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    Ria Kitler
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    The document discusses factors that affect drug absorption and transport in the gastrointestinal tract. It lists drug transporters in the GI tract, drug transport mechanisms, phase 1 oxidation reactions, and factors that influence volume of distribution, protein binding, efflux from the GI tract, hepatic metabolism, and drug excretion. It also defines pharmacokinetic terms, derives kinetic equations, and discusses drug transport mechanisms in the GI tract.

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    Ceutics CAT 2 (1)

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    The document discusses factors that affect drug absorption and transport in the gastrointestinal tract. It lists drug transporters in the GI tract, drug transport mechanisms, phase 1 oxidation reactions, and factors that influence volume of distribution, protein binding, efflux from the GI tract, hepatic metabolism, and drug excretion. It also defines pharmacokinetic terms, derives kinetic equations, and discusses drug transport mechanisms in the GI tract.

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    28 views9 pages

    Ceutics CAT 2

    Uploaded by

    Ria Kitler
    The document discusses factors that affect drug absorption and transport in the gastrointestinal tract. It lists drug transporters in the GI tract, drug transport mechanisms, phase 1 oxidation reactions, and factors that influence volume of distribution, protein binding, efflux from the GI tract, hepatic metabolism, and drug excretion. It also defines pharmacokinetic terms, derives kinetic equations, and discusses drug transport mechanisms in the GI tract.

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    of 9

    Section B (Graham)

    State the factors that affect drug absorption


     Drug product/dosage form
     Physiology/Anatomy of absorption site
     Drug solubility
     Ionization state of the drug
     The pKa and hence charge,
     Lipid solubility,
     Molecular weight,
     The number of hydrogen bonds in the molecule
     Its chemical stability.
    List any four drug transporters in the gastrointestinal tract
     The peptide transporters,
     The nucleoside transporters,
     The sugar transporters,
     The bile acid transporters,
     The amino acid transporters,
     The organic anion transporters and
     The vitamin transporters.
    List any four drug transport mechanisms
     Passive Diffusion
     Facilitated Diffusion
     Active Transport
     Endocytosis
     Efflux
    List any four phase 1 oxidation reactions
     N-oxidation
     Sulfoxidation
     Aromatic hydroxylation
     N-hydroxylation
     Deamination
     N-, O-,and S-dealkylation
     N- hydroxylation
     Side chain hydroxylation
    Write short notes on the volume of distribution
     It is used as a measure of the extent of distribution of the drug in the body
     Concentration = Mass/Volume
     Drug Plasma Concentration = Dose/Volume of Distribution
     Volume of Distribution = Dose/Drug Plasma Concentration
     If extensive distribution to the peripheral tissues occurs, then Vd can be very high
     If drug remains in plasma instead of diffusing to tissues, then Vd will be lower
    List any physiologic conditions that alter protein concentrations in plasma
     Renal failure
     Diabetes
     Surgery
     Multiple myeloma
     Leprosy
     Trauma
     Myocardial infarction
    List requirements necessary for efflux of drugs from the gastrointestinal tract
    This process;
     Requires energy,
     Can work against a concentration gradient,
     Can be competitively inhibited by structural analogues or by inhibitors of cell
    metabolism,
     Is a saturable process.
    Write short notes on hepatic metabolism
    The liver is the primary site of drug metabolism.
    It acts as a final barrier for oral absorption.
    The first pass of absorbed drug through the liver results in a low bioavailability of those drugs
    which are rapidly metabolized by the liver.
    This reduced bioavailability of a susceptible oral drug renders the gastrointestinal route of
    administration ineffective compared to IV route.
    First-pass metabolism can be avoided by drug administration to the mouth (buccal or sublingual;
    or to the rectum. The absorbed drug does not pass through the liver first, prior to entering the
    systemic circulation.
    Many metabolic reactions in the liver occur in the endoplasmic reticulum membranes in the
    cytoplasm of the cell
    List any four factors that affect metabolism
     Age
     Gender
     Disease
     Food/ diet
     Environment
     Genetics
     Pathophysiology
    Write short notes on urinary pH effects on drug excretion
     Urinary pH can influence the reabsorption of weak acids and weak bases
     Unionized drug is more lipid soluble and can be reabsorbed through the renal tubule
     Normal urinary pH may range from pH 4.5 – 8 (depends on diet and pathophysiology)
     Administration of sodium bicarbonate or ammonium chloride solutions can alter urinary
    pH and hence drug reabsorption.

    Discuss the Fick’s law of diffusion


    Driving force is concentration gradient

    Where;
    dQ/dT ~ diffusion rate
    D ~ diffusion coefficient
    A ~ surface area of the membrane
    K ~ lipid/water partition coefficient
    h ~ membrane thickness
    C1 ~ concentration of the drug in the donor side of the membrane
    C2 ~ concentration of the drug in the receptor side of the membrane

    List the importance of modeling pharmacokinetic data


     To understand relationship between dose and plasma concentration
     To understand the relationship between plasma concentration and pharmacological effect
     To determine optimal dosing regimen for individual patient
     To determine dosing adjustment for patients with altered physiological functions (e.g.
    liver or renal disease)

    Sketch a plasma concentration Vs time graph showing the basic pharmacokinetic


    parameters
    Calculate the clearance for a drug given IV infusion at a rate of 5.3mg/Kg hr resulting in a steady
    state plasma concentration of 17 ug/mL. Patient body weight is 70kg

    Calculate the half-life of a drug with a volume of distribution of 35L and clearance of
    650mL/min

    A drug has a volume of distribution of 10L and an elimination rate constant of 0.2hr-1.
    What infusion rate is required to obtain a steady state concentration of 10ug/mL.

    Determine the drug concentration after 6 hours of administration of a loading dose of 10mg plus
    an infusion of 2mg/hr. the half-life is 3 hours and volume of distribution is 10mL.
    For a drug eliminated by a first order process, calculate the initial plasma concentration if the
    drug level after 2 hours is 77mg/mL and the value of k is 0.7hr-1

    Show that the equation 1nCP=1nCp0-kt can also be written as Cp=Cp0.e-kt

    Section C
    Explain how the presence of food in the gastrointestinal tract can influence the rate and
    extent of drug absorption 10mks
    Complexation of drugs with components in the diet.
    Drugs are capable of binding to components within the diet. Tetracycline, forms non-absorbable
    complexes with calcium and iron, and thus patients are advised not to take products containing
    calcium or iron, such as milk, iron preparations.
    Alteration of pH.
    Food tends to increase stomach pH by acting as a buffer. This decreases the rate of dissolution
    and absorption of a weakly basic drug and increase that of a weakly acidic one.
    Alteration of gastric emptying.
    Some foods tend to reduce gastric emptying and thus delay the onset of action of certain drugs.
    Food slows the rate of absorption due to delayed gastric emptying.
    Stimulation of gastrointestinal secretions.
    Gastrointestinal secretions produced in response to food may result in the degradation of drugs
    that are susceptible to enzymatic metabolism and hence a reduction in their bioavailability.
    The ingestion of food stimulates the secretion of bile. Bile salts increase the dissolution of poorly
    soluble drugs, thereby enhancing their absorption.
    Competition between food components and drugs for specialized absorption mechanisms.
    In the case of those drugs that have a chemical structure similar to nutrients required by the body
    or which specialized absorption mechanisms exist, there is a possibility of competitive inhibition
    of drug absorption.
    Increased viscosity of gastrointestinal contents.
    The presence of food in the gastrointestinal tract provides a viscous environment which may
    result in a reduction in the rate of drug dissolution therefore decreased bioavailability of a drug.
    Food-induced changes in pre-systemic metabolism.
    Certain foods may increase the bioavailability of drugs that are susceptible to pre-systemic
    intestinal metabolism by interacting with the metabolic process.
    Food-induced changes in blood flow.
    Blood flow to the gastrointestinal tract and liver increases shortly after a meal, thereby increasing
    the rate at which drugs are presented to the liver. The effects of food serve to increase the
    bioavailability of some drugs that are susceptible to first-pass metabolism.

    Discuss transit of pharmaceuticals in the gastrointestinal tract under the following sub
    heading
    Gastric emptying of pharmaceuticals 5mks
    Refers to the time a dosage form takes to traverse the stomach.
    Depends on the dosage form and the fed/ fasted state of the stomach.
    Normal gastric residence times usually range between 5 minutes and 2 hours.
    In the fasted state, the electrical activity in the stomach governs the transit of dosage forms.
    It is characterized by a repeating cycle of four phases. The proximal stomach relaxes to
    receive food and gradual contractions of this region move the contents distally.
    Peristalsis –contractions of the distal stomach –serves to mix and break down food particles
    and move them towards the pyloric sphincter. The pyloric sphincter allows liquids and small
    food particles to empty.
    Factors that influence gastric emptying include
     type of dosage form
     presence of food
     the composition of the food
     effect of drugs
     Disease state.
    In general, food delays gastric emptying and hence the absorption of drugs.

    Drugs for which small intestinal residence time is particularly important 5mks
     Dosage forms that release their drug slowly as they pass along the length of the
    gastrointestinal tract
     Enteric-coated dosage forms which release drug only when they reach the small
    intestine.
     Drugs that dissolve slowly in intestinal fluids.
     Drugs that are absorbed by intestinal carrier-mediated transport systems.
     Drugs that are not absorbed well in the colon

    Define the following terms (2mks each)


    Area under the curve (AUC)
    Refers to the measure of the amount of drug reaching the systemic circulation.
    Can be calculated using the trapezoidal rule, Integration and Software
    C-max
    Refers to Maximum drug Plasma concentration
    T-max
    Refers to the time required for the drug to reach maximum plasma concentration
    T-1/2
    Refers to the time required for the initial drug to reduce by 50% in the body
    Absolute bioavailability

    Derive the zero order and first order reaction equations 5mks

    What is the difference between zero order and first order rate laws 2mks

    For a drug eliminated by a first order process, how many half-lives are required for drug
    concentration to decrease to 3% of initial value 4mks

    Discuss the drug transport mechanisms 15mks


    Passive Diffusion
     Drug molecules move from an area of high concentration to an area with low
    concentration Does not require energy
     Is the major transport mechanism for most drugs
     Driving force is concentration gradient
     For ionizable drugs, diffusion of the non-ionized form is favored.

    Facilitated Diffusion
     Drug molecules move from an area of high concentration to an area with low
    concentration
     Does not require energy
     Carrier mediated

    Active Transport
     Drug molecules move from an area of low concentration to an area with high
    concentration
     Requires energy
     Carrier mediated
     Drug-carrier complex transports drug across cell membrane
     Limited amount of carrier available
     Saturable (if drug concentration is too high)

    Endocytosis
     Cell membrane engulfs external fluid/dissolved substances
     Uptake of large polar molecules (e.g., proteins)
    Efflux
     Active transport mechanism
     Example is p-glycoprotein located in BBB and small intestine
     May contribute to decreased bioavailability
     May contribute to bacterial and anticancer drug resistance

    Pore/Channel transport
     Transmembrane protein channels
     Ions and small polar molecules

    Time (hr) Concentration (ng/mL)


    0 200
    2 186
    4 172
    6 158
    8 144
    10 130

    Graph the data above 3mks


    Is the elimination zero order or first order? 3mks

    What is the elimination rate constant? 3mks

    Write an equation that models the data. 3mks

    Calculate the drug concentration after 15 hours 3mks


    A drug is administered as an infusion at a rate of 80mg/hr. clearance is 2.81/hr and the
    half-life 8 hours.
    Calculate the average steady state drug concentration 3mks

    Calculate the expected drug concentration after 16 hours of infusion 6mks

    Calculate the expected drug concentration 8 hours after the infusion is stopped 6mks

    Explain drug delivery under the following subheading


    Oral drug delivery 7mks

    Parenteral delivery 8mks

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