Absorption of drugs

General pharmacology! Basics!

1. ABSORPTION OF DRUGS DR NIKITA INGALE JR1, DEPARTMENT OF PHARMACOLOGY GMC NAGPUR 23/08/17 ABSORPTION OF DRUGS 1

2. Definition Mechanism of action Factors affecting it Bioavailiability and Bioequivalence 23/08/17 ABSORPTION OF DRUGS 2 OVERVIEW -

3. Study of time course of drug absorption, distribution , metabolism & excretion and their relationship with its therapeutic and toxic effects of drug 23/08/17 ABSORPTION OF DRUGS 3 Pharmacokinetics

4. 23/08/17 ABSORPTION OF DRUGS 4 PHARMACOKINETICS DISPOSITION ABSORPTION E LIMINATION DISTRIBUTION METABOLISM EXCRETION

5. Administration Absorption Distribution Metabolism Excretion Removal oral Unchanged reabsorbed I V I V 23/08/17 ABSORPTION OF DRUGS 5

6. DEFINITION- Process of m ovement of unchanged drug from site of administration to systemic circulation 23/08/17 ABSORPTION OF DRUGS 6 ABSORPTION-

7. Cell membrane structure- 23/08/17 ABSORPTION OF DRUGS 7 A) ABSORPTION THROUGH GIT-

8. Mechanism of drug absorption 23/08/17 ABSORPTION OF DRUGS 8

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10. 23/08/17 ABSORPTION OF DRUGS 10 Mechanism of drug absorption

11. Non – energy dependant Major process for absorption of 90% of drugs Driving force- Concentration or electrochemical gradient It follows Fick’s first law of diffusion 23/08/17 ABSORPTION OF DRUGS 11 Passive diffusion

12. Responsible for transport of molecules into cells through the protein channels in cell membrane Driving force - hydrostatic force or osmotic differences across membrane Important in absorption of low molecular weight compounds up to 400 daltons E g- removal of drug from CSF 23/08/17 ABSORPTION OF DRUGS 12 Pore transport / convective transport/ bulk transport/ filtration

13. Penetration of membrane by forming reversible neutral complexes with endogenous ions of GIT ( mucin ) Example propranolol with oleic acid 23/08/17 ABSORPTION OF DRUGS 13 Ion-pair transport

14. Carrier (component of membrane) binds reversibly or non covalently with solute molecules and complex traverses to other side of membrane Carriers – no directionality Structure specific Capacity limited 23/08/17 ABSORPTION OF DRUGS 14 Carrier mediated transport

15. Carrier mediated transport operates down the concentration gradient ( downhill transport) Driving force – Concentration gradient No energy expenditure Example vitamin B12 23/08/17 ABSORPTION OF DRUGS 15 Facilitated diffusion

16. Requires energy in form of ATP Primary active transport direct energy required 1} Ion transporters Transporting ion in/out cell Example - Organic anion – provastatin , atorvastatin Organic cation – diphenhydramin 2} ABC [ATP binding cassette] transporters small foreign molecules out of cells ( exsorption ) Example – P – glycoprotien in pumping anticancer drugs out of the cell. 23/08/17 ABSORPTION OF DRUGS 16 Active transport

17. Secondary active transport No direct energy requirement 1 ] Symport ( co – transport) Transport of both molecules in same direction Example - H+ coupled peptide transporter (PEPT1) implicated in intestinal transport of beta lactam antibiotics 2] Antiport (counter – transport) Movement in opposite direction Example - expulsion H+ using Na+ gradient in kidneys 23/08/17 ABSORPTION OF DRUGS 17

18. 23/08/17 ABSORPTION OF DRUGS 18 CHARACTERISTICS SIMPLE DIFFUSION FACILITATED DIFFUSION ACTIVE TRANSPORT 1] incidence Commonest Less common Least common 2] process Slow Quick Very quick 3]movement Along gradient Along gradient Against gradient 4] direction Bidirectional Bidirectional Unidirectional 5]carrier No No Needed 6]energy No No Required 7]selectivity Absent Present Present 8]metabolic inhibition Cannot block it Cannot block it Can block it

19. Through the junction between G I epithelium Minor importance in drug absorption 23/08/17 ABSORPTION OF DRUGS 19

20. Energy dependant Only mechanism where drug does not have to be in aqueous form Responsible for uptake of Fats and starch Oil soluble vit like A,D,E,K Vit B12 insulin 23/08/17 ABSORPTION OF DRUGS 20

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24. Absorption from common routes of drug administration- 23/08/17 ABSORPTION OF DRUGS 24

25. Buccal Sublingual 23/08/17 ABSORPTION OF DRUGS 25

26. In buccal route the medicament is placed between the cheek and the gum. In sublingual the drug is placed under the tongue. Barrier to drug absorption from these route is epithelium of oral mucosa. Absorption of drug is by passive diffusion. 23/08/17 26 Examples— Antianginals – nitrates Antihypertensive - nifidipine Analgesics – morphine Estradiol and oxytocin

27. 23/08/17 ABSORPTION OF DRUGS 27 RECTAL ABSORPTION-

28. Important route for children & geriatric patients Drugs administered as solution [micro enemas] and suppositories Absorption is rapid from solutions compared to suppositories Highly vascularised but slower absorption due to limited surface area 1 ]Important route for children & geriatric patients 2]Drugs administered as solution [micro enemas] and suppositories 3 ]Highly vascularised but slower absorption due to limited surface area 23/08/17 ABSORPTION OF DRUGS 28 RECTAL ABSORPTION-

29. Advantages Disadvantages Useful in patients having nausea & vomiting Chances of rectal inflammation 50 % of drug bypasses 1 st pass effect Irritating suppositories promote defecation & drug loss Useful for gastric irritant drugs Limited surface area – slower absorption Cyp 3A4 is present in lesser amount in lower intestine Faecal matter retards absorption Inconvenient & embarrassing to patient RECTAL ABSORPTION- 23/08/17 ABSORPTION OF DRUGS 29

30. Examples – Bisacodyl & glycerine suppositories 23/08/17 ABSORPTION OF DRUGS 30

31. RATE OF ABSORPTION FROM FASTEST TO LOWEST- 23/08/17 ABSORPTION OF DRUGS 31 SUBLINGUAL > RECTAL > ORAL

32. 23/08/17 ABSORPTION OF DRUGS B ) ABSORPTION THROUGH OTHER NON-ORAL ROUTES: INTRAMUSCULAR SUBCUTANEOUS INTRAVENOUS INTRA-ARTERIAL INTRA-THECAL PULMONARY OCCUSERT S INTRA-OCULAR INTRA-NASAL

33. sites- Deltoid, gluteal mass and vastus muscle Example-depot injection of testesterone , haloperidol depot injections 23/08/17 ABSORPTION OF DRUGS 33 INTRAMUSCULAR ROUTE- LIMITATIONS- Irritant drugs can’t be given 2 . Large volume can’t be given (max 5 ml can be given) 3 . Chances of abscess formation 4 . Chances of nerve damage

34. Absorption - Slower than IM sites due to poor perfusion Used – 1. When slow response is desired 2. Drug degrade when taken orally Limitations – 1. Irritant drugs can’t be given as necrosis occurs 2. Large volume can’t be given(max -1ml ) Example - Insulin & low molecular weight heparin 23/08/17 ABSORPTION OF DRUGS 34 SUBCUTANEOUS ROUTE-

35. Site- in lumen of the artery -large amount of drug delivered at desired site - Diagnostic purpose - coronary angiography & cerebral angiography ( radiopaque contrast media) ,many anticancer drugs. 23/08/17 ABSORPTION OF DRUGS . 35 INTRA-ARTERIAL ROUTE-

36. Site- subarachnoid space Local rapid effects of drugs on meninges and spinal cord Limitation – strict aseptic condition & great expertise is required Examples – xylocaine in Spinal anesthesia, acute CNS infections (amphotericin –B ) 23/08/17 ABSORPTION OF DRUGS 36 INTRATHECAL ROUTE-

37. Site- inspiration by nose or mouth Extremely rapid absorption due to- Large surface area of alveoli High permeability of alveoli Rich perfusion Limitation- bronchial irritation Example – Oxygen, general anesthetics, salbutamol, beclomethasone , cromolyn sodium 23/08/17 ABSORPTION OF DRUGS 37 PULMONARY ROUTE-

38. - F or local effects as mydriasis , miosis , anesthesia and glaucoma -Sterile aqueous solution of drug -Cornea – Major barrier - both hydrophilic and lipophilic characters. - D rug should posses biphasic solubility 23/08/17 ABSORPTION OF DRUGS 38 INTRAOCULAR ROUTE-

39. -Elliptical micro units ( drug reservoir) -Drug -delivered slowly at steady rate - Example – pilocarpine occuserts 23/08/17 ABSORPTION OF DRUGS 39 OCCUSERTS-

40. Intended to act locally e.g. infection, contraception Used for systemic delivery of contraceptive and other steroids. Factors effecting— -vaginal secretions. -microbes at vaginal lumen. Examples-ointments, foams , pessaries of metronidazole 23/08/17 ABSORPTION OF DRUGS 40 Vaginal Administration

41. TOPICAL ABSORPTION- 23/08/17 ABSORPTION OF DRUGS 41

42. -Largest organ of body -Weight 2kg & area 2 m 2 -Skin is made up 3 distinct layers  1]Epidermis - Non vascular 2] Dermis - Highly vascular 3]Subcutaneous fat tissue 23/08/17 ABSORPTION OF DRUGS 42 SKIN-

43. Factors that influence passive percutaneous absorption of drugs are - 1]Skin conditions 2]Composition of topical vehicle 3]Application procedures or application condition Principal barrier is stratum corneum 23/08/17 ABSORPTION OF DRUGS 43

44. 1]Thickness : Very slow from foot & palm ( thickened stratum corneum) 2]Hair follicles : Rapid from Scalp (numerous hair follicles) 3]Trauma : Destruction of stratum corneum promote absorption e.g. Cuts, rashses ,inflammation, mild burns 4]Hydration of skin : Soaking of skin in water (using emollients, plastic film or dressing )promote hydration of skin and ↑drug absorption 5 ]Age : elderly more prone for allergy 23/08/17 ABSORPTION OF DRUGS 44 SKIN CONDITIONS--

45. Vehicle or base : In which drug is dissolved than dispersed promotes absorption Permeation enhancers : Incorporation of chemicals like propylene glycol , azone promote absorption 23/08/17 ABSORPTION OF DRUGS 45 COMPOSITION OF TOPICAL VEHICLES --

46. 1]Rubbing : ↑ blood circulation to area of application and thus ↑ drug permeation 2]Occlusion : Trapped moisture endogenous or exogenous → hydrates stratum corneum → promotes drug permeation 3]Loss of vehicle : Loss of vehicle ↓ transdermal permeation 23/08/17 ABSORPTION OF DRUGS 46 APPLICATION CONDITIONS--

47. Remain superficial - Sunscreen , insect repellants , cosmetics Delivery to appendages – Anti- infective , antiacne , antiperspirants /hair removers Delivery to local tissues – Antimitotics , anti-inflammatories , antihistamines , anaesthetics Systemic delivery – Clonidine , scopolamine, nicotine , fentanyl , oestradiol 23/08/17 ABSORPTION OF DRUGS 47 EXAMPLES--

48. 23/08/17 ABSORPTION OF DRUGS 48 TRANSDERMAL DRUG DELIVERY- When topically applied drugs are meant to produce systemic effects, the mode of administration is called Transdermal or percutaneous drug delivery. Useful for drugs with short oral availability and short action Example - Nitroglycerine Estradiol, Betamethasone

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50. Particle size ↓ particle size  Surface area ↑  Drug dissolves rapidly 23/08/17 ABSORPTION OF DRUGS 51 Eg-Micronisation of poorly soluble drugs like griseofulvin , chloramphenicol

51. Crystal form -Absorption rate depends on its crystalline form 23/08/17 ABSORPTION OF DRUGS 52 Amorphous chloramphenicol palmitate > crystalline chloramphenicol palmitate

52. Solid dosage form Solid drug particals Drug in sol at the absorption site Drug in the body Disintegration/ deaggregation Dissolution Permeation across the biomembrane Rate limiting step for lipophilic drugs Eg . Griseofulvin , spironolactone Rate limiting step for hydrophilic drugs Eg . Cromolyn sodium, neomycine ABSORPTION OF DRUGS 53 23/08/17 D RUG SOLUBILITY AND DISSOLUTION RATE-

53. Formulation of drug Excipient is a pharmacological inert substance but can modify absorption & bioavailiability 2 ) Ca /Mg never to be combined with tetracyclines  forms insoluble cholates 3 ) Calcium lactate used as adjuvant in calciferol can cause hypocalcemia 4)Use of calcium lactate/ lactose with phenytoin decreases bioavailability 23/08/17 ABSORPTION OF DRUGS 54

54. Vehicle - major component of liquid, oral and parenteral dosage form Diluents – commonly added to tablet and capsule formulations to produce the necessary bulk 23/08/17 ABSORPTION OF DRUGS 55 Commonly used excipients Binders and granulating agents – used to hold powders together to form granules or promote cohesive compact for directly compressible materials and to ensure that tablet remains intact after compression

55. Disintegrants – agent overcome cohesive strength of tablet and break them up on contact with water(mostly hydrophillic ) Lubricants – added to tablet formulation to aid flow of granules, to reduce interparticle friction and sticking or adhesion of particles Coatings – Deleterious effects of various coatings on drug dissolution Enteric coat> sugar coat> non enteric coat 23/08/17 ABSORPTION OF DRUGS 56

56. The more complex a dosage form, greater the number of rate limiting steps and greater the potential for bioavailability problems 23/08/17 ABSORPTION OF DRUGS 57 Nature & type of dosage form

57. ABSORPTION RATE Tablet Capsule Powders Suspension Emulsion Solution Granules Fine partials Dissolution Drug in sol In blood Slowest Fastest deaggregation Dissolution Disintegration absorption 23/08/17 ABSORPTION OF DRUGS 58

58. Patient related factors 23/08/17 ABSORPTION OF DRUGS 59

59. Gastric emptying and git motility -Factors that accelerate gastric emptying ↑ bioavailability of drugs 23/08/17 ABSORPTION OF DRUGS 60 Gastric emptying promoted by Fasting Anxiety Lying on right side Hyperthyroidism Gastro kinetic drugs Gastric emptying retarded by Fatty diet Endogenous depression Lying on left side Pyloric stenosis Hypothyroidism Drugs - Atropine

60. the residence time of drug in small intestine. Small intestine is major site for drug absorption :long intestinal transit time is desired for complete drug absorption. Residence time depends upon intestinal motility or contraction. Peristaltic contraction promote drug absorption by increasing the drug intestinal membrane contact, by enhancing drug dissolution. Metaclopropamide , laxative, promote intestinal transit time & enhance absorption of rapidly soluble drugs. 23/08/17 ABSORPTION OF DRUGS 61

61. Delayed intestinal transit is desirable for: Drugs that release slowly (sustained release) Drugs that dissolve only in intestine ( enteric coated ) Drugs which are absorbed from specific site in the intestine (Lithium carbonate, Vitamin B) When drug penetrate the intestinal mucosa very slowly (e.g. acyclovir) When absorption of drug from colon is minimal. 23/08/17 ABSORPTION OF DRUGS 62

62. 1 st pass effect ↓ - bioavailability and therapeutic response Examples 23/08/17 ABSORPTION OF DRUGS 63 1] L dopa 2] Morphine 3] Nitroglycerine 4] Isosorbide nitrate 5] Propranalol

63. 23/08/17 ABSORPTION OF DRUGS 64 BIOAVAILABILITY

64. --Rate and extent of absorption of unchanged drug from its dosage form 23/08/17 ABSORPTION OF DRUGS 65 Bioavailability of drugs

65. Determined by concentration-time curve in blood or by its excretion in urine 66 Measurement Of Bioavailability

66. -- Peak plasma concentration (C max) -- Time to attain peak plasma concentration (T max) -- Area under the curve (AUC) : Reflects extent of absorption --Drug bioavailability % =AUC (oral)/ AUC ( i.v. ) × 100 23/08/17 ABSORPTION OF DRUGS 67 CHARACTERISTICS OF GRAPH

67. 23/08/17 ABSORPTION OF DRUGS 68 EQUIVALENCE TYPES-

68. --Bioavailability after IV administration is 100% --Close to 100% with subcutaneous or intramuscular injection due to precipitation at site of administration --Difference in bioavailability less than 25% no significant effect on clinical outcome 23/08/17 ABSORPTION OF DRUGS 69 BIOEQUIVALENCE-

69. -2 or more dosage forms of same drug contain same labelled quantities of drugs as specified in pharmacopaie -2 brands may be chemically equivalent but may not be bioequivalent 23/08/17 ABSORPTION OF DRUGS 70 CHEMICAL EQUIVALENCE-

70. --If they provide identical in vivo pharmacological response ( control of symptoms or disease) 23/08/17 ABSORPTION OF DRUGS 71 THERAPEUTIC EQUIVALENCE- CLINICAL EQUIVALENCE- --Structurally different drugs provide same therapeutic or clinical response as another drug -- Example - trifluperazine (phenothiazine group) & Haloperidol ( butyrophenone group) may be therapeutic equivalent in schizophrenia

71. Absorption is very important aspect of pharmacokinetic study of drug Knowledge of absorption helps us to decide route of administration Knowledge of absorption gives us idea about bioavailability of drug which in turn helps us in deciding dose Pharmaceutical industry utilises knowledge of absorption to prepare different formulation 23/08/17 ABSORPTION OF DRUGS 72 Summary

72. 1)HL Sharma & KK Sharma . pharmacokinetics.sharma and sharma’s principles of pharmacology.3 rd edition.hyderabad,Paras Medical Publisher;2017. p 2]D.M Brahmankar & Sunil B. Jaiswal.Absorption of drugs.Biopharmaceutics & pharmacokinetics a treatise.1 st edition.Delhi,Vallabh prakashan;2008.p5-75 23/08/17 ABSORPTION OF DRUGS 73 REFERENCES-

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