Mental Health Lecture Notes PDF

Table of Contents Serotonin and Depression 2 Depression 11 Antidepressants 14 g - Aminobutyric Acid (GABA) 19 Benzodiazepines 26 Sleep and Insomnia 30 Evidence-Based Complementary Medicines for Depression 39 Perinatal Mental Health 43 Anxiety Disorders 47 Bipolar disorder 53 Glutamate 58 Epilepsy 64...

Table of Contents Serotonin and Depression 2 Depression 11 Antidepressants 14 g - Aminobutyric Acid (GABA) 19 Benzodiazepines 26 Sleep and Insomnia 30 Evidence-Based Complementary Medicines for Depression 39 Perinatal Mental Health 43 Anxiety Disorders 47 Bipolar disorder 53 Glutamate 58 Epilepsy 64 Lithium 77 Local and General Anaesthesia 83 Parkinson’s Disease 88 Dopaminergic Drugs Dopaminergic drugs for Parkinson’s disease: Acetylcholine in PD Dopaminergic drugs for schizophrenia Antipsychotics: Emesis and Antiemetics: 93 96 99 99 101 106 Dementia Pharmacology AChE inhibitors: NMDA receptor antagonists 108 109 111 Pharmacogenomics for neurology 114 Alzheimer’s and vascular dementia ALZHEIMER’S DISEASE (AD) Cholinesterase inhibitors: Memantine Monoclonal antibodies VASCULAR DEMENTIA (VAD) 117 117 119 120 121 121 Cognitive impairment and Dementia DELIRIUM: DEMENTIA 124 125 128 Psychotic Disorders – Schizophrenia 132 Caring for people with dementia MANAGEMENT CHECKLIST: MEDICATIONS USED IN DEMENTIA: BBEHAVIOURAL SYMPTOMS IN DEMENTIA RESTRICTIVE PRACTICES: ANTIPSYCHOTIC CONTINUATION AND WITHDRAWAL: 141 143 145 147 149 150 END OF LIFE CARE: 150 ADHD 150 Toxidromes Serotonergic toxidrome: Neuroleptic malignant syndrome: Anticholinergic toxidrome: 164 164 168 171 Multiple Sclerosis 173 Physical Health Management in Mental Illness 181 Clozapine and treatment of refractory schizophrenia 181 Smoking cessation 190 Clinical management of drug and alcohol 190 Serotonin and Depression Depression – mood disorder – 1 in 4 females and 1 in 6 males experience depression at some time in life Anxiety disorder – most common mood disorder, followed by depression Depression – leading cause of suicide Familial pattern: - 1.5 – 3x more common during 1st degree relatives - increased risk of alcohol dependence in 1st degree relatives Causes of depression: - spontaneous - traumatic emotional experience - Chronic stress - Symptoms of other diseases - Drugs - Genetics Types of depressive disorders: - Major depression à at least 2 weeks of depressed mood/anhedonia + additional symptoms - Persistent depressive disorder (Dysthymia) à 2 years depressed mood for more days than not + additional symptoms that don’t meet the criteria for major depression - Others: atypical depression, premenstrual dysphoria, disruptive mood dysregulation - Bipolar disorder (manic depression) and Cyclothymia also include features of depression. Clinical features: 1. Depressed mood and anhedonia + 3 other symptoms for 2 weeks: - Depressed mood: sad or empty, hopeless, tearful, irritable - Inability to experience pleasure (anhedonia) - Significant weight loss or gain - Decrease or increase in appetite - Insomnia or hypersomnia - Psychomotor agitation or retardation - Feelings of worthlessness, excessive or inappropriate guilt - Inability to concentrate - Recurrent thoughts of death or suicide 2. Symptoms affect social and occupational functioning 3. Symptoms not due to drugs or other medication condition Neural Circuitry of Mood à regulation of mood 1. Frontal cortex (FC) and hippocampus (HP) à cognition 2. Nucleus accumbens (NAc) and amygdala (Amy) à emotions 3. Hypothalamus (Hyp) and monoamine brainstem nuclei (DR, LC) à vegetative symptoms (appetite and energy) 4. Major neurotransmitters à Noradrenaline, serotonin, dopamine, GABA Hypothalamic – Pituitary – Adrenal Axis Monoamines: 1. Catecholamines: - Noradrenaline (NA) - Adrenaline - Dopamine (DA) 2. Indoleamines: - Serotonin (5-HT) à original recognised as autacoid mediator in blood Ø Serotonin – Location: Gastrointerstinal tract: (0% in enterochromaffin cells interspersed in mucosa, 10 à more selective for NAT - 0.1 – 10 à non-selective Monoamine Oxidase Inhibitors (MAOIs): - Irreversible, non-selective à phenelzine, tranylcypromine à bind covalently to MAO-A and MAO-B - Reversible à moclobemide à bind reversibly and selectively to MAO-A - Inhibit the enzymes that involved in the breakdown of NA, serotonin and DA à increase cytoplasmic pool of monoamines à increase leakage of monoamines into synapse/extracellular space Tetracyclic Antidepressants: - Block alpha-2 adrenoceptors and antagonise serotonin receptor 2 and 3 à increased NA and serotonin release à action on serotonin receptor 1 as receptor 2 and 3 are blocked Multimodal action Antidepressants: - Block presynaptic serotonin transporters à increased serotonin release - Vortioxetine à agonise serotonin 1A receptor - Vilazodone à partially agonise serotonin 1A receptors Long-term (few weeks) effects of antidepressants: Ø Downregulate postsynaptic NA (beta adrenoceptors) and serotonin receptors 2 - Reduction in binding sites - Reduction in agonist response Ø Increase activity/sensitivity of post-synaptic serotonin receptors 1 in hippocampus (except MAOIs) Ø Decrease activity/sensitivity of presynaptic alpha-1 adrenoceptors and/or serotonin receptor 1 (inhibit receptors that control release of NA and serotonin) - Facilitate monoamine release Antidepressants and Monoamine Theory: Ø Net effect of chronic treatment is an enhancement of monoaminergic functions à optimise monoamine levels and restore optimal receptor sensitivity Ø Slow adaptive changes correspond to the timecourse of therapeutic effect (downregulation of beta2 and alpha-2 adrenoceptors, and serotonin receptor 2) Antidepressants and Neuroplasticity Hypothesis: Ø Antidepressants enhance BDNF signalling, TrKB receptors and neurogenesis - BDNF stimulates gene transcription of SERT and tryptophan hydroxylase in raphe nuclei - Serotonin receptor activation stimulates BDNF expression - Antidepressants à increase serotonin synthesis, release and cell function à restore network function and mood Ø Serotonin and NA promote neurogenesis through serotonin 1A and 2B stimulation, beta adrenoceptor stimulation and alpha-2 adrenoceptor inhibition Antidepressants and Neuroendocrine mechanism: - Promote hippocampal neurogenesis à restore of HPA axis function (inhibit stress response) Depression ACE model à Activity, Cognition, Emotion Depression: - Lifetime risk 11-15% - In primary care, 1 in 10 - Onset of first episode à adolescent to mid-40s à average mid-20s - 40% with major depression experience first episode before age of 20 - More common in females Bipolar disorders: - Lifetime risk 1% (bipolar spectrum disorder 2.5%) - Recurrence within 2 years - Onset is late teens, mean age of diagnosis is late 20s - Manic episode : depressive episode = 1:3 - Highest suicide risk (30-60x) - Female = male Classification of mood disorders: Risk factors: - Genetics - Biochemical factors (brain chemistry) - Illness - Personality - Ageing - Long term pressure - Stressful or traumatic events Diagnostic Criteria – DSM-V à At least 5 of the followings during the same 2-week period (every or nearly every day) (including either depressed mood or loss of interest or both): - Depressed mood most of the day, nearly every day - Diminished interest or pleasure in activities most of the day, nearly every day - Significant weight loss - Insomnia or hypersomnia - Psychomotor agitation or retardation - Fatigue or loss of energy - Feelings of worthlessness or excessive guilt - Diminished ability to think, concentrate or indecisiveness Severity of depression: - Clinical impression - Hamilton scale - Beck scale - Montgomery-Asberg Depression Scale (MADRs) Theories of depression: - Monoamine hypothesis - Neurotransmitter receptor hypothesis - The monoamine hypothesis for gene expression - Neurokinin hypothesis of emotional dysfunction Ø Monoamine hypothesis: - Depression due to deficiency of monoamine neurotransmitters NA, serotonin and DA - Neurotransmitters are destroyed by pre-synaptic MAO (NA, DA, 5HT) and synaptic COMPT (NA and DA) - MAOIs à increase levels of NA, DA and 5HT by inhibiting MAO breakdown in presynapse - TCAs à increase levels by inhibiting their uptake in the synapses - Boost monoamine neurotransmitters immediately but there is a significant delay in therapeutic effect Stigma associated with mental illness: - Emotional weakness - Bad parenting - Victim’s fault - Incurable - Sinful behaviours Depression à mood disorder (affective disorder), unipolar or bipolar Difficult to distinguish mild forms from emotional changes associated with everyday life Major depressive disorder à chronic condition with frequent relapses Antidepressants SSRIs à selectively inhibit presynaptic reuptake of serotonin - Indications: major depression, anxiety disorder, bulimia nervosa, premenstrual dysphoric disorder, PTSD - Equi-effective à little difference in efficacy or tolerability between SSRIs and with other classes - Fluoxetine à has active metabolites, longer half-life à unlikely withdrawal effects but requires a longer wash out period before new antidepressant is commenced - Insomnia (except fluvoxamine, paroxetine) à take in the morning - Drowsiness (fluvoxamine and paroxetine) - Suicidal thoughts on initiation - Reduce seizure threshold - Provoke manic ep in bipolar disorder - Bleeding risk in elderly >80 - Not approved for use in children with depression (increased risk of suicidal ideation) à Antidepressants use in children are off-label à Fluvoxamine and sertraline are approved for OCD - Difference à CYP450 interactions: + CYP1A2 inhibitors à Fluvoxamine + CYP2D6 inhibitors à fluoxetine, paroxetine + CYP3A4 inhibitors – fluvoxamine Serotonin Toxicity à extremely rare but fatal TCAs à block the re-uptake of serotonin and NA into pre-synaptic terminals - Indications: depression, urge incontinence, nocturnal enuresis, adjunct in pain mx, ADHD, migraine prophylaxis. - Side effects: anticholinergic effects (esp in elderly), cardiotoxicity (QT interval prolongation, increased HR, postural hypotension, arrhythmia, slow cardiac conduction), reduce seizure threshold. - Nortriptyline –> less hypotension and ADRs in elderly SNRIs à serotonin and NA reuptake inhibitors: - Indications: major depression - Can cause seizures - Provoke manic eps - Bleeding risk in elderly (>80) - Suicidal thoughts on initiation MAOIs à second line treatment for depression and anxiety disorder - Hypertensive crisis à avoid food containing tyramine while taking this medicine and for 2 weeks after stopping treatment - Avoid matured or fermented or aged meat products, protein extracts, yeast extracts, soybean extracts, pineapple, avocadoà high in tyramine Other antidepressants: Ø Mirtazapine à post-synaptic blockade of 5HT2/3 receptors and enhances NA by blocking presynaptic alpha-2 adrenoceptors Ø Reboxetine à NRI and weak SRI Ø Agomelatine (Valdoxan) à melatonin receptor agonist (MT1 and 2) and 5HT2c receptor antagonist - Similar efficacy to other antidepressants - Considered when others are not tolerated or failed - Suicidal thoughts and behaviour on initiation - Monitor LFTs at baseline, 6, 12, and 24 weeks à stop if aminotransferases >3x ULN - Limited abuse potential or withdrawal effects - CYP1A2 substrate à caution when combined with 1A2 inhibitors (fluvoxamine, ciprofloxacin) ot 1A2 inducers (omeprazole, smoking) Ø Vortioxetine (Brintellix) à inhibit re-uptake of 5HT, 5HT3 antagonist and 5HT1A agonist à antidepressant and anxiolytic effects - Limited safety and efficacy in elderly - Limited info about use in renal and hepatic impairment - Dizziness à driving and operating machinery - May be ceased abruptly without tapering - Considered when others cannot be tolerated or failed Basic principles of prescribing in depression: - Patient choice of drug and utility of other non-pharmacological treatments - Discuss likely outcomes à gradual relief from depressive symptoms over several weeks - For single episode, continue treatment for at least 6-9 months after resolution of symptoms (multiple episodes à longer) - Withdraw very gradually, inform patients the risk and nature of discontinuation Use of antidepressants: - 20% will recover without treatment, 50% will respond to AD - Onset: 1 – 2 weeks - SSRIs à first line and better tolerated - SNRIs à less well tolerated than SSRIs but better tolerated than TCAs - Duration of Tx: 6 – 9 months after recovery from a single episode - Choose AD based on the prominent signs and symptoms à treat symptoms If treatment is not effective: Withdrawal Effects: Switching between antidepressants: Complementary Medicines: Ø St John Wort - Effective in mild-to-moderate major depression and have fewer SEs than antidepressants - Avoid taking with other antidepressants à increased risk of serotonin syndrome - Not a licensed medicine - Interact with many medicines à serious side effects Important Counselling Points: - Resistance to a mental illness diagnosis à resist drug therapy - Side effects à decreases with time but may limit compliance - Mood may not improve immediately - Not all people respond to the first drug - Missing dose reduces effectiveness - Do not stop medication abruptly à rebound symptoms/discontinuation syndrome à taper very slowly - Regular follow-up and monitor the early stage of treatment - A single episode of depression à 6-9 months of treatment - High risk of recurrence à increase with each episode à multiple episode means many years of treatment - Antidepressants: effective, not addictive, not losing efficacy over time, no long-term side effects g - Aminobutyric Acid (GABA) Brain is a controlled balance between excitation and inhibition - Too much net excitation à anxiety, hyperexcitability, epilepsy, convulsions - Too much net inhibition à sedation, depression, anaesthesia, coma Glutamic Acid (Glutamate) à major excitatory neurotransmitter in brain GABA à non protein amino acid found in high concentration in the mammalian CNS à major inhibitory neurotransmitter in the brain ALL CNS neurons have GABA receptors and up to 40% release GABA as a neurotransmitter Ion gradients and excitability: à Ion conductance directly influences cell excitability - Cation permeability à increase cell firing (Positive charge in à increase activation - Anion permeability à decrease cell firing (Negative charge in, for example Cl- à reduce membrane potential à inhibition) Synaptic transmission: - Electrochemical - Action potential generated by influx of Na+ through voltage-gated Na+ channels to cause terminal depolarisation 1. Na+ entry increase membrane potential from resting (-70mV) to threshold potential (-55mV) 2. Spatial and temporal summation leads to terminal depolarisation GABA transmission important for à memory, sleep, mood, stress response, analgesia, CV function, neuroendocrine function, control of food intake GABA transmission is disrupted in: epilepsy, schizophrenia, mood disorders, anxiety, migraine, memory disorders, sleep disorders, stress responses. GABA synthesis: - From glutamate - Decarboxylation catalysed by the enzyme glutamate decarboxylase (GAD) à GABA SHUNT - Inhibitors of GAD reduce the levels of GABA in the brain à Convulsants + 3-mercaptopropionic acid + allylglycine GABA storage: - In vesicles in synaptic terminals - Active transport into small clear vesicles via vesicular GABA transporter - Stored as bound complex with ATP, protein Ca2+, Mg2+ à prevent leakage into cytoplasm - Driven by H+ and electrical gradient across vesicular membrane - No selective inhibitor of GABA storage in vesicle GABA release: - Release of GABA from presynaptic terminals following depolarisation can be blocked by tetanus toxin - Tetanus toxin = convulsant à also block the release of glycine (inhibitory transmitter in the spinal cord) GABA Receptors à 3 main types (ionotropic and G-protein coupled) All GABA receptors are inhibitory Ionotropic GABA receptors (GABA A&C) - DNAs in human brain coding for proteins that can constitute GABA A&C receptors - These proteins are part of the cys loop or nicotinicoid superfamily of ligand gated ion channels - 5 transmembrane subunits around a central pore à the ion channel - Gating of anions and cations dependent on amino acid residues lining the channel pore à Antagonists are selective GABAA: - 15 subunits - most receptors made up of 2 alpha, 2 beta and 1 gamma subunits (heterooligomeric) - gamma subunit replaced with other subunit in different brain regions - 2 allosteric binding sites at the interfaces between 2 subunits alpha and beta à 2 GABA required Fast onset, rapid desensitisation GABAC: - 3 subunits - most made up of just 1 subunit type à homomeric (homooligomeric) - Slow onset, little desensitisation N (amine) terminal region à binding site Ion channel = Gate chloride ions Binding of GABA leads to conformational change à allow CL- in à reduce membrane excitability Metabotropic GABAB receptors: - G protein coupled second messengers - Activate K+ efflux channel (post-synaptic) and inhibit Ca2+ influx channel (pre-synaptic) à Overall reduces membrane excitability - Heterodimer and heterooligomeric - Agonist à Baclofen à treat spinal spasticity - Antagonist à Phaclofen - GABAB modulates release of glutamate and NA in many CNS regions GABA Reuptake: - Active transport into neurons via high affinity Na+ dependent membrane transporter protein à Main mechanism for terminating GABA synaptic action - Reducing GABA uptake à increase GABA mediated inhibition - Inhibitors of GABA uptake: + Nipecotic acid + Arecaidine GABA metabolism: - Converted to succinate (succinic acid) via the action of GABA transaminase and succinic semialdehyde dehydrogenase (SD) in mitochondria - Metabolic pathway α-ketoglutarate - glutamate - GABA - succinate à the GABA shunt à bypasses the normal TCA (Krebs) cycle in the brain (up to 30% of the turnover of the TCA cycle is via the GABA shunt) - Inhibitors of GABA metabolism à increase brain levels of GABA up to 10 fold à Anticonvulsants + Sodium valproate inhibits SD + Vigabatrin inhibits GABA-T Three strategies to enhance GABA mediated synaptic inhibition: - Increase GABA receptors activation - Inhibit GABA metabolism - Inhibit GABA uptake Indications of GABAergic drugs: - Anticonvulsant - Anxiolytic - Muscle relaxant - Sedative - Hypnotic - Analgesic - General anaesthetics Benzodiazepines Sedation = reduction in excitement, vigilance and physiological arousal Hypnosis = ability to induce drowsiness and sleep Sedatives and hypnotics à reduce time to fall in sleep and increase duration of sleep Anxiolysis: - Reduction in anxiety - Can be measured by elevated Plus Maze and other paradigms, physiological responses, and psychological measurements Fear and Anxiety à adaptive response to aversive stimuli (danger, pain, noxious conditions) - Fear = innate response to threatening stimuli à can be learnt à avoidance, escape, or defence - Anxiety = anticipation of danger, cues are less specific à learnt behaviour à vigilance, physiological autonomic arousal and subjective distress Classes of sedatives, hypnotics and anxiolytics: Sedatives and hypnotics: - Benzodiazepines - Barbiturates - Melatonin agonists - Sedative antihistamines Anxiolytics: - Benzodiazepines - Antidepressants (1st line) - 5HT1A partial agonists Benzodiazepines (“-lam”, “-pam”) Ø Indications: - Anxiety - Panic disorder - Acute alcohol withdrawal - Insomnia - Muscle spasm - Preoperative sedation - Conscious sedation - Induction of anaesthesia - Epilepsy Ø Chlordiazepoxide was the first BZ, followed by diazepam Ø Structure Activity: - Halide (2-Cl and 2-F) on the 5-phenyl group - Replacement of the 7-Chloro with a N or Br is tolerated - Methyl group at the 1-position may be absent - 1,2,4-triazolo group Ø Mechanism of action: - Positive allosteric modulators of GABAA receptors - Selective for GABAA receptors that have alpha-1,2,3,5 subunits and gamma-2L + Gamma-2L confers high affinity BZ binding + Up to 40% of GABA A receptors have gamma-2L subunit - BZ binds to allosteric site à interface between alpha and gamma subunits - Increase frequency of ion channel opening à increase Cl- conductance - Increase potency of GABA without changing the maximal effect (less GABA needed for the same level of inhibition) - BZ-sensitive GABAA receptors found in: amygdala, hippocampus, bed nucleus of the stria terminalis, striatum, hypothalamus, prefrontal cortex, cerebellum, brainstem Ø Benzodiazepine à rate mechanism à increase frequency of channel opening but same time of opening à tolerance can develop quickly because it might be less effective over time Ø Barbiturate and ethanol à occupancy mechanism à channels open for a longer time Ø Considerations with BZ use: - For insomnia à maximum duration is 1 month including tapering off - For anxiety à as short as possible but no longer than 2-3 months including tapering off - Risk of dependence in prolonged use à withdrawal symptoms when stop suddenly Ø Precautions: - Amnesia (memory loss) or memory impairment - Somnambulance (sleep walking) and bizarre sleep behaviours - BZ + ethanol/opioids à dangerous à lethal - Myasthenia gravis (muscle weakness) - Elderly à increased action of BZs Ø Alpha subunits: α1 => sedative/hypnotic, anticonvulsant α2 and α3 => anxiolytic α3 and α5 => myorelaxant α5 => learning and memory à BZs do not work on GABA receptors containing alpha-4 and 6 subunits Non-BZ sedative/hypnotics: Ø Imidazopyradine and cyclopyrrolone derivatives - Zolpidem, Zopiclone, Zaleplon - Selective for alpha-1 containing GABAA receptors with gamma-2L subunit (except zopiclone that binds to other types as well) - Black box warning à Zolpidem may be associated with potentially dangerous sleep related behaviours Not all anxiolytics cause sedation and hypnosis Ø Buspirone – 5HT1A partial agonist - No memory impairment or dependence - Delayed therapeutic effect - Not for panic or severe anxiety Ø Antidepressants - Long-term maintenance - No memory impairment or dependence - Can develop resistance Other sedatives/hypnotics: - Sedative antihistamines à doxylamine, diphenhydramine - Barbiturate à phenobarbitone (only used for specific indication) - Melatonin receptor agonist à agomelatine Ethanol: - Influences many ligand-gated ion channels - Can block some NMDA receptors - Enhance activity of some GABAA receptors à Reduce excitation and increase inhibition in the brain Ø Behavioural effects of ethanol: - Muscle relaxation (myorelaxation) - Anxiolysis - Sedation - Anticonvulsant - Impaired cognitive function Ø High doses à motor incoordination and ataxia, memory loss, sleep induction, respiratory depression Ø Ethanol and GABA receptors: - Ethanol is an allosteric modulator of GABAA receptors à increase GABA binding - At low dose (5mM) à act on GABA A receptor containing δ protein subunit - At sedative/motor incoordinating doses (20mM) à selectively on GABA A receptors containing gamma-2L subunit - At anaesthetic dose (50-100mM) à act on most GABA A receptors - High risk of dependence Ø BZ is used to treat ethanol withdrawal syndrome Herbal/Nutrient sedatives, hypnotics and anxiolytics: - Valerian - Chamomile - Passionflower - Skullcap - Flavonoids from red wine Sleep and Insomnia Sleep: - Reversible behavioural state of perceptual disengagement from and unresponsiveness to the environment - Not a passive state Circadian rhythms - Endogenous autonomous oscillations à in physiological activities/behaviours following the 24 hours cycles - For circadian rhythms to occur à 3 factors: inputs (sun light), core oscillator, output (the rhythm) The two process sleep model: - Homeostatic (process S) – energy debt (due to tiredness, build-ups during the day) - Circadian (process C) – clock based drive - ATP à marker of energy debt Neurobiology of sleep: - Flip-flop switch regulating sleep-wake - Mutual inhibition of sleep and wake promoting regions - Awake à increased orexin, decreased VLPO (ventrolateral preoptic nucleus – sleep promoting), increased monoaminergic neurons - Sleep à increased VLPO and GABA, decreased orexin and monoaminergic neurons Function of sleep: - Emotional regulation - Metabolic function regulation - Energy balance - Memory functions/consolidation - Toxic biproduct or metabolic waste removal - Prophylactic cellular maintenance - Macromolecule biosynthesis Sleep architecture: NREM - N1 à 5% of sleep à light sleep - N2 à 50% of sleep - N3 à 20% of sleep à deep sleep REM à vivid dream Sleep Disorders - Insomnia: 1. Symptoms: at least one of the followings: difficulty falling in sleep, difficulty maintaining sleep, early morning awakenings - Occurs despite adequate opportunity and circumstances for sleep Ø Insomnia Disorder à At least one form of daytime impairment: fatigue/malaise, difficulty concentrating, mood disturbance, poor school/work performance etc. 2. Diagnosis: based on clinical history, no need for a sleep study 3. Risk factors: female, ageing, occupation, educational level 4. Consequences of insomnia: 5. Neurobiology of insomnia: - Circadian process misalignment - Delayed or advanced melatonin secretion - Homeostatic process irregulation - Maladaptive sleep health behaviours/altered cognitive pattern - Overactivity in the hypothalamus, hippocampus, amygdala or prefrontal cortices - Cognitive, emotional, behavioural and autonomous hyperactivity - Comorbidity Circadian dysregulation: - Sleep disorders - Genetics - Shift work - Jet lag - Social jet lag (Delayed sleep phase syndrome à in teenagers/young people; Advanced sleep phase syndrome à elderly; Free running à no circadian rhythm) Homeostatic misalignment: - Irregular sleep wake patterns - Irregular diet and exercise patterns - Napping - Caffeine à adenosine receptor blocker MAINTAINING A REGULAR WAKE UP TIME IS VERY IMPORTANT (more important than sleeping at the same time every day) Neuro-psychological models 3Ps - P1 – predisposing factors: age, gender, anxiety level - P2 – precipitating factors: stress, medication, illness - P3 – perpetuating factors: poor sleep hygiene, sleep anxiety à chronic insomnia Hyperarousal stress: - Elevated blood levels of stress hormone cortisol in the late evening 6. Treatments: - First line: CBTi along with any pharmacological support - Long term use of pharmacotherapy is not recommended Prescription medications: Ø Benzodiazepine receptor agonists - Sleep effects: decreased SOL, N1, REM, SWS, WASO; increased N2 and TST - Activate VLPO à GABAergic inhibition through GABAA activation - Temazepam, oxazepam, zolpidem, zopiclone - Short-term use 85% and stable) - If not, continue. If yes, start sleeping 15 minutes earlier every 5-7 days, then advance bed time till you reach your desired sleep schedule of 7 hours Ø Of all the components of CBTi, sleep restriction therapy (SRT) is the most effective, sleep hygiene education (SH) is the least effective. Ø Sleep restriction therapy: - Restricts time in bed awake - Regularise sleep patterns - Re-condition the brain to avoid bed-insomnia association Evidence-Based Complementary Medicines for Depression Diet and Lifestyle: à adhere to a healthy diet (Mediterranean diet), away from pro-inflammatory diet - 3 – 9 serves of veggies - ½ - 2 serves of fruits - 1 – 13 serves of cereals - 65 in aged care + dark skin + wear long sleeve cloths + avoid sun + health conditions that prevent absortion of vit D à Crohn, coeliac + medicines that break down vit D à epilepsy medicines - High doses ≥ 275 mcg /d à hypercalcamia and vascular calcification Ø St Johns Wort: - Strongly recommended as monotherapy - For mild-to-moderate depression - Constituents: hyperforin and adhyperforin à modulate the effects of serotonin, DA and NA and may inhibit their reuptakes - Caution for use in bipolar à may induce mania - May cause photosensitivity - Avoid using with SSRIs and SNRIs à Serotonin Syndrome - Drug interactions due to CYP3A4 and p-glycoproteins - Avoid in pregnancy and breastfeeding Ø Curcumin: - Provisionally recommended as mono or adjunctive therapy - May be more beneficial in people with comorbid inflammatory disorders - Not safe in pregnancy Ø Saffron: - Provisionally recommended as mono or adjunctive therapy - Minor side effects: GI, increased perceived mental stimulation - Quality and standardisation of saffron extracts are essential - Likely unsafe in pregnancy Ø Nutraceuticals not recommended in MDD: - Creatine - Tryptophan and 5HTP - Inositol - Magnesium - Vitamin C - S-adenosyl methionine - Rhodiola SUMMARY: Deficiencies of zinc, vitamin D and folate have been associated with depression Diets low in omega 3 fatty acids specifically EPA have been associated with depression – encourage including fish in the diet or EPA supplementation Omega-3 (recommended+++), methylfolate and zinc (provisional recommendation ++), vitamin D (weak recommendation +) with antidepressants and standard treatments St Johns Wort (standardised extracts) recommended as monotherapy for mild to moderate depression but should not be combined with conventional antidepressants St Johns wort is unsuitable for patients taking a number of other medications due to its CYP3A4 and p-glycoprotein induction effects Perinatal Mental Health - Perinatal = during pregnancy until 1 year postpartum à perinatal depression = PND - Postnatal = postpartum = after giving birth PND à Postnatal depression PPD à Postpartum depression - Antenatal = prenatal = before birth à Antenatal depression = AND Baby Blues: - Different from a depressive disorder - Start hours/3-5 days after delivery - Last a few days or hours - > 50% of postpartum women - Labour + hormonal changes + physical changes à stress - Self-limiting - No treatment needed Risk factors for PND: - Antenatal anxiety - Major or negative life events - Low socioeconomic status - Genetics - Exposure to abuse and violence - Lack and social and partner support Perinatal anxiety symptoms: - Panic attacks à avoid places or situations for fear it may reoccur à social isolation - Constantly feeling restless, irritable - Tense muscles - Sleep problems - Tightness in chest - Constant worrying thoughts Postpartum/Puerperal psychosis (PP) - Rare (0.1% women) - Women with increased risk: history of bipolar disorder, schizophrenia, family history of postpartum psychosis - Severe mental illness à EMERGENCY - Usually begins within 2 weeks postnatally, symptoms may start within first few days - Symptoms: high mood, depression, confusion, hallucinations (false perception), delusions (false belief) Prevalence and disease burden: - Higher in low income countries - Higher in migrant pregnant women - Highest between 0-3 months after delivery - More common among: conformational change of the transmembrane domain à activation of Gprotein signalling Ø Group I à located postsynaptically à enhance excitation - mGluR1,5 respond to AMPA, coupled to phosphoinositol hydrolysis à Ca2+ release from intracellular stores Ø Group II and III à located presynaptically à activation of these receptors reduces glutamate release à inhibit excitation - mGluR2,3 respond to ACPD (trans-1-amino-cyclopentane-1,3-dicarboxylate) à inhibit adenylate cyclase to reduce cAMP - mGlu4,6,7,8 prefer L-AP4 (l-2-amino-4-phosphonobutyrate) à inhibit adenylate cyclase to reduce cAMP Ø Postsynaptic mGluR: - Activation of ALL 3 GROUPS inhibits L-type Ca2+ channels - Activation of group I and II inhibits N-type Ca2+ channels Ø Presynaptic mGluR: - Activation blocks both glutamatergic and GABAergic neurotransmission à may involve inhibition of presynaptic voltage-gated Ca2+ channels mGluRs – inhibitory autoreceptors à Negative feedback loop Glutamate transporters è Inhibit transporters that carry Glu out of the synapse à increase Glu in the synapse à increased Glu signalling Ø Vesicular glutamate transporters (VGLUTs): - Co-transporting of 1 Glu- out with 1 H+ - ATP required (energy) Ø Excitatory Amino acid transporters (EAATs) - Diffusion mechanism: + 1 Glu-, 3 Na+, and 1 H+ in + 1 K+ out - No energy needed - Can maintain a 106 fold of gradient across the membrane + High concentration of sodium in extracellular (outside) + High concentration of potassium in cytoplasm (inside) Crystal structure of GltPh (prokaryotic homologue of EAATs) - Forms a bowl shaped structure that sits in the membrane - 3 identical subunits - Each subunit can transport Glu Drugs inhibit glutamate transporters: Glutamate – Neuronal Plasticity: Ø Long term potentiation (LTP) - Long-lasting strengthening of synaptic connections between neurons - Activity-dependent changes in synaptic efficacy e.g. changes in receptor number or changes in receptor activity - Changes can last from hours to weeks/months - Formation of learning and memory - Involve the activation of NMDA and AMPA receptors (which often work together) + Activation of NMDA by release of Mg2+ à influx of Ca2+ à activation of CaMKII à bring more AMPA receptors to the surface of the cell membrane à enhance synaptic transmission Excitotoxicity à Cell death Epilepsy Definitions: Ø Seizure: - Brief, temporary disturbance in the electrical activity of the brain - Caused by neurons discharging abnormally Ø Epilepsy: - A neurological condition that affects the brain - Seizures due to enhanced electrical activity of neurons - Recurrent seizures (>2, 24 hours apart) - An isolated seizure or seizures secondary to a reversible cause such as alcohol withdrawal or hypoglycaemia is NOT epilepsy Mechanism: Ø Changes in: - Ion channel conduction - Membrane receptor response - Messenger systems - Gene transcription Ø Result in: - Imbalance between excitatory (glutamate) and inhibitory (GABA) neurotransmitters - Excessive acetylcholine, NAd, 5-HT levels may also precipitate seizures Epidemiology: Ø 5% - 1/3 neonate febrile convulsions - 1/3 single seizure - 1/3 epilepsy à most common serious neurological condition Ø Highest in neonates and elderly Ø 2-3x standardised mortality rate Aetiology: - Only 30% with a defined cause Ø Infancy and childhood: - Birth injury - Metabolic error - Congenital malformation Ø Childhood and adolescence: - Genetic syndrome - CNS infection Ø Young adult: - Head trauma Ø Older adult: - Stroke - Brain tumour Ø Often the cause is unkonw Prognosis: - 60% achieve seizure control with monotherapy - Can remain seizure free after drug withdrawal - Titrate downwards after 2 years seizure free over several months - Cannot drive until 3 months drug-free Diagnosis: - Primarily by patient/witness history (because we can’t predict seizures) - EEG - MRI Classification: Symptoms: Ø Partial (focal): - One hemisphere (can evolve into secondary generalised) - No definite symptoms - Can affect autonomic function, sensory perception, motor function, behaviour Ø Generalised: - Both hemispheres, with all area of the brain being hyper excitable - Loss of consciousness (LOC) and bilateral motor symptoms: absence (vacant stare) tonic (muscle rigidity, stiffening) clonic (rhythmic movements/jerking) myoclonic (jerking/twitching of muscles) tonic-clonic atonic (muscle flaccidity) - Idiopathic: Childhood/Juvenile absence epilepsy Juvenile myoclonic epilepsy à most common epilepsy in adults, less likely to be able to withdraw treatment Epilepsy with tonic-clonic seizures on awakening - Symptomatic (secondary) Lennox-Gastaut syndrome Treatments of seizure: Ø First Aids: - Remove hard objects (protect from injury) - Reassure patient - Recovery position - Time the seizure DO NOT restrain DO NOT put anything in mouth DO NOT give any food and drink until recovered Ø Status epilepticus – 5 minute continuous or repetitive seizures (12-30% of seizures, 20% mortality) - Immediate treatment à Benzodiazepines (IV clonazepam, diazepam, midazolam, buccal/intranasal midazolam) - Follow-up treatment à Levetiracetam, phenytoin, sodium valproate, phenobarbital (children) - Repetitive seizures à PO clobazam, buccal/intranasal midazolam, PR diazepam Anti-seizure drugs: about 30 Ø NO cure, only symptomatic treatment Ø First generation à barbiturate derivatives Ø Second generation à non barbiturate Ø Third generation à targeted based compounds Ø All discovered using animal models Classification of treatment by MOA: Mechanism of Action Modulation of Voltage-Gated Cation Channels Enhance GABAergic System Interacting with Synaptic Release Machinery Decrease Glutamate Transmission Receptors Sodium Channels Phenytoin, carbamazepine, lamotrigine Calcium Channel Ethosuxamide, pregabalin, zonisamide GABA Receptor Activation Barbiturates, felbamate GABA Potentiation Barbiturates, benzodiazepines GABA Reuptake Inhibitor Tiagabine GABA Metabolism Inhibitor Vigabatrin Binds to synaptic vesicle glycoprotein (SV2A) Levetiracetam NMDA Receptor Inhibition Felbamate AMPA Receptor Inhibition: Perampanel Kainate Non-NMDA Inhibition: Topiramate Glutamate Release Inhibition: Lamotrigine Stabilizes Ion-Gated Potassium Channels Drugs Retigabine Prophylaxis: Ø 1st drug monotherapy à 47% seizure free Ø 2nd drug monotherapy à 13% seizure free Ø Add second drug as combination (duotherapy) and consider 1st drug removal if seizure-free Ø Duration: 2 years Ø Rarely triple therapy Ø Refractory à surgery/vagal nerve stimulation, ketogenic (high-fat restrictive) diet in children - Poor adherence, GI disturbance, CV risk due to selenium deficiency Choice of therapy - 1st line drugs: Ø Partial à carbamazepine - Adult: 100 mg CR at night increasing by 100-200mg every week to 200-600 mg bd - Child: 2.5 mg/kg bd increasing to 5-10 mg/kg bd - Autoinduction metabolism (the drug makes the liver produce more CYP450 enzymes à it metabolises more than the amount you take) - ADR: + Diplopia (double vision) à earliest sign of toxicity + Morbilliform rash (looks like measles) à Asian HLA-B*1502 + Agranulocytosis - Partial seizure in children à use oxcarbazepine Ø Generalised à sodium valproate - Dose in adult à gender dependent: + Female (child-bearing potential who do not have reliable contraception): 400 mg daily for 1 week then 200 mg mane and 400mg nocte, max 600 mg/day. + Male (and Females that do not meet the criteria above): 500 mg daily for 1 week then 500 mg bd, max 1500 mg bd. - Child: 5 mg/kg bd increasing to 10-20 mg/kg bd - ADR: sedation, hair loss, weight gain, hepatotoxicity (more likely in infants) - Unpredictable drug-drug interactions - Worse teratogenicity then other AED (dose-related) v Titrate upwards to therapeutic dose (except for phenytoin) à start low and increase slow v Narrow therapeutic index v TDM à phenytoin, lamotrigine, and carbamazepine in pregnancy Ø Ethosuxamide: - 1st choice as monotherapy for absence seizure prophylaxis à better tolerance than sodium valproate but equal efficacy Does not prevent tonic-clonic activity à DO NOT USE IN MIXED SEIZURES 2nd line drugs: Ø Lamotrigine: - For both partial and general - Can be used as monotherapy or duotherapy - Non-inferior to carbamazepine - Significant ADR: skin reactions (SJS), toxic epidermal necrolysis, esp. when used with sodium valproate - If rash à Stop immediately Ø Oxcarbazepine: - For partial and generalised tonic-clonic - Monotherapy or duotherapy - Structurally related to carbamazepine but does not autoinduce metabolism and less interactions Replace carbamazepine for partial seizure in children (1st line) Other drugs: Ø Levetiracetam: - Less concern with cognitive deficit - Not as effective as older AEDs - 1st line for tonic-clonic seizures when generalised or focal (Partial) onset is unclear in females - 250mg PO bd for 1 week, then increase to 500mg bd. Up to 1500mg bd Ø Topiramate - 3rd line - Adjunct treatment for partial and generalised seizures Ø Phenytoin: - Adjunct for partial seizures - 300mg d - TDM: + 40-80 umol/L + Exhibit saturation PK due to elimination rate restriction over 40umol/L + Limit dose increments to 50mg/day + Wait 5 half-lives to measure response Ø Adjunct treatments for partial seizures: - Lacosamide - Pregabalin - Ticagabine - Gabapentin à in elderly - Zonisamide Ø Vigabatrin: - ONLY for REFRACTORY EPILEPSY - Significant ADR: visual field defects à problematic in paediatric epilepsy due to being unable to monitor visual field Bone health: - Long term AEDs à increase bone turnover - Calcium and vit D supplements Triggers avoidance: Common Triggers Occasional Triggers - AED non-adherence - Dehydration - Sleep deprivation - Hyperventilation - Alcohol withdrawal - Flashing lights - TV/monitor flicker - Diet and missed meals - Epileptogenic drugs (TCAs, phenothiazines, etc.) - Stress - Systemic infection - Intense exercise - Head trauma - Specific 'reflex' triggers - Recreational drugs - Benzodiazepine/barbiturate withdrawal - Menstruation Lifestyle modification: Ø Avoid situations where seizures can be dangerous: - Swimming alone - Climbing - Operating machinery Ø Driving à needs discussion with the doctor Dravet syndrome (DS): - Severe encephalopathy with a high seizure burden - Seizure often begin in the 1st year of life and may commence with febrile seizures - Progress to severe spontaneous generalised tonic-clonic seizures à unpredictable - Status epilepticus à seizures last 5-10 minutes - Sudden Unexpected Death in Epilepsy (SUDEP) – 15 – 20% - Developmental delays in achieving normal motor and cognitive milestones - 80% due to loss of function de novo – mutation in SCN1A gene (NO FAMILY HISTORY) - Rare, drug resistant so polypharmacy is common (often on 3 drugs) o 1st line: valproate and clobazam o 2nd line: CBD o Sodium channels inhibitors (lamotrigine) are contraindicated à worse Dravet Lennoz-Gastaut syndrome (LGS): Ø Severe encephalopathy with a high seizure burden Ø Seizures from years 1-8 (peak in 3-5 years), 30-40% develop from West syndrome (infantile spasms – stiffening and movement of head and limbs back and forth) - Stiffening (tonic) seizures - Drop (atonic) seizures - Atypical absence seizures - Generalised tonic-clonic seizures - Status epilepticus Ø Most have a history of delayed development before onset of seizure à worse post-seizure onset Ø Causes: - Structural (congenital brain malformation or brain injury incl. infections) - Genetic (D120N mutation) - Metabolic (rare) Ø Very rare, drug resistant so polypharmacy common (3 drugs) Tuberous Sclerosis Complex (TSC): - Autosomal dominant genetic condition – mutations in TSC1 or TSC2 - Affects multiple organs incl brain due to growth of non-cancerous tumours - > 90% patients intractable (hard to treat) - various seizure types: infantile spasms in 1st year, focal, generalised tonic-clonic, tonic, atonic and absence seizures - Rare 1/6000 - 25-50% develop autism or show signs of developmental delays - Drug resistant Purified CBD (Epidiolex): Ø 98% CBD with no THC content Ø indicated to treat drug-resistant epilepsies: - Dravet syndrome - Lennox-Gastaut syndrome - Tuberous sclerosis complex Ø Age must be 1 year and older Ø Dose: 10 mg/kg is effective at reducing seizures Ø Side effects: diarrhoea, vomiting, fatigue, fever, somnolence, and abnormal liver tests (likely DDI with valproate, clobazam) TDM Phenytoin Phenytoin à narrow safety margin and non-linear PK due to saturable metabolism TDM: Ø Multi-disciplinary clinical specialty à improve patient care by individually adjusting the dose of drugs for which clinical experience or clinical trials have shown it improved outcome in the general or special populations. Ø A priori à pharmacogenetics, demographic and clinical info Ø A posteriori à measurement of blood concentrations of drugs (PK monitoring) and/or biomarkers (PD monitoring) Quality use of medicine: Ø Select management option wisely Ø Choose suitable medicines Ø Use medicines safely and effectively Phenytoin target concentration range: 10 – 20 mg/L Phenytoin PK/PD: - Anticonvulsant - CYP2C9-mediated saturable metabolism à limited metabolic capacity - Modest changes in dose lead to a disproportionate increase in steady-state concentration - Dose dependent à half-life not clinically useful - Difficult to estimate time to steady-state (usually 5 - 7 days) - CNS toxicity is concentration-dependent à nystagmus (repetitive and uncontrolled movements of the eyes) and ataxia (poor muscle control) Non-dose related side effects: - Gingival hyperplasia - Hirsutism - Thickening of facial features - Vitamin D deficiency - Folic acid deficiency - Osteomalacia - Peripheral neuropathy - Purple glove syndrome à due to IV administration of phenytoin Phenytoin PK: Ø Bioavailability - Completely but slowly absorbed after oral administration Ø Volume of distribution: - Very small due to extensive protein binding to albumin (0.65L/kg) Ø Capacity limited metabolism - Clearance decreases with increasing plasma concentration - Vm - maximum metabolic rate = 7 mg/kg/day (5 - 15 mg/kg/day) - Km - phenytoin concentration at half Vm = 4 mg/L (range; 1- 20 mg/L) Mediated by CYP2C9 Major polymorphic CYPs: Ø CYP2D6, CYP2C9, CYP2C19 Ø Poor metabolism à loss of function à side effects due to drug accumulation Ø Rapid metabolism à gain of function à no effect due to the drug being broken down too quickly Ø Poor metabolisers (IM and PM) have a lower Vmax than extensive metabolisers (EM) Phenytoin loading dose: V = 0.65 L/kg C = Target phenytoin concentration Ø Serum concentrations can be measured 2 – 4 hours after an IV load or 24 hours after an oral load Ø Further monitoring required after initiating a maintenance dose Phenytoin concentration monitoring indicates: Ø Toxicity Ø Compliance and therapeutic failure Ø Appropriate dose adjustment Ø Effects of drug interactions Serum phenytoin concentrations 40 – 80 umol/L à Adequate to control seizures with a low risk of toxicity. Ø In some patients, 20 umol/L is adequate Ø Some patients can tolerate 100 umol/L Measure unbound concentration: Ø In patients with low serum albumin levels or CKF à total serum concentration of phenytoin is misleading - Normal albumin concentration: 32 – 45 g/L - 90% of circulating phenytoin bound to serum albumin - Unbound phenytoin (free fraction) à responsible for drug action and directly available to the liver for metabolism - Low albumin à free phenytoin remains pretty the same because excess free drug is metabolised by the liver à NET EFFECT: reduction in total phenytoin conc. Ø Total phenytoin range: 10 – 20 mg/L - Sheiner and Tozer equation (if serum albumin concentration is normal): Ø Unbound phenytoin range: 1 – 2 mg/L When to measure free phenytoin conc.: Ø Albumin < 30 g/L Ø Impaired renal function Ø On Valproate Ø Elderly patients with albumin at the low end of normal Dosing and concentration relationship for phenytoin: Ø Concentration-dependent clearance (CL) - Increase Css à decrease CL of phenytoin - Km is generally lower than therapeutic range à all patients display concentration-dependent CL Ø Capacity-limited metabolism: - Vmax = maximum rate of metabolism (capacity of enzyme system) - Km = Michaelis-Menten constant (measure of affinity - equal to the unbound concentration expected at half the maximum rate of metabolism) - C = unbound concentration of drug - Vo = rate of metabolism (mg/h) Ø Oral dose rate: - When dose rate > Vm à Css approaches infinity à Dangerous for the patient Ø Concentration-dependent half-life: - Usually reported as 22h - Half-life is not constant because CL is concentration-dependent - Time to reach steady-state is NOT 4 – 5 half-lives - Time to achieve 90% of steady state: Calculate Vm – 1st step for individualising phenytoin dose Ø Vm is the maximum rate of metabolism Ø A dose rate at or near Vm à dangerous increase in the phenytoin conc with risk of toxicity Ø Vm varies from person to person due to the impact of CYP2C9 genotype, concomitant drugs and comorbidities Ø Estimate Vm first à avoid selecting a dose regimen that leads to dangerously high concentrations Administration of phenytoin IV infusion: Ø Can be safely diluted with 0.9% sodium chloride Ø Should NOT be diluted with 5% glucose because it can precipitate Lithium First discovered in 1817 Indications: Ø Acute treatment and prevention of mania in BD Ø Augmentation for treatment-resistant depression 250mg and 450mg SR Lithium in Acute mania: Ø Reduce mania symptoms after 3-4 weeks Ø As effective at improving symptoms of mania as: – Haloperidol after 3 weeks – Olanzapine after 4 weeks – Valproate after 3–6 weeks – Carbamazepine after 4 weeks – Lamotrigine after 4 weeks – Quetiapine 3 weeks Ø Less effective than risperidone at reducing symptoms of mania after 4 weeks Ø More effective than topiramate at reducing the symptoms of mania after 3-12 weeks Ø Benefits: - Increase proportion of people who responded after 3-4 weeks - Number needed to treat (NNT) = 5 Ø Harms: - Dose (concentration) related side effects - GI disturbances, fine tremor, renal impairment (impaired urinary conc and polyuria), polydipsia, leucocytosis, weight gain, oedema (may respond to dose reduction), hypothyroidism Number needed to harm = 8 Lithium in acute bipolar depression: Ø Evidence less extensive Ø EMBOLEN I trial à lithium did not differ significantly from placebo but the serum concentration of lithium was low Ø Still regarded as an important agent for the treatment of acute bipolar depression Lithium – Prophylaxis of bipolar disorder Ø Reduce both number and severity of relapses - More effective in preventing manic than depressive relapse Ø NNT to prevent relapse into mania and depression = 10 and 14, respectively Ø In unipolar depression - Augment the efficacy of ADs for more than 30 years Ø Anti-suicidal effect 80% reduction in both attempted and completed suicide in patients with BD Lithium PK and PD: Ø Chemically simplest drug in therapeutic use Ø Complex MOA Ø Rapidly absorbed à bioavailability >85% Ø Complex distribution: 0.8 L/kg - Unbound - Significant delay to reach steady-state - Preferential uptake into kidney, thyroid, bone - Distribution into the brain takes up to 24hs to reach equilibrium Ø Chronic lithium toxicity with long term use à lithium accumulation Ø Elimination: - Not metabolised - 95% in urine (the rest in faeces, sweat, saliva, breastmilk) - Freely filtered, 80% reabsorbed in proximal tubule - Handled by the kidney in the same way as sodium - Any reduction in sodium (due to volume depletion, low salt diet) à increased reabsorption of lithium Ø Excretion: - Lithium CL = 26 mL/min < GFR à both filtration and reabsorption, not secreted à Lithium CL = Filtration – Reabsorption Ø Half-life 27h (varies 8 – 35 hrs) PK interactions with lithium: Ø Decrease lithium clearance à increase lithium concentration à increase risk of toxicity - Diuretics – thiazide and loop diuretics à decrease sodium reabsorption in the distal tubule - à sodium depleting à a compensatory increase in proximal tubule sodium and lithium reabsorption (increase lithium in blood) à reduce lithium clearance - NSAIDs à reduce renal lithium excretion - ACE-Is and sartans Ø Increase lithium clearance à poor response - Sodium bicarbonate - Potassium citrate PD interactions - NO change in lithium concentration Ø Anticonvulsants, SSRIs à increased risk of neurotoxicity Ø Serotonin toxicity Adverse effects of lithium: Ø Acute: metallic taste, nausea, diarrhoea, epigastric discomfort, weight gain, fatigue, headache, vertigo, tremor, acne, psoriasis, leucocytosis, nephrotoxicity, hypothyroidism (usually asymptomatic), hypercalcaemia, hyperparathyroidism, benign T wave changes on ECG Ø Long-term: - Renal à reduction in GFR + Nephrogenic diabetes insipidus with polydipsia and polyuria (reversible on stopping lithium) + 10% of patients + Due to reduced expression and translocation of the vasopressin-regulated water channel aquaporin 2 (AQP2) à distal tubules resistant to action o vasopressin à unable to concentrate urine à volume depletion and toxicity + Long term treatment (>10 years) à CKD incl CKF - Thyroid: because lithium concentrates in the thyroid + Hypothyroidism à most common à 6x higher than general population § Esp in patients with a background of autoimmune thyroid disease § May be misdiagnosed as a depressive relapse or lithium-induced weight gain § Monitor TSH and assessment of thyroid size + Hyperparathyroidism (alters proximal tubule function à decreased lithium excretion à toxicity) + Goitre + Hypercalcaemia Lithium toxicity: Ø When lithium concentration > 1.5 mmol/L (sometimes within therapeutic range) Ø Sequelae – renal impairment and cerebral damage Patient clinical status: Ø Can increase risk of lithium toxicity: - Renal impairment or dysfunction - Dehydration related to fever, vomiting, heavy sweating and low salt diet - Patient characteristics incl age, weight - Medication history - Therapeutic range of THIS patient Lithium monitoring: Ø Therapeutic range: - 0.8 – 1.2 mmol/L à acute mania - 0.4 – 1.0 mmol/L à prophylaxis Ø Toxic concentration: - 1.5 mmol/L in adult - 1.2 mmol/L in elderly Ø Post-distribution sample in needed - Flat concentration-time profile after distribution of the conventional or sustained release dosage form Lithium toxicity treatment: Ø Sufficient IV fluid (0.9% NaCl) replacement to ensure diuresis - Increase renal perfusion and GFR à increase lithium elimination - Increased requirements with NDI - Caution with AKI, CKD and HF Ø Haemodialysis increases lithium clearance - Indicated if GFR < 60mL/min, lithium > 2.5 mM, delirium, seizures, coma, persistent clinical effects inspite of fluids - Lithium usual CL = 25 – 35 mL/min - Haemodialysis adds 100 – 150 mL/min à increase CL and redistribution out of CNS + Intermittent haemodialysis (IHD) à most effective + Continuous renal replacement therapies (CRRT) + Peritoneal dialysis à low efficacy à no increased efficacy of CL of lithium over the natural CL of normal kidneys When to monitor lithium: Ø When staring lithium (once steady-state is achieved) – 5-7 d after starting à May also need other medicines initially as patient can take up to 2 weeks to respond Ø Prophylaxis: Every 3-6 months Ø Dose changes, interacting medications started / ceased Ø Clinical signs of toxicity, or of lack of efficacy Ø Dehydration, or changes in salt intake Ø Monitor kidney and thyroid function Practice points: Ø Signs of toxicity – extreme thirst and frequent urination, nausea and vomiting, neurological signs Ø Take with food – do not break or crush tablets Ø Maintain regular diet and intake of sodium Ø Hydration during hot weather is important Ø Onset of action may be delayed (6 – 10 days) Ø Do not stop abruptly- decrease dose gradually Local and General Anaesthesia 1. Local anaesthesia Major example of LAs: - Cocaine - Lignocaine - Prilocaine - Bupivacaine - Ropivacaine LAs – Mechanism of action: - Block voltage-gated Na+ channels in nerves and other excitable tissues - Some selectivity à small diameter fibres (pain) blocked before the larger ones (motor) but overlap does occur - Act on the Na+ channel at a site within the channel which is intracellular à LAs must first cross the membrane before binding Generation of action potentials: Process of depolarisation occurs progressively along the axon (the myelinated part of the nerve) resulting in nerve impulse conduction LAs à cross the membrane à bind to intracellular binding site on voltage-gated Na+ channel à inactivation of the channel à block pain stimulus Physiochemical properties: - Weak bases, poorly water soluble and unstable B + H+ = BH+ - Form water soluble and stable salts when combined with strong acid (HCl) (typical injection form) - pKa = pH at which both ionised and non-ionised forms of the drug are in equilibrium - pKa of most LAs is between 8-9 - Non-ionised form of LA crosses the membrane - Ionised forms bind to the Na+ channel Examples: log BH+/B = pKa – pH - At pH = 7.4, pKa = 8.4 à log BH+/B = 1 à BH+/B = 10:1 At pH 6.4 and pKa 8.4 à log BH+/B = 2 à BH+/B = 100:1 How LAs cross the membrane: Ø Hydrophilic pathway: à USE-DEPENDENT - Non-ionised form (B) cross the membrane - Ionised form (BH+) binds to the channel à channel needs to be open (in use) for binding to occurs Ø Hydrophobic pathway à NO USE-DEPENDENCE - Not common < 10% LAs - Can bind to the binding pocket within the lipid membrane, don’t need the sodium channel to be open LAs uses and administration: Comparisons of LAs: LAs with vasoconstrictors: Ø Vasoconstrictor: reduce blood flow by contracting circular smooth muscle and reduce diameter of blood vessels à keep the LA local, prevent it from going elsewhere Ø Adrenaline and Felypressin Ø Advantages: - Increase duration of action - Minimise dosage - Decrease toxicity Toxicity: Ø If absorbed into circulation à toxic effects related to action - CNS: initial stimulation (convulsions/seizures) followed by depression - Cardiotoxicity: profound bradycardia Ø Allergic reaction à rare 2. General anaesthesia: Critical for invasive surgery Loss of awareness (loss of consciousness) and responsiveness to painful stimuli (not sleep induction) GAs act on the CNS – LAs act on the peripheral senory nerves GAs are administered to induce (IV) and maintain (inhalational) anaesthesia - Pre-operative assessment and premedication - Induction - Maintenance - Reversal - Recovery Ø Premedication: - Relieve anxiety à benzodiazepines - Produce sedation and amnesia à benzodiazepines - Relieve pain à opioids - Reduce secretions à atropine - Reduce nausea and vomiting (common hang-over effects of GAs) à metoclopramide - Neuromuscular blockade à Suxamethonium à for paralysis (immobility) for surgery and endotracheal tube Ø Stages of anaesthesia: - 4 stages: analgesia à excitement à surgical anaesthesia à medullary depression - Stage 1 is variable - Stage 2 rapidly - Stage 3 is when surgery starts Stage 4 à need to be avoided à starts with respiratory arrest then cardiac arrest Intravenous GAs: Ø Thiopental (barbiturate – works on GABA-A receptor): - Ultra-short/fast acting barbiturate à loss of consciousness in 10 – 20 seconds, regained in 2 – 3 mins - Fat soluble and slowly released from adipose tissue à Hangover for up to 24 hours - Adverse effects: laryngeal spasm, cardiac and respiratory depression, hypersensitivity (anaphylaxis) Ø Midazolam: - A benzodiazepine - Water soluble - Slower onset and recovery but less risk of respiratory and cardiovascular depression Ø Propofol: - May be used alone for short procedure (< 1 hour) - Act in 30 seconds - No hangover and little/no nausea but cardiac and respiratory depression Inhalational GAs: à NAUSEA & VOMITING, lipid solubility (higher lipid solubility à higher potency) Ø NO2 (nitrous oxide gas) Ø Ether and chloroform (volatile liquids): more potent but explosive and toxic Ø Halogenated GAs (halothane): non explosive and safe - Metabolites associated with hepatotoxicity - Cardiovascular and respiratory depression à bradycardia and arrhythmia Ø Isoflurane: - Widely used - Hypotension, less cardio depression Ø Desflurane and Sevoflurane: faster induction and recovery Hangover: - Temporary confusion and memory loss à more common in elderly - Dizziness - Difficulty passing urine - Nausea and vomiting - Shivering and feeling cold - Sore throat due to the breathing tube Effects of GAs important for medical treatments: - Analgesia à blockade of pain pathways - Anterograde amnesia à suppression of hippocampus, prefrontal cortex and amygdala à inability to form new memories - Immobility à depression of spinal motor neurons à require very high concentration though - Loss of consciousness The more lipophilic the compounds à The greater the GA effect Effects on CNS: - Enhance inhibition via GABA-A receptor potentiation - Inhibit excitation by blocking NMDA or ACh receptors - Reduce excitation by opening K+ channels Parkinson’s Disease Definition: Ø A degenerative brain disorder affecting movement Ø Gradual loss of muscle control Ø Not fatal but progressive and incurable - Severely affects QOL Ø Loss of dopaminergic neurons in the substantia nigra part of the brain Abnormally low dopamine levels Epidemiology: Ø 10m worldwide, 100k in Australia Ø Second most common neurological disease after dementia Ø Most common age of diagnosis: 65 Ø Unknown aetiology - No remission Ø Disease progression is highly variable Median time from disease onset to death is 12 years Challenges: Ø Unknown cause Ø No diagnostic test available Ø Likely to be a multifactorial disease Ø Significant heterogeneity Risk factors: Ø Older age: - Due to acceleration of the normal, age-related deterioration of neurons Ø Oxidative damage: - Free radicals à damage molecules generated through normal chemical reactions in the body Ø Environmental factors: - An external or internal toxin which destroy the neurons Ø Genetics: - Family history of PD Ø Medications: Types: Ø Parkinsonism = an umbrella term for many conditions which share some of the symptoms of PD Ø PD or idiopathic (unknown) PD is the most common form of parkinsonism Ø Vascular parkinsonism: - Multiple small strokes in key areas of brain - No specific clinical features to differentiate PD and vascular parkinsonism Ø Dementia with Lewy bodies (DLB): - Progressive problems with memory and fluctuations in thinking, hallucinations - Slowness, stiffness and other symptoms similar to PD Ø Drug-induced parkinsonism: - Most common form of secondary parkinsonism - Side effects of certain medications esp. those affecting brain dopamine levels like antipsychotics and antiemetics Symptoms: Ø Motor symptoms: - Tremor – shaking usually starts on 1 side of body, in the hand or finger - Dystonia – repetitive muscle movements that makes body parts twist - Rigidity – stiffness where the limbs feel like lead - Akinesia/bradykinesia – difficulty in initiating movement and slowness of movement - Postural instability – problems with balance - Vocal symptoms Ø Nonmotor symptoms: - Mental/behavioural issues - Sense of smell - Sweating and melanoma - GI issues - Pain Treatment: Ø Functional neurosurgery: - Deep brain stimulation (DBS) - Relieve symptoms for a period of time only Ø Non-pharmacological measures: - Counselling and education for both patients and cares - Provide info about commonly prescribed medicines to avoid - Engage in physical activity and maintain core balance and strength à improve gait and postural stability - Physiotherapy with large amplitude physical training - Supportive care in very advanced phases of PD as drugs become poorly tolerated Ø Pharmacological treatment: - Goal à symptomatic relief - Medications à increase levels of dopamine or inhibit the actions of ACh in the brain - No agent slows disease progression - Important to distinguish idiopathic PD from other causes of parkinsonism à when tremor is the main symptom, consider other condition like hyperthyroidism or essential tremor. Ø Medications to manage motor symptoms: - Levodopa & dopa-decarboxylase inhibitors à replace missing dopamine in the brain - Dopamine agonists à mimic dopamine - Monoamine oxidase type B inhibitors (MAO-B inhibitors) -> conserve dopamine by blocking the enzyme responsible for the conversion - Anticholinergics Ø Treatment choice: - Patient age - Symptoms and severity - Duration of PD - Tolerability - Response Ø Levodopa combinations OR a dopamine agonist à 1st line treatment - Dopamine agonist preferred in younger patients - Levodopa in those > 70 - Start with a low dose and increase gradually to improve mobility while minimising adverse effects n Levodopa combinations: o Most effective symptomatic treatment o Used in early and advanced PD o 1st line treatment for most people, esp. older people and those with cognitive impairment o Well tolerated and lower adverse effect than others o Given with a peripheral dopa-decarboxylase inhibitor: à decrease peripheral metabolism of levodopa to dopamine à decrease in peripheral dopamine adverse effects (nausea, vomting) o Side effects: + nausea, vomiting + postural hypotension + cardiac arrhythmias + constipation + sudden sleep episodes + impulse control disorders + confusion, hallucinations o Drug interactions: § Dopamine antagonists (antipsychotics) à decrease in therapeutic effects § Drugs with dopamine agonist activity à increase side effects § Drugs that lower BP (methyldopa) à additional drop in BP n Dopamine agonists: o Effective 1st line o Improve bradykinesia and rigidity – less effective than levodopa o No significant difference in outcomes between levodopa combinations and dopamine agonists à can be used in combination as disease progresses o Efficacy and safety of oral dopamine agonists are similar o Ergot derivatives: Cabergoline, bromocriptine, pergolide: § Monitor interval echocardiograms, respiratory function and chest X-ray for those unable to switch from ergot preparations § Efficacy and safety similar § Pergolide à marketed for use as an adjunct to levodopa only § Bromocriptine and pergolide rarely used § Side effects: similar to levodopa + cardiac valvular disease and pleuro pulmonary retroperitoneal fibrosis o Non-ergot: Pramipexole, rotigotine, ropinirole à preferred due to no risk of fibrosis § Good symptomatic therapy § Less dyskinesia and motor fluctuations than levodopa § Once daily dosing in oral and topical forms § Side effects: similar to levodopa + peripheral oedema o Higher incidence of adverse effects, esp. impulse control disorders, hypersexuality and neuropsychiatric effects, which are usually treated with antipsychotics n Monoamine oxidase type B inhibitors o Rasagiline and selegiline o Reduce breakdown of dopamine and may block dopamine reuptake o Used as monotherapy and as an adjunct to levodopa in later stage disease o Less effective than levodopa and dopamine agonists o Side effects: orthostatic hypotension, dyskinesia, headache, insomnia, nausea, vomiting, accidental injury, rash o When used with levodopa à increase dopaminergic side effects n Anticholinergic agents: o To reduce excess cholinergic activity that accompanies dopamine deficiency in PD o Benzhexol, benztropine, biperiden o Not commonly used due to side effects and poor efficacy o Modest effect on tremor and little effect on rigidity and bradykinesia o No benefit for other motor symptoms o Consider for treatment of levodopa-resistance tremor in younger patients o Avoid use in older people and those with cognitive impairment o Side effects: confusion, hallucinations, memory disturbance, dry mouth, constipation, urinary retention, glaucoma Medications to avoid in PD: Ø Antinausea medications à metoclopramide, prochlorperazine Ø Antipsychotic medications à haloperidol, risperidone Management of non-motor symptoms: Ø Treatment of dementia in PD with anticholinesterases Ø Psychosis is rare in untreated disease and predominantly drug-induced à if needed, use Quetiapine and Clozapine as they are less likely to worsen parkinsonism Dopaminergic Drugs Neurotransmitters: Ø Monoamines: dopamine, noradrenaline, serotonin - Synthesised from amino acids (L-tyrosine for catecholamines, L-tryptophan for serotonin) - Synthesis is mainly catalysed by cytosolic enzymes - Activate mainly G-protein coupled receptors - Anatomical distribution: synthesis restricted to sub cortical or brainstem regions, which project to multiple cortical and limbic target regions Anatomy of dopamine in PD & psychosis: Ø Nigrostriatal pathway: - Substantia nigra to striatum - In PD: loss of dopaminergic neurons in the substantia nigra à not enough dopamine to striatum à motor symptoms of PD Ø Mesolimbic & mesocortical pathways - Ventral tegmental area (VTA) to limbic or cortical regions - Feedback loops o Striatum à posture, movement o Frontal lobe regions à emotion, motivation, decision making o Amygdala à emotion, esp. fear, anxiety o Nucleus accumbens à reward, pleasure, addiction o Hippocampus à memory o Thalamus/hypothalamus à autonomic regulation Dopamine receptors: Ø D1-like family: D1, D5: - Gs-coupled - Activate AC - Increase cAMP Ø D2-like family: D2, D3, D4: - Gi-coupled - Inhibit AC - Decrease cAMP Indications of dopaminergic drugs: Ø Parkinson’s disease: - Degenerative (motor) disorder - Loss of dopaminergic neurons in substantia nigra – 70% cell loss at time of diagnosis/motor symptom onset - 1% of people over 60%, Male > Female - Tremor at rest, muscle rigidity, hypokinesia (trouble initiating movements) - Non-motor symptoms: dementia, autonomic dysfunction (can come early than motor symptoms but no recognisable), sensory (smell), sleep (REM behaviour disorder) - Environmental risk factors: o Often idiopathic (no genetics link) o May follow head injuries, pesticides (vs coffee, tea, tobacco are protective), viral infection o Induced by neuroleptic drugs or toxins such as MPTP à drug-induced parkinsonism 7% - Treatment: o Pre-cursor to dopamine: Levodopa o Dopamine receptor agonist: Apomorphine, Rotigotine o Selective MAO-B inhibitors (non-selective exist): Selegiline, Safinamide o Peripheral inhibitors of levodopa breakdown (AADC or COMT inhibitors): Carbidopa, Benzerazide, Entacapone Ø Schizophrenia: - Illness of disordered thinking, continuous or relapsing psychosis - Complex: dopamine, serotonin, and glutamate are implicated à excessive dopamine activity implicated with positive symptoms - 1% of population, begins in teens – early adulthood, Male > Female - Positive symptoms: delusions, hallucinations - Negative symptoms: flattened emotions, anhedonia, withdrawal from social contact - Cognitive symptoms: memory, attention, executive function - Environmental risk factors: o Cannabis in adolescence o Pollution o Childhood trauma/psychosocial stress o Infections - Treatment: o Typical/FGAs à putative D2 antagonists: Chlorpromazine, Haloperidol o Atypical/SGAs à D2/5-HT2A antagonists: Clozapine, Olanzapine, Quetiapine, Amisulpride o 3rd generation antipsychotics à partial agonist at D2, 5-HT1A receptors AND antagonist at 5-HT2A, 5-HT1B receptors: Aripiprazole, Cariprazine, Brexiprazole Dopaminergic drugs for Parkinson’s disease: Synthesis: Ø Reduction of dopaminergic neurons in the substantia nigra in PD Ø Tyrosine hydroxylase (TH) is the rate limiting step in the synthesis of catecholamines Ø L-DOPA à the intermediary between L-tyrosine and dopamine à bypass the rate limiting step à allow for more dopamine synthesis Ø Aromatic L-amino acid decarboxylase (AADC or AAAD) - DOPA decarboxylase (DDC)/Tryptophan decarboxylase/5-hydroxytryptophan decarboxylase - Enzyme for the synthesis of L-DOPA to dopamine and L-tryptophan to serotonin o L-Dopa crosses BBB by amino acid transporters à dopaminergic effect in the CNS o If L-Dopa is converted to Dopamine by AADC in the periphery, dopamine can’t cross BBB à peripheral effects - DCC inhibitors: Carbidopa, Benzserazide à Do not cross the blood-brain barrier (BBB) à increase dopamine levels in the brain by inhibiting peripheral degradation of L-DOPA à prevent peripheral side effects of excessive dopamine (nausea, vomiting, hypotension) Storage: Ø Dopamine is storage in the vesicles Ø In and out through vesicular monoamine transporters (VMAT) - Non selective transporters - For all monoamines and similar structured molecules Release of dopamine: Ø Action potential Ø Influx of Ca2+ à allows the storage vesicles to dock into the membrane à exocytosis à release of neurotransmitters Receptor activation: Ø Apomorphine: - D1 and D2 receptor agonist - 1st dopamine receptor agonist used in PD - Used in late stage PD, adjunct to Carbidopa/Levodopa therapy à Rescue therapy - Conformationally restricted analogue of dopamine - SAR: o Dopamine à flexible à attain many different low-energy conformations o Trans-conformation of dopamine à active o Cis-transformation à inactive Ø Other D2 agonist for early to late PD: - Ergot derivatives: Bromocriptine, Cabergoline, Lisuride, Pergolide (withdrawn) o Ergot is a fungus that grows on rye plants à produce bioactive alkaloids o “Dirty” à not selective, acting on many receptors à serious side effects o D1, D2, 5HT, alpha-adrenergic activity o Side effects: cardiac (valves), lung fibrosis - Non-ergoline dopamine receptor agonists: Pramipexole, Ropinirole, Rotigotine (patch for early to late PD) o Better tolerated o Adjunct therapy to Carbi/Levo (the longer you take carbi/levo, the more likely you get the motor side effects and breakthrough symptoms) o Can be taken at early state of PD à postpone the initiation of carbi/levo o Favour D3 > D2 in vitro Impulse control disorder: Ø Side effect of dopaminergic therapy Ø DA-R agonists are the strongest risk factor à Activation of DA-reward system Ø Presentations: - Pathological gambling - Hypersexuality - Binge eating - Compulsive buying à Repetitive or compulsive behaviours, reduced control over these behaviours and pleasure feeling while doing these Inactivation – Reuptake: Ø DAT, NAT, SERT à selective dopamine, noradrenaline and serotonin reuptake transporters Ø Block these transporters à decrease reuptake à increase dopamine availability in synapses Inactivation – Degradation: Ø Monoamines are broken down by mitochondria-bound monoamine oxidase (MAO) via oxidative deamination Ø MAO isoforms: - MAO-A degrades 5HT, NA, A, DA - MAO-B degrades DA Ø Non-selective MAOIs = Antidepressants - Ladostigil: o Irreversible CNS – selective MAO-A/B inhibitors o Reversible acetylcholine/butyrylcholine esterase inhibitors à 2 pharmacophores from parent compounds (propargylamine from Rasigaline, and carbamate from Rivastigmine) Ø Selective MAO-BIs = PD treatment - Selegiline à irreversible - Safinamide à similar to tyrosine, reversible Ø Catecholamines and their intermediates are also degraded by Catechol-O-methyltransferase (COMT): - L-DOPA is converted to 3-O-Methyldopa by COMT - COMT inhibitors: Entacapone à selective, reversible Importance of Reversibility for safety: Ø Irreversible MAOIs: - Permanently change the enzyme via covalent bond formation - Modify key aa residues required for the enzyme’s activity Ø Reversible MAOIs: - Bind to the active site of the enzyme à inhibit its activity - Can be displaced by endogenous catecholamines or other ligands à Safer Hypertensive crisis: Ø Sudden increase in BP (≥ 180/120 mmHg) Ø Can lead to heart attack, hemorrhagic stroke, organ damage Ø Commonly headache Ø Causes: - Cheese effect = Dietary tyramine (cheese, esp. aged cheese, cured or smoked or processed meat, fermented food etc.) + MAOIs - Tyramine = amino acids à regulate BP - Elevated tyramine displaces NA, Ad from ventrolateral medulla - NA activates alpha and beta-1 adrenoceptors in blood vessels, myocardium à increased HR and BP Ø MAO-BIs and CNS-selective inhibitors and reversible inhibitors à less chance of causing hypertensive crisis Acetylcholine in PD Post-mortem degeneration of ChAT-expressing cells i.e. ACh-producing cells ACh reduction à cognitive decline Ratio between DA and ACh is important Rivastigmine: Ø Non-selective cholinesterase inhibitor Ø Treats cognitive dysfunction in PD and Alzheimer’s Ø Won’t improve and may worsen motor symptoms but improve overall health outcomes and prolong independence Ø Derived from Physotigmine Benzatropine: Ø Second-line treatment of PD for tremor, rigidity, and hypokinesia Ø Used to relieve drug-induced dystonia (from antipsychotic use) Ø Anticholinergic/antihistamine Ø M1 mAChR antagonist à boost dopamine release Ø Restores ACh/DA balance Ø Derived from Atropine Dopaminergic drugs for schizophrenia The dopamine hypothesis: Modulating dopamine has clinical efficacy but the underlying cause may be non-dopaminergic Ø 1st generation: - Antagonist at D2 receptors Ø 2nd generation: - Antagonist at D2 and 5HT2A receptors - 5-HT2A : D2 affinity ratio important (1.12 or higher) - Improved side effect profile - But no better for symptom management (positive, negative or cognitive) Ø 3rd generation: - Partial agonists at D2, 5HT1A - Antagonist at 5HT2A,1B - Still no better for symptom management Ø Treatment resistant, ultra-resistant - Do not respond to 1st-line antipsychotics - Will respond to clozapine - Ultra-resistant won’t respond to any antipsychotics incl. clozapine Ø Efforts to develop non-dopamine antipsychotics Ø Mechanisms: glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanism. à NONE are approved for the treatment of positive, negative or cognitive symptoms of SZ D2 agonists for SZ Ø Clinical potency of antipsychotics is tightly related to their affinity for the D2 receptor in vitro Ø Correlation ≠ Causation Ø Drug with the highest affinity (the most potent one) is not necessarily the most clinically useful Dopaminergic hypothesis of SZ: Ø Mesolimbic pathway: - Hyperactivity leads to positive symptoms - Increased D2 activation - Treatment aims to inhibit limbic D2 Ø Mesocortical pathway: - Hypoactivity leads to negative and cognitive symptoms - Decreased D1 activation - Treatment aims to increase cortical D1 Ø Nigrostriatal pathway: - DA hyperactivity in associative striatum (medial caudate & ventral putamen) à cognitive symptoms - DA hyperactivity correlated with symptom severity - Changes present in prodromal period à biomarkers: o Cognitive impairment o Elevated dopamine synthesis capacity (imaging) Drug-induced psychosis: Ø Drugs that increase synaptic dopamine availability - Cocaine - Amphetamine - PCP/ketamine - Scopolamine - LSD - L-dopa Ø Induce positive, negative and cognitive symptoms Ø Effects of drugs on dopamine storage: - Drugs such as amphetamine (MDMA) compete with native monoamines as substrates for VMAT (vesicular monoamines transporters) à leave excess monoamine including dopamine in the cell à spillover of neurotransmitters into the synapse à increased post-synaptic monoaminergic/dopaminergic activity Ø Effects of drugs on dopamine reuptake: - Cocaine blocks DAT, NAT and SERT - Amphetamines competes with monoamines at DAT, NAT and SERT à decreased reuptake à increased post-synaptic monoaminergic/dopaminergic activity Antipsychotics: Ø First generation: - Phenothiazines à chlorpromazine - Butyrophenones à haloperidol - Diphenylbutylpiperidines à pimozide - Thioxanthenes Ø Second generation: - Benzazepine derivatives (tricyclic) à clozapine, olanzapine, quetiapine - Benzisoxazoles/Benzisothiazoles à risperidone and its metabolite paliperidone - Benzamides à amisulpride Ø Third generation: Phenylpiperazines/quinolinones à aripiprazole, brexpiprazole, cariprazine Phenothiazines – Chlorpromazine: Ø 1st D2 antagonist Ø Also antagonist at 5-HT2,6,7, histamine H1, ɑ-adrenergic, mACh Rs Ø Highly sedating Ø Indications: drug-induced psychosis, bipolar/MDD, ADHD, antiemetic, pre-anaesthetic, intractable hiccups Ø Side effects: EPS, tardive dyskinesia, sedation, dry mouth, postural hypotension, weight gain Ø Extrapyramidal symptoms (EPS) à motor symptom - Tardive dyskinesia – ticks in lower faces, distal extremities - Dystonia – spasms and muscle contractions, can be painful - Parkinsonism – tremor, rigidity, hypokinesia - Akathisia – motor and psychological restlessness, fidgeting, agitation Ø Important chemical properties: - Tricyclic and electron withdrawing ring on A ring - Bend in B ring creates butterfly or A-shape - Amine side chain contains 3 carbon atoms - Protonated at physiological pH Butyrophenones – Haloperidol: Ø Most prescribed FGA Ø Antagonist at D2 and alpha-adrenergic > 5HT2A Ø Emerged from SAR of pethidine (a synthetic opiate) analogue Ø Indications: drug-induced psychosis, intractable hiccup, tic disorders, severe nausea/ emesis in chemotherapy Ø Side effects: EPS, hypotension, weight gain but no anticholinergic effects (dry mouth, blurred vision) Ø Important chemical properties: - Length of linker has to be 4C Ø Haloperidol decanoate (slow released formulation): added saturated fatty acid side chain à increased lipophilicity à slows the release à often injected in adipose tissue Benzazepine derivatives – clozapine: Ø 1st SGA Ø DA, 5HT, alpha-adrenoceptor, histamine receptor antagonist Ø Used in treatment-resistant SZ à alleviate negative symptoms - High compliance rate à Reduce suicide, hospitalisation, death etc. - Other uses: psychosis in PD, violence/self-harm in personality disorders Ø Side effects: neutropenia, agranulocytosis (highest risk in the first 18 months), weight gain (clozapine and olanzapine most likely), less risk of EPS, less hyperprolactinemia à Greater compliance and reduced mortality Ø Important chemical properties: - Based on TCA Imipramine - Benzene ring and azepine ring Benzisoxazoles – Risperidone: Ø Paliperidone à primary active metabolite of Risperidone Ø Widely prescribed, effective for negative and some evidence for cognitive symptoms Ø D2, 5-HT2A, ɑ-adrenoceptor, H1 antagonist Ø Other uses: bipolar disorder, severe agitation in acute psychosis, irritability/aggression/self-harm in autism Ø Side effects: - EPS, Orthostatic hypotension, sedation, weight gain - Significant hyperprolactinemia à more than other SGAs and less than FGAs à Higher compliance and lower relapse than Haloperidol Ø Important chemical properties: - Oral and injectable (long-acting) versions - Injectable form (different from haloperidol decanoate) has the drug encapsulated in polymer to create microspheres (rather than oil-based) Give every 2 weeks for risperidone, and every 4 weeks for paliperidone Benzamide derivatives – Amisulpride: Ø SGA – 1st line treatment for acute psychosis Ø D2 (D3) antagonist - Block D2 allows for dopamine to activate D1 - Treat negative symptoms/depression Ø Potent antagonist at 5-HT7 (antidepressant effect), binds 5-HT2B Ø Other uses: antiemetic (pre or post-operative), dysthymia (persistent mild depression) Ø Side effects: - Elevated prolactin, - Lower risk of movement disorders - Less cholinergic (dry mouth, blurred vision) à Greater compliance Ø Important chemical properties: - 2 enantiomers have different affinities for D2 vs 5HT7 - (R) favours 5HT7 receptor - (S) favours D2 receptor - 85:15 ratio of R to S à optimal for antidepressant, minimising EPS Phenylpiperazines/quinolinones - Aripiprazole, Brexpiprazole, Cariprazine: Ø 3rd generation Ø Partial agonists at D2, 5HT1A à dopamine stabiliser Ø Antagonists at 5HT (2A, 2C, 7), H1, alpha-adrenoceptor, low M1 Ø Lower efficacy, also lower side effects Ø Other uses: bipolar, tic disorders, irritability in ASD Ø Side effects: - Less EPS - Less weight gain/metabolic effects - Less hyperprolactinaemia - Less dry mouth or blurred vision à Poorer long-term efficacy, increased relapse Ø Important chemical properties: - Depot formulation avail - Full antagonist will inhibit dopamine to 0 regardless of intrinsic activity level - Partial agonist will stimulate when DA is low and inhibit when DA is high - Decreased hyper-dopaminergic activity à reduce positive symptoms - Increase hypo-dopaminergic activity à reduce EPS, negative/cognitive symptoms Antipsychotics – summary: Ø Mechanism of actions: - FGA: o Inhibit limbic DA receptors alleviate positive symptoms o Inhibit striatal Da receptors causes motor adverse effects - SGA: o Inhibit 5HT-2A leads to indirect, downstream elevation in striatal dopamine, minimising EPS - TGA: o More controlled modulation of dopamine levels o Partial agonists of DA and 5HT-1A receptors + Decrease hyperactivity in limbic and striatal regions à alleviate positive and cognitive symptoms respectively + Increase hypoactivity in cortical regions à improve negative symptoms Ø Efficacy: - Difficult to get high quality comparative data due to high drop-out rate - Location of brain binding important for efficacy and side effects o Atypical risperidone, clozapine, olanzapine, amisulpride) superior to typical antipsychotics for treating both positive and negative symptoms o Little difference in efficacy btw typical and atypical antipsychotics Ø Tolerability: - Clozapine à greatest efficacy and tolerability à for treatment-resistant SZ - Atypical antipsychotics à fewer motor side effects à greater tolerability - Depot formulations à improve adherence and thus overall symptom improvement Emesis and Antiemetics: MOA of emesis: Ø Vomiting centre: - Located in the medulla oblongata of the brainstem Ø Chemoreceptor trigger zone: - Located in the area postrema and part of the vomiting centre Ø Vagus nerve: - Together with the brainstem, control the vomit reflex Ø Major systems: - 5HT3 receptor system - NK1 receptor system - Dopaminergic receptor systems Antiemetics – treating nausea and vomiting Ø Dopamine antagonists: - E.g. haloperidol, levomepromazine, and other antipsychotics, metoclopramide, domperidone - Act centrally – block the chemoreceptor trigger zone - Not recommended in PD (except Domperidone) Ø Antihistamines: - E.g. cyclizine, promethazine - Effective against nausea and vomiting resulting from many underlying conditions Ø Serotonin (5-HT3) antagonists: - E.g. palonosetron, ondansetron, tropisetron, granisetron - 2nd line - Side effects: headache, constipation - Avoid in patients on MAO-Is Ø Neurokinin (NK1) receptor antagonists: - E.g. netupitant, rolapitant - Block substance P found in neurons of vagal afferent fibres innervating the brain-stem and the area postrema within the chemoreceptor trigger zone - Used in combination with 5-HT3 antagonists for chemo-induced N&V (CMINV) - For cisplatin-based cytotoxic chemo Chemotherapy-induced nausea and vomiting (CINV): - Chemo triggers 5HT release from the small intestine à stimulate 5HT-3 receptors on neurons in the GIT and in the brain that control vomiting - Substance P acts on neurokinin-1 (NK1) receptors in the brain à increase the desire to vomit - 5HT-3 receptor antagonists and NK1 receptor antagonists à act synergistically on these two pathways to alleviate side effects of chemo Ø Acute CINV: - Occurs within the first day of the administration of chemo - Largely mediated by 5HT-3 receptors in the intestine Ø Delayed CINV: - On days 2-5 following the administration of chemo - Driven by a central pathway involving substance P - Require agents that have a long half-life to be effective Akynzeo - Fixed dose combination of netupitant and palonosetron - Oral capsule taken 1 hour before chemo - Dexamethasone is used as adjunct therapy and given 30 mins before chemo Ø Netupitant: - NK1 receptor (GCPR) coupled to inositol phosphate signal-transduction pathway - Antagonist - Half-life 88 hours à help in acute and delayed phases of CINV - Moderately inhibit CYP3A4 and is metabolised by it - Use with caution in patients receiving concomitant medications that are primarily metabolised by CYP3A4 Ø Palonosetron: - 5HT-3 receptor is an ion channel (Cys-loop receptor like GABA-A) - Antagonist - Half-life 48 hours (+/- 19 hours) - Prevent nausea and vomiting during the acute phase Dementia Pharmacology Cholinergic hypothesis: Ø Cholinergic neurotransmission important in memory processing and storage Ø Cholinergic neuron degeneration occurs early and is most severe Ø Cholinergic hypothesis – enhance cholinergic transmission to treat symptoms of dementia Acetylcholinesterase (AChE): Ø Rapid hydrolysis of Ach terminates cholinergic neurotransmission Ø Very fast enzyme Ø Enhance rate of hydrolysis 100x106 times Ø Inhibiting AChE à increase in ACh and an overall effect of enhancing cholinergic neurotransmission Smart drugs: Ø Act in the CNS Ø Must cross BBB Ø Used to treat memory loss in AZD Ø AZ causes deterioration of cholinergic receptors in brain Ø Smart drugs inhibit ACh hydrolysis to increase activity at remaining receptors Drugs in clinical use: Ø Symptom modifying drugs à doesn’t prevent progression of the disease Ø AChE inhibitors: - Tacrine - Rivastigmine - Donepezil - Galantamine à US dietary supplement Ø N-Methyl-D-Aspartate (NMDA) antagonist: - Memantine AChE inhibitors: Ester hydrolysis reaction: AChE binding site: ACh is a quaternary ammonium ion (positively charged at N) Ø Catalytic triad: - An aspartate residue interacts with the imidazole ring of histidine to orientate and activate it Ø Peripheral anionic site: Rivastigmine (carbamate): Ø Positively charged N at physiological pH Ø Carbamate group instead of an ester Ø Pseudo irreversible (40h) Ø Predominantly target BuChE (more selective than others) à highest amount of side effects Tacrine (aminoacridine): Ø Lipid soluble Ø Competitive inhibitor Ø Cholinergic toxicity (liver toxicity) - More selective for BuChE than AChE Ø Butyrylcholinesterase (BuChE): - 65% sequence similarity to AChE - Acylation site is much larger - Mainly localised to glial cells which increase in AD - BuChE levels increase in AD patients + Normal BuChE : AChE ratio ≈ 0.3 + In AD à ratio can be as high as 11 - Side effects may be due to BuChE activity - BuChE as a target in later stages of AD Galantamine (tertiary alkaloid): Ø Relatively weak inhibitor Ø Even weaker at BuChE and AChE Ø Enhance production of ACh and other neurotransmitters Ø Well tolerated possibly due to lack of BuChE effects Donepezil: Ø Interact with both the active site (acylation site) and peripheral anionic site Ø Predominantly target AChE Ø Selective for the central cortex Ø Lowered Beta-amyloid in vitro, but no effects in humans Ø Well tolerated possibly due to lack of BuChE effects NMDA receptor antagonists NMDA receptors: Ø 2 binding sites: o NR1 à glycine o NR2 à glutamate or NMDA Ø Both sites need to be occupied by their agonists for the receptor to be active Ø Found across the brain Ø Need to inhibit the active receptors only to reduce the excess glutamate activity without affecting the rest of the processes that require normal NMDA receptors Glutamate: Ø Acts at NMDA receptors which important for learning and memory (synaptic plasticity) Ø Only activate the receptor very briefly Ø Over activation à excitotoxicity and cell death Ø Elevated levels of glutamate present in many neurodegenerative diseases Ø Beta-amyloid à increase NMDA responses Memantine: Ø Uncompetitive open channel blocker - High degree of channel blockade in presence of excessive glutamate - Little blockade at relatively lower levels of glutamate Ø Low affinity Ø Methyl groups prolong time in channel, increase affinity and slow off rate Disease modification: Drug design difficulties: - Scarcity of AD markers in preclinical stage - Scarcity of markers of AD phenotypes - Selective action on diseased cells - Distinguish btw disease modification and symptomatic action - Prolonged observation to show delayed progression - Require diversity and large numbers for clinical - High economic cost of trials Amyloid hypothesis: Ø Beta or gamma-secretase cleaves APP incorrectly to give beta-amyloid Ø Beta amyloid forms plaque deposits à neurotoxic cascade Ø Cholinergic links to APP processing Ø Some correlation btw elevated beta-amyloid levels and cognitive decline Ø Some cognitively normal people still have high levels of amyloid plaques Targets: Aducanumab: Ø Fully human mAb that binds to the N-terminus of beta-amyloid Ø Generated by a reverse translational approach - Antibodies derived from elderly that have not developed AD - They may have an unusual resistance to developing the disease Ø Binding is very selective for beta-amyloid aggregates - Both soluble oligomers and insoluble fibrils - But NOT soluble monomeric betaamyloid Ø High affinity Ø Binds to aggregated forms of beta-amyloid and preferentially binds to parenchymal amyloid over vascular amyloid Ø IV infusion Ø Aduhelm à 1st drug approved as a potential disease-modifying agents for AD and for mild dementia - Surrogate end-point à reduction in beta-amyloid plaques à improve cognition and overall functioning - Still controversial - Required to continue phase 4 trials and provide evidence of clinical efficacy - Very costly Lecanemab: humanised version of a mouse antibody, mAb158 à recognise protofibrils and prevent amyloid beta deposition à reduce amyloid plaques but NO reduction on ADCOMS - Infusion every 2 weeks - Can slow cognitive decline by 27% in mild cognitive impairment (mild stage dementia) Pharmacogenomics for neurology Roles of pharmacogenomics: Ø Identify responders and non-responders Ø Avoid adverse effects Ø Optimise dose for individual patient Examples: Epilepsy: - 50m people worldwide, 90% in developing countries - 1/3 develop refractory epilepsy (drug-resistant epilepsy) - Large inter-individual variability - Due to drugs having to cross the BBB à many genes can affect PK and PD Genetic variation in drug absorption and distribution & role of intestinal and BBB transporters Ø Gene ABCB1 or MDR1 encode for P-gp Ø Phenytoin (PHT) and phenobarbitone (PB) à substrate for P-gp Ø P-gp expressed in the intestine, liver, kidney and on the BBB P-gp 3435C>T genotype: Ø 3435C>T variant à variation in response to many drugs including AEDs with varying outcomes, possibly due to it being part of a halotype (when having more than one gene variant on the same chromosome, passed from parents to children altogether à difficult to determine individual response of one single variant) Ø 3435C>T is a synonymous SNP - A non-synonymous SNP leads to an amino acid change while a synonymous SNP does not - A silent SNP Ø C>T base pair change à a translational delay (change in the rate of mRNA to protein translation in ribosomes) Ø Affect folding of P-gp Ø Leads to difference in substrate affinity and reduce the transporter function (but not the amount of protein in the cell or the plasma membrane) (it doesn’t affect the trafficking of the transporters; it changes the 3D structure leading to interacting with substrates being reduced) Ø Study results: - CC variant (normal) has higher P-gp activity than TT à less drug across BBB in CC patients - C>T SNP (less P-gp activity) à more phenobarbitone (PB) in the CSF à lower doses required - CC (normal P-gp) à more prevalent in patient resistant to phenytoin therapy - TT (2 copies of reduced transporter function) à less people that are resistant Genetic variation in anti-epileptic drug metabolism and elimination: Ø Elimination à via hepatic and/or renal excretion Ø CYP2C9 and 2C19 Ø CYP3A4 not very predictive CYP2C9 polymorphism and Phenytoin metabolism: Ø 80 – 90% of phenytoin metabolised by CYP2C9, residual by CYP2C19 Ø Narrow therapeutic window 10 – 20 mg/L Ø CYP2C9 highly polymorphic à CYP2C9*2 and CYP2C9*3 (*1 is wildtype or normal) - Evidence is clear and strong Ø Rare genotypes à CYP2C9*6 allele à in African-Americas à Completely inactive CYP2C9 enzyme Ø TDM is important Genetic variations affect tolerability and safety of AEDs: Ø Major side effect of carbamazepine, phenytoin, phenobarbital and lamotrigine à allergic rash (10% of patients) Ø In severe cases: - Stevens-Johnson syndrome - Toxic epidermal necrolysis (TEN) - Drug hypersensitivity syndrome è Rare but high mortality rate, life-threatening Ø HLA-B*15:02 in Chinese/Asian (Han-Chinese, Thai, Malay) ethnicity à increased risk of AEDinduced SJS HLA-B*15:02: Ø Human leucocyte antigen genes - Encode for the HLA proteins (cell surface antigen à identify foreign peptides and generate immune response through attraction of T cells) - Used to check for compatibility before tissue and bone marrow transplants Ø Frequently expressed in Han-Chinese descents, rare in Caucasians Ø Risk of SJS/TEN after using carbamazepine is 10x higher in some Asian countries Ø Screen for the gene prior to starting the treatment (avoid use if HLAB1502 positive) Ø Routine testing is not recommended CPIC combined guidelines for phenytoin polymorphisms: Ø Standard loading dose for all *2 and *3 alleles Ø 25% reduction in maintenance dose if one CYP2C9 allele is *2 or *3 (intermediate metaboliser or IM) Ø 50% reduction in maintenance dose if both CYP2C9 alleles are *2 and/or *3 (poor metaboliser or PM) Ø Do not prescribe if patient carries HLA-B*1502 Interactions of phenytoin with food, OTC meds and other drugs: Ø St John Wort increases CYP2C9 activity à decrease phenytoin plasma levels Ø Acute alcohol intake increase phenytoin plasma levels Ø Calcium containing antacids interferes with phenytoin absorption à decrease phenytoin plasma levels Paroxetine: Ø Metabolised by CYP2D6 (to inactive metabolite) but also an inhibitor of CYP2D6 Ø Non-linear PK Ø CPIC guidelines: - CYP2D6 Ultrarapid metaboliser à increase metabolism à less active compounds à lower plasma concentrations à treatment failure è use alternatives that are not metabolised by CYP2D6 - CYP2D6 PM à reduced metabolism à higher plasma concentration à increased side effects è 50% reduction of recommended starting dose and titrate to response or use alternative drugs Sertraline: Ø Phase I: predominantly by CYP2C19 Ø Phase II metabolism by various UGT enzymes Ø Poor metaboliser à 50% reduction of recommended starting dose and titrate to response or use alternative drug Ø UM, EM, IM à start with the recommended starting dose Routine CYP450 genotyping is not recommended for selecting or modifying antidepressants è however, individual prescribers may choose to use guidelines that are available Alzheimer’s and vascular dementia ALZHEIMER’S DISEASE (AD) Abnormalities in the brain structure disrupts the health of neurons Ø Memory failure Ø Personality changes Ø Increasing inability to manage activities of daily living Average life span after diagnosis 8 – 10 years Risk factors: Ø Age Ø Family hx Ø Down’s syndrome Ø Head trauma (e.g. late in life) Ø Female Ø Ethnicity - Caucasians have the lowest risk Ø Late onset depression (after 65) Ø Mild cognitive impairment (MCI) Pathology: Ø 3 consistent neuro-pathological markers: - Accumulation of beta-amyloid senile plaques - Neurofibrillary tangles (TAU aggregation) - Neuronal degeneration Ø Destruction of cholinergic neurones and a reduction in ACh concentration Ø Changes may lead to clinical symptoms but they begin years before the onset of symptoms Ø Summary: Beta amyloid aggregation – TAU aggregation – Neurodegeneration – Symptom onset – Functional decline Disease progression: Early to moderate stages: Memory lapses – persistent and Severe stage Lost in own home frequent memory difficulties esp. of Unable to recognise family and friends Apparent loss of enthusiasm for Unable to speak (aphasia) previously enjoyed activities Taking longer to do routine tasks Forget well-known people or places Unable to process questions and instructions Unable to eat, walk or communicate recent events Vagueness in everyday conversation Final stage Extremely impaired judgment Deterioration of social skills Emotional unpredictability Management: è NONE of the available medications prevents dementia or modifies its pathology Symptomatic Therapy Disease-Modifying Agents Non-Drug Treatment - Behavioural symptoms - Symptom benefit - Counselling - Cognitive symptoms - Alter progression - Social support - Activities of daily living - Delay onset - Occupational therapy Pharmacological Treatment Cholinesterase inhibitors - Donepezil (Aricept) - Rivastigmine (Exelon) - Galantamine (Reminyl) - Respite care - General nursing - Environmental and behavioural therapy Neuropeptide-modifying agent (Disease-modifying agents) - Memantine mAbs (aducanumab, lecanemab