Mkgrady8 Neuro 5 Antipsychotic Agents Ii

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atypical antipsychotics: what do they do, why are they better

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all of the newer AGENTS ARE ATYPICAL ANTIPSYCHOTICS, HAVE HIGH AFFINITY FOR 5-HT2 RECEPTOR (AND ACT AS ANTAGONISTS), AND DOPAMINE D2 ANTAGONIST ACTIVITY; they BIND LESS AVIDLY TO D2 RECEPTORS IN THE STRIATUM and hypothalamus than the conventional antipsychotics, and THEREFORE PRODUCE LESS EPS AND ENDOCRINE DISTURBANCE; overall atypical drugs have better therapeutic profile and appear to improve cognitive function as compared to conventional drugs

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clozapine: what does it do, when is it used

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a dibenzodiazepine antipsychotic drug that blocs DOPAMINE RECEPTORS IN THE MESOLIMBIC-MESOCORTICAL SYSTEM showing less dopamine D2 receptor blocking activity in the extrapyramidal system; AN EFFECTIVE ANTIPSYCHOTIC AGENT PRODUCING MINIMAL EPS and an apparent LACK OF TARDIVE DYSKINESIA, pts with tardive dyskinesia improve while taking clozapine over the course of a few months; at appropriate doses clozapine DOES NOT ANTAGONIZE THE ANTIPARKINSON EFFECT OF L DOPA and may improve pscychotic systems sometimes associated with L dopa or bromocriptine therapy; A FEW CASES OF NEUROLEPTIC MALIGNANT SYNDROME REPORTED in pts receiving only clozapine

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clozapine: characterized how

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CHARACTERIZED AS AN ATYPICAL ANTIPSYCHOTIC AGENT SINCE IT PRODUCES MINIMAL EPS; at clinically effective doses CLOZAPINE AND OTHER ATYPICAL ANTIPSYCHOTICS BIND TO ONLY 20-60% OF STRIATAL D2 RECEPTORS BUT CONVENTIONAL compounds BIND 70-85% OF D2 RECEPTORS in basal ganglia leading to EPS; but conventional drugs have a much lower affinity for 5-HT2 receptors than new drugs, possible that ability of new drugs to affect serotonin receptors contributes to their improved antipsychotic effect

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clozapine: D2 receptors, caudate

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SEVERAL TIMES MORE POTENT IN BLOCKING 5-HT2 THAN D2 RECEPTORS; clozapine also has a high affinity for D4 dopamine receptors found in limbic areas; moreover clozapine HAS POTENT ANTICHOLINERGIC ACTIONS IN CAUDATE= may partially explain the lack of EPS, it causes only minimal elevation of serum prolactin conc

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clozapine: toxicity

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BECAUSE OF ITS TOXICITY IS RECOMMENDED ONLY FOR PTS NOT RESPONDING ADEQUATELY TO STANDARD ANTI PSYCHOTIC DRUGS; 40-60% of these pts may improve after treatment for 6 weeks or longer; clozapine treated pts more animated and their behavior more socially appropriate than pts treated with other anti psychotics (i.e. usually better quality of response)

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adverse effects of clozapine: agranulocytosis

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AGRANULOCYTOSIS IS THE MOST SERIOUS ADVERSE EFFECT OF CLOZAPINE; occurs in 1-2% of pts; onset within FIRST 6 MONTHS OF TREATMENT BUT THE CELL COUNT CAN DROP ABRUPTLY; in some cases agranulocytosis is reversible if drug stopped early however other pts who developed agranulocytosis died; bc of this adverse reaction physicians must assure than a system for WEEKLY WHIT EBLOOD CELL COUNT MONITORING is in place; reinstitution of clozapine therapy caused a reappearance of leukopenia or granulocytopenia with a more rapid onset the second time; IF TOTAL WHITE CELL COUNT FALLS BELOW 3000/MM3 OR THE GRANULOCYTE COUNT FALLS BELOW 1500 TREATMENT INTERRUPTED; if white cell count less than 2000 or granulocytes less than 1000 then the drug will be discontinued permanently

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adverse effects of clozapine: other

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seizures can occur (up to 5% risk seems dose related); withdrawal= clozapine discontinuation symptoms are 'atypical' differ from those noted after abrupt cessation of conventional neuroleptics; RAPID WITHDRAWAL MAY RESULT IN MARKED EXACERBATION OF PTS PSYCHOSIS worsening of pre existing tardive dyskinesia with prominent involuntary lingual movements and somatic symptoms, recommendation= schizophrenic PTS WHO HAVE REPSONDED WEL LTO CLOZAPINE SHOULD NOT BE TAKEN OFF WITHOUT A VALID REASON; WHEN NECESSARY THERE WHOULD BE A SLOWER TAPER WITH PRIOR INTRODUCTION OF CONVENTIONAL NEUROLEPTIC; other adverse effects of clozapine= sedation, tachycardia, dizziness, anti cholinergic effects, transient hyperthermia, sialorrhea, hypotension, potent alpha1 adrenergic receptor antagonism

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risperidone: how does it work, when is it used

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characterized as a 'quantitatively atypical' antipsychotic with relatively low incidence of EPS when given in low doses; effective on both positive and negative symptoms; can be a first line alternative to high potency conventional antipsychotics; it BLOCKS D2, 5-HT2, AND ALPHA1 RECEPTORS

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resperidone: EPS, side effects

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the INCIDENCE OF EPS AND TARDIVE DYSKINESIA WITH LOW DOSE THERAPY LOWER THAN WITH CONVENTIONAL DRUGS; it can cause insomnia, agitation, anxiety, sedation, and difficulty in concentration; orthostatic hypotension and reflex tachycardia occur initially specially in the elderly; other effects are elevated prolactin, weight gain, and sexual dysfunction; DOES NOT APPEAR TO PRODUCE AGRANULOCYTOSIS, CARDIAC EFFECTS OR SEIZURE INDUCTION BUT CAN CAUSE NEUROLEPTIC MALIGNANT SYNDROME

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olanzapine: how does it work, when is it used

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a clozapine analogue; effective in negative symptoms and HAS A VERY LOW EPS EFFECTS COMPARED TO CONVENTIONAL AGENTS; it blocks D2 and 5-HT2, and D1, D4, 5-HT3, alpha1, muscarinic1, and H1 receptors; like clozapine it exhibits selectivity for limbic/frontal cortex dopamine activity with much less effect on striatal function; BEEN USED IN PTS WITH PD WITHOUT MAKING THE EPS WORSE; generally well tolerated; WEIGHT GAIN DOES OCCUR

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olanzapine: side effects

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it CAN PRODUCE SOMNOLENCE, AGITATION, NERVOUSNESS, INSOMNIA, ANXIETY, ANTICHOLINERGIC EFFECTS, ORTHOSTATIC HYPOTENSION, dizziness, and elevation of liver transaminases; seizures occurred in a small number of pts; serum prolactin elevations generally mild and subsides with continued treatment; NO HEMATOLOGIC ABNORMALITIES REPORTED; TARDIVE DYSKINESIA AND AKATHISIA HAVE BEEN OBSERVED; once daily administration an advantage

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quetiapine: how does it work, when is it used

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clozapine analogue, LOW POTENCY antipsychotic; BINDS TO 5-HT2A, D1, D2, H1, ALPHA1 RECEPTORS WITH RELATIVELY LOW AFFINITY; low affinity for muscarinic receptors; may have less beneficial effect on negative symptoms than other atypicals; MILD EPS COMPARABLE WITH LOW POTENCY CONVENTIONAL DRUGS (e.g. thioridazine), low incidence of akathisia

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quetiapine: side effects

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only transient prolactin elevation; drowsiness, tachycardia, weight gain, agitation, dry mouth, constipation, minimal postural hypotension; may require multiple doses/day (2-3 times)

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ziprasidone: how does it work, when is it used

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it interacts with D2, D3, 5-HT2A-D, alpha1, and H1 receptors; clinical uses= schizophrenia, acute treatment of bipolar manic or mixed episodes, adjunct to lithium or valproate for maintenance treatment of bipolar disorder; also for acute treatment of agitation in schizophrenia

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ziprasidone: side effects

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othostatic hypotension, tachycardia, anorexia, nausea, vomiting, abdominal pain, fever, chills, dry mouth, respiratory tract infection, and increased cough; also observe relatively low levels of EPS, tremor, and somnolence

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ziprasidone: drug interactions and contraindications

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may antagonize effects of L-Dope and dopamine agonists; also may enhance effects of certain antihypertensive drugs; contraindications= recent acute MI, known history of QT prolongation (e.g. congenital long QT syndrome), there is a known association of fatal arrhythmias with QT prolongation by this drug and other antipsychotics known to cause QT prolongation (i.e. do not co administer ziprasidone with thioridizone, pimozide, or chlorpromazine), drug hypersensitivity

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aripiprazole: how does it work, when is it used

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has partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A and alpha1; has high affinity for D2, D3, 5-HT1A, 2A, and moderate affinity for D4, alpha1, and histamine H1; clinical uses= schizophrenia (or agitation associated with this disorder or with bipolar mania), acute treatment of mania and mixed episodes, maintenance treatment of bipolar disorder, adjunctive treatment of major depressive disorder (MDD), and irritability associated with autistic disorder

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aripiprazole: side effects, drug interactions, contraindications

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side effects= nausea, vomiting, orthostatic hypotension, somnolence, tremor, dizziness, blurred vision, restlessness, sedation, low EPS and akathisia; drug interactions= has alpha1 antagonism, and has potential to enhance effects of certain antihypertensive drugs; contraindication= drug sensitivity

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summary of therapeutic uses of antipshychotics

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therapy of psychosis, no clear difference in antipsychotic efficacy among the conventional antipsychotics; the atypical antipsychotics, especially risperidone, are viable first line drugs and effective in pts resistant to conventional agents, some acutely psychotic pts may improve within 24-48 hrs; hospitalized pts may require 3 weeks or more to show significant improvement and max benefit in chronically psychotic pts may require 1-6 months, for treating acute manic phase of bipolar disorder, haloperidol a preferred drug (used to gain rapid control due to slow onset of lithium action); for relief of panic reactions and psychosis associated with drug use, haloperidol preferred over phenothiazines due to less anticholinergic and hypotenzive effects; for relief of disturbed behavior in pts with alzheimer's disease (AD); potentiation of opioid analgesics for special surgery (an example is droperidol); antiemetic therapy= phenothiazines; treatment of tourette's disorder (haloperidol is effective and currently the most used), pimozide is specifically approved for tourette's and effective in cases where haloperidol is not; huntington's chorea; to control agitation and psychosis in combo with antidepressant drugs in depressed pts; long acting depot preps of fluphenazine and haloperidol available (fluphenzaine decanoate or enanthate, haloperidol deconate), these forms can be given by intramuscular injection once every 2-3 weeks to pts with compliance problem, they have same side effects and toxicities as non depot forms

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lithium: therapeutic effects

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a specific antimanic agent for treatment of bipolar manic-depressive disorder; THE DOC FOR MANAGEMENT OF MILD TO MODERATE MANIA and for prevention of both depressive and manic episodes in bipolar disorder (prophylactic use); LITHIUM TERMINATES MANIC ATTACKS AND DECREASE THE CYCLIC MOOD SWINGS; sometimes effective alone or combined with tricyclic antidepressants (lithium augmentation) for treatment of recurrent endogenous depression; a delayed onset due to time necessary to achieve effective brain levels (7-10 days) thus antipsychotic agents (e.g. haloperidol) used initially to control acute severe mania, antidepressant drugs sometimes added during depressive episodes; several mechanisms suggested, one interesting effect of lithium is its effect on inositol phosphates

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lithium: pharmacokinetics

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serum levels (recommended therapeutic levels may vary with different sources); acute mania- 0.75 to 1.2 mEq/L; long term maintenance= 0.6 to 1.2 mEQ/L; CONCENTRATIONS ABOVE 2.9 MEQ/L ARE TOXIC; for measurement blood should be drawn 10-12 hrs after the last dose; large variability between individuals; distributed in total body water; ELIMINATED BY KIDNEYS; renal excretion is markedly affected by sodium intake, in presence of sodium deficiency, ,lithium ion selectively reabsorbed in renal tubules and may accumulate to toxic levels (low Na in diet= increased lithium reabsorption, low Na in diet= increased lithium toxicity); sodium depleting diuretics markedly increase serum lithium and toxicity; thiazides are troublesome; NSAIDs can reduce renal excretion of lithium; excessive Na loss by other mechanisms (e.g. diarrhea) can also increase lithium retention; impaired renal function increases lithium retention and toxicity

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lithium: adverse reactions

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at therapeutic serum concentrations (0.6-1.2 mEq/L)= nausea, fatigue ,thirst, polyuria, fine tremor (especially hand tremor that responds to propranolol), GI irritation, mild diarrhea, weight gain, edema, acne, leukocytosis; at toxic serum concentrations (above 2 mEq/L)= confusion, vomiting, diarrhea, polyuria, albuminuria, hypotension, muscle weakness, ataxia, sedation or lethargy, slurred speech, tinnitus, blurred vision, nystagmus, delirium, stupor, coma, convulsions, permanent neurologic impairment; occasional= goiter, hypothyroidism, nephrogenic diabetes insipidus, renal tubular necrosis, and interstitial fibrosis, metallic taste, induction or exacerbation of psoriasis, folliculitis, ECG changes, cardiac arrhythmias, EPS effects; dangers in pregnancy= cardiac defects, renal and endocrine disorders in infants of mothers who took lithium during first trimester, generally contraindicated in pregnancy; renal toxicity= nephrogenic diabetes insipidus, may not be completely reversible, amiloride can reduce urine output in these pts but occasionally an increase in lithium levels produced, thiazides interfere with lithium excretion, risk of serious irreversible nephrotoxicity minimized by maintenance of lithium concentrations within the recommended range and by avoiding dehydration

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lithium: overdose toxicity

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serious problem with no specific antidote; IMPORTANT TO MONITOR SERUM LEVELS TO AVOID TOXICITY; treatment of overdose= fluid and electrolyte replacement, saline infusion (will enhance lithium excretion if serum Na is low), osmotic diuretics (urea, mannitol), aminophylline or actazolaminde facilitate excretion of lithium, peritoneal dialysis or hemodialysis may be necessary, treatment with thiazide diuretics should be avoided, necessary to follow cardiac and renal status, anticonvulsants for seizures

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alternatives to lithium

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valproic acid- medical letter consultants suggest that valproic acid is the best alternative to lithium for treatment of mania and or maintenance of bipolar disorder; carbamazepine= an alternative to lithium in treatment of bipolar disorder, effective in some pts who do not respond to lithium, at times combined with lithium; also used for treatment of certain other behavior disorders and as an adjunct with neuroleptics in treatment of schizophrenia

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A 40 y/o woman presents with a 6 month historyof missed menstrual periods. Shedescribes a milky secretion from her breasts. She is not sexually active. Shestates that she is on antipsychotics. Apregnancy test is negative and TSH is normal. What hormonal finding best correlates with this pts data? a. increase in FSH and a decrease in estradiol b. increase in LH (LH/FSH>2) and an increase inandrogens c. increase in prolactin with a decrease indopamine d. decrease in prolactin with an increase indopamine e. increase in the 17-OH progesterone level

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C increase in prolactin with an decrease in dopamine

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A 72 y/o man exhibits progressive tremors,bradykinesia, and muscular rigidity. Heis slow to initiate movements and shows other motor abnormalities. The most likely diagnosis of his disease isParkinson disease. What drug mimics theeffects of this disease and should be avoided in pts with this disease? a. lithium b. haloperidol c. diazepam d. penobarbital e. L-dopa

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B haloperidol (EPS)

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Which one of the following antipsychotics hasbeen shown to be a partial agonist at the D2 receptor? a. aripirazole b. clozapine c. haloperidol d. risperidone e. thioridazine

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A aripiprazole (this is the only antipsychotic with partial agonist activity)

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A 33 y/o woman is brought into the ER byambulance. She has been diagnosed ashaving schizophrenic disorder, disorganized type, since the age of 17. She has been on antipsychotic meds since thattime, which have controlled her symptoms well. PE reveals a well nourished female with a temp of 103.2 degrees F, BP of180/99, HR of 97, and copious perspiration. She is mute, has muscular rigidity, and appears to be obtunded. What is the likely diagnosis? a. acute dystonia b. akathisia c. neuroleptic malignant syndrome d. antiparkinsonism e. tardive dyskinesia

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C neuroleptic malignant syndrome