Pharmacology Unit 4 lecture 3.PDF

Pharmacology Unit 4 – Lecture 3 Serotonergic Neurotransmitter & Serotonergic Drugs 1) 5-HT (aka serotonin) – Location in the brain Most important site is: Cells bodies in raphe nuclei: Dorsal raphe nuclei project to the cortex, hippocampus, amygdala, striatum, and hypothalamus Ventral raphe nuclei p...

Pharmacology Unit 4 – Lecture 3 Serotonergic Neurotransmitter & Serotonergic Drugs 1) 5-HT (aka serotonin) – Location in the brain Most important site is: Cells bodies in raphe nuclei: Dorsal raphe nuclei project to the cortex, hippocampus, amygdala, striatum, and hypothalamus Ventral raphe nuclei project to the cerebellum, medulla and spinal cord Synthesis, storage, release, termination, metabolism 1. Tryptophan is taken into the neuron via carrier mediated transport 2. Tryptophan is converted to 5-HT in 2 steps catalysed by tryptophan hydroxylase and aromatic amino acid (DOPA) decarboxylase 3. 5-HT is actively packaged into vesicles by an amine transporter 4. Release is via classical Ca2+-mediated exocytosis 5. Termination is via uptake by a serotonin transporter 6. Degradation is via monoamine oxidase and aldehyde dehydrogenase (SSRIs used to treat range of conditions – OCD, anxiety…) Receptor targets - 5-HT exerts its effects via numerous receptor types and subtypes 1A on terminals of dorsal raphe nuclei – serotoin binds to the presynaptic neuron – inhibits serotonin release 3 is the only one located on a ligand-gated ion channel Physiological response – At the cellular level Physiological response – At the behavioural level 5-HT is required for - Sleep, wakefulness and mood - Feeding and appetite o 5-HT is required to control appetite (overall effect being to reduce appetite) Pathophysiological role Depression - Deficiency in monoamine (noradrenaline & 5-HT) transmission is thought to underlie depression - Selective serotonin reuptake inhibitors (SSRIs) are used to treat depression Anxiety - Buspirone is 5-HT1A receptor partial agonist used as an anxiolytic (anxiety will be covered in another lecture) - Remember … the 5-HT1A receptor is an inhibitory autoreceptor o Activating it will REDUCE 5-HT release (at least initially) o But over time it is thought that this may lead to desensitization of 5-HT1A receptors and ultimately INCREASED synaptic 5-HT Noradrenergic Neurotransmission & Noradrenergic Drugs Noradrenaline – location in the brain Most important site is: - Cells bodies in locus ceruleus which project to the hippocampus, cortex and cerebellum Synthesis, storage, release, termination, metabolism 1. Tyrosine is taken into the neuron via carrier mediated transport 2. Tyrosine is converted to noradrenaline in 3 steps catalysed by tyrosine hydroxylase, DOPA decarboxylase and dopamine β-hydroxylase 3. Dopamine is actively packaged into vesicles by an amine transporter and conversion to NA then occurs 4. Release is via classical Ca2+-mediated exocytosis 5. Termination is via uptake by a noradrenaline transporter 6. Degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o methyltransferase Receptor Targets - α-adrenoceptors o α1 via Gq (PLC & ↑ IP3/DAG) o α2 via Gi (AC and ↓ cAMP) - β-adrenoceptors o β1 via Gs (AC and ↑ cAMP) o β2 via Gs (AC and ↑ cAMP) o β3 via Gs (AC and ↑ cAMP) Physiological response - At the cellular level (same types/subtypes in brain as in periphery) α-adrenoceptors - Widespread in the brain - Located both presynaptically and postsynaptically - Presynaptic α2 adrenoceptors function as inhibitory receptors and autoreceptors reducing noradrenaline release. β-adrenoceptors - Widespread in the brain - Located both presynaptically and postsynaptically. - Inhibitory and excitatory effects on presynaptic and postsynaptic neurons. Physiological response – at the behavioural level Noradrenaline - Mood - CNS arousal Pathophysiological role Depression - Deficiency in monoamine (noradrenaline & 5-HT) transmission is thought to underlie depression Depression – general features - Depression is the most common affective (or mood) disorder - It includes both emotional and biological symptoms: - Emotional symptoms: o Misery, apathy, pessimism o Low self esteem, inadequacy, ugliness, guilt o Indecisiveness, loss of motivation o Anhedonia, loss of reward/pleasure - Biological symptoms: o Slowness of thought and action o Loss of libido o Sleep disturbances o Loss of appetite Depression – unipolar disorders - In unipolar depression, the mood swings are always in the same direction - In bipolar depression, depression alternates with mania - Mania is essentially the opposite of depression o Excessive exuberance, enthusiasm, self-confidence o Impulsive actions o Irritability, impatience, aggression o Grandiose delusions Depression - Neurochemical theories - Monoamine theory (most established and underpins current drug therapy) o States that depression is caused by a deficit of the monoamines noradrenaline and/or 5-HT in certain sites in the brain. - Neuroendocrine theory o States that depression is caused by overactivity in the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis. (chronic stress leads to depression) - Trophic factor theory o States that depression is caused by reduced levels/functional activity of brainderived neurotrophic factor (BDNF). - Glutamate theory o States that depression is caused by excessive glutamate activity at NMDA receptors. - Neurodegeneration theory o States that depression is caused by neurodegeneration and reduced neurogenesis in the hippocampus. Unifying the monoamine, neuroendocrine, trophic, glutamate and nneurodegeneration theories of depression (note these are just hypotheses, far from proven) Depression - types of antidepressant drugs 1) Monoamine Reuptake Inhibitors (prevent reuptake of serotonin and/or noradrenaline) o Selective serotonin reuptake inhibitors (SSRIs) o Tricyclic antidepressants (TCAs) o Serotonin/noradrenaline reuptake inhibitors (SNRIs) o Noradrenaline reuptake inhibitors o Other reuptake inhibitors (e.g. St John’s Wort (monoamine reuptake inhibitor)/hyperforin) 2) Monoamine Receptor antagonists 3) Monoamine Oxidase Inhibitors (MOA breaks down both serotonin and noradrenaline) Depression – mechanism of action of antidepressant drugs – ACUTE 1) Monoamine Reuptake Inhibitors - These block the reuptake of: o NA & 5-HT (TCAs and SNRIs) o 5-HT selectively (SSRIs) o NA selectively 2) Monoamine Receptor antagonists - These block the action of NA at α2 receptors and/or 5-HT at 5HT receptors 3) Monoamine Oxidase Inhibitors - These inhibit the metabolism of NA & 5-HT Depression – mechanism of action of antidepressant drugs – CHRONIC Given that the clinical effects of antidepressant drugs takes weeks to develop … their acute pharmacological effects cannot account for their antidepressant activity! - This has led investigators to look for longer-term adaptive changes that occur in the brain after chronic antidepressant treatment: o Some NA receptors are consistently downregulated (esp. β1 and α2) o The 5HT1A receptor (inhibits 5-TH release) may become desensitized over time leading to increased synaptic 5-HT levels o Possible changes in gene expression via transcription factors (e.g. CREB, Fos, NF-κB) leading to neurogenesis? - Ultimately, the mechanism of action underlying the delayed clinical effects of antidepressant drugs remains to be elucidated … Selective serotonin reuptake inhibitors The main SSRIs are: - Fluoxetine (Prozac®) - (also antagonist activity at 5-HT2C receptors) - Fluvoxamine - Paroxetine - Citalopram - Escitalopram - Sertraline - Vortioxetine - (also agonist/antagonist activity at several 5-HT receptors) Notes on SSRIs - Most commonly prescribed anti-depressants - Less side effects that TCAs - Less dangerous in overdose than TCAs - Do not cause “cheese reaction” - Also used to treat various anxiety disorders - Also used to treat premature ejaculation Selective serotonin reuptake inhibitors – side effects - At normal clinical doses, SSRIs can produce a number of side effects: o Nausea o Anorexia o Insomnia o Loss of libido, failure to orgasm - Not recommended for children and adolescents under 18 years o Potential risk of suicide ideation (some evidence that SSRIs can make it worse before better) - When given in combination with MAO inhibitors (increase serotonin) they can lead to ‘serotonin syndrome’: o Tremor o Hyperthermia o Cardiovascular collapse Tricyclic Antidepressants The main TCAs are: Imipramine - Desipramine - Clomipramine - Amitriptyline - Nortriptyline Notes on TCAs - Original “classical” anti-depressants - More side effects that SSRIs - More dangerous in overdose than SSRIs - Also used to treat neuropathic pain (pain caused by nerve damage – can persist even after damage “healed”) Tricyclic Antidepressants - Side effects Note: In addition to their effects on monoamine reuptake, TCAs also affect: 1) muscarinic acetylcholine receptors, 2) histamine receptors, and 3) 5-HT receptors. - At normal clinical doses, TCAs can produce a number of side effects: o Anticholinergic effects (due to muscarinic block) (dry mouth, constipation, blurred vision, urinary retention etc.) o Postural hypotension (due to α-adrenoceptor block) o Sedation (due to H1 block) (often causing daytime drowsiness and difficulty in concentrating) o Potentiation of the effects of alcohol (can lead to respiratory depression and even death) - In overdose, they can lead to: o Ventricular dysrhythmias; sudden cardiac death o Excitement, delirium and convulsions o Respiratory depression & coma Other Monoamine reuptake inhibitors 1) Other Reuptake Inhibitors - Serotonin/noradrenaline reuptake inhibitors (SNRIs) (Like TCA's but don't have same structure) o Venlafaxine o Desvenlafaxine o Duloxetine - Noradrenaline reuptake inhibitors o Bupropion o Reboxetine o Atomoxetine - Other reuptake inhibitors o St John’s Wort/hyperforin Notes on SNRIs - Also used to treat anxiety disorders, menopause symptoms, neuropathic pain, fibromyalgia, urinary incontinence Notes on NRIs - - Also used to treat nicotine dependence, attention deficit hyperactivity disorder (ADHD) Notes on St John’s Wort - Serious risk of drug-drug interactions due to effects on CypP450 enzymes Monoamine receptor antagonists The main monoamine receptor antagonists are: - Mirtazapine (antagonist at α2, 5HT2A, 5-HT2C, 5-HT3) - Trazodone (antagonist at 5-HT2A, 5HT2C) - Mianserin (antagonist at α1, α2, 5HT2A, histamine H1) Note: - The α2 adrenoceptor is on presynaptic terminals of 5-HT neurons where it reduces 5-HT release. - Therefore, antagonizing it will enhance 5-HT release. Monoamine Oxidase Inhibitors - The main non-selective MAO inhibitors are: o Phenelzine o Tranylcypromine o Isocarboxazid - The main MAO-A selective inhibitors are: o Moclobemide o Clorgyline Note: MAO exists in 2 isoforms – MAO-A and MAO-B - These metabolise the following transmitters: o MAO-A → 5-HT, NA, dopamine o MAO-B → NA, dopamine, phenylethylamine Monoamine Oxidase Inhibitors – interactions with other drugs - MAOIs interact with other drugs such as: o SSRIs 1. Can lead to ‘serotonin syndrome’ o Pethidine (an opiate analgesic) 1. Can lead to severe hyperpyrexia (high fever) with restlessness, coma and hypotension 2. Reason for this is unclear, but it is likely that an abnormal pethidine metabolite is produced due to the inhibition of the normal pethidine metabolic enzymes Monoamine oxidase Inhibitors - Interactions with food Tyramine - Indirectly-acting sympathomimetic amine - Diet-derived (e.g. fermented meats, ripe cheese, beers, Marmite®, Bovril® etc.) - Ordinarily metabolised by enzymes (monoamine oxidases) in gut so does not reach circulation - However … serious drug-food interaction risk will(“Cheese Reaction”) with such foods and MAO inhibitors as tyramine now enters blood stream - Effects of “Cheese reaction”: o Potentially fatal hypertensive crisis o Severe throbbing headaches o Intracranial haemorrhage (Sympatheric (NA via α or β) increases heart rate & contracts blood vessels)