Clinical Pharmacology

1
Clinical Pharmacology

• Jeff Baker, Ph.D.
• Associate Professor Chief Psychologist
• Adopted from Kaplan and Sadock (2003)
• This is a limited lecture designed to introduce
  you to clinical psychopharmacology to assist in
  the management of psychological and behavioral
  problems

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Psychopharmacology

• Drug an exogenous chemical that effects one or
  more biological processes.

3
Clinical Pharmacology

• Pharmacokinetics (quantitative)
• Movement of drugs through the body
• Pharmacodynamics
• Study of qualitative effects of drugs
• Actions
• Agonism facilitates normal functioning of
  synapse
• Antagonism hinder

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Effective Pharmacological Treatments

• Efficacy
• How good is the drug in diminishing the
  manifestations of the disorder
• Percent of patients responding to a medication in
  a controlled study
• Double-blind placebo controlled
• Relative efficacy
• One treatment vs. another

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Effective Pharmacological Treatments

• Effectiveness
• How in the real world is this treatment effective
• Ease of administration
• Side effects
• Patient compliance
• Usefulness with real patients

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Effective Pharmacological Treatments

• Clinical Response
• Pharmacologic effect
• Placebo response
• Spontaneous remission

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Prescribing

• Psychologists prescribe in New Mexico and
  Louisiana, psychiatrists prescribe in Texas
• Physician Assistants prescribe under the
  direction of a physician in Texas and most
  states.
• Family practitioners prescribe 80 of
  psychotropic medications.

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Goals of Pharmacotherapy

• Acute Treatment
• Used to alleviate the symptoms of an actively
  occurring disorder
• Continuation Treatment
• Goal To prevent a relapse into the same episode
  for which treatment began
• Maintenance Treatment
• Goal To prevent recurrences by the ongoing
  maintenance use of a medication

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Compliance

• Defined as Adherence to the recommended
  treatment plan of a health care professional

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Strategies to Increase Compliance

• Encourage active patient participation
• Adequate communication
• Empathetic approach/Trusting relationship
• Family and community involvement and support
• Emphasis on positive effects of medication
• Use the most simplified drug regimen

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Various Reasons for Noncompliance

• Stigma of disorder
• Denial of illness
• Disruption of cognitive process
• Side effects of medication
• Slow onset of beneficial effects
• Cost

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Clinical Characteristics to Suggest
Pharmacological Treatment

• Psychiatric Symptoms
• Sleep or Appetite Disturbance
• Fatigue
• Panic Attacks
• Ritualistic Behavior
• Cognitive Symptoms
• Psychosis such as Delusions or Hallucinations

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Clinical Characteristics to Suggest Psychiatric
Referral

• Prominent Physical Symptoms or Significant
  Medical Disorder Resulting in Significant
  Behavioral Changes
• Significant Suicidality
• Family History of Major Psychiatric Disorder
• Marked Mood Lability
• Intense Rage or Depressive Symptoms
• Nonresponse to Psychotherapy

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Brain Neurotransmitters

• Amines
• Serotonin
• Dopamine
• Norepinephrine
• Epinephrine
• Acetylcholine
• Amino Acids
• GABA
• Glycine
• Glutamic Acid

• Neuropeptides
• CRH, CRF
• TRH, LHRH
• GH, somatostatin
• Opioid Peptides
• Dynorphin
• ß-endorphin
• Gut hormones
• CCK, secretin
• Substance P

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Neurotransmission

• The receptor sites are specifically structured to
  bind with neurotransmitters.
• Soon after the neurotransmitter is released, it
  must quickly be inactivated in order for the
  postsynaptic neuron to be able to receive new
  messages.

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Most common means of inactivation

• Enzymatic degradation
• Reuptake
• Neurotransmitter is transported back into the
  presynaptic neuron where it is repackaged into
  the vesicles.

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Drug Development Treatment for Psychiatric Issues

• 1845 Hashish
• 1875 Cocaine
• 1892 Morphine, alcohol, ether
• 1903 Barbiturates
• 1927 Insulin Shock
• 1936 Frontal Lobotomies
• 1938 ECT
• 1949 Lithium Introduced
• 1950 Chlorpromazine (Thorazine)
• 1955 Tricyclics MAOs
• 1990s SSRIs SNRIs
• 2000 ER CR
• 2003 Cymbalta, Fluvoxamine (Luvox)

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Classes of Psychotropics

• Antipsychotics
• Antidepressants
• Mood Stabilizers
• Anxiolytics
• Anti-Abuse

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Antipsychotics

• Antipsychotics are given to control symptoms of
  schizophrenia and other kinds of psychosis.
  Patients need to remember that medications are
  helping in illnesses like diabetes and asthma.
  People with schizophrenia usually need to take
  medication even when they feel perfectly well.
  Antipsychotics are needed to maintain health with
  this population.

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Schizophrenia

• 1 get it approximately 10 million in the world
• Not sure as to why it occurs
• DA (dopamine) theory is best guess

• Positive effects
• delusions
• hallucinations
• inappropriate affect
• cognitive disorders
• Negative effects
• flattened affect
• social withdrawal
• catatonia

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Schizophrenia Drug Treatment

• Dopamine Receptor Antagonists
• Chlorpromazine (Thorazine)
• Haloperidol (Haldol)
• Dopamine and Serotonin Receptor Antagonists
• Clozapine
• Works on - and effects
• Serious side effect - 1-2 develop agranulocytosis

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Dopamine Receptor Antagonist Side Effects

• Vegetative disorders
• decrease in blood pressure, acceleration of pulse
  rate, modification of myocardial activity,
  sweating, dry mouth, constipation, impotence,
  ejaculation disorders, anorgasmia
• Extrapyramidal disorders
• Early dyskinesia
• Spasms of tongue, visual spasms, grimacing,
  gyratory and rotatory movements of the upper
  extremities

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Dopamine Receptor Antagonist Side Effects

• Extrapyramidal disorders cont.
• Neuroleptic Parkinsonoid
• akinesia (restriction of motor movement),
  hypomimia (loss of facial expression), rigor and
  tremor (in muscles)
• Akathisia
• Restlessness, urge to move continuously
• Tardive dyskinesia
• Involuntary chewing, smacking of lips, swallowing
  and rolling movements of the tongue
• Gyratory and flailing movements of the extremities

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Typical vs Atypical

• Typical (also called conventional) antipsychotics
  act primarily at dopamine receptors. Atypical
  antipsychotics are active on other receptors as
  well as dopamine, and are associated with fewer
  or no extrapyramidal side-effects, an effect on
  negative symptoms of schizophrenia.

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Antipsychotics (Neuroleptics)

• Typical Neuroleptics
• High potency (Haldol)
• Medium potency (Stelazine)
• Low potency (Thorazine)
• Depot/Decanoate (Prolixin-D or Haldol-D/LA)
• Atypical Neuroleptics
• Clozaril (Clozapine)
• Risperidol Pisperidone)
• Zyprexa (Olanzapine)
• Seroquel (Quetiapine)
• Geodon (Ziprasidone)

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Neuroleptics Indications

• Schizophrenic disorders
• Mania
• Acute Psychotic reactions
• Mood d/o with psychotic symptoms
• Delirium/dementia

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Depression Who Needs Meds?

• Depressed mood with neurovegetative symptoms 4
  weeks
• Previous episodes
• Severe, disabling, or presence of Sx Increase
• Comorbid anxiety d/o
• Psychotic symptoms
• Family history of suicide

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Depression

• During any 1 year period, 19 million American
  adults suffer from a depressive illness.
• Cost an estimated 44 billion a year.
• Nearly two-thirds of depressed people do not get
  appropriate treatment.
• 80 of those with depression can feel better with
  proper treatment.
• Antidepressants used
• Neurotransmitters involved NE, DA,
  5-Hydroxytryptamine

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How Effective are Antidepressant Medications

• Antidepressants can be very effective. They are
  generally non-addictive and do not lose
  effectiveness with prolonged use.  Three people
  out of four respond to antidepressants. Of those
  that don't, about half will respond to a
  different medicine.
• How long does it take for antidepressants to
  work?Most people with depression will respond to
  treatment after two weeks but in some people, it
  can take up to four weeks. All drugs work at the
  same speed.

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How long will the patient need treatment?

• Studies have shown that continuing
  antidepressants for at least six months after a
  first episode reduces the risk of further
  episodes. However, long-term studies of up to 10
  years have shown that half to three-quarters of
  all those who had suffered a depressive disorder
  suffered a relapse. Long term treatment of up to
  five years may be necessary for some people.

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How do antidepressants work?

• Depression is thought to be caused by a reduction
  in the level of the effectiveness of
  neurotransmitters. These affect mood by
  stimulating brain cells. Antidepressants increase
  the level of certain important neurotransmitters.

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Antidepressant Classes

• TCA (Elavil)
• MAOI (Nardil)
• Monoamine oxidase inhibitors
• Selective Reuptake Inhibitors
• SSRI (Prozac)
• SDRI (Wellbutrin)
• SNRI (Effexor)
• Serotonin Modulators
• Desyrel
• Remeron
• Serotonin Norepinehrine Reuptake Inhibitor
• Cymbalta (2004)

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TCA-Common Side Effects

• Weight gain
• Anticholinergic
• Dry mouth, cavities
• Blurred vision
• constipation
• Urinary retention
• Tachycardia
• Sedation, fatigue
• Tremor, dizziness
• Impotence

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TCA-Efficacy

• Depression
• Anxiety
• Panic
• OCD (Anafranil Only)
• PTSD
• Bulimia
• Chronic Pain
• Headaches

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Depression SSRIs

• Other treatments
• Biploar I disorder, dysthymic disorder, eating
  disorders, panic disorders, obsessive-compulsive,
  and borderline personality disorder.
• Prozac has been used for Anxiety, panic attacks,
  phobias, obsessive compulsivenss, anorexia and
  bulimia, seasonal affective disorder, obesity,
  PMS, chronic pain.

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Depression Commonly Used SSRIs

• Side Effects
• mostly involved the central nervous system and
  the gastrointestinal system
• sexual dysfunction or allergic reactions
• some adverse symptoms can disappear or lessen
  with time.
• Fluoxetine (Prozac, Lilly) (Selective for 5-HT)
• Paroxetine (Paxil)
• Sertraline (Zoloft)
• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluvoxamine (Luvox)
• Duloxetene (Cymbalta)

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Typical Actions

• PROZAC FLUOXETINE The first SSRI to hit the
  market, it stays in the body longer than other
  SSRIs.
• LEXAPRO ESCITALOPRAM One of the newer SSRIs.
  Patients may see benefits in about four weeks.
• LUVOX FLUVOXAMINEApproved for
  obsessive-compulsive disorder also used for
  depression.
• CELEXA CITALOPRAM Similar to Lexapro. Some
  find these newer drugs have fewer side effects.
• ZOLOFT SERTRALINE Used for panic disorders and
  posttraumatic stress, as well as depression.
• PAXIL PAROXETINE Available in two forms,
  regular Paxil and Paxil CR, which is a
  controlled-release drug.
• Updated November 20, 2005

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SSRI-Efficacy

• Depression
• Panic
• OCD
• PTSD
• Social Phobia
• Bulimia
• PMS, BDD
• Chronic Pain
• Kids Meds

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SSRI-Common Side Effects

• Insomnia, headache
• Nausea, anorexia
• Diarrhea
• Constipation (Paxil)
• Sexual dysfunction
• Decreased libido
• Anorgasmia
• Nervousness, tremor
• Myoclonus
• Teeth-clenching

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FDA Warning 3/22/2004

• The Food and Drug Administration (FDA) requests a
  Warning Statement in the labeling for certain
  antidepressants to encourage close observation of
  adult and pediatric patients treated with these
  agents for worsening depression or the emergence
  of suicidality.  The drugs that are the focus of
  this new Warning Statement include Prozac
  (fluoxetine) Zoloft (sertraline) Paxil
  (paroxetine) Luvox (fluvoxamine) Celexa
  (citalopram) Lexapro (escitalopram) Wellbutrin
  (bupropion) Effexor (venlafaxine) Serzone
  (nefazodone) and Remeron (mirtazapine). 

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Best Practice

• Whether medication is the best treatment option
  depends on how severe the person's depression is,
  their history of illness, their age
  (psychological treatments are usually the first
  choice for children and adolescents), and their
  personal preferences. Most people do best with a
  combination of medication and therapy.

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Postpartum Depression

• More women become depressed while their children
  are babies than at any other time in life (Clin
  Pharmacokinet 1994 Oct27(4)270-89) (Physician
  Assistant, 2003 Baker, Mancuso, and Lyon). With
  the surging tide of postpartum hormones, mounting
  sleep deprivation, persistent noise, shifting
  body image, the change of life structure, and the
  loss of control of one's own time, this
  depression is not surprising -- even with a
  brand-new bundle of joy in the home.

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Wellbutrin-Tolerability

• Excitation effects
• Insomnia
• Anxiety
• Tremor
• Menstrual irregularity
• Seizures linked to
• Single dose 150 mg.
• Daily dose 450 mg.
• Bulimia or eating disorders

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Wellbutrin- Special Factors

• Pro
• No sexual dysfunction
• No weight gain
• Smoking Cessation
• Preference in Bipolar depression?
• Con
• Poor anxiolytic not anti-panic
• Can worsen psychosis
• Seizure issue

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Effexor-Tolerability

• Nausea (
• Agitation, insomnia
• Anticholinergic effects
• Dry mouth, sweating
• Ur. Retention
• Constipation
• HTN linked to
• Doses 225 mg/day
• Dose changes

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Effexor- Special Factors

• Pro
• Energizing
• Rapid onset
• Severe depression
• Anti-panic?
• No weight gain
• Con
• Side Effexor
• Hypertension issue

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Serzone- Special Factors

• Pro
• Sleep enhancing
• No sexual dysfunction
• Anxiolytic anti-panic
• Con
• Taken off the market Nov 2003
• Important dangerous drug interactions

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Remeron-Special Factors

• Pro
• Sleep enhancing at 15 mg.
• limited sexual dysfunction
• Anti-nausea
• IBS improved?
• Chronic pain
• Anxiolytic anti-panic
• Con
• Weight gain

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SSRI Other Indications

• Anxiety/Panic
• Bulimia Nervosa
• PMDD
• OCD-Spectrum
• Impulse Control

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Eating Disorders

• Bulimia Nervosa
• SSRI
• All antidepressants
• Anorexia Nervosa
• SSRI

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Impulse Control SSRI-Responsive?

• Kleptomania
• Trichotillomania
• Compulsive D/O
• Paraphilias
• Pyromania
• Gambling

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Chronic Pain States

• TCA
• Toxicity/Intolerance
• Alcohol synergism
• Alternatives
• Remeron
• SSRI
• Potential Advantages
• Safe Well-tolerated
• Preserve sleep architecture

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Insomnia

• Trazodone
• Males priapism
• Safe, not abusable, cheap
• Remeron
• 15 mg dose
• Safe
• TCA
• Low dose
• Toxicity issues

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Anxiety

• That first date, an important job interview, the
  big speech, a critical test . . . times when most
  people feel a little anxious. Sweaty palms and
  "butterflies" in the stomach during challenging
  situations are normal. Anxiety disorders,
  however, are medical illnesses that differ
  dramatically from normal feelings of nervousness.
  The symptoms of these disorders often occur
  without warning and make the simplest of lifes
  routines sources of nearly unbearable discomfort.

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Anxiety Disorders Differentiation

• Disorder Core Fear Common Triggers
• OCD Obsession Obsession or
  Tension
• Panic Disorder Dying Crowds, bridges,
  etc.
• Agoraphobia Being Trapped Open spaces,
  crowds
• GAD Everything Anything
  stressful
• Social Phobia Public Public speaking,
• Embarrassment Performance anxiety
• PTSD Recurrence of Trauma-related
  places
• Traumatic Event or experiences

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Anxiolytics

• Antidepressants
• Benzodiazepines
• Buspirone
• Antihistamines
• over-rated
• tolerance develops fast
• Neuroleptics
• bad idea

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Anxiety Pharmacotherapy

• Disorder Acute/Situational Chronic
• GAD Buspirone or BZD AD
• Panic D/O BZD AD AD
• Social Phobia BZD or b-blocker AD
• OCD SSRI same
• PTSD BZD AD
• BZDbenzodiazepine ADantidepressant
• GADgeneralized anxiety disorder
• OCDobsessive-compulsive disorder
• PTSDpost-traumatic stress disorder

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Benzodiazepines

• Short-term use or situational anxiety
• Tolerability
• Cognitive effects
• Enhanced effects
• gender
• age
• alcohol

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Common Benzos Dosing
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Benzodiazepine Side Effects

• Behavioral Disinhibition
• hostility, aggressiveness, rage reactions
• paroxysmal excitement, irritability
• Psychomotor Impairment
• synergistic effects with ETOH
• Cognitive Impairment
• impaired visuospatial ability sustained
  attention tasks
• Withdrawal Phenomena
• flu-like symptoms (mild), psychotic s(x)s or
  seizures (severe

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Mood Stabilizers

• Used for Bipolar or Manic-Depressive to
  regulate mood
• Side Effects
• constipation, nausea, dry mouth, headache,
  fatigue
• occasionally hyperactivity, Akathisia, and
  Parkinsonism
• Lithium (naturally occurring mineral)
• Carbamazepine (Tegretol)
• Valporic Acid (anticonvulsant)

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Mood Stabilizers

• Mood Stabilizers are commonly listed as
  Anti-Convulsants because of their calming effect
  and action dealing with seizures. The have lately
  become very effective in treating such things as
  Bipolar Disorder, Depression, or Anxeity
  Disorders.

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Medication-Induced Movement Disorders

• Anti-parkinsonsism, anticonvulsant,
  anticholinergic
• Include beta-blockers, L-dopa, and others
• Side Effects
• hypotensions, nausea, vomiting, etc
• abuse potential, depression, anxiety, psychosis
• Atenolol (Tenormin),Metoprolol (Lopressor),
  Nadolol (Corgard), Propranolol (Inderal)

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Miscellaneous

• Alcohol withdrawal
• Disulfiram (antabuse)
• Side effects
• if alcohol used in conjunction - possible
  respiratory depression and even death
• w/o alcohol fatigue, impotence, mental changes,
  hepatic damage

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Anti-Abuse Medications

• Anti-Alcohol
• Revia
• Antabuse
• Buprenex
• Catapres
• Narcan
• Anti-Narcotic
• Methadone
• LAAM
• Buprenorphine
• Nicotine
• Habitrol
• Nicotrol
• Zofran
• Orlaam
• Nircorette Gum

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Miscellaneous

• Opioid withdrawal
• Methadone and Clonodine
• Side effects
• tolerance, psychological and physical dependence,
  dizziness, depression, euphoria, agitation

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Miscellaneous

• Alzheimer
• Aerocept
• Still being studied for AD, early results are
  hopeful.
• Memantine
• Approved for release Jan 2004, first med approved
  for mod to severe Alzheimers disease. Early
  reports suggest help with symptoms AND slows
  neruodegenerative process.
• Tacrine
• Studies are still being reviewed Pfizer claims
  no harm and some benefits have been documented.
• Side effects
• elevations in hepatic transaminase levels (can
  cause liver damage), nausea, vomiting, diarrhea

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Miscellaneous

• Autism
• Fenfluramine (Not used very often)
• Side Effects
• drowsiness, diarrhoea, dry mouth, dizziness,
  confusion, headache, fatigue, agitation

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Miscellaneous

• Sexual dysfunction
• Yohimbine
• Commonly used but major side effects Elevated
  blood pressure and heart rate, nausea, vomiting,
  sweating, urinary frequency Recent 2003 Studies
  show no effect on sexual performance.
• Sildenafil Citrate (Viagra) (2001)
• Originally developed to tx cardiovascular
  disease. Side Effects Combination with
  nitroglycerin might cause death (severe
  hypotension). Blurred vision, blue vision, temp
  color blindness, breast enlargement, priaprism.
  1 study showed 40 of men with heart disease
  using Viagra with ED had a serious reaction.
• Vardenafil (Levitra) (2003)
• Newly released by Bayer/SmithGlaxoKline for the
  tx of ED (similar side effect), similar
  effectiveness (80).

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Medication Increases for Children

• Medco released a major
  study of medication spending trends.
• According to the study, behavioral meds have now
  become the primary source of medication spending
  for kids "In 2003, spending on behavioral
  medications to treat children overtook both the
  antibiotic and asthma categories, which are
  traditionally high-use categories in pediatric
  medicine.... The number of children on
  behavioral medications has jumped more than 20
  percent between 2000 and 2003...
• Among the largest increases were medications
  primarily used to treat attention
  deficit/hyperactivity disorder (ADHD) -- where
  spending increased by 183 percent for children
  overall, and by 369 percent increase for children
  under age 5. Utilization in preschoolers was up
  49 percent from 2000 to 2003.
• Spending on antidepressants for children grew 25
  percent, while use of these drugs rose 27 percent
  between 2000 and 2003. A review of 2004 data
  shows that of the children on at least one
  prescription medication in the first quarter of
  this year, the number of children using
  antidepressants increased by 15 percent over the
  first three months of 2003.

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ADHD ADD
Perhaps ADHD kids are starting here and the drug
pushes them over the edge.

• In .1 to 6 of school population
• Treatment
• Ritalin (methylphenidate)
• Adderall (Dexedrine Amphetamine)
• from the amphetamine family
• No clinical proof one is better than the other
  (Dulcan, 1986)

Locomotive Activity
Dose