1.1 Background: What are Drugs
1.1.1 Drugs
Drugs are largely small, exogenous molecules, often less than 1000 Dalton (D or Unified Mass Unit=1/12th themass of a carbon atom), that can beneficially interfere with the physiological processes, especially in disease conditions. There are some macromolecules like insulin and growth hormone that are used in disease conditions (diabetes and growth hormone defficiency respectively). These molecules are endogenous to the body and are used in replacement therapy when the body is unable to produce enough of these molecules as per the need. Thus, these molecules should not be confused with drugs.
Monoclonal antibodies (mABs) are a new class of compounds that are increasingly being used as drugs. There are approximately 100 mABs that are designated and approved as drugs as of now (Manis, John P., 2021). Immunoglobulin molecules (antibodies) are proteins that are produced by the body’s immune system to fight off invasion of the body (infection). The production of antibodies is triggered by the presence of foreign molecules in the blood stream. Most natural antibodies are polyclonal in nature. It means that they are not identical in size, amino acid sequence and are produced by different B lymphocyte cells of the immune system. mABs, on the other hand, are homogeneous preparations of antibodies (or their fragments). Every mAB molecule in the product is identical in size, amino acid sequence and thus in functionality i.e. biological effects as a drug. mABs are usually very large molecules, ranging from a few thousand D up to millions of D, though most mABs range about 150 Kilo D. They are used in a large variety of conditions including infections, solid tumors, leukemea and autoimmune diseases. The names of mABs have three parts; prefix-infix-suffix. The prefix is random and designed to give a unique drug name. The infix (middle part) indicates the intended target (for example: ‘ci’ for cardiovascular, ‘so’ for bone and ‘tu’ for tumor) and the suffix is always mAB, to indicate the drug as a separate class. This discussion on monoclonal antibodies is to make sure that a contemporary pharmacy student does not assume that a drug is always a small molecule. The physico-chemical properties of the small molecules in vitro and their behavior in vivo are significantly different from those of the macromolecules (like mAbs).
Figure 1.1:
Mechanisms underlying the therapeutic efficacy of mAb-based immunotherapy. (a) mAbs can induce signaling inhibition and lead to apoptosis in targeted tumor cells by binding with their specific receptor, inducing modulation of the receptor or interfering with ligand binding and/or dimerization of the receptor. (b) The Fc region of an antibody recognizes the Fc gamma receptors (FcγR) on the surface of immune effector cells, while the Fab domain specifically bounds to a target cell. The FcγR ITAM is then phosphorylated, triggering the activation of the effector cell. (c) C1q binds to the antibody, triggering the complement cascade that leads to the formation of the membrane attack complex (MAC) (C5b to C9) on the surface of the target cell as a result of classic pathway complement activation.
1.1.2 What Do the Drugs Do
Drug molecules, also called Active Pharmaceutical Ingredients (APIs), once they are introduced to the body, get distributed throught the body through systemic circulation. Once they reach the designated site in the body where the problem is, drugs exert their effect. The area of the body where a particular disease or condition exists and where the API is designed to act on is called site of action. Once the API reaches the site of action, it binds to an endogenous macromolecule called receptor. The binding usually occurs through reversible intermolecular forces like hydrogen bonding, Van-der Waal’s forces. The receptor molecule is usually a large protein molecule that is capable of entering into these intermolecular interactions and they change their three dimentional conformation because of and due to the binding. The overall result of this binding process is initiation of a cascade of events like production and/or release of neurotransmitters, hormones and/or enzymes. This cascade of events is responsible for the beneficial change in the body (pharmacological effect) for which the API is used. It is to be appreciated that an API produces more than one effect once introduced to the body; one of them is the intended effect (pharmacological effect), while all other unintended effects are called side effects (toxicological effect).
The site of action is the general location of the receptors for the API in an organ or tissue of the body. The receptors can be on the cell membrane, in cytoplasm or in the nucleus of the cell. They can be static on an organ or tissue, or they can also be in the white blood cells (as in the case of many mABs). APIs can also show their pharmacological effect by interactiong with the DNA (in the nucleous of the cells) or RNAs. The APIs have to get distributed throughout the body to reach the site of action. The physical and chemical properties of the API are important in determining drug distribution in the body. The polarity, the ionic behavior (acidity, basicity, pKa etc.) in the body, the partition coefficient, complexation nature of the API are the most important physico-chemical properties that determine the drug distribution in the body. In addition to the drug potency, the drug distribution characteristics are also very important factors that determine the effectiveness and extent of clinical use of the drug.
Drugs circulate through the body (Distribution phase) until they find a receptor with a matching structural shape.
When the drug binds to the receptor, it changes the cell's activity. This "lock and key" fit triggers biochemical signals.
1.2 The Body
1.2.1 Body, Tissue and the Cells: the Environment
The human body is made up of cells. Neighboring cells with a similar function make a tissue. Each tissue has a small but well-defined role in the body. For example, epithelial tissue makes the boundary of a tissue and separates different tissue layers and organs in the body. Many different neighboring tissues often execute one bigger function of the body. These functional units of the body are called organs. For example, kidney, heart, liver, lung and skin are all organs with very well-defined functions in the body. Cells of all these organs are supplied with nutrition and oxygen and cleared off of their metabolic byproducts by the circulatory and lymphatic systems which are themselves considered organ systems. Just like nutrients and oxygen, drugs get distributed throughout the body through the circulatory system.
About 60% of the human body is composed of water. That is why the microenvironment of the body is reasonably polar, though there are reasonably non-polar regions like the brain and adipose tissue in the human body too. Most molecules that have an important role in the body are reasonably polar. Reasonably polar molecules can get dissolved in the body fluids and get carried through the circulatory system to their site of action more efficiently. The physico-chemical characteristics like polarity etc. of all molecules, including the drug molecules, are thus very important to ensure that the molecules can contribute effectively in the functioning of the body. These physico-chemical characteristics include solubility (in water), ionization, acidity or basicity, pKa, oil-water partition coefficient and diffusional mass transfer rate (coefficient of diffusion). Additionally, when the molecules move out of the circulatory system and penetrate through the tissue mass, they have to move through multiple barriers. These barriers include the epithelial lining of the circulatory system and each individual tissue and organ and then the cells of the tissues. All these barriers primarily consist of the plasma membrane of the cells. It is thus important to understand the basic structure of the plasma membrane.
1.2.2 The Plasma Membrane
Plasma membrane is the outer layer of the animal and human cells. This layer provides the structural integrity to the cell and it also controls the movement of molecules in and out of the cell in a selective manner.
Plasma membrane is the outer layer of the animal and human cells. This layer provides the structural integrity to the cell and it also controls the movement of molecules in and out of the cell in a selective manner. Plasma membrane is primarily made up of phospholipids arranged in a certain manner. The individual phospholipid molecules are not covalently bonded to one another; they remain as a structural unit by intermolecular forces of attraction. In chemical terms, a lipid is a relatively hydrophobic (non-polar) molecule that is an ester or a potential ester; like a fatty acid or a higher aliphatic alcohol and an ester of the two. A phospholipid is a molecule that contains at least one phosphate group (usually) attached to the lipid molecule through a glycerol molecule. Phospholipid molecules are amphiphilic molecules, which means that the molecules have both a strong polar region and a non-polar region. The phosphate groups of the phospholipid molecules are strongly polar and are depicted by round heads (figure 2), while the long lipid parts of the molecules are strongly non-polar and are depicted as tails in biology. In a polar microenvironment like that in human cells the phospholipid molecules arrange themselves as a lipid bi-layer in such a manner that the hydrophobic tails interact with hydrophobic tails of the neighboring phospholipid molecule and/or that of the neighboring phospholipid layer (figure 2). Despite having no covalent bonding, this phospholipid bi-layer arrangement is thermodynamically stable and constitutes the least energy state because of a simple principle of ‘like dissolves like’.
The human body is made up of cells. Neighboring cells with a similar function make a tissue. Each tissue has a small but well-defined role in the body. For example, epithelial tissue makes the boundary of a tissue and separates different tissue layers and organs in the body. Many different neighboring tissues often execute one bigger function of the body. These functional units of the body are called organs. For example, kidney, heart, liver, lung and skin are all organs with very well-defined functions in the body. Cells of all these organs are supplied with nutrition and oxygen and cleared off of their metabolic byproducts by the circulatory and lymphatic systems which are themselves considered organ systems. Just like nutrients and oxygen, drugs get distributed throughout the body through the circulatory system.
About 60% of the human body is composed of water. That is why the microenvironment of the body is reasonably polar, though there are reasonably non-polar regions like the brain and adipose tissue in the human body too. Most molecules that have an important
Figure 1.2:
The lipid bilayer
While phospholipids provide the main structure of the plasma membrane, there are many more small molecules like cholesterol and macromolecules like proteins, glycoproteins (sugars covalently bonded to proteins), and glycolipids (sugars covalently bonded to lipids) that are embedded to the lipid bi-layer. The entire plasma membrane structure survives by thermodynamic stability without any molecular unit being covalently bonded to any other. All of these molecules have their own functions in the plasma membrane. Some of the glycoproteins on the plasma membrane function as antibody, a transporter of an enzyme or even as a biomarker in various biological processes. The surface glycolipids have a role in stabilizing the plasma membrane and also facilitate the cellular recognition for body’s own immunologic activity. Some of the plasma membrane proteins are purely on the surface, while the others run all across the membrane. The surface proteins often act as a receptor system either for transport of nutrients, small molecules or ions. The membrane proteins that run all across the membrane often act as a transport channels for ions and small molecules like glucose. Many of these proteins go into the cytoplasm during the transport process and then recycle back to the plasma membrane. This is possible as these molecular units are not covalently bonded to the lipid bi-layer and the structure persists purely by thermodynamic stability of least energy state. The fluid mosaic model of plasma membrane is so named as the entire plasma membrane is conceived as a complex mosaic of molecules. The word ‘fluid’ indicates that the molecules forming the mosaic are capable of changing their position with respect to their molecular neighbors in the mosaic.
Figure 1.3:
Simplistic representation of the plasma membrane-the fluid mosaic model
1.2.3 Transport through the Plasma Membrane
In addition to providing the structural integrity to the cells, the plasma membrane serves one more important function in the cells; the function is to be the gate keeper or filter for the cells. It is the plasma membrane that decides what nutrient molecules or ions get in to the cells and how much and at what rate. Plasma membrane also facilitates the outflow of the metabolic byproducts from the cells.
The movement of solute or suspended molecules/ions or even particles through a medium is called Permeation. As a general principle, all molecules and ions (and indeed particles) in solution or suspension, move from a region of high concentration to a region of low concentration. This process is natural and is not energy dependent. The process is called diffusion or passive diffusion. Diffusion is one mode of permeation. Each molecule or ion has a specific rate constant by which the concentration difference and the velocity of diffusional movement is related in a specific solvent system. This rate constant is called coefficient of diffusion (D). Coefficient of diffusion is a property of the solute molecule/ion in that specific solvent system. Diffusion explains the movement of molecules and/or ions in body fluids when there is no membrane involved or movement across cell membrane when it permits uninhibited movement of the solute molecule.
Permeation or trans-membrane diffusion is largely governed by two parameters; polarity and size. Small nonpolar gases like oxygen, carbon dioxide and nitrogen permeate through the plasma membrane rather fast. The permeability coefficient of uncharged molecules across the plasma membrane is largely a function of size. The permeability coefficient of uncharged molecules is inversely related to the molecular mass; it means that the bigger the molecule, the slower the permeability coefficient. The permeability coefficients of biologically relevant molecules and ions have been determined (Yang, N.J. and Hinner, M.J. 2014; Table 1). Small but relatively polar molecules like water and ethanol permeate through the cell membrane a little slower (10-3 cm/sec range). The permeability coefficient for slightly larger metabolites like urea and glycerol are a little slower (10-6 cm/sec range). Larger polar molecules and the charged ions virtually cannot permeate through the cell membrane.
Table 1.1:
Relative permeability coefficient of small molecules, ions and large molecules. Reference of article given
at the end of the chapter
Some larger molecules cross the plasma membrane through a process called facilitated diffusion. This process is similar to passive diffusion. The movement of solute molecules across the membrane in facilitated diffusion takes place from a zone of high concentration to a zone of low concentration. This process is not energy intensive either. Facilitated diffusion requires a trans membrane carrier protein (like permeases). These carrier proteins change their conformation to allow the solute molecules to pass through. Sugar molecules like glucose and amino acids cross the cell membrane through facilitated diffusion.
Permeability coefficients of ions are typically very low and they do not cross the plasma membrane through passive diffusion. Some of the ions like Na+ cross the membrane through two different mechanisms. In the first mechanism, the ion crosses the membrane through a protein channel which has an aqueous core that remains open continuously. Such channels are specific for a specific ion. This process is known as channel mediated diffusion. It is also a facilitated diffusion and is not energy intensive.
The most prevalent process of movement of ions across the cell membrane is called active transport.
Figure 1.4:
Transport modes through the plasma membrane
Figure 1.4b:
Cotransport proteins (cotransporters or symporters) are found in many different cells and tissues and
perform a variety of important physiological functions. Six examples are shown here. See text for details. Na+, sodium;
K+, potassium; Cl-, chloride; I-, iodide; Pi, inorganic phosphate.
Active transport is a process in which a transporter protein carries one or more ion(s) across the cell membrane against the concentration gradient. The active transport is an energy intensive process in which either cellular ATP is consumed or an ion moving from a high concentration zone to a low concentration zone provides the energy for the transport of another ion against concentration gradient. Membrane proteins that function as cotransporters are very common (PhysiologyWeb Team. 2011).
Figure 1.4c:
Different forms of active transport
When a molecule is too big and assumes the dimensions of a particle, these active transport mechanisms cannot cope with their transport. The trans membrane movement of material at this dimension is called vesicular transport. It is a form of active transport in which a membranous vesicle from outside the cell fuses with the plasma membrane of the cell releasing the contents within the cell (endocytosis). Vesicles are often produced within the cell and reach the plasma membrane and fuse with all their contents and release them outside the cell (exocytosis). In both cases the phospholipid molecules of the vesicles become a part of the cell membrane. Both the endocytosis and exocytosis are energy intensive processes and thus qualify as active transport mechanisms.
Transport Mechanism Video
1.3 Drug-body Interaction
1.3.1 How a Drug is Used
Drug molecules are never introduced to the body in their pure form. They are always introduced to the body as a physical mixture or solution or suspension or emulsion, loosely called formulation. Formulation of drug is necessary to
(a) dilute the small amount of drug molecules into a workable amount
(b) make sure that these formulations are chemically stable for a reasonable amount of time on the shelf before they are introduced to the patient
(c) make sure that the drug is in a physically stable form so that dose uniformity is achieved
(d) make sure that the drug is absorbed well
(e) control the onset of action
(f) control the duration of action
(g) control the release of the drug in the appropriate area of the gastro-intestinal track
(h) make sure that the drug reaches the site of action
(i) control the drug exposure to the minimum space (tissue/organ) necessary
(j) minimize dosing to improve compliance (by the patient)
The art and science of making pharmaceutical formulation to maximize benefit (pharmacological effect) and minimize harm (toxicological effect) to the patient is called pharmaceutics or the formulation science. This is an interdisciplinary area of science that utilizes an understanding of biology, and physiology (to understand the body environment), physical chemistry (to understand the behavior of drug molecules), a combination of the two (to understand how the drug behaves in the environment and how to make the formulation) and also math (to understand the contributions of each of the factors in quantitative terms). This book covers physical chemistry as applied to the drug molecules. This branch of science is called physical pharmacy. Further, this book explains the principles of physical pharmacy and the application of those principles to make formulation.
1.3.2 Properties of Drugs
The physical and chemical properties of individual drug molecules are extremely important in the context of their use of pharmacy. The most important physical-chemical properties of drug molecules in the context of their use in pharmacy include the following.
(i) Physical state (solid, liquid or gas; mostly solid)
(ii) Polymorphism (amorphous or specific crystalline form)
(iii) Solubility (in water and aqueous solvent systems), boiling point, melting point and freezing point
(iv) Rate and extent of dissolution in aqueous media
(v) Polarity and/or ionic form (whether the molecule is non electrolyte, weak electrolyte or strong electrolyte)
(vi) Partitioning and behavior at the interface
(vii) Acidity, basicity and ionization status of the drug molecule in the body pH
(viii) Chemical stability and sources of instability (oxidation, hydrolysis etc.) in vitro (outside the body)
(ix) Chemical stability in vivo (inside the body)
(x) Drug molecule interaction with the environment in the body like ionization, complexation, protein binding (complexation nature with biologically relevant protein molecules in the human body, the dose, the dosing interval among many other things.)
The above mentioned physico-chemical properties of the drug molecules combined with the drug usage determine the route through which the drug is introduced to the body, the dose and the dosing interval among many other things.
1.3.3 Major Routes of Administration and Dosage Forms
Most of the formulations are solid dosage forms like tablets, capsules and powder chart. Powder chart is a mixture of drug powder with other pharmacologically inactive powder like starch, presented in a paper sachet. It is not used very often today. These are solid dosage forms intended to be taken orally. About 80% of all drugs are given through the oral route. Liquid dosage forms like solution, suspensions, emulsions are also often used through the oral route.
Syrup is a dosage form containing saturated sucrose solution (66.5-68% w/w) containing the drug in dissolved form. Examples include antipyretics (fever reducers) like Tylenol and cough syrups like Robitussin, Delsym etc. Suspensions are two-phase systems composed of solid drug phase suspended in aqueous phase. Non aqueous suspensions are rare and used for topical application, if ever used. Some suspensions are intended for oral use. Examples include amoxicillin, doxycycline, azithromycin suspensions. The emulsions are also two-phase systems but, both the phases in this case are immiscible liquid phases (like oil and water) and the drug molecule can be dissolved in either phase or distributed in both the phases. There are only a few oral emulsions like mineral oil emulsion, and magnesium hydroxide and liquid paraffin emulsion (Nesifin) that are used for improving gastro intestinal tract (GIT) motility. Oral formulations go through the GIT and get absorbed mostly in the intestine. As a result, some drug is lost and there is a delay (1-2 hours approximately) in the onset of action. Some formulations, though given orally, are intended to be kept under the tongue (sublingual route). Drug from the sublingual tablet is supposed to get dissolved in the saliva and get absorbed to the systemic circulation through the jugular vein and to the target tissue without going through the liver (called the first pass). One advantage of the sublingual dosage form is that the onset of action is faster and the extent of absorption of the drug is higher through this route because of avoidance of first pass through the liver (called the first pass effect). Sometimes the drug dosage form is supposed to be kept in the buccal cavity of the mouth for drug absorption to happen from there; the route of administration is called the buccal route.
Liquid dosage forms like solutions are very often used through the injectable route. In this route, the drug formulation, most of the time in the form of solution, is taken in a syringe and directly put in to the body through a needle. The injectables can be introduced in the vein (intra venous or IV), arteries (intra arterial IA, rarely used), under the skin (subcutaneous, SC), deep in the muscle (intra muscular, IM) or rarely in the abdominal cavity (intra peritoneal). IVs and IA reach the site of action very fast and the onset of action is immediate.
Figure 1.5:
The Oral route involves swallowing the drug, which exposes it to the digestive system and liver. The Sublingual route absorbs directly into the blood.
Formulations introduced through the IM and SC modes take some time to reach the site of action. Thus, the onset of action is a little longer than IV, but usually less than oral. One advantage of injectable dosage form is fast onset of action, another is that the formulation can be used at or near the site of action, resulting in minimization of the side effects to the other tissue.
Another route of drug administration is the topical route i.e. the skin route. The topical formulation is applied on the skin and the drug is intended to act right there or to be absorbed through it to the deeper tissue. Generally topical formulations are used to treat local conditions, although treating systemic (deep in the body supplied by systemic circulation) conditions is possible and practiced but rarely. Drug molecules have to penetrate through multiple layers of cells (plasma membranes) that can be dead or alive and in different states of hydration. That is why the molecules that are relatively non-polar and non-ionic in physiological pH are suitable for being formulated in topical preparations. Examples include lidocaine ointment USP (5% w/v lidocaine, local anaesthetics) and ketoconazole cream (2% ketoconazole, antifungal), Nystatin topical powder (solid) or cream (two-phase system, emulsion, topical antifungal).
Formulations are also applied on moist skin of the internal orifices of the body like vagina, rectum, nasal cavity etc. The formulations that are used in vagina and rectum are generally solid and called suppositories. Drugs from these formulations either leach out or are released by slow melting of the solid body of the formulation. Examples include progesterone suppositories (vaginal, replacement of progesterone) and H-E-B hemorrhoidal suppositories (rectal). The intra-nasal formulations can contain drug as solid powder or dissolved in aqueous droplets to be delivered by pressurized gas. These droplets or solid particles are designed to release the drug on the epithelial tissue of the nostrils and often act locally or regionally although systemic use of these dosage forms and this route are possible. Examples include Sprinx nasal spray (solid form, pain management) and fluticonazole propionate (liquid, allergy relief).
Drug formulations that are intended for local use to the eye are called ophthalmic preparations. These preparations are generally drug solutions that are used as droplets. Examples include chloramphenicol eye drop and tobramycin ophthalmic solution. As the name suggests, these are drug solutions to be applied as droplets to the eye.
1.4 Drug Disposition
Drug disposition commonly refers to what happens to the drug molecule once it is in our body. While we are mostly interested in what the drug molecule does to the body (pharmacological and toxicological effects), what happens to the drug molecule itself once it is introduced into the body is equally important as they are intricately related.
1.4.1 Absorption
Once a solid dosage form is taken orally, it starts its journey through the GIT. Solid tablets or capsules swell up with time as they travel through the esophagus to the stomach. Once they absorb enough water, the tablet or the capsule fragments and produce small particles. This process is called ‘disintegration’. Following disintegration, drug molecules dissolve in the available fluid usually in the stomach. There is usually very little absorption from the stomach as this part of human anatomy is not designed for absorption; there is less area of GIT wall available for absorption. The drug formulations like suspensions and solutions do not go through the disintegration process as they are already in the disintegrated state. Drug molecules do go through the dissolution process when they are introduced in the form of suspensions.
Absorption happens mostly in the small intestine. Unlike the stomach or the large intestine, the small intestine is full of small finger-like projections coming out of the internal epithelial lining called villi. The presence of these villis increase the area of absorption in the small intestine manyfold. As the drug molecules get absorbed from the GIT and go through the multiple layers of cells, they go through the plasma membrane many times. The rate of mass transfer through the plasma membrane each and every time is dictated by the physico-chemical properties of the particular drug molecule (like the ionic status and complexation or protein binding status). The rate of absorption of the drug molecule is thus not the same for each small molecular drug. Large molecular drugs like monoclonal antibodies do not get absorbed through the GIT membrane at all because of their size. They are typically given through the injectable route. Drug absorption is not always a phenomenon associated to the oral dosage form. Drugs given through the topical or intramuscular route have to go through the absorption process before they get into systemic circulation.
Figure 1.6a:
The molecules get into the systemic circulation through the hepatic portal vein which takes them to the liver and comes out of the liver through the hepatic vein. Once the drug comes out of the hepatic vein, the absorption process is over and the drug is assumed to be in systemic circulation.
Figure 1.6b:
Figure 1.6c:
1.4.2 Distribution
Once the drug is in systemic circulation, it has to travel to the site of action. The process is called drug distribution. The most important driver of drug distribution is the blood circulation. Drug molecules that enter the systemic circulation are taken all around the body by the movement of blood in the circulatory system. It takes blood to start its journey from the heart and come back to the heart in less than 2 minutes. So, the drug gets distributed in the systemic circulation fairly quickly once the absorption happens. The drug moves out of the blood stream in the next step by leaching out of the porous blood vessels through the layers of capillary wall. This process is mainly diffusion and is driven by the concentration gradient and happens from a zone of high concentration (the blood vessels) to a zone of low concentration (the interstitial space). This diffusion process then repeats and continues throughout the tissues and organs everywhere in the body and eventually the site of action receives the drug. It is to be understood that the drug is distributed all over the body and works only at the site(s) of action. Everywhere else, this drug is a liability to the body; it produces side effects and it has to be removed. The drug moves through many, many lipid bilayers to reach the target tissue or site of action. The physico-chemical properties of the drug molecule is thus important as these properties decide how much and how fast it crosses these lipid bilayers. It is also important to understand that passive diffusion is not the only process driving diffusion. All the processes described before (passive diffusion, facilitated transport, active transport and endocytosis) can take place during this distribution phase depending on the specific drug molecule. The drug concentration in systemic circulation and at peripheral tissue remains at dynamic equilibrium at all times. As the drug concentration in systemic circulation changes with time, its concentration in peripheral tissue changes proportionally. Distribution is also the process responsible for bringing the metabolic byproducts of cells and metabolites of drugs back to systemic circulation from which they are eventually eliminated.
1.4.3 Metabolism
The liver is the main organ responsible for most of the metabolism in the body. The main purpose of metabolism is to change the non-endogenous molecules in such a way (generally making them water soluble) that getting rid of them is easier for the body. Metabolism is a process by which a molecule is changed within the body to produce another molecule. Metabolism is, more often than not catalyzed by enzymes. The liver is full of enzymes that change the foreign molecules that get into the liver through the blood stream of the hepatic portal vein. Drug molecules are also no exception. But not all the drugs get metabolized in our body, only some drugs do. A fraction of the drug molecules that get metabolized as they go through the liver in the first pass is lost during the absorption process. The drug that comes out of the liver in the systemic circulation after the first pass is considered absorbed (as these are the molecules that can get into the site of action and have pharmacological action). It is also to be understood that metabolic enzymes are present all along the GIT; they are present in saliva, in the pancreatic juice, and also in the epithelial membrane of the intestine. Loss of drug can happen due to all of these enzymes available in the absorption path and process.
1.4.4 Excretion
Excretion is a process by which the drug metabolites and all other cellular byproducts are removed from the body. Kidney is the main excretory organ of the body. But excretion does happen through the feces, and / or expiration. Carbon-dioxide, the most abundant byproduct of cellular respiration is excreted through expiration. Most of the drugs and also their metabolites are excreted through the kidney through a filtration process.
1.5 Pharmacists and Drugs
1.5.1 Pharmacist
Pharmacists are the professionals who specialize in the preparation, properties, effects, interactions and use of medications. In short, pharmacists, also called chemists or druggists, are the only medical experts specializing on drugs. Prescription medications cannot be bought, sold or used without the approval of pharmacists. The chief responsibility of pharmacists is to ensure the safety and efficacy of drugs or medication.
1.5.2 Drug Safety and Efficacy
As the term implies, safety of a drug refers to the ability of the drug to be safe and do no harm to the patient. It is already mentioned that all drugs have some (often more than one) side effects or toxicological effects associated with them. These side effects are milder than the pharmacological effects at the dose that is used in the treatment or therapy. More than one drug, when used concomitantly to the same patient, often change or modify each other’s effect on the body. The individual drug molecule, say drug A, often shares the same receptor systems with another, say drug B. They may also interfere with each other in some other manner or mechanism. In these situations, both the pharmacological and toxicological effects of drug A are quantitatively different if it is dosed alone to the patient compared to if drug A is dosed to the patient who is also receiving drug B at the same time. It is not that only two or more different drugs, when used concomitantly, can produce interactions. There can be (a) drug-drug interactions, (b) drug-food interactions and also (c) drug-disease interactions. In all these cases of interactions, the extent of the pharmacological and toxicological effects can change (increase or decrease) or cause unexpected effects or events. It is the pharmacist’s responsibility to take all the drug interaction possibilities into account in the case of each patient to ensure drug safety to the patients.
The next important aspect of the pharmacist’s responsibility is to ensure the efficacy of the drug in the individual patient. Efficacy refers to the effectiveness of the drug. In other words, whether or not the drug or drug regimen is having the salubrious effect on the patient for which the drug has been prescribed is its efficacy. Efficacy is related to the quantum of the drug dose or the drug concentration in the body. The pharmacist is expected to ensure that the patient is getting a sufficient amount of the drug in a repeated and timely manner so that there is enough drug concentration in the systemic circulation at all times during the treatment. The dose along with the frequency of dosing is called the dosing regimen. Determination of dosing regimen is an involved topic by itself and is covered under a branch of science called Pharmacokinetics. Drug effectiveness also depends on the amount of drug that is in active form in the formulation at the time of dosing as opposed to the time of manufacture. Most of the drugs that are used in the clinical setting are manufactured as formulations by pharmaceutical companies in big batches. These formulations are kept in the market on the shelf for a long time (up to 2 years) before use. The drug molecules, no matter how chemically stable they are, often undergo degradation reactions in the formulation itself. The most common degradation reactions are oxidation and hydrolysis, though many other degradation reactions are possible. As a result of the degradation reactions, actual concentration of the drug molecule in formulation decreases progressively. The pharmaceutical companies, thus, assess the rate of these degradation reactions and determine the time it takes for the formulation to degrade 10% of the drug molecule under reasonable storage conditions (i.e. 90% of labeled amount remaining). This time is mentioned in the product label as expiry date or beyond use date. Expiry date is a term that is usually used by the pharmaceutical industry. It is arrived at following an in-depth study of the degradation kinetics of the drug molecule in the formulation itself. The compounded products in a pharmacy are generally labeled with beyond use date (for example ‘do not use beyond’ such and such date). Beyond use date is arrived at in a compounding pharmacy by using common existing knowledge without any experimental data on that particular formulation. Beyond use date is, thus, approximate and empirical. It is to be noted that as a general principle, degradation reactions are slower in solid state (tablet, capsule) than in liquid state (solution, emulsion and suspension). In the liquid dosage forms, degradation reaction is generally faster in solutions than in suspension.
Further, both drug safety and efficacy are related to dose uniformity. Dose uniformity refers to the amount of drug that is taken in a single dose. Dose uniformity is generally not an issue for solid dosage forms or even in simple liquid dosage forms like solutions (one phase systems). A phase is a space within which the molecules are homogeneously distributed throughout the space. For example, in tablets, capsules or solution dosage forms the drug concentration is the same throughout the entire body of the tablet, capsule or solution. The more complex dosage forms like suspensions or emulsions are, however, composed of two-phase systems. Emulsions are composed of two immiscible liquid phases; one is aqueous while another is hydrophobic liquid (oil phase). The drug concentration in aqueous phase is usually different from that of the oil phase. The two liquid phases in emulsion are homogeneously distributed as small water droplets in oil (water-in-oil or w/o) or as small oil droplets in water (oil-in-water or o/w) in each other. Drug is suspended as fine solid particles in liquid (usually aqueous) in suspension dosage form. Drug concentration in solid phase is different form that in liquid phase in suspension dosage form. Thus, suspension is also a two-phase system. All two-phase systems are quasi-stable. The term ‘quasi-stable’ means that they are made apparently stable by good formulation for a relatively short time but not stable forever. This is called the physical stability of drug formulations which refers to the stability of the two-phase system formulation as opposed to the chemical stability of the drug molecules incorporated in them. The better the formulation, the higher the stability of the two-phase system formulations. The physical stability (phase stability) of these complex formulations eventually is disrupted because they are inherently unstable in thermodynamic terms. When the physical stability is disrupted, the phases separate and the drug concentration in the two phases differ greatly and the dose uniformity is affected. Usually, in a well-made formulation, a simple shaking of the emulsion or suspension is enough to restore the quasi-stable phase equilibrium. But, the main point is that when the physical stability of complex formulation is compromised, dose uniformity is compromised. Lack of dose uniformity affects both the safety and efficacy of the drug. It is the responsibility of the pharmacist to ensure the safety and efficacy of the drug and treatment. In the context of physical stability of the formulation, the pharmacist often performs this responsibility by paying attention to the expiry date of manufactured products or beyond-use date of the compounded products. The maintenance of the physical stability can be prolonged through appropriate instructions to the patient like ‘keep in a cool and dark place’ or ‘at room temperature’ or ‘in refrigerator’ (4°C) or restored through instructions like ‘shake well before use’ etc. In aqueous preparations (solutions, suspensions and emulsions), lack of safety is also introduced by the growth of microorganisms in the aqueous phase. Avoiding all these situations and maximizing the safety and efficacy of the drug, dose and treatment is the principle responsibility of the pharmacists.
Further, both drug safety and efficacy are related to dose uniformity. Dose uniformity refers to the amount of drug that is taken in a single dose. Dose uniformity is generally not an issue for solid dosage forms or even in simple liquid dosage forms like solutions (one phase systems). A phase is a space within which the molecules are homogeneously distributed throughout the space. For example, in tablets, capsules or solution dosage forms the drug concentration is the same throughout the entire body of the tablet, capsule or solution. The more complex dosage forms like suspensions or emulsions are, however, composed of two-phase systems. Emulsions are composed of two immiscible liquid phases; one is aqueous while another is hydrophobic liquid (oil phase). The drug concentration in aqueous phase is usually different from that of the oil phase. The two liquid phases in emulsion are homogeneously distributed as small water droplets in oil (water-in-oil or w/o) or as small oil droplets in water (oil-in-water or o/w) in each other. Drug is suspended as fine solid particles in liquid (usually aqueous) in suspension dosage form. Drug concentration in solid phase is different form that in liquid phase in suspension dosage form. Thus, suspension is also a two-phase system. All two-phase systems are quasi-stable. The term ‘quasi-stable’ means that they are made apparently stable by good formulation for a relatively short time but not stable forever. This is called the physical stability of drug formulations which refers to the stability of the two-phase system formulation as opposed to the chemical stability of the drug molecules incorporated in them. The better the formulation, the higher the stability of the two-phase system formulations. The physical stability (phase stability) of these complex formulations eventually is disrupted because they are inherently unstable in thermodynamic terms. When the physical stability is disrupted, the phases separate and the drug concentration in the two phases differ greatly and the dose uniformity is affected. Usually, in a well-made formulation, a simple shaking of the emulsion or suspension is enough to restore the quasi-stable phase equilibrium. But, the main point is that when the physical stability of complex formulation is compromised, dose uniformity is compromised. Lack of dose uniformity affects both the safety and efficacy of the drug. It is the responsibility of the pharmacist to ensure the safety and efficacy of the drug and treatment. In the context of physical stability of the formulation, the pharmacist often performs this responsibility by paying attention to the expiry date of manufactured products or beyond-use date of the compounded products. The maintenance of the physical stability can be prolonged through appropriate instructions to the patient like ‘keep in a cool and dark place’ or ‘at room temperature’ or ‘in refrigerator’ (4°C) or restored through instructions like ‘shake well before use’ etc. In aqueous preparations (solutions, suspensions and emulsions), lack of safety is also introduced by the growth of microorganisms in the aqueous phase. Avoiding all these situations and maximizing the safety and efficacy of the drug, dose and treatment is the principle responsibility of the pharmacists.
Chapter 1: Introduction Flashcards
Master key concepts of Drugs, The Body, Interactions, and Pharmacists
References
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