Phrmacokinetics Bds

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Dr.U.P.Rathnakar MD.DIH.PGDHM

Slide 1 a1

admin, 8/7/2008

PK is the quantitative study of drug movement in, through and out of the body During these processes the drug has to cross various biological membranes

PK-Membrane Transport

Mechanism by which drugs cross biological membrane

Membrane Transport…..
Passive diffusion and Filtration
Specialized transport


Carrier transport  Facilitated diffusion  Active transport




Pinocytosis

Pa Passive ssive diffusion
Bidirectional process,
Movement of molecules from

•Ion trapping •Urine alkalanized in poisoning with acidic drugs

higher to lower conc [Down the gradient]
Lipid soluble drugs- Passive diffusion, after dissolving in the lipid of cell membrane
Acidic drugs are unionized in acidic medium
Alkaline drugs are unionized in alkaline Medium
Unionized drugs are readily absorbed
More lipid soluble » Diffuses quickly
Greater the difference in concn gradient »

Quicker diffusion

Filtration

FILTRATION
Capillaries (Except in brain-Tight

junction) have large pores & most drugs filter through these.
Lipid insoluble drugs cross biological membranes by filtration through these pores
Diffusion of drugs is dependent on Rate of Blood Flow

Specialized transport: Carrier mediated
Drug + CARRIER in the membrane → complex is transported from one side of the membrane to other.

Eg. Calcium & iron absorption
Carrier transport 1. Specific, 2. Saturable, 3. Competitively inhibited by - which utilize the same carrier.

Specialized transport: Carrier mediated Facilitated diffusion
No energy required • Drug + carrier[SLC Transporter] in the

membrane, → diffusion across the cell membrane.
Movement ONLY higher to lower conc [ALONG]

Eg. Vit. B12 absorption

Specialized transport: Active transport


Movements of molecules – Low

conc. To high conc.
Against the conc.gradient
Require energy.
P-glycoprotein

Primary

Specialized transport Active transport:


Primary Active Transport
ATP Binding Cassette-

Transporter
Only out of the cytoplasm
Energy derived from ATP

Specialized transport Active transport

:Secondary:
Energy derived from movement of another substance
In the same direction-Symport
In opp.direction

-Antiport


Pinocytosis; By formation of vesicles

Membrane Transport….. Facilitated diffusion

Primary active

Secondary active- Symport

Secondary active-Antiport


Absorption
[Movement from site of administration to

circulation]
ORAL:
S.c, i.m: Absorbed by capillaries or lymphatics
Topical: Lipid solubility-Hyoscine, Fentanyl, GTN,

Nicotine, Testosterone, Estradiol
Cornea

BA=30/150

First pass metabolism

Absorption: Bio-Availability
‘The fraction [F] of administered dose of a drug that reaches systemic circulation in the unchanged form’
I.V. –100% Bio-availablity
Oral-Not 100%. WHY? 1. Incompletely absorbed 2. First pass metabolism


i.m or s.c. also may be less than 100% -Local binding

Absorption

:Factors


Aqueous solubility
Concentration
Area of absorbing surface
Vascularity
pH and ionization
Food
Other drugs
Diseases
Route

DISTRIBUTION



  

‘Reversible

transfer of drugs between body fluid compartments’ After absorption drug enters various body fluid compartments. Plasma Interstitial fluid compartment Cellular fluid compartment.

Drug enters body Total body water: Plasma compartment: •Large mol.wt. •Bound to plasma proteins •Cannot cross capillaries •Remains trapped in vascular compartment [4L]

Extracellular fluid: •Low mol.wt. •Hydrophilic •Can cross capillaries(Slit junc) •Can not enter cells(Cross plasma membrane-Not lipid soluble) •Remains in Plasma+InterstitiaL fluid[14L]

•Low mol.wt. •Hydrophobic •Can cross capillaries •Can enter cells (Cross plasma membrane) •Distrbutes in vol. of 60% of body wt.[42L]

Other sites: •In pregnancy-Fetus •Fat-Thiopental

Usually drugs not confined One compt.

V.D
Factors affecting 1. Lipidsolubility & Ionization-Lignocaine and Heparin 2. Plasma protein binding 3. Tissue binding-Digoxin bound to heart,liver 4. Disease-CHF, Uremia 5. Fat:Lean body mass

Apparent Volume of Distribution Drug in beaker

Drug + Charcoal in beaker Drug=10mg Concn=20mg/L aVD=10/20mg/L =500ml =Vol.of beaker

Drug=10mg Concn=2mg/L aVD=10/2mg/L =5000ml =Much more thanVol.of Beaker and charcoal

Apparent volume of distribution
aVD: “The volume that would accommodate all the

drug in the body, if the concn.throughout was the same as in plasma”
Lipid insoluble: Small aVD-Eg.Gentamicin-.25L/kg
Highly protein bound-Eg.Diclofenac-0.15L/kg.
Highly tissue bound-Eg.Morphine-3.5L/kg  High vol. of distribution-poisoning-difficult to

remove by dialysis

Redistribution Highly lipid soluble Thiopentone-i.v

10 Sec

Distributed to organs with high blood flow. 10 Mts

Concious [Drug withdrawn from brain]

Eg.Brain site of action Plasma concn.falls

Unconcious

Less vascular areas Eg.Fat, muscle

Redistribution

Blood Brain Barrier
BBB
ONLY Lipid soluble and unionized drugs cross
Anesthetics, Barbiturates
Meningitis increase permeability- Impermiable substances Cross!

Placental barrier
Bet.mother and fetus
Lipid soluble and unionized cross-anesthetics, alcohol
High mol.wt.do not-insulin
Teratogenicity ( Teratos = Monster)
Tetracyclines, Thalidomide Anti-cancer drugs, Sex hormones

Plasma protein binding
Drug → ABSORPTION → Enters circulation

Free formActive

Binds to plasma proteins [acidic to albumin, basic to a-acid glycoprotein] •Bound- inactive •Temp. storage site, •Long duration, •Hemodialysis not effective

Plasma protein binding: Clinical Imp.
Favors drug absorption
Affects Vd
Delays metabolism, excretion,
Not available for action
Storage site
Displacement reactions-