Pharmacokinetics: Distribution PDF

istribution Distribution is the passage of the drug from the blood to the different tissues and organs. 29  istribution Important in the choice of drugs for the treatment of diseases located in speci...

istribution Distribution is the passage of the drug from the blood to the different tissues and organs. 29  istribution Important in the choice of drugs for the treatment of diseases located in special areas (CNS) and in pregnancy and lactation. UNIT 2: Pharmacokinetics 30  istribution The rate of drug distribution depends on many factors: 31  istribution 1. PLASMA PROTEIN BINDING (PP): Lots drugs have a physicochemical affinity for plasma proteins, the most important of which is ALBUMIN. The less bound a drug is, the more efficiently it can cross cell membranes or diffuse. Unbound drug fraction: available to produce pharmacologic effects/ be metabolized/ excreted *the part of the drug bound to plasma protein is not available can influence the drug's biological half-life in the body. Protein + drug ⇌ Protein-drug complex 32  istribution 1. PLASMA PROTEIN BINDING (PP): → Low PP-binding drugs: have a less prolonged action as they are more available for metabolism and excretion. → High PP-binding drugs : The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. Saturable binding sites: displacement of a drug by another drug with a higher affinity for the same binding site. 33  istribution 2. REGIONAL BLOOD FLOW The rate at which a drug is distributed to the various organs, after absorption, depends to a large extent on the amount of cardiac output the organs receive. -In less vascularised, or irrigated, tissues, it is more difficult for the drug to reach high concentrations. High vascularization Poor vascularization Heart Skin Kidney Adipose tissue Liver Bone Brain Skeletal muscle The drug is easily distributed in highly perfused organs (liver, heart, kidney, etc). less distributed in low perfused organs (muscle, fat, peripheral organs, etc). 34  istribution 3. LIPOSOLUBILITY: determines how quickly the drug is absorbed and whether the drug enters into the bloodstream, crosses membranes and settles in body tissues. → LIPOSOLUBLE DRUG DISTRIBUTION: - Better access to highly irrigated organs: brain, heart, liver or kidneys. - Slower access to muscle. - Slower fat and other poorly irrigated tissues. - Accumulation in fat (thiopental, BZP). → HYDROSOLUBLE DRUG DISTRIBUTION - It does not distribute well. - Good access to tissues with capillaries rich in intercellular clefts (hepatic sinusoids). - Difficulty accessing the CNS. 35  istribution 4.DISTRIBUTION IN SPECIAL AREAS: CNS, eye, fetal circulation and exocrine secretions (tears, saliva, milk or prostate fluid). BLOOD-BRAIN BARRIER (BBB) There are no intercellular spaces, presence of a Barriers basement membrane, pericytes, etc. BBB restricts the distribution of Drug entry into the Capillary circulation or diffusion through the cerebrospinal hydrophilic drugs CNS fluid in the brain. Drug Liposoluble Type Type of Passive diffusion, active transport transport 36  istribution 4.DISTRIBUTION IN SPECIAL AREAS: CNS, eye, fetal circulation and exocrine secretions (tears, saliva, milk or prostate fluid). 37  istribution VOLUME OF DISTRIBUTION The volume of distribution (VD) quantifies the extent of distribution between plasma and the rest of the body after oral or parenteral dosing. Volume of distribution may be increased by: – renal failure (due to fluid retention) – liver failure (due to altered body fluid and plasma protein binding). Conversely it may be decreased in dehydration. 38  istribution Dose of drug VOLUME OF DISTRIBUTION (VD)= Blood concentration Blood concentration 1000 mg Dose of drug 50 mg/mL (VD)= 1000 mg = 20 L 50 mg/mL Factors that alter the volume of distribution: -real volume in which the drug is distributed -plasma proteins binding, -tissue binding. 39  etabolism Biochemical transformation of drugs carried out by enzymes in the body (liver, lung, kidney, adrenal, intestine, blood, brain, placenta, etc.) to give rise to products that are more polar, more hydrosoluble and more easily eliminated than the original substance. -Drug metabolism can result in toxication or detoxication - the activation or deactivation of the chemical. -Determinant of the duration and intensity of the pharmacological action of drugs. Metabolism often converts lipophilic chemical compounds into more readily excreted polar products 40  Drug metabolism can result in: » Activation of an inactive drug (PRO-drug): Active metabolites Example: » Deactivation of a drug: inactive metabolites » Metabolism (biochemical modification): active metabolites. 41  Drug metabolism classification: – Phase I reactions (non-synthetic reactions). – Phase II reactions (synthetic reactions). Phase I reactions usually precede Phase II, but not necessarily. 42  Phase I reactions may occur mainly by oxidation, reduction and hydrolysis reactions, which results in (more) polar metabolites 1. Oxidation (oxidases) addition of oxygen or removal of hydrogen often in the liver. – Typically involve a cytochrome P450 monooxygenase, NADPH and oxygen Can turn a nontoxic molecule into a poisonous one (toxification). And an inactive drug to an active one. Ø If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. Ø However, many phase I products are not eliminated rapidly and undergo a subsequent reaction (phase II) to form a highly polar conjugate. 43 2. Reduction addition of hydrogen or removal of oxygen. typically involve cytochrome P450 enzymes. 3. Hydrolysis molecule degradation by addition of a molecule of water: Ester + H2O = Acid + Alcohol 44  Drug metabolism classification: – Phase I reactions (non-synthetic reactions). – Phase II reactions (synthetic reactions). 45  Phase II reaction: conjugation reactions (e.g., with glucuronic acid, sulfonates —sulfation, glutathione or amino acids) – detoxication in nature, and involve the interactions of the polar functional groups of phase I metabolites. – Sites on drugs where conjugation reactions occur include carboxyl (-COOH) hydroxyl (-OH) amino (NH2) and sulfhydryl (-SH) groups. 46 1. Glucuronidation: is the most important – mainly in the liver – UDP-glucuronyltransferase enzyme responsible – glucuronides: metabolites resulting from glucuronidation » much more water-soluble. » It allows the elimination of substances 47 2. Acetylation: involves acetyl-CoA conjugates. 3. Metylation: addition of metyl groups forming conjugates. 4. Sulfation: sulfonates conjugation. 5. Glicine conjugation. 6. Glutation conjugation: glutathione disulfide (GSSG) glutathione reductase. 7. Ribonucleosids and nucleotids syntesis: purine and pirimidine antimetabolites conjugation. 48  Comparing Phase I & Phase II Enzyme Phase I Phase II Types of Oxidation Conjugations reactions Reduction Hydrolysis Increase in Small Large hydrophilicity General Exposes Polar compound mechanism functional group added to functional group Consquences May result in Facilitates metabolic excretion activation *the more hydrophilic the substance, the more it will be eliminated  METABOLISM INHIBITION A drug can inhibit the metabolism of another drug if it uses the same enzyme or metabolism cofactors. This fact is rare since different drugs use different isoenzymes of the CYP (P-450). If metabolism is inhibited, toxicity effect can appear (no elimination). FUN Not only drugs can be metabolism inhibitors… even some foods: this is the FACT case with grapefruit juice. This is metabolised by an isoform of CYP450, thus avoiding metabolism of the drug that is not eliminated and prolonging its pharmacological effect. 50  METABOLISM INDUCTION A drug can induce the metabolism of another drug – by increasing the synthesis of proteins (metabolic enzymes) Inductor drugs are highly selective for determinate isoenzymes of the CYP (P-450). Induction process requires from 4 to 14 days to reach the maximum induction effect and last for 1 to 3 weeks. 51  METABOLISM INDUCTION can produce: – Lower (inactivated) or higher (activated) intensity and duration. – Tolerance: the drug itself induces its own metabolism. UNIT 2: Pharmacokinetics 52  First Pass Metabolism (PRE-systemic) The First Pass Metabolism is the metabolisation of a drug along its pass from the absorption site to the systemic circulation. » ORAL ADMINISTRATION exposes drugs to be metabolised in the intestine wall and liver (due to the enterohepatic circulation). » TRANSDERMAL ADMINISTRATION exposes drugs to skin metabolism (low relevance). » ALL ROUTES exposes drugs to be metabolised in the lungs (low relevance). First Pass Effect>>>Route of orally administered drugs: Absorbed in the gastrointestinal tract Then pass through the portal venous system to the liver where they are exposed to first pass effect, which may limit systemic circulation Once in the systemic circulation, drugs interact with receptors in target tissues >>>pharmacological effect 53  Intravenous Administration Oral Administration Liver Intestines  xcrection Expulsion of a drug and its metabolites to the outside Excretion is the process by which non-useful materials are eliminated from the organism (usually through the kidneys -by urine- or in the faeces). – It is an essential process in all forms of life. – accumulation of foreign substances can adversely affect normal physiological functions. 55  There are five sites where drug excretion occurs: – The kidney (most important. Urine) – Biliary excretion or faecal excretion – Air expiration – Saliva and sweat – Breast milk (Maternal milk). Very relevant for the baby that receives drug metabolites during lactance. Low MW and lipophilic drugs can easily pass through to the milk the amount of drug that reaches the maternal milk is low 56  Kidney excretion Responsible for water-soluble compounds. Total kidney excretion= (Glomerular filtration + Active tubular secretion) – (Tubular re-absorption) – Glomerular filtration of unbound drug. – Tubular re-absorption of lipophilic and non-ionised drugs by passive diffusion. It is affected by pH modifications. Basic drugs are more ionised and less re-absorbed in acid urine. Acid drugs are more ionised and less re-absorbed in alcaline urine. – Active secretion of (free & protein-bound) drug by transporters. 57  Excretion kinetics Allow the precise adjustment of the dosage intervals to the patient. Three main pharmacokinetic parameters must be considered: » Bioavailability (F). » Volume of distribution (V). » Clearance (CL). 59  Excretion kinetics Clearance (CL): Drug clearance is the teoretical volume of plasma from which the drug is completely eliminated as a function of time: Elimination rate CL= Drug concentration 61  Excretion kinetics Most of the drugs used in therapeutics follow non-saturated elimination kinetics: » First order kinetics (exponential). The elimination rate is directly dependent on the drug concentration and CL remains constant » A constant FRACTION of drug in the body is eliminated in a unit of time. 62  Excretion kinetics Few drugs, however, saturate the elimination mechanisms and follow other kinetics: » Zero order kinetics (lineal). The elimination rate is constant and independent from the drug concentration and CL decreases as drug concentration increases » A constant QUANTITY of drug is eliminated in a unit of time. 63  Excretion kinetics Clearance (CL). Drug clearance is the teoretical volume of plasma from which the drug is completely eliminated as a function of time: Elimination rate CL= Drug concetration Excretion Most of the drugs used in therapeutics ratenon-saturated follow is constant elimination kinetics: » First order kinetics (exponential). The elimination rate is directly dependent on the drug concentration and CL remains constant, or a constant FRACTION of drug in the body is eliminated in a unit of time. Few drugs, however, saturate the elimination mechanisms and follow other kinetics: » Zero order kinetics (lineal). The elimination rate is constant and independent from the drug concentration and CL decreasesThe moreconcentration as drug concentration, the more increases or a excretion constant QUANTITY of drug is eliminated in a unit of time. 64  Excretion kinetics Half-life or elimination half life (t1/2). – time that drug takes to lose half of its pharmacologic, physiologic, or radiologic activity. 65  Excretion kinetics Dosage interval. – reasonable and short doses. The drug tends to accumulate in the body until equilibrium is reached, then elimination starts and a steady-state plasma concentration (Css) is reached. Dosage interval Css = CL 66  Excretion kinetics Loading dose: – dose (unique or repeated) in order to reach a desired plasma concentration: Cdesired x VD Loading Dose = F 67  Excretion kinetics Maintenance dose: – dose administered at set intervals after Css is reached, in order to maintain this concentration and equilibrium with elimination. 68