88INDOLE DERIVATIVESINDOMETHACINIt is indole acetic acid derivative possess-ing potent antiinflammatory property andhaving a good analgesic and antipyretic ac-tion also. Mechanism of action is same asother NSAIDs.It is readily absorbed from the GI tract,99% bound to plasma proteins, distributedinto synovial fluid, the central nervous sys-tem, placenta and breast milk. It ismetabolised in the liver to glucuronide con-jugates, excretion of metabolites is predomi-nantly in the urine with some amount ap-pearing in the faeces.Adverse effects include nausea, vomiting,anorexia, gastric bleeding, diarrhoea, dizzi-ness, frontal headache, confusion, depression,psychosis, hallucination, leukopenia, epigas-tric distress and rarely aplastic anaemia.It is used in rheumatoid arthritis, osteo-arthritis, ankylosing spondylitis and gout.SULINDACIt is a fluorinated derivative of in-domethacin, has longer duration of actionand is used orally. It is prodrug, convertedto active sulfide metabolite.PROPIONIC ACID DERIVATIVESThe drugs like ibuprofen, flurbiprofen,ketoprofen etc. possess antiinflammatoryproperty similar to aspirin but toxicity andadverse effects are fewer and of lesser in-tensity. These preparations alone and incombination with other NSAIDs are used fortreatment of inflammatory disorders,muscle spasm and rheumatic disorders.They are all well absorbed orally and arehighly bound to plasma proteins (90-99%).Metabolized largely in liver by hydroxyla-tion and glucuronide conjugation and ex-creted in urine as well as in bile.Adverse effects include nausea, vomit-ing, epigastric discomfort, dizziness, head-ache, skin rash and thrombocytopenia.It is indicated in rheumatoid and osteo-arthritis, ankylosing spondylitis, mild tomoderate pain including dysmenorrhoea,soft tissue injuries, fractures and postopera-tive analgesia.FLURBIPROFENIt is NSAID used in musculoskeletal andjoint disorders. It acts by inhibition ofcyclooxygenase.It is readily absorbed from GI tract andis 99% bound to plasma proteins.Metabolised mainly by hydroxylation andconjugation and excreted in urine.KETOPROFENIt is an inhibitor of cyclooxygenase withanalgesic, antiinflammatory and antipyreticproperties.Readily absorbed from the GI tract. Foodslows the rate of absorption but not the totalbioavailability. Extensively bound to plasmaproteins and substantial concentrations arefound in synovial fluid. Metabolised mainlyby conjugation with glucuronic acid and ex-creted mainly in the urine.NAPROXENAfter oral administration, it is fullyabsorbed. It is 99% bound to plasma pro-
Non-Narcotic Analgesics (NSAID’s)89teins and crosses placenta. The metabo-lites of naproxen are almost entirely ex-creted in urine. Naproxen is more effica-cious and better tolerated. It is also longeracting and has the advantage of twicedaily dosing.Adverse effects include dyspepsia, gas-tric discomfort, nausea, vomiting, heartburn,dizziness, drowsiness, headache, fatigue,sweating, depression, ototoxicity, pruritusand thrombocytopenia.It is indicated in osteoarthritis, rheuma-toid arthritis, musculoskeletal disorders,primary dysmenorrhoea, acute gout, pelvicinflammation, ankylosing spondylitis, toothextraction, tendinitis, bursitis and juvenilearthritis.ANTHRANILIC ACID DERIVATIVESMEFENAMIC ACIDIt is an inhibitor of cyclooxygenase with an-algesic, antiinflammatory and antipyreticproperties.It is readily absorbed from the GI tract,extensively bound to plasma proteins andexcreted mainly in the urine as unchangeddrug or conjugated metabolites.Adverse effects include drowsiness, di-arrhoea, rashes (withdraw treatment),thrombocytopenia, haemolytic anaemia,aplastic anaemia. Convulsions may occur inoverdosage.It is indicated in muscle, joint and softtissue pain, dysmenorrhoea, rheumatoidand osteoarthritis, as antipyretic, in dentalpain, postoperative or postpartum pain.OXICAM DERIVATIVESPIROXICAMPiroxicam is a new NSAID and has anti-in-flammatory, analgesic and antipyretic activ-ity. It provides effective and long-lastingrelief of pain and stiffness. Its convenientonce daily dosage provides round the clockrelief of symptoms.It acts peripherally by inhibiting the syn-thesis of prostaglandins by reversible inhi-bition of cyclooxygenase. Inhibition of themigration of leukocytes to an inflammatorysite and inhibition of the release of lysoso-mal enzymes may also be involved in theantiinflammatory action.It is well absorbed from the GIT. The rate,but not the extent of absorption is decreasedby food and 99% plasma protein bound.Piroxicam is metabolised in liver. Because oflong half life single daily administration issufficient. The half life may be especially pro-longed in patients with renal function impair-ment. Excretion of piroxicam is through re-nal, fecal and as unmetabolised piroxicam.Adverse effects include, nausea, vom-iting, epigastric distress, skin rash, rarelyhaematuria, proteinuria, hepatitis and de-pression.It is indicated in acute or long term usein acute and chronic rheumatoid arthritisand other rheumatic disorders like osteoar-thritis, ankylosing spondylitis, cervicalspondylosis, acute gouty arthritis and acutemusculoskeletal disorders.Tenoxicam is a congener of piroxicamwith similar properties and uses.
90ARYL ACETIC ACID DERIVATIVESDICLOFENACIt is a NSAID with pronounced antirheu-matic, antiinflammatory, analgesic and an-tipyretic properties. Inhibition of prostag-landin biosynthesis is fundamental mecha-nism of action. In rheumatic diseases, it leadsto marked relief from pain at rest, pain onmovement, morning stiffness and swellingof the joints, as well as by an improvementin function.In posttraumatic and postoperative in-flammatory conditions, diclofenac rapidlyrelieves both spontaneous pain and pain onmovement and reduces inflammatory swell-ing and wound oedema.It also exerts a pronounced analgesic ef-fect in moderate and severe pain of non-rheumatic origin.After the passage of the tablet throughthe stomach, it is completely absorbed. Dueto the enteric coating, onset of absorption isdelayed. However, once the absorption setsin diclofenac is rapidly absorbed.Diclofenac enters the synovial fluid,where maximum concentrations are mea-sured two to four hours after peak plasmavalues have been attained.Adverse effects include nausea, vomit-ing, epigastric discomfort, skin rash, pepticulcer, fluid retention, edema and impair-ment of hepatic function rarely.It is used in the treatment of inflamma-tory and degenerative forms of rheumatism,rheumatoid arthritis, ankylosing spondyli-tis, osteoarthritis and spondyloarthritis,painful syndromes of the vertebral column,non-articular rheumatism and acute attacksof gout,Also used in posttraumatic and postop-erative pain, inflammation and swelling e.g.following dental or orthopaedic surgery,painful and/or inflammatory conditions ingynaecology e.g. primary dysmenorrhoea oradnexitis, in severe painful inflammatoryinfections of the ear, nose or throat e.g.pharyngotonsillitis, otitis etc.ACECLOFENACIt is newer COX-2 inhibitor and is a phe-nylacetic acid derivative. It also inhibits syn-thesis of IL-1b and TNF-a, thus inhibitingPGE2 production. It is rapidly and com-pletely absorbed after oral administration,highly protein bound and bioavailability isalmost 100%. It is metabolized to a majormetabolite 4′-hydroxyaceclofenac.It is indicated for the relief of pain andinflammation in osteoarthritis, rheumatoidarthritis, ankylosing spondylitis andmusculo-skeletal trauma.Adverse effects include dyspepsia, ab-dominal pain, nausea and diarrhoea.PARA-AMINOPHENOL DERIVATIVESPARACETAMOLIt is a para-amino phenol derivative, acts onCNS to produce analgesia and antipyreticeffect. It has negligible antiinflammatoryaction peripherally in therapeutic uses. It ispoor inhibitor of PG synthesis in peripheraltissues, but more active on COX in brain. Italso raises the pain threshold.
Non-Narcotic Analgesics (NSAID’s)91Paracetamol is given orally and is well ab-sorbed, peak plasma concentration is reachedin 30 to 60 minutes. About 1/3rd is bound toplasma proteins and the drug is inactivated inthe liver, being conjugated to give the glucu-ronide or sulphate which are excreted in urine.Adverse effects include nausea, epigas-tric distress. Rarely it can cause skin rash.Acute toxicity may result in hepatic failure.Paracetamol is used for the rapid reliefof fever, pains and aches such as headache,earache, toothache, fibrositis, myalgia, neu-ralgia, arthralgia, osteoarthritis and postop-erative pain.NEWER COX-2 INHIBITORSKETOROLACKetorolac is a NSAID chemically relatedto indomethacin and tolmetin.Ketorolac has antiinflammatory and an-tipyretic action that, together with its anal-gesic effects.The absorption is rapid with maximumplasma concentration being attained 30 to40 minutes after oral administration. Highlyplasma protein bound and metabolised byglucuronidation. 60% is excreted unchangedin urine.Adverse effects include, nausea, vom-iting, epigastric distress, diarrhoea, drowsi-ness, dizziness, skin rash etc.It is indicated in short term managementof acute pain, pain associated with surgicalprocedures.NIMESULIDENimesulide is a NSAID of the sulfonanilideclass. Nimesulide has exhibited potencysimilar to or greater than that of indometha-cin, diclofenac, piroxicam and ibuprofen instandard animal models of inflammation.Oral drug absorption is nearly completeand concomitant administration of food maydecrease the rate, but not the extent of ab-sorption. The drug is 99% bound to plasmaproteins and metabolised (1 to 3% of a doseis excreted unchanged in the urine) to sev-eral metabolites which are excreted mainlyin the urine or the faeces.The adverse effects are gastrointestinaldisturbances (epigastralgia, heart burns,nausea, diarrhoea and vomiting). It can alsolead to rash, pruritus, dizziness, somnolenceand headache.There were reports of hepatotoxicity es-pecially in children, due to which it shouldnot be used in children and in the presenceof hepatic dysfunction.It is indicated in the treatment of a vari-ety of painful inflammatory conditions, in-cluding osteoarthritis, oncology, postopera-tively, trauma, sports injuries, ear, nose andthroat disorders, dental surgery, bursitis/tendinitis, thrombophlebitis, upper airwaysinflammation and gynaecological disorders.Nimesulide has shown to be well toleratedeven by aspirin sensitive asthmatic patients.CELECOXIBIt is a NSAID which has COX-2 selec-tivity. It is a diaryl substituted pyrazole.It exhibits antiinflammatory, analgesicand antipyretic activities which are believedto be due to inhibition of COX-2. At thera-peutic concentrations in humans, celecoxibdoes not inhibit COX-1 enzyme.
92After oral administration it is rapidlyabsorbed from the GI tract and undergoespredominantly hepatic metabolism withlittle unchanged drug recovered in the urineand faeces. It is widely distributed into tis-sues. All metabolites are inactive.Adverse effects include headache, diar-rhoea, rhinitis, nausea, sinusitis, dyspepsia,abdominal pain etc.It is used in rheumatoid arthritis, osteo-arthritis and other conditions includingrheumatic pain, neuralgia, gout andankylosing spondylitis etc.NABUMETONENabumetone selectively inhibits COX-2. It is metabolised into 6-methoxy-2-naphthylacetic acid (MNA), that is a potentinhibitor of COX-2. It has no inhibitory ef-fect on COX-1 which is responsible for pros-taglandin synthesis in gastric mucosa,thereby minimising the risk of problems likeulcers and hypertension. After oral admin-istration 80% of dose is excreted in the urine.Peak plasma concentration is reached after2.5 to 4 hours.Adverse effects include nausea, vomit-ing, heartburn, diarrhoea, constipation,headache and dizziness.It is indicated in osteoarthritis, rheuma-toid arthritis, inflammatory conditions andsoft tissue injuries.DRUGS USED IN RHEUMATOID ARTHRITISRheumatoid arthritis (RA) is an autoim-mune chronic inflammatory joint disease. Itis a progressive symmetrical, destructiveand deforming polyarthritis affecting proxi-mal small joints of hand (usually) and largejoints as well. It is also associated with anumber of extra-articular and systemic fea-tures. There is joint inflammation, synovialproliferation and destruction of articularcartilage by inflammatory cells. There is nosingle treatment for RA and the principlesof treatment are directed towards relief ofsymptoms and suppression of active andprogressive disease with conservation andmaintenance of joint function.Initial treatment consists of NSAIDs, lowdose corticosteroids. If the symptoms are notcontrolled then second line/disease modi-fying drugs (DMDs) are added. Since it is aprogressive disease, spontaneous remis-sions are rare and joint damage occurs early,DMDs are started early and continued in-definitely with regular monitoring.The disease modifying drugs (DMDs/DMARDs) used are gold, d-penicillamine,hydroxychloroquine, sulfasalazine andimmuno-suppressants like methotrexate,azathioprine, cyclosporin etc.GOLD COMPOUNDSIt appears to reduce immune respon-siveness. It inhibits the migration of mono-nuclear cells in area of inflammation. It mayalso stabilise lysosomal membrane, hencedamage to cartilage is prevented.It can be used orally and bioavailabilityis 25%. After administration it binds exten-sively to plasma albumin and is distributedto inflamed synovium, liver and kidney.Adverse effects include diarrhoea, der-matitis, stomatitis, glossitis, pharyngitis,pruritus, exfoliative dermatitis, alopecia,blood dyscrasias including thrombocytope-
Non-Narcotic Analgesics (NSAID’s)93nia, leucopenia, renal and hepatic damageand encephalopathy.PENICILLAMINEThe exact mechanisms of action of peni-cillamine in rheumatoid arthritis is notknown. After oral administration it is partlymetabolised and partly excreted unchanged.Adverse effects include Gl upset, doserelated impairment of taste, thrombocytope-nia, aplastic anemia, allergic reactions, skinrash, fever, SLE and proteinuria.SULFASALAZINEWhen taken orally, it liberates 5-ASA (5-aminosalicylic acid) and sulfapyridine incolon. 5-ASA acts locally by inhibiting PGsynthesis and provide symptomatic relief inulcerative colitis. Sulfapyridine is absorbedsystemically and inhibits generation of su-peroxide radicals and cytokine elaborationby inflammatory cells and is responsible forbeneficial effects in RA.METHOTREXATEIt is a dihydrofolate reductase inhibitorimmuno-suppressant. Benefit in RA is dueto inhibition of cytokine production, chemo-taxis and cell mediated immune reaction.DRUGS FOR GOUTGout results from hyperuricemia i.e. in-creased serum uric acid levels. Normal se-rum uric acid level is 1-5 mg/dl. Uric acidis formed in the metabolism of purine. Whenthe blood levels of uric acid are high, it pre-cipitates in joints, cartilage, kidney and sub-cutaneous tissues and leads to various signsand symptoms. Hyperuricemia is alsoseen in various leukemias, lymphomas(increased production) or is drug induced(due to reduced renal excretion by uric acid).Drugs used for gout can be divided intotwo groups:a. Drugs for acute attack of gout: NSAIDs,colchicine, corticosteroids.b. Drugs for chronic gout/hyperuricemia:Can be uric acid synthesis inhibitors(allopurinol) and uricosurics (increaserenal excretion of uric acids) e.g.probenecid and sulfinpyrazone.NSAIDSDrugs useful are indomethacin,piroxicam or naproxen. Their usefulness isdue to strong antiinflammatory action andcan be continued for 3-4 weeks. They alsoinhibit chemotactic migration of leukocytesinto the affected joint.CORTICOSTEROIDSSystemic/intraarticular steroids can beused in those cases not responding to or tol-erating NSAIDs/colchicine.COLCHICINEIt is effective for treatment of acute at-tacks of gout. It has no effect on renal excre-tion of uric acid. It binds to tubulin, it in-terferes with function of mitotic spindles,causes depolymerization and disappear-ance of fibrillar microtubules in granulo-cytes. In gout, the useful of colchicine is dueto the inhibition of the release of glycopro-teins from granulocytes in inflamed jointthus preventing precipitation of uric acidcrystals and release of lysosomal enzymes.After oral administration it is rapidlyabsorbed. A major part of the drug is ex-creted in faeces.
94Adverse effects include nausea, vomit-ing, diarrhoea, abdominal pain, neuropathy,myopathy especially in patients with de-creased renal function. Prolonged therapymay lead to aplastic anaemia, agranulocy-tosis, alopecia and myopathy.It is used in the treatment of acute goutand prophylaxis of gout.ALLOPURINOLIt inhibits the terminal steps in uric acidbiosynthesis by inhibiting enzyme xan-thine oxidase. During therapy with allopu-rinol the uric acid plasma levels decline.After oral intake it is absorbed relativelyrapidly. It is converted to alloxanthine whichis active and non competitive inhibitor.Adverse effects include hypersensitiv-ity reactions, maculopapular rash, urticaria,myalgia, malaise fever, transient leucope-nia or leukocytosis, hepatic damage, nau-sea, vomiting, diarrhoea, headache anddrowsiness.It is indicated in primary hyperuricaemiaof gout, secondary hyperuricaemia due tomyeloid metaplasia, radiation, cancer chemo-therapy, thiazide diuretics.PROBENECIDIt increases the excretion of uric acid (byinhibiting its reabsorption from kidney tu-bules) and hence causes reduced serum lev-els of uric acid.After oral administration it is completelyabsorbed. It is 90% plasma protein bound. Itis partly metabolised and excreted in urine.The metabolites also have uricosuric action.Adverse effects include skin rash,gastro-intestinal irritation. Overdosage mayresult in convulsions and death due to res-piratory failure.It is used in chronic gout and secondaryhyperuricaemia.SULFINPYRAZONEPyrazolone derivative related to phe-nylbutazone. It has uricosuric action. It alsoinhibits platelet aggregation.It is well absorbed orally and 98%plasma protein bound. It is excreted by ac-tive secretion in proximal renal tubule.Adverse effects are gastric irritation(most common), hypersensitivity reactions.It is used in chronic gout.
(Mode of Action of Drugs)PharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsChapter1. 4Chapter2.5PsychotropicAgentsPsychotropicAgentsPsychopharmacological agents may be clas-sified into three broad groups used in vari-ous states of psychic disorders.1. Antipsychotic drugs or major tranquil-lizers used in all types of psychosismainly schizophrenia.2. Antianxiety drugs or minor tranquil-lizers used in anxiety.3. Antidepressants for minor and majordepressive disorders and moodstabilisers (antimanic drugs) for mania.ANTIPSYCHOTIC DRUGS(MAJOR TRANQUILLIZERS)They are classified as in table 2.5.1.Table 2.5.1: Classification of antipsychotic drugs.I. PhenothiazinesChlorpromazine (MEGATIL) 100-800 mg/dayTriflupromazine (SIQUIL) 50-200 mg/dayTrifluoperazine (NEOCALM) 5-15 mg BDII. ButyrophenonesHaloperidol (HEXIDOL) 5-10 mg/dayDroperidol (DROPEROL) 10 mg IM, 5-15 mg/day IVTrifluperidol (TRIPERIDOL) 0.5-8 mg/dayIII. Other newer compoundsLoxapine (LOXAPAC) 60-100 mg BD-QIDClozapine (SIZOPIN) 25-50 mg/dayPimozide (PIMODAC) 3-4 mg/dayZuclopenthixol (CLOPIXOL) 20-40 mg IM repeated 2-4 week intervalMolindone 20-200 mg/daySulpiride 0.4-2 g/daySertindole 4-24 mg/day
96PHENOTHIAZINESPHARMACOLOGICAL ACTIONSa. Action on CNS: Effects differ in nor-mal and psychotic individuals.1. Sedation: They produce sedationwhich does not progress to anaesthesia.They decrease the agitation, anxiety andaggressiveness in psychotic patient withoutaffecting wakefulness.2. Antipsychotic effect: In schizophrenicpatients, they improve thought disorders,blunted affect, withdrawal and self centeredbehaviour. They also improve the halluci-nations and delusions.They produce neuroleptic syndromewhich consists of motor retardation andemotional quietening.In animal studies, they reduce the spon-taneous motor activity and produce cata-lepsy (state of rigidity and immobility).3. Action on CTZ: Chlorpromazine de-presses the chemoreceptor trigger zone(CTZ) and acts as a powerful antiemeticagent.4. Effect on hypothalamus: They producehypothermia by acting on temperatureregulating centre. They also producecentral sympathoplegia resulting inmiosis and failure in ejaculation.They produce parkinsonism like reac-tion by increasing the spontaneous firing ofdopaminergic neurons of basal ganglia.b. Effect on CVS: Chlorpromazine mayproduce orthostatic hypotension prob-ably due to inhibition of centrally me-diated pressor reflexes. It also causesprolongation of QT interval in ECG.c. Effect on endocrine system: They canproduce amenorrhoea and galactor-rhoea due to increase in serum prolac-tin level in females. It also blocks therelease of growth hormone, ADH andgonadotrophin secretion.d. Local anaesthetic: Chlorpromazine hasa potent local anaesthetic action.e. ANS: They have varying degree of aadrenergic blocking activity. They alsohave weak anti-cholinergic, H1-antihistaminic and anti 5-HT actions aswell.They also cause blockade of postsynap-tic monoaminergic (including 5-HT, norad-renaline and dopamine) transmission in thebrain resulting in decrease in central sym-pathetic activity.PharmacokineticsPhenothiazines are well absorbed afteroral and parenteral administration. They aredistributed in all the body tissues andmetabolised in liver by hydroxylation andglucuronide conjugation and demethylation.The metabolites are excreted in urine and bilefor long period of time even after discontinu-ing the drug.Adverse ReactionsCNS side effects include lethargy,drowsiness, increase in REM sleep, restless-ness, excitement and impaired psychomo-tor functions.The other side effects include epilepticseizures, disturbances in body temperatureregulation. ANS side effects include tachy-cardia, difficulty in micturition, inhibitionof ejaculation, postural hypotension,blurring of vision (with thioridazine), con-stipation, nasal stuffiness etc.
Psychotropic Agents97Extrapyramidal reactions include par-kinsonism, acute muscular dystonias,akathisia, tardive dyskinesia and malignantneuroleptic syndrome. They can also causehypersensitivity reaction includingcholestatic jaundice, skin rash, urticaria,photosensitivity and contact dermatitis.There is also blue pigmentation of skin, len-ticular opacities on prolonged use of drug.Therapeutic Uses1. Treatment of psychosis (schizophre-nia): Schizophrenia is a split mind orsplitting of perception from reality.The patient of schizophrenia is dis-sociated from the world around himand lives in their own world whichis characterized by aggression, anxi-ety, restlessness, hallucinations anddelusions. Phenothiazines reduce thehallucinations, aggression, anxietyand make them acceptable and coop-erative.2. In the treatment of manic depressivepsychosis (treatment of mania).3. In alcoholic hallucinosis andHuntington’s disease.4. As an antiemetic in drug and diseaseinduced vomiting. Also useful in morn-ing sickness but are ineffective in mo-tion sickness.5. In the treatment of intractable hic-cough.6. In the treatment of behavioural disor-ders in children.7. As preanaesthetic medication.8. To produce hypothermia.TRIFLUOPERAZINEIt is a phenothiazine derivative andis used in hallucination, delusions, agi-tation, withdrawal and other schizo-phrenic symptoms in schizophrenia,schizoaffective disorders, mania, hypo-mania and panic anxiety.BUTYROPHENONESHALOPERIDOLIt is a potent antipsychotic drug. It doesnot cause weight gain. Its pharmacologicaleffects are similar to phenothiazines.Adverse effects include dystonia, hal-lucinations, restlessness, nausea, epigas-tric discomfort, anaemia, blurred vision,hypersensitivity reaction, blood dyscra-sia, jaundice, galactorrhoea, gynecomas-tia and amenorrhoea.It is indicated in acute and chronicschizophrenia, anxiety disorders, acute ma-nia, hypomania and behavioural disordersin children; antiemetic neuroleptanalgesia,Gilles de la Tourette’s syndrome andHuntington’s disease.DROPERIDOLIt is a short acting neuroleptic agent usedin anaesthesia.TRIFLUPERIDOLIt exerts sedative and tranquillizing ef-fect and it is postulated that it blocks dopam-ine receptors within CNS. It is used in acuteand chronic psychoses, anxiety disorders,mania and schizophrenia.Side effects include nausea, epigastricdistress, dry mouth, blurred vision, jaun-dice, skin rash and photosensitivity.
98NEWER COMPOUNDSLOXAPINEIt is the antipsychotic agent resemblingchlorpromazine in pharmacological actions.It is used in manifestation of psychoticdisorders, acute and chronic paranoidschizophrenia.CLOZAPINEIt is an atypical neuroleptic drug. It in-terferes with binding of dopamine at D1 andD2 receptors in CNS. It produces few ex-trapyramidal symptoms.After oral administration it is rapidly andalmost completely absorbed. The absorptionis not affected by food and it is almost com-pletely metabolised in liver. The metabolitesare much less potent and less toxic.Adverse effects include nausea, vomit-ing, heartburn, constipation, diarrhoea,agranulocytosis, eosinophilia, postural hy-potension, tachycardia, angina, headache,sedation, dizziness, syncope, seizures, hy-perthermia, neuroleptic malignant syn-drome, weight gain and sexual dysfunction.May lead to myocarditis.It is indicated in all types of schizophre-nia including resistant cases not respondingto conventional antipsychotics and chronicschizophrenia.PIMOZIDEIt is a diphenylbutylpiperidine deriva-tive. Pimozide causes low incidence of dys-tonic reactions.It acts by blocking dopaminergic recep-tors and has weak a-adrenergic and cholin-ergic blocking activity. It has long durationof action (several days) after a single dose.Adverse effects include mania, insomnia,nervousness, fatigue, drowsiness, nausea,extrapyramidal reactions and irritability.It is used in the treatment of acute andchronic schizophrenia and manic excite-ment.ZUCLOPENTHIXOLZuclopenthixol is a thioxanthene of highpotency with general property similar to thechlorpromazine. It has a piperazine side-chain.Adverse effects include extrapyramidalsymptoms and on prolonged administra-tion, occasionally tardive dyskinesia, hypo-thermia (occasionally pyrexia), drowsiness,apathy, pallor, nightmares, insomnia, de-pression, agitation, EEG changes, endocrineeffects such as menstrual disturbances, ga-lactorrhoea, gynaecomastia, impotence andweight gain, alterations in liver function.It is used in the maintenance therapy ofschizophrenia.ANTIANXIETY DRUGS(MINOR TRANQUILLIZERS)Anxiety is a emotional feeling of fear alongwith discomfort and uneasiness. Antianxi-ety drugs are used to control the symptomsof anxiety without affecting the other men-tal and physical functions of the body. Theyare classified as in table 2.5.2.BENZODIAZEPINESThe detailed pharmacology of all thebenzodiazepines used in anxiety disorders
Psychotropic Agents99is discussed in chapter ‘Sedative andhypnotics’.They have selective action on limbic sys-tem and have little effect on other body sys-tems. They help in improving the anxiety andstress related symptoms. They are widelyused because of lower dependence produc-ing liability and wide margin of safety.AZAPIRONESBUSPIRONEIt belongs to azapirones which is chemi-cally and pharmacologically distinct class.It acts as a partial agonist at serotonin anddopamine receptors and having no hypnoticand sedative action. It does not interact withbenzodiazepine receptor or modify GABA-ergic transmission.It is rapidly absorbed and undergoesextensive first pass metabolism and excretedthrough kidney and faeces.It is used in short-term management ofanxiety disorders and relief of symptoms ofanxiety with or without accompanying de-pression.Adverse effects include headache, ex-citement, tachycardia, palpitation (may raiseBP in patients on MAO inhibitors), nervous-ness, dizziness, drowsiness, confusion, fa-tigue, sweating etc.OTHER COMPOUNDSHYDROXYZINEIt is antihistaminic agent having anti-emetic, sedative, anticholinergic and localanaesthetic property. Used in anxiety, pru-ritus and dermatoses; as an adjunct therapyin acute/ chronic alcoholism.Side effects include epigastric distress,nausea and impaired alertness.BETA BLOCKERSBeta blockers provide symptomatic re-lief by decreasing the symptoms due to sym-pathetic overactivity e.g. palpitation, trem-ors, rise in BP, etc. They may be used as ad-juvant to benzo-diazepines.ANTIDEPRESSANTSThey are classified into two main categoriese.g. MAO inhibitors and tricyclic/tetracyclicantidepressants as in table 2.5.3.MAO INHIBITORSMonoamine oxidase (MAO) is an intra-cellular enzyme and metabolizes intracellu-Table 2.5.2: Classification of antianxiety drugs.I. BenzodiazepinesDiazepam, lorazepam, oxazepam, alprazolam. Details are already given in chapter ‘Sedative and hypnotics’along with trade name and dose also.II. AzapironesBuspirone (BUSPIDAC) 5-15 BD-TDSIII. OthersHydroxyzine (ATARAX) 25-100 mg TDS-QIDMeprobamateBeta blockers e.g. propranolol.
100lar catecholamines present in the non-granu-lar cytoplasmic pool. It also causes oxida-tive deamination of 5-hydroxytryptamine.Their antidepressant action may be relatedto increase in the brain catecholamines con-tent.MAO inhibitors increase the catechola-mine content of various organs so that morecatecholamine is to be released by indirectlyacting sympathomimetic amines.Adverse effects include tremor, insom-nia, delirium, convulsion, postural hypoten-sion, dry mouth, constipation, difficulty inmicturition, impotence, constipation. Theserious side effects include peripheral neu-ropathy and jaundice due to hepatocellularinjury.Interaction with Other Drugs and Foods1. Hypertensive crisis: MAO inhibitorswith ingestion of tyramine containingfood e.g. cheese, beer, red wine or fer-mented food can cause intracranialhaemorrhage due to hypertensive cri-sis because of release of noradrenalinefrom adrenergic nerve endings byunmetabolised tyramine.Table 2.5.3: Classification of antidepressant drugs.I. MAO inhibitorsi. Non-selectivePhenelzineIsocarboxazidPargylineii. SelectiveMoclobemide (RIMAPREX) 150-600 mg/dayII. Tricyclic and related compoundsi. Tricyclic antidepressantsImipramine (DEPSONIL) 50-200 mg/dayAmitriptyline (AMIXIDE) 150-225 mg/dayNortriptyline (PRIMOX) 50-150 mg/dayTrimipramine (SURMONTIL) 50-150 mg/dayDoxepin (DOXIN) 25-150 mg/dayDothiepin (EXODEP) 75-150 mg/dayii. Tetracyclic antidepressantsMianserin (SERIDAC) 30-100 mg/dayMirtazapine (MIRTAZ) 15-45 mg/dayIII. Serotonin reuptake inhibitorsSertraline (SERNATA) 50-200 mg/dayCitalopram (CITADEP) 20-40 mg ODParoxetine (PAROTIN) 20-50 mg/dayFluoxetine (FLUDAC) 20-60 mg/dayIV. Mood stabilizers (Antimania drugs)Lithium carbonate (LITHOSUN) 600-1000 mg/day
Psychotropic Agents1012. MAO inhibitors along with barbitu-rates, alcohol, narcotic analgesic can en-hance and prolong the action of thesedrugs.3. Potentiate the toxic effects of tricyclicantidepressants.4. It’s use with anticholinergic antiparkin-sonian drugs can lead symptoms simi-lar to atropine poisoning.Because of their toxic effects and seri-ous interactions, they are not commonlyused. However, a new selective inhibitor isused clinically.MOCLOBEMIDEIt is a reversible and selective MAO-Ainhibitor used in the major depression. It isdevoid of anticholinergic, sedative and car-diovascular effects of TCAs.Side effects include sleep disturbances,dizziness, nausea, headache, restlessness,agitation, confusion state and nausea.TRICYCLIC ANTIDEPRESSANTSTricyclic antidepressants are the mostcommonly used drugs. They produce an-tidepressant effect by blocking the neu-ronal uptake of noradrenaline and exertanti-cholinergic activity. They also inhibitneuronal uptake of 5HT and dopamine.The exact mechanism of action is notknown. The antidepressant effect is no-ticed after three to four weeks of drug ad-ministration.TCAs lower seizure threshold andoverdose leads to convulsions. The sideeffects are due to anticholinergic effectleading to dry mouth, blurring of vision,constipation, urinary hesitancy and tachy-cardia. They also lead to postural hypoten-sion due to a1 blockade and inhibition ofcardiovascular reflexes. They also produceT wave suppression or inversion. Oralabsorption is good and they are highlybound to plasma proteins. They are exten-sively metabolized in liver and metabo-lites are excreted in urine.IMIPRAMINEIt is an efficacious drug in alleviatingdepression. When the drug is given to de-pressed patients, elevation of mood occursin about three weeks. Tolerance to anticho-linergic effects occurs with continued use ofimipramine.It is highly protein bound and is metabo-lized to pharmacologically active metabo-lite. It crosses placental barrier.Adverse effects include dry mouth, ta-chycardia, palpitation, impotence, constipa-tion, difficulty in accommodation, rarely hy-perpyrexia and paralytic ileus; lethargy,headache, drowsiness, tremors, ataxia, sweat-ing, convulsion, urticaria, skin rash, pruritus,cholestatic jaundice, cardiac arrhythmias,orthostatic hypotension, agranulocytosis,gynaecomastia, galactorrhoea and depen-dence; loss of weight or gain.It is indicated in all types of depression,nocturnal enuresis, intractable chronic pain,narcolepsy, chorea, cachexia, mood distur-bances and sleep apnoea syndrome.AMITRIPTYLINEIt causes sedation and after oral admin-istration it is metabolised to nortriptylinewhich is active form.Adverse effects include epigastric dis-tress, sedation, drowsiness, orthostatic hy-
102potension, palpitation, dry mouth, urinaryretention, blurred vision, confusion and low-ering of seizure threshold.It is indicated in depression, illness accom-panied by anxiety, agitation, restlessness anddisturbances of sleep; masked depression;dysphoria and depression in alcoholics;childhood bed wetting. It is also useful forprophylaxis of migraine.NORTRIPTYLINEIt is same as amitriptyline and its anti-depressant effect may persist up to sixweeks.Adverse effects include dry mouth, con-stipation, nausea, epigastric discomfort, seda-tion, confusion, arrhythmias, altered vision,skin rash, jaundice and impaired alertness.It is indicated in neurotic, reactive,masked endogenous, recurrent depression;depression with insomnia, depression, en-uresis, panic disorder, neurogenic pain, ur-ticaria and nausea and vomiting during che-motherapy; maniac depressive psychosis indepressive phase.TRIMIPRAMINEIt has more sedative effect than other tri-cyclic antidepressants and is suitable forpatients showing depression with agitationand anxiety.DOTHIEPINThe mechanism of action is same as oftricyclic antidepressant and used in depres-sion and anxiety associated with depression.Adverse effects include dry mouth, ta-chycardia, palpitation, impotence, constipa-tion, difficulty in accommodation, rarelyhyperpyrexia and paralytic ileus. Lethargy,headache, drowsiness, tremors, ataxia,sweating, convulsion, urticaria, skin rash,pruritus, cholestatic jaundice, cardiacarrhythmias, orthostatic hypotension,agranulocytosis, gynecomastia, galactor-rhoea and dependence are also seen.TETRACYCLIC ANTIDEPRESSANTSMIANSERINIt exerts potent presynaptic central a2, adr-energic blocking activity which may causeincreased noradrenaline release. It does noteffect noradrenaline or 5-HT uptake inCNS.Adverse effects include hypersensitiv-ity reaction, nausea, drowsiness, jaundice,may precipitate seizures, blood dyscrasias,lethargy and tremors.It is used in psychotic and neuroticdepression and obsessive compulsive neu-rosis.MIRTAZAPINEIt acts as an antagonist at central presyn-aptic a2 inhibitory adrenergic auto-receptorsand hetero-receptors. This results in an in-crease in central noradrenergic and seroton-ergic activity. Mirtazapine is a potent an-tagonist of 5-HT2 and 5-HT3 receptors.Adverse effects include asthenia, flu likesyndrome, back pain, dry mouth, increasedappetite, constipation, weight gain, periph-eral edema, myalgia, somnolence, dizziness,abnormal dreams, abnormal thinking,tremor, confusion, dyspnea and urinaryfrequency.
Psychotropic Agents103SELECTIVE SEROTONINREUPTAKE INHIBITORSSelective serotonin reuptake inhibitors(SSRI) are currently used group of drug intreatment of depression. These have a fasteronset of action and are better tolerated.SERTRALINESertraline is a potent and selective inhibi-tor of neuronal serotonin (5-HT) reuptake.It has only a weak effect on neuronal up-take of norepinephrine and dopamine.Sertraline’s inhibition of serotonin reuptakeenhances serotonergic transmission.It has a wide therapeutic index and canbe administered in elderly patients andthose with underlying cardiovascular dis-orders.Adverse effects include nausea, head-ache, diarrhoea, insomnia, dry mouth,tremor and fatigue.It is indicated for the treatment of symp-toms of depressive illness including accom-panying symptoms of anxiety. It is also in-dicated in preventing relapse of the initialepisode of depression or recurrence of fur-ther depressive episodes including accom-panying symptoms of anxiety.It is indicated in the treatment of obses-sions and compulsions in patients with ob-sessive compulsive disorder.It is also indicated for the treatmentof panic disorder with or without agorapho-bia.CITALOPRAMIt is orally active SSRI. The mechanismof action is due to potentiation of serotoner-gic activity in the CNS resulting from its in-hibition of CNS neuronal reuptake of sero-tonin (5-HT).Following a single oral dose ofcitalopram, peak blood levels occur at aboutfour hours.Adverse effects include activation ofmania/hypomania, dizziness, insomnia,agitation, nausea and vomiting, dry mouth,diarrhoea, tachycardia, postural hypoten-sion, cardiac failure, MI, arthralgia, myal-gia, arthritis, purpura, anaemia, leukocyto-sis, decreased or increased weight, thirst,ejaculation disorder, impotence, dysmenor-rhoea, decreased or increased libido, cough-ing, epistaxis, bronchitis, rash, pruritus, pho-tosensitivity reaction, urticaria, acne, abnor-mal accommodation, conjunctivitis, eyepain, fatigue and fever.It is indicated in the treatment of depres-sion.PAROXETINEIt is an orally administered SSRI.Paroxetine is readily absorbed from theGIT with peak plasma concentration occur-ring within about five hours. It is widelydistributed throughout body tissues and isabout 95% bound to plasma proteins. Excre-tion is via the urine and the faeces, mainlyas metabolites.Adverse effects include asthenia, sweat-ing, nausea, decreased appetite, somno-lence, dizziness, insomnia, tremor, nervous-ness, constipation, ejaculatory disturbanceand impotence.It is indicated in the treatment of depres-sion, obsessive compulsive disorder andpanic disorder.
104FLUOXETINEA potent antidepressant drug, it does notcause sedation. In CNS it inhibits the neu-ronal uptake of 5-HT. It shows negligiblebinding to histaminergic, muscarinic, α1 adr-energic receptors, so it is devoid of anticho-linergic and hypotensive side effects.After oral administration the drug is con-verted to norfluoxetine which has a verylong lasting biological activity.Adverse effects include drowsiness,skin rash, insomnia, anxiety, weakness, fa-tigue, nausea, anorexia, epigastric distress,diarrhoea, tremor and sweating.It is used in the treatment of depressionwhere sedation is not required and for pro-phylaxis of recurrent depression.MOOD STABILIZERS (ANTIMANIC DRUGS)LITHIUM CARBONATEIt has narrow therapeutic index and treat-ment requires facility for therapeutic moni-toring of serum lithium levels.Exact mechanism of action is unknown.It brings the patient of mania towards nor-mal. Lithium decreases the neuronal uptakeof dopamine and noradrenaline and theirsynthesis. It increases the rate of 5-HT syn-thesis in brain. On continuous therapy cy-clic mood changes are prevented.It also inhibits ADH action on distal tu-bules (diabetes insipidus like state), also hasinsulin like action on glucose metabolismand decreases thyroxine synthesis by inter-fering with iodination of thyroxine.After oral administration it is well ab-sorbed and is not protein bound. It notmetabolised and is excreted mainly in urineand it inhibits the reabsorption of sodiumin renal tubules. It has narrow margin ofsafety.Adverse effects include nausea, vomit-ing, epigastric distress, polydipsia, polyuria,diarrhoea, dizziness, ataxia, nystagums,hyper-reflexia, arrhythmias, skin rash, gly-cosuria and blurred vision.It is indicated in acute hypomania, ma-nia, recurrent mania, depression – cyclicand recurring, unipolar depression, bipo-lar depression, schizoaffective psychosis,mental depression, cluster headache, che-motherapy induced leukopenia andagranulocytosis.
Epilepsy is a neurological disordercharacterized by short, recurrent andperiodic attacks of motor, sensory orpsychological malfunction. It is associatedwith paroxysmal abnormal electricaldischarge in the brain. According to Jackson,epilepsy is due to sudden, excessive andrapid discharge in the grey matter of thebrain. Anti-epileptic drugs inhibit the spreadof abnormal electrical discharge in the brainwith minimal general depressant action onthe central nervous system.The antiepileptic drugs belong tofollowing groups as classified in table 2.6.1.BARBITURATESPHENOBARBITONEPhenobarbitone raises the threshold ofelectro-shock seizures and modifiesmaximal electro-shock seizures and abolishthe tonic phase thus useful in the treatmentof grandmal epilepsy. The threshold ofpentylenetetrazol induced convulsion isslightly raised and has less usefulness in thetreatment of petitmal epilepsy.Phenobarbitone has long plasma half-life but slow oral absorption, is metabolizedin liver as well as excreted unchanged inurine.Phenobarbitone is useful in grandmal,focal and temporal lobe epilepsy andsometimes petitmal also. It is also useful inthe treatment of febrile convulsions.Phenobarbitone is cheap and producesless side effects which include sedation,behavioural abnormalities, mental confu-sion, impairment of learning and memoryand hyperactivity in children.MEPHOBARBITONEIt is N-methylphenobarbitone. It is moreexpensive than phenobarbitone and requiresdouble dose compared to phenobarbitone.It probably offers no advantage overphenobarbitone.PRIMIDONEChemically it is deoxybarbiturate (carbo-nyl oxygen of urea moiety in phenobarbitoneis changed by two hydrogen atoms) and istwice as active as phenobarbitone in modify-(Mode of Action of Drugs)PharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsPharmacodynamicsChapter1. 4Chapter2.6AntiepilepticAgentsAntiepilepticAgents
