Transcript Psychopharmacology and Other Biologic Treatments

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.
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’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 bloodbrain 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
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•
•
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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.
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)
Antidepressants
Table 9-9
Tricyclic: Tertiary Amines
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•
•
•
•
Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepine (Sinequan)
Imipramine (Tofranil)
Trimipramine (Surmontil)
Antidepressants
Secondary Amines
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•
•
•
Amoxapine (Asendin)
Desipramine (Norpramin)
Nortriptyline (Aventyl, Pamelor)
Protrypyline (Vivactil)
Side Effects – TCAs
•
Most common uncomfortable side effects:
– Sedation
– Orthostatic hypotension
– Anticholinergic
•
Others
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–
–
–
–
•
Tremors
Restlessness, insomnia, confusion
Pedal edema, headache, and seizures
Blood dyscrasias
Sexual dysfunction
Adverse
– Cardiotoxicity
Antidepressants
• Most antidepressants block the reuptake of a neurotransmitter of one or
more of the bioamines: serotonin,
norepinephrine, dopamine.
• SSRIs - selective to the serotonin
Serotonin Selective
Reuptake Inhibitors
(SSRI)
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–
–
–
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Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox)
Citalopram (Celexa)
Escitalopram (Lexapro)
Side Effects – SSRIs
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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
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•
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•
•
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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 SedativeHypnotic 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