Antidepressants and Anxiolytics Flashcards
The limbic system: brain regions involved in mood
The hypothalamus maintains homeostasis and motivational drives
The amygdala recognises and responds to emotions.
The hippocampusallows long-term storage of experiences and memory.
The nucleus accumbens is involved in reward and pleasure.
The cingulate cortex registers pleasant and painful stimuli. It is also involved in aggression.
The prefrontal cortex deals with decision making and the expression of mood.
Synaptic transmission
Neurotransmitters are stored in vesicles within the terminal of the presynaptic neurone.
With the arrival of a nerve impulse, the vesicles bind to the membrane and release their transmitters, which travel across the synaptic cleft. The transmitter binds to selective receptors on the postsynaptic neurone, but can also have an autoregulatory action through presynaptic receptors.
Transmission by monoamines is curtailed by uptake by specific transporters. The monoamines tend to be re-packaged in vesicles, or may be broken down
Serotonin inhibitors
Tricyclic antidepressants (also affect NA reuptake):
Desipramine
Imipramine
Selective serotonin-reuptake inhibitors:
Sertraline
Citalopram
Fluoxetine (Prozac)
SERT inhibitors/5-HT releasers:
Fenfluramine
Methylenedioxymethamphetamine (MDMA, “E”)
The synthesis of catecholamines
The rate limiting step in catecholamine synthesis is the hydration of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), by the enzyme tyrosine hydroxylase.
L-DOPA is then decarboxylated to dopamine the same enzyme that produces serotonin from 5-hydroxytryptophan, (often referred to as dopa decarboxylase).
In some neurones, dopamine is further processed by dopamine β-hydroxylase to make noradrenaline.
In other neurones and in the adrenal medulla it is further modified to produce adrenaline.
The degradation of dopamine
Transmission by dopamine, like the other monoamines, is terminated by reuptake via the dopamine transporter. Dopamine that is not broken down by enzymes is repackaged into vesicles for reuse.
If not, enzymatic breakdown is produced by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT).
Monoamine oxidase is not selective and will break down all the monoamine transmitters.
Dopamine Receptors
Dopamine receptors mediate all known pharmacological actions of dopamine
Classic seven transmembrane domain, G protein-coupled receptors
Fall into two major groups D1-like (increase cAMP) and D2-like (decrease cAMP)
The ascending noradrenergic system
Noradrenergic neurones exert effects on large areas of the brain to cause alertness and arousal, and to influence the reward system. Anatomically, the noradrenergic neurons of the ascending arousal system originate both in the locus coeruleus and the adjacent lateral tegmental field.
Adrenergic receptors
Adrenergic receptors bind both adrenaline and noradrenaline, but α receptors have a higher affinity for noradrenaline. α1-adrenergic receptors are linked to phospholipase C and α2-adrenergic receptors block adenylate cyclase. β receptors are linked positively to adenylate cyclase.
Summarise monoamine transmitter systems
Monoamine neurones are located in discrete nuclei
within the brainstem and midbrain
The neurones project widely throughout the forebrain
They affect broad functional states, such as arousal
and mood
Drugs that alter levels of monoamines are likely to
have profound effects on behaviour
mood disorders
Major (unipolar) depression Bipolar disorder (manic-depressive illness)
anhedonia
inability to feel pleasure in normally pleasurable activities
General adaptation syndrome: “fight or flight”
Stress causes the hypothalamus to produce corticotropin-releasing hormone (CRH).
CRH activates the sympathetic nervous system (SNS) and acts as a signal to the pituitary gland to produce adrenocorticotrophic hormone (ACTH), which in turn signals the adrenal gland to secrete cortisol.
These cause the physiological changes necessary for a heightened response to stress.
Cortisol also feeds back on glucocorticoid receptors in the hypothalamus and hippocampus.
CRH also acts as a signal to the pituitary gland to produce adrenocorticotrophic hormone (ACTH), which in turn signals the adrenal gland to secrete cortisol.
Sympathetic activation and cortisol release cause the physiological changes necessary for a heightened response to stress.
Normally a feedback mechanism inhibits further activation of the hypothalamo-pituitary-adrenal axis.
Depression involves over- and under-activity in the brain
Depression is characterised by over-activity in some areas of the brain, such as in the amygdala and hypothalamus, and under-activity in other areas, such as the hippocampus, nucleus accumbens and prefrontal cortex.
Monoamine oxidase inhibitors
Monoamine oxidase inhibitors (MAOIs) are non-selective blockers of the metabolism of all monoamines.
They are still used commonly for severe depression in patients who have failed to respond to other treatments, but are often thought of as a last line for pharmacological intervention.
Monoamine oxidase inhibitors
Phenelzine
Treatment of depression and bipolar disorder
Monoamine oxidase inhibitors
Tranylcypromine
Treatment of severe depression
MAOIs: adverse effects
Hypertensive crisis, especially due to interactions with
other drugs which produce increases in blood pressure.
Foods high in tyramine. “Cheese effect.”
Inhibition of cytochrome P450.
Tryptophan supplements or other psychoactive drugs should be
avoided or there is risk of “serotonin syndrome.”
Other adverse effects include weight gain, oedema, sexual dysfunction and sedation.
