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Psychopharmacology & Other Biologic Treatments
Chapter 9
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.
• Transport neurotransmitters across cell membranes
• Medications may block or inhibit this transport.
• Example: antidepressants
Carrier Proteins
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
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
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
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
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(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.
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-4502D6
• Pharmacogenomics (pharmacology and genetic knowledge)
– Understanding an individual’s genetic makeup
– Individualizing medications
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%)
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
Individual Variation in Drug Effects
• Age
• Ethnicity
• Polypharmacy
Age
• Alteration in gastric absorption
• Renal function altered in very young and old
• Liver metabolism decreases with age
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: typical and 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
– 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
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)
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), 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 and cold intolerance.
• Avoid during pregnancy.
Mood Stabilizers: Antimania Anticonvulsants
• Valporate and derivatives (divalproex sodium - Depakote)
• Carbamazapine (Tegretol)
• Gabapentin (Neurontin) (little support)
• Lamotrigine (Lamictal)
• Topiramate (Topamax)
Anticonvulsant Mood Stabilizers
• Used when patients have not responded to lithium
• Pharmacokinetics– Highly protein bound, metabolized by P450
system (potential drug-drug interaction)
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.
CarbamazepineSide Effects
• Dizziness, drowsiness, tremor, visual disturbances, nausea and vomiting
• Minimized by treating in low doses
• Given with food
• Weight gain
• Alopecia (hair loss)
Antidepressants Table 9-9
Tricyclic: Tertiary Amines
• Amitriptyline (Elavil)
• Clomipramine (Anafranil)
• Doxepine (Sinequan)
• Imipramine (Tofranil)
• Trimipramine (Surmontil)
AntidepressantsSecondary 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)– Citalopram (Celexa)– Escitalopram (Lexapro)
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: 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
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
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