2nd Week-Pharmacology I-ADME-PDF

ADME Dr. Oğuzhan Aydemir E mail: [email protected] 12th of October, 2023 Transport of Drugs Through Biological Membranes The aim of drug therapy is to diagnose, prevent, treat or control various diseases. In order for the drug t...

ADME Dr. Oğuzhan Aydemir E mail: [email protected] 12th of October, 2023 Transport of Drugs Through Biological Membranes The aim of drug therapy is to diagnose, prevent, treat or control various diseases. In order for the drug taken into the organism by any route to have an effect, it must be absorbed from its location, mixed into the bloodstream, and reach the target organ. 2 Structure of Biological Membranes Biomembranes are a selective semi-permeable membrane that separates the cell from the external environment or is composed of cellular components. Membranes are largely composed of a double layer of lipids, including phospholipids, cholesterol, glycolipids, glycoproteins, carbohydrates, and proteins. Lipids provide cell membranes with a fluid and lipophilic (hydrophobic) character. Proteins embedded in the lipid bilayer play a role in transporting most ions and water-soluble molecules across the membrane. 3  Passive (Simple) Diffusion Membrane Active Transport Transport Facilitated Diffusion Endocytosis and Exocytosis 4 Transport Mechanism Energy Satisfiability Transporter Protein Passive Diffusion Facilitated Diffusion Active Transport 5 Parts of Pharmacokinetics: Metabolism Distribution (biotransformation) Elimination Absorption (excretion) Pharmacokinetics generally consists of 4 parts: 1- Absorption Events such as absorption, distribution, metabolism, and elimination require the entry of drug molecules into target cells and their passage across biological membranes. ADME (Absorption-Distribution-Metabolism-Elimination) determines the concentration of a drug at the site of action. Absorption means that drugs pass from the site of administration into the systemic circulation. The factors on the rate of absorption, in other words, the amount of drug absorbed per unit time: A. Drug-related factors B. Biological factors related to the site of delivery 7 1. Drug-related Factors (Physicochemical Properties of the Drug Molecule) 1a. Molecule Size Molecular size and absorption rates of drugs show an inverse relationship. (Molecule size↑ Absorption ↓) Some small molecules can be made larger by adding special ester structures. The most commonly used ester for this purpose is the cypionate ester. Especially in hormone preparations, this ester is frequently used. (e.g. estrogen cypionate, testosterone cypionate) Some very large molecules cannot cross membranes at all. (e.g. dextrans, heparin…) 8 1b. Lipophilicity A measure of the tendency of a drug to dissolve in the lipid environment of the cell membrane is the lipid/water partition coefficient. «concentration of drug dissolved in lipid phase/ concentration of drug dissolved in water phase» Drugs exist in 2 states: ionized and non-ionized. Ionized drug molecules are very insoluble in lipids; therefore, they are not absorbed or hardly absorbed. The passage of drugs across biological membranes is inversely proportional to their degree of ionization in aqueous media. The non-ionized form of drugs in aqueous media is lipophilic. Acidic drugs are non-ionized in acidic media and basic drugs are non-ionized in basic media, in other words, their absorption is higher. 9 1. Drug-related Factors (Physicochemical Properties of the Drug Molecule) 1c. Physical Properties of the Pharmaceutical Form of the Drug Absorption of a drug in solution form is faster than in suspension or emulsion form. Drugs in a solid pharmaceutical form such as tablets and dragees need to be disintegrated (disintegration = crumbling) and then dissolved in gastrointestinal fluids (dissolution) before absorption. 1d. Particle Size The crystal or particle size of the drug changes the rate and extent of absorption from the gastrointestinal tract because it affects the dissolution rate. Reducing the crystal or particle diameter (microcrystallization or micronization) significantly increases the dissolution rate and absorption of poorly water-soluble drugs. 10 1. Drug-related Factors (Physicochemical Properties of the Drug Molecule) 1e. Cyrstal Form Some drugs have more than one crystal form (polymorphism) Available in stable, metastable, or amorphous forms. Absorption rates: Amorphous > metastable > stable 1f. Ionization Most drugs are weak acids or weak bases. pKa (ionization constant): The pH at which the ionized and non-ionized forms of drug molecules are equal. The pKa value affects drug absorption. This ratio is calculated by the Henderson-Hasselbach equation. 11  Ion Trap Ion trapping is the phenomenon of a drug being distributed between two compartments separated by a semipermeable membrane and accumulating on the side where it is more ionized due to the pH difference. The most common situation where ion traps are utilized is drug poisoning. 12 1. Drug-related Factors (Physicochemical Properties of the Drug Molecule) 1g. Drug Concentration Absorption is usually faster if the concentration of the drug at the site of administration is higher. 1h. Pharmacological Properties of the Drug The pharmacological properties of a number of drugs affect the rate of absorption. For example: Vasoconstrictor drugs reduce their own absorption by decreasing the blood flow through the site of administration. On the other hand, vasodilator drugs are the opposite, they are rapidly absorbed and accelerate the absorption of the drugs administered together with these drugs. 13 2. Biological Factors Related to Site of Delivery 2a. Tissue Perfusion The absorption rate is reduced in conditions that cause decreased blood flow (such as shock, hypotension, congestive heart failure, myxedema, and arterial occlusions). 2b. Width and Transmittance of the Absorbing Surface Absorption is faster when the drug is applied to a larger surface area. For example: Mucous membranes are more permeable than skin. The mucosa of the small intestine provides a larger surface area for the drug than the mucosa of the mouth, stomach, and rectum, so absorption is faster and greater there. 14 2. Biological Factors Related to Site of Delivery 2c. Contact Time of the Drug with the Absorption Area Conditions that delay gastric emptying (atropine) reduce drug absorption. This is because the drug cannot reach the intestines, which provide a large absorption area, and it is degraded in the stomach. Drugs that accelerate gastric emptying (metoclopramide) increase the absorption of acidic and basic drugs. In diarrhea, the passage through the intestine is accelerated and absorption is reduced. 15 2- Distribution After the drug is absorbed from the site of application, it is distributed first into the bloodstream and then into the tissues and organs. Absorbed drug passes into; Blood  tissue  capillary  out of the vessel  interstitial fluid or cell. This is called distribution.  Distribution The passage of drugs from the blood in the capillary network to the interstitial fluid depends on the rate of blood flow through the organ or structure. Heart, lung, kidney, liver are the structures with more blood supply fat, skin tissues, bones are the structures with less blood supply! Body Fluids 75% of body weight is water. The physiological fluid compartments in which the drug is distributed mainly divided into 2 main groups: extracellular and intracellular. I. EXTRACELLULAR FLUID COMPARTMENT II. INTRACELLULAR FLUID COMPARTMENT -PLASMA: Approximately half of the blood volume, 41% of body weight 4% of body weight -INTERSTITIAL FLUID: Intercellular fluid+BOS 13% of body weight Distribution of Drugs After the drug passes from the blood to the interstitial fluid, it passes first to the extracellular fluid and then to the intracellular fluid. Passage from blood to other body fluids occurs by passive diffusion. Distribution of Drugs The distribution of drugs between blood and other body fluids ends when diffusion equilibrium is reached, in other words, when there is equal exchange between the two compartments. When diffusion equilibrium is reached, there is a certain ratio between plasma and body fluids, but this does not mean that the drug concentration in the different compartments is equal.  Distribution of Drugs The main factors that cause drugs to be distributed at different rates in different tissues: Tissue perfusion rate Degree of ionization: According to the pH distribution hypothesis, the drug will accumulate on whichever side is more ionized. Affinity of the drug for tissue components: Intrinsic property of tissue = ability of tissue to absorb drug from blood Binding to plasma proteins  Drug Binding to Plasma Proteins Drugs bind to PLASMA PROTEINS at different rates in the blood. Binding is; reversible and non-selective directly proportional to affinity for the drug. Major proteins with drug binding properties: Albumin: acidic drugs ⍺1-acid glycoprotein: basic drugs (quinidine, imipramine, propranolol, chlorpromazine...) Globulins Lipoproteins  Drug Binding to Plasma Proteins Binding is represented as a percentage (%). Drugs with high binding to plasma proteins have a longer duration of action. Binding rate affected by: Affinity, Protein concentration, Number of attachment sites Drug concentration.  The drug which bound to plasma proteins is inactive. It cannot cross body membranes. Drug Binding to Plasma Proteins Therefore, it cannot pass into other body fluids (the dispersed drug is free drug). It does not undergo glomerular filtration. Drug Binding to Plasma Proteins The binding rate is a known constant value for drugs. Drug binding is not saturated in the presence of therapeutic concentrations of drug. BUT, A small number of drugs have saturated binding sites on plasma albumin at therapeutic concentrations (50-60%).  Drug Binding to Plasma Proteins This phenomenon determines the; the severity of distribution of their elimination the drugs in the and, pharmacological body, effect.  Drug Binding to Plasma Proteins The part of the drug that passes from the blood into the extracellular space is the free fraction. There is an equilibrium between the free drug fraction that passes into the interstitial fluid, and the free drug fraction that remains in the plasma. In the equilibrium state, the concentration of these two fractions is equal. Transmission of Medicines to the CNS The CNS is a structure with a lot of blood supply. BUT; the brain protects itself against the effects of drugs. BLOOD BRAIN BARRIER However, lipophilic drugs pass easily into the CNS. In conditions such as meningitis, the permeability of the blood-brain barrier increases.  Sequestration Sequestration is the tight binding of drugs to certain intracellular or extracellular structures in tissues. TISSUES ACT AS DRUG STORES. As a result of sequestration; -Unequal distribution between tissues -Late onset of effect Accumulation in adipose tissue !!! Barbiturates with short and very short duration of action (thiopental): Accumulate in the CNS and adipose tissue. Mepacrine: accumulates highly in the liver. Tetracyclines: Accumulates in bone and teeth by chelation with calcium.  Redistribution Drugs that are too liposoluble (general anesthetics, thiopental...) initially pass into tissues such as the brain, heart and kidneys due to their high blood supply. Then, it finds the opportunity to be distributed to less blood-supplying structures such as adipose tissue and muscle tissue over time with the circulating blood. Redistribution is an event that causes the drug to move away from the site of action and ends the effect. Transfer of Drugs from the Placenta to the Fetus The passage through the placenta occurs by passive diffusion. During pregnancy, any foreign substance, including drugs, should be chosen very carefully and should be taken under the supervision of a physician, because they can affect the fetus and have a harmful (teratogenic) effect. 31  Virtual Distribution Volume Virtual Distribution Volume (Vd) is defined as the total amount of drug in the body divided by its concentration in plasma. Thus, Vd reflects the degree to which the drug is present in extravascular tissues rather than in the plasma. Amount of drug in the body ( administered amount) Vd= Blood concentration (C) 3- Metabolism (Biotransformation) of Drugs Biotransformation (metabolism of a drug) is the process by which drugs undergo chemical changes through the action of enzymes. As a result of biotransformation, drugs are often converted into less effective or ineffective compounds. Thus, biotransformation is a bioactivation event in terms of its reflection on efficacy. Biotransformation is also called detoxication.  Bioactivation  Sometimes drugs are biotransformed into more potent (codeine to morphine) and/or more toxic (methyl alcohol to formaldehyde and formic acid) compounds. Pre-Drug = Inactive precursor = Prodrog Sometimes, an ineffective compound is converted into an effective compound by biotransformation in the body. Local application Cortisone INACTIVE!!! and Prednisone LIVER Systemic application Hidrocortisone Cortisone and and Prednisolone Prednisone  Why Prepare a Pre-Drug? Some drugs are formed into prodrugs to regulate certain physicochemical and pharmacokinetic properties. (i) For increased gastrointestinal absorption Ex: By converting ACE inhibitors into lipophilic prodrugs (ii)To slow the absorption of the drug at the site of administration and prolong the duration of action of doses Ex: Some steroid hormones can be given together with inert substances. (iii) To mask the unpleasant qualities of the drug during oral intake Ex: Chloramphenicol palmitate Hydrolysis Intestine Chlorampheni 36  Metabolism (Biotransformation) of Drugs METABOLITE: The compound into which the drug is transformed as a result of biotransformation.  The metabolite of the drug can be re-biotransformed.  Not all of the drug is usually biotransformed, some of it is excreted unchanged by the kidneys.  Most of some drugs are excreted unchanged (nitrogen protoxide, furosemide...). 37  Metabolism (Biotransformation) of Drugs Some metabolites of drugs are active metabolites. Sometimes the active metabolite may be more active and longer-acting than the main compound. As a result of biotransformation, not only the efficacy of drugs changes but also their pharmacokinetic properties. 38  Metabolism (Biotransformation) of Drugs As a result, drugs become more polar, their lipid/water partition coefficients decrease, their water solubility increases and they are more easily excreted from the body. The half-life of metabolites in the blood is usually shorter than that of the main compound. 39  Metabolism (Biotransformation) of Drugs Some biotransforming enzymes are found in all cells. Most of them are found specifically in certain organs (liver, blood, GI mucosa and lumen, kidney, lung, and other structures). The organ that plays a leading role in metabolism is the LIVER. 40  Hepatic Clearance The hepatic clearance of a drug can be defined as the volume of blood that is cleared of the drug by the liver per unit of time. 41  4- Elimination (Excretion) The kidneys are the most important organs involved in the elimination of drugs from the body. Gases and volatile liquids are excreted through the lungs. The half-life (t1/2) of a drug is the time it takes for the amount of a drug's active substance in your body to reduce by half.  Renal Excretion 2. Tubular Secretion 1. Glomerular 3. Tubular Filtration Reabsorption Renal excretion occurs in 3 ways:  Glomerular Filtration Glomerular filtration is a passive diffusion event that occurs very rapidly because of; Glomerular endothelium contains a large amount of intercellular pores, the presence of approximately 1,000,000 glomeruli in the renal cortex and the high rate of blood flow through the glomeruli.  Tubular Secretion This is an active transport event. It occurs mostly in the proximal tubules. In tubule cells, there are two different types of transporters specific for anionic (acidic) and cationic (basic) drugs. A cationic drug can inhibit the secretion of another cationic drug from the tubules. An anionic drug may inhibit the secretion of another anionic drug from the tubules.  Tubular Reabsorption It is a phenomenon that tries to reduce the extraction. It usually occurs by passive diffusion. A few substances or metabolites are reabsorbed by active transport. Reabsorption by active transport usually occurs in the proximal tubules. Urine is formed in the nephron as a result of glomerular filtration, tubular secretion, and tubular reabsorption.  Renal Clearance It is a term that refers to the body's clearance of a drug. Renal clearance is the volume of plasma cleared of an unmetabolized drug in one minute by renal excretion. It is affected by the rate of binding to plasma proteins and the rate of reabsorption from the tubules.  Excretion from the Liver into the Bile Drugs and their metabolites are secreted by liver cells into the bile ducts and transported into the small intestine, excreted in feces. Excretion into bile is mainly by passive diffusion and active transport. Sometimes drug molecules can be reabsorbed here. This is called the "enterohepatic cycle". It is a phenomenon that prolongs the duration of the action of drugs. Enterohepatic Cycle  Excretion from the Lungs Gases and volatile substances with small molecules and high lipid/water partition coefficients can cross the alveolar membrane and pass into the alveolar cavity. For example, nitrogen protoxide used for general anesthesia is expelled by expiration in air. This transfer occurs by passive diffusion.  Other Ways of Extraction Salivary glands excrete iodides, bromides, lithium, heroin, and amphetamines (passive diffusion). Glands in the intestinal mucosa excrete various lipophilic drugs, iodides and bromides (passive diffusion). Iodides and bromides are excreted through tears and sweat glands. Excretion in milk is also important for breastfeeding women because of the pass the drugs they take to their babies. Alcohol is also largely excreted in milk.