PHARMACOKINETICS- BPHARM SYLLABUS- UNIT I

This presentation includes the basic concepts of pharmacokinetics including absorption distribution, metabolism and excretion of drugs.
It covers key parameters like half-life, bioavailability and clearance as per the BPharm syllabus.

1. PHARMACOKINETICS Ms. FATHIMATH RAIHANA ASSISTANT PROFESSOR P A COLLEGE OF PHARMACY

2. Pharmacokinetics : It is the movement of drug in the body and the alteration of drug by the body. It is the study of A bsorption, D istribution, M etabolism and E limination, that is movement of drug into, within and out of the body what the body does to the drug.

3. Membrane transport 1. Passive Transport Simple diffusion Filtration 2. Carrier Mediated Transport Active transport Facilitated diffusion 3. Endocytosis and Exocytosis

4. 1. Passive transport : The drug moves across the membrane without any energy. Simple diffusion : It is the transfer of drug across the membrane in the direction of its concentration gradient . The rate of diffusion depends upon : Concentration gradient Lipid solubility Ionisation Higher concentration gradient faster the diffusion. Lipid soluble, unionized drugs pass across the membrane by simple diffusion. Also called lipid diffusion.

5. ii. Filtration : It is the passage of drugs through aqueous porous membrane. Water soluble drugs with smaller size cross by filtration. The movement is along the concentration gradient. Eg : Urea

6. 2. Carrier- mediated Transport : Transport of substances by the help of specific carriers. Transport of some substances which cannot move by diffusion is aided by the help of specific carriers. Active Transport : It is the transfer of drug against concentration gradient and needs energy. It is carried out by specific carrier protein. Eg : Levodopa, iron, sugars, amino acids. The compound binds to a specific carrier protein on one side of membrane and moves across the cell and dissociates on the other side of the cell.

7. There will be competition between two substrates to bind with the carrier. Eg : Penicillin and Probenecid When they are administered together, duration of action of penicillin is prolonged because both compete for renal tubular secretion. Active Transport

8. iii. Facilitated diffusion : It does not require energy. The movement occurs in the direction of concentration gradient. The carrier facilitates and highly specific. Eg : Uptake of glucose by cells, vitamin B12 from intestines.

9. 3.Endocytosis and Exocytosis Endocytosis : It is the process by which small droplets are engulfed by the cell membrane and carried into the cell as vesicle and then release the substance. Eg : Some proteins and Vitamin B12 are taken up by this process with the help of intrinsic factor.

10. Exocytosis : It is the process by which the substances are secreted from cells. Eg : Neurotransmitters from nerve endings.

11. I. ABSORPTION : It is defined as the passage of drug from the site of administration into the circulation . It occurs by passive diffusion or carrier- mediated transpo rt. Except IV, all other routes undergo this process. Site of administration Site of action

12. Factors influencing drug absorption Pharmaceutical factors Drug factors Biological factors Disintegration and dissolution time Formulation Particle size Lipid solubility pH and Ionisation Area and vascularity Gastrointestinal motility Presence of food Disease First pass metabolism

13. Pharmaceutical factors : Disintegration and dissolution time : The drug taken orally should break up into small particles to be absorbed. Poorly water-soluble drugs delay absorption. Eg – Aspirin . ii. Formulation : Inert substances used with drugs as diluents like starch and lactose may interfere with absorption. iii. Particle size : Smaller particle better absorption. Eg : Corticosteroids, griseofulvin , digoxin, aspirin and tolbutamide better absorbed when given in small amounts.

14. 2. Drug factors : Lipid solubility : Lipid soluble drugs are absorbed faster by dissolving in the phospholipids. ii. pH and ionisation : Ionised drugs are poorly absorbed and unionised drugs are lipid soluble and well-absorbed. The degree of ionisation depends on pH medium.

15. 3 . Biological factors : Area and vascularity : Larger surface area – more vascularity – better the absorption. So most drugs are absorbed from small intestine. ii. GI motility : Faster the gastric emptying quicker the passage of drug to the intestines, better the absorption. Intestinal motility – increases - drug absorption decreases as in diarrhoea. iii. Presence of food : It delays gastric emptying, dilution of drug and hence absorption.

16. Drugs may form complexes with food and such complexes are poorly absorbed. Eg : Tetracycline chelate calcium in stomach. Ampicillin, rifampicin well absorbed on empty stomach . iv. Diseases : Disease of the gut reduce absorption of acidic drugs. Eg : achlorhydria In the absence of intrinsic factor, vitamin B12 is not absorbed in pernicious anemia .

17. v. First pass metabolism : It is the metabolism of drug during its passage from the site of absorption to the systemic circulation . Also called as pre-systemic circulation. Gut wall portal vein live r systemic circulation. Such drugs should be given in higher doses to give required action. Drugs given orally enter gut wall and liver and gets metabolised.

18. Clinical significance : If first pass metabolism is partial , higher dose must be given. Eg : Nitroglycerine Propranolol Salbutamol Drugs that undergo complete first pass metabolism, route has to be changed . Eg : Insulin Hydrocortisone Bioavailability of many drugs increased with liver disease due to reduction in hepatic metabolism .

19. Bioavailability : It is the fraction of the administered drug that reaches the systemic circulation in unchanged form. IV route – 100% bioavailability Factors affecting bioavailability : ( Same of absorption you mention ).

20. II. Distribution : It is defined as the reversible transfer of drugs between various body fluid compartment. Unionized, lipid soluble drugs are easily distributed. Factors affecting distrib+ution : Lipid solubility – high lipid solubility, rate of distribution increases as lipophilic drugs can easily pass across the cell membrane. Ionisation – unionised form usually lipophilic, hence diffuses across membranes. Blood flow – distribution occurs most rapidly in tissues with greater number of blood vessels and least in tissues with fewer number of blood vessels. Plasma protein binding

21. Volume of distribution : It is defined as the volume necessary to accommodate the entire amount of drug administered, if the concentration throughout the body is equal to that of plasma. Vd = Amount of drug in the body Plasma concentration It is defined as the volume in which the drug can be evenly distributed , if drug concentration equals to plasma concentration.

22. Drugs with high MW (heparin) or bound to plasma protein ( Warfarin) are largely restricted to vascular compartment. Hence Vd is low. Drugs which accumulate in tissues have Vd which exceeds body water. Eg : chloroquine In Congestive cardiac failure, Vd of some drugs can increase due to increase in ECF volume or decrease because of reduced perfusion.

23. Plasma protein binding : After reaching circulation, most drugs bind to plasma proteins. Acidic drugs bind to albumin Basic drugs – α - glycoprotein Free or unbound drugs – produce action, metabolism and excretion . Bound form act as reservoir .

24. Enters systemic circulation Binds to plasma proteins Bound form cannot exert pharmacological actions Free form Pharmacologically active Drug

25. Clinical significance : Drugs that are bound to plasma proteins have a low volume of distribution. Plasma protein binding delays the metabolism of drugs. Highly bound plasma proteins have longer duration of action. Eg : Sulphadiazine – less plasma protein bound – short duration of action, 6 hours. sulphadoxime – highly bound – longer duration – 1 week. Hence in case of poisoning, highly bound are difficult to remove by hemodialysis . In diseases like anemia , liver disease, renal failure, plasma albumin levels are low, so decrease in bound form lead to drug toxicity. Plasma protein binding may cause displacement interactions : More than one drug can bind to same on plasma protein. So drug with higher affinity can replace the lower affinity drug. Thus resulting in increased concentration of lower affinity drug. Eg : Warfarin and indomethacin

26. Tissue binding : Some drugs bind to certain tissue because of special affinity. Tissue binding delays elimination and prolongs duration of action . Eg : Lipid-soluble drugs – bind to adipose tissue Thiopentone sodium Redistribution : Some highly lipid-soluble drugs are given IV or inhalation, they get rapidly distributed into highly vascular tissue brain, heart, kidney and get redistributed to low vascular tissue like muscle and fat. Thus results in termination. Eg : IV anaesthetic thiopental sodium which induces anaesthesia in 10-20 seconds and effect stops in 5-15 min.

27. Blood brain barrier : The endothelial cells of the brain capillaries lack intercellular pores and instead have tight junctions. Glial cells envelope the capillaries and form BBB. Only lipid soluble unionised drugs can cross BBB.

28. Placental barrier : Lipid soluble, unionised drugs cross the placenta. Thus drugs taken up by mother can cause unwanted effects in the foetus. Lipid-soluble drugs with MW 200-500 can easily cross placenta. High MW cannot pass. Eg : Insulin.

29. III. Biotransformation / Metabolism : It is the process of biochemical alteration of drug in the body . Body treats most drugs as foreign substances, called xenobiotics . Most of the drugs are lipophilic in nature, they are excreted after metabolism . But some drugs are hydrophilic – which are less metabolised and excreted as such . Eg : Streptomycin Neostigmine Site of biotransformation is : Liver To small extent in kidney, gut mucosa, lungs, blood and skin.

30. Metabolism is important for : Converting Lipophilic drugs Hydrophilic drugs Active drug Inactive metabolite Eg : Phenobarbitone – hydroxyphenobarbitone Active drug Active metabolite Eg : Codeine – morphine Diazepam - Oxazepam Inactive drug Active metabolite ( Prodrug ) Eg : Levodopa – dopamine Prednisone - prednisolone

31. Phase I reaction Phase II reaction Oxidation Reduction Hydrolysis Cyclization Decyclization Glucuronidation Acetylation Sulphation Methylation Glutathione conjugation Glycine conjugation Eg : Aspirin Salicylic acid Eg : Salicylic acid Microsomal glucuronyl transferase Salicyl acyl glucuronide Excretion

32. Oxidation Addition of oxygen or removal of hydrogen Eg : Phenytoin, phenobarbitone,propranolol Reduction Removal of oxygen or addition of hydrogen Eg : Chloramophenicol , methadone Hydrolysis Breakdown of a compound by addition of water Eg : Esters – procaine, succinyl choline Amides – Lignocaine, procainamide Cyclization Conversion of straight chain compound into ring structure Proguanil Decyclization Breaking up of ring structure Phenobarbitone , phenytoin Phase I reactions : At the end of phase I, metabolite may be active or inactive. Eg : Aspirin Salicylic acid

33. Phase II reactions : It consist of conjugation reaction. It is faster than phase I. Those not excreted in phase I undergoes phase II. If phase I metabolite is polar, it is excreted in urine or bile. Most of the metabolites are lipophilic Hence undergo conjugation with endogenous substrate like glucuronic acid, sulphuric acid, acetic acid or amino acid. These conjugates will be polar and hence inactive Not all drugs undergo phase I and phase II reactions in order. [ Isoniazid undergoes first phase II, then phase I ]

34. Conjugation reactions Enzymes Examples Glucuronidation UDP glucuronosyl transferase Aspirin Morphine Acetylation N-acetyl transferase Isoniazid Sulphation Sulphotransferase Paracetamol Methylation Transmethylase Adrenaline Dopamine Glutathione conjugation Glutathione transferase Paracetamol Glycine conjugation Acyl coA glycine transferase Salicylates

35. Factors affecting drug metabolism : i . Age : Neonate and elderly metabolize at different rate as neonates have less amount or activity of hepatic microsomal enzymes. Eg : In neonate, chloramphenicol conjugate slowly, hence leads to Grey baby syndrome. ii. Diet : Poor nutrition – decrease enzyme function. iii. Diseases : Chronic diseases of liver affect hepatic metabolism of some drugs. Eg : Increased duration of action of diazepam – in cirrhosis. iii. Genetic factors iv. Simultaneous administration of drugs

36. Drug- metabolizing enzymes : The drugs are metabolized with the help of enzymes. They are : Microsomal enzymes Non- microsomal enzymes Drugs can be inactivated without the use of enzymes – known as Hofmann elimination. Eg : Atracurium ( skeletal muscle relaxant)

37. Microsomal enzymes Non-microsomal enzymes Location : Smooth endoplasmic reticulum of cells, liver, kidney, lungs. Eg : Cyctochrome P450 Glucuronyl transferase Location : Cytoplasm, mitochondria, plasma Eg : Conjugase , esterase Reactions : Phase I reaction Glucuronide conjugation Reactions : Oxidation , reduction , hydrolysis All conjugation except Glucuronide

38. Enzyme induction : Repeated administration of certain drugs increases the synthesis of microsomal enzymes. Such drug is referred to as Enzyme inducer. Eg : Rifampicin Phenytoin Barbiturates Enzyme inducer - Cytochrome P450 - Metabolism Enzyme induction takes slowly but after 1-2 weeks it reaches the peak.

39. Clinical significance : Enzyme induction may increase the metabolism of drugs reducing duration of action. Eg : Rifampicin induces the metabolizing enzyme of oral contaceptives . This leads to contraceptive failure. ii. Autoinduction lead to drug tolerance. Eg : Carbamazepine iii. Induce drug toxicity . Eg : Increased metabolism of paracetamol in alcoholics – increased hepatotoxicity. iv. Prolonged phenytoin therapy – ostomalacia - due to enhanced metabolism of vitamin D3. v. Can also be beneficial. Eg : Phenobarbitone in neonatal jaundice . Phenobarbitone induces glucuronyl transferase enzyme – bilirubin is conjugated and jaundice is resolved.

40. Enzyme inhibition : Certain drugs inhibit the activity of drug metabolizing enzymes, known as enzyme inhibition . Inhibition of metabolism of one drug by another occurs, when both are metabolized by same enzyme. It is a rapid process.

41. Clinical significance : 1. Increase drug toxicity. Eg : Warfarin and chloramphenicol or erythromycin. Chloramphenicol inhibits the metabolic enzyme of warfarin Increased plasma concentration of warfarin Enhanced anticoagulant effect / Bleeding 2. It can be beneficial. Eg : Protease inhibitor regimen – Treatment of HIV infection

42. Excretion : The removal of drug and its metabolites from the body is called excretion. Drugs are excreted as water-soluble metabolites and some without metabolism. The major organs of excretion are : kidneys , intestines , biliary system and lungs. Also small amounts in saliva, sweat and milk.

43. The processes involved in the excretion of drugs through kidney are : Glomerular filtration Passive tubular reabsorption Active tubular secretion [ Rate of renal excretion = ( Rate of filtration + Rate of secretion ) – Rate of reabsorption ] Glomerular filtration : Drugs with small molecular size are more readily filtered. The extent of filtration is directly proportional to GFR and to the fraction of unbound drug.

44. 2. Passive tubular reabsorption : The factors affecting : pH of renal tubular fluid degree of ionisation Strongly acidic and basic drugs remain in ionized form at any pH of urine, hence are excreted in urine. Weakly acidic drugs : in acidic urine – remain unionized – so reabsorbed. So pH of urine is made alkaline by sodium bicarbonate. b. Weakly basic drugs : in alkaline urine – remain unionized- so reabsorbed by making acidic using ascorbic acid.

45. 3. Active tubular secretion: It is carrier-mediated transport which requires energy . Active secretion is unaffected by changes in the pH of urine and protein binding . Eg : Acidic drugs like penicillin , probenecid Basic drugs like Quinine, morphine The carrier system is relatively non-selective and having similar physicochemical properties compete for same. Eg : Probenecid and penicillin 2. Lungs : Alcohol, volatile general anaesthetics like ether, halothane are excreted via lungs. 3. Faeces : Purgatives like senna , cascara

46. 4. Bile : Some drugs are secreted in bile. They are reabsorbed in gut while small portion in faeces. Eg : Tetracyclines 5. Skin : Metals like arsenic, mercury. 6. Saliva : Phenytoin , metronidazole , lithium. 7. Milk : Drugs taken by lactating women may appear in milk. Eg : Amiodarone

47. Factors affecting excretion : Physicochemical properties of drug Plasma concentration od drug Distribution and binding characteristics of a drug Urine pH Blood flow to the kidney Biological factors Drug interactions Disease state

48. Clearance : It is the volume of plasma freed completely of drug in unit time . Cl = Rate of elimination It is important for determining drug concentration and should be considered when any drug is given for long-term administration. Plasma half-life (t 1/2 ) : It is the time taken for plasma concentration of a drug to be reduced to half of its value. 100mg to reach 50mg takes 4 hours. So t 1/2 is 4hours. Plasma concentration KINETICS OF ELIMINATION

49. Drugs are metabolised/eliminated from the body by : First order kinetics : (Elimination kinetics) The amount of drug eliminated over time is directly proportional to the concentration of drug in the body. A constant fraction of drug is metabolised/eliminated from the body in unit time. The t 1/2 of the drug will remain constant. Most drugs follow this. The rate of metabolism/excretion is dependent on their concentration in the body . It is exponential. As the plasma concentration of drug rises, metabolism and excretion proportionately increase. It holds good for absorption of drugs . Rate of elimination α Drug concentration

50. Time Plasma drug concentration 100mg 50mg 25mg 1 hour 1 hour 1/2 1/2

51. ii. Zero order kinetics : Saturation kinetics or non-linear kinetics The amount of drug eliminated is independent of concentration . A constant amount of drug present in the body is metabolised or eliminated per unit time. The amount metabolised remains same and does not increase with increase in drug concentration. When the metabolic enzymes get saturated, drug toxicity increases. Eg : Alcohol Phenytoin Heparin Aspirin Rate of elimination = constant

52. Time Plasma drug concentration 100 mg 90mg 80mg 1 hour 1 hour 10mg 10mg