Pharmacology: Basic Principles and Distribution (PDF)

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Pharmacokinetics Distribution YFRM202 2  Welcome to this topic Attendance password: Plasma protein binding Distribution YFR...

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic Pharmacokinetics Distribution YFRM202 2  Welcome to this topic Attendance password: Plasma protein binding Distribution YFRM202 3  Lecture Overview In this lecture you can expect to learn about the distribution drugs in the body. You have previously learned about how drugs are absorbed into the body from their site of administration. In this lecture you will build upon that knowledge and further explore what happens to drugs and where they go once they get to the systemic circulation. Throughout this lecture it will become clear that plasma protein binding is an important factor that affects distribution and excretion of drugs from the body. 4  Learning Outcomes At the end of this lecture, you should be able to:  Describe the distribution of drugs around the body, including the blood brain barrier, chemoreceptor trigger zone, adipose tissue, placenta, bone and liver, as well as the factors that influence drug distribution  Describe plasma protein binding, the factors affecting the binding of drugs to transporter proteins in the blood, and how the unbound portion is pharmacologically active.  Explain how 2 drugs with affinity for the same binding sites on transport proteins may affect the concentration of one or the other and the possible clinical consequences thereof.  Describe volume of distribution and the free water and extracellular compartments which drugs can distribute into 5  Pharmacokinetics Rang & Dale’s Pharmacology. 2023. Chapter 9. – page 130. Fig. 9.8 The main routes of drug administration and elimination. CSF, Cerebrospinal fluid. 6 Distribution 7  Plasma protein and tissue partition of drugs Once drug molecules reach the systemic circulation after the process of absorption (across barriers between different aqueous compartments), they need to be distributed to their site of action. Two additional factors have a major influence on drug distribution and elimination. These are: Binding to plasma proteins Partition into body fat and other tissues Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 127 Brenner & Stevens pharmacology. 2023. Chapter 2. – page 11 & 13 When studying pharmacokinetics, we study the movement of drug into, through, and out of the body in terms of 4 main characteristics: ADME 8  Plasma protein binding Many drugs circulate in the bloodstream bound to plasma proteins This binding is reversible The extent of binding depends on the affinity of a particular drug for protein-binding sites Plasma protein binding (PPB) is expressed as a % of the plasma concentration E.g. Warfarin is 99% PPB, so 99% of warfarin in plasma is bound to plasma proteins. The remaining 1% is unbound and free to bind to receptors and be eliminated Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 126-129. 9  Plasma protein binding Plasma proteins: Albumin – the most important plasma protein for drug binding Binds acidic drugs (e.g. warfarin, NSAIDs, sulfonamides ß-globulin and acid glycoproteins Bind to basic drugs (e.g. quinine) Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 126-129. 10  Plasma protein binding Unbound drug Bound drug Free in plasma Bound to plasma proteins Capable of binding to Can’t bind to receptors receptors Can’t exert Exerts pharmacological effect pharmacological effect Able to diffuse into interstitial Can’t move from plasma fluid and cells compartment Can be metabolised Can’t be metabolised Can be filtered at the Can’t be filtered at the glomerulus and excreted glomerulus and excreted Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 126-129. 11  Factors affecting the extent of plasma protein binding The amount of drug that is bound to protein depends on: The concentration of free drug Drug affinity for the binding sites Based on whether the drug is acidic or basic The concentration of plasma protein Disease states Drug-drug interactions due to competition for the same plasma protein binding sites Rang & Dale’s Pharmacology. 2023. Chapter 9 – page129. 12  Decreased plasma protein concentrations Disease states Hypoalbuminaemia Less albumin available to bind to → more free acidic drug Conditions resulting in the acute-phase reaction response (e.g. cancer, arthritis, myocardial infarction, Crohn’s disease, trauma, surgery) → elevated levels of α1-acid glycoprotein → enhanced binding of basic drugs Hepa c or renal failure → decreased albumin content → more free acidic drug Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 126-129. 13  Factors affecting the extent of plasma protein binding Drug-drug interactions? Usual concentration of albumin in plasma is approximately 0.6 mmol/L = two binding sites per albumin molecule i.e. drug-binding capacity 1.2 mmol/L. For most drugs, the total plasma concentration required for a clinical effect is much less than 1.2 mmol/L, so with usual therapeutic doses the binding sites are far from saturated Usually not a clinically relevant drug interaction Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 129. 14  Plasma protein and tissue partition of drugs Two additional factors have a major influence on drug distribution and elimination. These are: Binding to plasma proteins Partition into body fat and other tissues Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 127 Brenner & Stevens pharmacology. 2023. Chapter 2. – page 11 & 13 When studying pharmacokinetics, we study the movement of drug into, through, and out of the body in terms of 4 main characteristics: ADME 15  Partition into body fat and other tissues Based on the lipophilicity/hydrophilicity of the drug Organ blood flow Low blood supply is defined as less than 2% of cardiac output Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 130 Brenner & Stevens pharmacology. 2023. Chapter 2. – page 11 & 13 16  Adipose tissue Fat is a large, non-polar compartment with poor blood supply Acts as a drug reservoir for lipid soluble drugs Polar drugs are excluded (e.g. gentamicin) Thiopental and some highly lipophilic general anaesthetics have a high fat:water partition coefficient Accumulate in body fat - remember the brain is mostly fat! Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 130 17  Blood flow Drugs are rapidly distributed to highly perfused organs E.g. brain, heart, liver, kidneys Rapid onset of action of drugs affecting these tissues Slower distribution to less perfused tissues E.g. skeletal muscle, skin, bone, adipose tissue Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 135 Brenner & Stevens pharmacology. 2023. Chapter 2. – page 11 & 13 18 Netter’s Illustrated Pharmacology – Figure 1.27 After absorption, drugs enter the systemic circulation and are distributed widely in the body; they leave the bloodstream and enter cells, with the amount entering depending on local blood flow, capillary permeability, and relative drug lipophilicity. 19  Distribution in body water Four main fluid compartments The equilibrium pattern of distribution between compartments depend on: Permeability across tissue barriers Binding within compartments pH partition Fat:water partition Fig. 9.11 The main body fluid compartments, expressed as a percentage of body weight. Extracellular fluid comprises the blood plasma (about 4.5% of body weight), interstitial fluid (16%) and lymph (1.2%). Intracellular fluid (30%–40%) is the sum of the fluid contents of all cells in the body. Transcellular fluid (2.5%) includes the cerebrospinal, intraocular, peritoneal, pleural and synovial fluids and digestive secretions. The fetus may also be regarded as a special type of transcellular compartment. Within each of these aqueous compartments, drug molecules usually exist both in free solution and in bound form; furthermore, drugs that are weak acids or bases will exist as an equilibrium mixture of the charged and uncharged forms, the position of the equilibrium depending on the pH of the fluid and pK a of the drug. Rang and Dale’s pharmacology. 2023. Chapter 9. Page 135. 20  Distribution To move between body fluid compartments, a drug must cross cellular barriers There are some special cellular barriers to note: Blood-brain barrier (BBB) Placenta Bone Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 135 Brenner & Stevens pharmacology. 2023. Chapter 2. – page 11 & 13 21  Blood-brain barrier (BBB) Formed by: Tight junctions between the continuous layer of capillary endothelial cells Glial cells that surround the capillaries Inhibits the penetration of polar and ionised molecules into brain neurons Limits drug access to the CNS Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 135 Netter’s Illustrated Pharmacology – Figure 1.28 Because of various anatomical and physiologic features, endothelial cells of the capillaries can limit passage of drugs from the bloodstream to tissues. For example, endothelial cells of brain capillaries, whose tight junctions merge into a continuous wall, are highly impermeable to many substances. Thus, a blood-brain barrier is established that generally limits accessibility of a good number of drugs, many of which are ionized in the blood at pH 7.4, to the brain. Water-soluble drugs, polar drugs, and ionized forms of drugs cannot cross this blood-brain barrier because they cannot pass through slit junctions and have difficulty traversing the lipid cell membrane. The brain is consequently inaccessible to many drugs of low lipid solubility. 22  Blood-brain barrier (BBB) Alteration to the permeability of the BBB can affect the efficacy of drugs; This can be caused by a number of conditions e.g. Inflammation Bacterial meningitis Bradykinins Treatment of brain tumours Rang & Dale’s Pharmacology. 2023. Chapter 9 – page 136 Fig. 9.12 Plasma and cerebrospinal fluid concentrations of an antibiotic (thienamycin) following an intravenous dose (25 mg/kg). In normal rabbits, no drug reaches the cerebrospinal fluid (CSF), but in animals with experimental Escherichia coli meningitis the concentration of drug in CSF approaches that in the plasma. From Patamasucon, P., McCracken Jr, G.H., 1973. Antimicrob. Agents Chemother. 3, 270. 23  Placenta Selective barrier to protect the foetus against the harmful effects of drugs. Essentially all drugs cross the placenta to a certain extent Some accumulate in the placenta itself at levels that can even exceed those in maternal plasma Drug transfer across the placenta depends on the drug’s: Lipid solubility Extent of plasma binding Degree of ionisation Tetro, N., Moushaev, S., Rubinchik-Stern, M., & Eyal, S. (2018). The Placental Barrier: the Gate and the Fate in Drug Distribution. Pharmaceutical research, 35(4), 71. https://doi.org/10.1007/s11095-017-2286-0 Members of the ABC family of transporters limit the entry of drugs and other xenobiotics into the fetal circulation via vectorial efflux from the placenta to the maternal circulation. The fetal plasma is slightly more acidic than that of the mother (pH 7.0–7.2 vs. 7.4, respectively), so that ion trapping of basic drugs occurs. 24  Bone Certain drugs accumulate in bone by adsorption onto the bone crystal surface and eventual incorporation into the crystal lattice Tetracycline antibiotics Heavy metals Can be a reservoir for the slow release of toxic agents E.g. lead or radium Effects thus can persist long after exposure has ceased Therapeutic advantage of adsorption of drug onto the bone crystal surface and incorporation into the crystal lattice E.g. treatment of osteoporosis with bisphosphonates Goodman & Gilman's: The Pharmacological Basis of Therapeutics – Chapter 2 The accumulation of tetracyclines in bone is the reason for their contraindication during pregnancy and in children 0.55L/kg). Such drugs are not efficiently removed from the body by haemodialysis Rang & Dale’s Pharmacology. 2023. Chapter 9. – page 136 Total body water represents about 0.55 L/kg. This approximates the distribution of many drugs that readily cross cell membranes, such as phenytoin and ethanol. The binding of drugs outside the plasma compartment, or partitioning into body fat, increases V d beyond the volume of total body water. Consequently, there are also many drugs with V d greater than the total body volume, such as morphine, tricyclic antidepressants and haloperidol. Such drugs are not efficiently removed from the body by haemodialysis, which filters blood plasma and is therefore unhelpful in managing overdose with such agents. 30  Volume of distribution Volume of distribution of some drugs: Heparin Vd = 0.07L/kg Warfarin Vd=0.14L/kg Aspirin Vd = 0.17L/kg Amoxicillin Vd = 0.3L/kg Valproic acid Vd 0.1 – 0.4L/kg Paracetamol Vd = 0.9L/kg Diazepam Vd = 0.8-1 L/kg Fluoxetine Vd = 20-42L/kg Rang & Dale’s Pharmacology. 2023. Chapter 9. – page 136 Total body water represents about 0.55 L/kg. This approximates the distribution of many drugs that readily cross cell membranes, such as phenytoin and ethanol. The binding of drugs outside the plasma compartment, or partitioning into body fat, increases V d beyond the volume of total body water. Consequently, there are also many drugs with V d greater than the total body volume, such as morphine, tricyclic antidepressants and haloperidol. Such drugs are not efficiently removed from the body by haemodialysis, which filters blood plasma and is therefore unhelpful in managing overdose with such agents. 31  Checklist Can you...  Describe the distribution of drugs around the body, including the blood brain barrier, chemoreceptor trigger zone, adipose tissue, placenta, bone and liver, as well as the factors that influence drug distribution?  Describe plasma protein binding, the factors affecting the binding of drugs to transporter proteins in the blood, and how the unbound portion is pharmacologically active?  Explain how 2 drugs with affinity for the same binding sites on transport proteins may affect the concentration of one or the other and the possible clinical consequences thereof?  Describe volume of distribution and the free water and extracellular compartments which drugs can distribute into? Did you...  Complete The Attendance Register? 32  References Brenner and Steven’s pharmacology. 2023. Chapter 2 Pharmacokinetics or what the body does to the drug. Page 11- 26. Rang and Dale’s pharmacology. 2024. Chapter 9 Absorption and distribution of drugs. Page 123-139. 33  Feedback Please be kind enough to take a minute and rate this lesson and provide a little feedback to help us gain a better understanding of your learning experience. Let us know what you really enjoyed and what we can do better for you. Click on the link at the bottom of the lesson page on I-learn to provide feedback for this lesson. +- (2mins) 34 35 36