Pharm III Exam 1 - Antidepressants

Antidepressants/BiPD Monoamine hypothesis- deficient in serotonin and NE Class: SSRIs (Selective Serotonin Reuptake Inhibitors) Drugs in Class: Fluoxetine, Sertraline, Paroxetine, Citalopram, Escitalopram, Fluvoxamine MOA: selective action to block the reuptake of 5HT into the nerve endings, resulting in increased 5HT in the synaptic cleft (increase CNS stimulation) ADRs: - GI disturbances (N/D, xerostomia, anorexia, increased appetite - Paroxetine- most weight gain - Sexual dysfunction - - Decreased libido (disease related – drug may help) & orgasm (drug related) Headache, Insomnia QT prolongation (esp citalopram, escitalopram) - Careful with macrolide use Discontinuation syndrome - Dizziness, N, insomnia and anxiety– taper slowly Fluvoxamine- produces sedation rather than CNS stimulation; idiosyncratic response - OCD treatment BBW- suicidal tendencies Place in Therapy: - First-line treatment for MDD, PTSD, OCD - Fluoxetine, sertraline and paroxetine - Fluoxetine and Sertraline - PDD, MDD in children (Fluoxetine)! - Best for teens - Fluoxetine, Escitalopram, Sertraline - Postpartum depression - Sertraline – safest in pregnancy and ok during breastfeeding - Paroxetine – higher risk of heart defects when used in the first trimester Special Considerations: - Risk of serotonin syndrome: Confusion, fever, agitation, restlessness, seizures, muscle spasms, hyperreflexia, death - Avoid combining with MAOIs, tramadol, fentanyl, methadone, meperidine OTC dextromethorphan - Or with MAOI effects: Isoniazid, linezolid, metaxalone - Recommended frequent follow up when initiating therapy – link to increased risk of suicide - Q week for 4 weeks then QO 4 weeks Class: SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) Drugs in Class: Venlafaxine, Duloxetine, Desvenlafaxine, Levomilnacopran, Milnacopran MOA: Inhibit reuptake of 5HT and NE, increasing their synaptic levels– lesser extent DA ADRs: - Similar to SSRIs - Nausea - Dizziness - Sweating - increased blood pressure Place in Therapy: - Depression, anxiety disorders, chronic pain syndromes (eg, fibromyalgia, neuropathy) Milnacopran: fibromyalgia Special Considerations: - May work if SSRIs do not May have better efficacy for pain-related symptoms than SSRIs - Diabetic peripheral neuropathy, post-herpetic neuralgia, fibromyalgia, low back pain Class: Atypical Antidepressants Drugs in Class: Bupropion MOA: Increases dopamine and norepinephrine levels with minimal effects on 5HT ADRs: - Seizures (lowers seizure threshold) Insomnia may exacerbate anxiety less risk of sexual dysfunction Place in Therapy: - Depression with fatigue Smoking cessation Bipolar disorder to prevent switch to mania ADHD treatment Weight loss programs DOC with ADR complaints for sexual dysfunction (delayed orgasm not libido) Not used for anxiety and panic disorder Special Considerations: - Bupropion is C/I in seizure disorders Class: Atypical Antidepressants Drugs: Dextromethorphan + Bupropion (Auvelity) PK - - Dextromethorphan (DXM): - Primary antidepressant according to the manufacturer - Rapid onset of activity (other antidepressants take TOO LONG) - NMDA receptor antagonist (blocks N-Methyl-D-Aspartate receptors), modulating glutamate activity - Side effects include anticholinergic effects, nausea/vomiting (N/V), ataxia, and respiratory depression Bupropion: - Inhibits CYP2D6, increasing dextromethorphan levels in the bloodstream (not specifically for its antidepressant effects) MOA - NMDA (N-Methyl-D-aspartate) antagonist (receptor blocker) ADRs - Dextromethorphan - Anticholinergic - N/V - Ataxia - Respiratory Depression Place in Therapy: - Improvement in symptoms seen within 1 week - Full effects up to 6 weeks Special Considerations: - Dextromethorphan's role as an antidepressant is more potent when combined with bupropion due to CYP2D6 inhibition Class: Atypical Antidepressants Drugs in Class: Nefazodone and Trazodone MOA - Weak reuptake inhibitors of serotonin (5HT) and norepinephrine (NE) Block alpha-2 receptors and histamine (H1) receptors, contributing to their antidepressant and sedating effects Potent antagonists of 5HT-2A receptors - additional antipsychotic activity ADRs: - Sedation (helpful in MDD with insomnia) Orthostatic hypotension due to alpha-1 blockade Priapism Black Box Warning - Liver toxicity (nefazodone) Place in Therapy: - Reserved as second/third line treatment for Major Depressive Disorder (MDD) or for use in insomnia with MDD Trazodone- sleep aid for pts with both MDD & insomnia - Dosed at night Class: Atypical Antidepressants Drugs in Class: Mirtazapine MOA - Increases release of norepinephrine (NE) and dopamine (DA) by blocking α2-adrenergic receptors and 5-HT2C receptors - Disinhibition of dopamine and norepinephrine, leading to increased concentrations of these neurotransmitters - Antagonizes the 5-HT3 receptor - antiemetic effects similar to ondansetron– - Potent antihistamine properties ADRs - Sedation Weight gain Dry eyes Constipation Urinary retention Place in therapy: - Antidepressant Anxiolytic Hypnotic Antiemetic Antihistamine Appetite stimulant Special Considerations: - Little sexual dysfunction compared to other antidepressants Sleep sedative Useful for weight gain and patients undergoing chemotherapy that need to gain weight simultaneously helping nausea Class: TCAs (Tricyclic Antidepressants) Drugs: Amitriptyline, Nortriptyline, Imipramine - CYCLed but TRIPped and fell in the PRAirIE MOA: Block reuptake of norepinephrine and serotonin ADRs: - SEIZURES - Anticholinergic effects - dry mouth, constipation, urinary retention, tachycardia, sedation, blurred vision - Postural hypotension due to adrenergic blocking - CNS Stimulation - Tremors, convulsions, mania, restlessness - Sedation - Secondary amines < sedation - Clomparine, Desipramine, Nortriptyline - Inc NE > 5HT - Tertiary amines > sedation - Amitriptyline, Doxepin, Imipramine - Inc 5HT > NE - Cardiotoxicity - Na+ channel blockers - Alterations in T wave and ST segment - Potential for fatal arrhythmias - Hepatotoxicity - Obstructive jaundice - Reversible with drug d/c Place in Therapy: - Depression - chronic pain - migraine prophylaxis - Desipramine – cocaine withdrawal - Clomipramine – OCD, eating disorders - Imipramine - Enuresis - Chronic pain syndromes - HA, back pain, fibromyalgia - Lower doses are generally used for pain management Special Considerations: - Narrow therapeutic index - Full antidepressant effects may take 2-4 weeks to develop - Do not use in patients with glaucoma or prostatic hypertrophy - d/t anticholinergic ADRs - Overdose - Cardiac arrhythmias, seizures, death - Another reason (along with ADRs) why TCAs are not used first line - Drug Interactions - Barbiturates - Increased metabolism of TCA - Increased sedation - MAOIs - Increased stimulation - Phenothiazine - Anticholinergic effects - Alcohol - Increased sedation - Amphetamines - Additive CNS stimulation - Anticholinergics and antihistamines - Anticonvulsants Class: MAOIs (Monoamine Oxidase Inhibitors) Drugs in Class: Phenelzine, Tranylcypromine, Isocarboxazid, transdermal selegiline (MAO-B inhibitor) MOA: Inhibits the enzyme monoamine oxidase, preventing breakdown of serotonin, norepinephrine, and dopamine ADRs: - Hypertensive crisis with tyramine-containing foods orthostatic hypotension HA Hepatotoxicity Constipation, dry mouth, urinary retention, blurred vision Weight gain Sexual dysfunction Place in Therapy: - Refractory depression Special Considerations: - Require dietary restrictions - CHEESE REACTION avoid combining with serotonergic drugs Drug interactions: decongestants and bronchodilators→ potentiate sympathetic actions Report excessive dizziness, difficulty with urination, yellowing of the skin and agitation Drug: Ketamine PK: Active metabolite with a longer duration of action; oral bioavailability is 20%– give parentally (IV q3 weeks or nasal spray) MOA - - NMDA receptor antagonist: Binds to the NR2B subunit - Indirectly enhances BDNF (Brain-Derived Neurotrophic Factor) and suppresses GSK-3 (Glycogen Synthase Kinase) Interacts with opioid, NE, ACh, and 5HT3 receptors ADR - Psychiatric: Dissociative experience, confusion, emotional blunting, sedation Cardiovascular: Hypertension (HTN), tachycardia Other: Nausea, cystitis, biliary dilation Place In therapy - FDA-approved as a general anesthetic and used in pain management May be utilized in the acute management of excited delirium and agitation in hospital settings A rapid antidepressant with effects within 4 hours - Included on the WHO list of essential drugs Special considerations - - Dosing for Depression: - Induction: IV infusion, followed by a maintenance dose - Esketamine nasal spray (approved in 2019) for resistant depression - Intranasal formulation for resistant depression - Must be administered in a REMS-enrolled clinic or hospital Abuse Potential & Special Considerations: - C/I in schizophrenia and epilepsy - CIII controlled substance - Must continue an oral antidepressant during treatment Drug: Brexanolone PK: - Low concentrations in breast milk Low oral bioavailability MOA - - A progesterone analog: - Progesterone levels are high in the third trimester and fall rapidly postpartum - Mimic progesterone to level off levels Crosses the blood-brain barrier rapidly Binds to GABA-A receptors, resulting in antidepressant and anti-anxiety effects, among other effects ADRS - REMS drug - Sudden over-sedation and loss of consciousness Place in Therapy - Approved for the treatment of resistant post-partum depression in 2019 Schedule IV controlled substance Special Considerations - Administered as an IV infusion over 60 hours, with a single dose Requires hospital admission Drug: Zuranolone MOA - Similar mechanism of action to brexanolone An oral neuroactive steroid, acting as a GABA-A receptor-positive allosteric modulator The GABA system is the major inhibitory signaling pathway in the brain and CNS, playing a role in regulating brain functions like mood, arousal, behavior, and cognition ADRs - Drowsiness Dizziness Diarrhea Fatigue Nasopharyngitis Urinary tract infection (UTI) Black Box Warnings: - Impact on ability to drive and perform other potentially hazardous activities - Suicidal thoughts and behavior - Fetal harm Place in therapy - Recently approved for postpartum depression in 2023 Administered as an oral agent over 14 days Special considerations - Result in rapid remission of symptoms - Much cheaper than brexanolone and easier admin/ route Class: Stimulant Amphetamines Drugs - - Amphetamine (Adderall) Dexmethylphenidate (Focalin) Dextroamphetamine (Dexedrine) Methylphenidate (Ritalin, Adhansia XR, Jornay PM) Lisdexamfetamine (Vyvanse) - Prodrug of dextroamphetamine - Activated by GI enzymes for longer activity and lower abuse potential Dexmethylphenidate/serdexmethylphenidate (Azstarys) - New agent (2021) - Combines immediate-release and prodrug forms for once-daily (QD) dosing PK - Immediate- and extended-release formulations available Rapid onset for ADHD treatment; require careful dosing adjustments MOA - Focuses the activity of NE and DA in the brain: - Direct stimulation of NE and DA receptors - Stimulates release of NE and DA from nerve endings - Inhibits reuptake of NE and DA into nerve endings ADRs - Xerostomia (dry mouth), tachycardia, increased BP, restlessness, insomnia - Mania, tics, psychosis (paranoia), and weight loss - Psychosis: - More likely with amphetamines than methylphenidate, especially within the first few months of therapy - BBW- CV RISK and sudden cardiac death - CNS stimulation - Decreased appetite and weight loss - Rebound symptoms - Irritability and emotional lability (can confirm<3) - HTN - Hallucinations - Tics Place in Therapy - Narcolepsy - Used for hyperkinetic children and adults (eg, ADHD) - Short term use in MDD while waiting for antidepressant to kick in - Has a paradoxical effect: - Increases alertness and attention span - Decreases hyperactivity Special Considerations - These are Schedule II agents, indicating a high potential for abuse and dependence - DO NOT IMPROVE ACADEMIC ABILITY - Street Names - Bennies, Speed, Black Beauties, Meth, Crystal Meth, Uppers, Hot Ice Class: Stimulant Amphetamines Drug: Atomoxetine PK - Slower onset of activity compared to the stimulants - 2-4 weeks generally MOA - Selective NE reuptake inhibitor throughout the brain Inhibits the reuptake of DA in the prefrontal cortex ADRs - N/V, anorexia, HA, insomnia, fatigue, sedation, increased BP, urinary retention, QT - prolongation, liver injury CYP2D6 drug interactions Place in therapy - ADHD Some research in MDD Class: Stimulant Amphetamines Drug: Viloxazine PK - Slower onset of action compared to the stimulants - QD dosing MOA - – inhibits norepinephrine reuptake; potentiates 5HT activity by inhibiting reuptake (formerly marketed as an antidepressant) ADRs - Black box warning – suicidal ideation (antidepressant classification) N, insomnia, EKG, EEG abnormalities, increased BP, HR Place in therapy - Approved for use in patients 6-17 years Class: Stimulant Amphetamines Drug: Guanfacine, clonidine MOA - Act postsynaptically to increase blood flow in the prefrontal cortex ADRs - N, sedation, anorexia, constipation, hypotension, bradycardia Place in therapy - Not as effective for monotherapy; used primarily as add-on therapy to stimulants Class: Stimulant Agents Drug: Armodafinil, modafinil, Solriamfetol MOA - Inhibits DA reuptake centrally which increases DA levels in the synapse (frontal cortex) - Solriamfetol further inhibits NE ADRs - HA, N, anxiety, cardiac arrhythmia Schedule IV medications Place in therapy - Narcolepsy Class: Mood Stabilizer Drug: Lithium PK - Absorbed orally - Takes 1–2 weeks to achieve full therapeutic activity - Therapeutic Drug Monitoring (TDM): - Blood levels are monitored periodically - Competes with sodium for renal excretion - dec NA intake can promote lithium retention, inc toxicity risk MOA - Chemical properties similar to Na+ - The body utilizes Li+ as if it were sodium - Interferes with normal nerve conduction, decreasing nervous tissue excitability ADRs - Nausea, tremors (often improve with continued therapy), V/D, drowsiness, loss of equilibrium, tinnitus, frequent urination, convulsions, arrhythmias, nephrotoxicity, death - Pregnancy Category D: - Risk of Ebstein anomaly (tricuspid valve defect with hypoplastic right ventricle) - Psoriasis aggravation - Thyroid gland irregularities: - Inhibits iodine uptake, leading to hypothyroidism - C/I in thyroid disease - Arginine vasopressin deficiency: - Blocks peripheral vasopressin (ADH) receptors Overdose Symptoms: - Vomiting, diarrhea, drowsiness, loss of equilibrium, tinnitus, frequent urination, convulsions, arrhythmias, nephrotoxicity, and death Place in Therapy - Mania and bipolar disorder - anti-suicidal treatment with randomized evidence showing a >50% reduction in suicide risk - Often used in combination with antidepressant drugs Special Considerations - Regular monitoring of blood levels is necessary to prevent toxicity Sodium intake should remain consistent to avoid Li+ retention complications Class: Antiepileptics Drugs in Class: Valproic Acid, Lamotrigine, Carbamazepine PK - Valproic Acid: Extensively metabolized in the liver; monitor liver function due to potential hepatotoxicity MOA: - Valproic Acid: Increases GABA levels; inhibits sodium channels Lamotrigine, Carbamazepine: Blocking voltage gated channels (Na+ or Ca++) ADRs: - Valproic Acid - Hepatotoxicity, pancreatitis Carbamazepine - HLA-B*15:02 and HLA-A*31:01 - Associated with an increased risk of cutaneous hypersensitivity reactions Place in Therapy: - First-line treatment for bipolar disorder Special Considerations: - Valproic acid is teratogenic Class: Atypical Antipsychotics Drugs in Class: Quetiapine, Olanzapine, Lurasidone MOA: - DA/5 HT receptor antagonists - Lurasidone: DA/5HT 2A receptor antagonist/ 5HT1A partial agonist ADRs: - Sedation weight gain metabolic syndrome Place in Therapy: - Adjunctive therapy for manic or depressive episodes in bipolar disorder Lurasidone- schizophrenia and depression associated with bipolar disorder Special Considerations: - Quetiapine has FDA approval for bipolar depression Can be used with Li+ or valproic acid Antipsychotics/Anxiolytics - ACH NE and H are blocked by Chlorpromazine Clozapine and Thioridazine 5HT are blocked by Aripiprazole, Olanzapine, Risperidone DA are blocked by Fluphenazine, Haloperidol. Thiothixene Target Effect Limbic system ● Emotions (anxiolytic activity) ● Anterograde amnesia – temporary Reticular formation ● Hypnotic activity Cerebral cortex ● Anticonvulsant activity Spinal cord ● Skeletal muscle relaxant ALL Psych meds: - BBW: Increased mortality in elderly patients with dementia related psychosis Risk factors ○ First gen antipsychotics ○ male gender ○ Younger age - ADRs: Hyperprolactinemia - d/t blocking dopamine - risperidone or paliperidone orthostatic hypotension - D/t blocking alpha receptors - Chlorpromazine, thioridazine, clozapine, quetiapine, risperidone EKG changes - QT prolongation - Thioridazine, clozapine, iloperidone, ziprasidone lipid abnormalities - Metabolic syndrome - Clozapine, olanzapine, chlorpromazine, fluphenazine, thioridazine - - - First Gen Antipsychotics ⇒ ADRs: Hyperprolactinemia, gynecomastia, irregular menses, decrease libido, orthostatic hypotension, lipid abnormalities Class : Phenothiazine Drugs: Chlorpromazine, fluphenazine, trifluoperazine, prochlorperazine, promethazine MOA: Dopamine blocker ADR: - - Sedation, dependency, withdrawal symptoms, dry mouth, constipation, visual disturbances, decrease blood pressure + postural hypotension (Alpha blocking), Neuroleptic malignant syndrome, EPS anticholinergic/ antihistamine effects Place in Therapy: - Short-term management of anxiety, muscle relaxation, alcohol withdrawal. Prochlorperazine used low does for N/V - Due to decreased dopamine activity in the medulla Reduces bizarre behavior, hallucinations, and irrational though Intractable hiccups Promethazine (antihistamine and neuroleptic agent) motion sickness treatment Special Considerations: - Avoid in elderly due to fall risk; schedule tapering to prevent withdrawal. Reduce bizarre behaviors without depressing other intellectual effects Several weeks for full effect Controls NOT cures psychosis Formulations: Fluphenazine - LAIA Class : Butyrophenones Drugs: Haloperidol MOA: Dopamine blocker . ADR: High incidence of EPS, LOWER incidence of anticholinergic effects (lower incidence of alpha blockage, antihistamine and anticholinergic effects) Place in Therapy: - Suppresses motor tics associated with Tourette’s, treatment of highly agitated manic patients (injectable) Second line agent Formulations: Injectable form available Class : Thioxanthenes Drugs: Thioxanthene MOA: Dopamine blocker . ADR: High incidence of EPS, less sedation, fewer anticholinergic and alpha blocking effects Class: Second-Generation Antipsychotics (SGAs) - Atypical PK: CYP2D6 metabolism PD: - D2R receptors = motor effects HTR2C = limbic/ emotion/ appetite (why metabolic syndrome is a risk) - Weight gain, increased triglycerides, hypercholesterolemia, development of DM MOA: Serotonin-dopamine antagonists; block 5HT2 and D2 receptors. More serotonin blocking activity. ADRs: - Metabolic syndrome (weight gain, increased triglycerides, hypercholesterolemia, development of DM) sedation. Lower risk of EPS compared to FGAs. Place in Therapy: First-line agents for schizophrenia and bipolar disorder. Aripiprazole + quetiapine approved for MDD - Risperidone- 1st line tx for schizo Clozapine reserved for treatment-resistant cases. Special Considerations: - Clozapine requires regular WBC monitoring due to agranulocytosis risk. Risk of QT prolongation with certain agents. Drug: Clozapine Place in therapy: Used for treatment-resistant cases. - May be useful for treating dyskinesia/PD due to anticholinergic effects ADRs: - High incidence of sedation, seizures, weight gain, hypotension. Agranulocytosis (requires WBC monitoring) - Agranulocytosis most common during the first 3 months of life Contraindications: - Neutropenia, cardiac disease, seizures - Minimum ANC of 1500+ to initiate clozapine Drug: Risperidone MOA: SGA ADRs: Mildly sedating, low incense of EPS, poster oral hypotension, weight gain Place in therapy: Tourette’s, schizophrenia Special Considerations: - Must be conveyed with oral medication for 3 week prior Available IM Injection, LAIA - Must be refrigerated - Ideal for hospitalized and agitated patients Drug: Olanzapine PK: Regular release, fast release and IM products ⇒ (use for emergent manic situations) ADRs: - Dizziness Sedation Weight gain postural hypotension Low risk of EPS - **Must be closely monitored for 3 hours after injection due to possible post-injection delirium sedation syndrome PDSS** Place in therapy: Mania and bipolar disorder Drug: Ziprasidone Place in therapy: ADRs: QT-Prolongation, proarrhythmic potential Drug: Aripiprazole Place in therapy: ADRs: - Dizziness, constipation, anxiety, sleep disturbances impulse control behaviors (gambling, binge eating..), lower incidence of sedation and EPS Special Considerations: Must be conveyed with oral medication for 3 week prior Drug: Cariprazine Place in therapy: Schizophrenia, treating agitation in dementia **high safety ADRs: Drug: Tetrabenazine (TID), Deutetrabenazine (QD/BID) MOA: Central VMAT inhibitor, prevents monoamines (dopamine) from entering presynaptic vessels, decreasing the amount of dopamine that is released Place in therapy: Tardive Dyskinesia, Huntington’s and Tourette’s ADRs: Sedation, dysphagia, hypotension, suicide (BBW), QT Prolongation, NMS Drug: Valbenazine - Tetrabenazines tx for TD !! MOA: VMAT 2 inhibitor Place in therapy: - Tardive Dyskinesia - Tourette’s Buspirone MOA: Blocks serotonin receptors ADR: Dizziness and rash Place in therapy: - Alternative to other long term anti-anxiety agents. NOT useful for acute anxiety (NOT USED PRN) No sedative, anticonvulsant, or skeletal muscle relaxant activity. ➢ MUST be taken consistently ➢ Chronic use only Class : Benzodiazepines Drugs : Diazepam, Lorazepam, Alprazolam, Chlordiazepoxide, Clonazepam, Temazepam, Flurazepam, Triazolam PK: half life: - Alprazolam- 15 hours - Xanax short half life → good for short procedures - Diazepam- 20 hours - Lorazepam- 18 hours - Chlordiazepoxide - 100 hours - Flurazepam- Sedation/hypnotic, long half life - Triazolam- Sedation/hypnotic, short acting MOA: - Bind to GABA receptors, increasing chloride ion influx causing hyperpolarization - Decreases excitability of brain and spinal cord. ADR: - Sedation Dependency and withdrawal symptoms Drowsiness Impaired ability to drive impaired cognition/ short term memory Falls - Elderly most susceptible to ADRs** Alprazolam: avoid d/t short half life; fast onset causing rebound anxiety and withdrawal Black Box Warning - abuse, dependence and withdrawal Place in Therapy: - Relieves nervous tension and anxiety caused by neuroses. - Short-term management of anxiety, muscle relaxation. - (Back injuries, spinal cord injuries, muscular dystrophy, cerebral palsy) - Anticonvulsant treatment - Sedative, hypnotic agents - Temazepam, Flurazepam, Triazolam - Alcohol withdrawal - Panic attack (clonazepam, diazepam) - PTSD - Not suggest d/t abuse potential - Pre-op medications Target Effect Limbic system ● Emotions (anxiolytic activity) ● Anterograde amnesia – temporary Reticular formation ● Hypnotic activity Cerebral cortex ● Anticonvulsant activity Spinal cord ● Skeletal muscle relaxant Special Considerations: - Must taper off to avoid withdrawal - Schedule IV - Flumazenil - Benzodiazepine receptor antagonist - Reverses midazolam during procedures - Contraindications - Withdrawal sx - Pregnancy category D or X - Cleft palate, floppy baby syndrome, neonatal withdrawal - Drug interactions - Tapering schedules important - British tapering schedule listed as an example in ppt Anxiety Tx Anxiety Tx Strategies Treatment strategy Drugs Alter NE Neurotransmission ● Propranolol ○ Block postsynaptic beta receptors ● Clonidine ○ Stimulate pre synaptic central alpha 2 receptors ● Prazosin ○ Block postsynaptic alpha 1 receptors Alter 5-HT Neurotransmission ● SSRI ● SNRI Block calcium intake into presynaptic neuron ● Gabapentin ● Pregabalin Glutamate Alteration ● Memantine ○ MOA: blocks NMDA receptor Preferred Therapy for Anxiety Disorders GAD + Panic Disorder Short Term: Benzodiazepines Long Term: SSRI or SNRIs - Alternative: Pregablin, buspirone, hydroxyzine (prn quick onset) Refractory: TCAs ● More acute, rage, agitation ● Decreases agitation, rage and irritability ● POOR anxiolytic Anxiolytics Anxiety: Activation of the limbic system and SNS General MOA: Target GABA receptors to invite an inhibitory effect Class : Benzodiazepines Drugs : Diazepam, Lorazepam, Alprazolam, Chlordiazepoxide, Clonazepam, Temazepam, Flurazepam, Triazolam MOA: Bind to GABA receptors, increasing chloride ion influx causing hyperpolarization. Decreases excitability of brain and spinal cord. ADR: Sedation, dependency, withdrawal symptoms, drowsiness, Impaired ability to drive, impaired cognition, short term memory, Falls, **Elderly most susceptible to ADRs** Place in Therapy: Relieves nervous tension and anxiety caused by neuroses. Short-term management of anxiety, muscle relaxation. (Back injuries, spinal cord injuries, muscular dystrophy, cerebral palsy) Special Considerations: - Avoid in elderly due to fall risk; schedule tapering to prevent withdrawal. Discourages alprazolam (Xanax) bc short half life - Good for short procedures - Must taper off to avoid withdrawal ➢ Pregnancy Category D or X ○ Cleft palate, floppy baby syndrome, neonatal withdrawal Target Effect Limbic system ● Emotions (anxiolytic activity) ● Anterograde amnesia – temporary Reticular formation ● Hypnotic activity Cerebral cortex ● Anticonvulsant activity Spinal cord ● Skeletal muscle relaxant Reversal Agent: Flumazenil ● Benzodiazepine receptor antagonist ● Given IV to reverse depressant effects ● Commonly used pre procedure to reverse midazolam Anticonvulsant treatment - Diazepam, lorazepam, clonazepam Sedative, hypnotic agents – not recommend for this use beyond short term - Temazepam, flurazepam, triazolam Alcohol withdrawal - diazepam, chlordiazepoxide Panic Attack - clonazepam, diazepam Buspirone MOA: Blocks serotonin receptors Indication: Alternative to other long term anti-anxiety agents. NOT useful for acute anxiety (NOT USED PRN) No sedative, anticonvulsant, or skeletal muscle relaxant activity. ➢ MUST be taken consistently ➢ Chronic use only ADR: Dizziness and rash Psych Tx Antipsychotic drugs ⇒ Suppress the symptoms of schizophrenia and other psychotic conditions ● Better for positive symptoms ● Works at cerebral cortex and limbic system Psychosis ● Excess activity of dopamine and serotonin in the cortical and limbic pathways ● Secondary negative symptoms and cognitive effects from the mesocortical area Dopamine blocking ADRs - Nigrostriatal (inc risk of EPS→ akathisia, dystonic fractions, rigidity and tremors) Tuberoinfundibular areas and D-1 receptor blockade = inc prolactin levels Dystonic rxns Akathisia Parkinsonism Tardive Dyskinesia/ Chronic EPS → jaws tongue and lip movements Lowers seizure threshold Neuroleptic malignant syndrome - Hyperthermia, led pipe rigidity, catatonia and ans instability - Tx= stop drug Psychosis ⇒ Atypical Class Psychosis/Agitation in dementia ⇒ Nuedexta (Dextromethorphan/quinidine) Treatment Resistant Psychosis ⇒ Utilize plasma levels Neuroleptic Malignant Syndrome - Muscle cramps, rigidity, fever, delirium - Progresses to rhabdomyolysis, seizures, autonomic instability, coma - Treatment ⇒ Benzodiazepines, dantrolene, bromocriptine, reduce temp Dystonia - Treatment ⇒ Amantadine, benztropine, clonazepam/diazepam, lorazepam, diphenhydramine, propranolol, trihexyphenidyl Sedative/Hypnotics Sedative-Hypnotic Drugs Class: Benzodiazepines Drugs in Class: Flurazepam, Temazepam, Triazolam PK: - Flurazepam: long half life Triazolam: short half life MOA - Enhance inhibitory GABA activity by binding to GABA-A receptors. - Increase Cl- channel opening, leading to hyperpolarization and decreased neuronal activity. ADRs - - Drowsiness, dizziness, headache, confusion, rebound insomnia, respiratory depression. Rebound insomnia on d/c Potential for tolerance, dependence, and withdrawal. Black Box Warning - risk of profound sedation and respiratory depression from concomitant use with opioids Beers Criteria NREM Stage 4 (physical restoration) is decreased Place in Therapy: - Pts who require sedation at night + anti-anxiety medication during the day Pts with trouble falling asleep (problem is not STAYING asleep - just falling asleep) - Not often used as a sleep aid, though Adjunct in alcohol withdrawal. Flurazepam - LONG acting Special Considerations: - Schedule IV controlled substances. Avoid in pregnancy (Category D or X). Flumazenil - Benzodiazepine antagonist Class: Miscellaneous Hypnotics Drugs in Class: Eszopiclone, Zaleplon, Zolpidem PK - Eszopiclone Zaleplon- short acting Zolpidem MOA - Increase inhibitory GABA activity. ADRs: - Dizziness, headache, gastrointestinal disturbances, Memory disturbances Xerostomia Place in Therapy: - Eszopiclone ⇒ Sustained ability to induce & maintain sleep when taken daily for up to 6 months Zaleplon ⇒ Used for pts with trouble falling asleep (short DOA) Zolpidem ⇒ Decreases awakening during the night Special Considerations: - Lower risk of dependence compared to benzodiazepines. Black Box Warning for sleepwalking, driving, and other activities while not fully awake. Class: Melatonin Agonists Drugs in Class: Ramelteon MOA: Activates MT1 and MT2 melatonin receptors, regulating sleep-wake cycles. - Expensive melatonin basically ADRs: Headache, dizziness, nausea. Place in Therapy: - First-line for insomnia with a focus on sleep onset. Special Considerations: - Not associated with dependence or withdrawal. Top 200 Chart Chart of Top 200 Drugs Generic Name Brand Name Dose (Common) Duloxetine Cymbalta 30 mg BID / 60 mg QD Venlafaxine ER Effexor XR 75mg QD Bupropion ER Wellbutrin XL 150mg QD Trazodone Desyrel 50 mg TID Paroxetine Paxil 30mg QD Sertraline Zoloft 50mg QD Escitalopram Lexapro 10mg QD Imipramine Tofranil 100mg QD Citalopram Celexa 20mg QD Amitriptyline Elavil 50mg BID Fluoxetine Prozac 20mg QD Nortriptyline Pamelor 25 mg TID Methylphenidate Concerta 36mg QAM Amphetamine + Dextroamphetamine Adderall XR 10mg QAM Lisdexamfetamine Vyvanse 30mg QAM Atomoxetine Strattera 40mg QAM Clonazepam Klonopin .5 mg po TID Lorazepam Ativan 1 mg po TID Diazepam Valium 5 mg po TID Quetiapine Seroquel 400 mg po QD Risperidone Risperdal 8 mg po QD Aripiprazole Abilify 10 mg po QD Olanzapine Zyprexa 10 mg po QD Clozapine Clozaril 300 mg po QD Haloperidol Haldol 2 mg po TID Quiz