When we get a prescription from a doctor, the drug usually comes with instructions for how to use it. These include when we take the drug (before or after a meal), how many times a day and for how long we take it, and what we have to avoid while using the drug. Doctors also ask if we use any other medication or if we have any chronic disease before prescribing any new medication. Most medicines look similar, but drugs themselves can be very different. Have you thought about what happens to a drug when it gets into our body?

All body functions and disease processes—as well as most drug reactions—occur at the cellular level. Drugs are chemicals that alter basic processes in body cells. They cannot add functions and activities but can only affect normal cellular functions and activities. Drugs given for systemic effects must reach adequate concentrations in the blood and other tissue fluids surrounding our cells to have an effect. Drugs must circulate through their body, reach their intended cells, and, after affecting the cells, be eliminated from the body. But how do all these processes occur? How do systemic drugs reach, interact with, and leave the body’s cells?

The answers to these questions are answered by one of the main domains of pharmacology—pharmacokinetics. Pharmacokinetics is derived from the Greek words pharmakon (drug) and kinetikos (movement) and means “what the body does to a drug.” It refers to the movement of a drug into, through, and out of the body.

Knowledge of pharmacokinetic principles helps healthcare providers to adjust dosages more accurately and rapidly. Application of pharmacokinetic principles to individualize pharmacotherapy is termed therapeutic drug monitoring and aims to give the exact amount of drug to each person.

The four main parts of the pharmacokinetic processes are

• Absorption
• Distribution
• Metabolism
• Elimination

These processes are abbreviated as ADME.

Figure. Entry and movement of drug molecules through the body to sites of action, as well as metabolism and excretion 

Absorption

Absorption is the process that occurs when a drug enters the body until it enters the bloodstream to be circulated. The duration of a drug’s action is largely determined by the rate of absorption, and intensity is determined by the extent of absorption.

Numerous factors affect the rate and extent of drug absorption, including dosage, form, route of administration, blood flow to the site of administration, gastrointestinal function, and the presence of food or other drugs.

Most oral drugs must be swallowed, dissolved in gastric fluid, and delivered to the small intestine (which has a large surface area for absorption of nutrients and drugs) before they are absorbed. Liquid medications are absorbed faster than tablets or capsules because they need not be dissolved. Rapid movement through the stomach and small intestine may increase drug absorption by promoting contact with absorptive mucous membrane; it also may decrease absorption because some drugs may move through the small intestine too rapidly to be absorbed. For many drugs, the presence of food in the stomach slows the rate of absorption and may decrease the amount of drug absorbed. That is why some drugs are taken before meals and some after.

Drugs cannot be absorbed well when a patient has diarrhea and the intestines are working excessively; the effect of the drug will be reduced. Absorption may be increased if the patient has constipation and the intestines are working very slowly; this could have unforeseen adverse effects.

Drugs injected into subcutaneous (under the skin) or intramuscular (in the muscles) tissues are usually absorbed more rapidly than oral drugs because they move directly from the injection site to the bloodstream. Absorption is rapid from muscle sites because muscle tissue has abundant blood supply. Drugs injected intravenously (into the veins) do not need to be absorbed because they are placed directly into the bloodstream.

Other absorptive sites include the skin, mucous membranes, and lungs. Most drugs applied to the skin are given for local effects (e.g., muscle relaxant creams, itch relief ointments, and burn ointments). Systemic absorption is minimal from intact skin but may be considerable when the skin is inflamed or damaged. Also, a number of drugs have been formulated in adhesive skin patches for absorption through the skin. Some drugs applied to mucous membranes also are given for local effects. However, systemic absorption occurs from the mucosa of the oral cavity, nose, eyes, etc. Drugs absorbed through mucous membranes pass directly into the bloodstream. For example, nitroglycerin sublingual tablets are used to treat episodes of angina (chest pain) in people who have coronary artery disease. It is also used just before activities that may cause episodes of angina to prevent symptoms. It works by relaxing the blood vessels so the heart does not need to work as hard and therefore does not need as much oxygen. The lungs can be a good absorption site, as they have a large surface area for absorption of anesthetic gases and a few other drugs.

Distribution

Distribution involves the transport of drug molecules within the body. Once a drug is injected or absorbed into the bloodstream, it is carried by the blood and tissue fluids to its sites of pharmacologic action, metabolism, and excretion. Most drug molecules enter and leave the bloodstream at the capillary level, through gaps between the cells that form capillary walls.

Distribution depends largely on the adequacy of blood circulation. Drugs are distributed rapidly to organs receiving a large blood supply, such as the heart, liver, and kidneys. Distribution to other internal organs, muscle, fat, and skin is usually slower.

An important factor in drug distribution is protein binding. Most drugs form a complex with plasma proteins such as albumin. These proteins act as carriers for the drugs. Drug molecules bound to plasma proteins are pharmacologically inactive because the large size of the complex prevents their leaving the bloodstream through the small openings in capillary walls and reaching their sites of action. Only the free or unbound portion of a drug acts on the body’s cells. As the free drug acts on cells, the decrease in plasma protein levels causes some of the bound drug to be released.

Protein binding allows part of a drug dose to be stored and released as needed. Some drugs also are stored in muscle, fat, or other body tissues and released gradually when plasma drug levels fall. These storage mechanisms reduce the risk of toxicity. Drugs that are highly bound to plasma proteins or stored extensively in other tissues have a long duration of action. This affects the frequency of intake of a drug and is why some drugs are taken more frequently.

Drug distribution into the central nervous system (CNS) is limited because of the blood–brain barrier, which is composed of capillaries with tight walls and limits the movement of drug molecules into brain tissue. This barrier has been created to act as a selectively permeable membrane to protect the CNS. However, it also can make drug therapy for CNS disorders more difficult because drugs must pass through the cells of the capillary wall rather than between cells. As a result, only drugs that are lipid soluble or have a transport system can cross the blood–brain barrier and reach therapeutic concentrations in brain tissue.

Drug distribution during pregnancy and lactation is also unique. During pregnancy, most drugs cross the placenta and may affect the fetus. During lactation, many drugs enter breast milk and may affect the nursing infant. This barrier is also important and protects the fetus from the adverse effects of drugs.

If we have valuable things at home or at work, we put them in extra safe places and use extra security systems to protect them. So it is with our body: our brain and a fetus are extra protected by these barriers.

Metabolism

Metabolism is the chemical reaction by which drugs are inactivated or bio-transformed by the body. Most often, an active drug is changed into one or more inactive metabolites, which are then excreted. Some active drugs yield metabolites that are also active and that continue to exert their effects on the body’s cells until they are metabolized further or excreted. Other drugs (called prodrugs) are initially inactive and exert no pharmacologic effects until they are metabolized.

Most drugs are lipid soluble, a characteristic that aids their movement across cell membranes. However, the kidneys, which are the primary excretory organs, can excrete only water-soluble substances. Therefore, one function of metabolism is to convert fat-soluble drugs into water-soluble metabolites.

Hepatic drug metabolism—or clearance—is a major mechanism for terminating drug action and eliminating drug molecules from the body. Most drugs are metabolized by enzymes in the liver, red blood cells, plasma, kidneys, lungs, and gastrointestinal mucosa.

With long term administration, some drugs stimulate liver cells to produce larger amounts of drug metabolizing enzymes (a process called enzyme induction). Enzyme induction accelerates drug metabolism because larger amounts of the enzymes allow larger amounts of a drug to be metabolized during a given time. As a result, larger doses of the rapidly metabolized drug may be required to produce or maintain therapeutic effects. Metabolism also can be decreased or delayed in a process called enzyme inhibition, which most often occurs with concurrent administration of two or more drugs that compete for the same metabolizing enzymes. In this case, smaller doses of the slowly metabolized drug may be needed to avoid adverse reactions and toxicity from drug accumulation. Thus, doctors always ask about any medications already being used before prescribing a new medication. Also, some foods (eg. grapefruit), drinks (alcohol), and smoking affect the activity of the enzymes which are metabolizing the drugs in the liver. Thus, we must be careful and follow a doctor’s instructions while using any medication.

The rate of drug metabolism is also reduced in infants (their hepatic enzyme system is immature), in people with impaired blood flow to the liver or severe hepatic or cardiovascular disease, and in people who are malnourished or on low-protein diets. Metabolism in  elderly people and pregnant women also changes a lot; thus, the dose given to each individual should be carefully calculated—especially in children, the elderly, and pregnant women.

Excretion

Excretion refers to the elimination of a drug from the body. Effective excretion requires adequate functioning of the circulatory system and of the organs of excretion (kidneys, bowel, lungs, and skin). Most drugs are excreted by the kidneys and eliminated unchanged or as metabolites in urine. Some drugs or metabolites are excreted in bile, then eliminated in feces; others are excreted in bile, reabsorbed from the small intestine, returned to the liver (called enterohepatic recirculation), metabolized, and eventually excreted in urine. Some oral drugs are not absorbed and are excreted in the feces. The lungs mainly remove volatile substances, such as anesthetic gases. The skin has minimal excretory function. Factors impairing excretion, especially severe renal disease, lead to accumulation of numerous drugs and may cause severe adverse effects if dosage is not reduced. Doctors always ask about any chronic diseases before prescribing any medication.

The process of developing a drug is long and difficult. The instructions for usage are decided after many experimental and clinical trials. None of the instructions given with medications are decided randomly; thus, we must completely follow the instructions to maximize the positive effects of a drug and to avoid any possible adverse effects.

References

• Abrams, Anne Collins., Carol Barnett Lammon, and Sandra Smith Pennington. Clinical Drug Therapy: Rationales for Nursing Practice. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007.
• Basic&Clinical Pharmacology, 12^th Edition, McGrawHill Lange.
• Modern Pharmacology with Clinical Applications, Sixth Edition, Charles R. Craig and Robert E. Stitzel, Lippincott Williams &Wilkins.

What possible similarities could there exist between a human and a tree? Interestingly, the open wounds of human beings and trees are subject to the same laws and are healed in similar ways.

Have you ever wondered what kinds of similarities exist between human skin and the bark of a tree?

Trees are subject to major and minor injuries just like humans are. These injuries could be the result of a broken branch, insect infestation, animal damage, fire and human related damages. These kinds of injuries can lead to the infection of a plant which can cause rotting and damage to the transport tissues like phloem (nutrients) and xylem (water) by microorganisms and insects (bacteria, fungi, parasites).

Fluid excretion in wounds and development of scar tissue

Blood serum is secreted in human wounds, whereas gum and resin type fluids are secreted in various trees (Figure 2 and 3). Serum plays an important role in sterilization of the wound, along with blood coagulation. Defense mechanisms in trees involve excretion of different fluids (resin in needle-leaf trees, gum in broadleaf trees) that are synthesized via composition of various chemicals. The most important feature of these fluids is that with their special chemical make up, they can protect the wound from organisms like bacteria, fungi, and insects that are potentially harmful to the tree. These fluids also feature coagulation like the human serum; they congeal and solidify after excretion and trigger a biological healing process while physically covering the wounded area.

Wounds are repaired with new connective tissue cells (fibroblasts) in humans and by callus in trees. Healing of the wound following the coagulation takes place with proliferation of cells in this region (epithelialization). First, epithelial cells wrap the wound via proliferation. New transport tissue is developed during this process. Next, fibroblasts that are in charge of wound repair are transferred into coagulate via this transport tissue. Fibroblasts synthesize collagen protein of the required fiber structure needed for the wound repair. Injured area is woven with these, and recovers its former shape in time depending on the size of the wound.

Healing is granted through timely reproduction, transformation and maturation of paranchimatic cells that make up the callus, when only a portion of tree bark is damaged. Paranchimatic cells are fused side by side and they form a thick elevation of callus tissue around the wound (Figure 4). At the end, these are activated for the development of a new, healthy cambium and bark. Cambium tissue is responsible for vertical and lateral growth of a tree therefore it is vitally important that it does not suffer any damage. This tissue in growth season proceeds from the perimeter of the wound towards the center for a complete healing. The productive efficiency of the tree medium can speed up or slow down the curing process similar to humans.

The reality is that all living things are created with a dress suited for their environments so that their bodies can be protected from negative elements from the outside world. Organisms are armored from many harmful physical (mechanical, extreme temperatures, light etc.) and chemical effects with this perfectly bestowed dress as a manifestation of the divine compassion in the universe just as in the case of the wounds of humans, animals and plants which are subject to the similar laws found in nature.

Nephrology is the study of the kidneys, the essential organ of excretion, and elements related to it. If due observation and research are thoroughly carried out on every part of the human metropolis, when the integrated hierarchical mechanisms are analyzed, it can be seen that numerous events are constantly taking place; these can open new doors to various sciences and offer us new horizons of reflection on the Divine Wisdom. In this way, these events are an interpretation of the saying “If all the seas were to be made up of ink, and all the trees were pens, they would still not be able to write down the knowledge of God,” which points to the existence of an Omnipotent Being with infinite knowledge.

One of these constant activities in our body is the excretion system which works like a well-regulated clock. In the body of a healthy adult, the bladder, after an accumulation of urine that has been filtered through the kidneys, resembles a balloon that has been inflated. The bladder enlarges according with the amount of urine that has been filtered by the kidneys. The autonomous nervous system has a significant role in the wonderful functioning of this urine storage mechanism. If we assume that an average adult urinates 5-6 times a day, we can say that the average time adults spend for urination is about 5 minutes daily. The autonomous system of a baby however, is not properly developed and has a very limited capacity of urine storage. Therefore, the bladder of a baby is frequently emptied. As for newborn babies, the number of times that they empty their bladder can be as much as 20-25 times a day. In this way, both the urine that comes from the kidneys flows to the bladder freely, and the urination channels are automatically cleaned.

In order to allow the urine flowing from the kidneys to the bladder to pass freely through the small tubes that measure between 3-7 mm (the urethra) the inner pressure in the bladder needs to be kept at low levels. This is realized in the body of a baby by the frequent emptying of the bladder, until the autonomous nervous system has properly developed. After the sixth month, the autonomous nervous system develops, the urine storing capacity of the bladder increases, and the number of urination times decreases. As the child grows, the ability to store urine and to excrete it at the proper time and place is completed in a gradual process. Being only one of the hundreds of wonders in the human metropolis, this balance is maintained as a clear reflection of Divine Mercy.

Cooperation in the urinary tract

There is a fascinating cooperation between the departments of this metropolis. The urine that is excreted by the kidneys does an excellent job of cleaning all along the urinary tract, like a river cleaning the stones over which it passes. This cleaning includes not only any microorganisms, but also any gravel which might form in the urination channels. Research has proved that when bacteria are injected into the bladders of healthy people no infection is developed in the urinary tract, since the pressure of their urine excretion drives the bacteria away. The protection of the kidneys by both the expansion of the flexible bladder wall and the decrease in the pressure inside the bladder is a good example of the cooperation between the kidneys and the bladder. If the pressure was not able to be decreased by such flexibility, the kidneys could not function under the resulting high pressure. The smooth functioning of the kidneys is maintained through urine excretion in suitable amounts and at a suitable pressure. Taking all this for granted, one usually comes to realize what a blessing the excretion system is only when there is a problem.

The urination of a baby in the womb

The placenta has the duty of being the main regulator of the feeding and excretion systems of a fetus. The kidneys of a fetus also play significant roles. For instance, they balance acidity through liquid electrolytes, carry out the functions of hormone production, and growth. From the fourth month on, the fetus begins to produce urine and the bladder is filled and emptied every 30-60 minutes. The urine inside the bladder is emptied into the amniotic fluid which surrounds the fetus like a protective pad. The duty of the amniotic fluid includes protecting the fetus against the changes in the mother’s body temperature, providing space for normal development, providing suitable conditions for food and oxygen supply, and protecting the baby against any possible blows that the mother’s belly might be exposed to. The amniotic fluid in which a baby is placed is a liquid similar to urine, and it is produced for the comfort of this new guest to our world.

The formation of urine

The blood, which is charged with transmitting nutrients and oxygen even to the remotest parts of the body, brings the toxic disposal our body has produced due to various causes on its way back to the kidneys. The blood, which bears the responsibility of maintaining the health of metropolis of the body, is continuously filtered when it reaches the kidneys. In the kidneys, the waste material is so delicately separated that it as if the kidneys know “which substance is needed in what amounts,” without meticulous calculation and infinite knowledge. Artificial kidneys supported by latest technology (like modern devices of dialysis) are never a substitute for a real kidney. A healthy kidney, which is made to serve under the veil of causes created by the Owner of infinite knowledge and power, does its duty with divine guidance. It sends what is to be disposed of to the bladder in the form of urine.

The substances urine contains are used when diagnosing illnesses, for they possess different qualities. The color, smell, and density of the urine and the substances it contains give us various clues about the health of that person. Deviations in the sensitive balance established in the excretion system are considered to be a sign of something gone wrong in the human metropolis. In other words, a urine analysis is an important indication of health, for many factors, such as our lifestyle, our eating habits, disease, and the medicines we use can effect changes on the consistency and composition of the urine (figure 1-3). The urine of a healthy person is yellow and clear. This color is derived from the urochrome pigment along with urobilin and uroerythrin. Colorless urine can be seen if there has been recent fluid consumption, or the use of diuretics, or disorders such as different types of diabetes (diabetes mellitus, diabetes insipitus, etc). The color of urine can fluctuate between yellow and clear within the day (for example, 1-2 hours after a meal it can be clear, whereas it can turn to dark orange due when one has been making heavy effort). Beetroot, artificial colorings and some drugs can turn the urine red. When the complaints of a patient are taken together with a medical examination and lab analyses, urine samples which are colored red-brown, blue-grey, milky-white or which are cloudy may all be symptoms of disease.

As we learn new things about urine we will hopefully attain a deeper comprehension of the infinite divine blessings that have been bestowed upon us, offering thanks to our Creator from new perspectives.