L37 Antidepressant drugs Flashcards
What are the types of mood disorder?
- Depression, Mania (monopolar)
- Manic depression (bipolar= oscillate between high and low)
- side effects of drug treatment is often depression, eg rimonabant (for obesity and inteferon alpha for hep C)
What are the symptoms of depression?
1) Emotional
- mood and thought disorder
2) Biological
- motivational impairments
3) Cognitive
- difficulty decision making and poor concentration
4) Psychotic
* drug treatments aim to improve mood and motivational impairments
What are the symptoms of mania and bipolar disorder?
- sleep less, excessive enthusiasm and confidence
- increased libido
- behaviours inappropriate to circumstances
*drug treatments aim to control excessive oscillations between high and low mood
What causes depression?
1) chemical imbalance
- functional deficit in 5HT/ NA
2) Neurodegeneration
- Neural apoptosis and neuorgenesis
3) Immune response
4) Genes
5) Environment (Stress)
What are the treatments for depression?
1) Pharmacological
- enhance monoamine levels in CNS
by: monoamine re-uptake inhibitors; monoamine oxidase inhibitor; receptor antagonists
2) cognitive behavioural therapy
3) neurological interventions (only in severe depressive patients)
How to increase monoamine function in the CNS?
1) post-synaptic receptor agonist, eg Buspirone
2) pre-synaptic receptor antagonist, eg mirtazapine
3) monoamine oxidase enzyme inhibitors, eg moclobemide (reversible) ; phenylzine (irreversible)
4) re-uptake inhibitors, eg fluoxetine, venlafaxine
What are the classes of antidepressants?
1) Typical: tricyclic antidepressant and specific re-uptake inhibitors
2) Atypical: mixed uptake blockers and receptor blocking drugs
3) Mood stabilisers: lithium, anti-epileptic drugs, atypical antipsychotics
What are typical antidepressants?
=TCA and specific re-uptake inhibitors
- Monoamine oxidase inhibitors, eg Iproniazid, moclobemide
- Tricyclic antidepressants, eg imipramine, amitriptyline, clomipramine, despiramine
- Selective Serotonin reuptake inhibitors, eg fluozetine, paroxtine, clitalopram
- Selective NA reuptake inhibitors, eg Reboxetine
What are the atypical antidepressants?
= mixed uptake blockers and receptor blocking drugs
- Serotonin-NA Reuptake Inhibitors eg venlafaxine
- 5HT2 antagonist + SSRI eg Trazodone
- 5HT2 antagonist + SNRI eg nefazedone
- alpha 2 adrenoceptor and 5HT antagonist eg mianserin, mirtazapine
- Melatonin agonist and 5HT2 antagonist eg agomelatine
** all show delayed onset and similar efficacy despite different modes of action
What are mood stabilisers?
- lithium, anti-epileptic drugs, atypical antipsychotics
What is the food interaction with MAO inhibiters?
- individuals who take irreversible MAO inhibitors cannot metabolise ingested amines eg tyramine. =high level in blood
- tyramine displaces NA from its terminals leading to a sympathomimetic effect =acute hypertension
- drugs like amphetamine will also cause this reaction in people taking MAO inhibitors
- this interaction is observed with irreversible inhibitors such as phenylzine; not seen with reversible MAO inhibitors eg moclobemide
What are the drug interactions of MAO inhibitors with opioids?
- Pethidine (opioid) will cause hyperpyrexia (elevation in body temp) with restlessness, coma and hypotension with MAO inhibitors
What are the MAO inhibitors used in anti-depression?
- Iproniazid
- it inhibits breakdown of monoamines (MAO is found in all tissues including GI tract)
- MAO-A prefers 5HT; MAO-B prefers DA and NA
- side effects: cheese reaction (tyramine)
What are the examples of MAO inhibitors?
- iproniazid, phenelzine, tranylcypromine, moclobemide
What is the mechanism of tricyclic antidepressants?
- block reuptake of monoamines ( mainly NA and 5HT)
- some block alpha2 adrenoceptor
- Side effects= cardiotoxicity (tachycardia, arrhythmia, hypothension) and there is a low therapeutic index
What are the examples of tricyclic antidepressants?
- amitriptyline (NA/ 5HT), despiramine (NA) and clomipramine (5HT)
- amitriptyline is now mainly used in pain management
What are the examples of tricyclic antidepressants?
- amitriptyline (NA/5HT)
- desipramine (NA)
- clomipramine (5HT)
- amitriptyline is now mainly for pain managment
What are the therapeutic effects that tricyclic antidepressants exert?
- NA & 5HT reuptake inhibition
- alpha 2 adrenoceptor antagonists
What are the side effects that tricyclic antidepressants exert?
- Muscarinic antagonist
- alpha 1 adrenoceptor antagonist
- histamine antagonist
- cadiotoxic
Fluoxetine
- serotonin specific reuptake inhibitor = first line! - moderate efficacy - largest group of antidepressant prescribed - side effects: serotonin specific
Venlafaxine
- serotonin and NA specific reuptake inhibitor (=mixed reuptake inhibitor)
- moderate efficacy
- at low dose= act as serotonin specific inhibitor; high dose= mixed serotonin and NA reuptake inhibitor
= second line treatment for non-responders for fluoxetine
Reboxetine
- NA specific reuptake inhibitor
- limited efficacy
- muscarinic and NA side effects
What are the advantages of using selective re-uptake inhibitors over the tricyclic antidepressants?
- block the reuptake of NA/5HT or NA+5HT so reduce drug interactions, cholinergic effects, no food interaction AND LOW toxicity in overdose
- but have 5-HT related side effects:
nausea, anorexia, insomnia, sexual dysfunction - NA related side effects:
insomnia, constipation, sweating, sympathetic effects eg tachycardia, anxiety, aggression
What are the advantages using atypical antidepressants?
- improve efficacy, onset of action and reduce side effects
Venlafaxine
- mixed NA and 5HT reuptake inhibitor
Trazedone
- selective sertonin reuptake inhibitor and 5HT2 antagonist
Nefazodone
- selective NA reuptake inhibitor and 5HT2 antagonist
* 5HT2 antagonist= reduce 5HT2 side effects
Mirtazapine
- NA and 5HT receptor antagonists
- NA receptor antagonist= can increase release of NA because it binds to the autoreceptor so no NA can binds to it. This means it blocks the negative feedback mechanism
- increase NA can stimulate more 5HT release
Agomelatine
- melatonin agonist and 5HT antagonist
Why is there a delayed onset of clinical efficacy
-because it takes time for receptor adaptations, ie up/down regulation
What is discontinuation syndrome?
- it is where patients decided not to carry on with medication, usually present with moderate or severe symptoms
- common with patients who take paroxetine; less common with fluoxetine
What is the general guideline for treatment of depression?
- 1st line: selective serotonin reuptake inhibitor/ mirtazapine
- 2nd line: MAO inhibitors or mixed drugs
*Very severe/drug resistant: electroconvulsive shock therapy and then deep brain stimulation
How does lithium
- Lithium
: replace Na+ reducing neuronal excitability (attenuates glutamate signalling)
: alters signalling via effects on 2nd messengers
: effects on gene expression - effective in controlling mania but potential toxicity
- exact mechanism is unknown
Valproic acid
- weak inhibitor of GABA transaminase (prevent GABA breakdown) so increases inhibitory neurotransmitters on Na channels
Carbamazepine
- derived from TCA, induces use-dependent block of Na channels
What are the antipsychotics drugs that are used for mood stabilising?
- haloperidol when acute
- olanzapine in long term
What is the treatment of bipolar?
- acute= lithium/ carbamazepine; 2nd line= sodium valproate
- prophylaxis (preventative): lithium, olanzapine; 2nd line= carbamazepine
- antipsychotic drugs reduce manic symptoms in 1-2 days
What are the other applications for antidepressant drugs?
- selective serotonin reuptake inhibitors can also be used for:
OCD, social phobia, panic disorder, anxiety disorder, eating disorder
