MIDTERM Flashcards

Question

What is binding tissue sequestration?

Answer 1

typically refers to the phenomenon where drugs or substances become trapped or sequestered in certain tissues of the body due to binding interactions. This can affect the distribution and elimination of the substance, potentially altering its pharmacokinetic profile. The degree of binding effects: The initial concentration of drug available to bind to target (onset and strength of effect) The concentration of drug in the bloodstream over time (duration of effect) Example: Thiopental (anesthetic) is lipid soluble and does not bind very much to albumin in the blood, thus it has rapid initial effects. However, the effect wears off quickly as it is redistributed to fat tissue, and moderate effects are long-lasting as it is slowly released from fat. ## Footnote Binding: When a drug is administered, it circulates through the bloodstream and may bind to various tissues in the body. This binding can occur due to specific interactions between the drug molecules and molecules present in the tissues. Sequestration: After binding to tissues, the drug may become trapped or sequestered within these tissues. This means that the drug accumulates in certain areas of the body rather than being evenly distributed throughout. Effects: Tissue sequestration can impact the concentration of the drug in the bloodstream and other tissues. It can also affect the drug's effectiveness and duration of action. Additionally, sequestration may prolong the drug's presence in the body, leading to a slower elimination rate.

Answer 2

Routes: Kidneys Lungs Bile Skin Sweat Saliva Breast milk Kidney is most common route of elimination, once a drug is metabolized Made up of units called nephrons Molecule must be water-soluble, and large

Answer 3

Drug concentration will be higher for longer IN OLDER ADULTS Allows for optimal dosing regimen What dose should be given? How often? Maintenance of therapeutic levels over time Time required to completely clear system How long until you will pass the drug test? NOT necessarily the amount of time it takes for ½ the initial concentration to be metabolized! Determined by a concentration curve -> WHERE ITS FLATTENED OUT, AND MORE CONSISTENT Once drug is in the elimination phase (flat part of curve), how long does it take for the concentration in the blood to decrease by half? TIME is consistent, not the amount of drug metabolized Independent of initial concentration Allows us to estimate how long the drug will stay in the body The longer the half-life, the longer it takes to eliminate the drug from the body “drug hangover” -> the effects are less, but there’s still drugs in the system Effected by age Older adults are slower to metabolize drugs Drug concentration will be higher for longer. Effected by other drugs Some drug combinations can increase/decrease the rate at which one or both drugs are metabolized.

Answer 4

If a second dose of drug is given before the first dose is eliminated, the overall concentration in the blood will be greater than that of the first dose alone. With repeated administrations, concentrations are additive. If 100 mg of a drug with a half-life of 4 hrs is given at noon, at 4:00pm there will be 50 mg in the blood. If another 100 mg of drug is given at 4:00pm, how much drug will be in the blood at 8:00pm? 75 mg = 25mg (1st dose; 2nd half-life) + 50mg (2nd dose; 1st half-life) 25 is the half-life of the first dose, and 50 mg is the half life of the second dose

Answer 5

Consistent level of drug in body achieved by repeated, regular-interval dosing ~4-6 half-lives 1st = 50% 2nd = 75% 3rd = 87.5% 4th = 93.75% 5th = 96.875% 6th = 98.44% At steady state the amount of drug eliminated per unit time is equal to the amount of drug absorbed per unit time ## Footnote Continuous Dosing: When you take medication regularly, whether it's once a day or several times a day, the drug is being constantly introduced into your body. Absorption and Elimination: After taking a dose of medication, the drug is absorbed into your bloodstream. At the same time, the body works to eliminate the drug through processes like metabolism and excretion. Steady State: After repeated doses, there reaches a point where the amount of drug being absorbed into the bloodstream equals the amount being eliminated. This results in a stable concentration of the drug in the body, known as steady state concentration. Maintaining Steady State: To maintain steady state concentration, it's important to consistently take the medication as prescribed. If doses are missed or if the dosing schedule is irregular, it can disrupt steady state and lead to fluctuations in drug concentration.

Answer 6

Estimation of the amount of receptor interaction required to maintain a therapeutic response Based on large scale clinical studies that compare plasma levels to therapeutic effects Allows doctors to accurately prescribe optimal doses Depends on the client’s individual reaction to the drug

Answer 7

A progressive decline in response with repeated usage of a drug. Metabolic tolerance Usually due to upregulation of enzymes Pharmacodynamic tolerance Down-regulation of receptors or sensitivity Behavioral conditioning (learning) Homeostatic theory Physiological processes can be conditioned to specific stimuli or environments Just being in the environment can cause your body to release dehygrenous

Answer 8

Related to tolerance, but different Administration of drug is required to avoid withdrawal symptoms Abstinence syndrome This is why it is important to slowly wean off a drug, rather than stopping it abruptly Also why addicts continue to use even though experience is no longer pleasurable

Answer 9

Gender Females Smaller Less water Higher fat percentage Hormone fluctuations E.g. estrogen influences pain perception Slower gastrointestinal motility Less intestinal enzymatic activity E.g. Females produce less dehydrogenase Lower glomerular filtration rate Males Larger Bigger organs (liver, kidneys) More water More muscle mass

Answer 10

Not really a “membrane” Blood supply is contiguous between mother and child Small, lipid-soluble molecules cross readily Concentration of drug in fetus about the same as in mother

Answer 11

Established by the FDA to indicate the potential of a drug to cause birth defects if used during pregnancy. They do not take into account any risks from pharmaceutical agents or their metabolites in breast milk. Category A - Well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Examples: levothyroxine, folic acid, magnesium sulfate, liothyronine Category B - Animal reproduction studies have failed to demonstrate a risk to the fetus (there are no well- controlled studies in pregnant women). Examples: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin, pantoprazole Category C - Animal reproduction studies have shown an adverse effect on the fetus, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Examples: tramadol, gabapentin, amlodipine, trazodone, prednisone Category D – Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Examples: lisinopril, alprazolam, losartan, clonazepam, lorazepam Category X - Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Examples: atorvastatin, simvastatin, warfarin, methotrexate, finasteride Category N - FDA has not classified the drug. Examples: aspirin, oxycodone, hydroxyzine, acetaminophen, diazepam ## Footnote Dr. Preggo is on a mission to explore Pregnancy Land, but she needs to know which paths are safe for her and her little one. Luckily, she has her trusty guidebook with the FDA pregnancy categories to help her navigate! Category A: 🚼 "Absolutely Safe Avenue" Dr. Preggo skips down "Absolutely Safe Avenue" where she finds levothyroxine, folic acid, and magnesium sulfate. These are like magical potions that pose no risk to her little one, even in the first trimester! Category B: 🦄 "Baby Unicorn Boulevard" Next, Dr. Preggo glides along "Baby Unicorn Boulevard," where she discovers metformin, hydrochlorothiazide, and cyclobenzaprine. These are like rare baby unicorns because while animal studies show no risk, there haven't been enough human studies to confirm their safety. Category C: 🐾 "Courageous Cub Cave" Dr. Preggo ventures into the "Courageous Cub Cave," where she meets tramadol, gabapentin, and amlodipine. These are like brave little cubs because they may have some risks, but the potential benefits might still make them worth using during pregnancy. Category D: 🌟 "Dangerous Dragon Dungeon" Oh no! Dr. Preggo encounters the "Dangerous Dragon Dungeon" where she faces lisinopril, alprazolam, and losartan. These are like fiery dragons because they have shown evidence of risk to the little one, but in some cases, the benefits might outweigh the dangers. Category X: 🚫 "eXtreme Danger Zone" Finally, Dr. Preggo tiptoes into the "eXtreme Danger Zone," where she sees atorvastatin, simvastatin, and warfarin. These are like forbidden treasures because studies have shown they pose serious risks to the little one, and it's best to avoid them altogether during pregnancy! Category N: 🎈 "Not Yet Classified Neighborhood" Dr. Preggo stumbles upon the "Not Yet Classified Neighborhood" where she finds aspirin, oxycodone, and hydroxyzine. These are like mystery balloons because the FDA hasn't classified them yet, so it's a bit uncertain whether they're safe or not. With her adventure complete, Dr. Preggo can now safely navigate Pregnancy Land, armed with knowledge from the FDA pregnancy categories! 🌈🤰

Answer 12

Designated by the DEA Schedule I No currently accepted medical use and a high potential for abuse. Considered to be the most dangerous drugs with potentially severe psychological or physical dependence. Heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), ecstasy, methaqualone (quaaludes), peyote Schedule II Drugs with a high potential for abuse, with use potentially leading to severe psychological or physical dependence. Also considered dangerous. Cocaine, methamphetamine, methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, Ritalin Schedule III Drugs with a moderate to low potential for physical and psychological dependence. Combination products with less than 15 milligrams of hydrocodone per dosage unit (Vicodin), products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, testosterone Schedule IV Drugs with a low potential for abuse and low risk of dependence. Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien Schedule V Drugs with the lowest potential for abuse. Cough preparations with less than 200 milligrams of codeine or per 100 milliliters (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin

Answer 13

Neurotransmitter synthesis Increasing concentration of precursors (starting molecules) Decreasing concentration of synthetic enzymes Neurotransmitter storage VMAT Neurotransmitter release Ca++ Receptors and Channels Reuptake and enzymatic deactivation Transport molecules, degrading enzymes

Answer 14

A recognition site extends into the extracellular fluid, and a special protein called a G protein on the receptor’s intracellular side. G proteins can open nearby ion channels or activate second messengers Actions can be DIRECT or INDIRECT DIRECT -> G-protein can activate an ion channel INDIRECT -> stimulates the production of cyclic AMP (cAMP) which, in turns, activates several ion channels simultaneously 2nd messenger Signal amplification 1st messenger Neurotransmitters Drugs 2nd messenger Adenylate cyclase IP3 (inositol triphosphate) MAPK DAG/DG (diacylglycerol) 3rd messenger PKA PKB 4th messenger DNA transcription factors Fun: So, in Metabotropic Land, metabotropic receptors are like the operators of the roller coasters. They don't directly open the gates for excitement like the ionotropic receptors do in other parts of the park. Instead, they take their time, triggering a series of events that eventually lead to the fun and excitement happening all around the theme park.

Answer 15

Competitive Binding Drug occupies the same binding site on the receptor that the NT occupies Noncompetitive Binding Drug occupies a different binding site on the receptor than the NT

Answer 16

the availability of neurotransmitters Synthetic Tyrosine hydroxylase, dopa decarboxylase, etc. Degrading Acetylcholine esterase, monoamine oxidase, etc. Drugs that effect the synthesis/degradation of NTs can have broad and powerful effects Inhibiting tyrosine hydroxylase will decrease DA, NE and E!

Answer 17

Optical Isomers Isomers that are mirror images of each other Enantiomers Rotate a beam of light in opposite directions Clockwise, or to the right = “+”, “R”, or “D” Counter-clockwise, or to the left = “-”, “S”, or “L” The distinction is important, as often only one form will be biologically active, or the different forms will produce different effects Most substances contain both isomers in equal proportions (50% L and 50% D) Racemic mixture or racemate Only ½ the molecules are biologically active By purifying a racemic mixture so that the drug only contains the biologically active isomer, a drug’s potency can be increased. Potency is a measure of the drug’s ability to achieve a desired effect at a given dose. If a 10mg dose of Drug A produces the desired effect, and a 5mg dose of Drug B produces the desired effect, Drug B is more potent than Drug A. Example: Celexa – citalopram, racemic mixture Lexapro – escitalopram, S-citalopram

Answer 18

Molecules that have the same molecular formula, but a different shape Example C4H10

Answer 19

Many drugs have actions at more than one type of receptor Tricyclic antidepressants increase 5-HT, NE and block ACh receptors Actions at certain receptors might be responsible for the therapeutic effects Increased 5-HT and NE receptor binding relieve depression Actions at other receptors produce unwanted effects (side effects) Blocking ACh receptors produces sedation, dry mouth, blurred vision. Side effects can have different rates of tolerance than therapeutic effects

Answer 20

Population curves versus Single individual surves Potency Amount of drug required to elicit response Efficacy Maximum effect obtainable Slope The difference in concentration required between a minimal and maximal effect Variability Individual differences in response

Answer 21

Potential to cause adverse effects (side effects) Predictable Side effects that are expected given the various pharmacodynamic actions of the drug. May or may not be tolerable to individual patients. Most predictable side effects are mild. Unpredictable Allergic reactions, genetic-variance reactions. Can be mild or serious.

Answer 22

Placebo In drug trials a treatment that is similar in preparation and administration to the actual drug, but missing the active ingredients Different from “no treatment” Placebo Effect Pxt exhibits therapeutic response in absence of actual treatment Lasagna et al., (1945) estimated that it occurs in 30-40% of pxts.

Answer 23

Characterized by perceptual, emotional, and intellectual deficits; loss of contact with reality; and inability to function in life. The term means “split-mind,” and refers to a distortion of thought and emotion; it is not the same as multiple personality. Incidence 1% of general population (1 in 100) ~2.5 million Americans suffer from schizophrenia Seen throughout history, across cultures Most common dissociative disorder Cost to society is greater than cost of all cancers COMBINED Slightly more prevalent in M than F (1.4:1) Onset Late teens, early twenties (males earlier) Usually diagnosed by 30 5

Answer 24

Hallucinations Usually auditory, sometimes olfactory (e.g. poisonous gas) NOT NEEDED TO HAVE A SCHIZOPHRENIA DIAGNOSIS Delusions False beliefs not shared by others Persecution – feelings that one is being watched, spied upon, that one’s thoughts are being broadcast Grandeur – beliefs that one is important, patient may adopt a historical persona Very resistant to reason Disordered Thoughts Loosening of associations, thoughts jump around and are only tenuously connected to one another “Racing thoughts” Disorganized Behavior Sudden mood changes Inability to focus Inappropriate sexual behavior Inappropriate Affect Laughing at sad things, crying at happy things Picture the "positive" symptoms as things that are added on or exaggerated, like extra excitement on a roller coaster ride. These are things that shouldn't be there but are added on. Examples of positive symptoms include hallucinations (seeing or hearing things that aren't there), delusions (believing things that aren't true), and disorganized thinking or speech.

Answer 25

Flat affect No facial expressions or emotions Lack of movement Will not move Maintain odd postures for long periods of time (catatonia) Social withdrawal Don’t talk to people, even when spoken to Poverty of speech Don’t speak much Monosyllabic Poor hygiene/grooming

Answer 26

Nucleus accmbens is involved in reward processes. Some symptoms of schizophrenia may be related to a faulty reward system Dopamine Dysfunction: One of the key neurotransmitters associated with the nucleus accumbens is dopamine. In schizophrenia, there is evidence of dysregulation in the dopamine system, particularly an overactivity of dopamine transmission in certain brain regions, including the nucleus accumbens. This dysregulation is thought to contribute to the development of positive symptoms like hallucinations and delusions. Reward Processing Abnormalities: The nucleus accumbens plays a central role in the brain's reward circuitry. Dysfunction in this circuitry, including abnormalities in the nucleus accumbens, has been implicated in the motivational deficits often observed in schizophrenia. Individuals with schizophrenia may experience reduced motivation and anhedonia (reduced ability to experience pleasure), which could be related to dysfunction in the nucleus accumbens. Antipsychotic Medications: Many antipsychotic medications, which are commonly used to treat schizophrenia, work by blocking dopamine receptors, including those in the nucleus accumbens. By reducing dopamine transmission in this brain region, these medications can help alleviate positive symptoms of schizophrenia.

Answer 27

Amygdala is involved in conditioned emotional responses, especially to aversive stimuli Overall, while the precise mechanisms linking the amygdala to schizophrenia are complex and multifaceted, dysfunction in this brain region is thought to contribute to the emotional disturbances, social impairments, and psychotic symptoms characteristic of the disorder.

Answer 28

Different mechanisms i.e. reducing amount of NT produced vs. blocking receptor vs. increasing metabolic destruction Lipid solubility Affects how quickly the drug reaches its target Affinity for site of action How attracted the drug is to its target The higher the affinity, the lower the dose needed to produce an effect

Answer 29

-ED50; the dose at which a 50% response is achieved -LD50; the dose at which 50% of subjects die -TI = LD50/ED50 -The larger the TI, the safer the drug -If there is overlap between the curves, the safest estimate is LD1/ED99

Answer 30

any of a group of derivatives of phenothiazine with tranquilizing properties, used as tranquilizers in the treatment of mental illness. List of Phenotiazines: Promethezine Chlorpromazine (Thorazine) Prochlorperazine(Compazine) Fluphenazine (Prolixin) Trifluoperazine (Stelazine) Perphenazine (Trilafon) Acetophenazine (Tindal) Carphenazine (Proketazine) Trifulpromazine (Vesprin) Mesoridazine (Serentil) Thioridazine (Mellaril)

Answer 31

ROA: usually oral, sometimes given IM initially. Oral absorption is initially inconsistent, however with repeated dosing blood levels stabilize (steady state).

Answer 32

Distribution: Highest in lungs, liver, adrenals, spleen. Fairly low in brain. Half-life: 24-48 hrs, metabolized slowly by liver, and slow to leave tissues.

Answer 33

Binding Profile: Primarily block DA D2, but also AChM1, H1, NEα1 Blockade of AChM produces dry mouth, pupil dilation, blurry vision, cognitive impairment, constipation, urine retention, tachycardia (Sympathetic NS) H blockade produces sedation, antiemesis NE blockade produces sedation and hypotension Sites of Action Medulla Suppresses behavioral activation and vomiting. Reduces response to environmental stimuli. Limbic System/Frontal Lobes Blocks DA input from VTA. Decreases hallucinations, delusions, and improves cognitive function. Decreases restlessness and behavioral hyperactivity. Hypothalamus/Pituitary Changes in appetite, metabolic rates, sex drive, sleep patterns, body temp. Increases prolactin production. Produces sexual dysfunction and infertility. Basal Ganglia DA blockade in BG leads to motor deficits similar to PD. Akasthesia, bradykinesia, gait disturbance, tremor. Dystonia – involuntary muscle contractions, sustained contractions (particularly trunk and upper body) Tardive Dyskinesia – involuntary hyperkinetic movements (face, tongue, trunk, upper limbs). Presents after chronic use, cannot be resolved by stopping the antipsychotic. Possible txt with VMAT2 blocking drugs.

Answer 34

Side Effects Affinity for D2 receptors predicts incidence of extra-pyramidal symptoms (EPS) and tardive dyskinesia (TD) Affinity of AChM, H and NE predicts sympathetic effects, memory impairment, sedation and hypotensive effects. Pigment alterations, including retinal pigments which can produce visual problems Neuroleptic Malignant Syndrome (NMS); fever, muscle rigidity, autonomic fluctuations, alterations in consciousness Can lead to death. Tolerance and Dependence Not prone to abuse Blockade of DA receptors can lead to increases in DA-ergic tone (Neuroleptic Malignant Syndrome) Fever Muscular rigidity Autonomic dysfunction Altered mental status (agitation, delirium) Otherwise does not create dependence and/or tolerance

Answer 35

Thioxanthenes List of Thiocanthenes: Thiothixene (Navane) Chlorprothixene (Taractan) Clopenthixol (Sordinol) Flupenthixol (Depixol) Zuclopenthixol (Acuphase) Similar to phenothiazines D2 antagonists 5-HT, NE, H effects as well

Answer 36

Butyrophenone is synthetic agents containing the phenyl-1-butanone group, most Butyrophenones are neuroleptic (antipsychotic) drugs, such as haloperidol, droperidol, or azaperone, that control schizophrenic symptoms (hallucinations, delusions, dementia). List of Butyrophenones Haloperidol (Haldol) Droperidol (Inapsine) Used to control post-operative nausea and vomiting

Answer 37

ROA: usually oral, sometimes given IM (Haldol Decanoate) initially. Distribution: Equal throughout tissues. Half-life: 18 hrs (oral), 3 weeks (decanoate), metabolized slowly by liver, and slow to leave tissues. Binding Profile: very similar to phenothiazines Primarily block DA D2, but also AChM1, H1, NEα1 Sites of Action: brain stem, basal ganglia, limbic system/frontal lobe, hypothalamus S ide Effects High incidence of EPS, particularly PD-like symptoms, dystonia, TD Anticholinergic effects Neuroleptic Malignant Syndrome (NMS) Fever, cognitive problems, muscle rigidity, autonomic dysfunction Life threatening Tolerance and Dependence Not prone to abuse Does not produce tolerance/dependence

Answer 38

Another type of first-generation antipsychotic (FGA) Loxapine (Loxitane) Similar in structure to clozapine High affinity for D2 and 5-HT receptors Antipsychotic, antiemetic, sedative effects Induces EPS An inhaled version (Adasuve) approved by FDA in 2012

Answer 39

Another type of first-generation antipsychotic (FGA) Molindone (Moban) Structure similar to 5-HT Similar treatment profile to phenothiazines Induces weight loss, which is an important advantage over traditional antipsychotics Blocks MAO enzyme, thus increasing catecholamine tone

Answer 40

Another type of first-generation antipsychotic (FGA) Pimozide (Orap) In USA, used more for Tourette’s Syndrome Side effects include EPS, TD and cardiac abnormalities

Answer 41

-“Atypical” antipsychotics Do not induce motor side effects (at least not as many as FGAs) More effective at relieving “negative” symptoms Different, more varied, binding profiles Most are 5-HT2 antagonists as well as D2 antagonists -Common Side Effect – “Metabolic Syndrome” Weight Gain Diabetes/Hyperglycemia Cardiac Abnormalities -List of SGAs Clozapine (Clozaril) Olanzapine (Zyprexa) Risperidone (Risperidol) Sertindole (Serlect) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify) Amisulpride (Solian)

Answer 42

-FGAs vs SGAs General Efficacy Chlorpromazine < haloperidol < risperidone < olanzapine < clozapine General Potency Chlorpromazine < haloperidol < olanzapine < clozapine < risperidone See SGAs tend to be more efficacious and potent, come with fewer side effects, and more varied binding than just D2 antagonism SGAs have fewer motor side effects and different, more varied binding profiles Most are 5-HT2 antagonists as well as D2 antagonists

Answer 43

The first (1970’s) and still the model ROA: Oral Distribution: Equal throughout tissue. Half-life: 9-30 hrs. Binding Profile: DA antagonist, higher affinity for D1 than D2, also binds to D3 and D4 5-HT antagonist, high affinity for 5-HT2, also binds to 5-HT1A H, AChM, NE Effects Reduces positive symptoms Improves negative symptoms Decreases suicidality Effective in pxts previously txt resistant Side Effects Very little motor side effects, if any Can be used in PD pxts Weight gain Sedation Constipation Sialorrhea (excessive saliva) Seizures (usually only at high doses, >600mg/day) Agranulocytosis (“medication induced HIV”) 1-2% Reversible with discontinuation of the drug Requires constant monitoring Increases expense of treatment Contraindicated if pxt is taking other drugs that reduce WBC cell counts (i.e. antibiotics, anticonvulsants, chemotherapy drugs)

Answer 44

-Olanzapine (Zyprexa) When combined with fluoxetine = Symbyax 1996, Eli Lilly ROA: Intramuscular, Tablet, Disintegrating Tablet Absorption: Orally (~6 hours), Injection (~15-45 minutes) Distribution: Binds to plasma proteins (albumin & a1-glycoprotein) Metabolism: Liver (CYP2DA & CYP1A2) Elimination: Kidney (half life 21-54 hours) Binding Profile: H1, 5-HT2A, D2, α1, AChM Effects Reduces positive symptoms Improves negative symptoms Side Effects Very little motor side effects Weight gain Sedation/fatigue Constipation Low blood pressure Contraindications Heart or liver problems Pregnant (Category C), breastfeeding Diabetes, insulin resistance Stroke Dementia

Answer 45

Sertindole (Serlect) 1997 5-HT2 antagonist (highest affinity), D2 antagonist Does not bind to H receptors, so no sedative effects Low EPS Not FDA approved High incidence of QT prolongation and CSD Increased weight gain

Answer 46

Quetiapine (Seroquel) Seroquel, 1997; Seroquel XR (longer acting), 2007 Half-life = 6 hrs Effectively reduces positive symptoms Low EPS Abused more frequently than other antipsychotics, primarily due to sedative and anxiolytic effects

Answer 47

Ziprasidone (Geodon) 2001 5-HT2, D2 antagonist; 5-HT1A partial agonist; 5-HT, NE reuptake inhibitor Anxiolytic, antidepressant actions Used for schizoaffective disorder Effective at reducing positive symptoms Low EPS Half-life = 6 hrs Low weight gain QT prolongation

Answer 48

Amisulpiride (Solian) 1992 Highly selective D2/D3 antagonist, but only in limbic system (not basal ganglia) At low doses blocks autoreceptors (presynaptic) Relieves depression, dysthmia Higher doses blocks pre- and post-synaptic receptors Relieves psychotic symptoms Half-life = 12 hrs Low EPS Low diabetogenic effects Not FDA approved

Answer 49

U.S. 29.0% lifetime prevalence 17.8% current year Highest in world Worldwide 5% (~280 million) 2:1 F:M Exacerbates other illnesses, makes pxts more vulnerable to illness $382.4 billion in costs (Greenberg et al, 2023)

Answer 50

DSM-5: 5 must be present nearly every day for at least 2 weeks: Depressed or irritable mood* Anhedonia* Weight gain/loss (>5% in one month) Insomnia/hypersomnia Psychomotor agitation/slowing Fatigue Feelings of worthlessness or excessive guilt Impaired thinking or concentration Recurrent thoughts of death or suicide

Answer 51

Neurons can repair themselves New neurons are constantly being made (neurogenesis) Depression shares many characteristics with other neurodegenerative diseases. Antidepressant drugs increase the brain’s ability to protect neurons (both old and new) Increase neural density Therapeutic effect time course mirrors the time required for newly formed neurons to become functional.

Answer 52

Tricyclics Late 1950’s Named for their common molecular structure Monoamine oxidase inhibitors MAOIs Late 1950’s Reduce enzymatic deactivation of monoamines

Answer 53

mipramine (Tofranil) desipramine (Norpramin; active metabolite of Imipramine) trimipramine (Surmontil) protriptyline (Vivactil) amitriptyline (Elavil) nortriptyline (Pamelor, Aventil; active metabolite of amitriptyline) doxepin (Adapin, Sinequan) clomipramine (Anafranil)

Answer 54

It's a first generation antidepressant. Block reuptake of 5-HT, NE Therapeutic effects 5-HT, NE stay in synapse longer = more post-synaptic receptor binding Block post-synaptic H, AChM, NE Blockade of H = drowsiness, sedation Blockade of AChM = confusion, memory & cognitive impairment (hippocampus), dry mouth, blurred vision, tachycardia, urinary retention (ANS) Blockade of NE receptors = orthostatic hypotension (PNS) Side effect profiles vary, depending on affinity for H, AChM, NE Some “side effects” can actually be beneficial, i.e. trimipramine, amitriptyline & doxepin have high affinity for H receptors, and induce sedation, which can be good for pxts who have insomnia. Readily absorbed when taken orally Long half-lives (8-125 hrs) Sedative effects wear off first, so recommended to be taken at bedtime Cross placenta, safety not established, but no data indicating fetal abnormalities or lasting effects Pregnancy category C Cardiotoxic in large doses Risk of OD Not addictive, no tolerance Analgesic properties Chronic pain, fibromyalgia

Answer 55

Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants that treat depression and other nervous system disorders. MAOA – DA, NE, E, 5-HT, tyramine Found throughout the body MAOB – DA, tyramine Primarily in CNS Compounds selective for MAOB are currently under investigation MAOIs inhibit MAOA Most bind irreversibly to MAOA Moclobemide in an exception Concurrent administration of adrenergic/serotonergic drugs is problematic Cold medications, nasal sprays, antiasthma meds Consumption of foods containing high levels of tyramine is problematic Product of fermentation “Wine and Cheese Effect” Increases blood pressure Adherence to a strict diet eliminates danger Low TI, so OD is possible

Answer 56

Side Effects Sedation Orthostatic hypotension Dry mouth Nervousness Muscle ache Paresthesia (pricking or tingling sensation) May be from the MAOI’s interference with vitamin B6 metabolism 100 mg of vitamin B6 daily may reduce or eliminate these symptoms Insomnia Weight gain Sexual dysfunction Anorgasmia (inability to achieve orgasm) Impotency Urinary difficulty

Answer 57

Transdermal application developed (selegiline) No problems associated with GI tract Many drug interactions reduced Preferentially binds to MAOB at prescribed dose (10mg) Fast acting

Answer 58

maprotiline (Ludiomil) amoxapine (Ascendin) trazodone (Desyrel) clomipramine (Anafranil) SSRIs (SRIs) SSNRIs (SNRIs) SNRIs (NRIs) buproprion (Wellbutrin, Zyprexa)

Answer 59

A first attempt at second generation antidepressants maprotiline (Ludiomil) Modified TCA Similar to imipramine (NET antagonist, long half-life) Epileptogenic

Answer 60

A first attempt at second generation antidepressants amoxapine (Ascendin) NET antagonist Better than TCAs at relieving anxiety and behavioral agitation Blocks DA receptors – can induce Parkinsonian-like EPS

Answer 61

A first attempt at second generation antidepressants trazodone (Desyrel) Weak NET, SERT antagonist Blocks 5-HT2A Heavy sedative effects; primarily used as a hypnotic Oleptro (extended release); approved for MDD in 2010

Answer 62

A first attempt at second generation antidepressants clomipramine (Anafranil) NET, SERT antagonist, with higher affinity for SERT Used to treat anxiety and pain as well as depression, particularly OCD and Panic Disorder

Answer 63

Introduced in the late 1980’s Fluoxetine (Prozac) Sertraline (Zoloft) Fluvoxamine (Luvox) Citalopram (Celexa) Escitalopram (Lexapro) Also block NET to varying degrees -Primarily used to treat depression (MDD), but are also approved for: PMDD Generalized Anxiety Disorder (GAD) Panic Disorder OCD Social Anxiety Bulimia ADHD Diabetic Neuropathy Fibromyalgia Smoking Cessation

Answer 64

Do not bind to 5-HT receptors, rather make 5-HT more available to bind with receptors Stimulation of 5-HT1 mediates therapeutic effects Stimulation of 5-HT2 produces anxiety, agitation, insomnia, sexual dysfunction and “serotonin syndrome” Stimulation of 5-HT3 induces nausea Do not bind to other receptor systems, so few side effects related to NE, AChM, H -Can be sedating, nighttime dosing recommended -Safer than TCAs; no cardiac effects -Differences in efficaciousness between SSRIs is mainly due to different metabolic kinetics, particularly CYP-450 liver enzymes

Answer 65

Withdrawal Syndrome Usually due to abrupt discontinuation Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal (FINISH) Especially a concern in infants of mother’s who took SSRI’s during pregnancy Sexual Dysfunction Orgasm, erection, interest, arousal, ejaculatory “Serotonin Syndrome” High doses, combination of SSRI with another 5-HT agonist Cognitive disturbances, agitation, ANS dysfunction, motor problems, hallucinations

Answer 66

High doses, combination of SSRI with another 5-HT agonist Cognitive disturbances, agitation, ANS dysfunction, motor problems, hallucinations

Answer 67

fluoxetine (Prozac) 1st released Efficacy is comparable to TCAs, without AChM or H side-effects Slow onset of therapeutic effects (8 weeks) Active metabolite is norfluoxetine Has an even longer half-life (6-10 days), so not necessary to administer every day Common side effects: anxiety, agitation, sexual dysfunction

Answer 68

sertraline (Zoloft) As efficacious as TCAs More potent and selective than fluoxetine 24 hr half-life and no active metabolites Higher risk of serotonin syndrome and withdrawal syndrome

Answer 69

paroxetine (Paxil) More selective than fluoxetine Half-life of 24 hrs Highest risk for serotonin syndrome and withdrawal syndrome Possibly teratogenic (cleft palate/lip); not recommended in pregnant women Prevents biotransformation of the chemotherapeutic drug, Tamoxifen; not recommended in patients undergoing this therapy

Answer 70

fluvoxamine (Luvox) Efficacious as TCAs Half-life: ~16 hrs Shortest half-life of all SSRIs Fewer serious side effects, better compliance High affinity for NE α1, which produces anxiolytic effects Often used to treat anxiety disorders Inhibits CYP1A2, which is increased by elements of tobacco smoke; smokers may require a higher dose to experience therapeutic effects

Answer 71

SSNRIs (SNRIs) -Dual-action antidepressants TCAs actually do this too -Highly selective for NT and 5-HT, with little binding to other receptors Fewer side effects, particularly ones related to increased serotonergic tone

Answer 72

nefazodone (Serzone) 5-HT2 antagonist (high affinity), α1 and 5-HT1 (moderate affinity), also blocks reuptake of 5-HT and NE 5-HT2 actions might be why it is effective at treating migraines Half-life: 2-4 hrs Low risk for sexual dysfunction *****Increased risk for severe liver damage

Answer 73

milnacipran (Savella) Half-life of 8 hrs Comparable to TCAs, but better tolerated Comparable to SSRIs, no difference in tolerability Not yet approved by FDA for depression ****Approved for txt of fibromyalgia

Answer 74

duloxetine (Cymbalta) Half-life: 12 hrs Reduces depression, anxiety, pain Additional approvals for GAD, diabetic neuropathy and fibromyalgia *****Not recommended for bipolar pxts; may induce mania

Answer 75

venlafaxine (Effexor) Half-life 3-7 hrs Active metabolite O-desmethylvenlafaxine (ODV) 9-13 hrs Increases release of 5-HT, NE, and DA At low doses (25-150mg) only 5-HT At moderate doses (150-300mg)5-HT and NE At high doses (300+mg) 5-HT, NE, and DA May have amphetamine-like effects Not recommended for bipolar patients Primarily used for anxiety Increased liability for suicide Off-label use for cocaine dependence INCREASED LIABILITY FOR SUICIDE

Answer 76

(It is a tetracyclic) mirtazepine (Remeron) Half-life 10-20 hrs Does not block reuptake transporters Increases release of 5-HT and NE Blocks α2 receptors (NE autoreceptors) Blocks NE heteroreceptors on 5-HT terminals (stimulation inhibits 5-HT release) Blocks 5-HT2 and 5-HT3, so additional 5-HT primarily acts on 5-HT1 receptors Fewer 5-HT related side effects! Blocks H1 (sedation) ****Increased appetite/weight gain Good for txting pxts with eating or wasting disorders, and elderly pxts ****Very few sexual side effects

Answer 77

-reboxetine (Edronax) -atomoxetine (Strattera) -Not showing much promise as antidepressants -Use for treatment of ADHD

Answer 78

STAR*D Study -Conclusions: ~2/3 pxts achieved remission Substantial withdrawal after each phase: 21% phase 1, 30% phase 2, 42% phase 3 Before giving up on antidepressants Try 2 or 3 Give them at least 12 weeks It may be that antidepressant therapy works better in more severely depressed pxts (HAM-D >25)

Answer 79

Bipolar Disorder Info Episodic, alternating periods of depression and mania with periods of remission in between Depressive episodes usually 3x longer than manic Depressive symptoms can be present during manic phase – “mixed mania” BP-I At least one episode of mania, w/wo depression BP-II Hypomania with major depression “Rapid Cycler” 4 episodes/year

Answer 80

Bipolar Disorder Stats 1% prevalence worldwide ~4-5% BP I and II, USA, 2011 Onset before 25 Gender Differences BP-I equal prevalence (F more depression, M more mania) BP-II, rapid cyclers -> F Comorbidity for anxiety, thyroid disorders -> F Comorbidity for substance abuse -> M High rate of suicide (10x general population) Untreated/inadequately treated Male, alcoholism

Answer 81

Erratic sleep patterns Emotional elation Increased sex drive Increased physical activity Racing thoughts Impulsivity Poor judgment Reckless/aggressive behavior

Answer 82

Diagnostic Difficulties for Bipolar Disorder Majority of pxts seek treatment during episodes of depression Txt with antidepressants can trigger manic episodes Ways to differentially diagnose BD Time course of depression MDD has gradual onset Onset after 25 Family history Symptoms of mania

Answer 83

Mood Stabilizers Lithium Anticonvulsants Antipsychotics Antidepressants Others

Answer 84

Used since 1870’s Depression, gout, headaches -Recommended as a salt substitute for pxts with heart disease in the 1940’s Banned due to toxicity issues -John Cade used it for mania following the observation that administration in animals produced behavioral lethargy -Not widely accepted due to toxicity issues, but determined in 1970s to be markedly superior to placebo for the txt of BP Eskalith, Lithobid

Answer 85

Starting dose usually 600 mg, with increases to 900-1800mg/day Minimal protein binding (<10%) Peaks in blood ~3hr following oral administration Complete absorption by 8 hrs Absorption into brain slow and incomplete; blood levels can be much higher than brain levels Half-life: 18-24 hrs (can be up to 36 hrs in elderly) Steady state reached within 2 weeks of commencing oral dosing Variations in salt intake/loss can effect amount of Li+ in blood Excreted via kidneys Rate dependent on renal function

Answer 86

Drug Interactions Diuretics (effect excretion rates (tonicity) and kidney function) Angiotensin-converting enzyme (ACE) inhibitors NSAIDs -Toxicity TI: 1.25-2.5 (very narrow) 75% pxts Symptoms: renal failure, tremor, seizures, cognitive deficits, coma, death

Answer 87

Pharmacodynamics Does not produce effects in non-pxts Does not bind to receptors Does not produce sedation or euphoria Commonalities with antidepressants: Increase BDNF levels Increase NAA (N-acetyl-aspartate; marker of neuronal health) Neuroprotective Inhibits inositol monophosphatase phosphatidylinositol (PI) signaling pathway Evidence for increased PI signaling in BD pxts (Silverstone et al., 2005) Inhibits GSK-3 May increase plasticity Increase in β-catenin; increases neuronal health and stimulates axon growth Decreases formation of amyloid-β; may be neuroprotective Increases glutithione, which protects neurons from oxidative stress

Answer 88

Neurological – tremor, lethargy, impaired concentration, dizziness, muscle weakness, nystagmus (repetitive, uncontrolled movement of eyes) – GI – nausea, vomiting, diarrhea, pain. Weight gain can be substantial. – Skin – rash, acne, psoriasis, hair loss, mucosal lesions, brittle nails – Thyroid – enlargement, goiter – Kidneys – increased thirst, increased urine output, renal failure – Cardiovascular – arrythmia 11

Answer 89

Patient Noncompliance – Estimated at 50%! – Primarily due to cognitive effects, weight gain, lethargy, missing manic episodes – Increased morbidity, recurrence, suicide risk (14- fold!) 12

Answer 90

Teratogenic * Increased suicidality * Usually used in combination with lithium * Valproic Acid (valproate, Depakote) * Carbamazepine (Tegretol) * Oxcarbazepine (Trileptol) * Lamotrigine (Lamictal) * Gabapentin (Neurontin) * Pregabalin (Lyrica) * Topiramate (Topamax) * Zonisamide (Zonegran) * Tiagabine/retigabine

Answer 91

valproate * Depakote, Depakene, Stavzor * Anticonvulsant – FDA 1995 Mania * GABA agonist/glutamate antagonist – Better for mixed episodes than lithium * Oral, 750mg qid, half-life 9-16 hrs, M -> liver, E -> kidneys * Teratogenic * Interactions: aspirin, rifampin (Ab) BETTER FOR MIXED EPSIODES THAN LITHIUM TERATOGENIC

Answer 92

carbamazepine * Tegretol * ED 8-12 ug/ml * Block Na+ channels; decreases neuronal activity (anti-epileptic) * Has effects on 2nd messenger systems, similar to anti-depressants * Stimulates CYP-34A – Possible interaction with other drugs * Side effects: cognitive impairments, GI upset, sedation, motor ataxia, leucopenia/agranulocytosis, skin reactions – Carbamazepine-epoxide – Asian pxts * May be better than lithium for rapid cyclers, mixed mania * Pregnancy category: D * Extended-release form, Equetro, approved in 2005 LEUCOPENIA/AGRANULOCYTOSIS

Answer 93

oxcarbazepine * Trileptal * Addition of O molecule to carbamazapine * Eslicarbazepine acetate (metabolite) is therapeutic agent * As efficacious as carbamazepine ********** Better safety index; no GI issues, no alterations in liver enzymes (fewer drug interactions), no leucopenia (no monitoring required)

Answer 94

gabapentin/pregabalin * Neurontin, Lyrica * GABA analogues * Decrease Ca2+ entry into presynaptic terminals * **** Excellent safety profile; not metabolized by liver, excreted intact * Not a stand-alone txt, but may be beneficial in combination with Lithium * Gabapentin approved for txt of BP, pregabalin off -label

Answer 95

topiramate * Topamax * Originally developed as an anti-diabetic Rx * Used to txt migraines ******* Not super useful as a txt for BD, per se, however induces weight loss, which can counteract weight gain seen with other BD drugs * May increase lithium concentration in blood, so must monitor closely

Answer 96

Atypical Antipsychotics * risperidone (Risperdal) * olanzapine (Zyprexa) – olanzapine + fluoxetine = Symbyax * quetiapine (Seroquel) * aripiprazole (Abilify) * ziprasidone (Geodon) * lurasidone (Latuda) Atypical Antipsychotics * 1st txt for BP * Used as monotherapy, or as adjunct to a mood stabilizer * Ability to reduce mania is correlated to affinity for D2 receptors * May be particularly useful in conjunction with an antidepressant for the txt of BP-II (less likelihood of “switching”) * Haloperidol, a typical antipsychotic, is also effective at reducing acute mania – More motor side effects – BP pxts may be particularly vulnerable

Answer 97

Other Treatments * Omega-3 Fatty Acids – Incidence of BP, and other affective disorders, is lower in countries with high levels of omega-3 consumption – Adjunctive therapy may increase remission intervals * Acetylcholine agonists – Donepezil (Aricept) – AChE antagonist – Improves cognitive function – No recommended for Bipolar I (increases mood instability) * Hormonal Agents – Tamoxifen – inhibits PKC (alters intracellular signal transduction) * Modafinil – alleviates sedation/fatigue * Psychotherapy/Psychosocial Txt – important for mood stability in remission, txt adherence, recognizing early signs of relapse * ECT – Rapid effects, safe for pregnant women

Answer 98

STEP-BD Study * Similar to STAR*D (antidepressants) * 5 years, 4360 pxts * ~50% pxts achieved recovery, and ~50% of those pxts relapsed within 2 years – Residual symptoms at recovery, concurrent psychiatric diagnoses * Addition of an antidepressant did not give significantly better recovery rates * Valproate not recommended for female pxts (PCOS, teratogenic) * Lamotrigine is good for txt-resistant pxts * Psychosocial txt is very important for optimal recovery

Answer 99

Anxiety Disorders * Four categories of symptoms: – Apprehension – Vigilance – Motor Tension – Autonomic Hyperactivity * Prevalence of anxiety disorders – Overall (NIMH) * 19.1% of U.S. adults had any anxiety disorder in the past year. * Higher for females (23.4%) than males (14.3%). * Severity: Severe (22.8%), Moderate (33.7%), Mild (43.5%) * 31.1% lifetime prevalence – Specific (American Psychiatric Association) – 8-12% phobias; 1:2 M:F – 7% Social Anxiety Disorder; 1:1 – 5% Posttraumatic Stress Disorder; 1:2 – 3% General Anxiety Disorder; 1:2 – 2-3% Panic Disorder; 1:2 – 1-2% Obsessive Compulsive Disorder; 1:1

Answer 100

Common Features of Anxiety Disorders * Evidence for involvement of several NT systems. – GABA – NE – 5-HT * Genetics may predispose a person to an anxiety disorder, but not to a specific type. * “High-reactive” infants may be vulnerable to anxiety disorders. * Most effectively txtd with combination of medication and psychotherapy.

Answer 101

Possible Physiological Causes of Anxiety Disorders * Endocrine conditions (e.g. hyper/hypothyroidism, hypoglycemia, hyperadrenocorticism) * Cardiovascular conditions (e.g. congestive heart failure, myocardial infarction, arrhythmia) * Respiratory conditions (e.g. chronic obstructive pulmonary disease, pulmonary embolism, pneumonia, hyperventilation) * Metabolic conditions (e.g. obesity, vitamin B12 deficiency, porphyria) * Neurological conditions (e.g. brain tumors, encephalitis) * Drug abuse (including steroid use) * Drug withdrawal

Answer 102

Social Anxiety Disorder * Incidence – 15 million adults in US (7%) – Approximately the same M:F – Onset in adolescence * Symptoms – Fear of being judged unfavorably in social situations – Can lead to panic attacks * Causes – Genetics * Drugs – SSRIs: fluoxetine, paroxetine – Benzodiazepines: alprazolam – Beta Blockers

Answer 103

Posttraumatic Stress Disorder * Incidence – 13 million adults in US – 2-3x more females * Symptoms – Recurrent dreams of trauma – Flashbacks – Hyperarousal – Avoidance of stimuli associated with trauma * Causes – Reduced benzodiazepine activity? * Treatments – Benzodiazepines – SSRIs 7

Answer 104

Generalized Anxiety Disorder * Incidence – 6-7 million in US – F more than M (2-3x) – Onset in late 20’s * Can appear in childhood (3%) * Symptoms – Excessive, unfocused anxiety not attributable to a definite stimulus or situation lasting longer than 6 months – Tense, tired, change in sleep patterns, irritability, trembling, dizziness, nausea, heart palpitations * Causes – Genetic * Family, twin studies indicate significant heritability – GABAA receptors * Action site of BZDs * Pxts with GAD may have more receptors, or receptors may be super-sensitive – BZD/alcohol dependence * Common Treatments – Benzodiazepines – SSRIs

Answer 105

Panic Disorder * Incidence – 6 million adults in US – 1:2 – Onset in young adulthood * Symptoms – Attacks of overwhelming fear and terror – Sudden onset, brief (30 minutes) – Shortness of breath, clammy, irregular heartbeat, dizziness, faintness, feeling of unreality – Anticipatory anxiety occurs between episodes and can progress to agoraphobia * Causes – Genetic – GABAa receptors * Pxts with PD may have more receptors, or receptors may be super-sensitive * Alcohol can also stop panic attacks (self-medication) – 5-HT * SSRIs are effective at relieving PD, but mechanism in unclear – Brain Abnormalities * During panic attacks cingulate, prefrontal and anteriotemporal cortices show decreased activity * Treatments – Benzodiazepines – TCAs * Imipramine (Tofranil) – SSRIs * Particularly those that reduce activity of locus coeruleus

Answer 106

Obsessive Compulsive Disorder * Incidence – 2 million adults in US – Slightly more F than M – Onset usually in early childhood * Often associated with tic disorders * Symptoms – Recurrent obsessions or compulsions and the behaviors associated with them – Counting, checking, cleaning and avoidance * Causes – Genetics – Brain Damage – Group A beta-hemolytic streptococcal infection * Drugs – SSRIs: fluoxetine, fluvoxamine – TCAs: clomipramine, venlafaxine – Drugs that specifically increase 5-HT activity seem to be particularly useful at relieving compulsive behaviors – Drugs that block 5-HT make compulsive symptoms worse

Answer 107

Pathophysiology * GABA – Decreased GABAergic function may lead to increased excitation in cortical circuits that modulate anxiety. * Connections with insula, orbitofrontal cortex – -> impaired judgment? – Benzodiazepines and other anxiolytic drugs bind to the GABAA receptor increasing the inhibitory effect of GABA. – Supporting evidence includes * Increased sensitivity to GABAA antagonists in PD pxts * Decreased BZD binding in GAD pxts

Answer 108

Pathophysiology * NE – Locus coeruleus is involved in enhancing physiological responses to fear and panic * Excitatory effect on many brain circuits and structures including the cortex, amygdala, hippocampus and the hypothalamus * Activated by inputs from the cortex and amygdala. – LC stimulation can prime structures to produce an autonomic response via the hypothalamus. – In some GAD patients α2 receptors have been shown to be down-regulated * Produce negative feedback inhibiting the LC and further NE release within the brain. – Anxiolytic drugs (e.g. benzodiazipines) can inhibit LC firing. * 5-HT – Inhibitory connections between Raphe nuclei and LC – NE may inhibit 5-HT release – Supporting evidence includes * Abnormalities in 5HT(1A/1D) autoreceptor; upregulation/increased sensitivity inhibiting presynaptic 5- HT production and release * Abnormalities in SERT * Abnormalities of expression of post synaptic 5-HT receptors – Increased 5-HT2A/C density – Stimulation of the 5HT2A receptor in the limbic system results in avoidance and anxious responses.

Answer 109

* Oldest: alcohol * 1850’s: bromide(s), chloral hydrate (trichlorethanol), chloroform, paraldehyde, laudanum (opium + alcohol – Used primarily as sedatives and anesthetics – “Mickey Finn”; cholral hydrate + alcohol * Barbiturates (1862) * Non-barbiturate sedatives * Benzodiazepines (1960’s) * Non-BZRAs * SSRIs * TCAs * SNRIs * Anticonvulsants * Beta blockers

Answer 110

* GABA receptors – The hippocampus has a high density of GABA receptors * Amnesic effects of antianxiety meds – Cerebral cortex * Confusion, impaired cognition – VTA/Nucleus Accumbens * Rewarding effects/addiction – Spinal cord * Muscle relaxant effects – Cerebellum * Anticonvulsant effects * Can be very dangerous, especially when combined with other CNS depressants (e.g., alcohol) * Not recommended in pxts with decreased GABA function – Elderly – Dementia pxts

Answer 111

Barbiturates * Phenobarbital (1912) – More than 200 compounds synthesized – All end in “-al” * GABAA agonists – Hold Cl- channels open longer – Increases efficacy of GABA * Low TI – Very dangerous – Death usually results from respiratory depression – No txt for OD * Significant tolerance/dependence – metabolic * Half-life: 3 min – 120 hrs – Shorter ½ lives used primarily for anesthesia * Amytal, Nembutal – Longest ½ lives used for epilepsy * Mebaral, Luminal, Seconal – Mid-range ½ lives used for insomnia, anxiety * Butisol * Oral administration * Absorption dependent upon lipid solubility * Pregnancy: Category D * Generally not used as anxiolytics due to similar ED50s for sedative and amnesic effects * Serious withdrawal syndrome; similar to alcohol withdrawal

Answer 112

Non-barbiturate Sedatives * Very similar to barbiturates, but different molecular structure * Originally marketed for daytime sedation (rapid acting, short ½ life) or anxiolysis * Amnesic ED50 lower than sedative ED50 * Commonly known as “date rape” drugs – Placidyl, Noludar, Equanil, Soma, Quaalude, Noctec, GHB 19

Answer 113

Benzodiazepines * Alprazolam (Xanax) * Chlorazepate (Tranxene) * Chlordiazepoxide (Librium) * Clonazepam (Klonopin) * Diazepam (Valium; oral and injection) * Estazolam (ProSom) * Flurazepam (Dalmane) * Halazepam (Paxipam) * Lorazepam (Ativan; oral and injection) * Midazolam (Versed; iv only) * Oxazepam (Serax) * Prazepam (Centrax) * Quazepam (Dormalin) * Temazepam (Restoril) * Triazolam (Halcion) * Pharmacokinetic differences: – Absorption rates * Most absorbed quickly * Oxazepam & lorazepam take longer – Potency – Metabolism rates – Activity of metabolites * Some active metabolites have very long ½ lives!

Answer 114

Benzodiazepines * “A versatile clinical tool” * Introduced in late 1950’s – Chlordiazepoxide (Librium) – Roche Laboratories * BZRAs – BZR is found on GABAA receptors – Increases affinity of GABA binding site for GABA * Administration – Oral (majority) – Injection (diazepam, lorazepam, midazolam) * Half-life varies – Short acting – 2.5-12 hrs – Intermediate/long acting – 10-80 hrs * Absorption – Oral administration, peak in 1 hr * Many have active metabolites – Special precautions need to be taken in elderly and pxts with hepatic disease

Answer 115

* High TIs, low toxicity – UNLESS combined with other NS depressants (alcohol, I’m looking at you!) – OD txt with flumazenil (BZD antagonist) * Used to treat anxiety and stress- related insomnia * High rates of dependence limit use – Should only be used for short periods * Cognitive impairments can decrease effectiveness of behavioral therapy * Special Populations – Elderly, children/adolescents, pxts with history of drug abuse or currently abusing

Answer 116

* Side Effects – Sedation, ataxia, confusion, cognitive/motor impairment, amnesia – Especially problematic in children/adolescents and elderly – Some evidence that impairments are semi- permanent * High liability for tolerance/dependence/abuse – Zitman & Couvee (2001) * Pregnancy category D

Answer 117

Nonbenzodiazepine BZRAs * Different molecular structure than BZDs, but same effect at BZD receptor * Zolpidem (Ambien), zaleplon (Sonata), eszopliclone (Lunesta) * Shorter half-lives * Insomnia * CBT equally effective

Answer 118

Herbal Remedies * Used for ~60,000 years * Written evidence from 5000 years ago (Sumeria) * Easy and inexpensive to grow, prepare * Use began to decline in 19th century – Isolation/purification of “active” plant compounds * 20th century – Ability to synthesize molecules in the laboratory – Rise of the pharmaceutical industry

Answer 119

Anticonvulsants * gabapentin (Neurontin) – phobia, other anxiety disorders – GABA receptor agonist * tiagabine (Gabitril) – GAD – GABA reuptake blocker * lacosamide (Vimpat) – GAD – Sodium channel modulator

Answer 120

Serotonin Receptor Agonists * SSRIs have anti-depressant and anxiolytic effects * First choice for anxiety disorders – Well tolerated, high safety – Especially good for OCD, PTSD * BZDs are not * Drugs that stimulate post- synaptic 5-HT1A receptors also have these effects – Buspirone (BuSpar) – Gepirone (Exxua)

Answer 121

Serotonin-Norepinephrine Receptor Agonists * SSNRIs – Depression – Anxiety * Venlafaxine – Especially good for GAD, Social, Panic – At high doses also blocks DAT – No evidence for addiction/misuse – Can increase BP; not recommended in elderly – Higher toxicity risk than other SSNRIs

Answer 122

Beta Blockers * Block β-adrenergic receptors; decrease effects of epinephrine, NE, and cortisol * Primarily used to control cardiac arrhythmias and hypertension * Used most often for social anxiety and performance anxiety – Should only be used acutely * propanolol (Inderal) * atenolol (Tenormin)

Answer 123

Anxiety and Nutrition * High comorbidity with gut disorders (IBS, IBD, Chron’s, celiac/gluten sensitivity) * Good food: – Omega-3, antioxidants, magnesium, zinc, potassium * Bad food: – Omega-6, sugar, gluten * Can be as effective as anti-anxiety meds * Supports other forms of treatment

Answer 124

Herbal Remedies * Not FDA approved – Dietary Supplement Health Education Act, 1994 – “supplement” – Very few double-blind, placebo-controlled clinical trials – BUT does not mean “FDA reviewed and rejected” * Not regulated – No FDA oversight UNTIL there is a problem – Manufacturers can make any claim they wish – No guarantee that the preparation even contains the active substance * Newmaster et al., 2013 * Effects unknown – May do nothing, may be very effective, may interfere with other drugs * Snake Oil?

Answer 125

Herbal Remedies vs Modern Pharmaceuticals Herbal Remedies * Cost-effective * Unstandardized/Difficult to standardize * Not regulated * Efficacy/Safety not required prior to market * Often contain multiple beneficial compounds * Support general processes Modern Pharmaceuticals * Prices vary * Standardized * Regulated * Must be shown to be safe/effective prior to being approved/marketed * Purified * Targeted actions

Answer 126

St. John’s Wort

Answer 127

Anxiolytics – German chamomile – Kava – Lemon Balm – Passion Flower – Skullcap – Valerian

Answer 128

- German chamomile – Hops – Kava – Lemon Balm – Passion Flower – Skullcap – Valerian

Answer 129

Stimulants – Ma Huang Cognitive Enhancement – Gingko – Choline

Answer 130

Ma-Huang * Ephedra sinica – Ephedrine – active ingredient – Canes and roots of plant * Asthma, flu, increase alertness/focus, performance enhancement, weight loss Ma-Huang * Pharmacokinetics – Similar to ephedrine – ~85% bioavailability (oral ROI) – Half-life = 3-6 hrs * Pharmacodynamics – Increases release of adrenaline, NE, DA – Sympathomimetic – Thermogenic * Side Effects – Increased blood pressure – Increased cardiac load – Stroke/cardiac arrest ******* Especially if used in conjunction with caffeine

Answer 131

Omega-3 Fatty Acids * Eicosapentaenoic acid (EPA) * Docosahexaenoic acid (DHA) * Poorly synthesized in human body; dependent on diet for adequate quantities * Important for brain development, growth, and repair * Depression * Inflammation/allergies * Pain * Cardiac/stroke * Dementia * 500 mg/daily recommended – 180 mg/day found to reduce risk of dementia by 50%! * Counteract effects of omega-6 fatty acids – Increase inflammation and platelet aggregation – Ideal ratio is 1:1 (Omega-3: Omega-6) * Typical American diet high in Omega -6, with common ratios of 1:12) * Essentially side-effect free

Answer 132

MAKE TODAY YOUR BITCH