SECOND TIME - midterm Flashcards

Question

Define Cmax

Answer 1

Highest level of concentration in blood

Answer 2

The time for the plasma level of a drug to fall by 50% is called the

Answer 3

The ability of liver enzymes to degrade a drug more efficiently in the continued presence of the drug

Answer 4

Synapse/neuron; liver

Answer 5

Relative safety of a drug

Answer 6

The dose of a drug that produces the desired effects in half of the subjects is called the drug’s

Answer 7

A drug that blocks the effect of the naturally occurring (endogenous) compound

Answer 8

From slides: The more lipid soluble a drug is, the faster it reaches the blood stream and the brain From Google: it readily dissolves in fats and oils, which allows it to easily cross cell membranes and distribute throughout the body.

Answer 9

Larger molecules can't move through the barrier.

Answer 10

Foods, other drugs, and digestive disorders. Example: high fiber foods, and calcium supplements

Answer 11

Concentration level of drug in body achieved by repeated, regular-interval dosing. (about 4-6 half-lives). 1st is 50%, 2nd is 75%, and so on. At steady state the amount of drug eliminated per unit time is equal to the amount of drug absorbed per unit time.

Answer 12

For most drugs, the time to reach steady-state is four to five half-lives if the drug is given in regular intervals.

Answer 13

Tolerance: the body getting used to taking a substance and requiring higher doses. Dependence: refers to the physical or psychological symptoms that occur that make someone feel like they must continue taking a substance, From slides; dependence: 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

Answer 14

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 15

Pregnancy  Absorption  Progesterone decreases intestinal motility  Increased stomach pH (less acidic)  Increased heart rate and tidal volume of respiration increase absorption of inhalants  Distribution  Increased fluid volume (up to 8 liters!)  Affects CMAX  Metabolism  Some enzymes are induced by estrogen/progesterone, others are reduced  Elimination  Increased renal blood flow = increased elimination of drugs that are excreted unchanged

Answer 16

Young  Pharmacokinetic  Not fully ‘metabolically competent’  Pharmacodynamic  Developing tissues may have different sensitivity  Exposure to drugs may alter developmental pathways  Elderly  Pharmacokinetic  Diminished metabolism and excretion  Multiple medications (polypharmacy)  Pharmacodynamic  Increased vulnerability to balance issues

Answer 17

How drugs effect the body, particularly how they interact with their targets (i.e. receptors)

Answer 18

How attracted the drug is to it's target. The higher the affinity, the lower the dose needed to produce an effect

Answer 19

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 Different mechanisms - i.e. reducing amount of NT produced versus blocking receptor versus increasing enzymatic

Answer 20

Remember: pharmacodynamics is How drugs effect the body, particularly how they interact with their targets (i.e. receptors) It depends on: Receptor type/activity/location  Drug specificity  Affinity  Kd; dissociation constant  Amount of drug needed to occupy to 50% of receptors; smaller values indicate greater affinity  Ki; inhibition constant  Amount of drug needed to occupy 50% of receptors in the presence of a known inhibitor; smaller values indicate greater affinity

Answer 21

neurotransmitter synthesis - concentration precursors (starting molecules) - concentration of synthetic enzymes neurotransmitter storage - VMAT neurotransmitter release - Ca++ receptors and channels Reuptake and enzymatic deactivation - transport molecules, degrading enzymes

Answer 22

cytochrome P450 (CYP) enzymes (specifically the CYP3A4 isoform

Answer 23

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 (NT is neurotransmitter)

Answer 24

(or a racemate) is a 50:50 mixture of two enantimers (mirror-image isomers) of a chiral molemules,

Answer 25

non-superposable mirror images of each other (think how your hands are mirror images, but you can’t perfectly place one on top of the other). Usually only one enantiomer is biologically active.

Answer 26

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.

Answer 27

Efficacy  Maximum effect obtainable From google: the maximum response achievable from a pharmaceutical drug in research settings, and to the capacity for sufficient therapeutic effect or beneficial change in clinical settings

Answer 28

Google: The relative efficacy of two drugs that elicit the same effect can be measured by comparing the maximum effects of the drugs.

Answer 29

Potency  Amount of drug required to elicit response  Efficacy  Maximum effect obtainable

Answer 30

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 31

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.

Answer 32

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

Answer 33

(added features) Hallucinations, Delusions, disordered thoughts, disorganized behavior, inappropriate affect Hallucinations – Usually auditory, sometimes olfactory (e.g. poisonous gas) * 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 6

Answer 34

(features lacking) Flat affect, lack of movement, social withdrawal, poverty of speech, and poor hygiene/grooming 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 35

AFFINITY FOR D2 RECEPTORS

Answer 36

Basically: a lot of dopamine might be why positive symptoms develop in schizophrenia Dopamine Hypothesis of Schizophrenia – Overactivity of DA synapses in mesolimbic pathway – Seems to be related to the positive symptoms – DA agonists * DA agonists can induce psychotic symptoms * Cocaine, amphetamine – DA pathways * Mesolimbic Da pathway begins in VTA and projects to the nucleus accumbens/amygdala, frontal lobe – Nucleus accmbens is involved in reward processes. Some symptoms of schizophrenia may be related to a faulty reward system – Amygdala is involved in conditioned emotional responses, especially to aversive stimuli – Frontal lobe important for planning, personality – Evidence that schizophrenics have disturbed DA function * Injections of amphetamine cause increased release of DA in striatum of schizophrenics (compared to non- schizophrenics) * Some evidence that schizophrenics have more D2 receptors * Evidence that schizophrenics have more D3 and D4 receptors 8

Answer 37

FGAs – Phenothiazines – Thioxanthenes – Butyrophenones – Others

Answer 38

Phenothiazines ROA: oral Distribution: highest in lungs Half life: 24-48 hours Binding Profile: Binding Profile: Primarily block DA D2, but also AChM1, H1, NEα1 – H blockade produces sedation, antiemesis – NE blockade produces sedation and hypotension Sites of Action: Medulla, Limbic System, Hypothalamus, Basal Ganglia EXAMPLE: Chlorpromazine (Thorazine)

Answer 39

Basically: EPS, TD, NMS -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.

Answer 40

D2 antagonists 5-HT, NE, H effects 5-HT IS THE MAIN ONE SHE WROTE IN RED

Answer 41

ROA: usually oral Distribution: equal throughout tissues Half-life: 18 hours Binding profile: very similar to phenothiszines - primarily block DA D2, but alco AChM1, H1, NEa1 Site Action: brain stem, basal ganglia, limbic system, hypothalamus Side Effects: HIGH INCIDENCE OF EPS, PARTICULARLY PD-LIKE SYMPTOMS, DYSTONIA, TD - also anticholingergia effects, NMS

Answer 42

Loxapine (loxitane) Antipsychotic drug - Butyrophenones "lots a ping, lots of tang" -similar in structure to clozapine - high affinity for D2 and 5-HT receptors **AN INHALED VERSION (ADASUVE) APPROVED BY FDA IN 2012. From the textbook: black box warning for bronchospasm

Answer 43

Molindone (moban) Antipsychotic drug - Butyrophenones "mole dome, mole ban" - 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 44

Pimoside (Orap) Antipsychotic drug - Butyrophenones "ol rappin' pimp" -is USA, used more for Tourette's Syndrome - side effects include EPS, TD, and cardiac abnormalities

Answer 45

DO NOT INDUCE MOTOR SIDE EFFECTS TO THE SAME DEGREE AS FGA

Answer 46

"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

Answer 47

Clozapine (clozaril) Antipsychotic drug SGA "clothes pin" ***THE FIRST (1970'S) AND STILL THE MODEL ROA: oral Distribution: Equal throughout tissue Half-life: 9-30hours Binding Profile: Ca 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: - AGRANULOCYTOSIS - very little other side effects -> weight gain, sedation, constipation, sialorrhea, seizures

Answer 48

Olanzapine (Zyprexa) Antipsychotic drug SGA "Owl lands upon (cra)Zy pretzel" ***(Comes in tablet and *injection, improves negative symptoms) ROA: oral Absorption: 6 hours Distribution: binds to plasma proteins Metabolism: liver Elimination: kidney Effects: - reduces positive symptoms - ***improves negative symptoms

Answer 49

Quetiapine (Seroquel) Antipsychotic drug SGA "Sera! Quit typing!" - quit typing and go to sleep (mania) Abused more frequently than other antipsychotics, low incidence of EPS ***ABUSED MORE FREQUENTLY THAN OTHER ANTIPSYCHOTICS, primarily due to sedative and anxiolytic effects effectively reduces positive symptoms, low EPS

Answer 50

Sertindole serlect Antipsychotic drug SGA -5-HT2 antagonist (highest affinity), D2 antagonist - *** DOES NOT BIND TO H RECEPTOR, SO NO SEDATIVE EFFECTS - low EPS - not FDA approved

Answer 51

Ziprasidone (Geodon) Antipsychotic drug SGA "Geode Don's Zipper" Both anxiolytic, and antidepressant actions Low incidence of weight gain - 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 - ****LOW WEIGHT GAIN

Answer 52

Amisulpiride (solian) Antipsychotic drug SGA - not FDA approved - **** LOW DIABETOGENIC EFFECTS - low EPS highly selective D2/D3 antagonist, but only in limbis system (not basal ganglia)

Answer 53

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 54

Monoamine deficiency - Antidepressants increase monoaminergic tone within hours, but therapeutic effects do not appear for weeks – Changes in receptor sensitivity? – Other changes? Monoamines; TLDR * Dopamine: Yes! Do that again! * 5-HT: I like this. This is good. * NE: Pay attention! * E: Let’s GOOOOOO!!!!!

Answer 55

“Neurogenic Theory of Depression” 1. Neurons can repair themselves 2. New neurons are constantly being made (neurogenesis) Basically: The neurogenic theory of depression says that depression happens when the brain stops making enough new brain cells, especially in the hippocampus, which controls memory and emotions.

Answer 56

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

Answer 57

Basically: 5-HT and NE block reuptake, 8-125 hours for half-lives, side effects with sedation (but can be good for those with insomnia) ***CARDIOTOXIC IN LARGE DOSES * 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.

Answer 58

Basically: MAO-A breaks down dopamine (DA), norepinephrine (NE), epinephrine (E), serotonin (5-HT), and tyramine throughout the body, while MAO-B primarily affects DA and tyramine in the CNS. MAOIs (which mostly inhibit MAO-A irreversibly) can cause dangerous interactions with adrenergic/serotonergic drugs and tyramine-rich foods (e.g., aged cheese and wine), leading to high blood pressure unless a strict diet is followed. * 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

Answer 59

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

Answer 60

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

Answer 61

Searching for better efficacy, better safety, and fewer/different side effects -> led to Second-generation antidepressants From Chat: MAOIs (monoamine oxidase inhibitors) aren't commonly prescribed anymore because they have serious safety concerns and require strict dietary restrictions. They can cause dangerous drug interactions with antidepressants, cold medications, and other serotonergic or adrenergic drugs, leading to hypertensive crises or serotonin syndrome.

Answer 62

Searching for better efficacy, better safety, and fewer/different side effects

Answer 63

Trazodone (Desyrel) Second-generation antidepressants "trays o' bone, dizzy reel" - trays of bone make me sleepy - risk of prolonged boner, mouth "dry as a bone" - Weak NET, SERT antagonist – Blocks 5-HT2A – ***** Heavy sedative effects; primarily used as a hypnotic – Oleptro (extended release); approved for MDD in 2010

Answer 64

clomipramine (Anafranil) Second-generation antidepressant "Anne Frank's CLOMpulsion" - obsessive-"CLOMpulsive behavior of aligning tricycles – NET, SERT antagonist, with higher affinity for SERT – ******Used to treat anxiety and pain as well as depression, particularly OCD and Panic Disorder

Answer 65

maprotiline (Ludiomil) – Modified TCA – Similar to imipramine (NET antagonist, long half-life) *****– epileptogenic

Answer 66

amoxapine (Ascendin) TCA "ammo to ascend" - "I'm-a-sendin-ammo" - a bottole of amoxapine may provide the suicidal patient "ammo to ascend to heaven" – NET antagonist – Better than TCAs at relieving anxiety and behavioral agitation *****– Blocks DA receptors – can induce Parkinsonian-like EPS

Answer 67

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 68

* 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 69

Side Effects: – Withdrawal Syndrome * Usually due to abrupt discontinuation * Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal ******(FINISH) * Especially a concern in infants of mothers who took SSRIs during pregnancy ******– Sexual Dysfunction * Orgasm, erection, interest, arousal, ejaculation – “Serotonin Syndrome” * High doses, combination of SSRI with another 5-HT agonist * Cognitive disturbances, agitation, tachycardia, increased BP, motor problems, hallucinations, hyperpyrexia

Answer 70

fluoxetine (Prozac) SSRI "prolonged sack of the FLUstered OX" - prolonged presence in the body with half-life of 1 week ******– 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 71

sertraline (Zoloft) SSRI "so soft (on the) Shirt line" - preferred drug for pregnancy - zoloft makes your stools soft" – 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 72

fluvoxamine (Luvox) SSRI "Glove-OX" - wearing a glove (OCD) for overly clicking the light -> exclusively for OCD – 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 73

Paroxetine (Paxil)

Answer 74

Dual-action antidepressants – TCAs actually do this too * Highly selective for NE and 5-HT reuptake transporters, with little binding to other receptors – Fewer side effects, particularly ones related to increased serotonergic tone ****** Analgesic

Answer 75

nefazodone (Serzone) SSNRI *****Increased risk for severe liver damage

Answer 76

milnacipran (Savella) SSNRI ****Approved for txt of fibromyalgia

Answer 77

duloxetine (Cymbalta) "DUELing Cymbals" **** Not recommended for bipolar pxts; may induce mania

Answer 78

venlafaxine (Effexor) SSNRI "Vanilla faxing (eFax'er) - "i'm depressed, must fax for help" ****INCREASED LIABILITY FOR SUICIDE

Answer 79

Sequenced Treatment Alternatives to Relieve Depression * Large, multipatient, multisite study looking at antidepressant efficacy There were levels.

Answer 80

* 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 81

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

Answer 82

Diagnostic difficulties: * 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

Toxicity – TI: 1.25-2.5 (very narrow) – 75% pxts – Symptoms: renal failure, tremor, seizures, cognitive deficits, coma, death

Answer 85

Lithium * Pharmacokinetics – 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 affect amount of Li+ in blood – Excreted via kidneys * Rate dependent on renal function

Answer 86

* Toxicity – TI: 1.25-2.5 (very narrow) – 75% pxts – Symptoms: renal failure, tremor, seizures, cognitive deficits, coma, death

Answer 87

* Side Effects – 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

Answer 88

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

Answer 89

* Teratogenic * Increased suicidality * Usually used in combination with lithium Chat: Anticonvulsants are commonly prescribed for patients (pxts) with bipolar disorder because they help stabilize mood and prevent both manic and depressive episodes. They work by regulating neurotransmitter activity and reducing excessive neuronal excitability, which is thought to contribute to mood swings.

Answer 90

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)

Answer 91

carbamazepine (Tegretol) Anticonvulsant treatment for BD * 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

Answer 92

oxcarbazepine (Trileptal) Anticunvulsant treatment for BD * 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 93

Gabapentin (Neurontin) Anticonvulsant treatment for BD 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 94

topiramate (topamax) Anticonvulsant treatment for BD "top at max speed on top of pyramid" - kidney throwing stones at top of pyramid *** Not super useful as a txt for BD, per se, however induces weight loss, which can counteract weight gain seen with other BD drugs

Answer 95

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 96

risperidone (Risperdal) atypical antipsychotic SGA - and bipolar

Answer 97

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 98

GABA NE 5-HT CHAT: GABA receptors: The GABA-A receptors are involved in the brain’s calming system Norepinephrine receptors (alpha and beta receptors): The norepinephrine system is also involved in the fight-or-flight response. Serotonin receptors (5-HT receptors): Serotonin plays a significant role in mood regulation, and receptors like 5-HT1A are believed to have a calming effect. LECTURE: 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 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 99

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

Answer 100

To treat anixety disorders: - Benzodiazepines - SSRIs - SNRIs - Buspirone - Beta-blockers (social and environmental) - Antipsychotics (atypical) - Antidepressants (TCAs) -

Answer 101

* 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

Answer 102

Summary: Benzodiazepines (BZDs) have high therapeutic indices and low toxicity, but combining them with other CNS depressants (like alcohol) can be dangerous, and overdose can be treated with flumazenil. While effective for anxiety and insomnia, BZDs carry a high risk of dependence, tolerance, and abuse, and they can cause sedation, cognitive impairment, and motor issues, particularly in children, adolescents, and the elderly, making them unsuitable for long-term use. * 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 * 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 103

Alprazolam (Xanax): "Lil Xan, the Alp-raised Lamb" - lil xan was addicted to benzos benzo rapid onset short duration DEA schedule IV

Answer 104

CHAT: Barbiturates are more dangerous than benzodiazepines, with a narrow therapeutic index and a higher risk of overdose, respiratory depression, and abuse, making them largely obsolete today. Benzodiazepines, though safer, still pose risks of dependence, tolerance, and cognitive impairment, and should be used cautiously, especially in the elderly or those with a history of substance abuse.

Answer 105

CHAT: Anticonvulsants are sometimes prescribed with benzodiazepines to provide comprehensive Anticonvulsants * gabapentin (Neurontin) – phobia, other anxiety disorders – GABA receptor agonist * tiagabine (Gabitril) – GAD – GABA reuptake blocker * lacosamide (Vimpat) – GAD – Sodium channel modulator

Answer 106

used to control hypertension, often for social and performance anxiety

Answer 107

propanolol (Inderal) "prop ran, LOL (from) Ender"

Answer 108

Co-morbid with gut disorders, omega-3, antioxidants, magnesium 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 109

* 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? 5

Answer 110

* Ephedra sinica – Ephedrine – active ingredient – Canes and roots of plant * Asthma, flu, increase alertness/focus, performance enhancement, weight loss Side Effects – Increased blood pressure – Increased cardiac load – Stroke/cardiac arrest ******* Especially if used in conjunction with caffeine

Answer 111

Omega-3 fatty acids: Diet dependent, reduce inflammation