PPM1Pharmacokinetics and Pharmacodynamics

Objectives

1.         Define the following terms:

                        pharmacokinetics

                        pharmacodynamics

                        pharmacotherapeutics

Anonymous Brenner p. 3,9,26

Pharmacokinetics: is concerned with the relationship between the dose of a particular drug and the concenrtration of the drug in body fluids and tissues over time, as determined by the rates of drug absorption, drug distribution, and drugelimination. Action of BODY on Drug.

Pharmacodynamics: is concerned with the mechanism by which drugs produce their biochemical and physiologic effects. Action of DRUG on Body!

Pharmacotherapeutics: is the medical science concerned with the use of drugs in the treatment of disease.

Anonymous

Pharmacokinetics – is concerned with the relationship between the dose of a particular drug and the concentration of that drug in body fluids and tissues over time, as determined by the rates of drug absorption,distribution, and elimination.

Pharmacodynamics – is concerned with the mechanisms by which drugs produce their biochemical and physiologic effects.

Pharmacotherapeutics – is the medical science concerned with the use of drugs in the treatment of disease.

Anonymous

•        Pharmacokinetics- is concerned with the processes that determine the concentration of drugs in a body fluids and tissues over time, including drug absorption, distribution, biotransformation, and excretion.

•        Pharmacodynamics- is the study of the action of drugs on target organs.  It is particularly concerned with the biochemical mechanisms by which drugs produce their physiologic effects and with the dose-response relationship.

•        Pharmacotherapeutics- is the medical science concerned with the use of drugs in the treatment of disease.

Sung K, Kam’s handout

      Pharmacokinetics – the movement of a drug throughout the body via four processes: absorption, distribution, metabolism, and excretion (ADME). Relates to dose and concentration.

      Pharmacodynamics – refers to the drug’s mechanism of action and the biochemical and physiologic effects of the drug. Relates concentration and response.

Thus the common thread that ties these two processes together is concentration.

Anonymous

• Pharmacokinetecs – The study of how drugs are absorbed, distributed, metabolized, and excreted Ballweg:313

• Pharmacodynamics – How drugs produce an effect on the body Ballweg:313

• Pharmacotherapeutics – The medical science concerned with the use of drugs in the treatment of disease Brenner:3

2.         Define and give examples of the following routes of drug administration:  enteral, parenteral, transdermal, inhalational, and topical.

Anonymous Brenner p. 6 - 7

Enteral – those in which the drug is absorbed from the gastrointestinal tract. ie. Sublingual, buccal, oral, and rectal routes.

Parenteral – drug administration with a needle and syringe or with an intravenous infusion device. ie. Intravenous (IV), intramuscular (IM), and subcutaneous routes.

Transdermal – application of drugs to the skin for absorption into the circulation. ie. Skin patch, an ointment.

Inhalational – may be used to produce either a localized or a systemic drug effect on the respiratory tract ie. Inhaled

Topical – refers to the application of drugs to the surface of the body to produce a localized effect. ie. For treating disorders of the skin, eyes, nose, mouth, throat, rectum, and vagina.

Anonymous Brenner 6-7

•        Enteral- the enteral routes of administration are those in which the drug is absorbed from the GI tract.  These include sublingual, buccal, oral, and rectal routes.

•        Parenteral- refers to drug administration with a needle and syringe or with an intravenous infusion device.  The most commonly used routes are in the intravenous, intramuscular, and subcutaneous routes.

•        Transdermal- refers to the application of drugs to the skin for absorption into the circulation.

•        Inhalational- may be used to produce either a localized effect (as with asthma drugs), or a systemic effect (as seen with halothane as a general anesthetic).

•        Topical- refers to the application of drugs to the surface of the body to produce a localized effect.  Seen in the treatment of skin, eyes, mouth, throat, rectum, and vagina.

Anonymous

•        Enteral- the enteral routes of administration are those in which the drug is absorbed from the GI tract.  These include sublingual, buccal, oral, and rectal routes.

•        Parenteral- refers to drug administration with a needle and syringe or with an intravenous infusion device.  The most commonly used routes are in the intravenous, intramuscular, and subcutaneous routes.

•        Transdermal- refers to the application of drugs to the skin for absorption into the circulation.

•        Inhalational- may be used to produce either a localized effect (as with asthma drugs), or a systemic effect (as seen with halothane as a general anesthetic).

•        Topical- refers to the application of drugs to the surface of the body to produce a localized effect.  Seen in the treatment of skin, eyes, mouth, throat, rectum, and vagina.

Sung K, m Ansel Pharmaceutical Dosage Forms and Drug Delivery Systems, p.122-128

Anonymous Brenner:6-7

• Enteral – routes which the drug is absorbed form the GI tract.  These include:  sublingual, buccal, oral, and rectal routes.

• Parenteral – Refers to drug administration with a needle and syringe or with an intravenous infusion device.  Examples:  intravenous, intramuscular, and subcutaneous routes.

• Transdermal – Refers to the application of durgs to the skin for absorption into the circulation.  Examples:  skin patch, ointment.  Transdermal administration bypasses first-pass hepatic inactivation and is a reliable route of administration for drugs that are effective when given in a relatively low dosage and that are highly soluble in lipid membranes.

• Inhalation – May be used to produce either a localized or systemic drug effect.  A localized effect on the respiratory tract is obtained with drugs used to treat asthma or rhinitis, whereas a systemic effect is observed when a general anesthetic is inhaled.

• Topical – refers to the application of drugs to the surface of the body to produce a localized effect.  It is often used to treat disorders of the skin, eyes, nose, mouth, throat, rectum, and vagina.

3.         Identify absorption, distribution, and elimination as the key processes which determine how rapidly, in what concentration, and for how long a drug will appear at a target organ.  (Note that "elimination" includes both metabolism and excretion.)

Anonymous Brenner p. 9,11,17

Absorption: Topically administered drugs that are absorbed directly into the target tissue.

Distribution: Drugs are distributed to organs and tissues via the circulation, from which they may diffuse into interstitial fluid and cells.

Elimination: Most drugs are excreted in the urine, either as the most parent compound or as drug metabolites. Drugs are handled by the kidney the same manner as physiologic substances and undergo the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.

Anonymous.Brenner 9-22

•        Absorption-except for topically administered drugs that are absorbed directly into the target tissue, drug absorption refers to the passage of a drug from its site of administration into the circulation.  Absorption requires the passage of a drug across one or more layers of cells.  Drugs that are injected directly into the subcutaneous tissue and muscle bypass the epithelial layer and are more easily absorbed.  For this reason, drugs face a greater barrier to absorption after oral administration than after parenteral administration.

•        Distribution- drugs are distributed to organs and tissues via the circulation, from which they may diffuse into the interstitial fluid and cells.  Most drugs are not uniformly distributed throughout the total body water, and some drugs are restricted to the extracellular fluid or plasma compartment.  Drugs with sufficient lipid solubility can diffuse into the cells, and some drugs are concentrated in the cells by the phenomenon of ion trapping.

•        Elimination- most drugs are excreted in the urine, either as the parent compound or as drug metabolites.  Drugs are handled by the kidneys in the same manner as physiologic substances and undergo the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.  The amount of drug excreted is the sum of the amounts filtered and secreted minus the amount reabsorbed

Anonymous

•        Absorption-except for topically administered drugs that are absorbed directly into the target tissue, drug absorption refers to the passage of a drug from its site of administration into the circulation.  Absorption requires the passage of a drug across one or more layers of cells.  Drugs that are injected directly into the subcutaneous tissue and muscle bypass the epithelial layer and are more easily absorbed.  For this reason, drugs face a greater barrier to absorption after oral administration than after parenteral administration.

•        Distribution- drugs are distributed to organs and tissues via the circulation, from which they may diffuse into the interstitial fluid and cells.  Most drugs are not uniformly distributed throughout the total body water, and some drugs are restricted to the extracellular fluid or plasma compartment.  Drugs with sufficient lipid solubility can diffuse into the cells, and some drugs are concentrated in the cells by the phenomenon of ion trapping.

•        Elimination- most drugs are excreted in the urine, either as the parent compound or as drug metabolites.  Drugs are handled by the kidneys in the same manner as physiologic substances and undergo the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.  The amount of drug excreted is the sum of the amounts filtered and secreted minus the amount reabsorbed

Sung K, Kam’s HO

Absorption – a combination of the rate at which a drug leaves the site of administration and the amount of drug that is available to move. Absorption of drug from most sites requires transport across a membrane and there are many factors that affect the rate and amount absorbed:

1. pH

2. Drug solubility (aqueous solutions dissolve more rapidly than suspensions or solid dosage forms)

3. Different formulations of drugs (delayed release vs. immediate release)

4. Interference with food, minerals

5. Fast transit time, i.e. diarrhea

Distribution – movement of drug throughout the body as it becomes available to fluids and body tissues. Distribution is influenced by blood flow to the tissues, body tissue availability (drug may not enter bone or blood brain barrier), and protein binding (if drug highly protein bound then keeps drug mainly in circulation). High volume of distribution = high tissue penetration (may be only certain tissues and not all tissues)

Low volume of distribution = mainly circulating in the blood and not in the tissues.

Elimination – Drugs are mainly metabolized by the liver via phase I or phase II reactions or both. Lipophilic drugs are generally sent to the liver to be metabolized into hydrophilic metabolites for excretion by kidney. Other sites of excretion are via bile, feces, sweat. 

Anonymous

•         Brenner:9 Pharmacokinetics is concerned with the relationship between the dose of a particular drug and the concentration of that drug in body fluids and tissues over time, as determined by the rates of drug absorption, drug distribution, and drug elimination.  Drug elimination includes the biotransformation (metabolism) of a drug to one or more drug metabolites as well as the excretion of the drug from the body.  

•        Drugs are absorbed into the central compartment (the blood), distributed from the central compartment to the peripheral compartment (the tissues), and eliminated form the central compartment.  

•        Drug absorption refers to the passage of a drug form its site of administration into the circulation.  

•        Rate of absorption is proportional to the drug concentration gradient across the barrier and the surface area available for absorption at that site.

•        Brenner:11-12  Drugs are distributed to organs and tissues via the circulation, from which they may diffuse into interstitial fluid and cells.  Most drugs are not uniformly distributed throughout the total body water, and some drugs are restricted to the extracellular fluid or plasma compartment.

•        When drugs are administered orally, distribution occurs simultaneously with absorption.

•        Brenner:14  Drug biotransformation and excretion are the two processes responsible for the decline of the plasma drug concentration over time during the terminal elimination phase.  Drug biotransformtion, which is often call drug metabolism, is the enzyme-catalyzed conversion of drugs to their metabolites.  Most metabolism takes place in the liver, but there are drug-metabolizing enzymes in many other tissues, gut, kidney, brain, lungs, and skin for example.

•        Brenner:17  The amount of drug excreted is the sum of the amounts filtered and secreted minus the amount reabsorbed.  

4.         Identify and briefly describe factors which affect drug distribution.

Anonymous Brenner pp. 13, 14

Organ Blood Flow- rate of distribution depends largely on proportion of cardiac output received by the organs. Drugs are rapidly distributed to highly perfused tissues (brain, heart, etc.), so onset is rapid for drugs affecting these tissues. Distribution is slower to less perfused tissues (skeletal muscle, etc) and even more slowly to tissue with low blood flow, such as skin.

Plasma Protein Binding- Drugs are reversibly bound to plasma proteins. Extent of binding depends on affinity of drug for protein-binding sites. As unbound drug diffuses into cells/interstitial tissue, bound drug dissociates from protein to maintain equilibrium between bound and unbound drug. Drugs may be displaced from binding sites by other drugs w/ higher affinity, causing temporary increase in free (unbound) drug concentration.

Molecular Size- affects distribution of extremely large molecules (ie heparin). Large molecules are generally distributed to the plasma only.

Lipid Solubility- a MAJOR factor affecting extent of distribution, particularly to the brain, since blood-brain barrier restricts penetration by polar and ionized molecules

Anonymous Brenner 12-14

•        Organ blood flow- The rate at which a drug is distributed to various organs after a drug dose is administered depends largely on the proportion of cardiac output received by the organs Drugs are rapidly distributed to highly perfuse tissue like the brain, liver, heart, lungs, and kidneys.

•        Plasma protein binding- almost all drugs are reversibly bound to plasma proteins, primarily albumin.  The extent of binding depends on the affinity of a particular drug for the protein-binding sites and ranges from less than 10% to as high as 99% of the plasma concentration.  As the free (unbound) drug diffuses into the interstitial fluid and cells, drug molecules disassociate from albumin to maintain the equilibrium between free drug and bound drug.

•        Molecular size- molecular size is a factor affecting the distribution of extremely large molecules, such as heparin.  Heparin is largely confined to the plasma, although it does undergo some biotransformation in the liver.

•        Lipid Solubility- lipid solubility is a major factor affecting the extent of drug distribution, particularly to the brain, where the blood-brain barrier restricts the penetration of polar and ionized molecules.

Anonymous

•        Organ blood flow- The rate at which a drug is distributed to various organs after a drug dose is administered depends largely on the proportion of cardiac output received by the organs Drugs are rapidly distributed to highly perfuse tissue like the brain, liver, heart, lungs, and kidneys.

•        Plasma protein binding- almost all drugs are reversibly bound to plasma proteins, primarily albumin.  The extent of binding depends on the affinity of a particular drug for the protein-binding sites and ranges from less than 10% to as high as 99% of the plasma concentration.  As the free (unbound) drug diffuses into the interstitial fluid and cells, drug molecules disassociate from albumin to maintain the equilibrium between free drug and bound drug.

•        Molecular size- molecular size is a factor affecting the distribution of extremely large molecules, such as heparin.  Heparin is largely confined to the plasma, although it does undergo some biotransformation in the liver.

•        Lipid Solubility- lipid solubility is a major factor affecting the extent of drug distribution, particularly to the brain, where the blood-brain barrier restricts the penetration of polar and ionized molecules.

Sung K See question #3. 

Anonymous Brenner:13-14

•        Organ blood flow – The rate at which a drug is distributed to various organs after a drug dose is administered depends largely on the proportion of cardiac output received by the organs.  Drugs are rapidly distributed to highly perfused tissues, and more slowly distributed to less perfused organs.

•        Plasma protein binding – Almost all drugs are reversible bound to plasma proteins, primarily albumin.  The extent of binding depends on the affinity of a particular drug for protein-binding sites and ranges from less than 10% to as high as 99% of the plasma concentration.  Plasma protein binding is saturable, and drug may be displaced from binding sites by other drugs that have a higher affinity for such sites.

•        Molecular size – Molecular size is a factor affecting the distribution of extremely large molecules, such as heparin.

•        Lipid Solubility – Is a major factor affecting the extent of drug distribution, particularly to the brain, where the blood-brain barrier restricts the penetration of polar and ionized molecules.

•        (Ballweg:314)The distribution of a drug to carious body tissues is primarily influenced by its relative solubility in water and by the degree to which it becomes bound to plasma proteins.  The important thing to remember is that it is the free (unbound) drug that is dissolved in the plasma that is available to produce an effect.  Competition for protein-binding sites is one of the major mechanisms of drug-drug interactions.

5.         Define "first-pass effect" (or "first pass biotransformation") and describe how it affects bioavailability of drugs.

Anonymous

Drugs that are absorbed from the gut reach the liver via the hepatic portal vein before entering the systemic circulation. Many drugs are extensively converted to inactive metabolites during the first pass through the liver and have low bioavailability after oral administration. This phenomenon is called the first-pass effect. Drugs administered by the sublingual or rectal route undergo less first-pass metabolism and may have a higher degree of bioavailability than do drugs administered by the oral route

Anonymous Brenner 15

            First pass biotransformation- drugs that are absorbed through the gut reach the liver via the hepatic-portal vein before entering the systemic circulation.  Many drugs are extensively converted to inactive metabolites during the first pass through the liver and have low bioavailibility after oral administration.  This phenomenon is called first-pass effect.  Drugs administered through the rectal or sublingual route undergo less first-pass metabolism and may have a higher degree of bioavailabilty than do drugs administered through the oral route.

Anonymous

            First pass biotransformation- drugs that are absorbed through the gut reach the liver via the hepatic-portal vein before entering the systemic circulation.  Many drugs are extensively converted to inactive metabolites during the first pass through the liver and have low bioavailibility after oral administration.  This phenomenon is called first-pass effect.  Drugs administered through the rectal or sublingual route undergo less first-pass metabolism and may have a higher degree of bioavailabilty than do drugs administered through the oral route.

Sung K, Kam’s HO

            Following absorption of drug from the gut wall, the drug is carried from the enteric circulation to the portal vein where the drug is delivered first to the liver before entering the general systemic circulation. Thus, “first-pass effect” relates to some of the drug being metabolized by the liver before entering the systemic circulation. Thus bioavailability is decreased further by some of the drug being lost due to liver metabolism of the drug. 

Anonymous Brenner:15

• Drugs that are absorbed from the gut reach the liver via the hepatic portal vein before entering the systemic circulation.  Many drugs are extensively concerted to inactive metabolites during their first pass through the liver and have low bioavailability after oral administration.  This phenomenon is called the first-pass effect.  Drugs administered by the sublingual or rectal route undergo less first-pass metabolism.

6.         Identify the cytochrome P450 enzyme system as an important family of enzymes that catalyze the biotransformation of many drugs.

Anonymous

-First of all-what does biotransformation mean??? Drug biotransformation is also known as drug metabolism and is the enzyme-catalyzed conversion of drugs to their metabolites. Most of this process takes place in the liver but also occurs in the gut, kidneys, brain, lungs and skin.

The primary purpose of biotransformation enzymes is to inactivate and detoxify drugs and other foreign compounds that may cause harm to the body.

-Drug biotransformation can be divided into two phases. Phase I reactions create or unmask a chemical group required for a phase II reaction. Phase I biotransformation includes oxidative, hydrolytic and reductive reactions.

Oxidative reactions are the most common type of phase I biotransformation. The cytochrome P450 monooxygenase system is a family of enzymes that catalyzes the biotransformation of drugs with a wide range of chemical structures.

** FYI: I have consulted with my sources on this one and would prefer to get back to you. Thank you for your patience.

Brent K- Brenner pg.15-17

            Cytochrome P450s are a large group of monooxygenase enzymes responsible for the metabolism of toxic hydrocarbons, with their most relevant function of metabolizing drugs in humans by a class of P450s called hemoproteins.  Nicotinamide adenine dinucleotide phosphate (NADPH) is required as a coenzyme along with oxygen used as a substrate.   These enzymes are located in the endoplasmic reticulum and are highly concentrated in the liver and small intestine.  P450s are also found in the mitochondrial membrane.

Janelisa, Brenner 15 These enzymes are isolated in the microsomal fraction of liver homogenates. The reaction requires cytochrome P450, (a hemoprotein), NADPH-cytochrome P450 reductase, and membrane lipids in which the system is embedded. The most common reactions catalyzed by this system are aliphatic hydroxylation, aromatic hydroxylation, N-dealkylation, and O-dealkylation.

Anonymous Brenner pg 15

Biotransormation inactivates and detoxifies. The microsomal cytochrome P450 monooxygenase system is family of enzymes that catalyzes the biotransformation of drugs with a wide variety of structures. The most common reactions catalyzed by cytochrome P450 enzymes are aliphatic hydroxylation, aromatic hydroxylation, N-dealkylation, and O-dealkylation.

Anonymous Brenner 17

Biotransormation inactivates and detoxifies. The microsomal cytochrome P450 monooxygenase system is family of enzymes that catalyzes the biotransformation of drugs with a wide variety of structures. The most common reactions catalyzed by cytochrome P450 enzymes are aliphatic hydroxylation, aromatic hydroxylation, N-dealkylation, and O-dealkylation.

Anonymous Brenner:15

• The microsomal cytochrome P450 monooxygenase system is a family of enzymes that catalyzes the biotransformation of drugs with a wide range of chemical structures.  The most common chemical reactions catalyzed by cytochrome P450 enzymes are aliphatic hydroxylation, aromatic hydroxylation, N-dealkylation, and O-dealkylation.  The majority of drug biotransformations are catalyzed by three P450 families, called CYP1, CYP2, and CYP3.  The CYP3 family catalyzes over half of all microsomal drug oxidations.

7.         Identify the liver and the kidney as the two major sites of drug excretion; identify sweat and saliva as minor routes of excretion.

Anonymous pp17-18

Most drugs are excreted in the urine, either as the parent compound or as drug metabolites. Drugs are handled by the kidney in the same manner as physiologic substances and undergo the process of glomerular filtration, active tubular secretion, and passive tubular reabsorption. Glomerular filtration is the first step in renal drug excretion. In this process, the free drug enters the renal tubule as a dissolved solute in the plasma filtrate. If a drug has a large fraction bound to plasma proteins, it will have a low rate of glomerular filtration. Some drugs, particularly weak acids and bases, undergo active tubular secretion by transport system located primarily in proximal tubular cells. This process is competitively inhibited by other drugs of the same chemical class. For example, the secretion of penicillin and other weak acids is inhibited by probenecid. Active tubular secretion is not affected by plasma protein binding. This is because when the free drug is actively transported across the renal tubule, this fraction of drug is replaced by a fraction that dissociates from plasma proteins in order to maintain the equilibrium of free drug and bound drug. The extent to which undergoes passive reabsorption across renal tubular cells and into the circulation depends on the lipid solubility of the drug. Drug biotransformation facilitates drug elimination by forming polar drug metabolites that are not as readily reabsorbed as the less polar parent molecules. The proportion of ionized and nonionized drugs is affected by renal tubular pH, which may be manipulated in order to increase the excretion of a drug after a drug overdose.

Many drugs are excreted in the bile as the parent compound or a drug metabolite. Biliary excretion favors compounds with molecular weights that are higher than 300. Numerous conjugated drug metabolites, including the glucuronate and sulfate derivatives of steroids, are excreted in the bile. After the bile empties into the intestines, a fraction of the drug may be reabsorbed into the circulation and eventually return to the liver. This phenomenon is called enterohepatic cycling.

The sweat and saliva represent minor routes of excretion for some drugs. In pharmacokinetic studies, saliva measurements serve as a useful addition or alternative to plasma measurements, because the saliva concentration of a drug reflects the intracellular concentration of the drug in target tissues. For some drugs, the saliva concentration and plasma concentration are almost equal. For other drugs, one is much greater than the other is. Among the factors that influence saliva concentrations are whether a drug has an active transport system and whether a drug is subject to ion trapping.

Brent K- Brenner pg. 17

            Renal excretion of drugs are dealt with in the same manner as physiologic substances and undergo the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.

            Biliary excretion of drugs often occur with compounds that have a molecular weight higher than 300.  Steroids are often excreted in the bile.  Once the bile empties into the intestine, a fraction of the drug may be reabsorbed and eventually returned to the liver.  This process is called enterohepatic cycling.  The recycled compound is more easily absorbed than the parent compound.  Antibiotics that kill intestinal bacteria often reduce the effectiveness of the cycling.  This is sometimes responsible for the failure of oral contraceptives to prevent pregnancy.

            Sweat and saliva are minor routes of excretion for some drugs.  For some drugs, saliva and plasma concentrations are almost equal.  For others, one can be much greater than the other.

Janelisa, Brenner 17-18 KIDNEY: Most drugs are excreted in the urine, either as the parent compound or as drug metabolites. The amount of drug excreted is the sum of the amounts filtered and secreted minus the amount reabsorbed. If a drug has a large fraction bound to plasma proteins, it will have a low rate of glomerular filtration. Some drugs, particularly weak acids and bases, undergo active tubular secretion by transport systems located in proximal tubular cells; this is not affected by plasma protein binding due to the dissociation of acid/base to maintain equilibrium. Passive reabsorption across renal tubular cells is dependent on the drug’s lipid solubility. The less polar (parent drug) are absorbed more readily than the more polar (drug metabolites). LIVER: Many drugs, especially ones whose molecular weight is over 300, are excreted in the bile as the parent compound or drug metabolite. Conjugated drug metabolites are excreted in the bile, then emptied into the intestines where they may be reabsorbed into the circulation (enterohepatic cycling), or they may be hydrolyzed to the free drug form by intestinal bacteria which allows better reabsorption. SWEAT & SALIVA: minor routes of excretion for some drugs, and saliva can sometimes be used as an alternate to measuring plasma levels.

Anonymous Brenner 17-18.

Most drugs are excreted in the urine as the parent compound or metabolites. Drugs are handled by the kidneys in the same manner as physiologic substances by the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.

            Many drugs are excreted in the bile as the parent compound or metabolite. Biliary excretion favors compounds with molecular weights greater than 300. After the bile empties into the intestines some may be reabsorbed into the circulation and eventually return to the liver, a process called enterhepatic cycling.

            Sweat and saliva are minor routes of excretion for some drugs. The saliva concentration of a drug reflects the intracellular concentration of the drug in target tissue. For some drugs the saliva concentration and the plasma concentration are almost equal but for other drugs they may be much different.  

Anonymous Brenner 17-18

Most drugs are excreted in the urine as the parent compound or metabolites. Drugs are handled by the kidneys in the same manner as physiologic substances by the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.

            Many drugs are excreted in the bile as the parent compound or metabolite. Biliary excretion favors compounds with molecular weights greater than 300. After the bile empties into the intestines some may be reabsorbed into the circulation and eventually return to the liver, a process called enterhepatic cycling.

            Sweat and saliva are minor routes of excretion for some drugs. The saliva concentration of a drug reflects the intracellular concentration of the drug in target tissue. For some drugs the saliva concentration and the plasma concentration are almost equal but for other drugs they may be much different.  

Anonymous Brenner:17-18

• Most drugs are excreted in the urine, either as the parent compound or as drug metabolites.  Drugs are handled by the kidneys in the same manner as physiologic substances and undergo the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption.

• Many drugs are excreted in the bile as the parent compound or a drug metabolite.  After the bile empties into the intestines, a fraction of the drug may be reabsorbed into the circulation and eventually return to the liver.  This phenomenon is called enterohepatic cycling.

• The sweat and saliva represent minor routes of excretion for some drugs.  The saliva concentration of a drug reflects the intracellular concentration of the drug in target tissues.

8.         Define "bioavailability," and identify major factors which influence the bioavailability of orally administered drugs.

Anonymous Pharmacology Pg. 22

Bioavailability – is defined as the fraction of the administered dose of a drug that reaches the systemic circulation in an active form.

Factors that influence the bioavailability of orally administered drugs include the rate and extent of tablet disintegration and drug dissolution. Biologic factors include the effects of food, which may sequester or inactivate a drug; the effects of gastric acid which may inactivate a drug; and the effects of gut and liver enzymes, which may biotransform a drug during its absorption and first pass through the liver. (The bioavailability of drugs administered intramuscularly or via other routes may be determined in the same manner as the bioavailability of drugs administered orally.

Brent K- Brenner pg. 22

            Bioavailability is the fraction of the administered dose of a drug that reaches the systemic circulation in an active form.

Factors influencing bioavailability of oral drugs:

  -rate and extent of tablet disintegration and drug dissolution

  -food may inactivate or sequester a drug

  -drug inactivation by gastric acid

  -drug biotransformation from gut and liver enzymes

Janelisa, Brenner 22 Bioavailability is the fraction of the administered dose of a drug that reaches the systemic circulation in an active form. This fraction can be reduced by pharmaceutical factors such as the rate and extent of tablet disintegration and drug dissolution. Biologic factors include the effects of food, which may sequester or inactivate a drug; and the effects of gut and liver enzymes, which may biotransform a drug during its absorption and first pass through the liver.

Anonymous Brenner 22

Bioavailability is defined as the fraction of a drug that reaches the systemic circulation in an active form. Pharmaceutical factors that affect it in orally administered drugs are rate and extent of tablet disintegration and drug dissolution. Biologic factors include the effect of food, which may sequester or inactivate a drug; the effects of gastric acid which may inactivate a drug; and the effects of gut and liver enzymes which may biotransform a drug during its absorption and first pass through the liver.

Anonymous

Bioavailability is defined as the fraction of a drug that reaches the systemic circulation in an active form. Pharmaceutical factors that affect it in orally administered drugs are rate and extent of tablet disintegration and drug dissolution. Biologic factors include the effect of food, which may sequester or inactivate a drug; the effects of gastric acid which may inactivate a drug; and the effects of gut and liver enzymes which may biotransform a drug during its absorption and first pass through the liver.

Anonymous Brenner:22

• Defined as the fraction of the administered dose of a drug that reaches the systemic circulation in an active form.

• Orally administered drugs is a particular concern because it can be reduced by so many pharmaceutical and biologic factors.  Pharmaceutical factors include the rate and extent of tablet disintegration and drug dissolution.  Biologic factors include the effects of food, which may sequester or inactivate a drug; the effects of gastric acid, which may inactivate the drug; and the effects of gut and liver enzymes, which my biotransform a drug during its absorption and first pass through the liver.

• Ballweg:314Bioavailability of an orally administered drug is influenced by two major factors:  absorption of the drug by the gastric mucosa and metabolism of the drug as it passes through the liver from the portal system.  These in turn are influenced by the properties of the dug itself, as well as by host factors such as other gastric contents, gastric motility, and t state of liver enzymes.

9.         Define the following terms, and describe how they affect dosing considerations when you are trying to achieve a steady state of a particular drug in the body:

                        half-life

                        loading dose

                        maintenance dose

            (Note:  don't worry about the math, just describe the concepts)

Anonymous Brenner pp. 23

half-life: The elimination half-life is the time required to eliminate half of the amount of a drug in the body or to reduce the plasma drug concentration by 50%. Brenner pp. 20. Not in the book but seems apparent: the affect on dosing considerations when trying to achieve steady state is that you must know half-life in order to know how long the drug will stay in the body at an effective level. i.e., how long the drug lasts in the body is one of the things that dictates how much and how often to give the drug.

loading dose   The loading dose is also called the priming dose. It is the first dose of med. given to bring plasma drug concentration to therapeutic levels rapidly. Usually larger than maintenance dose, generally given as single dose but may be split into parts given over a number of hours.     Brenner pp. 23

maintenance dose definition obvious. Used to establish or maintain desired steady-state plasma drug concentration. Amount given based on the principle that at the steady state, the rate of drug admin. equals the rate of drug elimination. Maintenance dose is calculated as rate of drug elimination multiplied by dosage intervals, and equation must include fractional bioavailability if drug is administered orally.       

Brent K- Taber’s

Half-life:  the time required to eliminate half of the amount of a drug in the body or to reduce the plasma drug concentration by 50%.

Loading dose:  administration of an initial, large drug dose in order to reach therapeutic blood levels rapidly.

Maintenance dose:  the dose at which a drug maintains a desired steady-state plasma concentration.

Janelisa, Brenner 19-20, 23

half-life - Elimination half-life is the time required to eliminate half of the amount of a drug in the body or to reduce the plasma drug concentration by 50%. It can also be expressed in terms of the drug’s clearance and volume of distribution which are affected by disease, age, and other physiologic variables. Since the time to reach the steady state is dependent on the time it takes for the rate of drug elimination to equal the rate of drug administration, the time to reach the study state is a function of the elimination half-life of the drug (about 4-5 half-lives).

loading dose – is used to rapidly establish a therapeutic plasma drug concentration. It is usually much larger than the maintenance dose and is generally administered as a single dose, except with drugs that are more toxic.

maintenance dose – is used to establish or maintain a desired steady-state plasma drug concentration

Anonymous Brenner 22-23

• Half-life- The half-life of  drug is the time required to eliminate half of the amount of a drug in the body or to reduce the plasma drug concentration by 50%.

• Loading dose- Loading dose is the amount of a drug required to reach therapeutic plasma concentration levels. It is usually administered as single dose but may be divided into parts with more toxic drugs.

• Steady state - Steady state occurs when rate of drug elimination equals rate of administration. It takes about 4-5 half lives to reach steady state.

• Maintenance dose- Is the dose given to maintain a particular concentration. The usual purpose is to maintain a desired steady state plasma drug concentration.

• The steady state drug concentration can be calculated as the dose per unit of time divided by the clearance, this equation can be rearranged to determine the dose per unit of time required to establish a specified steady state drug concentration.  

Anonymous

• Half-life- The half-life of  drug is the time required to eliminate half of the amount of a drug in the body or to reduce the plasma drug concentration by 50%.

• Loading dose- Loading dose is the amount of a drug required to reach therapeutic plasma concentration levels. It is usually administered as single dose but may be divided into parts with more toxic drugs.

• Steady state - Steady state occurs when rate of drug elimination equals rate of administration. It takes about 4-5 half lives to reach steady state.

• Maintenance dose- Is the dose given to maintain a particular concentration. The usual purpose is to maintain a desired steady state plasma drug concentration.

• The steady state drug concentration can be calculated as the dose per unit of time divided by the clearance, this equation can be rearranged to determine the dose per unit of time required to establish a specified steady state drug concentration.  

Anonymous

• half-life – Brenner:19-20  The elimination half-life is the time required to eliminate half of the amount of a drug in the body or to reduce the plasma drug concentration by 50%.  The half-life may also be expressed in terms of the drug’s clearance and volume of distribution, indicating that the drug’s half-life will change when either of these factors is altered.  Disease, age, and other physiologic variables may alter drug clearance or volume of distribution and thereby change the half-life.

• loading dose – Brenner:23  The purpose of the loading dose, or Priming dose, is to rapidly establish a therapeutic plasma drug concentration.  The loading dose can be calculated by multiplying the volume of distribution by the desired plasma drug concentration.  The loading dose is usually larger than the maintenance dose and is generally administered as a single dose, but it may be divided into several parts that are given over a number of hours.  A loading dose is a single or divided dose given to rapidly establish a therapeutic plasma drug concentration

• maintenance dose – The purpose of a maintenance dose is to establish or maintain a desired steady-state plasma drug concentration,  For drugs given intermittently, the maintenance dose is one of a series of doses administered at regular intervals.  The amount of drug to be given is based on the principle that at the steady state, the rate of drug administration equals the rate of drug elimination.  To determine the rate of drug elimination, the drug clearance is multiplied by the average steady-state plasma drug concentration.  The maintenance dose is then calculated as the rate of drug elimination multiplied by the dosage intervals.  If the drug is administered orally, its fractional bioavailability must be included in the equation.

10.       Define the following terms:

                        receptor

                        agonist

                        antagonist

                        dose-response relationship

Anonymous Brenner

Receptors are specific cell molecules that most drugs interact with to produce their desired effects. Among the few drugs that produce their effects without interacting with receptors are drugs that neutralize gastric acid and drugs that exert an osmotic effect in tissue. There are many types of drug receptors. They include receptors for hormones and neurotransmitters, enzymes, membrane transport proteins, and other macromolecules such as membrane lipids and nucleic acids. pgs. 26-27

Agonists are drugs that have both receptor affinity and intrinsic activity which is the ability of a drug to initiate a cellular effect. There are three types of agonists. Full agonists have the ability to produce the maximal response obtainable in a tissue. Partial agonists can only produce a submaximal response. Inverse agonists, which are also called negative antagonists, are involved in a special type of drug-receptor interaction. pg. 27-28

Antagonists are drugs that have receptor affinity but lack intrinsic activity. pg. 27

Dose-response relationship is the relationship between the concentration of a drug at the receptor site and the magnitude of the response. pg. 30

Brent K- Taber’s, Brenner pg. 29-30

Receptor:  a portion of a cell or tissue that combines with a drug, hormone, or chemical mediator to alter the function of the cell.

Agonist:  a drug that combines with a receptor to produce a response.

Antagonist:  a drug that occupies a receptor and interferes with the action of an agonist, thereby reducing or preventing a pharmacologic effect.

Dose-response relationship:  The relationship between the concentration of a drug at the receptor site and the magnitude of the response.

Janelisa, Brenner 26-30                       

Receptor – specific cell molecule that interacts with a drug. The bonds formed, (hydrogen, ionic, and hydrophobic) are reversible and enable the drug to dissociate from the receptor as tissue concentration of the drug declines. Affinity is the tendency of a drug to combine with its receptor and is a measure of the strength of the drug-receptor bonding; it is the primary determinant of drug potency.

Agonist – drugs that have both receptor affinity and intrinsic activity (the ability to initiate a cellular effect).

Antagonist – drugs that have receptor affinity only

dose-response relationship – the relationship between the concentration of a drug at the receptor site and the magnitude of the response. It can be a graded or all-or-none response.

Anonymous Brenner 26-28

• Receptor - The part of a neuron or effector organ to which neurotransmitters, drugs, or hormones combine to produce a response. Receptors are located on skeletal muscle, smooth muscle, cardiac muscle, glands, organs, and neurons.

• Agonist - A drug that attaches to a receptor and produces an effect like that of the natural neurotransmitter.(has receptor affinity and intrinsic activity)

• Antagonist - A drug that interferes with, or blocks the action of an agonist. (has receptor affinity but no intrinsic activity)

• Dose-response relationship - The relationship of the concentration of a drug at the receptor site and the magnitude of the response is called the dose response relationship.

Anonymous

• Receptor - The part of a neuron or effector organ to which neurotransmitters, drugs, or hormones combine to produce a response. Receptors are located on skeletal muscle, smooth muscle, cardiac muscle, glands, organs, and neurons.

• Agonist - A drug that attaches to a receptor and produces an effect like that of the natural neurotransmitter.(has receptor affinity and intrinsic activity)

• Antagonist - A drug that interferes with, or blocks the action of an agonist. (has receptor affinity but no intrinsic activity)

• Dose-response relationship - The relationship of the concentration of a drug at the receptor site and the magnitude of the response is called the dose response relationship.

Anonymous

• receptor – Brenner:26  Most drugs produce their effects by interacting with specific cell molecules known as receptors.  These receptors are transmembrane proteins that have a ligand (drug or neurotransmitter) binding site on the external surface of the membrane and have an effector site on the internal surface.

• agonist – Brenner:27  Drugs that have both receptor affinity and intrinsic activity are call agonists.

• antagonist – Brenner:27  Drugs that have receptor affinity but lack intrinsic activity are called antagonists.

• dose-response relationship – (Brenner:30)  The relationship between the concentration of a drug at the receptor site and the magnitude of the response is called the dose-response relationship.  The relationship may be described in terms of a graded (arithmetic) response or a quantal (all-or-none) response.

11.       Describe the effect of major impairment of kidney, liver, or heart function on drug clearance (*see Brenner, Chp. 4, p. 40)

GR.  Brenner p. 40.

Liver and kidney disease ↓ the ability of the liver and kidneys to biotransform & excrete drugs, therefore, ↓ drug clearance.  Dosage reduction is required to avoid toxicity.  Heart failure may also reduce drug biotransformation.

Anonymous

Renal: function is lower in neonates and elderly adults that it is in young adults and this affects the renal excretion of many drugs.

Liver: Lower rate of oxidative reaction and glucuronate conjugation. In neonates, infants and elderly.

Heart: Incomplete blood-brain barrier; higher vol. Of distribution for water-soluble drugs for neonates. For elderly higher volume of distribution for fat-soluble drugs

Anonymous Brenner pg. 40

Heart and renal disease may reduce the capacity of the liver and kidneys to biotransform and excrete drugs, thereby reducing drug clearance and necessitating a dosage reduction to avoid toxicity.  Heart failure and other conditions that reduce hepatic blood flow may also reduce drug biotransformation.  Oxidative drug metabolism is usually impaired in patients with hepatic disease, whereas conjugation processes may be little affected. Guidelines for dosage adjustment in patients with hepatic or renal disease have been developed and published in clinical references and textbooks.  Dosage adjustments are made by:

•        reducing the dose

•        increasing the interval between doses

•        or both

Adjustments for individual patients are usually based on lab measurements of renal or hepatic function and on plasma drug concentrations.

Anonymous Brenner: Pg. 40

Hepatic and renal disease may reduce the capacity of the liver and kidneys to biotransform and excrete drugs, thereby reducing drug clearance and necessitating a dosage reduction to avoid toxicity.  Heart failure and other conditions that reduce hepatic blood flow may also reduce drug biotransformation.

Anonymous Brenner:40

•  Hepatic and renal disease may reduce the capacity of liver and kidneys to biotransform and excrete drugs, thereby reducing drug clearance and necessitating a dosage reduction to avoid toxicity.

• Heart failure and other conditions that reduce hepatic blood flow may also reduce drug biotransformation.  Oxidative drug metabolism is usually impaired in patients with hepatic disease, whereas conjugation processes may be little affected.

• Guidelines for dosage adjustment in patients with hepatic or renal disease have been developed and can be found in many clinical references and textbooks.  Dosage adjustments are made by reducing the dose, increasing the interval between doses, or both.  Adjustments are based on lab measurements of renal or hepatic function and on plasma drug concentration.

12.       Given the formula and the appropriate patient data (e.g., weight), be able to calculate a patient's ideal body weight.  (* not in textbook -- to be discussed in class)

GR.  Upcoming class, be patient.

Anonymous  This may not be the same as what is covered in class.

IBW.. Ideal Body Weight is calculated using a formula and two known items… the patients height in inches over 5 feet and their sex.  So after determining male vs female.. all you need to plug in is their height in inches over 5 feet.

Therefore,

            Female ideal body weight = 45.5 kg + (2.3 kg x height in inches over 5 feet)

            Male ideal body weight= 50.0 kg + (2.3 kg x height in inches over 5 feet)

Anonymous

IBW:  Males:                50   kg  + 2.3 kg/inch > 5 feet

           Females:            45.5 kg + 2.3 kg/inch > 5 feet

Example:  Female is 5”6”  so,     45.5 + (2.3 X 6) = 59.3kg ( or 130lbs) for IBW

Anonymous

Men:    IBW (kg) = 52 + (1.9kg X inches > 5’)

Women:           IBW (kg) = 49 + (1.7kg X inches > 5’)

13.       Given the formula and the appropriate patient data (e.g., serum creatinine and weight), be able to calculate a patient's creatinine clearance. (* not in textbook -- to be discussed in class)

GR.  Upcoming class, be patient.

Anonymous  This may not be the same as what is covered in class.  There is a computer program for this.

Creatinine Clearance is also called the Cockroft-Gault Equation

This is a measure of kidney function using the patient’s ideal body weight.  

(140 – Age in yrs) x body weight             

72 x serum creatinine (mg/dL)          = Male creatinine clearance

(140 – Age in yrs) x body weight              

72 x serum creatinine (mg/dL)          X 0.85     =  Female creatinine clearance

Anonymous

Cockcroft-Gault estimate of CrCl:  (140-age)(IBW in kg)(0.85 if female*)/72(Serum creatinine)

*correction factor for less muscle mass in female

Example: Male 68 yo, 5’11”, Scr=2.0    CrCl:    72(75) /72(2.0) = 37.5 (marked impairment)

Normal CrCl:

> 80ml/min (exact numbers will vary lab to lab and in texts)Tarascon Pharmacopoeia,2003

100ml/min (healthy young female) Current Med. Dx. & Tx.

120ml/min (healthy young male) Current Med. Dx. & Tx.

In patients with renal disease, serum creatinine values do not become elevated until clearance values fall to 50-60% of normal.  From my lab book

Anonymous

Men:    140 – age (IBW)

            72 (serum Creatinine)

Women:           140 – age (IBW)(0.85)

            72 (serum Creatinine)

Henry

 1.  Calculating creatinine clearance.  The formula for doing this is not in the book.  The Seattle speaker said in class that you should use the patient's Ideal Body Weight in the calculation, not actual weight.  I
checked 3 different pharm books and got slightly varying answers.  The bottom line is:  use ideal body weight.