Antipsychotic agents & Lithium by Dr. Nadeem Korai
Antipsychotic agents & LithiumDr. Nadeem AkhtarMBBS.M.PhilAsst. Professor PharmacologyAmna Inayat Medical CollegeShaikhupura
Schizophrenia• One of the most important psychiatric illness• Affects about 1 % in population• Strongly linked with hereditary• Characterized by positive and negativesymptoms
• Positive symptoms• Thought disorders• Delusions• Hallucinations• Paranoia• Negative symptoms• Amotivation• Social withdrawal• Flat affect• Poverty of speech
Hypotheses of schizophrenia• Dopamine hypothesis• Serotonin hypothesis• Glutamate hypothesis
Dopaminergic systems• Mesolimbic-mesocortical pathway:• Projects from cell bodies in ventraltegmentum in bundles of axons to limbicsystem and neocortex• Nigrostriatal pathway:• project from substansia nigra to dorsalstriatum, caudate and putamen. involved incoordination of voluntary movements
:• Tuberoinfundibular system:• Arises in arcuate nuclei and periventricularneurons and releases dopamine in pituitaryportal circulation. Dopamine release by theseneurons inhibit prolactin secretion• Incertohypothalamic:• Forms connections from medial zona incernato hypothalamus and amygdala. Involved incopulatory behavior in rats.
Major antipsychotics• Drug name Advantages Disavantages• TYPICALS• Chloropromazine inexpensive many adverse effects,esp. autonamic•• Thioridazine slight EPS cardiotoxic•• Fluphenazine available in depot form increase tardive dyskinesia•• Haloperidol available in parenteral form severe EPS• ATYPICALS• Clozapine treatment resistant patient may cause agranulocytosis•• Olanzopine no EPS,effective in –ve & +ve sympt wt gain•• Risperidone no EPS, effective –ve, +ve symptoms hypotension with high doses•• Airiprazole lower wt gain, parenteral form available QT prolongation•• Quetipine no EPS, effective in all symptoms short half life••
Absorption and distribution• Oral doses of chloropromazine and thioriazinehave systemic bioavailability of 25-35 %• Haloperidol has less first pass metabolism andsystemic availability about 65%• Most antipsychotics have large volume ofdistribution usually more than 7 L/kg• Metabolites of chlorpromazine excretedthrough urine weeks after the lost dose
• Long acting inject able formulations causeblockade of D2 receptors for 3-6 months afterlast injection.• The average time for relapse in stable patientswho discontinue treatment is 6 months• Without clozapine which has relapse usuallyrapid and severe• Thus clozapine should never be discontinuedabruptly
Metabolism• Most antipsychotics are metabolized bycytochrome 450 enzyme system• At the typical clinical doses antipsychoticdrugs don’t interfere with the metabolism ofother drugs
Drug combinations• Tricyclic antidepressants or SSRIs are oftenused with antipsychotics for associatedsymptoms of depression, complicatingschezophrenia.• ECT is useful adjunct for antipsychotic drugs• Lithium or valproic acid is added withantipsychotic agents to resistant patients
Adverse reactions• A). Behavioral effects:• A pseudodepression may develop due to druginduced akenesia with older antipsychoticswhich usually relieve with antiparkinsonismdrugs• B).Neurological effects:• Extrapyrammidal reactions include Parkinsonssyndrome, akathisia and acute dystonicreactions• C).A.N.S:
• A.N.S: orthostatic hypotension , retention ofurine or impaired ejaculation are most commonadverse effects of chloropromazine ormesoridazine.• Metabolic & Endocrine: wait gain is commonwith clozapine and olanzapine. Hyperglycemiamay develop secondary to wait gain.Hyperprolactinemia in women results inamenorrhea-galactorrhea syndrome andinfertility.
• In men loss of libido, impotency and infertilitymay develop. Hyperprolactinemia may causeosteoporosis in women. If such adverse affectsdevelop than drug should switch to atypicalagents that don’t raise prolactin e.gairipiprazole
• Toxic or allergic reactions: clozapine causesagranulocytosis in significant number of casesapproximately 1-2% who received treatment• Cholestatic jaundice and skin eruptions occurrarely with high potency antipsychotics.• Ocular complications: deposits in cornea andlens are common with chloropromazine.Thioridazine may cause retinitis pigmentosawith large doses
• Cardiac toxicity: larger doses of thioridazinemay produce ventricular arrythmias andsudden death. Among atypical agentsziprasidone may produce QT prolongation• Clozapine is linked with myocarditis andshould be discontinued if observed.
Neuroleptic malignant syndrome• This life threatening disorder is believed to bedue to excessively blockade of the dopaminereceptors usually due to treatment of older ortypical antipsychotics. Characterized withextreme muscle rigidity, loss of sweating, highgrade fever, raised level of creatine kinase,leukocytosis. Treatment: dopamine agonistse.g bromocriptine, diazepam are often usefulwith switch over to atypicals
Bipolar disorder• Also known as manic disorder occurs 1-3% ofpapulation, begin in early age but usually firsttime diagnosed in 3rd or 4th decade.• Symptoms• Excitement . aggression• Hyperactivity . diminished need for sleep• Impulsivity . psychotic symptoms• Disinhibition . may be with depression
Treatment• A. LITHIUM• B. Anticonvulsants• Carbamezipine• Valproic acid• Lamotrigine• Gabapentin• Oxcarbezepine• Topiramate• And atypical antipsychotics are used
Lithium• First used therapeutically in mid 19th centuryfor gout• It was briefly used as a substitute to patientsof hypertension but was withdrawnimmediately• In 1949, Cade discovered that it is effective forthe treatment of bipolar disorder
• Mode of action:• Acting as second messenger for norepinephrineand dopamine• Enhances serotonin and cholinergic action• Adverse effects:• Tremors• Dcreased thyroid functions• Diabetes insipdus• Edema• Cardiac effects