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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