Pharmacokinetics

Pharmacology

As defined in the Merriam-Webster dictionary pharmacology is: "1: The science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology 2: the properties and reactions of drugs especially with relation to their therapeutic value"

By studying drug action on living organisms,[1] mechanisms of action, biological distribution and processing, and both therapeutic and non-therapeutic effects it provides a better understanding of the underlying physiology.. A drug is an exogenous or endogenous chemical entity that causes a specific change in a biological function in an organism. Drugs can be of a variety of sources: elemental compounds (i.e. Lithium, Oxygen, Calcium (Ca²⁺), a molecule (i.e. Nitrous Oxide), an endogenous compounds given exogenously ( i.e. hormones, immunoglobulins), and other compounds ( i.e. plant alkaloids, minerals, synthetics). Drugs are formulated to conveniently deliver a precise dose intended to affect a short or long-term predictable, therapeutic biological change. Compounds which are exogenously administered and have medicinal properties are considered pharmaceuticals or colloquially "medicines" or "drugs".

Interactions of a drug within the body can be divided into two major principles: Pharmacokinetics and Pharmacodynamics; the former deals with absorption, distribution, metabolism and elimination of a given substance by the organism and the latter deals with the interactions of the substance with biological processes (i.e. receptor-binding, signaling pathways..).

PHARMACOKINETIC PROCESSES

Time, needed for achieving of maximal effect, its duration and intensity depends on route of administration, rate of catabolism (metabolism, breakdown to inert compound) and elimination of active and/or inactive drug. So it is necessary to consider peculiarities and principles of different introduction methods, while choosing. They are divided to enteral, passage through the digestive tract (i.e. oral, rectal, gastronomy, feeding tube in stomach, small intestines) and parenteral, bypassing digestive tract (i.e. intravenous (IV), arterial, intramuscular (IM), subcutaneous (subQ), sublingual (can be considered enteral), topical, inhalation, subdural, epidural...). [2]

Enteral route include oral, subglossal, and per rectum administration. Oral way is the most easy, convenient, and widely used way of administration. But a lot of factors influence on absorption and bioavailability of the drug.
Bioavailability is the ratio of unchanged drug reaching the systemic circulation to the given dose (in percentage). For an intravenous dose of the drug, bioavailability is equal to unity (100%). For example, if bioavailability of drug is 50 %, its mean that 50 % of ingested dose reach the serum. For a drug administered orally, bioavailability may be less than 100% for two main reasons - incomplete extent of absorption and first-pass elimination. The last one is mean that following absorption across the gut wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug can be metabolized in the gut wall, but most commonly in the liver that is responsible for metabolism before the drug reaches the systemic circulation.
The hepatic first-pass effect can be avoided to a great extent by use of sublingual route and by use of rectal suppositories. Sublingual absorption provides direct access to systemic - not portal - veins. This route is facile; the onset of action is fast; but the duration of action is short. Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena cava, thus bypassing the liver. However, partially drugs achieve superior hemorrhoidal that lead to the liver. In addition the absorptive ability of rectum mucosa lower than of small intestine. Thus, only about 50% of a rectal dose can be assumed to bypass the liver.
To parenteral routes we consider injections, inhalations, and transdermal route. The first one includes injection under the skin, intro the muscles (i.m.), in veins (i.v.) and arteries. The effect appears quickly, especially in case of intravenous injection, and provides precision of dosage. Bioavailability for intravenous route is 100 %. After intravenous injection the onset of action is quicker, but duration is shorter than during intramuscular or subcutaneous injection. It is not recommended to use the drugs with strong irritate action subcutaneously and intramuscularly. Also it is prohibited to use intravenously insoluble substances and oily solutions, because of embolism risk. Lack of these routes is tissue damages, necessity of sterility, and risk of non-specific reactions (shock, collapse, cramps). Gases and aerosols are introduced using inhalations. Therapeutic effect is reached quickly. Predominantly this route is desirable for the treatment of diseases of breathing ways. It causes topical action mainly. Lack of this method is irritation followed by spasm of larynx, bronchi.
Through the skin are introduced the oil-solved substances (in the form of ointments and liniments) and electrolytes (by electrophoresis). The transdermal route provides direct access to systemic - not portal – veins and prolong the duration of drug absorption.
In digestive tract drug absorption depends on many factors. Ionized forms of drugs are poorly dissolved in lipids and poorly absorbed. Salicylates in the stomach (pH 1,0 - 1,5) are poorly ionized and are absorbed to a great extend in the stomach. Alkaloids are better absorbed in intestine (pH in duodenum is ~ 6,6), due to the poor ionization in alkaline medium. It is necessary to consider, that pH in the stomach is the lowest during and just after meals, and the highest - 1 hour before and 1,5 - 2 hours after meals. So acid substances is necessary to administrate while or just after eating, alkaline substances - 1 hour before and 1.5 - 2 hours after eating.
Quantity and character of meals, that can change pH of surrounding, also considerably influence on drug's absorption. For example, tetracycline forms stable compounds with calcium, which are not absorbed. That’s why simultaneous using of tetracycline and milk that contain calcium can decrease the rate of tetracycline absorption. In the same time, lipids increase the absorption of fat-dissolved drugs (vitamins A, D, K, E, etc.). Alkaline promotes ionization of acid substances and impedes their absorption and vice versa.
Also drugs absorption in intestine considerably depends on motility of digestive tract. Substances that decrease motility of intestine (spasmolytics, cholinolytics, etc.) promote absorption; substances, hastening motility (cholinomimetics) impede absorption. Drug's form has a great meaning while oral administration. The most common rule is, that liquid forms are absorbed better, than powders, absorption of which depends on it's dispersion; powders are absorbed better then tablets, dragees and granules. So, bioavailability of drugs while enteral administration depends on many factors, various greatly and difficulty predicted.
After parenteral administration drugs are absorbed into the blood circulation from subcutaneous tissue, muscles and cavities (depending of injection types), from alveoli (during inhalations). Physician can easier predict serum's level of drug and it's effective dose. However, in the case of bloodstream delay the absorption after subcutaneous and intramuscular injections can decrease.
Choosing the route of administration it is important to consider some basic factors:
(1) stability of drug in digestive tract;
(2) possibility of absorption through the walls of digestive tract and bioavail¬ability;
(3) goal of therapy (in emergency cases parenteral route of administration, espe¬cially intravenous is preferred).
In organism drugs permeate through the various barriers that separate different compartments, e.g., gut, brain. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that comprise the wall of the intestine, the walls of the capillaries that perfuse the gut, and the "blood-brain barrier," the walls of the capillaries that perfuse the brain.
Drug permeation proceeds by four primary mechanisms.
1. Passive or lipid diffusion due to gradient of substance's concentration. Passive diffusion is the most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body. This way are transported the lipophilic substances. It occurs without energy using.
2. Filtration or aqueous diffusion is appear across epithelial membrane through pores that permit the passage of small molecules. Filtration is depends on the concentration gradient of the permeating drug. In this way are transported small hydrophilic molecules and some ions.
3. Active transport is provided by special carrier molecules exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes (e.g., peptides, amino acids, glucose). Active transport needs energy, which occur due to decomposition of ATP molecule.
4. Pinocytosis is the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane. This process is responsible for the transport of large substances.
There are many biological (blood-histological) barriers in organism, except mentioned above blood-brain barrier. They are placental, blood-follicular, blood-testicular, and epithelium of mamma's glands. Blood-histological barrier is the capillary wall that consists of endothelium cells, basal membrane, enzymes, and small pores. Lipophylic substances easily pass through cellular membranes, hydrophilic substances pass through basal membrane and pores. Substances with molecular weight smaller than 5000-6000 Da easily pass through capillary wall also.
Blood-brain barrier (BBB) consists of cerebral capillaries and astrocytes (neuroglia cells). It possesses selective permeability. Ionized molecules cannot pass trough it. In the case of inflammatory process brain BBB become more permeable; and brain is subjected by harmful influence of different substances. Placental barrier protects fetus from xenobiotics (not endogenous substances). Drugs with molecular weight smaller than 400 Da easily pass trough placenta by the way of passive diffusion. Permeability of placenta depends on many conditions and gradually increases to 33-35 weeks of pregnancy. Thus, it is necessary care administration of drugs especially in first trimester of pregnancy (period of fetus organ appearing). Blood-follicular and blood-testicular barrier protects sexual cells from action of xenobiotics. They consist of lipoprotein membranes and are easily passed by lipophylic non-ionized molecules (narcotics, alcohol, etc.). So, genetic material may be damaged (mutagenic effect). Epithelium of mamma glands is easily passed by lipophilic substances. If drugs, used by mother are toxic or may cumulate in breast milk, nursing have to be stopped or the drug have to be changed.
Distribution of drugs in organism is done by blood and lymph circulation. There are three fractions of substances in organism:
(1) free fraction in serum and tissues;
(2) connected with serum proteins;
(3) fixed in different tissues.
These fractions are in dynamic balance and constantly remove from one form to another. Only free fraction is biologically active, because it could be transformed and excreted. So, the high level of free fraction is associated with strong, quick, but short action. Level of free fraction in blood depends on albumin content. In case of low protein levels (diseases of liver, kidneys, starvation) concentration of free fraction considerably increases, that may cause strengthening of effect.
Some drugs may be deposited in tissues, forming extra-cellular and cellular depots. It occurs due to connection with proteins and phospholipids. Durability of connection is various. Some drugs (e.g., substances for narcosis) form not durable complexes with phospholipids and are quickly deleted from fat depots. Other (sulfanilamides of prolonged action, salts of heavy metals) form durable connections with proteins and for a long time stay in tissues.
Volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug in blood or plasma. Drugs with very high volume of distribution have much higher concentrations in extravascular tissue than in the vascular compartment. Mostly it is prefer for the drugs with high selectivity of action. Serum concentration is sum of free and connected with proteins drugs fractions. It shows different phases of pharmacokinetic: absorption, distribution and elimination of substance. Curve shows time from drug's administrat¬ion to appearance of primary effect (latent period of action), time from first appearance to minimal therapeutic effect (duration of action).
Biotransformation (chemical drug conversion) occurs, basically in liver, and also in kidneys, lungs, wall of intestines and other organs. Most part of drugs are biotransformed in organism, except drugs for narcosis and hydrophil non-ionized substances that are excreted non-transformed. Result of biotransformation is converting of lipid-soluble substances to water-soluble and their excretion. Metabolic products are often less pharmacodynamically active than the parent drug and may even be inactive.
There are two main phases of biotransformation - metabolism and conjugation.
Metabolism (I phase) is occur due activity of oxidase's systems, basic components of which are cytochrome P-450 and NADP. At this phase reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Metabolic transformation is done by oxidation, restoration and hydrolysis. For example, imipramin, ephedrine, and aminazine are subjected to oxidation; levomycetin and nitrazepam are metabolized by restoration; complex ethers (e.g., novocaine, atropine) are hydrolyzed. Most part of substances are metabolized by oxidation for which oxygen is necessary. So, changes of blood circulation, hypoxia sharply lower metabolism of drugs.
An interesting feature of some drugs (e.g., barbiturates, rifampicin) is their ability, on repeated administration, to "induce" cytochrome P-450 by enhancing the rate of its synthesis or reducing its rate of degradation. Induction results in an acceleration of metabolism and usually in a decrease in the pharmacologic action of the inducer and also of coadministered drugs. However, another drugs (e.g., valproic acid, cimetidine) inhibit activity of cytochrome P-450 that can result in an increasing of action of coadministered drugs.
Parent drugs or their phase I metabolites that contain suitable chemical groups often undergo conjugation (coupling) reactions with an endogenous substance to yield drug conjugates. For example, histamine and noradrenaline are methylated; sulfanilamides are acetylated; morphine and bilirubin bind with glucuronic acid, etc. In general, conjugates are polar molecules that are readily excreted and often inactive. Conjugate formation involves high-energy intermediates and specific transfer enzymes (transferases).
Excretion of drugs occurs basically via kidneys. Some drugs are excreted with bile into the lumen of intestine, via lungs, mammary glands, sweat and sebaceous glands. Drugs are excreted in changed form (metabolites, conjugates) and in unchanged (non-transformed) form. Almost all drugs are filtered at the glomerulus. If a drug is in a lipid-soluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by simple passive diffusion. If the goal is to accelerate excretion of the drug, it is important to prevent its reabsorption from the tubule. This can often be accomplished by adjusting urine to make certain that most of the drug is in the ionized state. As it is mentioned above, acids in acidic medium are poorly ionized and are easily reabsorbed. Alkaloids are better reabsorbed from alkaline urine. Thus, weak acids are usually excreted in alkaline urine; weak bases are better excreted in acidic urine. Also blood circulation in kidneys (hypotension diminish glomerular filtration), pathological processes in kidneys play an important role in excretion. It is necessary to remember that some drugs (e.g., tetracyclines, glycosides), which are excreted with bile, partially are reabsorbed in intestine. Some substances are excreted through stomach and intestine (morphine, salts of heavy metals).
Drugs excretion into breast-milk has especial meaning. Most part of the drugs, used by mother, are found in breast-milk and may cause side effects at infant. If the drug is excreted into milk and is dangerous for infant, feeding has to be avoided.
Elimination is the process of drug inactivation in result of biotransformation and excretion. It values by half-life of the drug, constant of elimination, and clearance. Half-life (t1/2) is the time required to change the amount of drug in the body (usually in blood) by one-half during elimination time. Constant of elimination is the drug quantity (in %), that was excreted by organism during period of time (usually during 1 day). Total clearance of a drug is the ratio of the rate of elimination by all routes to the concentration of drug in serum. Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to it yields the respective clearance at that organ.