TCAs at therapeutic dosage?
- Atropine-like effects with amitriptyline: dry mouth, blurred vision, constipation, urinary retention
- Amitriptyline seems to have more muscarinic antagonist activity than some of the other TCAs
- Postural hypotension (mediated through the vasomotor centre) – this is a CENTRAL EFFECT
- Sedation (TCAs cause H1 antagonism) – patients feel drowsy during the day - Many depressed patients have trouble sleeping, so this can be taken advantage of
What are the unwanted side effects of TCAs at acute toxicity?
- CNS: excitement, delirium, seizures -> coma and respiratory depression
- CVS: cardiac dysrhythmias -> ventricular fibrillation and sudden death
- With TCAs that are muscarinic antagonists, we also affect vagal input to the heart
*commonly utilised in attempted suicid
What are some interactions that TCAs undergo?
- PPB: we see increased TCA effects with co-administration with aspirin and phenytoin (anti-convulsant)
- Warfarin can displace TCAs from their binding sites, which moves plasma levels of TCA into a toxic range
- Hepatic microsomal enzymes metabolise TCAs, so TCA effects increase if co-administered with drugs that are metabolised by the same enzyme system (e.g. neuroleptics and oral contraceptives)
- Potentiation of CNS depressants with TCAs (alcohol in particular)
- There is an interaction with antihypertensive drugs (monitor BP closely) – difficult to predict
What are MOAIs?
monoamine oxidase inhibitors e.g phenelzine
- The mechanism of action involves monoamine oxidase-A (NA & 5-HT) and monoamine oxidase-B (DA)
- MAO-A has a preference for NA and 5-HT, whereas MAO-B has a preference for dopamine
- The inhibition is irreversible, which leads to a long duration of action (patients need to take these daily)
We see rapid neurochemical changes: rapid increase in cytoplasmic NA & 5-HT
-This is because we are blocking the breakdown of NA and 5-HT with MAOIs – enhanced activity in brain
- delayed effects with these drugs, in terms of the clinical response
- down-regulation of β-adrenoceptors & 5-HT2 receptors - corresponds with the onset of the clinical effectiveness of the drug
- MAOIs are not ENTIRELY SELECTIVE – they result in the inhibition of other enzymes
Describe the chemical structure of MAOI?
- All of the MAOIs have got a single ring structure
- There is a range of different chemical classes.
Phenelzine is a hydrazine. It has a single ring with a carbon side chain. On the end is a hydrazine functional group. This group is VERY REACTIVE. It is this functional group that forms the covalent bonds with the MAO enzyme (irreversible inhibition).
What are the pharmacokinetic features of MAOIs?
- Rapid oral absorption (MAOIs are taken orally, either once a day or every other day)
- Short plasma t1/2 (few hours) but longer duration of action due to irreversible inhibition
- Metabolised in the liver and excreted in the urine
What are the unwanted effects of MAOIs?
- Atropine-like effects (much less than with TCAs)
- Postural hypotension (common) – probably a vasomotor mediated effect
- Sedation with long-term usage (and seizures in over dose)
- Weight gain (possibly excessive) – associated with increase appetite with MAOIs
- Hepatotoxicity (due to hydrazines) – this is rare (e.g. 1 in 10,000 patients)
