Neuroanatomy-Antipsychotics Flashcards
(16 cards)
CONVENTIONAL ANTIPSYCHOTICS
several situations require their use:
a. parrental administration for acute agitation
b. lack of benefit or intolerance to novel agents
c. special populations (eg., pregnant patients)
d. noncompliant patients, for whom depot medication
may be indicated
Side Effects:
- Synergistic depression with ethanol & inhibition of alcohol metabolism (elevated blood alcohol)
- Reduced therapeutic effectiveness of L-dopa in PD
- Inhibition of phenytoin metabolism
PHENOTHIAZINES
Action:
Dopamine and slight serotonin Antagonists (blockade in mesolimbic-mesocortical dopaminergic system). High affinity for D2 receptors, & the degree of binding with D2 receptors correlates w/ clinical potency in alleviating schizophrenia.
- >60% and < 80% D2 occupancy needed for therapeutic effect.
Behavioral Effects: Sedation, reduced hallucinations, quieting patients, decreased spontaneous activity.
Negative Impacts:
- Lower seizure threshold,
- Toxic confusion (due to central anticholinergic effects),
- EPS: (30-40% of patients, keep D2 oc. below 75% if you can) (treat: anticholinergic, antiparkinson drugs)
Characterized by: Tremor (same mechanism), Acute dystonia (spasms), Akathisia (restlessness, reduce treatment to alleviate), **Tardive dyskinesia **(Caused by supersensitivity to dopamine receptors. Action is a Stereotyped repetitive involuntary movements of the mouth, lips,& tongue. Reduce dose gradually/switch to atypical), Perioral tremor,
- Antiemetic (Blockade of chemoreceptor trigger zone or CTZ, related to dopamine &/or serotonin receptor blockade). Not effective against motion sickness though usually. High potency ones can be.
- Alpha-adrenergic receptor blockade (orthostatic hypotension more common with aliphatics)
- Muscarinic receptor blockage (dry mouth, blurred vision, urinary retention)
- Cardiac: depressed T-wave & prolonged Q-T interval- reversible on discontinuation of drug.
- Endocrine: Dopamine receptor blockade results in increased prolactin secretion, decreased gonatotropin, GH, and ACTH release.
- Hypersensitivity: Photosensitivity, allergic rashes, blood dyscrasias (agranulocytosis)
- Eye: Toxic retinopathy
- Weight Gain: Molindone seems least bad
Temperature: Lose control (poikilothermic effect)
Structure:
- Substitution at position (2) imparts antipsychotic activity
- Substitution on the nitrogen at position(10) alters potency and adverse effects; principal substitutions are: aliphatic, piperidine and piperazine.
Potency:
- Aliphatic & piperidine are low potency Chlorpromazine & thioridazine are examples. (These types are more likely to cause sedation, orthostatic hypotension, hypersensitivity (jaundice, skin sensitization); BUT less likely to induce parkinsonism, extrapyramidal symptoms (EPS), & recommended as a second-line drug in treatment of acute psychosis).)
- Piperazine are high potency. This group includes fluphenazine & trifluoperazine. (These types are more likely to cause EPS & have antiemetic (patients just having surgery helps with nausea) activity, BUT cause less hypotension or sedation.)
Neuroleptic Malignant Syndrome
Fever, diaphoresis, marked muscular rigidity, stupor, respiratory & autonomic dysfunction, leukocytosis.
Incidence: 0.5-1% of patients who receive high-potency
neuroleptics. Mortality in this group now only 8%! way better than 22%. (Death from respiratory or renal failure, cardiovascular collapse, arrhythmias)
Treatment: Must stop therapy, Supportive therapy such as physically cooling the patient. The patient should not be re-exposed to a neuroleptic drug for at least 2 weeks.
Mechanism: sudden decrease in dopaminergic activity
Drug treatment:
Bromocriptine- effective for some of symptoms, including hyperthermia, respiratory problems, stupor, autonomic changes, & rigidity. D2 receptor agonist.
L-dopa-carbidopa & amantadine used w/ some success
HALOPERIDOL (Haldol)
Typical Antipsycotic
- 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 & psychosis associated w/ drug use, haloperidol preferred over phenothiazines due to less anticholinergic & hypotensive effects.
_- Treatment of Tourette’s disorder.Haloperidol is effective & currently the most used; _
- Considered a high potency conventional antipsychotic drug (Potent dopaminergic D2 receptor antagonist), (among the recommended first-line drugs for treatment of schizophrenia).
- Basic therapeutic effects similar to the phenothiazines,
but haloperidol preferred in certain types of disorders. - EPS common, & more frequent than with aliphatic or piperidine phenothiazines
Uses:
- Lacks anticholinergic effects;
- Particularly effective for acute mania
Side Effects:
- Orthostatic Hypotension
Thiothixene
Typical Antipsycotic
- Thiothixene similar in pharmacology& side effects to the piperazine-substituted phenothiazines.
- Thiothixene has no special advantages; an alternative to other agents. High potency.
Loxapine
Typical Antipsycotic
- An alternative for patients refractory to others; no proven superiority over other agents
- Hypertension rather than Hypotension.
Molindone
Typical Low potency Antipsychotic
Doesn’t cause weight gain!
Atypical Antipsychotics
- All of the newer agents are atypical antipsychotics, have high affinity for 5-HT2 receptors (main difference from conventional & act as antagonists) & dopamine D2 antagonist activity (not to same extent as conventional drugs).
- They bind less avidly to D2 receptors in the striatum &
hypothalamus than the conventional antipsychotics, &
therefore produce less EPS & endocrine disturbance. - appear to improve cognitive function as compared to conventional drugs.
CLOZAPINE (Clozaril)
Atypical Antipsychotic
- antipsychotic drug blocs dopamine receptors in the mesolimbic-mesocortical system showing less dopamine D2 receptor blocking (20-60% instead of ~60-80%) activity in the extrapyramidal system – less EPS. AND an apparent lack of tardive dyskinesia.
- Possible that affect/affinity for serotonin receptors (5-HT2) contributes to their improved antipsychotic effect
- does not antagonize the antiparkinson effect of L-dopa.
- has potent anticholinergic actions in caudate, not in the Hypothalamus- may partially explain the lack of EPS. It causes only minimal elevation of serum prolactin concentration.
Toxicity:
- Decreases granulocytes and White blood cells. That’s not so good = Agranulocytosis. (__occurs in 1-2% of patients. Onset w/in first 6 months of__ treatment, but the cell count can drop abruptly.) - Can be reversed if treatment stopped immediately, sometimes. (weekly white blood cell count monitoring is in place.) - white cell count falls below 3000/mm3 or the granulocyte count falls below 1500, treatment STOPPED!
- Seizures can occur
- Withdrawal: Rapid withdrawal may result in marked exacerbation of patient’s psychosis, worsening of pre-existing tardive dyskinesia. - Shouldn’t take patients off Clozapine if unnecessary. (if needed, slow taper with prior introduction of conventional neuroleptic.)
- Sedation (40%); tachycardia (25%); dizziness (20%);
Treatment:
- 40 to 60% of these patients may improve after treatment for six weeks or longer. Often with a better quality of response (better off) than with typical antipsychotics.
- Start with a low dose if you can manage it, just to avoid the adverse side effects.
RISPERIDONE (Risperdal)
Atypical Anti - _First line drug. _
- relatively low incidence of EPS when given in low doses.
- the most widely used single antipsychotic drug in 1996.
- Named as a first-line alternative to high-potency conventional antipsychotics.
- It blocks D2, 5HT2, & alpha1 receptors.
Side Effects:
- can cause insomnia, agitation, anxiety, sedation, & difficulty in concentrating.
- Orthostatic hypotension and reflex tachycardia occur initially, especially in the elderly
- Does not appear to produce agranulocytosis
OLANZAPINE (Zyprexa)
- A clozapine analogue
- Effective in positive & negative symptoms a little, & has a very low EPS effects compared to conventional agents.
- It blocks D2 & 5-HT2 & D1, D4, 5-HT3, alpha1, muscarinic1 and H1 receptors.
- exhibits selectivity for limbic/frontal cortex dopamine activity, w/ much less effect on striatal function.
Side Effects:
- Weight Gain DOES occur with this one.
- can produce somnolence, agitation, nervousness, insomnia, anxiety, anticholinergic effects, orthostatic hypotension
- Tardive dyskinesia & akathisia have been observed
QUETIAPINE (Seroquel)
- Clozapine analogue; low potency antipsychotic
- Binds to 5-HT2A, D1, D2, H1, alpha1 receptors w/ relatively low affinity
- Mild EPS comparable w/ low potency conventional drugs
SERTINDOLE (Serlect)
- Binds to 5-HT2, D2, alpha1 receptors; low affinity for H1, muscarinic receptors
- Low EPS, low incidence of akathisia, low incidence of tardive dyskinesia
- Mild weight gain
- No hematologic abnormalities
_- Abnormal ECGs! Big deal in Europe. _
- Appears to have potent antianxiety effects
- Not sedative (low H1)
LITHIUM
- drug of choice for management of mild to moderate mania & for prevention of both depressive & manic episodes in bipolar disorder (prophylactic use).
- terminates manic attacks & decrease the cyclic mood swings.
- 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
- Can be used for recurrent endogenous depression
- Concentrations above 2.0 mEq/L are toxic!! (Eliminated in the Kidneys - markedly affected by sodium intake; in presence of sodium deficiency, lithium ion selectively reabsorbed in renal tubules. __Impaired renal function increases lithium retention__ & toxicity)
- NSAIDs can reduce renal excretion of lithium.
- Therapeutic levels vary widely.
Side Effects:
- At Therapeutic levels: Nausea; fatigue; thirst; olyuria; fine tremor, Goiter; hypothyroidism.
- At Toxic levels: Confusion; vomiting; diarrhea; polyuria; albuminuria; hypotension; muscle weakness; ataxia
- Dangers in pregnancy: Cardiac defects, renal& endocrine disorders in infants of mothers who took lithium during first trimester. Generally contraindicated in pregnancy.
- Renal Toxicity
Valproic acid (Depakene, Depakote)
Lithium Alternative
_- valproic acid is the best alternative to lithium for treatment of mania &/or maintenance of bipolar disorder. _
Carbamazepine (Tegretol)
an alternative to lithium in treatment of bipolar disorder. Effective in some patients who do not respond to lithium.
