Drug action is the physiochemical interaction between the drug molecule and moleculesin the body that alters a physiological process of the body in one of three ways.
A drug action begins when the drug enters the body and is absorbed into thebloodstream where the drug is transported to receptor sites throughout the body(see Pharmacokinetics, in this chapter). Once the drug hooks onto a receptor site,the drug’s pharmacological response initiates. The pharmacological responseis the therapeutic effect that makes the patient well.
Drugs have multiple actions. These are the desired effect and effects otherthan the desirable effect. The desirable effect is what makes the patient well orprevents the disease or disorder. An effect other than the desirable effect is knownas a side effect. Some side effects are desirable and others are undesirable (see Side Effects, in this chapter).
The strength of a drug action is determined by how much of the drug is given,(the dose) and how often the drug is given (the frequency). For example, a patientwho has a sore throat can be given a large dose of an antibiotic loading dose on the first day of treatment and a normal or maintenance dose for the next five days.
Drug activity is divided into three phases. These are:
The pharmaceutic phase is the form of the drug such as a tablet, capsule, liquid,elixirs, or syrups. The drug in solid form must disintegrate before dissolution,which is the process by which a drug goes into solution before it becomes available for absorption. Drugs contain an active ingredient and inactive ingredients.
The active ingredient is the substance that causes the pharmaceutical response. The inactive ingredient, called excipient, is the substance that has no pharmaceutical response but helps in the delivery of the drug. These are fillers and inert substances that give the drug its shape and size. The coating around tiny particles of a capsule that causes a timed-release action of the drug is an inactive ingredient.
Nearly 80% of all drugs are administered orally (P.O.) and are carried to thesmall intestine by the gastrointestinal tract where the drug is absorbed into thebloodstream. The time necessary for the drug to disintegrate and dissolve so itcan be absorbed is called the rate limiting time.
A drug has a higher rate limiting time (Table (Rate limiting time rating for drug forms) ) if it is absorbed in acidicfluids rather than alkaline fluids. Children and the elderly have a lower pH in theirGI tract and therefore drugs are absorbed more slowly than in a healthy adult.
Some drugs are more effective if absorbed in the small intestine rather thanthe stomach. However, the stomach is more acidic than the small intestine.Therefore, pharmaceutical manufacturers place an enteric coating around thedrug that resists disintegration in the stomach. The coating disintegrates in thealkaline environment of the small intestine. Enteric coating is also used to delaythe onset of the pharmaceutical response and to prevent food in the stomachfrom interfering with the dissolution and absorption of the drug.
Tip: Never crush a capsule that contains enteric release beads or is coatedfor timed-release.
The form of a drug influences the drug’s pharmacokinetics and pharmacodynamics.
Table: Rate limiting time rating for drug forms.
Pharmacokinetics is the study of the drug concentration during absorption, distribution, and elimination of a drug in the patient. About 80% of all drugs areadministered orally and flow through the gastrointestinal tract (GI) into the smallintestine where the membrane of the intestine absorbs drug particles passingthem into the bloodstream, where plasma circulates the particles, throughout thebody. Drug molecules move to the intended site of action in the plasma butsometimes this journey can be limited because they have to get into the interiorof a cell or body compartment through cell membranes.
These membranes couldbe in the skin, the intestinal tract, or the intended site of action. Drug particlesthen attach themselves to receptor sites resulting in its therapeutic effect.
There are three ways in which drug particles are absorbed. These are:
Passive diffusion is the flow of drug particles from a high concentration to a lowConcentration similar to how water flows downstream. There is a higher concentration of water upstream than there is downstream. There is no energy expended in passive diffusion because drug particles are moving along the natural flow.
Active diffusion is how drug particles swim upstream against the natural flowwhen there is a higher concentration of plasma than there is of drug particles.Drug particles don’t have enough energy to go against the natural flow withouthelp. Help comes from an enzyme or protein carrier that transports drug particlesupstream across the membrane and into the plasma. The enzyme or proteincarrier expends energy to move drug particles.
Pinocytosis is the process of engulfing the drug particle and pulling it across themembrane. This is similar to how you eat an ice pop by engulfing a piece of itin with your mouth and swallowing it.
Absorption begins where the drug is administered. This can be by mouth, injection,through the skin, and many other sites. How quickly the drug becomes therapeutic will depend on how fast the drug is absorbed. How long the drug will beeffective and how much drug is needed depends on the route of administration,the dose of the drug, and the dosage form (tablet, capsule, or liquid).
The absorption rate of a drug is influenced by a number of factors thatmight increase or decrease the rate, This is similar to how more gasoline isused to drive at faster speeds. Absorption is affected by many factors thatinclude pain, stress, hunger, fasting, food, and pH. Hot, solid, fatty foods canslow absorption such as eating a Big Mac before taking medication. Evenexercise which is usually good for the body affects absorption of a drug.During exercise, circulation to the stomach is diverted to other areas of thebody and drug absorption is decreased.
Blood flow to the site of administration of the drug will help increase the rate ofabsorption. An area that has a lot of blood vessels and good circulation will helpabsorb the drug quickly and circulate it to the intended site. When a patient is inshock and has a low blood pressure due to decreased circulation (blood flow)drugs may not be absorbed very quickly.
Route of Administration
The rate at which drug particles are absorbed is determined by the amount ofblood vessels there are in the area where the drug is administered. Drug particlesare nearly instantaneously absorbed if the drug is injected intravenously (IV). Aslower absorption rate occurs if the drug is administered intramuscularly (IM).The IM rate is dependent on the amount of blood vessels there are at the site ofthe injection. For example, a drug is absorbed faster in the deltoid (arm) musclethan in the gluteal (butt) muscle because there are more blood vessels in the deltoid muscle. Drugs injected in subcutaneous (SC) tissue are absorbed slowerthan those injected via IM injections because there are fewer blood vessels insubcutaneous tissues than in muscles.
Drug particles dissolve in either lipid (fat) or water. Lipid-soluble drugs areabsorbed more quickly than water-soluble drugs because membranes in the GItract are composed of lipids making those membranes a perfect highway forlipid soluble drugs to move from the GI tract and into the bloodstream.However, membranes of the GI tract do not directly absorb large water-solublemolecules and a carrier must be used to transport the water-soluble drugs acrossthe GI membrane and into the bloodstream. This additional step causes water-soluble drugs to be absorbed more slowly than fat-soluble drugs.
The pH level of a drug determines how easily drug particles will be absorbed in the GI tract.Those drugs that are a weak acid such as aspirin can pass rapidly across the GI tract membrane while weak base drugs such as an antacid are absorbed more slowly than a weak acidic drug.Strong acids and bases destroy cells and are not absorbed.
The concentration of the drug will also affect the rate of absorption. If a high concentration of the drug is given, it will tend to be absorbed more rapidly.Sometimes larger(loading or priming)doses of a drug may be given that will bemore than the body can excrete. When this is done, the drug becomes therapeuticmuch faster. After the first large dose,small maintenance doses will help keep the therapeutic effect.
The form (solid, liquid) the drug is given can affect the absorption rate.Drugs can be processed when they are manufactured to add other ingredientsthat will help or hinder absorption.
Not all drug particles reach the circulatory system.Some particles are misdirected or destroyed during the absorption process.For example, hydrochloric acid in the stomach destroys some drug particles before it can pass through themembrane and into the bloodstream.
The percentage of a dose that reaches the blood stream is called the bio availabilityof a drug. Typically, between 20% and 40% of drugs that are administeredorally reach the blood stream. This is called the first pass effect and is thebeginning of the metabolism of a drug that is given orally. After a drug is absorbedin the GI tract it is carried to the liver and metabolism occurs. Sometimes very littleof the drug remains available for a therapeutic effect after the first pass. Onlydrugs administered intravenously have a 100% bio availability because they aredirectly injected into the vein.
Pharmaceutical manufacturers must consider bio availability when determiningthe dose for a drug. For example, the dose for a drug administered PO (orally)might be 4 times higher than if the same drug is administered intravenously.
There are a number of factors that alter bio availability.These are:
A drug contains an active ingredient, which produces the therapeutic effect, andother materials that give the drug form and protection. The percent of activeingredient in a dose is referred to as the drug concentration.
There are generally two levels of concentrations. These are primary loadinga large concentration that is used to achieve a fast therapeutic effect such as thefirst dose of an antibiotic, and maintenance do sea typical concentration ofthe drug that is used to provide an ongoing therapeutic effect such as subsequentdoses of an antibiotic.
Once absorbed, drug particles are transported in blood plasma. These arereferred to as “free” drugs because they are not bound to any receptor sites. Onlyfree drugs can cause a pharmacological response. Drugs bind to proteins inplasma, usually albumin or globulins. These drug protein complexes decreasethe concentration of free drug in the circulation. This protein–drug molecule istoo large to pass through the membrane of a blood vessel and is not available fortherapeutic use.
This process can be reversed when free drug is excreted fromthe body. The drug molecule is released from the protein and it becomes freedrug and can be absorbed for use. Drugs affect areas of the body with goodblood supply first, such as the heart, liver, kidney, and brain and then flow toareas with less blood supply, such as muscles and fat.
Drugs accumulate in an area of the body and form a reservoir by binding totissues. This is referred to as pooling. There are two types of pooling. These areprotein binding when a drug binds to plasma proteins, and tissue binding fatsoluble drugs are stored in adipose (fat) tissue. Inderal (propranolol) is a heartmedication that is highly bound to and only about 7% of free drug is availablefor use at a time. Thiopental (pentothal) is an anesthetic agent that is stored infat tissue. In addition, some drugs, such as the antibiotic Tetracycline like to bestored in bones which can interfere with growth of fetal skeletal tissues and candiscolor teeth if given to children under eight years of age.Distribution of drugs is affected by three factors.
Level of Plasma Protein
A low level of plasma protein and albumin might not provide enough bindingsites for drug particles. This results in a buildup of drugs which can reach a toxiclevel. This happens when there is liver or kidney disease or if the patient is malnourished resulting in low albumin levels (hypoalbuminemia). The elderly areprone to hypoalbuminemia. Healthcare professionals should monitor a patient’splasma protein and albumin levels and the protein-binding percentage of alldrugs before administering drugs to the patient.
There must be adequate blood flow to target areas of the body; otherwise, insufficient drug particles will reach affected parts of the body. Drugs can also bestored in fat, bones, muscle, and the eyes. Drugs that accumulate in fat are calledlipid soluble and remain for about three hours because there is low blood flowin fat tissue.
The body also has a blood–brain barrier that enables only lipid solubleDrugs such as general anesthetics and barbiturates into the brain and cerebralspinal fluid (CSF). The only way for non lipid soluble drugs to enter thebrain is if they are instilled intrathecally, that is, injected directly into the CSF,bypassing the blood-brain barrier.
Two drugs administered simultaneously might compete for the same bindingsites making some drug particles unable to find a binding site. The result is anaccumulation of free drug that could reach toxic levels. Two drugs that arehighly protein bound such as Coumadin (warfarin) and Inderal (propranolol) will compete for the protein sites. This can cause serious problems andcan result in toxic levels of one or both of the drugs when increased amounts offree drug become available.
Abscesses, exudates, body glands, and tumors hinder the distribution of drugsin the body. In addition, antibodies do not distribute well at abscess and exudatessites. The placenta metabolizes some drugs making then inactive and therebyprotecting the fetus from drugs given to the mother. However, steroids, narcotics,anesthetics, and some antibiotics can penetrate the placental barrier andcause adverse effects to the fetus.
Drugs accumulate in a reservoir and are gradually absorbed and eventually eliminated by the body. This metabolism called biotransformationoccurs in theliver where enzymes inactivate a drug by changing it into more water-solublecompounds that can be excreted from the body. Elimination occurs mainlythrough the kidneys, although some drugs are also eliminated in bile, feces,lungs, sweat, and breast milk.
Patients suffering from liver diseases are prone to drug toxicity because thediseased liver no longer metabolizes the drug sufficiently to allow eliminationthrough the kidneys. The result is a buildup of the drug, which can eventuallylead to a toxic effect on the body.
The amount of time for half of the drug concentration to be eliminated fromthe body is called the drug’s half-life and is a crucial measurement used to determine how often to administer a drug. Some drugs have a short half-life (less than 8 hours) while other drugs have a longer half-life (24 hours).
For example, Digoxin has a half-life of 36 hours. This means it takes 5 to7 days before there is a steady state of Digoxin in the serum. This is referredto as the steady state serum concentration and is the time it takes for the drug tohave a therapeutic effect.
Children and the elderly might be unable to absorb and/or eliminate drugs.This can result in toxicity should additional doses be given before the previousdoes is eliminated from the body. Free drugs, water-soluble drugs, andunchanged drugs are filtered by the kidneys and eliminated through urine.Protein-bound drugs do not filter through the kidneys until the drug is releasedfrom the protein.
The quantity of drugs that can be excreted by the kidneys is influenced by thepH of the urine, which normally is between 4.5 and 8.0. Acidic urine (4.5) elimi-nates weak base drugs; alkaline urine (8.0) eliminates weak acid drugs. The pH ofurine can be altered to increase the elimination of certain drugs. For example, urinecan be made more alkaline by giving the patient sodium bicarbonate or made moreacidic by giving the patient high doses of vitamin C or ammonium chloride.Kidney disease decreases the glomerular filtration rate (GFR) and therebyreduces the quantity of drugs that can be eliminated by the kidneys. This canresult in drug toxicity. A similar effect can be caused by a decrease in blood flow to the kidneys.
Kidney function is tested by the creatinine clearance test. A decrease in GFRcauses an increase in creatinine in serum and a decrease in creatinine in urine.The results of the creatinine clearance test vary with age and whenever there isdecreased muscle mass.
In some situations, it is important to reduce the excretion of a drug to prolongthe drug’s therapeutic effect, such as with penicillin. Giving the patient anotherdrug, such as Provence, blocks excretion of penicillin.
Drugs can be excreted artificially through the use of dialysis, which is a commontreatment in certain drug overdoses. Drugs that are excreted by the kidneyscan be eliminated using hemodialysis. These drugs include stimulants, depressants,and some non-narcotic analgesics.
Drugs that are metabolized by the liver are secreted into bile and then passedthrough the intestines and eliminated in feces. During this process, the bloodstreammight reabsorb fat-soluble drugs and return them to the liver where they aremetabolized and eliminated by the kidneys. This is called the enterohepatic cycle.The lungs eliminate drugs that are intact and not metabolites such as gasesand anesthetic drugs. The rate at which these drugs are eliminated correspondsto the respiratory rate. Some drugs, such as ethyl alcohol and paraldehyde, areexcreted at multiple sites. A small amount is excreted by the lungs and the restby the liver and the kidneys. Volatile drugs such as anesthetics and drugs that aremetabolized to CO2 and H20, are excreted through the lungs.
Sweat and salivary glands are not a major route of drug elimination becauseelimination depends on the diffusion of lipid-soluble drugs through the epithelialcells of the glands. However, side effects of drugs, such as rashes and skinreactions, can be seen at these sites. Some intravenously administered drugs areexcreted into saliva and cause the patient to taste the drug. Eventually, drugs thatare excreted into saliva are swallowed, reabsorbed, and eliminated in urine.Many drugs or their metabolites are excreted in mammary glands. Theseinclude narcotics such as morphine and codeine. Diuretics and barbiturates,which are weak acids, are less concentrated in breast milk. However, evensmall amounts of drugs can accumulate causing an undesirable effect on aninfant receiving breast milk.
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