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ANTIDEPRESSANTS Depression NOT an emotion Etiology/Cause 1. Biological ○ Can affect the person and other people...

ANTIDEPRESSANTS Depression NOT an emotion Etiology/Cause 1. Biological ○ Can affect the person and other people Major Depressive Disorder NO CHEMICAL IMBALANCE or NEUROTRANSMITTER Can lead to suicide DEFICIENCY! Experienced for at least two weeks Receptors being examined (upregulation) Leading cause of disability worldwide Brain-Derived Neurotrophic Factors (BDNF) ○ Sustains viability of brain neurons ○ Gene may be repressed under stress 2. Psychological Learned helplessness (Seligman) Signs and Symptoms of SIGECAPS Loss of self-esteem, sense of control Negative cognitive styles (Beck) Sleep MAJOR DEPRESSIVE Interest (decrease) 3. Sociocultural DISORDER Guilt Energy (decrease) Stress - epigenetics Concentration (trouble) ○ Depletes serotonin Appetite ○ Acutely increases DA, NE, then chronically decreases Psychomotor Retardation (sluggish) Social support Suicidality Sex, Gender Culture Notes: Depressed mood (sadness, emptiness, or hopelessness) Anhedonia (inability to feel pleasure) Insomnia/oversleeping Loss of interest Guilt Fatigue Diminished ability to think or concentrate / indecisiveness Significant weight loss / weight gain Psychomotor agitation or retardation (pacing a lot, d ka makabangon) Suicidal ideation Eating Disorders Signs and Symptoms 1. Psychotherapy 2. Lifestyle changes Management  ANTIDEPRESSANT DRUGS A. SEROTONIN TRANSPORTER BLOCKERS (SERT) II. NON-SERT BLOCKERS III. LESS FREQUENTLY USED IV. ADJUNCTS V. EXPERIMENTAL “Selective” Serotonin Reuptake Inhibitors (SSRI) Noradrenergic and Specific Tricyclic Antidepressant (TCAs) Lithium Racemic KetamineS2 (Intermittent IV infusion, 0.5 mg/kg) Escitalopram Serotonergic D2/5-HT antagonist, D2 Partial Psilocybin-assisted therapy: Phase II trials Fluoxetine Antagonist (NaSSA) Amitriptyline Agonist, 5-HT Antagonist Pipeline: NMDA modulators, n7AChR, opioid Sertraline Clomipramine ○ Aripiprazole Paroxetine Mirtazapine Trimipramine ○ Brexpiprazole Fluvoxamine ○ Olanzapine Dapoxetine (premature ejaculation only) Melatonergic Antidepressant ○ Quetiapine N/A: Citalopram ○ Risperidone Agomelatine Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) Venlafaxine Desvenlafaxine Duloxetine Glutamatergic Antidepressant N/A: Milnacipram, Levomilnacipran Esketamine Multimodal Serotonin Receptor Modulator Vortioxetine SERT BLOCKERS Common MOA for many (not all): Onset MDD: Blockade of Serotonin Transporter (SERT)* MDD: 1-2 weeks (They work!!! See Cipriani et al.) ○ SERT blockers prevent SERT from recycling 5-HT, this causes an increase in 5-HT. Anxiety and related disorders: 4 weeks (up to 8-12 weeks, especially OCD) ○ Increased 5-HT binds to, and downregulates pre-synaptic 5-HT1A receptors Safe duration (to reduce relapse risk): 6-9 months (MDD), 12 months (GAD, Downregulation associated with PD, SAD, OCD, PTSD) improvements in passive coping. Downregulation also causes further increase in 1-2 days: Premenstrual Dysphoric Disorder (PMDD) 5-HT. 1-2 weeks (MDD) ○ Increased 5-HT binds to, and eventually downregulates 4-12 weeks (anxiety disorders, OCD, PTSD) postsynaptic 5-HT receptors Initial binding → Increased Side Effects Downregulation → Side Effect Tolerance ○ Downregulation → Delayed increase in Brain-derived Neurotrophic Factor (BDNF) Expression → Binds to TrkB → Activates Akt/protein kinase B → activates mTOR/mechanistic target of rapamycin → synaptogenesis (increased connections between neurons) + removal of negative affective biases (Cognitive Neuropsychological Model)  Anxiety disorders: ○ Block SERT → Increased 5-HT → Adaptive Neuronal/Receptor events in brain circuits involved in fear (amygdala) and worry (prefrontal cortex, striatum, thalamus) Neurotrophic pain: NE involved in pain neurotransmission ○ Not all affect serotonin transporter (ex. Mirtazapine) INDICATIONS ADMINISTRATION CONTRAINDICATIONS SSRIs (Anti-DEPRESSANTS) With or without food (vilazodone needs food) Hypersensitivity, Linezolid, Methylene Blue, MAOI (all within 14 DEPRessive disorders ○ Recommend taking food for adherence and routine! days) Eating disorderS Serotonin = induces N/V Tamoxifen, Thioridazine (Contraindicated with Fluoxetine or ANxiety & anxiety-related disorders (pTSd, OCD) Oral, once daily (time depends) Paroxetine as potent CYP2D6 inhibitors) ○ Anxiety disorders: Generalized Anxiety Disorders (GAD), Panic Disorder (PD), Social ○ Tamoxifen converted to active metabolite Endoxifen via Anxiety Disorder (SAD) CYP2D6 ○ Body dysmorphic disorder ○ Alternative: Vasomotor Symptoms *Depending on individual SSRI ✓ Major Depressive Disorder (MDD) ✓ Generalized Anxiety Disorder (GAD) ✓ Panic Disorder (PD) ✓ Social Anxiety Disorder (SAD) ✓ Obsessive Compulsive Disorder (OCD) ✓ Post-traumatic Stress Disorder (PTSD) ✓ Binge Eating Disorder (BED) ✓ Bulimia Nervosa (BN) ✓ Body Dysmorphic Disorder (BDD) 2 nd line, vasomotor symptoms of menopause SNRIs Anti-DEPR_SSANTS - Not for eating disorders Neuropathic pain - esp Duloxetine Multimodal: MDD only MISSED DOSE WITHDRAWAL SYMPTOMS BLACK BOX WARNING Addiction – Craving, anticipation, binging a.k.a. “Brain zaps” (distinct from relapse) especially those with shorter Increased risk of suicidal ideation and behavior in children, half-lives (happen on abrupt discontinuation; most common in bold) adolescents, adults ≤ 24 years: Rare (0.07%); monitor ○ NEVER say small risk given the %, no matter how small Dependence – You can not stop, because once you stop, physical symptoms manifest (physiological Signs and Symptoms the percentage is. In 10,000 patients, there would be 7 dependence) Affective - anxiety, irritability, sadness, crying spells who may experience rare symptoms. Gastrointestinal - nausea Trend reverses at 65 and beyond Withdrawal – the immediate symptoms that the patient experiences when they suddenly stop taking the Neuromotor - ataxia (loss of muscle control) Benefits > Risk drug. It is due to dependence. Vasomotor - Diaphoresis (Abnormal sweating) Neurosensory - electric shock sensation/paresthesia Somatic - flu-like symptoms Usually, if a drug is addictive, it is also connected with dependence. However, an exception is Other neurologic - increased dreaming/vivid dreams, insomnia, Antidepressants. They may cause dependence and withdrawal symptoms upon sudden discontinuation, dizziness, headache but they are NOT ADDICTING. Tapering: proportional, hyperbolic, gradual towards lower doses Proposed tapering: x% mg/day corresponding with SERT occupancy (Horowitz & Taylor, 2019) Relapse – returning of initial symptoms before a drug was taken. It takes a while to remanifest. May need to retitrate depending on current dose (refer to Doctor ASAP!) Safe duration of treatment to reduce relapse risk: 6-12 months SIDE EFFECTS SIDE EFFECT MANAGEMENT DRUG INTERACTIONS Common: Tolerance develops with time to most common side effects TOLERANCE builds over time! a. NSAIDs may increase bleeding risk and decrease SSRI efficacy GIT: Nausea/vomiting (5-HT3 receptors in CTZ), diarrhea, constipation, dry mouth, GI: b. Anticoagulants, antiplatelets, and ω3 fatty acids may increase bleeding decreased/increased appetite risk (combine with effects of blocking platelet SERT) ○ Take with food N/V – take with food / move dose to bedtime - Including omega-3 supplements, vitamin E, garlic CNS: Insomnia/sedation (5-HT1A, 5-HT2C receptors), agitation, tremors (5-HT2A receptors), - 5-HT contributes to platelet aggregation dizziness, headache, fatigue, anxiety (5-HT1A receptors), nervousness, increased/decreased appetite Constipation – fiber, water, exercise (5-HT2C receptors) c. Serotonin syndrome (when combined with serotonergic agents): ginseng, ○ 1-2 weeks: Jitteriness (anxiety heightens a bit) but it normalizes after 2 weeks but usually for Diarrhea – maintain hydration, ORS (if needed), antispasmodic St. John’s wort, Tryptophan, Dextromethorphan, methylene blue, this, it is recommended to start half a dose and have them adjust from here on Linezolid, serotonergic drugs Others: Sexual dysfunction (spinal cord 5-HT2 receptors), sweating, bruising, weight gain/loss, CNS: asthenia, Improved FBG (Fasting Blood Glucose) control (SSRIs, esp Fluoxetine, Escitalopram) d. Levothyroxine efficacy decreased by SSRIs Insomnia/sedation – shift dosing to morning/ bedtime; sleep hygiene Rare/Serious e. Tramadol increases risk of seizures and serotonin syndrome when taken Manic switch in bipolar disorder (does NOT cause de novo bipolar disorder) Headache, dizziness – take at night together ↑risk of GI, peri-operative, uterine, cerebral bleeding (Blockade of SERT on platelets → platelet aggregation hindered; rare in absence of risk factors) NONPHARMACOLOGIC f. CYP drug interactions: Fluoxetine & Paroxetine Rare hyponatremia and SIADH, esp. in elderly and dehydrated persons Seizures Psychotherapy (all indications); psychological debriefing is not g. Desmopressin – ↑risk of hyponatremia Induction of mania (rapid cycling) recommended for trauma Osteoporosis / osteopenia (long-term) h. Antidepressants, Antipsychotics – ↑risk of serotonin syndrome & NMS Falls and fractures (long0term) Aerobic exercise (especially for MDD; Tx & prevention) respectively Increased prolactin (esp Venlafaxine, about 1.6% for SSRIs in French study) Rare post-SSRI sexual dysfunction (PSSD) Light exposure therapy (seasonal affective disorder) i. Radioactive iodine – SSRIs may decrease diagnostic/therapeutic effect Genital numbing  Tardive dysphoria St. John’s wort (MDD; multiple drug interactions as a CYP inducer) Causative drugs for NMS: Rare, increased suicidal ideation ≤ 24 years old (~0.09%) Antipsychotics (1st, 2nd gen) Lavender oil (GAD, single non-inferiority trial vs benzos) Causative drugs for Serotonin Syndrome: Progressive muscle relaxation (PMR) (phobias, PD) Serotonergic drugs mentioned Mindfulness GI, neuromuscular (clonus, tremor, hyperreflexia), altered mental status/agitation, autonomic instability (HTN, tachycardia, diaphoresis), hyperthermia) Dextromethorphan, Metoclopramide, opioids, serotonin modulators, ginseng, Methylphenidate, St. John’s Wort, tryptophan ○ Distinguished from NMS: hyperreflexia, myoclonus ○ Hyperreflexia - induced reflexes even without reflex hammer (sensitive reflex) Sustained clonus - Involuntary muscle movements ○ Myoclonus - A muscle contraction that feels like being pushed/lightning-like muscle movements Thiazide, thiazide-like diuretics – ↑hyponatremic effect Thyroid products – SSRIs may diminish therapeutic effect Tramadol – ↑ risk of seizures, SS Triptans – theoretical interaction of weakness, hyperreflexia, and incoordination Ginseng LAB INTERACTIONS Repetitive transcranial magnetic stimulation [rTMS] URINE DRUG TESTING Powerful (1.0-2.5 Tesla), focused magnetic field pulses to induce Fluoxetine – False positive for LSD electrical currents in neural tissue noninvasively Via an inductor coil placed against the scalp Sertraline - False positive for LSD, Benzodiazepines, (BDZ) Delivered by trained tech or nurse with MD supervision Desvenlafaxine - False positive for phencyclidine, amphetamines No anesthesia required Electroconvulsive therapy [ECT] Induction of a seizure by applying an electrical stimulus to the brain Delivered in a controlled clinical setting, after induction of general anesthesia and application of a muscle relaxant SERT BLOCKERS DRUGS SSRIs Escitalopram Fluoxetine Sertraline Paroxetine Fluvoxamine Dapoxetine ₱ – ₱₱ ₱₱ / ₱₱₱ (bulimia) ₱₱ ₱₱ ₱₱₱ ₱₱₱₱ MOA Pure SSRI 5-HT2C antagonist Slight DA reuptake inhibition M1 antagonist σ1 agonist pure SERT blockade (racemic Slight NE reuptake inhibition A1 binding NET blocker Weak NE transporter blockade Citalopram is H1 blocker) Also weakly blocks dopamine Also weak 5-HT2C antagonist and Nitric oxide synthase inhibitor transporters (DAT) and σ1 receptors NET blocker (may explain stimulating effects) Additional Specific Bulimia Nervosa, MDD with comorbid CAD (possible OCD Rapid absorption, onset, reduced incidence of myocardial elimination: Indications: MDD infarction) Indicated only for Eating disorders premature ejaculation; 1 dose prior to sexual activity ADR/Specific Side QT prolongation Possibly activating Possibly activating Anticholinergic ↑ Sexual dysfunction, preg. Sedating cat. D* effects OTHER SSRIs (available in the CNS-activating side effects, take in CNS-activating side effects PH) DO NOT SIGNIFICANTLY AM (increased Note: nitric oxide synthetase inhibition Nitric PROLONG QT INTERVAL irritability, impulsiveness, Oxide causes vasodilation in the genital area Less likely withdrawal Sx on abrupt restlessness), take in AM (which helps with sexual arousal) ○ Inhibition = stopping (long t1/2) decreased sexual arousal Contraindications: Anticholinergic side effects (M1 antagonism) TamoxifenBCMAP – Fluoxetine decreases amount of active metabolite Greater incidence of sexual dysfunction (nitric CONTRAINDICATION (Endoxifen) by preventing oxide synthetase inhibitor) S TamoxifenBCMAP metabolism via CYP2D6 inhibition Higher withdrawal risk on abrupt stopping (short t1/2) → Avoid in children, adolescents, adults≤24 y.o Contraindications: TamoxifenBCMAP – Fluoxetine decreases amount of active metabolite (Endoxifen) by preventing TamoxifenBCMAP metabolism via CYP2D6 inhibition Interactions Omeprazole/Esomeprazole Potent CYP inhibitor → multiple Caution in urine drug screens: potent CYP2D6 inhibitor Interactions: (CYP2C19 inhibitor) – may interactions, esp. w/ drugs metabolized false positive result for increase Escitalopram by CYP2D6 (ex: Tamoxifenbreast cancer benzodiazepines & LSD Potent CYP1A2 inhibition MAP/BCMAP concentrations since ) (↑↑Clozapine, ↑Melatonin & increase Escitalopram is metabolized by levels of others metabolized by CYP2C19 Caution in urine drug screens: false CYP1A2, ↓Caffeine clearance), positive result for LSD moderate CYP3A4 inhibitor QT prolonging meds – additive effects; monitor Smoking may decrease Fluvoxamine serum concentrations (CYP1A2 Emerging data of interaction induction) with smoking, possibly due to Escitalopram being potentially metabolized by CYP1A2, but needs verification through further studies CYP Inhibition 2D6 (weak modulator) 2C8, 2C9, 2D6 (weak for < 100 mg, 1A2, 2B6, 2C19 (moderate), 2C9, 2D6 (Potent) 1A2, 2C19 weak-mode rate for > 150 mg) 2D6 (potent), 2E1, 3A4 (weak-mode rate) CYP1A2 inhibitor Metabolized by 3A4, 2C19 2B6, 2C19, 2C9, 2D6, 3A4 2C19, 2D6 (major) 2D6 (Major) minor t1/2 27-32 h 22-36 h / 62-104 hours 2-3 days / 2 weeks 24 hours (withdrawal) 14 – 16 hours 1.3 – 1.4 hours Storage Controlled room temp Protect Controlled room temp Controlled room temp Protect from Controlled room temp Controlled room temp Controlled room temp from light light Protect from light and moisture Notes Escitalopram has QT Prevents MI from CAD Preferred in children Avoid in < 18 yr old Mainly used for OCD Only used for premature prolongation (leads to ejaculation; single dose arrhythmia) Best in children coronary artery disease (CAD)/heart contraindicated for children. prior to sexual activity attacks (Myocardial Infarction; MI) Take in the morning has a shorter half-life hence we do not want not used for depression Reward stimulation due to DA this (higher risk of withdrawal). preferred for Bulimia (5-HTC appetite) False positive for benzodiazepines Avoid angle-closure glaucoma It has a lot of CYP inhibition activity SNRI MULTIMODAL ANTIDEPRESSANT Venlafaxine ₱₱₱ Desvenlafaxine ₱₱₱₱ Duloxetine ₱₱ Vortioxetine Indication Added: Neuropathic pain Added: Neuropathic pain Added: Neuropathic Pain MDD 2 nd line, cataplexy (narcolepsy 2nd Line: Cataplexy type 1) C/Is Uncontrolled angle-closure glaucoma MOA Has some dopamine transporter Dose-dependent inhibition of NET More potent at SERT than NAT? Blocks serotonin transporter (DAT) binding Stronger M1 (mostly SERT at low doses) blockade M1 antagonist; 5-HT1A Agonist, 5-HT1B partial agonist, 5-HT1D antagonist, 5-HT7 antagonist (metabotropic) 5-HT3 antagonist (ionotropic) ADR Sweating Sweating Sweating Rare angioedema Urinary retention Urinary retention Urinary retention Rare hepatotoxicity Higher rates of withdrawal Financial toxicity Less Sexual Dysfunction (less than 10 mg) ↑ BP (up to 2 mmHg) Manic switch QT Prolongation Rare hepatotoxicity $$$ Interactions Caution in urine drug screens: false positive result for amphetamines CYP Inhibition 1A2, 2D6 Smoking Metabolized by 1A2, 2D6 2D6 (metabolized into Desvenlafaxine) 3A4 (minimal) 2D6, 3A4, 3A5, 2C19, 2C9, 2A6, 2C8, 2B6 T 1/2 12 hours Immediate release (IR): 3 – 7 hours 9 – 13 hours 66 hours Extended release (XL): 7.5 – 14 hours Storage Controlled room temp Controlled room temp Controlled room temp Controlled room temp Protect from light and moisture Protect from moisture and excessive heat Notes contraindicated for children. Financially toxic preferred for neuropathic pain financially toxic however there are rare liver Short half life, higher Venlafaxine’s active metabolite issues (enzymes). withdrawal risk and manic switch unless there is narcolepsy NON-SERT BLOCKERS NORADRENERGIC AND Melatonergic Antidepressant Glutamatergic Antidepressant TRICYCLIC ANTIDEPRESSANTS (TCAs) SPECIFIC SEROTONERGIC HAM BLOCKADE ANTIDEPRESSANT (NaSSA) Na channel blockade Mirtazapine (NaSSA) ₱₱ Agomelatine Esketamine Amitriptyline Clomipramine Trimipramine market n/A ₱₱ (neuropathic pain) / ₱₱₱ (depression) ₱₱₱₱ ₱₱₱₱ NEEDS S2 Indication MDD (monotherapy); MDD Adjunct, refractory MDD or MDD NET blocker, HAM antagonist, voltage-sensitive Na+ channel (VSSC) blocker; some also block GAD with suicidal ideation/behavior (This SERT,5-HT2A,5-HT2C receptors 2nd line for PD & OCD only means it is used in this Contraindications: population. It still does NOT reduce Na+ channel blockade (cardiotoxicity) → lowers seizure threshold, sudden death, sudden arrythmias, tachycardia Hepatic impairment, concomitant use suicide) (esp. at higher doses) with CYP1A2 inhibitors Dangerous drug Anticholinergic + NET blockade combo also enhances cardiotoxicity RAPID? Not really Does not reduce suicidal ONSET: 1 to 2 weeks for Depression. ideation/behavior NOT RECOMMEND FOR DEPRESSION Contraindications: Useful for refractory ○ Natry mo na Recovery from Myocardial Infarction (MI) lahat but this is still not stellar CYP (especially 2D6) QTc prolonging drugs Administration Administration: in the evening Administration: With or without food Intranasal; to be administered ONLY Oral – once daily before bedtime in clinics or hospitals under supervision of healthcare professional (DDB Board Resolution No. 5 s2021) Specific indications Has more NET blocker indications Has more potent SERT blockade indications Post-traumatic Stress Disorder (PTSD) General Anxiety Disorder (GAD) Migraine Parkinson’s Disease (PD) Neuropathic pain Obsessive-Compulsive Disorder (OCD) Body Dysmorphic Disorder Cataplexy MOA Antagonist at: (serotonergic and MT1, MT2 receptor agonist S-isomer of Ketamine; does NOT noradrenergic antagonist) reduce suicidal ideation. a2, H1 5-HT2B & 5-HT2C antagonist Non-selective, non-competitive 5-HT2A, NMDA receptor antagonist; exact 5-HT2C, Melatonin 1 (MT1) and MT2 agonist, mechanism for depression unclear 5-HT3 5-HT2B and 5-HT2C antagonist – (effect of parent compound and – α2 receptor antagonism → resynchronizes circadian rhythm S-norketamine metabolite blocked autoreceptor (brakes) (MT1/2 & 5-HT2C) dependent on mTOR kinase but → no brakes, 5-HT release independent of AMPA receptors) disinhibited → release of No SERT blockade = less sexual Serotonin dysfunction and less N/V Onset: NOT rapid (~22 days) At 15 mg (AT LOWER DOSE), ↑sedation due to prominent H1 antagonism (less sedation at higher doses w/ 5-HT2C antagonism) ADR Sedation (frequent) Less SERT Side effects (GI, sex) Dizziness, nausea/ vomiting, Common: Hepatotoxicity sedation, vertigo, hypertension, ↓ HAM blockade (H1 – sedation, α1 – orthostatic hypotension, M1 – anticholinergic), Weight Gain feeling/ sensitivity (hypoesthesia), Use limited by hepatotoxicity feeling drunk. anxiety, lethargy, serotonergic (see SSRIs), Flu-like symptoms concerns (rare: hepatitis & hepatic sedation, dissociation, addiction - GI (Appetite, N/V/D) CNS (fatigue, weakness, dizziness, sedation, headache, anxiety, nervousness, failure) potential restlessness) Blood Dyscrasia (rarely leads to blood dyscrasias like Likely no withdrawal on abrupt blue/green urine discoloration (Amitriptyline) neutropenias) cessation; minimal to no sexual dysfunction & less nausea/vomiting (no Rare/serious: Manic switch, suicidal thoughts/behavior, QT prolongation, hepatic failure, extrapyramidal symptoms Anticholinergic effects SERT blockade) (EPS), ↑intraocular pressure (IOP), seizures - VSSC Blockade ↑ Cholesterol Sedation/insomnia, anxiety, fatigue, - Rare seizures (Lower threshold) constipation, diarrhea, sweating - Sudden death Less Sexual Dysfunction - Sudden arrhythmias Rare manic switch (in undiagnosed - Tachycardia less nausea and vomiting bipolar disorder), rare increased - Induction of mania (rapid cycling) (likely due to absence of SERT suicidal ideation (see above - Activation of suicidal ideation and behavior (less than 24 yr old) blockade) - QT Prolongation - Hepatic Failure Rare manic switch (in - EPS undiagnosed bipolar disorder), - Increased Intraocular Pressure (IOP) rare increased suicidal ideation (see above) Withdrawal symptoms (on abrupt discontinuation): Flu-like symptoms, Gi distress, rebound insomnia, cholinergic  rebound (Clomipramine withdrawal ~SSRIs) Interactions α2 agonists – Mirtazapine can CYP1A2 modulators – can affect Minor substrate of CYP2B6, 2C19, CYP interactions (All three with CYP2D6 modulators, Clomipramine & CYP1A2modulators), Additive CNS depressant & antagonize their Agomelatine concentrations since 2C9, 3A4; additive CNS depression anticholinergic effects with similar drugs antihypertensive effects Agomelatine is metabolized by with CNS depressants; additive CYP1A2 (ex. smoking – reduces toxicity from serotonergic agents & Valproate – significantly increases levels of Amitriptyline CNS depressants – additive Agomelatine concentrations) NMDA antagonists CNS depressing effects False positive in urine drug tests for amphetamines (Trimipramine), LSD (Amitriptyline), and Methadone (Clomipramine); frequent false negatives (Clomipramine) CYP3A4 modulators – can affect Mirtazapine serum Anticholinergics – paralytic ileus, hyperthermia concentrations as Mirtazapine is metabolized by CYP3A4 Antihypertensives – TCAs may alter activity, may inhibit clonidine effects Serotonin syndrome (when CYP interactions combined with serotonergic agents): ginseng, Tryptophan, Methylphenidate – may inhibit TCA metabolism St. John’s wort, methylene blue, Linezolid, Dextromethorphan, Phenothiazines, haloperidol – may decrease TCA serum concentrations serotonergic drugs Sympathomimetics – TCAs may increase sympathomimetic activity ○ About 120,000 cases locally LAB INTERACTIONS: Amitriptyline – False positive for LSD Clomipramine – Frequent False-negatives; False positive for Methadone Trimipramine – False positive for amphetamines Need to measure both parent and metabolite drug of tertiary TCAs CYP inhibition Metabolized by 1A2, 3A4, 2D6 1A2 T 1/2 26 hours (Male) 37 hours (Female) Storage Controlled room temp Notes DANGEROUS DRUG (should not advertise) ADJUNCTS Lithium Aripiprazole Brexpiprazole Olanzapine Quetiapine Risperidone useless wag mo na aralin pero lagay nalang naten hehe  MOOD STABILIZERS BIPOLAR DISORDER QUICK DSM 5 DEFINITIONS ETIOLOGY Distinct from depression Major Depressive Disorder (MDD) - Unipolar Depression Bipolar I disorder ○ One mood episodes pool (going down) ≥1 manic episode ± hypomanic episode or major depressive episode ○ Treatment: Antidepressants + adjuncts Bipolar Disorder - Two poles Bipolar II disorder ○ Mania and Depression current or past hypomanic episode ± current or past major depressive episode ○ Treatment: comminution of 4 mood stabilizers + antipsychotics ○ No mania but has hypomania ○ “Manic-depressive” illness ○ Unusual shifts in mood, energy, activity levels Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of ○ Inability to carry out daily activities functioning ○ Experienced for at least 4-7 days ○ At its worst, can lead to SUICIDE Rule out: NOT Comorbidities and other drugs or substances ○ Weather or Personality trait Unipolar major depressive disorder (69% misdiagnosed, Tx delay 10 years) Anxiety disorders Cause: Biopsychosocial factors Substance use disorders Bio - mania ADHD Psychological - amenable to psychotherapy Social - meds or substance use Hypomania - less severe and less functional impairing Bipolar can be more noticeable once it crashes into depression (Bipolar depression) Mania - can be fast talking and jumpy/energetic, it may seem coherent but if you look at the patterns, it seems very different Depression: BDNF, inflammation, etc. Bipolar: Apoptosis is the issue MOOD STABILIZERS DRUG LIST focuses on which poles do you want to address Some drugs would only do mania, and some would be for depression Lithium Some drugs can do both but only to a certain extent (not potently) Psychotherapy can work for preventing bipolar depression but for bipolar mania Anticonvulsants: medication only works Valproate Carbamazepine Lamotrigine D2/5-HT antagonist, D2 Partial Agonist, 5-HT Antagonist Aripiprazole Olanzapine Paliperidone Quetiapine Risperidone MOOD STABILIZERS Lithium ₱₱ Valproate ₱₱ Carbamazepine ₱₱ Lamotrigine ₱₱ Notes Most effective drug DO NOT INTERCHANGE VICALPROEX, VALPROIC But have narrow therapeutic index  ACID, SODIUM VALPROATE Divalproex Specific ratio of sodium valproate and valproic acid. Valproic Acid unionized Sodium Valproate Ionized Indications 1st line Bipolar disorder, acute and maintenance treatment Seizures Seizures Seizures (Focal seizures, GTC; 2nd line for absence of manic and depressive phases ○ Focal, GTC, myoclonic 1st line for benign occipital seizures = 6 months Anticonvulsants (esp. A2delta ligands) ○ Excessive emotion Antipsychotics (usually adjunctive) Related behavioral disturbances Social Anxiety disorder 5-HT1A partial agonist Persist beyond developmentally appropriate periods Marked fear/anxiety of social situations A1 blocker???, H1 blocker Persist for long periods of time Obsessive-compulsive disorder (OCD) Different from anxiety: presence of obsessions and/or compulsion OCD - more of obsessions + compulsions Obsessions PTSD - trauma related Persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that in most individuals cause marked anxiety or distress Attempts to ignore/suppress these with other thought/action (ex. Compulsions) Compulsions Repetitive behaviors or mental acts that individual feels driven to perform in response to an obsession or according to rules that should be applied rigidly Compulsions do not extinguish Obsessions they may not even be connected Post-traumatic stress disorder Stress ○ Failure to adapt to change ○ Due to inflexibility, non-acceptance ○ Stress is normal but if its CHRONIC or intense can lead to TRAUMA Trauma ○ Event outside normal human exp. ○ Stressor causes intense fear, usually threat to one’s life ANXIOLYTIC DRUGS Benzodiazepines BARBITURATES Phenobarbital BUSPIRONE Gabapentin₱₱₱ & HYDROXYZINE NEED S2 ₱ – ₱₱ NEEDS S2 ₱ (tab) Pregabalin₱₱₱ INDICATIONS ✓ Panic disorder, generalized anxiety Focal and tonic-clonic seizures, myoclonic seizures, neonatal seizures; Only for Acute GAD Both Anxiety (psychoneurosis, pre/post-op and disorder, social anxiety disorder: 1 st line for neonatal/febrile seizures ○ Adjunctive for pre/postpartum, organic disease states, acute/short-term use only (in general; seizures, alcoholic withdrawal, delirium tremens) SSRIs 1st line) Risk of addiction and dependence postherpetic ✓ Insomnia (acute/short-term use neuralgia; 1st Generation Antihistamine only; CBTi = 1st line) Low unit cost not worth hidden cost of locating and paying for off-label for GAD Common brand name: Atarax  physician with S2 license\’ Pregabalin May cross the BBB → inhibit ✓ Acute alcohol withdrawal ○ Neuropathic pain histamine in the CNS → (SC injury), sedating ✓ Catatonia (Lorazepam) diabetic peripheral neuropathy, ✓ Epilepsy (1st line in status epilepticus: fibromyalgia IM Midazolam, IV Lorazepam, IV Gabapentin Diazepam) ○ Restless leg syndrome (only for Ineffective and potentially harmful in gabapentin PTSD and phobias enacarbil ER) & off-label Antidote for toxicity: Flumazenil (may crossovers precipitate seizures those with epilepsy) Adjunct for insomnia; if hindi Have S2 license in the pH nagana SSRIs MOA Non-selective GABA-A positive GABA A Positive Allosteric Modulator, BUT at higher doses: 5-HT1A partial agonist Bind to a2δ subunits of H1 and M1 receptor antagonists allosteric modulator; Goes INSIDE ion channel, keeps it open longer Not too strongly voltage-sensitive H1 receptor antagonist GABA effect is enhanced → Cl- Does not require GABA to work Ca2+ channels Some action at muscarinic and enters cell, “supercharging” ○ Closes N and 5-HT2 receptors neuron and making it less -> increased DURATION of Cl channel opening P/Q ○ Known to inhibit (to a responsive to other presynaptic lesser extent) neurotransmitters Ca2+ cholinergic receptors -> increased FREQUENCY of Consequence: lower therapeutic index vs Benzos channels ○ Anticholinergic effects Cl channel opening *May also block excitatory neurotransmission at NMDA system which ○ DIminishes excessive neuronal activity & NT release (neuropathic pain) ONSET Some immediate relief on 1st Up to 6 weeks for Few weeks 15 - 20 minutes (quick onset) dose (dependent on BA) similar efficacy with ○ Disrupts sleep BDZ 4x a day architecture (more light sleep, less REM and slow wave sleep -> more total sleep time) ○ Anxiolytic: 3-60 min Don’t use for insomnia! ADMINISTRATION Oral On administration: garlic/onion taste Absorption is affected With or without food Pregnancy (early stages) Before bed by food (be consistent Oral 2-3 times a day when giving with or evening; take extended Hypersensitivity without food) release dosage forms Oral, twice a day with food CONTRAINDICATIONS Narrow-angle glaucoma Porphyria; dyspnea /airway obstruction; marked hepatic Concurrent MAOI, Pregabalin Myasthenia gravis impairment/hepatic encephalopathy; intraarterial administration; history hypersensitivity Galactose intolerance, Respiratory disorders (e.g. of sedative/hypnotic addiction; nephritic service users/patients the Lapp lactase COPD, sleep apnea) deficiency or Significant hepatic disease glucose-galactose  Pregnancy, labor, lactation malabsorption Hypersensitivity to BZD/any component of the formulation Tapering (cross-sensitivity w/ other BZDs Relapse if not tapered may exist) properly, emerging History of substance use withdrawal disorder PTSD, phobias** Renal impairment BENEFITS VS RISK Dependence risk - duration Stigma (patient and Stigma (service user Stigma (patient and RPh) limited RPh) and RPh) ○ Anxiety disorders: Long-term anticholinergic use (some 1 MAC: vasodilation > ↓CMR = ↑ cerebral blood flow ○ “Immobility” substrate Transition to stage II (induction/emergence)  Receptors: Na + and K + channels (likely NOT GABAA or AChR) ○ Laryngospasm, emesis, aspiration of stomach contents – 5-HT3 potentiation (N2O: gas expansion) Target site: Spinal Cord Postoperative N/V (CTZ) ○ “Unconsciousness”/Hypnosis “Unresponsiveness” Reactions with CO2 adsorbents Network level action: breakdown of cortical connectivity trying to collect CO2 from the patient. Otherwise, the patient can rebreathe the CO2 , decreasing the Cellular, molecular: ? amount of oxygen and anesthetic gas that they have in the body. ○ Anterograde amnesia Receptors: GABA (others: nAChR, HCN1, Glu) Malignant hyperthermia Network: disrupting hippocampal θ rhythm (BZD, opioids) Muscle contraction and hypermetabolic activity Target site: hippocampus (explicit memory) For volatile anesthetics, but esp. w/ Halothane* One thing to note here (many effects) is analgesia; the patient can still feel pain; we still want to avoid the peripheral conduction of pain Environmental Hence we still give analgesic agents particularly opioids ○ Sedation Toxicity Receptor: α1 subunit of GABAA Transient Renal Changes For N2O/Xe, maybe NMDA antagonism ○ Prolonged exposure to Enflurane (liberated F- ions) Target Site: CNS (cortical, thalamus) ○ Others: low solubility, rapid elimination Transient LFT Increase FACTORS IN SELECTION: ○ LFT = Liver Function Volatile ○ Toxicity rare except w/ Halothane Bronchodilation ○ Halothane hepatitis – reactive Trifluoroacetylchloride + hepatic proteins, + autoimmune response Skeletal, smooth muscle relaxation (dose-dependent) ↓ cerebral metabolic rate (CMR), ↑ cerebral blood flow (CBF) Hematotoxicity Laryngospasm ○ N2O prolonged exposure → decrease methionine synthase → megaloblastic anemia Respiratory depression ○ Megaloblastic anemia is a form of anemia characterized by very large red blood cells and a decrease in Myocardial depression and vasodilation (hypotension) the number of those cells. Emergence delirium Postoperative nausea and vomiting (vs IV) Malignant hyperthermia Induction time takes longer GA INHALED DRUGS Sevoflurane Desflurane Halothane* Isoflurane Nitrous Oxide (N2O) (Not FDA registered ) INDICATION Induction ○ Pediatric patients (fear of needles) ○ Adults in need of spontaneous breathing ○ N2O adjuvant Speeds up induction via 2nd gas effect Maintenance (maintain stage III) - inhalation, total IV, or combination (balanced anesthesia) ○ Sevoflurane - procedures rapid onset) Adjunct for postoperative acute CONTRAINDICATIONS Avoid in patients with soy, egg allergies and chronic pain Note: hypersensitivity usually attributed to Propofol itself A2 agonist (increased affinity vs Clonidine) EFFECTS Hypnotic (no analgesia), respiratory depressant - CNS Cerebral vasodilation GABA A MOA: Activate seizure foci Increased cerebral brain flow, metabolism, intracranial A2a ↓ cerebral blood flow, metabolic rate pressure CNS - analgesia Reduced cerebral blood flow, intracranial pressure (spinal cord)  Vasodilation Psychotomimetic effects (on emergence) - NMDA Neuroprotection??? antagonism A2B Rare CNS - sedation Better hemodynamic stability - a2b receptor agonism - Dissociation and illusions ANS - vasoconstriction Propofol Infusion Syndrome (PRIS) - Feeling strange/weird, intoxicated (blood vessels) Adrenal insufficiency - 11B-hydroxylase inhibition - Excitement, confusion, euphoria, fear Metabolic acidosis Significance of short-term use? A2C Hyperkalemia Prevents bronchospasm CNS = sedation, Hyperlipidemia Injection site pain, phlebitis: low pH (propylene glycol) hypotension, analgesia Rhabdomyolysis Risk of addiction, tolerance, withdrawal ANS - presynaptic Hepatomegaly brakes on adrenaline Renal failure - Long-term: “Ketamine bladder”/ulcerative release (adrenal gland) ECG changes, arrhythmias, progression to cardiac cystitis (pain; nocturia) failure EFFECT: Cardiovascular: sympathomimetic (biphasic) Green urine 1st: myocardial depression, negative inotropy Sedation (non-REM 2nd: indirect stimulant effect (activation of sleep) Painful for patient so give small dose of Lidocaine sympathetic NS) Analgesia before administering (some anesthecians) ○ Reduced opioid NET blockage, vagal blockage (M2) needs Anxiolysis Tachycardia, HTN, increased CO and myocardial O2 (downregulation of consumption noradrenergic receptors)