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 P-

4502D6

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• Excretion: slow

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

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)

• Atypical or Novel– Clozapine (Clozaril)– Risperidone (Risperdal)– Olanzapine (Zyprexa)– Quetiapine (Seroquel)– Ziprasidone (Geodon)

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)

– Highly protein bound– Metabolized by the cytochrome P-540 system– Side effects: dizziness, drowsiness, tremor, visual disturbance, nausea, &

vomiting

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)

CarbamazepineSide 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)

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)

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 Sedative-Hypnotic 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