The Disposition of Drugs

1. The Disposition of Drugs Olaf H. Drummer Monash University, Melbourne AUSTRALIA olaf@vifm.org

2. Definitions • Disposition refers to total process of absorption, distribution, metabolism and excretion of drugs • Pharmacokinetics refers to the science which studies the relations between blood concentration and time

3. Absorption • All substances must be absorbed to be biologically active. • The extent and rate a drug is absorbed is dependent on the substance, the formulation, and the route of administration. • The biological activity will therefore be dependent on the absorption and its physiochemical properties

4. Drug Administration • Parenteral routes • dose delivered by injection and not through alimentary canal • includes all forms of injections and routes of administration which bypass mesenteric circulation • Enteral routes • drugs that are delivered through alimentary canal • includes oral, sublingual, buccal and rectal administration

5. Oral Intravenous Intramuscular Intraperitoneal Subcutaneous Rectal Intrathecal Inhalation Buccal Sublingual Percutaneous Ocular Intranasal Intraarterial Routes of Administration There are many routes by which drugs can be administered

6. Profiles of Absorption • Each route of administration has a different pharmacokinetic profile • The parenteral routes have the quickest onset of action, particularly IV, although inhalation and intranasal dosing can give very rapid absorption • Orally administered drugs have a much slower onset with Cmax occurring typically at 1-2 h post dose,

7. Profiles of Drug Absorption

8. Mechanisms of Drug Absorption The gastrointestinal barrier is best considered a semipermeable membrane, with two primary mechanisms to allow transport of drugs • Passive Diffusion • proportional to concentration gradient • highest for lipid soluble drugs • highest for unionised drugs • Facilitated Diffusion • endogenous substances eg glucose, amino acids • few drugs eg penicillamine, 5-fluorouracil

9. Factors Affecting Gastrointestinal Absorption • Gastrointestinal motility • Splanchnic blood flow • Particle size and formulation • Physiochemical factors

10. Gastrointestinal Motility • Most drugs are not absorbed in the stomach but rather the small intestine • Gastric emptying will therefore affect rate of delivery to the jejumen • Motility has a big effect on drug absorption • food affects motility and rate of gastric emptying • slowed by migraine, diabetic neuropathy etc • metoclopramide increases gut motility • morphine and other opioids reduces motility

11. Splanchnic Blood Flow • This refers to the flow of blood through the mesenteric system • Blood flow is reduced in hypovolaemic states such as those caused by disease or injury • following overdose to drugs causing coma • following serious injury including abdominal area • propranolol absorption increased dramatically following food

12. Gastric Emptying and Detection in Stomach Contents • It may take several hours for drugs to be removed from stomach • This time may extend to days in coma! • Drugs may appear in stomach contents from biliary excretion or vomiting! • Consider these factors when interpreting gastric data

13. Particle Size and Formulation • The formulation of orally administered drugs can greatly affect the extent and rate of absorption • tablets are more likely to be affected than capsules, suspensions and solutions in that order • This applies particularly to drugs with sparing solubility in acid medium • Certain excipients can retard absorption • eg dicalcium phosphate with tetracycline • Particle size of drug can be very important

14. Controlled Released Drugs • Formulation of some drugs are controlled to delay release or sustain release over a longer period of time • coated tablets (sugar and film-coated) • slow release formulations (verapamil etc) • enteric coated (to prevent release in stomach) • Aspirin, KCl, NSAIDs • Membrane-controlled delivery include patches for steroids, nicotine, nitroglycerine, fentanyl

15. Physiochemical Factors • These factors alter the chemical state of the drug for absorption by • binding drug to another molecule affecting absorption, or • alteration of pH of stomach and small intestine by other drugs, by food or disease state • the degree of ionization of the drug in the gut • the use of food which can increase, decrease or not alter the rate and extent of absorption

16. Gastric vs Intestinal Absorption • Acidic drugs tend to be at least partially absorbed in stomach since at the pH of the stomach the molecule is unionised, • eg acetylsalicyclic acid, NSAIDS, captopril • Basic drugs are only poorly absorbed in stomach • Most absorption occurs in small bowel, duodenum, jejumen and ileum • Large intestine inefficient in absorbing drugs

17. Effect of Food on Drug Absorption • Food may increase, decrease or not affect drug absorption • In most cases food alters the rate of absorption but doesn’t affect the extent • In some cases food may substantially alter the extent of absorption and rate of absorption

18. Examples of Food Effects • Food reduces ethanol absorption (5-10%) • Food effects many antibiotics - some increase others decrease (penicillins, erythromycin) • Food delays absorption of digoxin • Food increases absorption of thiazide diuretics • Food increases absorption of phenytoin

19. Blood Alcohol ConcentrationVariation with Time and Food CHO>protein>fat Fasting Food

20. Pharmacokinetic Constants • Half-life Time taken to halve level • Volume of distribution Artificial apparent volume to which drug equilibates • Clearance body’s ability to remove drug

21. Pharmacokinetic Terms 10 0 C Vd = Dose / C0 k k = 0.693/t1/2 mg/L Cl = Dose/AUC 4 2 t1/2 1 24 0 Time (hours)

22. Volumes of Distribution(L/kg) Frusemide 0.1 Diazepam 1 Morphine 2 Digoxin 6 Tetrahydrocannabinol 20 Chlorpromazine 20

23. Blood Burden v Vd Vd (L/kg)% Drug in blood 0.10 40 0.15 27 0.60 6.7 1.0 4.0 10 0.40

24. Estimation of Drug Consumption • Suspected overdose of diazepam. • Blood level 2.0 mg/L • What dose was consumed? • Vd = 2 L/kg • Dose = 2 x 2 = 4 mg/kg body weight • Amount of drug in body = 4x70=280 mg

25. Body Burden of Diazepam • Blood concentration suggests therapeutic use, ie 0.9 mg/L • No diazepam in gastric contents, ie no recent use of diazepam • Body burden 323 mg or 65 5-mg tablets! • Vd calculation gave an estimate of 42 mg!

26. Estimation of Drug Usage • The previous result is likely to be quite inaccurate and even misleading. • Vd assumes state of equilibration - usually not likely in overdoses. • Vd assumes linear kinetics - usually not likely in overdose when saturation kinetics apply. • 280 mg implies overdose, but could be accumulation with chronic use.

27. Estimation of Drug Usage • To estimate likely amounts of drugs consumed it is advisable to rely on case reports in which amount of drug consumed is known and have given a quantified result. • Alternatively, several key tissues reflecting substantial body burden is required.

28. Conclusions There are many factors affecting the disposition of drugs. Knowledge of the disposition of drugs is essential in order to properly assess toxicological results

29. Metabolism and Excretion

30. Definitions • Metabolism Refers to the process of biotransformation of the administered substance to another chemical substance. • Excretion Refers to the elimination or process of removal of foreign substances.

31. Schema Showing Drug Movement Receptors/Site of Action Tissue reservoirs free bound bound free Systematic Circulation Absorption Excretion free drug bound drug metabolites Biotransformation

32. Metabolism • There are two main types: • Phase 1 - introduce or expose a functional group, eg hydroxylation. • Phase II - are conjugation processes which lead to rapid excretion, eg glucuronidation reactions

33. Metabolic Pathways • Phase I Processes • N-dealkylation • O-dealkylation • Hydroxylation (aliphatic and aromatic) • Oxidation (nitrogen and oxygen) • Deamination • Hydrolytic

34. Metabolism • Dealkylation RNH RNHCH 2 3 • Hydroxylation R OH H R

35. Methamphetamine hydroxylation CH 3 { HO CH CHNHCH 2 3 N-dealkylation CH 3 CH CHNH 2 2

36. Alprazolam • doses 0.5-4 mg daily • blood levels 20-60 ng/ml • half-life 6-22 hours • metabolized by hydroxylation to -hydroxy alprazolam (also active)

37. Diazepam • doses 5-40 mg daily • blood levels <1000 ng/ml • half-life 40-100 hours • metabolized • by N-dealkylation to nordiazepam (also active), • hydroxylation to oxazepam (active) • Temazepam is N-methyl analog of oxazepam (active) Metabolites Nordiazepam Temazepam Oxazepam

38. Flunitrazepam • 1 or 2 mg tablets • peak blood concentrations 0.02 mg/L [2 mg] • half-life 17 hours • Metabolized to • 7-amino-flunintrazepam • 7-acetamido-flu… reduction 7-amino metabolite

39. Temazepam Hypnotic • 10-20 mg doses (night) • blood levels < 1000 ng/ml • half-life 4-15 hours • metabolized by N-demethylation (oxazepam) and conjugation • common benzodiazepine • impairs driving skills

40. Phase II Processes • Glucuronidation eg paracetamol, morphine, diazepam • Sulfation eg paracetamol, steroids, salbutamol • Acetylation eg clonazepam, sulfonamides

41. Oxazepam • 15-60 mg doses (night) • blood levels < 1000 ng/ml • half-life 4-15 hours • metabolized by conjugation • Other hydroxylated benzodiazepines also conjugated • Temazepam • Lorazepam

42. Morphine metabolism

43. Paracetamol (Acetaminophen) NHCOCH NHCOCH 3 3 SCH CHCOOH 2 OH NH OH 2 N-acetylation = mercapturic acid conjugate Sulfate and glucuronide conjugates

44. Paracetamol (Acetaminophen)Excretion Data • Paracetamol 2% • Paracetamol glucuronide 45-55% • Paracetamol sulfate 20-30% • Cysteine & mercapturates 15-55% • Parent drug excretion increases in overdosage to 10-20%

45. Hydrolysis and Esterification Cocaine metabolized to BZE and EME Also Transesterification to cocaethylene

46. Sites of Metabolism • Most drugs are metabolized by the liver since the liver is the major metabolic organ in terms of source of enzymes and size of organ. • Kidneys, lungs, skin and the gastrointestinal tract are also significant sources of metabolism. • Heroin for example is metabolized by esterases in blood.

47. Microsomal metabolism • Phase I processes are mainly mediated by enzymes found in the endoplasmic reticulum or microsomes. • Microsomal enzymes are largely the cytochrome P-450 group. • Twelve cytochrome P-450 gene families are known, these are called CYP1, CYP2 etc with several sub-groups.

48. Mechanisms of Excretion • Biliary and Fecal Excretion - Some drugs are excreted into bile eg morphine, when this occurs drugs are then excreted via feces or are reabsorbed in the GIT ie - entero-hepatic recirculation. - Some drugs are incompletely absorbed and are therefore excreted via feces. - High molecular weight drugs or conjugates are particularly good substrates.

49. Mechanisms of Excretion • Other routes of elimination. - respiration eg ethanol - saliva eg most “non-bound” drugs - sweat eg cocaine - hair eg most substances - breast milk eg lipophilic drugs

50. Adverse Drug Interactions