Pharmaco: Antidepressants Flashcards
What is the monoamine theory?
- Deficits in monoamine neurotransmitters (noradrenaline and 5-HT) cause depression
- Evidence: reserpine (inhibitor of NA and 5-HT storage), cause depressed mood
What are the limitations of monoamine theory?
- hypothesis originally formulated for NA, later emphasis shifted to 5-HT
- inconsistent and equivocal results
- inadequate to explain all pharmacological actions - possibly complex interactions with other neurotransmitter systems involved as well
[Monoamine Oxidase Inhibitors - MAOi]
- Where is MAO found?
- What is MAO function?
Found:
- MAO enzyme is found in nearly all tissues, including nerve terminals, intestine, and liver
- Found intracellularly, mostly on the mitochondrial surface (meaning it will be within the presynaptic membrane)
Function:
- Breaks down / oxidises monoamines (such as noradrenaline, serotonin, dopamine etc.) (*note that these are all excitatory neurotransmitters)
[Monoamine Oxidase Inhibitors - MAOi]
Difference between function of MAO-A and MAO-B
MAO-A:
- (IC9) Mainly breaks down 5-HT, but also breaks down NA and dopamine
- (IC17) Peripheral, mainly noradrenaline and 5HT; more relevant target for depression
MAO-B:
- (IC9) Breaks down NA and dopamine, 5-HT to a lesser extent
- (IC17) Central, mainly dopamine; more relevant target for PD
Rate of MAO regeneration: 14-28 days
[Monoamine Oxidase Inhibitors - MAOi]
Function of MAOi (e.g., Phenelzine)
Phenelzine is a non-selective MAO-A and MAO-B irreversible inhibitor => prevents serotonin and other monoamine transmitters from being degraded in the presynaptic membrane
[Monoamine Oxidase Inhibitors - MAOi]
Side effects of MAOi
- Postural hypotension
- Due to sympathetic block produced by accumulation of dopamine in cervical (neck) ganglia, where it acts as an inhibitory transmitter
- Restlessness and insomnia
- Due to CNS stimulation
[Monoamine Oxidase Inhibitors - MAOi]
Special precautions of MAOis
Do not combine with other serotonergic drugs (serotonin syndrome)
- Mental status change (agitation, hallucinations)
- Neuromuscular changes (myoclonus, tremor, rigid or twitching muscles)
- Autonomic instability (hyperthermia, tachycardia, sweating labile BP)
- Others: hyperreflexia, fever, GI (N/V/D)
[Monoamine Oxidase Inhibitors - MAOi]
What is the cheese reaction?
- E.g., of foods
- What is the mechanism?
- What are the adverse effects?
Drug-food interaction (with cheese, concentrated yeast products such as marmite, soy sauce, cured meats such as sausages etc.)
Mechanism:
- Tyramine found in cheese is usually broken down by MAO in the intestines and liver
- MAOi leads to accumulation of tyramine
- Tyramine is taken up into adrenergic terminals and competes with NA for the vesicular compartment, causing release of NA into synapses
- Increase release of NA causes sympathomimetic effects
Adverse effects:
- Hypertensive crisis
- => Throbbing headache
- => Intracranial hemorrhage
Note:
- this is less likely to occur with reversible MAO-A selective inhibitors such as Moclobemide rather than irreversible non-selective MAO inhibitors such as Phenelzine
[Tricyclic Antidepressants - TCAs]
MOA
Mechanism:
Non-selective for SERT/NET (serotonin transporter / NE transporter) => reuptake 5-HT/NE from synapse into presynaptic terminals, prevent overactivation of postsynaptic neuron
- E.g., Imipramine, Amitriptyline, Nortriptyline
Selective for NET (norepinephrine transporter)
- E.g., Desipramine
Note after reuptake, 5-HT can either be degraded by MAO or recycled for use
[Tricyclic Antidepressants - TCAs]
Nortriptyline VS Imipramine or Amitriptyline
Nortriptyline is a second generation TCA; Imipramine and Amitriptyline are first generation TCAs
Nortriptyline, Desipramine: secondary amine
Amitriptyline, Imipramine: tertiary amine
- Nortriptyline has milder SEs compared to amitriptyline and imipramine, hence improve compliance
[Tricyclic Antidepressants - TCAs]
Side effects of TCAs
- Sedation, weight gain
- H1 histamine receptor antagonism (however, tolerance to sedation can develop in 1-2 weeks)
- Postural hypotension
- a-adrenoceptor sympathetic block
- Dry mouth, blurred vision, constipation/urinary retention
- Muscarinic receptor antagonism
Also:
- GI effects (N/V/D) (5-HT3 agonism)
- Sexual dysfunction (5-HT2 agonism)
- seizures due to proconvulsant properties of TCAs
- conductance abnormalities - arrhythmias, ECG changes
- fatal on overdose
[Selective Serotonin Reuptake Inhibitors - SSRIs]
Selectivity of SSRIs
- 50-1000 fold selectivity for 5-HT over NA
- Fluoxetine approx. 50 fold selectivity for 5-HT
- Citalopram approx. 1000 fold selectivity for 5-HT
[Selective Serotonin Reuptake Inhibitors - SSRIs]
Advantages of SSRIs over TCAs
- Greater 5-HT reuptake selectivity than TCAs
- Fewer adverse effects than TCAs
- Low affinity for a-adrenoceptors => lack cardiovascular effects, safer in overdose
- Low affinity for muscarinic cholinergic receptors => minimal anticholinergic SEs
- Lack of effect at histamine receptors => reduced sedation
=> Safer in overdose, less side effects, better compliance
Paroxetine has the most anticholinergic, sedating, weight gain, and withdrawal effect => avoid in elderly
Citalopram still has some histamine receptor antagonism leading to sedation
[Selective Serotonin Reuptake Inhibitors - SSRIs]
Adverse effects of SSRIs
- GI: Nausea, Vomiting, Diarrhea (5-HT3 agonism)
- Sexual dysfunction (5-HT2 agonism)
- QTc prolongation (esp Escitalopram/Citalopram if high dose in elderly)
- Initial transient jitteriness (due to sudden incr in neurotransmitters)
- Insomnia (fluoxetine)
Note that nausea and insomnia may also be due to antidepressant discontinuation syndrome - maybe plasma levels of drug drop b/w doses
Antidepressant discontinuation syndrome worse with Paroxetine due to its short half-life
[Serotonin and Noradrenaline Reuptake Inhibitors - SNRIs]
Examples:
- Venlafaxine
- Desvenlafaxine
- Duloxetine
