Pharm Exam 6

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  1. Antipsychotic Drugs
    • Highest selling class (most money) in 2011
    • 70% of use off label
    • Atypical antipsychotics account for 93% of total antipsychotics prescribed, though incidence of schizo and bipolar has remained constant
  2. Clinical Uses of Antipsychotic Drugs (FDA-Approved Indications)
    • Schizophrenia
    • Pos Symptoms: delusions, hallucinations
    • Neg Symptoms: Blunted affect, withdrawal, apathy

    • Bipolar disorders (manic and/or depressive phases)
    • Adjuntive tx of resistant depression
    • Autism
  3. First Generation Antipsychotics (FGA)
    • Primary Mech: Block DA D2 Receptors in mesolimbic pathway
    • High occupancy rate of receptor blockage
    • Typically reduce positive but not neg symptoms of schizo
    • Also block D2 receptors in other DA pathways in brain - leading to worsening neg symptoms, movement disorders, increased prolactin levels
    • Adverse Effects:
    • Anticholinergic
    • Antihistaminic (weight gain)
    • Alpha-1 receptor blockade
    • Elevated prolactin levels
    • Lowered seizure threshold
    • Extrapyramidal syndromes (EPS)
    • Tardive dyskinesia
    • Neuroleptic malignant syndrome
  4. Extrapyramidal Syndromes (EPS)
    • Movement disorders
    • Secondary to imbalance of DA and ACh in nigrostriatal pathway
    • DA inhibits ACh release, suppresses its activity
    • When DA blocked by typical antipsychotic: relative increase in ACh activity which is assoc with EPS
    • Usually secondary to to agents with low antichol activity
    • Treat EPS with anti-cholinergic agents such as benztropine (Cogentin)

    • Three Potential Syndromes (Develop with time, dose, or both - can be any or all of the three)
    • Acute dystonia - painful spasms and contractions of eye, face, neck, and throat muscles
    • Akathisia - feeling of restlessness and urge to move
    • Pseudoparkinsonism - bradykinesia, rigidity, tremor
  5. Tardive Dyskinesia (TD)
    • Irreversible, long term consequence of typical antipsychotics (up to 20%)
    • Involuntary abnormal movements usually of the face, limbs, neck, and trunk - facial tics, grimacing, lip smacking, writhing, pill rolling
    • Theory: DA receptors become hypersensitive over time from continual blockade
    • Prevalence of TF and risk for irreversible symptoms increase with age
    • TD is reversible in some cases, but a long duration of therapy increases risk of irreversibility
  6. Neuroleptic Malignant Syndrome
    • Rare, but potentially fatal syndrome
    • Signs and symptoms include fever, extreme rigidity, altered consciousness, elevated creatinine kinase activity
    • Need to stop antipsychotic and tx with DA agonist and muscle relaxant
    • Can occur with both FGAs and SGAs
  7. Chlorpromazine and Thioridazine

    Low-potency drugs, produce more anticholinergic effects including sedation

    • Adverse: orthostatic hypotention
    • Arrhythmias at higher doses
  8. Haloperidol

    • High potency agent, significant EPS, even at low doses
    • Can cause cognitive deterioration
    • Has little anticholinergic or antihistaminic activity
    • Chronic use - often given with anticholinergic agent for prophylaxis to prevent EPS
    • Can be given parenterally
    • Used for emergency sedation
    • Very inexpensive
  9. Second Generation Antipsychotics (SGA)
    • Also called atypical antipsychotics
    • Block DA 2A receptors like FGA but with lower occupancy rate
    • Also block serotonin (5HT2a) receptors in mesocortical and nigrostriatil system to greater extent than DA 2A receptors
    • Several also 5HT1a partial agnoists
    • Effective for both positive and negative symptoms of schizo
    • Except for clozapine, all seem to be equally effective clinically for schizo/bipolar
    • -------------------
    • Compared to FGA -
    • Lower incidence of EPS
    • Lower prolactin levels
    • Increased incidence of endocrine adverse effects
    • Much more expensive
    • ----------------------
    • Selection depends on:
    • Indication, evidence of relative efficacy, adverse effect profile, drug interation potential, warnings/contraindications, non-adherence potential, cost
  10. Clozapine (Clorazil)
    • First SGA
    • Prototype of SGA drugs but has most adverse effects of the group
    • FDA-Approved Indications:
    • Treatment-resistant schizo
    • Schizo or schizoaffective disorder with suicidal behavior
    • Metabolism/Elimination:
    • Hepatic metabolism primarily via CYP1A2 and CYP2D6 enzymes
    • Adverse Effects:
    • Common: somnolence, dizziness, hypotension, weight gain
    • Severe: agranulocytosis (0.5-2%), myocarditis, seizures
    • Black box Warning:
    • Agranulocytosis, myocarditis, seizures, orthostatic hypotension, increased mortality in elderly with dementia
    • Monitoring:
    • Plasma drug levels b/w 300 and 450ng/mL
    • WBC and ANC at baseline and weekly for 1st 6 months, then every 2 weeks
    • Obesity and diabetes protocl
    • Other:
    • Requires patient-specific registration
    • Dosage Forms:
    • Generic Available - tablet and disintegrating tablet
    • Cost:
    • $150-580/month (Generic available)
  11. Risperidone (Risperdal)
    • SGA
    • FDA Approved Indications:
    • Schizophrenia
    • Bipolar I acute mania/mixed mania
    • Autism - associated with irritability/aggression
    • Metabolism/Elimination:
    • Hepatic metabolism primarily via CYP2D6 enzyme to active metabolite which is eliminated by kidney
    • Adverse Effects:
    • Somnolence, weight gain, diabetes risk
    • Dose-dependent EPS and hyperprolactinemia
    • Increased risk of CVA in elderly with dementia
    • Black Box Warnings:
    • Increased mortality in elderly with dementia
    • Monitoring
    • Obesity and diabetes protocol
  12. Olanzapine (Zyprexa)
    • SGA
    • FDA-Approved Indications:
    • Schizo
    • Acute agitation
    • Bipolar I acute mania/mixed mania
    • Bipolar maintenance
    • Bipolar depression in combination w/ fluoxetine (Symbyax)
    • Metabolism/Elimination
    • Hepatic metabolism via CYP 1A2 and CYP2D6
    • Adverse Effects
    • Somnolence, anticholinergic effects (significant)
    • Significant weight gain and high risk for diabetes and hyperlipidemia
    • Black Box Warnings
    • Increased mortality in elderly with dementia
    • Monitoring
    • Obesity and diabetes protocol
    • Dosage Forms
    • Tablet, disintegrating tablet, short-acting intramuscular injection (powder for reconstitution)
  13. Quetiapine (Seroquel)
    • SGA
    • FDA-Approved Indications:
    • Schizo
    • Bipolar I - acute mania
    • Bipolar disorder
    • Adjunct for major depressive disorder (Seroquel XR)
    • Metabolism/Elimination
    • Hepatic metabolism primarily via CYP3A4
    • Adverse Effects:
    • High incidence of sedation and dizziness
    • May be less anticholinergic than olanzapine
    • Weight gain, diabetes risk
    • Abuse Potential:
    • #1 Drug in prisons
    • Known as "Quell", "Suzie Q" or "Baby Heroin"
    • Black Box Warning:
    • Increased mortality in elderly with dementia
    • Monitoring
    • Obesity and diabetes protocol

  14. Ziprasidone (Geodon)
    • SGA
    • FDA-Approved Indications
    • Schizo
    • Bipolar I - acute mania/mixed mania
    • Acute agitation - schizo (IM)
    • Metabolism/Elimination
    • Hepatic metabolism via aldehyde oxidase
    • Only minor metabolism by CYP1A2 and 3A4
    • Adverse Effects
    • Low incidence of sedation, weight gain, and hyperglycemia
    • More likely to prolong QT interval than other SGAs
    • Possibly activating at low doses but not higher doses
    • Contraindications:
    • Related to QT interval prolongation - history of QT prolongation, recent MI or heart failure
    • Black Box Warnings
    • Increased mortality in elderly with dementia
    • Monitoring
    • Obesity and diabetes protocol
    • Dosage Forms
    • Capsule, short acting intramuscular injection (powder for reconstitution)
    • Take with food to double plasma levels - must be given twice daily
  15. Aripiprazole (Abilify)
    • Unique among SGA group
    • Mech
    • Partial D2 and 5HT1a receptor agonist properties (3rd gen?)
    • FDA-Approved Indications:
    • Schizo
    • Bipolar I acute mania/mixed mania
    • Bipolar maintenance
    • Agitation with schizo or bipolar (IM)
    • Adjunctive treatment of major depressive disorder
    • Metabolism/Elimination
    • Hepatic metabolism via CYP3A4 and 2D6
    • T1/2 = 75 hrs
    • Adverse Effects:
    • Akathisia (25%) nausea, vomiting, dizziness, insomnia
    • May be activating as doses increase
    • Low incidence of sedation, weight gain, diabetes
    • Black Box Warnings:
    • Increased mortality in elderly with dementia
    • Increase risk of suicide for depressed patients
    • Monitoring
    • Obesity and diabetes protocol
    • Dosage forms
    • Tablet, disintegrating tablet, solution, short acting IM injection (solution)
  16. Paliperidone (Invega)
    • SGA
    • Active metabolite of risperidone
    • FDA-Approved Indications
    • Schizo
    • Metabolism
    • Eliminated renally unchanged - adjust dose in renal impairment
    • Adverse Effects
    • Same as risperidone
    • Drug interaction potential less because not metabolized by CYP
    • Black Box Warnings
    • Increased mortality in elderly with dementia
    • Monitoring
    • Obesity and Diabetes protocol
  17. Asenapine (Saphris)
    • New SGA
    • Indication
    • Schizo
    • Bipolar
    • Dosage
    • Sublingual 2x/day
    • ---------------
    • Marginally better than placebo
    • Adverse Effects:
    • EPS including akathisia
  18. Iloperidone (Fanapt)
    • New oral SGA
    • Indication
    • schizo
    • Adverse:
    • QTc prolongation similar to ziprasidone
    • Caution with CYP 2D6 and 3A4 inhibitors
  19. Adverse Effects of SGA Drugs
    • Endocrine adverse effects - unique for SGA drugs secondary to 5HT2a block plus receptor X (?)
    • Hyperglycemia
    • Hyperlipidemia
    • Weight gain
    • ---------------------------
    • Agents differ slightly in:
    • Anticholinergic effects
    • Anithistaminic effects
    • Alpha-1 receptor blockade
    • Antagonsim of various DA receptors
    • ---------------------
    • EPS
    • Less common because of 5HT2a receptor blockade
    • ---------------------
    • Tardive dyskinesia
    • Risk is less in young adults but similar to FGAs for elderly
    • ------------------------
    • QTc interval prolongation
  20. Significant Adverse Effects for Specific SGA Agents
    • EPS - haloperidol
    • Agranulocytosis - clozapine
    • Severe weight gain, hyperglycemia - clozapine, olanzapine, asenapine
    • QT interval prolongation - ziprasidone, iloperidone
  21. Efficacy of FGA vs SGA
    SGA have 90% market share because they are perceived to cause less adverse effects

    Unknown if this is true - new studies coming out to dispute this
  22. Publicly funded trials for FGAs vs SGAs
    CATIE-SZ - no difference in effectiveness between FGAs and SGAs

    CUtLASS I - no disadvantage across 1 year in terms of QOL, symptoms, or costs of care between FGAs and non-colzapine SGAs
  23. Leading off label uses of SGAs
    • Agitation in dementia
    • Anxiety
    • Autism
    • Depression
    • Obsessive Compulsive Disorder
    • Personality disorders
    • PTSD
    • Tourette's
    • AHRQ Effective Health Care Program (2007): With few exceptions, there is insufficient high-grade evidence to reach conclusions about the efficacy of atypical antipsychotic medications for any of the off-label indications, either vs placebo or vs active therapy
  24. Risk of Death in Elderly with Antipsychotic Meds
    • Risk of death greater in SGA group compared to placebo group
    • NNH = 20

    Dose-related effects?

  25. Comparison of Four SGAs in Patients over 40 years old
    • Compared aripiprazole, olanzapine, quetiapine, and risperidone in 332 patients
    • Tx for psychotic syndromes for a variety of psychiatric disorders
    • Hypothesized sig diff in tolerability, adverse effects, efficacy
    • Results:
    • High discontinuation rate - median 26 wks
    • Lack of significant improvement of symptoms
    • High incidence of metabolic syndrome (37%), serious (24%) and non-serious (51%) adverse effects
  26. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes
    4 groups said baseline monitoring req

    • Personal/fam hx
    • Weight/height
    • Waist circumference
    • Blood Pressure
    • Fasting plasma profile
    • Fasting lipid profile
  27. CYP 450 Drug Interactions and SGA Use
    • All SGAs (except paliperidone) metabolized by CYP450 enzymes to some extent (1A2, 2D6, and 3A4)
    • Many common drugs either inhibit or induce one or more of these enzymes
    • The most significant interaction is SGA drugs depending on only one enzyme for metab

    Quetiapine ONLY metabolizated by 3A4
  28. Preferred SGAs for Specific Situations
    • Treatment resistant schizo - clozapine
    • Most effective non-clozapine SGAs for schizo - risperidone and olanzapine
    • Least likely to cause weight gain or diabetes - aripiprazole and ziprasidone
    • Most likely to cause dose-related EPS and elevate prolactin - risperidone
    • Most likely to prolong QTc interval - ziprasidone
    • Least costly - risperidone
    • For best compliance - risperidone depot injection
    • Elderly/Medicare - low dose risperidone
    • Smokers - caution with olanzapine and clozapine
    • Taking drugs that inhibit or induce CYP2D6 enzyme: caution with olanzapine and aripiprazole
    • Taking drugs that inhibit or induce CYP 3A4 enzyme: caution with quetiapine and aripiprazole
  29. SGA Take-Home Points
    • No clinically sig diff in effectiveness b/w FGAs and SGAs for Schizo
    • No clinically sig diff in quality of life between FGAs and SGAs studied so far (increase in EPS and motor symptoms with FGAs is offset by increase in weight, hyperglycemia, and lipids with SGAs)
    • Clozapine and, possibly, olanzapine more effective among SGA group for schizo but assoc with increased incidence of intolerable adverse effects
    • No clinically sig efficacy of SGAs for dementia-related aggression and psychosis
    • Clinically sig increase in risk of death with use of FGAs and SGAs for dementia-related aggression and psychosis
    • Always check for CYP450 drug interactions
    • All patients taking SGAs should have their weight, blood pressure, fasting glucose, and fasting lipids monitored at regular intervals
  30. Positive Reinforcement
    • Dopamine modulated striato-cortical pathways (ventral tegmental area --> N acc --> prefrontal cortex) 
    •   - ventral striatum--> reward and        
    •      motivation
    •  - the faster dopamine increases, the more
    •     intense the positive reinforcing effects
  31. Physical Dependence
    • 1. Tolerance --> need for greatly increased amounts of substance to achieve intoxication, markedly diminished effect with continued use of the same amount of substance
    • 2. Withdrawal --> maladaptive behavioral change with physiological and cognitive changes that occur when blood or tissue concentrations of a substance decline who had prolonged heavy use of the substance
  32. Negative Reinforcement
    • --> taking a substance to relieve or to avoid unpleasant withdrawal symptoms
    •       - withdrawal symptoms are generally opposite of the acute effects of a drug
  33. Alcohol
    MOA: CNS Depressent that impacts many neurochemical systems (see slide 19) 

    Absorption/Distribution: absorbed rapidly (delays in gastric emptying slow abs), distributes into total-body water. Peak blood levels w/i 30 mins. Oral ingestion=lower BALs vs intravenous

    • Metabolism: First pass by liver ADH (most metabolism occurs in the liver) acetaldehyde --> acetic acid. Exceeds supply of NAD+ in liver (limited EtOH metabolism). Zero order --> functionally saturates at low blood levels
    •     - increased NADH and elevated acetyl-CoA 
    •        --> storage of tryglycerides --> fatty 
    •        changes in liver --> eventual cirrhosis
  34. CNS effects of EtOH abuse
    • 1. Alcoholic dementia--> permanent
    • 2. Wernicke- Korsakoff syndrome --> Thiamine depletion 
    • 3. Cerebellar degeneration
    • 4. Peripheral neuropathy
    • 5. Sleep apnea
  35. Cardiovascular Effects of EtOH
    • 1. 1-3 drinks/day cardioprodective with 10-40% decreased risk of CAD
    • 2. 2-3 drinks/day --> increased risk of MI/arrhythmia/cardiomyopathy. 

    (J-shaped dose/mortality curve) 
  36. GHB
    MOA: Naturally occuring GABA derivative. Effects on GABA receptors. Sedative effect of high doses. Euphoric effects of low doses (disinhibition of dopaminergic activity) 

    Dose: clear liquid/white powder/tablet/capsule. 

    Pharm use: Treatment of narcolepsy (schedule III) otherwise a schedule I drug. 

    Absorption/Distribution: rapidly absorped. Small volume of distribution. Blood levels peak at 20-60 mins

    Metabolism/Excretion --> metabolized by the liver (GHB--> SSA --> GABA or succinic acid). Some eliminated unmodified in urine (2-5%). Eliminated within 4-8 hrs. 

    Adverse effects --> higher doses. dizziness, hypersalivation, LOC, hypotonia, anterograde amnesia. AKA: the 'date rape drug'
  37. Rohypnol/Flunitrazepam
    MOA: GABA agonist. Binds GABA receptor --> increases GABA affinity to GABA receptor. Sedation, anticonvulsant activity, anxiety reduction. Anterograde amnesia at higher doses

    Dose: pill form taken orally. Not legally available in US. Odorless and tasteless. Easily dissolved in H2O. Another date rape drug. 

    Metabolism: very quick. Detectable in blood and urine for up to 72 hrs after ingestion. Rapidly distributes

    Adverse effects: Overdose can lead to LOC and respiratory depression.
  38. MDMA/ecstasy
    MOA: ring substituted amphetamine. Effects related to amphetamine type drugs plus feelings of closeness to others, facilitation of relationships, and empathy. Potent releaser/re-uptake inhibitor of presynaptic serotonin (receptor agonist, inhibits tryptophan hydroxylase), dopamine, and norepinepherine. 

    • Metabolism: Tmax at 2 hrs, high volume of distribution, T1/2 of 8-9 hrs. 2 main metabolic pathways
    •      1) O-demethylation--> COMT methylation
    • and/or glucuronide/sulfate conjugation
    •      2) N-dealkylation--> deamination--> oxidation to benzoic acid derivatives conjugated with glycine

    Excretion: 80% eliminated after hepatic metabolism, 20% excreted unchanged in urine. 

    Adverse effects: Hyperthermia, serotonin syndrome, mid to long-term neurotoxic effects (cognitive and behavioral)
  39. Full Opioid agonist
    • 1. 3 main receptors: kappa, delta, and mu
    •      - Mu 1= analgesia and euphoria
    •      - Mu 2= respiratory depression, GI effects, and sedation
    • 2. Highly reinforcing --> phasic increase in dopamine
    • 3. Most abused type of opioid (heroin, oxycodone)
  40. Diacetylmorphine/Heroin
    MOA: Full opioid agonists. 

    Absorption/distribution: Lipophilic, widely distributed. High penetration of BBB

    Dose: taken by almost any route

    Metabolism: T1/2 = 3 minutes, Tmax= 2 minutes, Peak effects in 10 minutes, more potent and faster acting than morphine as analgesic. Metabolized in the liver  (hydrolyzed to morphine)

    Adverse effects: Infectious complications (HepB/C, HIV, endocarditis, deep tissue abscess, osteomyelitis)
  41. Oxycodone
    MOA: Full opioid agonist


    Dose: sustained release preparation, can be crushed and injected IV for rush

    Metabolism: CYP3A4 (noroxycodone, potential for interxns), CYP2D6 (Oxymorphone --> subsequently inactivated by UGT2B7, central opioid effects of oxycodone are governed by parent drug) 

    Adverse effects: Overdose triad= miosis, respirator depression, coma. Pulmonary edema. Tx with ventilatory support and IV naloxone. High risk of overdose among experienced opioid users
  42. Stimulants
    Stimulate activity in CNS and sympathetic nervous system. Enhance NT activity at catecholaminergic synapses (release NE, dopa, etc). Increase HR and BP

    • Absorption/Distribution:
    •    1) Cocaine/meth --> smoked reaches brain in 6-8 secs, IV peaks in brain in 4-7 mins, Intranasal/Oral peaks in 30-45 mins. 
    •    2) Cocaine volume of distribution is 2.7 L/Kg
    •    3) Meth volume of distribution is 4L/kg

    • Metabolism
    •      1) Cocaine: primarily hepatic (hydrolyzed to benzoylcgonine, ecgonine. 5% to norcocain via CYP3A4
    •      2) Amphetamine via 3 liver pathways
    •            - deamination
    •            - oxidation (CYP2C) 
    •            - parahydroxylation (CYP2D6) 

    Excretion: Primarily renal (benzoylconine urine drug test). Amphetamines: weak bases --> GI/Urinary absorption is pH dependent (pKa 9.9, acidification decreases absorption, alkanization increases absorption and decreases excretion)

    Adverse effects: Cocaine is a factor in 25% of non-fatal MIs in people under 45 yo. Seizures, CVA, movement disorders, hyperthermia
  43. Stimulant effects on neurotransmitters
    1. Dopamine: Cocaine blocks uptake via DAT. Methamphetamine is false substrate for DAT and is a substrate for VMAT to increase dopamine release

    • 2. Norepinepherine: increases NE/EPI
    • 3. Serotonin: increases 5HT (presynaptic membrane transporters) 
    • 4. Amphetamines inhibit monoamine oxidase
    • 5. Cocaine blocks voltage gated Na channels accounting for local anesthetic action. Blocks muscarinic receptors in brain and heart
  44. Treatment of Stimulant Overdose
    • 1. Paranoia/psychosis --> Tx diazepam/lorazepam. No restraints.
    • 2. Hyperthermia--> Monitor BP, cool room
    • 3. HTN/tachycardia --> no beta blockers. Administer nonselective alpha-adrenergic antagonists (phentolamine)
    • 4. Seizures: Diazepam, Lorazepam
  45. Nicotine
    MOA: bindes to nicotinic cholinergic receptors (nAChR) in both PNS and CNS. alpha-4-beta-2 receptor subtype in human brain mediates nicotine dependence. Stimulation of receptors releases dopamine, norepi, ACh, 5-HT, as well as GABA, glutamate, and endorphins

    Absorption/Distribution: Weak base absorbed best at alkaline pH. Enters circulation rapidly through lungs and reaches brain w/i seconds. 

    Metabolism: rapidly and excessively metabolized to cotinine by CYP2A6 in liver. Nicotine and cotinine are also metabolized by glucuronidation (minor) 

    Elimination: T1/2= 2 hrs. (T1/2 of cotinine=16 hrs). 5-10% excreted by kidneys

    Adverse effects: reduces insulin sensitivity, endothelial dysfunction, tumor promotor (possibly).
  46. THC/Marijuana
    MOA:interacts with CB1 (brain, fat cells, liver, duodenum, muscle) and CB2 (lymphocytes, macrophages, cytokines). Endocnnabinoids (annandamide, 2-AG) bind CB1>CB2. Effects include euphoria and Anxiolysis

    Absorption/Distribution: peak effect in < 10 minutes, duration 2-3 hrs (inhaled). Peak effect 2.5 hrs if ingested. Lipophilic, large distribution

    Metabolism: Liveer via CYP2C. 

    Elimination: 35% in urine, 65% in feces
  47. Synthetic Cannabinoids
    1) Donabinol --> FDA approved for nausea associated with chemo and AIDs related wasting

    2) Nabilone --> same indications as above
  48. Lysergic Acid Diethylamide (LSD)
    MOA: 5HT2 receptor agonists (locus coeruleus), disinhbition of norepinepherine from LC. "Illusionogen"

    Absorption/Distribution: Absorbed in digestive tract --> 30-45 mins for onset of effect, peaks at 1.5-2.5 hrs, duration 9-12 hrs. Lipophilic. 

    Metabolism: rapidly metabolized into several similar metabolites. 

    Excretion: less than 1% in urine or feces
  49. Phencyclidine (PCP)
    Absorption and Distribution: Well absorbed, penetrates CNS, large volume of distribution (6.2 L/kg). May be taken IV (peaks in 10 mins), intranasal (peaks in 30 mins) or oral (peaks in 90 mins). 

    Metabolism: T1/2= 3 days. Duration of CNS effects --> 7 hrs-7 days (lipid trapping in CNS). 90% metabolized on first pass by liver. Excreted renally. 9% is directly excreted

    Adverse effects: violence, tachycardia, HTN, anesthesia, Analgesia (see chart on slide 76), Nystagmus (57% of PCP intoxication).
  50. Tx of EtOH dependence
    • 1. Meds modify intoxication. Reduce high or increase adverse effects, or reduce cravings or urge to drink. 
    • 2. Meds also reduce signs and sx of withdrawal
  51. Disulfram
    MOA: inhibits acetaldehyde dehydrogenase. Increase adverse effects of EtOH consumptions --> palpitations, flushing, N/V, HA.  

    Dose: 250 mg/day (max of 500 mg/day)

    • Contraindications: patients with cardiovascular disease, hepatotoxicity. 
    • Pregnancy category C.
  52. Naltrexone
    MOA: opioid receptor antagonist. Blocks mu receptors. Reduces reinforcing effects of EtOH leading to fewer cravings

    Metabolism: First pass by liver. 5-40% oral bioavailability

    Dose: 50 mg/day in single dose, 

    Contraindications: patients on long term opioid therapy for chronic pain.Dose related hepatotoxicity. 

    Pregnancy Category C
  53. Acamprosate
    MOA: Effects on glutamate (NMDA) receptors in the brain (antagonism). Chronic alcoholics up regulate NMDA receptors, acamprosate mediates EtOH withdrawal. 

    • Metabolism: not hepatic
    • Excretion: kidneys
    • Contraindications: Advanced cirrhosis

    Pregnancy category C
  54. Burprenorphine
    MOA: partial agonist for opioid dependence. 

    Dose: Sublingual with naloxone added to prevent IV abuse. 1/day for maintenance

    Metabolism: Rapid onset of effect. First pass metabolism by liver P450 3A4. 

    Adverse effects: sedation, N/V, dizziness, HA, respiratory depression
  55. Methadone
    MOA: long acting mu-opioid receptor agonist. Relieves narcotic craving , prevents relapse

    Metabolism: Onset of action w/i 30 mints, good oral bioavailablity. Liver metabolism CYP 3A4

    Dose: once daily for maintenance. 50 mg minimum, mean dose is 400 mg/day

    Adverse effects: sweating, decreased libido, weight gain, constipation, irregular menstrual periods, debilitating sedation, fatal overdose
  56. Varenicline
    • MOA: partial agonist of alpha4beta2 nicotinic acetylcholine receptorsInhibits nicotine induced dopaminergic activation. 
    • Intended to help patients quit smoking 

    metabolism: T1/2= 24 hrs. Peaks at 1-4 hrs after dose. No significant hepatic metabolism. Renal clearance

    Adverse effects: nausea and insomnia. Black boxed warning for suicidal ideation
  57. Bupropion Sustained Release
    MOA: blockade of neuronal re-uptake of dopamine and norepinepherine

    Metabolism: P450B6 substrate. 2D6 inhibitor

    Adverse effects: seizures (don't give to patients with seizure disorders or eating disorders). Increased risk of suicidal ideation
  58. Nicotine Replacement Therapies
    Reduce craving and withdrawal sx by replacing lost nicotine intake. 

    Dose: gum, lozengers, patch, inhaler. 6-10 wks duration with taper
  59. Medications used for ADHD
    • (in general) drugs that inc synaptic NE and/or DA transmission in brain cortex -> greatest impact on ADHD Sx
    • First Line: stimulants-amphetamines and derivatives
    • Second line: nonstimulant-Atomoxetine (Strattera)
    • Third Line: (anti-depressants) tricyclic antidepressants; Burpropin
    • Fourth Line: (alpha2-adrenergic agonists) clonidine; guanfacine
  60. First line medications for ADHD
    • Stimulants:
    • Methylphenidate (Ritalin)
    • Dexmethylphenidate (Focalin)
    • Dextroamphetamine
    • Lisdexamfetamine (Vyvanse)
    • Mixed amphetamine salts (Adderall)
    • [all schedule 2 drugs-based on potential abuse and dependence]
  61. Stimulants for ADHD (description)
    • Effective drug unpredictable
    •      Equal efficacy in reducing ADHD symptoms
    • Effective dose unpredictable
    •      By weight
    •      Fixed, escalating, dose titration
    •      MTA medication management strategy
    • Differences in medications
    •      DEA classification
    •      Duration of action
    •      Adverse effects
    •      Drug interactions
  62. Mechanism of action of amphetamines vs methyphenidate
    • Amphetamines:
    • compete with NE/DA for NET (NE transport) rec==> amphetamine taken up into neuron => stimulate release of more NE/DA
    • Methylphenidate:
    • bins NET and blocks NE/DA re-uptake BUT does NOT enter neuron
    • (works like cocaine)

    Note: NET = re-uptake mechanism
  63. Schedule II drugs
    ie morphine, codeine, oxycodone, amphetamines, methylphenidate
  64. Methylphenidate
    • First line medication for ADHD
    • stimulant to tx ADHD; = amphetamine-like (very similar)
    • Mech: Inhibits reuptake of dopamine and norepinephrine by blocking the dopamine (DAT) and norepinephrine transporters (NET)
    • Variable oral absorption (11-53%)
    •      Rate of absorption increases with food
    •      Transdermal patch bypasses 1st pass effect
    • Metabolized by CYP 2D6
    •      Concern with polymorphisms & potential drug interactions
    • Half-life: 2-3 hrs
    • Schedule II controlled substance due to high abuse potential
    • ---------------------------
    • Immediate release (IR) tablet (Ritalin, etc)
    •      5,10, 20mg
    •      Effect onset: 30-60 min
    •      Effect duration: 3-5 hrs
    •      $20/month for generic
    • ------------------
    • Sustained release tablets or bead-filled capsules (Ritalin, etc)
    •      Single-pulse (Ritalin SR) or double-pulse (Ritalin LA)
    •      10, 20mg
    •      Effect onset: 2-3 hrs
    •      Effect duration: 6-8 hrs
    •      $30/month
    • ------------------
    • Osmotic release (OROS) tablets (Concerta)
    •      20% of dose is IR coating on outside of tablet
    •      18, 27, 36mg
    •      Effect onset: 30-60 min
    •      Effect duration: 10-14 hrs
    •      Tablet shell eliminated intact, do not chew!
    •      $200/month
    • ------------------
    • Transdermal patch  (Daytrana)
    •      1.1, 1.8, 2.2, 3 mg/hr
    •      Worn daily for 9 hours
    •      Effect lasts 12 hrs
    •      $225/month
  65. Dexmethylphenidate (Focalin)
    • First line medication for ADHD
    • stimulant to tx ADHD
    • D-isomer of methylphenidate
    • Available as immediate-release tabs (IR) and extended-release (XR) capsules (not different from immediate release ritalin)
    • Effective dose is 50% of methylphenidate dose
    • No clear benefit over methylphenidate
    • lIR available as generic & inexpensive
    • XR costs $160/month
  66. Methylphenidate Dosing
    • 70% response rate
    • Ia. Titration method with IR
    •      5mg in AM and at 12 noon, before meals (2 doses)
    •      Wait 3-4 days
    •      Optional 3rd dose at 4PM (50% of AM dose)
    •      Increase by 5mg increments up to total daily dose of 60mg
    • Ib. Convert effective daily dose to SR, LA, OROS, or patch if necessary
    •      Useful to prevent mid-day doses during school
    • II. Weight-based method
    •      Start at 0.3mg/kg/day and increase up to 1mg/kg/day
    • --------------
    • [main method is to start w/ immediate release to determine appropriate dose, then switch to sustained release for better compliance]
  67. Issues with Methylphenidate
    • Anorexia
    • Insomnia
    • Tic disorders (transient and chronic)
    • Growth retardation
    •      Drug holidays on weekends & during summer (suggested)
    • Dopamine agonist – may worsen pre-existing psychosis
    • Abuse potential
    • Drug Interactions
  68. Drug Interactions with Methylphenidate
    • Inhibitors of CYP 2D6 (ie. fluoxetine, paroxetine)
    • Monoamine oxidase inhibitors
    •      Increase in MPH effect
    • Tricyclic antidepressants
    •      Increase in TCA effect
    • Phenytoin
    •      Increase in phenytoin effect
    • Clonidine
    •      4 deaths reported
    •      Unknown interaction
  69. Amphetamines for ADHD
    • First line medication for ADHD
    • Competitive inhibitor and pseudosubstrate of DAT and NET. Taken up by synaptic vesicles, displacing dopamine which is released.
    • Possibly cause more insomnia and appetite suppression than methylphenidate, but otherwise similar adverse effects and drug interactions to methylphenidate
    • Schedule II drugs
    • ------------------------

    • 1. Dextroamphetamine
    •      IR tablets 5, 10mg
    •      Dexedrine Spansules (ER) 5,10,15mg
    • 2. Mixed amphetamine salts (d- and l- isomers)    (Adderall, Adderall XR, and generic)
    •      Mixture of amphetamine and dextroamphetamine
    •      5,10,20,30mg tablets
    •      Questionable advantage over dextroamphetamine
    • 3. Lisdexamfetamine dimesylate (Vyvanse)
  70. Dextroamphetamine
    • First line medication for ADHD
    • amphetamine to tx ADHD
    • 2x as potent as methylphenidate [does NOT mean better]
    •      (5mg dextroamphetamine = 10mg Ritalin)
    • All amphetamines are weak bases with pKa = 9.9
    • Half-life of 4-6 hrs
    • Metabolized by CYP 2D6
    •      Concern with polymorphisms & potential drug interactions
    • Longer duration of effect than Ritalin
    • IR effect for 4-6 hrs
    • Spansule effect for 8 hrs
    • Start at 2.5mg in AM and at 12 noon, if necessary
    • Possibly more adverse effects than MPH
  71. What metabolizes all amphetamines/amphetamine like drugs?
  72. Lisdexamfetamine (Vyvanse)
    • First line medication for ADHD
    • amphetamine to tx ADHD
    • Prodrug of dextroamphetamine
    •      Dextroamphetamine covalently bonded to l-lysine.
    •      Requires hydrolysis after oral administration for pharmacologic effect
    • Developed to limit intravenous or intranasal abuse
    •      for peopple w/hx of drug abuse
    • Dosage form: 30, 50, and 70 mg capsules
    •      50 mg = 30 mg dextroamphetamine
    •      Cost: $220 for 30 capsules (given once daily)
    • No significant advantage over current once daily stimulants
    • Marketed by Shire preferentially over Adderall XR which went off patent in 2009
  73. ADHD Stimulants and Cardiovascular Risk
    • lack box warning added to stimulant labels in 2006 describing cardiovascular risks
    • of stimulant drugs for ADHD [b/c = sympathomimetic]
    • Stimulants increase blood pressure and heart rate
    • FDA briefing documents described cases of myocardial infarction, stroke, and sudden death in children and adults taking ADHD stimulants
    • Guide for parents now required to be dispensed with new prescriptions
    • AHA (2008) recommends a thorough cardiovascular assessment  and baseline EKG before treatment
  74. Atomoxetine (Strattera)
    • Second line medication for ADHD
    • A non-stimulant -> less abuse potential [non-controlled substance]
    • Mech: Selective norepinephrine reuptake inhibitor (SNRI)
    • Originally developed as an antidepressant with the generic name, tamoxetine
    • Metabolized by CYP 2D6
    •      Serum levels may be 5-10 times normal in poor metabolizers (8% of population) [polymorphisms]
    •      Reason for cautious dose escalation
    • Dosing: Start at low dose of 0.5 mg/kg/day and increase weekly by 0.5 mg/kg to target dose of 1.2 mg/kg/day give QD or BID
    • Efficacy: more effective than placebo, but less effective than stimulants
    • Adverse effects: GI upset, fatigue, decreased appetite, hypertension, tachycardia. Possible growth retardation
    • FDA indication: for ADHD in both children and adults
  75. FDA Warnings for Atomoxetine
    • Bolded warning added to label about the potential for severe  liver disease after reports of a child and an adult who had developed severe liver disease after starting atomoxetine
    • Boxed warning added to label regarding potential suicidal ideation in children and adolescents after 6 cases reported of suicidal ideation or attempts in treatment groups versus no events in placebo groups
  76. Antidepressants for ADHD
    • (third line medication for ADHD)
    • Reduce ADHD symptoms, but not as well as stimulants
    • Narrower margin of safety than stimulants
    • Use if intolerable adverse effects to stimulants or abuse potential
    • Tricyclic antidepressants
    •      Dual serotonin and norepinephrine reuptake inhibitors
    •      Examples: Desipramine and imipramine
    • Bupropion (Wellbutrin)
    •      Dual dopamine and norepinephrine reuptake inhibitor
    •     Need to give 2-3x/day
    •     Contraindicated if predisposed to
    • seizures
    • [primarily inhibit NE rupture + other]
  77. Alpha2-Adrenergic Agonists
    • (fourth line medication for ADHD)
    • Stimulate presynaptic α2-adrenergic receptor to decrease adrenergic transmission (neg feedback rec for NE)
    • Extended-release versions used as adjunct to stimulant or alone
    • Used for children who are unusually insomniac, irritable, explosive, or labile
    • Clonidine extended-release (Kapvay)
    •      Dose titrated over weeks to 0.1-0.43 mg/day
    •      Sedation, dry mouth, headaches, bradycardia
    • Guanfacine extended-release (Intuniv)
    •      Longer half-life than clonidine
    •      1mg = 0.1mg clonidine
    •      Somnolence, bradycardia, and syncope may occur
  78. NIH Consensus Statement on Diagnosis and Treatment of ADHD
    • Most randomized clinical trials have been short term, up to 3 months
    • No long term studies testing stimulants for several years
    • No information on the long-term outcomes of medication-treated ADHD individuals in terms of educational and occupational achievement
    • Improvement in core symptoms but not in academic achievement or social skills
    • No conclusive data on treatment of ADHD in adolescents and adults
    • -------------
    • Risks
    •      No conclusive evidence that careful long-term therapeutic use is harmful
    •      Adverse drug reactions usually related to dose
    •      May be negative effects on growth rate,
    • but ultimate height not affected
    •      Adequate follow-up required for medications
    •      Abuse potential: conflicting evidence
  79. ADHD treatment comparison studies
    • Long Term Efficacy of ADHD Medications - The MTA Study: Only long term ADHD tx study
    • The Multimodal Treatment Study of Children with ADHD (MTA)
    • 14 month randomized trial in children ages 7-10 years
    • Compared 4 groups: medication management, intensive behavioral management, the two combined, or standard community care
    • Medication management used systematic titration of methyphenidate (MPH) and intensive monitoring
    • Result: medication management system superior to behavioral treatment or routine community care with medication
    • -------------------------------
    • MTA study medication management system:
    • 28 day, double-blind, daily switch titration of MPH
    • Randomly received placebo, 5mg, 10mg, and 15mg or 20mg (depending on weight) each day at 8AM, 12 noon, and 4PM (1/2 dose).
    • After 1 month, if no response to MPH, could switch to other meds
    • Response graphed each day by parents and teacher
    • 69% titrated to best dose of MPH
    • Monthly medication maintenance visits to adjust dose
    • Final medications after 14 months: MPH 73%, dextroamphetamine 10%, no meds 3.1%, pemoline 1.4%, imipramine 1%
    • ---------------------------
    • Follow-up of MTA Study (2009)
    • After 3 and 8 years, advantage associated with intensive medication management had dissipated compared to other study groups
    • After 3 years, children taking drugs were, on average, 1 inch shorter and 6 pounds lighter
    • Those few who continued with medications after 8 years had no clear behavioral advantage over those who did not
  80. Treatment Response to Antidepressants
    • Goals of treatment
    •      Remission
    •      Restoration of functioning
    • Minimum trial period:
    •      4-8 weeks at adequate doses of antidepressant
    •      (get ADE 1st, NOT therapeutic effects)
    • Three phases of treatment
    •      Acute phase: 12 weeks
    •      Continuation phase: 6-9 months
    •      Maintenance phase
    • It has been estimated that up to 40% of patients do not receive at least a moderate dose of an antidepressant for an adequate period of time
    •      (must titrate to appropriate dose to get response)
  81. General Guidelines for Selecting an Antidepressant
    • Currently all antidepressants are considered equal in efficacy for uncomplicated unipolar depression (can't predict which will work)
    • Full therapeutic effect takes 6 to 8 weeks after start
    • About 60% of patients will respond to the first antidepressant prescribed
    •      In placebo-controlled trials, about 40% of patients respond to placebo
    • 25% of non-responders will respond after switching
    • Failure to respond to one drug in a class does not predict failure for another drug in the same class (try another from same class = ok)
    • If there is failure to respond to 2 drugs in the same class, a different drug class should be considered
    • ---------------------
    • hoice of anti-depressant  often is based on:
    •      Adverse effect profile
    •      Potential drug interactions
    •      Safety
    •      Patient preference
    •      Cost
    •      ***Past response to antidepressants (=> try that Rx again)
    •      ***Family member’s response to antidepressants (=> try that Rx 1st)
  82. FDA Indications for Antidepressants
    • MDD – major depressive disorder
    • GAD – generalized anxiety disorder
    • SAD – social anxiety disorder
    • OCD – obsessive-compulsive disorder
    • PTSD – post-traumatic stress disorder
    • PMDD – premenstrual dysphoric disorder
    • BN – bulemia nervosa
    • Panic attacks
    • Neuropathic pain syndromes

    [lots of indications other than depression]
  83. Classes of Antidepressants
    • Selective Serotonin Reuptake Inhibitors (SSRI)
    • Selective Dual-Action Reuptake Inhibitors
    •      Inhibit reuptake of 2 neurotransmitters
    • Newer mixed action antidepressants
    •      Inhibit neurotransmitter reuptake as well as block various neurotransmitter receptors
    • Tricyclic Antidepressants (TCA)
    • Monoamine Oxidase Inhibitors (MAOI)
  84. Placebo effect of anti-depressant medications
    • very high placebo effect with anti-depressants
    • 33% of patients given a placebo will responds (with dec depression) within 8 wks
    • [compared to 67% of patients treated for depression will respond - w/ dec sx's)
  85. Selective Serotonin Reuptake Inhibitors (SSRIs): MECHANISM OF ACTION
    • Serotonin neurons in depressed patients are deficient in serotonin and have an overabundance of presynaptic and postsynaptic serotonin receptors (up regulated)
    • --------------------
    • Mechanism:
    • SSRIs block reuptake pump and initially increase serotonin in dendrite area of neuron – responsible for initial adverse effects
    • Over several weeks the number of presynaptic serotonin receptors decrease (down regulate) and neuronal discharge of serotonin slowly increases
    • Eventually postsynaptic receptors down regulate and tolerance to adverse effects develops
  86. Selective Serotonin Reuptake Inhibitors (SSRIs): DRUGS OF THIS CLASS
    • Fluoxetine (Prozac + generic)
    •      FDA approved for MDD, OCD, PMDD, BN
    • Sertraline (Zoloft + generic)
    •      FDA approved for MDD, SAD, PTSD, panic, OCD, PMDD
    • Paroxetine (Paxil + generic)
    •      FDA approved for MDD, SAD, GAD, PTSD, panic, OCD, PMDD
    • Citalopram (Celexa + generic)
    •       FDA approved for MDD
    • Escitalopram (Lexapro + generic)
    •      S-isomer of citalopram – same indications
    • Fluvoxamine (Luvox + generic)
    •      FDA approved for OCD only
    • ---------------------------------
    • sertraline (zoloft), citalopram (celexa), & escitalopram (lexapro) - most likely to be tried first
    • *not going to ask starting doses
  87. SSRIs – Pharmacokinetics and Dosing:
    1) Fluoxetine (Prozac and generic)
    2) Sertraline (Zoloft and generic)
    3) Paroxetine (Paxil and generic)
    4) Citalopram (Celexa and generic)
    5) Escitalopram (Lexapro and generic)
    • SSRIs usually given once daily. Start with ½ depression dose if anxiety present
    • -----------------
    • Fluoxetine (Prozac and generic)
    •      Longest T1/2 of SSRIs = 3-6 days (longest T1/2 -> more delays)
    •      Active metabolite, norfluoxetine, with T1/2 = 9 days
    •      Dose: Start 20 mg in AM and increase by 20mg every 4 weeks to max of 80mg/day
    •      Weekly dosage form of 90mg available for chronic dosing or elderly
    • --------------
    • Sertraline (Zoloft and generic)
    •      T1/2 = 24 hrs and active metabolite T1/2 = 66 hrs
    •      Dose: Start 50mg in AM and increase by 50mg every 4 weeks to max of 200mg/day
    • -----------------------
    • Paroxetine (Paxil and generic)
    •      T1/2 = 24 hrs
    •      Dose: Start 10mg in PM (b/c = sedating) and increase by 10mg every 4 weeks to max of 50mg /day
    • ----------------------
    • Citalopram (Celexa and generic)
    •      (QT interval prolongation-diff from escitalopram)
    • -------------------
    • Escitalopram (Lexapro and generic)
    •      S-isomer of citalopram
    •      T ½  = 30 hrs
    •      Citalopram dose: 20mg in AM, increased every 4 weeks to max of 60mg/day
    •      Escitalopram dose: 10mg in AM, increased in 4 weeks to max of 20mg/day
    • [not much difference btw citalopram & escitalopram]
  88. Selective Serotonin Reuptake Inhibitors – Adverse Effects
    • Adverse effects generally milder than older tricyclic  antidepressants
    • Associated with stimulation of serotonin receptor subtypes
    • Usual profile includes:
    •      GI effects (nausea and diarrhea) – most common in 1st month
    •      CNS disturbance (activation and insomnia)
    •     *Sexual dysfunction (decreased libido, ED, absence of orgasm)
    • Also may see headache, agitation, and tremor
    • Most SSRIs that activate should be given in AM
    •      However, Paxil has some anticholinergic activity and tends to be more sedating, so should be given at bedtime
    • Hyponatremia - (esp in elderly)
    •      12% of elderly receiving paroxetine in one study
    • Increased risk of GI and postoperative bleeding
    •      Impaired platelet aggregation
    •      Avoid NSAIDs and ASA
    • Increased risk of osteoporosis in both men and women
    • Citalopram: dose dependent QTc interval prolongation
    • Pregnancy Category C
    •      except paroxetine which is Category D
    • Serotonin syndrome can  occur at high doses or in combination with other serotonergic drugs
    • [for table see lecture slide 28]
  89. Serotonin Syndrome
    • Autonomic, behavioral, cognitive, and neuromuscular abnormalities from excessive serotonin production
    • Usually as a result of combining drugs that increase serotonin levels
    • Symptoms incld: agitation, diaphoresis, diarrhea, fever, hyperreflexia, incoordination, mental status changes, myoclonus, shivering, and/or tremor
    • Can be fatal if agents are not discontinued
    • -------------------
    • Rx to be careful of:
    • Serotonergic drugs include all antidepressants (except bupropion), buspirone, lithium, triptans, ondansetron, meperidine, dextromethorphan, tramadol, & linezolid
    • --------------
    • SHIVERS:
    • Shivering
    • Hyperreflexia & myoclonus
    • Inc T
    • Vital sign instability
    • Encephalopathy (mental status changes)
    • Restlessness & incoordination
    • Sweating
  90. SSRIs – Drug Interactions
    • All SSRIs are substrates and inhibitors of various CYP450 enzymes
    • They vary in their potency and specificity for the various CYP450 enzymes
    • Potency of inhibition increases with inc dose
    •      Low potency drugs in table can become high potency at higher doses
    • [see table slide 30 & 31]
  91. Selective Dual-Action Reuptake Inhibitors (list drugs in this category)
    • Venlafaxine (Effexor)
    • Desvenlafaxine (Pristiq)
    • Duloxetine (Cymbalta)
    • Bupropion (Wellbutrin)
  92. Venlafaxine (Effexor and Generic)
    • [Selective Dual-Action Reuptake Inhibitors]
    • MOA – inhibits reuptake of both serotonin and norepinephrine (=> slightly diff ADE)
    • Kinetics – metabolized by CYP 2D6 to active metabolite, ODV. Parent T1/2 = 5 hrs, ODV T1/2 = 10 hrs
    • Dosing: Start ER form at 75 mg once daily and titrate to max of  225 mg/day
    • Adverse effects: Nausea and vomiting 10% more common than with SSRIs. Nausea is less with ER dosage form. Doses > 200mg can elevate BP due to norepinephrine release
    • Drug interactions: inhibitors of CYP 2D6, BP medications
    • FDA indications: MDD, GAD, SAD
  93. Desvenlafaxine (Pristiq)
    • [Selective Dual-Action Reuptake Inhibitors]
    • Approved 2008
    • Active metabolite of venlafaxine (Effexor)
    • Minimum dependence on CYP2D6 for metabolism
    • Extended release tablet
    • No published studies of efficacy
    • No evidence of improved efficacy compared to venlafaxine
  94. Duloxetine (Cymbalta)
    • [Selective Dual-Action Reuptake Inhibitors]
    • MOA: inhibits reuptake of both serotonin and norepinephrine
    • Kinetics: metabolized by CYP 1A2 and 2D6  enzymes; T1/2 = 12 hrs
    • Dosing: start at 30-40 mg/day and increase to max of 60 mg/day
    • Adverse effects: similar to venlafaxine. Reports of elevated liver function tests: avoid if hepatic disease
    • Drug interactions: moderate inhibitor of CYP 2D6
    • FDA indications: MDD, GAD, diabetic neuropathic pain, fibromyalgia, back pain, osteoarthritis pain
    •      “Swiss army knife of antidepressants”
    • Approved in 2005 (new w/ new indications)
  95. Bupropion (Wellbutrin and Generic)
    • [Selective Dual-Action Reuptake Inhibitors]
    • MOA: inhibits reuptake of norepinephrine and dopamine (no serotonin activity) *different than others*
    • Kinetics: metabolized in liver with T ½ = 20 hrs: has active metabolite with T ½ = 37 hrs
    • Dosing: has IR, SR, and XL dosage forms (IR and SR available as generic). Must give IR 3 times a day. IR doses start at 200 mg/day and titrate to max of 450 mg/day. SR (twice daily) and XL (once daily) doses start at 150mg and titrate to max of 450 mg/day
    • Adverse effects: agitation, insomnia, but little sexual dysfunction; can cause modest weight loss; can decrease seizure threshold 10-fold with high doses – avoid if seizure disorder
    • Drug interactions: other drugs that lower seizure threshold; strong inhibitor of CYP 2D6
    • FDA indications: MDD
    • Also indicated for smoking cessation under brand name Zyban (same drug, differ name/pkg/dose)
  96. Mixed Action Antidepressants (list drugs in class)
    • Nefazodone (Serzone)
    • Trazodone (Desyrel)
    • Mirtazapine (Remeron)
  97. Nefazodone (Serzone & Generic)
    • [Mixed Action Antidepressants]
    • MOA: serotonin reuptake inhibitor and 5-HT2a receptor blocker
    • Kinetics: metabolized by CYP 3A4 to active metabolites; T ½ = 5 hrs
    • Dosing: start at 100 mg BID. Increase by 100mg per week to max of 300 mg BID
    • Adverse effects: moderately sedating but does not cause sexual dysfunction or agitation
    • Reports of liver failure have led to its removal from market in Europe and Canada and voluntary removal of brand drug from U.S. market by manufacturer
    •      Generic still available
    • Drug interactions: very potent inhibitor of CYP 3A4 enzyme
    • FDA indications: MDD
  98. Trazodone (Desyrel & Generic)
    • [Mixed Action Antidepressants]
    • Similar to nefazodone but more sedating.
    • Commonly used as hypnotic agent in doses of 25-50 mg at bedtime.
    • Rarely used as an antidepressant.
    • Antidepressant doses are 300-600 mg/day.
    • Not associated with liver failure or CYP 3A4 inhibition
  99. Mirtazapine (Remeron & Generic)
    • [Mixed Action Antidepressants]
    • MOA: α2-adrenergic receptor blocker that increases release of norepinephrine and serotonin. (very different)
    •      Also blocks 5-HT2a, 5-HT2c, and 5-HT3  receptors.
    •      Also is a histamine antagonist (AKA: anti-histamine)
    • Kinetics: metabolized by CYP 1A2, 2D6, and 3A4; T ½ = 20-40 hrs
    • Dosing: start at 15-30mg at bedtime and titrate to max of 60 mg/day. Doses higher than 30mg can be given in AM.
    • Adverse effects: very sedating at low doses but decreases with higher dose as NE transmission increases. Also weight gain and increased appetite. Few adverse GI effects or sexual dysfunction because of selective 5-HT receptor antagonism
    • Drug interactions: no significant interactions other than combining with other sedating agents
    • FDA indication: MDD
  100. Adverse Effects of Newer Antidepressants
    see lecture slide 46
  101. Accurate vs Apparent Evidence of Efficacy of New Antidepressants
    • 1)
    • Using the FOIA, both investigating teams obtained all trial data submitted to the FDA for drug approval, whether such data was published later or not
    • For 12 new antidepressant drugs approved, 74 studies were registered with the FDA
    •       Only 51% of studies had positive outcomes
    • per the FDA
    •      Most of the negative trials were never published
    •      According to published literature 94% of trials appear positive
    • ------------------
    • 2)
    • Complete datasets for 4 new antidepressants were reviewed for meta-analysis involving 35 submitted studies
    • For mild to moderate depression, based on baseline severity scores, there was no difference in effect between placebo and fluoxetine, paroxetine, venlafaxine, or nefazodone
    • Differences from placebo only for extremely depressed patients
  102. What If No Response to First Antidepressant? – The STAR*D Trial
    • Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
    • 727 patients who did not respond to initial therapy with citalopram (an SSRI)
    • Randomized to receive: (3 diff MOA)
    •      Sertraline (an SSRI)
    •      Venlafaxine (an SNRI)
    •      Bupropion (DA & NE reuptake inhibitor)
    • Primary outcome: remission using HRSD-17 tool
    • Secondary outcome: 50% response using QIDS-SR-16 tool
    • ----------------
    • Results:
    • Remission and response rates did not differ significantly between the three different antideprssants
    • Approximately 25% of individuals who fail to respond to an initial antidepressant (SSRI) will respond to a second one regardless of MOA
    •     [expectation before study = different responses]
  103. Tricyclic Antidepressants (TCA)
    • First line agents from 1960’s through 1980’s
    • -------------------------
    • >Mech:
    • All inhibit reuptake of serotonin and norepinephrine to varying degrees
    • Equally effective for treating depression compared to SSRI’s and newer antidepressants
    • -------------
    • >ADE:
    • Significant adverse effects from antagonism of acetylcholine (ie constipation), histamine (ie sedation), and α1-adrenergic receptors
    • Fatal arrhythmias associated with high doses or overdoses due to blockade of sodium channels in the heart
    •      (Class 1a antiarrhythmic activity)
    • Greater nonadherence rates with TCAs than newer antidepressants
    • ---------------
    • >other uses:
    • Also used for anxiety, ADHD, OCD, migraines, and neuropathic pain syndromes
    • ---------------
    • Usually given once daily at bedtime
    • All available as generic
    • --------------------------------
    • Types:
    • Tertiary amines
    • Secondary Amines
    • ------------------------
    • (he said just as effective as SSRIs BUT more ADE)
  104. Tertiary amine TCAs
    • More selective serotonin reuptake inhibition
    • More pronounced adverse effects
    • Metabolized primarily by CYP 2D6 and 3A4
    • Amitriptyline (Elavil)
    • Imipramine (Tofranil)
    • Doxepin (Sinequan)
  105. Secondary amine TCAs
    • More selective norepinephrine reuptake inhibition than tertiary amine TCAs
    • Less severe adverse effects that tertiary amine TCAs
    • Nortriptyline (Pamelor) – metabolite of amitriptyline
    • Desipramine (Norpramin) – metabolite of imipramine
    • (usu metabolite of tertiary TCAs
  106. Adverse effects of TCAs
    see lecture slide 61
  107. Nonselective Monoamine Oxidase Inhibitors (MAOI)
    • Phenelzine (Nardil)
    • Tranylcypromine (Parnate)
    • MOA: Inhibit MAO which is enzyme responsible for destroying serotonin, norepinephrine, and dopamine, thus increasing synaptic concentrations (all catecholamines)
    • Kinetics: MAOIs have short half-lives, but clinical effect can last for days. Metabolized by the liver
    • Adverse effects:orthostatic hypotension, weight gain, edema, and sexual dysfunction. Overdose can be fatal.
    • Use: refractory or atypical depression
    • -----------------------------
    • Drug-drug interactions
    •      Avoid other antidepressants, buspirone, meperidine, dextromethorphan, direct and indirect sympathomimetic agents, cocaine
    • Drug-food interactions
    •      Avoid foods with high tyramine concentrations
    •      If not metabolized by MAO, tyramine can cause surge release of norepinephrine resulting in hypertensive crisis
    •      Smoked or aged meats or fish, aged cheeses, red wine, beer, yeast extract, fava beans, avocados, liver, fish sauce, soy sauce
    • ------------
    • (used rarely)
  108. St. John’s Wort for Depression
    • Hypericum perforatum, an over-the-counter herbal
    • MOA: inhibits reuptake of multiple neurotransmitters
    • Studies demonstrate greater effectiveness than placebo and possibly equal effectiveness to TCAs and SSRIs
    • Adverse effects tend to be less severe
    • Average dose: 900 mg/day
    • One of the most widely prescribed drugs for depression in Europe
    • Drug interactions: will interact with many drugs since it induces CYP 2C9, 2D6, and 3A4 enzymes
    • *strong inducer of CYP enzymes
  109. Augmentation Therapy for Depression
    • To enhance antidepressant effectiveness or improve response time
    • Add to antidepressant if dose-limiting adverse effects
    • Agents used
    •      Atypical antipsychotics (aripiprazole and quetiapine)
    •      Bupropion
    •      Lithium
    •      Buspirone
    •      Thyroid hormone
    •      Stimulants
  110. Antidepressant Discontinuation (Withdrawal) Syndrome
    • SSRI and SNRI:
    •      Acute headache, dizziness, nausea, fatigue, muscle aches, chills, anxiety, irritability
    •      Most severe with paroxetine (paxil), venlafaxine, and duloxetine (Cymbalta)
    • TCA:
    •      Irritability, agitation, sleep disturbance, flu-like symptoms, cardiac arrhythmia
    • Must taper when discontinuing
    • (only fluoxitine doesn't req tapering b/c T1/2 = long/slow met)
  111. What warning must all anti-depressant meds have?
    • Patients treated with any antidepressant should be watched closely for worsening symptoms of depression and/or suicidal behavior. Monitoring should be particularly vigilant during initiation of therapy and during any change in dosage
    • ----------------
    • For all antidepressants
    • For children, adolescents, and adults
  112. Drugs for Bipolar Disorder
    • First line agents
    •      Lithium
    •      Valproate
    •      Atypical antipsychotics (FDA-approved)
    • Second line agents
    •      Carbamazepine (anti-seizure med)
    •      Oxcarbazepine (anti-seizure med)
    •      Atypical antipsychotics (off label)
  113. Lithium (Li)
    • Cation similar to sodium (compete, esp at renal tubular level)
    • MOA: still uncertain, but alters sodium transport in nerve and muscle cells
    • Kinetics: Not metabolized, excreted renally.
    •      Extensively reabsorbed from renal tubules
    •      Sodium can compete with Li for reabsorption causing an increase in excretion of Li
    •      Usual T1/2 = 18-24 hrs.
    •      T1/2 increases with renal failure
    • Dose: 300 mg BID-TID
    • Steady state reached in 5 days
    • Dose must be reduced in renal failure
    • Pretreatment workup: EKG, CBC, chemistry profile, thyroid function tests, pregnancy test
    • Routine monitoring: CBC, electrolytes, serum creatinine, thyroid function tests every 6 months
    • Drug levels: draw trough level every 6 months after stabilization
    • Therapeutic level: 0.8-1.0 mEq/L - very narrow
    • Uses: acute mania and maintenance therapy to prevent recurrence of mania
  114. Lithium - Adverse Effects
    • Narrow therapeutic index drug
    • Adverse effects:
    •      Neurologic: fine hand tremor, drowsiness, ataxia
    •      Hypothyroidism
    •      Nephrogenic diabetes insipidus – polyuria and polydipsia secondary to antagonism of antidiuretic hormone
    •      Weight gain
    •      Leukocytosis
    • Toxicity: when serum levels > 1.5 mEq/L
    •      Nausea and vomiting an early sign of toxicity
    •      Coarse tremor, increased tendon reflexes, seizures, coma, respiratory depression, arrhythmias
    • Pregnancy category D: teratogenic to human fetus
  115. Lithium – Drug Interactions
    • Any drugs that alter fluid and electrolyte balance
    • Diuretics – reduce lithium clearance by kidneys by 25% due to increased sodium excretion
    • Other drugs that reduce lithium clearance:
    •      NSAIDs
    •      ACE inhibitors
    •      Angiotensin receptor blockers
    • Compounds that increase lithium clearance
    •      High sodium in diet
    •      Caffeine
  116. Valproate (Depakene and Depakote)
    • Used for Bipolar
    • Anti-epileptic drug (AED)
    • MOA: blocks sodium and calcium channels, increases GABA transmission
    • Kinetics: metabolized by liver with T ½ = 12 hrs
    •      CYP 450 substrate: 2C9, 2C19
    • Dosage forms: (lots)
    •      Valproic acid (Depakene and generic)
    •      Divalproex sodium (Depakote and Depakote ER).
    •      Depakote ER dose 20% higher than Depakote
    • Adverse effects:
    •      Dose-related: nausea, vomiting, tremor , drowsiness, sedation (must slowly titrate dose)
    •      Severe/idiosyncratic: alopecia (10%), weight gain (50%), hepatotoxicty, thrombocytopenia
  117. GABA (NT)
    • Inhibitory regulator of other NTs
    • Regulates excitability of neurons
  118. Benzodiazepines
    • Second line agents for anxiety and insomnia
    • Schedule IV controlled substances

    Primary differences between drugs are pharmacokinetic

    • All can be teratogenic to human fetus (D or X)
    • All available in generic form
    • Half-life often dependent on active metabolites

    • Several metabolized to the active metabolite, desmethyldiazepam
    • (DMDZ) with T ½  > 100 hrs

    • Drug accumulation and prolonged clinical
    • effect:
    • Chlordiazepoxide (Librium)
    • Diazepam (Valium)

    Most benzodiazepines are metabolized by CYP 3A4 and clearance may be affected by  age or drugs that inhibit or induce CYP 3A4

    • Onset of action of benzodiazepines dependent on lipid solubility
    • Diazepam, although long-acting, has a rapid onset
    • Oxazepam, although short-acting, has a slow onset

  119. Benzodiazepines - Pharmacokinetics, pharmacodynamics, adverse effects
    • Pharmacodynamic interactions:
    • CNS depressants such as ethanol, barbiturates, and opiate analgesics can result in respiratory depression

    • Pharmacokinetic interactions:Inhibition of CYP 3A4 can increase plasma levels
    • CYP 3A4 inhibitors include macrolide  antibiotics, azole antifungals, protease inhibitors, nefazodone, diltiazem, verapamil, and grapefruit juice
    • Adverse Effects:
    • Sedation, ataxia, and cognitive impairment
    • Greater incidence of injury, such as falls, fractures, and auto accidents in elderly
    • Anterograde amnesia
    • Respiratory depression (high doses)
    • Rebound insomnia and anxiety
  120. Benzodiazepines - Tolerance, Abuse, Physical Dependence, Withdrawal, Pregnancy
    • Tolerance to effects:
    • Dose escalation and patient dissatisfaction
    • Within 1-2 weeks with shorter acting agents and within 1-3 months with longer acting agents

    • Abuse:
    • Generally limited to patients with history of substance abuse
    • Agents that have fast onset of effect (diazepam, alprazolam, and lorazepam)

    • Physical dependence:
    • Proportional to dosing and duration of use
    • Can expect if therapeutic dosing for more than two months
    • Intermittent dosing and short term use can minimize dependence

    • Withdrawal:
    • Expect intense withdrawal symptoms within 24 hours of discontinuing short acting agents and less severe symptoms within 1 week for long acting agents

    • Symptoms:
    • Anxiety, muscle and abdominal cramps, nausea, vomiting, sweating, irritability, tremors, headache, or seizures

    • Dose tapering absolutely necessary!
    • 10-25% dosage reduction every 1-2 weeks
    • Last half of taper is usually harder and takes longer
    • Only use same drug for tapering if physical dependence from therapeutic use, not abuse

    Pregnancy Category X or D
  121. Benzodiazepines - LOT Group
    • Lorazepam, Oxazepam, and Temazepam
    • Undergo Phase II metabolism (conjugation)
    • Not affected by CYP 3A4 and have no active metabolites
    • Favored for older individuals
  122. Benzodiazepine Uses
    • Anxiety (acute/chronic)
    • Sedation
    • Hypnosis
    • Alcohol dependence and withdrawal
    • Muscle relaxation
    • Seizures
    • Preanesthetic medication
    • Anterograde amnesia
  123. Flumazenil (Romazicon)
    • For Benzodiazepine Toxicity
    • Benzo-receptor antagonist
    • Can reverse respiratory depressant effects from high doses or additive effect with other CNS depressants

    • Useful for reversing conscious sedation with midazolam IV
    • Avoid if patient also overdosed with agents that lower seizure threshold such as tricyclic antidepressants or if patient has a head injury

    Give 0.2mg IV and repeat in 1 minute intervals. Has T ½ = 1 hr, so reversal effect may wear off quickly
  124. Buspirone
    For therapy of chronic anxiety, once acute anxiety controlled by benzodiazepines

    Still need to taper benzodiazepines but withdrawal symptoms milder

    • MOA
    • Partial agonist of serotonin 5-HT1a receptor. Has a delayed onset of effect of 2 to 4 weeks and has no CNS depressant effects

    • Kinetics:
    • Extensive 1st pass effect (BA = 5%), metabolized by CYP 3A4 to active metabolite, and T ½ = 3 hrs

    • Dose:
    • Start at 5-7.5mg BID and titrate slowly to usual dose of 15 mg BID with max dose = 30 mg BID

    • Adverse effects:
    • Nausea, dizziness, headache, nervousness

    Drug interactions: inhibitors and inducers of CYP 3A4 enzyme

    FDA indication: chronic (not acute) anxiety
  125. Insomnia - Defenition
    • Not a diagnosis, but a clinical problem:
    • Difficulty falling asleep (sleep latency)
    • Frequent awakenings
    • Waking up too early
    • Waking up feeling unrefreshed
    • Impaired daytime functioning
  126. Insomnia Classification
    • Transient
    • Occurs no more than a few consecutive nights
    • Short term
    • Up to 4 weeks duration
    • Result of bereavement, emotional trauma, pain, major life stresses such as divorce, etc.

    • Chronic
    • Lasts months to years
    • Results from chronic stressors such as illness, nursing home placement, poor sleep hygiene
    • Drug-related: alcohol, caffeine, SSRIs, decongestants
    • Major sleep disorders: obstructive sleep apnea, restless legs syndrome
  127. Non-Pharma Tx of Insomnia
    • Cognitive-behavior therapy (CBT)
    • As effective as drug therapy and effects last longer
  128. Drugs to Tx Insomnia
    • GABA receptor agonists
    • (Benzos, Non-benzos)
    • Melatonin agonists
    • Antidepressant
    • Antihistamines
    • Herbal
  129. Benzodiazepines for Insomnia
    • Triazolam
    • Temazepam
    • Estazolam
    • Lorazepam
    • Quazepam
    • Flurazepam

    • Decrease sleep latency and increase total sleep time
    • Decrease REM sleep

    • Can cause:
    • daytime sleepiness
    • rebound insomnia when discontinued
    • tolerance
    • physical dependence
  130. Non-Benzodiazepine GABAA Receptor Agonists (The Three Zs)
    • Zolpidem (Ambien)
    • Zaleplon (Sonata)
    • Eszopiclone (Lunesta)
    • Mech:
    • bind to alpha-1 subtype of GABAa receptor complex associated with less physical dependence and less anxiolytic activiy than benzodiazepine
    • Generally decrease sleep latency, increase total sleep time, but do not affect REM sleep at normal doses

    • Onset of action:
    • Zaleplon>zolpidem>eszopiclone
    • Duration of action:
    • Eszopiclone>zoplidem>zaleplon

    • Kinetics:
    • All metabolized by CYP 3A4 enzyme to inactive metabolites

    • Adverse Effects:
    • lower incidence of daytime sedation, anterograde amnesia, rebound insomnia, tolerance, and physical dependence than benzos

    All Schedule IV controlled substances similar to benzos
  131. Zolpidem
    Non-benzo for insomnia

    • Onset within 30 mins, last up to 8 hrs
    • FDA indication: short term treatment of insomnia
    • Preg Category C
    • Dose: 10mg @ bedtime, 5mg if elderly

    Ambien CR releases 5mg or 10mg immediately followed by remainder in 3 hrs to help maintain sleep

    Ambien defense, sleep walking/driving/eating/etc
  132. Zaleplon (Sonata)
    Z drug - non benzo for insomnia

    • Shortest acting of Z drugs
    • Onset of action within 10-20 min and duration of 4 hrs
    • Also useful for patients who may need to take agent in middle of night due to its short half-life

    Preg Category C

    FDA indication: short-term treatment of insomnia (7-10 days)
  133. Eszopiclone
    Z Drug - Non-benzo for insomnia

    • S-isomer of zopiclone
    • Not chemically related to other Z drugs

    Only Z drug to have 6 month efficacy data from placebo-controlled trial demonstrating no development of tolerance over that time

    Longest half life of Z drugs - (avg 6 hrs, elderly 9 hrs)

    Adverse effect: unlike other drugs, has unpleasant taste

    Preg Category C

    FDA Indication: Treatment of insomnia (note - not limited to short-term treatment)

  134. Z-Drugs - Tolerance/Abuse Potential
    • Generally lower risk than with benzos
    • Zolpidem (Ambien)
    • Premarketing - rare cases of physical dependence/withdrawal
    • Postmarketing - numerous cases of abuse, tolerance, withdrawal
    • More likely at higher doses and in individuals with history of drug abust

    • Zaleplon
    • Animal studies suggest abuse potentials with higher doses

    • Ezopiclone
    • Data from zopiclone use in Europe/Canada suggests risk of abuse potential similar to zolpidem
  135. Efficacy of GABAa Receptor Agonists for Insomnia in Adult Populations
    BDA and non-BDZ significantly decrease sleep latency

    • BDZ but not non-BZD significantly decrease wakefulness after sleep and increase total sleep time
    • Higher risk of harm compared to placebo, but non-BZD appear to be safer than BZD
    • Strong evidence of publication bias of true estimate of efficacy probably lower
  136. GABAa Receptor Agonists for Insomnia in Elderly
    • Improvement in sleep NNT = 13
    • Significant adverse effect NNH = 6 (elderly twice as likely to be harmed by hypnotic agents than helped)
  137. Cognitive Behavioral Therapy (CBT) Compared to Z drugs
    CBT provided greater benefit than zolpidem or placebo for sleep-onset insomnia

    • Treatment of 6 weeks and follow up for 6-months
    • CBT improved sleep efficiency, increased slow-wave sleep, and resulted in less awakenings during night compared to zopiclone or placebo
  138. Ramelteon (Rozerem)
    • Melatonin receptor agonist
    • Not a controlled substance

    • MOA:
    • Highly selective for melatonin Type 1 and type 2 receptors

    • Effectiveness:
    • statistically (not clinically) significant improvement in sleep latency but no effect on sleep maintenance

    • Kinetics:
    • Metab mostly by CYP1A2

    Adverse: no sig adverse effects, no hangover effect, no physical dependence, rebound insomnia or intolerance after long-term use

    • Drug interactions:
    • inhibitors of CYP1A2, Inhibitors/inducers of 3A4 may also interact

    Preg Cat C

    FDA Indication: for insomnia characterized by difficulty with sleep onset - not limited to short-term use
  139. Trazodone
    • Antidepressant for Insomnia
    • Low doses - 25-50 mg used for insomnia because of its very sedating properties
    • Mostly small trials for patients with insomnia secondary to depression
    • Only one placebo-controlled trial for primary insomnia - no difference from placebo in 2nd week
    • Risk probably greater than benefit in elderly
  140. Antidepressants for Insomnia
    • Tricyclic antidepressants (TCAs) should be avoided for insomnia
    • However:
    • Doxepin (Silenor)
    • TCA marketed years ago as Sinequan
    • Just approved in 2010 for patients with difficulty staying asleep
    • marketed as antihistamine
    • Expect typical antichol/antihistaminic effects, cardiovascular toxicity w high doses
  141. Anithistamines for Insomnia
    • OTC
    • Diphenhydramine
    • Doxylamine
    • Hydroxyzine
    • Can reduce sleep latency and increase total sleep time
    • However, anticholinergic effects, cognitive impairment, daytime sleepiness limit their usefulness, especially in elderly population

    Tolerance can develop after 4 days of continuous use

    Most useful for patients with allergies and pruritis that may disrupt sleep patterns

    However, anticholinergic effects, cognitive impairment, and daytime sleepiness limit their usefulness, especially in elderly population

    Tolerance can develop after 4 days of continuous use

    Most useful for patients with allergies and pruritis that may disrupt sleep patterns
  142. Valerian Root
    Herbal for Insomnia

    • Possible inhibits reuptake of GABA
    • Decreases sleep latency/wake time
    • Stew as tea, but has aroma of old socks
    • No hangover effect or known toxicities with chronic use
  143. Melatonin
    Hormone that regulates circadian rhythm and sleep initiation

    Short half life - 30 mins

    Statistical, not clinical significance in reduction of sleep latency

    May be more effective for patients with low melatonin levels, such as elderly or for jet lag

    Dose is .3-10mg two hours before bedtime
  144. Chloral hydrate
    • Older hypnotic still used in syrup form in children
    • Potential toxicities from 2 active metabolites - trichlorethanol and trichloroacetic acid

    Tolerance and physical dependence within 2 weeks of continuous use
  145. Barbiturates
    • Once used for anxiety and insomnia
    • Secobarbital, pentobarbital

    Very sedating, addictive, cause physical dependence

    Only barbiturates still commonly used are phenobarbital for seizure disorders and butalbital as ingredient in Fioricet for migraines

    No ceiling effect on adverse effects because they can activate GABA receptor in absence of GABA
  146. Principles of Pharmacological Therapy of Insomnia
    • Use medications that are efficacious and safe, proven with placebo-controlled trials
    • Give lowest effective dose
    • Give less than 4 weeks duration
    • Use intermittent dosing (every 2-3 nights)
    • To discontinue, gradually taper dose if use has been prolonged or high doses given
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Pharm Exam 6
Pharm Exam 6
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