Absorption & Distribution

Absorption & Distribution

Content

General Pharmacology

       Absorption and bioavailability

       Mechanisms of drug transport

       Factors affecting absorption and bioavailability of drugs

       Process of drug distribution

       Protein binding

       Volume of distribution

       Barriers to drug passage

Intended Learning Outcomes

At the end of this lecture, student will be able to

       Explain absorption and bioavailability

       Describe mechanisms of drug transport

       Explain the factors affecting absorption and bioavailability of drugs

       Explain the process of drug distribution

       Describe protein binding

       Explain volume of distribution

       Outline the barriers to drug passage

Absorption and Bioavailability

       Drugs – systemic circulation

       Drugs divided into 3 groups:

      Non ionised, non-polar, lipid soluble

      Ionised polar, water soluble

      Partly ionised and non ionised 

Absorption Process

Molecules cross biological membrane by:

       Simple or passive diffusion

      Lipid diffusion

      Aqueous diffusion

       Transport using transmembrane transporters

      Uptake transpoters

      Efflux transporters

Transport using transmembrane transporters

       Facilitated diffusion

      SLC moves down the chemical or electrical gradient

       By active transport

      Carrier protein against electrical or chemical gradient

      Via ion channels

      By endocytosis

Bioavailability

       Amount or % of drug absorbed from given dosage

       Following non vascular administration

       Available at the desired site of action

       IV bioavailability – 100%

       Valid test for F: level of drug in biological fluid

       Measurable parameter of therapeutic efficacy

                        AUC after oral dose

       F =  ---------------------------- X 100

                        AUC after IV dose

AUC

Drug

       Pharmaceutically equivalent:

      Same active ingredients

      Identical in strength, conc., dosage forms

·         Bioequivalent:

      Rate and extent of F

      Active ingredients in 2 formulations

      Do not differ significantly

      Likely to be therapeutically equivalent

Factors affecting drug absorption and bioavailability

Drug related

       Physical properties of the drug

       Nature of the dosage form

Patient related

       Physiological factors

       Pharmacogenetic factors

       Disease states

Physical properties

       Physical state

       Lipid/ water soubility

Nature of Dosage forms

       Particle size: Reduction – dosage can be reduced

       Disintegration time: Break up into drug granules

       Dissolution rate: Drug goes to solution

       Formulation: Diluents, fillers

Physiological Factors

       Ionisation

       pH of the GI fluid and blood

       GI transit time

       Enterohepatic cycling

       Area of the absorbing surface and local circulation

       First pass elimination

       Presence of other agents

Distribution

       Drug enters/ passes through several body fluid compartments:

      Plasma

      Intertitial fluid compartment

      Transcellular fluid compartment: GI, Bronchi, CSF

      Intracellular fluid compartment

       Apparent volume of distribution: volume into which the total amount of drug in the body appears to be uniformly distributed

       Vd (L) = Total amount administered / Plasma Conc

       Drugs penetrate into & exist in more than one compartment

       Rate of passage depends on pH & pK of body compartment

       pK ( Dissociation constant)

       Non – ionised: readily cross membrane, larger Vd

       Highly protein bound: low Vd

       Vd= 16 L – distributed in ECF includes plasma

Volume of distribution

       If Vd= 42 L

       Exceeds total body volume

       Possibility of drug accumulation in tissue

       Digoxin (420 L) : Accumulation in skeletal muscle

       Chloroquine (13000 L) : Conc in liver

Distribution of drugs

       Total body water – small water soluble (Alcohol)

       E.C space – large water soluble (Mannitol)

       I.V space  -  Very large, strongly protein bound (Heparin)

       Body fat – Highly lipid soluble (Thiopentone)

       Bones – Fluoride, lead

Protein binding of acidic and basic drugs

Acidic drugs to albumin

Basic to α1 acid glycoprotein

       BDZ

       Imipramine

       NASIDs

       Quinidine

       Valproic acid

       Verapamil

       Penicillin

       Methadone

       Warfarin

       Lidocaine

Protein binding

       Restricted to vascular compartment

       Temporary storage of drug

       Makes drug longer acting

       Plasma concentration refers to bound and free form

       Displacement interactions

      Salicylates displace sulfonyl urea, methotrexate

      Indomethacin, phenytoin displaces warfarin

To tissue proteins

       Digoxin

       Emetine

Miscellaneous

       Steroids – Transcortin

       Thyroxine – α Globulin

Drug storage

       Skeletal muscle, heart: Digoxin, emetine

       Kidney: Digoxin, chloroquine

       Brain: Chlorpromazine, isoniazid

       Bone, teeth: Tetracycline, heavymetals

       Thyroid: Iodine

       Retina: Chloroquine

       Iris: Ephedrine, atropine

       Liver: Chloroquine, tetracycline

       Adipose tissue: Thipentone, DDT

Termination of drug effects

       By biotransformation and excretion

       By redistribution

       Greater lipid solubility – faster the redistribution

       Eg. Thiopental redirtribution

Barriers to drug passage

       Placental barrier – incomplete

       Blood brain barrier

       Blood CSF barrier 

Summary

       Absorption: Process by which the drugs enter the systemic circulation

       Bioavailability: Amount or % of drug absorbed from given dosage

       Drug transport: Passive diffusion, facilitated transport

       Factors affecting absorption and bioavailability: Physical properties of the drug, nature of the dosage form, physiological factors, pharmacogenetic factors and disease states

       Drug transport: Passive diffusion, facilitated transport

       Acidic drugs bind to albumin

       Basic drugs bind to alpha 1 acid glycoprotein

       Apparent volume of distribution: volume into which the total amount of drug in the body appears to be uniformly distributed

       Greater lipid solubility – faster the redistribution (Eg. Thiopental redistribution)

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