ANTIPSYCHOTICS: Traditional Drugs (p.1) 1. Introduction antipsychotic drugs = “major tranquilizers”, “neuroleptics” these drugs have revolutionized the tx of schizophrenia since 1950s do not cure schizophrenia (or mania or Tourettes), but do significantly reduce their symptoms allow clearer thought, less agitation without marked sedation, dependence, addition, or tolerance (to the beneficial effects) there are twobroad categories of antipsychotic drugs:
a. 1st generation or traditional (phenothiazines & butyrophenomes) b. 2nd generation or atypicals (dual action drugs)
history of their development: French surgeon (Henri Laborit), 1950, searching for a drug to reduce surgical shock (fear, anxiety, high ANS arousal, high muscle tension)
started with a phenothiazine molecule (which was like histamine) --- no effect on ANS, but did calm pts while they were still awake French chemist (Paul Carpentier) experimented with phenothiazine, added Cl- atom --- chlor promazine (Thorazine)! Laborit persuaded MD colleague to try it on his patients (1952) significantly improved manic, agitated, hallucinating pts., enabled them to live as out-pts, without physical restraints in 1955 Thorazine was approved for use in USA --- immediate reduction in #s of hospitalized pts. and for the first time interest in the neural basis of “mental” illness began, suggested a biological cause (vs. learned) ANTIPSYCHOTICS: Traditional Drugs (p.2) 2. Neural Basis of Schizophrenia (summary) . Sxs significantly worsen in early 20s (as frontal lobes become fully active – damaged) . large overlap with depression (limbic system damaged) . sources of neural damage: pathological genetic expression, acquired damage (viral, CNS stimulant abuse, prenatal fever) . damage to DA, glutamate, 5HT, & GABA systems . widespread damage (multi NT systems, many symptoms): perceptual distortions (esp. auditory), language (disorganized speech), poor inferential thinking (delusions), poor social skills (blunted affect, distorted emotions), poor motor skills, anhedonia, poor cognitive/ executive function skills (poor focus, concentration, memory) . implies widespread, basic damage (in synaptogenesis, synaptic “pruning”, apoptosis, neural migration, muelination, neural meitosis) . Sxs associated with both “soft” and “hard” neurological signs 3. So-called “positive” and “negative” Sxs of schizophrenia + Sxs: delusions, hallucinations, bizarre behaviors/postures dissociated/fragmented thoughts, illogical thinking incoherent speech, impaired executive functioning most likely due to overly active DA system - Sxs: blunted affect, odd/reduced emotional reactions, apathy
no initiative, no motivation, no interests, no goals social withdrawal lack of spontaneous speech likely due to underactive glutamate/NMDA system, perhaps secondary to abnormalities in 5HT system drugs used to treat psychosis affect many RSs: DA2, AChMuscarinic, 5HT1A, 5HT2, H1, NE alpha#1&2, & more ANTIPSYCHOTICS: Traditional Drugs (p.3) 4. Traditional Antipsychotics are especially good at reducing the + Sxs (do not reduce – Sxs) major SEs – EPSEs (extrapyramidal side effects), TD (tardive dyskinesia) major affect on NS is to block DA2 postsynaptic RSs --- up-regulation? DA2 RSs are found in 4 systems in the CNS: mesocorticalhypothalamic-pituitary mesolimbic nigrostriatal-basal ganglia also block several other NTs: ACh, NE, 5HT, H (are “dirty drugs”) as + Sxs decrease, S becomes more aware of improvement all neuroleptics are about equal in decreasing the + Sxs but different pts. respond better to different drugs…implies that there are individual differences in exact underlying NTs/neural systems must also combine pharmacotherapy with supportive environment and cog.-behavioral therapy S can live as out-pt now…but increases stress of needing to cope with “real world” and increased risk for medication non-compliance general approach: treat S initially with higher doses, enough to reduce + Sxs when S stabilizes, the begin to reduce dose to lowest possible dose to still block + Sxs & yet has fewest SEs possible use only one drug at a time if possible use no/minimal other drugs to control SEs do not recommend “drug holidays”, may actually worsen SEs ANTIPSYCHOTICS: Traditional Drugs (p4) 4. Traditional Antipsychotics (cont.) there are high and low potency neuroleptics: high potency drugs - strongly block DA2 RS, weak antiACh effects lots of EPSEs, higher risk for TD fewer antiACh effects, but greater risk for NMS (neuroleptic malignant syndrome) less sedation, less orthostatic hypotension e.g. haloperidol (Haldol) fluphenazine (Prolixin,Permitil) trifluoperazine (Stelazine) thiothixene (Navane) molindone (Moban) perphenazine (Trilafon) pimozide (Orap) loxapine (Loxitane) low potency drugs – weakly block DA2 RSs, strong antiACh effects fewer EPSEs, less risk for TD severe antiACh effects (constipation, poor memory/concentration, dry mouth, urinary retention, worsened glaucoma, orthostatic hypotension; at higher doses --- delirium, tachycardia, bradycardia, blurred vision) more sedation, more orthostatic hypotension esp. in elderly Ss e.g. thioridazine (Mellaril) chlorpromazine (Thorazine) mesoridazine (Serentil) which drug is given to which pt. is mostly a matter of which set of SEs S will tolerate better like the antidepressants, may have to do trial&error approach fortunately, there is a large therapeutic index for all these meds ANTIPSYCHOTICS: Traditional Drugs (p. 5) 5. SE: Motor Disturbances found in 70-85% of all pts. on neuroleptics blockage of DA2 RSs in basal ganglia note: NC pts. develop Parkinson’s Disease when >80% of DA neurons have died these motor disturbances are often called EPSEs or “Parkinson-like” a. Parkinsonian effects (40% of all pts.) rigidity & tremors (resting) poverty of movement difficulty initiating a movement/ending a movement no (emotional) facial movements or gestures, stiff slowness of movement (bradykinesia) jerky handwriting short, rotating head movements become rigid & immobile as Sxs worsen (“frozen”) except for stiff, shaking limbs secondary to imbalance in DA & ACh (DA < ACh) . give pt.an antiACh drug as well (Artane, Cogentin, Symmetrel) . use an antipsychotic that blocks both DA & ACh e.g. thioridazine (Mellaril) . use a DA agonist(e.g.amantadine/Symmetrel,selegiline/Deprenyl) esp. a problem in elderly pts. who have already lost some DA neurons b. Akathesia (20% of all pts.) compulsive restlessness, repetitive & purposeless movements can look like anxiety but isn’t esp. in younger Ss tx. w/ DA agonists or w/ ACh antagonists…why? sometimes tx. with propranolol/Inderol (beta-blocker) very unpleasant SE ANTIPSYCHOTICS: Traditional (p.6) 5. SEs: Motor Disturbances (cont.) c. Dystonias (67% of all pts.) sudden, jerky movements usually seen shortly after start use of drug (w/i 4 days) or shortly after drug’s dose is increased continuous, involuntary writhings caused by widespread and sustained muscle contractions, spasms e.g. “oculogyric crisis” e.g. mouth puckers, tongue protrusion, inability to swallow, disrupted breathing movements (spasms in diaphragm), profuse sweating also tx. with DA agonists or antiACh drugs esp. in young males d. Akinesia reduced movements tremors, shuffling gait/steps, stiff posture muscle rigidity --- “catatonic” posture, “waxy flexibility” socially withdrawn, appear “depressed” – makes difficult to Dx pt. truly depressed psychotic or “iatrogenic” effects from meds? esp. w/ potent, low antiACh neuroleptics e.g. haloperidol (Haldol), thiothixene (Navane) is a reversible effect (when increase DA or decrease ACh or D/C antipsychotic…but psychotic Sxs return… e. Tardive Dyskinesia (25% of adults, 12.5% of adolescents) “late-appearing” Dyskinesia (>6 months after start of meds) poorly coordinated movements insidious onset of Sxs ANTIPSYCHOTICS: Traditional (p. 7) 5. SEs: Motor Disturbances (cont.) e. Tardive Dyskinesia (cont.) “worm-like” movements of tongue, tongue thrusting/protrusion darting tongue movements puffing out of cheeks eyelids flutter, upper lip trembles (“rabbiting”) head arches backward or turns to side rocking, pelvic thrusting fling or flail arms esp. in older (> 50 – 70 years), and female pts. more severe in pts. w/ - Sxs of schizophrenia gets worse after antipsychotic drug is D/Cd, at least initially…why? gets better if drug dose is increased…why? what is underlying mechanism?. “denervation supersensitivity” How to help with TD? use lower doses to traditional antipsychotics do not use these drugs, esp. in elderly females use newer antipsychotics D/C traditional antipsychotics at the very first sign of TD Sxs may still be reversible early on 7. SEs: Autonomic NS & Hormonal Imbalances occur because of blockage of DA2 RSs in hypothalamus e.g. weight gain, constipation e.g. faulty temperature regulation (including NMS) e.g. sexual disturbances (esp. thioridazine/Mellaril) ANTIPSYCHOTICS: Traditional (p.8) 7. SEs:Autonomic NS & Hormonal Imbalances (cont.) NMS = neuroleptic malignant syndrome 1 – 2.4% of pts. on neuroleptics, 14-30% of these die (renal failure) high fever (108 degrees F.), sweating confusion, muscle rigidity, tremors, depressed respiration, ANS hyper-reactivity, stupor, hypertension, increased heart rate esp. w/ high potency neuroleptics (e.g. Prolixin) esp. young adult males & non-schizophrenics 8. SEs: AntiACh Effects typical anticholinergic syndrome dry mouth, blurred vision (dilated pupils), constipation decreased memory increased intraocular pressure (worsens glaucoma) urinary retention esp. chlorpromazine/Thorazine 9. SEs: AntiNE Effects typical antiadrenergic effects lowered blood pressure, orthostatic hypotension (esp. in elderly) 10. SEs: AntiH Effects antihistaminergic effects sedation, weight gain, antiemetic effects 11. Other SEs agranulocytosis (35% of these pts. die) hepatitis and liver damage (esp. chlorpromazine/Thorazine) photosensitivity (skin “sunburn”, “night blindness”) note: patient non-compliance with medication is almost entirely due to inability to tolerate the negative SEs of traditional antipsychotics
ANTIPSYCOTICS: Traditional (p.9) 12. Other Uses of Traditional Antipsychotics to reduce Sxs of Tourette’s Syndrome to reduce nausea & vomiting (e.g. in pt. on chemotherapy for cancer) to reduce severe, continuous hiccups to sedate pt. before surgery, or in an agitated pt. to delay ejaculation (premature ejaculator) to relieve severe itching to reduce severe manic symptoms (while waiting for Li effects to start) to reduce withdrawal effects (esp. hallucinations) & delirium tremens to reduce psychedelic hallucinations all of the above have been successfully treated by use of traditional phenothiazines
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THE FUZZY FRONT END FOR INCREMENTAL , PLATFORM AND BREAKTHROUGH PRODUCTS AND SERVICES INTRODUCTION The innovation process may be divided into three areas: the Fuzzy Front End (FFE), the New Product Development Portion (NPD) and commercialization as indicated in the figure 1. Most projects, once the concept is defined in the FFE, are managed in the NPD portion using the traditional