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Preclineazy Sahana MaheshTW DISCLAIMER TW • All the content in this presentation is for educational purposes only • This presentation includes several references to mental health and mental health disorders • There is no intent to cause harm, however we apologize if some of the content can be triggering TW: depression, anxiety, psychosis, schizophrenia, recreational drugs NEUROTRANSMITTERS, PSYCH PHARMACOLOGY, SLEEP & APPETITE SYNAPSES & NEUROTRANSMITTERS DEPRESSION & PHARMACOLOGY PSYCHOSIS & PHARMACOLOGY DRUGS OF ABUSE SLEEP & SLEEP DISORDERS ADOLESCENT NEURO DEVELOPMENT EXTRA CONTENT: APPETITE REGULATION 45-50 MINSCHEMICAL SYNAPSESNEUROTRANSMITTER RELEASE PRE-SYNAPTIC NEURONE Ca2+Ca2+ Ca2+ Ca2+ Ca2+ SYNAPTIC CLEFT WHICH TOXINS ACT HERE? POST-SYNAPTIC NEURONE EPSP or IPSPNEUROTRANSMITTERSDOPAMINE NORADRENALINE SEROTONIN NEUROTRANSMITTERS GABA GLUTAMATE GLYCINE NEUROTRANSMITTER SYNTHESIS DOPAMINE SEROTONIN GLUTAMATE & GABA TRYPTOPHAN TYROSINE Tryptophan GLUCOSE Tyrosine Hydroxylase hydroxylase Krebs cycle (RLS) DOPA 5-HT GLUTAMATE DOPA 5-HTP decarboxylase decarboxylase Glutamate decarboxylase SEROTONIN DOPAMINE GABA Dopamine Beta hydroxylase monoamine oxidase NORADRENALINE 5-HIAA NEUROTRANSMITTER SYNTHESIS GLYCINE Serine hydroxymethyltransferase SERINE **FOLATE-DEPENDENT REACTION GLYCINE TW THE MONO AMINE MODEL OF DEPRESSION ⇩SEROTONIN, DOPAMINE, NORADRENALINE TW THE MONO AMINE MODEL OF DEPRESSION SEROTONIN, DOPAMINE, NORADRENALINE SO⬆ MONAMINES = MOOD THE BASIS OF ANTIDEPRESSANTS ANTIDEPRESSENT TW DRUGS INHIBITION OF INHIBITION OF MONOAMINE REUPTAKE ENZYMATIC BREAKDOWN PRESYNAPTIC INHIBITORS OF MONOAMINES AUTORECEPTORS TRICYCLICS MONOAMINE MIRTAZIPINE SSRIs OXIDASE INHIBITORS NRIs SNRIs AIM: ⬆ MONOAMINE AVAILABILITY IN SYNAPTIC CLEFT ANTIDEPRESSENT DRUGS MONOAMINE REUPTAKE INHIBITION OF INHIBITION OF ENZYMATIC BREAKDOWN PRESYNAPTIC INHIBITORS OF MONOAMINES AUTORECEPTORS TRICYCLICS MONOAMINE MIRTAZIPINE SSRIs OXIDASE INHIBITORS NRIs SNRIs Ca+ + a 2 C MONOAMINE TRANSPORTERS PRE-SYNAPTIC NEURONE POST-SYNAPTIC NEURONE SYNAPTIC CLEFT ANTIDEPRESSENT DRUGS MONOAMINE REUPTAKE INHIBITION OF INHIBITION OF ENZYMATIC BREAKDOWN PRESYNAPTIC INHIBITORS OF MONOAMINES AUTORECEPTORS TRICYCLICS MONOAMINE MIRTAZIPINE SSRIs OXIDASE INHIBITORS NRIs SNRIs Ca+ + a 2 C MONOAMINE OXIDASE PRE-SYNAPTIC NEURONE POST-SYNAPTIC NEURONE SYNAPTIC CLEFT ANTIDEPRESSENT DRUGS INHIBITION OF MONOAMINE REUPTAKE INHIBITION OF PRESYNAPTIC INHIBITORS ENZYMATIC BREAKDOWN AUTORECEPTORS OF MONOAMINES TRICYCLICS SSRIs MONOAMINE MIRTAZIPINE NRIs OXIDASE INHIBITORS SNRIs Ca + 2 + C a AUTORECEPTORS THAT RESTRICT NT RELEASE PRE-SYNAPTIC NEURONE POST-SYNAPTIC NEURONE SYNAPTIC CLEFT ANTIDEPRESSENTS TW DRUG NAMES REUPTAKE INHIBITORS MAOIs TRICYCLICS SSRIs CITALOPRAM AMITRIPTYLINE SERTRALINE ISOCARBOXAZID • Non-specific REUPTAKE FLUOXETINE (longer half life) INHIBITION action (serotonin, FLUVOXAMINE noradrenaline, alpha-1, PAROXETINE histamine, muscarinic) NRI REBOXETINE SNRI DULOXETINE ANTIDEPRESSENTS DRUG NAMES TW REUPTAKE INHIBITORS MAOIs TRICYCLICS SSRI side effects AMITRIPTYLINE ISOCARBOXAZID • Milder side effects • GI upset SIDE EFFECTS!!! • Insomnia & agitation SIDE EFFECTS!!! Anti-muscarinic effects, postural • Sexual dysfunction Hypertensive reactions (raised hypotension, sedation • SIADH ICP) due to excess tyramine build Toxic in overdose • SNRIs: ↑BP, sweating up. “cheese crisis” OVERDOSE: cardiotoxicity, comas, CITALOPRAM: prolonged QT interval seizures FLUOXETINE: CP450 inhibitor Generally safe in overdose **SEROTONIN SYNDROME SYNDROME WHEN USED WITH OTHER DRUGS THAT INCREASE SEROTONIN ANTIDEPRESSENTS TW DRUG NAMES AUTORECEPTOR INHIBITOR MIRTAZIPINE Apart from this, has effects on: • 5HT3 autoreceptors: increase appetiteweight gain • H1: antagonist, drowsiness IMPORTANT ADR!!! IDIOSYNCRATIC AGRANULOCYTOSISDOP AMINERGIC MESOLIMBIC • VTA to nucleus accumbens, amygdala • Reward pathway PATHWAYS • Overactivation implicated in positive symptoms of schizophrenia MESOCORTICAL • VTA to PFDC • Prioritization & planning • Underactivation implicated in negative symptoms of schizophrenia • Symptoms not improved by using typical antipsychotics NIGROSTRIATAL • Substantia nigra to basal ganglia • Movement TUBEROINFUNDIBULAR • Hypothalamus to pituitary • Regulation of prolactin release • More dopamine = less prolactin releaseTHE DOP AMINE MODEL OF PSY CHOSIS ⬆DOPAMINE ⬆PSYCHOTIC SYMPTOMS? TWTHE DOP AMINE MODEL OF PSY CHOSIS ⬆ DOPAMINE ⬆ PSYCHOTIC SYMPTOMS? SO⇩DOTHE BASIS OF ANTI-PSYCHOTICSTHE DOP AMINE MODEL OF PSYCHOSIS ⬆ DOPAMINEà ⬆ PSYCHOTIC SYMPTOMS? SO⇩ DOTHE BASIS OF ANTI-PSYCHOTICS*** ***exception: negative effects of schizophrenia TW ANTIPSYCHOTIC DRUGS FIRST GENERATION SECOND ANTIPSYCHOTICS GENERATION “TYPICAL” ANTIPSYCHOTICS ‘ATYPICAL” D2 RECEPTOR ANTAGONISTS 5-HT2 & D2 RECEPTOR ANTAGONISTS HALOPERIDOL CLOZAPINE OLANZAPINE LOWER DOPAMINE IN MESOLIMBIC PATHWAY, IMPROVES ONLY POSITIVE RISPERIDONE ARIPIPRAZOLE SYMPTOMS INCREASE DOPAMINE IN MESOCORTICAL & MESOLIMBIC PATHWAY, IMPROVES BOTH POSITIVE AND NEGATIVE SYMPTOMS ANTIPSYCHOTICS INDICATIONS FIRST SECOND GENERATION GENERATION ACUTE DELIRIUM ACUTE PSYCHOSIS DELUSIONAL OR AGITATED PSYCHOTIC SYMPTOMS CAUSED STATES IN ADULTS BY PARKINSON’SFOR SCHIZOPHRENIA CLOZAPINE FOR TREATMENT- RESISTANT SCHIZOPHRENIAA 34-year-old male was started on clozapine for his refractory schizophrenia one month ago. He presents to the emergency with a temp. of 38.4 degrees Celsius, sweaty and complains of malaise. What is the most likely complication caused by the drug he was started on? A. Prolonged QT B. Agranulocytosis C. Pericarditis D. Cushing’s Triad E. PneumothoraxA 34-year-old male was started on clozapine for his refractory schizophrenia one month ago. He presents to the emergency with a temp. of 38.4 degrees Celsius, sweaty and complains of malaise. What is the most likely complication caused by the drug he was started on? A. Prolonged QT B. Agranulocytosis C. Pericarditis D. Cushing’s Triad E. Pneumothorax ANTIPSYCHOTICS ADVERSE EFFECTS FIRST SECOND GENERATION GENERATION VERY FEW EXTRAPYRIMIDAL SIDE EFFECTS EXTRAPYRAMIDAL SYMPTOMS (Acute Dystonia, Akathesia, LESS SIGNIFICANT HYPERPROLACTINEMIA Parkinsonism, irreversible Tardive (risperidone) dyskinesia) “ADAPT” HYPERPROLACTINEMIA PROLONGED QT INTERVAL (block repolarisation of K+ channels in myocardium) RISK OF NEUROLEPTIC MALIGNANT SYNDROME ANTIPSYCHOTICS ADVERSE EFFECTS SECOND GENERATION FIRST VERY FEW EXTRAPYRIMIDAL SIDE EFFECTS GENERATION LESS SIGNIFICANT HYPERPROLACTINEMIA EXTRAPYRAMIDAL SYMPTOMS (risperidone) (Acute Dystonia, Akathesia, Parkinsonism, irreversible Tardive HIGH RISK OF METABOLIC SYNDROME dyskinesia) “ADAPT” PROLONGED QT INTERVAL HYPERPROLACTINEMIA SEDATION (anti-H1) PROLONGED QT INTERVAL POSTURAL HYPOTENSION (alpha-1 blockade (block repolarisation of K+ channels in myocardium) CLOZAPINE: agranulocytosis, myocarditis, cardiomyopathy RISK OF NEUROLEPTIC MALIGNANT SYNDROME RISK OF NEUROLEPTIC MALIGNANT SYNDROME AUTONOMIC INSTABILITY SEROTONIN SYNDROME • Side effect of antidepressants NMS HYPERACTIVITALTERED MENTAL STATUS • Excess serotonergic activity in CNS • Side effect of antipsychotics • Hyperreflexia, autonomic dysfunction, altered mental • Excess D2-blockade in CNS status VS • Muscle rigidity, hyperthermia, • Onset within 24 hrs akinesia, temor, altered mental • Non-specific bloods AUTONOMIC INSTABILITY status • Onset over days/weeks • Raised creatine kinase NEUROLEPTIC MALIGNANT NMS HYPOACTIVITYALTERED MENTAL STATUS SYNDROME SEROTONIN SYNDROME Tx • Stop all serotonergic drugs • A-E assessment • SUPPORTIVE CARE e.g. sedation • Give cyproheptadine (serotonin antagonist) • Stop the causative drug VS • A-E assessment • SUPPORTIVE CARE • Dantrolene, bromocriptine (D2 agonist) NEUROLEPTIC MALIGNANT SYNDROME Tx TW DRUGS OF ABUSE DRUGS OF ABUSE Stimulant Depressant COCAINE & NICOTINE CANNABIS AMPHETAMINES INCREASES MESOLIMBIC THC acts via CB1 & CB2 INHIBIT DOPAMINE & DOPAMINE LEVELS receptors in the brain, MONOAMINE REUPTAKE indirectly increases DOPAMINE RELEASE Cocaine also inhibits local REDUCES MONOAMINE Na+ channels OXIDASE ACTIVITY, INCREASING SEROTONIN Can also encourage opioid binding at mu & delta receptors DRUGS OF ABUSE CLINICAL FEATURES Stimulant Stimulant COCAINE & AMPHETAMINES NICOTINE CANNABIS Cocaine: perforated nasal Euphoria, perceptual septum, euphoria, disturbances, impaired tachycardia, Euphoria, tachycardia, mild reaction time, social tachyarrhythmia, hypertension, chest pain, hypertension, restlessness detachment mydriasis Amphetamines: psychosis, Tachycardia, conjunctival injection severe agitation, delusions, diaphoresis, tachycardia, hypertension, hyperthermia DRUGS OF ABUSE KETAMINE INHIBITS NMDA RECEPTORS ON GABAergic NEURONS Inhibits the inhibitor BIG GLUTAMATE RELEASE DRUGS OF ABUSE CLINICAL FEATURES KETAMINE Dissociative anesthesia Sympathomimetic effects Disorientation, hallucinations SLEEP & SLEEP DISORDERS • Your brain does more work whilst asleep than whilst you’re awake • The suprachiasmatic nucleus is the circadian pacemaker SLEEP: KEY • Neurotransmitters that interact with this structure are orexin, melatonin, GABA, POINTS adenosine • EEG waves change depending on the stage of sleep. Each cycle lasts 90 mins. • Adenosine makes you sleepy. Anything that messes with this disrupts sleep. SLEEP STAGES Non-REM REM WAKEFULNESS (n1, n2, n3) sleep 5% N1 nonREM 50% N2 nonREM 3 nonREM 15% N BEA WAVES 30%BATS Drink Blood Awake Beta Light Sleep Alpha N1 Theta Sleep Spindles N2 and K complexes N3 Delta REM BetaA patient’s wife complains that her partner has been snoring very loudly. You notice that the patient is quite overweight, and is very sleepy throughout the day. Which of the following scoring systems is used to screen excessive daytime sleepiness. A. Epsworth Score B. DAS28 C. Bishop’s score D. CHADSVASc E. Well’s ScoreA patient’s wife complains that her partner has been snoring very loudly. You notice that the patient is quite overweight, and is very sleepy throughout the day. Which of the following scoring systems is used to screen excessive daytime sleepiness. A. Epsworth Score B. DAS28 C. Bishop’s score D. CHADSVASc E. Well’s Score SLEEP DISORDERS INSOMNIA OBSTRUCTIVE SLEEP APNOEA • Decreased sleep quantity or • Partial or completblock of upper quality airway while sleeping • 3x a week • Typically associated with obesity • For > 3 months Treated with improving sleep hygiene, short term medication e.g. First line tx is CPAP benzodiazepines, CBT PARASOMNIA; REM or n -onM HYPERSOMNIA • REM sleep behaviour disorder: physically acting out vivid, • Nacrolepsy: excessive daytime sleepiness, cataplexy unpleasant dreams with vocal • Kleine-Levin syndrome: sounds and sudden, violent limb hypersomnia, hyperphagia, movements • Non-REM: sleep walking, sleep hypersexuality talking etc ADOLESCENT NEURO DEVELOPMENT Axonal myelination & synaptic pruning WHITE MATTER CHANGES • Progressive age-related axonal myelination male • Linear increase l female t W Age GREY MATTER CHANGES • Non-linear, region-specific pattern of development • Synaptic pruning: grey matter volume loss. Reorganization of the brain as a result of puberty, rarely used connections are eliminated TOTAL GREY MATTER VOLUME = PRE-PUBERTAL INCREASE + POST- PUBERTAL LOSS APPETITE REGULA TION AREAS OF THE BRAIN ASSOCIATED WITH APPETITE REGULATION INCREASING & INCREASING DECREASING DECREASING APPETITE APPETITE APPETITE LATERAL NUCLEI PARAVENTRICULAR NUCLEI DORSOMEDIAL NUCLEI VENTROMEDIAL NUCLEI ARCUATE NUCLEITHE ARCUATE NUCLEUS PARAVENTRICULAR NUCLEI NPY ALPHA-MSH MCR AGRP antagonize antagonize PO MC appetite ⬆ APPETITE ARCUATE NUCLEI SHORT-TERM HUMORAL REGULATION OF APPETITE CCK PYY Fat & proteins entering duodenum stimulate release Stimulated by increased calorie intake From duodenum Released by ileum & colon Acts on gall bladder, slows down gut Decreases food intake motility GLP GHRELIN Presence of food in the gut stimulates release Fasting triggers release Released from gut, nucleus tractus From gut solitarus Increases appetite Reduces appetite by increasing insulin production from pancreas PLEASE FILL OUT THE FEEDBACK FORM PLEASE TUNE IN TO OUR REMAINING SESSIONS THIS WEEK! @OSCEazyOfficial @osceazyofficial OSCEazy Osceazy@gmail.com