Anti-psychotics (Walworth) - 10/19/16 Flashcards
Describe the dopamine hypothesis of schizophrenia as it pertains to clinically useful antipsychotic drugs.
Schizophrenia results from increased and dysregulated levels of DA neurotransmission.
Describe dopamine pathways in the brain responsive to drugs used to treat psychosis.
- Nigrostriatal Pathway
- Substantia Nigra to Striatum
- Motor Control - death of neurons in this pathway –> PD
- Tuberoinfundibular Pathway
- Hypothalamus to Pituitary
- Hormonal Regulation
- Maternal Behavior
- Pregnancy
- Sensory processes
- Mesolimbic & Mesocortical Pathways
- Ventral Tegmental Area to Nucleus Accumbens, Amygdala, and Hippocampus and PFC
- Memory
- Motivation and emotional response
- Reward and desire
- Addiction
- Dysfunction associated with hallucinations and schizophrenia
Describe mechanisms of action by which clinically useful antipsychotics are thought to act
Most antipsychotics strongly block dopamine receptors (D2) in CNS (particularly in mesolimbic frontal system)
Some block D1 (post synaptic)
Describe limitations to dopamine hypothesis of schizophrenia
- All evidence is circumstantial
- Antipsychotic drugs = partly effective in most patients
- 2nd generation drugs are not very potent antagonists at D2 receptors, yet are effectively clinically!
- Clozapine
- Olanzapine
- Quetiapine
Differentiate typical from atypical antipsychotic drugs with regard to side effects and therapeutic benefit.
Examples of drugs in each category
Typical or atypical: presence or absence of side effects observed w/ conventional, 1st gen antipsychotics
Typical
- Substantial risk of EPS
- Reduce (+) symptoms only
- (+) correlate w hyperactivity of mesolimbic D2 receptors
Atypical
- Reduced risk of EPS
- Reduce (+) and (-) symptoms
- (+) correlate w hyperactivity of mesolimbic D2 receptors
- (-) correlate w/ hypoactivity of mesocortical neurons
Typical drugs:
- Chlorpromazine
- Phenothiazine
- Haloperidol
- Thioridazine
Atypical drugs:
- Clozopine
- Olanzapine
- Quetiapine
- Risperidone
- Ziprasidone
- Aripiprazole
List toxicities that accompany antipsychotic therapy
- Reversible neurologic effects (EPS)
- Tardive dyskinesias
- Neuroleptic malignant syndrome
- Endocrine and metabolic effects
- Autonomic effects
- Sedation (esp. phenothiazines)
- QT interval prolongation (quetiapine, ziprasidone)
- Agranulocytosis (only clozapine)
Reversible neurologic effects: EPS
Symptoms:
- Parkinson-like syndrome w/ bradykinesia, rigidity, and tremor
- Akathisia (motor restlessness)
- Dystonias (muscle spasms)
Occur most frequently with haloperidol, fluphenazine, trifluoperazine
To treat: toxicity reversed by decreasing dose and administration of antimuscarinic agent
Tardive dyskinesias
- Choreoathetoid movements of muscles of the lips and buccal cavity - may be irreversible even after discontinuation of drug
- Develop after several years (tardy…. tardive) –> though have appeared as early as 6 mo. afer drug initiation
To treat:
- Discontinue or reduce dose of current antipsychotic
- Eliminate all drugs with central anticholingeric action
- Add diazepam (high dose if necessary) to enhance GABAergic activity
Neuroleptic Malignant Syndrome (4)
Symptoms & Treatment
- Muscle rigidity
- Excessive sweating
- Hyperpyrexia
- Autonomic instability (may be life-threatening)
May be seen in patients who are particularly sensitive to extrapyramidal effects of antipsychotics → symptoms can persist for days after stopping neuroleptic
Treatment: dantrolene, muscle relaxant that acts at ryanodine receptor to restore calcium levels in muscle cells, and dopamine agonists (bromocriptine)
Endocrine Effects
D2 receptor blockade in pituitary
- Hyperprolactinemia
- Gynecomastia
- Amenorrhea-galactorrhea syndrome
- Infertility
Metabolic Effects
- Significant weight gain and hyperglycemia
- Hyperlipidemia
- Some patients may develop DM
FDA requires warnings about hyperglycemia and DM to be included on all 2nd generation (atypical) agents
Identify typical antipsychotic drugs
- Reconcile pharmacodynamics of typical agents with their major pharmacologic effects
Typical antipsychotics fall into chemically distinct classes:
- Phenothiazine derivates
- Thioxanthene derivates
- Butyrophenone
Clinically effective dose of antipsychotic agents correlates with binding at D2 receptors
Pharmacologic Effects of older (typical) agents?
The higher the affinity for the D2 receptor, the lower dose of drug you need
Dopamine receptor blockade is MAJOR effect that correlates with therapeutic benefit for OLDER (TYPICAL) agents
-
Extrapyramidal effects: Parkinson-like syndrome with TRAP symptoms
- Haloperidol
- Fluphenazine, trifluoperazine
Autonomic effects of typical agents
Due to blockade of peripheral alpha-adrenergic and/or muscarinic receptors
- Typicals:
- Thioridazine has strongest autonomic effects
- Haloperidol has weakest
Effect of alpha-adrenergic receptor blockade:
- Postural hypotension
- Failure to ejaculate
Effect of muscarinic blockade
- Atropine-like effects pronounced w/ use of thioridazine and phenothiazines w/ aliphatic side chains (e.g. chlorpromazine)
- CNS effects (confusional state)
- Urinary retention? → switch to agent w/ less antimuscarinic action
Identify atypical antipsychotic drugs
Reconcile pharmacodynamics of atypical agents with their major pharmacologic effects
Cannot be grouped chemically b/c don’t come from derivates
Atypicals have higher serotonin blockade activity than D2 blockade activity as compared to typical agents
Identify clozapine’s unique pharmacodynamic property and unique toxicity
- Limited D2 block; higher affinity for D4 and 5-HT2 block
- Unique toxicity: risk of agranulocytosis
- Effective, but reserved for treatment-resistant schizophrenia
- D4 receptors is highly expressed in limbic system
Describe the pharmacodynamic properties of aripiprazole as a partial agonist.
- Partial agonist at D2 and 5-HT1a receptors
- Antagonist at 5-HT2a receptors
Unlike haloperidol (at high dose) which completely inhibits DA response, aripiprazole sustains DA response… agonist activity
Aripiprazole does not completely inhibit DA
Summarize pharmacokinetics properties of antipsychotic agents as they pertain to routes of administration
- Absorption/Distribution
- Metabolism
- Excretion
- Absorption/Distribution
- Readily, though incompletely absorbed when given orrally
- High first-pass transformation (thus bioavilability is 25% to 35%… (65% for haloperidol);
- Lipid soluble
- Readily enter CNS
- Accumulate in brain, lung, and other tissues with rich blood supply
- Enter fetal circulation and breast milk
- Metabolism
- Metabolized by oxidative processes (P450s) and by glucuronidation, sulfation
- Metabolism by cytochrome P450s raises potential for significant drug interactions!!
- Excretion
- Little if any of the drugs are excreted unchanged due to extensive metabolism to more polar substances
Antipsychotic Agents: subclasses and preparations available
Selected Drug Interactions: Second-Generation Antipsychotics
