Pharmacokinetic

PHARMACOKINETICS: 

PHARMACOKINETICS KALPANA GHILDIYAL

PHARMACOKINETICS What the body does to the drug : 

PHARMACOKINETICS What the body does to the drug PHARMACODYNAMICS What the drug does to the body

The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components.: 

The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-effect) components.

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PHARMACOKINETICS

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Pharmacokinetic helps to optimize drug therapy: Dose Dose Regimen Dosage form PHARMACOKINETICS

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What happen to drug after its administration A bsorption D istribution M etabolism E xcretion PHARMACOKINETICS

ABSORPTION: 

ABSORPTION Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the route of administration. For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation. Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability.

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Transport of a drug from the GI tract Passive Diffusion: Drugs moves from higher concentration to the lower. Do not involve carrier. Active Transport: Involve specific carrier proteins is energy dependent and is driven by the hydrolysis of ATP capable of moving against conc. gradient. ABSORPTION

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Endocytosis Engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug filled vesicle Exocytosis It is reverse Used by cell to secrete many substances by a similar vesicle formation process ABSORPTION

Effect of pH on drug absorption: 

Effect of pH on drug absorption The nonionized molecules usually are more lipid-soluble and can diffuse readily across the cell membrane. In contrast, the ionized molecules usually are unable to penetrate the lipid membrane because of their low lipid solubility. pH= pKa + log [ nonprotonated species] protonated species For Acids: pH= pKa + log [A - ] [HA] For Bases: pH= pKa + log [B] [BH + ]

Physical factors influencing absorption: 

Physical factors influencing absorption Blood flow to the absorption site Total surface area available for absorption Contact time at the absorption surface:

Bioavailability: 

Bioavailability Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form

A. Determination of Bioavailability: 

A. Determination of Bioavailability Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration with plasma drug levels achieved by IV injection in which all of the agent rapidly enters the circulation. By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). This curve reflects the extent of absorption of the drug. Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection

B. Factors that influence bioavailability: 

B. Factors that influence bioavailability First-pass hepatic metabolism Solubility of the drug Chemical instability Nature of the drug formulation

C. BIOEQUIVALENCE: 

C. BIOEQUIVALENCE Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two related drugs with a significant difference in bioavailability are said to be bioinequivalent .

D. Therapeutic Equivalence: 

D. Therapeutic Equivalence Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety. Note: Clinical effectiveness often depends on both the maximum serum drug concentrations and on the time required (after administration) to reach peak concentration. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.

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Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on Blood flow, Capillary permeability, Degree of binding of the drug to plasma and tissue proteins, Relative hydrophobicity of the drug. DISTRIBUTION

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Blood flow Capillary Permeability Drug Structure DISTRIBUTION Cross-section of liver and brain capillaries

C. Binding of Drugs to Plasma Proteins: 

C. Binding of Drugs to Plasma Proteins Albumin is a major carrier for acidic drugs; a 1 -acid glycoprotein binds basic drugs The binding is usually reversible. The fraction of total drug in plasma that is bound is determined by the drug concentration, the affinity of binding sites for the drug, The number of binding sites.

PROTEIN BINDING: 

PROTEIN BINDING Absorption Drug Enters circulation Binds to plasma protein (Acidic drugs to albumin, basic drugs to alpha 1 acidic glycoprotein) Free form Bound Form (Pharmacologically Active) (Pharmacologically inactive, acts as temporary store of drugs)

Volume of Distribution: 

Volume of Distribution The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed. The volume of distribution ( V ) relates the amount of drug in the body to the concentration of drug ( C ) in the blood or plasma depending on the fluid measured. Amount of Drug in Body/V = C or V = Amount of Drug in Body/C

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Water compartments in the body Plasma compartment: Drug has a very large molecular weight OR binds extensively to plasma proteins Effectively trapped within the plasma compartment The drug distributes in a volume (the plasma) that is about six percent of the body weight or, in a 70-kg individual, about 4 L of body fluid. Volume of Distribution Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid. Hydrophilic drugs cannot move across the lipid membranes of cells to enter the water phase inside the cell. These drugs distribute into a volume that is the sum of the plasma water and the interstitial fluid, which together constitute the extracellular fluid. This is about twenty percent of the body weight, or about 14 L in a 70-kg individual.

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Total body water: If a drug has a low molecular weight and is hydrophobic, not only can it move into the interstitium through the slit junctions, but it can also move through the cell membranes into the intracellular fluid. The drug, therefore, distributes into a volume of about sixty percent of body weight, or about 42 L in a 70-kg individual. Other sites : In pregnancy, the fetus may take up drugs and thus increase the volume of distribution. Drugs that are extremely lipid-soluble, such as thiopental may also have unusually high volumes of distribution. Volume of Distribution

B. APPARENT VOLUME OF DISTRIBUTION : 

B. APPARENT VOLUME OF DISTRIBUTION A drug rarely associates exclusively with only one of the water compartments of the body. Instead, the vast majority of drugs distribute into several compartments, often avidly binding cellular components. for example, lipids (abundant in adipocytes and cell membranes), proteins (abundant in plasma and within cells), or nucleic acids (abundant in the nuclei of cells). Therefore, the volume into which drugs distribute is called the apparent volume of distribution, or V d .

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Determination of V d Distribution of drug in the absence of elimination: Distribution of drug when elimination is present: In reality, drugs are eliminated from the body, and a plot of plasma : Drug concentrations in serum after a single injection of drug at time = 0. Assume that the drug distributes but is not eliminated. Drug concentrations in serum after a single injection of drug at time = 0. Assume that the drug distributes and is subsequently eliminated.

Binding of Drugs to Plasma Proteins: 

Binding of Drugs to Plasma Proteins Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues, elicit a biologic response, and be available to the processes of elimination. Binding capacity of albumin Competition for binding between drugs

DRUG METABOLISM/ BIOTRANSFORMATION: 

DRUG METABOLISM/ BIOTRANSFORMATION Drugs are most often eliminated by biotransformation and/or excretion into the urine or bile. The process of metabolism transforms lipophilic drugs into more polar readily excretable products. The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines

DRUG METABOLISM: 

DRUG METABOLISM There are four ways in which the activity of a drug can be altered by its metabolism: Active drug to inactive metabolite : Phenobarbitone Hydroxyphenobarbitone Phenytoin p- Hydroxyphenytoin Active drug to active metabolite : Codein Morphine Diazepam Oxazepam Inactive drug to active metabolite : L-dopa Dopamine Prednisone Prednisolone Active drug to highly toxic metabolite : Paracetamol N-acetyl-p- benzoquinoneimine (NAPQ)

PHASE I REACTIONS: 

PHASE I REACTIONS OXIDATION: Addition of Oxygen and/or removal of Hydrogen Phenytoin , Phenobarbitone , Propranol , Pentobarbitone REDUCTION: Removal of Oxygen or addition of Hydrogen Chloramphenicol , Methadone HYDROLYSIS: Breakdown of compounds by addition of water Ester: Procaine, Succinylcholine Amides: Lignocaine , Procainamide

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Consist of Conjugation reactions If the phase I metabolite is polar. It is excreted by kidney. If metabolite is lipophilic than it is reabsorbed and undergoes subsequent conjugation with an endogenous substrate such as glucuronic acid, sulphuric acid, acetic acid or an amino acid. Glucuronic conjugation: Morphine, PCM Acetylation : Isoniazid , dapsone Glycine Conjugation Salicylic Acid, nicotinic acid Sulphate Conjugation PCM, steroids Glutathione Conjugation PCM Methylation Adrenaline, dopamine PHASE II REACTIONS

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Reversal of order of the phases : Not all drugs undergo Phase I and II reactions in that order. For example, isoniazid is first acetylated (a Phase II reaction) and then hydrolyzed to isonicotinic acid (a Phase I reaction). Drug Drug Drug Drug Drug Phase I Phase I INH Phase II Phase II Phase I Metabolite (inactive) Excreted

FACTORS AFFECTING DRUG METABOLISM: 

FACTORS AFFECTING DRUG METABOLISM Disease Age Genetics Environment Drugs and Alcohol Nutrition

DRUG ELIMINATION : 

DRUG ELIMINATION Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers. A patient in renal failure may undergo extracorporeal dialysis, which removes small molecules such as drugs.

DRUG ELIMINATION: 

DRUG ELIMINATION z Drug elimination by the kidney Effect of drug metabolism on reabsorption in the distal tubule.

RENAL ELIMINATION OF A DRUG . : 

RENAL ELIMINATION OF A DRUG . Glomerular filtration Proximal tubular secretion Distal tubular re-absorption Role of drug metabolism

Quantitative aspects of renal drug elimination: 

Quantitative aspects of renal drug elimination Plasma clearance is expressed as the volume of plasma from which all drug appears to be removed in a given time, for example, as mL /min. Clearance equals the amount of renal plasma flow multiplied by the extraction ratio, and because these are normally invariant over time, clearance is constant. Extraction ratio: This ratio is the decline of drug concentration in the plasma from the arterial to the venous side of the kidney. The drugs enter the kidneys at concentration C1 and exit the kidneys at concentration C2. The extraction ratio = C2/C1. Excretion rate: The excretion ratio is determined the equation: Exceretion rate (mg/min)=Clearance ( mL /min) X Plasma concentartion (mg/ mL )

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Total body clearance CL Total = CL Hepatic + CL Renal + CL Pulmonary + CL Other Clinical situations resulting in changes In drug half-life Quantitative aspects of renal drug elimination

Clinical situations resulting in changes In drug half-life : 

Clinical situations resulting in changes In drug half-life When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. The half-life of a drug is increased by diminished renal plasma flow or hepatic blood flow, ”for example, in cardiogenic shock, heart failure, or hemorrhage; decreased extraction ratio, ”for example, as seen in renal disease; and 3) decreased metabolism, ”for example, when another drug inhibits its biotransformation or in hepatic insufficiency, as with cirrhosis. On the other hand, the half-life of a drug may decrease by increased hepatic blood flow, decreased protein binding, and increased metabolism.

KINETICS OF CONTINUOUS ADMINISTRATION: 

KINETICS OF CONTINUOUS ADMINISTRATION Kinetics of IV infusion Steady-state drug levels in blood: Following the initiation of an IV infusion, the plasma concentration of drug rises until the rate of drug eliminated from the body precisely balances the input rate. Thus, a steady-state is achieved in which the plasma concentration of drug remains constant. The rate of drug elimination from the body = ( CL t )(C), where CL t = total body clearance C = the plasma concentration of drug.

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Influence of the rate of drug infusion on the steady state: A steady-state plasma concentration of a drug occurs when the rate of drug elimination is equal to the rate of administration , as described by the following equation: C SS =R O / Cl T where Css = the steady-state concentration of the drug, Ro = the infusion rate (for example, mg/min), KINETICS OF CONTINUOUS ADMINISTRATION Effect of infusion rate on the steady-state concentration of drug in the plasma. (Ro = rate of infusion of a drug.)

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Time required to reach the steady-state drug concentration: The concentration of drug rises from zero at the start of the infusion to its ultimate steady-state level, C ss . The fractional rate of approach to a steady state is achieved by a first-order process. Exponential approach to steady state Effect of the rate of drug infusion Rate of drug decline when the infusion is stopped Loading dose KINETICS OF CONTINUOUS ADMINISTRATION

KINETICS OF FIXED-DOSE/FIXED-TIME-INTERVAL REGIMENS: 

KINETICS OF FIXED-DOSE/FIXED-TIME-INTERVAL REGIMENS Administration of a drug by fixed doses rather than by continuous infusion is often more convenient. However, fixed doses, given at fixed-time intervals, result in time-dependent fluctuations in the circulating level of drug. Single IV injection Effect of the dose of a single intravenous injection of drug on plasma levels

KINETICS OF FIXED-DOSE/FIXED-TIME-INTERVAL REGIMENS: 

KINETICS OF FIXED-DOSE/FIXED-TIME-INTERVAL REGIMENS Multiple IV injections: Effect of dosing frequency Example of achievement of steady state using different dosage regimens Predicted plasma concentrations of a drug given by infusion (A), twice-daily injection (B), or once-daily injection (C). Model assumes rapid mixing in a single body compartment and a half-life of twelve hours

KINETICS OF FIXED-DOSE/FIXED-TIME-INTERVAL REGIMENS: 

KINETICS OF FIXED-DOSE/FIXED-TIME-INTERVAL REGIMENS ORALLY ADMINISTERED DRUGS: where D = the dose, F = the fraction absorbed (bioavailability), T = dosage interval, C ss = the steady-state concentration of the drug, k e = the first-order rate constant for drug elimination from the total body, and V d = the volume of distribution. Predicted plasma concentrations of a drug given by repeated oral administrations