Chapter 2: Pharmacodynamics

Section 1

Chapter 1: Pharmacokinetics

Welcome to Section 1 Chapter 1. This Chapter deals with the principles of Pharmacokinetics. When you think of Pharmacokinetics you think of the flow of a drug through the body. This includes the absorption of the drug, the distribution of the drug, the metabolism of the drug and the elimination of the drug from the body. When you prescribe a drug, you will be directly or indirectly thinking of these principles of Pharmacokinetics.

For a drug to be absorbed, it may need to pass several cell membrane layers on its way to a therapeutic effect. This process involves consideration for the molecular size of the drug, the ionization of the drug, whether the drug is lipid soluble and if the drug binds to blood proteins.

Let’s discuss these cell membranes for a minute. There are four common ways for drugs to cross a membrane.

First, on a basic level, cell membranes are permeable to water. If a drug is not bound to a protein in the blood, then the drug can potentially use the movement of water through the cell membrane to help it cross over into the cell. This is the process of water diffusion. The drug is, in effect, carried across a membrane as water moves across. Some cells, as in the central nervous system, have tighter membranes and a drug being carried by water diffusion is not as likely.

Secondly, the process of moving a drug across a membrane can be aided by a concentration differential. If a drug on the outside of a membrane has a higher concentration, then it can move across the membrane to equalize the concentration. Factors involved in this movement are the concentration gradient, the drug’s solubility in the lipid layer of the membrane and the amount of the drug spread out over the surface area of the membrane. This is the process of using a concentration gradient.

A third way a drug can be transported across a membrane in an active fashion. This activity involves the use of energy from the cell to accomplish the transfer of a drug. Active transport is needed if a drug is to be moved against a concentration gradient. This is the process of active transport.

The fourth and least likely mechanism of transfer across a cell membrane involves something called facilitated diffusion. This facilitation does not involve the use of energy. This facilitated diffusion involves what can be called an assist by another substance that attaches to the drug and helps it cross the membrane. This is the process of facilitated transport.

The ionized or unionized form of a drug can change the absorption profile in any of the four common ways to cross a membrane. It is the unionized form that most easily crosses a membrane.

Every drug will be absorbed to some extent, but it is the bioavailability that is in question. In other words, howmuch of the original drug isavailable to provide the clinicaleffect that isdesired. The factors involved in achieving a high bioavailability percentage are numerous. These factors include the route of administration, the extent of metabolism and consideration of extended release preparations.

At this point, let’s look at the multiple ways a drug can be given to a patient. There are over ten methods to deliver a drug. The list of drug delivery methods includes oral, sublingual, transdermal, rectal, intravenous, interosseous, subcutaneous, intrathecal, pulmonary, topical and intra-arterial. The choice of delivery method depends on the clinical situation and the patient’s condition. The clinical reasons for a specific mode of delivery include a need to target a specific area, the need to avoid first pass metabolism in the liver or possibly because there is a lack of access to other delivery methods. Examples of these would be to give a drug via the sublingual route to avoid the metabolism of the liver on the first pass, using an inhaler to focus on the lungs for COPD or giving an intrathecal dose to avoid the blood/brain barrier.

Let’s take a quick look at each method of drug delivery.

Oral delivery is the most common method of drug delivery. It usually provides easy access and is probably the safest. It has a disadvantage in the nauseated patient and provides low bioavailability.

Sublingual delivery of a drug gives quick access to the blood and has its advantage in an emergency situation.

Rectal delivery of a drug may be used due to persistent nausea or for site relief.

Intravenous delivery can be used if there is already access to a vein or the need for speed of delivery.

Subcutaneous delivery is easy and safe, but can only be used for drugs that are not irritating. Absorption of a drug can be distinctly variable in sick patients.

Intramuscular injections for drug delivery are not used too often due to patient discomfort and variable absorption rates. The drug must also be in an aqueous solution. Single dose antibiotics can be given this way.

Inter-arterialdeliveryisforveryspecificsituations.Thiscouldbeforsomeformofneuropathic pain syndrome.

Intrathecal delivery can be for pain relief or to delivery medications that otherwise could not get past the blood brain barrier.

Pulmonary deliveryfor COPDor asthma focusesthemedication whereitisneeded. Pulmonary delivery has also been used for specific antibiotics

Interosseous delivery is mostly for patients in which intravenous access is difficult and access to the central circulation is needed.

We will discuss the distribution of drugs next. In this context, we are talking about the time period after the drug has been absorbed into the blood stream. There are many factors that can affect the rate of distribution, up or down. Basic physiological principles apply to the ability of a drug to get maximal distribution. Cardiacoutput hasa clear effect ondistribution. Ifcardiac output is up, drug distribution will be up. If cardiac output is down, drug distribution will be down. Increased blood flow to certain areas can increase drug distribution, with the reverse also being true. The percentage of cardiac output received by an organ will determine its drug distribution. So, vital organs will have a high distribution of drug, muscles less and skin even less drug distribution.

The concept of volume of distribution is somewhat complicated. First, for each drug a volume of distribution can be calculated. After this, we see that the calculated volume of distribution does not tell you where it is specifically distributed. In equation form, volume of distribution is the amount of drug given divided by the concentration. The concentration is a plasma value. If the volume of distribution is large, this indicates a significant distribution throughout the body. A small volume of distribution indicates a small compartmental focus. An example of this could be a highly protein bound drug mostly carried in the blood. Two drugs with the same numerical volume of distribution value may not be distributed to the same areas of the body. This is not an exact volumetric calculation because the body is a dynamic organism, metabolism and elimination are occurring during the calculation and the plasma level may not be a perfect representative value.

Delivery of a drug to a tissue area makes it potentially available, but this is then limited by the amount of drug that is bound by blood proteins. The main protein involved in the carrying of drugs is albumin. These drugs are usually acidic. If a drug is of the basic variety, alpha-one glycoprotein is the carrier. This bond by these proteins is reversible. The unbound form of a drug is the form which can cross a membrane. In states of protein deficiency, the main drug percentage can be the unbound form. This situation can cause overdosed and excessive drug effects.

Determining the levelsat which a drug isbound or unbound hasmany factors. Most drugshave a somewhat unvarying bound and unbound percentage. Secondary factors that can affect the distribution of a drug are the binding of a drug in certain tissues, buildup of a drug in a non-vital reservoir like fatty tissue and even redistribution with a drug coming back into circulation.

Distribution of drugsto all tissuesisnot alwaysa goodthing. Thiscanbe the case ina pregnant patient. The placenta is basically a membrane and is slightly more acidic than the mother’s blood. This can lead to basic drugs crossing over and becoming trapped in the placenta.

Themetabolismandexcretionofdrugsisasimportantastheabsorptionanddistribution.Drugs can be eliminated through metabolism or released unchanged. Highly lipid soluble drugs usually need tohave their form changed through metabolism toenable elimination. Almost allorganshave

some capability to metabolize, but the kidney, liver and lungs are the main eliminating/metabolic organs. The kidney and gastrointestinal tract are mainly involved in elimination.

The kidney has several methods it uses for removal and elimination of a drug. These are the basic functioning properties of the kidney which include filtration, tubular secretion and passive reabsorption. Of the drug that presents to the kidney only the unbound form is filtered. Changing the pH of the blood being filtered by the kidney can aid in the elimination of the drug present in an overdose situation. If the overdose drug is an acid, then making the urine more basic could be appropriate.

The liver is active in metabolism and elimination of drugs. The liver has a major role in changing drugs so they present to the kidney as soluble. Many of the drugs that present to the liver are excreted into the gastrointestinal tract. The gastrointestinal tract can also be used to stop absorption of certain compounds like cholesterol.

The metabolism of a drug follows two basic pathways. These are classified as phase one or phase two. Both phase one and phase two pathways can leave the drugina modified but still active form. Phase one is similar to a hydrolysis reaction and phase two uses conjugation. Some drugs use these systems to become active after they are metabolized in the body. They are called prodrugs.

Conclusion

Each drug that is considered for a patient needs the determination of the pharmacokinetics of that drug. When this occurs then the drug will be safely prescribed. This needs to be an automatic thought process. Thoughts of the absorption, volume of distribution, half-life and elimination of a drug allpart ofthecompletepackageof ordering adrug,along with the disease processit isordered for.

Key Points

• Pharmacokinetics—how the drug flows through the body—absorption, distribution, metabolism and elimination

• Drugs move across membranes—this is by water diffusion, concentration gradients, transportation and facilitated diffusion

• Drugs in the unionized form pass membranes • There are over ten ways to give a drug to a patient.

• Rate of distribution is effected by many physiological parameters • Delivery of a drug to tissues is affected by the amount of protein binding