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69 Cards in this Set
- Front
- Back
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What is the definition of Psychosis?
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One of a variety of mental disorders characterized by thought disturbance or agitated state, especially one without any observable organic lesion; Generally applied to the more severe forms of mental derangement.
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List some positive symptoms of psychosis.
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Delusions, Hallucinations, Thought Disorder
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List some negative symptoms of psychosis.
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Inappropriate emotional displays (crying frequently, laughing abruptly)
Staring Flat emotional affect Poverty of speech Lack of motivation |
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When is the onset of Schizophrenia?
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Late adolescence, young adulthood - earlier in males than females
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Describe the Serotonin Hypothesis for Schizophrenia.
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5-HT(2A) agonists can be hallucinogenic
They lead to depolarization of glutamatergic neurons. Modulate stability of 5-HT(2A)-NMDA receptor complex. |
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What drugs are used to treat Schizophrenia, based on the Serotonin Hypothesis?
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5-HT(2A) inverse agonists can be antipsychotic
e.g. Clozapine, Quetiapine They block constitutive activity of the receptors |
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What is the Glutamate Hypothesis of Schizophrenia?
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Non-competitive inhibitors of NMDA receptors (especially NMDA receptors on GABAergic neurons) exacerbate cognitive impairment and psychosis
e.g. Ketamine, Phencyclidine (PCP, angel dust) Disinhibition = Hyperstimulation of cortical neurons |
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Describe the Dopamine Hypothesis of Schizophrenia.
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Excessive dopaminergic activity may contribute to the development of schizophrenia
Most antipsychotic drugs block D2 receptors Drugs that increase DA activity aggravate schizophrenia or produce it de novo DA receptor density has been found, post mortem, to be increased in the brains of schizophrenics PET scans show increases in DA receptor density Successful treatment leads to decrease in homovanillic acid (metabolite of DA) |
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What neurological problems are related to the nigrostriatal dopamine pathway (Substantia Nigra to Basal Ganglia)?
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Associated with Extrapyramidal Symptoms (EPS): hyperkinetic movements, dyskinesias
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What type of schizophrenia symptoms are associated with the mesolimbic dopamine pathway (Tegmentum to Nucleus Accumbens)?
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Associated with positive symptoms of schizophrenia
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What are the symptoms of schizophrenia associated with the mesocortical dopamine pathway (Tegmentum to Limbic Cortex)?
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Negative symptoms of schizophrenia and cognitive symptoms
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What is associated with the Tuberoinfundibular Pathway (Hypothalamus to Anterior Pituitary)?
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Associated with Prolactin secretion
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What behavior is associated with the medullary-periventricular pathway?
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Eating behavior
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What behavior is associated with the incertohypothalamic pathway?
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Sexual behavior
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What are the two main groupings of Dopamine Receptors?
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D1 and D5 - increase cAMP, increase PIP2 hydrolysis (Ca2+ mobilization, PKC activation)
D2, D3, D4 - decrease cAMP, increase K+ currents, decrease v-gated Ca2+ currents |
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Which dopamine receptors increase cAMP, and increase PIP2 hydrolysis (resulting in Ca2+ mobilization and PKC activation)?
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D1 and D5
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Which dopamine receptors decrease cAMP, increase K+ currents and decrease v-gated Ca2+ currents?
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D2, D3, and D4
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Where are D1 receptors generally located?
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Striatum
Neocortex |
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Where are D5 receptors generally located?
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Hippocampus
Hypothalamus |
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Where are D2 receptors generally located?
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Striatum
Substantia nigra |
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Where are D3 receptors generally located?
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Olfactory tubercle
Nucleus accumbens Hypothalamus |
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Where are D4 receptors generally located?
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Frontal cortex
Medulla Midbrain |
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Which dopamine receptors are targeted by 'typical' antipsychotics (as in, targeting these dopamine receptors yields the highest clinical potency)?
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D2 receptors
(In striatum and substantia nigra) |
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What categories of drugs are considered "First Generation" antipsychotics?
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Phenothiazine derivatives
Thioxanthine derivatives Butyrophenone (Classical, typical, neuroleptics) |
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List some phenothiazine-type antipsychotics.
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Chlorpromazine
Fluphenazine Perphenazine Thioridazine Trifluoperazine |
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What are some non-phenothiazine-type antipsychotics?
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Thiothixene - a Thioxanthine derivative
Haloperidol - a Butyrophenone |
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What are the second generation (atypical) antipsychotics?
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Aripiprazole
Clozapine Loxapine Molindone Olanzapine Pimozide Quetiapine Risperidone Ziprasidone |
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What range of receptors are blocked by 1st generation Antipsychotics?
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Wide variety of CNS, ANS, and Endocrine effects -
Dopamine receptors (most) Alpha-1 Adrenergic receptors Muscarinic ACh receptors H1 Histamine receptors 5-HT2 Serotonin receptors |
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What symptoms are produced by blocking D2 receptors in the nigrostriatal pathway?
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EPS - motor abnormalities (parkinsonism), tardive dyskinesia, hyperkinetic movement disorder
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What symptoms result from blockade of D2 receptors in the mesolimbic pathway?
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Reduced positive symptoms of schizophrenia
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What symptoms result from blockade of D2 receptors in the mesocortical pathway?
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The mesocortical pathway is already deficient in patients with schizophrenia
Results in cognitive symptoms or worsened negative symptoms |
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What symptoms result form blockade of D2 receptors in the tuberoinfundibular pathway?
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Results in hyperprolactinemia - which leads to amenorrhea-galactorrhea, false positive pregnancy tests, increased libido in women, decreased libido and gynecomastia in men
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What receptors are acted upon by second generation antipsychotics?
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Second generation antipsychotics are 5HT2a and D2 ANTAGONISTS
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How are second generation antipsychotics (5HT-2A antagonists) useful for schizophrenia?
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5HT(2A) antagonists cause the release of dopamine, because activation of that receptor inhibits dopamine release.
So this is very useful for relieving negative symptoms via the mesocortical pathway. |
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What are the relative binding affinities of Chlorpromazine?
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alpha1 = 5-HT2 > D2 > D1
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What are the relative binding affinities of Haloperidol?
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D2 > D1 = D4 > alpha1 > 5-HT2
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What are the relative binding affinities of Clozapine?
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D4 = alpha1 > 5-HT2 > D2 = D1
*Also potent at H1 --> sedation |
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What are the adverse effects of muscarinic cholinoceptor blockade in the ANS?
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Loss of accomodation, dry mouth, difficulty urinating, constipation
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What are the adverse effects of alpha adrenoceptor blockade in the ANS?
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Orthostatic hypotension, impotence, failure to ejaculate
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What are the adverse effects of dopamine receptor blockade in the CNS?
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Parkinson's syndrome, akathisia, dystonias
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What are the adverse effects of supersensitivity of dopamine receptors in the CNS?
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Tardive dyskinesia
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What are the adverse effects of a muscarinic blockade in the CNS?
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Toxic confusional state
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What are the side effects of dopamine receptor blockade resulting in hyperprolactinemia in the endocrine system?
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Amenorrhea-galactorrhea, infertility, impotence
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Do the antipsychotics have any teratogenic effects?
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dysmorphogenesis - small increase in teratogenic risk but otherwise safe during pregnancy
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Do the antipsychotics have a high or low therapeutic index?
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High therapeutic index
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What is neuroleptic malignant syndrome?
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Caused by excessive rapid blockade of dopamine receptors - extremely sensitive extrapyramidal effects
Marked muscle rigidity, sweating is impaired, fever, autonomic instability (altered BP and rate) |
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How do you treat neuroleptic malignant syndrome?
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Muscle relaxants - Diazepam, Dantrolene
Dopamine agonists - Bromocriptine Cooling by physical means (if fever) |
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What is tardive dyskinesia?
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Late-occurring choreoathetoid-like movements
Caused mainly by the older (typical, neuroleptic) antipsychotics Continue even when the drug is discontinued - MAY BE IRREVERSIBLE |
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What are some important characteristics of the antipsychotic Chlorpromazine?
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Inexpensive, lots of side effects
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What are some important characteristics of the antipsychotic Thioridazine?
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Cardiotoxicity and retinal pigmentation
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What are some important characteristics of the antipsychotic Haloperidol?
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Severe extrapyramidal syndrome
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What are some important characteristics of the antipsychotic Clozapine?
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May help treatment-resistant patients, but agranulocytosis occurs in 2% of patients - weekly blood counts mandatory
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What are some important characteristics of the antipsychotic Risperidone?
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Broad efficacy, few EPS at low dose, EPS and hypotension at high dose, and dosing daily or every 2 weeks
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What are some important characteristics of the antipsychotic Olanzapine?
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Good for negative and positive symptoms of schizophrenia, acute mania and bipolar disease
Few EPS Weight Gain |
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What are some important characteristics of the antipsychotic Thiothixene?
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Skin discoloration (blue-gray), rash
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Describe absorption and distribution of antipsychotics.
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Most readily but incompletely absorbed
Chlorpromazine and Thioridazine have systemic availability from 25-35% Haloperidol 65% bioavailability Most are highly lipid soluble and protein bound (92-99%) Large volume of distribution Much longer duration of action than predicted by half life |
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Describe the metabolism of the antipsychotics.
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Most are extensively metabolized
Extensive first pass metabolism except Thioridazine (Major metabolite is mesoridazine, which is more potent than parent compound. Fatal if overdosed --> ventricular tachyarrhythmias |
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What is the difference between Bipolar 1 and Bipolar 2?
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Bipolar 1 - occurs with mania
Bipolar 2 - occurs without mania |
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What are some mood stabilizers?
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Lithium carbonate
Valproic acid Carbamazapine Lamotrigine Aripiprazole, Chlorpromazine, Olanzapine, Quetiapine, Resiperidone, Ziprasidone Olanzapine + Fluoxetine combination, Quetiapine |
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What mood stabilizing agent is the main drug for mania disorders (anti-manic, mood stabilizer)?
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Lithium carbonate
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What mood stabilizing agent is used for bipolar if Lithium fails?
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Valproic acid
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What mood stabilizing agent is used for acute maniac or as a prophylactic?
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Carbamazapine
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What mood stabilizing agent is used to prevent recurrences of mania?
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Lamotrigine
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What mood stabilizing agents are approved for the manic phase of bipolar?
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Aripiprazole
Chlorpromazine Olanzapine Quetiapine Resiperidone Ziprasidone |
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Describe the pharmacokinetics of Lithium
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Monovalent cation that is well absorbed - complete in 6-8 hours, peak in 30 minutes - 2 hours
Distributed in total body water, some sequestration in bone. No protein binding Not metabolized Excreted in urine (90%) Plasma 1/2 life (20 hours) |
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Describe the pharmacodynamics of Lithium.
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Resembles Na+ ion, substitute for sodium in action potential, Li+/Na+ exchanger
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What are some effects of Lithium on Neurotransmitters?
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Enhances some actions of serotonin
Decreases norepinephrine and dopamine turnover May block the development of dopamine receptor sensitivity May augment the synthesis of acetylcholine, perhaps by increasing choline uptake into nerve terminals |
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What are the adverse effects of Lithium (many...)?
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GI - N/V/diarrhea
Neurologic - motor movement disorders (tremor), propranolol and atenolol reduce this effect; mental confusion (toxic doses) Thyroid (hypothyroid-like symptoms) Renal (polydipsia, polyuria) Edema Cardiac: "sick sinus" bradycardia-tachycardia Pregnancy: renal clearance increases during pregnancy and decreases postpartum (watch for toxicity) - enters breast milk at 30-50% of plasma levels --> poor suck reflex, cyanosis, hepatomegaly; Dismorphogenesis unclear - may cause cardiac malformations Leukocytosis |
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What are some alternatives to Lithium?
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Valproic acid - can be used with Lithium or fail to respond to Lithium
(Teratogenic - do not give during pregnancy, 1-2% risk of spina bifida) Carbamazapine - less efficacious, can be used as a monotherapy or in combination for refractory patients |
