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Chapter: Clinical Pharmacology: Fundamentals of clinical pharmacology


Kinetics refers to movement. Pharmacokinetics deals with a drug’s actions as it moves through the body.


Kinetics refers to movement. Pharmacokinetics deals with a drug’s actions as it moves through the body. Therefore, pharmaco-kinetics discusses how a drug is:


·                 absorbed (taken into the body)

·                 distributed (moved into various tissues)

·                 metabolized (changed into a form that can be excreted)

·                 excreted (removed from the body).


This branch of pharmacology is also concerned with a drug’s onset of action, peak concentration level, and duration of action.



Drug absorption covers a drug’s progress from the time it’s admin-istered, through its passage to the tissues, until it reaches systemic circulation.


On a cellular level, drugs are absorbed by several means—pri-marily through active or passive transport.


The lazy way


Passive transport requires no cellular energy becausediffusion allows the drug to move from an area of high-er concentration to one of lower concentration. Passive transport occurs when small molecules diffuse across membranes and stops when drug concentration on both sides of the membrane is equal.


Using muscle


Active transport requires cellular energy to move the drug froman area of lower concentration to one of higher concentration. Ac-tive transport is used to absorb electrolytes, such as sodium and potassium, as well as some drugs such as levodopa.


Taking a bite


Pinocytosis is a unique form of active transport that occurs whena cell engulfs a drug particle. Pinocytosis is commonly employed to transport fat-soluble vitamins (vitamins A, D, E, and K).


Watch the speed limit!


If only a few cells separate the active drug from the systemic cir-culation, absorption will occur rapidly and the drug will quickly reach therapeutic levels in the body. Typically, absorption occurs within seconds or minutes when a drug is administered sublin-gually, I.V., or by inhalation.


Not so fast


Absorption occurs at a slower rate when drugs are administered by the oral, I.M., or subQ routes because the complex membrane systems of GI mucosal layers, muscle, and skin delay drug pas-sage.


At a snail’s pace


At the slowest absorption rates, drugs can take several hours or days to reach peak concentration levels. A slow rate usually oc-curs with rectally administered or sustained-release drugs.


Not enough time


Other factors can affect how quickly a drug is absorbed. For ex-ample, most absorption of oral drugs occurs in the small intestine. If a patient has had large sections of the small intestine surgically removed, drug absorption decreases because of the reduced sur-face area and the reduced time that the drug is in the intestine.


Look to the liver


Drugs absorbed by the small intestine are transported to the liver before being circulated to the rest of the body. The liver may me-tabolize much of the drug before it enters the circulation. This mechanism is referred to as the first-pass effect. Liver metabolism may inactivate the drug; if so, the first-pass effect lowers the amount of active drug released into the systemic circulation. Therefore, higher drug dosages must be administered to achieve the desired effect.


More blood, more absorption


Increased blood flow to an absorption site improves drug absorp-tion, whereas reduced blood flow decreases absorption. More rapid absorption leads to a quicker onset of drug action.


For example, the muscle area selected for I.M. administration can make a difference in the drug absorption rate. Blood flows faster through the deltoid muscle (in the upper arm) than through the gluteal muscle (in the buttocks). The gluteal muscle, however, can accommodate a larger volume of drug than the deltoid mus-cle.


Slowed by pain and stress


Pain and stress can decrease the amount of drug absorbed. This may be due to a change in blood flow, reduced movement through the GI tract, or gastric retention triggered by the autonomic ner-vous system response to pain.


High fat doesn’t help


High-fat meals and solid foods slow the rate at which contents leave the stomach and enter the intestines, delaying intestinal ab-sorption of a drug.


Dosage form factors


Drug formulation (such as tablets, capsules, liquids, sustained-release formulas, inactive ingredients, and coatings) affects the drug absorption rate and the time needed to reach peak blood concentration levels.


Absorption increase or decrease?


Combining one drug with another drug, or with food, can cause in-teractions that increase or decrease drug absorption, depending on the substances involved.




Drug distribution is the process by which the drug is delivered from the systemic circulation to body tissues and fluids. Distribu-tion of an absorbed drug within the body depends on several fac-tors:


·                 blood flow


·                 solubility


·                 protein binding.


Quick to the heart


After a drug has reached the bloodstream, its distribution in the body depends on blood flow. The drug is quickly distributed to or-gans with a large supply of blood. These organs include the:

·                 heart


·                 liver


·                 kidneys.


Distribution to other internal organs, skin, fat, and muscle is slower.


Lucky lipids

The ability of a drug to cross a cell membrane depends on whether the drug is water or lipid (fat) soluble. Lipid-soluble drugs easily cross through cell membranes; water-soluble drugs can’t.


Lipid-soluble drugs can also cross the blood-brain barrier and enter the brain.


Free to work


As a drug travels through the body, it comes in contact with pro-teins such as the plasma protein albumin. The drug can remain free or bind to the protein. The portion of a drug that’s bound to a protein is inactive and can’t exert a therapeutic effect. Only the free, or unbound, portion remains active.


A drug is said to be highly protein-bound if more than 80% of the drug is bound to protein.



Drug metabolism, or biotransformation, is the process by which the body changes a drug from its dosage form to a more water-soluble form that can then be excret-ed. Drugs can be metabolized in several ways:


·                 Most drugs are metabolized into inactive metabolites (products of metabolism), which are then excreted.


·                 Other drugs are converted to active metabolites, which are capable of exerting their own pharmacologic action. Active metabolites may undergo further metabolism or may be excreted from the body unchanged.


·                 Some drugs can be administered as inactive drugs, called pro-drugs, which don’t become active until they’re metabolized.


Where metabolism happens


The majority of drugs are metabolized by enzymes in the liver; however, metabolism can also occur in the plasma, kidneys, and membranes of the intestines. In contrast, some drugs inhibit or compete for enzyme metabolism, which can cause the accumula-tion of drugs when they’re given together. This accumulation in-creases the potential for an adverse reaction or drug toxicity.


Conditional considerations


Certain diseases can reduce metabolism. These include liver dis-eases such as cirrhosis as well as heart failure, which reduces cir-culation to the liver.


Gene machine


Genetics allows some people to metabolize drugs rapidly and oth-ers to metabolize them more slowly.


Stress test


Environment, too, can alter drug metabolism. For example, ciga-rette smoke may affect the rate of metabolism of some drugs; a stressful situation or event, such as prolonged illness, surgery, or injury, can also change how a person metabolizes drugs.


The age game


Developmental changes can also affect drug metabolism. For in-stance, infants have immature livers that reduce the rate of metab-olism, and elderly patients experience a decline in liver size, blood flow, and enzyme production that also slows metabolism.





Drug excretion refers to the elimination of drugs from the body. Most drugs are excreted by the kidneys and leave the body through urine. Drugs can also be excreted through the lungs, ex-ocrine (sweat, salivary, or mammary) glands, skin, and intestinal tract.


Half-life = half the drug


The half-life of a drug is the time it takes for one-half of the drug to be eliminated by the body. Factors that affect a drug’s half-life include its rate of absorption, metabolism, and excretion. Know-ing how long a drug remains in the body helps determine how fre-quently it should be administered.


A drug that’s given only once is eliminated from the body al-most completely after four or five half-lives. A drug that’s adminis-tered at regular intervals, however, reaches a steady concentra-tion (or steady state) after about four or five half-lives. Steady state occurs when the rate of drug administration equals the rate of drug excretion.


Onset, peak, and duration


In addition to absorption, distribution, metabolism, and excretion, three other factors play important roles in a drug’s pharmacoki-netics:  

·                 onset of action

·                 peak concentration

·                 duration of action.


Lights, camera… action!

The onset of action refers to the time interval from when the drug is administered to when its therapeutic effect actually begins. Rate of onset varies depending on the route of administration and other pharmacokinetic properties.


Peak performance

As the body absorbs more drug, blood concentration levels rise. The peak concentration level is reached when the absorption rateequals the elimination rate. However, the time of peak concentra-tion isn’t always the time of peak response.


Sticking around


The duration of action is the length of time the drug produces its therapeutic effect.


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