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Dr.

Shane Bradley Psychopharmacology Outline Winter/Spring 2013

Drugs Used to Treat Anxiety


Benzodiazepines Bind to type A aminobutyric acid (GABAA) receptor complex on the alpha subunit, which is known as the benzodiazepine (BZ) or omega receptor. The GABAA complex is associated with neuronal chloride channels, and when benzodiazepines bind to their receptors, increasing the affinity of GABA for its receptor site enhances the channel opening effect. This increases the frequency of chloride-channel opening, creating a hyperpolarized cell membrane that prevents further excitation. From https://secure.pharmacytimes.com/lessons/200306-01.asp Indications/uses include anxiety d/o, panic d/o, mania, seizure d/o, phobias, insomnia, alcohol withdrawal, muscle spasm, agitation, catatonia, akathisia, night terrors Side effects sedation, cognitive impairment, anterograde amnesia respiratory depression at high doses or with alcohol may worsen obstructive sleep apnea symptoms disinhibition in susceptible individuals

Effect on sleep

decrease in sleep latency, increase in sleep time, an increase in Stage 2 sleep, and a small decrease in delta and REM sleep

Diazepam- very long half life; excellent muscle relaxant Chlordiazepoxide- very long half life; excellent for alcohol withdrawal Clonazepam- long half life; also used in many forms of seizures Estazolam- short to medium Temazepam- short to medium Oxazepam- short to medium Alprazolam- short to medium Lorazepam- medium Midazolam- very short, operation pre-sedate, amnestic Triazolam- very short

Antihistamine: Hydroxazine, very safe; side effects = anticholinergic at high doses Diphenhydramine, very safe, side effects = anticholinergic at high doses

Unique mechanism of action: Buspirone 5-HT 1A (presynaptic) agonist. This effect decreased serotonergic tone in the dorsal raphe, which is COMPLETELY counterintuitive to what you would expect from an anxiolytic. It also binds to dopamine type 2 (DA 2) receptors (presynaptic) as an antagonist, thereby increasing dopaminergic tone. It also increase noradrenergic tone in the locus ceruleus.

Considered less effective than benzodiazepines, but some studies show similar result. Considered particularly safe.

Alpha (2) adrenergic agonists prazosin prazosin found helpful in reducing PTSD related nightmares- evidence-based

Beta Blockers propranolol (Inderal) is primary BB of choice in mental health.used for akathisia, lithium-induced tremor, performance anxiety & aggressive behavior (hyperarousal) (other lipid soluble = pindolol, labetolol, metoprolol) avoid in asthma, diabetes if patient is prone to hypoglycemia (especially if prone to hypoglycemia unawareness), bradycardia, second or third degree heart blocks

Drugs Used to Promote Sleep


perspective: http://www.medscape.com/viewarticle/759336
Melatonin agonist: Ramelteon Side effect note: generally safe, rare hyperprolactinemia, half life 2-5 hours/fx last 8

Specific Gaba 1A agonists

positive allosteric modulators of GABA receptors; effects on sleep are less disruptive of normal sleep architecture; side effects usually involve amnesia, complex sleep behaviors, and psychosis; there may be less tolerance and rebound insomnia than with benzodiazepines Esczopiclone approved for long term use; half life 6 hours/fx last 8 Zopiclone- similar to eszopiclone Zolpidem- half life 2.6 hours/fx last 8 Zaleplon- 1 hour/fx last 4 Longer term studies have shown psychosocial/mind-body/psychotherapy better for sleep than hypnotics

Drugs Used to Treat Restless Legs (pathophys = impaired iron homeostasis [diminished iron, ?elevated
iron], AND decreased dopaminergic tone in basal ganglia)

Broad dopamine agonists (across many different dopamine receptors) Side effects: nausea, central neuropathy (dizziness, instability), psychosis, personality change (gambling, odd behaviors) Pramipexole Ropinorole

Drugs Used to Improve Mood and/or Decrease Anxiety


SSRIS Half-life Short: paroxetine & fluvoxamine (<24 hours, missed doses can result in withdrawal symptoms) Moderate: sertraline, citalopram, escitalopram (24-35 hours) Long: fluoxetine (good for people who may miss doses), 2-4 days and may be longer

Side effects- more common, less serious Decreased sex drive and impaired sexual function ---tend not to resolve with time Nausea, diarrhea, anorexia, vomiting ---all increase with dose and can resolve with time Small weight gain (esp. paroxetine) after initial GI effects; can be associated with feeling bloated Headache, dizziness, anxiety (esp. fluoxetine), rash, insomnia, sedation, sweating, vivid dreams, tremor, dry mouth (esp. paroxetine), bruising (anti-platelet aggregation)

Side effects- more serious, less common Suicidal ideation and suicide risk IN CHILDREN/ADOLESCENTS, controversial, Black Box warning based on increased ideation, not attempt SIADH
SIADH Presentation Hyponatremia

Plasma volume Euvolemic (or slightly hypervolemic) (awake patients)

Serum Serum Sodium Urine Volume

Hypotonic (< 275 mOsm/L) Falling (<135 mEq/L) Low (but not normally absent)

Urine Osmolarity Relatively high (>100 mOsm/L) Urinary Sodium >30 mEq/L Fluid restriction If Na < 120 mEq/L consider hypertonic saline to correct sodium (but no faster than 1 Treatment mEq/L/h) Intravenous urea Demeclocycline Lithium (rarely used) Table from: http://openanesthesia.org/index.php?title=SIADH:_lab_findings

Serotonin syndrome (hi risks: SSRI + MAOI, SSRI + lithium, SSRI + TCA) >> diarrhea, tremor, sweating, restlessness, hyperreflexia progression of symptoms if untreated disorientation, rigidity, fever >> coma, seizures >> >> death (approximately 10% mortality rate) .Many medications/substances have serotonin activity: dextromethorphan, fentanyl, meperidine, sumatriptan, St Johns Wort, MDMA (ecstasy), LSD, many others

Consider total serotonergic load- Supplements (tryptophan, 5-HT), Herbs (St. Johns Wort), other antidepressants (venlafaxine, bupropion, trazodone), other drugs with serotonergic effects (meperidine , dextromethorphan, and the triptans ) -------- In reality, usually only a problem with the pharmaceuticals.

NOTE on Drug-Drug Interaction and antidepressants

SSRI levels tend not to be altered by other drugs but can potentially increase levels (inhibit metabolism) of certain drugs . The drugs that are most likely to do this include: fluoxetine, fluvoxamine, paroxetine. Specific drug-drug interactions are less important than knowing SSRIS may inhibit P450 pathways of drugs sensitive to/dependent on P450 metabolism Paroxetine- especially strong level of evidence for PTSD, short half life can set stage for withdrawal Sertraline Fluoxetine- Numerous drug-drug interactions, very long half life prevents withdrawal Citalopram Escitalopram- understand this is the S-isomer, the more biologically active molecule Fluvoxamine Nefazodone- irreversible liver toxicity

SNRIS (mild elevations in blood pressure, hyperhidrosis, tachycardia, decreased appetite, headache, insomnia, delayed ejaculation) Atomoxetine- used primarily for attention/ADHD Duloxetine- extensive data in pain, FDA approved for fibromyalgia Venlafaxine- most effective antidepressant; severe withdrawal syndrome (anxiety, nausea, restlessness, irritability, electric shock paresthesias, fatigue, headache, dizziness) Dexvenlafaxine- metabolite of venlafaxine, idea was to create better steady state concentrations at lower doses therefore more potency with fewer side effects- hasnt really held up to scrutiny

Tricyclics (SNDRI) Pharmacologically promiscuous: Muscarinic M1 receptor antagonism - anticholinergic effects including altered mental status/confusion, resting tachycardia, dry mucous membraines, dilated pupils, dizziness, emesis, constipation, urinary retention, flushed/hot skin, emesis, fever Histamine H1 receptor antagonism - sedation and weight gain Adrenergic receptor antagonism (NE) - postural hypotension Direct membrane effects - reduced seizure threshold, arrhythmia Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety) NE amitriptyline (Elavil) low clomipramine (Anafranil) low desipramine (Norpramin) high doxepin (Sinequan). 5HT high high low Ach high high low mod mod mod mod Sed (hist) high high low high mod mod low Comments

pain, migraine, anxiety tx OCD; SSRI-like FDA approval OCD activating used for insomnia; very antihistaminic- used for hives, FDA approval insomnia pain; enuresis FDA approval enuresis chronic pain least sedating

low low

imipramine (Tofranil). low low nortriptyline (Pamelor).. mod low protriptyline (Vivactil) high low

MAOI Inhibitors

Inhibit degradation of monaomines (norepinephrine, serotonin, melatonin, dopamine). Phenelzine, Isocarboxazid, Tranylcypromine: non selective (MAO-A and B) and irreversible (enzyme is permanently inhibited and its activity will not be replaced until body makes more). These non-selective irreversible drugs create dangerous situations if dietary intake of certain amines is high. Tyramine = hypertensive crisis; foods rich in tyramine include Foods containing considerable amounts of tyramine include meats that are aged, smoked, pickled, most pork (except cured ham), chocolate; alcoholic beverages; and fermented foods, such as most cheeses (except ricotta, cottage, cream),sour cream, yogurt, shrimp paste, soy sauce, soybean condiments, tofu, tempeh, miso soup, sauerkraut, broad (fava) beans, green bean pods, snowpeas, avocados, bananas, pineapple, eggplants, figs, peanuts, Brazil nuts, yeast. Levodopa = psychosis, agitation, nausea; from fava beans Selegiline- selective for MAOI-B; no dietary concerns at lower doses; become less selective at higher doses

Unique mechanism: L-methylfolate; probably completely safe; especially useful in folks with MTHFR insufficiencies secondary to mutation L-methylfolate is the precursor to serotonin, norepinephrine, dopamine, that is able to cross BBB. MTHFR in the brain then begins process that ultimately leads to production of these psychoactive amines. See http://www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=1938 for nice article

Unique mechanism: Bupropion MOA: inhibition of presynaptic dopamine and norepinephrine reuptake transporters; Increased activity of vesicular monoamine transporter-2, the transporter pumping dopamine and norepinephrine from the cytosol into presynaptic vesicles FDA approved: smoking cessation (Zyban), Major Depression, Seasonal Affective Disorder High Yield Facts: Less sexual side effects (may actually help) Less weight gain, may help with weight loss Less likely to trigger mania than SSRIs Doses over 300 mg associated with seizures Unique mechanism:

Trazodone (priapism, low blood pressure) binds at 5-HT2 receptor----acts as a serotonin agonist at high doses and a serotonin antagonist at low doses --inhibits serotonin reuptake, as SSRIs --It weakly blocks presynaptic alpha2-adrenergic receptors and strongly inhibits postsynaptic alpha1 receptors DOES NOT affect the reuptake of norepinephrine or dopamine within the CNS.

Unique mechanism: Mirtazepine (somnolence, increased appetite) MOA: 1. antagonist at central pre-synaptic alpha(2)-receptors, inhibiting negative feedback to the presynaptic nerve and causing an increase in NE release. 2. Agonist/antagonist at multiple sites: ------Blocks alpha(2)-receptors contained in serotenergic neurons, enhances the release of 5-HT which increased activity at at 5-HT and 5-HT1 which decreases anxiety -----weak antagonist at 5-HT1 receptors and as a potent antagonist at 5-HT2 (particularly subtypes 2A and 2C) and 5-HT3 receptors. What you need to know: increases activity at some 5-HT, decreases at others, resulting in decreased anxiety ---very effective anxiolytic

Drugs Used to Treat Psychosis and Agitation


Mechanism: All block dopamine with various affinities Typical Antipsychotics: 1.Phenothiazines: a. Aliphatic side chain: Chlorpromazine b. Piperidine side chain: Thioridazine c. Piperazine side chain: Trifluoperazine, Fluphenazine 2.Butyrophenones: Haloperidol 3.Thioxanthenes: Thiothixene

4. Other heterocyclics: Pimozide, Loxapine High potency: fluphenazine, trifluoperizine, thiothixene, haloperidol, pimozide medium-low sedation, high EPS, low AC FTTHP: five truly terrible harsh pills Low potency: chlorpromazine, mesoridazine, thioridazine medium-high sedation, low-medium EPS, high AC MCT: medications creating tiredness Medium potency: perphenazine, loxapine, molindone low-medium sedation, high EPS, low-medium AC MLP: moderately lethal pills EPS: extrapyramidal symptoms AC: anticholinergic effects ALL OF THESE ARE EXTRAPYRAMIDAL SYMPTOMS Acute dystonia sustained muscular contraction of neck, eyes, throat generally occurs soon after starting medication Akathisia uncomfortable continuous motor restlessness can occur any time in treatment but generally in first week(s) easily misdiagnosed as the underlying psychiatric disorder Treat with Beta Blocker primarily propranolol (must be lipid soluble) Parkinsonism tremor, muscle stiffness, slowed movement, drooling, masked face generally occurs beyond 1 week after starting medication

Tardive dyskinesia (TD) spastic facial distortions and tongue movements, rhythmic small movements may extend to neck, trunk, and extremities delayed effect, usually beyond 6 months from starting medication risk increases with duration of exposure to antipsychotic, lithium, age, other neurological diagnosis known to occur without antipsychotic therapy may be permanent, occur on discontinuation or resolve on own Neuroleptic malignant syndrome (NMS) pipe-like rigidity, fever, tremor, altered level of consciousness hypotension, tachycardia laboratory abnormalities- elevated WBC & CK mortality 10-20% can occur any time in course of treatment SPECTRUM Also, Anticholinergic effects (NOT EPS) dry mouth, blurred vision, constipation, urinary retention, mydriasis (dilated pupils) AND Hyperlipidemia, weight gain, impaired glucose tolerance/diabetes

Haloperidol- treatment of choice for delirium, agitation Chlorpromazine heavily sedating; approved for use in children Thioridazine Black Box QTc prolongation Loxapine Molindone Perphenazine CATIE trial supported equivalent to atypicals

Thiothixene Trifluoperazine Fluphenazine Prochlorperazine Pimozide- approved for Tourettes

Atypical neuroleptics/antipsychotics: Dopamine blockade AND Serotonin blockade. Serotonin is like a brake to dopamine. When you block dopamine, there are side effects from that blockade. BUT, when you also block receptor activity that is itself braking dopamine, you ameliorate those effects. Also used for: schizophrenia and other psychotic disorders acute bipolar mania & maintenance augmentation of antidepressants & mood stabilizers aggression & impulsivity

Risperidone- approved for aggression in autism, like typicals at high doses Olanzapine- high likely diabetes/elevated lipids Clozapine- agranulocytosis, seizure risks, diabetes/elevated lipids Quetiapine- very low EPS risk Asenapine Ziprasidone- QTC prolongation

Iloperidone Lurasidone- may have less propensity for negative effects on cognition Aripiprazole- nausea, akithisia common side effects; other EPS very rare; DIFFERENT mechanism, sort of- works as partial agonist/antagonist, potentially titrating its own dopamine blockade

Drugs Used to treat extrapyramidal symptoms


Anticholinergics All these treat extrapyramidal symptoms (EPS): tremor, stiffness, drooling, dystonias akathisia may not respond to ACs tardive dyskinesia usually little response to ACs Side effects all anticholinergic: fever, hot/flushed skin, constipation, blurred vision, urinary retention, dry mucous membranes benztropine (Cogentin) M1 muscarinic acetylcholine receptor antagonist least sedating, most commonly used

trihexyphenidyl (Artane): M1 muscarinic acetylcholine receptor antagonist diphenhydramine (Benadryl) (antihistamine)

Drugs Used to Improve Attention


StimulantsSide effects for stimulants are all the same = agitation/aggression, tics, tremors, seizures, increased adrenergic tone: tachycardia/blood pressure, sweating, mood swings, hyperthermia, psychosis Amphetamines- block reuptake of norepinephrine and dopamine- when binding to presynaptic receptors, actually turn reuptake channels into releasing channels Dextroamphetamine Levoamphetamine/Dextroamphetamine- mixed salts; contains both isomers Lisdexamphetamine- prodrug; turns into dextroamphetamine upon cleavage of lysine; very long acting/smoother pharmacokinetic/dynamic curves = less abuse potential Methylphenidate- blocks reuptake of norepinephrine and dopamine Dexmethylphenidate- dextrorotatory enantiomer of methylphenidate

Drugs Used to Promote Wakefulness


Unique mechanism of action: Modafinil

Drugs Used to Decrease Hyperactivity


Stimulants/Amphetamines- Stimulate both improve attention, and decrease hyperactivity. SEE ABOVE Dextroamphetamine Levoamphetamine/Dextroamphetamine Methylphenidate Dexmethylphenidate---dextrorotatory enantiomer of methylphenidate Lisdexamphetamine-- prodrug; turns into dextroamphetamine upon cleavage of lysine; very long acting/smoother pharmacokinetic/dynamic curves = less abuse potential

alpha (2) adrenergic agonists clonidine AND guanfacine centrally acting alpha 2 agonism downregulates noradrenergic tone and is especially helpful in decreasing hyperactivity (and lowering blood pressure); main side effect of concern is orthostatic hypotension or symptoms of hypotension- changes in mental status, balance, etc.

Drugs Used to Stabilize Mood

Valproic Acid--- blocks high-frequency, repetitive neuronal firing by blocking voltage-dependent sodium channels, augment the action of GAD (glutamic acid decarboxylase), a GABA-synthesizing enzyme, restricts GABA-T (GABA transaminase), an enzyme that speeds the degradation of GABA. Carbamazepine.stabilizes the inactivated state of Voltage-gated sodium channels, making fewer of these channels available to subsequently openthe affected cells are less excitable until the drug dissociates. GI: nausea, constipation, diarrhea, appetite loss CNS: sedation, dizziness, unsteadiness, confusion benign rashes common, catastrophic rashes rare Stevens Johnson Syndrome- severe exfoliative erythematous rash with systemic inflammation many possible serious abnormalities in CBC- DECREASES..agranulocytosis can be dosed rapidly to treat acute mania more effective than lithium in rapid cycling & mixed states approved for migraine prophylaxis serum levels can be helpful in guiding dosing, 70-100 nausea, weight gain, unsteadiness (ataxia), hair loss, tremor liver dysfunction, decreased platelets (thrombocytopenia) pancreatitis (rare but potentially serious) polycystic ovary disease per reports ammonia levels can be increased particularly in those rare individuals with genetic metabolic deficits

may reduce sodium levels (hyponatremia) liver function abnormalities rare but possible used in acute mania and bipolar maintenance..effectiveness within two weeks more effective than lithium in rapid cycling & mixed states, less effective in bipolar related depression serum levels to guide dosing, 4-12 mcg/ml multiple significant drug-drug interactions (DDI) affecting both other medications (reducing their levels) & other medications affecting it (increasing carbamazepine levels) induces its own metabolism so may need to adjust dose over several weeks, half life decreases to 12-17 hours DECREASES levels of OCPs, tricyclics, prednisone, Coumadin; fluoxetine, diltiazem, verapamil, erythromycin all INCREASE levels of carbamazepine\

Oxcarbazepine Does not have the enzyme-inducing effects of carbamazepine tolerated better Less drug-drug interactions Hyponatremia, dizziness, ataxias, less blood dyscrasias

Lithium Lithium has been found to decrease the activity and function of the Na+/K+/-ATPase pump in the CNS and especially in the hippocampus.

Lithium induced ADP ribosylation of the Gi G protein (therefore inactive).. increases basal levels of CAMP.at the same time, lithium attenuates receptor-mediated activation of Adenylate Cyclase (AC) through a reduction in Gs subunit coupling. This results in a decrease in the peak levels of stimulus induced CAMP. ?BALANCING EFFECT rats....reduced levels of arachidonic acid and its products, which can contribute to inflammation AND increased levels of a metabolite called 17-OH-DHA in response to inflammation. 17-OH-DHA is formed from the omega-3 fatty acid DHA (docosahexaenoic acid) and is the precursor to a wide range of anti-inflammatory compounds known as docosanoids. Lithium- features Only mood stabilizer without significant anticonvulsant properties up to 70% response rate demonstrated effectiveness in reducing suicidality less effective in rapid cycling and mixed bipolar states serum levels guide dosing; above 1.3 toxic .7-1.2 therapeutic; above 3.5 dialyze lab draw 8-12 hrs after last dose excreted through the kidneys minimal liver mediated drug-drug interactions (but see next slide for other medication issues) Lithium- side effects fine tremor, weight gain, nausea increased thirst and urination more severe toxicities include coarse tremor, gait instability, vomiting, diarrhea, confusion

increased risk of toxicity with fluid or salt restriction, hot weather/sweating, use of anti-inflammatory drugs, ace inhibitors & angiotensin receptor blockers, diuretics may cause kidney and thyroid dysfunction so regular monitoring of creatinine, BUN and TSH are necessary females /kids are at much greater risk of lithium related thyroid dysfunction

Lamotrigine----Inhibits voltage-dependent sodium channels, resulting in decreased release of the excitatory neurotransmitters glutamate and aspartate.these act on NMDA receptors Minimally sedating unlike most other mood stabilizers Appears to be especially effective in bipolar depression. Early use as an anticonvulsant in children raised concerns about potentially life-threatening rash (Stevens-Johnson syndrome =toxic epidermal necrolysis). Levetiracetam----binds to SV2A (synaptic vesicle protein 2A)..which is thought to.block conduction propagation (may also be from influences on presynaptic calcium channels) Topiramate--blockage of voltage-dependent sodium channels, augmentation of gamma-aminobutyrate acid activity at receptor, antagonism of AMPA/kainate subtype at glutamate binding sites Side effects: weight loss, cognitive dulling, kidney stones, metabolic acidosis, at moderate to high doses makes oral contraceptives ineffective FDA Approved for MANIA Aripiprazole Carbamazepine Chlorpromazine Divalproex Lithium Olanzapine Quetiapine Risperidone Ziprasidone

FDA Approved for Bipolar Maintenance

Lithium, Ziprasidone, Quetiapine, Risperidone, Aripiprazole, Olanzapine, Lamotrigine

Drugs Used to Treat Dementia


Unique mechanism of action: Memantine (Namenda) ; moderate to severe Blocks the toxic effects associated with excess glutamate and regulates glutamate activation- thought to block flow of current through channels of N-methyl-d-aspartate (NMDA) receptors; may have more broad psychiatric application Well done study supported some help in severe dementia May be of more benefit in vascular dementia

Actylcholinesterase inhibitors GI side effects are very common. Also insomnia. Rare but serious side effects include GI bleed. Benefits are modest. Thorough examination of data suggests slowing of loss versus significant improvement. donepezil (Aricept); approved for mild, moderate, and severe; minimal side effects galantamine (Reminyl); mild to moderate; also stimulates nicotinic receptors rivastigmine (Exelon); mild to moderate tacrine (Cognex) not used due to liver toxicity

Drugs Used to Treat Substance Abuse

buprenorphine/naloxone (Suboxone) treatment for opioid dependence diminishes cravings, evidence-based for maintenance of sobriety from opioids contains both an agonist & antagonist----Buprenorphine: partial agonist activity at mu-opioid receptors, binds tightly and prevents agonism of opioids Naloxone: antagonist; Naloxone was added to Suboxone in an effort to dissuade patients from injecting the tablets---can trigger withdrawal, short half-life , attenuate any euphoria and abuse potential

naltrexone (ReVia) opioid antagonist, longer half life and active metabolite makes it useful for treatment Can trigger withdrawal if opioid dependent and using in last 7-10 days Evidence for ETOH abstinence maintenance in combination with psychotherapy Rationale for opioid abstinence but no data to support potential liver toxicity

disulfiram (Antabuse) for ETOH abuse deterrent makes you sick

requires motivated patient blocks the oxidation of alcohol at the acetaldehyde stage--- blocks aldehyde dehydrogenase

acamprosate (Campral) craving control efficacy shown in some studies; results more mixed in severe alcoholism GABA/taurine agonist?????

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