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Unit I, Principles of Drug Therapy Cheat Sheet by

Principles of Drug Therapy

DEFINI­TIONS

Pharma­cology: the science that studies the effect of chemical compounds (drugs, medicine) on the biological system (cells, organs..).
Pharmacy: the science or practice of the prepar­­ation and dispensing of medicinal drugs.
Pharma­cist: : a health­-care profes­sional licensed to engage in pharmacy with duties including dispensing prescr­iption drugs, monitoring drug intera­ctions, admini­stering vaccines, and counseling patients regarding the effects and proper usage of drugs and dietary supple­ments.
Toxico­logy: is the study of the adverse effects of chemicals (including drugs) on living systems and the means to prevent or ameliorate such effects. In addition to therap­eutic agents, toxico­logists examine many enviro­nmental agents and chemical compounds that are synthe­sized by humans or that originate in nature.
A pharma­ceu­tical drug: also called a medication or medicine, is a chemical substance used to treat, cure, prevent, or diagnose a disease or to promote well-b­eing. Tradit­ionally drugs were obtained through extraction from medicinal plants, but more recently also by organic synthesis.
Pharma­­co­k­i­ne­­tics: refers to what the body does to a drug.
Pharma­­co­d­y­na­­mics: describes what the drug does to the body. M­OA. the intera­­ction between the drug and the target. struct­ure­-ac­tivity relati­onship of the drug.
Absorp­­tion: First, absorption from the site of admini­­st­r­ation permits entry of the drug (either directly or indire­­ctly) into plasma. Its rate and efficiency depend on the route of admini­str­ation. Complete 100% after IV admini­str­ation.
Distri­­bu­tion: Second, the drug may then reve­rsi­bly leave the bloods­­tream and distribute into the inters­­titial and intrac­­el­lular fluids.
Metabo­­lism: Third, the drug may be biotra­­ns­f­ormed by metabolism by the liver or other tissues.
Elimin­­ation: Finally, the drug and its metabo­­lites are eliminated from the body in urine, bile, or feces.
Bioava­ila­bility: Amount of the drug in the blood/­amount of blood at the site of admini­str­ati­on*­100%. indicator for ABS.
Elimin­ation half-life: is the length of time required for the concen­tration of a particular substance (typically a drug) to decrease to half of its starting dose in the body
The duration of action of a drug: is the length of time that particular drug is effective. Duration of action is a function of several parameters including plasma half-life, the time to equili­brate between plasma and target compar­tments, and the off rate of the drug from its biological target.
Onset of action: is the duration of time it takes for a drug's effects to come to prominence upon admini­str­ation. With oral admini­str­ation, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question.
 

ROUTES OF DRUG ADMINI­STR­ATION

The route of admini­str­ation is determined by the properties of the drug (for example, water or lipid solubi­lity, ioniza­tion) and by the therap­eutic objectives (for example, the desira­bility of a rapid onset, the need for long-term treatment, or restri­ction of delivery to a local site). Major routes of drug admini­str­ation include enteral, parent­eral, and topical, among others.
A. Ente­ral: Enteral admini­str­ation (admin­ist­ering a drug by mouth) is the safest and most common, conven­ient, and economical method of drug admini­str­ation. The drug may be swallowed, allowing oral delivery, or it may be placed under the tongue (subli­ngual), or between the gums and cheek (buccal), facili­tating direct absorption into the bloods­tream.
1. Oral: Oral admini­str­ation provides many advant­ages. Oral drugs are easily self-a­dmi­nis­tered, and toxicities and/or overdose of oral drugs may be overcome with antidotes, such as activated charcoal. However, the pathways involved in oral drug absorption are the most compli­cated, and the low gastric pH inacti­vates some drugs. A wide range of oral prepar­ations is available including enteri­c-c­oated and extend­ed-­release prepar­ations.
a. Ente­ric­-coated prepar­ati­ons: An enteric coating is a chemical envelope that protects the drug from stomach acid, delivering it instead to the less acidic intestine, where the coating dissolves and releases the drug. Enteric coating is useful for certain drugs (for example, omepra­zole) that are acid unstable. Drugs that are irritating to the stomach, such as aspirin, can be formulated with an enteric coating that only dissolves in the small intestine, thereby protecting the stomach.
b. Exte­nde­d-r­elease prepar­ati­ons: Extend­ed-­release (abbre­viated ER or XR) medica­tions have special coatings or ingred­ients that control the drug release, thereby allowing for slower absorption and a prolonged duration of action. ER formul­ations can be dosed less frequently and may improve patient compli­ance. Additi­onally, ER formul­ations may maintain concen­tra­tions within the therap­eutic range over a longer period of time, as opposed to immedi­ate­-re­lease dosage forms, which may result in larger peaks and troughs in plasma concen­tra­tion. ER formul­ations are advant­ageous for drugs with short half-l­ives. For example, the half-life of oral morphine is 2 to 4 hours, and it must be admini­stered six times daily to provide continuous pain relief. However, only two doses are needed when extended release tablets are used. Unfort­una­tely, many ER formul­ations have been developed solely for a marketing advantage over immedi­ate­-re­lease products, rather than a documented clinical advantage.
2. Subl­ing­ual­/bu­ccal: Placement under the tongue allows a drug to diffuse into the capillary network and enter the systemic circul­ation directly. Sublingual admini­str­ation has several advant­ages, including ease of admini­str­ation, rapid absorp­tion, bypass of the harsh gastro­int­estinal (GI) enviro­nment, and avoidance of firstpass metabolism (see discussion of first-pass metabolism below). The buccal route (between the cheek and gum) is similar to the sublingual route.
B. Pare­nte­ral: The parenteral route introduces drugs directly into the systemic circul­ation. Parenteral admini­str­ation is used for drugs that are poorly absorbed from the GI tract (for example, heparin) or unstable in the GI tract (for example, insulin). Parenteral admini­str­ation is also used if a patient is unable to take oral medica­tions (uncon­scious patients) and in circum­stances that require a rapid onset of action. In addition, parenteral routes have the highest bioava­ila­bility and are not subject to first-pass metabolism or the harsh GI enviro­nment. Parenteral admini­str­ation provides the most control over the actual dose of drug delivered to the body. However, these routes of admini­str­ation are irreve­rsible and may cause pain, fear, local tissue damage, and infect­ions. The three major parenteral routes are intrav­ascular (intra­venous or intra-­art­erial), intram­usc­ular, and subcut­aneous.
1. Intr­avenous (IV): IV injection is the most common parenteral route. It is useful for drugs that are not absorbed orally, such as the neurom­uscular blocker rocuro­nium. IV delivery permits a rapid effect and a maximum degree of control over the amount of drug delivered. When injected as a bolus, the full amount of drug is delivered to the systemic circul­ation almost immedi­ately. If admini­stered as an IV infusion, the drug is infused over a longer period of time, resulting in lower peak plasma concen­tra­tions and an increased duration of circul­ating drug levels. IV admini­str­ation is advant­ageous for drugs that cause irritation when admini­stered via other routes, because the substance is rapidly diluted by the blood. Unlike drugs given orally, those that are injected cannot be recalled by strategies such as binding to activated charcoal. IV injection may inadve­rtently introduce infections through contam­ination at the site of injection. It may also precip­itate blood consti­tuents, induce hemolysis, or cause other adverse reactions if the medication is delivered too rapidly and high concen­tra­tions are reached too quickly. Therefore, patients must be carefully monitored for drug reactions, and the rate of infusion must be carefully contro­lled.
2. Intr­amu­scular (IM): Drugs admini­stered IM can be in aqueous solutions, which are absorbed rapidly, or in specia­lized depot prepar­ations, which are absorbed slowly. Depot prepar­ations often consist of a suspension of the drug in a nonaqueous vehicle such as polyet­hylene glycol. As the vehicle diffuses out of the muscle, the drug precip­itates at the site of injection. The drug then dissolves slowly, providing a sustained dose over an extended period of time. Examples of sustai­ned­-re­lease drugs are halope­ridol and depot medrox­ypr­oge­ste­rone.
3. Subc­uta­neous (SC): Like IM injection, SC injection provides absorption via simple diffusion and is slower than the IV route. SC injection minimizes the risks of hemolysis or thrombosis associated with IV injection and may provide constant, slow, and sustained effects. This route should not be used with drugs that cause tissue irrita­tion, because severe pain and necrosis may occur. Drugs commonly admini­stered via the subcut­aneous route include insulin and heparin.
C. Other: 1. Oral inhala­tion: Inhalation routes, both oral and nasal (see discussion of nasal inhala­tion), provide rapid delivery of a drug across the large surface area of the mucous membranes of the respir­atory tract and pulmonary epithe­lium. Drug effects are almost as rapid as those with IV bolus. Drugs that are gases (for example, some anesth­etics) and those that can be dispersed in an aerosol are admini­stered via inhala­tion. This route is effective and convenient for patients with respir­atory disorders (such as asthma or chronic obstru­ctive pulmonary disease), because the drug is delivered directly to the site of action, thereby minimizing systemic side effects. Examples of drugs admini­stered via inhalation include bronch­odi­lators, such as albuterol, and cortic­ost­eroids, such as flutic­asone.
2. Nasal inhala­tion: This route involves admini­str­ation of drugs directly into the nose. Examples of agents include nasal decong­est­ants, such as oxymet­azo­line, and cortic­ost­eroids, such as mometasone furoate. Desmop­ressin is admini­stered intran­asally in the treatment of diabetes insipidus.
3. Intr­ath­eca­l/i­ntr­ave­ntr­icu­lar: The blood–­brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebr­ospinal fluid. For example, intrat­hecal amphot­ericin B is used in treating crypto­coccal mening­itis.
4. Topi­cal: Topical applic­ation is used when a local effect of the drug is desired. For example, clotri­mazole is a cream applied directly to the skin for the treatment of fungal infect­ions.
5. Tran­sde­rmal: This route of admini­str­ation achieves systemic effects by applic­ation of drugs to the skin, usually via a transd­ermal patch. The rate of absorption can vary markedly, depending on the physical charac­ter­istics of the skin at the site of applic­ation, as well as the lipid solubility of the drug. This route is most often used for the sustained delivery of drugs, such as the antian­ginal drug nitrog­lyc­erin, the antiemetic scopol­amine, and nicotine transd­ermal patches, which are used to facilitate smoking cessation.
6. Rectal: Because 50% of the drainage of the rectal region bypasses the portal circul­ation, the biotra­nsf­orm­ation of drugs by the liver is minimized with rectal admini­str­ation. The rectal route has the additional advantage of preventing destru­ction of the drug in the GI enviro­nment. This route is also useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is uncons­cious. [Note: The rectal route is commonly used to administer antiemetic agents.] Rectal absorption is often erratic and incomp­lete, and many drugs irritate the rectal mucosa.
 

ABSORPTION OF DRUGS

Absorption is the transfer of a drug from the site of admini­str­ation to the bloods­tream. The rate and extent of absorption depend on the enviro­nment where the drug is absorbed, chemical charac­ter­istics of the drug, and the route of admini­str­ation (which influences bioava­ila­bil­ity). Routes of admini­str­ation other than intrav­enous may result in partial absorption and lower bioava­ila­bility.
A. Mech­anisms of absorption of drugs from the GI tract: Depending on their chemical proper­ties, drugs may be absorbed from the GI tract by passive diffusion, facili­tated diffusion, active transport, or endocy­tosis
1. Passive diffus­ion: The driving force for passive absorption of a drug is the concen­tration gradient across a membrane separating two body compar­tments. In other words, the drug moves from a region of high concen­tration to one of lower concen­tra­tion. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specif­icity. The vast majority of drugs are absorbed by this mechanism. Water-­soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas lipid-­soluble drugs readily move across most biologic membranes due to their solubility in the membrane lipid bilayers.
2. Faci­litated diffus­ion: Other agents can enter the cell through specia­lized transm­embrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo confor­mat­ional changes, allowing the passage of drugs or endogenous molecules into the interior of cells and moving them from an area of high concen­tration to an area of low concen­tra­tion. This process is known as facili­tated diffusion. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier.
3. Active transp­ort: This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabo­lites are actively transp­orted across cell membranes using specific carrier proteins. Energy­-de­pendent active transport is driven by the hydrolysis of adenosine tripho­sphate. It is capable of moving drugs against a concen­tration gradient, from a region of low drug concen­tration to one of higher drug concen­tra­tion. The process is saturable. Active transport systems are selective and may be compet­itively inhibited by other cotran­sported substa­nces.
4. Endo­cytosis and exocyt­osi­s:­This type of absorption is used to transport drugs of except­ionally large size across the cell membrane. Endocy­tosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drugfilled vesicle. Exocytosis is the reverse of endocy­tosis. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. Vitamin B12 is transp­orted across the gut wall by endocy­tosis, whereas certain neurot­ran­smi­tters (for example, norepi­nep­hrine) are stored in intrac­ellular vesicles in the nerve terminal and released by exocyt­osis.
B. Factors influe­ncing absorp­tion: 1. Effect of pH on drug absorp­tion: Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a proton (H+), causing a charged anion (A−) to form: HA --> H+ + A−
Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B): BH+ --> B + H+
A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A− cannot. For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not. Therefore, the effective concen­tration of the permeable form of each drug at its absorption site is determined by the relative concen­tra­tions of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is repres­ented by the ionization constant, pKa. [Note: The pKa is a measure of the strength of the intera­ction of a compound with a proton. The lower the pKa of a drug, the more acidic it is. Conver­sely, the higher the pKa, the more basic is the drug.] Distri­bution equili­brium is achieved when the permeable form of a drug achieves an equal concen­tration in all body water spaces.
2. Blood flow to the absorption site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach. [Note: Shock severely reduces blood flow to cutaneous tissues, thereby minimizing absorption from SC admini­str­ation.]
3. Total surface area available for absorp­tion: With a surface rich in brush borders containing microv­illi, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient.
4. Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conver­sely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. [Note: The presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly.]
5. Expr­ession of P-glyc­opr­ote­in: P-glyc­opr­otein is a transm­embrane transp­orter protein respon­sible for transp­orting various molecules, including drugs, across cell membranes (Figure 1.9). It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intest­ines, and brain capill­aries, and is involved in transp­ort­ation of drugs from tissues to blood. That is, it “pumps” drugs out of the cells. Thus, in areas of high expres­sion, P-glyc­opr­otein reduces drug absorp­tion. In addition to transp­orting many drugs out of cells, it is also associated with multidrug resist­ance.
C. Bioa­vai­lab­ili­ty: Bioava­ila­bility is the rate and extent to which an admini­stered drug reaches the systemic circul­ation. For example, if 100 mg of a drug is admini­stered orally and 70 mg is absorbed unchanged, the bioava­ila­bility is 0.7 or 70%. Determ­ining bioava­ila­bility is important for calcul­ating drug dosages for nonint­rav­enous routes of admini­str­ation.
1. Dete­rmi­nation of bioava­ila­bil­ity: Bioava­ila­bility is determined by comparing plasma levels of a drug after a particular route of admini­str­ation (for example, oral admini­str­ation) with levels achieved by IV admini­str­ation. After IV admini­str­ation, 100% of the drug rapidly enters the circul­ation. When the drug is given orally, only part of the admini­stered dose appears in the plasma. By plotting plasma concen­tra­tions of the drug versus time, the area under the curve (AUC) can be measured. The total AUC reflects the extent of absorption of the drug. Bioava­ila­bility of a drug given orally is the ratio of the AUC following oral admini­str­ation to the AUC following IV admini­str­ation
2. Factors that influence bioava­ila­bil­ity: In contrast to IV admini­str­ation, which confers 100% bioava­ila­bility, orally admini­stered drugs often undergo first-pass metabo­lism. This biotra­nsf­orm­ation, in addition to the chemical and physical charac­ter­istics of the drug, determines the rate and extent to which the agent reaches the systemic circul­ation.
a. Firs­t-pass hepatic metabo­lism: When a drug is absorbed from the GI tract, it enters the portal circul­ation before entering the systemic circul­ation. If the drug is rapidly metabo­lized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circul­ation is decreased. This is referred to as first-pass metabo­lism. [Note: First-pass metabolism by the intestine or liver limits the efficacy of many oral medica­tions. For example, more than 90% of nitrog­lycerin is cleared during first-pass metabo­lism. Hence, it is primarily admini­stered via the sublingual or transd­ermal route.] Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action.
b. Solu­bility of the drug: Very hydrop­hilic drugs are poorly absorbed because of their inability to cross lipid-rich cell membranes. Parado­xic­ally, drugs that are extremely lipophilic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely lipoph­ilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases.
c. Chemical instab­ili­ty: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degrad­ative enzymes.
D. Bioe­qui­val­ence: Two drug formul­ations are bioequ­ivalent if they show comparable bioava­ila­bility and similar times to achieve peak blood concen­tra­tions.
E. Ther­apeutic equiva­len­ce:­Two drug formul­ations are therap­eut­ically equivalent if they are pharma­ceu­tically equivalent (that is, they have the same dosage form, contain the same active ingred­ient, and use the same route of admini­str­ation) with similar clinical and safety profiles. [Note: Clinical effect­iveness often depends on both the maximum serum drug concen­tration and the time required (after admini­str­ation) to reach peak concen­tra­tion. Therefore, two drugs that are bioequ­ivalent may not be therap­eut­ically equiva­lent.]
 

DRUG DISTRI­BUTION

Drug distri­bution is the process by which a drug reversibly leaves the bloods­tream and enters the inters­titium (extra­cel­lular fluid) and the tissues. For drugs admini­stered IV, absorption is not a factor, and the initial phase (from immedi­ately after admini­str­ation through the rapid fall in concen­tra­tion) represents the distri­bution phase, during which the drug rapidly leaves the circul­ation and enters the tissues. The distri­bution of a drug from the plasma to the inters­titium depends on cardiac output and local blood flow, capillary permea­bility, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative lipoph­ilicity of the drug.
A. Blood flow:The rate of blood flow to the tissue capill­aries varies widely. For instance, blood flow to the “vesse­l-rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. Variation in blood flow partly explains the short duration of hypnosis produced by an IV bolus of propofol. High blood flow, together with high lipoph­ilicity of propofol, permits rapid distri­bution into the CNS and produces anesth­esia. A subsequent slower distri­bution to skeletal muscle and adipose tissue lowers the plasma concen­tration so that the drug diffuses out of the CNS, down the concen­tration gradient, and consci­ousness is regained.
B. Capillary permea­bil­ity: Capillary permea­bility is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between endoth­elial cells. In the liver and spleen, a signif­icant portion of the basement membrane is exposed due to large, discon­tinuous capill­aries through which large plasma proteins can pass. In the brain, the capillary structure is contin­uous, and there are no slit junctions. To enter the brain, drugs must pass through the endoth­elial cells of the CNS capill­aries or be actively transp­orted. For example, a specific transp­orter carries levodopa into the brain. By contrast, lipid-­soluble drugs readily penetrate the CNS because they dissolve in the endoth­elial cell membrane. Ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endoth­elial cells that have no slit junctions. These closely juxtaposed cells form tight junctions that constitute the blood–­brain barrier.
C. Binding of drugs to plasma proteins and tissues 1. Binding to plasma proteins: Reversible binding to plasma proteins sequesters drugs in a nondif­fusible form and slows their transfer out of the vascular compar­tment. Albumin is the major drug-b­inding protein and may act as a drug reservoir (as the concen­tration of free drug decreases due to elimin­ation, the bound drug dissoc­iates from the protein). This maintains the free drug concen­tration
2. Binding to tissue proteins: Many drugs accumulate in tissues, leading to higher concen­tra­tions in tissues than in the extrac­ellular fluid and blood. Drugs may accumulate as a result of binding to lipids, proteins, or nucleic acids. Drugs may also be actively transp­orted into tissues. Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity. (For example, acrolein, the metabolite of cyclop­hos­pha­mide, can cause hemorr­hagic cystitis because it accumu­lates in the bladder.)
D. Lipoph­ili­city: The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic membranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. The major factor influe­ncing the distri­bution of lipophilic drugs is blood flow to the area. In contrast, hydrop­hilic drugs do not readily penetrate cell membranes and must pass through slit junctions.
E. Volume of distri­but­ion: The apparent volume of distri­bution, Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same concen­tration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circul­ation by the plasma concen­tration at time zero (C0).
1. Distri­bution into the water compar­tments in the body: Once a drug enters the body, it has the potential to distribute into any one of the three functi­onally distinct compar­tments of body water or to become seques­tered in a cellular site.
a. Plasma compar­tment: If a drug has a high molecular weight or is extens­ively protein bound, it is too large to pass through the slit junctions of the capill­aries and, thus, is effect­ively trapped within the plasma (vascular) compar­tment. As a result, it has a low Vd that approx­imates the plasma volume or about 4 L in a 70-kg indivi­dual. Heparin (see Chapter 22) shows this type of distri­bution.
b. Extrac­ellular fluid: If a drug has a low molecular weight but is hydrop­hilic, it can pass through the endoth­elial slit junctions of the capill­aries into the inters­titial fluid. However, hydrop­hilic drugs cannot move across the lipid membranes of cells to enter the intrac­ellular fluid. Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the inters­titial fluid, which together constitute the extrac­ellular fluid (about 20% of body weight or 14 L in a 70-kg indivi­dual). Aminog­lyc­oside antibi­otics (see Chapter 39) show this type of distri­bution.
c. Total body water: If a drug has a low molecular weight and is lipoph­ilic, it can move into the inters­titium through the slit junctions and also pass through the cell membranes into the intrac­ellular fluid. These drugs distribute into a volume of about 60% of body weight or about 42 L in a 70-kg indivi­dual. Ethanol exhibits this apparent Vd.
2. Apparent volume of distri­bution: A drug rarely associates exclus­ively with only one of the water compar­tments of the body. Instead, the vast majority of drugs distribute into several compar­tments, often avidly binding cellular compon­ents, such as lipids (abundant in adipocytes and cell membra­nes), proteins (abundant in plasma and cells), and nucleic acids (abundant in cell nuclei). Therefore, the volume into which drugs distribute is called the apparent volume of distri­bution (Vd). Vd is a useful pharma­cok­inetic parameter for calcul­ating the loading dose of a drug.
3. Determ­ination of Vd: The fact that drug clearance is usually a first-­order process allows calcul­ation of Vd. First order means that a constant fraction of the drug is eliminated per unit of time. This process can be most easily analyzed by plotting the log of the plasma drug concen­tration (Cp) versus time (Figure 1.14). The concen­tration of drug in the plasma can be extrap­olated back to time zero (the time of IV bolus) on the Y axis to determine C0, which is the concen­tration of drug that would have been achieved if the distri­bution phase had occurred instantly.
4. Effect of Vd on drug half-life: Vd has an important influence on the half-life of a drug, because drug elimin­ation depends on the amount of drug delivered to the liver or kidney (or other organs where metabolism occurs) per unit of time. Delivery of drug to the organs of elimin­ation depends not only on blood flow but also on the fraction of the drug in the plasma. If a drug has a large Vd, most of the drug is in the extrap­lasmic space and is unavai­lable to the excretory organs. Therefore, any factor that increases Vd can increase the half-life and extend the duration of action of the drug. [Note: An except­ionally large Vd indicates consid­erable seques­tration of the drug in some tissues or compar­tme­nts.]

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