Biopharmaceutics study for Pharmaceutical Job Preparation)

Biopharmaceutics

Biopharmaceutics is the branch of pharmaceutical science that deals with the fate of drugs in the living system, particularly the release of the drug from its dosage form into the systemic circulation, metabolism, and elimination and the application of this knowledge to obtain the desired therapeutic effect.

Biopharmaceutical Classification System (BCS)

Biopharmaceutical Clsssification System (BCS) is a system of classification of drugs based on their solubility and their permeability through the gut wall. The system was introduced by Professor Gordon Amidon in 1995.

According to the Biopharmaceutical Classification system, drug substances are classified as follows:

• Class-I: High Permeability, High Solubility: These compounds are well absorbed and their absorptipn rate is usually higher than excretion. Example: Metoprolol


• Class-II: High Permeability, Low Solubility: The bioavailability of these products is limited by their solvation rate. A correlation between the in-vivo bioavailability and the in-vitro solvation can be found. Examples: Glibenclamide, Bicalutamide, Ezetimibe


• Class-III: Low Permeability, High Solubility: The absorption is limited by he permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then Class-I criteria can be applied. Example: Cimetidine


• Class-IV: Low Permeability, Low Solubility: These compound have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected. Example: Hydrochlorothiazide.

Bioavailability

Bioavailability means the rate and extent to which the active ingredient or moiety is apsorbed from a drug product and is available at the site of action.

The rate and extent of unchanged drug that reaches to the systemic circulation after administration is called bioavailability.

Absolute bioavailability

Absolute bioavailability of the systemic availability of a drug after extravascular administration compared to IV dosing.

Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following non- intravenous administration.

Relative bioavailability

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

Factors influencing bioavailability:

⇨ Food

⇨ First pass metabolism

⇨ Intestinal motility

⇨ Disease states

⇨ Physical properties of the drug

⇨ The drug formulation

⇨ Gastric emptying rate

⇨ Circadian differences

⇨ Interactions with other drugs

⇨ Interactions with foods

⇨ Enzyme induction of inhibition by other drugs/foods

First pass metabolism

First pass metabolism means metabolism of a drug during its passage from intestine to systemic circulation. It is the fraction of lost drug during the process of absorption which is generally related to the liver and gut wall.

Notable drugs that experience a significant first pass effects are:

⇨ Imipramine

⇨ Morphine

⇨ Propranolol

⇨ Buprenorphine (Opoid drug/ Long duration of action/ used to treat opioid dependence)

⇨ Diazepam

⇨ Midazolam

⇨ Demerol

⇨ Cimetidine

⇨ Lidocaine

IV Bolus dose

IV bolus dose is a single dose of a drug or other medicated preparation given all at once at a faster rate for rapid delivery of drugs into the bloodstream using needle and syringe.

Loading Dose

Loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down at a lower maintenance dose.

The loading dose or initial bolus dose of a drug is used to obtain desired concentration as rapidly as possible.

Calculation of Loading Dose (DL):

Loading dose (Dl)= (Volume of distribution × Plasma drug concentration)÷

(Salt form of the drug × Fraction of drug bioavilability)

DL=(Vd × Ca) ÷ (S×F)

Loading dose = desired peak concentration (mg/L) × Volume of distribution (L)

Differences between IV bolus dose and Loading dose:

⇨ IV bolus dose is a single dose of a drug or other medicated preparation given all at once at a faster rate for rapid delivery of drugs into the bloodstream using needle and syringe.

⇨ Loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down at a lower maintenance dose.

Maintenance dose

In most clinical situations, drugs are administered in a series of repetitive doses or as a continuous infusion to maintain a steady-state concentration of drug associated with the therapeutic window.

Maintenance dose (mg/hr)= desired peak concentration (mg/L) × Drug Clearance (L/hr)

Drug clearance

Drug clearance is the volume of plasma that is cleared of drug per unit time.

Drug clearance may be calculated without consideration of the compartment model.

Drug clearance is a term that is useful in calculating average drug concentrations.

Creatinine Clearance calculation:

CrCl for males= (98-0.8×(Patients age in years- 20))÷ Serum creatinine (mg/dL)

CrCl for females= 0.9 × CrCl for males

Excretion Ratio of drug = Renal clearance of drug (ml/min) ÷ Normal inulin clearance (ml/min)

Volume of Distribution 

The volume of fluid in which the drug appears to distribute with a concentration equal to that in plasma.

Volume of Distribution (Vd)= 

Total amount of drug in body (D) ÷ Plasma drug concentration (Cp)

Vd= D/Cp

Drugs with low volume of distribution:

⇨ Aspirin

⇨ Indomethacin

⇨ Frusemide

⇨ Tolbutamide

⇨ Salicylic acid

⇨ Amoxicillin

⇨ Gentamycin

⇨ Ampicillin

Drugs with high volume of distribution:

⇨ Diltiazem

⇨ Digoxin

⇨ Imipramine

⇨ Nortriptyline

⇨ Propranolol

⇨ Fluoxetine

⇨ Chloroquine

⇨ Pethidine

Stady state condition

At steady state conditions, the rate of drug entry into the tissue compartment from the central compartment is equal to the rate of drug exit from the tissue compartment into the central compartment.

The total amount of drug in the body at steady state is equal to the sum of the amount of drug in the tissue compartment, Dt, and the amount of drug in the central compartment, Dp

Apparent volume of distribution at steady state

This is a proportionally constant that relates the plasma concentration and the amount of drug remaining in the body at a time, following the attainment of practical steady state.

The apparent volume of distribution at steady state may be calculated by dividing the total amount of drug in the body by the concentration of drug in the central compartment at steady state.

Thus (Vd)ss = (Dp + Dt) ÷ Cp 

(Vd)ss⇨ Apparent volume of distribution at steady state, Dt⇨ Amount drug in the tissue compartment, Dp⇨ Amount of drug in the central compartment, Cp⇨ Concentration of drug in plasma]

Dose ratio = Loading dose/ Maintenance dose

Dose ratio= DL/Do

Dose rate (mg/hr) = Total dose (mg)/ dosing interval (hr)

Pharmacokinetics

Pharmacokinetics is the science of the kinetics of drug absorption, distribution, metabolism and excretion.

Pharmacodynamics

Pharmacodynamics is the study of the biochemical and physiochemical effects of drugs on the body. This includes the mechanisms of drug action and the relationship between drug concentration and effect.

Clinical Pharmacology

Clinical Pharmacokinetics is the application of pharmacokinetic method to drug therapy in patient care. Clinical pharmacokinetics involves a multidisciplinary approach to individually optimized dosing strategies based on the patients disease state and patient-specific considerations

MTC ⇨ Minimum Toxic concentration

MEC ⇨ Minimum Effective Concentration

TDM ⇨ Therapeutic Drug Maintaining

FPI ⇨ Full prescribing Information

Pharmacology

Pharmacology is the science that generally deals with the study of drugs, including its mechanism, effect and uses of drugs.

It includes pharmacognosy, pharmacokinetics, pharmacodynamics, pharmacotherapeutics and toxicology.

Pharmacogenetics

Pharmacogenetics is the study of drug effect including distribution and disposition due to genetic differences.

Drug exposure

Drug exposure refers to the dose and various measures of acute or integrated drug concentration in plasma and alter biological fluid.

Purpose of Pharmacokinetic model

Pharmacokinetic models are used to-

⇨ Predict plasma, tissue & urine drug levels with any dosage regimens

⇨ Calculate the optimum dosage regimen for each patient individuals.

⇨ Correlate drug concentration with pharmacologic activitis.

⇨ Explain drug interaction.

Physiologic Pharmacokinetic Model

Physiologic pharmacokinetic models are frequently used in describing drug distribution in animal.

Two Compartment Model

In a two-compartment model, drug can move between the central or plasma compartment to or from the tissue compartment.

Drug dissolution rate calculation

Drug dissolution rate  is calculated using Noyes-whiteney equation

Dissolution rate= dx/dt = (DA/L)(C1-C2)

D⇨ Diffusion coefficient

A⇨ Effective surface area of drug

L ⇨ Length of diffusion layer

C1⇨ Surface concentration of drug in diffusion layer

C2⇨ Concentration of drug in the bulk solution

AUC (Area Under the Curve)

AUC refers the extent of absorption for a drug from the site of administration into the circulation

In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time

AUC unit is based on the trapexoid rule

Trapezoid rule

Trapezoid rule is used in pharmacokinetics to calculate the area under the plasma drug concentration versus time curve, called AUC.

Chemical reactions

Zero order rate reaction:

Zero order rate constant is one that proceeds over time independent from the concentration of the drug.

Zero order rate = -dc/dt = Ko

First order process

First order process is dependent upon the concentration of the drug

A first order reaction has a rate proportional to the concentration of one of the reactants. 

Example: Phenomenone of radio active decay.

The rate is = K[A]

Therapeutic equivalence

Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety.

Clinical effectiveness often depends both on maximum serum drug concentrations and the time after administration required to reach peak concentration.

Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.

Pharmaceutical equivalents

For generic drug products to be pharmaceutical equivalents, they must be identical dosage forms that contain identical amounts of the chemically identical API. 

Pharmaceutical equivalents deliver identical amounts of the API over the identical dosing period.

They must meet the identical compendial or other applicable standards on potency, content uniformity, disintegration times, and dissolution rates where applicable.

Half life of drugs

Half life is the time in which the concentration of drug declines by one half.

Types of Half life:

a) Plasma Half life: It is the time taken for the plasma concentration of drugs in the body to be reduced to half of its original volume.

b) Elimination Half-life: The time in which the total amount of drug in the body after equilibrium of plasma with other compartments is halved.

c) Biological effective Half-life: The time in which the Pharmacological effect of the drug and of any avtive matabolites has declined of one half.

Drugs having long half life:

⇨ Chloroquine (214 hours)

⇨ Digitoxin (160 hours)

⇨ Phenobarbital (98 hours)

⇨ Eluoxetine (53 hours)

⇨ Digoxin (50 hours)

⇨ Diazepam (43 hours)

⇨ Warfarin (37  hours)

Drugs having short half life:

⇨ Aspirin (0.25 hours)

⇨ Cephalosporin (0.57 hours)

⇨ Cephalexin (0.9 hours)

⇨ Ampicillin (1.3 hours)

⇨ Amoxicillin (1.7 hours)

⇨ Lidocaine (1.8 hours)

⇨ Midazolam (1.9 hours)

Calculation of Half-life

Half life  t_1/2 = 0.693÷Kel

Kel ⇨ Elimination rate constant for first order kinetics

Bioequivalence Curve

Therapeutic Index

The therapeutic index is a quantitative measurement of the relative safety of a drug. 

It is a comparison of the amount of a therapeutic agent that causes the toxic effect to the amount that causes therapeutic effect. It is the ratio of the minimum concentration of drug to produce toxic effect and minimum concentration of drug to produce therapeutic effect.

TI = LD₅₀/ED₅₀

Difference between Potency and Efficacy

Potency	Efficacy
Comparative measure of different doses of two drugs that are needed to peoduce the same effect is callecalled Potency.	Ability of drug after binding with receptor to initiate change which leads to effects is called Efficacy.
It is the amount of drug in relation to its effeceffect.	It is the capacity of a drug to produce an effect andfers to maximum such effect.
Potency does not help to choose amon drugs.	Efficacy helps to choose among drugs.
It is absolute potency.	It is therapeutic potpotency.
Potency determines the administered dose of thethe cchosen drug.	Efficacy determines clinical effectiveness of a drug.