BasicKinetics1st,15-16(1).pptx

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Basic PharmacokineticsPrepared by: Ana Marie L. Rubenicia1st Sem - SY 2014-2015

Biopharmaceutics is the study of the relation of the physical and chemical properties of a drug to its bioavailability, pharmacokinetics, and pharmacodynamic and toxicologic effects.Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. Pharmacodynamics is thestudyofhowadrugactsonalivingorganism,includingthepharmacologicresponseandthedurationandmagnitudeofresponseobservedrelativetotheconcentrationofthedrugatanactivesiteintheorganism.

DIFFERENCE B/N PHARMACOKINETICS AND PHARMACODYNAMICS

BIOPHARMACEUTICSPHARMACOKINETICS and PHARMACODYNAMICShelp in designing the drug delivery systems and helps in generating the sub-therapeutic, therapeutic and toxic concentration of any drug in biological fluids.clinicians can design optimal drug regimens, including the route of administration, the dose, the frequency, and the duration of treatment.Introduction to PharmacokineticsPharmacokinetic PropertiesRoutes of AdministrationAbsorption of DrugsA. Physicochemical Characters of the Drug Molecule Affecting Absorption B. Mechanisms of absorption of drugs from the GI tractC. Biological Factors influencing absorptionD. Bioavailability, etclV. Drug DistributionDrug Clearance through metabolismDrug Clearance by the KidneyClearance by other routes Design and Optomization of Dosage RegimenI. Four pharmacokinetic properties

II. ROUTES OF DRUG ADMINISTRATIONThe route of administration is determined by 1. the properties of the drug2. the therapeutic objectives (for example, the desirability of a rapid onset, the need for long-term treatment, or restriction of delivery to a local site).Major routesEnteralParenteral, and TopicalII. ROUTES OF DRUG ADMINISTRATIONEnteral1. OralA: self-administered, and toxicities and/or overdose of oral drugs may be overcome with antidotes.D: oral drug absorption arethe most complicated, and the low gastric pH inactivates some drugs.a. Enteric-coated preparations. Ex ASA,Omeprazoleb. Extended-release preparations Ex Morphine2. Sublingual/buccal

8II. ROUTES OF DRUG ADMINISTRATIONParenteral1. Intravascular2. Intramuscular (IM)3. Subcutaneous (SC)

II. ROUTES OF DRUG ADMINISTRATION

I. Four pharmacokinetic properties

A. Physicochemical Characters of the Drug Molecule Affecting Absorption B. Mechanisms of absorption of drugs from the GI tractC. Biological Factors influencing absorptionD. Bioavailability, etc

A. Physicochemical Characters of the Drug Molecule Affecting Absorption

3. PHYSICAL FORM2. PARTICLE SIZE1. DISSOLUTION AND SOLUBILITY4. POLYMORPHISM5. CHIRALITY6. HYDRATES7. COMPLEXATIONrate processes and rate-limiting step>Noyes-Whitney Eq on dissolution . SolubilityPartition coefficient, Temperature of the mediumAgitationpH and drug solubility salt formation- Ionization and solubilityOther factors:Blood flow to the absorption siteTotal surface area available for absorptionContact time at the absorption surfaceExpression of P-glycoproteinNo. 1 QuizletA. What is the rate-limiting step in drug absorption of an immediate release solid oral dosage form that contains drugs with poor water solubility.

B. What is the rate-limiting step in drug absorption of an immediate release solid oral dosage form that contains drugs with high water solubility.

No. 2IdentifyThe mass of solute that dissolves in a specific mass or volume of a solvent at a given temperature.

The process by which a solid drug substance becomes dissolved in a solvent.No. 3A. True or false. According to the Noyes-Whitney equation, the smaller the surface area of the particle (A) the greater is the rate of dissolution (dC/dt) .

B. True or false. According to the Noyes-Whitney equation, the rate of dissolution (dC/dt) is directly proportional to the thickness of the stagnant layer around the particle (h).

No. 4A. True or false. Basic drug is more soluble in the intestines.

B. True or false. Acidic drug is more soluble in the stomach.No. 5A. True or false. As solid drug particle size decreases, particle surface area increases.

B. True or false. The greater the surface area, the more rapid is the rate of dissolution.No. 6A. True or false. The unionized form of the drug readily permeates the cell membrane of the GI tract.

B. True or false. The ionized form of the drug readily forms a solution.

No. 7A. True or false. A drug taken with a meal is generally absorbed more slowly.

B. True or false. The presence of food in slows gastric emptying.

No. 8True or false. The crystalline form has faster rate of absorption in contrast to amorphous form that is absorbed and eliminated slowly.

B. Mechanisms of absorption of drugs from the GI tract- PASSIVE DIFFUSION

B. Mechanisms of absorption of drugs from the GI tract- FACILITATED DIFFUSION

B. Mechanisms of absorption of drugs from the GI ACTIVE TRANSPORT

B. Mechanisms of absorption of drugs from the GI ENDOCYTOSIS and EXOCYTOSIS

No. 1 Quizlet A. the study of the time course of drug absorption, distribution, metabolism, and excretion. B. the study of the relation of the physical and chemical properties of a drug to its bioavailability, pharmacokinetics, and pharmacodynamic and toxicologic effects.

C.Thestudyofhowadrugactsonalivingorganism,includingthepharmacologicresponseandthedurationandmagnitudeofresponse observedrelativetotheconcentrationofthedrugatanactivesiteintheorganism.

No. 2 QuizletA. The drug may then reversibly leave the bloodstreamand distribute into the interstitial and intracellular fluids.

B. The drug and its metabolites are eliminated fromthe body in urine, bile, or feces.

C. Release of the drug molecules from the dosage form.

No. 3 QuizletA. Route of administration where the drug is placed under the tongueB. The type of parenteral administration with the slowest absorption.

C. Route of administration where the drug is placed between the cheek and gum

No. 4 QuizletPreferred Parenteral RouteA. Medroxyprogesterone

B. Insulin

C. Haloperidol

No. 5 QuizletPreferred Route of AdministrationA. Provides a local effect.B. It is the route necessary to introduce drugs directly into the cerebrospinal fluid.

C. The route is commonly used to administer antiemetic agents.

No. 6 QuizletIdentify the mechanism of absorption.

A. It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher drug concentration.

B. Agents can enter the cell through specializedtransmembrane carrier proteins that allows the passageof large molecules.

C. Involves engulfment of macromolecules by the cellmembrane and transport into the cell by pinching off the drugfilledvesicle.Introduction to Pharmacokineticsl. Pharmacokinetic Propertiesll. Routes of Administrationlll. Absorption of DrugsA. Physicochemical Characters of the Drug Molecule Affecting Absorption B. Mechanisms of absorption of drugs from the GI tractC. Biological Factors influencing absorptionD. Bioavailability, etclV. Drug DistributionV. Drug Clearance through metabolismVl. Drug Clearance by the KidneyVll. Clearance by other routes Vll. Design and Optomization of Dosage RegimenBioavailability and BioequivalenceBIOAVAILABILITY AND BIOEQUIVALENCE: INTRODUCTIONA multisource drug product is a drug product that contains the same active drug substance in the same dosage form and is marketed by more than one pharmaceutical manufacturer.

A single-source drug products are drug products for which the patent has not yet expired or has certain exclusivities so that only one can make it. Single-source drug products are usually brand-name (innovator) drug products.BIOAVAILABILITY AND BIOEQUIVALENCE: INTRODUCTIONAfter the patent and other exclusivities for the brand-name drug expires, a pharmaceutical firm may manufacture a generic drug product that can be substituted for the branded drug product.

Since the formulation and method of manufacture of the drug product can affect the bioavailability and stability of the drug, the generic drug manufacturer must demonstrate that the generic drug product is bioequivalent and therapeutically equivalent to the brand-name drug product.BIOAVAILABILITY AND BIOEQUIVALENCE: INTRODUCTIONthe U.S. Food and Drug Administration (FDA) publishes annually, in print and on the Internet, Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book

The Orange Book identifies drug products approved on the basis of safety and effectiveness by the FDA and contains therapeutic equivalence evaluations for approvedmultisource prescription drug products.DEFINITIONSBioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

Bioequivalent drug products - pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability. The test (generic) and reference listed drug (brand-name)shall be considered bioequivalent if:(1) the rate and extent of absorption of the test drug does not show a significant difference

(2) the extent of absorption of the test drug does not show a significant difference and the difference from the reference drug in the rate of absorption of the drug is intentional.>Bioequivalent drug products may contain different inactive ingredientsDEFINITIONSEquivalence. Relationship in terms of bioavailability, therapeutic response, or a set of established standards of one drug product to another.DEFINITIONSPharmaceutical equivalents. Drug products in identical dosage forms that contain the same active ingredient(s), ie, the same salt or ester, are of the same dosage form, use the same route of administration, and are identical in strength or concentration. Ex- chlordiazepoxide hydrochloride, 5-mg capsules

but they may differ in characteristics such as: (1)shape, (2)scoring configuration, (3)release mechanisms, (4) packaging, excipients (including colors, flavors, preservatives), (5) expiration time, and, within certain limits, (5) labeling.DEFINITIONSPharmaceutical alternatives.1. Drug products that contain the same therapeutic moiety but as different salts, esters, or complexes. Ex- tetracycline phosphate or tetracycline hydrochloride equivalent to 250 mg tetracycline base

2. Different dosage forms and strengths within a product line by a single manufacturer are pharmaceutical alternatives . Ex - an extendedrelease dosage form and a standard immediate-release dosage form of the same active ingredient

3. The FDA currently considers a tablet and capsule containing the same active ingredient in the same dosage strength as pharmaceutical alternatives.DEFINITIONSPharmaceutical substitution- the process of dispensing a pharmaceutical alternative for the prescribed drug product. Ex-ampicillin suspension is dispensed in place of ampicillin capsules, or- tetracycline hydrochloride is dispensed in place of tetracycline phosphate.

>Pharmaceutical substitution generally requires the physician's approval.DEFINITIONSBrand name- the trade name of the drug. This name is privately owned by the manufacturer or distributor and is used to distinguish the specific drug product from competitor's products . Ex

- Tylenol, McNeil LaboratoriesDEFINITIONSChemical name. The name used by organic chemists to indicate the chemical structure of the drug. Ex

- N-acetyl-p-aminophenolDEFINITIONSGeneric name. The established, nonproprietary, or common name of the active drug in a drug product. Ex- acetaminophenDEFINITIONSGeneric substitution The process of dispensing a different brand or an unbranded drug product in place of the prescribed drug product. >The substituted drug product contains the same active ingredient or therapeutic moiety as the same salt or ester in the same dosage form but is made by a different manufacturer. ExMotrin brand of ibuprofen might be dispensed by thepharmacist as Advil brand of ibuprofen or as a nonbranded generic ibuprofen if generic substitution is permitted and desired by the physician.

DEFINITIONSAbbreviated New Drug Application (ANDA). Drug manufacturers must file an ANDA for approval to market a generic drug product. The generic manufacturer is not required to perform clinical efficacy studies or nonclinical toxicology studies for the ANDA.

DEFINITIONSDrug product. The finished dosage form (eg, tablet, capsule, or solution) that contains the active drug ingredient, generally, but not necessarily, in association with inactive ingredients.DEFINITIONSTherapeutic equivalents. Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.DEFINITIONSTherapeutic alternatives. Drug products containing different active ingredients that are indicated for the same therapeutic or clinical objectives. Ex

-ibuprofen is given instead of aspirin-cimetidine may be given instead of ranitidine.DEFINITIONSTherapeutic substitution. The process of dispensing a therapeutic alternative in place of the prescribed drug product. Examoxicillin is dispensed instead of ampicillin ibuprofen is dispensed instead of naproxen. PURPOSE OF BIOAVAILABILITY STUDIESClinical studies are useful in determining the safety and efficacy of drug products. Bioavailability studies are used to define the effect of changes in the physicochemical properties of the drug substance and the effect of the drug product (dosage form) on the pharmacokinetics of the drug. Bioequivalence studies are used to compare the bioavailability of the same drug (same salt or ester) from various drug products.> If the drug products are bioequivalent and therapeutically equivalent , then the clinical efficacy and the safety profile of these drug products are assumed to be similar and may be substituted for each other.Determination of Bioavailability

Factors that influence bioavailabilitya. First-pass hepatic metabolism:

Factors that influence bioavailabilityFirst-pass hepatic metabolism Solubility of the drug. For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases.Chemical instabilityNature of the drug formulation

RELATIVE AND ABSOLUTE AVAILABILITYRelative AvailabilityRelative (apparent) availability is the availability of the drug from a drug product as compared to a recognized standard.Absolute AvailabilityThe absolute availability of drug is the systemic availability of a drug after extravascular administration (eg, oral, rectal, transdermal, subcutaneous) compared to IV dosing.The absolute bioavailability = FF = 1, or 100%. For drugs given intravascularly, such as by IV bolus injection, F = 1 For all extravascular routes of administration, such as the oral route (PO), the absolute bioavailability F may not exceed 100% (F > 1).Introduction to Pharmacokineticsl. Pharmacokinetic Propertiesll. Routes of Administrationlll. Absorption of DrugsA. Physicochemical Characters of the Drug Molecule Affecting Absorption B. Mechanisms of absorption of drugs from the GI tractC. Biological Factors influencing absorptionD. Bioavailability, etclV. Drug DistributionV. Drug Clearance through metabolismVl. Drug Clearance by the KidneyVll. Clearance by other routes Vll. Design and Optomization of Dosage RegimenDrug DistributionDrug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues.The distribution of a drug from the plasma to the interstitium depends onCardiac output and local blood flowcapillary permeabilitythe tissue volumethe degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug.1. Blood Flow

2. Capillary permeability

3. Binding of drugs to plasma proteins and tissues

Weak acidic drugs such as salicylates, phenylbutazone, and penicillinsare highly bound to albumin.binds primarily basic (cationic) drugs such aspropranolol, imipramine, and lidocaineresponsible for the binding of drugs if the albumin sites become saturated.4. Lipophilicity

5. Volume of distributionThe apparent volume of distribution, Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma.Distribution into the water compartments in the body. a. Plasma compartmentb. Extracellular fluidc. Total body water

2. Apparent volume of distribution3. Determination of Vd4. Effect of Vd on drug half-life:5. Volume of distribution a. Distribution into the water compartments in the body

about 4 L in a70-kg individua. Ex heparinlow molecular weight but is hydrophilic- 14 L in a 70-kg individualdrugslow molecular weight andis lipophilic-60% of body weight or about 42 L in a 70-kg individual

5. Volume of distribution b. Apparent volume of distribution

Vol of Distribution in a model, is used to estimate the extent of drug distribution in the body.Drugs distribute in the lipids (abundant in adipocytes and cell membranes), proteins (abundant in plasma and cells), and nucleic acids (abundant in cell nuclei).

c5. Volume of distribution. C. Determination of Vdif 10 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C0 = 1 mg/L

No. 1 QuizletThe process by which a drug reversibly leaves the bloodstream and enters the interstitial and intracellular fluids.No. 2 QuizletDrug distribution is greater in the muscles than in the adipose tissues due to greater blood flow.

Drug distribution is lesser in the adipose tissues than in the skeletal muscles due to lesser blood flow.

No. 3 QuizletA. The capillary in the brain is more permeable to ionized or polar drugs.

B. The capillary in the liver and spleen is more permeable to ionized or polar drugs.No. 4 QuizletA. Basic drugs binds with alpha1 acid glycoprotein.

B. Acidic drugs binds with albumin. No. 5 QuizletDrugs that is distributed in the intracellular fluids have larger volume of distribution.

Drugs that have high molecular weight have smaller volume of distribution.

No. 6 QuizletA if 60 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C0 = 2 mg/L.

B. if 30 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C0 = 2 mg/L.Introduction to Pharmacokineticsl. Pharmacokinetic Propertiesll. Routes of Administrationlll. Absorption of DrugsA. Physicochemical Characters of the Drug Molecule Affecting Absorption B. Mechanisms of absorption of drugs from the GI tractC. Biological Factors influencing absorptionD. Bioavailability, etclV. Drug DistributionV. Drug Clearance through metabolismVl. Drug Clearance by the KidneyVll. Clearance by other routes Vll. Design and Optomization of Dosage RegimenDrug ClearanceDrug elimination refers to the irreversible removal of drug from the body by all routes of elimination.drug elimination is described in terms of clearance .Clearance describes the process of drug elimination from the body or from a single organ without identifying the individual processes involved. Clearance may be defined as the volume of fluid cleared of drug from the body per unit of time. Units: milliliters per minute (mL/min) or liters per hour (L/hr)

the time it takes toreduce the plasma drug concentrationby halfDrug ClearancePROCESSES OF DRUG ELIMINATIONmetabolism (biotransformation) renal excretion liverlung, skin, GI mucosal cells, microbiological flora in the distal portion of the ileum, and large intestine. As well as the kidney kidneyDrug Clearance Through MetabolismKinetics of metabolism1. First-order kineticsthat the substrate (drug) concentration is very low. drug concentrations at therapeutic plasma levels for most drugs are much lower than the MichaelisMenten constant, K M, and do not saturate the enzymes involved in metabolism. first-order kinetics is also referred to as linear kinetics.

Drug Clearance Through MetabolismTime(hour)Amt of drug in the body (mg)Amt of drug eliminated (mg)Fraction of drug eliminated01000----18501500.1527231270.1536141090.154522920.155444780.15FIRST ORDER ELIMINATIONDrug Clearance Through MetabolismKinetics of metabolism2. Zero -order kineticsthat the substrate (drug) concentration is very high. drug concentrations at therapeutic plasma levels for most drugs are much higher than the MichaelisMenten constant, K M, and the enzymes are saturated involved in metabolism. the rate of metabolism remains constant over timenonlinear kineticsa constant amount of drug is metabolized per unit of time the rate of elimination is constant and does not depend on the drugconcentration.

Drug Clearance Through MetabolismTime(hour)Amt of drug in the body (mg)Amt of drug eliminated (mg)Fraction of drug eliminated01000----18501500.1527001500.1835501500.2144001500.2752501500.38ZERO ORDER ELIMINATION

DRUG METABOLISMPOLAR,WATER SOLUBLE PRODUCTSCOMPOUNDS RELATIVE NONTOXICCOMPOUNDS PHARMACOLOGICALLY INACTIVEENHANCE DRUG ELIMINATIONPRODRUGS TO PHARMACOLOGICALLY ACTIVE METABOLITESDrug clearance by metabolismB. Reactions of drug metabolism GENERAL PATHWAYS OF DRUG METABOLISM

PHASE I OR FUNCTIONALIZATION REACTIONInclude oxidative, reductive and hydrolytic biotransformation.

The purpose of these reactions is to introduce a functional polar group(s) into the xenobiotic molecule to produce a more water soluble compound. PHASE II OR CONJUGATION REACTIONS

Include glucoronic acid conjugation, sulfate conjugation, conjugation with glycine, glutamine and other amino acids, GSH, acetylation and methylation.

The purpose is to attach small, polar and ionizable endogenous compounds such as glucoronic acis, sulfate, glycine, and other amino acids to the functional handles of phase I metabolites or parent compoundsDelta-9- tetrahydrocannabinol

Sites of Drug Biotransformation

1. Gastrointestinal TractAbsorb orally administered drugs 2. Liver (hepatic metabolism or First Pass EffectThe most important organ in drug metabolismSome drugs may decrease Oral bioavailability Lidocaine (ineffective)IsoproterenolMeperidineMorphineNitroglycerinPentazocainePropoxyphenePropranololsalicylamide3. Blood CirculationAbsorb orally administered drugs DRUGS METABOLIZED IN THE GI TRACT:IsoproterenolLevodopaChlorpromazineDethylstilbestrolSulfanilamideMixed-Function OxidasesCytochrome P-450 EnzymesCYP-arabic#-capita letter-arabic #ex CYP 3A4Important features:

Plays a vital role in oxidation of lipophilic xenobiotics

metabolize almost unlimited number of diverse substrates by a variety of oxidative transformations.

-located in the endoplasmic reticulum

Role of Cytochrome P-450 Monooxygenases in Oxidative BiotransformationsCYP NomenclatureFamilies - CYP plus arabic numeral (>40% homology of amino acid sequence, eg. CYP1)Subfamily - 40-55% homology of amino acid sequence; eg. CYP1ASubfamily - additional arabic numeral when more than 1 subfamily has been identified; eg. CYP1A2Italics indicate gene (CYP1A2); regular font for enzyme

ENZYME INDUCERSCarbamazepineDexamethasonePhenobarbitalPhenytoinRifampinSt Johns WortKetokonazoleOmeprazoleErythromycinRitonavirGrapefruit juiceDrug Clearance by the kidneyDrug excretion is the removal of the intact drug. Nonvolatile drugs are excreted mainly by renal excretion, a process in which the drug passes through the kidney to the bladder and ultimately into the urine.

Drug Clearance by the kidney