49 - Drug Dependence and Antidepressants Flashcards
Monoamine theory of depression
Alteration of monoaminergic transmission (noradrenaline, serotonin, dopamine) influences mood.
Depletion leads to depression.
Acute elevation in synapse can elevate mood
1st generation of antidepressants
1
2
Tricyclics
Monoamine oxidase inhibitors
2nd generation of antidepressants
1
2
SSRIs
Selective serotonin/noradrenaline uptake inhibitors (SSNRIs)
3rd generation (atypical) antidepressants
1
2
Novel monoaminergic drugs
Non-monoaminergic drugs
Treatments for bipolar disorder
1
2
Lithium Some antiepileptics (EG carbamazepine)
Tricyclic structure
Structurally similar to phenothiazines used to
treat schizophrenia
Tricyclic mechanism of action
1
2
3
– Inhibit neuronal uptake of noradrenaline and serotonin
– Antagonise α-adrenoceptors, muscarinic receptors,
histamine receptors and serotonin receptors
– Quinidine-like membrane stabilising action at very high
concentrations
Clinical effect of tricyclics
1
2
3
– Takes weeks to develop despite pharmacological effects
manifest in hours
– Adaptive changes in neuronal function likely underlie
antidepressant activity
• Changes in receptor sensitivity / density
– Increased levels of transmitter can down-regulate receptor number / function
≈ β-adrenoceptors, α-adrenoceptors and 5-HT2 receptors
Therapeutic window of tricyclics
Narrow
Side-effects of tricyclics 1 2 3 4
Sedation, anti-muscarinic (dry mouth, blurred vision, constipation), postural hypotension, weight gain
Effects of overdose on tricyclics 1 2 3 4 5
Confusion, mania, cardiac dysrhythmias, seizures, impotence
Effects of MAOIs on neurotransmitter levels
Increase levels of NA, 5-HT and DA
MAOI cheese reaction
Monoamine oxidase present in gut walls, breaks down dietary amines (particularly tyramine) present in food (in cheese, wine, chocolate, bananas).
Tyramine can release NA from storage vesicles in peripheral nerve terminals (indirectly acting sympathomimetic, like amphetamine)
Inhibiting MAO allows tyramine to be absorbed, stops breakdown by nerves, enhancing sympathomimetic effect
Irreversible MAOIs
1
2
Iproniazid, Tranylcypromine
Reversible MAOI
Moclobemide
Moclobemide
• MAO A selective • Now the most commonly used – less likely to cause ”cheese reaction” » some tyramine breakdown in gut due to competition – Interaction with other drugs • Side effects – Dizziness, nausea, insomnia
Examples of SSRIs
1
2
3
Fluoxetine, Paroxetine, Sertraline
Example of SSNRI
Venlafaxine
Features of SSRIs
– Selective for 5-HT uptake
– Few adrenergic, histaminergic and cholinergic actions
– High therapeutic index
When can SSRIs become toxic?
When combined with other drugs.
– MAOI and TCA - “serotonin syndrome”
» Hyperthermia, muscle rigidity, cardiovascular collapse
Side effects of SSRIs
Nausea, insomnia, agitation, weight change, loss of libido
Example of a noradrenaline reuptake inhibitor
Reboxetine
Examples of non-monaminergic antidepressants 1 2 3 4 5
– Corticotrophin receptors • Hypothalamic-pituitary-axis in depression – Glutamate receptors – Opioid receptors – Neurokinin (Substance P) receptors – Growth factors • The role of supporting cells?
How does lithium carbonate work?
Interacts with inositol phosphate secondary messengers (regulates Ca2+ in nerves).
Therapeutic index of lithium
Very low
Side effects of lithium carbonate 1 2 3 4 5
Nausea, tremor, impaired renal, thyroid & neurological
function
