1. Psychopharmacology & Other Biologic Treatments Chapter 9

2. Psychopharmacology Subspecialty of pharmacology that includes medications affecting the brain and behavior used to treat mental disorders including: – Antipsychotics – Mood stabilizers – Antidepressants – Antianxiety medications – Stimulants Provides a basis for understanding specific biologic treatments of psychiatric disorders

3. 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.

4. Receptors Types of Action – Agonist: same biologic actin – 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

5. Ion Channels Drugs can block or open the ion channels. Example: Benzodiazepine drugs facilitate GABA in opening the chloride ion channel.

6. 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.

7. Transport neurotransmitters across cell membranes Medications may block or inhibit this transport. Example: antidepressants Carrier Proteins

8. Efficacy and Potency Efficacy - Ability of a drug to produce a response as a result of the receptor’s (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 being treatment refractory

9. Target Symptoms and Side Effects Target symptoms: – Specific symptoms for each class of medication – No drug attacks such a target symptom Side effects - Responses not related to target symptoms (Table 9.1, 9.2). Adverse effects: Unwanted effects with serious physiologic consequences

10. Drug Toxicity Toxicity: Point at which concentrations of the drug in the blood stream become harmful or poisonous to the body Therapeutic index: Ratio of the maximum nontoxic dose to the minimum effective dose 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

11. Absorption From site of administration into the plasma Oral - (tablet and liquid) (Table 9-3) – Most convenient – Most variable (food and antacids) First pass effect Decreased gastric motility (age, disease, medication) IM - Short- and long-acting IV - Rarely used

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

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

14. 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: – 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)

15. Crossing the Blood Brain Barrier 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.

16. Metabolism (Biotransformation) 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 metablism is carried out in the liver.

17. Cytochrome P450 Many processes are carried out by enzyme class Cytochrome. – P-450 high affinity for fat-soluble drugs – Involved in metabolism of most psychiatric medications – Example: SSRIs inhibitors of the subfamily P-450 2D6 Pharmacogenomics (pharmacology and genetic knowledge) – Understanding an individual’s genetic makeup – Individualizing medications

18. Excretion 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 in the liver – Excreted in the bile and delivered to the intestine – May be reabsorbed in intestine and “re-circulate” (up to 20%)

19. Dosing and Steady State 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 is determined by half life. – Reach steady state in about five times the elimination half-life

20. Individual Variation in Drug Effects Age Ethnicity Polypharmacy

21. Age Alteration in gastric absorption Renal function altered in very young and old Liver metabolism decreases with age

22. Pharmacokinetics: Cultural Considerations 9% of whites - genetically defective P-450 2D6 Asian descent – Metabolize ethanol to produce higher concentrations of acetaldehyde (flushing, palpitations) – Require 1/2 to 1/3 dose antipsychotics and more severe side effects Cardiovascular effects of propranolol – Asian descent - more sensitive – African descent - less sensitive

23. Phases of Drug Treatment Initiation Stabilization Maintenance Discontinuation

24. Psychiatric Medications Antipsychotic Medications Movement Disorders Medication Mood Stabilizers – Antimania – Antidepressants Antianxiety and Sedative-hypnotic Stimulants

25. Antipsychotic Medications Target symptoms: psychosis Types: typical and atypical Absorption: variable – Clinical effects seen 30-60 min – IM less variable (avoid 1 st pass) – When immobile, less absorption Metabolism: liver Excretion: slow – Accumulates in fatty tissues – 1/2 life of 24 hours or more

26. Antipsychotic Medications (cont.) Preparations – Oral – IM – Depot - haloperidol and fluphenazine – Long-acting injectable – Risperdal Consta Side Effects – Cardiovascular - orthostatic hypertension – Weight-gain: blocking histamine receptor – Endocrine and sexual: block dopamine, interfere with prolactin – Blood dyscrasias - agranulocytosis

27. Antipsychotic Medications Typical – Phenothiazines (Thorazine, Prolixin) – Thioxanthenes (Navane) – Dibenzoxazepines (Loxitane) – Haloperidol (Haldol) Atypical – Clozapine (Clozaril) – Risperidone (Risperdal) – Olanzapine (Zyprexa) – Quetiapine (Seroquel) – Ziprasidone (Geodon) – Aripiprazole (Abilify)

28. Antipsychotic Side Effects Cardiovasular Anticholinergic Weight Gain Endocrine and Side Effects Blood Disorders Miscellaneous

29. 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), tremor, masklike face, loss of spontaneous movements Akathisia: inability to sit still, restlessness

30. Movement Disorders: Acute (cont.) 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.

31. Movement Disorders: Chronic 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. Symptoms – Begin after 6 months, but also as antipsychotics are withdrawn – Irreversible - controversy

32. Movement Disorders: Chronic 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

33. Mood Stabilizers: Antimania Lithium 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)

34. 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 and cold intolerance. Avoid during pregnancy.

35. Mood Stabilizers: Antimania Anticonvulsants Valporate and derivatives (divalproex sodium - Depakote) Carbamazapine (Tegretol) Gabapentin (Neurontin) (little support) Lamotrigine (Lamictal) Topiramate (Topamax)

36. Anticonvulsant Mood Stabilizers Used when patients have not responded to lithium Pharmacokinetics – Highly protein bound, metabolized by P450 system (potential drug-drug interaction)

37. Kindling Repeated electrical stimulation of selected brain regions (e.g., amygdala) Stimulation may be subthreshold and work cumulatively to produce a mood swing. After a while, stimulation of these areas can be brought about by external events, memories, or spontaneously.

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

39. Antidepressants Table 9-9 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. Side Effects – TCAs 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

42. Antidepressants Most antidepressants block the re- uptake of a neurotransmitter of one or more of the bioamines: serotonin, norepinephrine, dopamine. SSRIs - selective to the serotonin

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

44. Side Effects – SSRIs Headache Anxiety Transient nausea Vomiting Diarrhea Weight gain Sexual dysfunction

45. SSRIs Usually given in morning, unless sedation occurs Higher doses, especially fluoxetine, can produce sedation. Venlafaxine (Effexor), only mildly sedating Paroxetine associated with weight gain

46. Antidepressants Others Mirtazapine (Remeron) Maprotiline (Ludiomil) Trazodone (Desyrel) Nefazodone (Serzone) Bupropion (Wellbutrin) Venlafaxine (Effexor)

47. Antidepressants Monoamine Oxidase Inhibitors (MAOIs) Action: Inhibits 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

48. Antianxiety and Sedative- Hypnotic Medication Used for anxiety, not long-term Benzodiazepines (Table 9.11) – Diazepam (Valium) – Lorazepam (Ativan) – Alprazolam (Xanax) Nonbenzodiazepines – Busipirone (BuSpar) – Zolpidem (Ambien) Side effects – Sedation and CNS depression – Tolerance and dependence (Benzos) – Avoid Benzo in elderly

49. Stimulants Amphetamines Used in narcolepsy, ADHD and obesity

50. Electroconvulsive Therapy Initiate generalized seizures by an electrical current Short-acting anesthetic and muscle relaxant given Repeat procedure 2-3 times per week. Produces rapid relief of depressive symptoms Side effects: hypo- or hypertension, bradycardia or tachycardia, and minor arrhythmias immediately after

51. Other Biological Treatment Light Therapy (Phototherapy) – Reset circadian rhythms – Used for SAD Nutritional Therapies