Lechure & ANTIPSYCHOTIC AGENTS Define the following terms: * Bipolar disorder © Extrapyramidal rea © Neuroleptic © Tardive dyskinesia You should be able to: © Des cribe the dopamine hypothesis of schizophrenia «Identify the major dopaminergic tracts in the CNS * Describe the behavioral effects of antipsychotic drugs on nonpsychotic individuals and on schizophrenic individuals List the adverse effects of the major antipsychotic drugs ‘* Describe the pharmacokinetics and pharmacodynamics of lithiumANTIPSYCHOTIC DRUGS THE NATURE OF SCHIZOPHRENIA ‘+ Schizophrenia psychotic illness is characterised by delusions, hallucinations and thought disorder (positive symptoms), together with social withdrawal, flattening of emotional responses and cognitive impairment (negative symptoms). «Acute episodes (mainly positive symptoms) frequently recur and develop into chronic schizophrenia, with predominantly negative symptoms. * Incidence is about 1% of population, with a strong, but nor invariable, hereditary component. «Pharmacological evidence is generally consistent with dopamine overactivity hypothesis, supported by biochemical findings and imaging studies. ‘© There is also evidence for involvement of glutamate and -HT. CLASSIFICATION OF ANTIPSYCHOTIC DRUGS © Main categories are: > classical ‘typical’ antipsychotics (e.g. chlorpromazine, haloperidol, fluphenazine, thioridazine, flupenthixol, clopenthixol) > tecent ‘atypical’ antipsychotics (e.g. clozapine, risperidone, sertindole, quetiapine) © Distinction between typical and atypical groups is not clearly defined, but rests on: receptor profile incidence of extrapyramidal side-effects (less in atypical group) efficacy in treatment-resistant group of patients efficacy against negative symptoms. vvvv MECHANISMS OF ACTION OF ANTIPSYCHOTIC DRUGS + All antipsychotic drugs are antagonists at dopamine Dz receptors but most also block other monoamine receptors, especially 5-H». Clozapine also blocks Ds receptors. © Antipsychotic potency generally runs parallel to activity on Dz receptors, but other activities may determine side-effect profile. «Antipsychotics take days or weeks to work, suggesting that secondary effects (e.g increase in number of Dy receptors in limbic structure) may be more important than direct effect of D2 receptor block. ANTIPSYCHOTIC-INDUCED MOTOR DISTURBANCES Major problem of antipsychotic drug treatment. © Two main types of disturbance occur: > acute, reversible dystonias and Parkinson-like symptoms > slowly developing tardive dyskinesia, often irreversible. © Acute symptoms comprise involuntary movements, of tremor and rigidity, and are probably the direct consequence of block of nigrostriatal dopamine receptors. « Tardive dyskinesia comprises mainly involuntary movements of face and limbs, appearing after months or years of antipsychotic treatment. It may be associated withproliferation of dopamine receptors (possibly presynaptic) in corpus striatum, Treatment is generally unsuccessful * Incidence of acute dystonias and tardive dyskinesia is less with atypical antipsychotics, and particularly low with clozapine. This may reflect relatively strong muscarinic receptor block with these drugs, or a degree of selectivity for the mesolimbic, as opposed to the nigrostriatal, dopamine pathways. UNWANTED EFFECTS OF ANTIPSYCHOTIC DRUGS + Important side-effects common to most drugs are extrapyramidal motor disturbances (see before) and endocrine disturbances (increased prolactin release); these are secondary to dopamine receptor block. Sedation, hypotension and weight gain are also common. * Other side-effects (dry mouth, blurred vision, hypotension, etc) result from blockade of other receptors, particularly o: adrenoceptors and muscarinic acetylcholine receptors, * Some antipsychotics cause agranulocytosis as a rare and serious idiosyncratic reaction. With clozapine leucopenia is common and requires routine monitoring, * Antipsychotic malignant syndrome is a rare but potentially dangerous idiosyncratic reaction (muscle rigidity, a rapid rise in body temperature and mental confusion. Generally reversible, but death from renal or cardiovascular failure occurs in 10-20%). CLINICAL EFFICACY OF ANTIPSYCHOTIC DRUGS. + Antipsychotic drugs are effective in controlling symptoms of acute schizophrenia, when lange doses may be needed. + Long-term antipsychotic treatment is often effective in preventing recurrence of schizophrenic attacks, and this is a major factor in allowing schizophrenic patients to lead normal lives. * Depot preparations are often used for maintenance therapy. * Antipsychotics are not generally effective in improving negative schizophrenic symptoms, though newer drugs are claimed to relieve these symptoms. * Approximately 40% of chronic schizophrenic patients are poorly controlled by antipsychotic drugs; clozapine may be effective in some of these ‘antipsychotic-resistant” patients. * There are small, if any, overall differences in efficacy between different antipsychotic drugs, though side-effects differ significantly._usfoypmnosnoaa #09 ‘aurfoyo1 iene auLRost Paenyeas ‘ssoxdsoouaipe » wo éureu Bune (oyu Londsoounspen 9 ‘uo|suarod.y odéy ‘uonspes pas ‘siaayo-apis feprumeatdanxa ga ‘oidaoo1 urwadop so sod Wiqh ‘uydouangy aropunas ToSSTUNS SUN TUT HSIN yeay> 899) auopuodsry. asupete 9) sssop_uBy aanou auras ‘yo apis axBsounoupn ssquodewwe roxnpusdnyy rodsp se aigeyieae (ensewesoeu®) uypejoid — poseorou Bae opis oxBiouyjoyonue somsy ‘oopuner | 44 | = | sos, ‘sim you s90p 1nq “suErEWOLMLONYD SY Aouapuen Sq Suons ‘Sup snoyossdnue Appa ‘ssojo suousydoutang, ado posn ropuadoreys ~eapo>, some! [| sutzepion Sd s9mo] im Susp rsag ‘sse19 ourzenouayg f 2sne> 20u soop ing ‘aurzewoudso;ys sy ue TRISTAN ago SURV Sip ee Sad 20w ‘UosuEIOdKY ssp ‘pum | axnannsqo SuonDEDL usnIDRSY rein asne> jou op ing ‘reyus oe suzendnyin f ‘soay> 218 veumorpodsy | ** | + | paeals) Surreeoydnig ‘sesso | onimaooo06%3) por SE ‘SBP oHOYDASAHUP Jo SONSTOIEIEY)SKELETAL MUSCLE RELAXANTS AND DRUG THERAPY OF PARKINSON’S DISEASE OBJECTIVES Define the following terms: © Depolarizing blockade © Desensitization © Malignant hyperthermia © Nondepolarizing blockade © Spasmolytic © Stabilizing blockade + Dopaminereceptor-agonists © Dopaminergic-cholinergic balance © Dyskinesia * Levodopa adjunct You should be able to: Describe the transmission process at the neuromuscular end-plate and the points at which drugs can modify this process * List 3 nondepolarizing neuromuscular blockers and one depolarizing neuromuscular blocker; compare their pharmocokinetics ‘© List the major drugs used in the treatment of skeletal muscle spasticity and describe their mechanisms. * Describe the mechanisms by which levodopa, bromocriptine, amantadine and muscarinic blocking drugs alleviate parkinsonism © Describe the therapeutic and toxic effects of the antiparkinsonism agents.DRUG TREATMENT OF PARKINSON’S DISEASE PARKINSON’ DRUGS USED IN P. ISEASE Parkinson’s disease (PD) is a degenerative disease of the basal ganglia causing tremor at rest, muscle rigidity and hypokinesia, often with dementia. PD is often idiopathic, but it may follow stroke, virus infection or can be drug-induced (antipsychotic drugs). PD is associated with early degeneration of dopaminergic nigrostriatal neurons, followed by more general neurodegeneration. PD can be induced by MPTP — a neurotoxin affecting dopamine neurons. Similar environmental neurotoxins, as well as genetic factors, may be involved in human PD. ON’S DISEASE Drugs act by counteracting deficiency of dopamine in basal ganglia or by blocking muscarinic receptors. None of the available drugs affects the underlying eurodegeneration. he most effective drug is levodopa, a dopamine precursor that passes the blood-brain barrier; it is given with an inhibitor of peripheral dopa decarboxylase (carbidopa, benserazide) to minimise side-effects, Sometimes a COMT inhibitor (entacapone) is also given, to retard dopamine metabolism. Levodopa is effective in most patients initially, but often loses efficacy after about 2 years. Main unwanted effects of levodopa are involuntary movements, which occur in most patients within 2 years, and unpredictable ‘on-off effect’ (rapid fluctuations in clinical state, with hypokinesia and rigidity suddenly worsened for anything from a few minutes to a few hours, and then improve again. Mechanism unknown). Others are nausea, postural hypotension and occasionally psychotic symptoms. Other useful drugs include bromocriptine (dopamine agonist), selegiline (monoamine oxidase B inhibitor), amantadine (? enhance dopamine release) and benztropine and trihexyphenidil, (muscarinic receptor antagonists used for parkinsonism caused by antipsychotic drugs).