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Vernon Rosario, MD, PhD Associate Clinical Professor

Vernon Rosario, MD, PhD Associate Clinical Professor Dept. of Psychiatry and Biobehavioral Sciences. Neurotransmission & pharmacodynamics Pharmacokinetics Some medications affecting the brain and behavior: antipsychotics mood stabilizers antidepressants antianxiety medications stimulants.

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Vernon Rosario, MD, PhD Associate Clinical Professor

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  1. Vernon Rosario, MD, PhD Associate Clinical Professor Dept. of Psychiatry and Biobehavioral Sciences

  2. Neurotransmission & pharmacodynamics • Pharmacokinetics • Some medications affecting the brain and behavior: • antipsychotics • mood stabilizers • antidepressants • antianxiety medications • stimulants Overview Adapted from Steven A. Fink, PhD, Jarred von Snellenberg, PhD, Heidi Combs & MD Shamim Nejad, MD

  3. Synaptic Transmission:Action Potentials http://videosift.com/video/Brain-Synapses-and-Neurotransmission-3D-Animation

  4. Pharamacodynamics:Where Drugs Act • Four sites of action • Receptors (those sites to which a neurotransmitter can specifically adhere to produce a change in the cell membranes) • Ion channels • Enzymes • Carrier Proteins • Biologic action depends on how its structure interacts with a receptor

  5. Types of Action • Agonist: same biologic action • Antagonist: opposite effect • Interactions with a receptor • Selectivity: specific for a receptor • Affinity: degree of attraction • Intrinsic activity: ability to produce a biologic response once it is attached to receptor Receptors

  6. Drugs can block or open the ion channels • Example: benzodiazepine drugs facilitate GABA in opening the chloride ion channel Ion Channels Potassium channel. Image Source Page: http://www.beckman.illinois.edu/news/Illinoisgating

  7. Enzymes • Enzymes catalyze specific biochemical reactions within cells and are targets for some drugs • Monoamine oxidase is an enzyme thatbreaks down most bioamine neurotransmitters (NE, DA, 5-HT) • Enzymes may be inhibited to produce greater neurotransmitter effect.

  8. Carrier Proteins • Transport neurotransmitters across cell membranes • Medications may block or inhibit this transport • Example: antidepressants (SSRI) on serotonin transporter protein Image Source Page: http://scientopia.org/blogs/scicurious/2010/08/25/back-to-basics-3-depression-post-6/

  9. Efficacy - Ability of a drug to produce a response as a result of the receptor or receptors being occupied. • Potency - Dose required to produce the desired biologic response. • Loss of effect • desensitization (rapid decrease in drug effect) • tolerance (gradual decrease in the effect of a drug at a given dose) • can lead to patient being treatment refractory Efficacy and Potency

  10. Target Symptoms and Side Effects • Target symptoms • Specific symptoms treated for each class of medication • Side effects • Responses (+ or -) not related to target symptoms • Adverse drug reaction • Unwanted effects with serious physiologic consequences.

  11. ToxicityPoint at which concentration of the drug in the blood stream becomes harmful or poisonous to the body. • Image Source Page: http://www.beltina.org/health-dictionary/narrow-therapeutic-index-nti.html Drug Toxicity

  12. Therapeutic indexRatio of the dose that produces toxicity in 50% to the dose that is therapeutically effective in 50% • TD50/ED50 • High therapeutic index: wide range between dose at which the drug begins to take effect and dose that would be considered toxic • Low therapeutic index: low range Drug Toxicity Image Source Page: http://quizlet.com/5151182/usmle-pharmacology-principles-flash-cards/

  13. Pharmacokinetics:How the Body Acts on the Drug • Absorption • Distribution • Metabolism • Elimination

  14. Pharmacokinetics Blood Brain Barrier P450 Enzymes J van Snellenberg 2007

  15. From site of administration into the plasma • Oral - (tablet and liquid) • Most Convenient • Most variable (food and antacids) • First pass effect • Decreased gastric motility (age, disease, medication) • IM - Short-and long acting • IV - Rarely used outside hospital Absorption

  16. Bioavailability • Amount of drug that reaches systemic circulation unchanged • Often used to compare one drug to another, usually the higher the bioavailability, the better

  17. Amount of drug found in various tissues, especially the intended ones • Psychiatric drugs must pass through blood-brain barrier (most fat-soluble) • Factors effecting distribution • Size of organ (larger requires more) • Blood flow (more, greater concentration) • Solubility (greater, more concentration) • Plasma protein (if bound, slower distribution, stays in body longer) • Anatomic barriers (tissues surrounding) Distribution

  18. Passive diffusion • Drug must dissolve in the structure of the cell • Lipid solubility is necessary for drugs passing through blood brain barrier (then, can also pass through placenta) • Binding to other molecules • Plasma protein binding • The more protein binding, the less drug activity. • Can bind to other cells, especially fat cells. Then are released when blood level decreases. Crossing the Blood Brain Barrier Image Source Page: http://www.nanowerk.com/spotlight/spotid=19339.php

  19. Metabolism • Process by which the drug is altered and broken down into smaller substances (metabolites) that are usually inactive. • Lipid-soluble drugs become more water soluble, so they may be more readily excreted. • Most metabolism is carried out in the liver

  20. Largest class of enzymes catalyzing oxidation of organic substances in all living things • 11,550+ identified ; 57 in humans • High affinity for fat-soluble drugs • Involved in metabolism of most psychiatric medications • Inactivate drugs (or in some cases activate them) • Chemicals may increase or decrease CYP activity • Example: • SSRIs inhibitors of the subfamily CYP2D6 • Compounds in grapefruit juice inhibit CYP3A4 • Tobacco induces CYP1A2 Cytochrome P450 (CYP)

  21. Clearance: Total amount of blood, serum, or plasma from which a drug is completely removed per unit time • Half-life: Time required for plasma concentrations of the drug to be reduced by 50% • Only a few drugs eliminated by kidneys (lithium) • Most excreted via the liver • excreted in the bile and delivered to the intestine • may be reabsorbed in intestine and “re-circulate” (up to 20%) Elimination

  22. Dosing: Administration of medication over time, so that therapeutic levels can be achieved. • Steady-state: • drug accumulates and plateaus at a particular level • rate of accumulation determined by half life • reach steady state in about five times the elimination half-life Dosing and Steady State

  23. Pharmacokinetics: Ethnicity • 9% of whites - genetically defective CYP2D6 • Asian descent • Metabolize ethanol to produce higher concentrations of acetaldehyde (flushing, palpitations) • Require 1/2 to 1/3 dose antipsychotics and have more severe side effects • Cardiovascular effects of propranolol • Asian descent - more sensitive • African descent - less sensitive

  24. Initiation • Stabilization • Maintenance • Discontinuation Phases of Drug Treatment

  25. Antipsychotic Medications • Movement Disorders Medication • Mood Stabilizers • Antimanic • Antidepressant • Antianxiety and Sedative-Hypnotic • Stimulants Psychiatric Medications

  26. Antipsychotic Medications • Target symptoms: psychosis • Types • Conventional • Atypical • Absorption: variable • clinical effects seen 30-60 min • IM less variable (avoid 1st pass) • when immobile, less absorption of IM • Metabolism: liver • Excretion: slow • accumulates in fatty tissues • 1/2 life of 24 hours or more

  27. Preparations • Oral • IM • Depot - haloperidol and fluphenazine • Side Effects • Cardiovascular: orthostatic hypotension • Weight-gain: blocking histamine receptor • Endocrine and sexual: block dopamine, interfere with prolactin • Blood dyscrasias: agranulocytosis Antipsychotic Medications

  28. Conventional • Phenothiazines (Thorazine, Prolixin) • Thioxanthenes (Navane) • Dibenzoxazepines (Loxitane) • Haloperidol (Haldol) • Atypical or Novel • Clozapine (Clozaril) • Risperidone (Risperdal) • Olanzapine (Zyprexa) • Quetiapine (Seroquel) • Ziprasidone (Geodon) • Aripiprazole (Abilify) • Asenapine (Saphris) • Iloperidone (Fanapt) • Lurasidone (Latuda) • Paliperidone (Invega) Antipsychotic Medications

  29. Cardiovascular: arrhythmia, incr. heart rate • Anticholinergic: dry mouth, dry eyes, imbalance, pupil dilatation, double vision, constipation, confusion, delirium • Weight Gain • Endocrine: hyperprolactinemia > milk production, irregular periods, hyperthermia, diabetes • Blood Disorders: decr. white blood count • Miscellaneous: jaundice, rash, photosensitivity Antipsychotic Side Effects

  30. Medication-Related Movement Disorders: Acute Syndromes • Can occur in 90% of all patients • Dystonia: involuntary muscle spasms, abnormal postures, oculogyric crisis, torticollis • Parkinsonism: rigidity, akinesia (slow movement), and tremor, masklike face, loss of spontaneous movements • Akathisia: Inability to sit still, restlessness • Extrapyramidal Symptoms (EPS) (11 min)

  31. Etiology (acute): • Related to dopamine in nigrostrial pathway that increases cholinergic activity • Treatment • Anticholinergic medication for dystonia, parkinsonism (Artane and Cogentin) • Akathisia does not usually respond to anticholinergic medication. Beta blockers have best success. Movement Disorders: Acute (cont.)

  32. Tardive Dyskinesia • Irregular, repetitive involuntary movements of mouth, face, and tongue, including chewing, tongue protrusion, lip smacking, puckering of the lips, and rapid eye blinking. Abnormal finger movements are common. More common in women and elderly. • Symptoms • Begin after 6 months, but also as antipsychotics are withdrawn • Irreversible - controversy Movement Disorders: Chronic

  33. Etiology • believed that chronic dopamine suppression in the EPS causes an overactivation of the system • increases in antipsychotic meds, suppresses • Treatment • prevention by using lowest possible dosage, minimize use of PRN, closely monitor individuals in high-risk groups • monitoring tools Movement Disorders: Chronic

  34. Action: uncertain, crosses cell membranes, altering sodium transport, not protein bound • Side Effects: thirst, metallic taste, increased frequency or urination, fine head and hand tremor, drowsiness, and mild diarrhea • Blood levels monitored (lithium toxicity - severe diarrhea, vomiting, drowsiness, muscular weakness, and lack of coordination, withhold) Mood Stabilizers: AntimaniaLithium Carbonate

  35. Monitor creatinine concentrations, thyroid hormones, and CBC every 6 months. • Kidney damage may be a risk • Thyroid function may be altered usually after 6-18 months. Observe for dry skin, constipation, bradycardia, hair loss, cold intolerance • Avoid during pregnancy (associated with cardiac defects and arrhythmia) Lithium Carbonate

  36. Mood Stabilizers: AntimaniaAnticonvulsants • Valporate and derivatives (divalproex sodium - Depakote) • Carbamazapine (Tegretol) • Gabapentin (Neurontin) (least side effects) • Lamotrigine (Lamictal) • Topiramate (Topamax) • Highly protein bound • Metabolized by the cytochrome P450 system • Side effects: dizziness, drowsiness, tremor, visual disturbance, nausea, & vomiting

  37. Only carbamazepine is approved for mania. • Used when patients have not responded to lithium • Pharmacokinetics • Highly protein bound, metabolized by P450 system (potential drug-drug interaction) Anticonvulsant Mood Stabilizers

  38. CarbamazepineSide Effects • Dizziness, drowsiness, tremor, visual disturbances, nausea, and vomiting • Minimized by treating in low doses • Give with food • Weight gain • Alopecia (hair loss)

  39. Antidepressants Tricyclic: Tertiary Amines • Amitriptyline (Elavil) • Clomipramine (Anafranil) • Doxepine (Sinequan) • Imipramine (Tofranil) • Trimipramine (Surmontil)

  40. Antidepressants:Secondary Amines • Amoxapine (Asendin) • Desipramine (Norpramin) • Nortriptyline (Aventyl, Pamelor) • Protrypyline (Vivactil)

  41. Most common uncomfortable side effects • sedation • orthostatic hypotension • anticholinergic • Others • tremors, • restlessness, insomnia, confusion • pedal edema, headache, and seizures • blood dyscrasias • sexual dysfunction • Adverse • cardiotoxicity TCAs: Side Effects

  42. Most antidepressants block the re-uptake of a neurotransmitter of one or more of the bioamines: serotonin, norepinephrine, dopamine • SSRIs = Selective Serotonin Reuptake Inhibitors Antidepressants

  43. Selective Serotonin Reuptake Inhibitors (SSRI) • Fluoxetine (Prozac) • Sertraline (Zoloft) • Paroxetine (Paxil) • Fluvoxamine (Luvox) • Citalopram (Celexa) • Escitalopram (Lexapro)

  44. Headache • Anxiety • Transient nausea • Vomiting • Diarrhea • Weight gain • Sexual dysfunction SSRI: Side Effects

  45. Usually given in morning, unless sedation occurs • Higher doses, especially paroxetine, can produce sedation • Paroxetine associated with weight gain SSRIs

  46. Action: Inhibit enzyme responsible for the metabolism of serotonin, dopamine, norepinephrine, and tyramine. • Increases levels of norepinephrine and serontonin in the CNS • Interacts with food -- low tyramine diet (no cheese, liver, fermented or cured foods) Antidepressants: Monoamine Oxidase Inhibitors (MAOIs)

  47. Antidepressants Others • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) • Venlafaxine (Effexor) • Desvenlafaxine (Pristiq) • Duloxetine (Cymbalta) • Mirtazapine (Remeron) • Trazodone (Desyrel) • Nefazodone (Serzone withdrawn due to rare liver failure) • Bupropion (Wellbutrin)

  48. Antianxiety and Sedative-Hypnotic Medication • Used for anxiety, not long-term • Benzodiazepines • diazepam (Valium) • lorazepam (Ativan) • alprazolam (Xanax) • Nonbenzodiazepines • busipirone (BuSpar) • zolpidem (Ambien) • Side effects • Sedation and CNS depression • Tolerance and dependence (benzos) • Avoid benzos in children & elderly

  49. Psychostimulants • This class of drugs, in low to moderate doses, generally have the following effects • Heightened mood (euphoria) • Increase vigilance and alertness • Reduce fatigue • Alertness • In order of prevalence of use • Caffeine • Nicotine • Amphetamines/Cocaine

  50. Amphetamine, etc (cont.) • Low to moderate doses • Facilitate performance on sustained attention tasks, and those requiring physical quickness or strength • Especially if fatigued (Benzedrine used extensively in WW II) • Increased energy, concentration, alertness, self-confidence, and mood • Social interactions may be enhanced • Suppresses appetite • High doses generally interfere with performance • Also can lead to dysphoria, social withdrawal, and depression Psychostimulants

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