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.
MAOIs Contraindications
Contraindications: impaired renal or hepatic function,
hypertension. Pregnant or lactating women.
MAOIs in the liver
deaminates tyramine; elevated tyramine levels release the higher-than-normal stores of noradrenaline at nerve endings, causing a dramatic increase in blood pressure (often known as the “cheese effect” as cheese is a major source). Tryptophan supplements or drugs that enhance serotonin, e.g. SSRIs, should be avoided or there is danger of “serotonin syndrome.” Care needs to be taken if swapping drug treatments.
Tricyclic antidepressants
Tricyclic antidepressants are most useful for treating major depressive episodes, though they can be prescribed for panic disorder and for obsessive-compulsive behaviour.
They work by non-selectively blocking the reuptake of noradrenaline and serotonin, leading to increase in the availability of these transmitters at their respective receptors.
Tricyclic antidepressants
Imipramine
Amitriptyline
Doxepin
Imipramine-Treatment of depression
Amitriptyline- Treatment of depression
Doxepin -Treatment of depression and anxiety
Tricyclic antidepressants: adverse effects
Weight gain, sexual dysfunction, inhibition of cytochrome P450.
Adrenergic effects. Contraindicated for patients with myocardial infarction, with coronary artery disease or any coronary instability.
Antihistaminergic effects. Sedation. Avoid other CNS depressants or anti-histamines, e.g. cimetidine
Anticholinergic effects. Dry mouth, blurred vision, dizziness,
headache and constipation.
Selective serotonin-reuptake inhibitors Fluoxetine Paroxetine Sertraline Citalopram
Fluoxetine - trade name - prozac - Treatment of depression and obsessive-compulsive disorder
Paroxetin - Treatment of depression and panic disorders
Sertraline -Treatment of depression and panic disorders
Citalopram- Treatment of depression
SSRIs: adverse effects
Sexual dysfunction.
Dependence and withdrawal.
MAOIs (serotonin syndrome)
Cimetidine; warfarin
Contraindications: Patients with a history of mania or anxiety
Miscellaneous next generation antidepressants
Bupropion
Venlafaxine
Bupropion is an aminoketone that inhibits the reuptake of serotonin, noradrealine and dopamine. Venlafaxine is a strong inhibitor of serotonin and noradrenaline reuptake, but a weak blocker of dopamine reuptake.
Third generation antidepressants under development include CRH receptor antagonists.
Mood stabilisers Lithium carbonate Lithium citrate Carbamazepine Valproate
Lithium carbonate - Prophylaxis and treatment of acute mania
Lithium citrate - Prophylaxis and treatment of acute mania
Carbamazepine - Mania, epilepsy.
Valproate - Mania, epilepsy
Patients with bipolar affective disorder need specific drugs for the stabilisation of acute mania.
Anticonvulsants can be used for treating both epilepsy and mania.
Mood stabilisers: adverse effects
Contraindicated for patients with renal dysfunction, leukaemia, dehydration or sodium depletion.
Sodium bicarbonate.
Other antipsychotic drugs, diuretics and non-steroidal
anti-inflammatory drugs.
Dizziness, headache, confusion, hair loss, oedema,
cardiac dysrhythmias and nephrotoxicity.
Toxicity and withdrawal.
(Anti-convulsants. Birth deformaties).
Anxiety disorders
Generalised anxiety disorder Panic disorder Phobias Post-traumatic stress disorder Obsessive-compulsive disorder
Sedative-hypnotics Thiopental Secobarbital Phenobarbital Zolpidem
Thiopental -Preparation for surgery
Secobarbital - Treatment of insomnia, anxiety and acute agitation
Phenobarbital- Treatment of insomnia, anxiety and seizures.
Zolpidem - Treatment of insomnia
Sedative-hypnotics: adverse effects
Avoid other CNS depressants.
Check for suicidal tendencies.
Drowsiness or hangover.
Dependence and tolerance. Possible seizure on
withdrawal.
Contraindications: Children under 18 years of age,
pregnant or nursing mothers.
Benzodiazepines Diazepam Alprazolam Temazepam Lorazepam
Diazepam- Treatment of anxiety and seizures
Alprazolam- Treatment of anxiety and panic disorders
Temazepam-Short-term treatment of insomnia
Lorazepam - Treatment of anxiety, status epilepticus, preoperative sedation, amnesia
Benzodiazepines adverse effects
Contraindications: Renal and hepatic dysfunction;
glaucoma; pregnancy and lactation.
Avoid other CNS depressants.
Accumulation of metabolites leads to over sedation and CNS depression and ataxia.
Anticholinergic effects (headache, dry mouth, blurred vision, dizziness, memory loss, hypotension and GI disturbances). “Date rape.”
Non-benzodiazepine anxiolytic
Buspirone
Buspirone- Short-term treatment of anxiety, depression.
azapirone drugs can be used for the short-term treatment of anxiety disorders. There is only really one that is marketed called buspirone.
It has a gradual onset to efficacy of approximately one to four weeks and is often used as a co-therapy when a patient is coming off BZDs or in treating depression that often accompanies anxiety.
It is thought to act as a partial agonist on postsynaptic 5-HT1A serotonin receptors, rather than on GABA receptors.
Non-benzodiazepine anxiolytics: adverse effects
Avoid other CNS depressants. Never with MAOIs. Anticholinergic effects (dizziness, headache, insomnia, nausea, dry mouth and blurred vision, mood changes and palpitations).
Patients with disorganised schizophrenia
Disorganised, thought disorder; flattened mood.
Difficult to understand - speech may be incomprehensible
Patients with paranoid schizophrenia
Experience hallucinations and delusions
Patients with catatonic schizophrenia
Psychmotor disturbances, e.g. catatonic stupor and waxy flexibility.
Typical antipsychotics / neuroleptics
Chlorpromazine
Fluphenazine
Chlorpromazine- Management of psychosis and schizophrenia; behavioural problems in children
Fluphenazine- Management of psychosis and schizophrenia
Haloperidol - Management of psychosis and severe behavioural problems
Loxapine - Management of mood disorders and schizophrenia
Typical antipsychotics/neuroleptics: adverse effects
Parkinsonism. Tardive dyskinesia.
Sedation and hypotension, impaired thermoregulation
and lactation.
Neuroleptic malignant syndrome.
CNS depressants, anticonvulsants or antihypertensives.
Antacids.
Contraindications: Cardiovascular disease, bone marrow
depression, renal, liver or thyroid dysfunction, or
Parkinson’s disease.
Atypical antipsychotics Clozapine Amisulpride Risperidone Olanzepine
Clozapine - Management of schizophrenia
Amisulpride - Management of schizophrenia
Risperidone- Management of schizophrenia
Olanzepine- Management of schizophrenia
Atypical antipsychotics: adverse effects
Risk of neuroleptic malignancy syndrome are low.
Avoid CNS depressants. Antihypertensives.
Headache, blurred vision, photosensitivity, insomnia,
nervousness, dizziness and GI distress.
Glaucoma, peptic ulcer disease or urinary retention.
Dysrhythmias or hepatic dysfunction.
Weight gain.
Depression has a triad of symptoms
low or depressed mood (dysphoria)
anhedonia
low energy or fatigue
Symptoms of mania
elation
talkativeness, creativity
fullness of energy and confidence
