Anti-depressants Flashcards
What is important to remember about Lithium
Strictly, it is not an anti-depressant
It is a mood stabilising drug.
Summarise ECT
Used in cases of ‘black depression’- where the patient is not responding to talking therapies or drugs
Current across temporal lobe
Give a shot of suxamethonium short-acting NMJ blocker- to prevent any damage to the limbs from convulsions.
Describe the different classification of psychoses
Split into: Schizophrenia (thought disorders) Affective disorders (mood-related)- which consist of mania (less common) and depression.
Describe the emotional (psychological) symptoms of depression
Misery, apathy, pessimism
Low self-esteem
Loss of motivation
Anhedonia (inability to enjoy life)
Describe the biological (somatic) symptoms of depression
Slowing of thought & action (psychomotor retardation)
Loss of libido
Loss of appetite, sleep disturbance
What are the two different types of depression
Unipolar depression/ depressive disorder
Bipolar depression/ Manic Depression
Describe unipolar depression / depressive disorder
Mood swings in same direction
Relatively late onset
Reactive depression (75%) - stressful life events (disproportionate response)
- non-familial
Endogenous depression (25%) - unrelated to external stresses
- familial pattern
What is important to remember about the drug treatment for unipolar depression
Same for both reactive and endogenous depression.
Describe bipolar depression
Oscillating depression/mania
Less common; Early adult onset
Strong hereditary tendency
Drug treatment (Lithium- oral lithium carbonate- effects I.C secondary messenger symtpoms (reduces cAMP and IP3)
Symptoms of mania- opposite to that of depression (increased exuberance, aggression etc).
What is the key difference between bipolar depression and unipolar depression
Bipolar depression- symptoms in common with schizophrenia
Unipolar depression- symptoms associated with fear and aggression.
Define what is meant by ‘psychoses’
Severe mental disorders, with or without, organic damage, characterised by derangement of personality and loss of contact with reality, and causing deterioration of normal social functioning.
Describe the monamine theory of depression
§ Monoamine theory of depression – depression is a functional deficit of central MA transmission; Mania is a functional excess of MA transmission.
o Related to NA and 5-HT (serotonin) deficits/excesses.
Summarise the pharmacological evidence that supports the monamine theory of depression
TCAs- block NA and 5-HT reuptake- Increase MOOD
MA oxidase inhibitors – Increase stores of NA and 5-HT – increase MOOD
Reserpine (MA deplete) - inhibits NA and 5-HT storage - decreases mood
a-methyltyrosine and methyldopa- inhibit NA synthesis- decreasing mood (and calming of manic patients)
ECT- increases CNS response to NA and 5-HT- increases mood.
Describe the pharmacological evidence that disagrees with the monoamine theory of depression.
Amphetamine- releases NA and blocks re-uptake- no effect on mood (but causes euphoria in normal subjects).
Cocaine- inhibits NA reuptake- no effect on mood (but causes euphoria in normal subjects)
Tryptophan -increases 5-HT synthesis- mood may increase in some subjects but not all
Alpha and beta adrenoreceptor antagonists - block NA action- mood slightly reduced, but no effect on manic patients
Methysegide- 5-HT antagonist- no effect
L-dopa - increases NA synthesis - no effect
Iprindole- no effect on monamine metabolism- increases mood.
Describe the inconsistency of the biochemical evidence of the monamine theory
Although a reduction of NA metabolites are seen in patients with clinical depression, there is no correlation i.e not necessarily an even greater reduction in NA metabolites for a patient with severe depression as opposed to mild depression.
There is a delayed onset of the clinical effects of drugs, when the reduction in monamines would take place acutely. This may be due to adaptive changes of the neurones of depressed patients (i.e down regulation of a2, beta and 5-HT receptors) which are only targeted by anti-depressants after a couple of weeks.
However the general conclusions remain firm- and many of the anti-depressants target monamine metabolism to have their effect
Describe some other theories for depression
HPA axis (↑ CRH levels)?- Hippocampal neurodegeneration? - anti-depressant drugs have been shown to reverse this.
The plasma cortisol concentration is usually high in depressed patients. Other hormones in plasma are also affected, for example, growth hormone concentration is reduced and prolactin is increased. While these changes are consistent with deficiencies in monoamine transmission, they are not specific to depressive syndromes.
But CRF1 receptor antagonists have not been effective.
Why may cocaine not be effective in treating depression
Adaptive changes of neurones in depressed patients- may not express cocaine receptors.
Describe Reserpine
Originally licenced as an anti-hypertensive- no longer used due to its association with depression.
Monamine depletor- that is it inhibits the synaptic proteins that package and store NA in vesicles- depleting its storage- less released.
Give an example of a TCA
amitriptyline
Summarise the chemical structures of TCAs
All have a tri-cyclic structure
Fall into two types:
Dibenzazepines
Dibenzcycloheptenes (amitriptyline).
Describe the mechanism of action of TCAs
Neural monamine reuptake inhibitors- effect NA and 5-HT roughly equally- but different TCAs have variable selectivity- inhibiting reuptake will acutely facilitate the transmission of monamines
Also acts on other receptors:
. § a2 – block pre-synaptic inhibition of NA release and 5-HT release). - this would contribute to anti-depressant actions
§ mAChR.
§ H2 (histamine) receptors.
§ 5-HT receptors
Explain the delayed effects of TCAs
Delayed down-regulation of β-adrenoceptors & 5-HT2 receptors, also A2 receptors.
Dysregulated, down-regulated to normal levels which allows them to function normally.
Describe the pharmacokinetics of TCAs
o Oral administration (rapid oral absorption)
o Highly PPB – 90-95%.
o Hepatic metabolism (liver microsomal enzymes) – to ACTIVE metabolites (with weak TCA like activity) à excreted in the urine (glucuronide conjugates).
o Plasma T1/2 = 10-20 hours – dose once daily.
Describe the unwanted effects of TCAs at a therapeutic dose
Atropine - like effects (amitriptyline)- muscarinic receptor block (Sedation Anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention, etc)
Postural hypotension (vasomotor centre)- blocks a2 receptors
Sedation (H1 antagonism) - may be useful if taken late at night- depression can hinder sleep quality and pattern.
Describe the acute toxic effects of TCAs due to overdose
CNS: excitement, delirium, seizures coma,
respiratory depression
CVS: cardiac dysrhythmias ventricular
fibrillation/sudden death (anti-muscarinic effects and increased NA effects on heart).
Care - attempted suicide
Describe the drug interactions of TCAs
PPB: TCA effects (aspirin, phenytoin) - aspirin-50% PPB- compete for same binding site- increasing conc of TCAs- toxic effects
Hepatic microsomal enzymes: TCA effects (neuroleptics; oral contraceptives)- compete for metabolism- TCA broken down more slowly- increasing toxicity
Potentiation of CNS depressants (alcohol)- additive effect with alcohol
Antihypertensive drugs (monitor closely) - sometimes BP goes up, sometimes it goes down- just monitor it initially.
Give an example of a monamine oxidase inhibitor
Phenelzine
Describe the mechanism of action of MAOIs
§ Mechanism of action:
o MAO enzymes:
§ MAO-A breaks down NA & 5-HT – key MoA!
§ MAO-B: breaks down DA – e.g. Selegiline.
o Most are non-selective MAOIs.
o Irreversible inhibition leads to a long duration of action.
We are trying to develop drugs which selectively target the MAO-A, MAO-B inhibitors are important in Parkinson’s.
What is the main function of MAO
1.
Within nerve terminals, MAO regulates the free intraneuronal concentration of noradrenaline or 5-HT. It is not involved in the inactivation of released transmitter.
2.
MAO in the gut wall is important in the inactivation of endogenous and ingested amines such as tyramine that would otherwise produce unwanted effects.
Describe the effects of MAOIs
§ Rapid effects – increase cytoplasmic (not enhanced release but more leakage) NA, 5-HT.
§ Delayed effects – delayed clinical response due to down-regulation of b-adrenoceptors and 5-HT2 receptors – again, fits with delayed clinical effect.
o Inhibits other enzymes – leads to side effects.
Slow the breakdown of monamines.
MAOI crosses BBB, reaches noradrenaline and serotinergic pre-synaptic terminals- inhibit MAO- increasing cytoplasmic conc of NA and 5-HT- thus increasing its release (mostly leakage) and transmission.
Summarise the structure of TCAs
Single ring- with reactive side chain:
Hydrazines (Phenelzine)
Cyclopropylamines
Proprygylamines
Clorygyline is MOA-A specific and used to treat depression.
Describe the pharmacokinetics of MOAIs
Rapid oral absorption
Short plasma t1/2 (few hrs) but longer d.o.a.- they irreversibly bind (covalently with reactive side chain) to (and thus inactivate) monamine oxidase.
Metabolised in liver; excreted in urine
Describe the unwanted effects of MOAIs
Atropine - like effects (< TCAs)
Postural hypotension (common)- effects on vasomotor centre. One possible explanation for this effect – the opposite of what might have been expected – is that amines such as dopamine or octopamine accumulate within peripheral sympathetic nerve terminals and displace noradrenaline from the storage vesicles, thus reducing noradrenaline release associated with sympathetic activity.
Sedation (Seizures in o.d.)
Weight gain (possibly excessive)- due to increase appetite.
Hepatotoxicity (hydrazines; rare) - due to reactive side chains- don’t prescribe to patients with liver problems
Describe the drug interactions associated with MAOIs
‘Cheese reaction’: Tyramine-containing foods + MAOI hypertensive crisis (throbbing headache, b.p., intracranial haemorrhage)
MAOIs + TCAs hypertensive episodes (avoid)
MAOIs + pethidine hyperpyrexia, restlessness, coma & hypotension- pethidine is a opioid analgesic- maybe that they are metabolised by the same enzyme- forcing pethidine into methabolism by a different enzyme- which results in the production of toxic metabolites.
Describe the ‘cheese’ reaction
Tyramine found in foods such as marmite, game, red wine and cheese.
Tyramine is normally digested by MOA-B in the gut wall
However if we inhibit MOA-B, we get a build up of tyramine
Tyramine, like amphetamine, is a sympathomimetic. That is, it increases the release of NA from post-ganglionic pre-synaptic nerve terminals (binds to the vesicles containing NA- facilitating their release) -hence we get hypertension seen.
Describe the reversible MAOI inhibitors
Moclobemide: reversible MAO-A inhibitor (RIMA). ↓ Drug interactions ↓ doa.
The irreversible MAOIs have been shown to be more efficacious.
Give an example of an SSRI
Fluoxetine
Describe the structure of Fluoxetine
2 cyclical rings with an aliphatic chain.
Describe the pros and cons of SSRIS
Less troublesome side-effects; safer in o.d.- no cheese reaction
But less effective vs severe depression - so still need other drugs
Describe the pharmacokinetics of SSRIs
p.o. administration
Plasma t1/2 (18-24 hrs)
Delayed onset of action (2-4 weeks)
Fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration) - otherwise the two will potentiate and you will see toxic effects.
Describe the unwanted effects of SSRIs
Fewer than TCAs/MAOIs
Nausea, diarrhoea, insomnia & loss of libido
Interact with MAOIs (avoid co-administration
What is important to remember about SSRIs
Fluoxetine (‘Prozac’): currently most prescribed antidepressant drug
No effective in all patients- so need to use other anti-depressants.
Describe Venlafaxine
Venlafaxine: Dose-dependent Reuptake inhibitor
5HT > NA»_space; DA (SNRI)- serotonin,noradrenaline reuptake inhibitor
2nd Line treatment for severe depression
Describe Mirtazapine
Mirtazapine: α2 Receptor antagonist
↑ NA & 5HT release- inhibit negative feedback.
Other R interactions (sedative)- Histamine receptors
Useful in SSRI-intolerant patients
What can lithium be used to treat
Inorganic ion taken orally as lithium carbonate- used to control mania as well as depression- mainly used prophylactically in bipolar depression.
Long plasma half-life and narrow therapeutic window, hence side effects common and monitoring of plasma concentration is essential.
Unwanted effects: nausea, thirst and polyuria, hypothyroidism, tremor, weakness, mental confusion, teratogenesis.
Acute overdose causes confusion, convulsions and cardiac dysrrythmias.
Action enhanced by diuiretic drugs.
Alternative mood-stabilisers include carbamazepine, valproate.
