Pharmacodynamics

0
724

Pharmacodynamics

The graded dose–response curve expresses an individual’s response to increasing doses of a given drug. The magnitude of a pharmacologic response is proportional to the number of receptors with which a drug effectively interacts (Fig. 1-2). The graded dose–response curve includes the following parameters:

1. Magnitude of response is graded; that is, it continuously increases with the dose up to the max- imal capacity of the system, and it is often depicted as a function of the logarithm of the dose administered (to see the relationship over a wide range of doses).

2. ED50 is the dose that produces the half-maximal response; the threshold dose is that which produces the first noticeable effect.

3. Intrinsic activity is the ability of a drug once bound to activate the receptor. a. Agonistsaredrugscapableofbindingto,andactivating,areceptor.

(1) Full agonists occupy receptors to cause maximal activation; intrinsic activity 1⁄4 1.

(2) Partial agonists can occupy receptors but cannot elicit a maximal response. Such drugs

have an intrinsic activity of less than 1 (Fig. 1-3; drug C).

b. Antagonists bind to the receptor but do not initiate a response; that is, they block the action

of an agonist or endogenous substance that works through the receptor.

(1) Competitive antagonists combine with the same site on the receptor as the agonist but have little or no efficacy and an intrinsic activity of 0. Competitive antagonists may be reversible or irreversible. Reversible, or equilibrium, competitive antagonists are not covalently bound, shift the dose–response curve for the agonist to the right, and increase the ED50; that is, more agonist is required to elicit a response in the presence of the antagonist (Fig. 1-4). Because higher doses of agonist can overcome the inhibition, the maximal response can still be obtained.

(2) Noncompetitive antagonists bind to the receptor at a site other than the agonist-binding site (Fig. 1-5) and either prevent the agonist from binding correctly or prevent it from acti- vating the receptor. Consequently, the effective amount of receptor is reduced. Receptors unoccupied by antagonist retain the same affinity for agonist, and the ED50 is unchanged.

4. Potency of a drug is the relative measure of the amount of a drug required to produce a speci- fied level of response (e.g., 50%) compared to other drugs that produce the same effect via the same receptor mechanism. The potency of a drug is determined by the affinity of a drug for its receptor and the amount of administered drug that reaches the receptor site. The relative po- tency of a drug can be demonstrated by comparing the ED50 values of two full agonists; the drug with the lower ED50 is more potent. (For example, in Fig. 1-3, drug A is more potent than drug B.)

5. The efficacy of a drug is the ability of a drug to elicit the pharmacologic response. Efficacy may be affected by such factors as the number of drug–receptor complexes formed, the ability of the drug to activate the receptor once it is bound, and the status of the target organ or cell.

6. Slope is measured at the midportion of the dose–response curve. The slope varies for different drugs and different responses. Steep dose–response curves indicate that a small change in dose produces a large change in response.

7. Variability reflects the differences between individuals in response to a given drug.

8. Therapeutic index (TI) relates the desired therapeutic effect to undesired toxicity; it is deter- mined using data provided by the quantal dose–response curve. The therapeutic index is defined as TD50/ED50 (i.e., the ratio of the dose that produces a toxic effect in half of the popu- lation to the dose that produces the desired effect in half of the population). Note that the ther- apeutic index should be used with caution in instances when the quantal dose–response curves for the desired and toxic effects are not parallel.

C. The quantal dose–response curve (Figs. 1-6A and B) relates the dosage of a drug to the fre- quency with which a designated response will occur within a population. The response may be an ‘‘all-or-none’’ phenomenon (e.g., individuals either do or do not fall asleep after receiving a sedative) or some predetermined intensity of effect. The quantal dose–response curve is obtained via transformation of the data used for a frequency distribution plot to reflect the cumulative frequency of a response. In the context of the quantal dose–response curve, ED50 indicates the dose of drug that produces the response in half of the population. (Note that this differs from the meaning of ED50 in a graded dose–response curve.)

DRUGABSORPTION

Drug absorption is the movement of a drug from its site of administration into the bloodstream. In many cases, a drug must be transported across one or more biologic membranes to reach the bloodstream.

A. Drugtransportacrossmembranes

1. Diffusion of un-ionized drugs is the most common and most important mode of traversing bio- logic membranes; drugs diffuse passively down their concentration gradient. Diffusion can be influenced significantly by the lipid–water partition coefficient of the drug, which is the ratio of solubility in an organic solvent to solubility in an aqueous solution. In general, absorption increases as lipid solubility (partition coefficient) increases. Other factors that also can influ- ence diffusion include the concentration gradient of the drug across the cell membrane, and the surface area of the cell membrane.

2. Diffusionofdrugsthatareweakelectrolytes

a. Onlytheun-ionizedformofdrugcandiffuseacrossbiologicmembranes.

b. The degree of ionization of a weak acid or base is determined by the pK of the drug and pH

of its environment according to the Henderson-Hasselbalch equation. (1) For a weak acid, A,

HA H+ +A,

pH = pK + log[A] / [HA], and log [A] / [HA] = pHpK

where HA is the concentration of the protonated, or un-ionized, form of the acid

and A– is the concentration of the ionized, or unprotonated, form.

2) For a weak base, B,

BH+ →H++B,

pH = pK + log[B] / [BH+], and log[B]/[BH+]=pHpK

where BH+ is the concentration of the protonated form of the base, and B is the

concentration of the unprotonated form.

c. When the pK of a drug equals the pH of the surroundings, 50% ionization occurs; that is,

equal numbers of ionized and un-ionized species are present. A lower pK reflects a stronger

acid; a higher pK corresponds to a stronger base.

d. DrugswithdifferentpKvalueswilldiffuseacrossmembranesatdifferentrates.

e. The pH of the biologic fluid in which the drug is dissolved affects the degree of ionization

and, therefore, the rate of drug transport.

3. Active transport is an energy-dependent process that can move drugs against a concentration

gradient, as in protein-mediated transport systems. Active transport occurs in only one direction and is saturable. It is usually the mode of transport for drugs that resemble actively

transported endogenous substances such as sugars, amino acids, and nucleosides.

4. Filtration is the bulk flow of solvent and solute through channels (pores) in the membrane. Fil- tration is seen with small molecules (usually with a molecular weight less than 100) that can pass through pores. Some substances of greater molecular weight, such as certain proteins, can be filtered through intercellular channels. Concentration gradients affect the rate of

filtration.

5. Facilitated diffusion is movement of a substance down a concentration gradient. Facilitated

diffusion is carrier mediated, specific, and saturable; it does not require energy.

B. Routesofadministration

1. Oral administration is the most convenient, economical, and common route of administration; it is generally safe for most drugs.

a. Sitesofabsorption

(1) Stomach

(a) Lipid-soluble drugs and weak acids, which are normally un-ionized at the low pH

(1 to 2) of gastric contents, may be absorbed directly from the stomach.

(b) Weak bases and strong acids (pK 1⁄4 2 to 3) are not normally absorbed from this site since they tend to exist as ions that carry either a positive or negative charge,

respectively.

(2) Smallintestine

(a) The small intestine is the primary site of absorption of most drugs because of the

very large surface area across which drugs, including partially ionized weak acids

and bases, may diffuse.

(b) Acids are normally absorbed more extensively from the small intestine than from

the stomach, even though the intestine has a higher pH (approximately 5).

b. Thebioavailabilityofadrugisthefractionofdrug(administeredbyanyroute)thatreaches the bloodstream unaltered (bioavailability 1⁄4 1 for intravenous administration). Bioequiva- lence refers to the condition in which the plasma concentration versus time profiles of two

drug formulations are identical.

(1) The first-pass effect influences drug absorption by metabolism in the liver or by biliary

secretion. After absorption from the stomach or small intestine, a drug must pass through the liver before reaching the general circulation and its target site. If the capacity of liver metabolic enzymes to inactivate the drug is great, only limited amounts of active drug will escape the process. Some drugs are metabolized so extensively as a result of hepatic metabolism during the first pass that it precludes their use.

(2) Other factors that may alter absorption from the stomach or small intestine include the following:

(a) Gastric emptying time and passage of drug to the intestine may be influenced by gastric contents and intestinal motility. A decreased emptying time generally decreases the rate of absorption because the intestine is the major absorptive site for most orally administered drugs.

(b) Gastrointestinal (GI) blood flow plays an important role in drug absorption by con- tinuously maintaining the concentration gradient across epithelial membranes. The absorption of small, very lipid-soluble molecules is ‘‘blood flow limited,’’ whereas highly polar molecules are ‘‘blood flow independent.’’

(c) Stomach acid and inactivating enzymes may destroy certain drugs. Enteric coating prevents breakdown of tablets by the acid pH of the stomach.

(d) Interactions with food, other drugs, and other constituents of the gastric milieu may influence absorption.

(e) Inert ingredients in oral preparations or the special formulation of those prepara- tions may alter absorption.

2. Parenteral administration includes three major routes: intravenous (IV), intramuscular (IM), and subcutaneous (SC). Parenteral administration generally results in more predictable bioa- vailability than oral administration.

a. WithIVadministration,thedrugisinjecteddirectlyintothebloodstream(100%bioavailable). It represents the most rapid means of introducing drugs into the body and is particularly use- ful in the treatment of emergencies when absolute control of drug administration is essential.

b. After IM and SC administration, many drugs can enter the capillaries directly through ‘‘pores’’ between endothelial cells. Depot preparations for sustained release may be admin- istered by IM or SC routes, but some preparations may cause irritation and pain.

3. Otherroutesofadministration

a. Inhalation results in rapid absorption because of the large surface area and rich blood sup-

ply of the alveoli. Inhalation is frequently used for gaseous anesthetics, but it is generally not practical. Inhalation may be useful for drugs that act on the airways, such as epineph- rine and glucocorticoids, which are used to treat bronchial asthma.

b. Sublingual administration is useful for drugs with high first-pass metabolism, such as nitro- glycerin, since hepatic metabolism is bypassed.

c. Intrathecal administration is useful for drugs that do not readily cross the blood–brain barrier.

d. Rectal administration minimizes first-pass metabolism and may be used to circumvent the nausea and vomiting that sometimes result from oral administration. Use of rectal adminis- tration may be limited by inconvenience or patient noncompliance.

e. Topical administration is used widely when a local effect is desired or to minimize systemic effects, especially in dermatology and ophthalmology. Preparations must be nonirritating. Note that drugs administered topically may sometimes produce systemic effects.

DRUGDISTRIBUTION

Drug distribution is the movement of a drug from the bloodstream to the various tissues of the body.

A. Distribution of drugs is the process by which a drug leaves the bloodstream and enters the extracellular fluids and tissues. A drug must diffuse across cellular membranes if its site of action is intracellular. In this case, lipid solubility is important for effective distribution.

1. Importanceofbloodflow

a. In most tissues, drugs can leave the circulation readily by diffusion across or between capil- lary endothelial cells. Thus, the initial rate of distribution of a drug depends heavily on blood flow to various organs (brain, liver, kidney > muscle, skin > fat, bone).

b. At equilibrium, or steady state, the amount of drug in an organ is related to the mass of the organ and its properties, as well as to the properties of the specific drug.

2. Volume of distribution (Vd) is the volume of total body fluid into which a drug ‘‘appears’’ to dis- tribute after it reaches equilibrium in the body. Volume of distribution is determined by administering a known dose of drug (expressed in units of mass) intravenously and measuring the initial plasma concentration (expressed in units of mass/volume):

Vd = amount of drug administered (m/g)/initial plasma concentration (mg/L)

Volume of distribution is expressed in units of volume. In most cases, the ‘‘initial’’ plasma concentration, C0, is determined by extrapolation from the elimination phase (see VII).

a. Standard values of volumes of fluid compartments in an average 70-kg adult are as follows:

plasma 1⁄4 3 liters; extracellular fluid 1⁄4 12 liters; and total body water 1⁄4 41 liters. b. Featuresofvolumeofdistribution:

(1) Vd values for most drugs do not represent their actual distribution in bodily fluids. The use of Vd values is primarily conceptual; that is, drugs that distribute extensively have relatively large Vd values and vice versa.

(2) A very low Vd value may indicate extensive plasma protein binding of the drug. A very high value may indicate that the drug is extensively bound to tissue sites.

(3) Among other variables, Vd may be influenced by age, sex, weight, and disease proc- esses (e.g., edema, ascites)

3. Drug redistribution describes when the relative distribution of a drug in the body changes with time. This is usually seen with highly lipophilic drugs such as thiopental that initially enter tis- sues with high blood flow (e.g., the brain) and then quickly redistribute to tissues with lower blood flow (e.g., skeletal muscle and adipose tissue).

4. Barrierstodrugdistribution a. Blood–brainbarrier

(1) Becauseofthenatureoftheblood–brainbarrier,ionizedorpolardrugsdistributepoorly to the CNS, including certain chemotherapeutic agents and toxic compounds, because they must pass through, rather than between, endothelial cells.

(2) Inflammation, such as that resulting from meningitis, may increase the ability of ionized, poorly soluble drugs to cross the blood–brain barrier.

(3) The blood–brain barrier may not be fully developed at the time of birth.

b. Placentalbarrier

(1) Lipid-soluble drugs cross the placental barrier more easily than polar drugs; drugs with a molecular weight of less than 600 pass the placental barrier better than larger molecules.

(2) The possibility that drugs administered to the mother may cross the placenta and reach the fetus is always an important consideration in therapy.

(3) Drug transporters (e.g., the P-glycoprotein transporter) transfer drugs out of the fetus.

B. Binding of drugs by plasma proteins. Drugs in the plasma may exist in the free form or may be bound to plasma proteins or other blood components, such as red blood cells.

1. Generalfeaturesofplasmaproteinbinding

a. Theextentofplasmaproteinbindingishighlyvariableandrangesfromvirtually0%tomore than 99% bound, depending on the specific drug. Binding is generally reversible.

b. Only the free drug is small enough to pass through the spaces between the endothelial cells that form the capillaries; extensive binding retards the rate at which the drug reaches its site of action and may prolong duration of action.

c. Someplasmaproteinsbindmanydifferentdrugs,whereasotherproteinsbindonlyoneora limited number. For example, serum albumin tends to bind many acidic drugs, whereas a1- acid glycoprotein tends to bind many basic drugs.

d. There are few, if any, documented changes in a drug’s effect due to changes in plasma pro- tein binding.

DRUGELIMINATIONANDTERMINATIONOFACTION

A. Mechanismsofdrugeliminationandterminationofaction

1. In most cases, the action of a drug is terminated by enzyme-catalyzed conversion to an inactive (or less active) compound and/or elimination from the body via the kidney or other routes.

2. Redistribution of drugs from the site of action may terminate the action of a drug, although this occurs infrequently. For example, the action of the anesthetic thiopental is terminated largely by its redistribution from the brain (where it initially accumulates as a result of its high lipid solubility and the high blood flow to that organ) to the more poorly perfused adipose tissue.

B. Rateofdrugeliminationfromthebody

1. First-order elimination. The elimination of most drugs at therapeutic doses is ‘‘first-order,’’ where a constant fraction of drug is eliminated per unit time; that is, the rate of elimination depends on the concentration of drug in the plasma, and is equal to the plasma concentration of the drug multiplied by a proportionality constant:

Rate of eliminiation from body (mass/time) = Constant × [Drug]plasma(mass/vol)

Because the rate of elimination is given in units of mass/time and concentration is in units of mass/volume, the units of the constant are volume/time. This constant is referred to as the ‘‘clearance’’ of the drug (see IV C).

2. Zero-order kinetics. Infrequently, the rate of elimination of a drug is ‘‘zero-order,’’ where a constant amount of drug is eliminated per unit time. In this case, the mechanism by which the body eliminates the drug (e.g., metabolism by hepatic enzymes, active secretion in the kidney) is saturated. The rate of drug elimination from the body is thus constant and does not depend on plasma concentration.

C. Clearance (CL). Conceptually, clearance is a measure of the capacity of the body to remove a drug. Mathematically, clearance is the proportionality constant that relates the rate of drug elimination to the plasma concentration of the drug. Thus, drugs with ‘‘high’’ clearance are rapidly removed from the body, and drugs with ‘‘low’’ clearance are removed slowly. As noted in IV B, the units of clearance are volume/time.

1. Specific organ clearance is the capacity of an individual organ to eliminate a drug. Specific organ clearance may be due to metabolism (e.g., ‘‘hepatic clearance’’ by the liver) or excretion (e.g., ‘‘renal clearance’’ by elimination in the urine).

or

Rate of eliminiation by organ = CLorgan × [Drug]plasma perfusing organ

CLorgan = Rate of elimination by organ/[Drug]plasma perfusing organ

2. Whole body clearance is the capacity of the body to eliminate the drug by all mechanisms. Therefore, whole body clearance is equal to the sum of all of the specific organ clearance mechanisms by which the active drug is eliminated from the body:

CLwhole body = CLorgan 1 + CLorgan 2 + + CLorgan N

The term ‘‘clearance’’ generally refers to whole body clearance unless otherwise specified.

In this case, and

Rate of elimination from body = CLwhole body × [Drug]plasma CL = Rate of elimination from body/[Drug]plasma

3. Plasma clearance is numerically the same as whole body clearance, but this terminology is sometimes used because clearance may be viewed as the volume of plasma that contains the amount of drug removed per unit time (recall that the units of clearance are volume/time). If not specified, this term refers to the volume of plasma ‘‘cleared’’ of drug by all bodily mecha- nisms (i.e., whole body clearance). The term may also be applied to clearance by specific organs; for example, renal plasma clearance is the volume of plasma containing the amount of drug eliminated in the urine per unit time.

. BIOTRANSFORMATION(METABOLISM)OFDRUGS

A. General properties

1. Biotransformationisamajormechanismfordrugelimination;mostdrugsundergobiotransfor- mation, or metabolism, after they enter the body. Biotransformation, which almost always produces metabolites that are more polar than the parent drug, usually terminates the pharma- cologic action of the parent drug and, via excretion, increases removal of the drug from the body. However, other consequences are possible, notably after phase I reactions, including similar or different pharmacologic activity, or toxicologic activity.

2. Manydrugsundergoseveralsequentialbiotransformationreactions.Biotransformationiscata- lyzed by specific enzyme systems, which may also catalyze the metabolism of endogenous substances such as steroid hormones.

The liver is the major site of biotransformation, although specific drugs may undergo biotrans- formation primarily or extensively in other tissues.

Biotransformation of drugs is variable and can be affected by many parameters, including prior administration of the drug in question or of other drugs; diet; hormonal status; genetics; disease (e.g., decreased in cardiac and pulmonary disease); age and developmental status (the very elderly and very young may be more sensitive to drugs, in part, because of decreased or undeveloped levels of drug-metabolizing enzymes); and liver function (in cases of severe liver damage, dosage adjustments may be required for drugs eliminated largely via this route). Possible consequences of biotransformation include the production of inactive metabolites (most common), metabolites with increased or decreased potencies, metabolites with qualita- tively different pharmacologic actions, toxic metabolites, or active metabolites from inactive prodrugs.

Metabolites carry ionizable groups, and are often more charged and more polar than the par- ent compounds. This increased charge may lead to a more rapid rate of clearance because of possible secretion by acid or base carriers in the kidney; it may also lead to decreased tubular reabsorption.

Hepatic extraction of drugs. General extraction by the liver occurs because of the liver’s large size (1500 g) and high blood flow (1 mL/g/min).

1. The extraction ratio is the amount of drug removed in the liver divided by the amount of drug

entering the organ; a drug completely extracted by the liver would have an extraction ratio of 1.

Highly extracted drugs can have a hepatic clearance approaching 1500 mL/min.

2. First-pass effect. Drugs taken orally pass across membranes of the GI tract into the portal vein

and through the liver before entering the general circulation.

a. Bioavailabilityoforallyadministereddrugsisdecreasedbythefractionofdrugremovedby

the first pass through the liver. For example, a drug with a hepatic extraction ratio of 1 would have 0% bioavailability; a drug such as lidocaine, with an extraction ratio of 0.7, would have 30% bioavailability.

b. In the presence of hepatic disease, drugs with a high first-pass extraction may reach the systemic circulation in higher than normal amounts, and dose adjustment may be required.

EXCRETIONOFDRUGS

A. Routes of excretion may include urine, feces (e.g., unabsorbed drugs and drugs secreted in bile), saliva, sweat, tears, milk (with possible transfer to neonates), and lungs (e.g., alcohols and anesthetics). Any route may be important for a given drug, but the kidney is the major site of excretion for most drugs.

1. Some drugs are secreted by liver cells into the bile, pass into the intestine, and are eliminated in the feces (e.g., rifampin, indomethacin, estradiol).

2. Drugs may be also be reabsorbed from the intestine (i.e., undergo enterohepatic circulation). In this manner, the persistence of a drug in the body may be prolonged.

B. Netrenalexcretionofdrugs

1. Net renal excretion of drugs is the result of three separate processes: the amount of drug fil- tered at the glomerulus, plus the amount of drug secreted by active transport mechanisms in the kidney, less the amount of drug passively reabsorbed throughout the tubule.

a. Filtration

(1) Most drugs have low molecular weights and are thus freely filtered from the plasma at the glomerulus.

(2) Serum protein binding reduces filtration because plasma proteins are too large to be filtered.

(3) The glomerular filtration rate is 30%–40% lower during newborns’ first year of life than in adults.

b. Secretion

(1) The kidney proximal tubule contains two transport systems that may secrete drugs into

the ultrafiltrate, one for organic acids and a second for organic bases. These systems require energy for active transport against a concentration gradient; they are a site for potential drug–drug interactions because drugs may compete with each other for bind- ing to the transporters.

(2) Plasma protein binding does not normally have a large effect on secretion because the affinity of the transport systems for most drugs is greater than the affinity of plasma binding proteins.

c. Reabsorption

(1) Reabsorption may occur throughout the tubule; some compounds, including endoge-

nous compounds such as glucose, are actively reabsorbed.

(2) Reabsorption of the un-ionized form of drugs that are weak acids and bases can occur by

simple passive diffusion, the rate of which depends on the lipid solubility and pK of the

drug and also on the concentration gradient of the drug between the urine and the plasma.

(3) Reabsorption may be affected by alterations of urinary pH, which also affect elimination of weak acids or bases by affecting the degree of ionization. For example, acidification of the urine will result in a higher proportion of the un-ionized form of an acidic drug and

will facilitate reabsorption.

2. Renalclearanceofdrugs

a. Renalclearancemeasuresthevolumeofplasmathatisclearedofdrugperunittime:

CL (mL/min) = U × V/P

where U 1⁄4 concentration of drug per milliliter of urine, V 1⁄4 volume of urine excreted per mi- nute, and P 1⁄4 concentration of drug per milliliter of plasma.

(1) A drug excreted by filtration alone (e.g., insulin) will have a clearance equal to the glo- merular filtration rate (GFR; 125–130 mL/min).

(2) A drug excreted by filtration and complete secretion (e.g., para-aminohippuric acid) will have a clearance equal to renal plasma clearance (650 mL/min).

(3) Clearance values between 130 and 650 mL/min suggest that a drug is filtered, secreted, and partially reabsorbed.

b. A variety of factors influence renal clearance, including age (some mechanisms of excretion may not be fully developed at the time of birth), other drugs, and disease.

c. Inthepresenceofrenalfailure,theclearanceofadrugmaybereducedsignificantly,result- ing in higher plasma levels. For those drugs with a narrow therapeutic index, dose adjust- ment may be required.

 

  • ED50is the dose that produces the half-maximal response
  • Threshold dose is that which produces the first noticeable effect.
  • Intrinsic activityis the ability of a drug once bound to activate the receptor
  • Agonistsare drugs capable of binding to, and activating,a receptor.
    • Full agonists occupy receptors to cause maximal activation; intrinsic activity =  1.
    • Partial agonists can occupy receptors but cannot elicit a maximal response
      • Such drugs have an intrinsic activity of less than 1
  • Antagonists
    • bind to the receptor but do not initiate a response
    • they block the action of an agonist or endogenous substance that works through the receptor.
    • Competitive antagonists
      • combine with the same site on the receptor as the agonist
      • have little or no efficacy and an intrinsic activity of 0
      • Competitive antagonists may be reversible or irreversible
      • Reversible, or equilibrium, competitive antagonists
        • not covalently bound
        • shift the dose–response curve for the agonist to the right
        • increase the ED50
        • more agonist is required to elicit a response in the presence of the antagonist
        • Because higher doses of agonist can overcome the inhibition, the maximal response can still be obtained.
    • Noncompetitive antagonists
      • bind to the receptor at a site other than the agonist-binding site
      • either prevent the agonist from binding correctly or prevent it from activating the receptor
      • Consequently, the effective amount of receptor is reduced
      • Receptors unoccupied by antagonist retain the same affinity for agonist, and the ED50 is unchanged. (MCQ)
  • Potency of a drug
    • relative measure of the amount of a drug required to produce a specified level of response (e.g., 50%) compared to other drugs that produce the same effect via the same receptor mechanism.
    • determined by the
      • affinity of a drug for its receptor
      • the amount of administered drug that reaches the receptor site.
    • The relative potency of a drug can be demonstrated by comparing the ED50 values of two full agonists
      • the drug with the lower ED50 is more potent
      • The efficacy of a drug
    • ability of a drug to elicit the pharmacologic response.
    • Efficacy may be affected by such factors as the
      • number of drug–receptor complexes formed
      • ability of the drug to activate the receptor once it is bound
      • status of the target organ or cell.
    • Slope of dose–response curve
      • is measured at the midportion of the dose–response curve
      • The slope varies for different drugs and different responses
      • Steep dose–response curves indicate that a small change in dose produces a large change in response.
    • Therapeutic index (TI)
      • relates the desired therapeutic effect to undesired toxicity
      • it is determined using data provided by the quantal dose–response curve.
      • The therapeutic index is defined as TD50/ED50 (i.e., the ratio of the dose that produces a toxic effect in half of the population to the dose that produces the desired effect in half of the population
  • The quantal dose–response curve
    • relates the dosage of a drug to the frequency with which a designated response will occur within a population.
    • In the context of the quantal dose–response curve, ED50 indicates the dose of drug that produces the response in half of the population.
  • Drug absorption
    • Drug transport across membranes
      • Diffusion of un-ionized drugs
        • most common and most important mode of traversing biologic membranes
        • drugs diffuse passively down their concentration gradient.
      • Lipid–water partition coefficient
        • It is ratio of solubility in an organic solvent to solubility in an aqueous solution
        • Diffusion can be influenced significantly by the lipid–water partition coefficientof the drug
        • In general, absorption increases as lipid solubility (partition coefficient) increases.
      •  Other factors that also can influence diffusion include
        • concentration gradient of the drug across the cell membrane
        • surface area of the cell membrane.
      • Diffusion of drugs that are weak electrolytes
        • Only the un-ionized form of drug can diffuse across biologic membranes  (MCQ)
        • The degree of ionization of a weak acid or base is determined by the pK of the drug and pH of its environment according to the Henderson-Hasselbalch equation.
        • When the pK of a drug equals the pH of the surroundings, 50% ionization occurs; that is, equal numbers of ionized and un-ionized species are present.
          • A lower pK reflects a stronger acid
          • a higher pK corresponds to a stronger base.
          • Drugs with different pK values will diffuse across membranes at different rates.
        • The pH of the biologic fluid in which the drug is dissolved affects the degree of ionization and, therefore, the rate of drug transport.
      • Active transport
        • an energy-dependent process that can move drugs against a concentration gradient, as in protein-mediated transport systems
        • occurs in only one direction and is saturable
        • It is usually the mode of transport for drugs that resemble actively transported endogenous substances such as sugars, amino acids, and nucleosides.
      • Filtration
        • bulk flow of solvent and solute through channels (pores) in the membrane.
        • seen with small molecules usually with a molecular weight less than 100  that can pass through pores.
        • Some substances of greater molecular weight, such as certain proteins, can be filtered through intercellular channels.
        • Concentration gradients affect the rate of filtration.
      • Facilitated diffusion
        • movement of a substance down a concentration gradient.
        • carrier mediated, specific, and saturable
        • it does not require energy.
    • Routes of administration
      • Oral administration
        • Sites of absorption
          • Stomach
            • Lipid-soluble drugsand weak acids
              • are normally un-ionized at the low pH of gastric contents,
              • may be absorbed directly from the stomach.
            • Weak bases and strong acids
              • not normally absorbed from this site since
              • they tend to exist as ions that carry either a positive or negative charge, respectively.
          • Small intestine
            • small intestine is the primary site of absorptionof most drugs because of the very large surface area across which drugs, including partially ionized weak acids and bases, may diffuse.
            • Acids are normally absorbed more extensively from the small intestine than from the stomach, even though the intestine has a higher pH (approximately 5).
        • Bioavailability of a drug
          • fraction of drug (administered by any route)that reaches the blood stream unaltered
          •  bioavailability =  1 for intravenous administration
        • Bioequivalence
          • refers to the condition in which the plasma concentration versus time profiles of two drug formulations are identical.
        • Factors that alter absorption from the stomach or small intestine
          • The first-pass effectinfluences drug absorption by metabolism in the liver or by biliary secretion
          • A decreased emptying time generally decreases the rate of absorption because the intestine is the major absorptive site for most orally administered drugs.
            • absorption of small, very lipid-soluble molecules is ‘‘blood flow limited,’’
            • absorption of highly polar molecules are ‘‘blood flow independent.’’
            • Enteric coating prevents breakdown of tablets by the acid pH of the stomach.
        • Sublingual administration is useful for drugs with high first-pass metabolism, such as nitroglycerin,since hepatic metabolism is bypassed.
        • Intrathecal administrationis useful for drugs that do not readily cross the blood–brain barrier.
      • Rectal administration
        • minimizes first-pass metabolism
        • used to circumvent the nausea and vomiting that sometimes result from oral administration.
    • Drug distribution
      • process by which a drug leaves the bloodstream and enters the extracellular fluids and tissues.
      • A drug must diffuse across cellular membranes if its site of action is intracellular.
      • In this case, lipid solubility is important for effective distribution.
      • Importance of blood flow
      • initial rate of distributionof a drug depends heavily on blood flow to various organs (brain, liver, kidney > muscle, skin > fat, bone) (MCQ)
    • Volume of distribution (Vd) (A High yield topic for MD Entrance)
      • volume of total body fluidinto which a drug ‘‘appears’’ to distribute after it reaches equilibrium in the body.
      • Vd is determined by administering a known dose of drug (expressed in units of mass) intravenously and measuring the initial plasma concentration (expressed in units of mass/volume)
      • Vd = amount of drug administered (m/g)/initial plasma concentration (mg/L)
      • Standard values of volumes of fluid compartments in an average 70-kg adult
        • plasma=  3 liters
        • extracellular fluid=  12 liters
        • total body water=  41 liters
      • Vd values for most drugs do not represent their actual distribution in bodily fluids (it is merely conceptual)
        • drugs that distribute extensively have relatively large Vd values and vice versa.
      • A very low Vd value may indicate extensive plasma protein binding of the drug.
      • A very high value may indicate that the drug is extensively bound to tissue sites.
      • Vd may be influenced by age, sex, weight, and disease processes(e.g., edema, ascites)
    • Drug redistribution
      • describes when the relative distribution of a drug in the body changes with time.
      • usually seen with highly lipophilic drugs such as thiopental
      • drug initially enter tissues with high blood flow (e.g., the brain) and then quickly redistribute to tissues with lower blood flow (e.g., skeletal muscle and adipose tissue).
    • Barriers to drug distribution
      • Blood–brain barrier
        • Ionized or polar drugs distribute poorly to the CNS,
        • Meningitis, may increase the ability of ionized, poorly soluble drugs to cross the blood–brain barrier.
        • The blood–brain barrier may not be fully developed at the time of birth.
      • Placental barrier
        • Lipid-soluble drugs cross the placental barrier more easily than polar drugs
        • drugs with a molecular weight of less than 600 pass the placental barrier better than larger molecules.
        • Drug transporters (e.g., the P-glycoprotein transporter) transfer drugs out of the fetus.
  • Binding of drugs by plasma proteins
    • The extent of plasma protein binding ranges from virtually 0% to more than 99%
    • Binding is generally reversible.
    • Extensive protein binding retards the rate at which the drug reaches its site of action and may prolong duration of action.
    • serum albumin tends to bind many acidic drugs (MCQ)
    • alpha 1- acid glycoprotein tends to bind many basic drugs (MCQ)
  • Mechanisms of drug elimination and termination of action
    • In most cases, the action of a drug is terminated by
    • enzyme-catalyzed conversionto an inactive (or less active) compound
    • elimination from the body via the kidney or other routes.
    • Redistribution of drugs from the site of action may terminate the action of a drug
    • the action of the anesthetic thiopentalis terminated largely by its redistribution from the brain (where it initially accumulates as a result of its high lipid solubility and the high blood flow to that organ) to the more poorly perfused adipose tissue (MCQ)
    • Biotransformation
      • Is a major mechanism for drug elimination
      • produces metabolites that are more polar than the parent drug
      • it usually terminates the pharmacologic action of the parent drug
      • via excretion, it increases removal of the drug from the body
      • The liver is the major site of biotransformation
      • the very elderly and very young may be more sensitive to drugs, in part, because of decreased or undeveloped levels of drug-metabolizing enzymes
      • Metabolites carry ionizable groups
      • Metabolites are often more charged and more polarthan the parent compounds.
        • This increased charge may lead to a more rapid rate of clearance because of possible secretion by acid or base carriers in the kidney
        • This increased charge may also lead to decreased tubular reabsorption.
  • Hepatic extraction of drugs.
    • General extraction by the liver occurs because of the liver’s large size (1500 g) and high blood flow (1 mL/g/min).
    • Extraction ratio
      • amount of drug removed in the liver divided by the amount of drug entering the organ
      • a drug completely extracted by the liver would have an extraction ratio of 1.
      • a drug such as lidocaine, with an extraction ratio of 0.7, would have 30% bioavailability.
  • Excretion of drugs
    • Some drugs are secreted by liver cells into the bile, pass into the intestine, and are eliminated in the feces (e.g., rifampin, indomethacin, estradiol).
    • Net renal excretion of drugs
      • Filtration
        • Most drugs have low molecular weights and are thus freely filtered from the plasma at the glomerulus.
        • Serum protein binding reduces filtration because plasma proteins are too large to be filtered.
        • The glomerular filtration rate is 30%–40% lower during newborns first year of life than in adults.
      • Secretion
        • The kidney proximal tubule contains two transport systems that may secrete drugs into the ultrafiltrate, one for organic acids and a second for organic bases.
          • These systems require energy for active transport against a concentration gradient
          • they are a site for potential drug–drug interactionsbecause drugs may compete with each other for bind- ing to the transporters.
        • Plasma protein binding does not normally have a large effect on secretion because the affinity of the transport systems for most drugs is greater than the affinity of plasma binding proteins.
      • Reabsorption
        • glucose, is  actively reabsorbed.
        • Reabsorption of the un-ionized form of drugs that are weak acids and bases can occur by simple passive diffusion
        • the rate of passive diffusion depends on the lipid solubility and pK of the drug and also on the concentration gradient of the drug between the urine and the plasma.
        • Acidification of the urine will result in a higher proportion of the un-ionized form of an acidic drug and will facilitate reabsorption.
    • Renal clearance of drugs
      • Measures the volume of plasma that is cleared of drug per unit time:
      • CL (mL/min) = U × V/P
      • U =  concentration of drug per milliliter of urine,
      • V =  volume of urine excreted per mi- nute,
      • P =  concentration of drug per milliliter of plasma.
    • A drug excreted by filtration alone(e.g., insulin) will have a clearance equal to the glomerular filtration rate (GFR; 125–130 mL/min).
    • A drug excreted by filtration and complete secretion(e.g., para-aminohippuric acid) will have a clearance equal to renal plasma clearance (650 mL/min).
    • Clearance values between 130 and 650 mL/min suggest that a drug is filtered, secreted, and partially reabsorbed.
    • Biotransformation
      • Is a major mechanism for drug elimination
      • produces metabolites that are more polar than the parent drug
      • it usually terminates the pharmacologic action of the parent drug
      • via excretion, it increases removal of the drug from the body
      • The liver is the major site of biotransformation
      • the very elderly and very young may be more sensitive to drugs, in part, because of decreased or undeveloped levels of drug-metabolizing enzymes
    • Metabolites carry ionizable groups
    • Metabolites are often more charged and more polarthan the parent compounds.
      • This increased charge may lead to a more rapid rate of clearance because of possible secretion by acid or base carriers in the kidney
      • This increased charge may also lead to decreased tubular reabsorption.
  • Hepatic extraction of drugs.
    • General extraction by the liver occurs because of the liver’s large size (1500 g) and high blood flow (1 mL/g/min).
  • Extraction ratio
    • amount of drug removed in the liver divided by the amount of drug entering the organ
      • a drug completely extracted by the liver would have an extraction ratio of 1.
      • a drug such as lidocaine, with an extraction ratio of 0.7, would have 30% bioavailability.
  • Excretion of drugs
    • Some drugs are secreted by liver cells into the bile, pass into the intestine, and are eliminated in the feces (e.g., rifampin, indomethacin, estradiol).
    • Net renal excretion of drugs
      • Filtration
        • Most drugs have low molecular weights and are thus freely filtered from the plasma at the glomerulus.
        • Serum protein binding reduces filtration because plasma proteins are too large to be filtered.
        • The glomerular filtration rate is 30%–40% lower during newborns first year of life than in adults.
      • Secretion
        • The kidney proximal tubule contains two transport systems that may secrete drugs into the ultrafiltrate, one for organic acids and a second for organic bases.
          • These systems require energy for active transport against a concentration gradient
          • they are a site for potential drug–drug interactionsbecause drugs may compete with each other for bind- ing to the transporters.
        • Plasma protein binding does not normally have a large effect on secretion because the affinity of the transport systems for most drugs is greater than the affinity of plasma binding proteins.
      • Reabsorption
        • glucose, is  actively reabsorbed.
        • Reabsorption of the un-ionized form of drugs that are weak acids and bases can occur by simple passive diffusion
        • the rate of passive diffusion depends on the lipid solubility and pK of the drug and also on the concentration gradient of the drug between the urine and the plasma.
        • Acidification of the urine will result in a higher proportion of the un-ionized form of an acidic drug and will facilitate reabsorption.
    • Renal clearance of drugs
      • Measures the volume of plasma that is cleared of drug per unit time:
      • CL (mL/min) = U × V/P
        • U =  concentration of drug per milliliter of urine,
        • V =  volume of urine excreted per mi- nute,
        • P =  concentration of drug per milliliter of plasma.
      • A drug excreted by filtration alone(e.g., insulin) will have a clearance equal to the glomerular filtration rate (GFR; 125–130 mL/min).
      • A drug excreted by filtration and complete secretion(e.g., para-aminohippuric acid) will have a clearance equal to renal plasma clearance (650 mL/min).
      • Clearance values between 130 and 650 mL/min suggest that a drug is filtered, secreted, and partially reabsorbed.

Pharmacodynamics Made Simple

PHARMACODYNAMICS

What is Pharmacodynamics?

Pharmacodynamics

Pharmacodynamics for Medical Students

Simply Pharmacokinetics & Pharmacodynamics