Psychopharmacology and Other Biologic Treatments

Chapter 8

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

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.

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

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

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.

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

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
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

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 8.1, 8.1). Adverse effects: Unwanted effects with serious physiologic consequences.

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 rug begins to take effect and dose that would be considered toxic. Low therapeutic index - low range

Absorption
From site of administration into the plasma Oral - (tablet and liquid) (Table 8-3)
Most Convenient Most variable (food and antacids)
First pass effect Decreased Gastric Motility (age, disease, medication)

IM - Short-and long acting IV - Rarely used

Pharmacokinetics: How the Body Acts on the Drug

Absorption
Distribution Metabolism Elimination

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

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)

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.

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 metablism is carried out in the liver.

Cytochrome P450
Many process 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 P4502D6

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 in the liver
excreted in the bile and delivered to the intestine may be reabsorbed in intestine and re-circulate (up to 20%)

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 determined by half life reach steady state in about five times the elimination half-life

Pharmacokinetics: Cultural Considerations

9% of whites - genetically defective P-4502D6 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

Phases of Drug Treatment

Initiation Stabilization Maintenance Discontinuation

Psychiatric Medications
Antipsychotic Medications Movement Disorders Medication Mood Stabilizers
Antimania Antidepressants

Antianxiety and Sedative-Hypnotic Stimulants

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

Metabolism: liver

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

Metabolism: liver Excretion: slow

accumulates in fatty tissues 1/2 life of 24 hours or more

Antipsychotic Medications (cont..)

Preparations
Oral IM Depot - haloperidol and fluphenazine

Side Effects
Cardiovascular - orthostatic Hypertension Weight-gain: blocking histamine receptor Endocrine and sexual: block dopamine, interfere with prolactin Blood Dyscrasias - agranulocytosis

Antipsychotic Medications
Conventional

Phenothiazines (Thorazine, Prolixin) Thioxanthenes (Navane) Dibenzoxazepines (Loxitane) Haloperidol (Haldol)

Clozapine (Clozaril) Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon)

Atypical or Novel

Antipsychotic Side Effects

Cardiovasular Anticholinergic Weight Gain Endocrine and Side Effects Blood Disorders Miscellaneous

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

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.

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

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

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)

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.

Mood Stabilizers: Antimania Anticonvulsants

Valporate and derivatives (divalproex sodium - Depakote) Carbamazapine (Tegretol) Gabapentin (Neurontin) (least side effects) Lamotrigine (Lamictal) Topiramate (Topamax)

Anticonvulsant Mood Stabilizers

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)

Carbamazepine Side Effects

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

Antidepressants
Table 8.11,12

Tricyclic: Tertiary Amines

Amitriptyline (Elavil) Clomipramine (Anafranil) Doxepine (Sinequan) Imipramine (Tofranil) Trimipramine (Surmontil)

Antidepressants Secondary Amines

Amoxapine (Asendin) Desipramine (Norpramin) Nortriptyline (Aventyl, Pamelor) Protrypyline (Vivactil)

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

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

Serotonin Selective Reuptake Inhibitors SSRI

Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Fluvoxamine (Luvox)

Side Effects -- SSRIs

Headache Anxiety Transient nausea Vomiting Diarrhea Weight gain Sexual dysfunction

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

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

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 (Table 18.3)

Antianxiety and SedativeHypnotic Medication

Used for anxiety, not long-term Benzodiazepines (Table 8.14)
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

Stimulants
Amphetamines Used in narcolepsy, ADHD, and obesity

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

Other Biological Treatment

Light Therapy (Phototherapy)
Reset circadian rhythms Used for SAD

Nutritional Therapies