Pharmacokinetics Lecture Notes PDF

Pharmacokinetics Pharmacokinetics: is the branch of pharmacology which studies the effect of the body on the drug  For an administered drug to exert a pharmacological effect at the site of action, it must pass four essential pathways of drug movement and modification in the body (ADME) Ab...

Pharmacokinetics Pharmacokinetics: is the branch of pharmacology which studies the effect of the body on the drug  For an administered drug to exert a pharmacological effect at the site of action, it must pass four essential pathways of drug movement and modification in the body (ADME) Absorption  drug enters the body and reaches the bloodstream. 1 Distribution  drug transfers to 3 different body tissues 2 Metabolism  How drug is changed by the body Excretion  The route by which drug, or its metabolites, leave the body 4  1) Absorption Absorption is the process which means the transfer of the drug from site of administration to blood. Drug absorption requires passage of the drug through various cell membranes Transmembranal Linear glycoprotein protein Peripheral protein Hydrophilic Surface phosphate protein head Oily non- polar core  Types of drug passage through cell membrane  Rate of drug transport through cell membranes depends on Drug lipophilicity and Drug concentration  The rate of passage of the drug is directly proportional to the concentration gradient of the drug across cell membrane.  Transfer of drug occurs till equilibrium a- Passive diffusion:  Is the most common mode of drug transport.  Drug is lipophilic  Drug transports according to gradient of concentration from  to  conc. b- Carrier-mediated transport (Facilitated) :  Drug transports according to gradient of concentration from  to  conc.  Drug is not lipid soluble  This type of transport needs Carrier but does not need energy C- Active transport :  Transport of substance across the phospholipid layers of the cell membrane goes against concentration gradient.  Energy is required. d- Para cellular transport :  This is diffusion and transport of the drug molecules (low size) and accompanying water across narrow junctions between cells or trans-endothelial channels. e- Vesicular transport:  This is the process of engulfing particles or dissolved materials by a cell. This includes: 1. Phagocytosis: which is the engulfment of large particles or macromolecules, usually by phagocytes 2. Pinocytosis: which is the engulfment of small solutes or fluids. 3. Endocytosis: which is the movement of macromolecules into of the cell. 4. Exocytosis: which is the movement of macromolecules out of the cell.  Factors affecting drug absorption Drug Body (host) 1. Drug molecular weight 1. Blood supply 2. Drug formulation 2. Gastric emptying rate (GER) 3. Drug combination: 3. Intestinal motility (peristalsis) ex: Vit C  absorption of Iron 4. Diseases: 4. Drug route of administration 5. Drug polarity and lipophilicity 6. Drug acid base nature  Factors due to body 1. Blood supply:  The  in blood supply to the site of administration   drug absorption and vice versa  Local anesthetics is preferred to be applied together with a vasoconstrictor like adrenaline????????? 2. Gastric Emptying Rate (GER)  Normal physiological process meaning Rate of transfer of gastric content from stomach to duodenum (normally, this occurs a few hours after eating)  It can be delayed or accelerated by certain conditions, such as diabetes, gastric ulcers, or neurological disorders. 3. Intestinal motility  The movement of food or intestinal content from small and large intestines to be expelled out of the body.  Factors due to drug 1. Drug molecular weight: 2. Drug formulation 3. Route of administration  Different routes of drug administration differ in drug bioavailability (rate and extent of drug absorption)  This may dramatically modify drug onset, drug effect and duration of action  There is a difference between the route of drug administration which may be (enteral, parenteral or topical) and the obtained action which may be (local or systemic). 4. Drug Polarity and lipophilicity  Drug Polarity (lipid/water partition coefficient)  Drug polarity is the ratio of the lipid-soluble portion to the water-soluble portion of the drug when distributed between water and an immiscible lipid. Non polar drugs Polar drugs Lipophilic Lipophobic Hydrophobic Hydrophilic Highly absorbed Poorly absorbed - Drug absorption from GIT - Weak GIT absorption - Blood brain barrier (BBB) - Cannot pass BBB - Placental barrier (PB) - Cannot pass PB - Reabsorption in the kidneys - Easily excreted Water or lipid solubility is a physical character which can affect drug kinetics (Absorption – Distribution – Metabolism – Excretion) but it has no effect on drug activity 5. Drug acid/base nature (effect of pH)  Most drugs are weak acids, weak bases or salts of either of them.  They become ionized or nonionized according to the pH of the medium around them weak acids drugs weak bases drugs example Morphine / acetylsalicylic acid amphetamine Acid media less ionized highly ionized more lipid soluble less lipid soluble Basic media highly ionized less ionized less lipid soluble more lipid soluble  pKa of drug   pKa: is the pH at which drug (50% ionized) and (50% non ionized). pKa of aspirin=3.5 pKa of amphetamine=10 - Drugs with low pKa is (acidic) and drugs with high pKa is (basic)  pKa is a constant value but it helps to illustrate drug dissolution in different pH media Aspirin in acid media (stomach) present highly in non-ionized form  highly absorbed Aspirin in alkaline media (intestine) present highly in ionized form  poorly absorbed Amphetamine in acid media (stomach) present highly in ionized form  poorly absorbed Amphetamine in alkaline media (intestine) present highly in non-ionized form  highly absorbed  Ion trapping  - Ion trapping: is the accumulation of drug across cell membrane due to 1- the pKa value of the drug 2- difference of pH across cell membrane Aspirin is not administrated on empty stomach or during lactation?????????????????  In the stomach:  Aspirin is more absorbable in stomach cells but once entered the cells, the pH changes from 1.5 outside to 7.4 inside the cell.  Aspirin become ionized inside cells and can not diffuse outside again  gastric ulcer  During lactation: pH of breast milk 7  Bioavailability  The of rate and extent (amount) of drug reached the systemic circulation after administration (Biological available for action).  Bioavailability affected by routes of administration and drug absorption.  Bioavailability calculated on time conc curve.  Selected dose of a drug injected iv (red curve)  Then you inject the same drug with same dose but with other route (blue curve) (AUC) oral = ------------ (AUC) iv  Oral bioavailability of drug 70% what does it mean????  Is it possible that oral bioavailability of drug >100% ??????  Why oral dose of a drug differ than iv dose of the same drug ?????  Doses of the same drug may differ according to dosage form ????  What is the difference between drug has low bioavailability and a drug its bioavailability decreased by other factor ????  2) Distribution  It is the process which represent the dispersion of the drug from the blood to the body cells  It is the process by which the drug reversibly leaves the blood stream to enter interstitium and/or body cell Plasma protein binding Volume of distribution  Plasma protein binding  After drug reaching the blood, it binds to plasma protein Albumin is the major plasma protein to which drugs bind. However, other plasma proteins like α1-glycoprotein are important in binding basic drugs like propranolol After binding, the drug is present in two forms a. Bounded form: pharmacologically inactive b. Free form: pharmacologically active  There is a balance between free and bound form of drug in blood  According to plasma protein binding, drugs are classified into a. Highly plasma protein binding drugs b. Low plasma protein binding drugs Characters of highly plasma protein binding drugs They are highly absorbed drug ????  Long duration: protein binding prolongs the action of the drug due to the presence of a bound form of the drug in equilibrium with the free form Drugs bound to plasma proteins become unable to penetrate the tissues because of large size (low Vd)   absorption -  T half /  Elimination -  Vd Clinical significance 1. Displacement reaction:  drugs with high plasma protein binding can displace other drugs causing an increase in the free form of the drug that may lead to drug toxicity  Highly bound drug  Narrow therapeutic index drugs Warfarin and salicylates take care????? 2. Hypoalbuminemia:  clinical case means a significant  in albumin conc in the blood which cause:   in the bounded form   the free form ratio of the drug that lead to drug toxicity  Volume of distribution  It is the apparent volume of fluid (water) into which the drug is distributed in the body after distribution equilibrium  Body fluid (Water) compartment (42 L) 3 1 2 2 3 1  Calculation Drug A Drug B Drug C 500 500 500 = ------ = 5 = ------ = 10 = ----- = 500 100 50 1  It is a theoretical value The VD of a drug represents the degree to which a drug is distributed in body tissue rather than the plasma.  A higher Vd indicates a greater amount of tissue distribution 1. Heparin  If the drug has a very large molecular weigh or binds extensively to plasma proteins: a) it is too large to move out of blood vessel b) It is trapped within plasma (vascular) compartment (6% - 4L) 2. Aminoglycosides  If the drug has a low molecular weigh but is hydrophilic: a) it can move through BV into the interstitial fluid b) it can not move across the lipid membranes if cells c) This drug distribute into a volume that is the sum of the plasma water and interstitial fluid (extracellular fluid=20% - 14L) 3. Ethanol  If the drug has a low molecular weigh and is lipophilic a) It can move through BV into the interstitial fluid b) It can move also across the lipid membranes of cell c) This drug distribute into a volume about 60% 42L Factor affecting Volume of distribution:  Drug size  Plasma protein binding (affecting drug size)  Diffusion drug lipophilicity  Perfusion: blood supply (liver < skin < bone)  Tissue affinity: (Iodine + thyroid)(Tetracycline + Ca)  Non polar drugs or low plasma protein binding capabilities have higher volumes of distribution  Volume of distribution may be increased by 1- Renal failure (due to fluid retention) 2- Liver failure (due to altered body fluid and plasma protein binding).  Conversely it may be decreased in dehydration Clinical significance 1- Hemodialysis in drug toxicity - Vd < 5L: drug is distributed in blood and can be removed by dialysis - Vd > 42L: drug is highly bounded to tissue protein and cannot be removed by dialysis - Vd 5-42L: means that the drug is restricted to EC 2- Detection of drug loading dose = Vd X plasma conc 3- Detection of t 1/2 a. Tissue accumulation  Drugs may accumulate in tissues based on their physicochemical characters or special affinity of the tissue for the drug.  Adipose tissue is an important reservoir for lipid-soluble drugs (thiopental).  Bone can be a reservoir for slow release into the blood of toxic agents such as lead. b. Penetration of the blood brain barrier (BBB):  The capillaries of the brain has no pores  They are surrounded by a thick lipid membrane layer create what is called BBB  Only lipophilic drugs can pass this barrier readily c. Placental barrier  The maternal and fetal blood are separated by what is called blood placental barrier.  Lipid-soluble drugs pass readily to the fetus while water- soluble drugs, specially large molecular weight drugs, pass slowly. d. Redistribution  Termination of drug action is usually produced by drug biotransformation or excretion. However, drug redistribution may terminate drug effect.  For example, the highly lipid-soluble ultra-short acting barbiturate (thiopental) rapidly penetrates the blood brain barrier causing CNS depression. However, the drug rapidly redistributes from the site of action to adipose tissue resulting in rapid fading of the effect.