Nursing Pharmacology Chapter 16: Antipsychotic Medications

Schizophrenia

• Clinical Manifestations

  • Group of illnesses that are etiologically heterogenous

  • Characteristics involve perturbations affecting:

    • Language

    • Perception

    • Thinking

    • Volition

    • Affect

    • Social activity

  • Syndrome overview:

    • Typically begins in late adolescence

    • Insidious onset

    • Poor outcome

    • Social withdrawal /perceptual distortions lead to chronic delusions/hallucinations

  • Positive Symptoms:

    • Conceptual disorganization

    • Delusions

    • Hallucinations

  • Negative Symptoms exhibit a frequency of about 33% and are associated with poor long-term outcome; poor drug responsiveness.

    • Loss of function

    • anhedonia

    • Decreased emotional expression

    • Impaired concentration

    • Diminished socialization

  • Four main syndromes subtypes:

    • Catatonic type with clinical presentations of:

      • Major changes in motor activity

      • Negativism

    • Paranoid-type:  clinical presentations:

      • Significant preoccupation with a specific delusional system

    • Disorganized-type -- clinical presentations:

      • Disorganized speech/behavior associated with superficial or silly affect.

    • Residual type disease -- clinical presentations:

      • Negative symptomatology in the absence of:

        • Illusions

        • Hallucinations

        • Motor disturbance

• Prognosis:

  • Dependent on patient responds to medication -- not on symptom severity

  • 10% of schizophrenic patients do commit suicide

  • Frequency: lifetime prevalence -- 1-1.5%

•  Societal Costs:

  • 300,000 acute schizophrenic episodes/year

  • 25% of all U.S. hospital beds

  • 20% of all Social Security days

  • Total cost: approximately $33 billion.

• Epidemiology:

  • Three principal risk factors--

    • Genetic:

      • Schizophrenia occurs in about 6.6% of all first-degree relatives of an affected proband (definition proband -- a patient who is the initial family member to come under study)

      • If both parents affected: offspring risk = 40%

      • Concordance rate -- monozygotic twins = 50%; dizygotic twins = 10%

    • Early developmental damage-- implicated:

      • Rh factor incompatibility

      • Influenza second trimester exposure

      • Prenatal nutritional deficiencies

      • Analysis of monozygotic discordance for schizophrenia noting neuroanatomic: morphological differences between the two suggest a "two strike" model involving genetic susceptibility +an environmental insult.

    • Winter births

• Proposed Pathophysiology:

  • Localized hypoxia during critical stages of neuronal maturation and migration

  • Structural/functional abnormalities (neuroimaging & postmortem studies)

    • Lateral and third ventricle enlargement: associated sulcal enlargement; cortical atrophy

      "Loss of brain volume associated with schizophrenia is clearly shown by magnetic resonance imaging (MRI) scans comparing the size of ventricles (butterfly shaped, fluid-filled spaces in the midbrain) of identical twins, one of whom has schizophrenia (right).  The ventricles of the twin with schizophrenia are larger.   This suggests structural brain changes associated with the illness."- Source:  Daniel Weinberger, MD, NIMH Clinical Brain Disorders Branch--used with permission

• Decreased volume:

  • Amygdala

  • Hippocampus

  • Right prefrontal cortex

  • Thalamus

    • Decreased thalamic and prefrontal cortex neuronal metabolism & altered brain metabolism (PET)

      "NIMH scientist shows PET scans from a study of identical (monozygotic) twins, who are discordant for schizophrenia (only one has the disorder) demonstrating that individuals with schizophrenia have reduced brain activity in the frontal lobes (top of scan)."--used with permission

      Positron Emission Tomography (PET) "PET ( positron emission tomography) is a brain imaging technique that uses a radioactive tracer to show chemical activity of the brain. The PET scanner pinpoints the destination of radioactively tagged glucose, oxygen, or drugs to reveal the parts of the brain involved in performing an experimental task. PET allows us to look at brain functions by measuring levels of energy - or activity - in specific areas of the brain. PET scans generate pictures of the working brain, providing maps of emotions, learning, vision, and memory. For example, patients may be injected with a form of radioactive glucose. The glucose winds its way to the brain through the bloodstream. Since glucose is normally the brain's fuel, the more active a part of the brain is during the task, the more glucose it uses. An array of radiation detectors in the scanner locates the radioactivity and sends the data to a computer that produces two-dimensional color-coded images (brighter colors indicate more activity) of where the brain is active. Identifying these brain functions is key in developing new ways to diagnose and treat schizophrenia and other mental disorders". Source:William Branson NIH Medical Arts

• Dopamine Hypothesis:

  • This idea was suggested by observation that drugs which reduced dopaminergic activity reduced acute symptoms/signs of psychoses.

    • Symptoms notably Decreased --

      • Agitation

      • Anxiety

      • Hallucinations

    • Symptoms less affected:

      • Delusions

      • Social withdrawal

  • Multiple receptor systems/transmitters may be involved including:

    • Serotonin

    • Acetylcholine

    • Glutamate

    • GABA

    • Excitatory amino acids

Antipsychotic drugs-chemical classifications

• Phenothiazine Compounds:

  • Three subclasses:

    • Aliphatic derivatives (e.g. chlorpromazine (Thorazine))

    • Piperidine derivatives( e.g. thioridazine (Mellaril) am): relatively less potent

    • Piperazine derivatives (e.g. fluphenazine (Prolixin)): relatively more potent

• Thioxanthene Compounds:

  • example: thiothixene (Navane)

• Butyrophenones:

  • Haloperidol (Haldol)-- most widely used butyrophenone

• Miscellaneous Chemical Structures:

  • Pimozide (Orap)

  • Olanzapine (Zyprexa)

  • Molindone (Moban)

  • Quetiapine

  • Clozapine (Clozaril)

  • Risperidone (Risperdal)

  • Loxapine (Loxitane)

• Antipsychotic Drug: Pharmacokinetics:

  • Absorption:

    • Readily; incompletely absorbed

    • Often significant first pass metabolism

    • Longer clinical duration of action compared to that expected from half-life

• Metabolism:

  • Generally metabolized -- metabolite usually not highly active

• Excretion:

  • Limited unchanged excretion

  • Mostly metabolized to more polar compounds

Basic Antipsychotic Drug Pharmacology

• Overview:-- phenothiazine prototype: chlorpromazine (Thorazine)

  • CNS effects, autonomic effects, endocrine effects -- multiple receptor blockade

    • Dopamine-- central focus

    • α-adrenergic receptor

    • serotonin (5-HT₂)

• Psychological Effects:

  • In nonpsychotic individuals-- unpleasant

    • Sleepiness

    • Restlessness

    • Autonomic side effects

    • Impaired performance

  • In psychotic individuals: improved performance

• Antipsychotic Drug-Induced Endocrine Changes

  • Women:

    • Amenorrhea/galactorrhea

    • False-positive pregnancy test results

    • Increased libido

  • Men:

    • Decreased libido

    • Gynecomastia

  • Possible Mechanisms:

    • Blockade of dopamine-mediated tonic inhibition of prolactin secretion

    • Increased peripheral androgen to estrogen conversion

    • Olanzapine, sertindole, quetiapine-- absence/minimal prolactin increases:

      • Perhaps indicative of reduced D₂ receptor blockade:

        • Consistent with reduced extrapyramidal dysfunction (tardive dyskinesia) and reduced endocrine anomalies

• Cardiovascular Effects

  • "High-dose" (low potency) phenothiazines-- (autonomic side effects)

    • Orthostatic (postural) hypotension

    • Tachycardia

    • Reduced:

      •  Mean arterial pressure

      •  Peripheral resistance

      •  Stroke volume

    • ECG changes:

      •  Q-T prolongation

      •  ST segmental and T wave shape changes

 Adverse Effects/Reactions

• Neurological Effects--Classical antipsychotic agents (as distinguished from more current, "atypical" drugs)

  • Extrapyramidal reactions:

    • Occurrence early in treatment:

      • Parkinson's syndrome

        • Managed with antimuscarinic agents or less commonly amantadine

        • May be self-limiting

      • Akisthisia (restlessness)

        • Antimuscarinic drugs; diphenhydramine

      • Acute dystonic reactions (spastic retrocollis or torticollis)

        • Antimuscarinic drugs; diphenhydramine

    • Occurrence late in treatment:

      •  Tardive dyskinesia -- choreoathetoid movements

        • Most significant adverse side effect of antipsychotic drug treatment

        • Most susceptible: older women following prolonged treatment

        • Overall frequency: 20%-40% in chronic treatment

        • Advanced cases: possibly irreversible

        • Management:

          1. Discontinuation or antipsychotic drug dose reduction

          2. Eliminate centrally acting anticholinergic drugs (anti-Parkinsonian drugs/tricyclic antidepressants)

          3. In absence those adequate therapeutic response: high-dose diazepam (30-40 milligrams per day)

•  Autonomic effects

  • Varies depending upon the antipsychotic used; side effect includes:

    • Antimuscarinic (may be temporary; tolerance develops)

      • May be ameliorated by cholinomimetic, e.g. bethanecol

    •  Orthostatic hypotension; impaired ejaculation (related to adrenergic receptor blockade)

•  Metabolic/Endocrine:

  • Weight gain (common)

  • Hyperprolactinemia--causes:

    • In women:

      • Amenorrhea-galactorrhea

      • Infertility

    • In men:

      • Impotence

      • Infertility

      • Diminished libido

•  Cardiotoxicity:

  • Thioridizine (doses > 300 mg per day; minor T wave abnormality)

    •  Overdosage:

      • Ventricular arrhythmias

      • Abnormal cardiac conduction

      • Sudden death

    • Thioridazine (Mellaril): drug-drug interactions

      • Thioridizine plus tricyclic antidepressants -- requires cautious use

      • Possible additive antimuscarinic + quinidine-like effects

•  Ocular Effects:

  • Cornea and lens deposits: complication of chlorpromazine treatment

  • Thioridazine (Mellaril): Retinal Deposits -- resembling retinitis pigmentosa

    • Dose limiting

•  Malignant Neuroleptic Syndrome

  • Life-threatening: observed in patients sensitive to antipsychotic extrapyramidal effects

  • Symptoms:

    • Muscle rigidity (initial symptom)

    • Fever (associated with impaired sweating -- possibly resulting from anticholinergic drug therapy)

    • Autonomic instability -- irregular pulse rate; unstable BP

    • Elevated creatinine kinase isozymes (indicative of muscle damage reprint

  • Pharmacological Intervention:

    • Anti-Parkinsonian drugs to treat extrapyramidal syndrome

    • Muscle relaxants: dantrolene (Dantrium); diazepam (Valium)

    • Dopamine agonists: bromocriptine (Parlodel) may be helpful

•  Allergic/Toxic reactions

  • Clozapine (Clozaril): agranulocytosis -- frequency = 1 to 2%

    • May develop rapidly (between 6 and 18th week of treatment)

    • Requires weekly blood counts

  • High-potency antipsychotic drugs may rarely cause:

    • Agranulocytosis

    • Cholestatic jaundice

    • Skin eruptions

•  Drug-Drug Interactions:

  • Additive effects-- with drugs that exhibit:

    • α-adrenergic blockade

    • Anticholinergic effects

    • Quinidine-like effects (thioridazine (Mellaril))

Clinical Indications for Antipsychotic Drugs

• Primary Indication: Schizophrenia

• Schizoaffective disorder:

  • Psychotic component: management with antipsychotic drugs

  • Other components: management with --

    • Antidepressants

    • Lithium

    • Valproic acid (Depakene, Depakote)

• Manic component in bipolar affective disorder

  • Management with antipsychotic agents

  • Milder cases: combination of lithium/valproic acid with certain benzodiazepines, e.g.lorazepam (Ativan)/clonazepam (Klonopin)

• Other Indications:

  • Tourette's syndrome

  • Disturbed behavior: senile dementia associated with Alzheimer's disease

•  Inappropriate Use:

  • Management of drug withdrawal syndromes (e.g. opioids)

  • Anxiety relief: not appropriate given availability of specific anxiolytic agents

• Nonpsychiatric Indications:

  • Antiemetic effects: older antipsychotic drugs {except thioridizine}

    • Prochlorperazine; benzquinamide-- used solely for antiemesis

  • Relief of puritis

  • Combination of the butyrophenones droperidol + the opioid fentanyl (innovar)= neuroleptanesthesia

• Prospective:

  • Enhanced efficacy of clozapine and rispiradone in reducing negative symptoms while reducing the risk of tardive dyskinesia is the basis of new atypical antipsychotic agents

  • These new agents may revolutionize the treatment of schizophrenia

    • Prominent new agents include

      • Clozapine (Clozaril)

      • Rsperidone (Risperdal)

      • Olanzapine (Zyprexa)

      • Trazodone (Desyrel)

   

Antipsychotic Drug Classes: Potencies and Toxicities

--low

--very high

adapted from Table 29-1: Potter, W. Z. and Hollister, L.E.,Antipsychotic Agents and Lithium, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 468.

Lithium

• Overview

  • Anti-manic/"mood-stabilizing"

    • Prevention of mood swings in patients with bipolar disorder (manic-depressive disorder)

  • Other mood stabilizers:

    • Carbamazepine

    • Valproic acid (valproate --space or management of mania)

    • Clonazepam

• Bipolar Affective Disorder

  • Serious psychiatric disorder

  • Characterized by cyclic manic attacks

  • Symptomatology-- similar to paranoid schizophrenic symptoms

    • Grandiosity

    • Bellicosity

    • Overactivity

    • Paranoid thoughts

  • Bipolar disorder: familial component/genetic linkage

Lithium Pharmacology

• Pharmacokinetics

  • Absorption:

    • Complete absorption within six to eight hours

    • Peak plasma levels within 30 minutes to two hours

  • Distribution: total body water; no protein binding

  • Metabolism: none

  • Excretion: urinary excretion; about 20 percent of creatinine clearance; half-life (plasma) = 20 hours

• Pharmacodynamics-- Possible mechanisms of action:

  1. Effects on electrolyte/ion transport

  2. Neurotransmitter -- neurotransmitter release modulation

  3. Influence on second messengers mediating transmitter action

  • Ion Transport Effects:

    • Lithium (related to sodium closely)a substitute for sodium in action potential generation and exchange mechanisms

      • Li :Na exchanges slowed

  • Neurotransmitter Effects -- variable; possible influences on noradrenergic, dopaminergic, and/or cholinergic systems

  • Second Messenger Effects:

    • Lithium influences IP₃/DAG systems

      • Inhibiting enzymes that control normal recycling of membrane phosphoinositides-- including:

        1. Inhibiting conversion of IP₂ to IP₁

        2. Inhibiting conversion of IP to inositol

      • These effects result in depletion phosphatidylinositol-4,5 bisphosphate (PIP₂)

        • PIP₂ : membrane precursor to inositol triphosphate and diacylglycerol (IP₃ and DAG)

    • Lithium may also inhibits norepinephrine-sensitive adenylyl cyclase

    • Effects on the IP₃/DAG system and Adenylyl cyclase second messenger systems suggest lithium may influence G protein coupled signal transduction systems.

      • For example lithium maycoupled receptors from G proteins -- lithium common side effects: polyuria and hypothyroidism may be due to vasopressin and TSH receptor -- G protein uncoupling.

Lithium Clinical Pharmacology

• Lithium carbonate: an effective, probably preferred treatment for bipolar disorder (manic phase particularly)

  • Valproate they also be used for this indication

  • In severely manic cases: concurrent use of benzodiazepines and antipsychotic agents may be required.

  • Remission rate for manic phase: 60%-80%-- outpatients; inpatient success rate lower

  • Severe mania: probably necessary to add lorazepam or clonazepam

• Depressive Phase:

  • May require use of antidepressant medication

    • Tricyclic antidepressants: may precipitate mania and mood cycling

    • Newer antidepressants: may also promote mania

    • MAO inhibitors: may be a preferred choice

  • Carbamazepine may also be useful in managing manic attacks not controlled by lithium monotherapy

• Prophylactic lithium may block both mania and depressive components

• Adverse Effect:nausea/tremor

•  Other Applications:

  • Schizoaffective disorders -- mixture schizophrenic symptoms/altered affect (excitement or depression)

  • Combination of antipsychotic drugs and lithium may be effective

  • Combination of antipsychotic drugs and carbamazepine may also be effective

•  Plasma Level Monitoring: crucial to avoid or minimize adverse effects

•  Drug-Drug Interactions:

  • Reduce lithium clearance also associated with:

    • Newer NSAIDs -- not reported for either aspirin or acetaminophen

  • Lithium enhances extrapyramidal syndromes associated with most classical antipsychotic agents (this finding may not applied to the "atypical" newer antipsychotics)

 Adverse Effects

•  Neurological/Psychiatric reactions

  • Tremor is a common side effect

    • Atenolol or propranolol may reduce lithium-induced tremor

  • Other neurological abnormalities:

    1. Choreoathetosis

    2. Motor hyperactivity

    3. Ataxia

    4. Dysarthria

    5. Aphasia

  •  Psychiatric manifestations observed at high/toxic doses include:

    • Mental confusion

    • Abnormal motor movements

    • Withdrawal

•  Thyroid function effects:

  • Typically decreases thyroid function-- reversible in

  • Few patients show symptoms of hypothyroidism or thyroid enlargement

•  Renal Effects:

  • Polydipsia; polyuria -- frequent and reversible -- occurs at therapeutic plasma concentrations

  • Mechanism of Action: collecting tubule does not conserve water under the influence of ADH.

    • Consequence: excessive free water clearance -- nephrogenic diabetes insipidus

      • Resistant to vasopressin

      • Responsive to amiloride

• Edema: frequent adverse effects; may be due to enhanced sodium retention due to lithium

• Cardiac Effects: bradycardia/tachycardia ("sick sinus syndrome") is the contraindication to lithium use -- lithium depresses the SA node.

• Lithium and Pregnancy:

  • Special monitoring required during pregnancy (levels are likely to be unstable)

  • Lithium: transferred to nursing infants through breast milk (1/3 to 1/2 of serum levels)

  • Lithium toxicity in the newborn:

    • Lethargy

    • Sinuses

    • Poor suck

    • Moro reflexes

  • Lithium: relatively low-risk of teratogenic effects; earlier studies had reported an increased risk of Ebstein's anomality (cardiac valvular defect) in lithium babies.

•   Management of Lithium Overdosage:

  • Peritoneal dialysis -- effective

  • Hemodialysis -- effective; preferred

  • Continued analysis until plasma concentration falls below normal therapeutic range

•  Alternative: Valproic acid:

  • Clear antimanic effects --FDA approved for this indication

  • Efficacy equal to lithium during early weeks of therapy; possibly effective for maintenance

  • May be effective in patients were resistant to lithium

  • Valproic acid: recognized as appropriate first-line therapy for mania

  • Combination of valproic acid and lithium may be indicated for patients did not respond adequately to either agent in monotherapy

• Alternative: Carbamazepine:

  • Reasonable alternative to lithium if lithium is inadequately effective

  • Useful in treatment acute mania; also for prophylaxis

  • Adverse effect profile --may be somewhat better than lithium

  • Carbamazepine may be effective in monotherapy; or for refractory patients in combination with lithium or occasionally valproate

  • Carbamazepine blood dyscrasias have not emerged as a major therapeutic problem with its use as a mood stabilizer