Distribution

1. Distribution • It the process by which a drug reversibly leaves blood and enter interstitium (extracellular fluid) and/ or cells of tissues. • Primarily depends on: 1.Regional blood flow. 2.Capillary permeability. 3.Protein binding. 4.Chemical nature of the drug.

2. Distribution of drugs • Definition: Penetration of a drug to the sites of action through the walls of blood vessels from the administered site after absorption is called drug distribution. • Drugs distribute through various body fluid compartments such as • (a) plasma • (b) interstitial fluid compartment • (c) trans-cellular compartment. • Apparent Volume of distribution (VD): The volume into which the total amount of a drug in the body would have to be uniformly distributed to provide the concentration of the drug actually measured in the plasma. It is an apparent rather than real volume.

3. Volume of distribution (Vd)

4. Volume of distribution (Vd) of a drug is the volume of body fluids into which drug is distributed in same concentration as in plasma • Total body fluid is about 60% of body weight i.e. about 42 L for a 70 Kg man. • 2 / 3 ICF ~ 28 L • 1 / 3 ECF ~ 14 L . This is divided into : • 3 – 4 L Plasma 9 – 10 L Tissue fluid

5. In 70 kg patient : If Vd = 3 - 4 L, drug is mainly localized in plasma e.g. bound to plasma albumin If Vd = 10 - 12 L , then drug is localized in ECF i.e. it is water soluble and poorly enter cells If Vd = 20 L , then drug is lipid soluble , and partially enter into cells across cell membranes of tissues If Vd = 40 L , then drug is enough lipid soluble to be uniformly distributed in total body fluid e.g. alcohol If Vd = > 42 L e.g.100 L, drug is highly lipid soluble & is stored in some tissues e.g. Digoxin Vd = 300 L; hemodialysis is not useful to remove this drug from body in poisoning. Because of this large Vd for stored drugs, Vd is named : apparent i.e. aVd

7. Volume of distribution (Vd) • Drugs confined to the plasma compartment (plasma volume 0.05L/kg BWT) (e.g. heparin and warfarin): very large molecular weight, low lipid solubility, or binds extensively to plasma proteins. • Drugs distributed in the extracellular compartment (intracellular volume 0.2L/kg) (e.g. aminoglycoside antibiotics): low molecular weight and hydrophilic

8. Volume of distribution (Vd) • Drug distributed throughout the body water (total body water 0.55L/kg): lipid-soluble drugs that readily cross membrane. • Other sites: Milk, bone, muscles. • Drugs that are extremely lipid soluble (e.g. thiopental) may have unusually high volume of distribution).

9. Factors determining the rate of distribution of drugs: • Protein binding of drug: • Many drugs circulate in the bloodstream bound to plasma proteins • Albumin is a major carrier for acidic drugs and α1-acid glycoprotein (AAG) binds basic drugs • The binding is usually reversible • Binding of a drug to plasma proteins limits its concentration in tissues and at its site of action because only unbound drug is in equilibrium across membranes

10. Protein Binding • Most drugs are bound to some extent to proteins in the blood to be carried into circulation. • The protein-drug complex is relatively large & cannot enter into capillaries & then into tissues to react. The drug must be freed from the protein’s binding site at the tissues.

11. Protein Binding • Tightly bound – released very slowly. these drugs have very long duration of action (not freed to be broken down or excreted) , slowly released into the reactive tissue. • Loosely bound – tend to act quickly and excreted quickly • Compete for protein binding sites – alters effectiveness or causing toxicity when 2 drugs are given together.

12. The extent of plasma protein binding also may be affected by disease-related factors and drug-drug interactions. • Hypoalbuminemia secondary to severe liver disease or nephrotic syndrome results in reduced binding and an increase in the unbound fraction • The active concentration of the drug is that part which is not bound, because it is only this fraction which is free to leave the plasma and site of action.

13. (a) Free drug leave plasma to site of action • (b) binding of drugs to plasma proteins assists absorption • (c) protein binding acts as a temporary store of a drug and tends to prevent large fluctuations in concentration of unbound drug in the body fluids • (d) protein binding reduces diffusion of drug into the cell and there by delays its metabolic degradation e.g. high protein bound drug like phenylbutazone is long acting. • Low protein bound drug like thiopental sodium is short acting.

14. 2. Plasma concentration of drug (PC): It represents the drug that is bound to the plasma proteins (albumins and globulins) and the drug in free form. It is the free form of drug that is distributed to the tissues and fluids and takes part in producing pharmacological effects. • The concentration of free drug in plasma does not always remain in the same level e.g. i) After I.V. administration plasma concentration falls sharply ii) After oral administration plasma concentration rises and falls gradually. iii) After sublingual administration plasma concentration rise sharply and falls gradually.

16. 3. Clearance: Volume of plasma cleared off the drug by metabolism and excretion per unit time. • Protein binding reduces the amount of drug available for filtration at the glomeruli and hence delays the excretion, thus the protein binding reduces the clearance.

17. 4. Physiological barriers to distribution: There are some specialized barriers in the body due to which the drug will not be distributed uniformly in all the tissues. These barriers are: a) Blood brain barrier (BBB) through which thiopental sodium is easily crossed but not dopamine. b) Placental barrier: which allows non-ionized drugs with high lipid/water partition coefficient by a process of simple diffusion to the foetus e.g. alcohol, morphine.

18. 5. Affinity of drugs to certain organs: • The concentration of a drug in certain tissues after a single dose may persist even when its plasma concentration is reduced to low. • Thus the hepatic concentration of mepacrine is more than 200 times that of plasma level. • Their concentration may reach a very high level on chronic administration. • Iodine is similarly concentrated in the thyroid tissue.

19. Elemination • Is the irreversible loss of drug from the body • It occurs by two processes: Excretion & Metabolism • Kidney and liver are the most common organs of drug elimination • The kidney is the most important organ for excreting drugs and their metabolites • Three fundamental processes account for renal drug excretion: glomerular filtration, active tubular secretion, passive tubular reabsorption

20. Metabolism • Drugs are chemical substances, which interact with living organisms and produce some pharmacological effects and then, they should be eliminated from the body unchanged or by changing to some easily excretable molecules. • The process by which the body brings about changes in drug molecule is referred as drug metabolism or biotransformation.

21. Metabolism • Involves enzymic conversion of one chemical entity to another within the body • The liver is the major site for drug metabolism • Specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestine

22. Enzymes responsible for metabolism of drugs: • Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT e.g. glucuronyltransferase, dehydrogenase, hydroxylase and cytochrome P450. • Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs.e.g. esterases, amidase, hydrolase.

23. Types of biotransformation • The chemical reactions involved in biotransformation are classified as phase-I and phase – II (conjugation) reactions. • In phase-I reaction the drug is converted to more polar metabolite. If this metabolite is sufficiently polar, then it will be excreted in urine. • Some metabolites may not be excreted and further metabolised by phase –II reactions.

24. Metabolism • The enzyme systems for drug metabolic biotransformation reactions can be grouped into two categories: • Phase-I: Oxidation, reduction and hydrolysis. • Phase-II: Glucuronidation, sulfate conjugation, acetylation, glycine conjugation and methylation reactions.

25. Excretion of drugs • Excretion of drugs means the transportation of unaltered or altered form of drug out of the body. The major processes of excretion include renal excretion, hepatobiliary excretion and pulmonary excretion. • The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid, nails and hair. • The rate of excretion influences the duration of action of drug. The drug that is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period.

28. Phase I reactions • Usually convert the parent drug to a more polar metabolite by introducing a functional group (-OH, -NH2, -SH). • Phase I metabolism may increase, decrease, activate (prodrug, e.g. enalapril) or leave unaltered the drug’s pharmacologic activity. • Phase I reactions are catalyzed by the cytochrome P450 (CYP450) system functional group ( -OH, - NH2 , -S H).

29. Species and strain variations exist in amount and activity of cytochrome P- 450 isoforms. • Isoforms are classified into families and further into subfamilies. Nomenclature : e.g. CYP3 A4 : • CYP : capital letters indicating the human enzyme, Cytochrome P450, designated as CYP is a superfamily of heme-containing isozymes that are located • in most cells, but primarily in the liver and GI tract 3 : numeral indicating the family number A : capital letter indicating the subfamily 4 : numeral that indicates the isoform number in the subfamily • Although they are large in number (hundreds), mainly isoforms of 3 families of CYP-450 are important for drug metabolism in man

30. Phase I reactions • CYP450 is composed of many families of isoenzymes known as isoforms • Six isoforms are responsible for the vast majority of CYP450-catalyzed reactions: CYP3A4, CYP2D6, CYP2C9/10, CYP2C19, CYP2E1, and CYP1A2 • Variability in the activity of CYP450 enzymes is linked to a range of factors including genetic, environmental, and developmental

32. Phase II reactions • Lead to the formation of a covalent linkage between a functional group on the parent compound or phase I metabolite and endogenously derived glucuronic acid, sulfate, glutathione, amino acids, or acetate • The highly polar conjugates generally are inactive and are excreted rapidly in the urine and feces • Nenates are deficient in this conjugation system, making them particularly vulnerable to drugs such as cholamphenicol (gray baby syndrome)

33. Clearance (CL) • Clearance: Volume of plasma cleared off the drug by metabolism and excretion per unit time. • The main PK parameter describing elimination. • It is the most important concept to consider when designing a rational regimen for long-term drug administration. • Drug clearance from the organ of elimination can be described as: Q: blood flow to the organ of elimination ER: Extraction ratio CpA: arterial drug concentration CpV: venous drug concentration

34. Total body (systemic) clearance ,Cltotal, is the sum of the clearance from various drug metabolizing (mainly the liver) and drug excreting organs (mainly the kidney) [Additive process]: • CLtotal = CLhepatic + Clrenal + CLpulmonary + Clother • Units of clearance are volume/time (e.g. L/h or ml/min)

35. Excretion • Is the elimination of drugs from the body

36. Phase I reactions utilizing the P450 system: • Inducers: The CYP450-dependent enzymes are an important target for pharmacokinetic drug interactions. • Xenobiotics (chemicals not normally produced or expected to be present in the body, for example, drugs or environmental pollutants) may induce the activity of these enzymes. • This results in increased biotransformation of drugs and can lead to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes, with concurrent loss of pharmacologic effect.

37. Inhibitors: Inhibition of CYP isozyme activity is an important source of drug interactions that lead to serious adverse events. • The most common form of inhibition is through competition for the same isozyme. • Numerous drugs have been shown to inhibit one or more of the CYP-dependent biotransformation pathways of warfarin. For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. • If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater anticoagulant effect and increased risk of bleeding.

38. Kinetics of metabolism • First-order kinetics: The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics. • In most clinical situations, the concentration of the drug, [C], is much less than the Michaelis constant, Km, and the Michaelis-Menten equation reduces to

39. That is, the rate of drug metabolism and elimination is directly proportional to the concentration of free drug, and first-order kinetics is observed. • This means that a constant fraction of drug is metabolized per unit of time (that is, with each half-life, the concentration decreases by 50%). First-order kinetics is also referred to as linear kinetics.

40. Zero-order kinetics: The enzyme is saturated by a high free drug concentration, and the rate of metabolism remains constant over time. • A constant amount of drug is metabolized per unit of time. The rate of elimination is constant and does not depend on the drug concentration.

41. Rational dosage design • Is based on the assumption that there is a target concentration that will produce the desired therapeutic effect • The intensity of a drug's effect is related to its concentration above a minimum effective concentration, whereas the duration of this effect reflects the length of time the drug level is above this value • By considering drug’s PKs, it is possible to individualize the dose regimen to achieve the target concentration

43. Half-Life (t1/2) • Half-Life (t1/2): • it is the time required for the plasma concentration or the amount of drug in the body to change by one-half (i.e. 50%) • The half-life is a derived parameter that changes as a function of both CL and Vd: