Pharmacokinetics

Question 1

Explain the ADME scheme

Answer 1

Question 2

Drug passages across the biological membrane: Types of diffusion

Answer 2

Diffusion 1:

• Diffusion of un-ionized drugs is the most common and most important mode of traversing biological membranes; drugs difffuse passively down their concentration gradient.
• only the un-ionized form of drug can diffuse across biological membranes

Diffusion of drugs that are weak electrolytes:

• the degree of ionization of a weak acid or base is determined by the pK of the drug and pH of its environment accordin to the Henderson-Hasselbalch equation
• When the pK of a drug equals the pH of surroundings, 50% ionization occurs.

Question 3

What is the bioavailability of a drug?

Answer 3

Is the fraction of drug (administered by any route) that reaches the bloodstream unaltered.

Question 4

What does it mean when a measurment is expressed as the letter F?

Answer 4

• A measurment of the extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action is expressed as the letter F

Question 5

What is Absolute bioavailability?

Answer 5

it measures the availability of the active drug in systemic circulation adter non-intravenous administration (i.e after oral, rectal, transdermal, sc administration)

Question 6

How do we determine absolute bioavailability of a drug?

Answer 6

By a pharmacokinetic study to obtain a plasma drug concentration vs. time plit and area under curve (AUC) for the drug after both IV and non-IV administration

Question 7

How will the bioavailability of a drug given IV be?

Answer 7

It will habe an absolute bioavailability of F=1 while drugs given by other routes usually have an absolute bioavailability of less than one. (explained from the graph)

Question 8

What is Relative bioavailability?

Answer 8

This measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route.

Question 9

The absolute bioavailability of a drug administered by an extravascular route?

Answer 9

is usually less than one (F<1)

Question 10

What are the factors that can influence the Bioavailability?

Answer 10

• Poor absorption: from the GI tract or from application site
• Degradation or metabolism of the drug prior to absorption or due to hepatic –> first-pass effect
• whether a drug is taken with or without food will affect oral absorption
• other drugs taken concurrently may alter abosrption and metabolism –> interactions
• intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora
• disease states affacting liver metabolism or GI function will also have an effect.

Question 11

Sites of absorption by Oral administration:

Answer 11

Stomach:

• lipid-soluble drugs and weak acids, which are normally un-ionized at the low pH of gastric contents, may be absorbed directly from the stomach.
• weak bases and strong acids are not normally absorbed from this site, since they tend to be protonated at the pH of gastric contents. (ion trapping - accumulation)

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.
• acids are normally absorbed more extensively from the small intestine than from the stomach, even though the intestine has a higher pH.

Question 12

What is the Noyes-Whitney equation?

Answer 12

It describes the rate of dissolution of oral administrated drugs.

Question 13

Factors that may alter absorption from the GI:

Answer 13

• Gastric emtpying: decreased emptying = decreased rate of aborption
• GI blood flow: difference between “blood flow limited” and “blood flow independent”
• Stomach acid and inactivating enzymes
• interaction with food or other drugs
• inert ingredients in oral preparation sor the special formulation
• the first-pass effect influences drug absorption by metabolism in the liver by biliary secretion

Question 14

Oral administration:

Tabel with location in the stomach, pH, membrane, blood supply, surface area, transit time, by-pass liver

Answer 14

Question 15

General considerations of parenteral administration:

Answer 15

• Parenteral generally results in more predictable bioavailability than oral administration
• With IV administration the drug is injected directly to the blood stream without absorption = 100% bioavailable
• its the most rapid means of introducing drugs to the body
• IM and SC: drugs can enter the capillaries directly thorugh pores between endothelial cells
• Depot preparations for sustained release may be administered by IM or SC routes, but some preparations may cause irritation and pain.

Question 16

Inhalation administration:

Answer 16

• results in rapid absorption because of the large surface area and rich blood supply of the alveoli.
• frequently used for gaseous anasthetics, but it is generally not practical.
• may be used for drugs that act on the airways, such as epinephrine and glucocorticoids to treat bornichal asthma.

Question 17

Intrathecal administration:

Answer 17

usefull for drugs that do not readily cross the blood-brain barrier

Question 18

Rectal administration:

Answer 18

• mnnimizes first-pass metabolism and may be used to circumvent the nausea and vomiting that sometimes result from oral administration

Question 19

Sublingual - Buccal administration:

Answer 19

useful for drugsh with high first-pass metabolism, such as nitroglycerin, since hepatic metabolism is bypassed.

(rarely in Veterinary medicine; eg uses for analeptics, sedatives)

Question 20

Topical administration:

Answer 20

• widely used when a local effect is desired or to minimize systemic effects, especially in dermatology and ophthalmology.
• preparations must be non-irritating.
• drugs administered topically may sometimes produce systemic effects.

Question 21

What is Distribution?

Answer 21

• It is a branch of PK which describes the reversible transfer of drug from one location to another within the body

Question 22

The process of distribution:

Answer 22

• the compund needs to be carried to its effector site, most often via the bloodstream
• drug distribution is the process which a drug leaces the blood stream and enters the extracellular fluids and tissues, or is the movement of a drug from the bloodstream to various tissues of the body
• From there, the compound may distribute into tissues and organs, usually to differing extents.

Question 23

The distribution of a drug between tissues is dependent on:

Answer 23

• permeability between tissues (between blood and tissue in particular)
• blood flow and perfusion rate of the tissue
• the ability of the drug to bind plasma proteins and tissue

Question 24

What is the VD of a drug?

Answer 24

• The Volume Distribution (VD) of a drug is a property that quantifies the extent of distribution
• “Volume of Distribution” is the volume of total body fluid into which a drug “appears” to distribute.
• it is defined as: the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration.
• Volume of distribution is determined by administering a known dose of drug (expressed in units of mass) IV and measruing the initial plasma concentration (mass/volume)

Question 25

What is important for distribution if the site of action is intracellular?

Answer 25

A drug must diffuse accross the cellular membranes, and in this case lipid solubility is imprtant for effective distribution

Question 26

What is the importance of blood flow in the distribution?

Answer 26

• in most tissues, drugs can leave the circulation readily by diffusion across or between capillary endothelial cells. Thus, the initial rate of distribution of a drug depends heavily on blood flow to various organs.

Bran, liver, kidney > muscle, skin > fat, bone

• at equilibrium 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 drug.

Question 27

What is Drug Redistribution?

Answer 27

• it descripves when the relative distributon of a drug in the body changes with time.
• this is usually seen with highly lipphilic drugs such as Thiopental that initially enter tissues with high blood flow (eg the brain) and then quickly redistribute to tisses with lower blood flow (eg skeletal muscle and adipose tissue)

Question 28

factors affecting drug distribution:

Answer 28

Question 29

Distribution: Binding of drugs by plasma proteins

Answer 29

• Drugs in the plasma may exist in the free form or may be bound to plasma proteins or other blood components, such as RBC´s.
• the extent of plasma protein binding is highly variable and ranges from virtually 0% to more than 99% bound, depending on the specific drug. Binding is generally reversible.
• only the free drug diffuses thorugh capillary walls; extensive binding retards the rate at which the drug reaches its site of action and may prolong duration of action
• some plasma proteins bind many different drugs, while other proteins bind only one or a limited number
• ef: serum albumin tends to bind many acidic drugs, while alpha1-acid glycoprotein and globulins tends to bind many basic drigs.
• there are a few, if any, documented changes in a grud´s effect due to changes in plasma protein binding.

Question 30

Distribution: Proteins with potenital binding sites for Various Drugs:

Answer 30

Question 31

Barriers to drug distribution:

Answer 31

1. Blood-brain barrier:
   - ionized or polar drugs distribute poorly to the CNS, including certain chemotherapeutic agents and toxic compunds, because they must pass thorugh, rather than between, endothelial cells.
   - inflammation, eg from meningitis, mau increase the ability of ionized, poorly soluble drugs to cross the blood-brain barrier.
2. Placental barrier:
   - lipid soluble drigs cross the placental barrier more easily than polar drugs; drugs with a molecular weight of less than 600 pass the placental barrier better than øarger molecules.
   - consider mother - foetus
   - drug transporters (eg P-glycoprotein transporter) transfer drugs out of the foetus.

Question 32

Standard values of volumes of fluid compartments in an average:

Answer 32

Question 33

Features of Volume of Distribution:

Answer 33

VD values for most drugs do not represent their actual distribution in body fluids. The use of VD values is primarily conceptual, that is:

• 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.
• among other variables, VD may be influenced by age, sex, weight, and disease processes (eg. oedema, ascites)

Question 34

What is Biotransformation?

Answer 34

a major mechanism for drug elimination; most drugs undergo biotransformation, or metabolism, after they enter the body.

• Compounds begin to be broken down as soon as they enter the body. As metabolism occurs, the initial (parent) compound is converted to new compunds called metabolites.
• Biotransformation, which almost always produces metabolites that are more polar than the parent drug, usually terminates the pharmacologic action of the parent drug and, via excretion, increases removal of the drug from the body.

Question 35

What are Xenobiotics?

Answer 35

• all organisms are constantly exposed to compound that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called Xenobiotics

Question 36

How are Xenobiotics detoxified?

Answer 36

• Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes.
• these include Cytochrome P450 oxidases, UDP-glucuronosyl transferases, and Glutathione S-transferases.
• This system of enzymes acts in two stages to firstly oxidize the xenobiotics (phase 1) and then conjugate water-soluble groups onto the molecule (phase 2)
• the majority of small-molecule drug emtabolism is carried out in the liver by redox enzymes, termed cytochrome P450 enzymes

Question 37

Possible consequences of biotransformation include:

Answer 37

the production of inactive metabolites (most common), metabolites with:

• increased or decreased potencies
• metabolites with qualitatively different pharmacologic actions
• toxic metabolites
• active metabolites from inactive prodrugs

Question 38

Why does metabolites lead to a more rapid rate of clearance?

Answer 38

• metabolites are often more polar than the parent compounds and this increased polarity may lead to a more rapid clearance,
• because of possible secretion by acid or base carriers in the kidney it may also lead to decreased tubular reabsorption

Question 39

Biotransformation of drugs is variable and can be affected by many parameters, such as:

Answer 39

• Prior administration of the drugs in question or of other drugs; diet, hormonal status, genetics, diseases (eg decreased in cardiac of pulmonary disease), age and developmental status (the very elderly and very young may be more sensitive to drugs, because of decreased or undeveloped levels of drug-metabolizing enzymes), and liver function (in case of severe liver damage).

Question 40

Classification of Biotransformation reactions:

Answer 40

1. Phase 1 (nonsynthetic) reactions:
   - involve enzyme-catalyzed biotransformation of the drug without any conjugates.
   - includes: oxidations, reductions and hydrolysis reactions; they frequently introduce a functional group (eg. OH-) that serves as the active centre for sequential conjugation in a phase 2 reaction.
2. Phase 2 (synthetic) reactions:
   - include conjugation reactions, which involve the enzyme-catalyzed combination of a drug (or drug metabolite) with an endogenous substance.
   - phase 2 reactions require a functional group - an active centre - as the site of conjugation with the endogenous substance.
   - phase 2 reactions require energy indirectly for the synthesis of “activated carriers”, the form of the endogenous substance used in the conjugation reaction (eg. UDP-glucuronate)

Question 41

Enzymes catalyzing phase 1 biotransformation reactions include:

Answer 41

• Cytochrme P-450, aldehyde and alcohol dehydrogenases, deaminases, esterases, amidases and epoxide hydratases

Question 42

Enzymes catalyzing phase 2 biotransformation reactions include:

Answer 42

• Glucuronly transferase (glucuronide conjugation), sulfotransferase (sulfate conjugation), transacylases (amino acid conjugation), acetulases, ethylases, methulases and glutathione transferase.

Question 43

Selected inducers and inhibitors of Cytochrome P-450 (CYP) enzymes 1:

Answer 43

Question 44

Selected inducers and inhibitors of Cytochrome P-450 (CYP) enzymes 2:

Answer 44

Question 45

Cytochrome P-450 catalyzes numerous reactions, including:

Answer 45

• Aromatic and aliphatic hydrocylations
• dealkylations at nitrogen, sulphur, and oxygen atoms
• heteroatom oxidations at nitrogen and sulphur atoms
• reductions at nitrogen atoms
• and ester and amide hydrolysis

Question 46

What are the CYP3A subfamily resposible for?

Answer 46

• for up to half of the total cytochrome P-450 in the liver and accounts for approx. 50% of the metabolism of clinically important drugs.
• CYP3A4 is a particular abundant enzyme

Question 47

Cytochrome P-450 monooxygenase Localization:

Answer 47

• primarily the liver, which has the greatest specific enzymatic activity and the highest total activity
• gut, lung, skin, kidneys
• adrenals, ovaries and testis, and tissues involved in steroidogenesis and steroid metabolism.
• the enzymes subcellular location is the Endoplasmic reticulum
• Lipid membrane location facilitates the metabolism of lipid soluble drugs

Question 48

Cytochrome P-450 monooxygenase Mechanism of reaction:

Answer 48

• in the overall reaction, the drug is oxidized and oxygen is reduced to water.
• reducing equivalents provided by Nicotinamide adenine dinucleotide phosphate (NADPH), and generation of this cofactor is coupled to cytochrome P-450 reductase.
• the overall reaction for aromatic hydrocylation can be described as:

Drug + O2 + NADPH + H+ –> Drug - OH + NADP+ + H2O

Question 49

Cytochrome P-450 monooxygenase Genetic polymorphism:

Answer 49

• Genetic polymorphism of several clinically important CYP-450s, particularly CYP2C and CYP2D, is a source of variable metabolism in humans, indlucing differences among radical and ethnic groups.
• these enzymes have substantially different properties (Vmax or Km)

Question 50

Cytochrome P-450 monooxygenase Induction:

Answer 50

• Induction is brought up by drugs and endogenous substances, such as hormones.
• any given drug preferentially induces one form of Cytochrome P-450 or a particular set of P-450s
• When caused by drugs, induction is pharmacologially important as a major source of drug interactions.
• a drug may induce its own metabolism (metabolic tolernace) and that of the other drugs catalyzed by the induved P-450
• Induction can be caused by a wide variety of clinically useful drugs (drug-drug interactions), such as: phenobarbital, omeprazole, rifampin, carbamazepine, and St. John´s wort.

Question 51

Cytochrome P-450 monooxygenase - Inhibition:

Answer 51

• Competitive or non-competitive inhibition of CYP-450 activity can result in the reduced metabolism of other drugs or endogenous substrates such as testosterone.
• inhibition ccan be caused by a number of commonly used drugs, including Cimotidine, fluconazole, fluoxetine, and eryhromycin, and is another major source of drug - drug interactions.
• some of the same drugs that inhibit CYP3A4 can inhibit the drug efflux transporter P-glycoprotein (eg. amiodarone, clarithromycin, erythromycin, ketoconazole).

Question 52

General features of Glucuronyl transferase:

Answer 52

(metabolism - biotransformation)

• it is a set of enzymes with unique but overlapping specificity that are involved in phase 2 reactions.
• it catalyzes the conjugation of glucuronic acid to a variety o active cetners, including -OH, -COOH, -SH, and -NH2

Question 53

Mechanism of reaction of Glucuronyl transferase:

Answer 53

• UDP-glucoronic acid, the active gluvuronide donor, is formed from UTP and glucose-1-phosphate
• Glucuronyl transferase then catalyzes the conjugaton to the active center of the drug

Question 54

Location and induction of Glucuronyl transferase:

Answer 54

• It is loated in the endoplasmic reticulum.
• it is the only ohase 2 reaction that is inducible by drugs and is a possible dite of drug interactions.

Question 55

Routes of excretion:

Answer 55

• urine, faeces (e.g unabsorbed drugs and drugs secreted in bile)
• saliva, sweat, tears, milk (with possible transfer to neonates)
• and lungs (e.g alcohols and anaesthetics)

Any route may be important for a given drug, but the kidney is the major site of excretion for most drugs.

Question 56

What is the Net renal excretion of drugs?

Answer 56

• it is the result of three separate processes: the amount f drug filtered 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.

Question 57

Filtration of drugs:

Answer 57

• most drugs have low molecular weight an 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 flomerular filtration rate is 30-40% lower during newborn´s firs year of life than adults

Question 58

Secretion of drugs:

Answer 58

• 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 concentratin gradient; they are a site for potential drug-drug interactions because drugs may compete with each other for binding 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

Question 59

Reabsorption of drugs:

Answer 59

• may occur throughout the tubule; some compounds, including endogenous compounds such as glucose, are 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 which depends on the lipid solubility and pK of the drug and also on the concetration gradient of the drug between urine and the plasma.
• Reabsorption may be affected by alterations of urinary pH, which also affect elimination of weak acids or bases by affecting the degree of ionization.
• Eg: acidification of the urine will result in a higher proportion of the un-ionized form of an acidic drug and will facilitate reabsorption

Question 60

Renal clearance of drugs:

Answer 60

• a drug eccreted by filtration alone (eg insulin) will have a clearance equal to the glomerular filtration rate (GFR; 125-130 mL/min)
• A drug excreted by filtration and complete secretion (eg. para-aminohippuric acid PAHA) will have a clearance equal to renal plasma clearance 650mL/min
• clearance values between 130 and 650 mL/min suggest that a drug is filtered, secreted and partially reabsorbed.

Question 61

Total body clearance (Cl):

Answer 61

• can be separated into clearance due to renal elimination, Cl, and clearance due to metabolism, Clm
• Clm = Km x VD (metabolic clearance)
• Cl = Clr + Clm
• Metabolic Clerance calculated from M and AUC and Cl = DOSE / AUC

Question 62

Factors influencing renal clearance:

Answer 62

• age (some mechanisms of excretion may not be fully developed at the time of birth), other drugs and disease.
• in the presence of renal failure (resulting in higher plasma levels)
• for those drugs with a narrow therapeutic index, dose adjustment may be required.

Question 63

Hepatic extraction of drugs:

Answer 63

• General extraction by the liver occurs because of the livers large size (1500g) and high blood flow (1 mL/g/min)
• the extraction rate 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 frugs can have a hepatic clearance approaching 1500 mL/min

Question 64

What are the First-pass effect?

Answer 64

• drugs taken orally pass across membranes of the GI tract into the portal vein and through the liver before entering the general circulation
• in the presence of a 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.

Question 65

Bioavailability of orally administered drugs is decreased by?

Answer 65

• the fraction of drug removed by the firs pass thorugh the liver.
• eg: a drug with a hepatic extraction ratio of 1 would have 0% bioavailabilty;
• a drug such as lidocaine, with an extraction ratio of 0,7, would have 30% bioavailability

Question 66

What are the Pharmacokinetic models?

Answer 66

• they are relatively simple mathematical schemes that represent complex physiologic spaces or processes.
• the most commonly used are Compartmental (one-compartment and two-compartment…) models.

Question 67

What is the Non-compartmental PK analysis?

Answer 67

• It is highly dependent on estimation of total drug exposure (based on AUC) and highly dependent on the blood/plasma sampling schedule.

Question 68

What is the Zero-order elimination?

Answer 68

• in this model, the plot of the log of the plasma concetration versus time will be concave upward, and a constant amoung of drug will be eliminated per unit time (e.g 10 mg of drug will be elininated every 8 hours)
• zero-order elimination may occur when therapeutic doses of drugs exceed the capacity of elimination mechanisms.

Question 69

What is the First-order elimination?

Answer 69

• accounts for elimination of most drugs.
• it refers to the elimination of a constant fracion of drug per unit time;
• that is the rate of elimination is a linear function of the plasma drug concentration
• First-order elimination occurs when elimination systems are not saturated by the drug
• drug elimination is firs order;

Question 70

What are the One-copartment open model?

Answer 70

• the body is seen as one continous fluid phase, into which drug is administered, and through which it diffuses.
• the term “open” describes the continous loss of drugs from the compartment due to metabolism and excretion.
• the openness of the body causes drug molecules to disengage from receptors and so terminated drug action.

Question 71

Mathematical formula of One-compartment open model:

Answer 71

Question 72

Elimination Half-life (T 1/2):

Answer 72

• Half life is the time it takes for the plasma drug concentration to be reduced by 50%
• this concept applies only to drugs eliminated by first-order kinetics.
• half-life is determined from the log plasma drug concentration versus time profile for drugs fitting a one-compartment model or from the elinimation phase for drugs fitting the two-compartment model.
• as long as the dose administered does not exceed the capacity of the elinimation systems (i.e the dose does not saturate those systems), the half-life will remain constant.
• the slope of the semilogarithmic plot is k, where k is the rate constant of elimination and has units of time-1, and the incercept on the y axis is C0.

Question 73

Calculation of Half-life:

Answer 73

Question 74

Pharmacokinetic parameters:

• C0, Cmax, Tmax, T 1/2el, AUC

Answer 74

Question 75

Two-compartment open model:

Answer 75

• is a more common model for distribution and elimination of drugs.
• initial rapid changes in the plasma concentrtion of a drug are observed because of a distriution phase, the time required for the drug to reach an equilibrium distribution between a central compartment, such as the plasma space, and a second compartment, such as the aggregate tissues and fluids to which the drug distributes.
• after distribution, a more linear decrease in the log drug concentration is observed if the elimination phase is first order.
• for drugs that obey a two-compartment model, the value of C0 obtained by extrapolation of the elimination phase is used to calculate Vd, and the elimination rate constant, k, is obtained from the slope of the elimination phase.

Question 76

The central compartment:

Answer 76

• allows rapid, more or less instantenous equilibrium.
• it can be though of as the blood, interstitial fluid and highly perfused organs such as heart, liver, lungs and kidney.
• the drug is both introduced and exists through the central compartment.

Question 77

The peripheral compartment:

Answer 77

• comes to equilibrium with the central compartment more slowly, and can be though of as less well perfused organs such as skin, bone and fat.

Question 78

Non-compartmental PK analysis:

Answer 78