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  1. 1. Vernon Rosario, MD, PhD Associate Clinical ProfessorDept. of Psychiatry and Biobehavioral Sciences
  2. 2. Overview• Neurotransmission & pharmacodynamics• Pharmacokinetics• Some medications affecting the brain and behavior: o antipsychotics o mood stabilizers o antidepressants o antianxiety medications o stimulants Adapted from Steven A. Fink, PhD, Jarred von Snellenberg, PhD, Heidi Combs & MD Shamim Nejad, MD
  3. 3. Synaptic Transmission: Action Potentials
  4. 4. Pharamacodynamics:Where Drugs Act• Four sites of action o Receptors (those sites to which a neurotransmitter can specifically adhere to produce a change in the cell membranes) o Ion channels o Enzymes o Carrier Proteins• Biologic action depends on how its structure interacts with a receptor
  5. 5. Receptors• Types of Action o Agonist: same biologic action o Antagonist: opposite effect• Interactions with a receptor o Selectivity: specific for a receptor o Affinity: degree of attraction o Intrinsic activity: ability to produce a biologic response once it is attached to receptor
  6. 6. Ion Channels• Drugs can block or open the ion channels• Example: benzodiazepine drugs facilitate GABA in opening the chloride ion channelPotassium channel. Image Source Page:
  7. 7. Enzymes• Enzymes catalyze specific biochemical reactions within cells and are targets for some drugs• Monoamine oxidase is an enzyme that breaks down most bioamine neurotransmitters (NE, DA, 5-HT)• Enzymes may be inhibited to produce greater neurotransmitter effect.
  8. 8. Carrier Proteins • Transport neurotransmitters across cell membranes • Medications may block or inhibit this transport • Example: antidepressants (SSRI) on serotonin transporter proteinImage Source Page:
  9. 9. Efficacy and Potency• 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 o desensitization (rapid decrease in drug effect) o tolerance (gradual decrease in the effect of a drug at a given dose) o can lead to patient being treatment refractory
  10. 10. Target Symptoms andSide 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. 11. Drug Toxicity• Toxicity Point at which concentration of the drug in the blood stream becomes harmful or poisonous to the body.• Image Source Page:
  12. 12. Drug Toxicity • Therapeutic index Ratio 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 rangeImage Source Page:
  13. 13. Pharmacokinetics:How the Body Acts on the Drug• Absorption• Distribution• Metabolism• Elimination
  14. 14. Pharmacokinetics Blood Brain Barrier P450 Enzymes J van Snellenberg 2007
  15. 15. Absorption• From site of administration into the plasma• Oral - (tablet and liquid) o Most Convenient o Most variable (food and antacids)  First pass effect  Decreased gastric motility (age, disease, medication)• IM - Short-and long acting• IV - Rarely used outside hospital
  16. 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. 17. Distribution• 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 o Size of organ (larger requires more) o Blood flow (more, greater concentration) o Solubility (greater, more concentration) o Plasma protein (if bound, slower distribution, stays in body longer) o Anatomic barriers (tissues surrounding)
  18. 18. Crossing the Blood BrainBarrier • Passive diffusion o Drug must dissolve in the structure of the cell o Lipid solubility is necessary for drugs passing through blood brain barrier (then, can also pass through placenta) • Binding to other molecules o Plasma protein binding o The more protein binding, the less drug activity. o Can bind to other cells, especially fat cells. Then are released when blood level decreases.Image Source Page:
  19. 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. 20. Cytochrome P450 (CYP)Largest class of enzymes catalyzing oxidation oforganic 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: o SSRIs inhibitors of the subfamily CYP2D6 o Compounds in grapefruit juice inhibit CYP3A4 o Tobacco induces CYP1A2
  21. 21. Elimination• 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 o excreted in the bile and delivered to the intestine o may be reabsorbed in intestine and “re-circulate” (up to 20%)
  22. 22. Dosing and Steady State• Dosing: Administration of medication over time, so that therapeutic levels can be achieved.• Steady-state: o drug accumulates and plateaus at a particular level o rate of accumulation determined by half life o reach steady state in about five times the elimination half-life
  23. 23. Pharmacokinetics: Ethnicity• 9% of whites - genetically defective CYP2D6• Asian descent o Metabolize ethanol to produce higher concentrations of acetaldehyde (flushing, palpitations) o Require 1/2 to 1/3 dose antipsychotics and have more severe side effects• Cardiovascular effects of propranolol o Asian descent - more sensitive o African descent - less sensitive
  24. 24. Phases of Drug Treatment• Initiation• Stabilization• Maintenance• Discontinuation
  25. 25. Psychiatric Medications• Antipsychotic Medications• Movement Disorders Medication• Mood Stabilizers o Antimanic o Antidepressant• Antianxiety and Sedative-Hypnotic• Stimulants
  26. 26. Antipsychotic Medications• Target symptoms: psychosis• Types o Conventional o Atypical• Absorption: variable o clinical effects seen 30-60 min o IM less variable (avoid 1st pass) o when immobile, less absorption of IM• Metabolism: liver• Excretion: slow o accumulates in fatty tissues o 1/2 life of 24 hours or more
  27. 27. Antipsychotic Medications• Preparations o Oral o IM o Depot - haloperidol and fluphenazine• Side Effects o Cardiovascular: orthostatic hypotension o Weight-gain: blocking histamine receptor o Endocrine and sexual: block dopamine, interfere with prolactin o Blood dyscrasias: agranulocytosis
  28. 28. Antipsychotic Medications• Conventional o Phenothiazines (Thorazine, Prolixin) o Thioxanthenes (Navane) o Dibenzoxazepines (Loxitane) o Haloperidol (Haldol)• Atypical or Novel o Clozapine (Clozaril) o Risperidone (Risperdal) o Olanzapine (Zyprexa) o Quetiapine (Seroquel) o Ziprasidone (Geodon) o Aripiprazole (Abilify) o Asenapine (Saphris) o Iloperidone (Fanapt) o Lurasidone (Latuda) o Paliperidone (Invega)
  29. 29. Antipsychotic Side Effects • 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
  30. 30. Medication-Related MovementDisorders: 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. 31. Movement Disorders: Acute(cont.)• Etiology (acute): o Related to dopamine in nigrostrial pathway that increases cholinergic activity• Treatment o Anticholinergic medication for dystonia, parkinsonism (Artane and Cogentin) o Akathisia does not usually respond to anticholinergic medication. Beta blockers have best success.
  32. 32. Movement Disorders:Chronic• Tardive Dyskinesia o 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 o Begin after 6 months, but also as antipsychotics are withdrawn o Irreversible - controversy
  33. 33. Movement Disorders:Chronic• Etiology o believed that chronic dopamine suppression in the EPS causes an overactivation of the system o increases in antipsychotic meds, suppresses• Treatment o prevention by using lowest possible dosage, minimize use of PRN, closely monitor individuals in high-risk groups o monitoring tools
  34. 34. Mood Stabilizers: AntimaniaLithium Carbonate• 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)
  35. 35. Lithium Carbonate• 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)
  36. 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. 37. Anticonvulsant Mood Stabilizers• Only carbamazepine is approved for mania.• Used when patients have not responded to lithium• Pharmacokinetics o Highly protein bound, metabolized by P450 system (potential drug-drug interaction)
  38. 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. 39. AntidepressantsTricyclic: Tertiary Amines• Amitriptyline (Elavil)• Clomipramine (Anafranil)• Doxepine (Sinequan)• Imipramine (Tofranil)• Trimipramine (Surmontil)
  40. 40. Antidepressants:Secondary Amines• Amoxapine (Asendin)• Desipramine (Norpramin)• Nortriptyline (Aventyl, Pamelor)• Protrypyline (Vivactil)
  41. 41. TCAs: Side Effects• Most common uncomfortable side effects o sedation o orthostatic hypotension o anticholinergic• Others o tremors, o restlessness, insomnia, confusion o pedal edema, headache, and seizures o blood dyscrasias o sexual dysfunction• Adverse o cardiotoxicity
  42. 42. Antidepressants• Most antidepressants block the re-uptake of a neurotransmitter of one or more of the bioamines: serotonin, norepinephrine, dopamine• SSRIs = Selective Serotonin Reuptake Inhibitors
  43. 43. Selective Serotonin Reuptake Inhibitors (SSRI)• Fluoxetine (Prozac)• Sertraline (Zoloft)• Paroxetine (Paxil)• Fluvoxamine (Luvox)• Citalopram (Celexa)• Escitalopram (Lexapro)
  44. 44. SSRI: Side Effects• Headache• Anxiety• Transient nausea• Vomiting• Diarrhea• Weight gain• Sexual dysfunction
  45. 45. SSRIs• Usually given in morning, unless sedation occurs• Higher doses, especially paroxetine, can produce sedation• Paroxetine associated with weight gain
  46. 46. Antidepressants:Monoamine Oxidase Inhibitors (MAOIs)• 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)
  47. 47. AntidepressantsOthers• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) o Venlafaxine (Effexor) o Desvenlafaxine (Pristiq) o Duloxetine (Cymbalta)• Mirtazapine (Remeron)• Trazodone (Desyrel)• Nefazodone (Serzone withdrawn due to rare liver failure)• Bupropion (Wellbutrin)
  48. 48. Antianxiety and Sedative-Hypnotic Medication• Used for anxiety, not long-term• Benzodiazepines o diazepam (Valium) o lorazepam (Ativan) o alprazolam (Xanax)• Nonbenzodiazepines o busipirone (BuSpar) o zolpidem (Ambien)• Side effects o Sedation and CNS depression o Tolerance and dependence (benzos) o Avoid benzos in children & elderly
  49. 49. Psychostimulants• This class of drugs, in low to moderate doses, generally have the following effects o Heightened mood (euphoria) o Increase vigilance and alertness o Reduce fatigue o Alertness• In order of prevalence of use o Caffeine o Nicotine o Amphetamines/Cocaine
  50. 50. Psychostimulants• Amphetamine, etc (cont.) o 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 o High doses generally interfere with performance  Also can lead to dysphoria, social withdrawal, and depression
  51. 51. Psychostimulants• Amphetamine, etc (cont.) o Extremely high doses or chronic use can lead to amphetamine- induced psychosis  Almost indistinguishable from paranoid schizophrenia o Simple movements are often repeated for long periods  E.g. continuous chewing, teeth grinding, tongue movement o Chronic use leads to marked tolerance and, in chronic users, the administration of very high doses
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