Drugsandthe Brain Part4 Neuroleptics


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Drugsandthe Brain Part4 Neuroleptics

  1. 1. Drugs and the Brain Part 4 The Neuroleptics or Tricyclics (Anti-schizophrenics)
  2. 2. History of Neuroleptics <ul><li>Started as a tool for anesthesia </li></ul><ul><li>Henri Laborit, a French neurosurgeon looking for a drug to calm patients before administering general anesthesia for surgery, made first discovery in 1950 </li></ul><ul><ul><li>He thought histamine released during anesthesia accounted for some patient deaths </li></ul></ul><ul><li>Decided to try an antihistamine as a calming agent </li></ul><ul><ul><li>First used promethazine </li></ul></ul><ul><li>This was so successful that he asked the manufacturer for related compounds </li></ul><ul><ul><li>He was given chlorpromazine, a drug the manufacturer had deemed to sedating to market. </li></ul></ul>
  3. 3. Psychiatric Use of Chlorpromazine <ul><li>Laborit was so impressed by the calming effect of chlorpromazine that he recommended it to his psychiatrist colleagues as possible treatment for agitated patients </li></ul><ul><li>First trials were unsuccessful </li></ul><ul><li>1951 – 2 French psychiatrists tried giving chlorpromazine in progressively increasing doses and reaching much higher levels </li></ul><ul><ul><li>This was very successful </li></ul></ul><ul><ul><li>Difficult patients became more manageable </li></ul></ul>
  4. 4. Chlorpromazine & Schizophrenia <ul><li>Chlorpromazine influenced schizophrenic patients in a unique way </li></ul><ul><ul><li>Concluded that chlorpromazine was a true anti-schizophrenic, not merely a sedative </li></ul></ul><ul><li>This suggested that the drug acted on a specific location in the brain </li></ul><ul><li>Improvement in schizophrenic symptoms with chlorpromazine was accompanied by developing Parkinson’s-like side effects </li></ul>
  5. 5. Schizophrenia <ul><li>A neurological disorder characterized by altered thought patterns and social withdrawal. </li></ul><ul><li>Etiology is unknown. </li></ul><ul><ul><li>There may be a genetic component. </li></ul></ul><ul><li>Two main categories of symptoms . </li></ul><ul><ul><li>Positive symptoms: delusions, hallucinations, disordered thought and disorganized speech. </li></ul></ul><ul><ul><li>Negative symptoms: flat affect, social withdrawal, emotional detachment, cognitive deficits and poverty of speech. </li></ul></ul>
  6. 6. Resperine & Schizophrenia <ul><li>Extracted from Indian snake-root plant, Rauwolfia serpentina </li></ul><ul><li>Used to treat high blood pressure </li></ul><ul><li>A trial of resperine on schizophrenics produced results similar to those with chlorpromazine </li></ul><ul><ul><li>Patients improved but developed Parkinsonian symptoms </li></ul></ul><ul><li>The 2 drugs are chemically unrelated </li></ul><ul><li>Antischizophrenic action and the Parkinsonian side effects must be caused by a the same biochemical event </li></ul><ul><ul><li>This event must be caused by both drugs </li></ul></ul>
  7. 7. Dopamine <ul><li>By the 1960’s several studies linked Parkinsonian symptoms to loss of dopamine </li></ul><ul><li>Swedish pharmacologist, Arvid Carlsson administered a series of neuroleptics to rats </li></ul><ul><ul><li>Found changes in the levels of metabolites for norepinephrine and dopamine </li></ul></ul><ul><ul><li>Levels of transmitters themselves were unchanged </li></ul></ul><ul><li>Higher levels of norepinephrine metabolites had no relation to the clinical actions of neuroleptics </li></ul><ul><li>Relative increases in dopamine metabolite levels by neuroleptics paralleled the clinical potency of the drugs </li></ul><ul><ul><li>The more a drug accelerated the firing of dopamine neurons, the more potent as an antischizophrenic </li></ul></ul>
  8. 8. Contradictions <ul><li>Increase in firing rate of dopamine neurons would mean more dopamine released and metabolized. </li></ul><ul><li>But resperine causes dopamine to almost vanish from the brain. </li></ul><ul><li>Chlorpromazine does not effect dopamine levels, but increases dopamine metabolites </li></ul><ul><li>So how can both drugs produce the same action? </li></ul>
  9. 9. A Hypothesis <ul><li>Carlsson suggested that neuroleptics block receptors for dopamine. </li></ul><ul><li>Neuroleptics are dopamine antagonists. </li></ul><ul><li>Reduce overall dopamine-like activity in the brain. </li></ul><ul><li>Feedback between neurons with dopamine receptors and neurons that produce dopamine would result in turning on dopamine neurons, causing them to fire more rapidly & produce more dopamine. </li></ul>
  10. 10. A Biochemical Test <ul><li>A biochemical method to demonstrate chlorpromazine action on dopamine receptors </li></ul><ul><li>Dopamine increases cyclicAMP in the corpus striatum </li></ul><ul><ul><li>Cyclic AMP is a 2 nd messenger </li></ul></ul><ul><ul><li>Mixing homogenate of corpus striatum with low concentrations of dopamine stimulates formation of cyclicAMP </li></ul></ul><ul><li>Chlorpromazine blocks ability of dopamine to stimulate formation of cyclicAMP </li></ul><ul><li>Therefore, chlorpromazine binds and blocks the dopamine receptor, without causing the subsequent 2 nd messenger actions = antagonist </li></ul>
  11. 11. Identifying Dopamine Receptors <ul><li>1975 – direct binding of radiolabeled dopamine allowed identification of dopamine receptors </li></ul><ul><li>Chlorpromazine blocked binding to these receptors </li></ul><ul><li>Haloperidol is a neuroleptic that does not block dopamine stimulation of cyclic AMP </li></ul><ul><li>Binding of radiolabeled haloperidol was different </li></ul><ul><ul><li>Bound sites that competed for dopamine </li></ul></ul><ul><ul><li>But not the same sites bound by radiolabeled dopamine in previous experiment </li></ul></ul><ul><li>Neurotransmitters will bind to more than one type of receptor </li></ul><ul><ul><li>Multiple dopamine receptors may be involved </li></ul></ul>
  12. 12. Dopamine Receptors <ul><li>Two types of receptors: D1 & D2 </li></ul><ul><li>Radiolabeled dopamine bound D1 </li></ul><ul><li>Increase in cAMP resulted only from binding D1 </li></ul><ul><li>Radiolabeled haloperidol bound only D2 </li></ul><ul><li>Therefore dopamine & chlorpromazine must bind both D1 & D2 receptors </li></ul><ul><li>Antischizophrenic properties of neuroleptics must be due to blocking D2 receptors </li></ul>
  13. 13. Different Dopamine Pathways <ul><li>Chemical staining techniques were used to reveal dopamine containing neuronal pathways </li></ul><ul><li>Major dopamine pathway has cell bodies in the substantia nigra of the brain stem </li></ul><ul><ul><li>These neurons terminate in the corpus striatum </li></ul></ul><ul><ul><li>This is the pathway involved in Parkinson’s </li></ul></ul><ul><li>2nd pathway has cell bodies in the tegumentum </li></ul><ul><ul><li>These neurons project to the limbic system, an area dealing with emotion </li></ul></ul><ul><ul><li>Blocking dopamine receptors in these areas accounts for the anti-schizophrenic actions of these drugs </li></ul></ul><ul><li>Another dopamine pathway has cell bodies in the hypothalamus projecting to the pituitary </li></ul><ul><ul><li>Accounts for sexual side effects </li></ul></ul>
  14. 14. Variety of Neuroleptics <ul><li>A variety of neuroleptic drugs are in use </li></ul><ul><li>All are tricyclic compounds </li></ul><ul><li>All are dopamine antagonists </li></ul><ul><ul><li>Generally D2 antagonists. </li></ul></ul><ul><ul><li>There is a strong positive correlation between the therapeutic dose of neuroleptics and their affinity for D2 receptors. </li></ul></ul><ul><li>Include the thioxanthines like flupenthixol and the phenothiazines such as fluphenazine. </li></ul><ul><ul><li>Thioxanthines lack the ring nitrogen of phenothiazines and the carbon chain begins with a double bond. </li></ul></ul>
  15. 15. Structure of Chlorpromazine <ul><li>A typical neuroleptic (tricyclic) </li></ul><ul><li>Includes three rings </li></ul><ul><li>An electronegative group on the ring determines the electron density around the ring system </li></ul><ul><li>The amino side chain must be on the same side of the molecule as the electronegative group approximating the conformation of dopamine </li></ul><ul><li>The number of carbons between the ring carbon or nitrogen and the side-chain amine must be three for maximal activity. </li></ul>
  16. 16. Thioxanthines & Phenothiazines
  17. 17. Atypical Neuroleptics <ul><li>Several new compounds have been developed with unique properties </li></ul><ul><li>Atypical neuroleptics generally effective in treating both the positive & negative symptoms of schizophrenia. </li></ul><ul><li>Clozapine was the first dopamine antagonist with a relatively low incidence of extrapyramidal side effects. </li></ul><ul><ul><li>may be due in part to its potent anticholinergic effects </li></ul></ul><ul><ul><li>also to a high affinity for 5-HT 2 (serotonin) receptors. </li></ul></ul><ul><li>Atypical neuroleptics generally have high affinity for 5-HT2, D2, M1, and H1 receptors. </li></ul>
  18. 18. Problems <ul><li>Drugs relieve schizophrenic symptoms, but they do not cure it </li></ul><ul><ul><li>Patients must continue to take drugs or symptoms return </li></ul></ul><ul><li>Not all symptoms associated with schizophrenia respond to these drugs </li></ul><ul><li>Parkinsonian side effects </li></ul><ul><li>Prolonged use results in uncontroled movement of tongue & limbs: tardive dyskinesia </li></ul><ul><li>Clozapine, perhaps the most effective drug in this group, produces a decrease in white blood cell production </li></ul><ul><ul><li>Action is on both dopamine & seratonin </li></ul></ul>