YSPM

K. K. Mali Assistant Professor Yashoda Technical Campus, Faculty of Pharmacy, M. Pharm

YSPM

Contents
Introduction
Tissue permeability of drugs Barrier to distribution of drugs

Factors affecting drug distribution

Physico-chemical properties of drugs Volume of distribution Drug-protein binding Factors affecting drug-protein binding Significance of drug protein binding
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YSPM

Introduction
Drug disposition Distribution Elimination

Introduction
Diffusion of drug from capillaries to interstitial spaces

Steps in drug distribution

Blood to ECF

Capillary wall- rapid Cell membrane Rate of perfusion Membrane perfusion

ECF to tissue

Factors affecting drug distribution

Tissue permeability of drug
Organ/tissue size and perfusion rate Binding of drug to tissue components Miscellaneous factors

Factors affecting drug distribution

Tissue permeability of drug

Physicochemical properties of drug Physiological barriers

Factors affecting drug distribution

Physicochemical properties of drug Capillary membrane Molecular weight < 500 600 daltons cross Cell membrane Molecular size < 50 dalton through pores Degree of ionisation- pH of ECF & ICF (7.4), pKa of drug Unionised and lipophilic drug cross cell membrane barrier Phenobarbital and SA same Ko/w but former is ionised less at blood pH shows rapid distribution. Thiopental- lipophilic, unionised Fast distribution (BBB/Fat Biphasic distribution) Penicillins- polar, water soluble and ionised Systemic Acidosis / Alkalosis (altered distribution of drugs)

Factors affecting drug distribution

Physiological barriers

Simple capillary endothelial barrier Simple cell Membrane barrier Blood-brain barrier Blood CSF barrier Blood-placental barrier Blood-tests barrier

Factors affecting drug distribution

Physiological barriers

Simple capillary endothelial barrier Simple cell Membrane barrier

Capillary barrier Blood

ECF

Cell membrane barrier ICF

D D D P D

Drug size < 50 d Lipophilic Drug Size 50-500 d Polar/ ionised size > 50 d

D D D D

D D

Bulk flow Passive Active

D+

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Factors affecting drug distribution

Physiological barriers

Blood-brain barrier
Brain ECF Glial cells Basement Memb. Astrocytes Pericytes Capillary endothelium

Blood

Tight intercellular Junctions

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Factors affecting drug distribution

Physiological barriers

Blood-brain barrier Intanasal drug direct passage to brain Passive diffusion- drugs Active transport - nutrients Thiopental Phenobarbital Penicillin Dopamine- levodopa Different approaches DMSO, osmotic disruption, dihydropyridine redox system
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Factors affecting drug distribution

Physiological barriers

Blood CSF barrier

CSF Chroid plexus Tight Junction ECF

Capillary endothelium

Blood
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Factors affecting drug distribution

Physiological barriers Blood-placental barrier

Mother
Polar drug

Fetus

Non-polar drug

Non-polar drug

Polar metabolite

Polar metabolite
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Factors affecting drug distribution

Blood-placental barrier
Factors

Placental blood flow

increased delivery of drug to placental membrane Molecular size of drug decreased transfer as size increases impermeable to drugs MW>1000 permeable to drugs MW<600 Lipid solubility of drug increased transfer as lipid solubility increases pKa of drug ion trapping on either side
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Factors affecting drug distribution

Permeability rate limited

Drug is ionic, polar or water soluble Physiological barriers

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Factors affecting drug distribution

Organ/ Tissue Size and perfusion rate Perfusion rate limited Drug highly lipophilic High permeability Rate limited- Blood flow Rate limited- Perfusion to tissue Perfusion rate Volume of blood that flows per unit time per unit volume of the tissue Highly perfused tissue: lung, kidney, liver, heart, brain Moderately perfused tissue: muscles, skin Poorly perfused tissue: Fat, bone
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Factors affecting drug distribution

Organ/ Tissue Size and perfusion rate Extent of distribution depend on tissue size Example: Thiopental (biphasic distribution) Initially- Brain Then- fats (adipose tissue)

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Factors affecting drug distribution

Tissue

Adrenals Kidneys Thyroid Liver Hepatic Portal Portal-drained viscera

Heart (basal) Brain Skin Muscle (basal) Connective tissue Fat

Percent Body Percent Car Blood Flow Weight diac Output (ml/100 g tissue/min) 0.02 1 550 0.4 24 450 0.04 2 400 2.3 27 2.0 5 20 20 75 2.0 20 75 0.4 2.0 7.0 40.0 7.0 15.0 4 15 5 15 1 2 70 55 5 3 1 1
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Factors affecting drug distribution

Age

Infants TBW and fat is greater Skeleton muscles and albumin content are less BBB poorly developed Elderly Fat is greater Skeleton muscles and albumin content less

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Factors affecting drug distribution

Pregnancy

Uterus, placenta and foetus increases volume available for distribution Plasma and ECF increased Albumin content decreased High adipose tissue content- lipophilic drugs distributed well High fatty acid contents- altered binding of acidic drugs Fat increases free fatty acid levels which alters binding of acidic drugs to albumin
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Obesity

Diet

Factors affecting drug distribution

Disease state

Altered albumin content Altered perfusion rate Altered tissue pH Meningitis increases permeation of polar drugs to brain

Drug interactions

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Volume of distribution
TBW: 42L
Volume of distribution Apparent volume of distribution

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Protein Binding of Drugs

Phenomenon of complex formation of drug with protein
Mechanisms of protein binding

Hydrogen bonds Hydrophobic bonds Ionic bonds Van der Walls forces

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Protein Binding of Drugs

Binding of drugs to blood component

Plasma protein- drug binding Blood cell- drug binding

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Protein Binding of Drugs

Binding of drugs to blood component

Plasma protein- drug binding Albumin > alpha acid glycoproteins > lipoproteins > globilins Binding of drug to HSA Molecular Wt 65000 Concentration- 3.5 to 5 g% Variety of drugs bind to albumin Endogenous material like fatty acids, bilirubin, tryptophans Four binding Sites Site I (Warfarin)- NSAIDS, Phenytoin, bilirubin, Sodium valproate
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Protein Binding of Drugs

Binding of drugs to blood component

Plasma protein- drug binding Binding of drug to HSA Four binding Sites Site I (Warfarin)- NSAIDS, Phenytoin, bilirubin, Sodium valproate, etc Site II (diazepam)- ibuprofen, tryptophan, ketoprofen, etc Site III (digitoxin) Site IV (tamoxifen)

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Protein Binding of Drugs

Binding of drugs to blood component

Plasma protein- drug binding Binding of drug to AAG Molecular Wt- 44000 Concentration- 0.44 to 0.1 g% Basic drugs: Imipramine, lidocaine, amitriptyline, etc.

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Protein Binding of Drugs

Binding of drugs to blood component

Plasma protein- drug binding Binding of drug to Lipoproteins Molecular Wt- 200000 to 3400000 Concentration- variable Basic lipophilic drugs: Chlorpromazine etc.

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Protein Binding of Drugs

Binding of drugs to blood component Plasma protein- drug binding Binding of drug to Globulins Alpha 1 globulin: transcortin Steroids Alpha 2 globulin: ceruloplasmin Vitamin A, D, E, K and cupric ions Beta 1 globulin: transferrin Ferrous ions Beta 2 globulin Carotinoids Gamma globulin Antigens
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Protein Binding of Drugs

Binding of drugs to blood component

Binding of drug to blood cells RBC (95%) components: Hemoglobin

MW- 64500, Concentration 21 to 15 g% Phenytoin, pentobarbital, phenothiazines

Acetazolamide, chlorthalidone Imipramine, chlorpromazine

Carbonic anhydrase

Cell membrane

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Protein Binding of Drugs

Binding of drugs to tissues

Tissue binding increases apparent Vd Tissue binding increases biological half life of drug Factors affecting tissue binding Lipophilicity Structure of drug Perfusion rate pH difference

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Protein Binding of Drugs

Binding of drugs to tissues

Liver: Paracetamol- hepatotoxicity Lungs: imipramine, chlorpromazine Kidney: Matallothionin (protein) bind to heavy metals Skin: Melanin- chloroquine, phenothiazines Eyes: Melanin- chloroquine, phenothiazines- retinopathy Hairs: Arsenicals, chloroquine, phenothiazines Bones: Tetracyclines Fats: Lipophilic drugs Nucleic Acids: chloroquine and quinacrine

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Protein Binding of Drugs

Parameter Binding Vd Half Life Toxicity DI Binding Protein- drug binding Weak bonds & thus reversible Small Short No Displacement Competitive Tissue- drug binding Covalent bonds & thus irreversible Large Long Common No Non Competitive

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Factors affecting drug -Protein binding

Drug related

Physicochemical characters of drug Concentration of drug in body Drug binding affinity towards binding component Physicochemical characters of protein or binding agent Concentration of protein in body Number of binding sites on binding agent

Protein/ tissue

Drug interactions Patient

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Factors affecting drug -Protein binding

Drug related
Protein/ tissue Drug interactions Competition between drugs for the binding sites Competition between drugs and normal body constituents for the binding sites Allosteric changes in protein molecules Patient Age Inter-subject variation Disease state

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Factors affecting drug -Protein binding

Drug related

Physicochemical characters of drug Lipophilicity- localized in tissues Thiopental- adipose tissues Acidic drugs- HAS Penicillins, sulphonamides Basic drugs- AAG Imipramine Neutral, unionised- lipoproteins

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Factors affecting drug -Protein binding

Drug related

Concentration of drug in body Therapeutic concentration of lidocaine can saturate AAG Drug concentration unable to saturate HSA Drug binding affinity towards binding component Lidocaine has greater affinity for AAG than for HAS Digoxin- protein of cardiac muscles Iophenoxic acid- plasma proteins (t1/2 2.5 years)

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Factors affecting drug -Protein binding

Protein/ tissue

Physicochemical characters of protein or binding agent Lipoproteins and adipose tissue bind to lipophilic drugs

Concentration of protein in body Albumin high percent

Number of binding sites on binding agent Albumin-Four binding sites

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Factors affecting drug -Protein binding

Drug interactions

Competition between drugs for the binding sites Warfarin + Phenylbutazone Competition between drugs and normal body constituents for the binding sites Free fatty acids- drugs- HSA Bilirubin - HSA Allosteric changes in protein molecules

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Factors affecting drug -Protein binding

Patient Related factors

Age Neonates: Low albumin content Young infants: Greater binding Elderly: Low albumin content, High levels of AAG Inter-subject variation Disease states Hypoalbuminaemia: aging, CCF, trauma, burns, inflammatory states, renal and hepatic disorders, pregnancy, surgery, etc Hyperlipoproteinaemia: hypothyroidiosm, obstructive liver disease, alcoholism etc
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Factors affecting drug -Protein binding

Disease States
Conditions Albumin hepatic cirrhosis burns nephritic syndrome pregnancy myocardial infarcts surgery trauma rheumatoid arthritis Change in concentration
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a-glycoprotein

Significance of Protein binding

Patient Related Factors

Absorption Systemic solubility of drugs Distribution Tissue binding Elimination Displacement interactions and toxicity Diagnosis Therapy and drug tageting

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Questions

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Bibliography
D. M. Bramhankar and S. B. Jaiswal. Biopharmaceutics and

Pharmacokinetics A Treatise. Delhi;Vallabh Prakashan. 2010 Jambhekar SS, Breen PJ. Basic Pharmacokinetics. London; Pharmaceutical Press. 2009. Shargel L, Wu-Pong S, Yu ABC. Applied biopharmaceutics and Pharmacokinetics. McGraw Hill. 2007

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