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    AlIsh BhanDari

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    Ce eee re ee eo re te Bestselling Book on the Subject Sra ced a eR Ld cH . = ” Review of a PHARMACOLOGY Thoroughly Revised and Updated Edition Including Latest Exam Pattern Questions and Image-Based Questions Beet mele Gobind Rai Garg Sparsh Gupta Explained Answers All Recent Questions (2014 All India (20012-1995) ATIMS (Now 2017-1995) POT Chandigarh (2017-200) 72 Latest NEET based Questions th Edition Image-Based Questions eee ee em ee aria —_—_—>—[=——z—— Image Based Questions 1. General Pharmacology 1 ice Questions 16 Nervous System 38 Multiple Choice Questions tions 71 Autacoids 83 FARE SE PE 10 a4 Golden Points 127 Chapter Review 155 a Collen Pons 160 Wadi Cte Questing 162 Multiple C Explana 6. Endocrinology Ouapter Review 169 169 Golden Points 189 Annexure 190 ‘Multiple Choice Questions 191 Explanations 207 7. Central Nervous System Chapter Review 219 29 Golden Points 240 Annexure 241 ‘Multiple Choice Questions 243 Explanations 265 8 Anaesthesia Chupter Review 281 281 Golden Points 292 Annexure 293 Multiple Choice Questions 294 Explanations 301 IMAGE BASED QUESTIONS 1, Identify the pharmacodynamic curve depicted in the picture: Percentage subjects responding (2) Graded dose response curve (b) Log dose response curve (©) Quantal dose response curve (@) Percentage dose response curve 2. Point A in the Fig, I1 corresponds to: (@) Potency (b)_ Efficacy (Q) ED50 (a) LD50 3, ‘The image shows the Log DRC of four drugs A,B,C and D. Which of the following statements about these drugs is true? (a) Drug A is most efficacious (0) Drug Band dr gC are equipotent (©) Drug D is most effective (d)_ Drug Bis less potent but more efficacious than drug A 4. Given image shows the Log DRC of a dr g alone (A) antagonism shown in the curve B and curve C in the presence of antagonists (B and C). Identify the type of Responding —» Log dose ——» Fig. 13 is non competitive antagonism Bis non-competitive an C is competitive antagonism Both are competitive antagonists id) Both are non-competitive antagonists Bis competitive a 5. Which of the following drug is likely to act by signal transduction mechanism shown in the image above? DngX | hey 6 6, wy Le @.Je Cytosol rosine NA Plasma eae it ig | Be ome F oA WP Dae) PA eorsing ions 4 i Bf rvatec” ef |p € py vhost 6 SGryrosine OY Croce yrosines Ince RT Rewsooty ela i Signal relayed by ‘activated signaling proteins into cel’ interior Fig. 14 (@) Salbutamo! () Growth Hormone (© Aldosterone (@) Nicotine ‘Till what date the drug salbutamol can be used in the image of the asthalin strip shown in Fig. 15 above? a eee Ohh ht tae Coy tat SA (@) 14 July 2017 (©) 31 July 2017 (©) 17June 2014 (@)_ 30 June 2017 Shelf life of salbutamol in this preparation (shown in Fig. 15) is: (@) 3years (b) Tyears (©) Syears (d)_Cannot be known from the information Expiry date shown in the strip of the tablet (shown in Fig. 15) means: (@)_ If this preparation is used after July 2017, it will lose its potency (b) If this preparation is used after July 2017, it will become toxic (©) Quality of this medicine is not assured after July 2017, (d) Botha'and b 1. What does IP in the above image (Fig. [5) stand for: (@) Drug is meant for Intra Pulmonary use (©) Intellectual Property right of the CIPLA (©). The standards according to Indian Pharmacopeia (@) Itis an Instant release Preparation |. A drug having half life of 12 hours is administered orally twice a day. A graph is plotted between plasma drug concentration and time which is shown in the graph. How much time will be taken for the plasma concentration to reach at point A? (@) 12hours () 24hours (©) 36hours (@) 60hours 11. The unknown dru likely to be: Fig. 17 (a) Low dose adrenaline (b) High dose adrenaline (9) Nor-Adrenaline (@) Isoprenaline 12. What is this effect known as: Fig. 18 (a) Tachyphylaxis (b) Nicotinic actions of Ach (©) Biphasic response of Adr (a) Vasomotor reversal of Dale 13. Whaat is this effect known as: Fig (a) Tachyphylaxis oe ) Nicotinic actions of Ach (©) Biphasic response of Adr (@) Vasomotor reversal of Dale 14. What is this phenomenon known as: Fig.110 (a) Tachyphylaxis (b) Nicotinic actions of Ach (©) Biphasic response of Adr (d) Vasomotor reversal of Dale 15, Apart from the effects shown in the image, the light and corneal reflex were present, Drug A is likely to Pe (a) Parasympathomimetic (b) Sympathomimetic (6) Parasympatholytic (a) Sympatholytic (a) Parasympathomimetic {b) Sympathomimetic {c) Parasympatholytic (4) Local anaesthetic 17. Identify the unknown drug by its action on rabbit ileu t Ach Wash Wend pt Aix _Wesh_ Drug Acetylcholine ® ‘Adrenaline (9) Barium chloride (a) Papaverine ‘Identify the unknown drug by its action on rabbit ileum: 16. Apart from the effects shown in the image, the light and corneal reflex were present. Drug. A is likely to be: hele ti {{itFine Org A Wash (@) Acetylcholine (©) Adrenaline (©) Barium chloride (@) Papaverine 19. Identify the unknown drug by its action on rabbit ileum: | f x | Apeeeeicaa | (a) Acetylcholine (&) Adrenaline (©) Barium chloride (d) Papaverine 20. Identify the unknown drug by its action on rabbit ileum: Fig. 116 (a) Acetylcholine i (b) Adrenaline (©) Barium chloride é (@) Papaverine ae 21. Identify the unknown drug by its action on rabbit ileum: (@) Acetylcholine (b) Adrenaline (©) Barium chloride (@) Papaverine 22. A 50 year old male presented with suicidal overdose of a drug. Patient is flabby and comatose with shallow failing respiration. The BP of the person is 80/40 mm Hg and the lesion on the right is shown in the image. The likely poisonins is: (a) Heroin {b) Phenobarbitone (©) Imipramine (d) Phenytoin t t ropanolol Fig. 117 Fig. 118 3. Which antiepilepti 25. Which antiepileptic drug can lead to this adverse effect: Fig. 119 (a) Phenytoin (b) Carbamazepine (©) Valproate (d) Lamotrigine 24. Drug A is likely to be: | Voltage-gated “kona q channel Vesieuar, ome] ea ca RR TE a pag ae | centr} anne! a Nar ca” Fig. 120 Phenytoin Ethosuximide Vigabatrin Benzodiazepines 25. Drug B is likely to be: r 4 f r BY votace gate Ny Na’ channel Kena" ¥ & release, he cape Glutamate K i ef og Kona receptor receptor channel or i Net on" Fig. 121 (@) Lamotrigine (b) Levetiracetam (©) Perampene! (d) Retigabine 26. Drug Cis likely to be +s ia ye { Votoge-gated Na’ channel kena oN 1 chanel ia Pereletetoh fi Vesicular, SV2A >. 7 release & 2 CN su TY) GABA, ‘AMPA "I recepior y receptor a Na’ a Fig. 122 (a) Gabapentin (®) Tiagabine (6) Vigabatrin (d) Retigabine 27. Drug Dis likely to be: aT aa receptor or (a) Phenytoin (b) Ethosuximide (©. Vigabatrin (d) Benzodiazepines 28. Drug Eis likely to be: : wate KC channel (a) Retigabine (b) Lamotrigine () Levetiracetam Type Cat channel Fm rears Jp Voltage-gated 29, Drug Fis likely to be: Re Voltage-gated exe x Na‘ channel K’ channel! ear Glutamate °° & Type 1 sal (@) Phenytoin (b) Ethosuximide (©) Vigabatrin (@) Perampanet 30. A patient of Parkinsonism developed this condition after treatment. Which of the following drugs is likely to c= this adverse effect? Fig.126 (a) Levo-dopa (b) Amantadine (6) Selegiline (d) Pramipexole SL. A patient with Schizophrenia w: What should be the treatment? {as prescribed haloperidol, Next day she returned with the features shown in the image, (a) Increase the dose of haloperidol (b) Give Propanolol (©) Give Benzhexol (@)_ Reassurance is enough Fig. 127 32. Mechanism of action of 3 antihypertensive drugs (X,Y and Z) is shown in the given figure. These are likely to be (in sequence): eed Blood vessels Vasoconstriction (a) Enalapril, Enalkerin and Losartan (b) Losartan, Enalapril and Enalkerin (©) Enalkerin, Enalapril, Losartan (a) Enalkerin, Losartan, Enalapril [Angjotenstogea <2. rd [[Araiotensie je wu Eee as «Sz | [aaa] ae aT |] [eee] Perea { Noradrenaline [Na" and H,0 retention. Fig. 128 33. Which of the following drug is likely to produce the effect on action potential as shown in the diagram: w, (@) Quinidine (b) Amiodarone (©) Lignocaine (@) Flecainide Drug which can act at both sites 1 and 2 as shown in the diagram is: + to coon ay) [Angiotensingen] (Rava ae WET] > ANT] [AcE] AT receptors f Na’ and H,0 Fig. 130 (a) Sacubitril (b) Samptrilat (6) Losartan (d) Nesiritide 35. Which of the following is likely to be drug A? {a) Digoxin (©) Levosimendan (©) Amrinone (a) None of these 36. Which of the following drugs are likely to cause the given change in ECG? QT interval QT interval Fig. 132 (a) Quinidine (b) Lignocaine (Q) Verapamil (d) Propanolol (a) Malaria (b) Congestive heart failure (©) Myocardial infarction (@) Iridocyclitis |. The drug obtained from the plant (shown in Fig, I 34) is used for the treatment of: Fig. 134 (@) Malaria (b) Congestive heart failure (©) Myocardial infarction (4) Iridocyclitis 39. The drug obtaine i ‘The drug obtained from the plant (shown in Fig, 135) is used for the treatment of: (@) Malaria ©) Congestive heart failure (©) Myocardial infarction (@) Iridocyclitis 40. The plant shown in the Fig. 1 36 is a source of: Fig. 136 (a) Atropine (b) Morphine (©) Quinine (@) Digoxin 41. 4.30 year old female was treated with an antihypertensive drug and presented with following features. The likely drug Fig. 137 (@) Minoxidil (b) Fenoldopam (©) Methyl Dopa (@) Enalapril 42. A 60 year old male presents with acute severe chest pain associated with sweating 30 min before. The ECG «th person is shown below. Which of the following drug should be given to this person: Boh bh hb hh ‘25min 10mivmv-*S0He 0068 128L 280 CID Fig. 138 (@) Atropine (b) Streptokinase (©) Amiodarone (d) Adenosine A 30 year old athlete wei " eres Id athlete went for routine examination. He has no symptoms. The ECG is shown below. What advise will See Se NnGGNBeeeouea Fig. 139 a) No treatment is required (b) Permanent pacemaker should be placed () Atropine should be (d)_ Electrical defibrillation should be done 7H. Anew drug X is given orally to a healthy volunteer in a dose of 100 mg. Plasma concentration of the drug is measured | athourly interval and a graph is plotted between plasma concentration and time as shown below in Fig. 140. 4 2” ao} ae zs “sles Sos ei ieee 5 feos cane as a é Zid, Smet eet ownO nn ti Time after drug administration (hr) —» Fig. 140 Which of the following statements about drug X is TRUE? (a) Its Cmax. Is 20 ug/dl. (b) AUC from the above graph reflects rate of absorption (6) Tmax for drug X is 7 hours. (d) Instead of 100 mg drug X should be given in div A 30 year old theatre actress developed few wrinkles on the face. The treating physician advised her to have local injections of a drug, This drug is also indicated in cervical dystonia and other spastic disorders like cerebral palsy. Very recently, it has also been approved for prophylaxis of migraine. The physician warned of the drug to cause dry mouth and blurring of vision. The actress searched the compound on internet and found the site of action of the drug as shown ded doses, in the Fig. 141. Chotine «Choline |e ar \ ACh Choline + Acetate Fig.141 Which of the following drug is being talked about? a) Hemicholinium )-Vesamicol (©) Botulinum toxin (@) Physostigmine 46. A new antiarchythmic drug is found to be effective against both atrial and ventricular arrhythmias. Its effect on > potential is shown as below in Fig. 142. The effect of this new drug is most similar to: (a) 1 (b) Propanol (©) Encainide (@) Quinidine ‘Action potential ~ after drug therapy Normal ‘Action potential Fig. 142 47. Which of the following drug is not indicated in a person with the given ECG? OT Peo me nl Aah amended avin Fig. 143 (a) Amiodarone (b) Propanolol (©) Verapamil (d) Adenosine Mdentify drug A (in Fig. 144) by its mechanism of action: © wp — See pat es POP ete JUDP.cieNAc f_UP-Murtiac (Drug C| Lipid 11 pb Trensgyconyesepe °7°7°7 ot or I [Drug 6] DreaA}> { Tronspeptidese Zed: (@) Cloxacillin (©) Vancomycin (©) Bacitracin (a) Fosfomycin 9. Identify drug B by its mechanism of action (as shown in Fig. 1 44): 2) Cloxaciliin (b) Vancomycin (©) Bacitracin (a) Fosfomycin |. Identify drug C by its mechanism of action (as shown in Fig. 144): (a) Cloxacillin (b) Vancomycin (0). Bacitracin (4) Fosfomycin |. Identify drug D by its mechanism of action (as shown in Fig. 1 44): (a) Cloxacillin (b) Vancomycin (©). Bacitracin (a) Fosfomycin In the given Fig. 145 at which site does penicillinase work? uoP UDP.Munac —P— | pentapeptide May (PP) Bactoprenol (pyrophosphate (a) Site A (b) SiteB © SiteC (a) Site D 53. The drug shown in the Fig. I 46 is treatment of choice for: Fig. 146 (@)_ Enteric Fever (b) QFever (© MRSA. (@) Gonorrhea 54, Identify drug A by its mechanism of action as shown in the Fig, 147: ‘Amino acid Fig. 147 (c) Azit (a) PenicillinG 55. Identify drug B by its mechanism of action as shown in the Fig. 147: (@) Doxycycline 56. Ge mechanism of action as shown in the Fig, 1 47: (©) Azithromycin (@) Penicillin G 7. Mechanism of transfer of drug resistance shown in the given figure 1 48 is: (@) Conjugation (®) Transformation (©) Transduction (@) Mutation Mechanism of transfer of drug resistance shown in the given figure 149 i: Release of GES!) Donor cell ‘Antibiot. Recipient cell, resistance gene Fig.149 (2) Conjugation (®) Transformation (©) Transduction (¢), Mutation Mechanism of transfer of drug resistance shown in the given figure I 50 is: Phage-infected donor cell of phage: Recipient col Fig. 150 (@) Conjugation (b) Transformation (©) Transduction (a) Mutation Biochemical mechanisms of drug resistance are shown in the given figure 51. Most important mode of resistance in MRSA is: Target site ‘modification fal tance to Enterococcus by which mechanism (as shown in Fig. 151)? 62, Cis the major mechanism of resistance (according to Fig, 151) against (@) Fluoroquinolones (b) Aminoglycosides (6) Tetracyclines (d) Sufonamides 63. Major mechanism of development of resistance against cotrimoxazole (in Fig, 151) is (@) B (b) C © D @ E 64, Eis the major mode of resistance against (as shown in Fig, 151): (@) Tetracycline (b) Chloramphenicol (o) Ampicillin (a) Ciprofloxacin 65, The only oral drug (among the given options) effective for the treatment of the condition shown in the figure T52 is: Brow prominent Soft tissues of nose, ears lips enlarges Jaw prominent Fig. 152 (a) Cctretide (b) Cabergoline (©) Pegvisomant (d) L- thyroxine 66. A 40 year old male presented to emergency (as shown 1.53) with fever, extreme restlessness, confusion and marked weakness, On examination, severe tachycardia and BP of 170/110 mmllg was noted. ECG revealed the presence of atrial fibrillation. Which among the following is the only life saving drug that should be given immediately to this person: (a) Carbimazole (b) Radioactive iodine (©) Propanolol (@) Liothyronine 67. A patient presented to OPD wi fatigue and cold intoerance. He but elevated TSH, The patie: h swelling in the neck as shown in the has gained 8 Kg of weight in last 4 nt should be treated with: ‘ig. 154, He complains of decreased appetite, nths. Thyroid function tests revealed normal T4 Fig. 154 (a) Liothyronine (b) L-thyroxine ) Carbimazole (d) Steroids 68. A 40 year old male suffering from a chronic disease presents to OPD with the features shown in the Fig. 155. This is likely to be adverse effect of Red cheeks Moon face Fat pads bufalo hump eae ecchymosis Thin skin High BP Red stration 7A — Pendulous Thin arms ¢ ‘abdomen and logs Poor wound hearing Osteoporosis: ‘compressed (codfish) vertebrae (a) Corticosteroids (b) NSAIDs (©) Infliximab (a) Androgens is used for: 69, The medicine shown in the Fig. 15 8 7; = 5 AG ded 17 Dede “et "‘eeeovee i i i en Fig. 158 (a) Multibacillary leprosy (b) Paucibacillary leprosy (©) Tuberculosis (@) Contraception ‘The oral contraceptives shown in the Fig. 157 are: Fig. 187 (a) Monophasic combined OCPs (b) Biphasic combined OCPs (c) Triphasic combined OCPs (a) Emergency Pills 71. The oral contraceptives shown in the Fig, 158 are: (©) Triphasic combined OCPs (a) Emergency Pills 72. A52-year-old male, Vivek was treated with enalapril for hyperter of the following -Itwas able to control his blood pressure. Which the most likely combination of changes in response to this patient’s treatment? ae) t 1 4 7 o [t 1 4 y v © |t 4 4 t + (@ 4 + + Ne change 73. The drug Z shown in the Fig. 159 is likely to be: sogments of: proximal tubule Reabsorption Collecting duct 83 segments of proximal tubule No glucose Fig. 159 (a) Pramlintide (b) Exenatide (¢) Canagiiflozin (@) Sitagliptin 7A. Based on the given mechanism of action as shown in Fig. 1 60, Drug, is likely to be: Meal ingested DPP4 on brush border of intestine Stomach pg (Ea ores [a ° Si of “Small “insulin ease itestne {Gcagon release Large Fig.160 (2) Exenatide ® © (@) Pramiintide 75, ‘The drug X used in osteoporosis has the mechanism shown in the Fig, I 61. X is likely to be: y RANKL z iy | Fig. 161 (a) Teriparatide (b) Alendronate (6) Denosumab (a) Estrogen 76. Ce le is in. i i ell eycle is shown in the figure 1 62 below. Which of the following drug act specifically at the stage marked with G1-Growih S-DNA synthesis G2.Growth and preparation for mitosis Nemitosis (Cell division (@) Mechlorethamine (b) Methotrexate (Q Vincristine (@) Paclitaxel 7. Figure I 63 shows the mechanism of action of: ‘Metaphase presonce of vines ‘alkaloids ‘Anaphase Fig. 163, 78. A patient present with the features shown in the figure I 64 after treatment with an anticancer drug. The likely drug i Fig. 164 (@) Cisplatin (b) 5-Fluorouracil (0) Methotrexate (q)_ Imatinib 79. A patient was given radiotherapy for head and neck cancer. After 6 months chemotherapy was started. The patient presented with the features shown in Fig. 1 65 after start of chemotherapy. Itis likely due to which drug? Fig. 165 (@) Doxorubicin (b) Cisplatin (©). Imatinib (d) Methotrexate 80. Figure I 66 shows the mechanism of action of which of the following drug? vie at” —> ADP Po, BCR. BL x t | Intracellular signals Fig. 166 gz (@) Nilotinib (&) Methotrexate (©) Pertuzumab (@) Cisplatin A baby was born with the the mother is ones ns shown in the figure I 67. The likely teratogenic drug received by Fig. 167 (@) Thalidomide (®) Alcohol (©) Carbimazole (@) Heparin Based on the mechanism shown in the figure 1 68 , Drug A is likely to be: (6) Piola GPIB Fig. 168, (a) Aspirin (b) Clopidogrel (©) Abciximab (@) Allof these 83. Based on the mechanism shown in the figure I 68, Drug B is likely to be: (a) Aspirin (b) Clopidogrel (0) Abciximab (@) Allof these 4, Based on the mechanism shown in the figure 1 68, Drug C is likely to be: (@) Aspirin (©) Clopidogrel (©) Abciximab (a) Allof these 85. A patient was started on an anticoagulant therapy for DVT, Next day he pr q Fig. 168. The implicated drug is PY tt day he presented with the features shown in the Fig. 169 (@) Warfarin (b) Heparin (0) Rivaroxaban (@) Dabigatran 86. A patient was started on an anticoagulant therapy for DVT. Next day he presented with the features shown in the Fig 170. The implicated drug is: Fig. 170 (@) Warfarin () Heparin (© Rivaroxaban (a) Dabigatran asthma, The most likely site of action of this 4 20-year-old male, Chintu is being treated with zafirlukast for bronc drug from the Fig. 171 can be deciphered as: @ A b) B © ¢ @ D Membrane phospholipids Phospholipase Ay Arachidonic acid cox Lox «) Prostanoids uA, ur, ue, uD, ie, CysLT receptors ¢---(C) Bronchoconstriction ¢--- (D) Fig. 171 88. A 50-year-old male, Rajesh presented to OPD with fever and sore throat with mouth ulcers. He has a history of shemic attack. His myocardial infarction and is taking several drugs. One month back he had an episode of tran: complete blood count shows: Hb 142 g/dL WBC 900/ mm Platelet 220000/ mm? the above symptoms of the patients, Which of the following drugs is most If an antiplatelet drug is responsible fi likely mechanism of the drug as shown in Fig. 172? (@ A (b) B © ¢ d) D Subendothelial vWF 1. Adhesion == Fig. 172 89. A syearold female, Rashmi presents to the emergency in comatose late. She sa known case of type dab slits Immediate blood sugar is measured by gucometer and found o be 58 m/l. Urine is found tobe postin or glucose as well as ketone bodies. Which of the following insulin types depicted in the Fig. 173 below i oe EGS Suit aay < en ©. oc (d) D Fallin blood glucose 2 4 6 & 10 12 14 16 18 20 22 Time (h) Fig. 173 90. Amarnath, a 58 year old businessman is a known case of type 2 diabetes and was well controlled on metformin, But ‘since last 3 years the different combinations of oral antidiabetic drugs were tried and still the blood sugar was not controlled, So, the physician thought of giving him insulin, Which of the following insulin (From Fig. 174) can be used to maintain the basal levels of insulin without producing significant risk of hypoglycemia in this patient: (a) A B Cc (d D In blood glucose Fi 2 4 6 & 10 12 14 16 18 20 22 Time (h) Fig. 174 A new inhaled anesthetic has been developed and is tested in a series of experiments. Anesthetic tension in the arterial blood is shown on the graph below (in Fig. 175) as a function of time after beginning inhalation (Drug A) A similar curve for nitrous oxide is also shown: Vhich of the following best describes the properties of the new anesthetic compared to nitrous oxide"? plood: gas partition coefficient in the blood Hig ) Low solubilit Rapid onset of action 4) Low potency Nitrous oxide ‘AResthetie tension in the arterial blood Time Fig. 175 ed to emergency with blunt injury to abdomen and crushing of his left leg under 80/40 mmHg, Emergency laparatomy was planned 1g. Suceynicholine was used for intubation 92, A 53 year old male Arjun pres ‘4 bus in a road traffic accident, His blood pressure was and to know the cause of internal ble for maintenance of muscle relaxation. Anaesthesia was induced by thiopentone and maintained However, during intraoperative period, the patient developed arrhythmias as shown in ECG below # the following is the likely cause of this ECG finding? pical pseudocholinesterase in this patient od hyperkalemia the tyres of to repair the ruptured viscera and vecuroni yy halothan (Fig, 176). Which of (a) Presence of aty (b) Succinylcholine induce Vecuronium overdose ©) (a). Accident intra-arterial injection of thiopentone eR Thott Heep Tha ep pope To Fig.176 99. You are studying pharmacokinetic properties of thiopentone. A dose-time relationship in various tissues after a single bolus of thiopentone is shown in the graph below (in Fig. 177). Curves A, B and C in the graph represent: Curve A Curve B Curve C Brain Blood Adipose tissue Blood Brain Adipose tissue Brain Adipose tissue Blood Adipose tissue Brain Blood 9%4, 72-year-old male, Hemraj was admitted to the hospital with severe dyspnoea and orthopnea. On investigations and Scrotal > Scalp > Dorsum of hand > Plantar area systemic Routes include oral, sublingual, transdermal, nasal, inhalational, rectal and other parenteral routes (intravenous, intramuscular, intradermal and subcutaneous). + Oral route is safer and economical but several drugs are not effective by this route because of high first puss netabolism in the liver and intestinal wall (e.g. nitrates, lignocaine, propanolel, pethidine), + ublingual route wooids frst pass metabolism, can be used in emergencies, can be self-administered and also after getting the desired action, rest of the drug can be spitted. Drugs like. nitroglycerine, isosorbide dinitrate, clonidine, nifedipine etc. can be administered by sublingual route. + ‘Transdermal route is used only for the drugs which are highly lipid soluble and can be absorbed through intact skin, By this route, there is a constant release of the drug (rate of drug delivery to skin is less than the maximum absorptive capacity of the skin so that absorption does not become the limiting factor and there is a constant level of the drug in the blood) and it may be administered less frequently. Nitroglycerine, nicotine, fentanyl and hyoscine are adminstered through transdermal patch. + Drugs administered by nasal route are nafarelin (GnRH agonist), calcitionin and desmopressin. + Inhalational route is the route by which the rate of drug delivery can be controlled like i.v. infusion. The drugs ‘administered by this route include drugs for asthma (¢., salbutamol, ipratropium, monteluknst and inhalational steroids) and inhalational anaesthetic agents like nitrous oxide. + Rectal route avoids first pass metabolism to 50% extent. Diazepam is given by this route in children for febrile seizures, + Intravenously, drugs can be given as bolus or via infusion. Other parenteral routes include im. and s., routes. Een It is the effect of body on the drug ie. movement of the drug in, through and out of the body. Pharmacokinetics is also called ADME study as it deals with Absorption, Distribution, Metabolism and Excretion of a drug 1. ABSORPTION It depends on several factors, Only lipid soluble drugsean cross the biological membranes. So, if a drug is administered by oral route, it has to cross the membranes of GIT and blood vessels toreach the blood. Therefore, it should be in lipid soluble form. Ifa drug is a weak electrolyte, itis the unionized form which is lipid soluble and the ionized form is water soluble. [WHEN MEDIUM IS SAME, DRUGS CAN CROSS THE MEMBRANE From this statement, we can find that acide drugs can cross the ‘membranes in acidic medium ie, acidic drugs are lipid soluble in acidic medium (for this acidic drugs must be mainly in the un ionized form in acidic medium). Opposite i ic ‘drugs. As gastric pH is acidic, therefore acidic drugs are more likely to be absorbed from the stomach, because these will be in unionized (lipid soluble) form here. Thus, aspirin is more likely to be absorbed in the stomach than morphine or abTOPINe ; Pharmacology (Greek pharmakory means drug) is a science dealing with the drugs. Its divided into several branches like Pharmacokinetics, pharmacodynamics, pharmacotherapeutics, chem therapy and toxicology et When a drug is administered to a person, it will exert some effect on the patient (Pharmacodynamics) and the patient's body will have some effect on the drug (Pharmacokinetics). These are the two major branches of pharmacology. Before discussing about these branches, we will summarize, the various routes by which drugs can be aciministered to a patient. Siar Topical Intra- intrathecal Enteral Parehiteral (skin and articular (through Git) = Intravenous mucous + Intramuscular membranes) Subcutaneous Oral Rectal + Sublingual cal Routes include topical application on the mucous membranes as well as the routes like intra-articular (eg. hydrocortisone) and intrathecal (eg. amphotericin B). Absorption of a drug from topical route depends upon thickness of skin. It is generally inversally proportional to ‘hiekness. The sequence of extent of absorption is Posterior auricular > Scrotal > Scalp > Dorsum of hand > Plantar area Systemic Routes include oral, sublingual, transdermal, nasal, inhalational, rectal and other parenteral routes (intravenous, intramuscular, intradermal and subcutaneous), + Oral route is safer and economical but several drugs are not effective by this route because of high first pass metabolism in the liver and intestinal wall (e.g. nitrates, lignocaine, propanol, pethidine). + Sublingual route avoids first pass metabolism, can be used in ‘emergencies, can be self-administered and also after getting the desired action, rest of the drug can be spitted. Drugs like nitroglycerine, isosorbide dinitrate, clonidine, nifedipine etc. can be administered by sublingual route, ‘Transdermal route is used only for the drugs which are ® highly lipid soluble and can be absorbed through intact 7 skin, By this route, there is a constant release of the drug (rate of drug delivery to skin is less than the maximum Airsorptive capacity of the skin so that absorption does not become the limiting factor and there is a constant level of the drug in the blood) and it may be administered less frequently. Nitroglycerine, nicotine, fentanyl and hyoscine are adminstered through transdermal patch. + Drugs administered by nasal route are nafarelin (GnRH agonist), calcitionin and desmopressin. + Inhalational route is the route by which the rate of drug delivery can be controlled like io. infusion. The drugs administered by this route include drugs for asthma (e., salbutamol, ipratropium, montelukast and inhalational steroids) and inhalational anaesthetic agents like nitrous oxide. * Rectal route avoids first pass metabolism to 50% extent. Diazepam is given by this route in children for febrile ‘+ Intravenously, drugs can be given as bolus or via infusion Other parenteral routes include im. and sc. routes. nad It is the effect of body on the drug ie. movement of the drug in, through and out of the body. Pharmacokinetics is also called ADME study as it deals with Absorption, Distribution, Metabolism and Excretion of a drug, 1. ABSORPTION edepends on several factors. Only lipid soluble drugs can cross the biological membranes. So, ifa drug is administered by oral route, it has to cross the membranes of GIT and blood vessels toreach the blood. Therefore, it should bein lipid soluble form. Ifa drugis a weak electrolyte, itis the unionized form which is lipid soluble and the ionized form is water soluble. WHEN MEDIUM IS SAME, DRUGS CAN CROSS THE MEMBRANE From this statement, we can find that acidic drags cam cross the membranes in acidic medium ie. acidic drugs are lipid soluble in acidic medium (for this acidic drugs must be mainly in the un- ionized form in acidic medium). Opposite is also true for basic drugs. As gastric pH is acidic, therefore acidic drugs are more ly to be absorbed from the stomach, because these will be in unionized (lipid soluble) form here. Thus, aspirin is more likely to be absorbed in the stomach than morpliine or amOpITe (basic drags) sotabie Bax i the pe ot he m happen? Obwanasir. i will become are ot be lipid sobuble because become cmiomued We need so remember Herdexson hamclbachs (Bp of Se meee s emul bo pK. then dng 8 30" somined and 50% ocean © See pH of the medio & more dur pK (meta becomes alkaline, — For acidic drags, ioniaed form increases and non sored form decrenses. - For bes Grom, unionized form incomes and iowized form 1 Ge pel of Se modem bs ies Gum pK cppente Iappens. Le anche drogs will be mi cuore coamized (@p between pHi and pK When pli = pKa (d-0) ionization is 50% and an ionined fraction is also 5%. ‘When pli - pKa = form is 10% When d=2 one form is 97% and other is 1% When d =3 one form is 99% and other is01% (@=1) one form is SE amt other aw | Ik is the fraction of administered drug that reaches the systemic circulation in the unchanged form. When we administer 2 drug orally. frst it is absorbed ‘imp the portal cimalatipn and reaches the liver Hew, some of the drug may be metabotizes (ft pass metabaiion or re- syst metubaisen) and rest of te drag reaches the s7Serac caociton Ties, abyereon and Sng pass memboliem ar ‘two important deserminants of tuoavatlatainy AUC tells about the extent of absorption of the: PPTs tla teh thei -eo-ronines concentration, ie. rate of absorption ‘Coun i8 the maximum concentration of a drug that ‘can be obtained (Fig. 1.2) proteins of a drug that is responsible for the action 2s, ‘well as the metabolism of a drug. Therefore plasma protein binding males a drug long acting by reducing its metabolism. = This property can also expose the drug to several interactions due to displacement from the Binding Ste by other drugs. ~The drugs which have low V, are restricted to the vascular compartment and thus their_poi i = It is the free form (which is not bound to plasm: Fig. 12: Plot between plasma concentration and time to calculate can be benefited by dialysis. Disks a a bioavailability int The posing due fo amphetamines, antidepres antipsychotics, heeaadiscepines, digoxin, opsods, Stackers, Bioequivalence ‘calcium charmel blockers and urine. Many different pharmaceutical companies can manufacture same compound (with same dose as well as dosage form) e.g. Clinical Importance of Plasma Protein Binding phenytoin is available as tab. Dilantin as well as Tab. Eptoin. If the difference in the bioavailability of these too preparations (same. Duration of acti wah high FPB ore moma drugs, same dose, same dosage forms) is less than 20%, theseare known lanjpacting rl to be bioequivalent. As the term implies, these are biologically + Distribution: High PPB drags stay in plasma, thas jual ie. will produce similar plasma concentrations, have low V,, z ae a ‘+ Displacement: Highly PPB drug can be displaced by another highly bound drug. 2. DISTRIBUTION ‘+ Dialysis: I is not effective for drags having high PPB. ‘After the drug reaches the blood, it may be distributed to various tissues. This is determined by a hypothetical parameter, ee If more amount of drug is entering tbe tissues, it has « higher § s anpen) wot Volume of distribution and vice-a-versa It depends on several here wad SS Gem id tty ‘and plasma protein binding, hich are lipid soluble are more likely to cups the i concentration in plasma, Thas, drags Tree jesse walland thushavediighVolume of distribution. Trade gh shes: of Sateen es ie oo «Ia drug is highly bound to plasma proteins, (68+ jg Plasma] are dificul! se romnced by dialysis warfarin, benzodiazepines, furosemide, calcium channel ious Blockers, digitoxin etc) it will behave like a large molecule ee eet ee ‘and more likely to sygy in the ‘Therefore, less will ~ candidates of. eg says go to tissues resulting of distribution. Ce £ 3 Fy} Ss m Volume of Distribution It can be calculated by dividing the plasma concentration attained to the dose of a drug administered i.v. Initial plasma concentration (Co) is calculated by extrapolating the graph of plasma concentration vs time to y-axis. vy, = Dose administrated (iv) “*” Plasma concentratin (C,) It is a measure of the distribution of a drug. If V, is more, it ‘means more amount of drug is in the tissues and less is in the plasma. Thus, higher dose has to be administered to attain the same plasma concentration for drugs having high V, than those having low V, This high dose is called loading dose. Thus, V, is the main determinant of loading dose. Chloroquine is the drug with highest V, (1300 L/Kg). 3. METABOLISM, ‘The primary site of metabolism is liver. Most of the drugs are inactivated by metabolism but some may be activated from the inactive compounds (Prodrugs) and others may give rise to active metabolites from the active compound (e.g. diazepam, Propanolol). Microsomal ezymes Non microsomal * Onsdations . a = Cytochrome PASO * Ondaton «oft monorygerases + Redveton + Reduction - Hydrolysis * The drug which is metabolized by a microsomal enzyme known as substrate and the chemical increasing or decreasing the number of enzymes is known as inducer or inhibitor respectively. Enzyme inducers will increase the metabolism of other drugs and thus their effect will decrease. Therefore dose of such drugs (which are metabolized by microsomal enzymes) should be increased when administered along, with microsomal enzyme inducers. Potent inducers of microsomal enzymes ncluderifampicin, phenobarbitone, phenytoin, griseofulvin, phenylbutazone and chloral hydrate, Further, rate-limiting enzyme of porphyrin synthesis ie. SALA synthase is a microsomal enzyme. Enzyme inducers like phenytoin and phenobarbitone induce it and increase porphyrin synthesis. Thus, these drugs are contra-indicated in acute intermittent porphyria, * Enzyme inhibitors will decrease the metabolism of drugs metabolized by microsomal enzymes, thus predisposes to the toxicity by such agents. Inhibitorsinclude ketoconazole, cimetidine, erythromycin and metronidazole. drug molecule whereas con} Phase II reactions serve to attach a Phase I reactions include oxi condugate to the drug molecule, After phase I reaction, drug, cyclzai — may be water soluble or lipid soluble whereas after phase Il include givcuronation, ‘on, all drugs become water soluble (lipid insoluble), and glycine conjugation etc. General Pharmacology IIE ion, reduction, hydrolysis, whereas phase I reaction acetylation, methylation, sulfation and decyclization etc Metaote Reetons nase (Both microsomal as well Mer es nonmiosan + Ontabon ncn = Dealkylation res = Blain cea "Suuaione™ 2 concen convonton foun Seteeee -sceyaten shat) has “sulen Cytochrome P450 Enzymes ‘These are one group of microsomal enzymes and are commonly abbreviated as CYP enzymes. In P450, P stands for pigment that has maximum light absorption at wavelength 450 nm. Several families of CYP enzymes are involved in oa Ex or 3h €-Cyclosporine Barbiturates (Metabolizes 50% of drugs, most __Galcium channel blockers —_—Rfempicin common) Phonyion $-Statins smazep) | C-CAT drugs St. John's wort | ~ Cisapride = Astemizole ro ~ Terfenadine E ‘A-Amiodarone g IN-Navirs (Protease inhibitors) bars i inigine Py 206 + Most antidepressants ‘No known inducer Qu m4 | (metabolizes ~ TCA Paroxetine Fl ~ SSRI cane! = MAO inhibitors Ey + Most beta blockers cr + Most antiarrhythmic 3 + Omeprazole Fifampicin Fluconazole \gew + Clopidogrel Barbiturates + Phenytion Rfampicin Erythromycin gee + Tolbutamide Barbitrates Cimetidine + Warfarin Az + Theophyling Smoking Giprotoxacin I warfarin Fafampicin 264 + Acetaminophen Ethanol Disutiram + Enflurane laa 2 Halothane < ate =) metabolism of xenobioties. These are named as CYP followed by a number (denotes family), then alphabet (subfamily) and” again a number (gene for the enzyme) eg, in CYP 34; 3 is family, A is subfamily and 4 is gene. Maximum number of ‘drugs are metabolized by CYP 3A4 followed by CYP2D6 BEBE] Review of Pharmacology 4. EXCRETION ‘The major route of excretion is kidney. Excretion through Kidneys occurs by glomerular filtration, tubular reabsorption and tubular secretion. Glomerular filtration depends on the plasma protein binding and renal blood flow. It does not depend on the lipid solubility because all substances (whether water soluble or lipid soluble) can cross the fenestrated glomerular membrane, Tubular reabsorption depends on the lipid solubility. If a drug is lipid soluble, more of it will be reabsorbed and less will be excreted. Opposite is true for lipid insoluble drugs. As lipid solubility depends on ionization, the ionized drug will bbe excreted by the kidney. Thus, in acidic drug poisoning (calicylate, barbiturates, chlorpropamide, methotrexate etc) urine should be alalinized with sodium bicarbonate because weak acids are in ionized form in alkaline urine and thus are easily excreted. Similiary for besic drug, poisoning (e.g, morphine, anyphetanine ‘etc), urine should be acidified using ammonium chloride. ‘Tubular secretion does not depend on lipid solubility or plasma protein binding, In the nephron, separate pumps are ppresent for acidic and basic drugs. Drugs utilizing the same transporter may show drug interactions e.g. probenecid decreases ‘the excretion of penicillin and increases the excretion of uric acid. Rememiber, exogenous substances e.g. penicillins are removed whereas endogenous substances like uric acid are retained by these pumps. First Order Kinetics (Linear kinetics) 4. Constant fraction of drug is eliminated per unitime, 4. 2. Rate of elimination is proportional to plasma in ‘concentration. 3. Clearance remains constant. a 4. Hall ite remains constant. 4 5. Most of the drugs follow fst order kinetics. 5 Peron en ‘Constant amount ofthe drug is eliminated per unit time, Rate of eliminetion is independent of plasma concentration. {thium, Kt and rifampicin are secreted in saliv KINETICS OF ELIMINATION Rate of Elimination isthe amount ofdrug eliminated per unit time. If itis seen as a function of plasma concentration, we derive an important parameter known as clearance (CL) ‘ci = Rate of Elimination Plasma concentration Order of Kinetics Drugs may follow zero order or first order kinetics, It depends on the following formula: Rate of Elimination « (Plasma Concentration|°"4er + Thus, if a drug follows zero order kinetics, (Plasma Concentration}? is equal to one, in other words rate of elimination is independent of plasma concentration or rate of elimination is constant. + Fromtheabove formula, rate of elimination is proportional to plasma concentration for the drugs following first order Kinetics, Tio) Clearance is more at law concentrations and less at high concentrations. Half life is less at iow concentrations and more at high concentrations, ‘Very few crugs follow pure zero order kinetics ©.g. alcoho! ‘Any drug at high concentration (when metabolic or elimination pathway is Saturated) may show zero order kinetics. : - ‘| Drugs Showing Zero/pseudo Zero Order Kinetics ro Zero order kinetics shown by Warfarin, Ze w a Alcohol and Aspirin ir 7 Theophylline Tolbutamide Phenytoin Half Life (t,,) It is the time required to reduce the plasma concentration to half (50%) of the original value. If metabolism is more, half life is less and vice-versa. Itis a secondary pharmacokinetic parameter derived from too primary parameter; V, and CL. It determines the dosing interval and time required to reach the steady state (It does not affect the dose of the drug). Drugs having short half lives, are administered more frequently than those having longer half life. It takes 4 to 5 haf lives for a drug to reach its steady state. 0.693 Vg a ty If a drug follows first order kinetics, its half life is constant This is true both for rising aswell as falling plasma concentrations. When a drug is given by-constant iv. infusion, initially the plasma level rises, it reaches a steady state and when infusion is stopped this Jeve! starts declining. Elimination of the drug, from plasma is 50% in one half life, 75% (60 + 25) in two half lives, 87.5% (60 + 25 + 125) in three half lives and so on. The same is true for rising plasma concentration also ie. with constant i.v. infusion, in one half life the plasma concentration is half of steady state and in two half lives it is 75% and so on. Steady State If fixed dose of a drug is administered after regular intervals, its plasma concentration starts increasing, However, as plasma concentration rises, rate of elimination also starts Increasing. When rate of administration becomes equal to rate of elimination, plasma concentration stabilizes. This is called steady state. 1. Time to reach steady state depends on t,, It takes approximately 5 half lives. 2, Steady state plasma concentration acheived depends ‘on dose rate. 3, Variation between peak and trough concentration at steady state depends on dosing interval. However, a steady state plasma concentration remains ayer 3B cxpoctteo dosing interval provided dose rate remains same. ‘Two Dose Strategy ‘The drugs having high volume of distribution are given by this strategy. First a large dose (loading dose) is administered General Pharmacology (II to atthe the steady stale quickly and ae or 4 main the plasma concentration smaller dove is given (uintenance ds) Loading dose: tis mainly used for drug having on and large valume of distribution It is given to oad ature) the dsue stores St lsmainly dependent on Ve Loading dose = V, x Target plasma concentration ‘Maintenance dose: It is mainly dependent on CL. ‘Maintenance dose = CL x Target plasma concentration ‘Therapeutic Drug Monitoring (TDM) + TDMisa process by which the dose of a drug is adjusted according to its plasma concentration. + Its done for drugs having known correlation between serum level and drug response or toxicity. + Itis done for drugs having wie variation in pharmacokinetics (absorption, metabolism or excretion), both intra- as well as inter- individual. + Tt is done for drugs having low therapeutic index like digitalis, aminoglycosides, tricyclic antidepressants, theophylline, lithium, antiepileptics, immuno-modulators and antiarthythmies et. + TDM is done for those drugs whose effect cannot be easily imeastred (ike effect of antihypertensive drugs can be easily ‘measured by monitoring BP, so TDM is not used). Due to same reason, TDM is not indicated for anticoagulants (e.g warfarin) or antidiabetics (e.g, metformin). + TDM is not done for the drugs which are activated i the body or produce active metabolites. TOM is required for | ‘Aminoalycosides A = (@.9. gentamicin) | Drug = Digitalis Possessing — Phenytoin {ant-epiloptios) Low = hithium Therapeutic — Tricyclic antidepressants Index = Immunomodulators ‘This isthe study dealing with the effect of drugs on the body. It ineludes actions of drugs as well as their mechanism. Drugs may act by physical mechanism (e.g, osmotic diuretics), chemical action (e.g, antacids), stimulation oF inhibition of enzymes (competitive and non-competitive inhibition) or via receptors. ENZYME INHIBITION Drugs may act by inhibiting the enzymes competitively, nom competitively or un-competitively. C eeu E SC L3} BEBE) Review of Pharmacology Competitive inhibition Important points about this type of enzy sulfonamides) are: + It binds only to enzyme and not to enzyme-substrate complex (FS) Drug should have similar stricture as that of substrate of the enzyme. Inhibitor binds to the active site ofthe enzyme, This type of inhibition is mostly surmountable, i.e. inhibition ‘can be overcome by increasing the dose of the substrate, Km is Michaelis menton’s constant and is calculated as amount of substrate required to produce half of the ‘maximal velocity whereas V,,. is maximum reaction velocity. Ttresults im increase in K,, but does not affect the V.,. If the drug binds very’ strongly to the active’ site, so that it cannot be displaced even by large concentration cf substrate, it can result in irreversible competitive inhibition. In this type of inhibition, K, rises and V.,. decreases. Organophosphates are irreversible competitive inhibitors. yyme inhibition (eg, TK. looks tke kilometers, in competition one need to run more Ihlometers is. K, increases Noncompetitive Inhibition Important points about this type of enzyme inhibition (eg. cyanide) are: + Itbinds to both enzyme as well as ES with equal affinity Drug nee! not have similar structure as that of substrate of the enzyme. It binds toa different site ofthe enzyme, known as allosteric site This type of inhibition is insurmountable, ic. inhibition ‘cannot be overcome by increasing the dose ofthe substrate Itresult in decrease in V,,, but doesnot affect the K,, Mostly non-competitive inhibitors are irreversible but carbonic anhydrase inhibitors are reversible non- competitive inhibitors. MUU Telia Un-Competitive Inhibition + _Ithas affinity for only ES and is not able to bind toenzyme. * It decreases the activity of enzyme-substrate complex, so ores Ze is removed, the binding of substrate to enzyme ncreases (affinity increases). resulting in decrease in Km. {ype of enzyme inhibition. ike Plot (Double Reciprocal Plot) (Fig, 1.5) Intercept of the graph on Yeaxis is a measure Of Vas (Higher intercept means lower V,..) and intercept on X-azis a measure of K,, (Lesser the negative lesser is K,) * Competitive inhibitors have same Y-intercept as uninhibited enzyme. Since V,,., is unaffected, 50 1/V,.. also does not change. Non-competitive inhibitors have same X-intercept as uninhibited enzyme. Since km is unaffected, so 1/ substrates also does not change Un-competitive inhibitor will have graph shifted to left for both X-and y-intercepts, as both V,. and Km decrease. Wr (Non-compettve inhibitor) E (Competitive irreversible inhibitor) 1B (Competitive inhibitor) (Un-competive inhibitor) ‘A (Control) 41S, “ike Fig, 1.5: Lineweaver-Burk plot showing different types of enzyme inhibitors a cc) nw Example Competitive E only T No Physostigmine change Neostigmine Non BonEandeS No Cyanide: Jcompettive complex change. (iiss ES complex 1 4 tithium VEE only. RECEPTORS ‘These are the binding sites of the drug with funtional correlate, ‘Two important terms related to the receptors are affinity and intrinsic activity (1A). Affinity is the ability of a drug to combine with Ifa drug has no affinity, it will not bind to the all type of drugs acting via. receptors ( the receptor. receptor, So, Agonist: It will bind to the receptor and activate il maxi- mally, i.e, LA is +1 Antagonist: Binds to the receptor but produces no ‘effect (IA is 0). But now ian nt able to bine the receptor because these are already occupied by the antagonist. Thus, it decreases the action af the agonist but itself has no effect. * Partial agonist: It activates the receptor submaximally (FA between 0 and +1), It will produce the similar effect in the absence of agonist but it will decrease the effect of a pure agonist. e.g. pindolol has partial agonistic activity at f, receptors. In the presence of agonists like adrenaline and noradrenaline it will produce antagonistic effect ie, decrease in heart rate but even in high doses it does not result in severe bradycardia due to some agonistic action + Inverse agonist: These type of drugs bind to the recep- tor and produce opposite effect (IA is negative) e.g. carboline is an inverse agonist at BZD receptors. ‘Types of Antagonism These may be physical, chemical, physiological or pharma- cological + Physical antagonist binds to the drug and prevents its absorption like charcoal binds to the alkaloids and prevents their absorption. + Chemical antagonist combines with a substance chemically like chelating agents bind with the metals. + Physiological antagonist produces an action opposite to a substance but by binding to the different receptors es. adrenaline is a physiological antagonist of histamine because adrenaline causes bronchodilation by binding, to Bi, receptors, which is opposite to bronchoconstriction caused by histamine through H, receptors. + Pharmacological antagonists produce opposite actions by binding tothe same receptor e.g. beta blockers. Classification of Receptors ‘The receptors are classified into four types based on the signal transduction mechanisms, G Protein Coupled Receptors (Fig. 1.6) ‘These are also called metabotropic receptors or heptahelical (serpentine) receptors ie, haveseven transmembrane spanning seements. Drugs bind to the receptor which in turn activates G protein (GTP activated protein). G-proteins consist of three ScPonits; o, B and y. When all three are joined together (along sth GDP), G-protein is inactive. When GTP replaces GDP, weubunit seperates from Bry subunit and become activated ‘Retivated a-subunit may result in one of the 3 actions: reactivation (by Gs) or inhibition (by Gi) of enzyme ade- pnyleyelase: It changes the concentration of cAMP that acts by activating protein kinases (eg. protein kinase A). Lat- ter produce action by phosphorylation of their substrates, Gone Prema” EI ‘eon (eal by ete g au a a * GawaiPleyzed DAG Peal ak nieces ae oe cam and ut acon eg, creep, vso 3. Stimulation oF inhibition of fon channels M, recep Cyclic AMP, IP, and DAG act as second messengers whereas Cais both a second as well as third messenger After the action, the intrinsic GTPase activity of alpha subunit result in joining it with -y subunits and thus G-protein isavailable for action again. kK Lgand 2 @. 2 ERK HPIRR TP) IGT: ti, Hifetannbmaunes as i Ni Oe ~ plat © sont | oO ze hath iain teachin Inotropic Receptors (Fig. 1.7) ‘The drug binds directly to the receptor located on anion channel without mediation by G proteins. These are the fastest acting, receptors. It includes GABA,, Ny Ny NMDA (receptors of glutamate) and 5-HT, receptors. Ione Neurotransmitter Fig. 4.7: Inotropic receptors Enzymatic Receptors (Fig: 1-8) towo sites, the drug binds on the has “This type of receptor ees extracellular site and the ‘enzymatic _— BEET) Review of Pharmacology activity (mostly tyrosine kinase). This enzyme can be via JAK-STAT pathway growth hormone acts via activated Cytokines, prolactin, insulin these receptors Isulin ae G ~ Growth hormone os Receptor tyrosine kinase 4. Single dimer binds Extragaluian Tyrosine-1) () —> ( kinase domain Inactive Active Active 2. Kinase 3, Tyrosines 4. Intracellular ‘activity is ‘re proteins stimulated phosphorylated ‘bind to ‘phosphotyrosine docking sites Fig. 1.8: Enzymatic receptors Intracellular Receptors (Fig. 1.9) These types of receptors are slowest acting, These may be present inthe cytoplasm (glucocorticoids, mineralocorticoids, and vitamin D) or in the nucleus (T, T,, Retinoic acid, PPAR, estrogen, progesterone and testosterone). Both lype of receptors finaly act by nuclear mechanisms (.e. by affecting transcription). All the intracellular receptors are considered a part of ‘Nuclear Receptor Superfamily’ Extracoluir uid Signating Plasmamperbie Fig. 4.9: Intracellular receptors DOSE RESPONSE CURVE (ORC) It is a graph between the dose of a drug administered (on X-axis) and the effect produced by the drug (on Y-axis). It consists of two components; dose-plasma concentration curve and plasma concentration-response curve. As plasma concentration is more closely related {0 response, the graph between plasma concentration and response is usually called DRC. Two types of DRC can be described: Quantal and graded. ‘Quantal DRC ‘When the response is an ‘all or none’ phenomenon (e.g, antiemetic drug stopping the vomiting or not), the y-axis (response axis) shows the number of person responding and X-axis shows the plasma concentration. Its used to calculate EDsg and LDso, Median Effective Dose (ED,,): tis the dose that will produce he half ofthe maximum (50%) response. More is ED,, lower is the Potency and vice a versa. Median Lethal Dose (LD,,): It is the dose that will result in death of 50% of the animals receiving the drug. More is LD. safer isthe drug, Therapeutic Index ([-): It isa mensure ofthe safety of adrug, Itis calculated as a ratio of LD, to ED, Drugs having high T are safer whereas those having low T.. are more likely to be toxic LDso EDs TL Graded DRC When the response can be graded (eg. reduction in BP), the yraxis shows the magnitude of response. DRC is usually hyperbola in shape, As curved lines cannot give good mathematical comparisons, so usually the dose is converted to log dose to form log DRC, which gives @ sigmoid shaped curve (Fig. 1.10, 1.11). The middle portion (which is of therapeutic importance) is straight line in the log DRC. Another advantage of converting it into logarithmic form is that large variation in doses can be plotted on the same curve, Three important parameters (potency, efficacy and slope of curve) can be determined from DRC. Potency It is the measure of the amount of a drug needed to produce the response. Drugs producing the sume response at lower dose are ‘more potent whereas those requiring large dose are less potent. Im DRC, more a drug ison let side of the graph, higher i its potency and vice a versa, In Figure 26, drug A is more potent than drug B, Efficacy It is the maximum effect produced by a drug. More the peak of the curve greater is the efcacy. It is clinically more important than potency. In Figure 26, drug B is more efficacious than drug A. Slope If the DRC is steeper, that means the response will increase dramatically with slight increase in dose. Thus, drugs having steeper DRC have narrow therapextic index (like barbiturates) than those having less steep curves (e.g, benzodiazepines). DRC can also be utilized to know whether a drug is competitive or non-competitive inhibitor. + In case of competitive inhibitor, curve will shift to right, Le. now the same agonist will have less potency in the presence of antagonist. It does not affect the efficacy. + In case of non competitive inhibitor, there will be flattening of DRC, ic. efficacy decreases. It usually does not affect potency. If the antagonist is irreversible ‘competitive, then there will be decrease in potency as well as efficacy. However, Log DRC is not always sigmoid in shape. For vitamins and essential metals, the curve is U-shaped (Fig. 1.12) as there are adverse effects at very low as well as very high doses. Fig. 1.11; Log DRC for most drugs Fig. 112: Log DRC for vitamins and essential metals, PHARMACOGENETIC CONDITIONS. Due to different genetic make up, some drugs have different effects in different individuals, so these drugs may show either toxicity or lack of effect in certain individuals, if used in conventional dosage. These conditions include: 1. Acetylator Polymorphism: Some individuals are slow ‘cetylators and some are fast acetylatos. The drugs metabolized by this route may be ineffective in fast acetylators and may show toxicity in slow acetylators. Important drugs metabolized by acetylation include (remembered as SHIP) + Sulfonamides including dapsone and PAS. + Hydralazine _ PSS isuniadd eee A ma ee + Procainamide Note: + All SHIP drugs can also cause lupus erythematosis. + Other drugs metabolized by acetylation include ace- bbutolol, amantadine, amrinone, benzocaine, clonaz~ ‘epam, nitrazepam and phenelzine etc. 2, Glucose-6-phosphate Dehydrogenase (G-6-PD) Deficiency: ‘Oxidant drugs may produce hemolysis in the patient with deficiency of this enzyme. The important drugs are: 3. Atypical Pseudocholinesterase and _Succinylcholine: Succinylcholine is a very short acting drug due to metabolism by pseucocholinesterase. In some individuals, this enzyme is not functioning well (atypical). In such individuals this drug may produce prolonged apres. 4. Inability to Hydroxylate Phenytoin 5. Resistance to Coumarin Anticoagulants 6. Malignant Hyperthermia by Halothane. ° g FA FE Fy BEED] (view of Pharmacology Ese Drug development process is broadly divide * Drug discovery phase Preclinical studies Clinical trials DRUG DISCOVERY PHASE Most new drugs are discovered through random compound oriented approach, target oriented a rational drug designing, all approaches result in ds (process called lead finding). These are then subjected to various procedures to identify one or two drug candidates (now called lead compounds) suitable investigations. (This process is called lead These lead compounds are then eval n screening, Pproach oF These compout selection of several for further optimization). ted in preclinical phase, sa dru Foramolecule to be developed. certain properties id be present. These properties determine the molecule to be drugilike and are called Lipinski’s Rule of Five. According to this rule, the molecule should have shi +

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