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