Q1.-Introduction to medical pharmcology. basic principales of medical pharmacolgy?

Pharmacolgy is study of drug, which deals with interaction of externaly administrated chemical molecules with living organism. drug- chemical stru. know substance other than a nutient or an essential dietery ingredient which when administreted to organism produce biologic effect or bring change in biolocal function. nature of durg--solid- asprine, atropine. liquid- nicotine, ethanol. gas- nitrous oxide. MEDICINE-chemical preparation which usually but not nessarly or or more drug administrated with intension of producing therapeutic effect. ACTIVE DRUG-xenobiotic- drug not synthesize in body. poison- drug have almost exclusive harmful effect. toxin- poison of biological origin. APOTHECARY-book cantian ratio of medical compound. METERIA MEDICA- book contian medicine. PHARMACOPECIA- book contain gerenal rule of use drug,also pediatric and rule of depostion of medicine. Q2.- WAYS AND MEANS OF THE INTRODUCTION MEDICINE(ROUTES OF ADM) ANS-routes of administration- most drud can give by many routes,it depend on drug and patients related factor. FACTORS-1. physical and chemical properties 2. site of action. 3. rate of absorption from diffrent routes. 4. effects of digestive juce. 5. dose dependence. 6. condistion of patient. LOCAL ROUTES- 1. topical- skin,eyes,ears, oesphargeal sites. 2. deeper tissue- by help of needle. 3.arterial supply- close intra arterial injection. SYSTEMIC ROUTES1.oral 2.sublingaul 3.rectal 4.cutaneous 5.inhalation 6.nasal 7.subcutanous 8.I/V 9.I/M 10.I/D Q3.THE ABSORPTION: dissolution, aqueous diffusion, lipid dif. ANS-ABSORPTION- passage of substance through some surface of the body fluid and tissue. Aqueous dif.-dif.in blood and other aq. solution. lipid dif.-- dif. in plasma and other lipid. -- special carriers(transpoters) 1. membrane transporters. 2. slc-solute carrier tran. 3. abc-atp- binding cassettae tran. ROLE OF IONISATION.

- weakly acidic drug form salt with cation - weakly basic drud form salt with anion. Q4. TRANSPORT MEDICINAL MATERIAL. drug tranport by 1.passive diffusion and filteration- trough membane in flow conc. gradiant. 2.specilized transport- by carreir mediated or pinocytosis. a)carrier tran.- by protiens. b)facillitated diffusion- by slc and tranport without energy. c) active tran.- requre energy. i)primary active t.- energy by direct hydrolysing atp. ii)sec.a.t.- by slc transport when ion channel mediate energy. Q5. BIOAVAILABILITY, BIOEQUIVALENCE, THE EFFECT OF FIRST-PASS HEPATIC ELIMINATION. BIOAVAI.- Fraction of administraction drug reaches to systemic circulation in uncharged form. BIOEQUI.- when the rate and extent and bioavail. is same for two drug in suitable condition. FIRST PASS HEPATIC METABOLISM- metabolism of drug during it passage from the site of absorption into the systemic circulation. drug reach by portal vein, where enzyme act on drug and a amount is deactivate so bioava. of drug is decrease. -for oral dose high than sublingaul. -oral bioaval.increase in liver disease. -also bioav. increase when another drug of high metabolism give simultaneously. PRODRUG- when drug not activated it need conversion in body to one or more active metabolite. DISTRIBUSION- depend on1.lipid/water solobility. 2.degree of plasma protien binding. 3.affinity for diff. tissue. 4. condistion 5. disease. Eg. Of prodrug fosinopril&nalpril Q6.DRUG CLEARANCE PRINCIPLES. it is factor that predicts the rate of elimination in relation to drug conc. 1. capicity limited elimination. 2. flow of elimination. 3.half life. PRINCIPLES1- repeated drug administraction- when a drug repeate at relatively short interval it accumulate in body until balance input and steady state plasma conc. attained. 2- plateau principles- when constant dose of a drug is repeated before the expiry of 4 t1/2, it would achive higher peak conc. because some remainent of previous drug p/s in body. 3- target level strategy- for drug whose effects are not easily quatifiable and softrly margin not Q7. METABOLISM OF THE DRUG. THE ROLE OF BIO-TRANSFORMATION IN DRUG DISPOSITION. Biotransformation/ metabolism- chemical alteration of the drug in body. 1.Inactivation- most drug and active metabolites get inactivated. 2.Active metabolite from active drug. 3.Activation of inactive(prodrug). 1)NONsynthetic- oxidation, reduction, hydrolysis, cyclization,decyclization.

2)SYnthetic reaction- glucoronide conjuction, acetylation, methylation, sulfate conjugation,glycine conj,glucothione conj,ribonuclaside. they take two types of enzymemicrosomal enz. non microsomal. Q9.DRUG AGONISM AND ANATAGONISM.TYPES OF THE DOSES. Agonist- drug bind and activate the receptor. 1.full ag.- bind and activate a receptor,displaying full efficacy at the receptor(isoproterenol) 2.partial ag.- also bind or activate a given receptor but only partial efficacy at the receptor to the full agonist(buspirone) 3.selective ag.- is selective for one certain type of receptor. Antagonist- by binding to receptor prevent binding of other molecule. 1.competitive antag. 2.irreversible antag. TYPES OF DOSES1.standard doses. 2.regulated d. 3.target level d. 4.titrated d. -other types of dose-1.1 time doses- amount of drug in start. 2.medium- amount of drug have therapeutic or pharmocolgical effect. 3.1 day doses- amount of drug in 1 day. 4.intial dose- amount of drug in 1st taking. Q10.SIDE EFFECT OF THE DRUG; depend on individuality. 1.idiosincrasia-genetic defect by drug. 2.allergic reaction- 2 types-1)igE. 2) cytotoxin. 3.immunocompletaion. 4.hypersenstivity. reation on repeatation of drug. 1.cummulation. 2.tolerance. 3.drug dependence. 4.syndrom of abulution 11)Drug use in pregnanacy ;can effect fetus there are marked and progressive phyicological changes during pregnancy especially in the 3 premestis ehich can alter drug desposition 1)GIT motility decrease :-delyed absorption of orally administrated drug 2)plasma and extracellular fluid volume expeuds :-vol of drug distribution increases 3)while plasma albumin level fall that of alpha 1 acid glycoprotein increases the Unbond intracction of acidic drug increases but that basic drugs decrease 4)renal blood flow increases was kedely polar drug eliminate faster 5)hepatic microsomal enzyme undergoes induction way drug are mettobolic faster 12-General principles of rational prescribing & prescription binding writing. medical prescription is the prescribers order to pripare a spesific treatment

rational prescribing:-prescriptin should be basd on a no. rational step 1. makea spesific dignosis 2. consider the pathphysiologic amplication of dignosis 3. select a spesific therapiotic objective 4. select a drug of choice 5. determine the appropriate dosing regimen 6. a plan for monitoring the drugs action & determine an end point for theropy 7. plan a program of patient edu. 13)Cholinoceptors drugs:2 type recepetor M1 (cns) muscurine 1)m1 (CNS) 2)m2(heart,smooth muscle,Nerves) 3)m3(gland endothelium) N type(nicotinic) Nm-Skeleton Corrseponding myorelaxt Nn-Ganglion (hypertensive) *not use in respiration :- Asthetemic effect *cant pass BBB(blood brain barrier) so not use in CNS ,M3:Iris ,M3 cilliary body(contraction) Miosis :-contraction(glaucoma), Spasm of accomadation (destroy path of introccous failed),Intrococullar pressure decrease Groups :Direct1)M,N cholinomemetic drugs Ex:-ach col,Carbocholaem(eye)metacholine(eye drops) 2)M-cholinomimetic drugs:Ex:-pilocarpin,Aceclidine Indirect Cholinosterase blockers-anticholinoterase Ex :-nesstigmine(proserive)physastigimine,Galasthamine Inhibit acheslerace so not destruction of receptors -Ach cl colplex so prolonged effect 14.)Cholinoreceptor bloking drugs 1)group of atropine A)Atropine sulfate-0.1 %----1 ml amp 1%-10ml B)Scopolamine-0.05---1 ml amp C)Henatropine hydroobromide---0.25%-------5 ml -----eyrdrop D)Platyphylline----0.2 ---1 ml amp

2)synthetic drugs A)Methacine-----0.1 % -----1ml amp B)tropicamicle (medium)--------1.7---15 ml ----eyedrop C)pirennzipine----0.05 tab 3)booncholyticA)iprotropium bromide B) trovents C)oxytropium bromide (use-opthalmoscopic (eye swelling) spam of accomedation D)thyohyoopium bromide pericardits atropine relax eye muscle ------ve gitolcer ( decrease reaction & motility and spam ----use in stomatolgy ----group open for decrease saliva reaction -----urology ---spam of urinary tract ,renal collagen -----cordiolgy ----brady cardia , artrio ventricular block ------anesthesia premedication after open (decrease P.S.N.S effect & decrease secretory effect ----dermatology ----hyperhydrosis -----toxiology-----position of chromatics drugs & phosphoorganic compound & position of musrroms 15) Adrenoreceptor activating drugs Alpha alpha1 (muscle and vessels) alpha 2 (activation increase Beta---Beta1 (heart) Beta 2(branches, vessels) symptoms activity Use vasification so B.P. increase (shock, heart failing) Hyperalycomic comma local anesthesia (vasoconstriction) Rhiniotis exadative (anti-congestional effect)so construct nasal mucosa (5-7 days) Mucosa may decrease perfusion for oxygen Drugs (sympathometric) 1)direct sympathomimetics Act directly as against of Alpha-beta receptor ---adrenaline,noadre,isoprenaline Phenylepurive,methaxamine,xylometazdive,solbotamol 2)indirect sympathaminetics-----act on adrenergic neroun to relase N.Ads Example..tyramine,amphetamine 3) mixed ----Examples.ephendrive , dopamine , mephentermine A)person agent N.A. ephedrine , dopamine , methoxamine B)cardiac stimulate---adro , dobutamine C)bronchodilators ----isoprenalive , tobulative , someterol

D)nasal decongestacts ---- naphozolive , psodoephedrive E)CNS stimulate ---- amphetamine , sibotromone F)Uterine relaxant --- sobotamol , terbolalive 16)Adrenoreceptor antagonist In eye decrease prodown intraocular fluid so urin glaucoma-----A)isoprotenol ---- Beta > Alpha ----bronchodilin so in asthma orchronic Disease B)dopamine --- metabolic proccertor D1 receptor ---in shock C)phenyldopan---- D1 use in hypertension and pheriphral vasodilin D)dobotamine ----- B1 > B2 as + intropic and chronotropic heart fail heart shock E)phenylephrive------ alpha (long AXN) mydriatic agent F)ephedrive------B1 , B2 use to increase cardiac fusion G)oxylometotdine-----alpha ti constrict nasal mucosa H)oxymetotozdive-----alpha some as nasal drop I)methaxamine J)midodrine K)phentolamo\ine L)paezasive -----alpha hypertension,,,,,,,,some muscle relaxant M)doxozosive / toma\solasive------van desease , hypero tumor effect 1) CVS B1 receptor ---ve in chromo ----ve traometotropic ..hypertension , tachycardial , ventricular fibiration 2) Respiration ----B2 blocking increase airway resistance so ----ve effect 3) Eyes ---glucomea (timolol) 4) Metabolic and endocrive ----stimulatin of lipolysis,,,,,,,,examples---propranolol , nodalol , sotalol Use -----hypor , IHD , arrithmia , heart fail , glaucoma , hypathyroidism Beta adrenergic bloking generation 1st 1)propanol 2)timolol 3)sotalol 4)pivdolol non relactive other 2nd 1)metaprolol 2)atenolok 3)acebotdol 4)bisoprolol B1 selective 3rd 1)lebetalol 2)carvdilo 3)ceriprolol 4)nebivolol with addition alpha ---bloking and vascular property

(17) -NSAID 1. Drugs which have more inflammatory effect a. Der. of indolacetate acid--Indometacin,Sulindac,Aetodalae. b. Salicylatis -Aspirin,Diflunizal c. Pyrosollidinas -Pheylbutasone d. Der. of Phenylacetate acid -Diclofenacs e. Oxycolnes -Piroxycom,Meloxycom f. Der. of propinoic acid -Ketoprofen.Ibuprofen,Maproren 2.)Drug which have less inflammatory effecta.deri. of antranillic acid-Mephenamic acid. b. Pirozolones-Metamisol,Aminofenuzon. c. Der. of Para-amino fenolum-Phenacetin,Paracetamol. d. Kiterolac Gout drugs:- NSAID, Glucocorticoid,Colchicine,aluprimol Rheumatic drugs:- NSAID,Glucocoticoid, Chloroqueinone, Hydroxychlorawinone,Perisalamide.. (18)- h1 receptor antagonists G- protein coupled receptor. Location:- Smooth Muscles, in heart, on vascular endothelial cells. Classification:1st generation a. Ethylenedia Mines- Antazoline,Pyrilamine. b. Ethanolamines- Doxylamine, Carbixomine. c. Alkyamines- Pheniramine, Chlorafenamine. d. Piperazimine- Cycizine. e. Tricyclics and Tetracyclines- Promethazine, Cyproheptadin 2nd generation a. Systemic- Cetirizine, Loratadine, Terefenadins. b. Tropical- Azelastine, Lellocbastine, Celopatadine 3rd generation Lellocetrizine, Desloratacline, Fexofenadine... (19) Sedative- hypnotic drugs? Classification:1. Benzodiazepine a. Diazeram b. Lorazeram c. Midozolam d. Nitrozepam Therapeutic use:1. Gemal Anesteresia, 2. Insomenea, 3. Muscle turitches,

2. Barburites a. Pento-Barbirtal b. Pheno-Barbuitone c. Treo-Pentone d. Buto-Barbitone

3. Newhypnotic drugs a.Zaleblon b. Zolpidem, Eszopiclone

4. Neurosis (emotional disease), 5. Anxiety in Alcoholic Diseases, 6. Myorelxant, 7. Schizophrenia.. Sedaction:- Effect that subdues excitement and calms the object without inducing deep.. Hypnotic:- dt induces sleep similar to normal arousable sleep. Side-effects:1. (downward) Cardiac func., 2. (downward) B.P, 3. Depretion of respiratory system, 4. Liver Mechanism.. Mechanism:- Binds with gabba receptor and forms complex and activated chloride channels changes Clconc.. Gabba receptors are found in spinal and brain.. Gabba receptor (alpha)1, (alpha)2, (beta)1, (beta)2 , (gama) and it has Pentagonic structure..... (20)- Opoid Classification:1. FUll agonist Morphine , 2. Partial agonist Coedine , 3. Antagonist Nalaxon. Mechanism:- Bind to G-Coupled protien receptor and block Ca+ ions channel in presefnaptic nerve terminal and neurotransmitter denot releses can hyperpolerization.. Effects:- 1. Analgesia, 2. Euphoria, 3. Respiration(down), 4. B.P(down), 5. Mioris (down), 6. Sedation, 7. Cough Supression.. Clinical use:1. Analgesia, 2. Acute Pulmonary Edema, 3. Cough, 4. Diarrhea, 5. Application in Anesthesia......... 21-Antipsychotic neuroleptic agent Drug having solutary against mental illness, Classification 1-pentothiazines-chlorpromazine,thioridazine,trifloperazine,fluphenazine 2-botyrophenones-haloperidol,trifluperidol,penfluridol 3-other heteocyclics-pinrozide, loxapre 4-atypical neuroleptics-clozapine,resperidone,donzapide Effect-in normal people-emotional quietening,no sleep,atexia,motor depression. In psychotic patient-dirritation behave,agitation and aggressiveness and control psychotic synptamatology. Mech.-all have D2 depamine receptor blacking action .

Action aalpha adr blocking,anesthatics,hypotension,muscol relax, prolactine Positive effect-drousiness,lethargy,conforon, weight,portural hypotension,drymouth,vision blurring,constipation,parkinsonism,myodrylonto,akathisia. Use-0psychoses(schizophrenia)anxiety relivent,as antiemetic(vomit),tetanus,alcoholism Mood stabilizing agent 1-lithiom carbonaton long administration act as mood stabilizer -replace not so stop ionic reflex Stop Na2 opamine -inhibit hydrolysis of inoritol 1-phosphate by inoitolmonophosphate Also stop axn of ADH on distal tubules of cause drpeler like state. -insulin like axn on glucose metabolism. -leucocyte. Negative effect-naosea, vomit,diarrhea,pumoria,CNS toxicity. Other mood stabilizer1-carbamazepine 2-sodium valproat 3-lamotrigin 22-Antidepressent drugsClassification1-RIMAs-reversible inhibitor of monoamine oxidase.example:moclobemide, clorgyline 2-tricyclic antidepressantExample:imipramine,amitripryline,desipramine,nortiptyline. 3-selective serotonin reuptakeinhibitor(SSRIS) Example:fluoxetive,flovoxamine,poroxetine,citaloprom. 4-Atypical antidepressentExample:trazodone,mianserin,bupropion,amineptine Mech. Of TCAInhibit reuptake of biogenic amines-NAand HT. Action 1-anti chnr. 2-tachycardia ,arrithmia Negative effect-dry mouth, bad taste, constipation, confusion, weight gain, soeation, portural hypotension, arrithmia. Uses1-endogenous(motor)depression 2-obsessive compulsive and phobic states 3-anxiety disorder4-neuropathic pain 5-attention deficit in children 6-enuresis(bed wetting) 7-migraine 8-pruritive

23.ALCOHOLAlcohol is- Hydroxy derivative of aliphatic hydrocarbon.Mainly ethyl alcohol or ethanol. It obtain by fermentation of sugars. ACTION- 1-Local anasthetics cobling on skin and muscles on infection,pain,swelling -Nural depressant MECH. By membrane action alter the lipid and promote GABA mediate synaptic inhibition by Cl- channel or may direct by reduce Neurotransmitting release ,by acting of voltage,regulated Ca+ channels. 1-CVS small dose vasodilation ,moderate dose tachycardia and increase blood pressure and large dose myocardial and vasomotor depression 2-in blood increaseHDL 3-body temperature-cutaneous and gastric vasodilation 4-GIT-acid secretion,gastritis 5-liver intoxication 6-muscle work depend on dose little increase and decrease. 7-Dlurakrin kidney 8-hyperglycemia SIDE EFFECT vomit,flushing,hangover,traffic accidents,hypotension,gastritis,hypoglycemia,respiration depression,coma and deathintoxication)Nausea, Anti-alcohol-benzodiazepines,barbiturate(Naltrexone) Clinical dose-1-antiseptic 2-sprains and joint pain 3-on skin to prevent bad sore,neuralgia,cold to methanol poisoning Aldehyde dehydrogenose inhibitor-disolfiram 24-Antiseizure drugs(anticonvulsant,antiepilectic) Classification1-barbitorates-phenobarbitone 2-deoxybarbiturate-primidene 3-hydantoin-phenytoin,fasphentoin 4-immostilbene-carbamaZEPIVE,OXCARBAZEPINE 5-succinamide-ethosoximide 6-aliphatic carboxylic acid-valproic acid 7-benzodiazepines-dizepan,larazepan,clobazain 8-phenyltriazine-lamotrigive 9-cyclic GABA analogue-Gabapentin 10-newer drug-vigabatrin,topiramate,tiadgabine Mech.-act on neuronal membrane repolarization shift. Normalize it *disturb in patient Negative gum hypertrophy and Hirsulin(pimple) At toxicity-cerebellar and vestibular manifestation,ataxia,vertigo,diplopia,nystagmus. Drowsiness,behavior alteration,hallucination,gastric pain,nausea,vomit,vasculart injury,blood pressure and bradycardia

Use 1-generalised toxic-clonic And simple partial seizure 2-complex partial seizures 3-assence seizures 4-myoclonic and atonic seizures 5-febrile convulsion 6-infantile spasm(hypsasrythmia) 25)General anesthetics stop CNS exclude vegetative reaction and reflex 1)- for inhalation a) gas- nitro oxide (myocardial infract) b) liquid- ether , halothase , enflorase , isoflurene , desforae , sevoforane 2) I / V a) includim\ng agent- thriopental , proponal , ethomidate, methohexilae sodium b)slowesacting drug- benzodiarepines , diazepam , loratepam , midazolam c) dissiciative anesthesia - kalamin d) opioid analgesics- pentanyl some. muscle relazant so easy for open , tetanus they block Nm chilinoceptor 2nd group 1)non depolazizing / antidepolarising drug----mechanism------so Ach cant activate it so myorelaxin exampletunoglarine , altracorarium , cidrctracorion , mivacurium , doxacoriom , pipercuronium , racosonium. 2)depolarizing agent Mechanism phase 1 ---block deporarissing ---bind Nm so muscle contraction for short time phase 2-----black desendtizing effect so muscle relaxation exampleonly one -----succinyl choline respirarion of bone , incubation trachea , small open , endoropy , telanous in opthaloic retraocularinfection

--ve effect -----fibrilation muscle , hyper k+ in blood , brachycardia Increase intraocular press , sable black ---after contraction Antodeplarising---- ve effect 1)histamine liberalization so broehasparm decrease BP 2)art hypotension 3)may syndrome of prolonged apnoe 26) Pharmacological management of Parkinsonism.. 1)drug affecting brain dopaminergic system a) dopamine precussor ----levodopa (1st dopa) b) peripheral decadecarboxylase inhibatior ----carbidopa, benseracid c) dopamivergic agonuit-----bromoscrpive, ropinerol , prancipexol d) Mao B inhibator -----seleginine e)comt inhibitor-----entacapove , tolcapone f)dopamine facilitator-----ancautacctive

2)drus offecting brain chloninergic system a)central auticholinergics-----trihexyphenidyl , brocyclidine biperidane b)auti histamine -----orphenodrine , prometharine levodopa-----procorssor of dopamine more than 95% of oral dose decaboxylated in peripheral tissue not effect CNS effect------1)CVS -----tachy cardia by acting on beta adrevergic receptor Inhibit prolactin increase grouth hormone Without food less effective digested by enzyme Ve effect ----naussea , vomiting , postosal hypotension , arrhythmia , angina , decrease taste Treat pastoral disturbance!!!!!! 27)Nootropic drug:- (neurometabolic drug ) This incre. Glucose level in neurons & activated metabolic fun. Of these cell Ex. Piracetam (nootropil), phenibut, pentagram aminolon, cerebrolism Clinical use: stroke (ischemic form), degenerative disorder of bran, trauma of bran, cerebral arthrosclerosis (encephalopathia with discirculation dicers. Mental fun. children

28.local anesthetics injectable a.low potency short duration-procain,chlorprocain b.inertmediate-lidocaine,prilocaine c.high-tetracaine,dibocaine,ropivacaine surface anastetics a.soluble-cocaine,lidocaine,tertracaine,benoxivate b.insoluble-benzocaine,botylaminobenzonate,oxethozine 29-HEART FAILURE (CONTRACTILITY DISORDER MYOCARD) Cause-M. infarct(necrose, so acute and chronic heart failure), arrythmicis, changes in tissues, amyloidesis, bacterial myocardites, congenital myocardial disorder. 1-increases contraction 1-cardioglycosides digitalis (positive inotropic drug) 2- diagnosis 2-decreases preload 1-diuretics 2-angiotensin converting enzyme inhibitor (ACEI) 3-vasodilators-example-nitroglycerine use in angina pectoris Cardiac glycardes Mech :-Na+, K+, ATPase (in mb myocardium) 1-inhibit Na+, K+, ATPase 2-decreases concentration of Na+ 3-increases Ca2+ in myocardium 4-tropomyosin move 5-actin myosin interaction 6-increases contraction Effects 1-increases contractility 2-decreases conduction-AV node velocity 3-decreases blood pressure 4-high systolic function So +ve I, -ve C, -ve D, -ve Bathmo 4increases vagul function, increases energy effect, so decreases rate but increases pumping. Use in heart failure and tachyarrythmia. Eg1-lipophillic-digitoxin, acetyl digitoxin (hepatic excretion) in chronic heart failure in non immediate condition. 2-hydrophillic-strophantine (Ilv) (renal elimination in immediate condition)- or glycan 3-intermidiate-digoxin (use in both condition). 30-ANTIARRYTHMIC DRUGS

Phases Phases 0- Na+ channel open, Na+enter (depolarization) Phase I- Na+ close, Ca2+ channel open Phase II- K+ channel closes Phase III-IV- repolarization (absolute refractory polarization) Classes- Wogen William classification1-Na+ blocker classes- prologue 0 phase use in tachyarrythmia, negative chronotropic, so increased P-Q interval, increased QRS prolong AV conduction use artriofibrilation, digitalis intoxication arrhythmia and tachyarrythmia. -ve effect- nausea, vomits, hypertension. Ia-chinidine, novoanamid, dizopiramid Ib-local areas (ventrical tachyarrythmia fibrillation) Lidocaine (10% 2ml amp) block fast Na+ channels Phenyltoin-digitalis tachyarrythmia Maxiletin (oral) Ic-drug block fast Na+ channels in bundle of His and purkinge fibres. Ex-flacianid (prearrythmic so may induce other arrhythmia). 2--adrenoblocker- decreases SA, Av activity, decrease phase IV and prevent 1 activation. a-cardioselective- metoprolol, atenolol. b-non selective- pindolol, timolol 3- K+channels blocker- increases absolute refractory period phase II and hyperpolarization. Ex-aminoderone, Bzetilium, block all channels (include Na+, Ca2+, very long half life block adrenoreceptor use in arterial and ventricular arrhythmia. 4- Ca2+ blocker- decrease SA AV node activity, decrease phase IV. Verapenile-tachyarrythmia and supraventricular arrhythmia Unclassified 1-adenosine solution-decreases SA AV activity, increases K+ efflux, increase refractory period. 2-Mg solution-antitwitches, antivomit, antihypertension, antiarrythmic. 31-ANTI anginal CAUSE-atherosclerotic occulosion(coronary/vasopressin,myocard hypotrophia) Drug>Increase in O2 delivery by decrease vaso spasm nitrates CCB-Ca2+ ch.blocker(verapamile) >decrease O2 requirement(-ve chronotropic effect) Nitrates CCB Beta-adreno blocker NITRATES(endogenous smooth muscle relaxation) Mech-in vessels we have endogenous endothelium factor NO so L-arginine increase NO synthatase so produce NO 31nitrate exogenicity donate NO after it increase cyclic guanasine monophosphate(CGMP)increase and

Ca2+decrease so muscle relaxation 32Dilate large vein (mainly) and artery (less) so decrease preload 33Decrease cardiac O2 requirement decrease cardiac work increase collateral blood flow.ex=nitroglycerine(O,S.L,I/V,T/D),Isosorbide-(SL,O) 34-ve effect-headache(veindilation)tachycardia have tachphylaxis so pd is more than 12 hours. CCB-nifedipine,verapamile -adrenoblocker-no direct action act on smooth muscle.decrease H.R decrease contraction force (-ve I,+C)so decrese O2 need In unstable angina use *Nitrates IV,opoid an Thrombolytic drug-heparine,ovarferine Block Ang II receptor -saolasin,lozartan,valsortan,irbesartazn.telmisarton -Renin change angiotensinogen into angiotensinI and it by ang con enz change into active angiostensinII *decrease 5-6 mmHg BH.P can decrease 40 risk of stroke 20% decrease CHD and decrease dementia,Ofail Classification ACE inhibitor 1-sulfahydroxylate containing-captopril,zofenopril 2-Dicarboxylate containing-enalpril,ramipril,avanpril,perindopril,lisinopril,benazopril 3-Phosphonate containing-Fosinopril,mono pril =>methyldopamine,clonidin,guanfacin,guanabenz

32- ANTHYPERTENSIVE DRUG Classification 1-inhibitor angiotensin convertive enzyme 2--adrenoblocker 3-angiotensin receptor blocker 4-diuretics 5--adrenoblocker drugs 6-drugs have CNS effect-quanidine, methyldopa 7-ganglion blocker drug-use only in no tension crises I- Inhibitor of angiotensin converting enzyme - enaspril, fosinopril, benasepril, spirapril, trandolaprilate, all activate in liver with suffix prilate -kaptopril, lisinopril, novopril are active drug use-nephroprotective and angioprotective effect, also in diabetes nephritis, diabetes angiopathy, protect peripheral vessels and diabetes proteinuria. -negative effect- long half life, dry cough II CCB 1-difenylalkytoaminer-verapanik 2-bnzodhiazepine (SH)-diltiazem 3-dihydropyridines-nifedipin, nemodipin, nicardipin, isardipin

4-difenylpiperazines-(innarisin, flonarisin) use in circulatory encephalopia and ear noice -mimodipin maintains stroke by dilate cerebral vessels Ia-blocke production of rennin 1-CNS (clonidin) 2--adrenoblocker 3-direct effect (enalcirin) Ib-inhibit angiotensin converting enzyme- enalpril, fosinopril, benasepril, spirapril, trandolapril. 33-DIURETICS Pituitary-ADH (vasopressin)-kidney-aldosterone 1-carbonic anhydrase inhibitor- it presents in many sites of nephrone, so block NaHCO3 reabsorption cause diuresin. Ex-acetalzolamide, dorzolamide, use in glaucoma, urinary alkalization -Na+ use in high blood pressure and peripheral adema. Increases diureasin, decreases blood pressure (volume dependent). 2-loop diureatics- selectively inhibit NaCl, reabsoption in tubule. Ex-forasemid, ethacrynic acid Tab-0.04gm solution No selective diureatics eliminate all ions. Indication to use- volume dependent arterial hypertension, arterial crisis, edema, acute renal failure, increase diureasis in poisonous codition, edema of brain. 3-thioides- hydrochorthiozid- effect same as loop diureatics -can use regular but negative effect on electrolyte dimination. Clinical use- hypertension, heart failure, renal edema. 4-K+ sparing diureatics -eliminate all electrolytes except K+, so prevent K+ secretion. Ex-amilorid, triamteren, spironolacetone-mild hot prolong action (effects after 2 weeks regular taking) Use- arterial hypertension, hyperaldosteronism, 0.25g tab 1-2 four times in a day. 5-osmtic diureatics- Ex- mannitol-effect in PCT in decending limb of loop of henle Use- decrease intracranial and intraocular pressure, cranial trauma, decrease brain edema. 34-Anti-atheroslerotic and anti dislipidemic drugs 1-anti artheroscleresis groups a-Anti HMG-CoA-3 hydroxymethyl glutanyl(enz)-CoA these enzyme convert fat to cholesterol if we block then cholesterol stop other name statins ex-lovastatin,provastatins,simvastatins,fluvastatins block endogenous cholesterol production

-ve-diurea,rhabdomyolisis(mus destruction) in fish color hepatotoxicity,alanine(aspartate transferesterase enz increase in liver) B-nicotinic acid-dilate peripg\heral vessel in high dose,rare use of this vitamin has antiatherosclerin effect cause it activate lipoprotein lipases -ve-fushin and pruritus(redsash)itchina,hyperarithmia,hyperglycemia hepatotoxic, C-hemfibrozil-activate lipoprotein lipase which promote catalysis od LDL and tri glyceride and increase HDL conc ]-ve-GiT distress,rash,hypocalamia D-Bile acid sequestrants Ex-cholestramine,cholesterol -prevent absorption of LDL in intestine increase bile salt decrease liver cholesterol increase LDL receptors and decrease plasma LDL -ve-constipation,decrease absorption of drug (digoxin.TTC,VaK) 35-DISORDER OF COAGULATION-DRUG USE 1-COAGULANT-SUBSTANCE PROMOTE COAGULATION Eg.-VIT.k K1-PHYLLOQUINONE(NATURAL K3-Synthetic 2-miscellaneous Fibrinogen.antihaemophillic factor.desmopressin ANTICOAGULANTS 1-parenteral-heparin.low mol.wt heparin Heparinoids-heparin sulfate,denaparoid lepirudin.ancrod 2-Oral-covmarine derivative-dicumarol,warferin rod nicoumalone Indaandione derivatives-phenindione Use-anticoagulate,antipletelate,lipemia cloaring -ve-bleeding moverdose,thrombocytopenia,osteoparesia ubocaria,fever Use-deep vein thrombosis and pulmonary embolism,MI unstable angina.rheumatic heart disease,cerebrovascular diseases,defibrination syndrome FIBRINOLYTICS/THROMOLYTICS-activat fibrinolytic system main use in coronar obstruction Ex-streptokinase,urokinase,alteplase Use-acutemyoTn. ,deep vein thrombosin,pulmonary embosis!

36-AGENTS IN ANEMIA 1-Fe-(have decrese heamoglobin of small RBC) Free iron is very toxic A plasma Fe bound to transferrin globulin that specifically bind 2 molecules of Fe2+ increase erithropoesis

USE Oral or Parental Fe -ve-nausea,epigastric discomfort,constipation or disease usually dose realated Necessary lactating wpmen,patient with chronic renal disease who lack RBC.inadequate Fe absorption 2-vit B12 syn form-(megaloblastic or microlytic anemia)use injection everyday upto 1-2week 3Folic acid-reqd for essential biochem reason that provide precursor for synthesis of amino acid purines and DNA,folic acid results in megaloblastic anemia.use in long time therapy 3-hemopoetoetic growth factor-factor stimulate hemtopoesis in bone marrow Reythropoetin in in chronic renal failure Primary bone marrow disease 37.Bronchodilators a.sympathomimetics-solbutamol,teributaline,bambuterol,salmeterol,formaterol,ephedrine. b.methylixanthines-theophylline,aminophylline,choline theophyllinate,hydroxythyle,theophylline,doxophylline,theophylline,ethanolate of piprezines. c.anticholinergic-ipratropium bromide,titropiums bromide. Leukotriene antagonist- zafirlokast,monetelokast Mast cell stabilizer-ketotifen,sodium chromoglycate Ccorticosteroid-a.systemic-hyrocortisone,prednisolone. b.inhalation-beclomethasone diproprionale, budesonide,fluticasone proprionate,fluinisolide,ciclesonide c.anti IgE anb-omalizomals -inhalation -adredergic drug cause bronchidilation by action on B2 receptor Co2 increase cAMP formation and relaxation Oral-Methyl xanthinel-CNS stimulation,bronchodilation,skeleton muscule,kidney disease,GIT mucosairritation,phosphodiesterase-inhibition Inhalation-anti chn drug causes bronchodilation by blocking chn constrtrictor act in large airways. Uses-bronchial asthama,allergic rhinitis,allergic conjuction of mast cells stabilizer 1.alpha ,beta-adrenomemtic Beta1 and beta2-adrenomemetic 2.M-cholinoblockers(atzovent,troventol)(tiotropin,oxitropium) 3.methylxantines;entillinum

38)Approchess for treatment of peptic ulcer: 1-red of gastric acid secretion; (a) h2 antihistamine: cimetidine, racitidine, famotidine, roxatidine. (b) proton pump inhibitor:omeprazole, lansoprasole, pantoprazole, rabeprazo;e,esomapresol. c)Anticholinorgic: pirenzepine, propantheline, oxyphenonium, rabeprazole (d) prostaglandins analogue: misoprostol , tnaplostal. 2-neutralization of gastric acid(antacids): (a) systematic: NAHCO3, sodium litrate. (b) nonsystemic: magnisum hydroxide, mg.teslicate, aluminium hydroxidegel , calcium carbonate . 3) ulcer protectives : sucralfate , colloidial bismuth sub litrate (cbs). 4) anti.h.pylori : amoxicillin, clarithromycin , metronidazole, tinidazole,tetracycline Adverse effect: 1) headache, dizziness, bowel upset. Dry mouth , rashes . 2) CNS effects,like confusional state restlessness, coma, renal impairment with high doses 3) Bolus: histamines release : bradycardia , arrhymias& cardic arrest must be given slowly 4) Cimetidine has antiadrogenic action . gyhaewmastia loss of libido, impotence& temporary less in sperm count. 5) Hepatotoxicity is rare. USES OF H2 ANTAGONASTISTS: 1)DUDINAL ULCER : rapid & marked pain relif (2-3 days) 2)Gastric ulcer: healing rate some what lower . mostly in bleeding peptic ulcers . 3)stress ulcer and gastritis 4) Zollinger ellisen syndrome (ze syndrome) 5) Gastroesophageal reflux disease ( GERD) 6) Prophylaxis of aspiration pneumonia. 7) Other uses : urtcaria. 39)Drugs stimulating gastrointestinal motility 1)cholinomimetic drugs

2)macrolides:-erythromycin 3)metoclopramide(dopamine antagonist) 4)cisprid(5ht4agonist) Metopclopramide , cispride release acetylcholine in enteric nervous system mysentric plexus Uses:-they fasten esophageal clearance 2)rise lower esophageal sphincter pressure 3)accelerate gastric empyting Metoclpramide 1)used in patient wid gastric motor failure 2)it is anti emeticparticularly in cancer theraphy 3)emergency operation 4)labour delivery Half life 2-4 hrs Negative effects:- nervousness,dystonic reaction,increase pitutory prolactin release, menstrual disorder 40)*Laxatives aperients, purgatives, cathartics these drugsremoves and contents of intestine. Classification: small and large intestine (12-17 hrs) actions 1) Bulk formation: dietary fibre- bran, methyl cellulose. 2) Stool softness : docusates, liq. paraffin. 3) Stimulant Purgativesa)diphenyl methane- bisacodyl, sod.picosulfate b) Antharaquinones-senna(6-10hrs) c) 5-st4 agonist- tegaserod. d) fixed oil castor oil- lubricants e) osmotic purgativesmg salts-sulfate,lactalose. - Calcium salt may cause constipations. - Laxatuves( or pyrgatives) are food comp. or drug taken to induce bowel movement or loosen decrease stool taken to treat constipation. Stimulant, lubricant and saline laxatives are useee -Some vegatable and foods can use1 Almonds, aloevera , apples juice, bananas, basil, beets, chicory, coconuts, grapes. 41 ) Anti diarrheaa drugs:1) ORS (hydration oral ) 2) antimicrobial- lipro, ampi, No ) 3) non specific anti diarrheal. a) Absorbant- ispaghula, psyllium, methyl cellulose. b) antisecratory- sulfasalizine, merasalasize., bismuth subsalicylate. c) antimotility- codein, loperamide, diphenoxylate. 42)Antiemetic drugs..... Classification--1) Anticholinergics- eg. Hycoscine( motion, sickness, Dicyclomine.) 2) H1-Antihistaminics. eg- promethazine, cloxacamine (motion sickness- cyclizine, meclozine.) 3) Neuroleptics- chlorpromazine, prochlormazine, 4) Prokinetic drugs. eg_ metoclopramide, domperidone, cisapride, mosapride. 5 ) 5-HT3 antagonist: oclansteron, guanisterone. 6) Adjuscuent antiemtics : dexamethasone, benzodizepines, cannabinoids.

Mechanism of vomittings. -vomiting regulated by vomitting center and CT 2 in medulla. - Neuron imput in GIT, CNS center, relayed to vomitting center and central (viscor & stomatic function in vomiting ) - Neurotransmiter ACH, histamine, 5 HT3 & dopamine use. Side Effects. 1) drousiness and anti-parasympathetic effects. 2) dystonias 3) CNS disturbance 4) headache. 44) Hypothalamic & Pituitary Hormones Hypothalamus Pituitary gland 1Anterior pituitary (Adenohypophysis) The anterior pituitary synthesizes and secretes important endocrine hormones: 1adrenocorticotropic hormone (ACTH), 2follicle-stimulating hormone (FSH) 3thyroid-stimulating hormone (TSH, thyrotropin), 4prolactin (PRL), 5growth hormone (GH), 6luteinizing hormone (LH). These hormones are released from the anterior pituitary under the influence of hypothalamus. Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called the hypothalamic-hypophyseal portal system. The anterior pituitary develops from a depression in the dorsal wall of the pharynx (stomodial part) known as Rathke's pouch. Thyroid-stimulating hormone, FSH, LH, and ACTH share similarities in the regulation of their release from the pituitary. All are under the control of a hypothalamic peptide that stimulates their production by acting on G protein-coupled receptors. Thyroid-stimulating hormone release is regulated by thyrotropin-releasing hormone (TRH), whereas the release of LH and FSH (known collectively as gonadotropins) is stimulated by pulses of gonadotropin-releasing hormone (GnRH). Adrenocorticotropin release is stimulated by corticotropin-releasing hormone (CRH).

PHARMACOLOGY OF GROWTH HORMONE (SOMATOTROPIN) Growth hormone: 1peptide hormon, 2produced by the anterior pituitary, 3required during childhood and adolescence for attainment of normal adult size and has important effects throughout postnatal life on lipid and carbohydrate metabolism, and on lean body mass. 4Its effects are primarily mediated via insulin-like growth factor 1 (IGF-1, somatomedin C) and to a lesser extent both directly and through insulin-like growth factor 2 (IGF-2). Individuals with congenital or acquired deficiency in GH during childhood or adolescence fail to reach their predicted adult height and have disproportionately increased body fat and decreased muscle mass. Adults with GH deficiency also have disproportionately small lean body mass. 2Chemistry & Pharmacokinetics Somatotropin is a 191-amino-acid peptide with two sulfhydryl bridges. Its structure closely resembles that of prolactin. In the past, medicinal GH was isolated from the pituitaries of human cadavers. However, this form of GH was found to be contaminated with prions that could cause Creutzfeldt-Jakob disease. For this reason, it is no longer used. Two types of recombinant human growth hormone (rhGH) are approved for clinical use. Somatropin has a 191-amino-acid sequence that is identical with the predominant native form of human growth hormone. Somatrem has 192 amino acids consisting of the 191 amino acids of GH plus an extra methionine residue at the amino terminal end. The two preparations appear to be equipotent. 1ABSORPTION, METABOLISM, AND EXCRETION Circulating endogenous GH has a half-life of 20-25 minutes and is predominantly cleared by the liver. Recombinant human GH is administered subcutaneously 3-6 times per week. Peak levels occur in 2-4 hours and active blood levels persist for approximately 36 hours. Somatropin injectable suspension is a long-acting preparation of rhGH enclosed within microspheres. These microspheres degrade slowly after subcutaneous injection such that the rhGH is released over about 1 month. 1Pharmacodynamics Growth hormone mediates its effects via cell surface receptors of the JAK/STAT cytokine receptor superfamily. Dimerization of two GH receptors is stimulated by a single GH molecule and activates signaling cascades mediated by receptor-associated JAK tyrosine kinases and STATs. Growth hormone has complex effects on growth, body composition, and carbohydrate, protein, and lipid metabolism. The growth-promoting effects are mediated through an increase in the production of IGF-1. Much of the circulating IGF-1 is produced in the liver. Growth hormone also stimulates production of IGF-1 in bone, cartilage, muscle, and the kidney, where it plays autocrine or paracrine roles.

Growth hormone stimulates longitudinal bone growth until the epiphyses close - near the end of puberty. In both children and adults, GH has anabolic effects in muscle and catabolic effects in lipid cells that shift the balance of body mass to an increase in muscle mass and a reduction in central adiposity. The effects of GH on carbohydrate metabolism are mixed, in part because GH and IGF-1 have opposite effects on insulin sensitivity. Growth hormone reduces insulin sensitivity, which results in mild hyperinsulinemia. In contrast, in patients who are unable to respond to endogenous GH because of mutated GH receptors, IGF-1 acting through its own IGF-1 receptors and through insulin receptors lowers serum glucose and reduces circulating insulin. 1Clinical applications Examples of other causes of shortness often treated with GH are Turner syndrome, chronic renal failure, Prader-Willi syndrome, intrauterine growth retardation, and severe idiopathic short stature Uses that are controversial include: 1GH treatment for remission of Multiple sclerosis 2GH treatment to reverse effects of aging in older adults 3GH treatment to enhance weight loss in obesity 4GH treatment for fibromyalgia 5GH treatment for Crohn's disease and ulcerative colitis 6GH treatment for idiopathic short stature 7GH treatment for bodybuilding or athletic enhancement 8The use of bovine somatotropin to increase milk production in cattle 2Toxicity & Contraindications Children generally tolerate GH treatment well. A rarely reported side effect is: 1intracranial hypertension (which may manifest as vision changes), 2headache, 3nausea, or vomiting. Side effects of the long-acting somatropin injectable suspension have included injection-site nodules that persist for 5-7 days (96%), edema, arthralgias, transient fatigue (24%), mild-moderate nausea (24%), and headache (36%). 1GROWTH HORMONE ANTAGONISTS acromegaly, gigantism. bromocriptine, pegvisomant 1Chemistry & Pharmacokinetics

A. STRUCTURE GnRH is a decapeptide found in all mammals. Gonadorelin is an acetate salt of synthetic human GnRH. Synthetic analogs include goserelin, histrelin, leuprolide, nafarelin, and triptorelin. These analogs all have D-amino acids at position 6, and all but nafarelin have ethylamide substituted for glycine at position 10. Both modifications make them more potent and longer-lasting than native GnRH and gonadorelin. B. PHARMACOKINETICS Gonadorelin can be administered intravenously or subcutaneously. GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant. The half-life of intravenous gonadorelin is 4 minutes, and the half-lives of subcutaneous and intranasal GnRH analogs are approximately 3 hours. The duration of clinical uses of GnRH agonists varies from a few days for ovulation induction to a number of years for treatment of metastatic prostate cancer. Therefore, preparations have been developed with a range of durations of action from several hours (for daily administration) to 1, 4, 6, or 12 months (depot forms). 1Clinical Pharmacology The GnRH agonists are occasionally used for stimulation of gonadotropin production. They are used far more commonly for suppression of gonadotropin release. A.STIMULATION Female infertility. Male infertility. Diagnosis of LH responsiveness. B. SUPPRESSION OF GONADOTROPIN PRODUCTION Controlled ovarian hyperstimulation Endometriosis. Uterine leiomyomata (uterine fibroids). Prostate cancer. Central precocious puberty. 45)Pancreatic Hormones 1THE ENDOCRINE PANCREAS The endocrine pancreas in the adult human consists of approximately 1 million islets of Langerhans interspersed throughout the pancreatic gland. Their hormone products include insulin, the storage and anabolic hormone of the body; islet amyloid polypeptide (IAPP, or amylin), which modulates appetite, gastric emptying, and glucagon and insulin secretion; glucagon, the hyperglycemic factor that mobilizes glycogen stores; somatostatin, a universal

inhibitor of secretory cells; and pancreatic peptide, a small protein that facilitates digestive processes by a mechanism not yet clarified. 1Type 1 Diabetes Mellitus The hallmark of type 1 diabetes is selective B-cell destruction and severe or absolute insulin deficiency. Administration of insulin is essential in patients with type 1 diabetes. Type 1 diabetes is further subdivided into immune and idiopathic causes. The immune form is the most common form of type 1 diabetes. Although most patients are younger than 30 years of age at the time of diagnosis, the onset can occur at any age. Type 1 diabetes is found in all ethnic groups, but the highest incidence is in people from northern Europe and from Sardinia. Susceptibility appears to involve a multifactorial genetic linkage but only 10-15% of patients have a positive family history. 1Type 2 Diabetes Mellitus Type 2 diabetes is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. A given individual may have more resistance or more B-cell deficiency, and the abnormalities may be mild or severe. Although insulin is produced by the B cells in these patients, it is inadequate to overcome the resistance, and the blood glucose rises. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein (HDL). Individuals with type 2 diabetes may not require insulin to survive, but 30% or more will benefit from insulin therapy to control the blood glucose. It is likely that 10-20% of individuals in whom type 2 diabetes was initially diagnosed actually have both type 1 and type 2 or a slowly progressing type 1, and ultimately will require full insulin replacement. Although persons with type 2 diabetes ordinarily do not develop ketosis, ketoacidosis may occur as the result of stress such as infection or use of medication that enhances resistance, eg, corticosteroids. Dehydration in untreated and poorly controlled individuals with type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma. In this condition, the blood glucose may rise to 6-20 times the normal range and an altered mental state develops or the person loses consciousness. Urgent medical care and rehydration is required. 1INSULIN Chemistry Insulin is a small protein with a molecular weight in humans of 5808. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges; there are species differences in the amino acids of both chains. Proinsulin, a long single-chain protein molecule, is processed within the Golgi apparatus and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids. Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues; a small quantity of unprocessed or partially hydrolyzed proinsulin is released as well. Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function. Granules within the B cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units. Originally, the unit was defined on the basis of the hypoglycemic activity of insulin in rabbits. With improved purification techniques, the unit is presently defined on the basis of weight, and present insulin standards used for assay

purposes contain 28 units per milligram. 1Insulin Secretion Insulin is released from pancreatic B cells at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli, especially glucose. Other stimulants such as other sugars (eg, mannose), certain amino acids (eg, leucine, arginine), hormones such as glucagon-like polypeptide-1 and vagal activity are recognized. As shown in the figure, hyperglycemia results in increased intracellular ATP levels, which close the ATP-dependent potassium channels. Decreased outward potassium efflux results in depolarization of the B cell and opening of voltage-gated calcium channels. The resulting increased intracellular calcium triggers secretion of the hormone. The insulin secretagogue drug group (sulfonylureas, meglitinides, and Dphenylalanine) exploits parts of this mechanism. One model of control of insulin release from the pancreatic B cell by glucose and by sulfonylurea drugs. In the resting cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases, potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secretagogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same mechanism. 1Insulin Degradation The liver and kidney are the two main organs that remove insulin from the circulation. The liver normally clears the blood of approximately 60% of the insulin released from the pancreas by virtue of its location as the terminal site of portal vein blood flow, with the kidney removing 35-40% of the endogenous hormone. However, in insulin-treated diabetics receiving subcutaneous insulin injections, this ratio is reversed, with as much as 60% of exogenous insulin being cleared by the kidney and the liver removing no more than 30-40%. The half-life of circulating insulin is 3-5 minutes. 1The Insulin Receptor After insulin has entered the circulation, it diffuses into tissues, where it is bound by specialized receptors that are found on the membranes of most tissues. The biologic responses promoted by these insulin-receptor complexes have been identified in the primary target tissues, ie, liver, muscle, and adipose tissue. The receptors bind insulin with high specificity and affinity in the picomolar range. The full insulin receptor consists of two covalently linked heterodimers, each containing an a subunit, which is entirely extracellular and constitutes the recognition site, and subunit that spans the membrane. Schematic diagram of the insulin receptor heterodimer in the activated state. IRS, insulin receptor substrate; P, phosphate; tyr, tyrosine.

The subunit contains a tyrosine kinase. The binding of an insulin molecule to the a subunits at the outside surface of the cell activates the receptor and through a conformational change brings the catalytic loops of the opposing cytoplasmic subunits into closer proximity. This facilitates mutual phosphorylation of tyrosine residues on the subunits and tyrosine kinase activity directed at cytoplasmic proteins. The first proteins to be phosphorylated by the activated receptor tyrosine kinases are the docking proteins, insulin receptor substrate-1 through -6 (IRS-1 to IRS-6). After tyrosine phosphorylation at several critical sites, the IRS molecules bind to and activate other kinases - most significantly phosphatidylinositol-3-kinase which produce further phosphorylations or to an adaptor protein such as growth factor receptor-binding protein 2, which translates the insulin signal to a guanine nucleotide-releasing factor that ultimately activates the GTP binding protein ras, and the mitogen-activated protein kinase (MAPK) system. The particular IRS-phosphorylated tyrosine kinases have binding specificity with downstream molecules based on their surrounding 4-5 amino acid sequences or motifs that recognize specific Src homology 2 (SH2) domains on the other protein. This network of phosphorylations within the cell represents insulin's second message and results in multiple effects, including translocation of glucose transporters to the cell membrane with a resultant increase in glucose uptake; increased glycogen synthase activity and increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis; and activation of transcription factors that enhance DNA synthesis and cell growth and division. The IRS-2 signaling pathway is associated with cellular proliferation and mitogenesis. Various hormonal agents (eg, glucocorticoids) lower the affinity of insulin receptors for insulin; growth hormone in excess increases this affinity slightly. Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance and functional receptor down-regulation. 1Effects of Insulin on Its Targets Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells and influences cell growth and the metabolic functions of a wide variety of tissues. Insulin promotes synthesis (from circulating nutrients) and storage of glycogen, triglycerides, and protein in its major target tissues: liver, fat, and muscle. The release of insulin from the pancreas is stimulated by increased blood glucose, incretins, vagal nerve stimulation, and other factors. 1Characteristics of Available Insulin Preparations Commercial insulin preparations differ in a number of ways, such as differences in the recombinant DNA production techniques, amino acid sequence, concentration, solubility, and the time of onset and duration of their biologic action. In 2006, 17 insulin formulations were available in the USA. Four principal types of injected insulins are available: (1) rapid-acting, with very fast onset and short duration; (2) short-acting, with rapid onset of action; (3) intermediate-acting; (4) long-acting, with slow onset of action.

An inhaled form of rapid-acting insulin also is marketed. Injected rapid-acting and short-acting insulins are dispensed as clear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf-life. Inhaled rapid-acting human insulin is available as a powder for alveolar absorption. Injected intermediate-acting NPH insulins have been modified to provide prolonged action and are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer (neutral protamine Hagedorn [NPH] insulin). Insulin glargine and insulin detemir are the soluble long-acting insulins. The goal of subcutaneous insulin therapy is to replace the normal basal (overnight, fasting, and between meal) as well as bolus or prandial (mealtime) insulin. Current regimens generally use long-acting insulins to provide basal or background coverage, and rapid-acting insulin to meet the mealtime requirements. The latter insulins are given as supplemental doses to correct transient hyperglycemia. Intensive therapy ("tight control") attempts to restore near-normal glucose patterns throughout the day while minimizing the risk of hypoglycemia. Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2-0.3 U/kg; with the exception of insulin lispro, aspart, and glulisine, duration increases considerably when dosage is increased. An exact reproduction of the normal glycemic profile is technically not possible because of the limitations inherent in subcutaneous administration of insulin. The most sophisticated insulin regimen delivers rapidacting insulin through a continuous subcutaneous insulin infusion device; alternative intensive regimens referred to as multiple daily injections (MDI) use long-acting insulins with multiple boluses of rapid-acting insulin. Conventional therapy presently consists of split-dose injections of mixtures of rapid- or short-acting and intermediate-acting insulins. 1Rapid-acting insulin Three injected rapid-acting insulin analogs: insulin lispro, insulin aspart, and insulin glulisine, and one inhaled form of rapid-acting insulin, human insulin recombinant inhaled, are commercially available. The rapid-acting insulins permit more physiologic prandial insulin replacement because their rapid onset and early peak action more closely mimic normal endogenous prandial insulin secretion than does regular insulin, and they have the additional benefit of allowing insulin to be taken immediately before the meal without sacrificing glucose control. Their duration of action is rarely more than 3-5 hours (with the exception of inhaled insulin, which may last 6-7 hours), which decreases the risk of late postmeal hypoglycemia. The injected rapid-acting insulins have the lowest variability of absorption (approximately 5%) of all available commercial insulins (compared to 25% for regular insulin and 25-50% for intermediate- and long-acting formulations). They are the preferred insulins for use in continuous subcutaneous insulin infusion devices. Insulin lispro, the first monomeric insulin analog to be marketed, is produced by recombinant technology wherein two amino acids near the carboxyl terminal of the B chain have been reversed in position: Proline at position B28 has been moved to B29, and lysine at position B29 has been moved to B28. Reversing these two amino acids does not interfere in any way with insulin lispro's binding to the insulin receptor, its circulating half-life, or its immunogenicity, which are similar to those of human regular insulin. However, the advantage of this analog is its very low propensity - in contrast to human insulin - to self-

associate in antiparallel fashion and form dimers. To enhance the shelf-life of insulin in vials, insulin lispro is stabilized into hexamers by a cresol preservative. When injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5-15 minutes and peak activity as early as 1 hour. The time to peak action is relatively constant, regardless of the dose. Insulin aspart is created by the substitution of the B28 proline with a negatively charged aspartic acid. This modification reduces the normal ProB28 and GlyB23 monomer-monomer interaction, thereby inhibiting insulin self-aggregation. Its absorption and activity profile is similar to that of insulin lispro, and it is more reproducible than regular insulin, but has similar binding properties, activity, and mitogenicity characteristics to regular insulin and equivalent immunogenicity. Insulin glulisine is formulated by substituting an asparagine for lysine at B3 and glutamic acid for lysine at B29. Its absorption, action, and immunologic characteristics are similar to the other injected rapid-acting insulins. After high-dose insulin glulisine-insulin receptor interaction, there may be downstream differences in IRS-2 pathway activation relative to human insulin. The clinical significance of such differences is unclear. Inhaled human insulin is a powder form of rDNA human insulin that is administered through an inhaler device and is marketed for pre-prandial and blood sugar correction use in adults with type 1 and 2 diabetes. Because of concerns about lung safety, it is not approved for use in children, teenagers, or adults with asthma, bronchitis, emphysema, smokers, or those within 6 months of quitting smoking. Although this route of administration is well tolerated, studies have shown that less than 30% of users were able to achieve target blood glucoses after 6 months of therapy with inhaled human insulin. 1Short-acting insulin Regular insulin is a short-acting soluble crystalline zinc insulin made by recombinant DNA techniques to produce a molecule identical to human insulin. Its effect appears within 30 minutes and peaks between 2 and 3 hours after subcutaneous injection and generally lasts 5-8 hours. In high concentrations, eg, in the vial, regular insulin molecules self-aggregate in antiparallel fashion to form dimers that stabilize around zinc ions to create insulin hexamers. The hexameric nature of regular insulin causes a delayed onset and prolongs the time to peak action. After subcutaneous injection, the insulin hexamers are too large and bulky to be transported across the vascular endothelium into the bloodstream. As the insulin depot is diluted by interstitial fluid and the concentration begins to fall, the hexamers break down into dimers and finally monomers. This results in three rates of absorption of the injected insulin, with the final monomeric phase having the fastest uptake out of the injection site. The delayed absorption results in a mismatching of insulin availability with need. Specifically, when regular insulin is administered at mealtime, the blood glucose rises faster than the insulin with resultant early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Regular insulin should be injected 30-45 or more minutes before the meal to minimize the mismatching. As with all older insulin formulations, the duration of action as well as the time of onset and the intensity of peak action increase with the size of the dose. Clinically, this is a critical issue because the pharmacokinetics and pharmacodynamics of small doses of regular and NPH insulins differ greatly from those of large doses. Short-acting soluble insulin is the only type that should be administered intravenously because the dilution causes the hexameric insulin to immediately dissociate into monomers. It is particularly useful for intravenous therapy in the management of diabetic ketoacidosis and when the insulin requirement is changing rapidly,

such as after surgery or during acute infections. 1Intermediate-acting and long-acting insulins NPH (neutral protamine Hagedorn, or isophane) insulin - NPH insulin is an intermediate-acting insulin wherein absorption and the onset of action are delayed by combining appropriate amounts of insulin and protamine so that neither is present in an uncomplexed form ("isophane"). Protamine is a mixture of six major and some minor compounds of similar structure isolated from the sperm of rainbow trout. They appear to be basic, arginine-rich peptides with an average molecular weight of approximately 4400. To form an isophane complex (one in which neither component retains any free binding sites), approximately a 1:10 ratio by weight of protamine to insulin is required, representing approximately six molecules of insulin per molecule of protamine. After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of insulin. NPH insulin has an onset of approximately 2-5 hours and duration of 4-12 hours; it is usually mixed with regular, lispro, aspart, or glulisine insulin and given two to four times daily for insulin replacement in patients with type 1 diabetes. The dose regulates the action profile; specifically, small doses have lower, earlier peaks and a short duration of action with the converse true for large doses. Insulin glargine - Insulin glargine is a soluble, "peakless" (ie, having a broad plasma concentration plateau), ultra-long-acting insulin analog. This product was designed to provide reproducible, convenient, background insulin replacement. The attachment of two arginine molecules to the B chain carboxyl terminal and substitution of a glycine for asparagine at the A21 position created an analog that is soluble in an acidic solution but precipitates in the more neutral body pH after subcutaneous injection. Individual insulin molecules slowly dissolve away from the crystalline depot and provide a low, continuous level of circulating insulin. Insulin glargine has a slow onset of action (1-1.5 hours) and achieves a maximum effect after 4-6 hours. This maximum activity is maintained for 11-24 hours or longer. Glargine is usually given once daily, although some very insulin-sensitive individuals benefit from split (twice a day) dosing. To maintain solubility, the formulation is unusually acidic (pH 4.0) and insulin glargine should not be mixed with other insulins. Separate syringes must be used to minimize the risk of contamination and subsequent loss of efficacy. The absorption pattern of insulin glargine appears to be independent of the anatomic site of injection, and this drug is associated with less immunogenicity than human insulin in animal studies. Glargine's interaction with the insulin receptor is similar to that of native insulin and shows no increase in mitogenic activity in vitro. It has sixfold to sevenfold greater binding than native insulin to the insulin-like growth factor-1 (IGF-1) receptor, but the clinical significance of this is unclear. Insulin detemir - This insulin is the most recently developed long-acting insulin analog. The terminal threonine is dropped from the B30 position and myristic acid (a C-14 fatty acid chain) is attached to the terminal B29 lysine. These modifications prolong the availability of the injected analog by increasing both self-aggregation in subcutaneous tissue and reversible albumin binding. Insulin detemir has the most reproducible effect of the intermediate- and long-acting insulins, and its use is associated with less hypoglycemia than NPH insulin. Insulin detemir has a dose-dependent onset of action of 1-2 hours and duration of action of more than 24 hours. It is given twice daily to obtain a smooth background insulin level. Mixtures of insulins - Because intermediate-acting NPH insulins require several hours to reach adequate therapeutic levels, their use in type 1 diabetic patients requires supplements of rapid- or short-acting insulin

before meals. For convenience, these are often mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH insulin without affecting their rapid absorption. However, premixed preparations have thus far been unstable. To remedy this, intermediate insulins composed of isophane complexes of protamine with insulin lispro and insulin aspart have been developed. These intermediate insulins have been designated as "NPL" (neutral protamine lispro) and "NPA" (neutral protamine aspart) and have the same duration of action as NPH insulin. They have the advantage of permitting formulation as premixed combinations of NPL and insulin lispro, and as NPA and insulin aspart, and they have been shown to be safe and effective in clinical trials. The FDA has approved 50%/50% and 75%/25% NPL/insulin lispro and 70%/30% NPA/insulin aspart premixed formulations. Additional ratios are available abroad. Insulin glargine and detemir must be given as separate injections. They are not miscible acutely or in a premixed preparation with any other insulin formulation. INSULIN PRODUCTION Human insulins Mass production of human insulin and insulin analogs by recombinant DNA techniques is carried out by inserting the human or a modified proinsulin gene into Escherichia coli or yeast and treating the extracted proinsulin to form the insulin or insulin analog molecules.

Insulin Delivery Systems The standard mode of insulin therapy is subcutaneous injection using conventional disposable needles and syringes. During the last three decades, much effort has gone into exploration of other means of administration, and inhaled insulin is now available. PORTABLE PEN INJECTORS To facilitate multiple subcutaneous injections of insulin, particularly during intensive insulin therapy, portable pen-sized injectors have been developed. These contain cartridges of insulin and replaceable needles. Disposable insulin pens are also available for selected formulations. These are regular insulin, insulin lispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, and several mixtures of NPH with regular, lispro, or aspart insulin. They have been well accepted by patients because they eliminate the need to carry syringes and bottles of insulin to the workplace and while traveling. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION DEVICES (CSII, INSULIN PUMPS) Continuous subcutaneous insulin infusion devices are external open-loop pumps for insulin delivery. The devices have a user-programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results. Normally, the 24-hour background basal rates are relatively constant from day to day, although temporarily altered rates can be superimposed to adjust for a short-term change in requirement. For example, the basal delivery rate might need to be decreased for several hours because of the increased insulin sensitivity associated with strenuous activity. In contrast, the bolus

amounts frequently vary and are used to correct high blood glucose levels and to cover mealtime insulin requirements based on the carbohydrate content of the food and concurrent activity. The pump - which contains an insulin reservoir, the program chip, the keypad, and the display screen - is about the size of a pager. It is usually placed on a belt or in a pocket, and the insulin is infused through thin plastic tubing that is connected to the subcutaneously inserted infusion set. The abdomen is the favored site for the infusion set, although flanks and thighs are also used. The insulin reservoir, tubing, and infusion set need to be changed using sterile techniques every 2 or 3 days. CSII delivery is regarded as the most physiologic method of insulin replacement. INHALED INSULIN The FDA has approved an inhaled insulin preparation of finely powdered and aerosolized human insulin. Insulin is readily absorbed into the bloodstream through alveolar walls, but the challenge has been to create particles that are small enough to pass through the bronchial tree without being trapped and still enter the alveoli in sufficient amounts to have a clinical effect. Insulin delivered by the inhaled route has pharmacokinetic and pharmacodynamic characteristics of both rapid- and short-acting insulin. It has a rapid onset and peak insulin levels (by 30 minutes) similar to insulin lispro, aspart, and glulisine, and peak effect (22.5 hours) and duration of action (6-8 hours) similar to regular insulin. Inhaled insulin can be used to cover mealtime insulin requirements or to correct high glucose levels, but not to provide background or basal insulin coverage.

First-Generation Sulfonylureas :Tolbutamide (Orinase) ,Acetohexamide (Dymelor),Tolazamide (Tolinase) ,Chlorpropamide (Diabinese Second-Generation Sulfonylureas : Glyburide,Glipizide,Glimepiride 46)Thyroid drugs The normal thyroid gland secretes sufficient amounts of the thyroid hormones triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine) - to normalize growth and development, body temperature, and energy levels. These hormones contain 59% and 65% (respectively) of iodine as an essential part of the molecule. Calcitonin, the second type of thyroid hormone, is important in the regulation of calcium metabolism. The recommended daily adult iodide intake is 150 mcg (200 mcg during pregnancy). Iodide, ingested from food, water, or medication, is rapidly absorbed and enters an extracellular fluid pool. The thyroid gland removes about 75 mcg a day from this pool for hormone synthesis, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the thyroid is diminished. Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that convert it into active thyroid hormone. The first step is the transport of iodide into the thyroid gland by an intrinsic follicle cell basement membrane protein called the sodium/iodide symporter (NIS). This can be inhibited by such anions as thiocyanate (SCN-), pertechnetate (TcO4-), and perchlorate (ClO4-). At the apical cell membrane a second I- transport enzyme called pendrin controls the flow of iodide across

the membrane. Pendrin is also found in the cochlea of the inner ear and if deficient or absent, a syndrome of deafness and goiter, called Pendred's syndrome, ensues. At the apical cell membrane, iodide is oxidized by thyroidal peroxidase to iodine, in which form it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is called iodide organification. Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs. Two molecules of DIT combine within the thyroglobulin molecule to form L-thyroxine (T4). One molecule of MIT and one molecule of DIT combine to form T3. In addition to thyroglobulin, other proteins within the gland may be iodinated, but these iodoproteins do not have hormonal activity. Thyroxine, T3, MIT, and DIT are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The MIT and DIT are deiodinated within the gland, and the iodine is reutilized. This process of proteolysis is also blocked by high levels of intrathyroidal iodide. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thyroxine. Most of the T3 circulating in the blood is derived from peripheral metabolism of thyroxine. T4 and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form. Many physiologic and pathologic states and drugs affect T4, T3, and thyroid transport. However, the actual levels of free hormone generally remain normal, reflecting feedback control. The primary pathway for the peripheral metabolism of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodination of the outer ring, producing 3,5,3-triiodothyronine (T3), which is three to four times more potent than T4. Alternatively, deiodination may occur in the inner ring, producing 3,3,5triiodothyronine (reverse T3, or rT3), which is metabolically inactive. Drugs such as amiodarone, iodinated contrast media, b blockers, and corticosteroids, and severe illness or starvation inhibit the 5-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum. The low serum levels of T3 and rT3 in normal individuals are due to the high metabolic clearances of these two compounds. A.THYROID-PITUITARY RELATIONSHIPS Control of thyroid function via thyroid-pituitary feedback. Briefly, hypothalamic cells secrete thyrotropinreleasing hormone (TRH). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyroid-stimulating hormone (TSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. The hypothalamic-pituitary-thyroid axis. Acute psychosis or prolonged exposure to cold may activate the axis. Hypothalamic TRH stimulates pituitary TSH release, while somatostatin and dopamine inhibit it. TSH stimulates T4 and T3 synthesis and release from the thyroid, and they in turn inhibit both TRH and TSH synthesis and release. Small amounts of iodide are necessary for hormone production, but large amounts inhibit T3 and T4 production and release. (Solid arrows, stimulatory influence; dashed arrows, inhibitory influence. H, hypothalamus, AP, anterior pituitary.)

B. AUTOREGULATION OF THE THYROID GLAND The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are independent of TSH. These mechanisms are primarily related to the level of iodine in the blood. Large doses of iodine inhibit iodide organification (Wolff-Chaikoff block). In certain disease states (eg, Hashimoto's thyroiditis), this can inhibit thyroid hormone synthesis and result in hypothyroidism. Hyperthyroidism can result from the loss of the Wolff-Chaikoff block in susceptible individuals (eg, multinodular goiter). C. ABNORMAL THYROID STIMULATORS In Graves' disease (see below), lymphocytes secrete a TSH receptor-stimulating antibody (TSH-R Ab [stim]), also known as thyroid-stimulating immunoglobulin (TSI). This immunoglobulin binds to the TSH receptor and turns on the gland in the same fashion as TSH itself. The duration of its effect, however, is much longer than that of TSH. TSH receptors are also found in orbital fibrocytes, which may be stimulated by high levels of TSH-R Ab [stim]. The structural formulas of thyroxine and triiodothyronine as well as reverse triiodothyronine (rT3) are shown in figure.

All of these naturally occurring molecules are levo (L) isomers. The synthetic dextro (D) isomer of thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of the L isomer as evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidism. Thyroxine is absorbed best in the duodenum and ileum; absorption is modified by intraluminal factors such as food, drugs, and intestinal flora. Oral bioavailability of current preparations of L-thyroxine averages 80%. In contrast, T3 is almost completely absorbed (95%). T4 and T3 absorption appears not to be affected by mild hypothyroidism but may be impaired in severe myxedema with ileus. These factors are important in switching from oral to parenteral therapy. For parenteral use, the intravenous route is preferred for both hormones. In patients with hyperthyroidism, the metabolic clearances of T4 and T3 are increased and the half-lives decreased; the opposite is true in patients with hypothyroidism. Drugs that induce hepatic microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin, imatinib, protease inhibitors) increase the metabolism of both T4 and T3. Despite this change in clearance, the normal hormone concentration is maintained in euthyroid patients as a result of compensatory hyperfunction of the thyroid. However, patients receiving T4 replacement medication may require increased dosages to maintain clinical effectiveness. A similar compensation occurs if binding sites are altered. If TBG sites are increased by pregnancy, estrogens, or oral contraceptives, there is an initial shift of hormone from the free to the bound state and a decrease in its rate of elimination until the normal hormone concentration is restored. Thus, the concentration of total and bound hormone will increase, but the concentration of free hormone and the steady-state elimination will remain normal. The reverse occurs when thyroid binding sites are decreased. A model of thyroid hormone action is depicted in figure, which shows the free forms of thyroid hormones,

T4 and T3, dissociated from thyroid-binding proteins, entering the cell by active transport. Within the cell, T4 is converted to T3 by 5-deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3 receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins A and D.) The T3 receptor exists in two forms, and . Differing concentrations of receptor forms in different tissues may account for variations in T3 effect on different tissues. TR-LBD, T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid X receptor DNA-binding domain; T3, triiodothyronine; T4, tetraiodothyronine, L-thyroxine; 5'DI, 5'deiodinase. Model of the interaction of T3 with the T3 receptor. A: Inactive phase - the unliganded T3 receptor dimer bound to the thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B: Active phase - T3 and T4 circulate bound to thyroid-binding proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within the cytoplasm, T4 is converted to T3 by 5'deiodinase; T3 then moves into the nucleus. There it binds to the ligand-binding domain of the thyroid receptor (TR) monomer. This promotes disruption of the TR homodimer and heterodimerization with retinoid X receptor (RXR) on the TRE, displacement of corepressors, and binding of coactivators. The TR-coactivator complex activates gene transcription, which leads to alteration in protein synthesis and cellular phenotype. Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA and subsequent protein synthesis, eg, increased formation of Na+/K+ ATPase. This is consistent with the observation that the action of thyroid is manifested in vivo with a time lag of hours or days after its administration. Large numbers of thyroid hormone receptors are found in the most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung, and intestine), while few receptor sites occur in hormoneunresponsive tissues (spleen, testes). The brain, which lacks an anabolic response to T3, contains an intermediate number of receptors. In congruence with their biologic potencies, the affinity of the receptor site for T4 is about ten times lower than that for T3. The number of nuclear receptors may be altered to preserve body homeostasis. For example, starvation lowers both circulating T3 hormone and cellular T3 receptors. Thyroid hormone is critical for nervous, skeletal, and reproductive tissues. Its effects depend on protein synthesis as well as potentiation of the secretion and action of growth hormone. Thyroid deprivation in early life results in irreversible mental retardation and dwarfism - symptoms typical of congenital cretinism. Effects on growth and calorigenesis are accompanied by a pervasive influence on metabolism of drugs as well as carbohydrates, fats, proteins, and vitamins. Many of these changes are dependent upon or modified by activity of other hormones. Conversely, the secretion and degradation rates of virtually all other hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status. Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity

(especially in the cardiovascular system), although catecholamine levels are not increased. Changes in catecholamine-stimulated adenylyl cyclase activity as measured by cAMP are found with changes in thyroid activity. Possible explanations include increased numbers of b receptors or enhanced amplification of the b receptor signal. Other clinical symptoms reminiscent of excessive epinephrine activity (and partially alleviated by adrenoceptor antagonists) include lid lag and retraction, tremor, excessive sweating, anxiety, and nervousness. The opposite constellation of symptoms is seen in hypothyroidism. Thyroid hormones are not effective and can be detrimental in the management of obesity, abnormal vaginal bleeding, or depression if thyroid hormone levels are normal. Anecdotal reports of a beneficial effect of T3 administered with antidepressants have not been confirmed with a controlled study. Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy because of its stability, content uniformity, low cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily administration. In addition, T4 is converted to T3 intracellularly; thus, administration of T4 produces both hormones. Generic levothyroxine preparations provide comparable efficacy and are more cost-effective than branded preparations. 1Although liothyronine (T3) is three to four times more potent than levothyroxine, it is not recommended for routine replacement therapy because of its shorter half-life (24 hours), which requires multiple daily doses; its higher cost; and the greater difficulty of monitoring its adequacy of replacement by conventional laboratory tests. Furthermore, because of its greater hormone activity and consequent greater risk of cardiotoxicity, T3 should be avoided in patients with cardiac disease. It is best used for short-term suppression of TSH. Because oral administration of T3 is unnecessary, use of the more expensive mixture of thyroxine and liothyronine (liotrix) instead of levothyroxine is never required. The use of desiccated thyroid rather than synthetic preparations is never justified, since the disadvantages of protein antigenicity, product instability, variable hormone concentrations, and difficulty in laboratory monitoring far outweigh the advantage of low cost. Significant amounts of T3 found in some thyroid extracts and liotrix may produce significant elevations in T3 levels and toxicity. Equivalent doses are 100 mg of desiccated thyroid, 100 mcg of levothyroxine, and 37.5 mcg of liothyronine. The shelf life of synthetic hormone preparations is about 2 years, particularly if they are stored in dark bottles to minimize spontaneous deiodination. The shelf life of desiccated thyroid is not known with certainty, but its potency is better preserved if it is kept dry. Reduction of thyroid activity and hormone effects can be accomplished by agents that interfere with the production of thyroid hormones, by agents that modify the tissue response to thyroid hormones, or by glandular destruction with radiation or surgery. Goitrogens are agents that suppress secretion of T3 and T4 to subnormal levels and thereby increase TSH, which in turn produces glandular enlargement (goiter). The antithyroid compounds used clinically include the thioamides, iodides, and radioactive iodine. The thioamides methimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis. In the United Kingdom, carbimazole, which is converted to methimazole in vivo, is widely used. Methimazole is about ten times more potent than propylthiouracil. The chemical structures of these compounds are shown in figure. The thiocarbamide group is essential for

antithyroid activity. The thioamides act by multiple mechanisms. The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. They do not block uptake of iodide by the gland. Propylthiouracil and (to a much lesser extent) methimazole inhibit the peripheral deiodination of T4 and T3. Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3-4 weeks before stores of T4 are depleted. Adverse reactions to the thioamides occur in 3-12% of treated patients. Most reactions occur early, especially nausea and gastrointestinal distress. An altered sense of taste or smell may occur with methimazole. The most common adverse effect is a maculopapular pruritic rash (4-6%), at times accompanied by systemic signs such as fever. Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia. Hepatitis (more common with propylthiouracil) and cholestatic jaundice (more common with methimazole) can be fatal; although asymptomatic elevations in transaminase levels also occur. The most dangerous complication is agranulocytosis (granulocyte count < 500 cells/mm3), an infrequent but potentially fatal adverse reaction. It occurs in 0.1-0.5% of patients taking thioamides, but the risk may be increased in older patients and in those receiving high-dose methimazole therapy (> 40 mg/d). The reaction is usually rapidly reversible when the drug is discontinued, but broad-spectrum antibiotic therapy may be necessary for complicating infections. Colony-stimulating factors (eg, G-CSF) may hasten recovery of the granulocytes. The cross-sensitivity between propylthiouracil and methimazole is about 50%; therefore, switching drugs in patients with severe reactions is not recommended. Monovalent anions such as perchlorate (ClO4-), pertechnetate (TcO4-), and thiocyanate (SCN-) can block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism. Since these effects can be overcome by large doses of iodides, their effectiveness is somewhat unpredictable. The major clinical use for potassium perchlorate is to block thyroidal reuptake of I- in patients with iodideinduced hyperthyroidism (eg, amiodarone-induced hyperthyroidism). However, potassium perchlorate is rarely used clinically because it is associated with aplastic anemia. Iodides have several actions on the thyroid. They inhibit organification and hormone release and decrease the size and vascularity of the hyperplastic gland. In susceptible individuals, iodides can induce hyperthyroidism (jodbasedow phenomenon) or precipitate hypothyroidism. In pharmacologic doses (> 6 mg/d), the major action of iodides is to inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis. Improvement in thyrotoxic symptoms occurs rapidly - within 2-7 days - hence the value of iodide therapy in thyroid storm. In addition, iodides decrease the vascularity, size, and fragility of a hyperplastic gland, making the drugs valuable as preoperative preparation for surgery. Disadvantages of iodide therapy include an increase in intraglandular stores of iodine, which may delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks. Thus, iodides should be initiated after onset of thioamide therapy and avoided if treatment with radioactive iodine seems likely. Iodide should not be used alone, because the gland will escape from the iodide block in 2-8 weeks, and its withdrawal may produce severe exacerbation of thyrotoxicosis in an iodine-enriched gland. Chronic use of iodides in pregnancy should be avoided, since they cross the placenta and can cause fetal goiter. In radiation

emergencies, the thyroid-blocking effects of potassium iodide can protect the gland from subsequent damage if administered before radiation exposure. Adverse reactions to iodine (iodism) are uncommon and in most cases reversible upon discontinuance. They include: 1acneiform rash (similar to that of bromism), 2swollen salivary glands, 3mucous membrane ulcerations, 4conjunctivitis, rhinorrhea, 5drug fever, 6metallic taste, 7bleeding disorders, 8rarely, anaphylactoid reactions. 131I is the only isotope used for treatment of thyrotoxicosis (others are used in diagnosis). Administered orally in solution as sodium 131I, it is rapidly absorbed, concentrated by the thyroid, and incorporated into storage follicles. Its therapeutic effect depends on emission of b rays with an effective half-life of 5 days and a penetration range of 400-2000 um. Within a few weeks after administration, destruction of the thyroid parenchyma is evidenced by epithelial swelling and necrosis, follicular disruption, edema, and leukocyte infiltration. Advantages of radioiodine include easy administration, effectiveness, low expense, and absence of pain. Fears of radiation-induced genetic damage, leukemia, and neoplasia have not been realized after more than 50 years of clinical experience with radioiodine. Radioactive iodine should not be administered to pregnant women or nursing mothers, since it crosses the placenta to destroy the fetal thyroid gland and is excreted in breast milk. Beta blockers without intrinsic sympathomimetic activity (eg, metoprolol, propranolol, atenolol) are effective therapeutic adjuncts in the management of thyrotoxicosis since many of these symptoms mimic those associated with sympathetic stimulation. Propranolol has been the b blocker most widely studied and used in the therapy of thyrotoxicosis. Beta blockers cause clinical improvement of hyperthyroid symptoms but do not alter thyroid hormone levels. 50)Beta-lactam antibiotic -lactam antibiotics are a broad class of antibiotics that include penicillin derivatives, cephalosporins, monobactams, carbapenems, and -lactamase inhibitors, that is, any antibiotic agent that contains a -lactam nucleus in its molecular structure. They are the most widely-used group of antibiotics. . -Lactam antibiotics are bactericidal, and act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls.

Resistance to penicillins and other -lactams is due to one of four general mechanisms: 1)inactivation of antibiotic by -lactamase, 2)modification of target PBPs, 3)impaired penetration of drug to target PBPs, 4)efflux. Antibiotic resistance in bacteria spreads in three ways: 1by transfer of bacteria between people 2by transfer of resistance genes between bacteria (usually on plasmids) 3by transfer of resistance genes between genetic elements within bacteria, on transposons. Classification of the Penicillins Beta-lactamase sensitive :benzathine penicillin ,benzylpenicillin (penicillin G) ,phenoxymethylpenicillin (penicillin V) ,procaine penicillin,oxacillin Penicillinase-resistant penicillins:methicillin,Oxacillin,nafcillin,cloxacillin,dicloxacillin,flucloxacillin -lactamase-resistant penicillins temocillin,amoxycillin,ampicillin,co-amoxiclav (amoxicillin+clavulanic acid) ,azlocillin,ticarcillin,mezlocillin,piperacillin Benzylpenicillin, commonly known as penicillin G, is the gold standard penicillin. A beta-lactamase inhibitor is a drug given in conjunction with a beta-lactam antibiotic. Ampicillin/sulbactam ,Ampictam The cephalosporins are a class of -lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium". Together with cephamycins they constitute a subgroup of -lactam antibiotics called cephems. Cephalosporins are bactericidal and have the same mode of action as other beta-lactam antibiotics (such as penicillins). Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. Cephalosporins are indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic. First-generation cephalosporins are predominantly active against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms).

Eg. Parental:Cefazolin,Cefalotin,Cefapirin,Cefaloridin,efradin Oral: efalexin,Cefadroxil,Cefradine spectrum of activity: Gram (+): Pn, St, Str ,Gr (-): Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis Second generation cephalosporins Cefuroxime,Cefamandol ,Cefoxitin ,Cefonicid ,Cefprozil ,Cefmetazol ,Cefotetan ,Ceforanid efaclor ,Cefuroxim axetil ,Loracarbef ,efprozil But have no activity against:Bacteroides fragilis, enterococci, methicillin-resistant staphylococci, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, Serratia. Common adverse drug reactions (ADRs) (1% of patients) associated with the cephalosporin therapy include: diarrhea, nausea, rash, electrolyte disturbances, and/or pain and inflammation at injection site. Second generation cephalosporins with antianaerobe activity: Cefmetazole Cefotetan ,Cefoxitin The following cephems are also sometimes grouped with second-generation cephalosporins: 1Carbacephems: loracarbef (Lorabid) 2Cephamycins: cefbuperazone, cefmetazole (Zefazone), cefminox, cefotetan (Cefotan), cefoxitin (Mefoxin). The second-generation cephalosporins have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. They are also more resistant to beta-lactamase. Third-generation cephalosporins: Cefotaxime (Claforan),Ceftriaxone (Rocephin),Ceftrizoxim ,Cefoperazone (Cefobid),Ceftazidime (Fortum),Ceftizoxime (Cefizox) ,Moxalactam Cefixime (Suprax),Cefpodoxime proxetil,Ceftibuten (Cedax),Cefetamet pivoxil Third-generation cephalosporins with antipseudomonal activity: Cefoperazone (Cefobid) Ceftazidime (Fortum, Fortaz) Fourth-generation cephalosporins : Cefepime (Maxipime),Cefpirome (Cefrom) Fourth-generation cephalosporins are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins. Monobactam: aztreonam,tigemonam. Mechanism of action It inhibits synthesis in the bacterial cell wall. It has a very high affinity for penicillin-binding protein 3 (PBP-3) and mild affinity for PBP-1a. Aztreonam binds the penicillin-binding proteins of gram-positive and anaerobic bacteria very poorly and is largely ineffective against them.

Indications:- Aztreonam has strong activity against susceptible gram-negative bacteria, including Pseudomonas aeruginosa. It has no useful activity against gram-positive bacteria or anaerobes. It is known to be effective against a wide range of bacteria including Citrobacter, Enterobacter, E coli, Haemophilus, Klebsiella, Proteus, and Serratia species. Common adverse effects:- rash, and rarely toxic epidermal necrolysis. Gastrointestinal side effects,diarrhea and nausea and vomiting. Aztreonam is considered Pregnancy category B. Carbapenems: are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity, and have a structure which renders them highly resistant to beta-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomyces cattleya. The following drugs belong to the carbapenem class:- Imipenem ,Meropenem,Ertapenem,Doripenem,Panipenem/betamipron ,Biapenem Imipenem/cilastatin Mechanism :- It has the ability to kill a wide variety of bacteria. It works by interfering with their ability to form cell walls, and therefore the bacteria break up and die. 1Imipenem, the active antibacterial agent, is rapidly degraded by the renal enzyme dehydropeptidase if administered alone (making it less effective). Cilastatin is a dehydropeptidase inhibitor, with no intrinsic antibacterial activity, and must be co-administered with imipenem to ensure its efficacy. Cilastatin blocks the effects of the renal enzyme. Cilastatin has no antibacterial effects and does not affect the antibacterial activity of the imipenim. 3Mechanism of action:- Meropenem is bactericidal except against Listeria monocytogenes where it is bacteriostatic. It inhibits bacterial wall synthesis like other beta-lactam antibiotics. In contrast to other betalactams, it is highly resistant to degradation by beta-lactamases or Cephalosporinase. Resistance generally arises due to mutations in penicillin binding proteins, production of metallo-beta-lactamases, or resistance to diffusion across the bacterial outer membrane. Unlike imipenem, it is stable to Dehydropeptidase-1 and can therefore be given without cilastatin 51-Aminoglycosides -ami. cry. molicule composed of gp suger grp. -bacteriostatic effect. -active against gram.-ve bacteria e.colie, klebsiella, pseudomonas aerginosa, asinobactes, enterobacter -adminisreted intravenously & intramuscularly. Mech.bind to the 30s ribosomal subunit (some work by binding to 50s sub unit) inhibit the translocatin & also causing misreading of mRNA leaving the bacteria unable to synthesize protien viral growth. Ex. Gentamicin, venomycin, Kanamycin, Amikacin, Streptomycin. Cooman uses:Infection caused by gram -ve Toxicity:nephro toxicity, aotoxity, hearing lass, untigo, kideny,damage. Amikasin giuen acid B- lactam to treat nephropenia+fever gentamycin not used for nesseria gonorrhoa, legionella, highly nephrotoxicity, different multipal- tasking,

particularly standing up, balance difficulty. 52.Macrolides:-(group of drug tipcally antibiotic ) Ex.azithromycin,clarithromycin, erythromycin, telithromycin, dirithromycin. macrolides are used to treat infection such as respiratory tract & soft tissue infection. The antimicrobial if high conc. two m.l. accumilates in lecosites and trasported to site of infection. -ve effects:- combination of microlids & statins leads to myepath -potent inhibition of cytoclome pyro -nausea lincosomids- eg;-lincomycin,clindamycin bind to 23s portion of 50s subunit of ribosomes and inhibit elongation to peptidyl chain. uses-styhylococci,streptococcus,bacteriods fragils in treatment to toxic shock syndrome pharmacodinamic-bacteriostatic drug streptogramins;-combination of quinupristin and dalfopristin. -bacteriocidal effect -treatment of vancomycin resistant staphylococcus aureus,vancomycin resistant enrococci eg-pristnamycin,quinoprestin,dalfopristin. 54-Dihydroptroaet synthesis inhibitors(group salfonamide) genral-salfamethizol,salfadiazine,multipal salfonamide special-mafenide,silver suladiazine mac of action-bacteriostatic inhibit growth by reversibly blocking folic acid synthesis activity agonist:>g+ve and g-ve bacteria 3group-1)oral absarbable 2)oral nonabsorbable 3)topical clinical use-respiractory tract inf.,lserative colitis,bacterial conjetivitis, sinositis, bronkitis, interitis, inf. of burn wound, pnumonia,disentry, inflametory dis. -ve effect:- fever,skin rashes,photosensitivity,nousia,vometing, diarrha, urinary tract distarbace,hemopoitic distarbance 55)Antifungal drug.. 1)anb a)polyemers-amphoterichin B(AMB),nyslatis hamycin,natamicin b)heterocyclic binzofuron ciriseofulvin 2)anti metabolite-flucytosine (5fC) 3)azoles a)imidazoles clotrimazol(T) econazol,micanozole,oxiconazole,kitoconazole b)tiriazoles (sys) flucanazol,traconazole,voricanazole 4)allylamine-tarbinafine 5)other topical agent-tolnaflat,undecycliae aciad,bezoic aciad,auxidochelor,ciclopirox claucine,butenafine, sodium thiosulfate 56)Antiviral 1)nucleoside analogue RTI-zidovudine,didanosine ,zalcitabin,savudine,lanovodine,abacavir,emtricitabine,apricitabin 2)NN RTI-efavirenz,navirapine,delovirdin,atravirine

Negative effects:-git symptoms including diarrehea ,nausea,loose stools,abdominal dis comfort. Injection site reacation(pain,hardening of skin,arythmia,nodules,cyst itch,peripheral neuropathy,insomnia,cough , dysponea. 57)Disinfectants, antiseptics and sterilants Mech-oxidation of bal.protoplasm ,denaturation of bal.protin & enz. Increase mb permeability Factor affect T & ph ,pd with contact microorganation Nature of microne ,D/S of blood,pus & other org . Classification 1) phenol derivative phenol ,cresol ,chloroxylenol, hexachloropheane 2)oxidizin agent poto permangnete ,benzyle peroxide 3)halogens iodine ,iodophores ,clorin ,clorophores 6)soap of Na & K 7)alcohol-ethanol, isopropanol 8)aldehyde formaldehyde ,glyceraldehydes 9)acid basic acid ,acidic acid . 10) metallic salt silver nitrate ,silver ,sulfodiazins ,mild silver protein ,zinc sulphate ,calamine zinc oxide 58) Anti parasitic chemotherapyDrug kill parasite on body Ex-lice, & mites Drug-parmetherine,lindane (BHC) Benzyle benzoale ,erotamilton,sulphur,dicofine (DDT),ivernectin guineaworm-metronidazole tapeworm-praziquantel, nicloremide round worm mebendazol ,albendazol pyrantel levamisole,piprazines,ivermectin hook worm- pyrantel,mebendazol ,albendazole teapworm-praziquantel, nicloremide hydatid disease-albendazole, mebendazole 59) Antihelmintic drugs Worm drugs 1)round worm mebendazol ,albendazol pyrantel levamisole,piprazines,ivermectin 2)hook worm- pyrantel,mebendazol ,albendazole 3)thredworm4)whipworm-mebendazole , albendazole 5)filarial-diethyl carbamezine,ivermectin 6)guineaworm-metronidazole 7)teapworm-praziquantel, nicloremide 8)hydatid disease-albendazole, mebendazole Mech- kill or expel -ve diarrhoea, nausea,abd pain,hair loss fatigue,inlomnia,drowsiness

60 . Anti cancer 1)drug act on direct cell wall a) alkylating agents and related agents Ex:-melphalan,cisplatin,busulfan,lomustine,cyclophosphanmide b)antimetabolities Ex:-cytarabine,flouruacil,thioguanine,pentostatin,methotrexate c)vinca alkolides:-vincristine,vinblastine d)taxens:-paclitaxes,docetaxels 2)drug altering hormonal milinue a)glucocrticoide:-prednisolone b)estrogen:-posfestrol,ethnylestradiol c)selective estrogen mediator:- tomoxifin,toremifin d)selective estrogen receptor down regulator:- fulvestrant e)anti endrogen:- flutamid, f)5 alpha reductase inhibitor:- phenasteriden g)progestin:- hydroxyl progestron negative effects:- depression bone marrow,granalocytopenia,granulocytosis,lymphocytopenia,diarrehea,mucocitis,nausea ,vomiting sexual function disturbance. 61)Immunosuprresent drug 1)calcineurin inhibitor(specific t cell inhibitor):-cyclosporin,tarcolimius 2)anti proliferative drug(cytotoxic drug):- azothioprin,cyclophosphamyte,methotrexate 3)glucocorticoide:-prednisolon 4)antibodies:-muromonabCD3, anti thimocyte globuline,RHO(D)immunoglobulin Mechanism:Glucocorticoide inhibit measure histocompatibility complex and IL production so helper t cell not activated. Cytotoxic drug block proliferation of T and B cells. Cyclosporine inhibit antigen stimulated activation and activation of helper Tcells. Anti bodies bind helper t cell and prevent there response 62)Toxicology Toxicology is concerned with deleterious effects of chemical in physical agents or all living system. toxicity is the ability of a chemical agent to injury. Type:-1)occupational toxicology, 2)environmental toxicology, 3)ecotoxicology AIR:- CO, sulphur dioxide ,NO, ozone Solvent:- halogenated aliphatic hydrocarbons,aromatic hydrocarbons Insecticides:-1)clorinated hydrocarbon insecticides human, environmental 2)organ phosphorous insecticide 3)carbamate 4)botanical insecticides Herbicides:-1)chlorophenoxy herbicides 2)bipyridyl herbicides Environmental pollutants:- polychlorinated bi phenyls 2)endocrine dys ruptures

63.)VaccinesVaccines are antigenic material consist of whole microorganism or its product, it has 4 types A- BACTERIAL TYPE-----1-Killed (Inactivated)- consist of microorganism killed by heat or chemical. Eg.-typhoid,paratyphoid,V1 typhoid polysaccharide,cholera,whooping cough,Meningococcal,H.influenza type B,plague. 2-Live attenuated vaccine-consist of live bacteria or viruses which is non virulent so cant grow in host. Eg.-Bacillus calmette,Guerin(BCG),Typhoid-ty21a. 3-Toxoids-Modified bacterial endotoxins so toxicity lossed but have antigenicity. Eg.-Tetanus(Fluid adsorbed),Diptheria(Adsorbed) 4.-Combined Vaccine- Double antigen(DT-DA),Triple antigen(DPT), Measels,Mumps,Rubella(MMR) B- VIRAL TYPE----1.)Killed- Polyiomyelitis inactivates, Rabies(Neural tissue), Rabies(Chick embryo), Rabies(Human diploid cell), Rabies(verocell), Influenza, Hepatitis B & A. 2.)Live---Poliomyelitis(Oral), Mumps, Measels, Rubella, Varicella.