Pharmacokinetics-2

Dr.U.P.Rathnakar
MD.DIH.PGDHM
24
DISTRIBUTION
Reversible transfer of drugs
between body fluid compartments
After absorption drug enters
various body fluid compartments.
Plasma
Interstitial fluid compartment
Cellular fluid compartment.

23
Body compartments
4 L
28 L
10 L
Plasma
Cellular Interstitial
Drug enters body
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]


Total body water:
Low mol.wt.
Lipophilic
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.
22


V.D
Factors affecting
1. Lipidsolubility & Ionization-
2. Plasma protein binding
3. Tissue binding-
4. Disease-CHF, Uremia
5. Fat
21
Drug in beaker
Drug + Charcoal in beaker
Drug=10mg
Concn=20mg/L
aVD=10/20mg/L
=0.5L
=Vol.of
beaker





Drug=10mg
Concn=2mg/L
aVD=10/2mg/L
=5L
=Much
more thanVol.of
Beaker
and charcoal





Apparent Volume of Distribution
V= Total drug in the body
Plasma concn.
20
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
19
Redistribution


Highly lipid soluble
Thiopentone-i.v
Distributed to
organs with high
blood flow.

Eg.Brain
site of
action
Unconcious
Less vascular
areas
Eg.Fat,
muscle
Plasma
concn.falls
Concious
[Drug
withdrawn
from brain]
Redistribution
10
Sec
10
Mts
18
Blood Brain Barrier
BBB
ONLY Lipid soluble and unionized drugs
cross
Anesthetics, Barbiturates
Meningitis increase permeability-
Impermeable substances Cross!

17
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
16
Plasma protein binding
Drug ABSORPTION Enters circulation

Binds to plasma proteins
[acidic to albumin, basic to
a-acid glycoprotein]

Bound- inactive
Temp. storage site,
Long duration,
Hemodialysis not
effective

Free form-
Active
15
Plasma protein binding: Clinical Imp.
Favors drug absorption
Affects Vd
Delays metabolism, excretion,
Not available for action
Storage site
Displacement reactions-
14
Dr.U.P.Rathnakar
MD.DIH.PGDHM
Fate of the drug
13
Biotransformation:Metabolism

Chemical alteration of the drug
in a living organism is called bio-
transformation.
Lipid soluble Water soluble
So that not reabsorbed in Kidney
Site-Mainly liver
Others-Kidney, lungs, plasma


12
Metabolism: Consequences
End result is usually inactivation of a drug-
But intermediate product need not be!
1. ActiveInactive
Eg. Phenytoin p-Hydroxyphenytoin
2. ActiveActive
Eg.Codeine Morphine,
3. Active Toxic. Eg. P.Mol NABQI
4. Inactive Active,
-Prodrug
Eg. Prednisone Prednisolone
L-Dopa Dopamine

11
Metabolism:Phases: I & II
Most drugs are metabolized by
many pathways, simultaneously or
sequentially producing a variety
of metabolites
Phase II
(Eg.INH)
Phase I Metabolite
10
Biotransformation
Administered drug
[Lipid soluble]
[Non-Polar]
[Lipophilic]
Excreted
[water soluble]
[Polar]
[Hydrophilic]

By
Phase I and Phase II reactions
Catalyzed by enzymes
Microsomal and Non-microsomal enzymes
9
Metabolism:Phase I[Non-synthetic]
1. Oxidation:
Addition of O
2
/Removal of H
+
Eg. Phenytoin, Phenobarbitone, Propranolol

2. Reduction:
Opp.of Oxidation
Eg. Choramphenicol, Methadone

3. Hydrolysis:
Addition of water
Eg.Esters-Procaine, Succinylcholine,
Amides- Procainamide, Lignocaine
4. Others-Cyclization and decyclization

End product active or inactive
8
Metabolism:Phase II(Synthetic)
Conjugation of a drug or phase I
metabolite with endogenous substrate
Glucuronic acid, Sulfuric acid, Acetic acid-
Making it water soluble for excretion.
End product usually inactive



Glucuronide conjugation
Eg.Morphine, Paracetamol
Acetylation
Eg.INH, Dapsone
Glycine conjugation
Eg.Salicylic acid, Nicotinic
acid
Sulphate conjugation
Eg.Sex steroids
Glutathione conjugation
Eg.Paracetamol
Methylation
Eg.Adrenaline, Dopamine
7
Biotransformation:Catalyzed by Enzymes
Microsomal
In endoplasmic
reticulum
Most of Phase I
and some Phase II
[Glucuronide
conjugation]
Inducible
CYP450
Eg. CYP2D6




Non-Microsomal
Cytoplasm,
Mitochondria of liver
cells and plasma
Most of Phase II and
some Phase I [Some
oxidation, most
reduction and
hydrolysis]
Not inducible
Genetic polymorphism
6
Enzyme induction and Inhibition
Induction
Inducers: Rifampicin,
Phenytoin, Barbiturate,
Carbamazapine
Increase synthesis of
Micro
enzymesAccelerate the
metabolism of substrate
Rifampicin X OCP
Reduced efficacy
Increased toxicity-P.mol
and alcoholics
Beneficial
Phenobarbitone in newborn
jaundice
Long time
Inhibition
Inhibitors:
Chloramphenicol, Cipro,
E.Mycin
Warfarin &
E.MycinIncreased
incidence of bleeding
Quick
5
Microsomal Enzyme induction
Drug A
Metabolism[24hrs] Enzyme
Drug B
[Inducer]
Enzyme+Enzyme+Enzyme+Enzyme
Metabolism[6hrs]
Effect
=No drug effect
OCP
Metabolism[24hrs] Enzyme
Drug B
[Rifampicin]
Enzyme+Enzyme+Enzyme+Enzyme
Metabolism[6hrs]
Prevents pregnancy
=Pregnancy!
+
+
4
Microsomal Enzyme inhibition
Drug A
[Toxic]
Metabolism[24hrs] Enzyme
Drug B
[Inhibitor]
Metabolism[72hrs]
Effect
=Drug accumulates
Warfarin
Metabolism[24hrs] Enzyme
Drug B
[Erythrymycin]
Enzyme
Metabolism[72hrs]
Anticogulant
=Bleeding
+
+
Enzyme
Drug A
[Toxicity]
Warfarin
[Toxicity]
3
Non-microsomal enzymes
Genetic polymorphism
INH
Long duration of action=Lower dose
Non-microsomal Enzyme
Slow acetylators
INH
Short duration of action=Higher dose
Non-microsomal Enzyme
Fast acetylators
2
Factors affecting Biotransformation
1. Age-Extremes of age enzymes may be
deficient Eg.Chloramphenicol in premature
babies causes Gray baby syndrome.
2. Malnutrition:- metabolism due to enz.
proteins.
3. Liver disease:- metabolism-- so..dose
of drug
4. Genetic: Genetically determined variation in
metabolism
Slow and fast acetylators-INH
SCH


1
Prodrug
Inactive drug
Converted to active form by metabolism
Improved B.A.-L-Dopa and Dopamine
Prolongs duration of action- Fluphenazine
Improves taste- Clindamycin palmitate
Reduces ADE-Bacampicillin
Methenamine release Formaldehyde in
acidic urine
last